Clinical trial NCT02278250
Conditions: Solid Tumor Advanced Solid Tumor
Keywords: VX14-803-001 VX-803 M4344 Advanced Solid Tumor Cytotoxic Chemotherapy Carboplatin
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2015-01-26; Completion date: 2021-09-24
Enrollment: 97 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the safety and tolerability of multiple ascending doses of single-agent M4344 administered twice-weekly (BIW), twice daily (BID) or once daily dose schedule in participants with advanced solid tumors. This investigation is a three part study examining M4344 alone and in combination with carboplatin to determine the safety and maximum tolerated dose.

Detailed description:

Arms: arm 1: Participants received M4344 at a dose of 10 milligrams (mg) orally twice weekly (BIW) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 2: Participants received M4344 at a dose of 20 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 3: Participants received M4344 at a dose of 40 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 4: Participants received M4344 at a dose of 80 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 5: Participants received M4344 at a dose of 160 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 6: Participants received M4344 at a dose of 300 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 7: Participants received M4344 at a dose of 450 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 8: Participants received M4344 at a dose of 700 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 9: Participants received M4344 at a dose of 1050 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 10: Participants received M4344 at a dose of 1200 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 11: Participants received M4344 at a dose of 100 mg orally twice daily (BID) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 12: Participants received M4344 at a dose of 150 mg orally once daily (QD) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 13: Participants received M4344 at a dose of 250 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 14: Participants received M4344 at a dose of 350 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 15: Participants received M4344 at a dose of 350 mg orally on Day 2 and Day 9 in combination with intravenous infusion of Carboplatin at a dose of Area under the concentration versus time curve 5 (AUC5) on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 16: Participants received M4344 at a dose of 400 mg orally on Day 2 and Day 9 in combination with intravenous infusion of Carboplatin at a dose of AUC5 on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 17: Participants received M4344 at a dose of 500 mg orally on Day 2 and Day 9 in combination with intravenous infusion of Carboplatin at a dose of AUC5 on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. arm 18: Participants received M4344 at a dose of 250 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Interventions: intervention 1: M4344 10 mg BIW intervention 2: M4344 20 mg BIW intervention 3: M4344 40 mg BIW intervention 4: M4344 80 mg BIW intervention 5: M4344 160 mg BIW intervention 6: M4344 300 mg BIW intervention 7: M4344 450 mg BIW intervention 8: M4344 700 mg BIW intervention 9: M4344 1050 mg BIW intervention 10: M4344 1200 mg BIW intervention 11: M4344 100 mg BID intervention 12: M4344 150 mg QD intervention 13: M4344 250 mg QD intervention 14: M4344 350 mg QD intervention 15: M4344 400 mg intervention 16: M4344 500 mg intervention 17: Carboplatin
Intervention descriptions: intervention 1: Participants received M4344 at a dose of 10 milligrams (mg) orally twice weekly (BIW) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 2: Participants received M4344 at a dose of 20 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 3: Participants received M4344 at a dose of 40 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 4: Participants received M4344 at a dose of 80 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 5: Participants received M4344 at a dose of 160 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 6: Participants received M4344 at a dose of 300 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 7: Participants received M4344 at a dose of 450 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 8: Participants received M4344 at a dose of 700 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 9: Participants received M4344 at a dose of 1050 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 10: Participants received M4344 at a dose of 1200 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 11: Participants received M4344 at a dose of 100 mg orally twice daily (BID) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 12: Participants received M4344 at a dose of 150 mg orally once daily (QD) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 13: Participants received M4344 at a dose of 250 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 14: Participants received M4344 at a dose of 350 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 15: Participants received M4344 at a dose of 400 mg orally on Day 2 and Day 9 until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 16: Participants received M4344 at a dose of 500 mg orally on Day 2 and Day 9 until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal. intervention 17: Participants received intravenous infusion of Carboplatin at a dose of Area Under Curve5 (AUC5) on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Protocol documents:
Prot_000.pdf: 
M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 9
Cli nic al St u d y Pr ot oc ol
Cli nic al St u d y Pr ot oc ol 
N u m ber
M S 2 0 1 9 2 2 - 0 0 0 1
Title
A n 
O pe n -La bel 
St u d y 
of t he Safet y , 
Tolera bilit y , a n d 
P har mac o ki netic/ P har mac o d y na mic Pr ofile of M 4 3 4 4 (f or merly 
V X -8 0 3) as a S i n gle A ge nt a n d i n C o m bi nati o n wit h C yt ot o xic 
C he m ot hera p y i n Partici pa nt s wit h A d va nce d S oli d T u m ors
P h ase
I
I N D N u m ber
E u dr a C T N u m ber
2 0 1 4- 0 0 3 8 3 8- 8 6
C o or di n ati n g 
I n vesti g at or
Tele p h o ne: 
S p o ns or
I n t he U K, S pai n, a n d the Net herla n ds: 
Merc k K G a A
Fra n kf urter Strasse 2 5 0 
Dar msta dt, Ger ma n y
I n t he U S A a n d Ca na da: 
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, I nc. , 
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
Bi llerica, M A, U S A
Me dical Res p o nsi ble:
Merc k 
K Ga A, 
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, 
Ger ma n y
Tele p h o ne: 
Fa x: 
Cli nic al St u d y Pr ot oc ol 
Versi o n
2 9 Ja n uar y 2 0 2 0 Versi o n 8 . 0 i ncl u di n g A me n d me nt 7
Re pl aces Versi o n
2 8 A pril 2 0 1 9 Versi o n 7 . 0 i ncl u di n g A me n d me nt 6
D oc u me nt N o. 
O bject N o. 
C CI
P P D
P P D
P P D
P P D
P P D
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Pr ot oc ol A me n d me nt S u m m ar 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
1 9 -S e p -2 0 1 4
2. 0
Gl o b al A m e n d m e nt 1
1 4 -N o v -2 0 1 4
3. 0
Gl o b al A m e n d m e nt 2
3 1 -A u g -2 0 1 5
4. 0
Gl o b al A m e n d m e nt 3
0 3 -J u n -2 0 1 6
5. 0
Gl o b al A m e n d m e nt 4
1 6 -A u g -2 0 1 7
6. 0
Gl o b al A m e n d m e nt 5
0 2 -F e b -2 0 1 8
7. 0
Gl o b al A m e n d m e nt 6
2 8 -A pr -2 0 1 9
8. 0
Gl o b al A m e n d m e nt 7
2 9- J a n -2 0 2 0
Pr ot oc ol Versi o n [ 8. 0 ] (2 9 J a n u ar y 2 0 2 0 )
T his a me n d me nt is s u bsta ntial base d o n t he criteria i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of 
t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.
O ver all R ati o n ale f or t he A me n d me nt
T his a me n d me nt ser ves mai nl y  to clarif y that e val uati o n of a dr u g h oli da y  sc he d ule m a y  be 
c o n d ucte d i n parallel t o ot her parts of t he st u d y. T o facilitate t hat, dr u g h oli da y  sc he d ules are 
defi ne d a n d arra n ge d i n a ne w P art A 3.
F urt her m ore , t his a me n d me nt i nc or p orates clarificati o ns a n d c ha n ges t o all o w i n vesti gati ve sites 
a d diti o nal ease i n e nr olli n g a n d a d heri n g t o t he 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
T hr o u g h o ut w h er e a p pli c a bl e
R e or g a ni z ati o n of dr u g h oli d a y 
s c h e d ul e e v al u ati o n i n s e p ar at e 
P art A 3 , wit h m et h o d ol o g y, 
o bj e cti v e s / e n d p oi nt s, S o A s, et c. 
s p e cifi e d.
T o cl arif y t h at t h e e v al u ati o n of a dr u g 
h oli d a y s c h e d ul e m a y b e p erf or m e d 
i n d e p e n d e nt fr o m c o n d u ct of P art s C
T hr o u g h o ut w h er e a p pli c a bl e
A d diti o n al P art s C 4, C 5, C 6 
a d d e d a s o pti o n al e x p a n si o n 
c o h ort s f or P art A 3 si mil ar t o P art 
A 2 wit h P art s C 1, C 2, a n d C 3, 
t h e s e ar e c oll e cti v el y r ef err e d t o 
a s “ P art s C ”.
T o a d d t h at a d o s e a n d/ or s c h e d ul e 
t h at h a s b e e n e x pl or e d i n o pti o n al 
e x p a n si o n P art A 3 b ut i s diff er e nt 
fr o m t h at e v al u at e d i n P art s C 1, C 2, 
a n d C 3 m a y b e e v al u at e d i n f urt h er 
P art s C.
S y n o p si s Pl a n n e d st u d y a n d 
tr e at m e nt d ur ati o n p er p arti ci p a nt
T h e pr e s cr e e ni n g a n d S cr e e ni n g 
p eri o d s m er g e d i nt o 1 S cr e e ni n g 
p eri o d wit h a d ur ati o n of 4 2 d a y s 
f or P art s C.
T o cl arif y a n d si m plif y t h e S cr e e ni n g 
pr o c e d ur e s f or P art s C
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
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 a bl e 2 S c h e d ul e of A s s e s s m e nt s: 
S cr e e ni n g ( P art s C ) 5. 2. 8 
S cr e e ni n g
5. 3. 1 I n cl u si o n Crit eri a # 2
5. 4 Crit eri a f or I niti ati o n of st u d y 
tr e at m e nt
7. 1 S c h e d ul e of a s s e s s m e nt s
7. 2 D e m o gr a p hi c a n d ot h er 
b a s eli n e c h ar a ct eri sti c s
7. 7. 5 A s s e s s m e nt of bi o m ar k er s f or 
P art s C: Eli gi bilit y Crit eri a
S y n o p si s: Pl a n n e d n u m b er of 
p arti ci p a nt s
U p d at e d t h e n u m b er of 
p arti ci p a nt s f or P art s A 3 a n d n e w 
C p art s
T o a dj u st a c c or di n g t o n e w p art s C 4 - 6
T a bl e 7 Tr e at m e nt a n d F oll o w- u p 
P eri o d ( M 4 3 4 4 si n gl e a g e nt 
t h er a p y i n e x p a n si o n P art s C 1, C 2, 
a n d C 3 )
R e m o v e d e v al u ati o n s o n D a y 2 
i n C y cl e 1 i n P art s C 1 , C 2, a n d 
C 3
T h e C 1 D 2 a s s e s s m e nt s s er v e f or P K
a n d a d diti o n al s af et y l a b s. Si n c e t h e 
d o s e u s e d i n P art s C 1, C 2, a n d C 3 
h a s b e e n e x pl or e d i n P art A 2 a n d 
d e cl ar e d s af e, t h e s e ar e n ot n e e d e d
S e cti o n 3. 1 S ci e ntifi c R ati o n al e
A d d e d i nf or m ati o n r e g ar di n g 
pr e v al e n c e of m ut ati o n s.
T o e n h a n c e r ati o n al e cl arit y.
S e cti o n 3. 2 T o xi c ol o g y a n d 
C o m p o u n d S af et y
U p d at e d M 6 6 2 0 e x p o s ur e 
i nf or m ati o n.
F or a c c ur a c y of d at a.
S e cti o n s 5. 1. 2 P art A 2, 5. 1. 3 P art 
A 3
A d d e d t h at “ C a n di d at e 
p arti ci p a nt s wit h a d v a n c e d s oli d 
t u m ors c arr yi n g alt er ati o n s t h at 
ar e s u s p e ct e d t o s e n siti z e f or 
tr e at m e nt wit h a n A T R i n hi bit or 
( e s p e ci all y t h o s e d efi n e d f or t h e 
P art s C) m a y b e pr ef er e nti all y 
e nr oll e d.”
T o i n cr e a s e t h e p ot e nti al f or b e n efit of 
p arti ci p ati n g p ati e nt s
S e cti o n 5. 1. 3 P art A 3
A d d e d t h at t h e p ur p o s e of 
P art A 3 i s t o i n v e sti g at e dr u g 
h oli d a y d o si n g s c h e d ul e s wit h 
t h e g o al of i m pr o v e d l o n g-t er m 
t ol er a bilit y r el ati v e t o c o nti n u o u s 
r e gi m e n s i n P art A 2, cl arifi e d t h e 
b a si s f or d et er mi n ati o n of R P 2 D 
f or P art A 3 , d o si n g s c h e d ul e 
pl a n, a n d o utli n e d e nr oll m e nt 
pri oriti z ati o n b et w e e n P art s A 3 
a n d C.
F or cl arifi c ati o n.
S e cti o n 5. 1. 3 P art A 3, 
5. 2. 1 R ati o n al e of st u d y d e si g n
8. 2 S a m pl e si z e
8. 5. 7. 2 S af et y i n P art s A 2 a n d A 3
A d d e d B a y e si a n o pti m al i nt er v al 
m o d el ( B OI N) f or d o s e e s c al ati o n 
i n P art A 3
T o i n cr e a s e fl e xi bilit y a n d b ett er 
o p er ati n g c h ar a ct eri sti c s c o m p ar e d t o 
3 + 3 d e si g n
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
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
S e cti o n 5. 1. 5 All P art s C
S e cti o n 6. 3 A s si g n m e nt t o 
tr e at m e nt gr o u p s
A d d e d t h at P art s C 1, C 2, a n d C 3 
m a y b e i niti at e d i n p ar all el or i n a 
st a g g er e d m a n n er u si n g a d o s e 
a n d s c h e d ul e d et er mi n e d t o b e a 
R P 2 D i n eit h er P art A or P art A 2 
at t h e di s cr eti o n of t h e S p o n s or 
a n d I n v e sti g at or s. A d diti o n al
P art s C 4, C 5 or C 6 u si n g d o s e s
a n d s c h e d ul e s d et er mi n e d t o b e 
R P 2 D i n P art A3 m a y b e i niti at e d 
at a n y ti m e.
T o cl arif y d et a il s of c o n d u ct of P art s C
S e cti o n 5. 1. 5 All P art s C; Fi g ur e 5
A d d e d a s c h e m ati c of eli gi bilit y 
a s s e s s m e nt s f or P art s C.
F or cl arifi c ati o n.
S e cti o n 5. 2. 2 R ati o n al e f or St u d y 
Dr u g D o s e a n d D ur ati o n
A d d e d t h at if t h e BI D or Q D 
r e gi m e n i s u nf a v or a bl e , n e w
d o si n g s c h e d ul e s, u si n g dr u g 
h oli d a y s c h e d ul e s, m a y b e 
e x pl or e d i n P art A 3 at t h e 
di s cr eti o n of t h e S p o n s or a n d 
I n v e sti g at or s.
D e p e n di n g o n t h e R P 2 D a n d M T D 
o bt ai n e d i n P art A 2 wit h a BI D or Q D 
r e gi m e n, t h er e mi g ht b e a d e sir e t o 
e x pl or e dr u g h oli d a y s c h e d ul e s. 
5. 2. 8 S cr e e ni n g
A d d e d t h at S cr e e ni n g F ail ur e s 
f or P art C m a y b e c o n si d er e d f or 
p arti ci p ati o n i n P art A 3 a n d 
i n di c at e d a s s e s s m e nt s t h at 
s h o ul d b e r e p e at e d.
F or cl arifi c ati o n.
7. 5. 2. 1 Pr e g n a n c y
A d d e d l a ct ati o n st at e m e nt.
F or cl arif i c ati o n a n d ali g n m e nt wit h I B.
7. 5. 2. 2 C o ntr a c e pti o n
A d d e d t h at stri ct c o ntr a c e pti o n 
u s e d uri n g d o si n g a n d f or at l e a st 
6 m o nt h s aft er t h e l a st d o s e of 
M 4 3 4 4 i s r e q uir e d.
Al s o 
r e c o m m e n d e d t h at p arti ci p a nt s 
s h o ul d b e i nf or m e d t h at f ertilit y 
mi g ht b e i m p air e d l o n g -t er m a n d 
m a y o pt t o cr y o pr e s er v e s p er m 
or o v a pri or t o tr e at m e nt.
F or cl arifi c ati o n a n d ali g n m e nt wit h I B.
S e cti o n 6. 6. 1 P er mitt e d 
M e di c ati o n s
C o n c o mit a nt m e di c ati o n s s u c h 
a s l e u pr oli d e, g o s er eli n , 
tri pt or eli n, hi str eli n, d e g ar eli x, 
a bir at er o n e, e n z al ut a mi d e, a n d 
nil ut a mi d e a d d e d f or p arti ci p a nt s 
wit h pr o st at e c a n c er
T o m ai nt ai n a c a str at e l e v el of 
t e st o st er o n e i n p arti ci p a nt s wit h 
pr o st at e c a n c er
S e cti o n 7. 6. 1. 3 P h ar m a c o ki n eti c 
S a m pli n g: P art A 3
T a bl e 1 7 P h ar m a c o ki n eti c 
s a m pli n g s c h e d ul e f or P art A 3
T a bl e 1 8 P h ar m a c o ki n eti c 
s a m pli n g s c h e d ul e f or P art s C 4, 
C 5, a n d C 6
A d d e d a s e p ar at e s e cti o n wit h 
P K s a m pli n g t a bl e f or P art A 3 
a n d P art s C 
T o e n h a n c e cl arit y a cr o s s t h e 
s e p ar at e p ot e nti al dr u g h oli d a y 
s c h e d ul e s
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
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
S e cti o n 7. 5. 3 Cli ni c al L a b or at or y 
A s s e s s m e nt s;  T a bl e 1 5 S af et y 
L a b or at or y T e st P a n el s
A d d e d r eti c ul o c yt e s t o 
h e m at ol o g y a s s e s s m e nt s
T o i n cr e a s e s af et y i nf or m ati o n
S e cti o n 9. 3 P arti ci p a nt 
I d e ntifi c ati o n a n d Pri v a c y
A d d e d s e nt e n c e i n di c ati n g t h at i f 
a p arti ci p a nt i s a S cr e e ni n g 
f ail ur e a n d i s r e-s cr e e n e d or 
c o n s e nt s t o p arti ci p at e i n a 
diff er e nt p art of t h e st u d y, t h at 
p arti ci p a nt will r e c ei v e a n e w 
u ni q u e i d e ntifi c ati o n n u m b er.
F or cl arit y.
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 sio n s .
Mi n or, t h er ef or e, h a v e n ot b e e n 
i n di vi d u all y s u m m ari z e d.
- C o nfi de ntial –
T his d oc u me nt is t he pr o pert y of Merc k K G a A, Dar msta dt, Ger ma n y, or o ne of its s u bsi diaries. It 
is i nte n de d f or restricte d use o nl y  an d m a y  not – i n f ull or part – be passe d o n, re pr o d uce d, 
p u blis he d or use d wit h o ut e x press per missi o n of Merc k K G a A, Dar msta dt, Ger ma n y,  or its 
s u bsi diar y. C o p yri g ht © 2 0 2 0 b y  Merc k KG a A, Dar msta dt, Ger ma n y, or its s u bsi diar y. All ri g hts 
reser ve d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Pr ot oc ol T a ble of C o nte nts
Pr ot oc ol Ta ble of C o nte nts .................................................................................................. 6
Ta ble of I n -Te xt Ta bles ..................................................................................................... 1 3
Ta ble of I n -Te xt Fi g ures .................................................................................................... 1 3
List of A b bre viati o ns ......................................................................................................... 1 5
1
S y n o psis ..............................................................................................1 8
2
S p o ns or, I n vesti gat o rs a n d St u d y A d mi nistrati ve Str uct ure............... 5 2
3
Bac k gr o u n d I nf or mati o n ..................................................................... 5 2
3. 1
Scie ntific Rati o nale ............................................................................. 5 2
3. 2
T o xic ol o g y  a n d C o m p o u n d Safet y..................................................... 5 4
3. 3
St u d y  Rati o nale................................................................................... 5 6
4
St u d y  O bjecti ves................................................................................. 5 7
4. 1
Pri mar y  O bjecti ves ............................................................................. 5 7
4. 1. 1
Part A .................................................................................................. 5 7
4. 1. 2
Part A 2 ................................................................................................ 5 7
4. 1. 3
Part A 3 ................................................................................................ 5 7
4. 1. 4
Part B 1 ................................................................................................ 5 7
4. 1. 5
All Parts C ........................................................................................... 5 7
4. 2
Sec o n dar y  O bjecti ves ......................................................................... 5 8
4. 2. 1
Part A .................................................................................................. 5 8
4. 2. 2
Part A 2 ................................................................................................ 5 8
4. 2. 3
Part A 3 ................................................................................................ 5 8
4. 2. 4
Part B 1 ................................................................................................ 5 8
4. 2. 5
All Parts C ........................................................................................... 5 8
5
I n vesti gati o nal Pla n ............................................................................6 0
5. 1
O verall St u d y  Desi g n a n d Pla n........................................................... 6 0
5. 1. 1
Part A .................................................................................................. 6 1
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
5. 1. 2
Part A 2 ................................................................................................6 4
5. 1. 3
Part A 3 ................................................................................................ 6 6
5. 1. 4
Part B 1 ................................................................................................ 6 9
5. 1. 5
All Parts C ........................................................................................... 7 1
5. 1. 6
O n -treat me nt T u m or Bi o ps y S u bst u d y............................................... 7 3
5. 2
Disc ussi o n of St u d y  Desi g n................................................................ 7 4
5. 2. 1
Rati o nale f or t he St u d y  Desi g n...........................................................7 4
5. 2. 2
Rati o nale f or St u d y Dr u g D ose a n d D urati o n ..................................... 7 4
5. 2. 3
Rati o nale f or Partici pa nt Selecti o n ..................................................... 7 6
5. 2. 4
Rati o nale f or St u d y  Assess me nts........................................................ 7 7
5. 2. 5
I ncl usi o n of S pecial P o p ulati o ns ........................................................ 7 8
5. 2. 6
Defi niti o n of D ose Li miti n g T o xicit y ................................................. 7 8
5. 2. 7
Partici pa nt E val ua bilit y ...................................................................... 7 9
5. 2. 7. 1
Parts A, A 2, A 3, a n d B 1 ..................................................................... 7 9
5. 2. 7. 2
All Parts C ........................................................................................... 8 0
5. 2. 8
Scree ni n g ............................................................................................ 8 0
5. 2. 9
Treat me nt Pe ri o d ................................................................................ 8 2
5. 2. 1 0
D ose Escalati o n Decisi o n Ma ki n g ...................................................... 8 2
5. 2. 1 1
F oll o w -u p............................................................................................ 8 2
5. 3
Selecti o n of St u d y  P o p ulati o n ............................................................ 8 4
5. 3. 1
I ncl usi o n Criteria ................................................................................ 8 4
5. 3. 2
E xcl usi o n Criteria ............................................................................... 8 5
5. 4
Criteria f or I nitiati o n of St u d y  Treat me nt........................................... 8 7
5. 5
Criteria f or Partici pa nt Wit h dra wal .................................................... 8 7
5. 5. 1
Wit h dra wal fr o m St u d y  T hera py ........................................................8 7
5. 5. 2
Wit h dra wal fr o m t he St u d y
................................................................ 8 8
5. 5. 3
Re place me nt of Partici pa nts ...............................................................8 9
5. 6
Pre mat ure Ter mi nati o n of t he St u d y ................................................... 8 9
5. 7
Defi niti o n of E n d of St u d y ................................................................. 8 9
6
I n vesti gati o nal Me dici nal Pr o d uct a n d Ot her Dr u gs Use d i n t he 
St u d y ...................................................................................................8 9
6. 1
Descri pti o n of t he I n vesti gati o nal Me dici nal Pr o d uct........................ 8 9
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
6. 2
D osa ge a n d A d mi nistrati o n................................ ................................9 0
6. 2. 1
A d mi nistrati o n .................................................................................... 9 0
6. 2. 2
Criteria f or St u d y  Dr u g A d mi nistrati o n.............................................. 9 0
6. 2. 3
D ose M o dificati o n f or T o xicit y .......................................................... 9 1
6. 2. 4
Misse d D oses a n d St u d y  Visits........................................................... 9 3
6. 3
Assi g n me nt t o Treat me nt Gr o u ps ....................................................... 9 3
6. 4
St o p pi n g R ules .................................................................................... 9 4
6. 5
N o n -i n vesti gati o nal Me dici nal Pr o d ucts t o be Use d .......................... 9 4
6. 6
C o nc o mita nt Me dicati o ns a n d T hera pies ........................................... 9 4
6. 6. 1
Per mitte d Me dici nes ........................................................................... 9 4
6. 6. 2
Pr o hi bite d Me dici nes .......................................................................... 9 5
6. 6. 3
Ot her I nter ve nti o ns ............................................................................. 9 7
6. 6. 3. 1
Meals a n d Dietar y  Restricti o ns........................................................... 9 7
6. 6. 3. 2
Acti vit y ...............................................................................................9 7
6. 6. 4
S pecial Preca u ti o ns............................................................................. 9 7
6. 6. 5
Ma na ge me nt of S pecific A d verse E ve nts or A d verse Dr u g 
Reacti o ns ............................................................................................. 9 7
6. 7
Pac ka gi n g a n d La beli n g of t he I n vesti gati o nal Me dici nal Pr o d uct .... 9 7
6. 8
Pre parati o n, Ha n dli n g, a n d St ora ge of t he I n vesti gati o nal 
Me dici nal Pr o d uct ............................................................................... 9 8
6. 9
I n vesti gati onal Me dici nal Pr o d uct Acc o u nta bilit y ............................. 9 8
6. 1 0
Assess me nt of I n vesti gati o nal Me dici nal Pr o d uct C o m plia nce ......... 9 9
6. 1 1
Bli n di n g ..............................................................................................9 9
6. 1 2
E mer ge nc y  U n bli n di n g....................................................................... 9 9
6. 1 3
Tre at me nt of O ver d ose ....................................................................... 9 9
6. 1 4
Me dical Care of Partici pa nts after E n d of St u d y .............................. 1 0 0
7
St u d y  Pr oce d ures a n d Assess me nts.................................................. 1 0 0
7. 1
Sc he d ule of Assess me nts ..................................................................1 0 0
7. 2
De m o gra p hic a n d Ot her Baseli ne C haracteristics ............................ 1 0 0
7. 3
Partici pa nt a n d Disease C haracteristics ............................................1 0 0
7. 4
Efficac y  Assess me nts .......................................................................1 0 0
7. 5
Assess me nt of Safet y................................ ........................................1 0 2
7. 5. 1
A d verse E ve nts .................................................................................1 0 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
7. 5. 1. 1
A d ve rse E ve nt Defi niti o ns................................................................1 0 3
7. 5. 1. 2
Met h o ds of Rec or di n g a n d Assessi n g A d verse E ve nts .................... 1 0 5
7. 5. 1. 3
Defi niti o n of t he A d verse E ve nt Re p orti n g Peri o d ........................... 1 0 6
7. 5. 1. 4
Pr oce d ure f or Re p orti n g Seri o us A d verse E ve nts, A d verse E ve nts 
of S pecial I nterest a n d D ose L i miti n g T o xicities ............................. 1 0 6
7. 5. 1. 5
Safet y  Re p orti n g t o Healt h A ut h orities, In de pe n de nt Et hics 
C o m mittees/ I nstit uti o nal Re vie w B oar ds a n d I n vesti gat ors............ 1 0 7
7. 5. 1. 6
M o nit ori n g of Partici pa nts wit h A d verse E ve nts .............................. 1 0 7
7. 5. 2
Pre g na nc y  a n d I n Uter o Dr u g E x p os ure........................................... 1 0 7
7. 5. 2. 1
Pre g na nc y ......................................................................................... 1 0 7
7. 5. 2. 2
C o ntrace pti o n .................................................................................... 1 0 8
7. 5. 3
Cli nical L a b orat or y Assess me nts ..................................................... 1 1 0
7. 5. 4
Vital Si g ns, P h y sical E xa mi nati o ns, a n d Ot her Assess me nts........... 1 1 2
7. 5. 4. 1
P h y sical E xa mi nati o n a n d Vital Si g ns.............................................. 1 1 2
7. 5. 4. 2
Electr ocar di o gra m ............................................................................. 1 1 2
7. 6
P har mac o ki netics .............................................................................. 1 1 3
7. 6. 1
Bl o o d Sa m pli n g ................................................................................ 1 1 3
7. 6. 1. 1
P har mac o ki netic Sa m pli n g: Part A ................................................... 1 1 4
7. 6. 1. 2
P har mac o ki netic Sa m pli n g: Part A 2 ................................................. 1 1 4
7. 6. 1. 3
P har mac o ki netic Sa m pli n g: Part A 3 ................................................. 1 1 4
7. 6. 1. 4
P har mac o ki netic Sa m pli n g: Part B 1 ................................................. 1 1 6
7. 6. 1. 5
P har mac o ki netic Sa m pli n g: Parts C ................................................. 1 1 6
7. 6. 3
Pr ocessi n g a n d Ha n dli n g of P har mac o ki netic Sa m ples .................... 1 1 8
7. 6. 4
Bi oa nal ys is........................................................................................1 1 8
8
Statistics ............................................................................................ 1 2 1
8. 1
Se q ue nce of A nal ys es .......................................................................1 2 2
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
8. 3
Ra n d o mizati o n ..................................................................................1 2 5
8. 4
E n d p oi nt s.......................................................................................... 1 2 5
8. 4. 1
Pri mar y  E n d p oi nts............................................................................ 1 2 5
8. 4. 1. 1
Part A ................................................................................................ 1 2 5
8. 4. 1. 2
Parts A 2 a n d A 3 ................................................................................ 1 2 5
8. 4. 1. 3
Part B 1 ..............................................................................................1 2 5
8. 4. 1. 4
Parts C ...............................................................................................1 2 5
8. 4. 2
Sec o n dar y  E n d p oi nts........................................................................ 1 2 6
8. 4. 2. 1
Part A ................................................................................................ 1 2 6
8. 4. 2. 2
Parts A 2 a n d A 3 ................................................................................ 1 2 6
8. 4. 2. 3
Part B 1 ..............................................................................................1 2 6
8. 4. 2. 4
Parts C ...............................................................................................1 2 6
8. 4. 3. 5
A nal y sis Sets..................................................................................... 1 2 7
8. 5
Descri pti o n of Statistical A nal y ses ................................................... 1 2 8
8. 5. 1
Part C ................................................................................................ 1 2 8
8. 5. 1. 1
Se q ue nce of a nal ys es ........................................................................ 1 2 8
8. 5. 1. 2
Data C ut off ....................................................................................... 1 2 8
8. 5. 1. 3
Si g nifica nce le vel .............................................................................. 1 2 9
8. 5. 1. 4
S u m mar y  statistics a n d c o nfi de nce i nter vals....................................1 2 9
8. 5. 1. 5
Baseli ne meas ure me nt ......................................................................1 2 9
8. 5. 1. 6
O n -treat me nt peri o d..........................................................................1 2 9
8. 5. 1. 7
P o oli n g acr oss ce nters .......................................................................1 2 9
8. 5. 2
Ge neral C o nsi derati o ns..................................................................... 1 2 9
8. 5. 3
Bac k gr o u n d C haracteristics.............................................................. 1 3 0
8. 5. 3. 1
Partici pa nt Dis p ositi o n ......................................................................1 3 0
8. 5. 3. 2
De m o gra p hics a n d Baseli ne C haracteristics................................ .....1 3 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
8. 5. 3. 3
Pri or a n d C o nc o mita nt Me dici ne ...................................................... 1 3 0
8. 5. 3. 4
St u d y  Dr u g E x p os ure C o m plia nce ................................................... 1 3 0
8. 5. 4
Efficac y  A nalys is i n Parts A, A 2, A 3 a n d B 1................................... 1 3 1
8. 5. 4. 1
A nal y sis of Pri mar y Varia bles.......................................................... 1 3 1
8. 5. 4. 2
A nal y sis of Sec o n dar y Efficac y Varia bles....................................... 1 3 1
8. 5. 5
Efficac y  A nalys is i n Parts C.............................................................1 3 1
8. 5. 6
Cli nical P har mac ol o g y  A nal ysis....................................................... 1 3 2
8. 5. 6. 1
P har mac o ki netic A nal y sis ................................................................ 1 3 2
8. 5. 6. 3
E x p os ure - Q Tc A nal ys es ................................................................. 1 3 3
8. 5. 6. 4
P har mac o ki netic/
 A nalys es ................................. 1 3 3
8. 5. 7
A nal y sis of Safety a n d Ot her E n d p oi nts ........................................... 1 3 3
8. 5. 7. 1
Safet y  i n Parts A a n d B 1................................................................... 1 3 3
8. 5. 7. 2
Safet y  i n Parts A 2 a n d A 3 ................................................................ 1 3 4
8. 5. 7. 3
Safet y  i n Parts C ............................................................................... 1 3 5
8. 6
Cli nical L a b orat or y Assess me nt....................................................... 1 3 6
8. 7
Electr ocar di o gra m ............................................................................. 1 3 7
8. 8
Vital Si g ns ........................................................................................ 1 3 7
8. 9
P h y sical E xa mi nati o n ....................................................................... 1 3 7
8. 1 0
I nteri m a n d A d diti o nal Pla n ne d A nalys es ........................................ 1 3 7
9
Et hical a n d Re g ulat or y  As pects........................................................ 1 3 7
9. 1
Res p o nsi bilities of t he I n vesti gat or .................................................. 1 3 7
9. 2
Partici pa nt I nf or mati o n a n d I nf or me d C o nse nt ................................ 1 3 8
9. 3
Partici pa nt I de ntificati o n a n d Pri vac y .............................................. 1 3 8
9. 4
E mer ge nc y  Me dical S u p p ort a n d Partici pa nt Car d .......................... 1 3 9
9. 5
Cli nical St u d y  Ins ura nce a n d C o m pe nsati o n t o Partici pa nts ............ 1 3 9
9. 6
I n de pe n de nt Et hics C o m mittee or I nstit uti o nal Re vie w B oar d........1 3 9
9. 7
Healt h A ut h orities .............................................................................1 4 0
1 0
St u d y  Ma na ge me nt........................................................................... 1 4 0
1 0. 1
Case Re p ort F or m Ha n dli n g .............................................................1 4 0
1 0 . 2
S o urce Data a n d Partici pa nt Files ..................................................... 1 4 0
1 0. 3
I n vesti gat or Site File a n d Arc hi vi n g................................................. 1 4 1
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
1 0. 4
M o nit ori n g, Q ualit y Ass ura nce a n d I ns pecti o n b y Healt h 
A ut h orities........................................................................................ 1 4 2
1 0. 5
C ha n ges t o t he Cli nical St u d y  Pr ot oc ol............................................ 1 4 2
1 0. 6
Cli nical St u d y  Re p ort a n d P u blicati o n P olic y.................................. 1 4 2
1 0. 6. 1
Cli nical St u d y  Re p ort ....................................................................... 1 4 2
1 0. 6. 2
P u blicati o n ........................................................................................ 1 4 2
1 1
Refere nces Cite d i n t he Te xt .............................................................1 4 4
1 2
A p pe n dices ....................................................................................... 1 4 7
A p pe n di x I :
Si g nat ure Pa ges a n d Res p o nsi ble Pers o ns f or t he St u d y .................. 1 4 8
Si g nat ure Pa ge – Pr ot oc ol L ea d ....................................................................................... 1 4 9
Si g nat ure Pa ge – C o or di nati n g I n vesti gat or..................................................................... 1 5 0
Si g nat ure Pa ge – Pri nci pal I n vesti gat or ........................................................................... 1 5 1
A p pe n di x II:
Pr ot oc ol A me n d me nt Hist or y ........................................................... 1 5 2
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble of I n-Te xt T a b les
Ta ble 1
Sc he d ule of Assess me nts: Scree ni n g ( Parts A, A 2, A 3 a n d B 1) ........ 2 9
Ta bl e 2
Sc he d ule of Assess me nts: Scree ni n g ( Parts C) .................................. 3 0
Ta ble 3
Treat me nt a n d F oll o w -U p Peri o d ( M 4 3 4 4 si n gle A ge nt T hera p y , 
Part A) ................................................................................................. 3 2
Ta ble 4
Treat me nt a n d F oll o w -U p Peri o d ( M 4 3 4 4 Si n gle A ge nt T hera p y , 
Part A 2, a n d 1 4 d +/ 7 d - sc he d ule of Part A 3) ...................................... 3 5
Ta ble 5
Treat me nt a n d F oll o w -U p Peri o d - M 4 3 4 4 Si n gle A ge nt T hera p y , 
Part A 3 ( dr u g h oli da y  wit h eit her 3 d +/ 4 d-, 5 d +/ 2 d-, or 7 d +/ 7 d-
sc he d ule) ............................................................................................. 3 8
Ta ble 6
Treat me nt a n d F oll o w -U p Peri o d ( M 4 3 4 4 a n d Car b o plati n 
C o m bi nati o n T hera p y , Part B 1).......................................................... 4 1
Ta ble 7
Treat me nt a n d F oll o w -u p Peri o d ( M 4 3 4 4 si n gle a ge nt t hera p y  i n 
Parts C 1, C 2, a n d C 3 a n d t he 1 4 d +/ 7 d - sc he d ule descri be d i n Parts 
C 4, C 5, a n d C 6) .................................................................................. 4 4
Ta ble 9
Treat me nt a n d F oll o w -u p Peri o d ( M 4 3 4 4 si n gle a ge nt t hera p y  i n 
Parts C 4, C 5 a n d C 6, e xce pt f or t he 1 4 d +/ 7 d - sc he d ule).................... 4 8
Ta ble 1 2
La b orat or y  Val ues Re q uire d f or A d mi nistrati o n of C he m ot hera p y 
or M 4 3 4 4 ............................................................................................ 9 1
Ta ble 1 3
St u d y  Restricti o ns............................................................................... 9 6
Ta ble 1 4
St u d y  Dr u g.......................................................................................... 9 8
Ta ble 1 5
Safet y  La b orat or y Test Pa nels.......................................................... 1 1 1
Ta ble 1 6
Acce pta ble P har mac o ki netic Sa m pli n g Wi n d o ws ............................ 1 1 4
Ta ble 1 7
P har mac o ki netic Sa m pli n g Sc he d ule f or Part A 3 ............................ 1 1 5
Ta ble 1 8
P har mac o ki netic Sa m pli n g Sc he d ule f or Parts C 4, C 5, a n d C 6 .......1 1 7
T a ble of I n-Te xt Fi g ures
Fi g ure 1
Sc he matic of St u d y  Desi g n.................................................................6 1
Fi g ure 2
Part A: D ose Escalati o n Sc he matic f or M 4 3 4 4 as a Si n gle A ge nt .....6 4
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Fi g ure 3
Part A 2: D ose Escalati o n Sc he matic f or M 4 3 4 4 wit h De nse 
M o n ot hera p y Sc he d ule ....................................................................... 6 6
Fi g ure 4
D ose Escalati o n Sc he matic f or M 4 3 4 4 i n C o m bi nati o n Wit h 
Car b o plati n ( Part B 1) .......................................................................... 7 1
Fi g ure 5
Sc he matic of Eli gi bilit y  Assess me nts i n Parts C................................ 7 2
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
List of A b bre vi ati o ns
A E
A d verse E ve nt
A L P
Al kali ne p h os p hatase
A L T
Ala ni ne a mi n otra nsferase
A T M
Ata xia tela n giectasia m utate d
A T R
Ata xia tela n giectasia m utate d a n d Ra d 3 -relate d pr otei n
A S T
As partate a mi n otra nsferase
A U C
Area u n der t he c o nce ntrati o n vers us ti me c ur ve
β- h C G
β- h u ma n c h ori o nic g o na d otr o pi n
BI D
T wice dail y
BI W
T wice wee kl y
B OI N
Ba yesia n o pti mal i nter val
B R C A -1/ 2
Breast ca ncer earl y o nset ge nes 1 a n d 2
C a v g
A vera ge c o nce ntrati o n
C A - 1 2 5
Ca ncer a nti ge n 1 2 5
C A 1 9 - 9
Ca ncer a nti ge n 1 9 - 9
C E A
Ca ncer e m br y o nic a nti ge n
C P A P
Cli nical p har mac ol o g y  a nal ysis pla n
C R O
C o ntract Researc h Or ga nizati o n
C T
C o m p uterize d t o m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C Y P
C y t oc hr o me P 4 5 0
D E M
D ose E scalati o n M eeti n g
D L
D ose le vel
D L T
D ose li miti n g t o xicit y
D N A
De o x yri b o n ucleic aci d
D S B
D o u ble- stra n d D N A brea ks
E C G
Electr ocar di o gra m
e C R F
Electr o nic case re p ort f or m
F S H
F ollicle sti m ulati n g h or m o ne
γ H 2 A X
P h os p h or y late d H 2 A X
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
G C P
G o o d Cli nical Practice
GI
Gastr oi ntesti nal
G L P
G o o d La b orat or y  Practice
H E D
H u ma n e q ui vale nt d ose
H N S T D
Hi g hest n o nse verel y  t o xic d ose
H R T
H or m o nal re place me nt t hera p y 
I A P
I nte grate d A nalys is Pla n
I B
I n vesti gat ors br oc h ure
I CF
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 de pe n de nt Et hics C o m mittee
I R
I o nizi n g ra diati o n
I RB 
I nstit uti o nal Re vie w B oar d
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
M RI
Ma g netic res o na nce i ma gi n g
M R S D
Ma xi m u m rec o m me n de d starti n g d ose
M T D
Ma xi m u m t olerate d d ose
M T D
car b o
T he ma xi m u m t olerate d d ose of M 4 3 4 4 i n c o m bi nati o n wit h t he hi g hest t olerate d 
d ose of car b o plati n
M T D
Si n gle BI W
T he M T D of si n gle a ge nt M 4 3 4 4 a d mi nistere d t wice wee kl y
M U G A
M ulti ple Gate d Ac q uisiti o n
N CI
Nati o nal Ca ncer I nstit ute
O R
O bjecti ve t u m or res p o nse
O R R
O verall res p o nse rate
P C W G 2
Pr ostate Ca ncer Cli nical Trials W or ki n g Gr o u p
P D
P r o gressi o n of disease
P F S
Pr o gressi o n -free s ur vi val
P K
P har mac o ki netics
p C h k 1
p h os p h or y late d c hec k p oi nt ki nase 1
P S A
Pr ostate -s pecific a nti ge n
R B C
Re d bl o o d cell
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
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 P 2 D
Rec o m me n de d P hase II d ose
R S
Re plicati o n stress
S A E
Seri o us a d verse e ve nt
S E
Sta n dar d err or
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
W H O
W orl d Healt h Or ga nizati o n
W H O -D D E
W orl d Healt h Or ga nizati o n- Dr u g Dicti o nar y  
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
1
S y n o psis
Cli nic al St u d y Pr ot oc ol N u m ber
M S 2 0 1 9 2 2 - 0 0 0 1
Title
A n O pe n -La bel St u d y  of t he Safet y, T olera bilit y , 
a n d P har mac o ki netic/ P har mac o d y n a mic Pr ofile 
of M 4 3 4 4 (f or merly V X - 8 0 3) as a Si n gle A ge nt 
a n d 
i n 
C o m bi nati o n 
wit h 
C y t ot o xic 
C he m ot hera p y i n Partici pa nt s wit h 
A d va nce d 
S oli d T u m ors
St u d y P h ase
I
I N D N u m ber
E u dr a C T N u m ber
2 0 1 4- 0 0 3 8 3 8- 8 6
St u d y sites/c o u ntries
T he st u d y will be c o n d ucte d at a p pr o xi matel y 
1 0 t o 1 5 sites i n t he U K, t he U S A, S pai n, a n d the 
Net herla n ds
Pl a n ne d st u d y peri o d
(first p artici p a nt i n-l ast p artici p a nt
o ut)
Ja n uar y 2 0 1 5 t o Dece m ber 2 0 2 1
Tri al Re gistr y
Cli nical Trials. g o v a n d E u dra C T
O bjecti ves:
Pri m ar y o bjecti ves:
Part A :

T o e val uate t he safety a n d t olera bilit y of m ulti ple asce n di n g d oses of si n gle a ge nt 
M 4 3 4 4 
( he ncef ort h referre d t o as M 4 3 4 4) 
a d mi nistere d t wice wee kl y  (BI W) i n 
partici pa nt s wit h a d va nce d s oli d t u m ors

T o deter mi ne t he ma xi m u m t olerate d d ose ( M T D) a n d/ or rec o m me n de d P hase II d ose 
(R P 2 D ) of si n gle a ge nt M 4 3 4 4 a d mi nistere d BI W i n partici pa nt s wit h a d va nce d s oli d 
t u m ors.
Part A 2:

T o e val uate t he safet y a n d t olera bilit y of m ulti ple asce n di n g d oses of si n gle a ge nt 
M 4 3 4 4 a d mi nistere d i n a t wice dail y or o nce dail y  dose sc he d ule i n partici pa nt s wit h 
a d va nce d s oli d t u m ors

T o deter mi ne t he M T D a n d/ or R P 2 D of si n gle a ge nt M 4 3 4 4 a d mi nistere d i n a t wice 
dail y  or o nce daily d ose sc he d ule i n partici pa nt s wit h a d va nce d s oli d t u m ors.
Part A 3:

T o e val uate t he safety a n d t olera bilit y of m ulti ple asce n di n g d oses of si n gle a ge nt 
M 4 3 4 4 w he n a d mi nistere d i n a dr u g h oli da y  d ose sc he d ule ( 3 da ys of d osi n g f oll o we d 
b y  4 da ys of pa usi n g [3 d +/ 4 d -] or 5 da y s of d osi n g f oll o we d b y  2 da ys of pa usi n g 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M4344
M4344 First in Human Study
MS201922-0001
C O N F I D E N T I A L
I N F O R M A T I O N
19/159
[5d+/2d-] or 7 days of dosing followed by 7 days of pausing [7d+/7d-]) or 14 days of 
dosing followed by 7 days of pausing [14d+/7d-]) in participants with advanced solid 
tumors

To determine the MTD and/or RP2D of single agent M4344 administered in a drug 
holiday dose schedule in participants with advanced solid tumors.
Part B1:

To evaluate the safety and tolerability of M4344 when administered in combination
with carboplatin in participants with advanced solid tumors

To determine the MTD and/or RP2D of M4344 administered in combination with
carboplatin in participants with advanced solid tumors.
Parts C:

To evaluate the safety, tolerability, and efficacy in terms of confirmed objective 
response of M4344 administered at doses and schedules determined as RP2D in Parts
A, A2, or A3 in participants with solid tumor harboring loss-of-function mutations in 
the genes ARID1A (Parts C1, C4), ATRX and/or DAXX (Parts C2, C5), or ataxia 
telangiectasia mutated (ATM) (Parts C3, C6).
Secondary objectives:
Part A:

To evaluate pharmacokinetics (PK) of single agent M4344 when administered BIW in 
participants with advanced solid tumors

To assess potential antitumor activity of single agent M4344 when administered BIW 
in participants with advanced solid tumors.
Part A2:

To evaluate PK of single agent M4344 (and metabolites as appropriate) when 
administered in a twice daily (BID) or once daily dose schedule in participants with
advanced solid tumors.

To assess potential antitumor activity of single agent M4344 when administered in a 
BID or once daily dose schedule in participants with advanced solid tumors.
Part A3

To evaluate the PK of single agent M4344 (and metabolites as appropriate) when 
administered in a drug holiday dose schedule in participants with advanced solid 
tumors.

To assess preliminary antitumor activity of single agent M4344 when administered in 
a drug holiday dose schedule in participants with advanced solid tumors.
Part B1:

To evaluate the PK profile of M4344 when administered in combination with 
carboplatin in participants with advanced solid tumors
Document No. 0900babe812f8f49v1.0
Object No. 0900babe8138cc6e


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9

T o e v alu ate p o ten tial a ntit u m or activit y af ter ad mi nis teri n gM 4 3 4 4 i n c o m bi natio n wit h
car b o plati n i n partici pa nt s wit h a d va nce d so li d t u m ors.
Parts C:

T o f urt her e val uate efficac y i n ter ms of c o nfir me d best o verall res p o nse, d urati o n of 
res p o nse, pr o gressi o n -free s ur vi val, a n d o verall s ur vi val ti me of M 4 3 4 4 
w he n 
a d mi nistere d i n partici pa nts wit h l oss- of-f u ncti o n m utati o ns i n t he ge nes A RI D 1 A, 
A T R X a n d/ or D A X X, or A T M

T o e val uate t he P K of M 4 3 4 4 (a n d meta b olites as a p pr o priate) i n i n di vi d ual partici pa nts 
wit h l oss- of-f u ncti o n m utati o ns.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Met h o d ol o g y: T his is a P hase I, first-i n-h u ma n cli nical st u d y  usi n g M 4 3 4 4. T he st u d y w ill be
co n d uc te d i n m ulti ple p arts (P arts A , A 2, A 3, B 1, C 1, C 2, C 3 a n d p ote ntiall y f urt her Parts C 4, 
C 5, a n d C 6 ). Eli gi ble partici pa nt s i n Parts A, A 2 a n d A 3 will ha ve 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 ble w hic h m a y  c o n vey c li nical be nefit. Eli gi ble partici pa nt s 
i n Part B 1 will ha ve 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 py is a vaila ble w hic h 
ma y  co n ve y  cli nical be nefit, a n d/ or partici pa nt s m ust ha ve disease pr o gressi o n after at least 
1 pri or c he m ot hera p y re gi me n i n t he metastatic setti n g, a n d f or w hic h car b o plati n w o ul d be 
c o nsi dere d sta n dar d of care. Eli gi ble partici pa nts i n Part s C will ha ve a d va nce d s oli d t u m ors 
f or w hic h n o rec o m me n de d sta n dar d t hera py is a vaila ble a n d w h o carr y certai n l oss- of-f u ncti o n 
m utati o ns (see bel o w f or details).
I n Part A, d oses of M 4 3 4 4 will be escalate d t o deter mi ne M T D a n d/ or R P 2 D w he n 
a d mi nistere d BIW as a si n gle -a ge nt.
Part A 2 will esta blis h t he M T D/ R P 2 D of M 4 3 4 4 as a si n gle a ge nt a d mi nistere d BI D or o nce 
dail y .
Part A 3 will esta blis h t he M T D/ R P 2 D of M 4 3 4 4 as a si n gle a ge nt a d mi nistere d i n a dr u g 
h oli da y  sc he d ule ( 3 da ys of d osi n g f oll o we d b y 4 da ys of pa usi n g [3 d +/ 4 d -] or 5 da ys of 
d osi n g f oll o we d b y 2 da ys of pa usi n g [ 5 d +/ 2 d -] or 7 da y s of d osi n g f oll o we d b y 7 da ys of 
pa usi n g [ 7 d+/ 7 d- ]) or 1 4 da y s of d osi n g f oll o we d b y 7 da ys of pa usi n g [1 4 d +/ 7 d- ]).
I n Part B 1, d oses of M 4 3 4 4 will be escalate d i n c o m bi nati o n wit h car b o plati n t o deter mi ne a 
c o m bi nati o n t hera p y M T D a n d/ or R P 2 D . 
Res ults of Parts A, A 2 a n d A 3 will i nf or m t he d ose a n d sc he d ule i n Parts C.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
I n st u d y Parts C t he safet y, t olera bility a n d efficac y of M 4 3 4 4
a d mi nistere d as a si n gle a ge nt 
at d ose s a n d sc he d ules deter mi ne d as R P 2 D i n Part s A, A 2 , or A 3 will be e val uate d i n t hree 
differe nt 
 selecte d p o p ulati o ns (l oss- of-f u ncti o n m utati o ns i n t he ge n es A RI D 1 A i n
C 1 a n d C 4, i n A T R X a n d/or D A X X i n C 2 a n d C 5, a n d A T M i n C 3 a n d C 6). Parts C 1, C 2, a n d 
C 3 will use a d ose a n d sc he d ule esta blis he d i n Parts A or A 2 . Parts C 4, C 5, a nd C 6 are o pti o nal 
a n d will use a d ose a n d sc he d ule esta blis he d i n Part A 3. Prese nce of eli gi ble 
 will 
be assesse d d uri n g Scree ni n g i n a ma n dat or y fres h t u m or bi o ps y  (a bi o ps y o btai ne d after t he 
e n d of t he pre vi o us treat me nt re gi me n is als o acce pta ble) or, if n ot p ossi ble f or me dical reas o ns, 
a n arc hi val t u m or tiss ue sam ple c o ul d be use d . T he  
 f or par tici pa nt selecti o n will be 
assesse d b y  a ce ntral trial assa y or b y  an assa y wit h a p pr o priate re g ulat or y stat us. Details of 
t his pr ocess are pr o vi de d i n s u p p orti ve d oc u me nts.
E nr ol lme nt is restricte d t o partici pa nts w h o ha ve e x ha uste d all sta n dar d of care o pti o ns 
acc or di n g t o N C C N G ui da nce.
 
 
 
 
Pl a n ne d 
n u m ber 
of 
p artici p a nt s: 
A p pr o xi matel y  
3 0 0 partici pa nt s 
(a p pr o xi matel y 
2 5 partici pa nt s i n Part A, 3 1 partici pa nt s i n Part A 2, 4 0 partici pa nts i n Part A 3, 2 5 partici pa nt s 
i n Part B 1 a n d 1 9 0 i n Parts C.
Pri m ar y e n d p oi nts: 
Part A :

Safet y  para meters, i ncl u di n g A Es, cli nical la b orat or y val ues (ser u m c he mistr y an d 
he mat ol o g y ), vital si g ns, a n d electr ocar di o gra m (E C G ) assess me nts

M T D a n d/ or R P 2 D of si n gle a ge nt M 4 3 4 4 a d mi nistere d BIW.
Part A 2:

Safet y  para meters, i ncl u di n g A Es, cli nical la b orat or y val ues (ser u m c he mistr y an d 
he mat ol o g y ), vital si g ns, a n d E C G assess me nts

M T D a n d/ or R P 2 D of si n gle a ge nt M 4 3 4 4 a d mi nistere d wit h a t wice dail y or o nce 
dail y  d ose sc he d ule.
Part A 3:

Safet y  para meters, i ncl u di n g A Es, cli nical la b orat or y val ues (ser u m c he mistr y an d 
he mat ol o g y ), vital si g ns, a n d E C G assess me nts

M T D 
a n d/ or R P 2 D
of si n gle a ge nt M 4 3 4 4 
a d mi nistere d wit h a dr u g h oli da y 
sc he d ule.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C
C
I
C
C
I
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Part B 1 :

Safet y  para meters, i ncl u di n g A Es, cli nical la b orat or y val ues (ser u m c he mistr y an d 
he mat ol o g y ), vital si g ns, a n d E C G assess me nts

M T D a n d/ or R P 2 D of M 4 3 4 4 a d mi nistere d i n c o m bi nati o n wit h car b o plati n.
Parts C:

Occ urre nce of :
o
Treat me nt -e mer ge nt a d verse e ve nt (T E A Es ) a n d treat me nt-relate d A Es 
gra de d acc or di n g t o 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 La b orat or y a b n or malities
o
Cli nicall y  si g nifica nt a b n or mal vital si g n
o
Cli nicall y  si g nifica nt a b n or mal E C G

O bjecti ve res p o nse (i. e. c o nfir me d c o m plete res p o nse [C R ] or partial res p o nse [P R ]) 
acc or di n g t o Res p o nse E val uati o n Criteria i n S oli d T u m ors (R E CI S T ) v1. 1 assesse d 
b y  t he In vesti gat or .
Sec o n d ar y e n d p oi nts :
Part A :

P K para meter esti mates of si n gle a ge nt M 4 3 4 4 a d mi nistere d BI W, deri ve d fr o m 
plas ma c o nce ntrati o n -ti me data

O bjecti ve t u m or res p o nse O R a n d disease sta bilizati o n as e val uate d b y  RE CI S T 1. 1.
Part A 2 :

P K para meter esti mates of si n gle a ge nt M 4 3 4 4 (a n d meta b olites as a p pr o priate)
a d mi nistere d wit h a t wice dail y  or o nce dail y  dose sc he d ule, deri ve d fr o m plas ma 
c o nce ntrati o n-ti me data

O R a n d disease sta bilizati o n as e val uate d b y R E CI S T 1. 1.
Part A 3:

P K para meter esti mates of si n gle a ge nt M 4 3 4 4 (a n d meta b olites as a p pr o priate)
a d mi nistere d wit h 
a dr u g 
h oli da y  
dose 
sc he d ule, deri ve d 
fr o m plas ma 
c o nce ntrati o n-ti me data

O R a n d disease sta bilizati o n as e val uate d b y R E CI S T 1. 1.
Part B 1 :

P K para meter esti mates of M 4 3 4 4 a d mi nistere d i n c o m bi nati o n wit h car b o plati n 
deri ve d fr o m plas ma c o nce ntrati o n -ti me data

O R as e val uate d b y R E CI S T 1. 1.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Parts C:

C o nfir me d Best O verall Res p o nse (res p o nse assess me nt acc or di n g t o R E CI S T 1. 1 
as assesse d b y t he In vesti gat or will be use d)

D urati o n of res p o nse assesse d fr o m C R or P R u ntil pr o gressi o n of disease, deat h, or 
last t u m or assess me nt

Pr o gressi o n -free s ur vi val

O verall s ur vi val

P K para meter esti mates of M 4 3 4 4 (a n d meta b olites as a p pr o priate) i n i n di vi d ual
partici pa nts wit h l oss- of-f u ncti o n m utati o ns.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
P h ar m ac o ki netics: 
Bl o o d sa m pli n g f or plas ma P K a nal ysis will be c o n d ucte d i n all st u d y parts. Ric h sa m pli n g is 
i m ple me nte d i n Parts A, A 2, A 3 a n d B 1. S parse sa m pli n g is i m pleme nte d i n Parts C. Detaile d 
sa m pli n g ti mes are liste d i n t he S o A a n d Secti o n 7. 6.
Effic ac y assess me nts: 
I ma gi n g sca ns (e. g., C T, M RI) will be perf or me d at Scree ni n g a n d at t he e n d of e ver y 2 c ycles 
(i.e. 6 wee ks) u p t o 6 c ycles of treat me nt, a n d e ver y 3 c ycles (i.e., 9 wee ks) t hereafter u ntil 
disease pr o gressi o n occ urs . I n Parts C, p artici pa nt s w h o disc o nti n ue t he st u d y treat me nt f or 
reas o ns ot her t ha n disease pr o gressi o n or wit h dra wal of c o nse nt will c o nti n ue t u m or 
assess me nts acc or di n g t o t he sa me sc he d ule as partici pa nt s recei vi n g trial treat me nt. B o ne sca n 
(if p ositi ve at S cree ni n g) will be perf or me d at t he e n d of C y cle 4 a n d e ver y 4 to 6 c ycles 
t hereafter f or t h ose partici pa nt s c o nti n ui n g b e y o n d 6 c ycles or as cli nicall y in dicate d. F or 
partici pa nt s wit h pr ostate ca ncer, or ot her ca ncers t hat ha ve b o ne metastases, b o ne sca ns will 
als o be use d f or e val uati o n of disease. I n a d diti o n, f or partici pa nt s wit h ser o us o varia n ca ncer, 
c ol o n ca ncer, pr ostate ca ncer, or ot her t u m ors w here a p pr o priate ser ol o gic t u m or mar kers are 
a vaila ble, t hese will als o be use d t o m o nit or a ntit u m or effects.
I n Parts C , per R E CI S T 1. 1 o bjecti ve res p o nses nee d t o be c o nfir me d. C o nfir mati o n s h o ul d be 
deter mi ne d at a sca n n o less t ha n 4 wee ks after t he ori gi nal assess me nt of o bjecti ve res p o nse is 
ma de; c o nfir mati o n of res p o nse at t he ne xt sc he d ule d t u m or assess me nt is acce pta ble.
S afet y assess me nts:
A d verse e ve nts; cli nical la b orat or y val ues (ser u m c he mistr y, c oa g ulati o n, a n d he mat ol o g y 
st u dies); sta n dar d 1 2-lea d E C Gs; vital si g ns; a n d p h ysical e xa mi nati o ns.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Di a g n osis a n d ke y i ncl usi o n a n d e xcl usi o n criteri a: Male a n d fe male partici pa nt s at least 
1 8 ye ars of a ge, wit h t u m ors meas ura ble b y  RE CI S T 1. 1. I n a d diti o n, partici pa nt s will ha ve t he 
f oll o wi n g c haracteristics:

Parts A, A 2, A 3, a n d B 1 : 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 py is 
a vaila ble a n d t hat m a y  c o n ve y cli nical be nefit

All Parts C: A d va nce d s oli d t u m ors f or w hic h n o rec o m me n de d sta n dar d t hera p y is 
a vaila ble a n d t hat har b or l oss- of-f u ncti o n m utati o ns i n o ne or m ore of t he f oll o wi n g 
ge nes A RI D 1 A ( C 1 , C 4), A T R X a n d/ or D A X X ( C 2, C 5), A T M ( C 3, C 6). Prese nce 
of eli gi ble bi o mar kers will be assesse d d uri n g Scree ni n g i n a ma n dat or y  fres h t u m or 
bi o ps y  (a bi o ps y o btai ne d after the e n d of t he pre vi o us treat me nt re gi me n is als o 
acce pta ble) or, if n ot p ossi ble f or me dical reas o ns, a n arc hi val t u m or tiss ue sa m ple
c o ul d be use d . T he bi o mar kers f or par tici pant selecti o n will be assesse d b y  a ce ntral 
trial assa y or by a n assa y wit h a p pr o priate re g ulat or y  stat us.
I n vesti g ati o n al Me dici n al Pr o d uct: d ose/ m o de of a d mi nistr ati o n/ d osi n g sc he d ule: 
M 4 3 4 4: A n A T R pr otei n ki nase i n hi bit or; 5 0
m g ta blets a d mi nistere d orall y.
Car b o plati n: A D N A -al k ylati n g a ge nt a d mi nistere d u p t o t he A U C = 6 m g m i n/ m L vi a 
i ntra ve n o us i nf usi o n.
T he S p o ns or will n ot s u p pl y car b o plati n f or t his st u d y. Sites will use car b o plati n as s u p plie d 
b y  t heir p har mac y.
Refere nce t her a p y: d ose/ m o de of a d mi nistr ati o n/ d osi n g sc he d ule: N ot a p plica ble .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Pl a n ne d st u d y a n d tre at me nt d ur ati o n per p artici p a nt : 
P artici pa nts i n Parts A, A 2, A 3 , a n d B 1
will ha ve a S cree ni n g peri o d of u p t o 2 1 d a y s. 
Partici pa nts i n Parts C will ha ve a Scree ni n g peri o d of u p t o 4 2 da y s. 
F oll o wi n g Scree ni n g, treat me nt will last until disease pr o gressi o n. F oll o w u p will i ncl u de: 

U p t o 1 4 d a y s ( ± 7 d a y s) f or Safety F oll o w -u p ( Parts A, A 2, A 3, a n d B 1 ) a n d u p t o 
3 0 da y s ( ± 7 d a y s) f or all Parts C;

Ra di ol o gic F oll o w - u p e ver y 6 t o 9 wee ks f oll o wi n g t he last c ycle of c he m ot hera p y
f or t h ose partici pa nt s i n Parts B 1, a n d all Parts C wit h o ut pr o gressi ve disease ;

A d diti o nall y , partici pa nt s ma y  be f oll o we d f or o verall s ur vi val or pr o gressi o n -free 
s ur vi val f or u p t o 1 y ear or m ore o r u ntil st u d y cl os ure, w hic he ver c o mes first.
St atistic al met h o ds: A nal y sis of all data will be perf or me d b y  the S p o ns or or desi g nee. 
E val uati o n of efficac y, safet y a n d t olera bilit y of M 4 3 4 4 as a si n gle a ge nt (Parts A, A 2 , A3 a n d 
all Parts C ) a n d i n c o m bi nati o n wit h car b o plati n ( Part B 1) will be pr o vi de d se parately. T he 
o verall safet y  pr ofile of M 4 3 4 4 will be assesse d i n ter ms of t he f oll o wi n g safety e n d p oi nts: 

I nci de nce of d ose li miti n g t o xicit ies (D L Ts ) f or Parts A, A 2, A 3, a n d B 1 o nl y

I nci de nce of 
T E A Es, 
i ncl u di n g A Es 
lea di n g t o d ose 
m o dificati o ns 
or 
disc o nti n uati o ns

Cli nical la b orat or y  val ues

E C G o utc o mes

Vital si g ns .
Safet y  data will be s u m marize d b y treat me nt gr o u p a n d b y  st u d y part, a n d o verall. I n ge neral, 
safety a nal ys es will be base d o n t he Safet y Set, defi ne d as all partici pa nt s w h o recei ve d at least 
1 d ose of st u d y  dr u g.
T he s u m mar y  of D L Ts will be base d o n t he D L T E val ua ble Set. 
Efficac y  data will be s u m marize d b y  treat me nt gr o u p a n d b y  st u d y part, a n d o verall. Efficac y 
data m a y  als o be s u m marize d b y  ty p e of ca ncer, t u m or sta ge at baseli ne, W H O perf or ma nce 
stat us at baseli ne, ti me ela pse d si nce ca ncer dia g n osis, pri or c he m ot hera p y a n d ra diati o n 
t hera py, ti me ela pse d si nce m ost rece nt t hera p y, d urati o n of m ost rece nt ca ncer t hera p y, a n d 
me dical hist or y .
M 4 3 4 4 P K data will be a nal yz e d o n a n o n g oi n g basis d uri n g d ose escalati o n i n Parts A, A 2,
A 3, a n d B1 usi n g sta n dar d n o nc o m part me ntal met h o ds. P har mac o ki netic data f or M 4 3 4 4 will 
be re vie we d al o n g wit h safet y data t o i nf or m d ose escalati o n. Fi nal P K data f or all st u d y parts
wil l be a nalyz e d a n d re p orte d i n acc or da nce wit h t he i nte grate d a nal ys is pla n (I A P).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
All P arts C:
F or eac h of t he Parts C a 3-sta ge desi g n t o e val uate t he cli nical efficac y of M 4 3 4 4
will be use d . 
After eac h Sta ge, of eac h part, e nr ollme nt will o nl y be c o nti n ue d if t he pres pecifie d n u m ber of 
partici pa nts ha ve s h o w n a best o verall res p o nse of c o nfir me d C R or P R acc or di n g R E CIS T 1. 1
a n d safety has bee n e val uate d .
T he a nal ys es of efficac y a n d safety will be perf or me d se paratel y f or eac h o n e of t he Parts C.
I n Sta ge 1, 9 partici pa nts will be e val uate d a n d if n o res p o n der is o bser ve d, S ta ge 2 will n ot 
o pe n f or e nr oll me nt a n d t he res pecti ve treat me nt ar m will be cl ose d. If at least o ne res p o n der 
is o bser ve d after 9 e val ua ble partici pa nts are e nr olle d i n S ta ge 1, t he n t he st u d y will pr ocee d t o 
S ta ge 2. At c o m pleti o n of Sta ge 2, t he criteri o n is t o o bser ve at least 4 o ut of 2 0 partici pa nts i n 
Sta ges 1 a n d 2 wit h a best o verall res p o nse of c o nfir me d C R or P R. If t his criteri o n is n ot 
reac he d, t he st u d y part will be st o p pe d. Ot her wise t he st u d y part will c o nti n ue t o e nr oll 
a d diti o nal 5 3 partici pa nt s i nt o S ta ge 3.
Pri m ar y a n al ysis:
T he pri mar y  a nal ysis will be perf or me d se parately f or all Parts C after S ta ge 3 is c o m plete d f or 
t hat part, or w he n t he st u d y part is st o p pe d after Sta ge 1 or 2 , if a p plica ble. 
T he 9 5 % Cl o p per -Pears o n c o nfi de nce i nter val f or o verall res p o nse rate (O R R ) will be 
calc ulate d. W he n 1 4 res p o n ders are o bser ve d o ut of 7 3 partici pa nts, t he c orres p o n di n g 2 -si de d 
9 5 % Cl o p per -Pears o n c o nfi de nce i nter vals f or O R R is [ 1 1 %, 3 0 %] a n d e x cl u des a n O R R of 
1 0 %.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 1
Sc he d ule of Assess me nts: Scree ni n g ( P arts A, A 2, A 3 a n d B 1 )
A s s e s s m e nt
S cr e e ni n g Vi sit s
( D ay -2 1 t o D a y - 1) a
I nf or m e d c o n s e nt
X
D e m o gr a p hi c s
X
M e di c al hi st or y
X
I m a gi n g s c a n di s e a s e a s s e s s m e ntb
X
B o n e s c a n c
X
Tr a n st h or a ci c e c h o c ar di o gr a m d
X
Pri or a n d c o n c o mit a nt m e di c ati o n s
X
H ei g ht
X
W e i g ht a n d vit al si g n s
X
P h y si c al e x a mi n ati o n
X
Cli ni c al di s e a s e a s s e s s m e nt
X
W H O p erf or m a n c e st at u s
X
St a n d ar d 1 2 -l e a d E C G
X
S er u m F S H ( P o st m e n o p a u s al f e m al e p arti ci p a nt s 
< 6 0 y e ar s ol d o nl y)
X
S er u m β- h C G (f e m al e p arti ci p a nt s of c hil d b e ari n g 
p ot e nti al o nl y)
X
H e m at ol o g y
X
C o a g ul ati o n
X
S er u m c h e mi str y
X
Uri n al y si s
X
T h yr oi d sti m ul ati n g h or m o n e g
X
S er u m t ot al t e st o st er o n e ( m al e p arti ci p a nt s o nl y [ P art A 
a n d P art B 1 ])
X
Ar c hi v al t u m or ti s s u e bl o c ke
O pti o n al fr e s h t u m or bi o p s y ( P art s A 2 a n d A 3 o nl y) f
X
X
A E s
C o nti n u o u s fr o m si g ni n g of I C F t hr o u g h S af et y 
F oll o w -u p vi sit
A E = A d v er s e e v e nt, β -h C G = β- 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 eri z e d t o m o gr a p h y, 
E C G = el e ctr o c ar di o gr a m, F F P E = f or m ali n fi x e d p ar affi n e m b e d d e d ti s s u e, F S H = F olli cl e sti m ul ati n g h or m o n e, 
M RI
=
M a g n eti c r e s o n a n c e i m a gi n g, W H O = W o rl d H e alt h Or g a ni z ati o n.
a
P arti ci p a nt s will h a v e a S cr e e ni n g p eri o d of u p t o 2 1 d a y s ( D a y -2 1 t o D a y - 1) b ef or e t h e fir st d o s e of t h e st u d y 
dr u g. 
b
P arti ci p a nt s will h a v e a c h e st a n d a b d o mi n al i m a gi n g s c a n ( e . g., C T, M RI) a s a p pr o pri at e a n d, if cli ni c all y 
i n di c at e d, i m a gi n g s c a n s of ot h er b o d y ar e a s (e. g., p el vi s). I m a gi n g s c a n s p erf or m e d wit hi n 2 w e e k s of S cr e e ni n g 
m a y s u b stit ut e f or a s s e s s m e nt of eli gi bilit y. F or e a c h p arti ci p a nt, t h e s a m e i m a gi n g t e c h ni q u e s h o ul d b e u s e d t o 
f oll o w t h e di s e a s e (if p o s si bl e).
c 
F or all p arti ci p a nt s wit h pr o st at e c a n c er or f or p arti ci p a nt s wit h ot h er m ali g n a n ci e s wit h k n o w n or s u s p e ct e d b o n e 
m et a st a s e s or a s cli ni c all y i n di c at e d. If a b o n e s c a n h a s b e e n p erf or m e d i n t h e 8
w e e k s b ef or e S cr e e ni n g, r e s ult s 
fr o m t hi s m a y b e u s e d i n st e a d.
d
F or p arti ci p a nt s i n P art s A a n d B 1 o nl y. If a tr a n st h or a ci c e c h o c ar di o gr a m h a s b e e n p erf or m e d wit hi n 3 m o nt h s of 
S cr e e ni n g p eri o d of 2 1 d a y s ( D a y -2 1 t o D a y -1), r e s ult s fr o m t hi s m a y b e u s e d i n st e a d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
e 
A n ar c hi v al t u m or F F P E ti s s u e bl o c k will b e o bt ai n e d f or all p arti ci p a nt s b ef or e t h e fir st d o s e of st u d y dr u g (if 
a v ail a bl e). 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 m or e t h a n 
1 2 m o nt h s b ef or e S cr e e ni n g, or at t h e di s cr eti o n of t h e I n v e sti g at or, p arti ci p a nt will b e r e q u e st e d t o u n d er g o a 
pr etr e at m e nt bi o p s y d uri n g S cr e e ni n g.
f 
P art s A 2 a n d A 3 o nl y: a n o pti o n al fr e s h F F P E bi o p s y c a n b e c oll e ct e d f or p h ar m a c o d y n a mi c a n al y s e s d uri n g 
S cr e e ni n g a s pr e d o s e bi o p s y. T h e p o st d o s e bi o p s y c a n b e c oll e ct e d o n C y cl e 1 D a y 1, 1 t o 3 h o ur s aft er M 4 3 4 4 
a d mi ni str ati o n. If t a k e n, t hi s pr e d o s e 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 ti s s u e bl o c k t o b e c oll e ct e d d uri n g 
S cr e e ni n g.
g
N ot r e q uir e d f or P art A 3.
T a ble 2
Sc he d ule of Assess me nts: Scree ni n g ( P arts C)
A s s e s s m e nt
S cr e e ni n g Vi sit s
( D ay -4 2 t o D ay -1) a, b
I nf or m e d c o n s e nt
X
D e m o gr a p hi c s
X
L o c al b i o m ar k er d at a f or p arti ci p a nt s el e cti o n c
X
M a n d at or y
fr e s h t u m or bi o p s yd
X
M e di c al hi st or y
X
I m a gi n g s c a n di s e a s e a s s e s s m e nte
X
B o n e s c a n f
X
Pri or a n d c o n c o mit a nt m e di c ati o n s
X
H ei g ht
X
W e i g ht a n d vit al si g n s
X
P h y si c al e x a mi n ati o n
X
Cli ni c al di s e a s e a s s e s s m e nt
X
W H O p erf or m a n c e st at u s
X
St a n d ar d 1 2 -l e a d E C G
X
S er u m F S H ( P o st m e n o p a u s al f e m al e p arti ci p a nt s < 6 0 y e ar s ol d o nl y)
X
S er u m β- h C G (f e m al e p arti ci p a nt s of c hil d b e ari n g p ot e nti al o nl y)
X
H e m at ol o g y
X
C o a g ul ati o n
X
S er u m c h e mi str y
X
Uri n al y si s
X
A E s
C o nti n u o u s fr o m si g ni n g of I C F 
t hr o u g h S af et y F oll o w-u p V i sit
A E = A d v er s e e v e nt, β -h C G = β- 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 eri z e d t o m o gr a p h y, 
E C G = el e ctr o c ar di o gr a m, F S H = F olli cl e sti m ul ati n g h or m o n e, M RI =
M a g n eti c r e s o n a n c e i m a gi n g , WH O = W o rl d 
H e alt h Or g a ni z ati o n , F F P E = f or m ali n fi x e d p ar affi n e m b e d d e d ti s s u e.
a 
P arti ci p a nt s will h a v e a m a xi m u m
S cr e e ni n g p eri o d of u p t o 4 2 d a y s ( D a y -4 2 t o D a y -1) b ef or e t h e fir st d o s e of 
t h e st u d y dr u g.
b
P arti ci p a nt s will u n d er g o c o nfir m ati o n/ a s s e s s m e nt of s el e cti o n bi o m ar k er s /l o s s- of -f u n cti o n m ut ati o n s i n t h e g e n e s 
A RI D 1 A f or P art s C 1 a n d C 4, i n A T R X a n d/ or D A X X i n P art s C 2 a n d C 5 , a n d A T M i n P arts C 3 a n d C 6 (r e s ult s 
e x p e ct e d t o b e a v ail a bl e wit hi n 2 1 d a y s) . F or p a rtici p a nt s wit h u n k n o w n bi o m ar k er st at u s at t h e ti m e of c o n s e nt, 
bi o p s y bi o m ar k er re s ult s m u st b e a v ail a bl e
b ef or e c o m pl eti n g all ot h er S cr e e ni n g a s s e s s m e nt s. P arti ci p a nt s wit h 
k n o w n p o siti v e bi o m ar k er s st at u s c a n u n d er g o all S cr e e ni n g a s s e s s m e nt s c o n c urr e ntl y . 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
e
P arti ci p a nt s will h a v e a c h e st a n d a b d o mi n al i m a gi n g s c a n ( e. g., C T, M RI) a s a p pr o pri at e a n d, if cli ni c all y 
i n di c at e d, i m a gi n g s c a n s of ot h er b o d y ar e a s ( e. g., p el vi s). I m a gi n g s c a n s p erf or m e d wit hi n 2 w e e k s of S cr e e ni n g 
m a y s u b stit ut e f or a s s e s s m e nt of eli gi bilit y. F or e a c h p arti ci p a nt, t h e s a m e i m a gi n g t e c h ni q u e s h o ul d b e u s e d t o 
f oll o w t h e di s e a s e (if p o s si bl e).
f
F or all p arti ci p a nt s wit h pr o st at e c a n c er or f or p arti ci p a nt s wit h ot h er m ali g n a n ci e s wit h k n o w n or s u s p e ct e d b o n e 
m et a st a s e s or a s cli ni c all y i n di c at e d. If a b o n e s c a n h a s b e e n p erf or m e d i n t h e 8
w e e k s b ef or e S cr e e ni n g, r e s ult s 
fr o m t hi s m a y b e u s e d i n st e a d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C
C
I


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 3
Tre at me nt a n d F oll o w -U p Peri o d ( M 4 3 4 4
si n gle A ge nt T her a p y, P art A)
E v e nt/ A s s e s s m e nt
C y cl e ( 2 1 d a y s)
S af et y  F oll o w-u p 1 4 d a y s 
( ± 7 d a y s) aft er t h e l a st d o s e of 
st u d y  dr u ga
D a y 1
D a y 2
D a y 4
D a y 8
D a y 9
D a y 1 1
D a y 1 5
D a y 1 8
Cli ni c al vi sit s
X 
X
X b
X b
X
X
S af et y  As s e s s m e nt s
P h y si c al e x a mi n ati o n c
X
X
C T S c a n di s e a s e 
a s s e s s m e nt d
At t h e e n d of e v er y 2 c y cl e s u ntil di s e a s e pr o gr e s si o n e,f
Cli ni c al di s e a s e a s s e s s m e nt g
X
B o n e s c a n h
At t h e e n d of e v er y 4 c y cl e s u ntil di s e a s e pr o gr e s si o n
W H O p erf or m a n c e st at u s
X
X
A d C A -1 2 5 or P S A
B e gi n ni n g of C y cl e s 1, 3, a n d 5 i
W e i g ht
X
X
Vit al Si g n s
X j
X b,j
X j
X
St a n d ar d 1 2 -l e a d E C Gk
X
X
S er u m c h e mi str y l, m
X m
X b,l
X b,l
X b,l
X l
X
H e m at ol o g y l, m
X l
X b,l
X l
X
Uri n e β- h C G n
X
X
S er u m t ot al t e st o st er o n e 
( m al e p arti ci p a nt s o nl y)
X
C o n c o mit a nt m e di c ati o n s
C o nti n u o u s fr o m si g ni n g of I C F t hr o u g h S af et y F oll o w -u p Vi sit
A E s
St u d y  Dr u g A d mi ni str ati o n
M 4 3 4 4
d o si n g
X
X 
X
X 
X 
X
P h ar m a c o ki n eti c A s s e s s m e nt s
M 4 3 4 4 ( Pl a s m a P K 
c oll e cti o n) o
X 
X
X 
X
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
E v e nt/ A s s e s s m e nt
C y cl e ( 2 1 d a y s)
S af et y  F oll o w-u p 1 4 d a y s 
( ± 7 d a y s) aft er t h e l a st d o s e of 
st u d y  dr u ga
D a y 1
D a y 2
D a y 4
D a y 8
D a y 9
D a y 1 1
D a y 1 5
D a y 1 8
A E = A d v er s e e v e nt, β -h C G = β- h u m a n c h ori o ni c g o n a d otr o pi n, 
, C A-1 2 5 = C a n c er a nti g e n 1 2 5, 
C A 1 9 - 9 = C a n c er a nti g e n 1 9 -9, C E A = C a n c er e m br y o ni c a nti g e n, C T = c o m p ut eri z e d t o m o gr a p h y, E C G = El e ctr o c ar di o gr a m, I C F = I nf or m e d c o n s e nt f or m, 
P K = P h ar m a c o ki n eti c, P S A = Pr o st at e s p e cifi c a nti g e n, W H O = W orl d H e alt h Or g a ni z ati o n .
a
P arti ci p a nt s w h o d o n ot h a v e d o c u m e nt e d di s e a s e pr o gr e s si o n u p o n c o m pl eti n g t h e S af et y F oll o w -u p Vi sit s h o ul d b e f oll o w e d, if p o s si bl e, f or u p t o 1 y e ar aft er 
t h e F oll o w-u p Vi sit or u ntil st u d y cl o s ur e, w hi c h e v er c o m e s fir st, o n a n a p pr o xi m at el y 3 -m o nt hl y b a si s u ntil di s e a s e pr o gr e s si o n, i niti ati o n of n e w t h er a p y, or 
d e at h.
b
R e q uir e d f or C y cl e 1 o nl y; h o w e v er, a s s e s s m e nt s m a y b e p erf or m e d at ot h er u n s c h e d ul e d ti m e p oi nt s at t h e I n v e sti g at or’ s di s cr eti o n.
c
S y m pt o m - dir e ct e d p h y si c al e x a mi n ati o n s will b e p erf or m e d a s cli ni c all y i n dic at e d i n t h e I n v e sti g at or ’ s j u d g m e nt.
d
C T s c a n of c h e st a n d a b d o m e n s h o ul d b e p erf or m e d, i n a d diti o n t o C T s c a n of ot h er b o d y ar e a s ( e. g., p el vi s), a s cli ni c all y i n di c at e d.
e
C T s c a n s will b e p erf or m e d e v er y 2 c y cl e s d uri n g t h e i niti al 6 c y cl e s of t h e pl a n n e d tr e at m e nt p eri o d a n d e v er y 3 c y cl e s t h er e aft er f or t h o s e p arti ci p a nt s 
c o nti n ui n g b e y o n d 6 c y cl e s.
f
If a p arti ci p a nt di s c o nti n u e s t h e st u d y pr e m at ur el y wit h o ut e vi d e n c e of pr o gr e s si v e di s e a s e o n t h e m o st r e c e nt s c a n, a f oll o w- u p C T s c a n will b e p erf or m e d 
wit hi n 2 1 d a y s aft er t h e pl a n n e d l a st d a y of t h e c y cl e d uri n g w hi c h t h e p arti ci p a nt di s c o nti n u e d fr o m t h e st u d y.
g
A s s e s s m e nt i n cl u d e s t u m or st a gi n g (I t o I V) a n d T u m or -N o d e- M et a st a si s.
h
F or all p arti ci p a nt s wit h pr o st at e c a n c er, or f or p arti ci p a nt s wit h ot h er s oli d t u m or s wit h k n o w n or s u s p e ct e d b o n e m et a st a s e s.
i
C A -1 2 5 will b e a s s e s s e d f or p arti ci p a nt s wit h o v ari a n c a n c er a n d P S A will b e a s s e s s e d i n p arti ci p a nt s wit h pr o st at e c a n c er. If tr e at m e nt i s e xt e n d e d b e y o n d 
6 c y cl e s, C A -1 2 5 or P S A will b e m e a s ur e d at t h e b e gi n ni n g of e v er y 3 c y cl e s or m or e fr e q u e ntl y a s cli ni c all y i n di c at e d. A d diti o n al s er ol o gi c t u m or m ar k er s m a y 
b e c oll e ct e d at t h e s e ti m e p oi nt s a s d e e m e d a p pr o pri at e d e p e n di n g o n t h e p arti ci p a nt ' s pri m ar y m ali g n a n c y (e. g., C A 1 9 -9 f or p arti ci p a nt s wit h p a n cr e ati c 
c a n c er or C E A f or p arti ci p a nt s wit h c ol o n c a n c er).
j
Vit al si g n s will b e m e a s ur e d at 0 h o ur s o n D a y s 1, 8, a n d 1 5, a n d at 4 ( ± 1) h o ur s aft er M 4 3 4 4
d o si n g o n D a y 1 of C y cl e 1. F or all s u b s e q u e nt c y cl e s, vit al 
si g n s will b e m e a s ur e d at 0 h o ur s o n D a y s 1 a n d 1 5.
k
1 2 -l e a d E C G will b e m e a s ur e d b ef or e M 4 3 4 4
d o si n g ( u p t o 6 0 mi n ut e s b ef or e) o n D a y
1 of e v er y c y cl e. I n a d diti o n, 1 2- l e a d E C G will b e m e a s ur e d 1, 2, a n d 
3 h o ur s aft er M 4 3 4 4
d o si n g o n D a y 1 ( ± 1 0 mi n ut e s) d uri n g C y cl e
1 o nl y.
l
T o f a cilit at e ti m el y a d mi ni str ati o n of st u d y dr u g, s af et y l a b s m a y b e o bt ai n e d u p  t o 3 d a y s b ef or e d o si n g. If l a b s ar e dr a w n b ef or e t h e d a y of d o si n g, t h e y s h o ul d 
b e r e c or d e d a s c orr e s p o n di n g t o d a y of pl a n n e d st u d y dr u g a d mi ni str ati o n. S e e T a bl e 1 5 f or li st of a n al yt e s a n d f urt h er d et ail s r e g ar di n g l a b or at or y t e sti n g 
s c h e d ul e.
m
S er u m c h e mi str y a n d h e m at ol o g y will b e p erf or m e d o n D a y s 1, 8, a n d 1 5 of C y cl e 1. F or all s u b s e q u e nt c y cl e s, s er u m c h e mi str y a n d h e m at ol o g y will b e 
p erf or m e d o n D a y s 1 a n d 1 5 o nl y. I n a d diti o n, s er u m c h e mi str y will b e p erf or m e d o n D a y s 2 a n d 9 of C y cl e 1.
n
F e m al e p arti ci p a nt s of c hil d b e ari n g p ot e nti al o nl y.
o
M 4 3 4 4
( a n d it s m et a b olit e s a s a p pr o pri at e) pl a s m a P K s a m pl e s will b e c oll e ct e d d uri n g C y cl e 1 o n D a y s 1 a n d 8 at 0 ( b ef or e d o si n g) a n d 0. 5, 1, 1. 5, 2, 3, 4, 8, 
a n d 2 4 h o ur s ( D a y s 2 a n d 9) aft er d o si n g, a n d o n D a y 1 5 at 0 h o ur s ( b ef or e d o si n g).
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
 
r
Pl a s m a D N A will b e c oll e ct e d fr o m all p arti ci p a nt s o n D a y 1 of e a c h c y cl e a n d at S af et y F oll o w- u p Vi sit or at di s e a s e pr o gr e s si o n if t h e p arti ci p a nt ' s di s e a s e 
pr o gr e s s e s b ef or e t h e S af et y F oll o w -u p Vi sit.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 4
Tre at me nt a n d F oll o w -U p Peri o d ( M 4 3 4 4 S i n gle A ge nt T her a p y, P art A 2 , a n d 1 4 d +/ 7 d - sc he d ule of P art 
A 3 )
E v e nt/ A s s e s s m e nt
E a c h C y cl e ( 2 1 d a y s)
S af et y  F oll o w-u p 1 4 d a y s 
( ± 7 d a y s) aft er t h e l a st d o s e of 
st u d y  dr u gb
D a y 1
D a y 2 a
D a y s  3- 7
D a y 8
D a y s 9- 1 4
D a y 1 5
D a y s  
1 6 -2 1
Cli ni c al vi sit s
X
X c
X b
X
X
S af et y  As s e s s m e nt s
P h y si c al e x a mi n ati o n d
X
X
C T S c a n di s e a s e 
a s s e s s m e nt e
At t h e e n d of e v er y 2 c y cl e s u ntil di s e a s e pr o gr e s si o n f, g
Cli ni c al di s e a s e a s s e s s m e nt h
X
B o n e s c a n i
At t h e e n d of e v er y 4 c y cl e s u ntil di s e a s e pr o gr e s si o n
W H O p erf or m a n c e st at u s
X
X
C A -1 2 5 or P S A
B e gi n ni n g of C y cl e s 1, 3, a n d 5 j
W e i g ht
X
X
Vit al Si g n s
X j
X c, k
X k
X
St a n d ar d 1 2 -l e a d E C Gl
X
X
S er u m c h e mi str y m, n
X n
X c, m
X c, m
X m
X
H e m at ol o g y m, n
X m
X c, m
X m
X
Uri n e β- h C G o
X
X
C o n c o mit a nt m e di c ati o n s
C o nti n u o u s fr o m si g ni n g of I C F t hr o u g h S af et y F oll o w -u p Vi sit
A E s
St u d y  Dr u g A d mi ni str ati o n
M 4 3 4 4 d o si n g
p
X
X
X
X
X
X y
X y
P h ar m a c o ki n eti c A s s e s s m e nt s
M 4 3 4 4 ( Pl a s m a P K 
c oll e cti o n) q
X
X
X
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
E v e nt/ A s s e s s m e nt
E a c h C y cl e ( 2 1 d a y s)
S af et y  F oll o w-u p 1 4 d a y s 
( ± 7 d a y s) aft er t h e l a st d o s e of 
st u d y  dr u gb
D a y 1
D a y 2 a
D a y s  3- 7
D a y 8
D a y s 9- 1 4
D a y 1 5
D a y s  
1 6 -2 1
A E = A d v er s e e v e nt, β -h C G = β- h u m a n c h ori o ni c g o n a d otr o pi n, C A - 1 2 5 = C a n c er a nti g e n 1 2 5, C A 1 9- 9 = C a n c er a nti g e n 1 9 -9, C E A = C a n c er e m br y o ni c a nti g e n, 
C T = c o m p ut eri z e d t o m o gr a p h y, E C G = El e ctr o c ar di o gr a m, I C F = I nf or m e d c o n s e nt f or m, 
, P K = P h ar m a c o ki n eti c, 
P S A = Pr o st at e s p e cifi c a nti g e n, W H O = W orl d H e alt h Or g a ni z ati o n.
a
C y cl e 1 D a y 2 a s s e s s m e nt s a p pli c a bl e o nl y f or P art A 2.
b
P arti ci p a nt s w h o d o n ot h a v e d o c u m e nt e d di s e a s e pr o gr e s si o n u p o n c o m pl eti n g t h e S af et y F oll o w -u p Vi sit s h o ul d b e f oll o w e d, if p o s si bl e, f or u p t o 1 y e ar aft er 
t h e F oll o w-u p Vi sit or u ntil st u d y cl o s ur e, w hi c h e v er c o m e s fir st, o n a n a p pr o xi m at el y 3 -m o nt hl y b a si s u ntil di s e a s e pr o gr e s si o n, i niti ati o n of n e w t h er a p y, or 
d e at h.
c
R e q uir e d f or C y cl e 1 o nl y; h o w e v er, a s s e s s m e nt s m a y b e p erf or m e d at ot h er u n s c h e d ul e d ti m e p oi nt s at t h e I n v e sti g at or’ s di s cr eti o n.
d
S y m pt o m - dir e ct e d p h y si c al e x a mi n ati o n s will b e p erf or m e d a s cli ni c all y i n di c at e d i n t h e I n v e sti g at or’ s j u d g m e nt.
e
C T s c a n of c h e st a n d a b d o m e n s h o ul d b e p erf or m e d, i n a d diti o n t o C T s c a n of ot h er b o d y ar e a s ( e . g., p el vi s), a s cli ni c all y i n di c at e d.
f
C T s c a n s will b e p erf or m e d e v er y 2 c y cl e s d uri n g t h e i niti al 6 c y cl e s of t h e pl a n n e d tr e at m e nt p eri o d a n d e v er y 3 c y cl e s t h er e aft er f or t h o s e p arti ci p a nt s 
c o nti n ui n g b e y o n d 6 c y cl e s.
g
If a p arti ci p a nt di s c o nti n u e s t h e st u d y pr e m at ur el y wit h o ut e vi d e n c e of pr o gr e s si v e di s e a s e o n t h e m o st r e c e nt s c a n, a f oll o w- u p C T s c a n will b e p erf or m e d 
wit hi n 2 1 d a y s aft er t h e pl a n n e d l a st d a y of t h e c y cl e d uri n g w hi c h t h e p arti ci p a nt di s c o nti n u e d fr o m t h e st u d y.
h
A s s e s s m e nt i n cl u d e s t u m or st a gi n g (I t o I V) a n d T u m or-N o d e -M et a st a si s.
i
F or all p arti ci p a nt s wit h pr o st at e c a n c er, or f or p arti ci p a nt s wit h ot h er s oli d t u m or s wit h k n o w n or s u s p e ct e d b o n e m et a st a s e s.
j
C A -1 2 5 will b e a s s e s s e d f or p arti ci p a nt s wit h o v ari a n c a n c er a n d P S A will b e a s s e s s e d i n p arti ci p a nt s wit h pr o st at e c a n c er. If tr e at m e nt i s e xt e n d e d b e y o n d 
6 c y cl e s, C A -1 2 5 or P S A will b e m e a s ur e d at t h e b e gi n ni n g of e v er y 3 c y cl e s or m or e fr e q u e ntl y a s cli ni c all y i n di c at e d. A d diti o n al s er ol o gi c t u m or m ar k er s m a y 
b e c oll e ct e d at t h e s e ti m e p oi nt s a s d e e m e d a p pr o pri at e d e p e n di n g o n t h e p arti ci p a nt ' s pri m ar y m ali g n a n c y ( e. g., C A 1 9 -9 f or p arti ci p a nt s wit h p a n cr e ati c 
c a n c er or C E A f or p arti ci p a nt s wit h c ol o n c a n c er).
k
Vit al si g n s will b e m e a s ur e d at 0 h o ur s o n D a y s 1, 8, a n d 1 5, a n d at 4 ( ± 1) h o ur s aft er M 4 3 4 4 d o si n g o n D a y 1 of C y cl e 1. F or all s u b s e q u e nt c y cl e s, vit al 
si g n s will b e m e a s ur e d at 0 h o ur s o n D a y s 1 a n d 1 5.
l
1 2 -l e a d E C G will b e m e a s ur e d b ef or e M 4 3 4 4 d o si n g ( u p t o 6 0 mi n ut e s b ef or e) o n D a y
1 of e v er y c y cl e. I n a d diti o n, 1 2- l e a d E C G will b e m e a s ur e d 1, 2, a n d 
3 h o ur s aft er M 4 3 4 4 d o si n g o n D a y 1 ( ± 1 0 mi n ut e s) d uri n g C y cl e
1 o nl y.
m
T o f a cilit at e ti m el y a d mi ni str ati o n of st u d y dr u g, s af et y l a b s m a y b e o bt ai n e d u p  t o 3 d a y s b ef or e d o si n g. If l a b s ar e dr a w n b ef or e t h e d a y of d o si n g, t h e y s h o ul d 
b e r e c or d e d a s c orr e s p o n di n g t o d a y of pl a n n e d st u d y dr u g a d mi ni str ati o n. S e e T a bl e 1 5 f or li st of a n al yt e s a n d f urt h er d et ail s r e g ar di n g l a b or at or y t e sti n g 
s c h e d ul e.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
n
S er u m c h e mi str y a n d h e m at ol o g y will b e p erf or m e d o n D a y s 1, 8, a n d 1 5 of C y cl e 1. F or all s u b s e q u e nt c y cl e s, s er u m c h e mi str y a n d h e m at ol o g y will b e 
p erf or m e d o n D a y s 1 a n d 1 5 o nl y. I n a d diti o n, s er u m c h e mi str y will b e p erf or m e d o n D a y s 2 a n d 9 of C y cl e 1.
o
F e m al e p arti ci p a nt s of c hil d b e ari n g p ot e nti al o nl y.
p
P arti ci p a nt s i n P art A 2 a n d P art A 3 will i niti all y b e a d mi ni st er e d M 4 3 4 4 a s a si n gl e a g e nt u n d er f a sti n g c o n diti o n s a s d e s cri b e d i n S e cti o n 6. 2. 1 . 
q
M 4 3 4 4 ( a n d m et a b olit e s a s a p pr o pri at e) pl a s m a P K s a m pl e s will b e c oll e ct e d d uri n g C y cl e 1 o n D a y s 1 0 h o ur s ( b ef or e 1 st d o s e ) a n d 0. 5, 1, 1. 5, 2, 3, 4, a n d 8
h o ur s aft er d o si n g ( b ef or e 2 n d d o s e, if a p pli c a bl e) a n d D a y 2 at 0 h o ur s ( at ti m e of P B M C s a m pl e b ef or e 1 st D a y 2 d o s e), D a y 8 at 0 h o ur s ( b ef or e 1 st d o s e) 
a n d 0. 5, 1, 1. 5, 2, 3, 4, a n d 8 h o ur s aft er d o si n g ( b ef or e 2 n d d o s e, if a p pli c a bl e) a n d o n D a y 1 5 at 0 h o ur s ( b ef or e 1 st d o s e ) a n d 2 h o ur s . S u b s e q u e nt c y cl e s, 
D a y 1: 0 h o ur s ( b ef or e 1 st d o s e) a n d 2 h o ur s. A n o pti o n al s a m pl e m a y al s o b e c oll e ct e d o n D a y s 1 a n d 8 at 1 2 h o ur s aft er d o s i n g, if t h e o n c e a d a y s c h e d ul e i s 
e v al u at e d. F or p arti ci p a nt s u n d er g oi n g ti m e d -t u m or bi o p si e s, P K s a m pl e s o n C y cl e 1 D a y 1 at 2 a n d 3 h o ur s aft er d o si n g s h o ul d b e c oll e ct e d o nl y if f e a si bl e
t
Pl a s m a D N A will b e c oll e ct e d fr o m all p arti ci p a nt s o n D a y 1 of e a c h c y cl e a n d at S af et y F oll o w -u p Vi sit or at di s e a s e pr o gr e s si o n if t h e p arti ci p a nt ' s di s e a s e 
pr o gr e s s e s b ef or e t h e S af et y F oll o w -u p Vi sit.
y
N o t a p pli c a bl e t o par tic i p ant s i n P art A 3 f o ll o wi n g t h e 1 4 d +/ 7 d - dr u g s c h e d ul e .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 5
Tre at me nt a n d F oll o w -U p Peri o d - M 4 3 4 4 Si n gle A ge nt T her a p y, P art A 3 ( dr u g h oli d a y wit h eit her 3 d +/ 4 d -, 
5 d +/ 2 d-, or 7 d +/ 7 d - sc he d ule)
N O T E: Part A 3 1 4 d +/ 7 d - sc he d ule will use t he sc he d ule of assess me nts fr o m Part A 2 (see Ta ble 4 ).
C y cl e 1 ( 2 8 d a y s)
C y cl e 2 o n w ar d
E n d of tr e at m e nt
E v e nt/ A s s e s s m e nt
D a y 1
D a y 8
D a y 1 5
D a y 2 2
D a y 1
D a y 1 5
S af et y  Foll o w -u p 1 4 d a y s  
( ± 7 d a y s) aft er t h e l a st 
d o s e of st u d y  dr u ga
Cli ni c al vi sit s
X 
X b
X b
X b
X 
X
X
S af et y  As s e s s m e nt s
P h y si c al e x a mi n ati o n c
X
X
W e i g ht
X
X
X
Vit al Si g n s
X b, d
X b, d
X d
X d
X d
X d
X
St a n d ar d 1 2 -l e a d E C Ge
X
X
S er u m c h e mi str y f, g
X b, g
X b,
X f
X f
X f
X f
X
H e m at ol o g y f, g
X b,f
X b,f
X f
X f
X f
X f
X
Uri n e β -h C G h
X
X
X
C o n c o mit a nt m e di c ati o n s
C o nti n u o u s fr o m si g ni n g of I C F t hr o u g h S af et y F oll o w -u p Vi sit
A E s
Cli ni c al di s e a s e a s s e s s m e nt i
X
X
W H O p erf or m a n c e st at u s
X
X
X
C A -1 2 5 or P S A
B e gi n ni n g of C y cl e s 1, 3, a n d 5 j
I m a gi n g A s s e s s m e nt s
C T S c a n di s e a s e a s s e s s m e nt k
E v er y 6 w e e k s u ntil di s e a s e pr o gr e s si o n l, m
At t h e e n d of e v er y 3 c y cl e s u ntil di s e a s e pr o gr e s si o n
B o n e s c a n n
St u d y Dr u g A d mi ni str ati o n
M 4 3 4 4 d o si n g
o
3 d a y s o n/ 4 d a y s off ( D a y 1 -3, 8 -1 0, 1 5 -1 7, 2 2 -2 4)
5 d a y s o n/ 2 d a y s off ( D a y 1 -5, 8 -1 2, 1 5 -1 9, 2 2 -2 6)
7 d a y s o n/ 7 d a y s off (D a y s 1 -7, 1 5 -2 1)
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
C y cl e 1 ( 2 8 d a y s)
C y cl e 2 o n w ar d
E n d of tr e at m e nt
E v e nt/ A s s e s s m e nt
D a y 1
D a y 8
D a y 1 5
D a y 2 2
D a y 1
D a y 1 5
S af et y  Foll o w -u p 1 4 d a y s  
( ± 7 d a y s) aft er t h e l a st 
d o s e of st u d y  dr u ga
P h ar m a c o ki n eti c A s s e s s m e nt
M 4 3 4 4 ( Pl a s m a P K c oll e cti o n) p
X
X 
( 3 d +/ 4 d-
a n d 
5 d +/ 2 d -
o nl y)
X 
X
A E = A d v er s e e v e nt, β -h C G = β- h u m a n c h ori o ni c g o n a d otr o pi n, C A - 1 2 5 = C a n c er a nti g e n 1 2 5, C A 1 9- 9 = C a n c er a nti g e n 1 9 -9, C E A = C a n c er e m br y o ni c a nti g e n, 
C T = c o m p ut eri z e d t o m o gr a p h y, E C G = El e ctr o c ar di o gr a m, I C F = I nf or m e d c o n s e nt f or m, 
, P K = P h ar m a c o ki n eti c, 
P S A = Pr o st at e s p e cifi c a nti g e n, W H O = W orl d H e alt h Or g a ni z ati o n.
a
P arti ci p a nt s w h o d o n ot h a v e d o c u m e nt e d di s e a s e pr o gr e s si o n u p o n c o m pl eti n g t h e S af et y F oll o w -u p Vi sit s h o ul d b e f oll o w e d, if p o s si bl e, f or u p t o 1 y e ar aft er 
t h e F oll o w-u p Vi sit or u ntil st u d y cl o s ur e, w hi c h e v er c o m e s fir st, o n a n a p pr o x i m at el y 3-m o nt hl y b a si s u ntil di s e a s e pr o gr e s si o n, i niti ati o n of n e w t h er a p y, or 
d e at h.
b
R e q uir e d f or C y cl e 1 o nl y; h o w e v er, a s s e s s m e nt s m a y b e p erf or m e d at ot h er u n s c h e d ul e d ti m e p oi nt s at t h e I n v e sti g at or’ s di s cr eti o n.
c
S y m pt o m -dir e ct e d p h y si c al e x a mi n ati o n s will b e p erf or m e d a s cli ni c all y i n di c at e d i n t h e I n v e sti g at or’ s j u d g m e nt.
d
Vit al si g n s will b e m e a s ur e d at 0 h o ur s o n D a y s 1, 8, a n d 1 5, a n d at 4 ( ± 1) h o ur s aft er M 4 3 4 4 d o si n g o n D a y 1 of C y cl e 1. F or all s u b s e q u e nt c y cl e s, vit al 
si g n s will b e m e a s ur e d at 0 h o ur s o n D a y s 1 a n d 1 5
e
1 2 -l e a d E C G will b e m e a s ur e d b ef or e M 4 3 4 4 d o si n g ( u p t o 6 0 mi n ut e s b ef or e) o n D a y
1 of e v er y c y cl e. I n a d diti o n, 1 2- l e a d E C G will b e m e a s ur e d 1, 2, a n d 
3 h o ur s aft er M 4 3 4 4 d o si n g o n D a y 1 ( ± 1 0 mi n ut e s) d uri n g C y cl e
1 o n l y.
f
T o f a cilit at e ti m el y a d mi ni str ati o n of st u d y dr u g, s af et y l a b s m a y b e o bt ai n e d u p  t o 3 d a y s b ef or e d o si n g. If l a b s ar e dr a w n b ef or e t h e d a y of d o si n g, t h e y s h o ul d 
b e r e c or d e d a s c orr e s p o n di n g t o d a y of pl a n n e d st u d y dr u g a d mi ni str ati o n. S e e T a bl e 1 5 f or li st of a n al yt e s a n d f urt h er d et ail s r e g ar di n g l a b or at or y t e sti n g 
s c h e d ul e.
g
S er u m c h e mi str y a n d h e m at ol o g y will b e p erf or m e d o n D a y s 1, 8, a n d 1 5 of C y cl e 1. F or all s u b s e q u e nt c y cl e s, s er u m c h e mi str y a n d h e m at ol o g y will b e 
p erf or m e d o n D a y s 1 a n d 1 5 o nl y. I n a d diti o n, s er u m c h e mi str y will b e p erf or m e d o n D a y 2 of C y cl e 1.
h 
F e m al e p arti ci p a nt s of c hil d b e ari n g p ot e nti al o nl y.
i
A s s e s s m e nt i n cl u d e s t u m or st a gi n g (I t o I V) a n d T u m or -N o d e - Met a st a si s.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
j
C A -1 2 5 will b e a s s e s s e d f or p arti ci p a nt s wit h o v ari a n c a n c er a n d P S A will b e a s s e s s e d i n p arti ci p a nt s wit h pr o st at e c a n c er. If t r e at m e nt i s e xt e n d e d b e y o n d 
6 c y cl e s, C A -1 2 5 or P S A will b e m e a s ur e d at t h e b e gi n ni n g of e v er y 3 c y cl e s or m or e fr e q u e ntl y a s cli ni c all y i n di c at e d. A d diti o n al s er ol o gi c t u m or m ar k er s m a y 
b e c oll e ct e d at t h e s e ti m e p oi nt s a s d e e m e d a p pr o pri at e d e p e n di n g o n t h e p arti ci p a nt' s pri m ar y m ali g n a n c y ( e. g., C A 1 9 -9 f or p arti ci p a nt s wit h p a n cr e ati c 
c a n c er or C E A f or p arti ci p a n t s wit h c ol o n c a n c er).
k
C T s c a n of c h e st a n d a b d o m e n s h o ul d b e p erf or m e d, i n a d diti o n t o C T s c a n of ot h er b o d y ar e a s ( e. g., p el vi s), a s cli ni c all y i n di c at e d.
l  
C T s c a n s will b e p erf or m e d e v er y 6 w e e k s u ntil di s e a s e pr o gr e s si o n .
m
If a p arti ci p a nt di s c o ntin u e s t h e st u d y pr e m at ur el y wit h o ut e vi d e n c e of pr o gr e s si v e di s e a s e o n t h e m o st r e c e nt s c a n, a f oll o w -u p C T s c a n will b e p erf or m e d 
wit hi n 2 8 d a y s aft er t h e pl a n n e d l a st d a y of t h e c y cl e d uri n g w hi c h t h e p arti ci p a nt di s c o nti n u e d fr o m t h e st u d y.
n
F or all p ar ti ci p a nt s wit h pr o st at e c a n c er, or f or p arti ci p a nt s wit h ot h er s oli d t u m or s wit h k n o w n or s u s p e ct e d b o n e m et a st a s e s.
o 
P arti ci p a nt s i n P art A 3 will i niti all y b e a d mi ni st er e d M 4 3 4 4 a s a si n gl e a g e nt u n d er f a sti n g c o n diti o n s a s d e s cri b e d i n S e cti o n 6. 2. 1 . T h e dr u g h oli d a y s c h e d ul e s 
s el e ct e d f or P art A 3 ( e. g. “ 3 d a y s o n f oll o w e d b y 4 d a y s off” or “ 7 d a y s o n f oll o w e d b y 7 d a y s off” will b e s el e ct e d b a s e d o n t h e R P 2 D aft er P art A 2).
p
M 4 3 4 4 ( a n d m et a b olit e s a s a p pr o pri at e ) pl a s m a P K s a m pl e s will b e c oll e ct e d a s d e s cri b e d i n S e cti o n 7. 6. 1. 3 , T a bl e 1 7 .
q
G e n o mi c D N A s a m pl e s will b e c oll e ct e d d uri n g C y cl e
1 o nl y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 6
Tre at me nt a n d F oll o w - Up Peri o d ( M 4 3 4 4
a n d C ar b o pl ati n C o m bi n ati o n T her a p y, P art B 1)
E v e nt/ A s s e s s m e nt b
E a c h C y cl e ( 2 1 d a ys)
F oll o w -u p a
D a y 1
D a y 2
D a y 3
D a y 5
D a y 8
D a y 9
D a y 1 2
D a y 1 5
All p arti ci p a nt s:
S af et y  F oll o w-u p 
1 4 d a y s ( ± 7 d a y s ) 
P arti ci p a nt s wit h o ut 
P D o nl y : R a di ol o gi c 
F oll o w -u p: e v er y  
6- 9 w e e k s c
Cli ni c al vi sit s
X 
X d
X e
X f
X 
X e
X 
X
X
S af et y  As s e s s m e nt s
P h y si c al e x a mi n ati o n g
X h
X
X h
I m a gi n g s c a n di s e a s e 
a s s e s s m e nt i
At t h e e n d of e v er y 2 c y cl e s f or t h e fir st 6 c y cl e s, t h e n e v er y 3 c y cl e s u ntil 
di s e a s e pr o gr e s si o n j
Cli ni c al di s e a s e a s s e s s m e nt k
X
B o n e s c a n l
At t h e e n d of C y cl e 4, t h e n e v er y 4 t o 6 c y cl e s u ntil di s e a s e pr o gr e s si o n
X
W H O p erf or m a n c e st at u s
X
X
C A -1 2 5 or P S A
B e gi n ni n g of C y cl e s 1, 3, 5 m
W e i g ht
X
X
Vit al Si g n s
X n
X o
X e, o
X
St a n d ar d 1 2 -l e a d E C G
X p
X
S er u m c h e mi str y
X q
X e, q
X e, q
X q
X
H e m at ol o g y
X q
X e, q
X e, q
X q
X
Uri n e β- h C G r
X
X
S er u m t ot al t e st o st er o n e 
( m al e p arti ci p a nt s o nl y)
X
C o n c o mit a nt m e di c ati o n s
C o nti n u o u s fr o m si g ni n g of I C F t hr o u g h S af et y F oll o w -u p Vi sit
A E s
St u d y  Dr u g A d mi ni str ati o n
M 4 3 4 4 d o si n g
X
X s
X
C ar b o pl ati n d o si n g 
X
P h ar m a c o ki n eti c A s s e s s m e nt
M 4 3 4 4 ( Pl a s m a P K c oll e cti o n)
X t
X t
X u
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
E v e nt/ A s s e s s m e nt b
E a c h C y cl e ( 2 1 d a ys)
F oll o w -u p a
D a y 1
D a y 2
D a y 3
D a y 5
D a y 8
D a y 9
D a y 1 2
D a y 1 5
All p arti ci p a nt s:
S af et y  F oll o w-u p 
1 4 d a y s ( ± 7 d a y s ) 
P arti ci p a nt s wit h o ut 
P D o nl y : R a di ol o gi c 
F oll o w -u p: e v er y  
6- 9 w e e k s c
A E = A d v er s e e v e nt, β -h C G = β- h u m a n c h ori o ni c g o n a d otr o pi n, B R C A = Br e a st c a n c er e arl y o n s et g e n e s 1 a n d 2, C A -1 2 5 = C a n c er a nti g e n 1 2 5 , C A 1 9-9 = 
C a n c er a nti g e n 1 9 - 9, C E A = C a n c er e m br y o ni c a nti g e n, C T = C o m p ut eri z e d t o m o gr a p h y,
, E C G = el e ctr o c ar di o gr a m, M R I = 
M a g n eti c r e s o n a n c e i m a gi n g, M T D = M a xi m u m t ol er at e d d o s e, 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 s, P S A = Pr o st at e s p e cifi c a nti g e n, R P 2 D = 
R e c o m m e n d e d P h a s e II D o s e , W H O = W o rl d H e alt h Or g a ni z ati o n.
a
F oll o w -u p will i n cl u d e a S af et y F oll o w -u p Vi sit 1 4 ( ± 7) d a y s f oll o wi n g t h e l a st d o s e of st u d y dr u g a n d R a di ol o gi c F oll o w -u p e v er y 6 t o 9 w e e k s f oll o wi n g t h e l a st 
c y cl e of c h e m ot h er a p y. R a di ol o gi c F oll o w -u p Vi sit s ar e n ot r e q uir e d f or t h o s e p arti ci p a nt s wit h pr o gr e s si v e di s e a s e o n pri or i m a gi n g s c a n. P arti ci p a nt s w h o d o 
n ot h a v e d o c u m e nt e d di s e a s e pr o gr e s si o n u p o n c o m pl eti n g t h e S af et y F oll o w -u p Vi sit s h o ul d b e f oll o w e d u p f or s ur vi v al, if p o s si bl e, f or u p t o 1 y e ar aft er t h e 
F oll o w -u p Vi sit or u ntil st u d y cl o s ur e, w hi c h e v er c o m e s fir st, o n a n a p pr o xi m at el y 3 -m o nt hl y b a si s u ntil di s e a s e pr o gr e s si o n, i niti ati o n of n e w t h er a p y, or d e at h
( s e e S e cti o n 5. 2. 1 1 ).
b
Pl e a s e s e e S e cti o n 6. 2. 4 f or g ui d a n c e o n mi s s e d a s s e s s m e nt s.
c
R a di ol o gi c F oll o w -u p Vi sit s ar e n ot r e q uir e d f or t h o s e p arti ci p a nt s wit h pr o gr e s s i v e di s e a s e o n pri or i m agi n g s c a n . P arti ci p a nt s s h o ul d att e n d R a di ol o gi c F oll o w-
u p Vi sit s u ntil di s e a s e pr o gr e s si o n i s o b s er v e d, n e w a nti c a n c er tr e at m e nt i s st art e d, d e at h, or t h e e n d of t h e st u d y, w hi c h e v er c o m e s fir st. F or t h e fir st 6 m o nt h s 
aft er t h e st art of st u d y tr e at m e nt, R a di ol o gi c F oll o w -u p Vi sit s s h o ul d o c c ur e v er y 6 w e e k s, s u b s e q u e ntl y t h e y s h o ul d o c c ur e v er y 9 w e e k s.
d
R e q uir e d f or C y cl e s 1 a n d 2 o nl y.
e
R e q uir e d f or C y cl e 1 o nl y; h o w e v er, a s s e s s m e nt s m a y b e p erf or m e d at ot h er u n s c h e d ul e d ti m e p oi nt s at t h e I n v e sti g at o r’ s di s cr eti o n.
f
R e q uir e d f or C y cl e 1 at M T D/ R P 2 D if a d diti o n al d o si n g d a y s f or M 4 3 4 4 ar e a d d e d.
g
S y m pt o m - dir e ct e d p h y si c al e x a mi n ati o n s will b e p erf or m e d a s cli ni c all y i n di c at e d i n t h e I n v e sti g at or’ s j u d g m e nt.
h
A h e ari n g a s s e s s m e nt will b e p erf or m e d o n D a y 1 of e a c h c y cl e a n d at t h e S af et y F oll o w -u p Vi sit a s p art of t h e p h y si c al e x a mi n ati o n.
i
I m a gi n g s c a n ( e. g., C T, M RI) of c h e st a n d a b d o m e n s h o ul d b e p erf or m e d, i n a d diti o n t o i m a gi n g s c a n of ot h er b o d y ar e a s ( e. g., p el vi s), a s cli ni c all y i n di c at e d. 
I m a gi n g s c a n s m a y b e p erf or m e d ± 5 d a y s b ef or e t h e e n d of i n di c at e d c y cl e s; h o w e v er, t h e i m a gi n g s c a n m u st b e p erf or m e d b ef or e D a y 1 d o si n g of t h e 
s u b s e q u e nt c y cl e. F or e a c h p arti ci p a nt , t h e s a m e i m a gi n g t e c h ni q u e s h o ul d b e u s e d t o f oll o w t h e di s e a s e (if p o s si bl e).
j
If a p arti ci p a nt di s c o nti n u e s t h e st u d y pr e m at ur el y wit h o ut e vi d e n c e of pr o gr e s si v e di s e a s e o n t h e m o st r e c e nt s c a n, a f oll o w -u p i m a gi n g s c a n will b e p erf or m e d 
wit hi n 2 1 d a y s aft er t h e pl a n n e d l a st d a y of t h e c y cl e d uri n g w hi c h t h e p arti ci p a nt di s c o nti n u e d fr o m t h e st u d y.
k
A s s e s s m e nt i n cl u d e s t u m or st a gi n g (I t o I V) a n d T u m or -N o d e -M et a st a si s.
l
F or all p arti ci p a nt s wit h pr o st at e c a n c er, or f or p arti ci p a nt s wit h ot h er s oli d t u m or s wit h k n o w n or s u s p e ct e d b o n e m et a st a s e s.
D oc u me nt N o. 0 9 0 0 ba be 8 1 2f 8f 4 9 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 3 8cc 6e
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
m
C A -1 2 5 will b e a s s e s s e d i n p arti ci p a nt s wit h o v ari a n c a n c er a n d P S A a s s e s s e d i n p arti ci p a nt s wit h pr o st at e c a n c er. If tr e at m e nt i s e xt e n d e d b e y o n d 6 c y cl e s, 
C A -1 2 5 or P S A will b e m e a s ur e d at t h e b e gi n ni n g of e v er y 3 c y cl e s or m or e fr e q u e ntl y a s cli ni c all y i n di c at e d . A d diti o n al s er ol o gi c t u m or m ar k er s m a y b e 
c oll e ct e d at t h e s e ti m e p oi nt s a s d e e m e d a p pr o pri at e d e p e n di n g o n t h e p arti ci p a nt ' s pri m ar y m ali g n a n c y ( e. g., C A 1 9 -9 f or p arti ci p a nt s wit h p a n cr e ati c c a n c er 
or C E A f or p arti ci p a nt s wit h c ol o n c a n c er).
n
Vit al si g n s will b e m e a s ur e d o n D a y 1 at 0 h o ur s ( b ef or e c ar b o pl ati n d o si n g).
o
Vit al si g n s will b e m e a s ur e d o n D a y 2 of C y cl e s 1 a n d 2 at 0 h o ur s ( b ef or e M 4 3 4 4 d o si n g), o n D a y 2 of C y cl e 1 o nl y at 4 ( ± 1) h o ur s aft er M 4 3 4 4 d o si n g, a n d 
o n D a y 9 of C y cl e 1 at 0 h o ur s ( b ef or e M 4 3 4 4 d o si n g).
p
1 2 -l e a d E C G will b e m e a s ur e d b ef or e M 4 3 4 4 d o si n g ( u p t o 6 0 mi n ut e s b ef or e) o n D a y
2 of C y cl e s 1 a n d 2 o nl y. I n a d diti o n, o n D a y 2 of C y cl e 1 o nl y, 1 2 -l e a d 
E C G will b e m e a s ur e d 1, 2, a n d 3 h o ur s aft er M 4 3 4 4 d o si n g ( ± 1 0 mi n ut e s).
q
T o f a cilit at e ti m el y a d mi ni str ati o n of st u d y dr u g, s af et y l a b s o n D a y 1 m a y b e o bt ai n e d u p t o 3 d a y s b ef or e st u d y dr u g d o si n g. If l a b s ar e dr a w n b ef or e t h e d a y  
of d o si n g, t h e y s h o ul d b e r e c or d e d a s c orr e s p o n di n g t o d a y of p l a n n e d st u d y dr u g a d mi ni str ati o n. S e e S e cti o n 7. 5. 3 f or li st of a n al yt e s a n d f urt h er d et ail s 
r e g ar di n g l a b or at or y t e sti n g s c h e d ul e. S e e S e cti o n 6. 2. 2 f or crit eri a f or a d mi ni str atio n of c h e m ot h er a p y or M 4 3 4 4.
r
F e m al e p arti ci p a nt s of c hil d b e ari n g p ot e nti al o nl y.
s
R e q uir e d o nl y at M T D/ R P 2 D i n P art B 1 if a d diti o n al d o si n g d a y s f or M 4 3 4 4 ar e a d d e d.
t
M 4 3 4 4 pl a s m a P K s a m pl e s will b e c oll e ct e d d uri n g C y cl e
1 o n D a y 2 at 0 ( b ef or e d o si n g) a n d at 0. 5, 1, 1. 5, 2, 3, 4, 8, a n d 2 4 h o ur s ( D a y 3) aft er d o si n g. F or 
p arti ci p a nt s u n d er g oi n g t h e ti m e d -t u m or bi o p si e s, P K s a m pl e c oll e cti o n at 2 a n d 3 h o ur s aft er d o sin g will b e o pti o n al a n d will b e c oll e ct e d o nl y if f e a si bl e.
u
M 4 3 4 4 pl a s m a P K s a m pl e s will b e c oll e ct e d d uri n g C y cl e
1 o n D a y 9 at 0 h o ur s ( b ef or e d o si n g).
v
M 4 3 4 4 uri n e P K s a m pl e s will b e c oll e ct e d d uri n g C y cl e 1 o n D a y 2 at 0 h o ur ( b ef or e d o si n g) a n d at 0 t o 4, 4 t o 8, 8 t o 1 2, a n d 1 2 t o 2 4 h o ur s ( D a y 3) aft er 
d o si n g.
y
F or p arti ci p a nt s wit h br e a st c a n c er or o v ari a n c a n c er d uri n g C y cl e 1 o nl y. T hi s i s n ot r e q uir e d if a s s e s s m e nt h a s b e e n p erf or m e d pr e vi o u sl y a n d r e s ult s ar e
a v ail a bl e f or u s e i n t hi s st u d y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 7
Tre at me nt a n d F oll o w -u p Peri o d (M 4 3 4 4
si n gle a ge nt t her a p y i n P arts C 1, C 2, a n d C 3 a n d t he 1 4 d +/ 7 d-
sc he d ule descri be d i n P arts C 4, C 5, a n d C 6)
E v e nt/ A s s e s s
m e nt
a
C y cl e 1 ( 2 1 D a y s) 
C y cl e 2 ( 2 1 D a y s) 
S u b s e q u e nt 
c y cl e s ( 2 1 
d a y s) 
F oll o w -u p b
D a y 1
D a y 8
D a y 1 5
D a y 1
D a y 8
D a y 1 5
D a y 1
All p arti ci p a nt s:
S af et y  F oll o w-u p 
3 0 d a y s ( ± 7 d a y s ) 
P arti ci p a nt s wit h o ut P D 
o nl y:
R a di ol o gi c F oll o w -u p c
e v er y  6-9 w e e k s
Cli ni c al vi sit s
X 
X 
X 
X 
X 
X
X
X
X
S af et y  As s e s s m e nt s
P h y si c al 
e x a mi n ati o n d
X
X
W e i g ht
X
X
X
Vit al Si g n s e
X 
X 
X 
X 
X 
X
X
X
St a n d ar d 1 2 -
l e a d E C Gf
X f
X
Tri pli c at e 
1 2 -l e a d E C G
( St a g e 1 a n d 2 
o nl y) g
X g
S er u m 
c h e mi str y
X h
X h
X h
X h
X h
X h
X h
X
H e m at ol o g y
X h
X h
X h
X h
X h
X h
X h
X
Uri n e β -h C G i
X j
X
X
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
E v e nt/ A s s e s s
m e nt
a
C y cl e 1 ( 2 1 D a y s) 
C y cl e 2 ( 2 1 D a y s) 
S u b s e q u e nt 
c y cl e s ( 2 1 
d a y s) 
F oll o w -u p b
D a y 1
D a y 8
D a y 1 5
D a y 1
D a y 8
D a y 1 5
D a y 1
All p arti ci p a nt s:
S af et y  F oll o w-u p 
3 0 d a y s ( ± 7 d a y s ) 
P arti ci p a nt s wit h o ut P D 
o nl y:
R a di ol o gi c F oll o w -u p c
e v er y  6-9 w e e k s
C o n c o mit a nt 
m e di c ati o n s
C o nti n u o u s fr o m si g ni n g of I C F t hr o u g h S af et y F oll o w -u p Vi sit
A E s
Cli ni c al 
di s e a s e 
a s s e s s m e nt k
X
X
X
X
W H O 
p erf or m a n c e 
st at u s
X
X
X
X
I m a gi n g A s s e s s m e nt s
C T s c a n 
di s e a s e 
a s s e s s m e nt n
E v er y 6 w e e k s, at t h e e n d of e v er y 2 c y cl e s f or t h e fir st 6 c y cl e s, t h e n e v er y 
3 c y cl e s u ntil di s e a s e pr o gr e s si o n o
X
B o n e s c a n p
E v er y 4 t o 6 c y cl e s u ntil di s e a s e pr o gr e s si o n
X
St u d y  dr u g a d mi ni str ati o n
M 4 3 4 4 d o si n g
q
C o nti n u o u s d o si n g q
P h ar m a c o ki n eti c A s s e s s m e nt s
M 4 3 4 4 
( Pl a s m a P K 
c oll e cti o n)
X r
X 
X r
X r
X r
A E = A d v er s e e v e nt, 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 E A = C a n c er e m br y o ni c a nti g e n, C T = 
C o m p ut eri z e d t o m o gr a p h 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, I C F = I nf or m e d c o n s e nt f or m, 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 = pr o gr e s sio n of di s e a s e, P K = P h ar m a c o ki n et i c s, 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 P 2 D = 
R e c o m m e n d e d P h a s e II d o s e , W H O = W o rl d H e alt h Or g a ni z ati o n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
a
Pl e a s e s e e S e cti o n 6. 2. 4 Mi s s e d D o s e s a n d St u d y Vi sit s f or g ui d a n c e o n mi s s e d a s s e s s m e nt s.
b
F oll o w -u p Vi sit will i n cl u d e a S af et y F oll o w -u p Vi sit 3 0 ( ± 7) d a y s f oll o wi n g t h e l a st d o s e of st u d y dr u g a n d R a di ol o gi c F oll o w -u p e v er y 6 t o 9 w e e k s f oll o wi n g 
t h e l a st c y cl e of c h e m ot h er a p y. R a di ol o gi c F oll o w -u p Vi sit s ar e n ot r e q uir e d f or t h o s e p arti ci p a nt s wit h pr o gr e s si v e di s e a s e o n pri or i m a gi n g s c a n. P arti ci p a nt s 
s h o ul d b e f oll o w e d u p f or s ur vi v al e v er y 3 m o nt h s u ntil t h e e n d of st u d y ( s e e S e cti o n 5. 2. 1 1 ).
c
R a di ol o gi c F oll o w -u p Vi sit s ar e n ot r e q uir e d f or t h o s e p arti ci p a nt s wit h pr o gr e s si v e di s e a s e o n pri or i m a gi n g s c a n . P arti ci p a nt s s h o ul d att e n d R a di ol o gi c F oll o w-
u p Vi sit s u ntil di s e a s e pr o gr e s si o n i s o b s er v e d, n e w a nti c a n c er tr e at m e nt i s st art e d, d e at h, or t h e e n d of t h e st u d y, w hi c h e v er c o m e s fir st. F or t h e fir st 6 m o nt h s 
aft er t h e st art of st u d y tr e at m e nt, R a di ol o gi c F oll o w -u p Vi sit s s h o ul d o c c ur e v er y 6 w e e k s, s u b s e q u e ntl y t h e y s h o ul d o c c ur e v er y 9 w e e k s .
d
S y m pt o m - dir e ct e d p h y si c al e x a mi n ati o n s will b e p erf or m e d a s cli ni c all y i n di c at e d i n t h e In v e sti g at or’ s j u d g m e nt. 
e
Vit al si g n s will b e m e a s ur e d pr e d o s e.
f
I n St a g e 3 of P art s C 1 , C 2 , a n d C 3 : 1 2 -l e a d E C G will b e m e a s ur e d b ef or e M 4 3 4 4 d o si n g ( u p t o 6 0 mi n ut e s b ef or e) o n D a y 1.
g
I n St a g e s 1 a n d 2 of P art s C 1 , C 2, a n d C 3 o nl y : tri pli c at e 1 2 -l e a d E C G wit h di git al u pl o a d f or c e ntr ali z e d a n al y si s will b e m e a s ur e d at t h e ti m e s of M 4 3 4 4 P K 
s a m pli n g o n D a y 1 of C y cl e 1 o nl y. D a y 1 pr e d o s e E C G m a y b e m e a s ur e d u p t o 6 0 mi n b ef or e d o si n g. E C G a s s e s s m e nt s h o ul d b e p erf or m e d wit hi n 1 0 
mi n ut e s pri or t o P K bl o o d s a m pl e c oll e cti o n, s u c h t h at t h e bl o o d s a m pl e i s c oll e ct e d at t h e n o mi n al ti m e.
h 
T o f a cilit at e ti m el y a d mi ni str ati o n of st u d y dr u g, s af et y l a b s m a y b e o bt ai n e d u p t o 3 d a y s b ef or e d o si n g. If l a b s ar e dr a w n b ef or e t h e d a y of d o si n g, t h e y s h o ul d 
b e r e c or d e d a s c orr e s p o n di n g t o d a y of pl a n n e d st u d y dr u g a d mi ni str ati o n. S e e  T a bl e 1 5 f or li st of a n al yt e s a n d f urt h er d et ail s r e g ar di n g l a b or at or y t e sti n g 
s c h e d ul e. S e e S e cti o n 6. 2. 2 f or crit eri a f or a d mi ni str ati o n of M 4 3 4 4 .
i
F e m al e p arti ci p a nt s of c hil d b e ari n g p ot e nti al o nl y.
j
If β-h C G i s m e a s ur e d o n D a y -7, a s s e s s m e nt will n ot b e r e p e at e d o n D a y 1.
k
A s s e s s m e nt i n cl u d e s t u m or st a gi n g (I t o I V) a n d T u m or-N o d e -M et a st a si s.
n
I m a gi n g s c a n ( e. g., C T, M RI) of c h e st a n d a b d o m e n s h o ul d b e p erf or m e d e v er y 6 w e e k s , i n a d diti o n t o i m a gi n g s c a n of ot h er b o d y ar e a s ( e. g., p el vi s), a s 
cli ni c all y i n di c at e d. I m a gi n g s c a n s m a y b e p erf or m e d ± 5 d a y s b ef or e t h e e n d of i n di c at e d c y cl e s; h o w e v e r, t h e i m a gi n g s c a n m u st b e p erf or m e d b ef or e D a y 1 
d o si n g of t h e s u b s e q u e nt c y cl e. F or e a c h p arti ci p a nt , t h e s a m e i m a gi n g t e c h ni q u e s h o ul d b e u s e d t o f oll o w t h e di s e a s e (if p o s si bl e). P er R E CI S T 1. 1, o bj e cti v e 
r e s p o n s e s n e e d t o b e c o nfir m e d. C o nfir m ati o n sh o ul d b e d et er mi n e d at a s c a n n o l e s s t h a n 4 w e e k s aft er t h e ori gi n al a s s e s s m e nt of o bj e cti v e r e s p o n s e i s 
m a d e; c o nfir m ati o n of r e s p o n s e at t h e n e xt s c h e d ul e d t u m or a s s e s s m e nt i s a c c e pt a bl e.
o
If a p arti ci p a nt di s c o nti n u e s t h e st u d y pr e m at ur el y wit h o ut e vi d e n c e of pr o gr e s si v e di s e a s e o n t h e m o st r e c e nt s c a n, a f oll o w- u p i m a gi n g s c a n will b e p erf or m e d 
wit hi n 2 1 d a y s aft er t h e pl a n n e d l a st d a y of t h e c y cl e d uri n g w hi c h t h e p arti ci p a nt di s c o nti n u e d fr o m t h e st u d y.
p
F or p arti ci p a nt s wit h p o siti v e b o n e s c a n s at S cr e e ni n g.
q
M 4 3 4 4 will b e a d mi ni st er e d at a d o s e a n d s c h e d ul e t h at h a s b e e n d et er mi n e d a s R P 2 D i n eit h er st u d y P art A or A 2 , or if u si n g t h e 1 4 d +/ 7 d - s c h e d ul e, 
d et er mi n e d i n st u d y P art A 3 .
r
M 4 3 4 4 ( a n d m et a b olit e s a s a p pr o pri at e) pl a s m a P K s a m pl e s will b e c oll e ct e d d uri n g C y cl e 1 o n D a y 1 at 0 ( b ef or e d o si n g) , b et w e e n 0. 5 t o 2 h o ur s aft er 
d o si n g , a n d at t h e e n d of vi sit at l e a st 1 h o ur s aft er t h e pr e vi o u s s a m pl e , o n C y cl e 1 D a y 8 a n d D a y 1 5 ( at t h e st art a n d e n d of t h e vi sit, at l e a st 1 ho ur s a p art -2 
s a m pl e s) , c o nti n ui n g o n D a y 1 of e v er y s e c o n d c y cl e d uri n g C y cl e s 2 -8 a n d e v er y f o urt h c y cl e fr o m C y cl e 1 2 o n w ar d s . I n c a s e of t h e 1 4 d +/ 7 d - dr u g h oli d a y 
s c h e d ul e, P K s a m pli n g ti m e p oi nt s li st e d a b o v e t h at f all o n d a y s wit h o ut d o si n g will b e o mitt e d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 8
E x pl or at or y Assess me nts ( M 4 3 4 4 si n gle a ge nt t her a p y i n P a rts C 1, C 2 a n d C 3 a n d t he 1 4 d +/ 7 d- sc he d ule 
descri be d i n P arts C 4, C 5, a n d C 6)
E v e nt/ A s s e s s m e nt a
C y cl e 1
C y cl e 2
S u b s e q u e nt 
C y cl e s
Di s e a s e Pr o gr e s si o n or 
S af et y  F oll o w-u p b
D a y 1
D a y 1 5
D a y 1
D a y 1 5
D a y 1
a
Pl e a s e s e e S e cti o n 6. 2. 4 Mi s s e d D o s e s a n d St u d y Vi sit s f or g ui d a n c e o n mi s s e d a s s e s s m e nt s.
b
F oll o w -u p Vi sit will i n cl u d e a S af et y F oll o w -u p Vi sit 3 0 ( ± 7) d a y s f oll o wi n g t h e l a st d o s e of st u d y dr u g .
f
St a g e 1 o nl y. T h e s a m pl e s m u st
b e t a k e n o n D a y 1 pr e d o s e, 3 a n d 5 h o ur s aft er M 4 3 4 4 a d mi ni str ati o n i n C y cl e 1, a n d o n D a y 1 pr e d o s e a n d 3 h o ur s aft er 
M 4 3 4 4 a d mi ni str ati o n
i n C y cl e 2 .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 9
Tre at me nt a n d F oll o w -u p Peri o d ( M 4 3 4 4 si n gle a ge nt t her a p y i n P arts C 4, C 5 a n d C 6 , e xce pt f or t he 
1 4 d +/ 7 d- sc he d ule)
E v e nt/ A s s e s s m e nt a
C y cl e 1 ( 2 8 D a y s) 
C y cl e 2 ( 2 8 D a y s) 
S u b s e q u e nt 
c y cl e s ( 2 8 
d a y s) 
F oll o w -u p b
D a y 1
D a y 8
D a y 1 5
D a y 2 2
D a y 1
D a y 8
D a y 1 5
D a y 2 2
D a y 1
All 
p arti ci p a nt s:
S af et y  
F oll o w -u p 
3 0 d a y s 
( ± 7 d a y s) 
P arti ci p a nt s 
wit h o ut P D 
o nl y:
R a di ol o gi c 
F oll o w -u p c
e v er y  6-9 
w e e k s
Cli ni c al vi sit s
X 
X 
X 
X 
X
X
X
X
X
S af et y  As s e s s m e nt
P h y si c al e x a mi n ati o n d
X
X
W e i g ht
X
X
X
Vit al Si g n s e
X 
X 
X 
X 
X 
X 
X 
X
X
X
St a n d ar d 1 2 -l e a d E C Gf
X f
X
Tri pli c at e 1 2 -l e a d E C G
( St a g e 1 a n d 2 o nl y)g
X
S er u m c h e mi str y
X i
X h
X h
X 
X h
X h
X h
X h
X
H e m at ol o g y
X h
X h
X h
X 
X h
X h
X h
X h
X
Uri n e β -h C G i
X j
X
X
X
C o n c o mit a nt 
m e di c ati o n s
C o nti n u o u s fr o m si g ni n g of I C F t hr o u g h S af et y F oll o w -u p Vi sit
A E s
Cli ni c al di s e a s e 
a s s e s s m e nt k
X
X
X
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
E v e nt/ A s s e s s m e nt a
C y cl e 1 ( 2 8 D a y s) 
C y cl e 2 ( 2 8 D a y s) 
S u b s e q u e nt 
c y cl e s ( 2 8 
d a y s) 
F oll o w -u p b
D a y 1
D a y 8
D a y 1 5
D a y 2 2
D a y 1
D a y 8
D a y 1 5
D a y 2 2
D a y 1
All 
p arti ci p a nt s:
S af et y  
F oll o w -u p 
3 0 d a y s 
( ± 7 d a y s) 
P arti ci p a nt s 
wit h o ut P D 
o nl y:
R a di ol o gi c 
F oll o w -u p c
e v er y  6-9 
w e e k s
W H O p erf or m a n c e 
st at u s
X
X
X
X
I m a gi n g A s s e s s m e nt s
C T s c a n di s e a s e 
a s s e s s m e nt n
E v er y 6- w e e k s u ntil di s e a s e pr o gr e s si o n o
X
B o n e s c a n p
E v er y 3 t o 4 c y cl e s u ntil di s e a s e pr o gr e s si o n
X
St u d y  Dr u g A d mi ni str ati o n
M 4 3 4 4 d o si n g
q
3 d a y s o n/ 4 d a y s off ( D a y 1 -3, 8 -1 0, 1 5 -1 7, 2 2 -2 4)
7 d a y s o n/ 7 d a y s off ( D a y s 1 -7, 1 5 -2 1)
5 d a y s o n/ 2 d a y s off ( D a y 1- 5, 8 -1 2, 1 5 -1 9, 2 2 -2 6) q
P h ar m a c o ki n eti c A s s e s s m e nt s
M 4 3 4 4 ( Pl a s m a P K 
c oll e cti o n) r
X r
X r
X r
X r
X r
A E = A d v er s e e v e nt, 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 E A = C a n c er e m br y o ni c a nti g e n, C T = 
C o m p ut eri z e d t o m o gr a p h y, 
, E C G = El e ctr o c ar di o gr a m, I C F = I nf or m e d c o n s e nt f or m, 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 = pr o gr e s si o n of di s e a s e, P K = P h ar m a c o ki n eti c s, 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 P 2 D = 
R e c o m m e n d e d P h a s e II d o s e , W H O = W o rl d H e alt h Or g a ni z ati o n
a
Pl e a s e s e e S e cti o n 6. 2. 4 Mi s s e d D o s e s a n d St u d y Vi sit s f or g ui d a n c e o n mi s s e d a s s e s s m e nt s.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
b
F oll o w -u p Vi sit will i n cl u d e a S af et y F oll o w -u p Vi sit 3 0 ( ± 7) d a y s f oll o wi n g t h e l a st d o s e of st u d y dr u g a n d R a di ol o gi c F oll o w -u p e v er y 6 t o 9 w e e k s f oll o wi n g 
t h e l a st c y cl e of c h e m ot h era p y. R a di ol o gi c F oll o w -u p Vi sit s ar e n ot r e q uir e d f or t h o s e p arti ci p a nt s wit h pr o gr e s si v e di s e a s e o n pri or i m a gi n g s c a n. P arti ci p a nt s 
s h o ul d b e f oll o w e d u p f or s ur vi v al e v er y 3 m o nt h s u ntil t h e e n d of st u d y ( s e e S e cti o n 6. 2. 4 ).
c
R a di ol o gi c F oll o w -u p Vi sit s ar e n ot r e q uir e d f or t h o s e p arti ci p a nt s wit h pr o gr e s si v e d i s e a s e o n pri or i m a gi n g s c a n. P arti ci p a nt s s h o ul d att e n d R a di ol o gi c F oll o w-
u p Vi sit s u ntil di s e a s e pr o gr e s si o n i s o b s er v e d, n e w a nti c a n c er tr e at m e nt i s st art e d, d e at h, or t h e e n d of t h e st u d y, w hi c h e v er c o m e s fir st. F or t h e fir st 6 m o nt h s 
aft er t h e st art of st u d y tr e at m e nt, R a di ol o gi c F oll o w -u p Vi sit s s h o ul d o c c ur e v er y 6 w e e k s, s u b s e q u e ntl y t h e y s h o ul d o c c ur e v er y 9 w e e k s.
d
S y m pt o m - dir e ct e d p h y si c al e x a mi n ati o n s will b e p erf or m e d a s cli ni c all y i n di c at e d i n t h e I n v e sti g at or’ s j u d g m e nt. 
e
Vit al si g n s will b e m e a s ur e d pr e d o s e.
f
I n St a g e 3 of P art s C4 , C5 , a n d C6 : 1 2 -l e a d E C G will b e m e a s ur e d b ef or e M 4 3 4 4 d o si n g ( u p t o 6 0 mi n ut e s b ef or e) o n D a y 1.
g
I n St a g e s 1 a n d 2 of P art s C 4 , C5 , a n d C6 o nl y : tri pli c at e 1 2 -l e a d E C G wit h di git al u pl o a d f or c e ntr ali z e d a n al y si s will b e m e a s ur e d at t h e ti m e s of M 4 3 4 4 P K 
s a m pli n g o n D a y 1 of C y cl e 1 o nl y. D a y 1 pr e d o s e E C G m a y b e m e a s ur e d u p t o 6 0 mi n b ef or e d o si n g. E C G a s s e s s m e nt s h o ul d b e p erf or m e d wit hi n 1 0 
mi n ut e s pri or t o P K bl o o d s a m pl e c oll e cti o n, s u c h t h at t h e bl o o d s a m pl e i s c oll e ct e d at t h e n o mi n al ti m e.
h 
T o f a cilit at e ti m el y a d mi ni str ati o n of st u d y dr u g, s af et y l a b s m a y b e o bt ai n e d u p t o 3 d a y s b ef or e d o si n g. If l a b s ar e dr a w n b ef or e t h e d a y of d o si n g, t h e y s h o ul d 
b e r e c or d e d a s c orr e s p o n di n g t o d a y of pl a n n e d st u d y dr u g a d mi n i str ati o n. S e e  T a bl e 1 5 f or li st of a n al yt e s a n d f urt h er d et ail s r e g ar di n g l a b or at or y t e sti n g 
s c h e d ul e. S e e S e cti o n 6. 2. 2 f or crit eri a f or a d mi ni str ati o n of M 4 3 4 4 .
i
F e m al e p arti ci p a nt s of c hil d b e ari n g p ot e nti al o nl y.
j
If β-h C G i s m e a s ur e d o n D a y -7, a s s e s s m e nt will n ot b e r e p e at e d o n D a y 1.
k
A s s e s s m e nt i n cl u d e s t u m or st a gi n g (I t o I V) a n d T u m or-N o d e -M et a st a si s.
n
I m a gi n g s c a n ( e. g., C T, M RI) of c h e st a n d a b d o m e n s h o ul d b e p erf or m e d e v er y 6 w e e k s , i n a d diti o n t o i m a gi n g s c a n of ot h er b o d y ar e a s ( e. g., p el vi s), a s 
cli ni c all y i n di c at e d. I m a gi n g s c a n s m a y b e p erf or m e d ± 5 d a y s b ef or e t h e e n d of i n di c at e d c y cl e s; h o w e v er, t h e i m a gi n g s c a n m u st b e p erf or m e d b ef or e D a y 1 
d o si n g of t h e s u b s e q u e nt c y cl e. F or e a c h p arti ci p a nt , t h e s a m e i m a gi n g t e c h ni q u e s h o ul d b e u s e d t o f oll o w t h e di s e a s e (if p o s si bl e). P er R E CI S T 1. 1, o bj e cti v e 
r e s p o n s e s n e e d t o b e c o nfir m e d. C o nfir m ati o n s h o ul d b e d et er mi n e d at a s c a n n o l e s s t h a n 4 w e e k s aft er t h e ori gi n al a s s e s s m e nt of o bj e cti v e r e s p o n s e i s 
m a d e; c o nfir m ati o n of r e s p o n s e a t t h e n e xt s c h e d ul e d t u m or a s s e s s m e nt i s a c c e pt a bl e.
o
If a p arti ci p a nt di s c o nti n u e s t h e st u d y pr e m at ur el y wit h o ut e vi d e n c e of pr o gr e s si v e di s e a s e o n t h e m o st r e c e nt s c a n, a f oll o w -u p i m a gi n g s c a n will b e p erf or m e d 
wit hi n 2 1 d a y s aft er t h e pl a n n e d l a st d a y of t h e c y cl e d uri n g w hi c h t h e p arti ci p a nt di s c o nti n u e d fr o m t h e st u d y.
p
F or p arti ci p a nt s wit h p o siti v e b o n e s c a n s at S cr e e ni n g.
q
M 4 3 4 4 will b e a d mi ni st er e d at a d o s e a n d s c h e d ul e t h at h a s b e e n d et er mi n e d a s R P 2 D i n eit h er st u d y P art A 3 .
r
M 4 3 4 4 ( a n d m eta b olit e s a s a p pr o pri at e) pl a s m a P K s a m pl e s will b e c oll e ct e d a s d e s cri b e d i n S e cti o n  7. 6. 1. 4 , T a bl e 1 8 .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 1 0
E x pl or at or y Assess me nts
( M 4 3 4 4 si n gle a ge nt t her a p y i n P arts C 4, C 5 a n d C 6 , e xce pt f or t he 1 4 d +/ 7 d-
sc he d ule)
E v e nt/ A s s e s s m e nt a
C y cl e 1
C y cl e 2
S u b s e q u e nt C y cl e s
Di s e a s e Pr o gr e s si o n or 
S af et y  F oll o w-u p b
D a y 1
D a y 1 5
D a y 1
D a y 1 5
D a y 1
D N A = D e o x yri b o n u cl ei c a ci d, P B M C = P eri p h er al bl o o d m o n o n u cl e ar c ell s.
a
Pl e a s e s e e S e cti o n 6. 2. 4 Mi s s e d D o s e s a n d St u d y Vi sit s f or g ui d a n c e o n mi s s e d a s s e s s m e nt s.
b
F oll o w -u p Vi sit will i n cl u d e a S af et y F oll o w -u p Vi sit 3 0 ( ± 7) d a y s f oll o wi n g t h e l a st d o s e of st u d y dr u g.
e 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
2
S p o ns or, I n vesti g at ors a n d St u d y A d mi nistr ati ve Str uct ure
T his cli nical st u d y is s p o ns ore d b y : Merc k 
K Ga A , Dar msta dt, Ger ma n y
a n d E M D Ser o n o 
Researc h & De vel o p me nt I nstit ute, I nc., Billerica, M A, U S A i n N ort h A merica.
T he st u d y will be c o n d ucte d at a p pr o xi matel y 1 0 t o 1 5 sites. C o u ntries partici pati n g i n t his st u d y  
will i ncl u d e t he U K, t he U S A, the Net herla n ds a n d S pai n .
T he C o or di nati n g I n vesti gat or (
), 
re prese nts all I nvesti gat or s f or decisi o ns a n d disc ussi o ns re gar di n g t his st u d y, c o nsiste nt wit h t he 
I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) T o pic E 6 G o o d C li nical P ractice ( G C P; hereafter 
referre d t o as I C H G C P ). T he C o or di nati n g I n vesti gat or will pr o vi d e e x pert me dical i n p ut a n d 
a d vice relati n g t o st u d y desi g n a n d e xec 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 o n be half of all I n vesti gat ors .
Si g nat ure pa ges f or t he Pr ot oc ol Lea d a n d t he C o or di nati n g I n vesti gat or as well as a list of S p o ns or 
res p o nsi ble pers o ns are i n A p pe n di x I .
T he st u d y will a p pear i n t he f oll o wi n g cli nical trial re gistries: Cli nical Trials. g o v a n d E u dra C T .
Details of str uct ures a n d ass ociate d pr oce d ures will be defi ne d i n a se parate Ma n ual of O perati o ns , 
w hic h will be pre pare d u n der t he s u per visi o n of t he Cli nical St u d y Lea der.
3
B ac k gr o u n d I nf or m ati o n
Ca ncer is a gr o u p of diseases c haracterize d b y  d ysre g ulati o n of cell differe ntiati o n, pr oliferati o n, 
a n d s ur vi val. I n a d va nce d sta ges, t u m or cells ca n s prea d t o ot he r areas of t he b o d y i ncl u di n g vital 
or ga ns a n d b o ne, w hic h ca n be fatal if n ot br o u g ht u n der c o ntr ol (A merica n Ca ncer S ociet y 2 0 1 1) . 
T hr o u g h a d va nce me nts i n detecti o n, s ur ger y, a n d t hera py, patie nts’ pr o g n oses are ge nerall y 
i m pr o vi n g, a n d 5- ye ar s ur vi val rates f or a n u m ber of cancers are risi n g. H o we ver, t he nee d f or 
better treat me nt o pti o ns re mai ns. T he I nter nati o nal A ge nc y f or Researc h o n Ca ncer esti mates t hat 
t otal ca ncer-relate d deat hs w orl d wi de i n 2 0 0 8 were 7. 6 milli o n, w hic h is e x pecte d t o rise t o 
1 3. 2 milli o n ca ncer deat hs b y  2 0 3 0 (A merica n Ca ncer S ociet y 2 0 1 1 , Ferla y  2 0 1 0).
De o x yri b o n ucleic aci d (D N A )-da ma gi n g a ge nts a n d i o nizi n g ra diati o n (I R) are wi del y  use d as 
sta n dar d of care f or t he treat me nt of ma n y s oli d t u m ors. H o we ver, f or m ost patie nts, t he y  pr o vi de 
o nl y  mo dest be nefit d ue t o hi g hl y p r oficie nt cell ular pr ocesses t hat are a ble t o detect a n d re pair t he 
da ma ge d D N A (Ola usse n 2 0 0 6 , He gi 2 0 0 5 , N or q uist 2 0 1 1 ).
3. 1
Scie ntific R ati o n ale
T he pr otei n ki nase ata xia tela n giectasia m utate d ( A T M) a n d Ra d 3 -relate d ( A T R) are t he pri mar y  
me diat or of a n i m p orta nt D N A da ma ge s ur veilla nce a n d re pair pat h wa y  that res p o n ds t o 
re plicati o n stress ( R S) (Ci m pric h 2 0 0 8 ). Re plicati o n stress arises w he n t he cell's D N A re plicati o n 
mac hi ner y  atte m pts t o c o p y t hr o u g h a n u nres ol ve d da ma ge lesi o n. S uc h e ve nts are c o m m on after 
cells are treate d wit h D N A -da ma gi n g a ge nts. Left u nres ol ve d, R S ca n lea d t o d o u ble -stra n d D N A 
D oc u me nt N o. 
O bject N o. 
P P D
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
brea ks ( D S B) a n d cell deat h. T he R S pat h wa y  is cl osel y ass ociate d wit h a D S B re pair pat h wa y  
me diate d b y  the A T R -relate d ki nase, A T M (Kasta n 2 0 0 4) . I nhi biti o n of A T R i n n o nca ncer cells 
has bee n s h o w n t o lea d t o acti vati o n of a c o m pe nsat or y AT M me diate d res p o nse t hat pr otects cells 
fr o m t he let hal c o nse q ue nces of u nre paire d R S (Rea per 2 0 1 1) . I n co ntrast, ma n y ca ncer cells 
de pe n d o n A T R f or s ur vi val fr o m D N A da ma ge as a res ult of defects i n t he A T M si g nali n g 
pat h wa y  an d/ or as a res ult of hi g h bac k gr o u n d le vels of R S t hat ca n arise fr o m a n u m ber of 
mec ha nis ms, 
i ncl u di n g e x pressi o n of certai n o nc o ge nes
(Ca ncer Ge n o me 
Atlas 
N 
2 0 1 2 , 
Di n g 2 0 0 8, Gree n ma n 2 0 0 7 , Jia n g 2 0 0 9). S uc h defects i n A T M si g nali n g ca n ca use a de pe n de nce 
o n A T R f or s ur vi val fr o m R S ca use d b y  treat me nt wit h D N A -da ma gi n g a ge nts (Rea per 2 0 1 1,  
T ole d o 2 0 1 1,  M ur ga 2 0 0 9 , N g hie m 2 0 0 2,  Sa n gster -G uit y 2 0 1 1,  N g hie m 2 0 0 1) . Acc or di n gl y, 
w hile n o nca ncer cells ha ve bee n s h o w n t o t olerate c o m bi nati o ns of A T R i nhi bit ors a n d 
D N A -da ma gi n g dr u gs, it is e x pecte d t hat a n A T R i n hi bit or will se nsitize ma n y  ca ncer cells t o 
vari o us D N A - da ma gi n g a ge nts (Rea per 2 0 1 1 ). Hi g h le vels of R S are e vi de nt i n s o me ca ncer cells 
e ve n i n t he a bse nce of D N A -da ma gi n g a ge nts. T his ca n res ult fr o m e x pressi o n of o nc o ge nes t hat 
dri ve d y sre g ulate d re plicati o n, a h y p o xic e n vir o n me nt, or fr o m defects i n ot her D N A re pair 
pat h wa y s. T his hi g h R S i n ca ncer cells ca n dri ve a relia nce o n A T R f or s ur vi val a n d t hus, A T R 
i n hi bit ors ma y ha ve be nefit as si n gle a ge nts (Gila d 2 0 1 0 , Sc h o p p y  2 0 1 2, M ur ga 2 0 1 1 , Pires 2 0 1 2 , 
Ha m m o n d 2 0 0 4 ).
M 4 3 4 4 (i nitiall y  de vel o pe d b y Verte x P har mace uticals I nc or p orate d u n der t he c o de V X - 8 0 3) is a 
p ote nt a n d selecti ve i n hi bit or of A T R (i n hi biti o n c o nsta nt < 1 5 0 p M) wit h a c o nce ntrati o n res ulti n g 
i n 5 0 % ma xi mal i n hi biti o n of 8 n M f or t he treat me nt of a d va nce d mali g na ncies. M 4 3 4 4
se nsitizes 
ma n y  hu ma n ca ncer cell li nes t o t he c yt ot o xic effects of vari o us D N A -da ma gi n g a ge nts. I n 
c o ntrast, e xte nsi ve st u dies wit h ot her A T R i n hi bit ors ha ve s h o w n t hat n o nca ncer cells t olerate 
A T R i n hi biti o n wit h o nl y  a re versi ble i ncrease i n gr o wt h arrest attri b uta ble t o acti vati o n of 
c o m pe nsat or y, A T M-me diate d, D N A re pair si g nali n g (Rea per 2 0 1 1 ). 
M utati o ns i n s pecific D N A da ma ge res p o nse relate d ge nes (i ncl u di n g A RI D 1 A, A T R X/ D A X X 
a n d A T M) ha ve bee n s h o w n t o i ncrease relia nce o n A T R si g nali n g f or t u m or cell s ur vi val a n d 
gr o wt h (Fl y n n 2 0 1 5,  Willia ms o n 2 0 1 6,  Mi n 2 0 1 7 ). P u blis he d data s u g gest t hat l oss- of-f u ncti o n 
m utati o ns i n s pecific t u m or ge nes i n v ol ve d i n t he D N A da ma ge re pair pr ocess as ca n di dates t o
pre dict se nsiti vit y to A T R i n hi bit ors as m o n ot hera p y . Willia ms o n a n d c o-a ut h ors s h o we d i n a n 
ri b o n ucleic aci d i nterfere nce Scree ni n g i n cell li nes t hat A RI D 1 A was t he t o p hit ge ne t hat was 
s ynt hetic all y let hal wit h t he A T R i n hi bit or V X - 8 2 1, a n d t hat t here was a n oticea ble statisticall y 
si g nifica nt differe nce i n se nsiti vit y to M 6 6 2 0
( V X- 9 7 0) bet wee n t he A RI D 1 A w il d ty pe a n d 
m ut ate d xe n o grafts (Willia ms o n 2 0 1 6) . Fl y n n a n d c oa ut h ors de m o nstrate d i n vitr o a n d i n vi v o t hat 
t u m or cells preser vi n g c hr o m os o me i nte grit y thr o u g h o ut t he alter nati ve le n gt he ni n g of tel o mere
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
pr ocess, a mec ha nis m ass ociate d wit h l oss- of-f u ncti o n m utati o ns i n eit her t he ge nes A T R X or 
D A X X
w hic h i n v ol ves D N A h o m ol o g o us rec o m bi nati o n, are se nsiti ve t o A T R i n hi biti o n
(Fl y n n 2 0 1 5 ). Antit u m or acti vit y of M 4 3 4 4
as m o n ot hera p y has bee n s h o w n i n precli nical 
xe n o graft har b ori n g s uc h m utati o ns (Verte x Re p ort E 0 4 5 3 -U 1 6 0 7 -G 2 9 2 & S K - N-F 1 _ V X - 8 0 3).
T he c o-i nacti vati o n of A T M a n d A T R f u ncti o ns res ults i n s ynt hetic let halit y, w hic h has bee n 
s h o w n i n a gastric ca ncer xe n o graf t m o del carr yi n g a m utati o n i n A T M wit h t he A T R i n hi bit or 
A Z D 6 7 3 8 (Mi n 2 0 1 7) . T o get her, t hese data s u p p ort t he rati o nale t hat patie nts wit h s oli d t u m ors 
har b ori n g l oss- of-f u ncti o n m utati o ns i n A RI D 1 A, A T R X or D A X X, a n d A T M m a y  be nefit fr o m
treat me nt wit h M 4 3 4 4 m o n ot hera py , i n de pe n de nt of a nat o mic t u m or l ocalizati o n. 
T he pre vale nce of t hese l oss of f u ncti o n m utati o ns
is varia ble a n d ge nerall y l o w acr oss t u m or 
t ypes. Acc or di n g t o a st u d y Sp o n s or a nal ys is c o n d ucte d i n Se pte m ber 2 0 1 8 o n data of T he Ca ncer 
Ge n o me Atlas ( T C G A) i n t he Nati o nal Ca ncer I nstit ute Ge n o mic Data C o m m o ns ( N CI G D C), the 
fre q ue nc y of l oss of f u ncti o n m utati o ns i n A RI D 1 A, A T R X, D A X X, A T M is e x pecte d t o be 6. 7 %, 
3. 3 %, 0. 2 % , 2. 1 %, res pecti vely, i n t he o nc ol o g ic patie nt p o p ulati o n ( defi niti o n of “l oss of 
f u ncti o n” is re p orte d i n S ecti o n 7. 7. 5 ). T he i n dicati o ns wit h t he hi g hest pre vale nce of m utati o ns 
are 
i n e n d o metrial 
carci n o ma, 
st o mac h 
a de n ocarci n o ma, 
ur ot helial 
carci n o ma, 
a n d 
c h ola n gi ocarci n o ma f or A RI D 1 A ( 3 0 %, 2 0 %, 1 4 %, 1 1 % of cases, res pecti vel y), i n l o wer gra de 
gli o ma a n d sarc o ma f or A T R X ( 3 1 % a n d 1 1 %, res pecti vel y), a n d c ol o n a de n ocarci n o ma f or A T M 
( 1 1 %).
3. 2
T o xic ol o g y a n d C o m p o u n d S afet y
M 4 3 4 4 has bee n e val uate d i n n o n- G o o d La b orat or y  Practice ( G LP) d ose -ra n ge fi n di n g a n d G L P 
t o xic ol o g y st u dies. F oll o wi n g BI W
a d mi nistrati o n of M 4 3 4 4 at d oses of 1 0, 3 0, a n d 4 5 m g/ k g f or 
1 4 da y s i n a n o n -G L P d ose -ra nge fi n di n g st u d y, a ma xi m u m t olerate d d ose ( M T D) of 4 5 m g / k g 
was esta blis he d f or rats (I T R La b orat ories Re p ort f or 7 2 1 7 1 2 0 1 3). I n a G L P st u d y, w he n M 4 3 4 4 
was a d mi nistere d BI W
t o rats at d oses of 3, 1 0, a nd 3 0 m g/ k g f or 2 8 d a y s (M PI  Researc h f or 8 6 3-
1 6 5 2 0 1 4 ), t he i de ntifie d tar get or ga ns of t o xicit y were c o nsiste nt wit h b ot h t he p har mac ol o g y  of 
A T R i n hi biti o n (R uza n ki na 2 0 0 7) a n d t he n o n -G L P fi n di n gs a n d i ncl u de d: b o ne marr o w 
(re ge nerati o n) wit h c orres p o n di n g c ha n ges t o t he he mat o p oietic s yste m (re d ucti o ns i n w hite bl o o d 
cell [ W B C] a n d re d bl o o d cell [ R B C] mass); t h y mus (l ym p h oi d de pleti o n); s plee n ( decrease d 
l ym p h oc y tes/e xtra me d ullar y he mat o p oiesis); li ver (e xtra me d ullar y he mat o p oiesis); a n d testes 
(s per mat oc yte/s per mati d de ge nerati o n wit h 
c o nc o mita nt oli g os per mia/ ger m cell de bris i n 
e pi di d ymi des) (M PI  Researc h f or 8 63- 1 6 5 2 0 1 4 ). All fi n di n gs, wit h t he e xce pti o n of t h ose i n t he 
testes, ha d res ol ve d b y  the e n d of t he 1 4- d a y  rec o ver y peri o d (M PI  Researc h f or 8 6 3 - 1 6 5 2 0 1 4)
h o we ver, a d urati o n of 1 4 da y s is i ns ufficie nt f or s per m pr o d ucti o n t o c o m pletel y rec o ver
(Creas y 2 0 0 2) . A se verel y t o xic d ose t o 1 0 % of t he p o p ulati o n c o ul d n ot be deter mi ne d i n rats.
I n a n o n-G L P 1 4 -d a y  d ose-ra n ge fi n di n g st u d y c o n d ucte d i n d o gs at d oses of 3, 1 0, a n d 3 0 m g/ k g 
BI W , a si n gle d ose of 3 0 m g/ k g res ulte d i n m ori b u n dit y  due t o se vere gastr oi ntesti nal ( GI) t o xicit y; 
b o d y  wei g ht l oss a n d c o nti n ue d deteri orati n g healt h le d t o t he earl y ter mi nati o n of the hi g h -d ose 
( 3 0 m g/ k g) gr o u p o n St u d y  Da y 3 (I T R La b orat ories Re p ort f or 6 1 3 8 8 2 0 1 3 ). M 4 3 4 4
was als o 
p o orl y  tolerate d at 1 0 m g / k g res ulti n g i n e mesis, i na p pete nce, li q ui d st o ol, br o w n/ gree n material 
i n t he ca ge tra y, a n d b o d y  wei g ht l oss ( u p t o 2 3 %); h o we ver, effects n ote d at 3 m g/ k g were 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
mi ni mal. Base d o n t hese fi n di n gs, it was c o ncl u de d t hat t he M T D was e xce e de d at 1 0 m g/ k g (I T R 
La b orat ories Re p ort f or 6 1 3 8 8 2 0 1 3 ). 
I n a GL P 2 8- d a y  st u d y co n d ucte d i n d o gs assessi n g BI W
a d mi nistrati o n at d oses of 1, 2, a n d 
4 m g/ k g, M 4 3 4 4
was p o orl y  tolerate d (s oft/ water y/ m uc oi d feces, re d material i n t he feces a n d/ or 
i n t he ca ge tr a y, a n d b o d y  wei g ht l oss) at t he hi g hest d ose ( 4 m g / k g) (M PI  Researc h Re p ort f or 
8 6 3- 1 6 6 2 0 1 4) . M ori b u n dit y , d u e t o GI  to xicit y  an d e xtre me wei g ht l oss ( 1 4 %), o bser ve d i n 
1 hi g h -d ose ( 4 m g / k g) male 
le d t o t he earl y sacrifice of t hat a ni mal o n St u d y  
Da y 2 4
(M PI
Researc h Re p ort f or 8 6 3- 1 6 6 2 0 1 4) . C o nsiste nt wit h t he n o n- G L P fi n di n gs a n d t he 
p har mac ol o g y  of A T R i n hi biti o n (R uza n ki na 2 0 0 7) , tar get or ga ns of t o xicit y ide ntifie d i n t his G L P 
st u d y in d o gs at d oses of ≥2 m g/ k g were: b o ne marr o w (re ge nerati o n) wit h c orres p o n di n g c ha n ges 
i n t he he mat o p oietic s yste m ( decrease i n R B C mass); s plee n (e xtra me d ullar y he mat o p oiesis); li ver 
(e xtra me d ullar y he mat o p oiesis); t h ym us 
(l ym p h oi d de pleti o n); GI  (i nfla m mati o n of la mi na 
pr o pria a n d g ut ass ociate d l ym p h oi d tiss ue); a n d testes (s per mat oc yte/s per mati d de gra dati o n a n d 
sec o n dar y effect o n e pi di d ymi des; ger m cell de bris) (M PI  Researc h Re p ort f or 8 6 3- 1 6 6 2 0 1 4) . 
F oll o wi n g a 1 4- d a y  rec o ver y peri o d, all he mat ol o g y  fi n di n gs ha d res ol ve d, a n d a n o n g oi n g 
re ge nerati ve res p o nse was e vi de nt i n t he b o ne marr o w, t h ym us, s plee n, a n d li ver. A d diti o nall y , 
t he fi n di n gs n ote d i n t he GI ha d res ol ve d at t he 2 m g/ k g d ose; h o we ver, as e x pecte d, t he testic ular 
fi n di n gs ha d n ot res ol ve d at t he e n d of t he rec o ver y peri o d (M PI  Researc h Re p ort f or 8 6 3 -1 6 6 
2 0 1 4) si nce d urati o n of 1 4 d a y s is n ot s ufficie nt f or s per m pr o d ucti o n t o c o m pletel y rec o ver
(Creas y 2 0 0 2 ). Base d o n t hese data, t he hi g hest n o nse verel y  to xic d ose ( H N S T D) i n d o gs is 
c o nsi dere d t o be 2 m g/ k g BI W. T he a ni mal-t o-h u ma n e x p os ure m ulti ple calc ulate d o n a n area 
u n der t he c o nce ntrati o n vers us ti me c ur ve ( A U C) basis at t he H N S T D is e x pecte d t o be 2 -f ol d t he 
pr ojecte d h u ma n e x p os ure at t he efficaci o us d ose.
I n a d diti o n t o t o xic ol o g y data f or M 4 3 4 4 , Verte x P har mace uticals I nc or p orate d a n d Merc k K Ga A 
als o ha ve o btai ne d i nitial cli nical safety data o n V X - 9 7 0/M 6 6 2 0, t he first-i n-class i ntra ve n o usly
a d mi nistere d A T R i n hi bit or c urr e ntl y in t w o P hase I cli nical st u dies, M S 2 0 1 9 2 3 - 0 0 0 1 a n d 
V X 1 3 - 9 7 0- 0 0 2, i n t h e U S A a n d U K . M 6 6 2 0
has bee n a d mi nistere d i n Merc k -/Verte x -s p o ns ore d 
st u dies t o o ver 3 0 0 partici pa nt s wit h a d va nce d s oli d t u m ors, eit her as a si n gle a ge nt or i n 
c o m bi nati o n wit h eit her ge mcita bi ne or cis plati n. 
F urt her m ore, i nitial cli nical safety data are a vaila ble fr o m 4 0 partici pa nt s recei vi n g M 4 3 4 4 at d oses 
ra n gi n g fr o m 1 0 m g t o 1 2 0 0 m g) o btai ne d i n t he o n g oi n g Part A of t his st u d y a n d 1 3 partici pa nts 
i n St u d y  00 0 1 Part B 1 w h o recei ve d M 4 3 4 4 at d oses of 3 5 0 t o 5 0 0 m g i n c o m bi nati o n wit h 
car b o plati n at t he d ose A U C 5 . Refer t o t he c urre nt versi o n of t he I n vesti gat or’s Br oc h ure ( M 4 3 4 4 
I B) f or f urt her d etails.
Base d o n t he e val uati o n of safet y d ata fr o m St u d y  0 0 0 1, ele vati o ns i n he patic tra nsa mi nases ( A L T 
a n d A S T) 
ha ve bee n esta blis he d as a ne w i m p orta nt p ote ntial ris k ass ociate d wit h 
t he 
a d mi nistrati o n of M 4 3 4 4. 
M 4 3 4 4 
ca uses h y per bilir u bi ne mia ( pre d o mi na ntl y in direct or u nc o nj u gate d bilir u bi n) via 
i n hi biti o n of bilir u bi n gl uc ur o ni dati o n b y  UG T 1 A 1. I nitiall y, seri o us a d verse e ve nts ( S A Es) of 
i ncrease d bl o o d bilir u bi n a n d h y per bilir u bi ne mia were re p orte d as d ose-li miti n g t o xicities ( D LTs) 
i n 3 partici pa n ts a n d res ulte d i n st u d y dr u g wit h dra wal. After t he mec ha nis m of h y per bilir u bi ne mia 
was deter mi ne d base d o n a re vie w of cli nical a n d n o ncli nical data a n d o utsi de e x pert assess me nt, 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
t he defi niti o n of a D L T was re vise d i n a 2 0 1 6 pr ot oc ol a me n d me nt t o e xcl u de i ncreases i n bilir u bi n 
t hat are assesse d as arisi n g fr o m i n hi biti o n of bilir u bi n gl uc ur o ni dati o n, as l o n g as t he bilir u bi n 
le vel re mai ns bel o w 1 5 m g/ d L ( 2 5 7 μ m ol/ L) (see Secti o n 5. 2. 6 ).
I n Part A, bilir u bi n ele vati ons were d ose -de pe n de nt, o bser ve d at d oses ≥ 3 0 0 m g. T he o nset of 
i ncrease d bl o o d bilir u bi n was wit hi n 1 da y  of a d mi nistrati o n of t he dr u g a n d was se vere 
(i.e. Gra de ≥3 ) a n d was n ot t y picall y ass ociate d wit h ot her a d verse c o nse q ue nces. T he i nci de nce 
of i ncrease d bl o o d bilir u bi n as a n S A E was als o d ose - de pe n de nt, a n d was re p orte d at d oses 
≥7 0 0 m g. At 1, 2 0 0 m g, t he hi g hest M 4 3 4 4 d ose a d mi nistere d i n St u d y  00 0 1 Part A, 4 partici pa nts 
of 7 partici pa nts ( 5 7. 1 %) ha d S A Es of bl o o d bilir u bi n i ncrease d. I n Part B 1, 3 partici pa nts ( 2 3. 1 %) 
re p orte d A Es of bl o o d bilir u bi n i ncrease d ( 1 partici pa nt at eac h of t he 3 M 4 3 4 4 d oses of 3 5 0, 4 0 0, 
a n d 5 0 0 m g); 1 partici pa nt ( 7. 7 %) re p orte d a n S A E of h y per bilir u bi ne mia w hile recei vi n g 4 0 0 m g 
M 4 3 4 4.
I n Part A, D L Ts c o nfir me d i n d o se escalati o n meeti n gs ( D E Ms) occ urre d i n 3 of 4 0 partici pa nts 
i n t he safet y set. O ne partici pa nt i n t he 1, 0 5 0 m g gr o u p ha d D L Ts of A L T a n d A S T i ncrease d, 
bl o o d bilir u bi n i ncrease d, a n d ne utr o pe nia. T w o partici pa nts i n t he 1, 2 0 0 m g gr o u p ha d a D L T of 
bl o o d bilir u bi n i ncrease d. N o D L Ts occ urre d at M 4 3 4 4 d oses fr o m 1 0 t o 7 0 0 m g t wice wee kl y.
I n Part B 1, D L Ts c o nfir me d i n D E Ms occ urre d i n 4 of 1 3 partici pa nts i n t he safet y set. All D L Ts 
were re p orte d i n partici pa nts recei vi n g M 4 3 4 4 5 0 0 m g + A U C 5 car b o plati n. T hree partici pa nts 
ha d a D L T of ne utr o pe nia; D L Ts of fe brile ne utr o pe nia, gastr oi ntesti nal i nfla m mati o n, 
t hr o m b oc yt o pe nia, a n d v o miti n g were re p orte d i n 1 partici pa nt eac h.
Na usea a n d v o miti n g are c o nsi dere d a d verse dr u g reacti o ns ( A D Rs) f or M 4 3 4 4 d ue t o a p ossi ble 
ca usal ass ociati o n bet wee n M 4 3 4 4 treat me nt a n d t hese e ve nts. I n St u d y 0 0 0 1 Part A, na usea 
occ urre d i n 6 7. 5 % of partici pa nts a n d v o miti n g i n 4 7. 5 %. T hese e ve nts were us uall y  no nseri o us, 
of Gra de 1 or Gra de 2 i nte nsit y, a n d ma n y occ urre d o n t he sa me da y  as M 4 3 4 4 a d mi nistrati o n; t he 
maj orit y  di d n ot res ult i n i nterr u pti o n or per ma ne nt disc o nti n uati o n of M 4 3 4 4 treat me nt. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
4
St u d y O bjecti ves
4. 1
Pri m ar y O bjecti ves
4. 1. 1
P art A

T o e val uate t he safety a n d t olera bilit y of m ulti ple asce n di n g d oses of si n gle a ge nt 
M 4 3 4 4
a d mi nistere d BI W i n partici pa nt s wit h a d va nce d s oli d t u m ors

T o deter mi ne t he M T D a n d/ or rec o m me n de d P hase II d ose (R P 2 D ) of si n gle a ge nt 
M 4 3 4 4
a d mi nistere d BI W ( M T DS i n gle BI W) i n partici pa nt s wit h a d va nce d s oli d t u m ors.
4. 1. 2
P art A 2

T o e val uate t he safety a n d t olera bilit y of m ulti ple asce n di n g d oses of si n gle a ge nt 
M 4 3 4 4 w he n a d mi nistere d i n a t wice dail y or o nce dail y d ose sc he d ule i n partici pa nt s 
wit h a d va nce d s oli d t u m ors

T o deter mi ne t he M T D a n d/ or R P 2 D of si n gle a ge nt M 4 3 4 4 a d mi nistere d i n a t wice 
dail y  or o nce daily d ose sc he d ule i n partici pa nt s wit h a d va nce d s oli d t u m ors.
4. 1. 3
P art A 3

T o e val uate t he safety a n d t olera bilit y of m ulti ple asce n di n g d oses of si n gle a ge nt 
M 4 3 4 4 
w he n a d mi nistere d i n a dr u g h oli da y  dose sc he d ule i n partici pa nt s wit h 
a d va nce d s oli d t u m ors

T o deter mi ne t he M T D a n d/ or R P 2 D of si n gle a ge nt M 4 3 4 4 a d mi nistere d i n a dr u g 
h oli da y  d ose sc he d ule i n partici pa nt s wit h a d va nce d s oli d t u m ors.
4. 1. 4
P art B 1

T o e val uate t he safety a n d tolera bilit y  of M 4 3 4 4
w he n a d mi nistere d i n c o m bi nati o n 
wit h car b o plati n i n partici pa nts wit h a d va nce d s oli d t u m ors 

T o deter mi ne t he M T D a n d/ or R P 2 D of M 4 3 4 4
a d mi nistere d i n c o m bi nati o n wit h 
car b o plati n i n partici pa nt s wit h a d va nce d s oli d t u m ors.
4. 1. 5
All P arts C

T o e val uate t he safety,  tolera bilit y , a n d efficac y i n ter ms of c o nfir me d o bjecti ve 
res p o nse of M 4 3 4 4 
w he n a d mi nistere d i n partici pa nts wit h s oli d t u m or har b ori n g 
l oss- of-f u ncti o n m utati o ns i n t he ge nes A RI D 1 A ( Parts C 1 , C 4), A T R X a n d/ or D A X X 
( Parts C 2 , C 5), or A T M ( Parts C 3 , C 6).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
4. 2
Sec o n d ar y O bjecti ves
4. 2. 1
P art A

T o e val uate t he p har mac o ki netics ( P K) of si n gle a ge nt M 4 3 4 4
w he n a d mi nistere d BI W
i n partici pa nt s wit h a d va nce d s oli d t u m ors

T o assess p ote ntial a ntit u m or acti vit y of si n gle a ge nt M 4 3 4 4
w he n a d mi nistere d BI W
i n partici pa nt s wit h a d va nce d s oli d t u m ors.
4. 2. 2
P art A 2

T o e val uate t he p har mac o ki netics ( P K) of si n gle a ge nt M 4 3 4 4 (a n d meta b olites as 
a p pr o priate) w he n a d mi nistere d i n a t wice dail y or o nce dail y d ose sc he d ule i n
partici pa nt s wit h a d va nce d s oli d t u m ors

T o assess a ntit u m or acti vit y  of si n gle a ge nt M 4 3 4 4 w he n a d mi nistere d i n a t wice dail y 
or o nce dail y d ose sc he d ule i n partici pa nt s wit h a d va nce d s oli d t u m ors.
4. 2. 3
P art A 3

T o e val uate t he p har mac o ki netics ( P K) of si n gle a ge nt M 4 3 4 4 (a n d meta b olites as 
a p pr o priate) w he n a d mi nistere d i n a dr u g h oli da y  dose sc he d ule i n partici pa nt s wit h 
a d va nce d s oli d t u m ors

T o assess preli mi nar y  a ntit u m or acti vit y of si n gle a ge nt M 4 3 4 4 w he n a d mi nistere d i n a 
dr u g h oli da y  d ose sc he d ule i n partici pa nt s wit h a d va nce d s oli d t u m ors.
4. 2. 4
P art B 1

T o e val uate t he P K pr ofile of M 4 3 4 4
w he n a d mi nistere d i n c o m bi nati o n wit h 
car b o plati n i n partici pa nt s wit h a d va nce d s oli d t u m ors 

T o e val uate p ote ntial a ntit u m or acti vit y after a d mi nisteri n g M 4 3 4 4
i n c o m bi nati o n wit h 
car b o plati n i n partici pa nt s wit h a d va nce d s oli d t u m ors.
4. 2. 5
All P arts C

T o f urt her e val uate efficac y in ter ms of c o nfir me d best o verall res p o nse, d urati o n of 
res p o nse, pr o gressi o n free s ur vi val a n d o verall s ur vi val ti me of M 4 3 4 4 
w he n 
a d mi nistere d i n partici pa nts wit h l oss- of-f u ncti o n m utati o ns i n t he ge nes A RI D 1 A 
( Parts C 1 , C 4), A T R X a n d/ or D A X X ( Parts C 2 , C 5), or A T M ( Parts C 3 , C 6)

T o e val uate t he P K of M 4 3 4 4
(a n d meta b olites as a p pr o priate) i n i n di vi d ual partici pa nts
wit h l oss - of-f u ncti o n m utati o ns.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
5
I n vesti g ati o n al Pl a n
5. 1
O ver all St u d y Desi g n a n d Pl a n
T his is a n o pe n -la bel P hase I, first-i n-h u ma n cli nical st u d y co n d ucte d i n m ulti ple Parts (Parts A , 
A 2 , A 3, B 1, C 1, C 2, C 3, C 4, C 5, a n d C 6 ). Part A will esta blis h t he M T D/ R P 2 D of M 4 3 4 4
as a 
si n gle a ge nt a d mi nistere d BI W . Part A 2 will esta blis h t he M T D/ R P 2 D of M 4 3 4 4 as a si n gle a ge nt 
a d mi nistere d BI D (t wice dail y ) or o nce dail y. Part A 3 is o pti o nal a n d will esta blis h t he M T D/ R P 2 D 
of M 4 3 4 4 as a si n gle a ge nt a d mi nistere d i n a dr u g h oli da y  sc he d ule a p pl yi n g a 3-d a y s-o n/ 4 -d a y s-
off , 5-d a y s-o n/ 2 -d a y s-off, 7- d a y s- o n/ 7-d a y s-off a n d/ or 1 4- d a y s- o n/ 7-d a y s-off sc he d ule. Part B 1
will esta blis h t he M T D/ R P 2 D of M 4 3 4 4
a d mi nistere d i n c o m bi nati o n wit h car b o plati n. Parts C 1, 
C 2, a n d C 3 will be e x pa nsi o n c o h orts t o e val uate t he t olera bilit y an d a ntit u m or acti vit y of si n gle 
a ge nt c o nti n u o us M 4 3 4 4
a d mi nist rati o n i n partici pa nt s wit h s oli d t u m ors wit h l oss- of-f u ncti o n 
m utati o ns a n d will use a d ose a n d sc he d ule esta blis he d i n Part A or A 2 . Parts C 4, C 5, a n d C 6 are 
o pti o nal e x pa nsi o n c o h orts t o e val uate t he t olera bilit y an d a ntit u m or acti vit y of si n gle a ge nt 
M 4 3 4 4 
a d mi nistere d i n a dr u g h oli da y  sc he d ule i n partici pa nt s wi t h s oli d t u m ors wit h 
l oss- of-f u ncti o n m utati o ns a n d will use a dr u g h oli da y d ose a n d sc he d ule esta blis he d i n Part A 3.
Res ults of Part A will i nf or m t he starti n g d ose of M 4 3 4 4
i n Part B 1. Res ults of Part s A a n d A 2 
will i nf or m t he d ose a n d sc he d ule i n Parts C 1, C 2, a n d C 3 . Res ults of Part A 3 will i nf or m t he d ose 
a n d sc he d ule i n Parts C 4, C 5, a n d C 6. If safet y a n d t olera bilit y precl u de escalati o n of M 4 3 4 4
d ose 
i n Part A or A 2 t o a d ose t hat c orres p o n ds t o efficac y i n precli nical m o dels , t he n t he S p o ns or ma y 
deci de n ot t o i nitiate t he e x pa nsi o n c o h ort s i n Parts C.
T he st u d y was desi g ne d i n acc or da nce wit h t he E ur o pea n Me dici ne A ge nc y’s g ui da nce d oc u me nt, 
“ G ui deli ne o n Strate gies t o I de ntif y an d Miti gate Ris ks f or First I n H u ma n Cli nical St u dies Wit h 
I n vesti gati o nal Me dici nal Pr o d ucts.”
A sc he matic of t he st u d y  desi g n is i ncl u de d i n Fi g ure 1 .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Fi g ure 1
Sc he m atic of St u d y Desi g n
A T M = At a xi a t el a n gi e ct a si a m ut at e d, BI D = T wi c e d ail y, BI W = T wi c e w e e kl y, Q D = O n c e d ail y
5. 1. 1
P art A
Part A will be a d ose escalati o n st u d y, t o e val uate t he safet y, t olera bilit y, a n d P K, as well as 
esta blis h t he M T D/ R P 2 D of M 4 3 4 4
w he n a d mi nistere d as a si ngle a ge nt i n partici pa nt s wit h 
a d va nce d s oli d t u m ors. A p pr o xi matel y  25 partici pa nt s will 
be i ncl u de d i n Part A. 
T hese 
partici pa nt s will be a d mi nistere d M 4 3 4 4
as a si n gle a ge nt, o n Da y s 1, 4, 8, 1 1, 1 5, a n d 1 8 of a 
2 1- d a y  c ycle u n der fasti n g c o n diti o ns as d escri be d i n Secti o n 6. 2. 1 .
T he ma xi m u m 
rec o m me n de d starti n g d ose ( M R S D) of si n gle
a ge nt M 4 3 4 4
f or BI W  
a d mi nistrati o n will 
be 1 0 m g 
base d o n t he H N S T D 
i de ntifie d i n d o gs f oll o wi n g BI W 
a d mi nistrati o n f or 2 8 da ys. T he i nitial d ose escalati o n of M 4 3 4 4
will utilize a si n gle partici pa nt
per c o h ort P hase I st u d y desi g n. O ne partici pa nt will be e nr olle d a t t he M R S D. If t he starti n g d ose 
of M 4 3 4 4
is t olerate d i n t his partici pa nt t hr o u g h 1 c ycle ( 2 1 d a y s) wit h o ut a n y Co m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E) Gra de 2 or greater t o xicit y that is p ossi bl y , 
pr o ba bl y , or defi nitel y relate d t o st u d y dr u g, t he d ose of M 4 3 4 4
m a y  be i ncrease d b y u p t o 1 0 0 % 
i n a s u bse q ue nt partici pa nt , de pe n di n g o n t o xicities a n d t olera bilities o bser ve d. I n t his wa y , t he 
d ose of M 4 3 4 4
m a y  be escalate d i n s u bse q ue nt c o h orts of si n gle partici pa nts u ntil a C T C A E 
t o xicit y of G ra de 2 or greater t hat is p ossi bl y , pr o ba bl y , or defi nitel y dr u g -relate d is o bser ve d. I n 
a d diti o n, at t he discreti o n of t he S p o ns or a n d I nvesti gat or s u p t o 2 a d diti o nal partici pa nt s ( 3 per 
c o h ort) m a y  be e nr olle d i n t he si n gle partici pa nt c o h ort at a n y d os e le vel, irres pecti ve of t he 
t o xicit y, t o f urt her e x pl ore safety a n d/ or P K.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
If a n y of t he f oll o wi n g C T C A E Gra de 2 t o xicities t hat are p ossi bl y, pr o ba bl y , or defi nitel y 
dr u g -relate d are o bser ve d i n a si n gle partici pa nt c o h ort, t he d ose of M 4 3 4 4
will be i ncrease d b y  
u p t o 5 0 % i n a s u bse q ue nt c o h ort of 3 partici pa nt s:

Na usea

V o miti n g

Diarr hea

Fati g ue
If n o D L Ts are o bser ve d t hr o u g h 1 c ycle i n t his e x pa n de d c o h ort of 3 partici pa nt s, t he d ose will 
be i ncrease d b y  up t o 5 0 % a n d e val uate d i n a ne w c o hort of 3 partici pa nt s, f oll o wi n g a sta n dar d 
3 + 3 desi g n. I n t his ma n ner, t he d ose will be i ncrease d b y  up t o 5 0 % i n s u bse q ue nt c o h orts of 
3 partici pa nt s, u ntil a D L T is o bser ve d (Fi g ure 2 ).
F or a n y ot her C T C A E Gra de 2 or greater t o xicit y that is p ossi bl y , pr o ba bl y , or defi nitel y 
dr u g -relate d, w hic h d oes n ot q ualif y  as a D L T o bser ve d i n a si n gle partici pa nt c o h ort, t he 
t olera bilit y of t hat d ose of M 4 3 4 4
will be e val uate d i n a n e x pa n de d c o h ort of at least 3 partici pa nt s 
( 2 a d diti o nal partici pa nt s) bef ore f urt her d ose escalati o n. If t his d ose of M 4 3 4 4
is t olerate d i n t he 
a d diti o nal 2 partici pa nt s wit h o ut a D L T, t he d ose of M 4 3 4 4
will be i ncrease d b y  up t o 5 0 % a n d 
e val uate d i n a ne w c o h ort of 3 partici pa nt s. If n o D L Ts are o bser ve d t hr o u g h 1 c ycle i n t his c o h ort 
of 3 partici pa nt s, t he d ose will be i ncrease d b y  up t o 5 0 % a n d e val uate d i n a ne w c o h ort of 
3 partici pa nt s, f oll o wi n g a sta n dar d 3 + 3 desi g n. I n t his ma n ner, t he d ose will be i ncrease d b y u p 
t o 5 0 % i n s u bse q ue nt c o h orts of 3 partici pa nt s, u ntil a D LT is o bser ve d (Fi g ure 2 ).
If a si n gle D L T occ urs d uri n g t he si n gle partici pa nt c o h ort d ose escalati o n, t he n 2 a d diti o nal 
partici pa nt s will be e nr olle d a n d e val uate d at t hat sa me d ose le vel of M 4 3 4 4
t o e x pa n d t he c o h ort 
size t o 3 partici pa nt s. If n o D L Ts are o bser ve d i n t he 2 a d diti o nal partici pa nt s, t he n 3 a d diti o nal 
partici pa nt s will be e val uate d at t he sa me d ose le vel of M 4 3 4 4 , f or a t otal c o h ort size of 
6 partici pa nt s. If a si n gle D L T occ urs d uri n g t he 3 + 3 d ose escalati o n i n a 3- partici pa nt c o h ort, 
t he n 3 a d diti o nal partici pa nt s will be e nr olle d a n d e val uate d at t hat sa me d ose le vel of M 4 3 4 4
i n 
or der t o e x pa n d t he c o h ort size t o 6 partici pa nt s. If t here are n o f urt her D L Ts i n t he a d diti o nal 
partici pa nt s, t he n u p t o a 5 0 % d ose escalati o n ma y  pr ocee d i n a s u bse q ue nt c o h ort of 3 partici pa nt s.
If t here are ≥2 D L Ts i n t he i nitial c o h ort of 3 partici pa nt s, d ose escalati o n will cease, a n d t he d ose 
le vel bel o w will be e x pa n de d t o 6 partici pa nt s, or a n i nter me diate d ose le vel will be e nr olle d wit h 
3 ne w partici pa nt s t o f urt her e x pl ore t he safet y an d t olera bi lit y of t his d ose. Si milarl y, if a c o h ort 
of 3 partici pa nt s nee ds t o be e x pa n de d t o 6 partici pa nt s d ue t o ≥1 D L Ts a n d a n a d diti o nal D L T 
occ urs i n t he 3 s u bse q ue nt partici pa nt s, d ose escalati o n will cease, a n d t he d ose le vel bel o w will 
be e x pa n de d t o 6 par tici pa nts, or a n i nter me diate d ose le vel will be e nr olle d wit h 3 ne w 
partici pa nt s t o f urt her e x pl ore t he safet y a n d t olera bilit y of t his i nter me diate d ose (Fi g ure 2 ). 
T he M T D
Si n gle BI W will be t he hi g hest d ose le vel at w hic h t here is n o m ore t ha n 1 D L T i n 
6 partici pa nt s (Fi g ure 2 ). If, at t he discre ti o n of t he S p o ns or a n d I nvesti gat or s, t he t o xicit y an d 
t olera bilit y pr ofile of M 4 3 4 4
re mai ns a m bi g u o us after d osi n g of 6 partici pa nt s at a n y dose le vel, 
i ncl u di n g t he M T D or if a d diti o nal P K data is felt necessar y at a n y d ose le vel bef ore M T D, u p t o 
6 a d diti o nal partici pa nt s ma y be st u die d at t hat d ose le vel t o better defi ne t he t o xicit y, t olera bilit y, 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
a n d P K of M 4 3 4 4 . A d diti o nall y , if e vi de nce of a ntit u m or acti vit y is o bser ve d i n t he d ose escalati o n 
of M 4 3 4 4
as a si n gle a ge nt, u p t o 6 a d diti o nal partici pa nt s ma y  be st u die d at t he M T D
Si n gle BI W at 
t he discreti o n of t he S p o ns or a n d I nvesti gat or s. If at a gi ve n d ose le vel bef ore M T D, o bser ve d 
e x p os ure e xcee ds tar get e x p os ure of A U C = 7 0 0 n g hr/ m L , t his d ose le vel m a y  be c o nsi dere d as 
t he R P 2 D a n d Part B1 m a y  be i nitiate d.
D uri n g si n gle a ge nt M 4 3 4 4
treat me nt, c o m p uterize d t o m o gra p hy ( C T) sca ns will be perf or me d 
e ver y 2 c ycles d uri n g t he i nitial 6 c ycles of t he pla n ne d treat me nt peri o d a n d e ver y 3 c ycles 
t hereafter f or t h ose partici pa nt s c o nti n ui n g be yo n d 6 c ycles or as cli nicall y i n dicate d. Partici pa nt s 
will c o nti n ue o n treat me nt u ntil t here is e vi de nce of disease pr o gressi o n (as deter mi ne d usi n g 
Res p o nse E val uati o n Criteria i n Soli d T u m ors [R E CI S T 1. 1] [Sc her 2 0 0 8 ]) or treat me nt is n o 
l o n ger t olerate d. If a partici pa nt
disc o nti n ues t he st u d y pre mat urely wit h o ut e vi de nce of 
pr o gressi ve disease o n t he m ost rece nt sca n, a f oll o w- u p C T sca n will be perf or me d wit hi n 2 1 d a y s 
after c o m pleti o n of t he fi nal 2 1- da y  c ycle of t hera py. F or all partici pa nt s wit h pr ostate ca ncer, or 
f or partici pa nt s wit h ot her s oli d t u m ors wit h k n o w n or s us pecte d b o ne metastases, b o ne sca ns will 
be perf or me d as descri be d i n Ta ble 3 at t he e n d of e ver y 4 c ycles u ntil disease pr o gressi o n. I n 
a d diti o n, at t he be gi n ni n g of C ycles 1, 3, a n d 5, partici pa nt s wit h o varia n ca ncer will ha ve ser u m 
ca ncer a nti ge n 1 2 5 ( C A - 1 2 5) (R usti n 2 0 0 4 ) assesse d a n d partici pa nt s wit h pr ostate ca ncer will 
ha ve ser u m P S A assesse d. If treat me nt is e xte n de d b e y o n d 6 c ycles, C A - 1 2 5 or P S A will be 
meas ure d at t he be gi n ni n g of e ver y 3 c ycles or m ore fre q ue ntl y as clinicall y i n dicate d. A d diti o nal 
ser ol o gic t u m or mar kers ma y  be c ollecte d as dee me d a p pr o priate de pe n di n g o n t he partici pa nt 's 
pri mar y  mali g na nc y (e. g., ca ncer a nti ge n 1 9- 9 ( C A 1 9 -9) f or partici pa nt s wit h pa ncreatic ca ncer or 
ca ncer e m br yo nic a nti ge n ( C E A) f or partici pa nt s wit h c ol o n ca ncer). Disease res p o nse i n pr ostate 
ca ncer partici pa nt s m a y  be deter mi ne d usi n g t he Rec o m me n dati o ns of t he Pr ostate Ca ncer Cli nical 
Trials W or ki n g Gr o u p ( P C W G 2) a n d R E CI S T 1. 1 (Sc her 2 0 0 8 ).
I ntrapartici pa nt d ose escalati o n :
I ntrapartici pa nt d ose escalati o n is n ot per mitte d, e xce pt i n t he case w here t he M 4 3 4 4
st u d y dr u g 
at t hat d ose le vel is n o l o n ger a vaila ble f or t he partici pa nt w h o is c o nti n ui n g d osi n g, res p o n di n g t o 
treat me nt a n d has n o si g nifica nt t o xicit y. In t his case, t he partici pa nt m a y  be escalate d t o t he ne xt 
a vaila ble M 4 3 4 4
d ose aft er pri or c o ns ultati o n wit h t he S p o ns or. N o f urt her d ose escalati o n will be 
per mitte d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Fi g ure 2
P art A: D ose Esc al ati o n Sc he m atic f or M 4 3 4 4
as a Si n gle A ge nt
C T C A E = C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s, D L T = d o s e li miti n g t o xi cit y, M T D Si n gl e BI W = T h e 
m a xi m u m t ol er at e d d o s e of si n gl e a g e n t M 4 3 4 4
a d mi ni st er e d t wi c e w e e kl y , P K = P h ar m a c o ki n eti c
Pr o vi si o n al d o s e e s c al ati o n s c h e m e i s f or ill u str ati v e p ur p o s e s. N u m b er of d o s e e s c al ati o n  gr o u p s, n u m b er of 
p arti ci p a nt s p er gr o u p, a n d a m o u nt of d o s e e s c al ati o n s m a y diff er, a s d e s cri b e d i n S e cti o n 5. 1. 1 .
a
At t h e di s cr eti o n of t h e S p o n s or a n d I n v e sti g at or s u p t o 2 a d diti o n al p arti ci p a nt s ( 3 p er c o h ort) m a y b e e nr oll e d 
i n t h e si n gl e p arti ci p a nt c o h ort at a n y d o s e l e v el, irr e s p e cti v e of t h e t o xi cit y, t o f urt h er e x pl or e s af et y a n d/ or P K.
b 
I n cl u d e s C T C A E Gr a d e 2 t o xi citi e s or gr e at er t h at ar e p o s si bl y, pr o b a bl y, or d efi nit el y dr u g- r el at e d.
c 
Li mit e d t o i n cl u d e o nl y Gr a d e 2 t o xi citi e s of n a u s e a, v o miti n g, di arr h e a, a n d/ or f ati g u e t h at ar e p o s si bl y, 
pr o b a bl y, or d efi nit el y d r u g-r el at e d.
5. 1. 2
P art A 2
Part A 2 will be a d ose escalati o n st u d y, t o e val uate t he safety, t olera bilit y, a n d P K, as well as 
esta blis h t he M T D/ R P 2 D of M 4 3 4 4 w he n a d mi nistere d as a si n gle a ge nt i n partici pa nt s wit h 
a d va nce d s oli d t u m ors i n a de nser sc he d ule t ha n e val uate d i n Part A. C a n di date partici pa nts wit h 
a d va nce d s oli d t u m ors carr yi n g alterati o ns t hat are s us pecte d t o se nsitize f or treat me nt wit h a n 
A T R i n hi bit or (es peciall y  t h ose defi ne d f or t he Parts C) ma y be prefere ntiall y e nr olle d.
A p pr o xi matel y  3 1 partici pa nt s will be i ncl u de d i n Part A 2. Partici pa nt s i n Part A 2 will i nitiall y be 
a d mi nistere d M 4 3 4 4 as a si n gle a ge nt BI D o n a dail y  re gi me n a n d u n der fasti n g c o n diti o ns as 
descri be d i n Secti o n 6. 2. 1 . 
T he M 4 3 4 4 starti n g d ose i n Part A 2 will be 1 0 0 m g (si n gle d ose) a d mi nistere d BI D (2 0 0 m g  dail y) . 
T he d ose escalati o n of M 4 3 4 4 will f oll o w a 3 + 3 desi g n . D ose escalati o ns will occ ur i n ste ps of 
5 0 m g
or 1 0 0 m g  per d ose (Fi g ure 3 ). S u bse q ue nt d ose le vels will be deter mi ne d i n a gree me nt 
bet wee n I n vesti gat ors a n d S p o ns or . 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Wit h n o Gra de 3 or greater t o xicit y that is p ossi bl y , pr o ba bl y, or defi nitel y relate d t o st u d y dr u g, 
t he si n gle d ose of M 4 3 4 4 ma y be i ncrease d b y u p t o 1 0 0 m g i n s u bse q ue nt d ose le vels, de pe n di n g 
o n t o xicities a n d t olera bilities o bser ve d , a n d i n a gree me nt bet wee n t he I n vesti gat or a n d S p o ns or . 
If n o DL Ts are o bser ve d t hr o u g h o ut t he first c ycle i n a d ose c o h ort of 3 partici pa nt s, t he d ose will 
be escalate d t o t he ne xt d ose le vel. If a si n gle D L T occ urs d uri n g t he 3 + 3 d ose escalati o n i n a 
3- partici pa nt c o h ort, t he n 3 a d diti o nal partici pa nt s will be e nr olle d a n d e val uate d at t hat sa me d ose 
le vel of M 4 3 4 4 i n or der t o e x pa n d t he c o h ort size t o 6 partici pa nt s. If t here are n o f urt her D L Ts i n 
t he a d diti o nal partici pa nt s, t he n t he d ose escalati o n ma y  pr ocee d i n a s u bse q ue nt c o h ort of 
3 partici pa nt s.
If t here are ≥2 D L Ts i n a c o h ort, t he d ose escalati o n will cease, a n d t he d ose le vel bel o w will be 
e x pa n de d t o 6 partici pa nt s, or a n i nter me diate d ose le vel will be e nr olle d wit h 3 ne w partici pa nt s 
t o f urt her e x pl ore t he safet y an d t olera bilit y of t his d ose. Si milarl y , if a c o h ort of 3 partici pa nt s 
nee ds t o be e x pa n de d t o 6 partici pa nt s d ue t o 1 D L Ts a n d a n a d diti o nal D L T occ urs i n t he 
3 s u bse q ue nt partici pa nt s, d ose escalati o n will cease, a n d t he d ose le vel bel o w will be e x pa n de d 
t o 6 partici pa nt s, or a n i nter me diate d ose le vel will be e nr olle d wit h 3 ne w partici pa nt s t o f urt her 
e x pl ore t he safet y a n d t olera bilit y of t his i nter me diate d ose (Fi g ure 3) . 
T he M T D will be t he hi g hest d ose le vel at w hic h t here is n o m ore t ha n 1 D L T i n 6 partici pa nt s
(Fi g ure 3) . If, at t he discreti o n of t he S p o ns or a n d I n vesti gat ors, t he t o xicit y an d t olera bility p r ofile 
of M 4 3 4 4 re mai ns a m bi g u o us after d osi n g of 6 partici pa nt s at a n y d ose le vel, i ncl u di n g t he M T D 
or if a d diti o nal P K data is felt necessar y  at a n y d ose le vel bel o w t he M T D, u p t o 6 a d diti o nal 
partici pa nt s m a y  b e st u die d at t hat d ose le vel t o better defi ne t he t o xicit y, t olera bilit y, a n d P K of 
M 4 3 4 4. 
A d diti o nall y , if e vi de nce of a ntit u m or acti vit y is o bser ve d i n t he d ose escalati o n of M 4 3 4 4 as a 
si n gle a ge nt, u p t o 1 2 a d diti o nal partici pa nt s ma y be st u die d at t he R P 2 D at t he discreti o n of t he 
S p o ns or a n d I n vesti gat ors.
O nce a n M T D is reac he d wit h t he BI D dail y re gi me n or if t he safety pr ofile of t he BI D dail y 
re gi me n is c o nsi dere d u nfa v ora ble, a ne w sc he d ule wi t h o nce dail y d osi n g ma y be e x pl ore d at t he 
discreti o n of t he S p o ns or a n d I n vesti gat ors. T he si n gle dail y  starti n g d ose m a y  n ot e xcee d t he t otal 
dail y  dose of t he M T D of t he BI D sc he d ule. T he starti n g d ose of a n y ne w sc he d ule will be 
deter mi ne d base d o n a vaila ble safety a n d/ or P K data i n a gree me nt bet wee n t he S p o ns or a n d 
In vesti gat or s. D ose escalati o n w o ul d f oll o w t he sa me pri nci p les as descri be d a b o ve.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Fi g ure 3
P art A 2: D ose Esc al ati o n Sc he m atic f or M 4 3 4 4 wit h De nse M o n ot her a p y 
S c he d ule
N ot e: T hi s s c h e m ati c a p pli e s f or a n y d o si n g s c h e d ul e i n P art A 2
A b br e vi ati o n s: D L = d o s e l e v el; D L T = d o s e -li miti n g t o xi cit y.
5. 1. 3
P art A 3
Part A 3 will be a n o pti o nal d ose escalati o n st u d y, t o e val uate t he safety, t olera bilit y, a n d P K, as 
well as esta blis h t he M T D/ R P 2 D of M 4 3 4 4 w he n a d mi nistere d as a si n gle a ge nt i n partici pa nts 
wit h a d va nce d s oli d t u m ors i n a dr u g h oli da y  sc he d ule. T he p ur p ose of Part A 3 is t o i n vestigate 
dr u g h oli da y d osi n g sc he d ules wit h t he g oal of i m pr o ve d l o n g-ter m t olera bilit y relati ve t o 
c o nti n u o us re gi me ns i n Part A 2. Part A 3 will be c o n d ucte d at selecte d sites.
M 4 3 4 4 will be a d mi nistere d t o p artici pa nts i n Part A 3 as a si n gle a ge nt o n a dr u g h oli da y  sc he d ule. 
D iffere nt sc he d ules wit h eit her 3 d a y s Q D or BI D d osi n g f oll o we d b y  4 da ys of pa usi n g ( 3 d +/ 4 d-),
5 d a y s of Q D or BI D d osi n g f oll o we d b y  2 da ys of pa usi n g ( 5 d +/ 2 d -), 7 d a y s of Q D or BI D d osi n g 
f oll o we d b y  7 d a y s of pa usi n g ( 7 d+/ 7 d -) or 1 4 da y s of Q D or BI D d osi n g f oll o we d b y  7 da ys of 
pa usi n g ( 1 4 d+/ 7 d- ) m a y  be e x pl ore d u n der fasti n g c o n diti o ns as descri be d i n Secti o n  6. 2. 1. O ne 
c ycle will c o nsist of 4 wee ks f or a t otal of 2 8 da ys e xce pt f or t he 1 4 d +/ 7 d- sc he d ule, f or w hic h a 
c ycle will be 2 1 da y s. T he first sc he d ules t o be e x pl ore d i n Part A 3 m a y  be 3 da y s of BI D d osi n g 
f oll o we d b y  4 d a y s of pa usi n g ( 3 d +/ 4 d-) a n d 7 da y s of Q D d osi n g f oll o we d b y 7 d a y s of pa usi n g 
(7 d +/ 7 d -). Ot her d osi n g h oli da y  sc he d ul es ma y be e x pl ore d if a gree d b y  t he S p o ns or a n d 
In vesti gat ors . Differe nt sc he d ules m a y  be o pe n c o nc urre ntl y, a n d c o nc urre nt sc he d ules m a y  e nr oll
i n a sta g gere d ma n ner, e. g. e nr oll me nt i n 3 d +/ 4 d - d ose le vel (D L ) 1 wo ul d be c o m plete d bef ore 
starti n g e nr oll me nt i n 7 d+/ 7 d- D L 1 a n d t his w o ul d a p pl y t o all s u bse q ue nt c o h orts. 
T he starti n g d ose f or all dr u g h oli da y s c he d ules will be deter mi ne d i n a gree me nt bet wee n S p o ns or 
a n d In vesti gat ors. F or Q D sc he d ules, t he daily d ose w ill be n o m ore t ha n 1 0 0 m g hi g her t ha n t he 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
R P 2 D or M T D deter mi ne d i n Part A 2. F or BI D sc he d ules, t he c u m ulati ve wee kl y  starti n g d ose 
will n ot e xcee d t he wee kl y c u m ulati ve d ose of t he M T D assesse d i n a n y pre vi o usl y  e x pl ore d BI D 
sc he d ule.
A R P 2 D ( d ose a n d s che d ule) will be deter mi ne d fr o m Part A 3 b y  agree me nt bet wee n I n vesti gat ors
a n d t he S p o ns or a n d ma y be differe nt fr o m t he M T D.
Deter mi nati o n of R P 2 D will be base d o n 
cli nical safet y data, t otal wee kl y d ose, d ose per a d mi nistrati o n, a vaila ble P K data a n d a n y a vaila ble 
efficac y data i n a gree me nt bet wee n I n vesti gat ors a n d t he S p o ns or.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Part A 3 a n d Parts C ma y
e nr oll i n parallel b ut e nr oll me nt i n Part s C will be pri oritize d vers us 
Part A 3 : 

Ca n di date partici pa nts wit h a d va nce d s oli d t u m ors carr yi n g t he q ualif y i n g m utati o ns 
f or P arts C (see Secti o n 7. 7. 5 f or f ull details ) s h o ul d be c o nsi dere d f or e nr oll me nt i n 
Parts C 1, C 2 or C 3 bef ore bei n g c o nsi dere d f or partici pati o n i n Part A 3. 

If a partici pa nt is n ot eli gi ble for P arts
C, t he partici pa nt ma y  be c o nsi dere d f or 
partici pati o n i n Part A 3 (see  Fi g ure 5 , Sc he matic of Eli gi bilit y  Assess me nts i n Parts C)
pr o vi de d t hat t he i ncl usi o n / e xcl usi o n criteria f or Part A 3 ar e met.

Ca n di date partici pa nts ma y  solel y be c o nsi dere d f or partici pati o n i n Part A 3 at t he 
discreti o n of t he I n vesti gat or.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
5. 1. 4
P art B 1
P art B 1 will be a sta n dar d P hase I st u d y desi g n 3 + 3 d ose escalati o n t o e val uate t he safety,  
t olera bilit y, a n d P K, as well as t o esta blis h t he M T D/ R P 2 D of M 4 3 4 4
w he n a d mi nistere d i n 
c o m bi nati o n wit h car b o plati n i n partici pa nt s wit h a d va nce d s oli d t u m ors. 
F o r eac h M 4 3 4 4
d ose le vel teste d, partici pa nt s will recei ve car b o plati n o n Da y 1 a n d M 4 3 4 4
o n 
D a y s 2 a n d 9 of a 2 1 -d a y  c ycle. M 4 3 4 4
will be a d mi nistere d u n der fasti n g c o n diti o ns as descri be d 
i n Secti o n 6. 2. 1 .
T he starti n g d ose of M 4 3 4 4
will n ot e xcee d 5 0 % of t he M 4 3 4 4
M T D
S i n gle BI W or R P 2 D o btai ne d i n 
Part A. T he starti n g d ose of car b o plati n f or Part B 1 will be A U C 5 m g ∙mi n/ m L. T he starti n g d oses 
of M 4 3 4 4
a n d car b o plati n will be e val uate d i n a c o h ort of 3 partic i pa nts.
Safet y  data, i ncl u di n g a d verse e ve nts (A Es ), la b orat or y val ues, a n d electr ocar di o gra m (E C G )
res ults, o btai ne d t hr o u g h t he e n d of C y cle 1, as well as a vaila ble P K data (as nee de d), will be 
assesse d t o deter mi ne t he ne xt d ose le vel of M 4 3 4 4 . Eac h d os e le vel will be e val uate d i n a ne w 
c o h ort of partici pa nt s.
If t he i nitial d ose of M 4 3 4 4
i n c o m bi nati o n wit h car b o plati n at A U C = 5 m g ∙mi n/ m L is t olerate d 
i n a c o h ort of 3 partici pa nt s wit h o ut a si n gle D L T t hr o u g h t he e n d of C ycle 1, t he n i n s u bse q ue nt 
c o h orts of 3 partici pa nt s eac h, t he M 4 3 4 4
d ose m a y  be escalate d b y  up t o 5 0 %, u ntil a M 4 3 4 4
c o m bi nati o n M T D or R P 2 D wit h car b o plati n A U C = 5 m g ∙mi n/ m L is reac he d (Fi g ure 4 ). T he 
M T D is defi ne d as t he hi g hest t olerate d d ose at w hic h t here is n o m ore t ha n 1 D L T i n 6 partici pa nt s 
treate d wit h b ot h M 4 3 4 4
a n d car b o plati n. I n s u bse q ue nt c o h orts, t he car b o plati n d ose m a y  be 
i ncrease d t o yi el d a tar get A U C of 6 m g ∙mi n/ m L, w hile eit her kee pi n g t he d ose of M 4 3 4 4
at t he 
M T D/ R P 2 D esta blis he d wit h car b o plati n A U C = 5 m g ∙mi n/ m L co nsta nt, or de- escalati n g t o l o wer 
M 4 3 4 4
d ose le vels, i n or der t o esta blis h t he M T D/ R P 2 D
of M 4 3 4 4
wit h 
car b o plati n 
A U C = 6 m g ∙mi n/ m L (Fi g ure 4 ).
If t he i nitial d ose of M 4 3 4 4
wit h car b o plati n A U C = 5 m g ∙mi n/ m L is n ot t olerate d, t he n eit her t he 
car b oplati n d ose m a y  be re d uce d t o yi el d a n A U C of 4 m g ∙mi n/ m L or t he M 4 3 4 4
d ose ma y  be 
re d uce d b y  ≥2 5 %. T hese d oses will be e x pl ore d i n s u bse q ue nt c o h orts, at t he discreti o n of t he 
S p o ns or 
a n d 
I nvesti gat or s, u ntil 
t he M T D 
or 
R P 2 D
of 
M 4 3 4 4
wit h 
car b o plati n 
A U C = 4 or 5 m g ∙mi n/ m L (Fi g ure 4 ) is o btai ne d.
O nce t he M T D 
of t he c o m bi nati o n or t he R P 2 D
d ose is o btai ne d, a n a d diti o nal c o h ort of
partici pa nt s m a y  be e nr olle d t o e val uate t he safety of 1 a d diti o nal d ose of M 4 3 4 4
o n Da y 5 d uri n g 
t he 2 1- da y  c ycle. T hese partici pa nt s will recei ve car b o plati n o n Da y 1, a n d M 4 3 4 4
o n Da y s 2, 5, 
a n d 9 of a 2 1- d a y  cyc le. If t he esta blis he d M T D of t he c o m bi nati o n is n ot t olerate d wit h t he 
a d diti o nal da y of d osi n g, t he d osi n g sc he d ule will re vert bac k t o d osi n g car b o plati n o n Da y 1 a n d 
M 4 3 4 4
o n Da y s 2 a n d 9 of a 2 1-d a y  c ycle.
If, at t he discreti o n of t he S p o ns or a n d I n vesti gat ors, t he t o xicit y a n d t olera bilit y pr ofile of M 4 3 4 4
a n d car b o plati n re mai ns a m bi g u o us after d osi n g of 6 partici pa nt s at a n y d ose le vel, i ncl u di n g t he 
M T D, or if a d diti o nal P K data is felt necessar y  at a n y dose le vel bef ore M T D, u p t o 6 a d diti o nal 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
partici pa nt s m a y  b e st u die d at t hat d ose le vel t o better defi ne t he t o xicit y, t olera bilit y, a n d P K of 
M 4 3 4 4
a n d car b o plati n.
At all d ose le vels of M 4 3 4 4 , partici pa nts will c o nti n ue treat me nt u ntil t here is e vi de nce of disease 
pr o gressi o n (as deter mi ne d usi n g R E CI S T 1. 1) or treat me nt is n o l o n ger t olerate d. I ma gi n g sca ns 
(e. g., C T a n d ma g netic res o na nce i ma gi n g [M RI ]) will be per f or me d e ver y 2 c ycles f or t he first 
6 c ycles of treat me nt a n d e ver y 3 c ycles t hereafter f or t h ose partici pa nt s c o nti n ui n g be y o n d 
6 c ycles, or as cli nicall y i n dicate d. F or eac h partici pa nt , t he sa me i ma gi n g tec h ni q ue s h o ul d be 
use d t o f oll o w t he disease (if p ossi ble). B o ne sca n will be perf or me d as descri be d i n Ta ble 6 at t he 
e n d of C ycle 4 a n d e ver y 4 t o 6 c ycles t hereafter f or partici pa nt s c o nti n ui n g be yo n d 6 c y cles or as 
cli nicall y in dicate d. If t here is e vi de nce of pr o gressi ve disease as deter mi ne d usi n g R E CI S T 1. 1, 
t he partici pa nt ’s treat me nt will be disc o nti n ue d. I n a d diti o n, at t he be gi n ni n g of C y cles 1, 3, a n d 
5, partici pa nt s wit h o v aria n ca ncer will ha ve ser u m C A -1 2 5 assesse d, a n d partici pa nt s wit h 
pr ostate ca ncer will ha ve ser u m P S A assesse d. If treat me nt is e xte n de d be y o n d 6 c ycles, C A-1 2 5 
or P S A will be meas ure d at t he be gi n ni n g of e ver y 3 c ycles or m ore fre q ue ntly as cli nicall y 
in dicate d. A d diti o nal ser ol o gic t u m or mar kers ma y be c ollecte d as dee me d a p pr o priate de pe n di n g 
o n t he partici pa nt 's pri mar y  mali g na nc y (e. g., C A 1 9 - 9 f or partici pa nt s wit h pa ncreatic ca ncer or 
C E A f or partici pa nt s wit h c ol o n ca ncer). Disease res p o nse i n pr ostate ca ncer partici pa nt s m a y b e 
deter mi ne d usi n g t he Rec o m me n dati o ns of t he P C W G 2 a n d R E CI S T 1. 1 (Sc her 2 0 0 8 ).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Fi g ure 4
D ose Esc al ati o n Sc he m atic f or M 4 3 4 4
i n C o m bi n ati o n Wit h C ar b o pl ati n 
( P art B 1)
BI W  = T wi c e We e kl y, M T D = M a xi m u m t ol er at e d d o s e, M T D Si n gl e BI W = M a xi m u m t ol er at e d d o s e of M 4 3 4 4
a d mi ni st er e d BI W  fr o m P art A, M T D c ar b o = M a xi m u m t ol er at e d d o s e of M 4 3 4 4
i n c o m bi n ati o n wit h t h e hi g h e st 
t ol er at e d d o s e of c ar b o pl ati n
Pr o vi si o n al d o s e e s c al ati o n s c h e m e i s f or ill u str ati v e p ur p o s e s. N u m b er of d o s e e s c al ati o n gr o u p s, n u m b er of 
p arti ci p a nt s p er gr o u p, a n d a m o u nt of dr u g e s c al ati o n m a y diff er, a s d e s cri b e d i n S e cti o n 5. 1. 3 .
5. 1. 5
All P arts C
S t u d y Parts C will be e x pa nsi o n c o h orts t o e x pl ore p ote ntial a ntit u m or efficac y  a n d t o c o nfir m t he 
safety a n d t olera bilit y of si n gle a ge nt M 4 3 4 4 a d mi nistere d at a d ose a n d sc he d ule t hat has bee n 
deter mi ne d as R P 2 D i n st u d y Part A , A 2 or A 3. 
Parts C 1, C 2, a n d C 3 ma y be i nitiate d i n parallel or i n a sta g gere d ma n ner usi n g a d ose a n d sc he d ule 
deter mi ne d t o be a R P 2 D i n eit her Part A or Part A 2 at t he discreti o n of t he S p o ns or a n d 
I n vesti gat ors. A d diti o nal P arts C 4, C 5, a n d/or C 6 usi n g a R P 2 D deter mi ne d i n Part A 3 ma y  be 
i nitiate d at a n y ti me. T he decisi o n o n t he R P 2 D fr o m Part A 3 t o be use d i n Parts C 4, C 5 a n d C 6 
will be ma de base d o n cli nical safety data, t otal wee kl y d ose, d ose per a d mi nistrati o n, a vaila ble 
P K data a n d a n y a vaila ble ef ficac y data i n a gree me nt bet wee n I n vesti gat ors a n d t he S p o ns or. T he 
decisi o n o n w het her t o pr ocee d t o Parts C 4, C 5 a n d C 6 will als o c o nsi der w het her a R P 2 D fr o m 
Part A 3 is c o nsi dere d m ore fa v ora ble t ha n t hat of Part A or A 2.
T he tar get p o p ulati o n will c o ns ist of partici pa nts w h ose t u m ors ha ve certai n 
 t hat ha ve 
bee n i de ntifie d t o se nsitize t o A T R i n hi biti o n i n precli nical m o dels a n d f or w h o m n o sta n dar d 
treat me nt o pti o ns are a vaila ble. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Part s C 1 a n d C 4 will e nr oll partici pa nt s w h ose t u m or carr y a l oss- of-f u ncti o n m utati o n i n t he ge ne 
f or A RI D 1 A .
Part s C 2 a n d C 5 will e nr oll partici pa nt s w h ose t u m or carr y a l oss-of -f u ncti o n m utati o n i n t he ge nes 
f or A T R X a n d/or D A X X (lea di n g t o a n alter nati ve le n gt he ni n g of tel o meres- p ositi ve p he n ot y p e ).
Part s C 3 a n d C 6 will e nr oll partici pa nt s w h ose t u m or carr y a l oss- of-f u ncti o n m utati o n i n t he ge ne 
f or A T M .
Fi g ure 5 pr o vi des a sc he matic of eli gi bilit y assess me nts i n Parts C.
Fi g ure 5
Sc he m atic of Eli gi bilit y Assess me nts i n P arts C
a
L o s s -of -f u n cti o n m ut ati o n( s) i n A RI D 1 A, A T R X, D A X X, or A T M. S e e S e cti o n 7. 7. 5 f or f ull d et ail s.
b
If i nf or m ati o n o n bi o m ar k er st at u s i s n ot a v ail a bl e at ti m e of I nf or m e d C o n s e nt, c a n di d at e p arti ci p a nt s m u st 
c o nfir m t h e  
 eli gi bilit y ( pr e s e n c e of m ut ati o n s) pri or t o p erf or mi n g a n y of t h e a d diti o n al S cr e e ni n g 
a s s e s s m e nt s (l o w er p art of t h e fi g ur e). If i nf or m ati o n o n bi o m ar k er m ut ati o n s i s a v ail a bl e at ti m e of I nf or m e d C o n s e nt, 
t h e p ati e nt i s all o w e d t o p erf or m t h e bi o p s y a n al y si s a n d t h e r e m ai n d er of S cr e e ni n g pr o c e d ur e s i n p ar all el ( u p p er 
p art of t h e fi g ur e).
c 
A bi o p s y o bt ai n e d aft er t h e e n d of t h e pr e vi o u s tr e at m e nt r e gi m e n i s al s o a c c e pt a bl e. If c oll e cti o n of a fr e s h 
t u m or bi o p s y i s n ot p o s si bl e f or m e di c al r e a s o n( s) a n d a bi o p s y o bt ai n e d aft er t h e e n d of t h e pr e vi o u s tr e at m e nt 
r e gi m e n i s n ot a v ail a bl e, a v ail a bl e ar c hi v al t u m or m at eri al m a y b e u s e d ( hi st ori c al d at a s h o ul d n ot b e u s e d t o c o nfir m 
bi o m ar k er st at u s).
d  
O nl y aft er c o nfir m ati o n fr o m t h e c e ntr al l a b of t h e pr e s e n c e of t u m or m ut ati o n s ( a n d all ot h er 
i n cl u si o n/ e x cl u si o n crit eri a ar e m et) c a n p arti ci p a nt s st art t h e tr e at m e nt p eri o d.
e 
If a n al y si s of bi o p s y d o e s n ot r e v e al a q u alif yi n g m ut ati o n , b ut all ot h er I n cl u si o n / E x cl u si o n crit eri a ar e m et, 
t h e n t h e c a n di d at e p arti ci p a nt m a y b e c o n si d er e d f or p arti ci p ati o n i n P art A 3.
Partici pa nts ma y be selecte d f or Scree ni n g base d o n l ocall y availa ble data s h o wi n g prese nce of 
≥1 selecti o n bi o mar kers ( e. g. fr o m arc hi val t u m or material ). Partici pa nts wit h k n o w n p ositi ve
bi o mar ker stat us at t he ti me of c o nse nt, acc or di n g t o l ocall y availa ble data, ca n u n der g o t he 
Scree ni n g Bi o ps y a nal ysis a n d t he rest of Scree ni n g assess me nts c o nc urre ntl y
(Ta ble 2) .
Partici pa nts wit h u n k n o w n bi o mar ker stat us at t he ti me of c o nse nt ca n o nl y u n der g o t he Scree ni n g 
assess me nts o nce t he prese nce of ≥ 1 selecti o n bi o mar kers (defi ne d i n Secti o n 7. 7. 5 ) is c o nfir me d. 
T he b i o ps y a nal ysis will c o nsist of a n assess me nt of t he prese nce of s uc h m utati o ns b y  a ce ntral 
trial assa y or by a n assa y wit h a p pr o priate re g u lat or y stat us. T his assess me nt s h o ul d be c o n d ucte d 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
o n a fres h t u m or bi o ps y ( or a bi o ps y t hat was o btai ne d after t he e n d of t he pre vi o us treat me nt 
re gi me n). If t his is n ot p ossi ble f or me dical reas o n(s), a vaila ble arc hi val t u m or material ma y  be 
use d f or t his assess me nt ( hist orical data s h o ul d n ot be use d t o c o nfir m bi o mar ker stat us). 
Partici pa nts will c o nse nt t o S cree ni n g pr oce d ures pri or t o a n y S cree ni n g acti vities.
Treat me nt will c o nti n ue u ntil disease pr o gressi o n, u nacce pta ble t o xicit y , partici pa nt’s wit h dra wal 
or a n y ot her reas o n t o e n d st u d y treat me nt. After disease pr o gressi o n, partici pa nt s will be 
f oll o we d-u p f or s ur vi val u ntil t he E n d of S t u d y. T u m or assess me nt acc or di n g t o R E CI S T 1. 1 will 
be perf or me d at baseli ne a n d at t he e n d of e ver y 6 wee ks f or the first 6 c ycles, t he n e ver y 9 wee ks
t hereafter u ntil disease pr o gressi o n or start of ne w a nti-ca ncer treat me nt li ne.
Eac h of t he selecte d 
 p o p ulati o ns (a n y Part C) will f oll o w a si n gle ar m 3- sta ge desi g n. 
T he i nitial sta ge will c o nsist of 9 partici pa nts i n eac h part. If 1 or m ore res p o nses (partial res p o nse 
[P R ] or c o m plete res p o nse [ C R ], as per R E CIS T 1. 1) are o bser ve d i n a part, t his part will pr ocee d 
t o t he S ta ge 2, a d di n g 1 1 partici pa nts t o a t otal of n = 2 0. If at least 4 res p o n ders o ut of 2 0 e val ua ble 
partici pa nts are o bser ve d a t hir d sta ge m a y  be starte d , w hic h will c o nsist of 5 3 partici pa nts.
Efficac y  rea d o ut will be base d o n t he res p o nse rate, deter mi ne d acc or di n g t o R E CIS T 1. 1.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
5. 2
Disc ussi o n of St u d y Desi g n
5. 2. 1
R ati o n ale f or t he St u d y Desi g n
M 4 3 4 4
is a p ote nt, selecti ve i n hi bit or of A T R, a n e nz y m e t hat is critical f or D N A da ma ge 
s ur veilla nce a n d re pair. Ma n y  antica ncer treat me nts act b y  da ma gi n g D N A; h o we ver, resista nce 
t o t hese a ge nts is c o m m o n. T his resista nce ca n be attri b ute d t o effecti ve D N A d a ma ge re pair 
pr ocesses t hat i ncl u de t he pat h wa y me diate d b y A T R. I n n o ncli nical e x peri me nts, A T R i n hi biti o n 
b y  M4 3 4 4 has bee n s h o w n t o mar ke dl y e n ha nce t he a ntica ncer effects of D N A -da ma gi n g a ge nts 
s uc h as car b o plati n i n a ra n ge of h u ma n ca ncer cell li nes a n d pa rtici pa nt-deri ve d e x pla nts. I n 
a d diti o n, M 4 3 4 4 e x hi bits m o n ot hera p y efficac y in a  mo use xe n o graft m o del of c ol orectal ca ncer 
c haracterize d b y  defecti ve A T M si g nali n g (Verte x Re p ort K 2 3 5 2 0 1 4 ) a n d m o dels c haracterize d 
as utilizi n g a n alter nati ve le n gt he ni n g of tel o meres mec ha nis m (Fl y n n 2 0 1 5 ).
Parts A, A 2, a n d B 1 of t he st u d y use c o n ve nti o nal P hase I d ose escalati o n st u d y 3 + 3 desi g ns t o 
esta blis h R P 2 Ds of eit he r si n gle a ge nt M 4 3 4 4 treat me nt or of t he c o m bi nati o n of M 4 3 4 4 wit h 
car b o plati n . Part A 3 use s a B OI N desi g n f or d ose escalati o n. I n vie w of t he n o ncli nical t o xicities 
o bser ve d, safety assess me nts will be carrie d o ut at eac h i n vesti gati o nal ce nter. T he decis i o n t o 
decrease t he ma g nit u de of d ose escalati o n of M 4 3 4 4
bet wee n c o h orts t o less t ha n 1 0 0 % will be 
base d o n re vie w of dr u g -relate d or p ossi bl y  dr u g-relate d D L Ts a n d n o n- D L T A Es of Gra de 2 or 
hi g her, ot her safet y tre n ds, a n d/ or res ults fr o m P K data as s pecifie d i n Secti o n 5. 1. Parts C ai m at 
esta blis hi n g safety a n d de m o nstrati n g a ntit u m or acti vit y of si n gle a ge nt M 4 3 4 4 a d mi nistere d at 
t he R P 2 D i n partici pa nts w h ose t u m ors carr y certai n m olec ular defects t hat are e x pecte d t o c o nfer 
se nsiti vit y t o war ds A T R i n hi biti o n.
5. 2. 2
R ati o n ale f or St u d y Dr u g D ose a n d D ur ati o n
T he starti n g d ose of M 4 3 4 4
is base d o n t he H N S T D deter mi ne d i n t he G L P 2 8 -d a y  re peat d ose 
t o xicit y st u d y i n d o gs (M PI  Researc h Re p ort f or 8 6 3-1 6 6 2 0 1 4 ). T he M R S D of 1 0 m g is 1/ 6 t h t he 
h u ma n e q ui vale nt d ose ( H E D) of t he H N S T D deter mi ne d i n d o gs, w hic h was t he m ost se nsiti ve 
s pecies.
After a n i nitial partici pa nt recei ves M 4 3 4 4
at t he M R S D, 
d ose escalati o n wil l c o nti n ue i n 
s uccessi ve c o h orts wit h a 1 0 0 % i ncrease (i.e. d o u bli n g of d ose), u nless a tre n d i n n o n- D L T Gra de 2 
or hi g her C T C A E gra de t o xicit y  is o bser ve d. At t hat p oi nt, de pe n di n g o n re vie w of all safety a n d 
a vaila ble P K data, d ose escalati o n will be c o nd ucte d as descri be d i n Secti o n 5. 2. 1 0 u ntil t he M 4 3 4 4
M T D is i de ntifie d. D oses ma y  increase b y  less t ha n 1 0 0 % or less t ha n 5 0 % at a n y p oi nt, if 
i n dicate d base d o n re vie w of safety a n d P K data. I n ad diti o n, f oll o win g re p orts of a D L T, a n 
i nter me diate l o wer d ose ma y be e val uate d i n a ne w c o h ort of partici pa nt s.
T he M R S D of 1 0 m g  is a p pr o xi matel y 1/ 9t h t he pre dicte d o pti mall y efficaci o us d ose base d o n 
m o use xe n o graft m o dels of 9 0 m g
(Verte x Re p ort K 0 8 4 2 0 1 4). Wit h si n gle-partici pa nt c o h orts 
a n d 1 0 0 % d ose escalati o n bet wee n c o h orts, a p pr o xi matel y 4 partici pa nt s will recei ve d oses of 
M 4 3 4 4
t hat fall bel o w t he pre dicte d o pti mall y  efficaci o us d ose. T he si n gle-partici pa nt c o h ort 
escalati o n t h us mi ni mizes t he n u m ber of pa rtici pa nts e x p ose d t o p ote ntiall y su bt hera pe utic d oses 
of M 4 3 4 4 .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
I n Part A of cli nical st u d y M S 2 0 1 9 2 2- 0 0 0 1 (f or merl y VX 1 4 - 8 0 3-0 0 1), t he ma xi m u m a d mi nistere d 
d ose was 1 2 0 0 m g, 
t wice wee kl y. At t his d ose, t he o bser ve d plas ma e x p os ure, a vera ge 
c o nce ntrati o n (C a v g), was bel o w t he tar get efficaci o us e x p os ure deter mi ne d i n precli nical m o dels 
testi n g M 4 3 4 4 as m o n ot hera p y. T h o u g h t he criteria f or ma xi m u m t olerate d d ose were n ot yet  
f ulfille d, o ne D L T of Gra de 3, fe ver, was o bser ve d. T here was als o a n u nacce pta ble p ill b ur de n 
wit h t he c urre nt 5 0 m g  stre n gt h ta blet. T o get her t his i n dicates t hat t he 1 2 0 0 m g t wice wee kl y 
re gi me n ma y n ot be a p pr o priate t o s u p p ort its use as m o n ot hera p y. 
Part A 2 of st u d y  M S 2 0 1 9 2 2-0 0 0 1 is desi g ne d t o e val uate w het her s ufficie nt C a v g ca n be ac hie ve d 
a n d is t olerate d t o s u p p ort M 4 3 4 4 use as m o n ot hera p y. T he BI D dail y re gi me n t hat will be 
e val uate d i n Part A 2 is base d o n (i) precli nical xe n o graft st u dies, a n d (ii) cli nical P K data o btai ne d 
fr o m Part A, descri be d bel o w. If t he BI D re gi me n is co nsi dere d u nfa v ora ble, a ne w sc he d ule wit h 
o nce dail y d osi n g ma y  be e x pl ore d at t he discreti o n of t he S p o ns or a n d I n vesti gat ors.
F urt her m ore, i n Part A 3, dr u g h oli da y sc he d ule (s) ma y  be e x pl ore d (see Secti o n 5. 1. 3 f or details). 
Ge nerall y , A T R si g nali n g is re q uire d t o e na ble ca ncer cells t o pr o gress t hr o u g h t o S/ G 2 -p hase, a n d 
i n hi biti o n of A T R let hall y co m pr o mises t his pr ocess. Re peate d or pr ol o n ge d A T R i n hi biti o n is 
e x pecte d t o res ult i n i ncrease d a ntit u m or effica c y (M 6 6 2 0
I n vesti gat or Br oc h ure ). F or M 4 3 4 4 
m o n ot hera p y, p recli nical m uri ne xe n o graft st u dies of M 4 3 4 4 i n A L T + m o dels de m o nstrate t hat 
i ncrease d fre q ue nc y of d osi n g is ass ociate d wit h, a n d p ossi bl y  re q uire d f or o pti mal a ntit u m or 
acti vit y in t he m o n ot hera p y
setti n g (Verte x Re p ort E 0 4 5 3 -U 1 6 0 7 2 0 1 6 ) w hile mai ntai ni n g 
t olera bilit y base d o n b o d y  wei g ht a n d m ortalit y. T hese data s u g gest t hat pr ol o n ge d or re peate d
in hi biti o n of A T R n ot o nl y  p ote ntiates t he c yt ot o xic effects of D N A da ma ge, b ut it m a y  als o be 
efficaci o us as m o n ot hera p y i n ca ncers w hic h are relia nt o n A T R si g nali n g (Fl y n n 2 0 1 5 ). Of n ote , 
si milar a ntit u m or acti vit y was o bser ve d f or t he sa me t otal wee kl y d ose w he n a d mi nistere d o nce 
dail y  or t wice dail y i n t he prec li nical st u d y (Verte x Re p ort E 0 4 5 3 -U 1 6 0 7 2 0 1 6). Dail y  dosi n g of 
M 4 3 4 4 m o n ot hera p y of 2 0 m g/ k g per da y ( 1 0 m g/ k g BI D a n d 2 0 m g/ k g o nce dail y ) de m o nstrate d 
i ncrease d a ntit u m or acti vit y co m pare d t o e ver y ot her or e ver y 3r d d a y  dosi n g i n t he S K N F 1 
( ne ur o blast oma utilizi n g t he alter nati ve le n gt he ni n g of tel o meres pat h wa y ) xe n o graft m o del. 
Si milar res ults were als o o btai ne d i n t he G 2 9 2 ( A L T p ositi ve) oste osarc o ma m o del. T hese 
precli nical data s u g gest t hat s ustai ne d A T R i n hi biti o n i n t he m o n ot hera p y setti n g a n d hi g h 
a ntit u m or acti vit y ma y b e ac hie ve d wit h m ore fre q ue nt BI D d osi n g c o m pare d wit h t wice wee kl y 
d osi n g. 
T u m or gr o wt h i n hi biti o n m o deli n g of t he S K N F 1 a n d G 2 9 2 xe n o graft data was perf or me d a n d 
i de ntifie d t he plas ma c o nce ntrati o n ( Ca v g) t hat m ust be mai ntai ne d t o ac hie ve t u m or stasis. T his 
val ue was use d as a tar get t o ac hie ve i n h u ma n.
I n li g ht of t he relati vely s h ort half -life of M 4 3 4 4 ( 1- 4 h, esti mate d i n Part A V X - 8 0 3 ( M 4 3 4 4) 
I n vesti gat or’s Br oc h ure), m ore fre q ue nt di vi de d d osi n g is e x pecte d t o s ustai n A T R i n hi biti o n 
t hr o u g h o ut t he d ose i nter val wit h re d uce d fl uct uati o n, a n d a l o wer ma xi m u m c o nce ntrati o n ( Cma x ) 
re q uire d t o ac hie ve a n i ncrease d plas ma C a v g. F urt her m ore, t he ass ociate d re d ucti o n i n C ma x ma y  
i m pr o ve safety a n d t olera bilit y. Fi nall y , more fre q ue nt, s maller d oses w o ul d als o pr o vi de m ore 
ma na gea ble d oses per a d mi nistrati o n (i.e. re d uce pill b ur de n) t o t he partici pa nt .
T heref ore, BI D dail y  d osi n g was selecte d as t he i nitial sc he d ule f or Part A 2.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
A 1 0 0 -m g si n gle d ose a d mi nistere d BI D ( 2 0 0 m g dail y ) was selecte d as starti n g d ose f or Part A 2.
T his starti n g d ose is base d o n t he a vaila ble cli nical e x perie nce i n 3 6 partici pa nt s treate d wit h u p 
t o t he 1 2 0 0 m g t wice wee kl y d osi n g sc he d ule i n Part A. As of Dec e m ber 2 0 1 7, i n t otal 
7 partici pa nts ha ve c o m plete d t he D L T peri o d at t he 1 2 0 0 m g  dose le vel. One D L T of Gra de 3
fe ver was o bser ve d a n d t he criteria f or M T D were n ot yet f ulfille d. T he 1 2 0 0 m g t wice wee kl y 
sc he d ule res ults i n a t otal wee kl y d ose of 2 4 0 0 m g . A 1 0 0- m g d ose a d mi nistere d t wice d a il y res ults 
i n a t otal wee kl y d ose of 1 4 0 0 m g a n d is t heref ore e x pecte d t o be a t olera ble starti n g d ose. 
W he n M 4 3 4 4 is a d mi nistere d t wice dail y, t he sec o n d dail y  dose is h y p ot hesize d t o be o pti mall y  
a d mi nistere d at 1 2- h o ur i nter vals t o pr o vi de s ustai ne d A T R i n hi biti o n. H o we ver , a 4- h o ur wi n d o w 
( 8 t o 1 6 h o urs) is per mitte d f or partici pa nt c o n ve nie nce. Si nce t he ter mi nal half -life of M 4 3 4 4 is 
a p pr o xi matel y 2 h o urs, mi ni mal dr u g acc u m ulati o n is e x pecte d wit h t he t wice dail y or o nce dail y 
sc he d ules.
Precli nical m o deli n g of t he P K -efficac y relati o ns hi p f or M 4 3 4 4 m o n ot hera p y  in t he M V 4. 1 1 
xe n o graft m o del has bee n use d t o pre dict h u ma n efficaci o us d ose a n d sc he d ules. T he h u ma n P K 
pr ofile wa s i nc or p orate d i nt o a t u m or gr o wt h i n hi biti o n m o del a n d use d t o i de ntif y doses a n d 
sc he d ules t o ac hie ve at least a 6 0 % t u m or gr o wt h i n hi biti o n. Wit h c o nti n u o us d osi n g a h u ma n 
efficaci o us d ose of a p pr o xi matel y 2 7 5 m g o nce dail y is pre dicte d. 
F urt her precli nical data s u g gest t hat efficac y ca n be achie ve d wit h differe nt d oses a n d sc he d ules, 
i ncl u di n g vari o us dr u g h oli da y  sc he d ules. I n ge neral, treat me nt i nterr u pti o ns i m pr o ve d t olera bilit y 
b ut wit h p ote ntial re d ucti o n i n efficac y. T his i m plies t hat dr u g h oli da y  sc he d ule(s) m a y o nl y be 
preferre d if t he y e na ble escalati o n t o hi g her d ose s per a d mi nistrati o n a n d, i deall y, are a ble t o meet 
or e xcee d t he t otal wee kl y d ose . T heref ore, Part A 3 of t his st u d y is desi g ne d t o e x pl ore o ne or 
m ore dr u g h oli da y  sc he d ules.
T he d osi n g sc he d ule f or M 4 3 4 4
i n c o m bi nati o n wit h car b o plati n i n P art B 1 is base d o n t he o pti mal 
ti mi n g of A T R i n hi biti o n after dr u g e x p os ure t o D N A da ma gi n g a ge nts. I n vitr o cell c ult ure 
e x peri me nts a n d a ni mal m o dels s u g gest t hat dela yi n g d osi n g of M 4 3 4 4 f or a p pr o xi matel y 24 h o urs 
after t he d osi n g of D N A -da ma gi n g a ge nts will pr o m ote cell deat h i n t u m or cells (M 6 6 2 0 I B). 
F urt her m ore, cell st u dies, a ni mal st u dies, a n d P K data s u p p ort i nfre q ue nt d osi n g of M 4 3 4 4
t o 
pr o vi de o pti mal efficac y, t olera bilit y, a n d e x p os ure i n c o m bi nati o n wit h che m ot hera p y . T he 
sta n dar d d ose of car b o plati n use d f or treat me nt of o varia n ca ncer per Nati o nal C o m pre he nsi ve 
Ca ncer 
Net w or k 
(N C C N )
g ui deli nes
(N C C N 
G ui deli nes 
2 0 1 3 )
is 
a p pr o xi matel y 
A U C = 5 m g ∙mi n/ m L. Car b o plati n d osi n g at A U C = 4 m g ∙mi n/ m L, or at A U C = 6 m g ∙mi n/ m L, is 
use d i n certai n cli nical sit uati o ns or f or certai n i n dicati o ns. T he 2 1- d a y  dosi n g c ycle a n d t he d osi n g 
fre q ue nc y of car b o plati n use d i n t his st u d y are base d o n sta n dar d of care re gi me ns.
T he d ose a nd sc he d ule of si n gle a ge nt M 4 3 4 4 t o be use d i n all Parts C will be a R P 2 D , deter mi ne d 
i n P arts A , A 2, or A 3 of t his st u d y .
5. 2. 3
R ati o n ale f or P artici p a nt Selecti o n
Eli gi ble partici pa nt s i n Parts A, A 2, a n d A 3 will ha ve 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 py is a vaila ble w hic h ma y  co n ve y  cli nical be nefit. Eli gi ble partici pa nt s i n Part B 1 will ha ve 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
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 ble w hic h m a y  co n ve y  cli nical 
be nefit, a nd/ or partici pa nt s m ust ha ve disease pr o gressi o n after at least 1 pri or c he m ot hera p y 
re gi me n i n t he metastatic setti n g, a n d f or w hic h car b o plati n ( Part B 1), w o ul d be c o nsi dere d 
sta n dar d of care. I n ge neral, res p o nse rates of ma n y a d va nce d s oli d t u m ors t o sec o n d- a n d t hir d-li ne
t hera pies are li mite d. T h us, t here is a p ote ntial f or t his p o p ulati o n t o be nefit fr o m t he a d diti o n of a 
c he m ot hera p y s e nsitizi n g a ge nt.
Partici pa nt s e nr olle d i n Part s C will
ha ve a d va nce d s oli d t u m ors f or w hic h n o rec o m me n de d 
sta n dar d t hera py is a vaila ble, i.e. partici pa nts w h o ha ve e x ha uste d all sta n dar d of care o pti o ns 
acc or di n g t o N C C N G ui da nce a n d f or w h o m M 4 3 4 4
ma y  co n ve y  cli nical be nefit. F urt her m ore, 
t he y will be selecte d base d o n t he f oll o wi n g bi o mar kers:

Part s C 1 or C 4 : will e nr oll partici pa nt s w h ose t u m ors carr y a l oss- of-f u ncti o n m utati o n i n 
t he ge ne A RI D 1 A

Part s C 2 or C 5 : will e nr oll partici pa nt s w h ose t u m or carr y a l oss- of-f u ncti o n m utati o n i n 
A T R X a n d/or D A X X

Part s C 3 or C 6 : will e nr oll partici pa nt s w h ose t u m or carr y a loss- of- f u ncti o n m utati o n i n 
t he ge ne A T M .
T he se bi o mar kers f or pa rtici pa nts selecti o n will be assesse d b y  a ce ntral trial assa y or b y a n assa y 
wit h a p pr o priate re g ulat or y  stat us (see Secti o n 5. 1. 4 ).
5. 2. 4
R ati o n ale f or St u d y Assess me nts
Partici pa nt s will be m o nit ore d fre q ue ntl y for A E s t hat are pre dicte d t o be p ote ntial c o nse q ue nces 
of t hera py wit h M 4 3 4 4 , base d o n n o ncli nical t o xic ol o g y , a n d of c o nc urre nt c he m ot hera p y , base d 
o n pri or e x perie nce i n partici pa nt s.
Base d o n n o n -G L P d ose -ra n ge fi n di n g st u dies a n d G L P 2 8-d a y  t o xicit y st u dies i n rat a n d d o g, t he 
f oll o wi n g tar get or ga ns f or M 4 3 4 4
t o xicit y ha ve bee n i de ntifie d: he mat o p oietic s yste m ( decrease 
i n R B C 
a n d or W B C); 
s plee n (e xtra me d ullar y he mat o p oiesis); li ver (e xtra me d ullar y 
he mat o p oiesis); t h ym us (l ym p h oi d de pleti o n); a n d testes (s per mat oc yte/s per mati d de gra dati o n a n d 
sec o n dar y effect o n e pi di d ymi des; ger m cell de bris) (I T R La b orat ories Re p ort f or 7 2 1 7 1 2 0 1 3 , 
M PI  Researc h Re p ort f or 8 6 3-1 6 5 2 0 1 4 , I TR L a b orat ories Re p ort f or 6 1 3 8 8 2 0 1 3 , M PI  Researc h 
Re p ort f or 8 6 3- 1 6 6 2 0 1 4) . A d diti o nall y , i n d o gs, GI  was als o n ote d as a tar get (i nfla m mati o n of 
la mi na pr o pria a n d g ut ass ociate d l ym p h oi d tiss ue) (M PI  Researc h Re p ort f or 8 6 3-1 6 6 2 0 1 4 ). 
Base d o n t hese fi n di n gs, partici pa nt s will be m o nit ore d wee kl y d uri n g C y cle 1, a n d at least t wice 
per c ycle t hereafter f or a d verse effects t o t he b o ne marr o w or li ver. Male partici pa nt s i n Parts A 
a n d B 1 will ha ve test oster o ne meas ure me nts at baseli ne a n d at Safet y F oll o w - u p t o assess f or 
c hr o nic effects o n g o na dal f u ncti o n. Partici pa nt s will be ma na ge d s y m pt o maticall y  f or GI a d verse 
effects.
I ma gi n g sca ns will be use d peri o dicall y t o m o nit or f or t u m or res p o nse t o treat me nt, a n d res p o nse 
will be j u d ge d usi n g R E CI S T 1. 1. Par tici pa nts w h o ha ve disease pr o gressi o n, or f or w h o m t he 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
treati n g p h y sicia n c o nsi ders t hat it is n ot i n t heir best i nterest t o c o nti n ue, will disc o nti n ue 
treat me nt.
5. 2. 5
I ncl usi o n of S peci al P o p ul ati o ns
F or defi niti o n of partici pa nts f or Parts C , please see Secti o n  5. 2. 3.
5. 2. 6
Defi niti o n of D ose Li miti n g T o xicit y
Partici pa nt s will be m o nit ore d f or D L Ts t hr o u g h o ut d osi n g c ycles. D L Ts will be defi ne d usi n g t he 
Nati o nal Ca ncer I nstit ute ( N CI) C T C A E ( Part A a n d B 1: Versi o n 4. 0 ; Parts A 2 , A 3: Versi o n 5. 0).
A D L T is defi ne d as relate d or p ossi bl y  dr u g-relate d:

Ne utr o pe nia Gra de 4 f or > 7 d a y s d urati o n or re q uiri n g he m o p oietic gr o wt h fact ors
o
In t he e ve nt of Gra de 4 ne utr o pe nia, a f ull bl o o d c o u nt m ust be perf or me d n o m ore 
t ha n 7 da y s after t he o nset of t he e ve nt t o deter mi ne if a D L T has occ urre d. T he 
partici pa nt will be cl osel y  m o nit ore d u ntil res ol uti o n t o Gra de 3 or less .

Fe brile ne utr o pe nia ( fe ver of u n k n o w n ori gi n wit h o ut cli nicall y or micr o bi ol o gicall y 
d oc u me nte d i nfe cti o n i n t he setti n g of Gra des 3 or 4 ne utr o pe nia)

I nfecti o n ( d oc u me nte d cli nicall y or micr o bi ol o gicall y ) wit h Gra des 3 or 4 ne utr o pe nia 
(a bs ol ute ne utr o p hil c o u nt < 1. 0 x 1 09/ L)

T hr o m b oc y t o pe nia Gra de 3:
o
ass ociate d wit h cli nicall y si g nifica nt blee di n g
o
re quiri n g platelet tra nsf usi o n or he m o p oietic gr o wt h fact ors

T hr o m b oc y t o pe nia Gra de 4 f or > 7 d a y s d urati o n or re q uiri n g he m o p oietic gr o wt h 
fact ors
o
I n t he e ve nt of Gra de 4 t hr o m b oc yto pe nia, a f ull bl o o d c o u nt m ust be perf or me d n o 
m ore t ha n 7 d a y s after t he o n set of t he e ve nt t o deter mi ne if a D L T has occ urre d. 
T he partici pa nt will be cl osel y  m o nit ore d u ntil res ol uti o n t o Gra de 3 or less.

Gra des 3 or 4 t o xicit y to or ga ns ot her t ha n t he b o ne marr o w i ncl u di n g Gra des 3 a n d 4 
bi oc he mical A Es a n d D L Ts, e xcl u di n g t he f oll o wi n g:
o
Gra de 3 na usea or v o miti n g i n partici pa nt s w h o ha ve n ot recei ve d o pti mal treat me nt 
wit h a nti- e metics
o
Gra de 3 diarr hea i n partici pa nt s w h o ha ve n ot recei ve d o pti mal treat me nt wit h 
a nti-diarr heal
o
Gra de 3 fati g ue
o
A n y  Gra de 3 ele vati o n of as partate a mi n otra nsferase ( A S T ) “a n d ” “or ” ala ni ne 
a mi n otra nsferase (A L T ) lasti n g ≤7 d a y s (in t he e ve nt of a Gra de 3 or hi g her 
ele vati o n i n A L T or A S T, f oll o w- u p la b orat or y assess me nts s h o ul d be perf or me d 
e ver y 4 8 t o 7 2 h o urs u ntil re d uce d t o Gra de 2 or less ).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9

A n y  Gra de 3 or 4 i ncrease i n bilir u bi n u nless t he i ncrease is assesse d as arisi n g fr o m 
i n hi biti o n of bilir u bi n gl uc ur o ni dati o n. If t he i ncrease i n bilir u bi n is assesse d as arisi n g 
fr o m i n hi biti o n of bilir u bi n gl uc ur o ni dati o n, t he n o nl y bilir u bi n le vels a b ove 1 5 m g/ d L 
( 2 5 7 µ m ol/ L) will be c o nsi dere d D L Ts

Deat h d ue t o dr u g -relate d c o m plicati o ns

Car diac:
o
Q Tc pr ol o n gati o n ( a n y QTc i nter val ≥5 0 0 msec or a n y c ha n ge i n Q Tc i nter val 
≥6 0 msec fr o m baseli ne) o n E C G, u nless relate d t o a n electr ol yt e a b n or malit y a n d 
pr ol o n gati o n res ol ves wit h c orrecti o n of electr ol yt e a b n or malit y
o
A n y  of t he f oll o wi n g ( C T C A E criteria): Gra de 2 or greater ve ntric ular arr h yt h mia 
(sec o n d or t hir d de gree atri o ve ntric ular bl oc k), se vere s ustai ne d/sy m pt o matic si n us 
bra d ycar dia less t ha n 4 5 b p m or si n us tac hyc ar dia > 1 2 0 b p m n ot d ue t o ot her 
ca uses ( e. g., fe ver), persiste nt s u pra ve ntric ular arr h yt h mia (e. g., u nc o ntr olle d/ ne w 
atrial fi brillati o n, fl utter, atri o ve ntric ular n o dal tac h ycar dia, etc.) lasti n g m ore t ha n 
2 4 h o urs, ve ntric ular tac h ycardia defi ne d as > 9 beats i n a r o w or a n y le n gt h of 
t orsa des de p oi ntes ( p ol ym or p hic ve ntric ular tac h ycar dia wit h l o n g Q Tc), or 
u ne x plai ne d rec urre nt s y nc o pe
o
S y m pt o ms s u g gesti ve of c o n gesti ve heart fail ure wit h c o nfir me d ejecti o n fracti o n 
< 4 0 % ( b y  2 D-ec h ocar di o gra m or M ulti ple Gate d Ac q uisiti o n [ M U G A] sca n) or a 
relati ve decrease > 2 0 % fr o m hist orical assess me nt of ejecti o n fracti o n perf or me d 
wit hi n 1 2 m o nt hs
o
Tr o p o ni n -T: le vel w hic h is c o nsiste nt wit h m y ocar dial i nfarcti o n

A n y  dr u g-relate d t o xicit y that ca uses i nterr u pti o n of treat me nt f or > 2 wee ks 
( 1 4 s uccessi ve d a y s). If a partici pa nt is dee me d fit t o restart treat me nt o n Da y 1 5 t he n 
t his is n ot a D LT.
If a n y c ha n ge is ma de t o t he gra de or ca usalit y of a n A E d uri n g t he st u d y that ma y  alter its D L T 
stat us, t he Sp 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.
5. 2. 7
P artici p a nt E v al u a bilit y
5. 2. 7. 1
P art s A, A 2, A 3, a n d B 1
All partici pa nt s w h o meet t he eli gi bilit y criteria a n d recei ve at least 1 d ose of M 4 3 4 4
will b e 
e val ua ble f or safet y.
Partici pa nts m ust meet 1 of t he 2 criteria bel o w t o be c o nsi dere d e val ua ble f or d ose escalati o n 
decisi o ns:
1.
Partici pa nt m ust ha ve recei ve d t he f oll o wi n g mi ni m u m re q uire d d oses of st u d y dr u g(s) i n 
C y cle 1 (i.e. t he D L T peri o d). See Secti o n 6. 2. 4 f or g ui da nce o n acce pta ble ti me wi n d o ws f or 
dr u g a d mi nistrati o n:

Part A: at least 8 0 % ( 5 o ut of 6) of sc he d ule d M 4 3 4 4
d oses. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9

Part A 2: at least 8 0 % of sc he d ule d M 4 3 4 4 d oses. O ne c ycle is defi ne d as 2 1 cale n dar 
da y s of daily d osi n g.

Part A 3: at least 8 0 % of sc he d ule d M 4 3 4 4 d oses. Refer t o secti o n 5. 1. 3 f or defi niti o n 
of c y cle le n gt h.

Part B 1: car b o plati n d ose o n Da y 1 a n d M 4 3 4 4
d ose o n Da y  2. If t he a d diti o nal d osi n g 
da y  ( Da y 5) is e x pl ore d, M 4 3 4 4
d os e o n Da y 5 will be re q uire d i n a d diti o n t o t he ot her 
d oses .

Part s A/ A 2/ A 3 / B 1: C o m plia nce wit h pr o hi bite d me dici ne a n d dietar y restricti o ns 
d uri n g C ycle 1.
Or
2.
T he partici pa nt m ust ha ve ha d a D L T bef ore t he e n d of C y cle 1.
Partici pa nt s w h o d o n ot meet 1 of t he 2 criteria a b o ve will n ot be e val ua ble f or d ose escalati o n 
decisi o ns a n d will be re place d. Als o, if a n a d diti o nal partici pa nt is e nr olle d d uri n g d ose-escalati o n 
i n Part s A 2 / A 3, a n d B 1 i n or der t o o btai n a ti me d-t u m or bi o ps y , t he safety or P K data fr o m t his 
a d diti o nal partici pa nt m a y  not be re q uire d f or ma ki n g d ose -escalati o n decisi o ns. If t he d ose 
escalati o n decisi o n ha d bee n ma de; t his a d diti o nal partici pa nt will be c o nsi dere d n o n- e val ua ble f or 
d ose escalati o n decisi o n -ma ki n g. 
5 . 2. 7. 2
All P art s C
Eli gi ble partici pa nts are re q uire d t o ha ve meas ura ble disease acc or di n g t o R E CI S T 1. 1. All 
partici pa nt s w h o meet t he eli gi bilit y criteria a n d are a d mi nistere d at least 1 d ose of M 4 3 4 4
will be 
e val ua ble f or safety. All partici pa nt s w h o recei ve at least 1 c ycle of treat me nt, ha ve a baseli ne 
assess me nt d uri n g Scree ni n g, will be e val ua ble f or res p o nse a n d f or disease pr o gressi o n or 
s ur vi val.
5. 2. 8
Scree ni n g
Scree ni n g Visit assess me nts are liste d i n Ta ble 1 f or Parts A, A 2, A 3 , a n d B 1. Scree ni n g Visit 
assess me nts are liste d i n  Ta ble 2 f or Parts C.
Partici pa nts will c o nse nt t o S cree ni n g pr oce d ures pri or t o a n y S cree ni n g acti vities. 
I n Parts C, partici pa nts will u n der g o a Scree ni n g Bi o ps y (Ta ble 2) t o c o nfir m/assess t he selecti o n 
bi o mar kers (l oss- of-f u ncti o n m utati o ns i n t he ge nes A RI D 1 A f or Part s C 1 a n d C 4 , i n A T R X 
a n d/ or D A X X i n Part s C 2 a n d C 5, a n d A T M i n Part s C 3 a n d C 6): 

P artici pants wit h k n o w n p ositi ve bi o mar ker stat us at t he ti me of c o nse nt, acc or di n g t o 
l ocall y availa ble data, ca n u n der g o t he S cree ni n g B i o psy a nal ysis a n d t he rest of 
S cree ni n g assess me nts c o nc urre ntl y (Ta ble 2) . 

Partici pa nts wit h u n k n o w n bi o mar ker stat us at t he ti me of c o nse nt ca n o nl y u n der g o t he 
S cree ni n g assess me nts o nce t he prese nce of ≥ 1 selecti o n bi o mar kers is c o nfir me d
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
ce ntral trial assa y or b y  an assa y wit h a p pr o priate re g ulat or y stat us ( bi o ps y res ults 
e x pecte d wit hi n 2 1 da ys). 
Scree ni n g assess me nts t o c o nfir m t hat partici pa nt s meet t he selecti o n criteria will be c o m plete
wit hi n 2 1 da y s fr o m ti me of c o nse nt i n Parts A, A 2, A 3 , a n d B 1 a n d wit hi n 4 2 da y s i n Pa rts C
(all o wi n g f or Bi o ps y  res ults t o bec o me a vaila ble bef ore t he rest of t he Scree ni n g assess me nts ca n 
be c o n d ucte d) bef ore t he first d ose of st u d y  dr u g f or all partici pa nt s.
If a partici pa nt is a Scree n Fail ure f or Part C, t he pa rtici pa nt m a y  be c o nsi dere d f or partici pati o n 
i n Part A 3. Scree ni n g res ults fr o m Part C m a y be use d t o deter mi ne eli gi bilit y f or Part A 3 wit h n o 
necessit y t o re peat t he assess me nts (at t he S p o ns or’s discreti o n) . H o we ver, if start of treat me nt i n 
Part A 3 is pla n ne d o utsi de of t he 2 1- d a y wi n d o w
(see pre vi o us para gra p h ), t he f oll o wi n g 
assess me nts m ust be re peate d:

Pri or a n d c o nc o mita nt me dicati o ns:

Wei g ht a n d vital si g ns

P h y sical e xa mi nati o n

Cli nical disease assess me nt

He mat ol o g y

C oa g ulati o n

Ser u m c he mistr y

Uri nal y sis

A Es
T he I n vesti gat or ( or a n a p pr o priate a ut h orize d desi g nee at t he I n vesti gat or site) will o btai n 
i nf or me d c o nse nt fr o m eac h partici pa nt . If t he ti me bet wee n Scree ni n g a n d d osi n g e xcee ds t he 
s pecifie d S cree ni n g W i n d o w as a res ult of o perati o nal dela ys (e. g., dela y e d dr u g s hi p me nt, dela y 
i n ce ntral trial assa y res ults, cli nic cl os ures or s h ort-ter m, re versi ble me dical 
c o n diti o ns 
[e. g., i nter ve ni n g u p per res pirat or y ill ness, c orrecti ble a ne mia]), t he n partici pa nt s d o n ot re q uire 
rescree ni n g if la b orat or y res ults wit hi n 7 d a y s of t he first d ose of st u d y dr u g meet t he eli gi bilit y 
criteria. Partici pa nt s w h o are u na ble t o d ose wit hi n t he Scree ni n g Wi n d o w beca use of s u bsta ntial 
c o m plicati o ns of disease pr o gressi o n will be re place d.
T o pre pare f or st u d y partici pati o n , partici pa nt s will be i nstr ucte d o n t he Li festyl e G ui deli nes 
( Secti o n 6. 6. 3 ) a n d use of c o nc o mita nt me dicati o ns ( Secti o n 6. 6 ). A partici pa nt w h o q ualifie d, b ut 
d i d n ot e nr oll f or a n earlier c o h ort, m a y  be use d i n a s u bse q ue nt c o h ort wit h n o re q uire d rescree ni n g 
if t he D a y 1 la b orat or y res ults a n d W orl d Healt h Or ga nizati o n ( W H O) Perf or ma nce Stat us meet 
t he eli gi bilit y criteria. A c hest a n d a b d o mi nal i ma gi n g sca n a nd, if cli nicall y in dicate d, a pel vic 
i ma gi n g sca n m ust be re peate d if m ore t ha n 2 8 d a y s ha ve tra ns pire d si nce m ost rece nt i ma gi n g 
sca n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Partici pa nt s w h o fail Scree ni n g o nce m a y  be rescree ne d if, i n t he I nvesti gat or ’s o pi ni o n, t he reas o n 
f or i nitial scree n fail ure is d ue t o a clearl y te m p orar y co n diti o n (e. g., i nc o m plete rec o ver y fr o m 
rece nt s ur ger y; i na de q uate ti me fra me fr o m pri or c he m ot hera p y).
5. 2. 9
Tre at me nt Peri o d
Treat me nt Peri o d assess me nts are prese nte d i n Ta ble 3, Ta ble 4, Ta ble 5 , Ta ble 6 , Ta ble 7,  a n d 
Ta ble 9 . F or details o n d osi n g, see Secti o n 6.
5. 2 . 1 0
D ose Esc al ati o n Decisi o n M a ki n g
A Me dical 
M o nit ori n g 
Pla n will be pr o vi de d w hic h details a pla n f or r o uti ne a n d ur ge nt 
c o m m u nicati o n bet wee n t he S p o ns or, t he I nvesti gat or s, a n d t he c o ntract researc h or ga nizati o n 
( C R O) i n v olve d i n assisti n g sites a n d t he S p o ns or wit h m o nit ori n g partici pa nt safety. T he Me dical 
M o nit ori n g Pla n will descri be t he a ntici pate d fre q ue nc y an d mea ns of c o m m u nicati o n bet wee n 
S p o ns or, sites, a n d C R Os t o re vie w partici pa nt data t o i nf or m decisi o ns o n d ose escalati o n bet wee n 
c o h orts.
Decisi o ns re gar di n g d ose escalati o n bet wee n c o h orts i n Parts A , A 2, A 3, a n d B 1 will be ma de b y 
t he D E M c o nsisti n g of S p o ns or, re prese ntati ves fr o m t he st u d y sites, a n d me dical re prese ntati ves 
fr o m t he C R Os (if a p pr o priate) after a re vie w of safet y inf or ma ti o n. A Es occ urri n g u p t o a n d 
i ncl u di n g t he e n d of C y cle 1 will be re vie we d as s o o n as t he y are a vaila ble f or a gi ve n c o h ort. 
D L Ts t hat m a y  ha ve occ urre d t hr o u g h t he e n d of C y cle 1 of t he c urre nt c o h ort, as well as D L Ts 
t hat ha ve occ urre d i n pri or c o h orts i n later c ycles, will be i de ntifie d.
T he M 4 3 4 4
M T D will pri maril y be deter mi ne d b y D L Ts t hat occ ur u p t o a n d i ncl u di n g t he e n d of 
t he D L T peri o d . T he M 4 3 4 4
M T D is defi ne d usi n g t he N CI -C T C A E ( Parts A a n d B 1: Versi o n 4. 0 ; 
Part s A 2 a n d A 3 : Versi o n 5. 0 ). If ≥2 o ut of u p t o 6 partici pa nt s at t he sa me d ose le vel ha ve a D L T, 
as defi ne d i n Secti o n 5. 2. 6,  t he M 4 3 4 4
M T D will be deter mi ne d as t he d ose le vel bel o w or a n 
i nter me diate d ose. T he e xact d ose will be deter mi ne d f oll owi n g disc ussi o n bet wee n t he S p o ns or 
a n d t he I n vesti gat ors of all t he rele va nt t o xicit y, i ncl u di n g D L Ts t hat occ ur i n pri or c o h orts b e y o n d 
t he e n d of t he D L T peri o d.
A R P 2 D s h o ul d be deter mi ne d f or eac h a p plica ble part of t he st u d y in a gree me nt bet wee n S p o ns or 
a n d I n vesti gat ors. It m a y  n ot be hi g her t ha n t he M T D.
5. 2. 1 1
F oll o w -u p
P artici pa nt s i n Parts A, A 2, A 3 , a n d B 1 , re gar dless of reas o n f or disc o nti n uati o n, will ha ve a Safet y 
F oll o w - u p Visit 1 4 da y s ( ± 7 da y s) f oll o wi n g t he last d ose of st u d y dr u g, d uri n g w hic h t he 
pr oce d ures liste d i n Ta ble 3, Ta ble 4 , Ta ble 5 , a n d Ta ble 6 will be c o m plete d. Partici pa nts i n 
Parts C will ha ve a Safet y F oll o w - u p Visit 3 0 d a y s ( ± 7 d a y s) f oll o wi n g t he last d ose of st u d y dr u g, 
pr oce d ures liste d i n  Ta ble 7, Ta ble 8 , Ta ble 9 , a n d Ta ble 1 0 will be c o m plete d .
Partici pa nt s i n Parts B 1 a n d C wit h o ut pr o gressi ve disease o n a pri or i ma gi n g sca n s h o ul d atte n d 
Ra di ol o gic F oll o w - u p Visits u ntil disease pr o gressi o n is o bser ve d, ne w a ntica ncer treat me nt is 
starte d, deat h, or t he e n d of t he st u d y, w hic he ver c o mes first. F or t he first 6 m o nt hs after t he start 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
of st u d y treat me nt, Ra di ol o gic F oll o w - u p Visits s h o ul d occ ur e ver y 6 wee ks, s u bse q ue ntl y the y 
s h o ul d occ ur e ver y 9 wee ks. Duri n g t hese visits, t he pr oce d ures liste d i n Ta ble 5 , Ta ble 6, Ta ble 7 , 
a n d Ta ble 9 will be c o m plete d.
Partici pa nt s i n Parts A , A 2, A 3, a n d B 1 w h o d o n ot ha ve d oc u me nte d disease pr o gressi o n u p o n 
c o m pleti n g t he Safet y F oll o w -u p Visit s h o ul d be f oll o we d f or o verall s ur vi val, if p ossi ble, f or u p 
t o 1 ye ar after t he F oll o w -u p Visit , or u ntil st u d y cl os ure, w hic he ver c o mes first.
Partici pa nts i n Parts C s h o ul d be f oll o we d f or overall s ur vi val, if p ossi ble, u ntil st u d y  cl os ure.
Data m a y  be o btai ne d eit her per r o uti ne site partici pa nt f oll o w- u p (if t he site c o nti n ues t o f oll o w 
t he partici pa nt ) or via tele p h o ne, electr o nic, or mail c o m m u nicati o n. T he f oll o wi n g i nf or mati o n 
s h o ul d be o btai ne d, if p ossi ble, o n a 3 -m o nt hl y  basis: 

If t he partici pa nt is decease d, a n d if s o, date of deat h a n d w het her deat h is relate d t o 
pri mar y  mali g na nc y

If t he partici pa nt is ali ve, if t he disease pr o gresse d, a n d if s o, w hat is t he date of 
pr o gressi o n

If t he partici pa nt starte d o n a s u bse q ue nt li ne of t hera p y for t he pri mar y  mali g na nc y, 
a n d if s o, date of starti n g ne w t hera p y

If t he partici pa nt is decease d, has pr o gressi ve disease, or has starte d o n ne w t hera p y 
t he n f urt her f oll o w-u p i nf or mati o n d oes n ot nee d t o be c ollecte d.
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 by t he st u d y  site.
T he f oll o wi n g acti o ns m ust 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 dy 
visit:

T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule 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”, t he I n vesti gat or or desi g nee m ust 
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 
tele p h o ne calls; 2) if necessar y , se 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 pa nt has gi ve n t he 
a p pr o priate c o nse nt, c o ntact t he partici pa nt’s ge neral practiti o ner f or i nf or mati o n. T hese 
c o ntact atte m pts s h o ul d be d oc u me nte d i n t he partici pa nt’s me dical rec or d.

S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve 
wit h dra w n fr o m t he st u d y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
5. 3
Selecti o n of St u d y P o p ul ati o n
O nl y pers o ns meeti n g all i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria ma y be e nr olle d i nt o 
t he st u d y as partici pa nt s. Pri or t o perf or mi n g a n y st u d y assess me nts 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 e ns ure t hat t he partici pa nt or t he partici pa nt ’s le gal 
re prese ntati ve has pr o vi de d writte n i nf or me d c o nse nt f oll o wi n g t he pr oce d ure descri be d i n 
Secti o n 9. 2 .
5. 3. 1
I ncl usi o n Criteri a
1.
Me n a n d w o me n ≥1 8 ye ars of a ge
2.
Disease stat us:

Part s A, A 2 , a n d A 3 : Partici pa nt s wit h 1 hist ol o gicall y  or c yt ol o gicall y co nfir me d mali g na nt 
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 ble w hic h ma y  c o n ve y cli nical 
be nefit

Part B 1 : Partici pa nt s wit h 1 hist ol o gicall y  or c yt ol o gically c o nfir me d mali g na nt a d va nce d 
s oli d t um ors f or w hic h n o sta n dar d t hera py is a vaila ble w hic h ma y  co n ve y cli nical be nefit, 
a n d/ or partici pa nt s m ust ha ve pr o gresse d after at least 1 pri or c he m ot hera p y re gi me n i n t he 
metastatic setti n g, a n d f or w hic h car b o plati n w o ul d be c o nsi dere d sta n dar d of car e

Parts C : Partici pa nt s wit h 1 hist ol o gicall y  or c yt ol o gically c o nfir me d mali g na nt a d va nce d 
s oli d t u m ors f or w hic h n o rec o m me n de d sta n dar d t hera py is a vaila ble (i.e. partici pa nts w h o 
ha ve e x ha uste d all sta n dar d of care o pti o ns acc or di n g t o N C C N G ui da nce)
w hic h ma y 
c o n ve y cli nical be nefit, a n d w h ose t u m or has at least 1 of t he f oll o wi n g bi o mar kers as 
deter mi ne d b y  a ce ntral trial assa y or b y  an assa y wit h a p pr o priate re g ulat or y stat us (see 
Secti o n  7. 7. 5 f or f urt her details):
o
C 1 or C 4: l oss- of-f u ncti o n m utati o ns i n t he ge ne A RID 1 A
o
C 2 or C 5: l oss- of-f u ncti o n m utati o ns i n t he ge nes A T R X a n d/ or D A X X
o
C 3 or C 6: l oss- of-f u ncti o n m utati o n i n t he ge ne A T M
T his ma n dat or y  bi o mar ker assess me nt m ust be c o n d ucte d d uri n g S cree ni n g o n a fres h t u m or 
bi o ps y  (or a bi o ps y  obtai ne d after t he e n d of t he pre vi o us treat me nt re gi me n). If t his is n ot 
p ossi ble f or me dical reas o n(s), a vaila ble arc hi val t u m or material ca n be use d ( hist orical data 
s h o ul d n ot be use d t o c o nfir m bi omar ker stat us) .
3.
Meas ura ble disease eit her acc or di n g t o R E CIS T criteria (Versi o n 1. 1 ) 
4.
W H O perf or ma nce stat us of 0 or 1
5.
Life e x pecta nc y  of ≥1 2 wee ks
6.
He mat ol o gical a n d bi oc he mical i n dices wit hi n t he ra n ges s h o w n bel o w at Scree ni n g. T hese 
val ues m ust be c o nf ir me d at t he first da y of d osi n g, bef ore st u d y dr u g a d mi nistrati o n:
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9

He m o gl o bi n: ≥9. 0 g/ d L f or Parts A a n d B; ≥8. 0 g/ d L a n d n o bl o o d tra nsf usi o ns i n t he 
prece di n g 2 8 d a y s f or Parts C

A bs ol ute ne utr o p hil c o u nt: ≥2. 0 x 1 0 9/ L

Platelet c o u nt: ≥1 2 5 x 1 0 9/ L

Ser u m bilir u bi n: ≤1. 5 x u p per li mit of n or mal ( U L N), e xce pt i n t he case of k n o w n or 
s us pecte d Gil bert’s sy n dr o me

A L T, A S T, a n d al kali ne p h os p hatase (li ver ori gi n): ≤2. 5 x U L N or ≤5 x U L N i n prese nce 
of li ver metastases

Ser u m al b u mi n: ≥2. 5 g/ d L

Esti mate d gl o mer ular filtrati o n rate: ≥5 0 m L / mi n f or Parts A a n d B; ≥4 0 m L / mi n f or 
Part s C

Pr ot hr o m bi n ti me: < 1. 2 5 x U L N

I n ad diti o n, t here s h o ul d n ot be ot her cli nicall y  si gnifica nt meta b olic or he mat ol o gic 
a b n or malities t hat are u nc orrecta ble or t hat re q uire o n g oi n g, rec urre nt p har mac ol o gic 
ma na ge me nt.
7.
Si g n a n d date a n i nf or me d c o nse nt d oc u me nt
8.
Willi n g a n d a ble t o c o m pl y wit h sc he d ule d visits, treat me nt pla n, lifest yle, la b orat or y tests, 
c o ntrace pti ve g ui deli nes, a n d ot her st u d y pr oce d ures .
5. 3. 2
E xcl usi o n Cri teri a
1.
Ra di ot hera p y, u nless brief c o urse f or palliati ve t hera p y, e n d ocri ne t hera p y, tar get-s pecific 
t hera py, i m m u n ot hera p y, or c he m ot hera p y d uri n g t he 4 wee ks ( 6 wee ks f or nitr os o ureas a n d 
Mit o m y ci n-C, a n d 4 wee ks f or i n vesti gati o nal me dici nal pr o d ucts) or 4 dr u g half -li ves bef ore 
first d ose of st u d y dr u g, w hic he ver is greater
2.
Part B 1 : M ore t ha n 6 c ycles of pri or t hera py wit h car b o plati n, u nless disc usse d wit h a n d 
a p pr o ve d b y t he Me dical M o nit or.
3.
O n g oi n g t o xic ma nifestati o ns of pre vi o us treat me nts. E xce pti o n s t o t his are al o pecia or certai n 
Gra de 1 t o xicities, w hic h i n t he o pi ni o n of t he I nvesti gat or s h o ul d n ot e xcl u de t he partici pa nt

Part B 1: A n y k n o w n hist or y  of Gra de 4 t hr o m b oc yt o pe nia wit h a n y pri or c he m ot hera p y 
re gi me n ( n ot a p plica ble f or Parts C)
4.
B rai n metastases u nless as ym pt o matic, treate d, sta ble, a n d n ot re q uiri n g ster oi ds f or at least 
4 wee ks bef ore first d ose of st u d y  dr u g
5.
Fe male partici pa nt s w h o are alrea dy pre g na nt or lactati n g, or pla n t o bec o me pre g na nt wit hi n 
6 m o nt hs of t he last d ose of st u d y dr u g are e xcl u de d. Fe male partici pa nt s of c hil d beari n g 
p ote ntial m ust a d here t o c o ntrace pti o n g ui deli nes as o utli ne d i n Secti o n 7. 5. 2 . Fe male 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
partici pa nt s will be c o nsi dere d t o be of n o nc hil d beari n g p ote ntial if t he y ha ve u n der g o ne 
s ur gical h y sterect o my or bilateral o o p h orect o m y or ha ve bee n a me n orr heic f or o ver 2 ye ars 
wit h a S cree ni n g ser u m f ollicle-sti m ulati n g h or m o ne ( F S H) le vel wit hi n t he la b orat or y’s 
refere nce ra n ge f or p ost me n o pa usal fe males
6.
Male partici p a nts wit h part ners of c hil d beari n g p ote ntial m ust a gree t o a d here t o c o ntrace pti o n 
g ui deli nes i n Secti o n 7. 5. 2. 2 . Me n wit h pre g na nt or lactati n g part ners or part ners w h o pla n t o 
bec o me pre g na nt d uri n g t he st u d y or wit hi n 6 m o nt hs of t he last d ose of st u d y dr u g are 
e xcl u de d
7.
Maj or s ur ger y ≤4 wee ks bef ore first d ose of st u d y  dru g or i nc o m plete rec o ver y  fr o m a pri or 
maj or s ur gical pr oce d ure
8.
Car diac c o n diti o ns as f oll o ws:

Cli nicall y  si g nifica nt car di o vasc ular e ve nt wit hi n 6 m o nt hs bef ore st u d y e ntr y:
o
c o n gesti ve heart fail ure re q uiri n g t hera p y
o
u nsta ble a n gi na pect oris
o
m y ocar dial i nfarcti o n
o
Class II/III/I V car diac disease ( Ne w Y or k Heart Ass ociati o n)
o
prese nce of se vere val v ular heart disease
o
prese nce of a ve ntric ular arr h y t h mia re q uiri n g treat me nt

Hist or y  of arr h yt h mia t hat is s ym pt o matic 
or re q uires treat me nt ( C T C A E Gra de 2), 
s ym pt o matic or u nc o ntr olle d atrial fi brillati o n des pite treat me nt, or as y m pt o matic s ustai ne d 
ve ntric ular tac h ycar dia. Partici pa nt s wit h atrial fi brillati o n c o ntr olle d b y me dicati o n are 
per mitte d

U nc o ntr olle d h y perte nsi o n ( bl o o d press ure ≥1 6 0/ 1 0 0 des pite o pti mal t hera p y )

Sec o n d or t hir d de gree heart bl oc k wit h or wit h o ut s y m pt o ms

Q Tc > 4 7 0 msec ( by eit her Fri dericia’s or Baz ett’s c orrecti o n) n ot d ue t o electr ol yte 
a b n or malit y a n d t hat d oes n ot res ol ve wit h c orrecti o n of electr olyt es

Hist or y  of c o n ge nital l o n g Q T sy n dr o me

Hist or y of t orsa des de p oi ntes ( or a n y  c o nc urre nt me dicati o n wit h a k n o w n ris k of i n d uci n g 
t orsa des de p oi ntes)

Cli nicall y -si g nifica nt a b n or malit y, i ncl u di n g ejecti o n fracti o n bel o w n or mal i nstit uti o nal 
li mits, prese nt o n tra nst h oracic ec h ocar di o gra m perf or me d at Scree ni n g, f or Parts A a n d B
9.
Pri or b o ne marr o w tra ns pla nt or e xte nsi ve ra di ot hera p y t o greater t ha n 1 5 % of b o ne marr o w
1 0. Partici pati o n, or pla n of partici pati o n, i n a n ot her i nter ve nti o nal cli nical st u d y while ta ki n g part 
i n t his P hase I st u d y of M 4 3 4 4 . Partici pati o n i n a n o bser vati o nal st u d y w o ul d be acce pta ble
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
1 1. A n y  ot her c o n diti o n w hic h i n t he I nvesti gat or ’s o pi ni o n w o ul d n ot ma ke t he partici pa nt a g o o d 
ca n di date f or t he cli nical st u d y , i ncl u di n g:

Hist or y  of HI V-1, HI V - 2, or u nres ol ve d He patitis B or u nres ol ve d He patitis C i nfecti o n

Hi g h me dical ris k beca use of n o n mali g na nt s yste mic disease i ncl u di n g acti ve u nc o ntr olle d 
i nfecti o n

Pa rtici pa nts w h o 
ha ve bee n dia g n ose d wit h 
Li -Fra u me ni S y n dr o me or wit h 
ata xia 
tela n giectasia
1 2. C urre nt mali g na ncies of ot her t ypes, wit h t he e xce pti o n of a de q uatel y treate d c o ne-bi o psie d 
i n sit u carci n o ma of t he cer vi x uteri a n d basal or s q ua m o us cell carci n o m a of t he s ki n; pri or 
ca ncer t hat has bee n i n re missi o n f or at least 3 ye ars w o ul d n ot be e xcl u de d
1 3. C urre nt t hera p y:

Partici pa nt s recei vi n g treat me nt wit h me dicati o ns t hat are k n o w n t o be str o n g i n hi bit ors or 
i n d ucers of c yt oc hr o me P 4 5 0 ( C Y P) 3 A 4 t hat ca n n ot be disc o nti n ue d at least 1 wee k bef ore 
first d ose of st u d y dr u g a n d f or t he d urati o n of t he st u d y. E xa m ples of str o n g C Y P 3 A 4 
i n hi bit ors or i n d ucers are pr o vi de d i n Ta ble 1 3

Partici pa nt s recei vi n g treat me nt wit h pr ot o n-p u m p i n hi bit ors t hat ca n n ot be disc o nti n ue d at 
least 1 wee k bef ore first d ose of st u d y dr u g a n d f or t he d urati o n of t he st u d y. E xa m ples of 
pr ot o n -p u m p i n hi bit ors are pr o vi de d i n  Ta ble 1 3

F or Part B 1: partici pa nt s recei vi n g treat me nt wit h ot ot o xic or ne p hr ot o xic me dicati o ns t hat 
ca n n ot be disc o nt i n ue d at least 7 da y s bef ore first d ose of st u d y dr u g a n d f or t he d urati o n of 
t he st u d y. S h ort -ter m use o n st u d y will n ot ca use a partici pa nt t o be i neli gi ble. If a s h ort 
c o urse of t hera p y wit h ne p hr ot o xic or ot ot o xic me dicati o n is a ntici pate d a n d re q uire d, 
car b o plati n or cis plati n s h o ul d be disc o nti n ue d u ntil 7 da y s after t his c o urse is c o m plete d

Partici pa nts recei vi n g pri or treat me nt wit h a n y A T R in hi bit or
1 4. Partici pa nt s w h o ca n n ot c o m pl y wit h restricti o ns f or me dicati o ns or f o o d as s pecifie d i n 
Ta ble 1 3.
5. 4
Criteri a f or I niti ati o n of St u d y Tre at me nt
Eli gi bilit y  f or partici pati o n i n t his st u d y will be c hec ke d at Scree ni n g f or Parts A, A 2, A 3 , a n d B 1 
(see Ta ble 1) a n d Parts C (see Ta ble 2) .
5. 5
Criteri a f or P artici p a nt Wit h dr a w al
5. 5. 1
Wit h dr a w al fr o m St u d y T her a p y 
A partici pa nt m ust be wit h dra w n fr o m M 4 3 4 4
if a n y of t he f oll o wi n g occ ur:

Partici pa nt wit h dre w c o nse nt

Partici pa nt l ost t o f oll o w u p
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9

Partici pati o n i n a n ot her cli nical st u d y or start of ne w a nti -ca ncer treat me nt

N o nc o m plia nce of st u d y dr u g d osi n g or st u d y pr oce d ure

A n y  e ve nts t hat u nacce pta bl y e n da n ger t he safety of t he partici pa nt .
If partici pa nts dr o p o ut f or a n y reas o n ot her t ha n disease pr o gressi o n, e very eff ort s h o ul d be ma de 
t o c o nti n ue t o f oll o w t he participa nt i n t he trial f or t u m or assess me nt.
5. 5. 2
Wit h dr a w al fr o m t he St u d y
Partici pa nt s m a y wit h dra w fr o m t he st u d y at a n y ti me wit h o ut gi vi n g a reas o n, or at t he discreti o n 
of t he I n vesti gat or f or a d mi nistrati ve reas o ns.
Wit h dra wal of c o nse nt will be c o nsi dere d 
wit h dra wal fr o m t he st u d y. Partici pa nt s w h o pre mat urel y  disc o nti n ue st u d y dr u g d osi n g wi ll be 
as ke d t o ret ur n t o t he cli nica l site f or Safety F oll o w -u p Vis it 1 4 da y s ( ± 7 da ys) after t heir last d ose 
of st u d y dr u g ( 30 d a y s [ ± 7 d a y s] f or Parts C) . S af et y Foll o w - u p Visit assess me nts are prese nte d 
i n Ta ble 3 , Ta ble 4 , Ta ble 5 , Ta ble 6, Ta ble 7 , a n d Ta ble 9.
If a partici pa nt d oes n ot ret ur n f or a sc he d ule d visit, reas o na ble eff ort will be ma de t o c o ntact t he 
partici pa nt . I n a n y circ u msta nce, reas o na ble eff ort will be ma de t o d oc u me nt partici pa nt o utc o me. 
T he I n vesti gat or will i n q uire a b o ut t he reas o n f or wit h dra wal, re q uest t hat t he partici pa nt ret ur n 
f or a Safet y F oll o w-u p Visit (see Secti o n 5. 2. 1 1) , if a p plica ble, a n d f oll o w u p wit h t he partici pa nt
re gar di n g a ny u nres ol ve d A Es.
It m a y  b e ap pr o priate f or t he partici pa nt t o ret ur n t o t he cli nic f or fi nal safet y assess me nts a n d t o 
be q uesti o ne d re gar di n g t heir reas o n f or wit h dra wal. Ass ess me nts ma y i ncl u de:

P h y sical e xa mi nati o n

Bl o o d press ure a n d p ulse rate meas ure me nts

E C G

Bl o o d a n d uri ne s peci me n’s c ollecti o n (f or safet y la b orat or y t ests a n d pre g na nc y test, if 
a p plica ble)

Bl o o d sa m ple f or P K a nal y sis.
If t he partici pa nt wit h dra ws c o nse nt, n o f urt her e val uati o ns will be perf or me d, a n d n o a d diti o nal 
data will be c ollecte d. T he S p o ns or ma y  retai n a n d c o nti n ue t o use a n y data c ollecte d bef ore s uc h 
wit h dra wal of c o nse nt.
Partici pa nt s ma y  be disc o nti n ue d fr o m st u d y dr u g f or t oxicit y  or lac k of efficac y, as s pecifie d i n 
Secti o n 6. 4.
F or partici pa nts i n Parts C w h o ha ve n ot pr o gresse d, see Secti o n  5. 2. 1 1 f or m ore details.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
5. 5. 3
Re pl ace me nt of P artici p a nt s
I n Parts A , A 2, A 3, or B 1, partici pa nt s w h o wit h dra w or are wit h dra w n fr o m treat me nt f or reas o ns 
ot her t ha n D L T bef ore t he assess me nt o n Da y 1 of C y cle 2, a n d w h o ha ve n ot ha d t he mi ni m u m 
e x p os ure t o st u d y dr u gs descri be d i n Secti o n 5. 2. 7 , will be re place d t o mai ntai n t he d ose escalati o n 
sc he me. Partici pa nt s i n Parts A , A 2, A 3, a n d B1 be y o n d t he assess me nt o n Da y 1 of C y cle 2, a n d 
all partici pa nt s i n Part s C, w h o wit h dra w or are wit h dra w n f or n o n- safet y reas o ns m a y  be re place d 
at t he S p o ns or’s discreti o n.
5. 6
Pre m at ure Ter mi n ati o n of t he St u d y
T he cli nical st u d y m a y  be ter mi nate d pre mat urel y or s us pe n de d at t he re q uest of Healt h A ut h orities 
or i f n e w safety o r efficac y i nf or mati o n lea ds t o a n u nfa v ora ble ris k be nefit j u d g me nt f or a n y st u d y 
dr u g . T he S p o ns or ma y  disc o nti n ue t he st u d y if it bec o mes u nj ustifia ble f or me dical or et hical 
reas o ns, f or p o or e nr oll me nt, or beca use of d isc o nti n uati o n of cli nical de vel o p me nt of a st u d y dr ug
or w it h dra wal of a st u d y dr u g or c o m parat or fr o m t he mar ket f or safety reas o ns.
Healt h A ut h orities a n d I nde pe n de nt Et hics C o m mittees (I E Cs)/I nstit uti o nal Re vie w B oar ds (I R Bs)
will be i nf or me d a b o ut t he disc o nti n uati o n of t he st u d y i n acc or da nce wit h a p plica ble re g ulati o ns.
5. 7
Defi niti o n of E n d of St u d y
T he st u d y  will e n d w he n:

All partici pa nts i n Parts A, A 2 , a n d A 3 ha ve c o m plete d t he Safet y F oll o w - u p Visit 1 4 
da y s ( ± 7 da ys) after t he last d ose of t he st u d y dr u g, A N D

All partici pa nts i n Parts B 1 a n d C ha ve c o m plete d treat me nt a n d bee n f oll o we d u p f or 
a mi ni m u m of 1 year fr o m t he start of st u d y  treat me nt.
At t he e n d of t he c urre nt st u d y, partici pa nts w h o c o nti n ue t o be nefit fr o m treat me nt wit h M 4 3 4 4 
after m ore t ha n 1 2 m o nt hs of treat me nt m a y  be s witc he d t o a n ot her st u d y pr ot oc ol , if a vaila ble, 
w hic h ser ves t o m o nit or t he l o n g -ter m safety of treat me nt wit h M 4 3 4 4 a n d w here t he partici pa nts 
ca n c o nti n ue o n t he sa me sc he d ule a n d d ose of M 4 3 4 4 as i n t he c urre nt st u d y .
6
I n vesti g ati o n al Me dici n al Pr o d uct a n d Ot her Dr u gs Use d i n 
t he St u d y
T he ter m “In vesti gati o nal Me dici nal Pr o d uct” refers t o a n acti ve s u bsta nce or a place b o bei n g 
teste d or use d as a refere nce t hera p y i n a cli nical st u d y, i ncl u di n g pr o d ucts t hat ha ve a mar keti n g 
a ut h orizati o n b ut are f or m ulate d , pac ka ge d , or a d mi nistere d differe ntl y  fr o m t he a ut h orize d f or m, 
use d f or a n u na ut h orize d i n dicati o n, or use d t o gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.
6. 1
Descri pti o n of t he I n vesti g ati o n al Me dici n al Pr o d uct
M 4 3 4 4 will be s u p plie d as 5 0 m g  ta blets i n 
, eac h 
c o ntai ni n g 2 0 ta blets. 
D oc u me nt N o. 
O bject N o. C CI
C CI
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T he S p o ns or will n ot s u p pl y car b o plati n f or t his st u d y. Sites will use car b o plati n as s u p plie d b y  
t heir p har mac y.
6. 2
D os a ge a n d A d mi nistr ati o n
6. 2. 1
A d mi nistr ati o n
M 4 3 4 4 , 5 0 m g ta blets, will be a d mi nistere d orall y wit h 2 4 0 m L  (8 fl ui d o u nces) of a m bie nt 
te m perat ure water. Car b o plati n will be a d mi nistere d via i ntra ve n o us i nf usi o n. 
M 4 3 4 4
will be a d mi nistere d u n der fasti n g c o n diti o ns t hr o u g h o ut t he st u d y; all partici pa nt s will 
a bstai n fr o m all f o o d f or at least 3 h o urs bef ore oral a d mi nistrati o n of M 4 3 4 4
a n d f or 1 h o ur after 
a d mi nistrati o n of M 4 3 4 4. Water ca n be c o ns u me d as desire d.
Ti me a n d date of a d mi nistrati o n of t he last d ose pri or t o eac h P K sa m ple is t o be rec or de d o n t he 
electr o nic case re p ort f or m ( e C R F).
All partici pa nt s will f oll o w t he dietar y  an d meal 
restricti o ns o utli ne d i n Secti o n 6. 6. 3. 1 . 
Partici pa nt s will s wall o w t he st u d y dr u g w h ole a n d will n ot c he w t he dr u g bef ore s wall o wi n g. 
Partici p a nts will be i nstr ucte d n ot t o lie d o w n (sitti n g i n a n u pri g ht or recli ni n g p ositi o n is 
acce pta ble) f or 2 h o urs after ta ki n g t he st u d y dr u g, e xce pt w he n re q uire d f or st u d y pr oce d ures. 
W he n M 4 3 4 4 is a d mi nistere d t wice dail y , t he sec o n d dail y dose s h o ul d be a d mi nistere d wit hi n 8 
t o 1 6 h o urs after t he first d ose.
A nti- e metics a n d ot her s u p p orti ve t hera pies will be a d mi nistere d or dis pe nse d t o partici pa nt s f or 
use i n c o m bi nati o n wit h car b o plati n acc or di n g t o i n di vi d ual site sta n dar d of care. A nti- e metics, 
a nti-diarr heals, a n d he mat o p o ietic gr o wt h fact ors will n ot be a d mi nistere d pr o p h ylacticall y d uri n g 
Part A d uri n g C y cle 1. A nti- e metics, a nti -diarr heals, a n d gr o wt h fact ors ca n be use d per 
i nstit uti o nal g ui deli nes f or ma na ge me nt of s ym pt o ms.
6. 2. 2
Criteri a f or S t u d y Dr u g A d mi nistr ati o n
W he n cli nical c he mistr y a n d/ or he mat ol o g y  la b orat or y testi n g is re q uire d bef ore a d mi nistrati o n of 
c he m ot hera p y or M 4 3 4 4
as prese nte d i n t he Sc he d ule of Assess me nts (Ta ble 3, Ta ble 4 , Ta ble 5 ,
Ta ble 6 , Ta ble 7,  a n d Ta ble 9 ), t he la b orat or y criteria s pecifie d i n Ta ble 1 2 m ust be met bef ore 
d osi n g. T o facilitate ti mel y a d mi nistrati o n of st u d y dr u g, t his  la b orat or y testi n g ma y be perf or me d 
u p t o 3 da y s bef ore d osi n g.
After C ycl e 1, D a y 1, if a partici pa nt d oes n ot meet 1 or m ore criteria, d osi n g ma y  be pa use d a n d 
res u me d o nce t he la b orat or y ab n or malit y (ies) has res ol ve d wit h or wit h o ut me dical i nter ve nti o n, 
at t he discreti o n of t he I nvesti gat or a n d M e dical M o nit o r.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 1 2
L a b or at or y V al ues Re q uire d f or A d mi nistr ati o n of C he m ot her a p y or 
M 4 3 4 4
L a b or at or y  P ar a m et er
C y cl e 1 D a y 1
D a y 1 of S u b s e q u e nt 
C y cl e s
Ot h er D a y s M 4 3 4 4
i s 
A d mi ni st er e d a
H e m o gl o bi n
≥9. 0 g/ d L (P art s A a n d B)
≥8 . 0 g/ d L ( P arts C)
≥7. 0 g/ d L
(if a s y m pt o m ati c)
≥7. 0 g/ d L
(if a s y m pt o m ati c)
A b s ol ut e n e utr o p hil v al u e
≥2. 0 x 1 0 9 / L
≥1. 5 x 1 0 9 / L
≥1. 5 x 1 0 9 / L
Pl at el et c o u nt
≥1 2 5 x 1 0 9 / L
≥1 0 0 x 1 0 9 / L
≥1 0 0 x 1 0 9 / L
A S T, A L T, a n d A L P (li v er 
ori gi n)
≤2. 5 x U L N or ≤5 x U L N 
i n pr e s e n c e of li v er 
m et a st a s e s
≤2. 5 x b a s eli n e v al u e 
or ≤5 x b a s eli n e v al u e 
i n pr e s e n c e of li v er 
m e t a st a s e s
≤2. 5 x b a s eli n e v al u e 
or ≤5 x b a s eli n e v al u e 
i n pr e s e n c e of li v er 
m e t a st a s e s
E sti m at e d gl o m er ul ar 
filtr ati o n r at e
≥5 0 m L/ mi n ( P art s A a n d 
B)
≥4 0 m L/ mi n ( P art s C)
D o e s n ot m e et D L T 
crit eri a
D o e s n ot m e et D L T 
crit eri a
T ot al bilir u bi n ( s er u m) b
≤1. 5 x U L N
≤1 5 m g/ d L
≤1 5 m g/ d L
S er u m al b u mi n
≥2. 5 g/ d L
≥2. 5 g/ d L
≥2. 5 g/ d L
A L P = Al k ali n e p h o s p h at a s e, A L T = Al a ni n e a mi n otr a n sf er a s e, A S T = a s p art at e a mi n otr a n sf er a s e; 
D L T = D o s e -li miti n g t o xi cit y, U L N = U p p er li mit of n or m al
a
B a s e d o n m o st c urr e nt l a b or at or y v al u e s a v ail a bl e. L a b or at or y t e sti n g will b e c o n d u ct e d a s d e s cri b e d i n 
T a bl e 3 , T a bl e 4 , T a bl e 5, T a bl e 6 , T a bl e 7 , a n d T a bl e 9;  a d diti o n al t e sti n g will n ot b e r e q uir e d t o c o nfir m t h e s e 
v al u e s pri or t o e v er y d o s e.
b
P arti ci p a nt s wit h k n o w n or s u s p e ct e d Gil b ert’ s s y n dr o m e ar e e x e m pt fr o m s er u m bilir u bi n e x cl u si o n.
6. 2. 3
D ose M o dific ati o n f or T o xicit y
N o d ose m o dificati o ns of M 4 3 4 4
ma y  be ma de d uri n g C y cle 1 of Parts A, A 2 , A 3, or B 1, e xce pt 
as s pecifie d i n Secti o ns 5. 1. 1 a n d 5. 1. 3.
P arts A , A 2, a n d A 3 :
D oses of M 4 3 4 4
m a y  be re d uce d ot her t ha n i n C y cl e 1 of Part s A, A 2 , a n d A 3 f or t o xicit y usi n g 
t he f oll o wi n g g ui deli nes:

F or Gra de 4 he mat ol o gic t o xicit y : t he d ose of M 4 3 4 4
will be re d uce d b y 2 5 %

F or Gra de 3 n o n- he mat ol o gic t o xicit y : t he d ose of M 4 3 4 4
will be re d uce d b y 2 5 %

F or Gra de 4 n o n- he mat ol o gic t o xicit y : t he d ose of M 4 3 4 4
will be re d uce d b y 5 0 %
P art s A 2, A 3:
Pa rtici pa nts i n Part s A 2 a n d A 3 , w h o e x perie nce a n A D R meeti n g D L T criteria after c o m pleti o n 
of t he D L T assess me nt peri o d nee d t o i nterr u pt st u d y treat me nt b ut m a y  co nti n ue o n st u d y 
treat me nt at a re d uce d d ose pr o vi de d t he reacti o n has res ol ve d t o baseli ne val ue or Gra de ≤ 1 
wit hi n 2 wee ks a n d t here is n o pr o gressi ve disease. T he d ose of M 4 3 4 4 will be re d uce d t o 1 d ose 
le vel bel o w t he c urre nt d ose. If i n dicate d, a f urt her d ose re d ucti o n is p ossi ble o n a gree me nt 
bet wee n t he S p o ns or a n d I n vesti gat or. O nce t he d ose of M 4 3 4 4 has bee n re d uce d i n a n i n di vi d ual 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
pa rtici pa nt, it m ust n ot be escalate d a gai n. If m ore t ha n 2 d ose re d ucti o ns are i n dicate d, t he 
pa rtici pa nt wil l be per ma ne ntl y disc o nti n ue d fr o m st u d y treat me nt.
See Secti o n  5. 2. 6 f or a d diti o nal details of t o xicit y  m o dificati o ns.
P art B 1 :
D oses of M 4 3 4 4
a n d/ or car b o plati n m a y  be re d uce d or dela y e d b e y o n d C y cle 1 of Part B 1 f or 
t o xicit y usi n g t he f oll o wi n g g ui deli nes. T he fi nal d ose re d ucti o n or dela y f or eac h partici pa nt ma y 
be deter mi ne d b y t he S p o ns or a n d I nvesti gat or s. H o we ver, t hese g ui deli nes pr o vi de t he mi ni m u m 
d ose re d ucti o n or dela y criteria. A d diti o nall y , if a parti ci pa nt w h o is res p o n di n g t o treat me nt 
e x perie nces t o xicit y eve n after 2 d ose re d ucti o ns, t he partici pa nt m a y  co nti n ue t o recei ve treat me nt 
if i n t he j u d g me nt of t he I n vesti gat or it is i n t he best i nterest of t he partici pa nt . I n t his case t he d ose 
of eit her t he c he m ot hera pe utic a ge nt a n d/ or M 4 3 4 4
will f urt her be re d uce d b y  at least 2 5 %.

I n case of Gra de 3 or hi g her t o xicit y (e xcl u di n g fati g ue or na usea/ v o miti n g/ diarr hea 
a de q uatel y ma na ge d b y  su p p orti ve care), treat me nt will be i nterr u pte d a n d m a y  be 
res u me d w he n all t o xicities ha ve ret ur ne d t o Gra de 2 or l o wer, at t he discreti o n of t he 
I n vesti gat or. D ose m o dificati o ns ma y  be a p plie d acc or di n g t o t he rec o m me n dati o ns 
gi ve n f or P arts A, A 2, a n d A 3 (see a b o ve).

F or t he f oll o wi n g he mat ol o gic t o xicities, o nce t he t o xicit y has ret ur ne d t o Gra de 2 or 
l o wer, 
d osi n g 
ca n 
be 
res u me d 
at 
a 
l o wer 
d ose 
of 
c he m ot hera p y 
(car b o plati n = A U C 4 m g ∙mi n/ m L or 2 5 % re d ucti o n i n d ose of c he m ot hera p y) a n d/ or 
l o wer d ose of M 4 3 4 4
( 2 5 % re d ucti o n):

Gra de 4 t hr o m b oc y t o pe nia 

Fe brile ne utr o pe nia ( gr o wt h fact or s u p p ort, per site pr ot oc ol, ma y  be use d i n lie u of d ose 
re d ucti o n)

Gra de 4 ne utr o pe nia lasti n g m ore t ha n 7 d a y s ( gr o wt h fact or s u p p ort, per site pr ot oc ol, ma y 
be use d i n lie u of d ose re d ucti o n)

F or t he f oll o wi n g n o n -he mat ol o gic t o xicitie s, o nce t he t o xicit y has ret ur ne d t o Gra de 2 
or l o wer, d osi n g ca n be res u me d at a l o wer d ose of c he m ot hera p y (car b o plati n = A U C 
4 m g ∙mi n/ m L or 2 5 % re d ucti o n i n d ose of c he m ot hera py) a n d/ or l o wer d ose of M 4 3 4 4
( 2 5 % re d ucti o n):

Gra de 3 n o n- he mat ol o gic t o xicit y (e xce pt f or fati g ue or na usea, v o miti n g, or diarr hea 
a de q uatel y c o ntr olle d b y me dicati o n) 

A n y  Gra de 2 or l o wer n o n -he mat ol o gic t o xicit y  re q uiri n g d ose dela y of m ore t ha n 2 wee ks

F or Gra de 4 n o n- he mat ol o gic t o xicit y, treat me nt will be i nterr u pte d a n d ma y b e 
res u me d at a l o wer d ose of c he m ot hera p y (car b o plati n = A U C 4 m g ∙mi n/ m L or 2 5 % 
re d ucti o n d ose of c he m ot hera p y) a n d at a l o wer d ose of M 4 3 4 4
( 2 5 % re d ucti o n) w he n 
t o xicit y has ret ur ne d t o Gra de 2 or l o wer.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
If a n y t o xicit y not descri be d a b o ve res ults i n d ela y in d osi n g i n a n y part of t he st u d y an d t he 
partici pa nt m a y  be be nefitti n g fr o m t hera py, t he n at t he discreti o n of t he I nvesti gat or , t he d oses of 
M 4 3 4 4
or c he m ot hera p y ma y  be f urt her re d uce d.
P arts C :
D oses of M 4 3 4 4 ma y  be re d uce d f or t o xicit y usi n g t he f oll o wi n g g ui deli nes:

F or Gra de 4 he mat ol o gic t o xicit y : t he d ose of M 4 3 4 4 will be re d uce d by 2 5 %

F or Gra de 3 n o n- he mat ol o gic t o xicit y : t he d ose of M 4 3 4 4 will be re d uce d b y 2 5 %

F or Gra de 4 n o n- he mat ol o gic t o xicit y : t he d ose of M 4 3 4 4 will be re d uce d b y 50 %
I n agree me nt bet wee n I nvesti gat or a n d S p o ns or, a n y dose re d ucti o n f or t o xicit y de viati n g fr o m t he 
a b o ve g ui deli nes ma y be a p plie d.
6. 2. 4
Misse d D oses a n d St u d y Visits
Treat me nt will be i nterr u pte d beca use of Gra de 3 or hi g her t o xicit y duri n g a n y c ycle b e yo n d 
C y cle 1. Treat me nt ma y  be res u me d w he n all t o xicities ha ve ret ur ne d t o Gra de 2 or less.
St u d y  visits t hat are misse d beca use of cli nic or partici pa nt u na vaila bilit y  (e. g., f or reas o ns of 
p u blic h oli da y , cli nic cl os ure, ur ge nt pers o nal matter, tra ns p ortati o n pr o ble ms), s h o ul d be ma de 
u p w he n a n d if reas o na bl y p ossi ble.
F or Part s A 2 a n d A 3 , a n d all Parts C , a n y misse d d oses will be s ki p pe d. F or Parts A a n d B 1 , a n y 
misse d d ose of st u d y  dr u g ( wit h t he e xce pti o n of M 4 3 4 4
d oses sc he d ule d t o occ ur 2 4 h o urs after 
car b o plati n, d osi n g i n C y cle 1 of Part B 1 ) s h o ul d be ta ke n wit hi n 2 d a y s ( 4 8 h o urs) of t he 
sc he d ule d d ose. If m ore t ha n 4 8 h o urs ha ve tra ns pire d si nce t he sc he d ule d d ose, t he n t he d ose 
s h o ul d be s ki p pe d a n d will be c o nsi dere d a misse d d ose f or t he p ur p ose of e val ua bilit y  i n C ycle 1 
of Parts A or B 1. F or d oses of M 4 3 4 4
t hat are sc he d ule d t o occ ur 2 4 h o urs after car b o plati n d osi n g 
i n C y cle 1 of Part B 1, if m ore t ha n 3 6 h o urs ha ve tra ns pire d si nce t he d ose of c he m ot hera p y 
(i.e., m ore t ha n 1 2 h o urs fr o m t he sc he d ule d d ose of M 4 3 4 4 ), t he M 4 3 4 4
d ose will be c o nsi dere d 
a misse d d ose f or t he p ur p ose of e val ua bilit y. F or dela y e d d oses, t he d osi n g sc he d ule s h o ul d 
c o nti n ue fr o m t he date of t he dela y e d d ose, wit h o ut o mi tti n g a n y doses of c he m ot hera p y or a n y 
rest i nter vals bet wee n c he m ot hera p y, if p ossi ble. W he ne ver 
p ossi ble, s u bse q ue nt d oses of 
c he m ot hera p y s h o ul d be a d va nce d i n ti me t o s y nc hr o nize wit h t he act ual date of a d mi nistrati o n of 
t he dela ye d d ose.
T he relati ve ti mi n gs of all ot her assess me nts a n d dr u g d osi n g m a y  be m o ve d t o acc o m m o date 
partici pa nt a n d cli nic a vaila bilit y. Dela y s bet wee n se q ue ntial c ycles i n t hera py, ot her t ha n f or 
reas o ns of t o xicit y, s h o ul d n ot e xcee d 7 d a y s, e xce pt as a p pr o ve d by t he Me dical M o nit or.
6. 3
Assi g n me nt t o Tre at me nt Gr o u ps
T his is a n o pe n -la bel st u d y. Partici pa nt s will be e nr olle d i nt o d ose le vel c o h orts acc or di n g t o t he 
d ose escalati o n sc he me descri be d a b o ve i n Secti o n 5 .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Partici pa nt s m a y be scree ne d i n parallel or sta g gere d ma n ner f or Parts A 2 , A 3, a n d C a n d will be 
e nr olle d i nt o Parts C acc or di n g t o t he m olec ular lesi o n of t heir t u m or (see S ecti o n 5. 1. 4 f or details). 
If a partici pa nt’s t u m or has m ore t ha n o ne q ualif y i n g m olec ular lesi o n, t he partici pa nt will be 
assi g ne d t o all res pecti ve st u d y parts.
6. 4
St o p pi n g R ules
Partici pa nt s ma y be disc o nti n ue d fr o m st u d y dr u g f or t o xicit y or lac k of efficac y, as f oll o ws:

Partici pa nt s e x perie nci n g n o nre versi ble or life-t hreate ni n g t o xicit y ma y be disc o nti n ue d 
fr o m st u dy dr u g at t he I nvesti gat or ’s discreti o n. Partici pa nt s w h o e x perie nce re versi ble 
a n d n o nlife -t hreate ni n g t o xicit y an d, i n t he j u d g me nt of t he I n vesti gat or, w h o m a y  be 
e x hi biti n g cli nical be n efit, ma y  res u me t hera p y after t he t o xicit y has decrease d t o 
Gra de 2 or bel o w

Partici pa nt s w h o e x perie nce a D L T d uri n g C y cle 1 will be disc o nti n ue d fr o m st u d y dr u g 

Partici pa nt s wit h pr o gressi ve disease b e y o n d C y cle 1 will be disc o nti n ue d fr o m st u d y 
dr u g. Partici pa nt s wit h pr o gressi ve disease bef ore t he e n d of C y cl e 1 m a y  be 
disc o nti n ue d at t he discreti o n of t he I nvesti gat or .
Partici pa nt s w h o are disc o nti n ue d fr o m st u d y dr u g will c o nti n ue t o c o m plete t he a p pr o priate 
f oll o w- u p assess me nts. F oll o w - u p pr oce d ures are disc usse d Secti o n 5. 2. 1 1. F or st o p pi n g criteria 
of e nr oll me nt f or Parts C, see Secti o n  8. 1 f or details
6. 5
N o n- i n vesti g ati o n al Me dici n al Pr o d ucts t o be Use d
N ot a p plica ble.
6. 6
C o nc o mit a nt Me dic ati o ns a n d T her a pies
All c o nc o mita nt me dicati o ns ta ke n b y  t he partici pa nt d uri n g t he st u d y, fr o m t he date of si g nat ure 
of i nf or me d c o nse nt are t o be rec or de d i n t he a p pr o priate secti o n of t he e C R F, n oti n g t he na me, 
d ose, d urati o n a n d i n dicati o n of eac h dr u g. N o n dr u g i nter ve nti o ns a n d a n y c ha n ges t o a 
c o nc o mita nt me dicati o n or ot her i nter ve nti o n s h o ul d als o be rec or de d i n t he eC R F .
6. 6. 1
Per mitte d Me dici nes
A n y  me dicati o ns t hat are c o nsi dere d necessar y t o pr otect partici pa nt welfare a n d will n ot i nterfere 
wit h t he st u d y me dicati o n ma y  be gi ve n at t he I n vesti gat or’s discreti o n.
Resc ue me dicati o ns ma y be a d mi nistere d t o a d dress i neffecti ve treat me nt, a ntici pate d a d verse 
reacti o ns or a ntici pate d e mer ge nc y sit uati o ns.
C o nc o mita nt treat me nt wit h t he f oll o wi n g c o m p o u n ds t o mai ntai n a castrate le vel of te st oster o ne 
i n partici pa nts wit h pr ostate ca ncer is per mitte d: le u pr oli de, g osereli n , tri pt oreli n, histreli n, 
de gareli x, a birater o ne, e nzal uta mi de, a n d nil uta mi de. F or t hese c o m p o u n ds, n o ris k f or dr u g -dr u g -
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
i nteracti o n wit h M 4 3 4 4 
is a ntici pate d, h o we ver, n o dr u g -dr u g -i nteracti o n st u dies ha ve bee n 
c o n d ucte d.
6. 6. 2
Pr o hi bite d Me d ici nes
I n vitr o dr u g meta b olis m st u dies s u g gest t hat M 4 3 4 4
is a s u bstrate of C y t oc hr o me P 4 5 0 (C Y P ) 
3 A 4 (Verte x Re p ort K 2 2 0 2 0 1 4, Verte x Re p ort K 0 6 4 2 0 1 4) a n d s yste mic e x p os ure ma y  be 
affecte d b y  co nc o mita nt me dicati o ns t hat are str o n g C Y P 3 A 4 i n hi bit ors or i n d ucers. Restricti o ns 
f or pri or a n d c o nc o mita nt me dicati o ns t hat are str o n g i n hi bit ors or i n d ucers of C Y P 3 A 4 are 
pr o vi de d i n  Ta ble 1 3 a n d i n t he s u p ple me ntal St u d y Pr o hi bite d a n d Ca uti o ne d List. Base d u p o n i n 
vitr o data, M 4 3 4 4
is n ot a p ote nt i n hi bit or or i n d ucer of h u ma n C Y P e nz y mes i n isolate d e nz y m e
s yste ms a n d t heref ore t he pr o ba bilit y of M 4 3 4 4
i nteracti o n wit h ot her me dicati o ns t hat are 
s u bstrates of C Y P meta b olis m i s e x pecte d t o be l o w. H o we ver, I n vesti gat ors s h o ul d use sta n dar d 
preca uti o ns w he n prescri bi n g me dicati o ns, as wit h a n y no vel t hera pe utic f or w hic h t here is li mite d 
cli nical e x perie nce.

Partici pa nt s will a bstai n fr o m c o nc o mita nt me dicati o ns as descri be d i n Ta ble 1 3.  If a 
pr o hi bite d me dicati o n is c o nsi dere d me dicall y necessar y  for a partici pa nt , t he 
partici pa nt will be wit h dra w n fr o m t he st u d y .

Partici pa nt s s h o ul d n ot recei ve pr o p h yl actic treat me nt wit h he mat o p oietic gr o wt h 
fact ors, a nti-e metic, a n d a nti-diarr heal me dicati o ns d uri n g C y cle 1 of Part A of t he 
st u d y. T hese treat me nts ma y  be use d t o s pecificall y ad dress partici pa nt s ym pt o ms, per 
i nstit uti o nal practice, as l o n g t he y ad here t o restricti o ns liste d i n Ta ble 1 3 . Ne utr o p hil 
gr o wt h fact ors (e. g., gra n ul oc y te-c ol o n y sti m ulati n g fact or) s h o ul d n ot be use d i n 
Part B 1 d uri n g C y cle 1. Ot her wise, a nti-e metics, a nti-diarr heals , a n d gr o wt h fact ors ca n 
be use d f or partici pa nt s i n Part B 1
of t he st u d y, per i nstit uti o nal practice f or 
a d mi nistrati o n of car b o plati n a n d t o treat s y m pt o ms.

T he I n vesti gat or s h o ul d refer t o t he pac ka ge i nserts f or car b o plati n f or g ui da nce o n 
pr o hi bite d me diati o ns 
d uri n g treat me nt w it h t his a ge nt
(Car b o plati n 
S m P C ). 
Partici pa nt s e nr olle d i n Part B 1 s h o ul d n ot use ne p hr ot o xic or ot ot o xic me dicati o ns 
fr o m 7 d a y s bef ore t he first d ose of st u d y dr u g t hr o u g h t he Safet y F oll o w - u p Visit. 
S h ort -ter m use o n st u d y will n ot ca use a partici pa nt t o be i neli gi ble. If a s h ort c o urse of 
t hera py w it h ne p hr ot o xic or ot ot o xic me dicati o n is a ntici pate d a n d re q uire d, car b o plati n 
or cis plati n s h o ul d be disc o nti n ue d u ntil 7 da y s after t his c o urse is c o m plete d.

Me dicati o ns ta ke n fr o m 2 8
da y s bef ore t he first d ose of st u d y d r u g will be d oc u me nte d 
as a pri or me dicati o n. Me dicati o ns ta ke n after t he first d ose of st u d y dr u g t hr o u g h t he 
e n d of t he st u d y will be d oc u me nte d as c o nc o mita nt me dicati o ns. All me dicati o ns m u st 
be rec or de d wit h na me a n d d ose, i n dicati o n, r o ute of a d mi nistrati o n, a n d start a n d st o p 
dates of a d mi nistrati o n. All 
partici pa nt s will 
be q uesti o ne d a b o ut c o nc o mita nt 
me dicati o n at eac h cli nic visit.
I n vitr o data i n dicates t hat a bs or pti o n of M 4 3 4 4
ma y  be affecte d b y aci d-m o dif y i n g a ge nts. 
Restricti o ns f or aci d -m o dif y i n g a ge nts s uc h as pr ot o n-p u m p i n hi bit ors, H 2-rece pt or a nta g o nists, 
a n d a ntaci ds w hic h ma y  re d uce t he a bs or pti o n a n d effects of M 4 3 4 4 are pr o vi de d i n  Ta ble 1 3.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 1 3
St u d y Restricti o ns
R e stri ct e d M e di c ati o n/ F o o d/ A cti vit y
St u d y  P eri o d
S cr e e ni n g P eri o d
Tr e at m e nt P eri o d
F o o d
Gr a p efr uit/ gr a p efr uit j ui c e
S e vill e or bl o o d or a n g e s
N o n e all o w e d wit hi n 
7 d a y s b ef or e t h e fir st 
d o s e of st u d y dr u g
N o n e all o w e d t hr o u g h t h e 
S af et y F oll o w -u p Vi sit
Str o n g C Y P 3 A 4 i n hi bit or s or i n d u c er s

E x a m pl e s of str o n g C Y P 3 A 4 i n hi bit or s 
i n cl u d e
cl arit hr o m y ci n, 
itr a c o n a z ol e, 
H e p atiti s 
C 
vir u s a n d 
HI V 
pr ot e a s e 
i n hi bit or s, k et o c o n a z ol e, 
n ef a z o d o n e, 
p o s a c o n a z ol e, 
t elit h o m y ci n, 
a n d 
v ori c o n a z ol e.

E x a m pl e s of p ot e nt C Y P 3 A 4 i n d u c er s 
i n cl u d e 
a v a si mi b e,  
c ar b a m a z e pi n e, 
rif a m pi n, p h e n yt oi n, a n d St. J o h n’s w ort a
N o n e all o w e d wit hi n 
7 d a y s b ef or e t h e fir st 
d o s e of st u d y dr u g
N o n e all o w e d t hr o u g h t h e 
S af et y F oll o w -u p Vi sit
A nti -e m eti c s or a nti -di arr h e al s
All o w e d f or s y m pt o m 
m a n a g e m e nt
Pr o p h yl a cti c u s e n ot 
all o w e d d uri n g C y cl e 1 of 
P art A. All o w e d if gi v e n p er 
i n stit uti o n al pr a cti c e 
(P art s B a n d C), or f or 
s y m pt o m m a n a g e m e nt
H e m at o p o ieti c gr o wt h f a ct or s
N ot all o w e d f or P art s A or 
B
Pr o p h yl a cti c u s e n ot 
all o w e d. T h er a p e uti c u s e 
all o w e d p er i n stit uti o n al 
pr a cti c e
N e p hr ot o xi c m e di c ati o n s
P art B 1 o nl y: N o n e 
all o w e d wit hi n 7 d a y s 
b ef or e t h e fir st d o s e of 
st u d y dr u g
N o n e all o w e d t hr o u g h t h e 
S af et y F oll o w -u p Vi sit 
( e x c e pt a s s p e cifi e d i n 
S e cti o n 6. 6 )
Pr ot o n - P u m p I n hi bit or s
E x a m pl e s of pr ot o n - p u m p i n hi bit or s i n cl u d e 
o m e pr a z ol e ( Pril o s e c ®, O m e s e c Z e g eri d ®), 
l a n s o pr a z ol e ( Pr e v a ci d ®), e s o m e pr a z ol e 
( E s o m e pr a z ol e Str o nti u m, N e xi u m ®), p a nt o pr a z ol e 
( Pr ot o ni x ®), a n d r a b e pr a z ol e ( A ci p H e x ®)
N o n e all o w e d wit hi n 
7 d a y s b ef or e t h e fir st 
d o s e of st u d y dr u g
N o n e all o w e d u ntil 
p er m a n e nt di s c o nti n u ati o n 
of M 4 3 4 4 , u nl e s s di s c u s s e d 
wit h a n d a p pr o v e d b y t h e 
M e di c al M o nit or
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

E x a m pl e s 
of 
H 2 -r e c e pt or a nt a g o ni st s 
i n cl u d e r a niti di n e ( Z a nt a c ®), f a m oti di n e 
( P e p ci d ®), ci m eti di n e ( T a g a m et ®), a n d 
ni z ati di n e ( A xi d ®).

E x a m pl e s 
of 
a nt a ci d s 
i n clu d e 
Al k a -S elt z er ®, 
G el u sil, 
M a al o x ®, 
M yl a nt a ®, 
P e pt o -Bi s m ol ®, 
R ol ai d s ®, 
a n d T u m s ®

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 c a n b e 
t a k e n wit h o ut r e stri cti o n o n all d a y s w h e n 
M 4 3 4 4
i s n ot a d mi ni st er e d.

O n all d a y s w h e n M 4 3 4 4
i s a d mi ni st er e d b
o n c e 
d ail y,
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 will n ot b e p er mitt e d wit hi n 1 2 h o ur s 
b ef or e d o si n g of M 4 3 4 4 a n d u ntil 4 h o ur s aft er  
d o si n g of M 4 3 4 4 .
O n all d a y s w h e n M 4 3 4 4 i s a d mi ni st er e d b t wi c e d ail y, 
n o n e ar e all o w e d u ntil p er m a n e nt di s c o nti n u ati o n of t h e 
m e di c ati o n 
M 4 3 4 4, 
u nl e s s 
di s c u s s e d 
wit h 
a n d 
a p pr o v e d b y t h e M e di c al M o nit or.
C Y P = C yt o c hr o m e P 4 5 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
a
R ef er t o t h e st u d y r ef er e n c e m a n u al f or a m or e c o m pl et e li st of pr o hi bit e d or c a uti o n e d m e di c ati o n s i n t hi s 
st u d y.
b
M 4 3 4 4
will b e a d mi ni st er e d a s d e s cri b e d i n  T a bl e 3 f or P art A, T a bl e 4 f or P art A 2 a n d t h e 1 4 d +/ 7 d - s c h e d ul e 
of P art A 3 , T a bl e 5 f or A3 , T a bl e 6 f or P art B1, T a bl e 7 f or P arts C 1, C 2, a n d C 3 , T a bl e 9 f or P art s C 4, C 5, a n d C 6.
6. 6. 3
Ot her I nter ve nti o ns
6. 6. 3. 1
Me als a n d Diet ar y Restricti o ns
M 4 3 4 4 will be a d mi nistere d u n der fasti n g c o n diti o ns t hr o u g h o ut t he st u d y.
T he st u d y dr u g will be a d mi nistere d wit h 2 4 0 m L  (8 fl ui d o u nces) of a m bie nt te m perat ure water. 
Partici pa nt s will a bstai n fr o m all f o o d f or at least 3 h o urs bef ore st u d y dr u g a d mi nistrati o n a n d f or 
1 h o ur after st u d y dr u g a d mi nistrati o n. Water ca n be c o ns u m e d as desire d.
Restricti o ns f or c o ns u m pti o n of s pecific f o o ds a n d n o n- alc o h olic be vera ges are pr o vi de d i n 
Ta ble 1 3.
6. 6. 3. 2
Acti vit y
Partici pa nt s will a bstai n fr o m stre n u o us e xercise (e. g., hea v y  lifti n g, wei g ht trai ni n g, a n d aer o bics) 
f or at least 4 8 h o urs bef ore eac h bl o o d c ollecti o n f or cli nical la b orat or y tests. Wal ki n g at a n or mal 
pace will be per mitte d.
Partici pa nt s s h o ul d a v oi d pr ol o n ge d or i nte nse s u n e x p os ure, s u nla m ps, a n d ta n ni n g be ds. Use of 
s u nscree n, cl ot hi n g, a n d e ye wear t hat decrease s u n e x p os ure is rec o m me n de d.
6. 6. 4
S peci al Prec a uti o ns
N ot a p plica ble.
6. 6. 5
M a n a ge me nt 
of S pecific A d verse E ve nts or A d verse Dr u g 
Re acti o ns
N ot a p plica ble.
6. 7
P ac k a gi n g a n d L a beli n g
of t he I n vesti g ati o n al Me dici n al 
Pr o d uct
T he S p o ns or will s u p pl y 5 0 m g M 4 3 4 4
ta blets. St u d y  dr u g la beli n g will be i n c o m plia nce wit h 
a p plica ble l ocal a n d nati o nal re g ulati o ns. A d diti o nal details re gar di n g pac ka gi n g, la beli n g, a n d 
dis pe nsi n g f or M 4 3 4 4
will be i ncl u de d i n t he P har mac y  Ma n ual.
All st u d y dr u gs will be pac ka ge d a n d la bele d i n acc or da nce wit h all a p plica ble re g ulat or y 
re q uire me nts a n d Go o d M a n ufact uri n g Practice G ui deli nes.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
6. 8
Pre p ar ati o n, H a n dli n g , a n d St or a ge of t he I n vesti g ati o n al 
Me dici n al Pr o d uct
St u d y  dr u g m a y  be dis pe nse d o nl y u n der t he s u per visi o n of t he I n vestigat or or a n a ut h orize d 
desi g nee a n d o nl y f or a d mi nistrati o n t o t he st u d y  partici pa nt s.
Ta blets will be dis pe nse d i nt o i n di vi d ual d osi n g c o ntai ners at t he cli nical site b y  2 o perat ors, 1 of 
w h o m is a q ualifie d p har macist, a n d f oll o wi n g nati o nal a n d l ocal la ws a n d re g ulati o ns.
T he I n vesti gat or, or a n a ut h orize d desi g nee (e. g., a lice nse d p har macist), will e ns ure t hat all 
i n vesti gati o nal pr o d uct is st ore d i n a sec ure d area, u n der rec om me n de d st ora ge c o n diti o ns, a n d i n 
acc or da nce wit h a p plica ble re g ulat or y re q uire me nts ( See Ta ble 1 4 ). T o e ns ure a de q uate rec or ds, 
all st u d y dr u gs will be acc o u nte d f or as detaile d i n Secti o n 6. 9 or via t he dr u g acc o u nta bilit y f or ms 
as i nstr ucte d b y t he S p o ns or.
T a ble 1 4
St u d y Dr u g
Dr u g N a m e
F or m ul ati o n/
R o ut e
D o s a g e
P a c k a gi n g
St or a g e
C o n diti o n
M 4 3 4 4
T a bl et/ Or al
5 0 m g M 4 3 4 4
 
H D P E = Hi g h d e n sit y p ol y et h yl e n e .
6. 9
I n vesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bilit y
T he p har macist or desi g nate d st u d y site staff is res p o nsi ble f or e ns uri n g st u d y dr u g acc o u nta bilit y, 
i ncl u di n g rec o nciliati o n of dr u gs a n d mai nte na nce of rec or ds.

U p o n recei pt of st u d y dr u g, t he res p o nsi ble pers o n will c hec k f or acc urate deli ver y  an d 
ac k n o wle d ge recei pt b y  si g ni n g or i nitiali n g a n d dati n g t he a p pr o priate d oc u me ntati o n a n d 
ret ur ni n g it t o t he l ocatio n s pecifie d . A c o p y will be arc hi ve d f or t he I n vesti gat or Site File

St u d y  dr u g dis pe nsi n g will be rec or de d o n t he a p pr o priate dr u g acc o u nta bilit y for ms s o t hat 
acc urate rec or ds will be a vaila ble f or verificati o n at eac h m o nit ori n g visit

St u d y site st u d y dr u g acc o u nta bilit y rec or ds will i ncl u de t he f oll o wi n g:
o
C o nfir mati o n of st u d y dr u g recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m perat ure ra n ge
o
T he i n ve nt or y  of st u d y dr u g 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 use of eac h d ose b y eac h partici pa nt
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 use d st u d y dr u g
o
Dates, q ua ntities, batc h n u m bers, kit n u m ber , e x pir y dates, f or m ulati o n (f or st u d y dr u g
pre pare d at t he site), a n d t he i n di vi d ual partici pa nt st u d y n u m bers
T he I n vesti gat or site s h o ul d mai ntai n rec or ds, w hic h a de q uatel y d oc u me nt t hat partici pa nt s were 
pr o vi de d t he d oses s pecifie d i n t his pr ot oc ol, a n d all st u d y dr u gs pr o vi de d were f ull y rec o ncile d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Partici pa nt s will be i nstr ucte d t o ret ur n all use d a n d u n use d materials ass ociate d wit h t he st u d y 
dr u g t o t he site. T hese materials ass ociate d wit h t he st u d y dr u g will be retai ne d at t he site acc or di n g 
t o i nstr ucti o ns pr o vi de d b y t he S p o ns or or its desi g nee u ntil i n ve nt orie d b y t he S t u d y M onit or. 
T he st u d y site staff or p har mac y  pers o n nel will retai n all materials ret ur ne d b y  the partici pa nt s 
u ntil t he st u d y mo nit or has perf or me d dr u g acc o u nta bilit y. At t he e n d of t he st u d y, t he st u d y 
m o nit or will pr o vi de i nstr ucti o ns as t o t he dis p ositi o n of a n y  u n use d i n vesti gati o nal pr o d uct. After
st u d y mo nit or a ut h oriz ati o n st u d y dr u g s h o ul d be destr uct e d at t he st u d y site. The I nvesti gat or will 
e ns ure t hat t he materials are destr o ye d i n c o m plia nce wit h a p plica ble e n vir o n me ntal re g ulati o ns, 
i nstit uti o nal p olic y , a n d a n y special i nstr ucti o ns pr o vi de d b y  the S p o ns or. Destr ucti o n will be 
a de q uatel y d oc u me nte d.
T he St u d y  Mo nit or will re vie w st u d y dr u g rec or ds a n d i n ve nt or y thr o u g h o ut t he st u d y, a n d will 
peri o dicall y c ollect t he st u d y dr u g acc o u nta bilit y f or ms.
6. 1 0
Assess me nt of I n vesti g ati o n al Me dici n al Pr o d uct C o m pli a nce
F or st u d y dr u g d oses a d mi nistere d d uri n g t he i n patie nt peri o ds of t he st u d y, d oses will be 
a d mi nistere d u n der t he direct s u per visi o n of t he I nvesti gat or or desi g nee.
F or st u d y dr u g d oses a d mi nistere d d uri n g t he o ut patie nt peri o ds of t he st u d y, dr u g acc o u nta bilit y 
will be assesse d at eac h visit b y  co u nti n g ret ur ne d d osa ge u nits. Discre pa ncies will be disc usse d 
wit h t he partici pa nt a n d rec or de d i n t he s o urce d oc u me nts. If partici pa nt s de m o nstrate c o nti n ue d 
n o nc o m plia nce of st u d y dr u g d osi n g de s pite e d ucati o nal eff orts, t he I n vesti gat or will c o ntact t he 
me dical m o nit or t o disc uss disc o nti n ui n g t he partici pa nt fr o m t he st u dy.
F or all d oses of st u d y dr u g, t he n u m ber of u nits a d mi nistere d a n d m isse d d oses will be rec or de d. 
All m o dificati o ns i n st u d y dr u g d ose or i nter val bet wee n d osi n g will be rec or de d, as we ll as t he 
reas o n f or m o dificati o ns.
I n di vi d ual partici pa nt c o m plia nce will be m o nit ore d b y  the S p o ns or a n d cli nical site desi g nee 
e ver y 2 w ee ks a n d partici pa nt s will be n otifie d w he n t he y are bei n g n o nc o m plia nt wit h d osi n g 
sc he d ule. C o nti n ue d n o nc o m plia nce t o d osi n g sc he d ule will res ult i n t he partici pa nt bei n g re m o ve d 
fr o m t he st u d y.
6. 1 1
Bli n di n g
Bli n di n g n ot a p plica ble as t his is a n o pe n-l a bel st u d y.
6. 1 2
E mer ge nc y U n bli n di n g
N ot a p plica ble.
6. 1 3
Tre at me nt of O ver d ose
A n o ver d ose is defi ne d as a n y d ose greater t ha n t he hi g hest dail y d ose i ncl u de d i n a cli nical st u d y
pr ot oc ol or pla n ne d f or a n i n di vi d ual partici pa nt e nr olle d i n t he st u d y. E ve n if it d oe s n ot meet 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
ot her criteria f or a S A E, an y  over d ose m ust be rec or de d i n t he st u d y me dicati o n secti o n of t he 
eC R F a n d re p orte d t o Dr u g Safet y i n a n e x pe dite d ma n ner usi n g t he S A E Re p ort F or m , a n d 
f oll o wi n g t he pr oce d ure i n Secti o n 7. 5 .
6. 1 4
Me dic al C are of P artici p a nt s after E n d of St u d y
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 nt s after t hey l ea ve t he st u d y beca use 
s uc h care s h o ul d n ot differ fr o m w hat is n or mall y e x pecte d f or partici pa nt s wit h a d va nce d s oli d 
t u m ors.
7
St u d y Pr oce d ures a n d Assess me nts
7. 1
Sc he d ule of Assess me nts
Pri or t o perf or mi n g a n y st u d y assess me nts t hat are n ot part of r o uti ne me dical care f or t he 
partici pa nt , t he I n vesti gat or will o btai n writte n i nf or me d c o nse nt as descri be d i n Secti o n 9. 2. T he 
ti mi n g of assess me nts are prese nte d i n Ta ble 1 f or Scree ni n g, Ta ble 3 f or Part A,
Ta ble 4 f or 
Part A 2 a n d t he 1 4 d +/ 7 d- sc he d ule of Part A 3, Ta ble 5 f or A 3 , a n d Ta ble 6 f or Part B1. F or P arts 
C, the ti mi n g of assess me nts are prese nte d i n Ta ble 2 f or Scree ni n g a n d Ta ble 7 a n d Ta ble 8 f or 
Parts C 1, C 2, a n d C 3 a n d t he 1 4 d +/ 7 d - h oli da y  sc he d ule descri be d i n Parts C 4. C 5, a n d C 6, a n d
Ta ble 9 a n d Ta ble 1 0 f or Parts C 4, C 5, a n d C 6 (e xce pt t he 1 4 d +/ 7 d- sc he d ule).
Partici pa nt s i n a n y of t he Parts C ca n o nl y start treat me nt o nce eli gi bilit y has bee n c o nfir me d base d 
o n t he prese nce of t hese l oss- of-f u ncti o n m utati o ns, w hic h are defi ne d i n Secti o n 7. 7. 5,  a n d t he 
rest of Scree ni n g assess me nts. Fi g ure 5 pr o vi des a sc he matic of eli gi bilit y  assess me nts i n Parts C. 
7. 2
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics
At S cree ni n g, t he f oll o wi n g de m o gra p hic data will be c ollecte d: d ate of birt h , se x ( ge n der), race, 
et h nicit y.
7. 3
P artici p a nt a n d Dise ase C h ar acteristics
Partici pa nt a n d disease c haracteristics i ncl u de t he f oll o wi n g: me dical hist or y, hei g ht, wei g ht, t y pe 
of ca ncer (i ncl u di n g hist ol o gic s u bt y pe), t u m o r sta ge at Scree ni n g, date of ca ncer dia g n osis, pri or 
c he m ot hera p y a n d ra diati o n t hera p y, date a n d d urati o n of m ost rece nt ca ncer t hera py, a n d W H O 
perf or ma nce stat us at baseli ne.
7. 4
Effic ac y Assess me nts
P arts A, A 2, A 3 , a n d B 1
Alt h o u g h efficac y  res p o nse is n ot t he P ri mar y En d p oi nt of Parts A, A 2, A 3, a n d B 1 of t his st u d y, 
t u m or res p o nse, cli nical disease assess me nt, a n d W H O perf or ma nce stat us will be assesse d i n t hese 
parts .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
Partici pa nt s wit h meas ura ble disease will be assesse d b y  sta n dar d criteria ( R E CIS T 1. 1) or b y 
P C W G 2 criteria ( pr ostate ca ncer) . C ha n ges i n t he lar gest dia meter ( u ni di me nsi o nal meas ure me nt) 
of t he t u m or lesi o ns a n d t he s h ortest dia meter i n t he case of mali g na nt l ym p h n o des are use d i n t he 
R E CI S T criteria. 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) .
Partici pa nt s m ust ha ve a n i ma gi n g sca n (e. g., C T, M RI ) at Scree ni n g t o d oc u me nt t he e xte nt of 
i nitial disease. Partici pa nt s 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 T, M RI ) as 
a p pr o priate a n d, if cli nicall y in dicate d, i ma gi n g sca ns of ot her b o d y  areas (e. g., pel vis). F or all 
Parts , partici pa nt s s h o ul d ha ve a re peat i ma gi n g sca n as descri be d i n Ta ble 3, Ta ble 4,  Ta ble 5,  
a n d Ta ble 6.  All i ma gi n g sca ns t o assess disease pr o gressi o n s h o ul d be perf or me d usi n g si milar 
C T platf o r 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 nce of c o ntrast, a n d s h o ul d be of 
c o nsiste nt a nat o mic l ocati o ns wit h pri or i ma gi n g sca ns, w he ne ver p ossi ble.
I ma gi n g sca ns will be l ocall y rea d f or all parts of t he st u d y. T he 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 disease 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 e C R F. Deter mi nati o n of partici 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) wil l 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. C o pies of t he i ma gi n g sca ns s h o ul d be a vaila ble f or i n de pe n de nt assess me nt 
if re q uire d.
B o ne sca ns will be perf or me d as descri be d i n Ta ble 3, Ta ble 4 , Ta ble 5, Ta ble 6 , Ta ble 7 , a n d 
Ta ble 9.  I n a d diti o n, partici pa nt s wit h o varia n ca ncer will ha ve ser u m C A -1 2 5 assesse d (Parts A
a n d B), a n d partici pa nt s wit h pr ostate ca ncer will ha ve ser u m P S A assesse d (Parts A a n d B) as 
descri be d i n  Ta ble 3, Ta ble 4 , Ta ble 5, Ta ble 6, Ta ble 7, a n d Ta ble 9.
T o esti mate t he a ntit u m or acti vit y of treat me nt i n partici pa nt s wit h pr ostate ca ncer, w h o are n ot 
e val ua ble at baseli ne acc or di n g t o R E CI S T 1. 1 , res p o nse will be defi ne d o n t he basis of t he 
f oll o wi n g o utc o mes; if a n y of t hese occ ur, partici pa nt s will be c o nsi dere d t o ha ve res p o n de d:

P S A decli ne ≥5 0 % criteria (P C W G 2 ) c o nfir me d 4 wee ks or later, a n d/ or

C o nfir me d s oft tiss ue o bjecti ve res p o nse ( R E C I ST 1. 1) (Sc her 2 0 0 8 ).
T he P C W G 2 a n d R E CI S T criteria will be use d t o deter mi ne P S A res p o nse a n d s oft tiss ue res p o nse. 
Fail ure of treat me nt will be defi ne d as:

Pr o gressi o n b y  R E CI S T 1. 1 (Sc her 2 0 0 8 ) a n d/ or

Pr o gressi o n of b o ne sca n (Sc her 2 0 0 8 ).
P arts C
F or all Parts
C,
safet y (o cc urre nce of treat me nt-e mer ge nt a d verse e ve nts [T E A Es ] a n d 
treatme nt -relate d A Es gra de d acc or di n g t o N CI -C T C A E ) a n d efficac y (i.e. c o nfir me d C R or P R ) 
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
are t he pri mar y e n d p oi nts. I n a d diti o n t o t he defi niti o ns gi ve n a b o ve f or Parts A, A 2, A 3 , a n d B 1, 
t he f oll o wi n g will a p ply:
T u m or assess me nt acc or di n g t o R E C IS T 1. 1 will be perf or me d at baseli ne a n d at t he e n d of e ver y 
2 c ycles f or t he first 6 c ycles, t he n e ver y 3 c ycles t hereafter u ntil disease pr o gressi o n or start of 
ne w a nti -ca ncer treat me nt li ne.
All t u m or assess me nts s h o ul d be ma de e ver y ti me wit h t he sa me met h o ds ( C T or M RI) use d at t he 
baseli ne assess me nt.
I n Parts C, partici pa nts w h o disc o nti n ue t he st u d y treat me nt f or reas o ns ot her t ha n disease 
pr o gressi o n or wit h dra wal of c o nse nt will c o nti n ue t u m or assess me nts acc or di n g t o t he sa me 
sc he d ule as partici pa nts recei vi n g trial treat me nt.
O bjecti ve res p o nse, best o ver all res p o nse, d urati o n of res p o nse a n d pr o gressi o n free s ur vi val (P F S )
will be deri ve d o n t he basis of t hese t u m or assess me nts. T he assess me nt will be perf or me d b y  t he 
In vesti gat or. Per R E CI S T 1. 1, o bjecti ve res p o nses nee d t o be c o nfir me d. C o nfir mati o n s h o ul d be 
deter mi ne d at a sca n n o less t ha n 4 wee ks after t he ori gi nal assess me nt of o bjecti ve res p o nse is 
ma de; c o nfir mati o n of res p o nse at t he ne xt sc he d ule d t u m or assess me nt is acce pta ble.
I n de pe n de nt re vie w of t he i ma gi n g-base d t u m or assess me nts ma y  be c on d ucte d at t he discreti o n 
of t he S p o ns or. C o pies of t he i ma gi n g sca ns s h o ul d be a vaila ble t o all o w f or t his.
F or o verall s ur vi val, partici pa nt s will be f oll o we d u p f or s ur vi val e ver y 3 mo nt hs u ntil t he st u d y 
cl os ure.
7. 5
Assess me nt of S afet y
T he safet y pr ofile of t he st u d y dr u g 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 y sis
of B aseli ne M e dical C o n diti o ns, A Es, p h y sical e xa mi nati o n fi n di n gs i ncl u di n g vital si g ns, E C G,
a n d la b orat or y tests.
Me dical hist or y  an d p h ysical e xa mi nati on i nf or mati o n will be c ollecte d d uri n g t he c o urse of t he 
st u d y a n d will be ca pt ure d i n t he s o urce d oc u me ntati o n. P h ysical e xa mi nati o ns p ost-baseli ne will 
n ot be ca pt ure d f or i ncl usi o n i nt o t he st u d y data base. H o we ver, a n y u nt o war d fi n di n gs i de ntifie d 
i n p hys ical e xa mi nati o ns c o n d ucte d after t he a d mi nistrati o n of t he first d ose of st u d y dr u g will be 
ca pt ure d as a n A E if t h ose fi n di n gs meet t he defi niti o n of a n A E. 
C o m pre he nsi ve assess me nt of a n y a p pare nt t o xicit y ex perie nce d b y  eac h partici pa nt will be 
perf or me d fr o m t he ti me of gi vi n g i nf or me d c o nse nt a n d t hr o u g h o ut t he st u d y. T he I n vesti gat or
will re p ort a n y A Es, w het her o bser ve d b y  the I n vesti gat or or re p orte d b y  the partici pa nt (see 
Secti o n 7. 5. 1. 2 ). T h e re p orti n g peri o d f or A E s is descri be d i n Secti o n 7. 5. 1. 3 .
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
7. 5. 1
A d verse E ve nts
7. 5. 1. 1
A d verse E ve nt Defi niti o ns
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a partici pa nt a d mi nistere d a p har mace utic al pr o d uct, 
re gar dless of ca usal relati o ns hi p wit h t his treat me nt. T heref ore, a n A E ca n be a ny u nfa v ora ble a n d 
u ni nte 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 ym pt o m, or disease te m p orally 
ass ociate d wit h t he use of a me dici nal pr o d uct, re gar dless if it is c o nsi dere d relate d t o t he me dici nal 
pr o d uct.
F or s ur gical or dia g n ostic pr oce d ures, t he c o n diti o n/ill ness lea di n g t o s uc h a pr oce d ure is 
c o nsi dere d as t he A E rat her t ha n t he pr oce d ure itself.
T he I n vesti gat or is re q uire d t o gra de t he se verity or t o xicit y of eac h A E .
I n vesti gat ors will refere nce t he Nati o nal Ca ncer I nstit ute – C o m m o n Ter mi n ol o g y Criteria f or A E s 
( C T C A E), V ersi o n 4. 0, a descri pti ve ter mi n ol o g y t hat ca n be use d f or A E re p orti n g.
A ge neral gra di n g (se verit y/i nte nsit y; hereafter referre d t o as se verity ) scale is pr o vi de d at t he 
be gi n ni n g of t he a b o ve refere nce d d oc u me nt, a n d s pecific e ve nt gra des are als o pr o vi de d.
If t he se verit y for a n A E is n ot s pecificall y gra de d b y NCI -C T C A E, t he I n vesti gat or is t o use t he 
ge neral N CI -C T C A E def i 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 des are:

Gra de 1 or Mil d

Gra de 2 or M o derate

Gra de 3 or Se vere 

Gra de 4 or L ife-t hreate ni n g

Gra de 5 or Deat h 
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 ab n or malit y o f Gra de 4, s uc h as a ne mia or ne utr o pe nia, is c o nsi dere d seri o us o nl y  if t he 
c o n diti o n meets o ne of t he seri o us criteria s pecifie d bel o w .
If deat h occ urs , t he pri mar y  ca use of deat h or e ve nt leadi n g t o deat h s h o ul d be rec or de d a n d 
re p orte d as a n S A E. “ Fatal” will be rec or de d as t he o utc o me of t h is s pecific e ve nt a n d deat h will 
n ot be rec or de d as se parate e ve nt. O nl y, if n o ca use of deat h ca n be re p orte d (e. g., s u d de n deat h, 
u ne x plai ne d deat h), t he deat h per se mi g ht t he n be re p orte d as a n S A E.
I n vesti gat ors m ust als o s yste maticall y assess t he ca usal relati o ns hi p of A Es t o st u d y dr u g(s)/st u d y 
treat me nt (i ncl u di n g a n y ot her n o n -st u d y dr u gs, ra diati o n t hera p y, etc.) usi n g t he f oll o wi n g 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
defi niti o ns. Decisi ve fact ors f or t he assess me nt of ca usal relati o ns hi p of a n A E t o M 4 3 4 4
i ncl u de, 
b ut ma y  not be li mite d t o, te m p oral relati o ns hi p bet wee n t he A E a n d t he st u d y dr u g k n o w n si de 
effects of M 4 3 4 4 , me dical hist or y , c o nc omita nt me dicati o n, c o urse of t he u n derl yi n g disease, 
st u d y pr oce d ures.
U nrel ate d:
N ot reas o na bly relate d t o t he st u d y dr u g/st u d y treat me nt. A E c o ul d n ot me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he st u d y  dr u g/st u d y treat me nt u n der 
st u d y in t his cli nical st u d y pr ot oc ol. A reas o na ble alter nati ve e x pla nati o n m ust be 
a vaila ble.
Rel ate d:
R eas o na bl y relate d t o t he st u d y dr u g/st u d y treat me nt. A E 
c o ul d me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he st u d y  dr u g/st u d y treat me nt u n der 
stu d y  i n t his cli nical st u d y pr ot oc ol. 
A b n or m al L a b or at or y Fi n di n gs a n d Ot her A b n or m al I n vesti g ati o n al Fi n di n gs
A b n or mal la b orat or y fi n di n gs a n d ot her a b n or mal i n vesti gati o nal fi n di n gs ( e. g., o n a n E C G trace) 
s h o ul d n ot be re p orte d as A Es u nless t he y are ass ociate d wit h cli nical si g ns a n d s y m pt o ms, lea d t o 
treat me nt disc o nti n uati o n or are c o nsi dere d ot her wise me dicall y  im p orta nt b y  the I n vesti gat or. If 
a la b orat or y a b n or malit y f ulfills t hese criteria, t he i de ntifie d me dical c o n diti o n (e. g., a ne mia or
i ncrease d A L T) m ust be re p orte d as t he A E rat her t ha n t he a b n or mal val ue itself.
Seri o us A d verse E ve nt s
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h.

Is life-t hreateni n g. “ Life-t hreate ni n g” refers t o a n e ve nt i n w hic h t he partici pa nt is at 
ris k of deat h at t he ti me of t he e ve nt, n ot a n e ve nt t hat h y p ot heticall y  mi ght ha ve ca used
deat h if it was m ore se vere.

Re q uires i n patie nt h os pitalizati o n or pr ol o n g s a n e xisti n g h o s pitalizati o n.

Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacity.

Is a c o n ge nital a n o maly or birt h defect.

Is ot her wise c o nsi dere d t o be me dicall y  im p orta nt. I mp orta nt me dical e ve nts t hat ma y 
n ot res ult i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n ma y  be c o nsi dere d as 
S A Es w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o par dize t he 
partici pa nt or m a y  re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
o utc o mes liste d a b o ve. E xa m ples of s uc h e ve nts i ncl u de aller gic br o nc h os pas m 
re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y ro o m or at h o me, bl o o d d y scrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g 
de pe n de nc y  or dr u g a b use.
F or t he p ur p oses of re p orti n g, a n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a st u d y dr u g
is als o c o nsi dere d a n S A E, as descri be d i n Secti o n 7. 5. 1. 4 .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
E ve nts t h at D o N ot Meet t he Defi niti o n of a n S A E
Electi ve h os pitalizati o ns t o a d mi nister, or t o si m plif y st u d y treat me nt or st u d y pr oce d ures (e. g., a n
o ver ni g ht st a y to facilitate i ntra ve n o us t hera p y) are n ot c o nsi dere d S A Es. H o we ver, all e ve nts 
lea di n g t o u n pla n ne d h os pitalizati o ns or u n pla n ne d pr ol o n gati o n of a n electi ve h os pitalizati o n (f or 
e xa m ple, u n desira ble effects of a n y ad mi nistere d treat me nt) m ust be d oc u me nte d a n d re p orte d as 
S A Es.
E ve nts N ot t o Be C o nsi dere d as A Es/ S A Es 
Me dical c o n diti o ns prese nt at t he i nitial st u d y visit t hat d o n ot w orse n i n se verity or fre q ue nc y 
d uri n g t he st u d y are defi ne d as Baseli ne Me dical C o n diti o ns a n d are n ot t o be c o nsi dere d A Es.
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 disease/ dis or der bei n g st u die d assesse d b y  
meas ure me nt of lesi o ns o n 
ra di o gra p hs or ot her met h o ds as well as ass ociate d cli nical si g ns or s ym pt o ms (i ncl u di n g 
la b orat or y ab n or malities) s h o ul d n ot be re p orte d as a n ( S) A E, u nless t he partic i 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 partici pa nt’s c o n diti o n a n d/ or u nless t he o utc o me 
is fatal wit hi n t he a d verse e ve nt re p orti n g peri o d (as defi ne d i n Secti o n 7. 5. 1. 3 ).
7. 5. 1. 2
Met h o ds o f Rec or di n g a n d Assessi n g 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. D uri n g t he 
re p orti n g peri o d , a n y u nfa v ora ble c ha n ges i n t he partici pa nt ’s c o n diti o n will be rec or de d as A Es, 
re gar dless if re porte d b y  t he partici pa nt or o bser ve d b y  t he I nvesti gat or. 
C o m plete, acc urate a n d c o nsiste nt data o n all A Es e x perie nce d f or t he d urati o n of t he re p orti n g 
peri o d ( defi ne d bel o w) will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate secti o n of t he eC R F. 
All S A Es m ust be a d diti o nall y doc u me nte d a n d re p orte d usi n g t he a p pr o priate Re p ort F or m as 
descri be d i n Secti o n 7. 5. 1. 4 .
It is i m p orta nt t hat eac h A E re p ort i ncl u des a descri pti o n of t he e ve nt, its d urati o n ( o nset a n d 
res ol uti o n dates a n d als o o nset a n d res ol uti o n ti mes), w he n it is i m p orta nt t o assess t he ti me of A E 
o nset relati ve t o t he rec or de d treat me nt a d mi nistrati o n ti me, its se verit y, its ca usal relati o ns hi p 
wi t h t he st u d y treat me nt, a n y ot her p ote ntial ca usal fact ors, a n y treat me nt gi ve n or ot her acti o n 
ta ke n, i ncl u di n g d ose m o dificati o n or disc o nti n uati o n of t he st u d y dr u g, a n d its o utc o me. I n 
a d diti o n, seri o us cases s h o ul d be i de ntifie d, a n d t he a p pr o priate seri o us ness criteria d oc u me nte d. 
If a n A E c o nstit utes a D L T t his is d oc u me nte d acc or di n gl y.
S pecific g ui da nce ca n be f o u n d i n t he e C R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns pr o vi de d 
b y  t he S p o ns or.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
7. 5. 1. 3
Defi niti o n of t he A d verse E ve nt Re p orti n g Peri o d
T h e A E re p orti n g peri o d f or safet y s ur veilla nce be gi ns w he n t he partici pa nt is i nitiall y incl u de d i n 
t he st u d y ( date of first si g nat ure of i nf or me d c o nse nt/ date of first si g nat ure of first i nf or me d 
c o nse nt) a n d c o nti n ues u ntil t he Safet y F oll o w-u p Visit . 
A n y S A E assesse d as relate d t o t he st u d y dr u g m ust be rec or de d a n d re p orte d w he ne ver it occ urs, 
irres pecti ve of t he ti me ela pse d si nce t he last a d mi nistrati o n of st u d y dr u g.
7. 5. 1. 4
Pr oce d ure f or Re p orti n g Seri o us A d verse E ve nts, A d verse 
E ve nts of S peci al I nterest a n d D ose Li miti n g T o xicities
Seri o us A d verse E ve nts
I n t he e ve nt of a n y ne w S A E occ urri n g d uri n g t he re p orti n g peri o d, t he I n vesti gat or m ust 
i m me diatel y (wit hi n a ma xi m u m of 2 4 H O U R S after bec o mi n g a ware of t he e ve nt) i nf or m t he 
S p o ns or or its desi g nee i n writi n g. All writte n re p orts s h o ul d be tra ns mitte d usi n g t he S A E Re p ort 
F or m, w hic h m ust be c o m plete d b y  t he I n vesti gat or f oll o wi n g s pecific c o m pleti o n i nstr ucti o ns.
I n e xce pti o nal circ u msta nces, a n S A E ( or f oll o w- u p i nf or mati o n) m a y  be re p orte d b y  tele p h o ne; 
i n t hese cases, a writte n re p ort m ust be se nt i m me diatel y thereafter b y  fa x or e-mail. Na mes, 
a d dresses, a n d tele p h o ne a n d fa x n u m b ers f or S A E re p orti n g will be i ncl u de d i n t he st u d y-s pecific 
S A E Re p ort F or m.
Rele va nt pa ges fr o m t he e C R F m a y  be pr o vi de d i n parallel (f or e xa m ple, me dical hist or y , 
c o nc o mita nt dr u gs). A d diti o nal d oc u me nts ma y  be pr o vi de d b y  the I n vesti gat or, if a vaila ble (f or 
e xa m ple, la b orat or y res ults, h os pital re p ort, a ut o ps y re p ort). I n all cases, t he i nf or mati o n pr o vi de d 
o n t he S A E Re p ort F or m m ust be c o nsiste nt wit h t he data a b o ut t he e ve nt rec or de d i n t he e C R F.
T he I n vesti gat or m ust 
res p o n d t o a n y re q uest f or f ollo w- u p i nf or mati o n (e. g., a d diti o nal 
i nf or mati o n, o utc o me, fi nal e val uati o n, ot her rec or ds w here nee de d) or t o a n y questi o n t he 
S p o ns or/ desi g nee m a y  h ave o n t he A E wit hi n t he sa me ti meli nes as t h ose n ote d a b o ve f or i nitial 
re p orts. T his is necessar y  to e ns ure pr o m pt assess me nt of t he e ve nt b y  the S p o ns or or desi g nee a n d 
(as a p plica ble) t o all o w t he S p o ns or t o meet strict re g ulat or y ti meli nes ass ociate d wit h e x pe dite d 
safety re p orti n g o bli gati o ns.
Re q uests f or f oll o w -u p will us uall y  be ma de via t he res p o nsi ble M o nit or, alt h o u g h i n e xce pti o nal 
circ u msta nces t he Gl o bal Dr u g Safet y de part me nt ma y  co ntact t he I n vesti gat or directl y t o o btai n 
f urt her i nf or mati o n or t o disc uss t he e ve nt.
D ose Li miti n g T o xicities 
Eac h e ve nt meeti n g t he criteria of a D L T (see S ecti o n 5. 2. 6 ) m ust be rec or de d i n t he eC R F wit hi n 
2 4 H O U R S after t he I n vesti gat or bec o m es a ware of t he e ve nt. Seri o us D L Ts m ust be re p orte d i n 
a n e x pe dite d ma n ner as S A Es as o utli ne d a b o ve.
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
7. 5. 1. 5
S afet y Re p orti n g t o He alt h A ut h orities, I n de pe n de nt Et hics 
C o m mittees/ I nstit uti o n al Re vie w B o ar ds a n d I n vesti g at ors
T he S p o ns or will se n d a p pr o priate safety n otificati o ns t o Healt h A ut h orities i n acc or da nce wit h 
a p plica ble la ws a n d re g ulati o ns.
T he I n vesti gat or m ust c o m pl y wit h an y  ap plica ble site-s pecific re q uire me nts relate d t o t he 
re p orti n g of S A Es ( partic ularl y deat hs) i n v ol vi n g st u d y partici pa nt s t o t he I E C/IR B t hat a p pr o ve d 
t he st u d y.
I n acc or da nce wit h I C H G C P, t he S p o ns or/ desi g nee will i nf or m t he I n vesti gat or of “fi n di n gs t hat 
c o ul d a d versel y affect t he safety of partici pa nt s, i m pact t he c o n d uct of t he st u d y or alter t he 
I E C’s/I R B’s a p pr o val/fa v ora ble o pi ni o n t o c o nti n ue t he st u d y.” I n partic ular a n d i n li ne wit h 
res pecti ve re g ulati o ns, t he S p o ns or/ desi g nee will i nf or m t he I nvesti gat or of A Es t hat are b ot h 
seri o us a n d u ne x pecte d a n d are c o nsi dere d t o be relate d t o t he a d mi nistere d pr o d uct (“s us pecte d 
u ne x pecte d seri o us a d verse reacti o ns” or S U S A Rs). T he I n vesti gat or s h o ul d place c o pies of Safet y 
Re p orts i n t he I n vesti gat or S ite File. Nati o nal re g ulati o ns wit h re gar d t o Safet y  Re p ort n otificati o ns 
t o I nvesti gat or s will be c o nsi dere d .
W he n 
s pecificall y re q uire d b y  re g ulati o ns a n d g ui deli nes, t he S p o ns or/ desi g nee will pr o vi de 
a p pr o priate Safet y Re p orts directl y  to t he c o ncer ne d lea d I E C/IR B a n d will mai ntai n rec or ds of 
t hese n otificati o ns. W he n 
direct re p orti n g is n ot clearl y defi ne d b y  nati o nal or site-s pecific 
re g ulati o ns, t he I n vesti gat or will be res p o nsi ble f or pr o m ptl y  n otif yi n g t he c o ncer ne d I E C/IR B of 
a n y Safet y Re p orts pr o vi de d b y  the S p o ns or/ desi g nee a n d of fili n g c o pies of all relate d 
c orres p o n de nce i n t he I nvesti gat or Site File.
F or st u dies c o vere d b y  the E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C, t he S p o ns or’s res p o nsi bilities 
re gar di n g t he re p orti n g of S A Es/ S U S A Rs/ Safet y  Iss ues will be carrie d o ut i n acc or da nce wit h t hat 
Directi ve a n d wit h t he relate d Detaile d G ui da nce d oc u me nts.
7. 5. 1. 6
M o nit ori n g of P artici p a nt s wit h A d verse E ve nts
A Es are rec or de d a n d assesse d c o nti n u o usl y thr o u g h o ut t he st u d y (see Secti o n 7. 5. 1. 3 ) a n d are 
assesse d f or fi nal o utc o me at t he Safet y F oll o w - u p Visit .All S A Es o n g oi n g at t he Safet y  Foll o w - u p 
Visit m ust be m o nit ore d a n d f oll o we d u p b y  the I n vesti gat or u ntil sta bilizati o n or u ntil t he o utc o me 
is k n o w n, u nless t he partici pa nt is d oc u me nte d as “l ost t o f oll o w-u p”. Reas o na ble atte m pts t o 
o btai n t his i nf or mati o n m ust be ma de a n d d oc u me nte d. It is als o t he res p o nsi bilit y of t he 
I n vesti gat or t o e ns ure t hat a n y necessar y ad diti o nal t hera pe utic meas ures a n d f oll o w- u p pr oce d ures 
are perf or me d. 
7. 5. 2
Pre g n a nc y a n d I n Uter o Dr u g E x p os ure 
7. 5. 2. 1
Pre g n a nc y
T he pre g na ncies c o nsi dere d t o be relate d t o t he st u d y inter ve nti o n b y  t he I n vesti gat or (e. g., 
res ulti n g fr o m a dr u g i nteracti o n wit h a c o ntrace pti ve met h o d) are A Es. H owe ver, all pre g na ncies 
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
wit h a n esti mate d c o nce pti o n date d uri n g t he peri o d defi ne d i n Secti o n  7. 5. 1. 3 m ust be rec or de d 
i n t he A E pa ge/secti o n of t he eC R F f or b ot h pre g na ncies i n fe male partici pa nts a n d pre g na ncies  i n 
fe male part ners of male partici pa nts. T he I n vesti gat or m ust n otif y  the S p o ns or/ desi g nee i n a n 
e x pe dite d ma n ner of a n y pre g na nc y usi n g t he Pre g na nc y Re p ort F or m, w hic h m ust be tra ns mitte d 
b y  t he sa me pr ocess s pecifie d f or S A E re p orti n g.
I n vesti gat ors m ust 
acti vel y foll o w - u p, d oc u me nt a n d re p ort o n t he o utc o me of all t hese 
pre g na ncies, e ve n if t he partici pa nts are wit h dra w n fr o m t he st u d y .
T he I n vesti gat or m ust n otif y  t he S p o ns or/ desi g nee of t hese o utc o mes usi n g t he Pre g na nc y Re p ort 
F or m. If a n a b n or mal o utc o me occ urs, t he S A E Re p ort F or m will be use d if t he partici pa nt s ustai ns 
a n e ve nt a n d t he Pare nt -C hil d/ Fet us A d verse E ve nt Re p ort F or m if t he c hil d/fet us s ustai ns a n 
e ve nt. A n y a b n or mal o utc o me (e. g., s p o nta ne o us a b orti o n, fetal deat h, still birt h, c o nge nital 
a n o malies, ect o pic pre g na nc y ) m ust 
be re p orte d i n a n e x pe dite d ma n ner, 
as s pecifie d i n 
Secti o n 7. 5. 1. 3, w hile n or mal o utc o mes m ust be re p orte d wit hi n 4 5 da y s after deli ver y.
I n t he e ve nt of a pre g na nc y  in a partici pa nt occ urri n g d uri n g t he st u d y, t he partici pa nt m ust be 
disc o nti n ue d fr o m st u d y inter ve nti o n. T he S p o ns or/ desi g nee m ust be n otifie d wit h o ut dela y  an d 
t he partici pa nt m ust be f oll o we d as i n dicate d a b o ve.
L act ati o n
It is u n k n o w n if M 4 3 4 4 is e xcrete d i n h u ma n breast mil k . Beca use of t he p ote ntial f or seri o us 
reacti o ns i n breastfee di n g i nfa nts, w o me n s h o ul d be a d vise d n ot t o breastfee d w hile ta ki n g M 4 3 4 4 
a n d f or 6 m o nt hs after cessati o n of treat me nt.
7. 5. 2. 2
C o ntr ace pti o n
S trict use of c o ntrace pti o n is re q uire d f or at least 6 m o nt hs after t he last d ose of M 4 3 4 4. Male
partici pa nts treate d wit h M 4 3 4 4 are a d vise d t o use effecti ve c o ntrace pti o n a n d t o a v oi d fat heri n g 
a c hil d d uri n g a n d u p t o 3 m o nt hs after treat me nt. Partici pa nts s h o ul d be i nf or me d t hat fertilit y 
mi g ht be i m paire d l o n g- ter m a n d ma y o pt t o cr yo preser ve s per m or o va pri or t o treat me nt.
Fe male partici pa nt s of c hil d beari n g p ote ntial ( defi ne d bel o w) a n d male partici pa nt s wit h part ners 
of c hil d beari n g p ote ntial m ust a d here t o c o ntrace pti o n g ui deli nes as descri be d bel o w.
W o m a n of C hil d be ari n g P ote nti al 
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 nclear (e. g., a me n orr hea i n a d olesce nts or at hletes) a n d a me nstr ual c ycle ca n n ot be 
c o nfir me d bef 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 ma n of c hil d beari n g p ote ntial is n ot :
1.
Pre me narc hal
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
2.
A pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:
o
D oc u me nte d h ys terect o m y
o
D oc u me nte d bilateral sal pi n gect o m y
o
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 he fe male’s me dical rec or ds, 
me dical e xa 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 dical 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), In 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 male
o
A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n 
alter nati ve me dical ca use.

A hi g h F S H le vel i n t he p ost me n o pa usal ra n ge ma y  be 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 nal re place me nt t hera p y  ( H R T). H o we ver, 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 uire d 
i n t he p ost me n o pa usal ra n ge.
o
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 H R T d uri n g t he st u d y. Ot her wise, t he 
partici pa nts 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 dy e nr oll me nt.
Acce pta ble c o ntrace pti ve met h o ds m ust be use d fr o m t he 2 8 da y s (f or fe male partici pa nts) or fr o m 
t he Scree ni n g Visit (f or male partici pa nts) bef ore first d ose of st u d y dr u g t hr o u g h 6 m o nt hs after 
t he last d ose of st u d y dr u g a n d i ncl u de t he f oll o wi n g: 

I m pla nta ble pr o gest o ge n -o nl y  hor 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 sys te m (I U S)

Bilateral t u bal occl usi o n

Vasect o mize d part ner: a hi g hl y e ffecti ve c o ntrace pti ve met h o d pr o vi de d t hat t he part ner 
is t he s ole se x ual part ner of a W O C B P a n d t he a bse nce of s per m has bee n c o nfir me d. 
Ot her wise, 
use a n a d ditio 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 matel y 9 0 da ys.
N otes:

C o ntrace pti ve use b y  me n or w o me n is c o nsiste nt wit h l ocal re g ulati o ns o n t he use of 
c o ntrace pti ve met h o ds f or cli nical st u d y  partici pa nts.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9

Hi g hl y effecti ve met h o ds are t h ose wit h a fail ure rate of < 1 % per ye ar w he n use d 
c o nsiste ntl y an 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.

If l ocall 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.

Peri o dic a bsti ne nce (cale n dar, s ym pt ot her 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 hea met h o d are n ot 
acce pta ble met h o ds of c o ntrace pti o n f or t his st u d y. 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 her ( d ue t o ris k of fail ure wit h fricti o n).
Male partici pa nt s m ust n ot d o nate s per m fr o m t he Scree ni n g Visit t hr o u g h 6 m o nt hs after t he last 
d ose of st u d y  dr u g.
7. 5. 3
Cli nic al L a b or at or y Assess me nts
Bl o o d sa m ples will be a nal yze d at a l ocal or ce ntral la b orat or y . O n all st u d y da ys, bl o o d sa m ples 
s h o ul d be c ollecte d bef ore t he first d ose of t he st u d y dr u g. C he mistr y an d he mat ol o g y  testi n g will 
be perf or me d o n t he da ys  specifie d i n t he Sc he d ule of Assess me nts (see Ta ble 1 , Ta ble 2 , Ta ble 3 , 
Ta ble 4, Ta ble 5 , Ta ble 6, Ta ble 7 , a n d Ta ble 9 ).
T he list of a nal ytes f or eac h pa nel is s h o w n i n Ta ble 1 5.  All a nal ytes will be teste d at Scree ni n g. 
F or ot her visits, certai n a nal y tes will n ot be assesse d at e ver y c he mistr y or he mat ol o g y ti me p oi nt. 
La b orat or y  test res ults t hat are a b n or mal a n d c o nsi dere d cli nicall y si g nifica nt m ust be re p orte d as 
A E s.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 1 5
S afet y L a b or at or y Test P a nels
S er u m C h e mi str y a
H e m at ol o g y a
Uri n al y si s a, d
Gl u c o s e
Bl o o d ur e a nitr o g e n/ Ur e a b
Cr e ati ni n e
S o di u m
P ot a s si u m
C al ci u m
C hl ori d e
M a g n e si u m
Bi c ar b o n at e
I n or g a ni c p h o s p h at e
T ot al bilir u bi n
Dir e ct bilir u bi n
T ot al pr ot ei n
Al b u mi n
Cr e ati n e ki n a s e c
Al k ali n e p h o s p h at a s e
A s p art at e a mi n otr a n sf er a s e 
Al a ni n e a mi n otr a n sf er a s e
L a ct at e d e h y dr o g e n a s e
Uri c a ci d c
T h yr oi d sti m ul ati n g h or m o n e c
H e m o gl o bi n
Er yt hr o c yt e s
M e a n c or p u s c ul ar 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 
c o n c e ntr ati o n
M e a n c or p u s c ul ar v ol u m e
R eti c ul o c yt e s
Pl at el et s
L e u k o c yt e s
Diff er e nti al ( a b s ol ut e a n d/ or p er c e nt e ):
E o si n o p hil s
B a s o p hil s
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
C o a g ul ati o n st u di e s a, c
A cti v at e d p arti al t hr o m b o pl a sti n ti m e
Pr ot hr o m bi n ti m e
Pr ot hr o m bi n ti m e I nt er n ati o n al 
N or m ali z e d R ati o
L e u k o c yt e e st er a s e
Ni trit e
Ur o bili n o g e n
Uri n e pr ot ei n
p H
Uri n e bl o o d
S p e cifi c gr a vit y
Uri n e k et o n e
Uri n e bilir u bi n
Uri n e gl u c o s e
a
L a b s will b e p erf or m e d at S cr e e ni n g ( P art s A, A 2, A 3 , a n d B 1 : T a bl e 1 ; P art s C 1, C 2, a n d C 3: T a bl e 2 ) a n d 
at s p e cifi e d ti m e s d uri n g t h e Tr e at m e nt a n d F oll o w - up P eri o d (T a bl e 3, T a bl e 4, T a bl e 5, T a bl e 6 , T a bl e 7 , a n d 
T a bl e 9 ).
b
If bl o o d ur e a nitr o g e n c a n n ot b e c oll e ct e d, ur e a m a y b e s u b stit ut e d . 
c  
Cr e ati n e ki n a s e, uri c a ci d, t h yr oi d sti m ul ati n g h or m o n e, a n d c o a g ul ati o n p ar a m et er s will o nl y b e t e st e d at 
S cr e e ni n g. T h yr oi d sti m ul ati n g h or m o n e n ot r e q uir e d f or P art A 3 or P art s C
d
If uri n al y si s r e s ult s ar e p o siti ve f or l e u k o c yt e e st er a s e, nitrit e, pr ot ei n, or bl o o d, mi cr o s c o pi c e x a mi n ati o n of 
uri n e will b e p erf or m e d, a n d r e s ult s pr o vi d e d f or l e u k o c yt e s, er yt hr o c yt e s, cr y st al s, b a ct eri a a n d c a st s.
e 
P er l o c al l a b or at or y a v ail a bilit y.
Safet y  la b orat or y tests fr o m Scree ni n g m ust ha ve n o cli nicall y si g nifica nt fi n di n gs t hat precl u de 
partici pati o n i n t he st u d y , as j u d ge d b y t he I n vesti gat or, i n or der f or a partici pa nt t o be e nr olle d.
Uri nal y sis will be perf or me d at Scree ni n g a n d as cli nicall y i n dicate d.
Ser u m t otal test oster o ne will be meas ure d at Scree ni n g a n d Safet y F oll o w -u p i n male partici pa nt s 
i n Parts A a n d B.
Ser ol o gic t u m or mar kers, i ncl u di n g P S A or C A - 1 2 5, will be meas ure d as per t he Sc he d ule of 
Assess me nts (Ta ble 1,  Ta ble 2,  Ta ble 3,  Ta ble 4 , Ta ble 5, Ta ble 6 , Ta ble 7,  a n d Ta ble 9 ) f or 
partici pa nt s wit h rele va nt t u m ors. A d diti o nal ser ol o gic t u m or 
 m a y  be c ollecte d at ti me 
p oi nts s pecifie d i n t he Sc he d ule of Assess me nts as dee me d a p pr o priate, de pe n di n g o n t he 
partici pa nt 's pri mar y  mali g na nc y (e. g., C E A f or partici pa nt s wit h c ol o n ca ncer or C A 1 9 - 9 f or 
D oc u me nt N o. 
O bject N o. C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
partici pa nt s wit h pa ncreatic ca ncer). Of n ote, ser ol o gic t u m or mar ker data sh o ul d n ot be use d f or 
R E CI S T res p o nse assess me nts or f or treat me nt decisi o ns. 
Pre g na nc y  testi n g f or fe male partici pa nt s of c hil d beari n g p ote ntial (i ncl u des t h ose wit h t u bal 
li gati o n):

At Scree ni n g, o n Da y 1 of C ycle 1, a n d c o nti n ui n g t hr o u g h t he Safet y F oll o w -u p Visit, 
fe male partici pa nt s of c hil d beari n g p ote ntial will be f oll o we d wit h uri ne β- h u ma n 
c h ori o nic g o na d otr o pi n ( β-h C G) testi n g a n d, w he n t here are n o sc he d ule d st u d y visits, 
wit h uri ne h o me pre g na nc y  test kits pr o vi de d b y t he site; a n d

Bi m o nt hl y  (a p pr o xi matel y ever y  8 wee ks) f or 6 m o nt hs f oll o wi n g t he last d ose of st u dy 
dr u g wit h a uri ne h o me pre g na nc y  test kits pr o vi de d b y t he site.
If a ur i ne pre g na nc y  test is p ositi ve, all st u d y dr u g d osi n g will st o p, a n d t he pre g na nc y  will be 
c o nfir me d wit h a ser u m β- h C G test. If c o nfir me d, t he pre g na nc y  will be re p orte d, a n d t he 
partici pa nt will be per ma ne ntl y  wit h dra w n fr o m st u d y dr u g d osi n g as disc usse d i n Secti o n 7. 5. 2 . 
If a pre g na nc y test is p ositi ve, t he pr oce d ures o utli ne d i n Secti o n 7. 5. 2 will be f oll o we d.
A d diti o nal E val uati o ns: A d diti o nal cli nical la b orat or y eval uati o ns will be perf or me d at ot her ti mes 
if j u d ge d t o be cli nically a p pr o priate.
7. 5. 4
Vit al Si g ns, P h ysic al E x a mi n ati o ns, a n d Ot her Assess me nts
7. 5. 4. 1
P h ysic al E x a mi n ati o n a n d Vit al Si g ns
A
p h y sical e xa mi nati o n of all b o d y  sys te ms a n d vital si g ns assess me nt will be perf or me d at 
Scree ni n g a n d selecte d st u d y visits (see Ta ble 1,  Ta ble 2,  Ta ble 3 , Ta ble 4 , Ta ble 5, Ta ble 6,  
Ta ble 7,  a n d Ta ble 9 ). At ot her visits, s ym pt o m -directe d p h y sical e xa mi nati o n a n d s ym pt o m -
directe d vital si g n assess me nts ca n be perf or me d at t he discreti o n of t he I nvesti ga t or or healt hcare 
pr o vi der .
A p h y sical e xa mi nati o n will i ncl u de a re vie w of t he f oll o wi n g s yste ms: hea d/ nec k /t h yr oi d; 
e yes/ears/ n ose/t hr oat ; res pirat or y; car di o vasc ular; l ym p h n o des; a b d o me n; s ki n; m usc ul os keletal; 
a n d ne ur ol o gical. F or partici pa nt s i n Par ts B a n d C, a heari n g assess me nt will be perf or me d as part 
of t he p h y sical e xa mi nati o n at t he Scree ni n g Visit, o n Da y 1 of eac h treat me nt c ycle, a n d at t he 
Safet y  Foll o w - u p Visit. Breast, a n orectal, a n d ge nital e xa mi nati o ns will be perf or me d w he n 
me dicall y
i n dicate d. After Scree ni n g, a n y cli nicall y si gnifica nt a b n or mal fi n di n gs i n p h y sical 
e xa mi nati o ns will be re p orte d as A Es.
Vital si g ns i ncl u de bl o o d press ure (s ys t olic a n d diast olic), te m perat ure, p ulse rate, a n d res pirati o n 
rate. T hese will be assesse d foll o wi n g a 5- mi n ute rest i n t he s u pi ne p ositi o n.
7. 5. 4. 2
Electr oc ar di o gr a m
Sta n dar d 1 2- lea d E C Gs will be perf or me d usi n g a mac hi ne wit h pri nt o ut acc or di n g t o t he Sc he d ule 
of Assess me nts (Ta ble 1,  Ta ble 2,  Ta ble 3,  Ta ble 4,  Ta ble 5, Ta ble 6,  Ta ble 7,  a n d Ta ble 9 ). 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
A d diti o nal sta n dar d 1 2 -lea d E C Gs will be perf or me d at a ny ot her ti me if cli nicall y i n dicate d. T he 
perf or ma nce of all E C Gs will a d here t o t he f oll o wi n g g ui deli nes:

T he partici pa nt will be i nstr ucte d t o rest i n t he s u pi ne p ositi o n f or at least 5 mi n utes 
bef ore ha vi n g a n E C G perf or me d

If p ossi ble, t he E C G will be perf or me d bef ore a n y ot her pr oce d ures t hat ma y  affect heart 
rate, s uc h as bl o o d dra ws.
T he E C G traces will be ma n uall y  rea d at t he st u d y site at t he Scree ni n g a n d Safet y F oll o w -u p 
Visits. T he E C G mac hi ne will c o m p ute t he P R, Q T, a n d Q Tc i nter vals, Q R S d urati o n, a n d heart 
rate. R R i nter vals will be calc ulate d later d uri n g a nal ys is. A pri nt o ut of t he E C G traces will be 
ma de f or safet y re vie w b y t h e I n vesti gat or a n d mai ntai ne d wit h s o urce d oc u me ntati o n. Cli nicall y 
si g nifica nt E C G a b n or malities occ urri n g d uri n g t he st u d y t hr o u g h t he Safet y F oll o w-u p Visit will 
be rec or de d as A Es.
F or partici pa nts i n Sta ges 1 a n d 2 of Parts C, tri plicate 1 2- lea d E C Gs wit h di gital u pl oa d f or 
ce ntralize d a nal ys is will be meas ure d at t he ti mes of M 4 3 4 4 P K sa m pli n g o n Da ys 1 a n d Da y 2 of 
C y cle 1 o nl y.
7. 6
P h ar m ac o k i netics
7. 6. 1
Bl o o d S a m pli n g
F or t he e val uati o n of plas ma co nce ntrati o ns of M 4 3 4 4
(a n d meta b olites
as a p pr o priate), bl o o d 
sa m ples will be c ollecte d fr o m all partici pa nt s acc or di n g t o t he Sc he d ule of Assess me nts (Ta ble 3,  
Ta ble 4,  Ta ble 5 , Ta ble 6 , Ta ble 7 , Ta ble 8,  Ta ble 9,  a n d Ta ble 1 0 ). T hese sa m ples ma y  als o be 
use d f or e val uati o ns of meta b olites of M 4 3 4 4 , f or f urt her e val uati o n of t he bi oa nal ytical met h o d, 
a n d f or a nal ys es t hat pr o vi de i nf or mati o n o n t he meta b olic pat h wa y s use d b y  or affecte d b y  
M 4 3 4 4 .
F or t he deter mi nati o n of M 4 3 4 4 (a n d meta b olites as a p pr o priate ) c o nce ntrati o ns at eac h ti me p oi nt, 
a p pr o xi matel y 4 m L  of bl o o d will be c ollecte d f or plas ma P K ass a ys. Bl o o d sa m ples will b e 
c ollecte d via direct ve ni p u nct ure or b y  an i n d welli n g cat heter i nt o Vac utai ner ® t u bes c o ntai ni n g 
K 2E D T A a ntic oa g ula nt. Detaile d P K bl o o d sa m ple c ollecti o n, pr ocessi n g, ha n dli n g, a n d st ora ge 
i nstr ucti o ns will be pr o vi de d i n t he L a b orat or y Ma n ual. T he s hi p me nt a d dress a n d assa y la b orat or y 
c o ntact i nf or mati o n will be pr o vi de d t o t he i n vesti gati o nal site bef ore i nitiati o n of t he st u d y .
T he P K sa m pli n g sc he d ule m a y  be m o difie d u p o n a gree me nt of t he cli nical p har mac ol o gist a n d 
I n vesti gat ors t o o pti mize t he sa m pli n g ti me f or M 4 3 4 4
dis p ositi o n. All eff orts will be ma de t o 
o btai n t he P K sa m ples at t he e xact n o mi nal ti me relati ve t o d osi n g. Act ual ti me of d osi n g –
i ncl u di n g last pri or d ose f or pre d ose sa m ples a n d act ual P K sa m ple c ollecti o n ti mes m ust be 
d oc u me nte d at t he site a n d rec or de d o n t he e C R F. Acce pta ble wi n d o ws f or sa m pli n g ti mes are 
s h o w n i n Ta ble 1 6.  T hese wi n d o ws a p pl y to b ot h t he fi xe d sa m pli n g ti me p oi nts, as t o t he 
b o u n daries of t he s parse sa m pli n g wi n d o ws i n Parts C . Sa m ples c ollecte d o utsi de of t hese 
acce pta ble wi n d o ws will be c o nsi dere d pr ot oc ol de viati o ns. Details of ha n dli n g t hese data will be 
s pecifie d i n t he i nte grate d a nalys is pla n (I A P).
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 1 6
Acce pt a ble P h ar m ac o ki netic S a m pli n g Wi n d o ws
S a m pli n g Ti m e
Ti m e Fr o m S c h e d ul e d S a m pli n g All o w e d
Pr e d o s e
-1 2 0 mi n ut e s
Fr o m 0. 5 0 u p t o ≤1 2 h o ur s aft er d o si n g
± 1 5 mi n ut e s
Fr o m > 1 2 u p t o ≤2 4 h o ur s aft er d o si n g
± 6 0 mi n ut e s
7. 6. 1. 1 
P h ar m ac o k i netic S a m pli n g: P art A
I n Part A, M 4 3 4 4
(a n d meta b olites as a p pr o priate) P K will be assesse d i n plas ma as f oll o ws:

C y cle 1, D a y 1: 0 ( bef ore d osi n g) a n d at 0. 5, 1, 1. 5, 2, 3, 4, 8, a n d 2 4 h o urs ( Da y 2) after 
d osi n g

C y cle 1, D a y 8: 0 ( bef ore d osi n g) a n d at 0. 5, 1, 1. 5, 2, 3, 4, 8, a n d 2 4 h o urs ( Da y 9) after 
d osi n g

C y cle 1, Da y 1 5: 0 h o urs ( bef ore d osi n g).
7. 6. 1. 2
P h ar m a c o ki netic S a m pli n g: P art A 2
I n Part A 2, M 4 3 4 4 (a n d meta b olites as a p pr o priate) P K will be assesse d i n plas ma as f oll o ws:

C y cle 1, Da y 1: 
o
0 h o urs ( bef ore 1 st d ose) a n d at 0. 5, 1, 1. 5, 2, 3, 4, a n d 8 h o urs ( bef ore 2 n d
d ose , if a p plica ble).
o
F or partici pa nt s u n der g oi n g ti me d-t u m or bi o psies, M 4 3 4 4 
P K will be 
assesse d i n plas ma as f oll o ws: C y cle 1, Da y 1: 0 h o urs ( bef ore 1 st d ose) a n d 
at 0. 5, 1, 1. 5, 4, 8 h o urs ( bef ore 2 n d d ose , if a p plica ble). If feasi ble, P K 
sa m ples s h o ul d als o be c ollecte d at 2 a n d 3 h o urs af ter first d osi n g o n Da y  1.
o
A n o pti o nal 1 2- h o ur sa m ple ( bef ore 2 n d d ose , if a p plica ble) m a y  als o be 
c ollecte d.

C y cle 1 Da y 2: 0 h o urs (at ti me of P B M C sa m ple bef ore Da y  2 d ose) .

C y cle 1, Da y 8: 
o
0 h o urs ( bef ore 1 st d ose) a n d at 0. 5, 1, 1. 5, 2, 3, 4, a n d 8 h o urs ( bef ore 2 n d
d ose , if a p plica ble ). A n o pti o nal 1 2- h o ur sa m ple ma y  als o be c ollecte d 
( bef ore 2n d d ose, if a p plica ble).

C y cle 1, Da y 1 5: 0 h o urs ( bef ore 1 st d osi n g), 2 h o urs . 

S u bse q ue nt c y cles o n D a y  1: 0 h o urs ( bef ore 1 st d osi n g), 2 h o urs .
7. 6. 1. 3
P h ar m ac o k i netic S a m pli n g: P art A 3
I n Parts A 3 , M 4 3 4 4 (a n d meta b olites as a p pr o priate) P K will be assesse d i n plas ma as f oll o w s f or 
eac h of t he p ote ntial dr u g- h oli da y  sc he d ules.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 1 7
P h ar m ac o ki netic S a m pli n g Sc he d ule f or P art A 3
M 4 3 4 4 Sc he d ule
P K s a m pli n g
3 da y s o n/ 4 d a y s 
off
Or
5 da y s o n/ 2 d a y s 
off
M 4 3 4 4
(a n d meta b olites) plas ma P K sa m ples will be c ollecte d d uri n g 
t he f oll o wi n g ti mes:
-C y cle 1 Da y 1: pre d ose at 0 h o urs, p ost d ose at 0. 5, 1, 1. 5, 2, 3, 4 a n d 8
h o urs. A n o pti o nal sa m ple ma y  be c ollecte d at 1 2 h o urs ( bef ore 2 n d
d ose, if BI D d osi n g).
-C y cle 1 Da y 8: pre d ose at 0 h o urs, p ost d ose at 0. 5, 1, 1. 5, 2, 3, 4 a n d 8 
h o urs. A n o pti o nal sa m ple ma y  be c ollecte d at 1 2 h o urs ( bef ore 2 n d
d ose, if BI D d osi n g).
-C y cle 1 Da y 1 5: pre d o se at 0 h o urs a n d p ost d ose at 2 h o urs.
-S u bse q ue nt c ycles o n Da y  1:  pre d ose at 0 h o urs a n d p ost d ose at 2 
h o urs
F or partici pa nts u n der g oi n g ti me d-t u m or bi o psies, P K sa m ples o n 
C y cle 1 Da y 1 at 2 a n d 3 h o urs after d osi n g s h o ul d be c ollecte d o nl y if 
feasi ble.
If Cycle 1, Da y 8 occ urs d uri n g a d ose i nterr u pti o n, C ycle 1, Da y  8 P K 
sa m pli n g will be c ollecte d o n C ycle 2, Da y 1 i nstea d.
7 da y s o n/ 7 d a y s 
off
M 4 3 4 4 (a n d meta b olites) plas ma P K sa m ples will be c ollecte d d uri n g 
t he f oll o wi n g ti mes:
-C y cle 1 Da y 1: pred ose at 0 h o urs, p ost d ose at 0. 5, 1, 1. 5, 2, 3, 4 a n d 8
h o urs. A n o pti o nal sa m ple ma y  be c ollecte d at 1 2 h o urs ( bef ore 2 n d
d ose, if BI D d osi n g).
-C y cle 1 Da y 1 5: pre d ose at 0 h o urs a n d p ost d ose at 2 h o urs .
-C y cle 2 D a y  1: pre d ose at 0 h o urs, p ost d ose at 0.5, 1, 1. 5, 2, 3, 4 a n d 8 
h o urs. A n o pti o nal sa m ple ma y  be c ollecte d at 1 2 h o urs ( bef ore 2 n d
d ose, if BI D d osi n g).
-S u bse q ue nt c ycles o n Da y  1:  pre d ose at 0 h o urs a n d p ost d ose at 2 
h o urs
F or partici pa nts u n der g oi n g ti me d-t u m or bi o psies, P K sa m ples o n 
C y cle 1 Da y  1 at 2 a n d 3 h o urs after d osi n g s h o ul d be c ollecte d o nl y if 
feasi ble.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
1 4 da y s o n/ 7 d a y s
off
T his re gi me n will use t he P K sa m pli n g sc he d ule fr o m Part A 2 wit h t he 
C y cle 1 Da y 2 pre d ose a n d C y cle 1 Da y  1 5 p ost d ose sa m ples o mitte d.
7. 6. 1. 4
P h ar m ac o k i netic S a m pli n g: P art B1
I n Part B 1 , f or partici pa nt s n ot u n der g oi n g ti me d-t u m or bi o psies, M 4 3 4 4 P K will be assesse d i n 
plas ma as f oll o ws:

C y cle 1, D a y 2: 0 h o urs ( bef ore d osi n g) a n d at 0. 5, 1, 1. 5, 2, 3, 4, 8, a n d 2 4 h o urs 
( Da y 3) after d osi n g

C y cle 1, Da y 9: 0 h o urs ( bef ore d osi n g).
I n Part B 1 , f or partici pa nt s u n der g oi n g ti me d-t u m or bi o psies, M 4 3 4 4 P K will be assesse d i n 
plas ma as f oll o ws:

C y cle 1, D a y 2: 0 h o urs ( bef ore d osi n g) a n d at 0. 5, 1, 1. 5, 4, 8, a n d 2 4 h o urs ( Da y 3) 
after d osi n g. If feasi ble, P K sa m ples s h o ul d als o be c ollecte d at 2 a n d 3 h o urs after 
d osi n g

C y cle 1, Da y 9: 0 h o urs ( bef ore d osi n g).
7. 6. 1. 5
P h ar m ac o k i netic S a m pli n g: P arts C
I n Parts C 1- 3, M 4 3 4 4
(a n d meta b olites as a p pr o priate) P K will be assesse d i n plas ma usi n g s parse 
sa m pli n g d uri n g sa m ple c ollecti o n wi n d o ws as f oll o ws:

C y cle 1, Da y 1 ( 3 sa m ples): 
o
0 ( bef ore d osi n g) 
o
bet wee n 0. 5 -2. 0 h o urs after d osi n g
o
e n d of visit, at least 1 h after t he pre vi o us sa m ple

C y cle 1, D a y s 8 a n d 1 5: at t he start a n d e n d of t he visit, at least 1 h o urs a part ( 2 sa m ples)

C y cle 2, Da y 1 a n d e ver y sec o n d c ycle u ntil C ycle 8, Da y 1: at t he start a n d e n d of t he 
visit, at least 1 h o ur a part ( 2 sa m ples)

C y cle 1 2, D a y  1 a n d e ver y f o urt h c ycle: at t he start a n d e n d of t he visit, at least 1 h a part
( 2 sa m ples)
F or dr u g h oli da y  sc he d ules i n P arts C 4 - 6, P K sa m pli n g ti me p oi nts are pr o vi de d i n t he f oll o wi n g 
ta ble, s pecificall y f or eac h sc he d ule.
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
T a ble 1 8 
P h ar m ac o ki netic S a m pli n g Sc he d ule f or P arts C 4, C 5, a n d C 6
M 4 3 4 4 Sc he d ule
P K s a m pli n g
3 da y s o n/ 4 d a y s 
off
Or
5 da y s o n/ 2 d a y s 
off
M 4 3 4 4 (a n d meta b olites) plas ma P K sa m ples will be c ollecte d d uri n g 
t he f oll o wi n g ti mes:
-C y cle 1 Da y 1: pre d ose at 0 h o urs, p ost d ose at 0. 5 t o 2 h o urs, a n d e n d 
of visit (at least 1 h o urs after t he pre vi o us sa m ple).
-C y cle 1 D a y  8: 2 sa m ples, at t he start a n d e n d of visit, at least 1 h o ur 
a part.
-C y cle 1 Da y 1 5: 2 sa m ples, at t he start a n d e n d of visit, at least 1 h o ur 
a part.
-E ver y  sec o n d c ycle d uri n g C ycles 2 -8 o n Da y 1: 2 sa m ples, at t he start 
a n d e n d of visit, at least 1 h o ur a part.
-E ver y  fo urt h c ycle fr o m C y cle 1 2 o n war ds o n Da y  1: 2 sa m ples, o ne 
at start a n d o ne at e n d of visit, at least 1 h o ur a part.
7 da y s o n/ 7 d a y s
off
M 4 3 4 4 (a n d meta b olites) plas ma P K sa m ples will be c ollecte d d uri n g 
t he f oll o wi n g ti mes:
-C y cle 1 Da y 1: pre d ose at 0 h o urs, p ost d ose at 0. 5 t o 2 h o urs, a n d e n d 
of visit (at least 1 h o urs after t he pre vi o us sa m ple).
-C y cle 1 Da y 1 5: 2 sa m ples, at t he start a n d e n d of visit, at least 1 h o ur 
a part.
-E ver y  sec o n d c ycle d uri n g C ycles 2 -8 o n Da y 1: 2 sa m ples, at t he start 
a n d e n d of visit, at least 1 h o ur a part.
-E ver y  f o urt h c ycle fr o m C ycle 1 2 o n war ds o n Da y 1 : 2 s a m ples, at t he 
start a n d e n d of visit, at least 1 h o ur a part.
1 4 da y s o n/ 7 d a y s
off
See P K sa m pli n g sc he d ule fr o m Part C 1 - 3.
Ti me a n d date of a d mi nistrati o n of t he last d ose ta ke n pri or t o eac h P K sa m ple is t o be rec or de d 
o n t he e C R F. Partici pa nt s ma y  co nti n ue t o ta ke dr u g at t heir us ual sc he d ule a n d are re q uire d t o 
re p ort ti me of a d mi nistrati o n w he n atte n di n g t heir P K visit.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
7. 6. 3
Pr ocessi n g a n d H a n dli n g of P h ar m ac o ki netic S a m ples
Detaile d pr oce d ures f or t he c ollecti o n of bl o o d a n d 
 sa m ples a n d f urt her pr oce d ures f or 
pr ocessi n g a n d ha n dli n g of sa m ples f or P K a nal ysis will be pr o vi de d i n t he Sa m ple Ha n dli n g 
G ui deli nes. T he s hi p me nt a d dress a n d assa y la b orat or y c o ntact i nf or mati o n will be pr o vi de d t o t he 
i n vesti gati o nal site bef ore i nitiati o n of t he st u d y.
7. 6. 4
Bi o a n al ysis
Plas ma sa m ples will be a nal y ze d usi n g a vali date d a nal ytical met h o d i n c o m plia nce wit h S p o ns or
or desi g nee sta n dar d o perati n g pr oce d ures. A descri pti o n of t he assa y an d vali dati o n data will be 
pr o vi de d i n se parate re ports. Uri ne sa m ples will be a nal yz e d usi n g a q ualifie d assa y. A descri pti o n 
of t he assa y  will be i ncl u de d i n a se parate re p ort.
If re q uire d, w h ole bl o o d, plas ma, or uri ne sa m ples ma y  be utilize d f or assa y vali dati o n or 
q ualificati o n a n d m a y  be f urt her a nal yz e d t o d oc u me nt t he prese nce of circ ulati o n meta b olites 
usi n g q ualifie d researc h met h o ds. Sa m ples o btai ne d f or P K a nal ys es m a y  be use d f or t he f ut ure 
meta b olite i de ntificati o n a n d/ or ot her e x pl orat or y  eval uati o ns. T hese data will be use d f or 
e x pl orat o r y p ur p oses a n d ma y n ot be i ncl u de d i n t he cli nical st u d y re p ort. I n a d diti o n, P K sa m ples 
ma y  be st ore d f or f ut ure a nalys es of pr otei n bi n di n g, ot her pr otei n relate d a nal ys es, bi oc he mistr y, 
bi o mar ker, a n d meta b olite pr ofili n g. Sa m ples will be a nal yz e d usi n g a n o nc haracterize d assa y 
( n o n vali date d). 
 
S u bse q ue nt a nal ys es wit h vali date d met h o ds, w hic h were first de vel o pe d i n 
parallel t o t he c o n d uct of Part A 2, will be re p orte d i n t he cli nical st u d y  re p ort.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 0 / 1 5 9
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C
C
I
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
8
St atis tics
A nal y sis of all data, i ncl u di n g safety, a n d P K pr ofiles will be perf or me d b y  the S p o ns or or its 
desi g nee. T he res ults of all parts of t he st u d y will be re p orte d i n t he C li nical S t u d y Re p ort. A 
detaile d a nal ys is pla n f or t he a nal ysis of safet y, efficac y, a n d P K data will be prese nte d i n t he IA P 
bef ore t he data base is l oc ke d f or a nal ys is. A detaile d pla n f or t he a nal ys is of e x pl orat or y bi o mar ker 
data will be prese nte d i n a se parate bi o mar ker a nal y sis pla n.
D oc u me nt N o. 
O bject N o. C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 9
8. 1
Se q ue nce of A n al yses
P art s C
A n I n depe n de nt Data M o nit ori n g C o m mittee (I DM C ) will be i m ple me nte d f oc usi n g o n t he re vie w 
of safet y data after Sta ge 1 a n d Sta ge 2 of eac h st u d y part. Details will be pr o vi de d i n a n I D M C 
c harter.
I nteri m effic ac y a n al yses after St a ge 1
T he a nal ys es f or Parts C w ill be perf or me d se paratel y.
T he i nteri m a nal yses will be perf or me d o nce all partici pa nts i n Sta ge 1 ha ve bee n e nr olle d. T he 
e nr ol lme nt f or Sta ge 2 will be starte d o nce at least 1 partici pa nt i n Sta ge 1 has s h o w n at least 
1 c o nfir me d C R/ P R. I n case n o res po n ders are re p orte d, e nr ollme nt will be st o p pe d o nce t he last 
partici pa nt is e nr olle d i n Sta ge 1.
T he c ut off date of t he i nteri m a nal ys is is defi ne d b y  the ti me p oi nt at w hic h e ver y partici pa nt i n 
Sta ge 1 has met at least 1 of t he f oll o wi n g criteria:

Ha ve pr o gresse d acc or di n g t o R E CI S T 1. 1, 

Ha ve s h o w n a n o bjecti ve res p o nse, 

Ha ve st o p pe d pla n ne d o n -st u d y t u m or assess me nt f or a ny reas o n, 

Starte d treat me nt at least 6 m o nt hs a g o.
I nteri m effic ac y a n al yses after St a ge 2
T he (i nteri m) a nal ys is f or eac h st u d y part will be perf or me d after all partici pa nts i n Sta ge 2 of t hat 
part ha ve bee n e nr olle d. T he e nr ollme nt f or Sta ge 3 will n ot start u ntil at least 4 partici pa nts i n 
Sta ge 1 a n d 2 ha ve s h o w n a c o nfir me d C R/ P R. I n case 3 or fe wer res p o n ders are re p orte d, 
e nroll me nt will be st o p pe d w he n t he last partici pa nt is e nr olle d i n Sta ge 2.
T he c ut off date of t he i nteri m a nal ys is is defi ne d b y  t he ti me p oi nt w he n all partici pa nts i n Sta ge 1 
a n d 2 meet at least 1 of t he f oll o wi n g criteria:

Ha ve pr o gresse d acc or di n g t o R E CI S T 1. 1, 

ha ve s h o w n a n o bjecti ve res p o nse, 

St o p pe d pla n ne d o n -st u d y t u m or assess me nt f or a n y reas o n, 

Starte d treat me nt at least 6 m o nt hs a g o.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 3 / 1 5 9
Pri m ar y a n al ysis
T he pri mar y  anal y sis is pla n ne d t o occ ur o nce all e nr olle d partici pa nts ha ve met at least 1 o f t he 
f oll o wi n g criteria:

S h o w n a c o nfir me d B est O verall R es p o nse of P R or C R, 

Ha ve pr o gresse d acc or di n g t o R E CI S T 1. 1, 

St o p pe d pla n ne d o n -st u d y t u m or assess me nt f or a n y reas o n

Starte d treat me nt at least 1 2 m o nt hs a g o .
F oll o w -U p a n al yses
T he f oll o w- u p a nal ys is will be perf or me d at t he e n d of t he st u d y. Details will be pr o vi de d i n t he 
I A P.
T he o verall safet y pr ofile of M 4 3 4 4 will be assesse d i n ter ms of t he f oll o wi n g safet y e n d p oi nts: 

I nci de nce of D L Ts ,

I nci de nce of T E A Es, i ncl u di n g A Es lea di n g t o d ose m o dificati o ns or disc o nti n uati o ns ,

Cli nical la b orat or y  val ues,

E C G o utc o mes ,

Vital si g ns .
D oc u me nt N o. 
O bject N o. C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 4 / 1 5 9
D oc u me nt N o. 
O bject N o. C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 5 / 1 5 9
8 . 3
R a n d o miz ati o n
N ot a p plica ble.
8. 4
E n d p oi nts
8. 4 . 1
Pri m ar y E n d p oi nts
8. 4 . 1. 1
P art A

Safet y  para meters, i ncl u di n g A Es, cli nical la b orat or y val ues (ser u m c he mistr y an d 
he mat ol o g y ), vital si g ns, a n d E C G assess me nts

M T D a n d/ or R P 2 D of si n gle a ge nt M 4 3 4 4
a d mi nistere d BIW.
8. 4 . 1. 2
P art s A 2 a n d A 3

Safet y  para meters, i ncl u di n g A E s, cli nical la b orat or y val ues (ser u m c he mistr y an d 
he mat ol o g y ), vital si g ns, a n d E C G assess me nts

M T D a n d/ or R P 2 D of si n gle a ge nt M 4 3 4 4 a d mi nistere d wit h a d ose de nse sc he d ule.
8. 4 . 1. 3
P art B 1

Safet y  para meters, i ncl u di n g A E s, cli nical la b orat or y val ues (ser u m c he mistr y an d 
he mat ol o g y ), vital si g ns, a n d E C G assess me nts

M T D a n d/ or R P 2 D of M 4 3 4 4
a d mi nistere d i n c o m bi nati o n wit h car b o plati n .
8. 4 . 1. 4
P art s C

Occ urre n ce of:
o
T E A Es a n d treat me nt -relate d A Es gra de d acc or di n g t o N CI-C T C A E
( Versi o n 5)
o
L a b orat or y a b n or malities
o
Cli nicall y  si g nifica nt ab n or mal vital si g n
o
Cli nicall y  si g nifica nt a b n or mal E C G

O bjecti ve res p o nse (i.e. c o nfir me d C R or P R) acc or di n g t o R E CI S T 1. 1 as assesse d b y  
t he In vesti gat or .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 6 / 1 5 9
8. 4 . 2
Sec o n d ar y E n d p oi nts
8. 4 . 2. 1
P art A

P K para meter esti mates of si n gle a ge nt M 4 3 4 4
a d mi nistere d BI W, deri ve d fr o m plas ma 
c o nce ntrati o n-ti me data

O R a n d disease sta bilizati o n as e val uate d b y R E CI S T 1. 1.
8. 4 . 2. 2
P art s A 2 a n d A 3

P K para meter esti mates of si n gle a ge nt M 4 3 4 4 
(a n d meta b olites as a p pr o priate) 
a d mi nistere d wit h 
a t wice dail y or o nce d ail y  sc he d ule, deri ve d fr o m plas ma 
c o nce ntrati o n-ti me data

O R a n d disease sta bilizati o n as e val uate d b y R E CI S T 1. 1
8. 4 . 2. 3
P art B 1

P K para meter esti mates of M 4 3 4 4
a d mi nistere d i n c o m bi nati o n wit h car b o plati n 
deri ve d fr o m plas ma c o nce ntrati o n -ti me data

O R as e val uate d b y Res p o nse Criteria E val uati o n R E CI S T 1. 1.
8. 4 . 2. 4
P art s C

C o nfir me d Best O verall Res p o nse (res p o nse assess me nt acc or di n g t o R E CI S T 1. 1 as 
assesse d b y t he In vesti gat or will be use d)

D urati o n of res p o nse assesse d fr o m C R or P R u ntil pr o gressi o n of disease ( P D), deat h, 
or last t u m or assess me nt

Pr o gressi o n -free s ur vi val

O verall s ur vi val

P K para mete r esti mates of M 4 3 4 4 
(a n d meta b olites as a p pr o priate) i n i n di vi d ual 
partici pa nts wit h l oss- of-f u ncti o n m utati o ns.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 7 / 1 5 9
8. 4 .3. 5
A n al ysis Sets
P art s A, A 2, A 3, a n d B 1
T he Safet y A nal ysis Set
Defi ne d as all e nr olle d partici pa nt s w h o recei ve d at least 1 d ose of st u d y dr u g. T he safety a nal ys is 
set will be use d f or safet y a n al yses.
T he D L T E val ua ble Set
Defi ne d as all partici pa nt s e nr olle d i n Parts A or B w h o eit her:

E x perie nce d a D L T bef ore t he e n d of C y cle 1 or
D oc u me nt N o. 
O bject N o. C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 8 / 1 5 9

Recei ve d all sc he d ule d assess me nts t hr o u g h t he e n d of C y cle 1 (i ncl u di n g Da y 1 of 
C y cle 2) a n d recei ve d d oses of M 4 3 4 4 a n d/ or car b o plati n, as s pecifie d i n Secti o n
5. 2. 7
wit h c o m plia nce t o st u d y pr o hi bite d me dici ne a n d dietar y  restricti o ns (Ta ble 1 3 ).
T he F ull A nal ys is Set
F or Parts A a n d B, t he f ull a nal y sis set is defi ne d as all e nr olle d partici pa nt s w h o recei ve d at least 
1 d ose of st u d y  dr u g, ha ve a baseli ne sca n a n d ha ve at least 1 disease assess me nt o n treat me nt. 
P art C
T he a nal ys is p o p ulati o ns are s pecifie d bel o w. T he fi nal decisio n t o e xcl u de partici pa nts fr o m a n y 
a nal ys is p o p ulati o n will be ma de d uri n g t he data re vie w meeti n g pri or t o data base l oc k. 
A n al y s i s S et
D e s cri pti o n
E nr oll e d
All p arti ci p a nt s, w h o si g n 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)
All 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 M 4 3 4 4.
8. 5
Descri pti o n of St atistic al A n al yses
T his secti o n prese nts a s u m mar y of t he pla n ne d statistical a nal yses of efficac y an d safet y  for t his 
st u d y. Met h o d ol o gical details (e. g., missi n g data ha n dli n g) will be pr o vi de d i n the IA P f or t his 
st u d y, w hic h will be fi nalize d bef ore cli nical data base l oc k.
8. 5. 1
P art C
All efficac y  a nal yses will be perf or me d o n t he f ull a nalys is set (F A S ). 
A nal y sis o n baseli ne c haracteristics a n d de m o gra p hics as well as t he safet y anal ys is will be
perf or me d o n t he safet y a nal yses set (S A F ).
T he statistical a nal ysis of P K, 
a n d 
 data will be perf or me d o n t he res pecti ve 
a nal ys is sets.
8. 5. 1. 1
Se q ue nce of a n al yses
I nteri m a nalys is is p la n ne d after Sta ge 1 a n d after Sta ge 2.
T he pri mar y a nal ys is will ta ke place w he n all partici pa nts are e nr olle d (f or details see Secti o n  8. 1 ), 
w hereas t he fi nal F U -a nal ysis is pla n ne d w he n all partici pa nts ha ve c o m plete d t he st u d y.
8. 5. 1. 2
D at a C ut o ff
T he c ut off dates f o r all a nalys es are defi ne d i n Secti o n  8. 1.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C C
I
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 9 / 1 5 9
8. 5. 1. 3
Si g nific a nce le vel
A n o mi nal si g nifica nce le vel of 5 % will be use d. N o a dj ust me nt f or m ulti plicit y  will be ma de.
8. 5. 1. 4
S u m m ar y st atistics a n d c o nfi de nce i nter v als
C o nti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics, i.e., n u m ber of partici pa nt s 
( N), mea n, me dia n, sta n dar d de viati o n, 2- si de d 9 5 % CI s w here a p pr o priate, 2 5 t h a n d 7 5 t h
perce ntiles, mi ni m u m , a n d ma xi m u m.
Q ualitati ve varia bles a n d rates wi ll be s u m marize d b y co u nts a n d perce nta ges al o n g wit h 2- si de d 
e xact Cl o p per -Pears o n 9 5 % CI s. U nless ot her wise state d, t he calc ulati o n of pr o p orti o ns will be 
base d o n t he sa m ple size of t he a nal ysis set of i nterest. C o u nts of missi n g o bser vati o ns will be 
i ncl u de d i n t he de n o mi nat or a n d prese nte d as a se parate cate g or y .
8. 5. 1. 5
B aseli ne me as ure me nt
T he last meas ure me nt 
pri or t o first a d mi nistrati o n of M 4 3 4 4 
will ser ve as t he baseli ne 
meas ure me nt.
8. 5. 1. 6
O n- tre at me nt peri o d
T he O n -treat me nt peri o d is defi ne d b y  the start of treat me nt u ntil 2 8 da y s after t he last 
a d mi nistrati o n of M 4 3 4 4.
8. 5. 1. 7
P o oli n g acr oss ce nters
T o pr o vi de o verall esti mates of t he treat me nt effects, data will be p o ole d acr oss ce nters. T he fact or 
ce nter will n ot be c o nsi dere d i n statistical m o dels or f or s u b gr o u p a nal ys es beca use of t he hi g h 
n u m ber of partici pati n g ce nters a n d t he a ntici pate d s mall n u m ber of partici pa nt s e nr olle d at eac h 
ce nter.
N o f urt her a nal ys es are pla n ne d.
8. 5. 2
Ge ner al C o nsi der ati o ns
F or all parts, c o nti n u o us data wil l be s u m marize d b y  dose a n d visit usi n g t he f oll o wi n g descri pti ve 
s u m mar y statistics: t he n u m ber of o bser vati o ns ( n), mea n, S D, sta n dar d err or ( S E), me dia n, 
mi ni m u m val ue, a n d ma xi m u m val ue. Cate g orical data will be s u m marize d usi n g c o u nts a n d 
perce nta ges. All partici pa nt data, i ncl u di n g t h ose deri ve d, will be prese nte d i n t he partici pa nt data 
listi n gs; listi n gs will dis pla y all partici pa nt s w h o were e nr olle d, re gar dless of w het her or n ot t he y 
recei ve d t he st u dy dr u g.
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 0 / 1 5 9
8. 5. 3
B ac k gr o u n d C h ar acteristics
8. 5. 3. 1
P artici p a nt Dis p ositi o n
T he n u m ber a n d perce nta ge of partici pa nt s i n eac h dis p ositi o n cate g or y (e. g., ra n d o mize d, 
i ncl u de d i n safety a nal ys is set, D L T E val ua ble S et, f ull a nal ys is set, c o m pleti n g treat me nt peri o d, 
c o m pleti n g t he 1 4- d a y  S afety F oll o w -u p Visit, a n d disc o nti n ui n g st u d y  [ wit h a brea k d o w n of t he 
reas o ns f or disc o nti n uati o n]) will be s u m marize d b y d ose gr o u p.
8. 5. 3. 2
De m o gr a p hics a n d B aseli ne C h ar acteristics
F or all st u d y parts, de m o gra p hics a n d baseli ne c haracteristics will be s u m marize d b y  treat me nt 
gr o u p f or t he safet y a nal ysis set. De m o gra p hics will i ncl u de varia bles s uc h as se x, race, et h nicit y, 
a ge, wei g ht, hei g ht, b o d y mass i n de x, a n d b o d y  s urface area. Baseli ne c haracteristics will i ncl u de 
varia bles s uc h as t y pe of ca ncer, t u m or sta ge, W H O perf or ma nce stat us, ti me ela pse d si nce ca ncer 
dia g n osis, a n d pri or c he m ot hera p y.
Statistical tests of baseli ne c haracteristics t o c hec k f or i m bala nce bet wee n treat me nt gr o u ps will 
n ot be perf or me d.
8. 5. 3. 3
Pri or a n d C o nc o mit a nt Me dici ne
Me dicati o ns take n 1 4 da ys bef ore t he Scree ni n g Visit a n d u p t o t he 1 4- Da y Safet y  Foll o w -u p Visit 
will be s u m marize d b y  Preferre d Na me usi n g t he W orl d Healt h Or ga nizati o n -Dr u g Dicti o nar y 
( W H O-D D E) f or t he f ull a nal ys is set fre q ue nc y ta bles i n 2 p arts:

Pri or me dicati o n: m e dicati o n t hat starte d bef ore t he first d ose of st u d y  dr u g, re gar dless 
of w he n d osi n g of t he me dicati o n e n de d

C o nc o mita nt me dicati o n: me dicati o n recei ve d at or after t he first d ose of st u d y dr u g, or 
me dicati o n t hat was recei ve d bef ore i nitial d osi n g a n d c onti n ue d after i nitial d osi n g of 
st u d y dr u g, or wit h missi n g st o p date.
Me dicati o n t hat starte d bef ore t he first d ose of st u d y dr u g a n d c o nti n ue d after t he first d ose of 
st u d y dr u g will be s u m marize d as pri or me dicati o n a n d se parately as c o nc o mita nt me dicati o n. 
Me dicati o ns wit h a missi n g start date will be c o nsi dere d t o ha ve a start date bef ore t he first d ose 
of st u d y  dr u g.
8. 5. 3. 4
St u d y Dr u g E x p os ure C o m pli a nce
St u d y  dr u g e x p os ure will be s u m marize d base d o n t he safety a nal ys is set. T otal n u m ber of cycles 
is defi ne d as t he ma xi m u m n u m ber of treat me nt c ycles t hat a partici pa nt recei ves. T otal c u m ulati ve 
d ose is defi ne d as t he s u m of t he act ual d oses t hat a partici pa nt recei ves acr oss c ycles. T he t otal 
n u m ber of c ycles a n d t otal c u m ulati ve d ose will be s u m marize d f or eac h c o m p o ne nt of t he d osi n g 
re gi me n f or all Parts of t his st u d y .
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 1 / 1 5 9
8. 5. 4
Effic ac y A n al ysis i n P art s A, A 2, A 3 a n d B 1
Efficac y  data will be s u m marize d b y  treat me nt gr o u p a n d st u d y part, a n d o verall. Efficac y  data 
ma y  als o be s u m marize d b y  t ype of ca ncer, t u m or sta ge, W H O perf or ma nce stat us, ti me ela pse d 
si nce ca ncer dia g n osis, a n d pri or c he m ot hera p y. Efficac y  anal ys is will be base d o n t he f ull a nal ysis 
set.
8. 5. 4 . 1
A n al ysis of Pri m ar y V ari a bles
N ot a p plica ble.
8. 5. 4 . 2
A n al ysis of Sec o n d ar y Effi c ac y V ari a bles
All efficac y  e n d p oi nts are sec o n dar y.
T he pr o p orti o n of partici pa nt s ac hie vi n g a gi ve n cate g orical efficac y en d p oi nt will be s u m marize d 
b y  treat me nt gr o u p a n d st u d y part. F or eac h pr o p orti o n, a 9 0 % c o nfi de nce i nter val will be pr o vi de d 
usi n g t he e xact met h o d.

O bjecti ve res p o nse b y visit: C R or P R de m o nstrate d b y  visit

Disease c o ntr ol rate b y visit: C R , or P R , or sta ble disease de m o nstrate d by visit

Best o verall res p o nse: C R or P R de m o nstrate d at a n y ti me after i nitiati o n of treat me nt.
T u m or res p o nse will als o be de picte d via waterfall pl ots. Ti me t o e ve nt e n d p oi nts s uc h as 
pr o gressi o n -free s ur vi val (P F S ) a n d res p o nse d urati o n will be esti mate d usi n g t he Ka pla n -Meier 
met h o d if t he n u m ber of e ve nts is a de q uate.
8. 5. 5
Effic ac y A n al ysis i n P art s C
All efficac y  a nal yses will be perf or me d o n t he F A S.
O bjecti ve res p o nse is defi ne d as a c o nfir me d assess me nt of C R or P R b y t he In vesti gat or usi n g 
R E CI S T 1. 1 .
C o nfir me d Best O verall Res p o nse is defi ne d as t he best c o nfir me d res p o nse fr o m start of 
treat me nt. T u m or assess me nts perf or me d after start of f urt her a ntica ncer treat me nt li ne will n ot be 
use d i n t he deter mi nati o n of t he best o verall res p o nse.
D urati o n of res p o nse is defi ne d as t he ti me fr o m t he earliest assess me nt of c o nfir me d C R or P R 
u ntil P D, deat h , or last a de q uate t u m or assess me nt. 
Pr o gressi o n -free s ur vi val is defi ne d as t he ti me bet wee n t he start of st u d y treat me nt t o P D or deat h 
(i n case P D is n ot o bser ve d pri or t o deat h). Deat h is o nl y ta ke n i nt o acc o u nt, if o bser ve d wit hi n 
2 c o nsec uti ve misse d pla n ne d t u m or assess me nts. after t he last t u m or assess me nt s h o wi n g C R, P R, 
or S D.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 2 / 1 5 9
If t he deat h is o bser ve d after m ore t ha n t w o c o nsec uti ve misse d pla n ne d t u m or assess me nts after 
t he last t u m or assess me nt s h o wi n g C R, P R, or S D, P F S will be ce ns ore d at t he last t u m or 
assess me nt.
Res p o nse assess me nt b y t he In vesti gat or will be use d f or t he calc ulati o n of efficac y  e n d p oi nts.
E n d p oi nt
St ati sti c al A n al y si s M et h o d s
Pri m ar y: 

O bj e cti v e 
r e s p o n s e

O bj e cti v e 
r e s p o n s e r at e, i n cl. 9 5 % 
2- si d e d Cl o p p er -P e ar s o n 
C o nfi d e n c e i nt er v al
S e c o n d ar y

B O R

C o u nt a n d p er c e nt a g e p er B O R c at e g or y

D o R 

P F S

O v er all 
s ur vi v al

K a pl a n -M ei er pl ot

K a pl a n -M ei er e sti m at e s a n d c orr e s p o n di n g st ati sti c s
N o a dj ust me nt f or m ulti plicit y  will be ma de.
Selecte d s u b gr o u p a nal ys es will be perf or me d per i n dicati o n wit h eac h st u d y  part.
Sec o n dar y  efficac y e n d p oi nts will be a nal yze d descri pti vel y o nl y.
Details of all a nal ys is will be pr o vi de d i n t he I A P.
8. 5. 6
Cli nic al P h ar m ac ol o g y A n al ysis
8. 5. 6 . 1
P h ar m ac o k i netic A n al ysis
U p o n recei pt of bi oa nal ytical data, M 4 3 4 4
P K will be assesse d o n a n o n g oi n g basis d uri n g t he 
d ose escalati o n p hase i n Parts A, A 2, A 3 , a n d B 1, usi n g sta n dar d n o nc o m part me ntal a nal ys is 
met h o ds. W he n p ossi ble, P K res ults f or M 4 3 4 4
will be re vie we d al o n g wit h safety data t o i nf or m 
d ose escalati o n.
F urt her details of t he P K a nal yses f or M 4 3 4 4 i n Parts A, A 2, A 3, B 1, a n d C will be pr o vi de d i n 
t he IA P .
P o p ul ati o n P K A n alysis
S parse P K sa m ples c ollecte d i n Parts C will be c o m bi ne d wit h P K data fr o m ot her st u d y parts 
(a n d/ or a d diti o nal f ut ure st u dies) i n a p o p ulati o n P K a nal ysis t o de vel o p a p o p ulati o n P K m o del 
f or M 4 3 4 4 a n d deri ve i n di vi d ual partici pa nt e x p os ure esti mates. 
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 3 / 1 5 9
F urt her details of t he P K a nal yses f or M 4 3 4 4 i n Parts A, A 2, A 3, B 1, a n d C will be pr o vi de d i n 
t he IA P .
8. 5. 6. 3
E x p os ure - Q Tc A n al yses
Ti me matc he d P K a n d E C G sa m ples fr o m Parts A, A 2, A 3, a n d C will be use d t o assess t he 
relati o ns hi p bet wee n c o nce ntrati o n of M 4 3 4 4 
(a n d meta b olites, if a p plica ble) a n d Q T/ Q Tc 
i nter val. T he relati o ns hi p(s) will be e x pl ore d gra p hicall y i nitiall y an d m a y  be f urt her e x pl ore d 
mat he maticall y . F urt her details will be pr o vi de d i n t he I A P.
8. 5. 7
A n al ysis of S afet y a n d Ot her E n d p oi nts
8. 5. 7 . 1
S afet y i n P art s A a n d B 1
T he o verall safety pr ofile of M 4 3 4 4
will be assesse d i n ter ms of t he f oll o wi n g pri mar y  (safet y) 
e n d p oi nts: 

I nci de nce of treat me nt-e mer ge nt A Es (i ncl u di n g A Es lea di n g t o d ose m o dificati o ns or 
disc o nti n uati o ns)

I nci de nce of D L Ts ( Parts A, B 1)

Cli nical la b orat or y val ues (i ncl u di n g ser u m c he mistr y, he mat ol o g y , a n d c oa g ulati o n 
st u dies)

E C G o utc o mes

Vital si g ns
Safet y  data will be s u m marize d b y treat me nt gr o u p a n d st u d y part, a n d o verall.
I n ge neral, safety a nal ys es will be base d o n t he safet y a nalys is set. T he s u m mar y of D L Ts will be 
base d o n t he D L T e val ua ble set.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 4 / 1 5 9
All safet y data will be prese nte d i n i n di vi d ual partici pa nt data listi n gs.
A d verse e ve nts will be c o de d acc or di n g t o Me dical 
Dicti o nar y  for Re g ulat or y  Acti vities 
(Me d D R A ). T he n u m ber a n d perce nta ge of partici pa nt s e x perie nci n g a n A E will be s u m marize d 
b y  the Me d D R A S y ste m Or ga n Class a n d Preferre d Ter m, as well as b y  do se gr o u p, c o nc urre nt 
re gi me n a n d st u dy p art, a n d o verall. A Es will be classifie d as pretreat me nt or treat me nt -e mer ge nt.
Pretre at me nt A Es are defi ne d as A Es t hat were re p orte d or w orse ne d after si g ni n g t he I CF u p t o 
start of st u d y dr u g d osi n g.
Tre at me nt -e mer ge nt a d verse e ve nts ( T E A Es) are defi ne d as A Es t hat were re p orte d or w orse ne d 
o n or after start of st u d y dr u g d osi n g t hr o u g h t he Safet y  F oll o w-u p Visit.
O nl y  TE A Es will be s u m marize d i n ta bles. All s u m maries of T E A Es will be prese nte d b y  the 
se verity of the A E a n d relati o ns hi p t o t he st u d y dr u g. S o me r ules t hat will a p pl y t o t he 
s u m marizati o n of A Es are ( 1) a partici pa nt wit h m ulti ple occ urre nces of t he sa me A E or c o nti n ui n g 
A Es will o nl y  be c o u nte d o nce; ( 2) o nl y  the ma xi m u m se verit y le vel will be prese nt e d i n t he 
se verity s u m mar y; a n d ( 3) o nl y  the w orst relati o ns hi p le vel will be prese nte d i n t he relati o ns hi p 
s u m mar y. Treat me nt e mer ge nt a d verse e ve nts lea di n g t o st u d y dr u g d ose m o dificati o n or 
per ma ne nt disc o nti n uati o n will be s u m marize d.
A Es lea di n g t o deat h, S A Es, d ose i nterr u pti o n of st u d y dr u g, or per ma ne nt disc o nti n uati o n of st u d y 
dr u g, a n d S A Es will be liste d se paratel y. Pretreat me nt A Es a n d T E A Es will be liste d i n i n di vi d ual 
partici pa nt data listi n gs. U nres ol ve d, o n g oi n g A Es re p orte d t hr o u g h t he 1 4- Da y Safet y  F oll o w-u p 
will be liste d se paratel y i n a n i n di vi d ual partici pa nt data listi n g.
8. 5. 7. 2
S afet y i n P art s A 2 a n d A 3
A nal y ses t o deci de o n d ose escalati o n will be base d o n safety a n d preli mi nar y  PK/ P d data as 
a vaila ble.
F or t he l o west d ose le vel, t he st o p pi n g criteria are base d o n t he p osteri or pr o ba bilit y t hat t he tr ue 
M T D is greater t ha n t he tar get pr o ba bilit y . If t his p osteri or pr o ba bilit y  is 9 0 % or hi g her f or t he 
l o west d ose le vel t he d ose escalati o n will be st o p pe d. 
I n case t he p osteri or pr o ba bilit y t hat t he tr ue M T D is greater t ha n t he tar get pr o ba bilit y f or t he 
c urre nt d ose le vel is at least 9 5 %, the c urre nt d ose le vel a n d all hi g her d oses will b e eli mi nate d
fr o m t he set of pla n ne d d ose le vels, i.e. t hese d ose le vels ca n n ot be c h ose n f or a n y f urt her c o h ort.
D oc u me nt N o. 
O bject N o. C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 5 / 1 5 9
After t he c o m pleti o n of t he d ose escalati o n, t he M T D will be deter mi ne d base d o n is ot o nic 
re gressi o n (Li u a n d Y ua n, 2 0 1 5 ). 
A nal y ses f or t he BOI N m o del will be perf or me d o n t he D L T E val ua ble Set . 
8. 5. 7. 3
S afet y i n P art s C
All a nal ys is of safety will be base d o n t he S A F a nal ysis set defi ne d as all partici pa nt s w h o were 
a d mi nistere d at least 1 d ose of M 4 3 4 4 .
A d verse E ve nts
A d verse e ve nts will be c o de d acc or di n g t o t he latest a vaila ble versi o n of t he Me d D R A. Se verit y 
of A Es will be gra de d b y  the I n vesti gat or usi n g t he N CI -C T C A E ( Versi o n 5 ) t o xicit y gra des. 
A d verse e ve nts relate d t o trial me dicati o n will be defi ne d as a n y A E c o nsi dere d as relate d t o 
M 4 3 4 4 . Missi n g classificati o ns c o ncer ni n g st u d y i nter ve nti o n will be c o nsi dere d relate d t o t he trial 
treat me nt.
A n y  treat me nt- e mer ge nt A Es will be s u m marize d, i.e. t h ose e ve nts t hat:

are e mer ge nt d uri n g o n- treat me nt p eri o d ha vi n g bee n a bse nt pretreat me nt or

w orse n relati ve t o t he pretreat me nt state a n d wit h o nset dates occ urri n g i n t he o n-
treat me nt peri o d.
F or la b orat or y val ues, vital si g ns a n d ot her safet y para meter o nl y t he baseli ne val ue a n d val ues 
d uri n g t he o n -treat me nt peri o d will be s u m marize d. 
L a b or a t or y v ari a bles
La b orat or y  res ults will be classifie d b y gra de acc or di n g t o N CI-C T C A E v 5. 0. 
Res ults f or varia bles t hat are n ot part of N CI-C T C A E will be prese nte d as bel o w, wit hi n, or 
a b o ve n or mal li mits. 
E n d p oi nt
St ati sti c al A n al y si s M et h o d s

T E A Es

S A E

Relate d T E A Es

Relate d S A Es

T E A E of Gra de ≥ 3

Relate d T E A E of Gra de ≥ 3

T E A Es 
lea di n g 
t o 
treat me nt 
i nterr u pti o ns or m o dificati o ns
I nci de nce of T E A E o verall a n d b y  S O C a n d 
P T
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 6 / 1 5 9

T E A Es 
lea di n g 
t o 
per ma ne nt 
treat me nt disc o nti n uati o n

T E A Es lea di n g t o deat hs

A E SI s.

Deat h
C o u nt a n d perce nta ge of deat hs o verall a n d 
b y  pri mar y reas o n of deat h

Deat hs after start of treat me nt

Deat hs wit hi n 3 0 da y s after t he last d ose 
of trial i nter ve nti o n

Deat hs wit hi n 6 0 da y s after t he first 
d ose of trial i nter ve nti o n

La b orat or y  varia bles
Para meter wit h C T C gra di n g: S u m mar y 
statistics

W orst o n -treat me nt gra de

S hifts fr o m baseli ne t o w orst o n-
treat me nt

B o x -pl ot ( L a b orat or y val ues o ver ti me)

Vital si g ns
S u m mar y  statistics

Hi g hest i ncrease fr o m baseli ne

Hi g hest decrease fr o m baseli ne

S hifts fr o m baseli ne t o hi g hest i ncrease 
o n- treat me nt

S hifts fr o m baseli ne t o hi g hest decrease 
o n- treat me nt
8. 6
Cli nic al L a b or at or y Assess me nt
All statistical a nal yses of la b orat or y val ues will be perf or me d usi n g SI  units. C o nti n u o us -val ue d 
ser u m c he mistr y, he mat ol o g y, a n d c oa g ulati o n res ults will be s u m marize d b y treat me nt gr o u p, by 
st u d y part, a n d o verall at eac h sc he d ule d ti me p oi nt. C ha n ge fr o m baseli ne res ults will als o be 
s u m marize d.
T he n u m ber a n d perce nta ge of partici pa nt s wit h s hift c ha n ges base d o n C T C A E t o xicit y gra des 
will be ta b ulate d.
A listi n g of i n di vi d ual partici pa nt he mat ol o g y , ser u m c he mistr y, a n d c oa g ulati o n val ues o utsi de 
t he refere nce ra n ges will be pr o vi de d. T his listi n g will i ncl u de data fr o m sc he d ule d a n d 
u nsc he d ule d ti me p oi nts.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 7 / 1 5 9
Gra de 3 a n d a b o ve t o xicit y la b orat or y val ues will be pr o vi de d i n i n di vi d ual partici pa nt data 
listi n gs. Cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs will be re p orte d as A Es.
8. 7
Electr oc ar di o gr a m
A s u m mar y  of ra w val ues a n d c ha n ge fr o m baseli ne val ues b y treat me nt gr o u p a n d st u d y part f or 
eac h sc he d ule d visit will be pr o vi de d f or t he f oll o wi n g E C G para meters: P R, Q T, Q R S, a n d Q Tc 
i nter vals, a n d heart rate. I n ad diti o n, t he n u m ber a n d perce nta ge of partici pa nt s b y  ma xi m u m 
o n- treat me nt val ue of Q T/ Q Tc i nter vals, cate g orize d as ≤4 5 0 msec, > 4 5 0 msec a n d ≤4 8 0 msec, 
> 4 8 0 msec a n d ≤5 0 0 msec, a n d > 5 0 0 msec, as well as ma xi m u m o n- treat me nt c ha n ge fr o m 
baseli ne val ue of Q T/ Q Tc i nter vals, cate g orize d as ≤3 0 msec, > 3 0 msec a n d ≤6 0 msec, a n d 
> 6 0 msec, will be pr o vi de d. Cli nicall y  si g nifica nt a b n or mal fi n di n gs will be re p orte d as A Es.
8. 8
Vit al Si g n s
A s u m mar y of val ues a n d c ha n ge fr o m baseli ne val ues b y  treat me nt gr o u p a n d st u d y part, a n d 
o verall f or eac h sc he d ule d visit will be pr o vi de d f or t he f oll o wi n g vital si g n para meters: s yst olic 
a n d diast olic bl o o d press ure ( m m H g), b o d y  te m perat ure, p ulse rate ( b p m), a n d res pirat or y rate 
( breat hs per mi n ute). Cli nicall y  si gnifica nt a b n or mal fi n di n gs i n vital si g ns will be re p orte d as 
A Es.
8. 9
P h ysic al E x a mi n ati o n
P E res ults will be prese nte d i n i n di vi d ual partici pa nt data listi n gs o nl y . Cli nicall y rele va nt res ults 
i de ntifie d after Scree ni n g will be re p orte d as A Es.
8. 1 0
I nteri m a n d A d diti o n al Pl a n ne d A n al yses
I nteri m a nalys es ma y be c o n d ucte d f or t he p ur p ose of data re vie w a n d re g ulat or y u p dates.
F or all Part s C, i nteri m a nal y ses are pla n ne d after eac h sta ge, see S ecti o n 8. 1 .
9
Et hic al a n d Re g ul at or y As pects
9. 1
Res p o nsi bilities of t he I n vesti g at or
T he I n vesti gat or is res p o nsi ble f or t he c o n d uct of t he st u d y at t he site a n d will e ns ure t hat t he st u d y
is perf or me d i n acc or da nce wit h t his pr ot oc ol, t he et hical pri nci ples o utli ne d i n t he Declarati o n of 
Helsi n ki, I CH G C P , a n d a n y ot her a p plica ble re g ulati o ns. T he I n vesti gat or m ust e ns ure t hat o nl y 
partici pa nt s w h o ha ve gi ve n i nf or me d c o nse nt are i ncl u de d i n t he st u d y.
Acc or di n g t o U nite d States C o de of Fe deral Re g ulati o ns Part 5 4. 2 (e), f or st u dies c o n d ucte d i n a n y 
c o u ntr y that c o ul d res ult i n a pr o d uct s u b missi o n t o t he U nite d States F o o d a n d Dr u g 
A d mi nistrati o n f or mar keti n g a p pr o val a n d c o ul d c o ntri b ute si g nifica ntl y t o t he de m o nstrati o n of 
efficac y a n d safet y of a st u d y dr u g ( w hic h are c o nsi dere d “c o vere d cli nical st u dies” b y t he F D A), 
t he I n vesti gat or a n d all s u b-I n vesti gat ors are o bli ge d t o discl ose a ny fi na ncial i nterest w hic h t he y, 
t heir s p o uses or t heir de pe n de nt c hil dre n ma y ha ve i n t he S p o ns or or t he S p o ns or’s pr o d uct u n der 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 8 / 1 5 9
st u d y. 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 2 m o nt hs f oll o wi n g c o m pleti o n of 
t he st u d y.
9. 2
P artici p a nt I nf or m ati o n a n d I nf or me d C o nse nt
A n u nc o n diti o nal prer e q uisite f or eac h partici pa nt pri or t o partici pati o n i n t he st u d y is writte n 
i nf or me d c o nse nt, w hic h m ust be gi ve n bef ore a n y st u d y-relate d acti vities are carrie d o ut.
A de q uate i nf or mati o n m ust t heref ore be gi ve n t o t he partici pa nt b y  the I n vesti gat or or a n 
a p pr o priate desi g nee (if l ocal re g ulati o ns per mit) bef ore i nf or me d c o nse nt is o btai ne d. 
A partici pa nt i nf or mati o n s heet m ust be pre pare d i n t he l ocal la n g ua ge i n acc or da nce wit h I CH
G C P
a n d will be pr o vi de d b y  the S p o ns or f or t he p ur p ose of o btai ni n g i nf or me d c o nse nt. I n 
a d diti o n t o pr o vi di n g t his writte n i nf or mati o n t o a p ote ntial partici pa nt , t he I nvesti gat or or a
desi g nate will i nf or m t he partici pa nt ver ball y of all perti ne nt as pects of t he st u d y, usi n g la n g ua ge 
c h ose n s o t hat t he i nf or mati o n ca n be f ull y  an d rea dil y  u n derst o o d b y l a ypers o ns. T he partici pa nt
will be gi ve n s ufficie nt ti me t o rea d t he i nf or mati o n a n d t he o p p ort u nit y  to as k q uesti o ns a n d t o 
re q uest a d diti o nal i nf or mati o n a n d clarificati o n.
If per mitte d b y  nati o nal re g ulati o ns, a pers o n ot her t ha n t he I nvesti gat or ma y i nf or m t he partici pa nt
a b o ut t he st u d y a n d si g n t he I CF, as a b o ve.
After t he i nf or mati o n is pr o vi de d b y t he I n vesti gat or, t he Inf or me d C o nse nt F or m m ust be si g ne d 
a n d date d b y t he partici pa nt a n d t he I n vesti gat or. 
T he sig ne d a n d date d declarati o n of i nf or me d c o nse nt will re mai n at t he I n vesti gat or’s site, a n d 
m ust be safel y arc hi ve d s o t hat t he f or ms ca n be retrie ve d at a n y t i me f or m o nit ori n g, a u diti n g a n d 
i ns pecti o n p ur p oses. A c o p y of t he si g ne d a n d date d i nf or mati o n a n d I CF s h o ul d be pr o vi de d t o 
t he partici pa nt pri or t o partici pati o n.
W he ne ver i m p orta nt ne w i nf or mati o n bec o mes a vaila ble t hat ma y  be rele va nt t o i nf or me d c o nse nt, 
t he I n vesti gat or will re vise t he partici pa nt i nf or mati o n s heet a n d a n y ot her writte n i nf or mati o n t o 
be pr o vi de d t o t he partici pa nt s a n d s u b mit t he m t o t he I RB f or re vie w a n d o pi ni o n. Usi n g t he 
a p pr o ve d re vise d partici pa nt i nf or mati o n s heet a n d ot her writte n i nf or mati o n, T he I nvesti gat or will 
e x plai n t he c ha n ges t o t he pre vi o us versi o n t o eac h st u d y partici pa nt a n d o btai n ne w writte n 
c o nse nt f or c o nti n ue d partici pati o n i n t he st u d y. The partici pa nt will be gi ve n s ufficie nt ti me t o 
rea d t he i nf or mati o n a n d t he o p p ort u nit y  to as k q uesti o ns a n d t o re q uest a d diti o nal i nf or mati o n 
a n d clarificati o n a b o ut t he c ha n ges.
9. 3
P artici p a nt I de ntific ati o n a n d Pri v ac y
A u ni q ue n u m ber will be assi g ne d t o eac h partici pa nt , i m me diatel y after i nf or me d c o nse nt has 
bee n o btai ne d. T his n u m ber will ser ve as t he partici pa nt ’s i de ntifier i n t he st u d y as well as i n t he 
cli nical st u d y data base. If a partici pa nt is scree n fail ure a n d is re-scree ne d or c o nse nts f or
partici pati o n i n a differe nt part of t he st u d y, t hat partici pa nt will be assi g ne d a ne w u ni q ue n u m ber. 
Al l partici pa nt data c ollecte d i n t he st u d y will be st ore d u n der t h e a p pr o priate partici pa nt n u m ber. 
O nl y  the I n vesti gat or will be a ble t o li n k st u d y data t o a n i n di vi d ual partici pa nt via a n i de ntificati o n 
list ke pt at t he site. F or eac h partici pa nt , ori gi na l me dical data will be accessi ble f or t he p ur p oses 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 9 / 1 5 9
of s o urce data verificati o n b y  the M o nit or, a u dits a n d re g ulat or y ins pecti o ns, b ut partici pa nt
c o nfi de ntialit y will be strictl y mai ntai ne d.
Data pr otecti o n a n d pri vac y  re g ulati o ns will be o bser ve d i n ca pt uri n g, f or war di n g, pr ocessi n g, a n d 
st ori n g partici pa nt data. Partici pa nt s will be i nf or me d acc or di n gl y a n d will be re q ueste d t o gi ve 
t heir c o nse nt o n data ha n dli n g pr oce d ures i n acc or da nce wit h nati o nal re g ulati o ns.
Bl o o d a n d t u m or tiss ue sa m ples f or 
 a n d 
 will be st ore d f or u p t o 1 0 years after 
st u d y c o m pleti o n. D uri n g t his ti me, t he sa m ples ma y be rea nalyz e d f or ne wl y  ide ntifie d 
 
or wit h
n e w or i m pr o ve d tec h n ol o gy . After 1 0 ye ars, t he sa m ples wil l be destr o ye d or f ull y 
a n o n ymize d or a ne w I E C/IR B a p pr o val a n d i nf or me d c o nse nt will be re q ueste d t o kee p t he
sa m ples f or a n a d diti o nal peri o d. If t u m or tiss ue re mai ns, t he site will be n otifie d, a n d t he t u m or 
tiss ue will be ret ur ne d t o t he site u p o n re quest. If t he site d oes n ot re q uest t he ret ur n of t he t u m or 
tiss ue, it will be destr o ye d.
9. 4
E mer ge nc y Me dic al S u p p ort a n d P artici p a nt C ar d
Partici pa nt s will be pr o vi de d wit h E mer ge nc y Me dical S u p p ort car ds s u p plie d b y t he S p o ns or f or 
use d uri n g st u d y part ici pati o n i n or der t o pr o vi de cli nical st u d y partici pa nt s wit h a wa y  of 
i de ntif yi n g t he msel ves as partici pati n g i n a cli nical st u d y a n d t o 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 deter mi ne t he c o urse of me dical 
treat me nt f or t he partici pa nt . T he i nf or mati o n pr o vi de d o n t he E mer ge nc y Me 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 ncies will be t he cli nical st u d y I n vestigat or cari n g f or t he 
affecte d partici pa nt . T he I n vesti gat or a grees t o pr o vi de his or her e mer ge nc y  co ntact i nf or mati o n 
o n t he car d f or t his p ur p ose. If t he I nvesti gat or is a vaila ble w he n a n e ve nt occ urs, t he y will a ns wer 
a n y questi o ns. A n y  su bse q ue nt acti o n (f or e xa m ple, 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 vesti gat ors.
I n cases w here t he I n vesti gat or is n ot a vaila ble, t he P hase I facility will pr o vi de t he a p pr o priate 
mea ns t o c o ntact a p h y sicia n. T his i ncl u des t he pr o visi o n of a 2 4- h o ur c o ntact n u m ber at t he 
facilit y, w here b y t he healt h care pr o vi ders will be gi ve n access t o a n a p pr o priate p h y sicia n t o assist 
wit h t he me dical e mer ge nc y  an d t o pr o vi de s u p p ort f or t he p ote ntial u n bli n di n g of t he partici pa nt
c o ncer ne d.
9. 5
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 nt s
I ns ura nce c o vera ge wi ll be pr o vi de d f or eac h c o u ntr y partici pati n g t o t he st u d y. I ns ura nce 
c o n diti o ns s hall meet g o o d l ocal sta n dar ds, as a p plica ble.
9. 6
I n de pe nde nt Et hics C o m mittee or I nstit uti o n al Re vie w B o ar d
Pri or t o c o m me nce me nt of t he st u d y at a gi ve n site, t his cli nical st u d y pr ot oc ol will be s u b mitte d 
t o get her wit h 
its ass ociate d d oc u me nts
(pr ot oc ol, I n vesti gat or's 
Br oc h ure, sa m ple I CF, 
a d vertise me nts [if a p plica ble], writte n i nf or mati o n gi ve n t o t he partici pa nt s [i ncl u di n g diar y  car ds], 
safety u p dates, a n n ual pr o gress re p orts, a n d a n y re visi o ns t o t hese d oc u me nts ) t o t he res p o nsi ble 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 0 / 1 5 9
I n de pe n de nt Et hics C o m mittee (I E C) or I nstit uti o nal Re vie w B oar d (I R B) f or its fa v ora ble o pi ni o n
or a p pr o val , w hic h will be file d i n t he I n vesti gat or Site File . A c o p y will be file d i n t he S p o ns or
Trial Master File at t he S p o ns or.
T he I E C or I RB will be as ke d t o d oc u me nt t he date of t he meeti n g at w hic h t he fa v ora ble o pi ni o n
or a p pr o val was gi ve n a n d t he me m bers a n d v oti n g me m bers prese nt. Writte n 
e vi de nce of 
fa v ora ble o pi ni o n or a p pr o val t hat clearl y i de ntifies t he st u d y, t h e cli nical st u d y pr ot oc ol versi o n 
a n d t he Partici pa nt I nf or mati o n a n d I CF versi o n re vie we d s h o ul d be p r o vi de d. W here p ossi ble, 
c o pies of t he meeti n g mi n utes s h o ul d be o btai ne d.
A me n d me nts t o t his cli nical st u d y pr ot oc ol will als o be s u b mitte d t o t he c o ncer ne d I E C or I R B, 
bef ore i m ple me ntati o n of s u bsta ntial c ha n ges (see Secti o n 1 0. 5 ). Rele va nt safety i nf or mati o n will 
be s u b mitte d t o t he I EC
or I RB d uri n g t he c o urse of t he st u d y i n acc or da nce wit h nati o nal 
re g ulati o ns a n d re q uire me nts.
9. 7
He alt h A ut h orities
T he cli nical st u d y pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n (f or e xa m ple, I n vesti gati o nal 
Me dici nal Pr o d uct D ossier, Partici pa nt I nf or mati o n a n d I CF ) will be s u b mitte d or n otifie d t o t he 
Healt h A ut h orities i n acc or da nce wit h all l ocal a n d nati o nal re g ulati o ns f or eac h site.
1 0
St u d y M a n a ge me nt
1 0. 1
C ase Re p ort F or m H a n dli n g
Refer t o t he Ma n ual of O perati o ns
f or e C R F ha n dli n g g ui deli nes. 
T he mai n p ur p ose of t he e C R F is t o o btai n data re q uire d b y  the cli nical st u d y pr ot oc ol i n a 
c o m plete, acc urate, le gi ble a n d ti mel y. T he data i n t he e C R F s h o ul d be c o nsiste nt wit h t he rele va nt 
s o urce d oc u me nts.
T he I nvesti gat or or desi g nee is res p o nsi ble f or e ns uri n g t hat t he data c ollecte d i n t he c o urse of t his 
st u d y is acc urate a n d d oc u me nte d a p pr o priatel y o n all a p plica ble f or ms. T he y  will t he n be 
pr ocesse d, e val uate d, a n d st ore d i n a n o n ym o us f or m i n acc or da nce wit h a p plica ble data pr otecti o n 
re g ulati o ns. T he I n vesti gat or m ust e ns ure t hat t he e C R Fs a n d a n y ot her ass ociate d d oc u me nts 
f or war de d t o S p o ns or or its desi g nate d or ga nizati o n c o ntai n n o me nti o n of a n y partici pa nt na mes.
T he data will be e ntere d i nt o a vali date d data base. T he S p o ns or or its desi g nee will be res p o nsi ble 
f or data pr ocessi n g, i n acc or da nce wit h t he S p o ns or’s data ma na ge me nt pr oce d ures. Data base l oc k 
will occ ur o nce q ualit y c o ntr ol a n d q ualit y ass ura nce pr oce d ures ha ve bee n c o m plete d. P D F files 
of t he e C R Fs will be pr o vi de d t o t he I nvesti gat or s at t he c o m pleti o n of t he st u d y.
1 0. 2
S o urce D at a a n d P artici p a nt Files
T he I n vesti gat or m ust kee p a file ( me dical file, ori gi nal me dical rec or ds) o n pa per or electr o nicall y 
f or e ver y partici pa nt i n t he st u d y. It m ust be p ossi ble t o i de ntif y eac h partici pa nt b y  usi n g t his 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 1 / 1 5 9
partici pa nt file. T his file will c o ntai n t he de m o gra p hic a n d me dical i nf or mati o n f or t he partici pa nt
liste d bel o w a n d s h o ul d 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, h ei g ht, wei g ht

Me dical hist or y  a n d c o nc o mita nt diseases

Pri or a n d c o nc o mita nt t hera pies (i ncl u di n g c ha n ges d uri n g t he st u d y)

St u d y  ide ntificati o n , t hat is, t he S p o ns or st u d y n u m ber f or t his cli nical st u d y, a n d 
partici pa nt n u m ber

Date s f or e ntr y i nt o t he st u d y (i nf or me d c o nse nt) a n d visits t o t he site

A n y  me dical e xa mi nati o ns a n d cli nical fi n di n gs pre defi ne d i n t his cli nical st u d y
pr ot oc ol

All A E s

Date t hat t he partici pa nt left 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 dr u g (if a p plica ble).
A ll d oc u me nts c o ntai ni n g s o urce data m ust be file d , i nclu di n g , b ut n ot li mite d t o C T or M RI sca n 
i ma ges, E C G rec or di n gs, a n d la b orat or y res ults. S uc h d oc u me nts m ust bear t he partici pa nt n u m ber 
a n d t he date of t he pr oce d ure. If p ossi ble, t his inf or mati o n s h o ul d be pri nte d b y  the i nstr u me nt 
use d t o perf or m t he assess me nt or meas ure me nt. As necessar y , m edical e val uati o n of s uc h rec or ds 
s h o ul d be perf or me d; all e val uati o ns s h o ul d be d oc u me nte d , si g ne d, a n d date d b y the I nvesti gat or .
Electr o nic partici pa nt files will be pri nte d w he ne ver t he M o nit or perf or ms s o urce data verificati o n. 
Pri nt o uts m ust be si g ne d a n d date d b y  t he I n vesti gat or, c o u ntersi g ne d b y  t he M o nit or a n d ke pt i n 
a safe place at t he site. Pri nti n g t he files will n ot be necessar y if t he m o nit or is per mitte d t o access 
a n d re vie w electr o nic partici pa nt files or ot her electr o nic st u d y rec or ds at In vesti 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 “ Rea d O nly. ”
1 0. 3
I n vesti g at or Site File a n d Arc hi vi n g
U p o n i nitiati o n of t he st u d y, t he I n vesti gat or will be pr o vi de d wit h a n I n vesti gat or Site File 
c o ntai ni n g all necessar y st u d y d oc u me nts , w hic h
will be c o m plete d t hr o u g h o ut t he st u d y a n d 
u p date d as necessar y . T he file m ust be a vaila ble f or re vie w by t he M o nit or, d uri n g S p o ns or a u dits 
a n d f or i ns pecti o n b y  Healt h A ut h orities d uri n g a n d after t he st u d y, a n d m ust be safel y arc hi ve d 
f or at least 1 5 ye ars ( or l o nger, per l ocal re q uire me nts or as ot her wise n otifie d b y  the S p o ns or) 
after t he e n d of t he st u d y. T he d oc u me nts t o be arc hi ve d i ncl u de t he Partici pa nt I de ntificati o n List 
a n d t he si g ne d partici pa nt I CFs . If arc hi vi n g of t he I n vesti gat or Site File is n o l o n ger p ossi ble at 
t he site, t he I n vesti gat or m ust n otif y  t he S p o ns or/ desi g nee.
All ori gi nal partici pa nt files ( me dical rec or ds) m ust be st ore d at t he site ( h os pital, researc h i nstit ute, 
or practice) f or t he l o n gest p ossi ble ti me per mitte d b y  the a p plica ble reg ulati o ns, a n d/ or as per I CH 
G C P g ui deli nes, w hic he ver is l o n ger. I n a n y case, t he I n vesti gat or s h o ul d e ns ure t hat n o 
destr ucti o n of me dical rec or ds is perf or me d wit h o ut t he writte n a p pr o val of t he S p o ns or.
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 2 / 1 5 9
1 0. 4
M o nit ori n g, 
Q u alit y Ass ur a nce 
a n d I ns pecti o n b y He alt h 
A ut h orities
T his st u d y will be m o nit ore d i n acc or da nce wit h t he I CH G C P,
a n d a n y ot her a p plica ble 
re g ulati o ns. T he site M o nit or will perf or m visits t o t he st u d y site at re g ular i nter vals.
T he cli nical st u d y pr ot oc ol, eac h ste p of t he data ca pt ur e pr oce d ure, a n d t he ha n dli n g of t he data, 
i ncl u di n g t he fi nal cli nical st u d y re p ort, will be s u bject t o i n de pe n de nt Q ualit y  Ass ura nce 
acti vities. A u dits ma y be c o n d ucte d at a n y ti me d uri n g or after t he st u d y t o e ns ure t he vali dit y a n d 
i nte grity of t he st ud y data. Re prese ntati ves of t he Q ualit y  Ass ura nce u nit fr o m t he S p o ns or or a 
desi g nate d or ga nizati o n, as well as Healt h A ut h orities, m ust be per mitte d t o access all st u d y
d oc u me nts a n d ot her materials at t he site, i ncl u di n g t he I nvesti gat or Site File, t he c o m plete d 
eC R Fs, all st u d y dr u g a n d st u d y dr u g acc o u nta bilit y rec or ds, a n d t he ori gi nal me dical rec or ds or 
files f or eac h partici pa nt .
1 0. 5
C h a n ges t o t he Cli nic al St u d y Pr ot oc ol
C ha n ges t o t he cli nical st u d y pr ot oc ol will be d oc u me nte d i n writi n g . S u bsta n ti ve a me n d me nts 
will us uall y  re q uire s u b missi o n t o t he Healt h A ut h orities a n d t o t he rele va nt I E C/I R B f or a p pr o val 
or fa v ora ble o pi ni o n. I n s uc h cases, t he a me n d me nt will be i m ple me nte d o nl y  after a p pr o val or 
fa v ora ble o pi ni o n has bee n o btai ne d.
Mi n or ( n o ns u bsta ntial) pr ot oc ol a me n d me nts, i ncl u di n g a d mi nistrati ve c ha n ges, will be file d b y  
t he S p o ns or a n d at t he site. T he y  will be s u b mitte d t o t he rele va nt I E C/IR B or t o Healt h A ut h orities 
o nl y  w here re q ueste d b y perti ne nt re g ulati o ns. A n y  ame n d me nt t hat c o ul d affect t he partici pa nt ’s 
a gree me nt t o partici pate i n t he st u d y re q uires a d diti o nal i nf or me d c o nse nt pri or t o i m ple me ntati o n 
f oll o wi n g t he pr ocess as descri be d i n Secti o n 9. 2 .
1 0. 6
Cli nic al St u d y Re p ort a n d P u blic ati o n P olic y
1 0. 6. 1  
Cli nic al St u d y Re p ort
A cli nical st u d y re p ort, writte n i n acc or da nce wit h t he I CH E 3 G ui deli ne
b y  the S p o ns or i n 
c o ns ultati o n wit h t he C o or di nati n g I n vesti gat or, will be s u b mitte d i n acc or da nce wit h l ocal 
re g ulati o ns.
1 0. 6. 2 
P u blic ati o n
T he res ults of t his st u d y ma y b e pu blis he d or prese nte d at scie ntific meeti n gs. If t his is f oresee n, 
t he I n vesti 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 prietar 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 nt er st u dies o nl y  in t heir e ntiret y 
a n d n ot as i n di vi d ual site data. I n t his case, a C o or di nati n g I n vesti 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 nati 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 me nts.
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 3 / 1 5 9
P osti n g of res ults fr o m t his trial o n Cli nical Trials. g o v a n d E u dra C T is pla n ne d a n d will occ ur 
1 2 m o nt hs after t he last cli nic visit of t he fi nal st u d y partici pa nt or a n ot her a p pr o priate date t o meet 
a p plica ble re q uire me nts.
D oc u me nt N o. 
O bject N o. C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 4 / 1 5 9
1 1
Refere nces Cite d i n t he Te xt
A merica n Ca ncer S ociet y. Ca ncer facts a n d fi g ures 2 0 1 2. Atla nta: A merica n ca ncer s ociety; 2 0 1 1.
Ca ncer Ge n o me Atlas Researc h N et w or k. C o m pre he nsi ve m olec ular p ortraits of h u ma n breast 
t u m o urs. Nat ure. 2 0 1 2; 4 9 0: 6 1- 7 0.
Car b o plati n. S u m mar y  of Pr o d uct C haracteristics [I nter net].
Ci m pric h K A, C ortez D. A T R: a n esse ntial re g ulat or of ge n o me i nte grity. Nat ure Re vie ws 
M olec ular Cell Bi ol o g y . 2 0 0 8; 9: 6 1 6- 2 7.
Cis plati n. S u m mar y  of Pr o d uct C haracteristics [Inter net]. 
Creas y D M, F oster P M D ( 2 0 0 2). Male Re pr o d ucti ve S y ste m. I n W M Hasc he k, C G R o ussea u x, 
M A Walli g ( E ds.), Ha n d b o o k of T o xic ol o gic Pat h ol o g y ( p p. 7 8 5). Sa n Die g o, Calif or nia: Else vier 
Scie nce.
Di n g 
L, Getz 
G, 
W heeler 
D A, 
et al. S o matic m utati o ns 
affect ke y  pat h wa ys i n l u n g 
a de n ocarci n o ma. Nat ure. 2 0 0 8; 4 5 5: 1 0 6 9- 7 5.
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse criteria i n s oli d t u m o urs: Re vise d 
R E CI S T g ui deli ne ( versi o n 1. 1). E ur o pea n J o ur nal of Ca ncer. 2 0 0 9; 4 5: 2 2 8 - 4 7.
Ferla y  J, S hi n H R, Bra y F, et al. Esti mates of w orl d wi de b ur de n of ca ncer i n 2 0 0 8: G L O B O C A N 
2 0 0 8. I nt J Ca ncer. 2 0 1 0; 1 2 7: 2 8 9 3 - 2 9 1 7.
Fl y n n R L , C o x K E, Jeita n y M, et al. Alter nati ve le n gt he ni n g of tel o meres re n ders ca ncer cells 
h y perse nsiti ve t o A T R i n hi bit ors. Scie nce. 2 0 1 5; 3 4 7( 6 2 1 9): 2 7 3- 7.
F urt her a nal ys is of t he data i n t he Cr o w n Bi o re p ort e ntitle d “ E val uati o n of efficac y  an d safet y  of 
Verte x’s test c o m p o u n d V Xc - 8 0 3 a n d i n c o m bi nati o n wit h car b o plati n i n t he treat me nt of 
s u bc uta ne o us M D A -M B - 4 6 8 h u ma n breast ca ncer xe n o graft m o del”. Re p ort K 2 4 3. Re p ort date 
1 9 A u g ust 2 0 1 4.
Ge mcita bi ne. S u m mar y  of Pr o d uct C haracteristics [Inter net]. 
Gila d O, Na bet B Y, Ra gla n d R L , et al. C o m bi ni n g A T R s u p pressi o n wit h o nc o ge nic Ras 
s yner gisticall y  increases ge n o mic i nsta bilit y, ca usi n g s ynt hetic let hality or t u m ori ge nesis i n a 
d osa ge -de pe n de nt ma n ner. Ca ncer Researc h. 2 0 1 0; 7 0: 9 6 9 3 - 7 0 2.
Gree n ma n C, Ste p he ns P, S mit h R, et al. Patter ns of s o matic m utati o n i n h u ma n ca ncer ge n o mes. 
Nat ure. 2 0 0 7; 4 4 6: 1 5 3 - 5 8.
Ha m m o n d E M, D orie MJ, 
Giaccia AJ. I n hi biti o n of A T R lea ds t o i ncrease d se nsiti vit y to 
h y p o xia/re o x y ge nati o n. Ca ncer Researc h. 2 0 0 4; 6 4: 6 5 5 6 - 6 2.
He gi M E, Disere ns A C, G orlia T, et al. M G M T ge ne sile nci n g a n d be nefit fr o m te m oz ol o mi de i n 
gli o blast o ma. Ne w E n gla n d J o ur nal of Me dici ne. 2 0 0 5; 3 5 2: 9 9 7- 1 0 0 3.
H o wla der N, N o o ne A M, Kra pc h o M, et al (e ds). S E E R Ca ncer Statistics Re vie w , 1 9 7 5- 2 0 1 1, 
Nati o nal 
Ca ncer 
I nstit ute. Bet hes da, 
M D,
htt p://seer.ca ncer. g o v/csr/ 1 9 7 5 _ 2 0 1 1/, base d o n 
N o ve m ber 2 0 1 3 S E E R data s u b missi o n, p oste d t o t he S E E R we b site, A pril 2 0 1 4.
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 5 / 1 5 9
I T R La b orat ories. V R T -1 2 2 8 6 9 2: A 1 4 -d a y  oral ra n ge fi n di n g t o xicit y an d t o xic o ki netic st u d y  i n 
S pra g ue -Da wle y  rats. Verte x st u d y nu m ber: V R T - 1 2 2 8 6 9 2-T X -0 0 1. I T R st u d y nu m ber: 7 2 1 7 1. 
Re p ort date: 1 5 N o ve m ber 2 0 1 3.
I T R La b orat ories. V R T -1 2 2 8 6 9 2: A 1 4 -d a y  oral ra n ge fi n di n g t o xicit y an d t o xic o ki netic st u d y  i n 
Bea gle d o gs. Verte x st u d y n u m ber: V R T -1 2 2 8 6 9 2 -T X - 0 0 2. I T R st u d y nu m ber: 6 1 3 8 8. Re p ort 
date: 1 8 N o ve m ber 2 0 1 3.
I va n o va A. Escalati o n, gr o u p a n d A + B desi g ns f or d ose -fi n di n g trials. Statist Me d. 2 0 0 6; 2 5: 3 6 6 8 -
7 8.
Jia n g H, Rei n har dt H C, Bart k o va J, et al. T he c o m bi ne d stat us of A T M a n d p 5 3 li n k t u m or 
de vel o p me nt wit h t hera pe utic res p o nse. Ge nes & De vel o p me nt. 2 0 0 9; 2 3: 1 8 9 5 - 9 0 9.
Kasta n M B , Barte k J. Cell -c ycle c hec k p oi nts a n d ca ncer. Nat ure. 2 0 0 4; 4 3 2: 3 1 6 - 2 3.
Li J, Z h a o, T, Z ha n g Y, et al. Perf or ma nce e val uati o n of pat h o ge nicit y- c o m p utati o n met h o ds f or 
misse nse varia nts . N ucleic Aci ds Res. 2 0 1 8; 4 6( 1 5): 7 7 9 3 - 8 0 4.
Mi n A, I m SA, Ja n g H, et al. A Z D 6 7 3 8, A N o vel Oral I n hi bit or of A T R, I nd uces S y nt hetic 
Let halit y  wit h A T M Deficie nc y i n Gastric Ca ncer Cells. M ol Ca ncer T her. 2 0 1 7; 1 6( 4): 5 6 6 - 5 7 7.
M PI  Researc h. V R T -1 2 2 8 6 9 2: A 2 8- d a y  oral ( ga va ge) t o xicit y an d t o xic o ki netic st u d y in rats wit h 
a 1 4-d a y  rec o ver y peri o d. Verte x st u dy n u m ber: V R T -1 2 2 8 6 9 2- T X -0 0 4. M PI  st u d y n u m ber: 8 6 3-
1 6 5. Re p ort date: 2 8 A u g ust 2 0 1 4.
M PI  Researc h. V R T -1 2 2 8 6 9 2: A 2 8- d a y  oral ( ga va ge) t o xicit y an d t o xic o ki netic st u d y in d o gs 
wit h a 1 4 -d a y  rec o ver y peri o d. Verte x st u d y n u m ber: V R T-1 2 2 8 6 9 2- T X -0 0 5. M PI  st u d y n u m ber: 
8 6 3- 1 6 6. Re p ort date: 2 8 A u g ust 2 0 1 4.
M ur ga M, B u nti n g S, M o nta na M F, et al. A m o use m o del of A T R -Sec kel s h o ws em br y o nic 
re plicati ve stress a n d accelerate d a gi n g. Nat ure Ge netics. 2 0 0 9; 4 1: 8 9 1- 8.
M ur ga M, Ca m pa ner S, L o pez -C o ntreras AJ, et al. E x pl oiti n g o nc o ge ne -i n d uce d re plicati ve stress 
f or t he selecti ve killi n g of M y c-dri ve n t u m ors. Nat ure 
Str uct ural & 
M olec ular 
Bi ol o g y 
2 0 1 1; 1 8: 1 3 3 1 - 5.
N C C N Cli nical Practice G ui deli nes i n O nc ol o g y f or N o n -S mall Cell L u n g Ca ncer. Versi o n 2. 
2 0 1 3. A vaila ble fr o m: htt p:// w w w. ncc n. or g/ pr ofessi o nals/ p h y sicia n _ gls/f _ g ui deli nes.as p
Li u S, Y ua n, Y. Ba yesia n O pti mal I nter val Desi g ns f or P h ase I Cli nical Trials. J o ur nal of t he R o y al 
Statistical S ociet y : Series C, 6 4, 5 0 7- 2 3.
N g hie m P, Par k P K, Ki m Y, et al. A T R i n hi biti o n selecti vel y se nsitizes G 1 c hec k p oi nt -deficie nt 
cells t o let hal pre mat ure c hr o mati n c o n de nsati o n. Pr ocee di n gs of t he Nati o nal Aca de m y  of 
Scie nces of t he U nite d States of A merica. 2 0 0 1; 9 8: 9 0 9 2 - 7.
N g hie m P, Par k P K, Ki m Ys, et al. A T R is n ot re q uire d f or p 5 3 acti vati o n b ut s y ner gizes wit h p 5 3 
i n t he re plicati o n c hec k p oi nt. J o ur nal of Bi ol o gical C he mistr y. 2 0 0 2; 2 7 7: 4 4 2 8- 3 4.
N or q uist B, W urz K A, Pe n nil C C, et al. Sec o n dar y s o matic m utati o ns rest ori n g B R C A 1/ 2 pre dict 
c he m ot hera p y resista nce i n here ditar y o varia n carci n o mas. J o ur nal of Cli nical O nc ol o g y . 
2 0 1 1; 2 9: 3 0 0 8 - 1 5.
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 6 / 1 5 9
Ola usse n K A, D u na nt A, F o uret P, et al. D N A re pair b y  E R C C 1 i n n o n- s mall-cell l u n g ca ncer a n d 
cis plati n-base d a dj u va nt c he m ot hera p y. Ne w E n gla n d J o ur nal of Me dici ne. 2 0 0 6; 3 5 5: 9 8 3 - 9 1.
Pires I M, Olci na M M, A n bala ga n S, et al. Tar geti n g ra diati o n-resista nt h y p o xic t u m o ur cells 
t hr o u g h A T R i n hi biti o n. Britis h J o ur nal of Ca ncer. 2 0 1 2; 1 0 7: 2 9 1 - 9.
Rea per P M, Griffit hs M R, L o n g J M, et al. Selecti ve killi n g of A T M- or p 5 3 -deficie nt ca ncer cells 
t hr o u g h i n hi biti o n of A T R. Nat ure C he mical Bi ol o g y. 2 0 1 1; 7: 4 2 8- 3 0.
R usti n GJ, Q ui n n M, T hi g pe n T, et al. Re: Ne w g ui deli nes t o e val uate t he res p o nse t o treat me nt i n 
s oli d t u m ors ( o varia n ca ncer). J o ur nal of t he Nati o nal Ca ncer I nstit ute. 2 0 0 4; 9 6: 4 8 7- 8.
R uza n ki na Y, Pi nz o n -G uz ma n C, Asare A, et al. Deleti o n of t he de vel o p me ntall y  esse ntial ge ne 
A T R i n a d ult mice lea ds t o a ge-relate d p he n ot y pes a n d ste m cell l oss. Cell Ste m Cell. 2 0 0 7; 1: 1 1 3 -
2 6.
Sa n gster - G uit y N, C o nra d B H, Pa pa d o p o ul os N, et al. A T R me diates cis plati n resista nce i n a p 5 3 
ge n ot y p e-s pecific ma n ner. O nc o ge ne. 2 0 1 1; 3 0: 2 5 2 6- 3 3.
Sc her HI , Hala bi S, Ta n n oc k I, et al: Desi g n a n d e n d poi nts of cli nical trials f or patie nts wit h 
pr o gressi ve pr ostate ca ncer a n d castrate le vels of test oster o ne: Rec o m me n dati o ns of t he Pr ostate 
Ca ncer Cli nical Trials W or ki n g Gr o u p. J o ur nal of Cli nical O nc ol o g y . 2 0 0 8; 2 6: 1 1 4 8- 5 9.
Sc h o p p y  DW, 
Ra gla n d R L , Gila d O, et al. O nc o ge nic stress se nsitizes m uri ne ca ncers t o 
h y p o m or p hic s u p pressi o n of A T R. T he J o ur nal of Cli nical I n vesti gati o n 2 0 1 2; 1 2 2: 2 4 1 - 5 2.
T ole d o LI, M ur ga M, Z ur R, et al. A cell-base d scree n i de ntifies A T R i n hi bit ors wit h s ynt hetic 
let hal pr o perties for ca ncer- ass ociate d m utati o ns. 
Nat ure Str uct ural & 
M olec ular 
Bi ol o g y . 
2 0 1 1; 1 8: 7 2 1 - 7.
Willia ms o n C T, Miller R, Pe m bert o n H N, et al. A T R i n hi bit ors as a s ynt hetic let hal t hera p y for 
t u m o urs deficie nt i n A RI D 1 A. Nat C o m m u n. 2 0 1 6; 7: 1 3 8 3 7
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 7 / 1 5 9
1 2
A p pe n dices
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 8 / 1 5 9
A p pe n di x I:
Si g n at ure P a ges a n d Res p o nsi ble Pers o ns f or t he St u d y
D oc u me nt N o. 
O bject N o. 
C CI
C CI


P P D
P P D
P P D
P P D
P P D
P P D
P P D
C CI
C CI
C CI


C CI
C CI
P P D
P P D
P P D
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 / 1 5 9
Si g n at ure P a ge – Pri nci p al I n vesti g at or
St u d y Title
A n O pe n -La bel St u d y  of t he Safet y , T olera bilit y , a n d 
P har mac o ki netic/ P har mac o d y na mic Pr ofile of M 4 3 4 4 
(f or merly V X -8 0 3) as a Si n gle 
A ge nt 
a n d i n 
C o m bi nati o n 
wit h 
C y t ot o xic C he m ot hera p y 
i n 
Partici pa nt s wit h A d va nce d S oli d T u m ors
I N D N u m ber
E u dr a C T N u m ber
2 0 1 4- 0 0 3 8 3 8- 8 6
Cli nic al St u d y Pr ot oc ol D ate / 
Versi o n
2 9 Ja n uar y 2 0 2 0 / Versi o n 8. 0
Ce nter N u m ber
Pri nci p al In vesti g at or
I, the u n dersi g ne d, a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site a n d affir m t hat I 
u n dersta n d a n d will c o n d uct t he st u d y acc or di n g t o t he cli nical st u d y pr ot oc ol, a n y ap 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 (I CH ) g o o d La b orat or y Practice 
(G C P ) ( T o pic E 6) a n d all a p plica ble Healt h A ut h orit y re q uire me nts a n d nati o nal la ws.
I als o affir m t hat I u n dersta n d t hat Healt h A ut h orities ma y re q uire t he S p o ns ors of cli nical st u dies 
t o o btai n a n d s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I n vesti gati o nal Me dici nal 
Pr o d uct a n d a n y  ot her fi na ncial ties wit h t he S p o ns or. T he S p o ns or will use a n y s uc h i nf or mati o n 
s olel y for t he p ur p ose of c o m pl yi n g wit h t he re g ulat or y re q uire me nts. I t heref ore a gree t o s u p pl y 
t he S p o ns or wit h a n y necessar y  inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties 
i ncl u di n g t h ose of my s p o use a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y t o meet 
Healt h A ut h orit y  re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
Fa x n u m ber:
E -mail a d dress:
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 2 / 1 5 9
A p pe n di x II: 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 me nt is o n t he title pa ge.
Pr ot oc ol Hist or y
Versi o n a n d D ate of Pr ot oc ol
C o m me nts
Versi o n 7. 0, 2 8 A pril 2 0 1 9
C ha n ge of St u d y Desi g n a n d Pla n

T he de vel o p me nt of M 4 3 4 4 i n c o m bi nati o n wit h c yt ot o xic a ge nts li ke 
car b o plati n, ge mcita bi ne, a n d cis plati n was de pri oritize d, a n d 
c o nse q ue ntl y t he i nitiall y pla n ne d Parts B 2, B 3, a n d C were re mo ve d.

3 ne w  st u d y parts ( Parts C 1, C 2, a n d C 3) were a d de d t o i n vesti gate t he 
p ote ntial a ntit u m or efficac y i n partici pa nts w h ose t u m ors ha ve certai n 
bi o mar kers t hat ha ve bee n i de ntifie d t o se nsitize t o A T R i n hi biti o n i n 
precli nical m o dels a n d f or w h o m n o sta n dar d treat me nt o pt i o ns are 
a vaila ble. T he rec o m me n de d P hase II d ose ( R P 2 D) deter mi ne d i n Part 
A or A 2 will be use d i n Parts C 1, C 2, a n d C 3.

Part A 2: O nce Pr ot oc ol Versi o n 7. 0 ( 2 8 A pril 2 0 1 9) has bee n a p pr o ve d 
a n d i m ple me nte d at all partici pati n g ce nters, a B a y esia n o pti mal 
i nter val desi g n will re place t he 3 + 3 desi g n if a n y c ha n ge i n t he 
sc he d ule of M 4 3 4 4 a d mi nistrati o n occ urs (e. g., t o a o nce dail y 
a d mi nistrati o n, or a dr u g h oli da y sc he d ule ).

Te xt w as m o difie d t o all o w partici pa nts w h o re q uire c o nc o mita nt 
treat me nt wit h pr oto n p u m p i n hi bit ors ( P PI) t o c o nti n ue treat me nt i n 
t he trial. 

T he rati o nale f or i ntr o d ucti o n of BI D d osi n g i n Part A 2 (i n t he 
pre vi o us a me n d me nt) w as i m pr o ve d f or clarit y.
C ha n ge i n N u m ber a n d L ocati o n of Sites E x pecte d t o Partici pate

T he n u m ber of sites a n d c o u ntries partici pati n g i n t he st u d y was 
u p date d t o reflect c urre nt e x pectati o ns.
C ha n ge i n P har mac o d y na mic/ Bi o mar ker te xt

A d de d assess me nt of treat me nt-relate d c ha n ges i n p har mac o d y na mic 
mar kers i n P B M C i n Part A 2 t o e x pa n d t he assess me nt of 
treat me nt-relate d c ha n ges i n p har mac o d y na mic mar kers .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 3 / 1 5 9
U p date t o C o ntrace pti o n Met h o ds

Details a n d defi niti o ns f or a p pr o priate a n d acce pta ble met h o ds of 
c o ntrace pti o n were u p date d.
E dit orial C ha n ges

F urt her m ore , t his a me n d me nt i nc or p orated clarificati o ns a n d c ha n ges 
t o all o w i n vesti gati ve sites a d diti o nal ease i n e nr olli n g a n d a d heri n g t o 
t he pr ot oc ol.

Date of last partici pa nt o ut was c ha n ge d fr o m 2 0 1 9 t o 2 0 2 1 t o reflect 
c ha n ge i n st u d y parts.
Versi o n 6. 0, 0 2 Fe br uar y 2 0 1 8
C ha n ge of St u d y Desi g n a n d Pla n

Ge nerall y, Ata xia tela n giectasia m u tate d a n d Ra d 3-relate d pr otei n 
(A T R) si g nali n g is re q uire d t o e na ble ca ncer cells t o pr o gress t hr o u g h 
t o S/ G 2-p hase, a n d i n hi biti o n of A T R let hall y c o m pr o mises t his 
pr ocess. Re peate d or pr ol o n ge d A T R i n hi biti o n is e x pecte d t o res ult i n 
i ncrease d a ntit u m or efficac y ( V X -9 7 0 I n vesti gat or Br oc h ure 2 0 1 7 ). 
F or M 4 3 4 4 m o n ot hera p y, precli nical m uri ne xe n o graft st u dies of 
M 4 3 4 4 i n alter nati ve le n gt he ni n g of tel o meres (A L T + ) m o dels 
de m o nstrate t hat i ncrease d fre q ue nc y of d osi n g is ass ociate d w it h, a n d 
p ossi bl y re q uire d, f or o pti mal a ntit u m or acti vit y i n t he m o n ot hera p y 
setti n g (Verte x Re p ort E 0 4 5 3 -U 1 6 0 7 2 0 1 6 ) w hile mai ntai ni ng 
t olera bilit y base d o n b o d y wei g ht a n d m ortalit y. T hese data s u g gest
t hat pr ol o n ge d or re peate d i n hi biti o n of A T R n ot o nl y p ote ntiates t he 
c yt ot o xic effects of de o x yri b ose n ucleic aci d ( D N A ) d a m a ge, b ut it 
ma y als o be efficaci o us as m o n ot hera p y i n ca ncers w hic h are relia nt o n 
A T R si g nali n g ( Fl y n n 2 0 1 5 ). Of n ote, si milar a ntit u m or acti vit y was 
o bser ve d f or t he sa me t otal wee kl y d ose w he n a d mi nistere d o nce dail y 
or t w ice dail y i n t he precli nical st u d y (Verte x Re p ort E 0 4 5 3 -U 1 6 0 7 
2 0 1 6 ). T heref ore, t wice dail y (BI D ), dail y d osi n g was selecte d as t he 
i nitial sc he d ule f or Part A 2 t o s ustai n A T R i n hi biti o n a n d mi ni mize 
p ote ntial f or ma xi m u m c o nce ntrati o n ( C ma x ) relate d a d verse e ve nts. 

A 1 0 0 -m g si n gle d ose a d mi nistere d BI D ( 2 0 0 m g dail y) was selecte d 
as starti n g d o se f or Part A 2.

T his starti n g d ose is base d o n t he a vaila ble cli nical e x perie nce i n 3 6 
partici pa nts treate d w it h u p t o t he 1 2 0 0 m g t wice wee kl y d osi n g 
sc he d ule i n Part A. As of D e c e m ber 2 0 1 7, i n t otal 1 0 partici pa nts ha ve 
c o m plete d t he d ose li miti n g t o xicit y (D L T ) peri o d at t he 1 2 0 0 m g d ose 
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 4 / 1 5 9
le vel. O ne D L T of Gra de 3 fe ver was o bser ve d a n d t he criteria f or 
M T D w ere n ot yet f ulfille d. T he 1 2 0 0 m g t wice wee kl y sc he d ule 
res ults i n a t otal wee kl y d ose of 2 4 0 0 m g. A 1 0 0-m g d ose a d mi nistere d 
t wice dail y res ults i n a t otal wee kl y d ose of 1 4 0 0 m g a n d is t heref ore 
e x pecte d t o be a t olera ble starti n g d ose. 

T he tar get d ose f or o pti mal acti vit y as m o n ot hera p y i n h u ma ns is 
a p pr o xi matel y 4 0 0 m g BI D dail y base d o n precli nical st u dies. At t his 
d ose, t he maj orit y of pa rtici pa nts are pre dicte d t o ha ve a n a vera ge 
wee kl y c o nce ntrati o n of M 4 3 4 4 t hat meets or e xcee ds t he o pti mal 
a vera ge c o nce ntrati o n i de ntifie d fr o m precli nical m o dels. Si nce t he 
ter mi nal half-life of M 4 3 4 4 is a p pr o xi matel y 2 h o urs, mi ni mal dr u g 
acc u m ulati o n is e x pecte d wit h t he t wice dail y or o nce dail y sc he d ules.

W he n M 4 3 4 4 is a d mi nistere d t wice dail y, t he sec o n d dail y d ose is 
h y p ot hesize d t o be o pti mall y a d mi nistere d at 1 2 -h o ur i nter vals t o 
pr o vi de s ustai ne d A T R i n hi biti o n. H o w e ver, a 4 -h o ur w i n d o w ( 8 t o 1 6
h o urs) is per mitte d f or partici pa nt c o n ve nie nce.
Clarificati o n of P har mac o d y na mic/ Bi o mar ker te xt

S o m e c ha n ges i n p har mac o d y na mic / bi o mar ker e x pl orat or y o bjecti ves 
a n d e n d p oi nts, t he Part B a n d Part C sc he d ule of assess me nts, a n d 
ot her bi o mar ker te xt were m a de i n or der t o pr o vi de clarit y a n d 
c orrect ness of c o nce pts a n d re d uce re d u n da ncies.
E dit orial C ha n ges

Mi n or e dit orial c ha n ges (i ncl u di n g t he c ha n ge fr o m “s u bject” or 
“ patie nt” t o “ partici pa nt”, w here a p plica ble) were ma de f or rea da bilit y, 
clarit y, a n d fl o w,  a n d, al o n g wit h ne w refere nces, are n ot i ncl u de d i n 
t he f oll o wi n g c o m paris o n ta ble.
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 5 / 1 5 9
Versi o n 5. 0, 1 6 A u g ust 2 0 1 7
C ha n ge of S p o ns or

T he st u d y will tra nsiti o n fr o m Verte x P har mace uticals I nc or p orate d, t o 
Merc k K Ga A, Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y f or 
sites i n t he U K a n d T he Net herla n ds, a n d t o E M D Ser o n o Researc h & 
De vel o p me nt I nstit ute, I nc., 4 5 A Mi d dlese x T ur n pi ke, Billerica, M A, 
U S A f or sites i n t he U S A. 
C ha n ge of Dr u g na me

T he dr u g na me V X -8 0 3, use d i n t he Verte x st u dies, c h a n ge d t o M 4 3 4 4 
d uri n g t he tra nsiti o n t o Merc k.
Delete 1 0 m g ta blets of st u d y dr u g
O nl y 5 0 m g ta blets of M 4 3 4 4 will be s u p plie d.
Versi o n 4. 0, 0 3 J u ne 2 0 1 6
T he f oll o w i n g c ha n ges t o t he o verall st u d y desi g n were ma de t hat affecte d 
m ulti ple secti o ns i n t he pr ot oc ol:

D ue t o s p o ns or decisi o n t o f oc us o n s oli d t u m ors, s u bjects wit h 
l y m p h o mas will n o l o n ger be i ncl u de d i n t he st u d y. 

I n or der t o e val uate t he safet y a n d t olera bilit y of V X-8 0 3 i n 
c o m bi nati o n wit h ge mcita bi ne a n d wit h cis plati n, d ose escalati o n of 
V X -8 0 3 i n c o m bi nati o n wit h ge mcita bi ne ( Part B 2) a n d i n 
c o m bi nati o n wit h cis plati n ( Part B 3) were a d de d. Parts B 2 a n d B 3 are 
o pti o nal a n d ma y be p urs ue d de pe n di n g o n t he safet y a n d t olera bilit y 
data fr o m t he i nitial d ose le vels e x pl ore d i n Part B 1 a n d s p o ns or 
decisi o n.

O n -treat me nt t u m or bi o ps y s u bst u d y was a d de d t o Part B i n a n eff ort 
t o de m o nstrate A T R i n hi biti o n i n res p o nse t o V X -8 0 3 i n c o m bi nati o n 
wit h car b o plati n ( Part B 1), ge mcita bi ne ( Part B 2), a n d cis plati n ( Part 
B 3).

S u bject n u m bers i n Parts A a n d B w ere u p date d t o reflect c ha n ges i n 
t he st u d y desi g n.

Part C w as u p date d t o i ncl u de t he o pti o n of d osi n g V X -8 0 3 i n 
c o m bi nati o n wit h cis plati n if t his c o m bi nati o n is felt t o be m ore 
a p pr o priate f or a patie nt t ha n t he c o m bi nati o n of V X -8 0 3 wit h 
car b o plati n.
F o o d -effect st u d y was delete d fr o m Part C as it was deter mi ne d fr o m 
m o deli n g t hat d osi n g i n t he fe d state is u nli kel y t o i m pr o ve t he s yste mic 
e x p os ure of V X -8 0 3. 

T o f urt her e val uate t he p har mac o ki netic ( P K ) of V X -8 0 3 a n d its 
meta b olites, uri ne P K c ollecti o n w as a d de d t o Part B 1.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 6 / 1 5 9

I n or der t o f oll o w s u bjects after t he 2-wee k S afet y F oll o w -u p V isit, a 
Ra di ol o gic F oll o w - u p Visit was a d de d t o Part B. Als o, a d diti o nal 
i ma gi n g sca ns we re a d de d t o Part C f or s u bjects w h o c o m plete at least 
6 c ycles of treat me nt a n d disc o nti n ue treat me nt f or reas o ns ot her t ha n 
disease pr o gressi o n. 

F l u or ot h y mi di ne p ositr o n e missi o n t o m o gra p h y [1 8F] -F L T -P E T sca ns 
were delete d fr o m Part B a n d circ ulati n g t u m or cells ( C T Cs ) we re 
delete d fr o m Parts B a n d C. [ 1 8F] -F L T -P E T sca ns w ere re m o ve d 
beca use sites i n dicate d t hat 3 sca ns i n o ne c ycle are n ot feasi ble. 
C ollecti o n of C T Cs were re m o ve d beca use, i n a se parate cli nical st u d y, 
we ha ve de m o nstrate d t hat t he n u m bers of tra diti o nal C T Cs/ m L of 
bl o o d are e xtre mel y l o w (a p pr o xi matel y 1 -5 C T Cs/ m L) , ma ki n g 
assess me nt of g H 2 A X le vels i n C T Cs c halle n gi n g as a tar get 
e n ga ge me nt rea d o ut. 

I ntras u bject d ose escalati o n was a d de d t o Part A a n d is per mitte d o nl y 
if V X-8 0 3 st u d y dr u g at t hat d ose le vel is n o l o n ger a vaila ble f or t he 
s u bject w h o is c o nti n ui n g d osi n g, res p o n di n g t o treat me nt, a n d has n o 
si g nifica nt t o xicit y.

Base d o n re vie w  of t he a vaila ble cli nical a n d n o ncli nical data a n d 
o utsi de e x pert o pi ni o n, t he f oll o w i n g c ha n ges were ma de t o t he D L T 
defi niti o n:
o
E xcl u de tra nsie nt ele vati o ns i n li ver f u ncti o n tests. 

E xcl u de Gra de 3 or 4 i ncrease i n bilir u bi n, if t he i ncrease is assesse d 
as arisi n g fr o m i n hi biti o n of bilir u bi n gl uc ur o ni dati o n. If t he i ncrease 
i n bilir u bi n is assesse d as arisi n g fr o m i n hi biti o n of bilir u bi n 
gl uc ur o ni dati o n, t he n o nl y bilir u bi n le vels a b o ve 1 5 m g/ d L 
( 2 5 7 µ m ol/ L) will be c o nsi dere d D L Ts. 

I ncl usi o n criteri o n 6f was u p date d t o i ncl ud e m i ni m u m ser u m al b u mi n 
val ue nee de d at Scree ni n g.

E xcl usi o n criteri o n 1 1c was u p date d t o e xcl u de s u bjects w h o ha ve 
bee n dia g n ose d wit h Li -Fra u me ni S y n dr o me or ata xia tela n giectasia. 
T his c ha n ge was ma de beca use i n cell st u dies, de pleti o n of a ta xia 
tela n giectasia m utate d (A T M)
or p 5 3 i n n o n -ca ncer cells lea ds t o 
mar ke d se nsitizati o n t o t he c o m bi nati o n of a n A T R i n hi bit or a n d t he 
D N A da ma gi n g dr u g cis plati n. T his ma y i n dicate t he p ote ntial f or 
n or m al tiss ue t o be se nsiti ve t o t he c o m bi nati o n of a n A T R i n hi bit or 
a n d t he D N A da ma gi n g dr u g i n t he e ve nt eit her p 5 3 or A T M is 
f u ncti o nall y i m paire d.
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 7 / 1 5 9

Clarificati o n was a d de d i n Parts B a n d C t hat ma g netic res o na nce 
i ma gi n g ( M RI ) ma y be use d as a n alter nati ve t o c o mp ute d t o m o gra p h y 
(C T ) sca ns f or disease assess me nt, b ut eac h s u bject s h o ul d be f oll o w e d 
usi n g t he sa me sca n tec h ni q ue f or assessi n g res p o nse t hr o u g h o ut t he 
st u d y if p ossi ble.

D ose m o dificati o n secti o n was u p date d t o pr o vi de m ore details f or 
d ose escalati o ns f or t he differe nt c he m ot hera pe utic a ge nts.

T he defi niti o n of F ull A nal ysis Set was u p date d.

Pr ot oc ol s y n o psis was u p date d t o ali g n wit h c ha n ges ma de t hr o u g h o ut 
t he pr ot oc ol.
Versi o n 3. 0, 3 1 A u g ust 2 0 1 5

Part A wa s re vise d t o all o w e nr oll me nt of u p t o 2 a d diti o nal s u bjects ( 3 
per c o h ort) at t he discreti o n of t he In vesti gat ors a n d S p o ns or, i n t he 
si n gle s u bject c o h ort at a n y d ose le vel, irres pecti ve of t he t o xicit y, t o 
f urt her e x pl ore safet y a n d/ or P K.

Clarificati o n was a d de d t hat V X -8 0 3 d oses w ill be escalate d b y u p t o 
5 0 % d uri n g d ose esc alati o n i n Parts A a n d B.

T he Safet y F oll o w -u p Visit wi n d o w  f or all Parts wa s e xte n de d fr o m 
3 da ys t o 7 d a y s a n d t he Ra di ol o gic F oll o w-u p Visit f or Part C was 
c ha n ge d fr o m 4 wee ks t o 5 we e ks f oll o wi n g t he last c ycle of treat me nt 
t o all o w s u bjects a d diti o nal fle xi bilit y.

W h ole bl o o d (all Parts ) a n d peri p heral bl o o d m o n o n uclear cell 
( P B M C) c ollecti o n (Parts B a n d C) f or p ote ntial e x pl orat or y e val uati o n 
of c orrelati o ns bet w ee n bi o mar kers a n d P K, p har mac o d y na mic ( P D) 
were delete d beca use of tec h nical diffic ulti es wit h t he pla n ne d assa ys.

I n res p o nse t o re g ulat or y fee d bac k, a heari n g assess me nt at t he 
Scree ni n g Visit, o n Da y 1 of eac h treat me nt c ycle, a n d at t he Safet y 
F oll o w -u p Visit was a d de d as part of t he p h ysical e xa mi nati o n i n 
Parts B a n d C.

I n res p o nse t o re g ulat or y fee d bac k, E xcl usi o n Criteri o n 1 3 was u p date d 
t o s pecif y t hat s u bjects recei vi n g treat me nt wit h ot ot o xic or 
ne p hr ot o xic me dicati o ns t hat ca n n ot be disc o nti n ue d at least 7 da ys 
bef ore t he first d ose of st u d y dr u g a n d f or t he d urati o n of t he st u d y, 
will be e xcl u de d i n Parts B a n d C.
Versi o n 2. 0, 1 4 N o ve m ber 2 0 1 4

A d de d f o ot n ote t o t he Sc he d ule of Assess me nts f or Parts A, B, a n d C
t o pr o vi de g ui da nce o n misse d assess me nts

Clarifie d eli gi bilit y criteria relate d t o t he disease stat us of s u bjects i n 
Parts A a n d B
D oc u me nt N o. 
O bject N o. C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 8 / 1 5 9

Re vise d te xt relate d t o C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts ( C T C A E) Gra de 2 or greater dr u g -relate d t o xicities t o i ncl u de 
a n y C T C A E Gra de 2 or greater t o xicit y t hat is p ossi bl y, pr o ba bl y, or 
defi nitel y relate d t o st u d y dr u g.

Clarifie d d ose escalati o n of V X -8 0 3 f or s u bjects i n t he si n gle s u bject 
c o h ort i n Part A w h o e x perie nce a C T C A E Gra de 2 t o xicit y t hat is 
p ossi bl y, pr o ba bl y, or defi nitel y dr u g -relate d a n d d oes n ot q ualif y as a 
d ose -li miti n g t o xicit y ( D L T).

Decrease d t he n u m ber of a d diti o nal s u bjects e val uate d i n t he i nitial 
e x pa nsi o n c o h ort w he n a si n gle D L T occ urs fr o m 5 s u bjects t o 
2 s u bjects. A n a d diti o nal 3 s u bjects wo ul d be i ncl u de d at t he sa me d ose 
o nl y if n o D L Ts occ ur i n t he 2 a d diti o nal s u bjects.

U p date d d urat i o n of l o n g-ter m f oll o w-u p f or s u bjects i n Part C wit h o ut 
d oc u me nte d disease pr o gressi o n at last st u d y visit t o e ver y 3 m o nt hs t o 
ma ke c o nsiste nt wit h Secti o n 3 a n d Secti o n 8. 1. 1 0 .

M o difie d t he defi niti o n of a D L T t o n o l o n ger e xcl u de Gra des
3 or 4 
m uc ositis i n s u bjects w h o ha ve n ot recei ve d o pti mal t hera p y; Gra des 3 
or 4 m uc ositis w o ul d n o w be c o nsi dere d a D L T.

Clarifie d t hat i n a d diti o n t o all safet y data, re vie w of a vaila ble 
p har mac o ki netic ( P K) data w o ul d be c o n d ucte d d uri n g d ose escalati o n 
i n Part A.

I ncl usi o n criteria were ma de m ore s pecific:
1.
S u bjects wit h k n o w n or s us pecte d Gil bert’s s y n dr o me are 
e xe m pte d fr o m ser u m bilir u bi n e xcl usi o n
2.
Al kali ne p h os p hatase m ust be of li ver ori gi n

U p date d he m o gl o bi n a n d esti mate d gl o mer ular filtrati o n rate val ues 
re q uire d f or a d mi nistrati o n of V X-8 0 3 or c he m ot hera p y o n Da y 1 of 
C y cle 1 i n Ta ble 1 0 - 1 f or c o nsiste nc y wit h i ncl usi o n criteria s pecifie d 
i n Secti o n 9. 1 . I n res p o nse t o i n vesti gat or fee d bac k, esti mate d 
gl o mer ular filtrati o n rate val ues re q uire d f or a d mi nistrati o n of V X -8 0 3 
or c he m ot hera p y o n Da y 1 of all c ycles be y o n d C ycle 1 i n Ta ble 1 0 - 1
wa s c ha n ge d fr o m "≥2 0 m L/ mi n" t o " D oes n ot meet D L T criteria."

M o difie d E xcl usi o n Criteri o n
2 t o all o w  f or t he i ncl usi o n of s u bjects i n 
Part B 1 w h o ha ve recei ve d m ore t ha n 6 c ycles of pri or t hera p y wit h 
car b o plati n if disc usse d wit h a n d a p pr o ve d b y t he Verte x me dical 
m o nit or.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M 4 3 4 4
M 4 3 4 4 First i n H u m a n St u d y
M S 2 0 1 9 2 2- 0 0 0 1
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 9 / 1 5 9

Clarifie d t hat i nterr u pti o n of treat me nt is re q uire d, a n d was n ot at t he 
discreti o n of t he i n vesti gat or, f or Gra de 3 or greater t o xicit y be y o n d 
C y cle 1.

Clarifie d details re gar di n g st u d y dr u g s u p pl y a n d ha n dli n g.

Clarifie d t he defi niti o n of a n a d verse e ve nt.

Clarifie d t he seri o us a d verse e ve nt criteria relate d t o h os pitalizati o ns 
a n d m o ve d t his te xt fr o m Secti o n 1 3. 1. 1. 1 t o Secti o n 1 3. 1. 2. 1 .
V ersi o n 1. 0, 1 9 Se pte m ber 2 0 1 4
Ori gi nal versi o n
D oc u me nt N o. 
O bject N o. 
C CI
C CI

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