Conditions: Multiple Myeloma
Keywords: M3258 Dexamethasone Pharmacokinetics Relapsed Refractory Multiple Myeloma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 10
Healthy volunteers: no

Brief summary:
The purpose of this study was to determine the safety, tolerability, pharmacokinetics, pharmacodynamics and early efficacy signs of M3258 as a single agent and co-administered with dexamethasone in participants with Relapsed Refractory Multiple Myeloma (RRMM).

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: M3258 intervention 2: M3258 20 mg
Intervention descriptions: intervention 1: Participants received M3258 at a dose of 10 milligrams (mg) orally, once daily (QD) or twice per week on Day 1 and Day 4 until disease progression. intervention 2: Participants received M3258 at a dose of 20 mg orally, twice per week on Day 1 and Day 4 until disease progression.

Protocol document:
Prot_000.pdf: 
M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1/ 1 5 5
Title P a ge
Cli nic al St u d y Pr ot oc ol Title:
A P hase I O pe n 
La bel First i n H u ma n D ose 
Escalati o n of t he I m m u n o pr oteas o me I n hi bit or 
M 3 2 5 8
as a S i n gle A ge nt a n d E x pa nsi o n St u d y  of 
M 3 2 5 8 
i n C o m bi nati o n wit h De xa met has o ne i n 
Partici pa nts wit h Rela pse d Refract or y  
Multi ple 
M y el o ma
St u d y N u m ber:
M S 2 0 1 8 1 4 - 0 0 1 0
A m e n d me nt N u m ber
3 . 0
Merc k C o m p o u n d N u m ber:
M 3 2 5 8
S h ort Title:
First i n H u ma n D ose Escalati o n of M 3 2 5 8 as a
S i n gle A ge nt a n d E x pa nsi o n St u d y  of M 3 2 5 8 i n 
C o m bi nati o n wit h De xa met has o ne
C o or di n ati n g I n vesti g at or:
 
S p o ns or N a me a n d Le g al Re gistere d 
A d dress:
F or all c o u ntries, e xce pt t he U S:
Merc k
Healt hcare K Ga A
Fra n kf urter Str. 2 5 0
Dar ms ta dt, Ger ma n y
I n t he U S:
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
Billerica, M A, 0 1 8 2 1, U S A
Me dical Res p o nsi ble:
Na me :
P h o ne :
Fa x :
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:
I ND
E u dra C T 2 0 1 9- 0 0 0 9 4 7 -2 8
Pr ot oc ol Versi o n:
1 1 Ma y 2 0 2 0 / Versi o n 4 . 0
Re pl aces Versi o n:
1 2 Se p 2 0 1 9 / Versi o n 3. 0
A p pr o v al D ate:
1 1 Ma y  2 0 2 0
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
2/ 1 5 5
Me dic al 
M o nit or 
N a me a n d C o nt act 
I nf or m ati o n:
 
Tel: 
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges
T y p e
S c o p e
V er si o n N u m b er
N ot e s
Ori gi n al Pr ot o c ol
Gl o b al
1. 0
I niti al v er si o n a p pr o v e d 
b y fir st I R B
Gl o b al A m e n d m e nt t o t h e 
Ori gi n al Pr ot o c ol
Gl o b al
2. 0
R e vi s e d 
a c c or di n g 
t o 
H e alt h A ut h orit y R e q u e st 
( Unit e d S t at e s F o o d & 
D r u g A d mi ni str ati o n [U S 
F D A])
Gl o b al A m e n d m e nt
Gl o b al
3. 0
R e vi s e d 
a c c or di n g 
t o 
H e alt h A ut h orit y R e q u e st
( A N S M [ Fr a n c e])
Gl o b al A m e n d m e nt 
Gl o b al
4. 0
A d d e d
d o s e s 
a n d 
r e gi m e n o pti o n s f or m or e 
fl e xi bilit y.
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 5 A pril 2 0 1 9
2 . 0
Gl o b al A m e n d m e nt
0 1 -J ul -2 0 1 9
3. 0
Gl o b al A m e n d m e nt
1 2 -S e p -2 0 1 9
4. 0
Gl o b al A m e n d m e nt
1 1 -M a y -2 0 2 0
Pr ot oc ol Versi o n 4 . 0 (1 1 -M a y - 2 02 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. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
P P D
P P D
P P D


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
3/ 1 5 5
O ver all R ati o n ale f or t he A me n d me nt
Maj or c ha n ges t o t he pr ot oc ol a n d t he rati o nale f or t hese c ha n ges are liste d i n t he ta ble bel o w. 
Mi n or re visi o ns, i ncl u di n g mi n or e dit orial re visi o ns
a n d clarificati o ns , are n ot liste d.
S e cti o n N u m b er 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
M ulti pl e s e cti o n s 
I ntr o d u cti o n of a d diti o n al tr e at m e nt r e gi m e n s, i n cl u di n g 
2 1 -d a y tr e at m e nt r e gi m e n s, w hi c h m a y 
b e u s e d if 
r e q uir e d. I n cl u d e s t h e a d diti o n of S c h e d ul e of A cti viti e s 
f or t h e 2 1-d a y tr e at m e nt r e gi m e n s f or P art A ( T a bl e 2) 
a n d P art B ( T a bl e 4) i n S e cti o n 1. 3.
Ali g n m e nt of d e x a m et h a s o n e tr e at m e nt i n P art B t o t h e 
n e wl y i ntr o d u c e d tr e at m e nt r e gi m e n s.
P K s a m pli n g ti m e s alt er e d i n or d er t o ali g n s a m pli n g 
a cr o s s t h e tr e at m e nt r e gi m e n s. T a bl e s 1, 3 (f or m erl y 
T a bl e 2), 5 (f or m erl y T a bl e 3) , a n d 6 (f or m erl y T a bl e 4) 
r efl e ct t h e s e c h a n g e s.
A d di n g
r e gi m e n c h a n g e f or m or e 
fl e xi bilit y.
M ulti pl e s e cti o n s  
D L T p eri o d i s d efi n e d a s t h e fir st c y cl e of tr e at m e nt
D L T d efi niti o n r efl e ct s o n e tr e at m e nt 
c y cl e f or eit h er t h e 2 1 -d a y or 2 8 -d a y 
tr e at m e nt r e gi m e n.
M ulti pl e s e cti o n s
All o w a n c e f or a dr u g h oli d a y if a c o n si st e nt d e c e a s e i n 
pl at el et c o u nt s i s o b s er v e d i n t h e 2 8 -d a y d o si n g 
r e gi m e n. 
A d di n g a dr u g h oli d a y t o all o w f or 
tr e at m e nt if a c o n si st e nt d e cr e a s e i n 
pl at el et s , w hi c h m a y b e a tr a n si e nt 
eff e ct o n m e g a k ar y o c yt e 
f u n cti o n, 
p o s si bl y r el at e d t o pl at el et b u d di n g 
si mil ar t o p a n -pr ot e a s o m e i n hi bit or s, 
i s o b s er v e d.
M ulti pl e s e cti o n s
A d diti o n t h at p arti ci p a nt s w h o di d n ot e x p eri e n c e a D L T 
a n d w h o eit h er di d n ot r e c ei v e at l e a st 8 0 % of t h e 
pl a n n e d c u m ul ati v e d o s e of tr e at m e nt d uri n g t h e D L T 
p eri o d, or at l e a st 8 0 % of t h e pl a n n e d a d mi ni str ati o n s 
[ a d d e d] or di d n ot c o m pl et e t h e D L T o b s er v ati o n p eri o d 
will n ot b e c o n si d er e d f or D L T e v al u ati o n.
A d diti o n t h at i n or d er t o b e e v al u a bl e 
i n D L T a n al y si s s et, it i s n ot o nl y 
n e c e s s ar y t o h a v e r e c ei v e d a c ert ai n 
a m o u nt of t h e pl a n n e d c u m ul ati v e 
d o s e, b ut al s o t o h a v e r e c ei v e d a 
mi ni m u m n u m b er of a d m i ni str ati o n s.
M ult ipl e s e cti o n s
F or P art B, t e xt m o difi e d t o st at e: “ If d at a o bt ai n e d 
d uri n g t h e s af et y r u n -i n of P art B i n di c at e t h at a hi g h er 
d o s e t h a n t h e R D E m a y b e t ol er at e d w h e n M 3 2 5 8 i s 
a d mi ni st er e d i n c o m bi n ati o n wit h 
d e x a m et h a s o n e, 
t h e n a  car ef ul e s c al ati o n b e y o n d t h e m o n ot h er a p y 
R D E 
i n c o m bi n ati o n wit h 
d e x a m et h a s o n e c a n b e 
r e c o m m e n d e d i n d o si n g st e p s of m a xi m u m 2 5 % d o s e
i n cr e a s e i n P art B. S M C will r e vi e w all a v ail a bl e d at a t o 
pr o vi d e r e c o m m e n d ati o n s o n t h e n e xt d o s e l e v el.”
D at a o bt ai n e d d uri n g t h e s af et y r u n-
i n of P art B m a y i n di c at e t h at a hi g h er  
d o s e t h a n t h e R D E f or M 3 2 5 8 m a y b e 
t ol er at e d w h e n
M 3 2 5 8 i s c o m bi n e d 
wit h d e x a m et h a s o n e . If s o, S M C will 
r e vi e w all a v ail a bl e d at a t o pr o vi d e 
r e c o m m e n d ati o n s o n t h e n e xt d o s e 
l e v el a s n o w i n di c at e d i n t e xt. 
M ulti pl e s e cti o n s
R e vi si o n s
a n d u p d at e s t o re q uir e d pr ot o c ol t e m pl at e 
l a n g u a g e w er e i n c or p or at e d wit hi n t h e pr ot o c ol.
Pri or t o t hi s a m e n d m e nt, t h e pr ot o c ol 
t e m pl at e w a s 
r e vi s e d. Wi t h thi s 
a m e n d m e nt, 
r e q uir e d
pr ot o c ol 
t e m pl at e 
l a n g u a g e 
h a s 
b e e n 
i n c or p or at e d to ali g n wit h t h e c urr e nt 
t e m pl at e. 
1. 3 
S c h e d ul e 
of 
A cti viti e s, 
T a bl e s 
1
a n d 
3 ( T a bl e 3 w a s 
f or m erl y T a bl e 2)
A d diti o n of s af et y 1 2 -l e a d E C G t e sti n g o n D a y s 8 a n d 
2 2 C y cl e 1 a n d D a y 1 C y cl e 2. 
T o ali g n s a m pli n g ti m e s/ vi sit s f or t h e 
2 1 - a n d 2 8 -d a y r e gi m e n s.
S a m pli n g ti m e p oi nt s f or L -citr ulli n e r e d u c e d.
A s 
a n 
e x pl or at or y 
bi o m ar k er ,
t o 
d et er mi n e if citr ulli n e c a n b e u s e d t o 
pr e di ct s m all i nt e sti n e i nj ur y.  Ba s e d 
u p o n 
pr e cli ni c al 
st u di e s 
t hi s i s 
e x p e ct e d 
to 
o c c ur 
e arl y 
d uri n g 
tr e at m e nt. 
S k el et al S ur v e y m o v e d fr o m D a y 1 C y cl e 1 t o wit hi n 
t h e 2 8-d a y s cr e e ni n g p eri o d
Sit e a n d p arti ci p a nt c o n v e ni e n c e. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
4/ 1 5 5
1. 3 
S c h e d ul e 
of 
A cti viti e s, T a bl e s 1 , 3 , 
5, a n d 6 ( T a bl e 3 w a s 
f or m erl y 
T a bl e 
2 , 
T a bl e 5 w a s f or m erl y 
T a bl e 3, a n d T a bl e 6
w a s f or m erl y T a bl e 4)
M o v e d a s s e s s m e nt s fr o m D a y 1 5 t o D a y 8 f or 1 2-L e a d 
Q T c A s s e s s m e nt a n d L M P 7 a cti vit y & β 5 c .
T o ali g n s a m pli n g ti m e s/ vi sit s f or t h e 
2 1 - a n d 2 8 -d a y r e gi m e n s.
1. 3 
S c h e d ul e 
of 
A cti viti e s, 
T a bl e s 
3 
a n d
6 ( T a bl e 3 w a s 
f or m erl y T a bl e 2 a n d 
T a bl e 6 w a s f or m erl y 
T a bl e 4)
A d d e d 3 P K s a m pli n g ti m e s o n D a y 8 C y cl e 1 ( P art B).
A d d e d 1 L M P 7 a cti vit y & β 5 c s a m pli n g o n D a y 2 C y cl e 
1. 
I n cr e a s e d t h e n u m b er of P K s a m pl e s 
i n or d er t o e n h a n c e t h e P K d at a o n 
t hi s d a y. A d d e d 1 L M P 7 a cti vit y & 
β 5 c s a m pli n g o n D a y 2 C y cl e 1 t o 
c orr e s p o n d wit h P K s a m pli n g. .
5. 1 I n cl u si o n Crit eri o n 
# 5
A d diti o n t h at pl at el et tr a n sf u si o n s ar e p er mitt e d u ntil 5 
d a y s b ef or e t h e fir st d o s e of st u d y i nt er v e nti o n a n d t h at 
a t D a y 1 C y cl e 1 t h e H b s h o ul d m e et i n cl u si o n crit eri o n 
wit h o ut tr a n sf u si o n > 7 d a y s w a s h -o ut wi n d o w. 
Cl arifi c ati o n
5. 1 I n cl u si o n Crit eri o n 
# 6
A s p art at e a mi n otr a n sf er a s e l e v el r e d efi n e d a s ≤ 3. 0 × 
U L N ( w a s ≤ 2. 5 × U L N) a n d al a ni n e a mi n otr a n sf er a s e 
l e v el r e d efi n e d a s ≤ 3. 0 × U L N ( w a s ≤ 2. 5 × U L N). 
Ali g n e d wit h N CI -C T C v 5 .
6. 1 
St u d y 
I nt er v e nti o n( s) 
A d mi ni str ati o n t a bl e
A d diti o n 
of 
t h e 1 m g 
u n it t o t h e U nit 
D o s e 
Str e n gt h( s)/ D o s a g e L e v el( s)
A v ail a bl e f or m ul ati o n w hi c h m a y b e 
u s e d i n t hi s st u d y. 
6. 6 
D o s e 
S el e cti o n 
a n d M o difi c ati o n
A dj u st m e nt a n d cl arifi c ati o n t o t h e d efi niti o n of D L T a n d 
t o t h e D L T p eri o d. 
A dj u st m e nt a n d cl arifi c ati o n t o ali g n 
f or all tr e at m e nt r e gi m e n s. 
A dj u st m e nt t o a s s e s s i n g a D L T if a p arti ci p a nt mi s s e s 
d a y s or d o s e s. 
A dj u st m e nt t o ali g n f or all tr e at m e nt 
r e gi m e n s. 
D ur ati o n of e x c e pti o n s of Gr a d e ≥ 3 n o n h e m at ol o gi c 
A E c o n si d er e d D L T s w er e l e n gt h e n e d t o < 1 w e e k
(fr o m ≤7 2 h) f or Gr a d e 3 f ati g u e, l o c al r e a cti o n s, a n d 
fl u-li k e s y m pt o m s
t h at r e s ol v e t o Gr a d e 
≤ 1 wit h 
a d e q u at e tr e at m e nt.
A d diti o n of Gr a d e 4 t hr o m b o c yt o p e ni a l a sti n g > 7 d a y s, 
or pl at el et s < 1 0 ,0 0 0/ m m 3 at a n y ti m e a s a D L T
A dj u st m e nt t o A E s j u d g e d a s D L T s
A d diti o n of p er mi s si o n of tr a n sf u si o n s if cl e arl y r el at e d 
t o m ulti pl e m y el o m a
All o w a n c e f or tr a n sf u si o n s if r e q uir e d 
f or m ulti pl e m y el o m a
F or P art s A a n d B, i n str u cti o n o n a d mi ni str ati o n of 
mi s s e d d o s e s or if a p arti ci p a nt v o mit s aft er t a ki n g a 
M 3 2 5 8
d o s e. 
A d diti o n al g ui d a n c e o n mi s s e d 
or 
v o mit e d M 3 2 5 8 d o s e s. 
T a bl e 1 1 R e c o m m e n d e d D o s e M o difi c ati o n f or N e w 
O n s et 
or 
W o r s e ni n g 
N e ur o p at hi c 
P ai n 
a n d/ or 
P eri p h er al S e n s or y or M ot or N e ur o p at h y ( o ut si d e of 
D L T P eri o d) : a dj u st m e nt s t o t h e r e c o m m e n d ati o n s f or 
d o s e a n d r e gi m e n m o difi c ati o n f or Gr a d e 1 wit h p ai n or 
Gr a d e 2 a n d f or Gr a d e 2 wit h p ai n or Gr a d e 3. 
Cl arifi c ati o n 
T a bl e 
1 2 
D o s e 
M o difi c ati o n s 
a n d 
T e m p or ar y/ P er m a n e nt Tr e at m e nt Di s c o nti n u ati o n f or 
H e m at ol o gi c 
T o xi cit y 
( o ut si d e 
of 
D L T 
P eri o d) : 
a dj u st m e nt t o t h e d o s e m e di c ati o n r e c o m m e n d ati o n f or 
Gr a d e 
3 
n e utr o p e ni a 
a s s o ci at e d 
wit h 
f e v er or 
n e utr o p e ni a Gr a d e 4 a n d f or pl at el et c o u nt < 2 5 0 0 0/ µ L 
or Gr a d e 3 t hr o m b o c yt o p e ni a wit h bl e e di n g.
Cl arifi c ati o n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
5/ 1 5 5
T a bl e 1 5 A d v er s e E v e nt s of S p e ci al I nt er e st (f or m erl y 
T a bl e 1 3):  

s e v er e a n e mi a r e m o v e d fr o m 
my el o s u p pr e s si o n 
( Gr a d e > 3) wit h c o m pli c ati o n s; 

C O VI D -1 9 i n cl u d e d i n o p p ort u ni sti c i nf e cti o n s; 

s ki n 
r a s h a d d e d 
t o a ll er gi c / hy p er s e n siti vit y 
re a cti o n; 

g ui d a n c e o n li miti n g d e x a m et h a s o n e a d d e d t o 
a ll er gi c /h y p er s e n siti vit y r e a cti o n g ui d a n c e
A dj u st m e nt s t o a d v er s e e v e nt s of 
s p e ci al 
i nt er e st f or M 3 2 5 8 
a n d 
a d diti o n of c o n si d er ati o n of C O VI D -
1 9. 
8. 1 
Effi c a c y 
A s s e s s m e nt s 
a n d 
Pr o c e d ur e s
R e pl a c e d “ s k el et al s ur v e y s” wit h “ a s s e s s m e nt of b o n e 
l e si o n s”, r e m o v e d t h at s k el et al s ur v e y s c o ul d b e 
o mitt e d at D a y 1 C y cl e 1 if ot h er i m a gi n g i s c o n d u ct e d, 
i n di c at e d t h at a s pir at e s ar e pr ef err e d f or t h e b o n e 
m arr o w e x a mi n ati o n s a n d cl arifi e d t h at all r e sp o n s e s 
r e q uir e 2 c o n s e c uti v e a s s e s s m e nt s wit h t h e s a m e, 
w or s e, 
or b ett er o ut c o m e i n t h e li st of di s e a s e 
e v al u ati o n s 
f or effi c a c y 
a s s e s s m e nt s 
p er 
I MW G  
r e s p o n s e crit eri a. 
Cl arifi c ati o n of effi c a c y e v al u ati o n s 
f or di s e a s e a s s e s s m e nt s. 
8. 4 
Tr e at m e nt 
of 
O v er d o s e
O v er d o s e w a s r e d efi n e d a s a n y d o s e hi g h er t h a n t h e 
c al c ul at e d d o s e f or t h at p arti c ul ar a d mi ni str ati o n wit hi n 
a 1 2 - h o ur ti m e p eri o d.
R e d efi niti o n of o v er d o s e f or stri ct er 
li mit s. 
8. 8 Bi o m ar k er s
R e vi s e d 
i n str u cti o n al g ui d eli n e s f or b o n e m arr o w 
s a m pl e s u s e d f or d et er mi ni n g c yt o g e n eti c ri s k f a ct or s 
a n d mi ni m al r e si d u al di s e a s e. 
Pr o vi d e d r e vi s e d g ui d a n c e f or b o n e 
m arr o w s a m pli n g. 
1 0 S af et y M o nit ori n g 
C o m mitt e e
A d d e d g ui d a n c e t h at b a s e d o n t h e s af e t y, P K a n d P d 
d at a (if a v ail a bl e) c oll e ct e d fr o m t h e p arti ci p a nt s i n a 
c o h ort, t h e S M C m a y 
r e c o m m e n d t h at n o f urt h er 
p arti ci p a nt s ar e r e q uir e d i n a c o h ort b ef or e t h e pl a n n e d 
c o h ort si z e i s r e a c h e d .
T o cl arif y t h at b a s e d o n t h e s af et y, 
P K 
a n d 
P d 
d at a 
(if a v ail a bl e) 
c oll e ct e d fr o m t h e p arti ci p a nt s i n a 
c o h ort, t h e S M C m a y 
r e c o m m e n d 
t h at n o 
f urt h er 
p arti ci p a nt s ar e 
r e q uir e d i n a 
c o h ort b ef or e 
t h e 
pl a n n e d c o h ort si z e i s r e a c h e d
A p p e n di x 
1 0 
D e s cri pti o n 
of 
B a y e si a n 
D o s e 
E s c al ati o n M o d el
A d d e d g ui d a n c e f or t h e a d d e d tr e at m e nt r e gi m e n s. 
Cl arifi c ati o n o n
h o w t o h a n dl e t h e 
diff er e nt r e gi m e n i n t h e B a y e si a n 
m o d eli n g 
- C o nfi d e nti al –
T hi s d o c u m e nt i s t h e pr o p ert y of M er c k H e alt h c ar e K G a A, D ar m st a dt, G er m a n y, or o n e of it s s u b si di ari e s. It i s 
i nt e n d e d f or r e stri ct e d u s e o nl y a n d m a y n ot – i n f ull or p art – b e p a s s e d o n, r e pr o d u c e d, p u bli s h e d or u s e d 
wit h o ut e x pr e s s p er mi s si o n of M er c k H e alt h c ar e K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y. C o p yri g ht © 2 0 2 0
b y M er c k H e alt h c ar e K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y. All ri g ht s r e s er v e d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
6/ 1 5 5
T a ble of C o nte nts
Title Pa ge
..............................................................................................................1
Ta ble of C o nte nts
.............................................................................................................. 6
1
Pr ot oc ol S u m ma r y .............................................................................. 1 0
1. 1
S y n o psis ..............................................................................................1 0
1. 2
Sc he ma ................................................................................................ 1 7
1. 3
Sc he d ule of Acti vities ......................................................................... 1 8
2
I ntr o d ucti o n......................................................................................... 6 2
2. 1
St u d y  Rati o nale................................................................................... 6 2
2. 2
Bac k gr o u n d ......................................................................................... 6 3
3
O bjecti ves a n d E n d p oi nts ................................................................... 6 7
4
St u d y  Desi g n....................................................................................... 7 2
4. 1
O verall Desi g n .................................................................................... 7 2
4. 2
Scie ntific Rati o nale f or St u d y  Desi g n ................................................ 7 6
4. 3
J ustificati o n f or D ose .......................................................................... 7 7
4. 4
E n d of St u d y  Defi niti o n...................................................................... 7 9
5
St u d y  P o p ulati o n................................................................................. 7 9
5. 1
I ncl usi o n Criteria ................................................................................ 8 1
5. 2
E xcl usi o n Criteria ............................................................................... 8 4
5. 3
Lifest yl e C o nsi derati o ns ..................................................................... 8 6
5. 3. 1
Meals a n d Dietar y  Restricti o ns........................................................... 8 6
5. 3. 2
Caffei ne, Alc o h ol, a n d T o bacc o ......................................................... 8 6
5. 3. 3
Acti vit y ...............................................................................................8 7
5. 4
Scree n Fail ures .................................................................................... 8 7
6
St u d y  Inter ve nti o n(s) ..........................................................................8 7
6. 1
St u d y  I nter ve nti o n(s) A d mi nistrati o n.................................................8 7
6. 1. 1
Me dical De vice(s) Use
....................................................................... 8 7
6. 2
St u d y  Inter ve nti o n(s) Pre parati o n, Ha n dli n g, St ora ge, a n d 
Acc o u nta bilit y .....................................................................................8 7
6. 3
Meas ures t o Mi ni mize Bias: St u d y  Inter ve nti o n Assi g n me nt 
a n d Bli n di n g ........................................................................................ 8 8
6. 3. 1
St u d y  Inter ve nti o n Assi g n me nt .......................................................... 8 8
6. 3. 2
Bli n di n g ..............................................................................................8 8
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C C
I


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
7/ 1 5 5
6. 3. 3
E mer ge nc y  U n bli n di n g.......................................................................8 8
6. 4
St u d y  Inter ve nti o n C o m plia nce .......................................................... 8 9
6. 5
C o nc o mita nt T hera p y ......................................................................... 8 9
6. 5. 1
Resc ue Me dici ne ................................................................................. 8 9
6. 5. 2
Per mitte d Me dici nes ........................................................................... 9 0
6. 5. 3
Pr o hi bite d Me dici nes .......................................................................... 9 0
6. 5. 4
Ot her I nter ve nti o ns ............................................................................. 9 1
6. 6
D ose Selecti o n a n d M o dificati o n ........................................................ 9 1
6. 7
St u d y  Inter ve nti o n at t he E n d of t he St u d y ......................................... 9 6
6. 8
S pecial Preca uti o ns ............................................................................. 9 6
6. 9
Ma na ge me nt of A d verse E ve nts of S pecial I nterest ........................... 9 6
6. 9. 1
M o nit ori n g a n d Ma na ge me nt of Ot her T o xicities (e. g., O ver -
Arc hi n g T o xicities i n Part B).............................................................. 9 7
7
Disc o nti n uati o n of St u d y I nter ve nti o n a n d Partici pa nt 
Disc o nti n uati o n/ Wit h dra wal ...............................................................9 9
7. 1
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................ 9 9
7. 1. 1
Te m p orar y  Disc o nti n uati o n..............................................................1 0 0
7. 1. 2
Rec halle n ge ....................................................................................... 1 0 1
7. 2
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y ................. 1 0 1
7. 3
L ost t o F oll o w -U p ............................................................................. 1 0 1
8
St u d y  Assess me nts a n d Pr oce d ures.................................................. 1 0 1
8. 1
Efficac y  Assess me nts a n d Pr oce d ures .............................................. 1 0 2
8. 2
Safet y  Assess me nts a n d Pr oce d ures................................................. 1 0 6
8. 2. 1
P h y sical E xa mi nati o ns ...................................................................... 1 0 7
8. 2. 2
Vital Si g ns ........................................................................................ 1 0 7
8. 2. 3
Electr ocar di o gra ms ........................................................................... 1 0 7
8. 2. 4
C hest X -Ra y  at Pretreat me nt............................................................ 1 0 8
8. 2. 5
Cli nical Safet y  La b orat or y Assess me nts.......................................... 1 0 8
8. 2. 6
S uici dal I deati o n a n d Be ha vi oral Ris k M o nit ori n g ..........................1 0 9
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts................................ ...1 0 9
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E ve nt I nf or mati o n.................................................. 1 0 9
8. 3. 2
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts ...............................................................................................1 0 9
8. 3. 3
F oll o w - U p of A d verse E ve nts a n d Seri o us A d verse E ve nts............1 0 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
8/ 1 5 5
8. 3. 4
Re g ulat or y  Re p orti n g Re q uire me nts f or Seri o us A d verse 
E ve nts ...............................................................................................1 1 0
8. 3. 5
Pre g na nc y ......................................................................................... 1 1 0
8. 4
Treat me nt of O ver d ose ..................................................................... 1 1 1
8. 5
P har mac o ki netics .............................................................................. 1 1 1
8. 6
P har mac o d y na mics ........................................................................... 1 1 2
8. 8
Bi o mar kers ........................................................................................ 1 1 2
8. 9
Healt h Ec o n o mics ............................................................................. 1 1 3
8. 1 0
I m m u n o ge nicity Assess me nts .......................................................... 1 1 3
9
Statistical C o nsi derati o ns .................................................................. 1 1 3
9. 1
Statistical H y p ot heses ....................................................................... 1 1 3
9. 2
Sa m ple Size Deter mi nati o n ..............................................................1 1 3
9. 3
P o p ulati o ns f or A nal y ses .................................................................. 1 1 4
9. 4
Statistical A nal y ses ........................................................................... 1 1 4
9. 4. 1
Efficac y  A nalys es ............................................................................. 1 1 4
9. 4. 2
Safet y  A nalys es ................................................................................ 1 1 6
9. 4. 3
Ot her A nal ys es .................................................................................. 1 1 8
9. 4. 4
Se q ue nce of A nal ys es ....................................................................... 1 1 8
1 0
Safet y  M o nit ori n g C o m mittee.......................................................... 1 1 9
1 1
Refere nce s......................................................................................... 1 2 1
1 2
A p pe n dices ....................................................................................... 1 2 3
A p pe n di x 1
A b bre viati o ns .................................................................................... 1 2 4
A p pe n di x 2
St u d y  G o ver na nce............................................................................. 1 2 7
A p pe n di x 3
C o ntrace pti o n .................................................................................... 1 3 3
A p pe n di x 4:
Pr o hi bite d C o me dicati o n Pr ol o n gi n g t he Q T/ Q Tc I nter val .............. 1 3 5
A p pe n di x 5
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E val uati n g, F oll o w -U p, a n d Re p orti n g ............................................. 1 3 6
A p pe n di x 6
Li ver Safet y:  S u g geste d Acti o ns a n d F oll o w -U p Assess me nts ........ 1 4 0
A p pe n di x 7
La b orat or y  Tests...............................................................................1 4 1
A p pe n di x 8
P har mac o ki netic Para meters .............................................................1 4 2
A p pe n di x 1 0
Descri pti o n of t he Ba y esia n D ose Escalati o n M o del ....................... 1 4 6
A p pe n di x 1 1
Pr ot oc ol A me n d me nt Hist or y ........................................................... 1 4 8
A p pe n di x 1 2
S p o ns or Si g nat ure Pa ge ....................................................................1 5 3
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C C
I
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 1 5 5
A p pe n di x 1 3
C o or di nati n g I n vesti gat or Si g nat ure Pa ge ........................................ 1 5 4
A p pe n di x 1 4
Pri nci pal I n vesti gat or Si g nat ure Pa ge ............................................... 1 5 5
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 / 1 5 5
1
Pr ot oc ol S u m m ar y
1. 1
S y n o psis
Pr ot oc ol Tit le: 
A P hase I O pe n La bel First i n H u ma n D ose Escalati o n of t he I mm u n o pr oteas o me I n hi bit or 
M 3 2 5 8 as a Si n gle A ge nt a n d E x pa nsi o n St u d y  of M 3 2 5 8 i n C o m bi nati o n wit h De xa met has o ne 
i n Partici pa nts wit h Rela pse d Refract or y M ulti ple M y el o ma
S h ort Title: 
First i n H u ma n D ose Escalati o n of M 3 2 5 8 as a S i n gle A ge nt a n d E x pa nsi o n St u d y  of M 3 2 5 8 
i n C o m bi nati o n wit h De xa met has o ne
R ati o n ale: 
M 3 2 5 8 is a n oral, p ote nt a n d selecti ve c o vale nt-re versi ble i n hi bit or of t he c h ym otr y psi n -li ke 
acti vit y of t he lar ge m ultif u ncti o nal pr otease 7 ( L M P 7, β 5i, P S M B 8) s u b u nit of t he 
i m m u n o pr oteas o me, w hic h has t he p ote ntial t o deli ver a t hera pe utic be nefit t o patie nts wit h 
rela pse d or refract or y m ulti ple m yel o ma ( R R M M).
M 3 2 5 8 de m o nstrate d p ote nt a n d selecti ve i n hi biti o n of L M P 7. T his in dicates t hat M 3 2 5 8 has 
a relate d, yet m ore selecti ve pr ofile c o m pare d t o t he a p pr o ve d pa n - pr oteas o me i n hi bit ors 
b ortez o mi b, carfilz o mi b, a n d i xaz o mi b, w hic h i n discri mi natel y in hi bit m ulti ple pr ote ol y tic 
s u b u nits of t he i m m u n o pr oteas o me a n d c o nstit uti ve proteas o me.
M 3 2 5 8 de m o nstrate d str o n g a ntit u m or acti vities, u p t o c o m plete re gressi o ns, i n n o ncli nical 
m ulti ple m y el o ma m o dels. O pti mal efficac y was o bser ve d u p o n o nce dail y  (Q D ) oral d osi n g 
of M 3 2 5 8, a sc he d ule ass ociate d wit h s ustai ne d s u p pressi o n of L M P 7 acti vit y in t u m or cells 
a n d peri p heral bl o o d m o n o n uclear cells. M 3 2 5 8 als o de m o nstrate d s u peri or i n vi v o efficac y 
c o m pare d t o t he a p pr o ve d pa n -pr oteas o me i n hi bit ors i n differe nt n o ncli nical m o dels i ncl u di n g 
c yt o ge netic hi g h -ris k m o dels, s u g gesti n g t he p otential f or M 3 2 5 8 t o deli ver a n efficacy b e nefit 
t o patie nts wit h m ulti ple m y el o ma ( M M) w h o d o n ot dis pla y  an o pti mal res p o nse t o t hese 
a p pr o ve d t hera pe utic a ge nts.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 / 1 5 5
O bjecti ves a n d E n d p oi nts:
St u d y O bjecti ves a n d E n d p oi nts - D ose Esc al ati o n - P art A
O bjecti ves
E n d p oi nts ( O utc o me Me as ures)
Pri m ar y

T o deter mi ne safet y, t olera bilit y an d t he 
ma xi m u m 
t olerate d d ose ( M T D)
(if 
o bser ve d) of M 3 2 5 8
as a si n gle a ge nt i n 
partici pa nts wit h R R M M

Occ urre nce 
of d ose -li miti n g t o xicities 
(D L Ts ) i n partici pa nts recei vi n g M 3 2 5 8 
as a si n gle a ge nt d uri n g t he D L T peri o d

Occ urre nce of a n y a d verse e ve nts (A Es )
re p orte d (seri o us or n o nseri o us) will be 
c o nsi dere d 
st u d y treat me nt-e mer ge nt 
a d verse 
e ve nts 
(T E A Es )
a n d 
st u d y 
treat me nt-relate d 
a d verse 
e ve nts 
(T R A Es ) (i ncl u di n g T E A Es lea di n g t o 
deat h or disc o nti n uati o n of treat me nt) i n 
partici pa nts recei vi n g M 3 2 5 8
as a si n gle 
a ge nt fr o m start of st u d y i nter ve nti o n t o 
3 0 da y s after E n d of S t u d y Inter ve nti o n

Occ urre nce of T E A Es o utsi de of t he D L T 
peri o d t hat safety m o nit ori n g c o m mittee 
(S M C ) dee ms rele va nt f or deter mi nati o n 
of t he M T D

St u d y  treat me nt-e mer ge nt c ha n ges i n 
cli nical 
la b orat or y 
meas ures 
fr o m 
Baseli ne ,  
safety 
electr ocar di o gra m 
(E C G ) meas ures, vital si g ns, Easter n C o -
o perati ve 
O nc ol o g y  
Gr o u p ( E C O G)
p erf or ma nce 
stat us
i n 
partici pa nts 
recei vi n g M 3 2 5 8 as a si n gle a ge nt fr o m 
start of st u d y inter ve nti o n t o 3 0 da y s after
en d of st u d y i nter ve nti o n
Sec o n d ar y

T o i n vesti gate t he p har mac o ki netic ( P K) 
pr ofile of M 3 2 5 8 
(si n gle a n d m ulti ple 
d ose 
e x p os ure) i n partici pa nts 
wit h 
R R M M

P K pr ofile of M 3 2 5 8 i n ter ms of C ma x, 
A U C 0-t, A U C 0- 2 4 at Da y  1 Cycle 1, (si n gle 
d ose): pre d ose, 1, 2, 3, 4, 5, 6, 8 a n d 2 4 h 
after a d mi nistrati o n

P K pr ofile of M 3 2 5 8 i n ter ms of C ma x , 
A U C 0- 2 4 at Da y  8 C y cle 1 ( m ulti ple d ose): 
pre d ose , 1, 2, 3, 4, 5, 6, a n d 8 h after 
a d mi nistrati o n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 / 1 5 5
O bjecti ves
E n d p oi nts ( O utc o me Me as ures)

T o i n vesti gate t he rec o m me n de d d ose
a n d re gi me n f or e x pa nsi o n (R D E ) i n 
partici pa nts wit h R R M M

I n a d diti o n t o safety, t olera bilit y an d P K,
f or selecti o n of rec o m me n de d d ose a n d 
re gi me n f or e x pa nsi o n (R D E ), c ha n ges i n 
p har mac o d y n a mics (P d ) ( LM P 7 acti vit y ) 
i n pre 
a n d p ost
st u d y inter ve nti o n 
sa m ples o n Da y  1 C y cle 1
pre a n d 
p ost d ose, D a y 2 C y cle 1 pre d ose a n d 
Da y 8 C y cle 1 pre a n d p ost d ose 

C ha n ges fr o m Baseli ne
i n ser u m M-
pr otei n or uri ne M- pr otei n or free li g ht 
c hai n pr otei n le vels (f or free li g ht c hai n 
disease) o n Da y  1 of e ver y  c ycle 

T o e val uate preli mi nar y  cli nical acti vit y 
usi n g I nter nati o nal M y el o ma 
W or ki n g 
Gr o u p ( I M W G) criteria

O verall
res p o nse
(O R ), d urati o n 
of 
res p o nse (D O R ), ti me t o res p o nse u ntil 
c o m plete 
res p o nse 
( C R), 
stri n ge nt 
c o m plete res p o nse (s C R), ver y  go o d 
partial 
res p o nse (V G P R ), or 
partial 
res p o nse ( P R) acc or di n g t o IM W G
St u d y O bjecti ves a n d E n d p oi nts - D ose E x p a nsi o n - P art B
O bjecti ves
E n d p oi nts
Pri m ar y

T o deter mi ne safety a n d t olera bilit y of 
M 3 2 5 8
at 
rec o m me n de d d ose
a n d 
re gi me n f or e x pa nsi o n (R D E ) w he n c o-
a d mi nistere d wit h 
de xa met has o ne 
i n 
partici pa nts wit h R R M M

Occ urre nce 
of D L Ts 
i n partici pa nts 
recei vi n g M 3 2 5 8 
i n c o m bi nati o n wit h 
de xa met has o ne d uri n g t he D L T peri o d

Occ urre nce of st u d y treat me nt-e mer ge nt 
seri o us a d verse e ve nts ( S A Es) (i ncl u di n g 
deat hs ) i n partici pa nts recei vi n g M 3 2 5 8 
i n c o m bi nati o n wit h 
de xa met has o ne,
fr o m start of st u d y inter ve nti o n u p t o 3 0 
da y s after e n d of st u d y i nter ve nti o n

Occ urre nce 
of 
T E A Es 
a n d 
T R A Es 
(i ncl u di n g 
deat hs) 
i n 
partici pa nts 
recei vi n g M 3 2 5 8 
i n c o m bi nati o n wit h 
de xa met has o ne
fr o m start of 
st u d y 
i nter ve nti o n u p t o 3 0 da y s after e n d of 
st u d y i nter ve nti o n

St u d y  
treat me nt-e mer ge nt 
cli nicall y 
rele va nt a b n or mal c ha n ges i n cli nical 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 / 1 5 5
O bjecti ves
E n d p oi nts
la b orat or y 
meas ures 
fr o m Baseli ne, 
E C Gs 
meas ures, 
vital si g ns, E C O G 
perf or ma nce 
stat us 
i n 
partici pa nts 
recei vi n g M 3 2 5 8 
i n c o m bi nati o n wit h 
de xa met has o ne
fr o m start of 
st u d y 
i nter ve nti o n t o 3 0 da y s after en d of st u d y 
i nter ve nti o n

T o deter mi ne rec o m me n de d P hase II 
d ose of M 3 2 5 8 
w he n c o-a d mi nistere d 
wit h de xa met has o ne i n partici pa nts wit h 
R R M M base d o n earl y si g ns of safet y a n d
efficac y i n t he e x pa nsi o n p hase

Occ urre nce 
of 
T E A Es 
a n d 
T R A Es 
(i ncl u di n g 
deat hs) 
i n 
partici pa nts 
recei vi n g 
M 3 2 5 8 
w he n 
gi ve n 
i n 
c o m bi nati o n wit h de xa met has o ne fr o m 
start of st u d y inter ve nti o n t o 3 0 da y s after 
e n d of st u d y i nter ve nti o n

O R, D O R, ti me t o res p o nse u ntil C R, 
s C R, V G P R, or P R acc or di n g t o I M W G
Sec o n d ar y

T o c ollect preli mi nar y  efficac y data i n 
partici pa nts wit h R R M M u n der treat me nt 
wit h M 3 2 5 8, w he n c o-a d mi nistere d wit h 
de xa met has o ne

O R, D O R, ti me t o res p o nse u ntil C R, 
s C R, V G P R, or P R acc or di n g t o I M W G

Pr o gressi o n -Free 
S ur vi val 
( P F S) per 
I n vesti gat or

O vera ll S ur vi val ( O S) ce ns ore d at E n d of 
St u d y

T o i n vesti gate t he P K pr ofile of M 3 2 5 8 
(si n gle a n d m ulti ple d ose e x p os ure) w he n 
c o-a d mi nistere d wit h de xa met has o ne i n 
partici pa nts wit h R R M M

P K pr ofile of M 3 2 5 8 i n ter ms of C ma x, 
A U C 0-t, A U C 0- 2 4 at Da y  1 Cycle 1 , (si n gle 
d ose): pre d ose, 1, 2, 3, 4, 5, 6 a n d 2 4 h 
after a d mi nistrati o n

P K pr ofile of M 3 2 5 8 i n ter ms of C ma x , 
A U C 0- 2 4 at Da y  8 C y cle 1, ( m ulti ple 
d ose): pre d ose, 2, 4,
a n d 6 h
after 
a d mi nistrati o n
O ver all Desi g n: 
T his is a P hase I, o pe n -la bel, First i n H u ma n ( Fi H), 2 -part ( d ose escalati o n a n d e x pa nsi o n) , 
n o nc o ntr olle d, m ultice nter cli nical st u d y  desi g ne d t o deter mi ne t he safety, t olera bilit y, P K, P d 
a n d earl y si g ns of efficac y of M 3 2 5 8 as a si n gle a ge nt ( Part A)
a n d c o -a d mi nistere d wit h 
de xa met has o ne ( Part B) i n partici pa nts wit h R R M M w h o se disease has pr o gresse d f oll o wi n g
> 3 pri or li nes of t hera p y a n d f or w h o m n o effecti ve sta n dar d t hera p y e xists . 
T he d ose escalati o n p hase is ai me d at deter mi ni n g t he rec o m me n de d d ose a n d re gi me n f or 
e x pa nsi o n (R D E ) base d o n safety, t olera bilit y, P K , P d (i ncl u di n g L M P 7 acti vit y) a n d i nitial 
efficac y data. F oll o wi n g t he d ose -escalati o n p hase, t he safety a n d t olera bilit y of M 3 2 5 8 wit h 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 / 1 5 5
de xa met has o ne will be i n vesti gate d i n a n e x pa nsi o n c o h ort f or assess me nt of earl y cli nical 
acti vit y.
N u m ber of P artici p a nts: 
I n t he m o n ot hera p y , d ose -escalati o n p hase ( Part A) , ap pr o xi matel y  1 8 partici pa nts will be
e nr olle d i n c o h orts of 3 starti n g at t he 1 0 m g  Q D d ose le vel. T he rec o m me n dati o n f or d osi n g 
i n t he ne xt c o h ort will be ma de b y  t he S M C base d o n safet y, t olera bilit y, a n d preli mi nar y P K 
a n d, if a p pr o priate, P d data. Details are descri be d i n t he S M C c harter. T he f oll o wi n g d ose le vels 
are pla n ne d : 1 0 m g, 2 0 m g, 3 5 m g, a n d 5 0 m g .
I n the d ose -ex pa nsi o n p hase of M 3 2 5 8 
i n c o m bi nati o n wit h de xa met has o ne ( Part B) ,
a p pr o xi matel y 3 0 pa rtici pa nts wit h R R M M will be e nr olle d at t he rec o m me n de d d ose a n d 
re gi me n f or e x pa nsi o n ( R D E) deter mi ne d i n t he d ose -escalati o n p hase of t he st u dy. T his 
n u m ber ma y i ncrease b y  ap pr o xi matel y  3t o 2 1 partici pa nts if a c ha n ge i n d ose of M 3 2 5 8 occ ur s
i n t he e x pa nsi o n c o h ort. A n i nteri m a nal ysis will be c o n d ucte d w he n data f or 1 5 partici pa nts 
e val ua ble f or res p o nse a n d treate d o n t he sa me d ose are a vaila ble. T he S M C will m o nit or t he 
safety of pa rtici pa nts d uri n g t he e x pa nsi o n c o h ort.
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n: 
D uri n g d ose escalati o n ( Part A) , M 3 2 5 8 will be a d mi nistere d Q D as a si n gle a ge nt i n 2 8- da y
c ycles. I n t he e x pa nsi o n c o h ort ( Part B) , M 3 2 5 8 will be a d mi nistere d i n c o m bi nati o n wit h 
d e xa met has o ne at a c u m ulati ve d ose of 4 0 m g/ wee k . T he treat me nt peri o d will be gi n at t he first 
d ose of M 3 2 5 8 i n Da y  1 C y cle 1. Partici pa nts t olerati n g M 3 2 5 8 wit h o ut si g nifica nt cli nicall y 
rele va nt t o xicities ma y c o nti n ue t o recei ve assi g ne d M 3 2 5 8 d ose u ntil disease pr o gressi o n.
If Q D treat me nt is n ot t olerate d at a d ose le vel s h o wi n g efficac y  a n d/ or P d mar ker si g nals, t he 
f oll o wi n g o pti o ns will be c o nsi dere d b y  t he S M C base d o n a vaila ble data:

Q D d osi n g at d oses bel o w t he n o n -t olerate d d ose ( d o w n t o 1 m g) i n 2 8- d a y  cycl es
( base d o n S M C rec o m me n dati o n)
O R

T wice -per -wee k d osi n g o n D a ys 1, 4, 8, 1 1, 1 5, 1 8, 2 2 a n d 2 5 i n 2 8-d a y  c ycles
I n a d diti o n , if a c o nsiste nt re d ucti o n i n platelet c o u nts t o t hr o m b oc yt o pe nia ≥Gra de 3 is 
o bser ve d d uri n g t he 2 8- da y d osi n g re gi me n wit h o u t rec o ver y to baseli ne or ≤ Gra de 2 b y  th e 
e n d of t he c ycle, t he S M C ca n c o nsi der a dr u g h oli da y  of at least 7 da y s i n t he pr o p ose d 
re gi me n. Si milar t o p a n -pr ote as o me i n hi bit ors, a tra nsie nt effect o n me ga kar y o c y te f u ncti o n, 
p ossi bl y  relate d t o platelet b u d di n g nee ds t o be c o nsi dere d rat her t ha n a direct c yt ot o xic effect 
o n me ga kar y o c y tes (L o nial et al, 2 0 0 5). A pre dicte d ti me f or rec o ver y of platelet c o u nts fr o m 
na dir t o baseli ne val ues has bee n descri be d t o b e ar o u n d 7 d a y s (L o nial et al, 2 0 0 5). T h us, a
dr u g h oli da y (i nter mitte nt) of at least 7 da y s t o 1 0 da y s is i ncl u de d i n t he pr o p ose d re gi me n
w hic h c o nse q ue ntl y c ha n ges t he c ycle le n gt h t o 2 1 da ys.

Q D d osi n g o n D a ys 1 t o 1 4 , n o d osi n g o n Da ys 1 5 t o 2 1, i n 2 1-da y  c ycles 
O R
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 / 1 5 5

T wice -per - wee k d osi n g o n D a ys 1, 4, 8, 1 1 , n o d osi n g o n Da y s 1 2 t o 2 1, i n 2 1- d a y  
c ycles
If a s witc h i n d os e a n d/ or re gi me n is rec o m me n de d, t he first teste d d ose le vel i n t he ne w 
re gi me n m ust n ot e xcee d t he hi g hest teste d dail y  d ose / or t he wee kly c u m ulati ve d ose m ust be 
e q ual t o or l o wer t ha n t he hi g hest wee kl y c u m ulati ve d ose of re gi me n(s) teste d s o far.
T he selecte d M 3 2 5 8 d os e a n d re gi me n ( R D E) will be c o m bi ne d wit h de xa met has o ne f or t he 
e x pa nsi o n c o h ort ( Part B) .
D e xa met has o ne will be gi ve n at a c u m ulati ve d ose of 4 0 m g/ wee k :

2 0 m g/ da y  at D a ys 1, 4, 8, 1 1, 1 5, 1 8, 2 2 a n d 2 5 i n a 2 8- d a y c ycle
O R

2 0 m g/ da y  at D a ys 1, 4, 8, 1 1, 1 5, a n d 1 8 i n a 2 1- d a y c ycle (re gi me n wit h dr u g 
h oli da y ) 
D ose Esc al ati o n P art A 
Partici pa nts wit h M M w h o se disease has pr o gresse d f oll o wi n g > 3 li nes of t hera py a n d f or 
w h o m n o effecti ve sta n dar d t hera p y e xists will be e nr olle d i n Part A . T he first d ose-escalati o n 
c o h ort will recei ve M 3 2 5 8 at t he starti n g d ose of 1 0 m g Q D as a si n gle a ge nt. F or f urt her d ose 
c o h orts, a S M C will meet a n d re vie w all a vaila ble data t o pr o vi de rec o m me n dati o ns o n t he 
ne xt d ose le vel. T he f oll o wi n g pre s pecifie d d oses of 1 0 m g, 2 0 m g ( 1 0 0 % i ncrease), 3 5 m g 
( 4 3 % i ncrease) a n d 5 0 m g ( 3 0 % i ncrease) are pla n ne d u nless M T D is reac he d. T he S M C, 
f oll o wi n g re vie w of preli mi nar y  safet y, t olera bilit y, P K a n d P d i nf or mati o n, will rec o m me n d 
t he d ose a n d/ or t he s witc h t o a n alter nati ve re gi me n pres pecifie d i n t his pr ot oc ol f or t he ne xt 
c o h ort as a p plica ble. 
T his ma y  incl u de pr o p osi n g s maller d ose i ncreases c o m pare d t o t he pres pecifie d d oses a n d de -
escalati o n of t he d ose p ote ntiall y d o w n t o 1 m g. 
T he S M C ma y  als o rec o m me n d e x pa n di n g a gi ve n c o h ort at t he sa me d ose le vel. 
If a d diti o nal d ose le vels a b o ve 5 0 m g  are j ustifie d f oll o wi n g re vie w of preli mi nar y  safet y,  
t olera bilit y, P K, a n d P d i nf or mati o n fr o m t he i nitial c o h orts, a pr ot oc ol a me n d me nt will be 
s u b mitte d. 
De pe n di n g o n t he o bser ve d t o xicit y pr ofile, t he S M C ma y  deci de o n differe nt d oses as 
pres pecifie d a n d/ or c ha n ge t o re gi me ns pres pecifie d i n t his pr ot oc ol . H o we ver, escalati o n ma y 
n ot pr ocee d t o a n y d ose hi g her t ha n 5 0 m g . I n case escalati o n s h o ul d pr ocee d t o d oses hi g her 
t ha n 5 0 m g, a n a me n d me n t will be s u b mitte d. At eac h d ose le vel, t he first partici pa nt e nr olle d 
will be o bser ve d f or ac ute t o xicit y f or at least 4 8 h o urs d uri n g t he D L T peri o d bef ore f urt her 
partici pa nts are e nr olle d . 
T he R D E of si n gle-a ge nt M 3 2 5 8 will be base d o n all a vaila ble safet y, t olera bilit y, P K, P d 
(i ncl u di n g L M P 7 acti vit y) a n d i nitial efficac y data fr o m at least 6 partici pa nts at t he gi ve n d ose. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 / 1 5 5
T his d ose a n d re gi me n will be t he rec o m me n de d d ose f or Part B of t he st u d y, pe n di n g S M C 
a greeme nt . 
D ose E x p a nsi o n P art B
O nce a n R D E ( d ose a n d re gi me n) of M 3 2 5 8 has bee n defi ne d w hic h is c o nsi dere d safe b y t he 
S M C, d ose e x pa nsi o n ( Part B) m a y  be gi n. I nitiati o n of Part B ma y start wit h o ut reac hi n g t he 
M T D i n Part A ; d ose escalati o n f or defi ni n g t he m o n ot hera p y M T D ( Part A) ma y  pr ocee d i n 
parallel.
Partici pa nts wit h M M w h o se disease has pr o gresse d f oll o wi n g > 3 li nes of t hera py f or w h o m 
n o effecti ve sta n dar d t hera p y e xists wil l be e nr olle d. I n Part B , p artici pa nts will recei ve M 3 2 5 8 
at t he R D E selecte d i n Part A i n c o m bi nati o n wit h de xa met has o ne at a c u m ulati ve d ose of 4 0 
m g/ wee k . T he first 2 c o h orts of 3 partici pa nts eac h (first 6 partici pa nts) will be use d f or a 
safety r u n-i n. T he partici pa nts i n t hese 2 c o h orts will be e nr olle d i n a se q ue ntial a p pr oac h. Eac h 
c o h ort of t he safety r u n-i n will be e val uate d b y t he S M C f or t he pres pecifie d D L T criteria f or 
t his c o m bi nati o n bef ore a d diti o nal partici pa nts are e nr olle d. T hese S M C
meeti n g s will be hel d 
after 3 a n d 6 partici pa nts i n t he safet y ru n- i n ha ve fi nis he d C ycle 1 or d isc o nti n ue d treat me nt
i n or der t o e val uate safet y, c u m ulati ve a n d u nacce pta ble t o xicit y of partici pa nts fr o m t heir 
treat me nt c ycles. After t he safety r u n-i n, S M C meeti n g s will be hel d at t he c o m pleti o n of C ycle 
1 or disc o nti n uati o n of treat me nt f or e ver y 6 partici pa nts ( wit h o ut pa usi n g e nr oll me nt) i n or der 
t o assess safety, c u m ulati ve a n d u nacce pta ble t o xicit y of all partici pa nts i n t he e x pa nsi o n 
c o h ort, u nless a c ha n ge i n d osi n g has occ urre d. I n case d osi n g i n t he e x pa nsi o n c o h ort was 
c ha n ge d, t he ne xt S M C will be hel d after 3 partici pa nts ha ve fi nis he d t he D L T peri o d or 
disc o nti n ue d.
T he S M C decisi o ns i n t he e x pa nsi o n p hase will als o be s u p p orte d b y  Ba yesia n m o deli n g . If 
data o btai ne d d uri n g t he safety r u n-i n of Part B i n dicate t hat a hi g her d ose t ha n t he R D E ma y 
be t olerate d w he n M 3 2 5 8 is a d mi nistere d i n c o m bi nati o n wit h de xa met has o ne, t he n a caref ul 
escalati o n b e y o n d t he m o n ot hera p y R D E
i n c o m bi nati o n wit h de xa met has o ne ca n be 
rec o m me n de d i n d osi n g ste ps of ma x i m u m 2 5 % i ncreases i n Part B. S M C will re vie w all 
a vaila ble data t o pr o vi de rec o m me n dati o ns o n t he ne xt d ose le vel. W he n 1 5 partici pa nts treate d 
at t he sa me d ose le vel are e val ua ble f or res p o nse, a n i nteri m a nal ys is will be perf or me d. 
I n v ol ve me nt of S peci al C o m mittee(s): 
T he S M C , c o m prise d of i nter nal a n d e xter nal me m bers , will ma ke decisi o ns o n d os e a n d 
re gi me n of M 3 2 5 8
d uri n g t he d ose -escalati o n p hase ( Part A) a n d will re g ularl y mo nit or t he 
safety of t he partici pa nts d uri n g t he d ose -e x pa nsi o n p hase ( Part B) a n d deci de if t he d osi n g 
nee ds t o be c ha n ge d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  
M3 2 5 8 as a Si n gle A ge nt a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 / 1 5 5
1. 2
Sc he m a
Fi g ure 1
O ver all St u d y Desi g n
  
N ot e: If r e q uir e d i n P art A, ot h er d o s i n g a n d r e gi m e n o pti o n s ar e pr e s e nt e d i n S e cti o n 1. 1 . P ot e nti al m o difi c ati o n s 
t o P art B d o si n g ar e al s o pr e s e nt e d i n S e cti o n  1. 1 .
3 L = t hir d li n e of t h er a p y;; d = d a y s; d e x = d e x a m et h a s o n e; 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; m a x = 
m a xi m u m; M T D = m a xi m al t ol er at e d d o s e; N = n u m b er; P d = p h ar m a c o d y n a mi c s; P K = p h ar m a c o ki n eti c s; Q D = 
o n c e d ail y; R D E = r e c o m m e n d e d d o s e a n d r e gi m e n f or e x p a n si o n; S M C = S af et y M o nit ori n g C o m mitt e e.
R D E b a s e d  on 
s af et y , P K a n d 
P d
D o s e E s c al ati o n P art A
B a y e si a n  mo d el  a s si st e d d o s e 
e s c al ati o n  with M 3 2 5 8 t o d efi n e 
M T D/ R D E . D o s e a n d r e gi me n  
d e ci si o ns t ak e n b y  SM C aft er e a c h  
c o hor t. 
D L 3
D L n
D L 1
D L 4
St arti n g d o s e 1 0 m g Q D
M a x 5 0 m g  QD
D L 2
N =  a p pr o x . 1 8 ( s a m pl e si z e d e p e n d s o n t oxi cit y pr of il e)
D L T p eri o d = fir st tr e at m e nt c y cl e
M 3 2 5 8 u ntil pr o gr e s si o n 
N = 3 0
M 3 2 5 8 + d e x at  R D E u ntil pr o gr e s si o n
D o s e E x p a n si o n P art B
S cr e e ni n g
U p t o 2 8 d
R D E + d e x
I nt eri m a n al ysis 
f or f utilit y aft er 
1 5 p artici p a nts  
ar e e v al u a bl e 
f or r es p o ns e
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 / 1 5 5
1. 3
Sc he d ule of Acti vities
T a ble 1
Sc he d ule of Acti vities – D ose Esc al ati o n - P a rt A (f or 2 8-d a y c ycles)
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p /
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5 
2 2
1 
8
1 5
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n /
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
I nf or m e d C o n s e nt
X
I n cl u si o n a n d 
E x cl u si o n Crit eri a
X 
X
R e c h e c k cli ni c al st at u s 
b ef or e fir st d o s e of 
st u d y i nt er v e nti o n
D e m o gr a p h y / H ei g ht
X
P h y si c al 
E x a mi n ati o n wit h 
W e i g ht 
X 
X
X ᵃ
X ᵃ
X ᵃ
X
X ᵃ 
X ᵃ
X ᵃ
X
X ᵃ 
X ᵃ 
X ᵃ
X
D et ail s i n S e cti o n
8. 2. 1 .
a = bri ef p h y si c al 
e x a mi n ati o n i n cl u di n g 
p eri p h er al m ot or a n d 
s e n s or y n er v o u s 
s y st e m
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 9 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p /
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5 
2 2
1 
8
1 5
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n /
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
M e di c al Hi st or y 
(i n cl u d e s s u b st a n c e 
u s a g e a n d f a mil y 
hi st or y of pr e m at ur e 
C V di s e a s e)
X
S u b st a n c e u s a g e: 
Dr u g s, al c o h ol, 
t o b a c c o, a n d c aff ei n e
P a st a n d C urr e nt 
M e di c al C o n diti o n s
X
E C O G P erf or m a n c e 
St at u s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X E v er y  
3 r d c y cl e
X 
X
Vit al Si g n s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X E v er y  
3 r d c y cl e
X 
X
S e e d et ail s i n S e cti o n 
8. 2. 2 .
C h e st X -r a y
X
T o e x cl u d e i nf e cti o n s,
i nt er stiti al p n e u m o niti s, 
a n d l u n g i nfiltr ati o n t o 
b e d o n e b ef or e C T or 
M RI . S e e d et ail s i n 
S e cti o n 8. 2. 4 .
1 2 -l e a d S af et y E C G 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X E v er y  
3 r d c y cl e
B ef or e a n y bl o o d 
s a m pli n g
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 0 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p /
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5 
2 2
1 
8
1 5
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n /
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
1 2 -l e a d Q T c 
A s s e s s m e nt
X 
X 
X
S e e  T a bl e 5 f or d et ail s. 
E c h o c ar di o gr a p h y 
or
M U G A s c a n
X
E c h o c ar di o gr a p h y or 
M U G A s c a n t o e v al u at e 
c ar di a c l eft v e ntri c ul ar 
ej e cti o n fr a ct i o n 
M RI ( C h e st, 
a b d o m e n, p el vi s) or 
C T s c a n if c o ntr a st 
c a n b e gi v e n
X
At S cr e e ni n g a n d t o 
c o nfir m C R, a n d f or P R
a n d M R
if 
e xtr a m e d ull ar y di s e a s e 
d et e ct e d at b a s eli n e , 
C T wit h c o ntr a st o nl y if 
r e n al a cti vit y all o w s. If 
p erf or m e d b y P E T/ C T 
or M RI, o st e ol yti c 
l e si o n s a n d 
e xtr a m e d ull ar y di s e a s e 
c a n b e e v al u at e d wit hi n 
t h e s a m e i m a gi n g.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 1 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p /
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5 
2 2
1 
8
1 5
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n /
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
St u d y I nt er v e nti o n
M 3 2 5 8 
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
>
Q D
I n c a s e of t o xi cit y w hi c h 
c a n n ot b e m a n a g e d 
d uri n g tr e at m e nt 
alt er n ati v e d o s e a n d
r e gi m e n will b e t e st e d: 
s e e S e cti o n  4. 1 .
F or d o s e m o difi c ati o n, 
s e e S e cti o n  6. 6 .
F or P K a n d P d s e e 
T a bl e 5 f or d et ail s.
A nti vir al Pr o p h yl a xi s 
f or H er p e s Z o st er 
( v al a c y cl o vir or 
a c y cl o vir)
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- > 
A c c or di n g t o 
i n stit uti o n al g ui d eli n e s
A E & S A E R e vi e w
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
> 
X 
X
U ntil 3 0 d a y s aft er t h e 
l a st d o s e
C o n c o mit a nt 
M e di c ati o n R e vi e w
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
> 
X 
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 2 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p /
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5 
2 2
1 
8
1 5
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n /
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
L a b or at or y A s s e s s m e nt s ( D et ail s r e g ar di n g l o c al a n d c e ntr al l a b or at or y a s s e s s m e nt s t o b e f o u n d i n A p p e n di x 7 a n d t h e L a b or at or y M a n u al, r e s p ecti v el y .)
S er u m Pr e g n a n c y 
T e st ( W O C B P o nl y)
at S cr e e ni n g a n d i n 
uri n e t h er e aft er
X 
X
X
X 
X 
X 
X 
X 
X 
X
S e e  A p p e n di x 7 .
Uri n al y si s
X 
X
X
X 
X 
X E v er y  
3 r d c y cl e
X 
X
S e e  A p p e n di x 7 . 
H e p atiti s B a n d C 
a n d HI V S cr e e ni n g
X
S e e  A p p e n di x 7 .
Cli ni c al L a b or at or y 
T e st s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
H e m at ol o g y, s er u m 
c h e mi str y, a n d 
c o a g ul ati o n s e e 
A p p e n di x 7 .
Al b u mi n -c orr e ct e d 
C a
X
X
X 
X 
X 
X 
X 
X
P K M 3 2 5 8
X 
X 
X 
X
S e e  T a bl e 5 f or d et ail s
L M P 7 & β 5 c A cti vit y
X 
X 
X
S e e  T a bl e 5 f or d et ail s
L- citr ulli n e
X
X 
X
X
Pr e d o s e
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 3 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p /
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5 
2 2
1 
8
1 5
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n /
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
Di s e a s e/ Effi c a c y A s s e s s m e nt (D et ail s r e g ar di n g l o c al a n d c e ntr al l a b or at or y a s s e s s m e nt s t o b e f o u n d i n  A p p e n di x 7 a n d t h e L a b or at or y M a n u al, r e s p e cti v el y)
A s s e s s m e nt f o r 
M R D i n B o n e 
M arr o w
X
(- 3
d a y s)
B o n e m arr o w s a m pl e at 
D a y 1 C y cl e 1 ( wi n d o w: 
- 3 d a y s) f or 
a s s e s s m e nt of cl o n alit y 
wit h N G S. A d diti o n all y, 
a b o n e m arr o w s a m pl e 
f or M R D b y N G S a n d/ or 
fl o w c yt o m etr y at C R 
(c e ntr al l a b or at or y, s e e 
S e cti o n  8. 8 ).
Di s e a s e St a gi n g i n 
B o n e M arr o w
X (- 3
d a y s)
M or p h ol o g y, 
c yt o g e n eti c s, a n d eit h er 
i m m u n o hi st o c h e mi str y 
or fl o w c yt o m etr y i n 
b o n e m arr o w a s pir at e 
at pr e d o s e (l o c al 
l a b or at or y). 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 4 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p /
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5 
2 2
1 
8
1 5
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n /
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
S k el et al S ur v e y
X
A s s e s s m e nt of 
o st e ol yti c l e si o n s b y 
i m a gi n g at B a s eli n e 
a c c or di n g t o I M W G  
g ui d a n c e a n d s u s pi ci o n 
of n e w l e si o n s ( s k el et al 
s ur v e y, s e e S e cti o n  8 ).
F oll o w -U p o nl y w h e n 
cli ni c al s u s pi ci o n of 
n e w l e si o n s.
Di s e a s e/ Effi c a c y 
A s s e s s m e nt
X
X
X 
X 
X 
X 
X 
X
Q u a ntit ati v e 
I m m u n o gl o b uli n s
I g G, I g A, I g M, I g E, 
I g D i n S er u m 
(i m m u n ofi x ati o n)
X
W h e n C R i s s u s p e ct e d 
a n d n o d et e ct a bl e M -
Pr ot ei n i n s er u m
S er u m -β 2 
Mi cr o gl o b uli n
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 5 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p /
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5 
2 2
1 
8
1 5
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n /
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
Fr e e Li g ht C h ai n i n 
S er u m 
X
D uri n g st u d y w h e n C R 
i s s u s p e ct e d
Fr e e Li g ht C h ai n 
(i m m u n ofi x ati o n) i n 
Uri n e
X
D uri n g st u d y, w h e n C R 
i s s u s p e ct e d
S er u m M -Pr ot ei n 
El e ctr o p h or e si s 
X 
X
X
X 
X 
X 
X 
X 
X
S e e S e cti o n  8 a n d 
A p p e n di x 7
Q u a ntit ati v e Uri n e 
I g (i m m u n ofi x ati o n 
i n 2 4 h uri n e)
X
W h e n C R i s s u s p e ct e d 
a n d n o d et e ct a bl e M -
Pr ot ei n i n s er u m
Uri n e M -Pr ot ei n 
El e ctr o p h or e si s (i n 
2 4 h uri n e s a m pl e) 
X 
X
X
X 
X 
X 
X 
X 
X
S e e S e cti o n  8 a n d 
A p p e n di x 7
I n C a s e of Fr e e 
Li g ht C h ai n 
Di s e a s e: Fr e e Li g ht 
C h ai n i n S er u m
X
X
X 
X 
X 
X 
X 
X
F or p arti ci p a nt s wit h 
c o m m o n M M, t h e fr e e 
li g ht c h ai n i n s er u m will 
b e t e st e d w h e n C R i s 
s u s p e ct e d
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 6 / 1 5 5
A E = A d v er s e e v e nt, BI D = t wi c e d ail y; C a = C al ci u m, C T = C o m p ut e d t o m o gr a p h y, C V = C ar di o v a s c ul ar, C R = C o m pl et e r e s p o n s e, HI V = H u m a n 
i m m u n o d efi ci e n c y vir u s, E C G = El e ctr o c ar di o gr a m, E C O G = E a st er n C o-o p er ati v e of O n c ol o g y Gr o u p, I g = I m m u n o gl o b uli n, I M W G = I nt er n ati o n al M y el o m a 
W o r ki n g Gr o u p, M RI = M a g n eti c r e s o n a n c e i m a gi n g; M R D = Mi ni m al r e si d u al di s e a s e, M U G A = M ulti g at e d a c q ui siti o n, N G S = N e xt - Ge n er ati o n - Se q u e n ci n g, P K = 
P h ar m a c o ki n eti c s, P d = P h ar m a c o d y n a mi c s , P R = P arti al r e s p o n s e, Q D = O n c e d ail y, S A E = S eri o u s a d v er s e e v e nt; W O C B P = W o m e n of c hil d b e ari n g p ot e nti al .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 7 / 1 5 5
T a ble 2
Sc he d ule of Acti vities – D ose Esc al ati o n - P a rt A (f or 2 1-d a y c ycles)
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p/
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n/ 
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
I nf or m e d C o n s e nt
X
I n cl u si o n a n d 
E x cl u si o n Crit eri a
X 
X
R e c h e c k cli ni c al st at u s 
b ef or e fir st d o s e of 
st u d y i nt er v e nti o n
D e m o gr a p h y/ H ei g ht
X
P h y si c al 
E x a mi n ati o n wit h 
W e i g ht 
X 
X
X ᵃ 
X ᵃ
X
X ᵃ
X ᵃ
X ᵃ
X
X ᵃ 
X ᵃ 
X ᵃ
X
D et ail s i n S e cti o n 
8. 2. 1 .
a = bri ef p h y si c al 
e x a mi n ati o n i n cl u di n g 
p eri p h er al m ot or a n d 
s e n s or y n er v o u s 
s y st e m
M e di c al Hi st or y 
(i n cl u d e s s u b st a n c e 
u s a g e a n d f a mil y 
hi st or y of pr e m at ur e 
C V di s e a s e)
X
S u b st a n c e u s a g e: 
Dr u g s, al c o h ol, 
t o b a c c o, a n d c aff ei n e
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 8 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p/
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n/ 
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
P a st a n d C urr e nt 
M e di c al C o n diti o n s
X
E C O G P erf or m a n c e 
St at u s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X E v er y  
3 r d c y cl e
X 
X
Vit al Si g n s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X E v er y  
3 r d c y cl e
X 
X
S e e d et ail s i n S e cti o n 
8. 2. 2 .
C h e st X -r a y
X
T o e x cl u d e i nf e cti o n s,
i nt er stiti al p n e u m o niti s, 
a n d l u n g i nfiltr ati o n t o 
b e d o n e b ef or e C T or 
M RI . S e e d et ail s i n 
S e cti o n 8. 2. 4 .
1 2 -l e a d S af et y E C G 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X E v er y  
3 r d c y cl e
B ef or e a n y bl o o d 
s a m pli n g
1 2 -l e a d Q T c 
A s s e s s m e nt
X 
X 
X
S e e  T a bl e 5 f or d et ail s. 
E c h o c ar di o gr a p h y 
or
M U G A s c a n
X
E c h o c ar di o gr a p h y or 
M U G A s c a n t o e v al u at e 
c ar di a c l eft v e ntri c ul ar 
ej e cti o n fr a cti o n 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 9 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p/
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n/ 
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
M RI ( C h e st, 
a b d o m e n, p el vi s) or 
C T s c a n if c o ntr a st 
c a n b e gi v e n
X
At S cr e e ni n g a n d t o 
c o nfir m C R, a n d f or P R
a n d M R if 
e xtr a m e d ull ar y di s e a s e 
d et e ct e d at b a s eli n e.
C T wit h c o ntr a st o nl y if 
r e n al a cti vit y all o w s. If 
p erf or m e d b y P E T/ C T 
or M RI, o st e ol yti c 
l e si o n s a n d 
e xtr a m e d ull ar y di s e a s e 
c a n b e e v al u at e d wit hi n 
t h e s a m e i m a gi n g.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 0 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p/
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n/ 
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
St u d y I nt er v e nti o n
M 3 2 5 8 
< 
- 
- 
- 
- 
- 
- 
- - 
- 
- 
- 
- 
- 
>
Q D
I n c a s e of t o xi cit y w hi c h 
c a n n ot b e m a n a g e d 
d uri n g tr e at m e nt 
alt er n ati v e r e gi m e n will 
b e t e st e d: S e e S e cti o n 
4. 1 .
F or d o s e m o difi c ati o n, 
s e e S e cti o n  6. 6 .
F or P K a n d P d s e e 
T a bl e 5 f or d et ail s.
A nti vir al Pr o p h yl a xi s 
f or H er p e s Z o st er 
( v al a c y cl o vir or 
a c y cl o vir)
< 
- 
- 
- 
- 
- 
- 
- - 
- 
- 
- 
- 
- 
- 
- 
- > 
A c c or di n g t o 
i n stit uti o n al g ui d eli n e s
A E & S A E R e vi e w
< 
- 
- 
- 
- 
- 
- 
- - 
- 
- 
- 
- 
- 
> 
X 
X
U ntil 3 0 d a y s aft er t h e 
l a st d o s e
C o n c o mit a nt 
M e di c ati o n R e vi e w
< 
- 
- 
- 
- 
- 
- 
- - 
- 
- 
- 
- 
- 
> 
X 
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 1 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p/
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n/ 
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
L a b or at or y A s s e s s m e nt s ( D et ail s r e g ar di n g l o c al a n d c e ntr al l a b or at or y a s s e s s m e nt s t o b e f o u n d i n A p p e n di x 7 a n d t h e L a b or at or y M a n u al, r e s p e cti v el y.)
S er u m Pr e g n a n c y 
T e st ( W O C B P o nl y)
at S cr e e ni n g a n d i n 
uri n e t h er e aft er
X 
X
X
X 
X 
X 
X 
X 
X 
X
S e e  A p p e n di x 7 .
Uri n al y si s
X 
X
X
X 
X 
X E v er y  
3 r d c y cl e
X 
X
S e e  A p p e n di x 7 . 
H e p atiti s B a n d C 
a n d HI V S cr e e ni n g
X
S e e  A p p e n di x 7 .
Cli ni c al L a b or at or y 
T e st s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
H e m at ol o g y, s er u m 
c h e mi str y, a n d 
c o a g ul ati o n s e e 
A p p e n di x 7 .
Al b u mi n -c orr e ct e d 
C a
X
X
X 
X 
X 
X 
X 
X
P K M 3 2 5 8
X 
X 
X 
X
S e e  T a bl e 5 f or d et ail s
L M P 7 & β 5 c A cti vit y
X 
X 
X
S e e  T a bl e 5 f or d et ail s
L- citr ulli n e
X
X 
X
X
Pr e d o s e
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 2 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p/
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n/ 
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
Di s e a s e/ Effi c a c y A s s e s s m e nt (D et ail s r e g ar di n g l o c al a n d c e ntr al l a b or at or y a s s e s s m e nt s t o b e f o u n d i n  A p p e n di x 7 a n d t h e L a b or at or y M a n u al, r e s p e cti v el y)
A s s e s s m e nt f or 
M R D i n B o n e 
M arr o w
X
(- 3
d a y s )
B o n e m arr o w s a m pl e at 
D a y 1 C y cl e 1 ( wi n d o w: 
- 3 d a y s) f or 
a s s e s s m e nt of cl o n alit y 
wit h N G S. A d diti o n all y, 
a b o n e m arr o w s a m pl e 
f or M R D b y N G S a n d/ or 
fl o w c yt o m etr y at C R 
(c e ntr al l a b or at or y, s e e 
S e cti o n  8. 8 ).
Di s e a s e St a gi n g i n 
B o n e M arr o w
X (- 3
d a y s)
M or p h ol o g y, 
c yt o g e n eti c s, a n d eit h er 
i m m u n o hi st o c h e mi str y 
or fl o w c yt o m etr y i n 
b o n e m arr o w a s pir at e 
at pr e d o s e (l o c al 
l a b or at or y). 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 3 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p/
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n/ 
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
S k el et al S ur v e y
X
A s s e s s m e nt of 
o st e ol yti c l e si o n s b y 
i m a gi n g at B a s eli n e 
a c c or di n g t o I M W G  
g ui d a n c e a n d s u s pi ci o n 
of n e w l e si o n s ( s k el et al 
s ur v e y, s e e S e cti o n  8 ).
F oll o w -U p o nl y w h e n 
cli ni c al s u s pi ci o n of 
n e w l e si o n s.
Di s e a s e/ Effi c a c y 
A s s e s s m e nt
X
X
X 
X 
X 
X 
X 
X
Q u a ntit ati v e 
I m m u n o gl o b uli n s
I g G, I g A, I g M, I g E, 
I g D i n S er u m 
(i m m u n ofi x ati o n)
X
W h e n C R i s s u s p e ct e d 
a n d n o d et e ct a bl e M -
Pr ot ei n i n s er u m
S er u m -β 2 
Mi cr o gl o b uli n
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 4 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er-
v e nti o n
F oll o w -U p/
Di s c o n -
ti n u ati o n
N ot e s
u p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3 C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y   
c y cl e 
aft er 
C y cl e 6 
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s aft er 
l a st i nt er-
v e nti o n/ 
i nt a k e
3 0 d a y s 
aft er l a st 
d o s e
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
±
3 d
±
3 d
±
7 d
±
3 d
±
7 d
d = d a y s
Fr e e Li g ht C h ai n i n 
S er u m 
X
D uri n g st u d y w h e n C R 
i s s u s p e ct e d
Fr e e Li g ht C h ai n 
(i m m u n ofi x ati o n) i n 
Uri n e
X
D uri n g st u d y, w h e n C R 
i s s u s p e ct e d
S er u m M -Pr ot ei n 
El e ctr o p h or e si s 
X 
X
X
X 
X 
X 
X 
X 
X
S e e S e cti o n  8 a n d 
A p p e n di x 7
Q u a ntit ati v e Uri n e 
I g (i m m u n ofi x ati o n 
i n 2 4 h uri n e)
X
W h e n C R i s s u s p e ct e d 
a n d n o d et e ct a bl e M -
Pr ot ei n i n s er u m
Uri n e M -Pr ot ei n 
El e ctr o p h or e si s (i n 
2 4 h uri n e s a m pl e) 
X 
X
X
X 
X 
X 
X 
X 
X
S e e S e cti o n  8 a n d 
A p p e n di x 7
I n C a s e of Fr e e 
Li g ht C h ai n 
Di s e a s e: Fr e e Li g ht 
C h ai n i n S er u m
X
X
X 
X 
X 
X 
X 
X
F or p arti ci p a nt s wit h 
c o m m o n M M, t h e fr e e 
li g ht c h ai n i n s er u m will 
b e t e st e d w h e n C R i s 
s u s p e ct e d
A E = A d verse e ve nt, BI D = t wice dail y; Ca = Calci u m, C T = C o m p ute d t o m o gra p h y, C V = Car di o vasc ular, C R = C o m plete res p o nse, H I V = H u ma n 
i m m u n o deficie nc y vir us, E C G = Electr ocar di o gra m, E C O G = Easter n C o -o perati ve of O nc ol o g y Gr o u p, I g = I m m u n o gl o b uli n, I M W G = I nter nati o nal M yel o ma 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 5 / 1 5 5
W or ki n g Gr o u p, M RI = Ma g netic res o na nce i ma gi n g; M R D = Mi ni mal resi d ual disease, M U G A = M ulti gate d ac q uisiti o n, N G S = N e xt - Ge nerati o n - Se q ue nci n g, 
P K = P har mac o ki netics, P d = P har mac o d y na mics , P R = P artial res p o nse , Q D = O nce dail y, S A E = Seri o us a d verse e ve nt; W O C B P = W o me n of c hil d beari n g 
p ote ntial .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 6 / 1 5 5
T a ble 3
Sc he d ule of Acti vities – D ose E x p a nsi o n - P art B
(f or 2 8-d a y c ycles)
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
2 2
1 
8
1 5 
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 
d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
I nf or m e d C o n s e nt
X
I n cl u si o n a n d 
E x cl u si o n Crit eri a
X 
X
R e c h e c k cli ni c al st at u s 
b ef or e fir st d o s e of 
st u d y i nt er v e nti o n.
D e m o gr a p h y / 
H ei g ht
X
P h y si c al 
E x a mi n ati o n wit h 
W e i g ht 
X 
X
X ᵃ
X ᵃ
X ᵃ
X
X ᵃ 
X ᵃ 
X ᵃ
X
X ᵃ 
X ᵃ 
X ᵃ
X
D et ail s i n S e cti o n
8. 2. 1 . 
a = bri ef p h y si c al 
e x a mi n ati o n i n cl u di n g 
p eri p h er al m ot or a n d 
s e n s or y n er v o u s 
s y st e m
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 7 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
2 2
1 
8
1 5 
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 
d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
M e di c al Hi st or y 
(i n cl u d e s 
s u b st a n c e u s a g e 
a n d f a mil y hi st or y 
of pr e m at ur e C V 
di s e a s e)
X
S u b st a n c e u s a g e: 
Dr u g s, al c o h ol, 
t o b a c c o, a n d c aff ei n e
P a st a n d C urr e nt 
M e di c al 
C o n diti o n s
X
E C O G 
P erf or m a n c e 
St at u s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X E v er y  
3 r d c y cl e
X 
X
Vit al Si g n s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X E v er y  
3 r d c y cl e
X 
X
S e e S e cti o n  8. 2. 2 .
C h e st X -r a y
X
T o e x cl u d e i nf e cti o n s,
i nt er stiti al p n e u m o niti s, 
a n d l u n g i nfiltr ati o n t o 
b e d o n e b ef or e C T or 
M RI . S e e d et ail s i n 
S e cti o n 8. 2. 4 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 8 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
2 2
1 
8
1 5 
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 
d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
1 2 -l e a d S af et y 
E C G 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X E v er y  
3 r d c y cl e
E C G b ef or e a n y bl o o d 
s a m pli n g. 
1 2 -l e a d Q T c 
A s s e s s m e nt
X
S e e  T a bl e 6 f or d et ail s.
E c h o c ar di o gr a p h y 
or M U G A s c a n
X
E c h o c ar di o gr a p h y or 
M U G A s c a n t o 
e v al u at e c ar di a c l eft 
v e ntri c ul ar ej e cti o n 
fr a cti o n 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 9 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
2 2
1 
8
1 5 
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 
d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
M RI ( C h e st, 
a b d o m e n, p el vi s) 
or C T s c a n if 
c o ntr a st c a n b e 
gi v e n
X
At S cr e e ni n g a n d t o 
c o nfir m C R, a n d f or 
P R a n d M R if 
e xtr a m e d ull ar y di s e a s e 
d et e ct e d at b a s eli n e,  
C T wit h c o ntr a st o nl y if 
r e n al a cti vit y all o w s. If 
p erf or m e d b y P E T/ C T 
or M RI, o st e ol yti c 
l e si o n s a n d 
e xtr a m e d ull ar y di s e a s e 
c a n b e e v al u at e d 
wit hi n t h e s a m e 
i m a gi n g. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 0 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
2 2
1 
8
1 5 
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 
d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
St u d y I nt er v e nti o n
M 3 2 5 8 
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
>
Q D
I n c a s e of t o xi cit y 
w hi c h c a n n ot b e 
m a n a g e d d uri n g 
tr e at m e nt alt er n ati v e 
d o s e a n d r e gi m e n will 
b e t e st e d:
S e e S e cti o n  4. 1 .
F or d o s e m o difi c ati o n, 
s e e S e cti o n  6. 6 . F or 
P K a n d P d s e e  T a bl e 6
f or d et ail s.
D e x a m et h a s o n e
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
>
D e x a m et h a s o n e will b e 
gi v e n at a c u m ul ati v e 
d o s e of 4 0 m g / w e e k ;. 
s e e S e cti o n  4. 1 . 
A nti vir al 
Pr o p h yl a xi s 
( a c y cl o vir or 
v al a c y cl o vir)
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- >
A c c or di n g t o 
i n stit uti o n al g ui d eli n e s
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 1 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
2 2
1 
8
1 5 
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 
d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
A E & S A E R e vi e w
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
> 
X 
X
U ntil 3 0 d a y s aft er t h e 
l a st d o s e
C o n c o mit a nt 
M e di c ati o n 
R e vi e w
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
> 
X 
X
L a b or at or y A s s e s s m e nt s ( D et ail s r e g ar di n g l o c al a n d c e ntr al l a b or at or y a s s e s s m e nt s t o b e f o u n d i n  A p p e n di x 7 a n d t h e L a b or at or y M a n u al, r e s p e cti v el y)
S er u m Pr e g n a n c y 
T e st ( W O C B P 
o nl y) at S cr e e ni n g 
a n d i n uri n e 
t h er e aft er
X 
X
X
X
X 
X 
X 
X 
X
S e e  A p p e n di x 7 .
Uri n al y si s
X
X 
X
X 
X
X E v er y  
3 r d c y cl e
X 
X
S e e  A p p e n di x 7 .
H e p atiti s B a n d C 
a n d HI V 
S cr e e ni n g
X
S e e  A p p e n di x 7 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 2 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
2 2
1 
8
1 5 
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 
d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
Cli ni c al L a b or at or y 
T e st s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
H e m at ol o g y, s er u m 
c h e mi str y a n d 
c o a g ul ati o n s e e 
A p p e n di x 7 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 3 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
2 2
1 
8
1 5 
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 
d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
Al b u mi n -c orr e ct e d 
C a
X
X
X
X 
X 
X 
X 
X
P K M 3 2 5 8
X 
X 
X
X
S e e  T a bl e 6 f or d et ail s.
P K 
D e x a m et h a s o n e
X
S e e  T a bl e 6 f or d et ail s.
L M P 7 & β 5 c 
A cti vit y 
X 
X 
X
S e e  T a bl e 6 f or d et ail s.
L- citr ulli n e
X
X 
X
X
Pr e d o s e
F o o d Eff e ct
X
S e e  T a bl e 6.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 4 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
2 2
1 
8
1 5 
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 
d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
Di s e a s e/ Effi c a c y A s s e s s m e nt (D et ail s r e g ar di n g l o c al a n d c e ntr al l a b or at or y a s s e s s m e nt s t o b e f o u n d i n  A p p e n di x 7 a n d t h e L a b or at or y M a n u al, r e s p e cti v el y)
A s s e s s m e nt f or 
M R D i n B o n e 
M arr o w
X (- 3
d a y s)
B o n e m arr o w s a m pl e 
at D a y 1 C y cl e 1 
( wi n d o w: - 3 d a y s) f or 
a s s e s s m e nt of 
cl o n alit y f or N G S. 
A d diti o n all y, a b o n e 
m arr o w s a m pl e f or 
M R D b y N G S a n d/ or 
fl o w c yt o m etr y at C R 
(c e ntr al l a b or at or y, s e e 
S e cti o n  8. 8 ).
Di s e a s e St a gi n g 
i n B o n e M arr o w
X (- 3
d a y s)
M or p h ol o g y, 
c yt o g e n eti c s, a n d 
eit h er 
i m m u n o hi st o c h e mi str y 
or fl o w c yt o m etr y i n 
b o n e m arr o w a s pir at e 
at pr e d o s e (l o c al 
l a b or at or y).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 5 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
2 2
1 
8
1 5 
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 
d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
S k el et al S ur v e y
X
A s s e s s m e nt of 
o st e ol yti c l e si o n s b y 
i m a gi n g at B a s eli n e 
a c c or di n g t o I M W G  
g ui d a n c e a n d at 
s u s pi ci o n of n e w 
l e si o n s ( s k el et al 
s ur v e y, s e e S e cti o n  8 ).
F ol l o w-U p o nl y w h e n 
cli ni c al s u s pi ci o n of 
n e w l e si o n s. 
Di s e a s e/ Effi c a c y 
A s s e s s m e nt
X
X
X
X 
X 
X 
X 
X
Q u a ntit ati v e 
I m m u n o gl o b uli n s
I g G, I g A, I g M, I g E, 
I g D i n S er u m 
(i m m u n ofi x ati o n)
X
W h e n C R i s s u s p e ct e d 
a n d n o d et e ct a bl e M -
Pr ot ei n i n s er u m
S er u m -β 2 
Mi cr o gl o b uli n
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 6 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
2 2
1 
8
1 5 
2 2
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 
d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
Fr e e Li g ht C h ai n 
i n S er u m a n d 
Uri n e
X
D uri n g st u d y, w h e n C R 
i s s u s p e ct e d
S er u m M -Pr ot ei n 
El e ctr o p h or e si s 
X 
X
X
X
X 
X 
X 
X 
X
S e e S e cti o n  8 a n d 
A p p e n di x 7 .
Q u a ntit ati v e Uri n e 
I g (i m m u n ofi x ati o n 
i n 2 4 h uri n e)
X
W h e n C R i s s u s p e ct e d 
a n d n o d et e ct a bl e M -
Pr ot ei n i n s er u m 
Uri n e M -Pr ot ei n 
El e ctr o p h or e si s (i n 
2 4 h uri n e s a m pl e) 
X 
X
X
X
X 
X 
X 
X 
X
S e e S e cti o n  8 a n d 
A p p e n di x 7
I n c a s e of fr e e 
li g ht c h ai n 
di s e a s e: Fr e e 
L i g ht C h ai n i n 
S er u m
X
X
X
X 
X 
X 
X 
X
F or p arti ci p a nt s wit h 
c o m m o n M M, t h e fr e e 
li g ht c h ai n i n s er u m will 
b e t e st e d w h e n C R i s 
s u s p e ct e d
S ur vi v al F oll o w -
U p
X
S ur vi v al F oll o w -U p 
e v er y 1 2 w e e k s u ntil 
E n d of St u d y.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 7 / 1 5 5
A E = A d v er s e e v e nt, BI D = t wi c e d ail y; C a = C al ci u m, C T = C o m p ut e d t o m o gr a p h y, C V = C ar di o v a s c ul ar, C R = C o m pl et e r e s p o n s e, HI V = H u m a n 
i m m u n o d efi ci e n c y vir u s, E C G = El e ctr o c ar di o gr a m, E C O G = E a st er n C o-o p er ati v e of O n c ol o g y Gr o u p, I g = I m m u n o gl o b uli n, I M W G = I nt er n ati o n al M y el o m a 
W o r ki n g Gr o u p, M RI = M a g n eti c r e s o n a n c e i m a gi n g; M R D = Mi ni m al r e si d u al di s e a s e, M U G A = M ulti g a t e d a c q ui siti o n, N G S = N e xt - Ge n er ati o n - S e q u e n ci n g, P K = 
P h ar m a c o ki n eti c s, P d = p h ar m a c o d y n a mi c s; P D = Pr o gr e s si v e di s e a s e, P R = P arti al r e s p o n s e , Q D = O n c e d ail y, S A E = S eri o u s a d v er s e e v e nt; W O C B P = 
W o m e n of c hil d b e ari n g p ot e nti al .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 8 / 1 5 5
T a ble 4
Sc he d ule of Acti vities – D ose E x p a nsi o n - P art B (f or 2 1-d a y c ycles)
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
I nf or m e d C o n s e nt
X
I n cl u si o n a n d 
E x cl u si o n Crit eri a
X 
X
R e c h e c k cli ni c al st at u s 
b ef or e fir st d o s e of 
st u d y i nt er v e nti o n.
D e m o gr a p h y/ 
H ei g ht
X
P h y si c al 
E x a mi n ati o n wit h 
W e i g ht 
X 
X
X ᵃ 
X ᵃ
X
X ᵃ 
X ᵃ 
X ᵃ
X
X ᵃ 
X ᵃ 
X ᵃ
X
D et ail s i n S e cti o n 
8. 2. 1 . 
a = bri ef p h y si c al 
e x a mi n ati o n i n cl u di n g 
p eri p h er al m ot or a n d 
s e n s or y n er v o u s 
s y st e m .
M e di c al Hi st or y 
(i n cl u d e s 
s u b st a n c e u s a g e 
a n d f a mil y hi st or y 
of pr e m at ur e C V 
di s e a s e)
X
S u b st a n c e u s a g e: 
Dr u g s, al c o h ol, 
t o b a c c o, a n d c aff ei n e
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 9 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
P a st a n d C urr e nt 
M e di c al 
C o n diti o n s
X
E C O G 
P erf or m a n c e 
St at u s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X E v er y  
3 r d c y cl e
X 
X
Vit al Si g n s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X E v er y  
3 r d c y cl e
X 
X
S e e S e cti o n  8. 2. 2 .
C h e st X -r a y
X
T o e x cl u d e i nf e cti o n s,
i nt er stiti al p n e u m o niti s, 
a n d l u n g i nfiltr ati o n t o 
b e d o n e b ef or e C T or 
M RI . S e e d et ail s i n 
S e cti o n 8. 2. 4 .
1 2 -l e a d S af et y 
E C G 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X E v er y  
3 r d c y cl e
E C G b ef or e a n y bl o o d 
s a m pli n g. 
1 2 -l e a d Q T c 
A s s e s s m e nt
X
S e e  T a bl e 6 f or d et ail s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 0 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
E c h o c ar di o gr a p h y 
or M U G A s c a n
X
E c h o c ar di o gr a p h y or 
M U G A s c a n t o 
e v al u at e c ar di a c l eft 
v e ntri c ul ar ej e cti o n 
fr a cti o n 
M RI ( C h e st, 
a b d o m e n, p el vi s) 
or C T s c a n if 
c o ntr a st c a n b e 
gi v e n
X
At S cr e e ni n g a n d t o 
c o nfir m C R, a n d f or 
P R a n d M R if 
e xtr a m e d ull ar y di s e a s e 
d et e ct e d at b a s eli n e, 
C T wit h c o ntr a st o nl y if 
r e n al a cti vit y all o w s. If 
p erf or m e d b y P E T/ C T 
or M RI, o st e ol yti c 
l e si o n s a n d 
e xtr a m e d ull ar y di s e a s e 
c a n b e e v al u at e d 
wit hi n t h e s a m e 
i m a gi n g. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 1 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
St u d y I nt er v e nti o n
M 3 2 5 8 
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
>
Q D
I n c a s e of t o xi cit y 
w hi c h c a n n ot b e 
m a n a g e d d uri n g 
tr e at m e nt alt er n ati v e 
r e gi m e n will b e t e st e d:
s e e S e cti o n  4. 1 .
.
F or d o s e m o difi c ati o n, 
s e e S e cti o n  6. 6 . F or 
P K a n d P d s e e  T a bl e 6
f or d et ail s.
D e x a m et h a s o n e
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
>
D e x a m et h a s o n e will b e 
gi v e n at a c u m ul ati v e 
d o s e of 4 0 m g / w e e k:
s e e S e cti o n  4. 1 .
A nti vir al 
P r o p h yl a xi s 
( a c y cl o vir or 
v al a c y cl o vir)
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- >
A c c or di n g t o 
i n stit uti o n al g ui d eli n e s
A E & S A E R e vi e w
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
> 
X 
X
U ntil 3 0 d a y s aft er t h e 
l a st d o s e
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 2 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
C o n c o mit a nt 
M e di c ati o n 
R e vi e w
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
> 
X 
X
L a b or at or y A s s e s s m e nt s ( D et ail s r e g ar di n g l o c al a n d c e ntr al l a b or at or y a s s e s s m e nt s t o b e f o u n d i n  A p p e n di x 7 a n d t h e L a b or at or y M a n u al, r e s p e cti v el y)
S er u m Pr e g n a n c y 
T e st ( W O C B P 
o nl y) at S cr e e ni n g 
a n d i n uri n e 
t h er e aft er
X 
X
X
X
X 
X 
X 
X 
X
S e e  A p p e n di x 7 .
Uri n al y si s
X
X 
X
X 
X 
X E v er y  
3 r d c y cl e
X 
X
S e e  A p p e n di x 7 .
H e p atiti s B a n d C 
a n d HI V 
S cr e e ni n g
X
S e e  A p p e n di x 7 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 3 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
Cli ni c al L a b or at or y 
T e st s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
H e m at ol o g y, s er u m 
c h e mi str y a n d 
c o a g ul ati o n s e e 
A p p e n di x 7 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 4 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
Al b u mi n -c orr e ct e d 
C a
X
X
X
X 
X 
X 
X 
X
P K M 3 2 5 8
X 
X 
X 
X
S e e  T a bl e 6 f or d et ail s.
P K 
D e x a m et h a s o n e
X
S e e  T a bl e 6 f or d et ail s.
L M P 7 & β 5 c 
A cti vit y 
X 
X 
X
S e e  T a bl e 6 f or d et ail s.
L- citr ulli n e
X
X 
X
X
Pr e d o s e
F o o d Eff e ct
X
S e e  T a bl e 6.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 5 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
Di s e a s e/ Effi c a c y A s s e s s m e nt (D et ail s r e g ar di n g l o c al a n d c e ntr al l a b or at or y a s s e s s m e nt s t o b e f o u n d i n  A p p e n di x 7 a n d t h e L a b or at or y M a n u al, r e s p e cti v el y)
A s s e s s m e nt f or 
M R D i n B o n e 
M arr o w
X (- 3
d a y s)
B o n e m arr o w s a m pl e 
at D a y 1 C y cl e 1 
( wi n d o w: - 3 d a y s) f or 
a s s e s s m e nt of 
cl o n alit y f or N G S. 
A d diti o n all y, a b o n e 
m arr o w s a m pl e f or 
M R D b y N G S a n d/ or 
fl o w c yt o m etr y at C R 
(c e ntr al l a b or at or y, s e e 
S e cti o n  8. 8 ).
Di s e a s e St a gi n g 
i n B o n e M arr o w
X
(- 3
d a y s)
M or p h ol o g y, 
c yt o g e n eti c s, a n d 
eit h er 
i m m u n o hi st o c h e mi str y 
or fl o w c yt o m etr y i n 
b o n e m arr o w a s pir at e 
at pr e d o s e (l o c al 
l a b or at or y).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 6 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
S k el et al S ur v e y
X
A s s e s s m e nt of 
o st e ol yti c l e si o n s b y 
i m a gi n g at B a s eli n e 
a c c or di n g t o I M W G  
g ui d a n c e a n d at 
s u s pi ci o n of n e w 
l esi o n s ( s k el et al 
s ur v e y, s e e S e cti o n  8 ).
F oll o w -U p o nl y w h e n 
cli ni c al s u s pi ci o n of 
n e w l e si o n s. 
Di s e a s e/ Effi c a c y 
A s s e s s m e nt
X
X
X
X 
X 
X 
X 
X
Q u a ntit ati v e 
I m m u n o gl o b uli n s
I g G, I g A, I g M, I g E, 
I g D i n S er u m 
(i m m u n ofi x ati o n)
X
W h e n C R i s s u s p e ct e d 
a n d n o d et e ct a bl e M-
Pr ot ei n i n s er u m
S er u m -β 2 
Mi cr o gl o b uli n
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 7 / 1 5 5
A s s e s s m e nt s & 
Pr o c e d ur e s
S cr e e n -
i n g
I nt er v e nti o n P eri o d
E n d of 
St u d y  
I nt er v e nti o n
F oll o w -
U p /
Di s c o n -
ti n u ati o n
N ot e s
U p t o 2 8 
d a y s 
b ef or e 
D a y 1 
C y cl e 1
C y cl e 1
C y cl e 2
C y cl e 3
C y cl e 
4
C y cl e 
5
C y cl e 
6
E v er y  
c y cl e 
aft er 
C y cl e 6
D a y 
1 
2 
8
1 5
1 
8
1 5
1
1 5
1 
1 
1 
1
wit hi n 7 
d a y s of 
i nt er v e nti o n/
i nt a k e
3 0 d a y s, 
aft er l a st 
d o s e
D a y 2 C y cl e 1 vi sit i s 
o nl y f or p arti ci p a nt s i n 
s af et y r u n -i n or t h e fir st 
3 p arti ci p a nt s at a 
c h a n g e d d o s e .
Vi sit 
Wi n d o w
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
1 d
±
3 d
± 
3 d
± 
3 d
± 
7 d
± 
3 d
± 
7 d
d = d a y s
Fr e e Li g ht C h ai n 
i n S er u m a n d 
Uri n e
X
D uri n g st u d y, w h e n C R 
i s s u s p e ct e d
S er u m M -Pr ot ei n 
El e ctr o p h or e si s 
X 
X
X
X
X 
X 
X 
X 
X
S e e S e cti o n  8 a n d 
A p p e n di x 7 .
Q u a ntit ati v e Uri n e 
I g (i m m u n ofi x ati o n 
i n 2 4 h uri n e)
X
W h e n C R i s s u s p e ct e d 
a n d n o d et e ct a bl e M -
Pr ot ei n i n s er u m 
Uri n e M -Pr ot ei n 
El e ctr o p h or e si s (i n 
2 4 h uri n e s a m pl e) 
X 
X
X
X
X 
X 
X 
X 
X
S e e S e cti o n  8 a n d 
A p p e n di x 7
I n c a s e of fr e e 
li g ht c h ai n 
di s e a s e: Fr e e 
Li g ht C h ai n i n 
S er u m
X
X
X
X 
X 
X 
X 
X
F or p arti ci p a nt s wit h 
c o m m o n M M, t h e fr e e 
li g ht c h ai n i n s er u m will 
b e t e st e d w h e n C R i s 
s u s p e ct e d
S ur vi v al F oll o w -
U p
X
S ur vi v al F oll o w -U p 
e v er y 1 2 w e e k s u ntil 
E n d of St u d y.
A E = A d verse e ve nt, BI D = t wice dail y; Ca = Calci u m, C T = C o m p ute d t o m o gra p h y, C V = Car di o vasc ular, C R = C o m plete res p o nse, H I V = H u ma n 
i m m u n o deficie nc y vir us, E C G = Electr ocar di o gra m, E C O G = Easter n C o-o perati ve of O nc ol o g y Gr o u p, I g = I m m u n o gl o b uli n, I M W G = I nter nati o nal M yel o ma 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h 
De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 8 / 1 5 5
W or ki n g Gr o u p, M RI = Ma g netic res o na nce i ma gi n g; M R D = Mi ni mal resi d ual disease, M U G A = M ulti gate d ac q uisiti o n, N G S = N e xt - Ge nerati o n - Se q ue nci n g, 
P K = P har mac o ki netics, P d = p har mac o d y na mics ; P D = Pr o gressi ve disease, P R = Partial res p o nse, Q D = O nce dail y, S A E = Seri o us a d verse e ve nt; W O C B P = 
W o m e n of c hil d beari n g p ote ntial.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 9 / 1 5 5
T a ble 5
Sc he d ule of Electr oc ar di o gr a m, 
P h ar m ac o ki netic, 
a n d Bi o m ar ker 
Assess me nts d uri n g D ose Esc al ati o n - P art A (f or 2 1- a n d 2 8 -d a y c ycles)
Tr e at m e nt D a y  a
Ti m e
h ( ± mi n) b, c
E C G 
d
P K M 3 2 5 8
L M P 7 
& β 5 c 
a cti vit y
D 1 C 1
Pr e d o s e
X
X
X
1 ( ± 5)
X
2 ( ± 1 0)
X
X
X
3 ( ± 1 5)
X
4 ( ± 1 5)
X
X
5 ( ± 1 5)
X
6 ( ± 1 5)
X
X
X
8 ( ± 3 0)
X
X
D 2 C 1
2 4 ( Pr e d o s e)
X
X
X
D 8 C 1
Pr e d o s e
X
X
X
1 ( ± 5)
X
2 ( ± 1 0)
X
X
X
3 ( ± 1 5)
X
4 ( ± 1 5)
X
X
5 ( ± 1 5)
X
6 ( ± 1 5)
X
X
X
8 ( ± 3 0)
X
X
D 1 5 C 1
Pr e d o s e
X
β 5c = C o nstit uti ve pr oteas o me s u b u nit β 5; C = C ycle; D = Da y; E C G = Electr ocar di o gra m; L M P 7 = L ar ge m ultif u ncti o nal 
pr otease 7; 
; P d = P har mac o d y na mics; P K = P har mac o ki netics.
a:
Ta ble 5 is a p plica ble f or all pr o p ose d re gi me ns i n Part A.
b:
At visits w here assess me nt ti me p oi nts ( E C G, P K a n d P d) c oi nci de wit h eac h ot her :
1) Perf or m vital si g ns assess me nts at first 
2) E C G assess me nts sli g htl y bef ore t he s pecific c ollecti o n ti me p oi nt 
3) P K assess me nts at sc he d ule d c ollecti o n ti me p oi nt a n d 
4) P d assess me nts as last assess me nt
c:
Act ual c ollecti o n ti mes s h o ul d be c ollecte d i n t he electr o nic Case Re p ort F or m al o n g wit h t he ti mes of t he last d ose 
a d mi nistrati o n.
d:
Tri ple E C G f or t he Q T/ Q Tc a nal ysis after at least 1 0 mi n utes’ rest a n d wit hi n 2 mi n utes a n d ha ve t o be ta ke n bef ore a n y 
bl o o d sa m pli n g. See  T a bl e 1 a n d T a bl e 2 f or 1 2 -lea d Safet y E C G ti mi n g ( n ote t hat tri ple E C G f or t he Q T/ Q Tc a nal ysis 
here is liste d a s 1 2 -l e a d Q T c A s s e s s m e nt i n T a bl e s 1 a n d 2).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
6 0 / 1 5 5
T a ble 6
Sc he d ule of Electr oc ar di o gr a m, 
P h ar m ac o ki netic, 
a n d Bi o m ar ker 
Assess me nts d uri n g D ose E x p a nsi o n - P art B (f or 2 1- a n d 2 8 -d a y c ycles)
Tr e at m e nt 
D a y a
Ti m e
h ( ± mi n) b , c
E C G d
P K M 3 2 5 8
P K 
d e x a m e t h a s o n e
L M P 7 a cti vit y  
& β 5 c
D 1 C 1
Pr e d o s e
X
X
1 ( ± 5)
X 
2 ( ± 1 0)
X
X
3 ( ± 1 5)
X
4 ( ± 1 5)
X 
5 ( ± 1 5)
X
6 ( ± 1 5)
X
X
D 2 C 1 f
2 4 ( Pr e d o s e)
X
X
D 8 C 1
Pr e d o s e
X
X
X
1 ( ± 5)
X 
2 ( ± 1 0)
X
X 
X
3 ( ± 1 5)
X
4 ( ± 1 5)
X
X
5 ( ± 1 5)
X
6 ( ± 1 5)
X
X
X
D 1 C 2
Pr e d o s e
X e
X e
1 ( ± 5)
X e
X e
2 ( ± 1 0)
X e
X e
3 ( ± 1 5)
X e
X e
4 ( ± 1 5)
X e
X e
5 ( ± 1 5)
X e
6 ( ± 1 5)
X e
X e
8 ( ± 3 0)
X e
β 5c = C o nstit uti ve pr oteas o me s u b u nit β 5; C = C ycle; D = Da y; E C G = Electr ocar di o gra m; L M P 7 = Lar ge m ultif u ncti o nal 
pr otease 7; 
; P d = P har mac o d y na mics; P K = P har mac o ki netics.
a:
Ta ble 6 is a p plica ble f or all pr o p ose d re gi me ns i n Part B . 
b:
At visits w here assess me nt ti me p oi nts ( E C G, P K a n d P D) c oi nci de wit h eac h ot her 
1) Perf or m vital si g ns assess me nts at first 
2) E C G assess me nts sli g htl y bef ore t he s pecific c ollecti o n ti me p oi nt
3) P K assess me nts at sc he d ule d c ollecti o n ti me p oi nt a n d 
4) P d assess me nts as last assess me nt
c:
Act ual c ollecti o n ti mes s h o ul d be c ollecte d i n t he e C R F al o n g wit h t he ti mes of t he last d ose a d mi nistrati o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y wit h M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
6 1 / 1 5 5
d:
Tri ple E C G f or t he Q T/ Q Tc a nal ysis after at least 1 0 -mi n utes rest a n d wit hi n 2 mi n utes a n d ha ve t o be ta ke n bef ore a n y 
bl o o d sa m pli n g. See  T a bl e 3 a n d T a bl e 4 for 1 2 -lea d Safet y E C G ti mi n g ( n ote t hat tri ple E C G f or t he Q T/ Q Tc a nal ysis here 
is liste d as 1 2 -l e a d Q T c A s s e s s m e nt i n T a bl e s 3 a n d 4 ).
e:
P K sa m ples f or f o o d effect e val uati o n ta ke n f or at least t he first 1 8 partici pa nts. Decisi o n o n sa m pli n g i n f urt her partici pa nts 
will be ta ke n d uri n g i nteri m a nal ysis.
f:
F or partici pa nts i n t he safet y r u n-i n a n d t he first 3 partici pa nts at a ne w d ose.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
6 2 / 1 5 5
2
I ntr o d ucti o n
M ulti ple m y el o ma is c haracterize d b y  the prese nce of m o n ocl o nal plas ma cells i n b o ne 
marr o w, e xtra me d ullar y or ga ns, or b ot h. S y m pt o matic M M is defi ne d b y e n d or ga n da ma ge 
s uc h as l ytic b o ne lesi o ns, h y percalce mia, a ne mia, a n d re nal i m pair me nt. Rela pse d M M is 
defi ne d as a rec urre nce of disease after pri or res p o nse base d o n o bjecti ve la b orat or y an d 
ra di ol o gical criteria. Re fract or y M M is defi ne d as disease t hat bec o mes n o nres p o nsi ve or 
pr o gressi ve o n t hera p y or wit hi n 6 0 da y s of last treat me nt i n partici pa nt s w h o ha d ac hie ved a 
mi ni mal res p o nse or better o n pri or t hera p y. O nce rela pse treat me nt is re q uire d, i n di vi d ual 
partici pa nt c haracteristics will i nfl ue nce t he o pti mal treat me nt c h oice. T he ris k stat us m ust be 
deter mi ne d base d o n esta blis he d criteria. T we nt y  perce nt of par tici pa nts ha ve a g gressi ve 
rela pse acc or di n g t o I MW G 
criteria, base d o n u nfa v ora ble c yt o ge netics [ del 1 7 p, t( 4; 1 4), 
a d d 1 q/ del 1 p, t ( 1 4; 1 6) a n d ot hers , hi g h -ris k ge ne e x pressi o n pr ofile, hi g h b- 2- M] or l o w 
al b u mi n, hi g h-ser u m lactate de h y dr o ge nase (S o n ne vel d 2 0 1 7 ).
M 3 2 5 8 
is a n o vel, orall y -a d mi nistere d hi g hl y selecti ve first i n class i n hi bit or of t he 
i m m u n o pr oteas o me s u b u nit L M P 7 t hat is bei n g de vel o pe d f or t he treat me nt of partici pa nt s 
wit h R R M M.
T he c o m bi nati o n of M 3 2 5 8 wit h de xa met has o ne is e x pecte d t o deli ver i ncrease d efficac y  wit h 
si milar safet y as c o m pare d t o M 3 2 5 8 m o n ot hera p y. T his is base d o n t he prece de nt of cli nical 
e x perie nce wit h pa n -pr oteas o me i n hi bit ors i n c o m bi nati o n wit h de xa met has o ne.
C o m plete i nf or mati o n o n M 3 2 5 8
is i n t he In vesti gat or’s Br oc h ure (I B).
2. 1
St u d y R ati o n ale
M 3 2 5 8 is a n oral, p ote nt a n d selecti ve c o vale nt-re versi ble i n hi bit or of t he c h ym otr y psi n -li ke 
acti vit y of L M P 7 (β 5i, P S M B 8) s u b u nit of t he i m m u n o pr oteas o me, w hic h has t he p ote ntial t o 
deli ver a t hera pe utic be nefit t o patie nts wit h R R M M.
M 3 2 5 8 de m o nstrate d p ote nt a n d selecti ve i n hi biti o n of L M P 7 i n h u ma n M M cell li nes as well 
as i n peri p heral bl o o d m o n o n uclear cell (P B M Cs ) fr o m vari o us s pecies i ncl u di n g h u ma n. I n 
c o ntrast t o t he pa n -pr oteas o me i nhi bit ors b ortez o mi b, carfilz o mi b a n d i xaz o mi b w hic h 
i n discri mi natel y in hi bit m ulti ple 
pr ote ol y tic s u b u nits of t he i m m u n o pr oteas o me a n d 
c o nstit uti ve pr oteas o me, M 3 2 5 8 de m o nstrate d m ore t ha n 5 0 0 -f ol d bi oc he mical selecti vit y  for 
L M P 7 vers us t he β 5c pr ote ol y tic s u b u nit of t he c o nstit uti ve pr oteas o me.  
M 3 2 5 8 de m o nstrate d str o n g a ntit u m or acti vities, u p t o c o m plete re gressi o ns, i n n o ncli nical 
m ulti ple m y el o ma m o dels. O pti mal efficac y was o bser ve d u p o n Q D oral d osi n g of M 3 2 5 8, a 
sc he d ule ass ociate d wit h s ustai ne d s u p pressi o n of L M P 7 acti vit y i n t u m or cells a n d peri p heral 
bl o o d m o n o n uclear cells. M 3 2 5 8 als o de m o nstrate d s u peri or i n vi v o efficac y  c o m pare d t o t he 
a p pr o ve d pa n -pr oteas o me i n hi bit ors i n differe nt n o ncli nical m o dels i ncl u di n g c yt o ge netic 
hi g h -ris k m o dels, s u g gesti n g t he p ote ntial f or M 3 2 5 8 t o deli ver a n efficac y be nefit t o patie nts 
wit h M M w h o d o n ot dis pla y  a n o pti mal res p o nse t o t hese a p pr o ve d t hera pe utic a ge nts.
L M P 7 acti vit y as P d rea d o ut has bee n de m o nstrate d i n se veral n o n cli nical s pecies a n d tiss ues. 
N o n cli nical data fr o m p har mac ol o g y , P K a n d t o xic ol o g y st u dies s u g gest a n acce pta ble safety 
pr ofile a n d wi n d o w of M 3 2 5 8 i n h u ma n s. Cli nical e x perie nce wit h pa n-pr oteas o me i n hi bit ors 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
6 3 / 1 5 5
s u g gests n o o verla p pi n g safety a d verse e ve nts ( A Es ) i n c o m bi nati o n wit h de xa met has o ne a n d 
i m m u n o m o d ulat or y imi de dr u gs (I Mi Ds) a n d e nc o ura gi n g cli nical a ntit u m or acti vit y in 
partici pa nt s wit h M M .
2. 2
B ac k gr o u n d
Treat me nt of ne wl y dia g n ose d a n d rela pse d m yel o ma has bee n a ra pi dl y m o vi n g ﬁel d beca use 
of a n i m pr o ve d u n dersta n di n g of disease bi ol o g y  an d access t o ne w dr u gs (K u mar et al, 2 0 1 8 , 
L o nial et al, 2 0 1 5 ). Pri or c o m bi nati o n atte m pts s h o we d t hat c o m bi ni n g m ulti ple c yt ot o xic 
dr u gs w o ul d n ot i m pr o ve t hera py es peciall y w he n c o m bi nati o ns of al k ylat ors wit h ster oi ds 
were i n v ol ve d, w hic h i nstea d le d t o a m ore pr o n o u nce d t o xicit y  pr ofile ( O ke n, 1 9 9 7). 
W he n t he “ n o vel” I Mi Ds a n d pr oteas o me i n hi bit ors ( PIs) were br o u g ht t o t he ﬁel d a de ca de 
a g o, t he y s u bse q ue ntly de m o nstrate d greater ef ﬁcac y  a n d were dee me d safer i n c o m bi nati o ns, 
lea di n g t o a p us h t o c o m bi ne a ge nts f or ne wl y  dia g n ose d patie nts. T his m uc h -nee de d c ha n ge 
is n o w e xte n di n g t o t he rela pse setti n g as well. Rece nt P hase III st u dies ha ve s u g geste d t hat 
c o m bi nati o ns of t hese ne w a ge nts wit h eac h ot her, or wit h al k ylat or base d t hera p y, res ulte d i n 
greater res p o nses a n d pr ol o n ge d d urati o n of re missi o n a n d O S (Ca v o et al, 2 0 1 1 ; S o n ne vel d et 
al, 2 0 1 2 ; Ste wart et al, 2 0 1 5 ; L o nial et al, 2 0 1 5 ). T he u bi q uiti n - pr oteas o me pat h wa y  is 
res p o nsi ble f or de gra dati o n of u bi q uiti nate d pr otei ns i n e u kar y otic cells, i ncl u di n g p r otei ns t hat 
c o ntr ol cell-c ycle pr o gressi o n, a p o pt osis, a n d D N A re pair a n d t heref ore, pla y s a n esse ntial r ole 
i n mai ntai ni n g n or mal cell ular h o me ostasis (Micale et al, 2 0 1 4 ). T he i m m u n o pr oteas o me a n d 
c o nstit uti ve pr oteas o me are m ulti -s u b u nit c yli n drical c o m ple xes t hat pr ocess u bi q uiti nate d 
pr otei ns a n d ge nerate pe pti des w hic h ca n be prese nte d o n maj or hist oc o m pati bilit y  co m ple x
Class I. In c o ntrast t o t he c o nstit uti ve pr oteas o me, w hic h 
is br oa dl y  ex presse d, t he 
i m m u n o pr oteas o me is s pecifically prese nt i n n or mal he mat o p oietic cells a n d he mat o p oietic 
ca ncers s uc h as M M . I n n or mal a n d ca ncer o us cells of n o n he mat o p oietic ori gi n, e x pressi o n of 
t he i m m u n o pr oteas o me is t ypicall y  lo w, b ut ca n be i n d uce d b y  infla m mat or y  co n diti o ns s uc h 
as e x p os ure t o i nterfer o n ga m ma (Haller mal m et al, 2 0 0 1 ).
Pa n- pr oteas o me i n hi bit ors s uc h as b ortez o mi b, carfilz o mi b a n d i xaz o mi b i n discri mi natel y 
i n hi bit t he pr ote ol y tic acti vities of m ulti ple s u b u nits of t he i m m u n o pr oteas o me a n d c o nstit uti ve 
pr oteas o me (re vie we d i n  Ettari et al, 2 0 1 8 ). T hese a ge nts are a p pr o ve d f or use i n patie nts wit h 
M M
eit her as m o n ot hera p y  or i n c o m bi nati o n wit h ot her a ge nts s uc h as I Mi Ds (e. g.,
le nali d o mi de) a n d t he c ortic oster oi d de xa met has o ne (re vie we d i n Bra y er et al, 2 0 1 7 ). 
E x peri me ntal data has i n dicate d t hat pa n -pr oteas o me i n hi bit ors elicit di verse effect o n M M 
cells, w hic h ma y p ote ntiall y u n der pi n t heir t hera pe utic efficac y (re vie we d i n K u bicz k o va et al, 
2 0 1 4 a n d Mc Bri de et al, 2 0 1 3 ). H o we ver, t he lac k of selecti vit y of t hese a ge nts, i n partic ular 
t he i n hi biti o n of t he c o nstit uti ve pr oteas o me i n di verse tiss ues, is ass u me d t o dri ve t heir a d verse 
safety pr ofiles, wit h c o m m o n si de effects s uc h as peri p heral ne ur o pat h y, car diac dis or ders, 
gastr oi ntesti nal dist ur ba nces, fati g ue a n d t hr o m b oc yt o pe nia (re vie we d i n  Ettari et al, 2 0 1 8 a n d 
Ce n giz Se val et al, 2 0 1 8 ). Selecti ve i n hi biti o n of t he i m m u n o pr oteas o me ma y  pote ntiall y  
mai ntai n a ntit u m or efficac y  i n M M , w hile circ u m ve nti n g t he se vere t o xicities ass ociate d wit h 
pa n - pr oteas o me i n hi bit ors (revie we d i n  Ettari et al, 2 0 1 8 a n d Miller et al, 2 0 1 4 ). 
M 3 2 5 8 is a n oral, p ote nt, selecti ve, c o vale nt-re versi ble i n hi bit or of t he c h y m otr y psi n -li ke 
pr ote ol y tic acti vit y of L M P 7 (β 5i, P S M B 8) s u b u nit of t he i m m u n o pr oteas o me. M 3 2 5 8 dis pla y s 
p ote nt a ntit u m or efficac y, u p t o c o m plete t u m or re gressi o n, i n n o n cli nical m o dels of M M , 
i ncl u di n g m o dels 
har b ori n g t he t( 4; 1 4)-tra nsl ocati o n; a hi g h -ris k bi o mar ker c o m m o nl y 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
6 4 / 1 5 5
detecte d i n patie nts wit h M M 
dis pla y i n g p o or pr o g n osis a n d s h orter ti me t o pr o gressi o n 
(re vie we d i n B ust or os et al, 2 0 1 7 a n d S o n ne vel d, 2 0 1 7 ). F urt her m ore, M 3 2 5 8 de m o nstrates a n 
i m pr o ve d t hera pe utic i n de x c o m pare d t o b ortez o mi b, carfilz o mi b a n d i xaz o mi b base d o n 
n o ncli nical a ni mal safet y st u dies. Fi nall y , M 3 2 5 8 
is orall y bi oa vaila ble i n a ni mals a n d 
de m o nstrate d a dr u g -dr u g i nteracti o n pr ofile p ote ntiall y  co m pati ble wit h c o m bi nati o n wit h 
ot her a ge nts s uc h as de xa met has o ne. 
 
 
 
N o n cli nical st u dies i n differe nt s pecies ha ve c o nfir me d t hat oral a d mi nistrati o n of M 3 2 5 8 
res ults i n i n hi biti o n of L M P 7 acti vit y in n or mal a n d i n t u m or tiss ue. A n L M P 7 acti vit y assa y 
as P d rea d o ut i n h u ma n P B M Cs is c urre ntl y vali date d f or cli nical use.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
6 5 / 1 5 5
 
 
 
 
 
 
 
I n t he a bse nce of cli nical e x perie nce wit h M 3 2 5 8, all st u d y partici pa nts will be m o nit ore d f or 
a n y pote ntial occ urre nce of a S A E irres pecti ve t o its attri b uta bilit y to st u d y i nter ve nti o n. W he n 
necessar y , M 3 2 5 8 a d mi nistrati o n s h o ul d be disc o nti n ue d a n d a p pr o priate me dical i nter ve nti o ns 
i nitiate d i n acc or da nce t o l ocal me dical sta n dar ds. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 T o better 
u n dersta n d a n d c haracterize t he rele va nt t o xicities, i n a d diti o n t o e ns uri n g safet y of cli nical 
st u d y partici pa nts, A Es
s uc h as GI  he m orr ha ge, GI  
muc ositis ( diarr hea, v o miti n g), 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
6 6 / 1 5 5
o p p ort u nistic i nfecti o ns a n d aller gic reacti o ns/h y perse nsiti vit y  will be c o nsi dere d a d verse 
e ve nts of s pecial i nterest ( A E SI) a n d a g ui da nce , i n li ne wit h sta n dar d me dical practices, t o 
ma na ge s uc h t o xicities are pr o vi de d i n Secti o n s 6. 9 a n d 6. 9. 1.  
D uri n g cli nical st u d y, a S M C will pr o vi de rec o m me n dati o ns o n d ose a n d re gi me ns d uri n g d ose 
escalati o n base d o n re vie w of st u d y partici pa nt’s a vaila ble data (cli nical a n d P K) i n 
c o nsi derati o n of a n a ntici pate d stee p d ose -res p o nse t o xicit y as well as t he p ote ntial t o xicit y du e 
t o acc u m ulati o n o ver ti me.
C o m bi n ati o n of M 3 2 5 8 wit h De x a met h as o ne
Pa n- pr oteas o me i n hi bit ors s uc h as b ortez o mi b, carfilz o mi b a n d i xaz o mi b are a p pr o ve d i n 
vari o us c o u ntri es f or use i n patie nts wit h M M i n c o m bi nati o n wit h ot her a ge nts s uc h as t he 
c ortic oster oi d de xa met has o ne. A detaile d retr os pecti ve a nal ys is of safet y an d efficac y si gnals 
fr o m m ulti ple sec o n d-li ne cli nical st u dies i n partici pa nts wit h M M usi n g eit her b ortez o mi b or 
t he c o m bi nati o n of b ortez o mi b wit h de xa met has o ne was p u blis he d (Di m o p o ul os et al, 2 0 1 5 ). 
T his a nal ysis c o ncl u de d t hat t he c o m bi nati o n of b ortez o mi b wit h de xa met has o ne deli vere d a 
greater efficac y vers us b ortez o mi b m o n ot hera p y , e xe m plifie d b y  hi gher o verall res p o nse rate 
(O R R ) ( 7 5 % vs. 4 1 %; o d ds rati o = 3. 4 6 7; P < 0. 0 0 1) a n d l o n ger me dia n ti me-t o-pr o gressi o n 
( 1 3. 6 vs. 7. 0 m o nt hs; hazar d rati o [ H R] = 0. 3 9 4; P = 0. 0 0 3) a n d P F S ( 1 1. 9 vs. 6. 4 m o nt hs; H R 
= 0. 5 9 5; P = 0. 0 5 1). F urt her m ore, t he rates of a n y- gra de A Es, m ost c o m m o n Gra de 3 or hi g her 
A Es, a n d disc o nti n uati o ns d ue t o A Es were c o m para ble i n partici pa nts recei vi n g b ortez o mi b 
wit h de xa met has o ne c o m pare d t o b ortez o mi b m o n ot hera p y. T hese fi n di n gs were br oa dl y 
s u p p orte d b y a sec o n d p u blicati o n (Harri s o n et al, 2 0 1 5).
 
 
 
 
 
 
 
 
Base d u p o n a vaila ble n o n cli nical data fr o m M 3 2 5 8 a n d k n o w n class effects fr o m a p pr o ve d 
pa n - pr oteas o me i n hi bit ors, t he meas ures f or safet y re p orti n g, safety m o nit ori n g, a n d ris k 
miti gati ve acti vities f or t his pr o p ose d Fi H st u d y are c o nsi dere d a de q uate.
F urt her, d e xa met has o ne at a c u m ulati ve d ose of 4 0 m g/ wee k will be a d mi nistere d i n t he 
esta blis hed l o w -d ose re gi me n i n t he e x pa nsi o n part of t he st u d y, as is use d i n sta n dar d of care 
i n c o m bi nati o n wit h t he oral pa n-pr oteas o me i n hi bit or i xaz o mi b.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 / 1 5 5
3
O bjecti ves a n d E n d p oi nts
T a ble 7
St u d y O bjecti ves a n d E n d p oi nts - D ose Esc al ati o n - P art A
O bjecti ves
E n d p oi nts ( O utc o me Me as ures)
Pri m ar y

T o deter mi ne safet y, t olera bilit y an d t he 
M T D
(if o bser ve d) of M 3 2 5 8
as a si n gle 
a ge nt i n partici pa nts wit h R R M M

Occ urre nce of D L Ts i n partici pa nts wit h 
R R M M recei vi n g M 3 2 5 8 
as a si n gle 
a ge nt d uri n g t he D L T peri o d

Occ urre nce of a n y A Es re p orte d (seri o us 
or n o nseri o us) will be c o nsi dere d T E A Es 
a n d T R A Es (i ncl u di n g T E A Es lea di n g t o 
deat h or disc o nti n uati o n of treat me nt) i n 
partici pa nts recei vi n g M 3 2 5 8 as a si n gle 
a ge nt fr o m start of st u d y i nter ve nti o n t o 
3 0 da y s after E n d of S t u d y Inter ve nti o n

Occ urre nce of T E A Es o utsi de of t he D L T 
peri o d t hat S M C
dee ms rele va nt f or 
deter mi nati o n of t he M T D

St u d y  treat me nt-e mer ge nt c ha n ges i n 
cli nical 
la b orat or y 
meas ures 
fr o m 
Baseli ne , safet y EC Gs meas ures, vital 
si g ns, E C O G 
perf or ma nce stat us
i n 
partici pa nts recei vi n g M 3 2 5 8 as a si n gle 
a ge nt fr o m start of st u d y i nter ve nti o n t o 
3 0 da y s after en d of st u d y i nter ve nti o n
Sec o n d ar y

T o i n vesti gate t he P K pr ofile of M 3 2 5 8 
(si n gle a n d m ulti ple d ose e x p os ure) i n 
partici pa nts wit h R R M M

P K pr ofile of M 3 2 5 8 i n ter ms of C ma x, 
A U C 0-t, A U C 0- 2 4 at Da y 
1, C y cle 1, 
(si n gle d ose): pre d ose, 1, 2, 3, 4, 5, 6, 8
a n d 2 4 h after a d mi nistrati o n

P K pr ofile of M 3 2 5 8 i n ter ms of C ma x , 
A U C 0- 2 4 at Da y  8 C y cle 1, ( m ulti ple
d ose): pre d ose, 1, 2, 3, 4, 5, 6, a n d 8 h 
after a d mi nistrati o n

T o i n vesti gate t he rec o m me n de d d ose
a n d re gi me n f or e x pa nsi o n (R D E ) i n 
partici pa nts wit h R R M M

I n a d diti o n t o safety, t olera bilit y a n d P K,
f or selecti o n of rec o m me n de d d ose a n d 
re gi me n f or e x pa nsi o n (R D E ), c ha n ges i n 
P d ( L M P 7 acti vit y ) i n pre a n d p ost st u d y 
i nter ve nti o n sa m ples o n Da y  1 C y cle 1 
pre a n d p ost d ose, D a y 2 C y cle 1 pre d ose 
a n d D a y 8 C y cle 1 pre a n d p ost d ose 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
6 8 / 1 5 5
O bjecti ves
E n d p oi nts ( O utc o me Me as ures)

C ha n ges fr o m Baseli ne
i n ser u m M-
pr otei n , uri ne M- pr otei n, or free li g ht 
c hai n pr otei n le vels (f or free li g ht c hai n 
disease) o n Da y  1 of e ver y  c ycle

T o e val uate preli mi nar y  cli nical acti vit y 
usi n g I M W G criteria

O R, D O R , Ti me t o R es p o nse u ntil C R , 
sC R, V G P R or P R acc or di n g t o I M W G
E x pl or at or y

T o i n vesti gate t he c ha n ges i n t he P d
mar ker of M 3 2 5 8 
as a si n gle a ge nt i n 
partici pa nts wit h R R M M

C ha n ges i n P d ( L M P 7 acti vit y) i n pre a n d 
p ost st u d y i nter ve nti o n sa m ples o n Da y  1 
C y cle 1 pre a n d p ost d ose, D a y 2 C y cle 1 
pre d ose a n d Da y 8
C y cle 1 pre a n d 
p ost d ose

T o i n vesti gate f urt her P K para meter s of 
M 3 2 5 8 
(si n gle 
a n d 
m ulti ple 
d ose 
e x p os ure) i n partici pa nts wit h R R M M

P K pr ofile of M 3 2 5 8 i n ter ms of t ma x , tla g, 
t1/ 2, C L/ F, Vz/ F at Da y  1 C ycle 1, (si n gle 
d ose): pre d ose, 1, 2, 3, 4, 5, 6, 8 a n d 2 4 h 
after a d mi nistrati o n

P K pr ofile of M 3 2 5 8 i n ter ms of A U C 0 →∞
(if calc ula ble), tma x , tla g, t1/ 2, C L ss/ F, at 
Da y  8 C y cle 1, ( m ulti ple d ose): pre d ose, 
1, 2, 3, 4, 5, 6 a n d 8 h after a d mi nistrati o n

P K pr ofile of M 3 2 5 8 i n ter ms of C tr o u g h at 
Da y s 8 a n d 1 5 ( Q D re gi me n o nl y ) C y cle 
1 : pre d ose

P K pr ofile of M 3 2 5 8 i n ter ms of R acc ( A U C)
a n d R acc ( C ma x) after Da y 1 (si n gle d ose) 
a n d Da y  8 ( m ulti ple d ose), C y cle 1 a n d 
d ose -n or malize d C ma x, A U C 0-t, A U C 0- 2 4 
f or si n gle a n d m ulti ple d ose

T o i n vesti gate t he relati o ns hi p bet wee n 
e x p os ure of M 3 2 5 8 as a si n gle a ge nt a n d 
Q Tc i n partici pa nts wit h R R M M

Relati ve c ha n ges fr o m Baseli ne i n E C G 
para meter Q Tc 
i n relati o n t o M 3 2 5 8 
plas ma c o nce ntrati o n: all ti mes after 
si n gle 
a n d 
m ulti ple 
d osi n g 
wit h 
c o nc urre nt 
Q Tc 
a n d 
plas ma 
c o nce ntrati o n assess me nts

T o i n vesti gate ge netic variati o ns t hat m a y  
affect P K of M 3 2 5 8 as a si n gle a ge nt

Assess me nt 
of ge netic variati o ns t hat 
affect 
dr u g 
meta b olis m 
a n d 
dr u g 
tra ns p ort of M 3 2 5 8 a n d ot her p ote ntial 
ge nes t hat ma y  acc o u nt f or differe nces i n 
t he P K pr ofile 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
6 9 / 1 5 5
O bjecti ves
E n d p oi nts ( O utc o me Me as ures)

T o 
e x pl ore p ote ntial 
meta b olites 
of 
M 3 2 5 8 
i n plas ma i n partici pa nts wit h 
R R M M

Assess me nt
of p ote ntial meta b olites of 
M 3 2 5 8 i n plas ma 

T o e x pl ore L-citr ulli ne as a n e x pl orat or y 
bi o mar ker 

C ha n ges i n t he L-citr ulli ne bl o o d le vels 
d uri n g t he st u d y at Da y 1 a n d Da y  1 5
pre d ose, C y cle 1, a n d Da y
1 pre d ose, 
C y cle 2 a n d C y cle 3

T o 
i n vesti gate relati o ns hi p of 
dr u g 
treat me nt a n d Mi ni mal Resi d ual Disease 
( M R D) i n partici pa nts wit h R R M M

Assess me nt of M R D u p o n C R or s C R
T a ble 8
St u d y O bjecti ves a n d E n d p oi nts - D ose E x p a nsi o n - P art B
O bjecti ves
E n d p oi nts
Pri m ar y

T o deter mi ne safety a n d t olera bilit y of 
M 3 2 5 8
at t he rec o m me n de d d ose a n d 
re gi me n f or e x pa nsi o n (R D E ) w he n c o-
a d mi nistere d wit h 
de xa met has o ne 
i n 
partici pa nts wit h R R M M

Occ urre nce 
of d ose -li miti n g t o xicities 
( D L Ts) i n partici pa nts recei vi n g M 3 2 5 8 
i n c o m bi nati o n 
wit h 
de xa met has o ne 
d uri n g t he D L T peri o d

Occ urre nce of st u d y treat me nt-e mer ge nt 
S A Es i ncl u di n g deat hs fr o m first d ose of 
st u d y i nter ve nti o n t o 3 0 da ys after e n d of 
st u d y i nter ve nti o n
Occ urre nce 
of 
T E A Es 
a n d 
T R A Es 
(i ncl u di n g deat hs) fr o m start of st u d y 
i nter ve nti o n u p t o 3 0 da y s after e n d of 
st u d y i nter ve nti o n

St u d y  
treat me nt-e mer ge nt 
cli nicall y 
rele va nt a b n or mal c ha n ges i n cli nical 
la b orat or y 
meas ures 
fr o m Baseli ne, 
E C Gs 
meas ures, 
vital si g ns, E C O G 
perf or ma nce stat us fr o m start of st u d y 
i nter ve nti o n t o 3 0 da y s after e n d of st u d y 
i nter ve nti o n

T o deter mi ne rec o m me n de d P hase II 
d ose of M 3 2 5 8 
w he n c o-a d mi nistere d 
wit h de xa met has o ne i n partici pa nts wit h 
R R M M base d o n earl y si g ns of safet y a n d
efficac y i n t he e x pa nsi o n p hase

Occ urre nce 
of 
T E A Es 
a n d 
T R A Es 
(i ncl u di n g 
deat hs) 
i n 
partici pa nts 
recei vi n g 
M 3 2 5 8 
w he n 
gi ve n 
i n 
c o m bi nati o n wit h de xa met has o ne fr o m 
start of st u d y inter ve nti o n t o 3 0 da y s after 
e n d of st u d y i nter ve nti o n
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
7 0 / 1 5 5
O bjecti ves
E n d p oi nts

O R, D O R. Ti me t o Res p o nse u ntil C R, 
s C R, V G P R, or P R acc or di n g t o I M W G
Sec o n d ar y

T o c ollect preli mi nar y  efficac y data i n 
partici pa nts wit h R R M M u n der treat me nt 
wit h M 3 2 5 8, w he n c o-a d mi nistere d wit h 
de xa met has o ne

O R, D O R. Ti me t o Res p o nse u ntil C R, 
s C R, V G P R, or P R acc or di n g t o I M W G

Pr o gressi o n -Free 
S ur vi val 
( P F S) per 
I n vesti gat or

O verall S ur vi val ( O S) ce ns ore d at E n d of 
St u d y

T o i n vesti gate t he P K pr ofile of M 3 2 5 8 
(si n gle a n d m ulti ple d ose e x p os ure) w he n 
c o-a d mi nistere d wit h de xa met has o ne i n 
partici pa nts wit h R R M M

P K pr ofile of M 3 2 5 8 i n ter ms of C ma x, 
A U C 0-t , A U C 0- 2 4 at Da y  1 Cycl e 1, (si n gle 
d ose): pre d ose, 1, 2, 3, 4, 5, a n d 6 a n d 2 4 h
after a d mi nistrati o n

P K pr ofile of M 3 2 5 8 i n ter ms of C ma x , 
A U C 0 - 2 4 at Da y  8 C y cle 1, ( m ulti ple 
d ose): pre d ose, 2, 4,
a n d 6 h
after 
a d mi nistrati o n
E x pl or at or y

T o 
i n vesti gate t he c ha n ges 
i n t he 
p har mac o d y n a mic mar ker 
of M 3 2 5 8 
w he n 
c o-a d mi nistere d 
wit h 
de xa met has o ne 
i n partici pa nts 
wit h 
R R M M 

C ha n ges i n L M P 7 acti vit y on D a y  1 
C y cle 1 pre a n d p ost d ose a n d D a y 8
C y cle 1 pre a n d p ost d ose 

T o i n vesti gate f urt her P K p ara meters of 
M 3 2 5 8 
(si n gle 
a n d 
m ulti ple 
d ose 
e x p os ure) w he n 
c o-a d mi nistere d wit h 
de xa met has o ne 
i n partici pa nts 
wit h 
R R M M

P K pr ofile of M 3 2 5 8 i n ter ms of t ma x , tla g, 
t1/ 2, C L/ F, Vz/ F at Da y  1 C ycle 1, (si n gle 
d ose): pre d ose, 1, 2, 3, 4, 5, 6 a n d 2 4 h 
after a d mi nistrati o n

P K 
pr ofile of M 3 2 5 8 
i n ter ms of 
A U C 0 →∞, tma x , tla g, t1/ 2, C L ss/ F, at Da y  8
C y cle 1, ( m ulti ple d ose): pre d ose , 2, 4,
a n d 6 h after a d mi nistrati o n

P K pr ofile of M 3 2 5 8 i n ter ms of d ose -
n or malize d C ma x, A U C 0-t, A U C 0- 2 4 f or 
si n gle a n d m ulti ple d ose

T o i n vesti gate t he f o o d effect o n t he P K 
of M 3 2 5 8 
w he n c o-a d mi nistere d wit h 
d e xa met has o ne 
i n partici pa nts 
wit h 
R R M M

Area u n der t he plas ma c o nce ntrati o n-
ti me c ur ve ( A U C0- 8 h) wit h a n d wit h o ut 
f o o d fr o m ti me zer o ( = d osi n g ti me) t o 
8 h a n d C ma x of M 3 2 5 8 o bser ve d o n D a y  
1 C ycl e 2 : pre d ose, 1, 2, 3, 4, 5, 6 a n d 8 h 
p ost d ose 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
7 1 / 1 5 5
O bjecti ves
E n d p oi nts

T o i n vesti gate t he relati o ns hi p bet wee n 
e x p os ure wit h M 3 2 5 8 a n d Q Tc, w he n c o-
a d mi nistere d wit h 
de xa met has o ne 
i n 
partici pa nts wit h R R M M 

Relati ve c ha n ges fr o m Baseli ne i n E C G 
para meters ( Q Tc) i n relati o n t o M 3 2 5 8 
plas ma c o nce ntrati o n: all ti mes after 
si n gle 
a n d 
m ulti ple 
d osi n g 
wit h 
c o nc urre nt 
Q Tc 
a n d 
plas ma 
c o nce ntrati o n assess me nts

T o i n vesti gate ge netic variati o ns t hat m a y  
affect 
P K 
of 
M 3 2 5 8, 
w he n 
c o-
a d mi nistere d wit h 
d e xa met has o ne i n 
partici pa nts wit h R R M M

Assess me nt 
of ge netic variati o ns t hat 
affect 
dr u g
meta b olis m 
a n d 
dr u g 
tra ns p ort of M 3 2 5 8 a n d ot her p ote ntial 
ge nes t hat ma y  acco u nt f or differe nces i n 
t he P K pr ofile 

T o 
e x pl ore p ote ntial 
meta b olites 
of 
M 3 2 5 8 i n plas ma, w he n c o-a d mi nistere d 
wit h de xa met has o ne i n partici pa nts wit h 
R R M M

Assess me nt of p ote ntial meta b olites of 
M 3 2 5 8 

T o 
i n vesti gate t he P K
pr ofile 
of 
de xa met has o ne
w he n 
c o-a d mi nistere d 
wit h M 3 2 5 8 i n partici pa nts wit h R R M M

Area u n der t he plas ma c o nce ntrati o n-
ti me c ur ve ( A U C0- 8 h) fr o m ti me zer o ( = 
d osi n g 
ti me) t o 8 h 
a n d 
C ma x
of 
de xa met has o ne o bser ve d o n Da y  1, C y cle 
2 : pre d ose, 1, 2, 3, 4, a n d 6 h p ost d ose

T o e x pl ore L-citr ulli ne as a n e x pl orat or y 
bi o mar ker 

C ha n ges i n t he L-citr ulli ne bl o o d le vels 
d uri n g t he st u d y at Da y 1 a n d Da y  1 5
pre d ose, C y cle 1, a n d Da y  1 pre d ose, 
C y cle 2 a n d C y cle 3 

T o i n vesti gate c ha n ge β 5c acti vit y after 
M 3 2 5 8, 
w he n 
c o-a d mi nistere d 
wit h 
de xa met has o ne 
i n partici pa nts 
wit h 
R R M M

C ha n ges i n β 5c acti vit y on Da y  1 Cycle 1 
pre a n d p ost d ose a n d Da y 8 C y cle 1 pre 
a n d p ost d ose

T o 
i n vesti gate relati o ns hi p of 
dr u g 
treat me nt a n d M R D, w he n M 3 2 5 8 is c o-
a d mi nistere d wit h 
de xa met has o ne 
i n 
partici pa nts wit h R R M M

Assess me nt of M R D u p o n C R or s C R
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
7 2 / 1 5 5
4
St u d y Desi g n
4. 1
O ver all Desi g n
T his is a P hase I, o pe n -la bel, Fi H, 2- part ( d ose escalati o n a n d e x pa nsi o n), n o nc o ntr olle d, 
m ultice nter cli nical st u d y desi g ne d t o deter mi ne t he safet y, t olera bilit y, P K, P d a n d earl y s i gns 
of efficac y of M 3 2 5 8 as a si n gle a ge nt a n d c o -a d mi nistere d wit h de xa met has o ne i n partici pa nts 
wit h R R M M w h o se disease has pr o gresse d f oll o wi n g > 3 pri or li nes of t hera p y a n d f or w h o m 
n o effecti ve sta n dar d t hera p y  e xists (Fi g ure 1 ). 
T he d ose escalati o n p hase is ai me d at deter mi ni n g t he rec o m me n de d d ose a n d re gi me n f or t he 
e x pa nsi o n p hase ( R D E) a n d t he M T D
base d o n safet y, t olera bilit y, P K , P d (i ncl u di n g L P M 7 
acti vit y) a n d i nitial efficac y data of M 3 2 5 8 as a si n gle a ge nt . F oll o wi n g t he d ose -escalati o n 
p hase, t he safet y an d t olera bilit y of M 3 2 5 8 wit h de xa met has o ne will be i n vesti gate d i n a n
e x pa nsi o n c o h ort of a p pr o xi matel y 30 partici pa nts i n a d diti o n t o assess me nt of earl y cli nical 
acti vit y. If t he d ose is m o difie d d uri n g t he e x pa nsi o n p hase , t his sa m ple size will i ncrease b y  
a p pr o xi matel y 3- 2 1 partici pa nts.
Eac h p hase of t he st u d y will i ncl u de a Scree ni n g peri o d of u p t o 2 8 da y s, a st u d y i nter ve nti o n 
peri o d c o nsisti n g of 2 1- or 2 8- d a y  cycles of eit her M 3 2 5 8
al o ne ( Part A) or M 3 2 5 8 
i n
c o m bi nati o n wit h de xa met has o ne ( Part B) , a n E n d of St u d y  Inter ve nti o n v isit ( wit hi n 7 ± 3
da y s), a n d a Safety F oll o w -U p peri o d of 3 0 ( ± 7 ) da ys. I n P art B, partici pa nts will be f oll o w e d 
u p u ntil 6 m o nt hs after t he last-partici pa nt -last-st u d y-i nter ve nti o n i nta ke. Partici pa nts w h o 
t olerate M 3 2 5 8 ± c o m bi nati o n wit h de xa met has o ne wit h o ut si g nifica nt cli nicall y rele va nt 
t o xicities ma y  co nti n ue t o recei ve their assi g ne d d ose if t here is n o e vi de nce of c o nfir me d 
disease pr o gressi o n ( Secti o n 4. 4 ). Partici pa nts w h o disc o nti n ue st u d y inter v e nti o n f or a n y 
reas o n will c o m plete t he E n d of St u d y Inter ve nti o n a n d Safet y F oll o w -U p v isits.
Scree ni n g Peri o d
Scree ni n g will be perf or me d wit hi n 2 8 d a y s pri or t o Da y  1 of M 3 2 5 8 a d mi nistrati o n. T he 
Scree ni n g peri o d s h o ul d start bef ore t he S M C decisi o n t o e nr oll partici pa nts t o t he ne xt st u d y  
i nter ve nti o n c o h ort. Treat me nt of t he partici pa nt s scree ne d f or f ut ure d osi n g c o h orts will o nl y 
start after t he S M C decisi o n t o pr ocee d t o t he ne xt d osi n g c o h ort. If t here are n o cli nicall y 
si g nifica nt fi n di n gs at Scree ni n g a n d t he partici pa nt meets all t he pr ot oc ol -defi ne d i ncl usi o n 
criteria a n d n o ne of t he e xcl usi o n criteria, t he partici pa nt will be c o nsi dere d as eli gi ble a n d will 
be e nr olle d i nt o t he st u d y. Partici pa nt s w h o fail t o meet t he pr ot oc ol-s pecifie d criteria or w h o 
wit h dra w t heir c o nse nt will be c o nsi dere d Scree ni n g Fail ures. 
Tre at me nt Peri o d
D uri n g d ose escalati o n ( Part A), M 3 2 5 8 will be a d mi nistere d Q D as a si n gle a ge nt i n 2 8- da y
c ycles. I n t he e x pa nsi o n c o h ort ( Part B), M 3 2 5 8 will be a d ministere d i n c o m bi nati o n wit h 
de xa met has o ne at a c u m ulati ve d ose of 4 0 m g/ wee k . T he treat me nt peri o d will be gi n at t he first 
d ose of M 3 2 5 8 i n D a y  1 C y cle 1. Partici pa nts w h o t olerate M 3 2 5 8 wit h o ut si g nifica nt cli nicall y 
rele va nt t o xicities ma y  co nti n ue t o recei ve t heir assi g ne d d ose if t here is n o e vi de nce of disease 
pr o gressi o n.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
7 3 / 1 5 5
If Q D treat me nt is n ot t olerate d at a d ose le vel s h o wi n g efficac y  a n d/ or P d mar ker si g nals, t he 
f oll o wi n g o pti o ns will be c o nsi dere d b y  t he S M C base d o n a vaila ble data:

Q D d osi n g at d oses bel o w t he n o n -t olerate d d ose (d o w n t o 1 m g ) i n 2 8- d a y  cycl es
( base d o n S M C rec o m me n dati o n)
O R

T wice -per -wee k d osi n g o n D a ys 1, 4, 8, 1 1, 1 5, 1 8, 2 2 a n d 2 5 i n 2 8-d a y c y cles
I n a d diti o n , if a c o nsiste nt re d ucti o n i n platelet c o u nts t o t hr o m b oc yt o pe nia ≥Gra de 3 is 
o bser ve d d uri n g a 2 8 -d a y d osi n g re gi me n wit h o ut rec o ver y to baseli ne or ≤ Gra de 2 b y  the e n d 
of t he c ycle, t he S M C ca n c o nsi der a dr u g h oli da y  of at least 7 da y s i n t he pr o p ose d re gi me n
bel o w . Si milar t o p a n-pr ote as o me i n hi bit ors, a tra nsie nt effect o n me ga kar y o c y te f u ncti o n, 
p ossi bl y  relate d t o platelet b u d di n g nee ds t o be c o nsi dere d rat her t ha n a me ga kar y o c y te 
c yt ot o xicit y (L o nial et al, 2 0 0 5). A pre dicte d ti me f or rec o ver y of platelet c o u nts fr o m na dir 
t o baseli ne val ues has bee n descri be d t o be ar o u n d 7 da y s (L o nial et al, 2 0 0 5). T h us, a dr u g 
h oli da y (i nter mitte nt) of at least 7 t o 1 0 d a y s is i ncl u de d i n t he pr o p ose d re gi me n bel o w w hic h 
c o nse q ue ntl y c ha n ges t he c ycle le n gt h t o 2 1 da ys .

Q D d osi n g o n Da y s 1 t o 1 4, n o d osi n g o n Da ys 1 5 t o 2 1, i n 2 1 -da y  c ycles 
O R

T wice -per -wee k d osi n g o n Da y s 1, 4, 8, a nd 1 1, n o d osi n g o n Da y s 1 2 t o 2 1, i n 
2 1- d a y  c ycles 
If a s witc h i n d os e a n d/ or re gi me n is rec o m me n de d, t he first teste d d ose le vel i n t he ne w 
re gi me n m ust n ot e xcee d t he hi g hest teste d dail y d ose or t he wee kl y c u m ulati ve d ose m ust be 
e q ual t o or l o wer t ha n t he hi g hest wee kl y c u m ulati ve d ose of re gi me n(s) teste d s o far.
T he selecte d M 3 2 5 8 d ose a n d re gi me n ( R D E) will be c o m bi ne d wit h de xa met has o ne f or t he 
e x pa nsi o n c o h ort ( Part B).
D e xa met has o ne will be gi ve n at a c u m ulati ve d ose of 4 0 m g/ wee k :

2 0 m g/ da y  at D a ys 1, 4, 8, 1 1, 1 5, 1 8, 2 2 a n d 2 5 i n a 2 8- d a y c ycle
O R

2 0 m g/ da y  at D a ys 1, 4, 8, 1 1, 1 5, a n d 1 8 i n a 2 1- d a y c ycle (re gi me n wit h dr u g 
h oli da y )
D ose Esc al ati o n P art A 
Partici pa nts wit h M M w h ose disease has pr o gresse d f oll o wi n g > 3 li nes of t hera py a n d f or
w h o m n o effecti ve sta n dar d t hera p y  exists (see defi niti o n i n Secti o n  5 ) will be e nr olle d i n t he 
d ose -escalati o n part of t his st u d y. T he first d ose escalati o n c o h ort will recei ve M 3 2 5 8 at t he 
starti n g d ose of 1 0 m g Q D as a si n gle a ge nt. F or f urt her d ose c o h orts, a S M C will meet a n d 
re vie w all a vaila ble data t o pr o vi de rec o m men dati o ns o n t he ne xt d ose le vel. T he M T D is 
defi ne d b y  the S M C wit h a tar get D L T rate of 2 5 %. T he f oll o wi n g pre s pecifie d d oses of 1 0
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
7 4 / 1 5 5
m g, 2 0 m g ( 1 0 0 % i ncrease), 3 5 m g ( 4 3 % i ncrease) a n d 5 0 m g ( 3 0 % i ncrease) are pla n ne d
u nless M T D is reac he d. T he S M C, f oll o wi n g re vie w of preli mi nar y  safet y, t olera bilit y, P K a n d 
P d i nf or mati o n, will rec o m me n d t he d ose a n d/ or t he s witc h t o a n alter nati ve re gi me n pre -
s pecifie d i n t his pr ot oc ol f or t he ne xt c o h ort as a p plica ble. 
T his ma y  incl u de pr o p osi n g s maller d ose i ncreases c o m pare d t o t he pres pecifie d d oses a n d 
deescalati o n of t he d ose p ote ntiall y  d o w n t o 1 m g. 
T he S M C ma y  als o rec o m me n d e x pa n di n g a gi ve n c o h ort at t he sa me d ose le vel. 
If a d diti o nal d ose le vels a b o ve 5 0 m g  are j ustifie d f oll o wi n g re vie w of preli mi nar y  safety,  
t olera bilit y, P K, a n d P d i nf or mati o n fr o m t he i nitial c o h orts, a pr ot oc ol a me n d me nt will be 
s u b mitte d.
De pe n di n g o n t he o bser ve d t o xicit y pr ofile, t he S M C ma y  deci de o n differe nt d oses as 
pres pecifie d a n d/ or c ha n ge t o re gi me ns s pecifie d i n t his pr o t oc ol. H o we ver, escalati o n m a y  not 
pr ocee d t o a n y d ose hi g her t ha n 5 0 m g. I n case escalati o n is rec o m me n de d t o pr ocee d t o d oses 
hi g her t ha n 5 0 m g , a n a me n d me n t will be s u b mitte d. At eac h d ose le vel, t he first partici pa nt 
e nr olle d will be o bser ve d f or D L Ts f or at least 4 8 h o urs bef ore f urt her partici pa nts are e nr olle d. 
T he S M C will rec o m me n d a d ose a n d re gi me n f or t he e x pa nsi o n c o h ort base d o n a n i nte grate d 
re vie w o n all a vaila ble safet y, t olera bilit y, P K, P d (i ncl u di n g L M P 7 acti vit y) a n d 
i nitial efficac y data.
Resi d ual L M P 7 acti vit y reac hi n g a platea u c o m pari n g at least 3 i ncreasi n g d ose le vels will 
s u p p ort t he R D E selecti o n.
At least 6 partici pa nts nee d t o be treate d at t he selecte d R D E
as M 3 2 5 8 
m o n ot hera p y . 
A d diti o nall y , t he me dia n esti mate d D L T rate of t he R D E nee ds t o be ≤2 5 % a n d t he 7 5 % 
perce ntile of t he esti mate d D L T pr o ba bilit y  of t he R D E nee ds t o be bel o w 3 0 %.
If f urt her data is re q uire d t o deter mi ne t he R D E, a d diti o nal partic i pa nts ma y  be e nr olle d i n Part 
A (see Secti o n 9. 2).
D ose E x p a nsi o n P art B
O nce a n R D E ( d ose a n d re gi me n) of M 3 2 5 8 has bee n defi ne d w hic h is c o nsi dere d safe b y  t he 
S M C, d ose e x pa nsi o n ( Part B) m a y  be gi n. I nitiati o n of Part B ma y  start wit h o ut reac hi n g t he 
M T D i n Part A; d ose escalati o n f or defi ni n g t he m o n ot hera p y M T D ( Part A) ma y  pr ocee d i n 
parallel.
Partici pa nts wit h M M w h ose disease has pr o gresse d f oll o wi n g > 3 li nes of t hera py f or w h o m 
n o effecti ve sta n dar d t hera p y exists (see defi niti o n i n Secti o n  5) will be e nr olle d. I n Part B , 
p artici pa nts will recei ve M 3 2 5 8 
at t he R D E selecte d i n Part A i n c o m bi nati o n wit h 
de xa met has o ne at a c u m ulati ve d ose of 4 0 m g / wee k . T he first 2 c o h orts of 3 partici pa nts eac h 
(first 6 partici pa nts) will be use d f or a safety r u n -i n. T he partici pa nts i n t hese 2 c o h orts will be 
e nr olle d i n a sta g gere d a p pr oac h. Eac h c o h ort of t he safety r u n-i n will be e val uate d b y  the S M C 
f or t he pres pecifie d D L T criteria (see Secti o n 6. 6 ) of t his c o m bi nati o n bef ore a d diti o nal 
partici pa nts are e nr olle d. T he S M C meeti n gs will be hel d after t he first 3 a n d 6 partici pa nts 
ha ve fi nis he d C y cle 1 or disc o nti n ue d treat me nt. T he S M C will e val uate safety, c u mulati ve 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
7 5 / 1 5 5
a n d u nacce pta ble t o xicit y (see defi nit i o n of acce pta ble t o xicit y bel o w). SM C decisi o ns o n 
p ote ntial d ose a dj ust me nts i n t he safety r u n-i n (a n d later o n) will be s u p p orte d b y  Ba yesia n 
m o deli n g. After t he safet y  ru n- i n, S M C meeti n gs will be hel d at the c o m pleti o n of C ycle 1 or 
disc o nti n uati o n of treat me nt f or e ver y 6 partici pa nts ( wit h o ut pa usi n g e nr oll me nt) i n or der t o 
assess safet y, c u m ulati ve a n d u nacce pta ble t o xicit y of all partici pa nts i n t he e x pa nsi o n c o h ort, 
u nless a c ha n ge i n d osi n g has occ urre d. I n case d osi n g i n t he e x pa nsi o n c o h ort was c ha n ge d, 
t he ne xt S M C will be hel d after 3 partici pa nts ha ve fi nis he d t he D L T peri o d or d isc o nti n ue d.
T he d ose -e x pa nsi o n p hase of t his st u d y is desi g ne d t o o btai n a d diti o nal safet y, t olera bilit y, P K, 
P d a n d preli mi nar y  cli nical acti vit y data of M 3 2 5 8 i n c o m bi nati o n wit h de xa met has o ne .
T he S M C decisi o ns i n t he e x pa nsi o n p hase will als o be s u p p orte d b y  Ba yesia n m o deli n g. If 
data o btai ne d d uri n g t he safety r u n-i n of Part B i ndicate t hat a hi g her d ose t ha n t he R D E ma y 
be t olerate d w he n M 3 2 5 8 is a d mi nistere d i n c o m bi nati o n wit h de xa met has o ne, t he n a caref ul 
escalati o n b e y o n d t he m o n ot hera p y R D E
i n c o m bi nati o n wit h de xa met has o ne ca n be 
rec o m me n de d i n d osi n g ste ps of ma x i m u m 2 5 % increase s i n Part B. S M C will re vie w all 
a vaila ble data t o pr o vi de rec o m me n dati o ns o n t he ne xt d ose le vel.
U nacce pta ble t o xicit y  i n t he e x pa nsi o n c o h ort is defi ne d as A Es t hat meet t he D L T criteria (as 
defi ne d i n Secti o n 6. 6 ) re gar dless of w he n t he y occ ur d uri n g treat me nt; st o p pi n g r ules f or 
u nacce pta ble t o xicit y  f or partici pa nts treate d at t he sa me d ose are detaile d i n Secti o n 7. 1.  
If at a n y ti me i n t he e x pa nsi o n c o h ort, t he n u m ber of u nacce pta ble t o xicit y e ve nts i n dicate t hat 
t here is a ris k of safety t o t he partici pa nts (i.e., if defi ne d b o u n dar ies are met, see S ecti o n 7. 1) , 
accr ual t o t he c o h ort will be pa use d a n d t he S M C will meet t o re vie w t he data, als o c o nsi deri n g 
fee d bac k fr o m i n vesti gat ors, t o deter mi ne if f urt her e nr oll me nt s h o ul d be halte d. I n this case,
t he S M C will deci de w het her partici pa nts w h o are still o n treat me nt a n d are t olerati n g t he 
treat me nt s h o ul d c o nti n ue treat me nt or w het her treat me nt s h o ul d be re d uce d or wit h dra w n . T he 
Healt h A ut h orities ( H A ) will be n otifie d of t he S M C decisi o n.
If a situati o n of u nacce pta ble t o xicit y occ urs t hat d oes n ot meet
t he defi ne d b o u n daries f or 
st o p pi n g criteria (as o utli ne d i n Secti o n  7. 1), t he S M C will deci de w het her t he d ose f or ne wl y 
e nr olle d partici pa nt s s h o ul d be l o were d (i ncl u di n g t o w hat d ose). I n case d osi n g is de -escalate d 
f or t o xicit y i n t he e x pa nsi o n c o h ort, o nl y  3 partici pa nts will be treate d i nitiall y wit h t he ne w 
d ose ; e nr oll me nt of a d diti o nal partici pa nts will pa use u ntil t he S M C has e val uate d t he safety 
of t his c o h ort. E x pa nsi o n c o h ort S M C mee ti n gs will als o be s u p p orte d b y  the res ults of a 
Ba yesia n l o gistic 2 par a meter re gressi o n m o del .
W he n 1 5 partici pa nts treate d at t he sa me d ose are e val ua ble f or res p o nse (as defi ne d i n S ecti o n 
8. 1) , acc or di n g t o I MW G,
an i nteri m a nal ysis will be perf or me d . At t hat ti me t he f oll o wi n g 
decisi o n will be ma de:
i)
C o nti n uati o n o n t he sa me d ose u ntil a d diti o nal 1 5 partici pa nts are treate d at t he 
sa me d ose a n d are e val ua ble f or res p o nse acc or di n g t o I M W G , 
ii)
S t o p f or f utilit y, or
iii)
C ha n ge t he d ose of M 3 2 5 8
a n d e nr oll partici pa nts at t he ne w d ose u ntil 1 5 
partici pa nts treate d at t he ne w d ose are e val ua ble f or res p o nse acc or di n g t o I M W G. 
S u bse q ue ntl y  a new i nteri m a nal y sis will be perf or me d.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
7 6 / 1 5 5
F or a n y ot her o pti o n , a pr ot oc ol a me n d me nt will be s u b mitte d. A d diti o nall y , t he e nr oll me nt of 
partici pa nts f or i n vesti gati n g t he f o o d effect will be e val uate d at t he i nteri m a nal ys is a n d 
decisi o n ta ke n w het her e nr oll me nt of a d diti o nal partici pa nts is re q uire d.
A d diti o nal details o n t he i nteri m a nal ysis ca n be f o u n d i n S ecti o n 9. 4. 1 .
F o o d effect 
D a y  1 C ycle 2 will be a n e val uati o n of t he effect of f o o d o n P K. If t he healt h of t he partici pa nt 
all o ws, t he partici pa nt will be all ocate d t o a treat me nt c o h ort (a d mi nistrati o n of M 3 2 5 8 i n 
c o m bi nati o n wit h de xa met has o ne wit h or wit h o ut f o o d at Da y  1 Cycl e 2, als o see Secti o n 
5. 3. 1) .
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
T he p ur p ose of t his P hase I t w o-part [d ose -escalati o n f or M 3 2 5 8 as a si n gle a ge nt a n d d ose -
e x pa nsi o n i n c o m bi nati o n treat me nt] st u d y is t o esta blis h a safe a n d t olera ble d ose of M 3 2 5 8 
as a si n gle a ge nt a n d i n c o m bi nati o n wit h de xa met has o ne a n d t o i n vesti gate P K, P d a n d t he 
first cli nical efficac y si g nals of M 3 2 5 8 w he n gi ve n i n c o m bi nati o n wit h de xa met has o ne i n 
partici pa nts wit h R R M M. D ose escalati o n will be f oll o we d by a d ose e x pa nsi o n o nce t he R D E 
has bee n defi ne d.
R ati o n ale f or t he C o m bi n ati o n of M 3 2 5 8 wit h De x a met h as o ne
Pa n- pr oteas o me i n hi bit ors s uc h as b ortez o mi b, carfilz o mi b a n d i xaz o mi b are a p pr o ve d i n 
vari o us c o u ntries f or use i n patie nts wit h M M i n c o m bi nati o n wit h ot her a ge nts s uc h as t he 
c ortic oster oi d de xa met has o ne. A detaile d retr os pecti ve a nal ys is of safet y an d efficac y si gnals 
fr o m m ulti ple sec o n d-li ne cli nical st u dies i n partici pa nt s wit h M M usi n g eit her b ortez o mi b or 
t he c o m bi nati o n of b ortez o mi b wit h de xa met has o ne was p u blis he d (Di m o p o ul os et al, 2 0 1 5 ). 
T his a nal ysis c o ncl u de d t hat t he c o m bi nati o n of b ortez o mi b wit h de xa met has o ne deli vere d a 
greater efficac y vers us b ortez o mi b m o n ot hera p y , e xe m plifie d b y  hi gher O R R ( 7 5 % vs. 4 1 %; 
o d ds rati o = 3. 4 6 7; P < 0. 0 0 1) a n d l o n ger me dia n ti me-t o-pr o gressi o n ( 1 3. 6 vs. 7. 0 m o nt hs; H R 
= 0. 3 9 4; P = 0. 0 0 3) a n d P F S ( 1 1. 9 vs. 6. 4 m o nt hs; H R = 0. 5 9 5; P = 0. 0 5 1). F urt her m ore, t he 
rates of a n y- gra de A Es , m ost c o m m o n Gra de 3 or hi g her A Es , a n d disc o nti n uati o ns d ue t o A Es
were c o m parable i n partici pa nt s recei vi n g b ortez o mi b wit h de xa met has o ne c o m pare d t o 
b ortez o mi b m o n ot hera p y. T hese fi n di n gs were br oa dl y  su p p orte d b y  a sec o n d p u blicati o n 
(Harris o n et al, 2 0 1 5 ).
M 3 2 5 8, a selecti ve i n hi bit or of t he L M P 7 s u b u nit of t he i m m u n o pr oteas o me, has a relate d 
m olec ular mec ha nis m of acti o n t o t he a p pr o ve d pa n - pr oteas o me i n hi bit ors b ortez o mi b, 
carfilz o mi b a n d i xaz o mi b. Base d o n t he prece de nt of cli nical e x perie nce wit h pa n -pr o teas o me 
i n hi bit ors i n c o m bi nati o n wit h de xa met has o ne, t he c o m bi nati o n of M 3 2 5 8 wit h de xa met has o ne 
ma y  p ote ntially deli ver i ncreased efficac y an d c o m para ble a n d acce pta ble safety c o m pare d t o 
M 3 2 5 8 m o n ot hera p y.
R ati o n ale f or St u d y P o p ul ati o n
Partici pa nts wit h
M M 
ma y
ha ve a be nefit fr o m a selecti ve dr u g tar geti n g t he i m m u ne 
pr oteas o me f u ncti o n (refer t o Secti o n  2. 2). T he d ose escalati o n will be o pe n t o partic i pa nts 
wit h
R R M M w h ose disease has pr o gresse d f oll o wi n g > 3 pri or li nes of t hera py f or M M 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
7 7 / 1 5 5
i ncl u di n g a PI , a n I Mi D a n d a n a nti-C D 3 8 m A b or w h o are refract or y to at least a PI  age nt 
(carfilz o mi b or b ortez o mi b) a n d I Mi D acc or di n g t o t he I M W G criteria a n d f or w h o m n o 
effecti ve sta n dar d t hera p y exists (K u mar et al, 2 0 1 6 ). Mai nte na nce is n ot c o nsi dere d t o be a 
se parate li ne of t hera py. 
M 3 2 5 8 will be i n vesti gate d as a si n gle a ge nt i n t he d ose -escalati o n p hase of t his st u d y  ( Part A) 
a n d i n c o m bi nati o n wit h de xa met has o ne i n t he e x pa nsi o n c o h ort ( Part B). Partici pa nt s i n b ot h 
parts of t he st u d y will i ncl u de p artici pa nts wit h M M w h ose disease has pr o gresse d f oll o wi n g
> 3 pri or li nes of t hera p y f or M M i ncl u di n g a PI, a n I Mi D a n d a n a nti-C D 3 8 m A b or w h o are 
refract or y t o at least a PI a ge nt (carfilz o mi b or b ortez o mi b) a n d IMi D acc or di n g t o t he I M W G 
criteria a n d f or w h o m n o effecti ve sta n dar d t hera p y e xists (K u mar et al, 2 0 1 6). Mai nte na nce is 
n ot c o nsi dere d t o be a se parate li ne of t hera p y. 
Details of t he st u d y  p o p ulati o n are f urt her descri be d i n Secti o ns 5. 1 a n d 5. 2.
4. 3
J ustific ati o n f or D ose
T he starti n g d ose f or t his Fi H st u d y of M 3 2 5 8 i n partici pa nt s wit h a d va nce d disease a n d li mite d 
t hera pe utic o pti o ns was deter mi ne d base d o n t he f oll o wi n g a p pr oac hes:

 
 
 

C o nsi deri n g P K/ P d m o deli n g of t he pre dicte d p har mac ol o gical acti ve d ose ra n ge i n 
h u ma ns .
T he I C H S 9 has bee n c o nsi dere d f or t he deter mi nati o n of t he F iH starti n g d ose, i .e., a d ose t hat 
is e x pecte d t o ha ve p har mac ol o gic effects a n d is reas o na bly safe t o use.
 
 
 
 
 
 
 
 
 
 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
7 8 / 1 5 5
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
7 9 / 1 5 5
 
 
 
4. 4
E n d of St u d y Defi niti o n
A partici pa nt has c o m plete d t he st u d y if he/s he has c o m plete d all st u d y parts, i ncl u di n g t he 
st u d y i nter ve nti o n as defi ne d b y t he pr ot oc ol, u nless ha vi n g wit h dra w n c o nse nt, f or w hic h t he 
details ca n be f o u n d i n t he sc he d ule d pr oce d ure s h o w n i n t he Sc he d ule of Acti vities (S o A ).
T he E n d of S t u d y is defi ne d as t he date of t he last visit of t he last partici pa nt i n t he st u d y 
gl o ball y acc or di n g t o t he last sc he d ule d pr oce d ure s h o w n i n t he S o A .
Part A of t he st u d y will e n d after all partici pa nts ha ve passe d t he Sa fety F oll o w -U p visit or 
ha ve die d or wit h dra w n c o nse nt or st u d y partici pati o n, w hic he ver occ urs earlier.
Part B of t he st u d y will e n d 6 m o nt hs after all partici pa nts meet at least o ne of t he f oll o wi n g 
criteria:

P er ma ne ntl y disc o nti n ue d st u d y i nter ve nti o n

D ie d 

Misse d at least t w o c o nsec uti ve t u m or assess me nts after Baseli ne

Wit h dra wal of c o nse nt or wit h dra wal of st u d y partici pati o n

Start of a n ot her a ntica ncer t hera p y.
T he st u d y  or eit her part of it ma y be st o p pe d u p o n t he S p o ns or’s decisi o n t hat c o nti n uati o n of 
t he st u d y is u nj ustifia ble f or me dical or et hical reas o ns or if t he S p o ns or st o ps de vel o p me nt of 
M 3 2 5 8 i n t he p o p ulati o n c o vere d b y  this pr ot oc ol. T he S p o ns or m a y  als o deci de t o st o p t he 
st u d y if s u p p orte d by t he res ults of t he i nteri m a nal ysis i n Part B. F or safet y st o p pi n g r ules, see 
S ecti o n 7. 1 .
5
St u d y P o p ul ati o n
T he criteria i n Secti o ns 5. 1 (Incl usi o n Criteria) a n d 5. 2 (E xcl usi o n Criteria) are desi g ne d t o 
e nr oll o nl y  partici pa nts w h o are a p pr o priate f or t he st u d y, t here b y ens uri n g t he st u d y f ulfills its 
o bjecti ves. All rele va nt me dical a n d n o n me dical c o n diti o ns s h o ul d be ta ke n i nt o c o nsi derati o n 
w he n deci di n g w het her a pa rtici pa nt is s uita ble f or t his st u d y.
Selecti o n of t he partici pa nt p o p ulati o n is base d o n t he e x pectati o n t hat M 3 2 5 8 
is well 
differe ntiate d fr o m pa n - pr oteas o me i n hi bit ors, i m pl yi n g t hat t he dr u g w o ul d be efficaci o us i n 
partici pa nt s w h o are refract or y to or are pr o gressi n g u n der treat me nt wit h pa n -pr oteas o me 
i n hi bit ors. M 3 2 5 8 de m o nstrate d s u peri or i n vi v o efficac y co m pare d t o t he a p pr o ve d pa n -
pr oteas o me i n hi bit ors i n differe nt n o ncli nical m o dels i ncl u di n g c yt o ge netic hi g h -ris k m o dels, 
s u p p orti n g a Fi H st u dy i n partici pa nts wit h R R M M.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
8 0 / 1 5 5
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o i ncl usi o n a n d e xcl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
Bef ore perf or mi n g a n y  st u d y assess me nts t hat are n ot part of t he partici pa nt’s r o uti ne me dical 
care, t he I n vesti gat or will c o nfir m t hat t he partici pa nt or t he partici pa nt’s le gal re prese ntati ve 
has pr o vi de d writte n i nf or me d c o nse nt, as i n dicate d i n  A p pe n di x 2.
Partici pa nt s m ust ha ve d oc u me nte d M M
dia g n osis as defi ne d b y t he criteria bel o w:

M o n ocl o nal plas ma cells i n t he b o ne marr o w ≥1 0 % or prese nce of a bi o ps y -pr o ve n 
plas mac y t o ma. 

Meas ura ble disease w hic h ca n be f oll o we d i n t he bl o o d a n d uri ne as defi ne d b y  an y  
of t he f oll o wi n g:

Ser u m m o n ocl o nal para pr otei n ( M-pr otei n ) le vel ≥1. 0 g/ d L or uri ne M -pr otei n le vel 
≥2 0 0 m g/ 2 4 h o urs; 
or

I g A M M : ser u m M- pr otei n le vel ≥0. 5 g/ d L or uri ne M- pr otei n le vel ≥2 0 0 m g/ 2 4 
h o urs; 
or

Li g ht c hai n M M : Ser u m i m m u n o gl o b uli n free li g ht c hai n > 1 0 m g / d L a n d a b n or mal 
ser u m i m m u n o gl o b uli n ka p pa la m b da free li g ht c hai n rati o.
Partici pa nt s m ust ha ve d oc u me nte d e vi de nce of cli nical rela pse or pr o gressi ve disease ( P D ) o n 
or after t heir last treat me nt re gi me n as defi ne d b y t he IM W G criteria (Ta ble 1 6 ).
P art A

Partici pa nt m ust ha ve recei ve d > 3 pri or li nes of t hera py f or M M
i ncl u di n g a PI , a n 
I Mi D a n d a n a nti-C D 3 8 m A b a n d ha ve disease pr o gressi o n d uri n g or wit hi n 6 0 da y s 
of c o m pleti n g of t he m ost rece nt re gi me n or w h o are refract or y  t o a n I Mi D a n d / or a 
PI  a ge nt acc or di n g t o t he IM W G criteria a n d f or w h o m n o effecti ve sta n dar d t hera p y 
e xists or w h o d o n ot t olerate a n y of t he sta n dar d treat me nt. Mai nte na nce 
is n ot 
c o nsi dere d t o be a se parat e li ne of t hera p y. 

Partici pa nt m ust ha ve d oc u me nte d e vi de nce or pr o gressi ve disease as defi ne d b y  the 
I M W G criteria eit her o n or after t heir last re gi me n (Ta ble 1 6) .

Partici pa nt m ust ha ve m eas ura ble disease as me nti o n e d a b o ve.
P art B

Partici pa nt m ust ha ve recei ve d > 3 pri or li nes of t hera py f or M M i ncl u di n g a PI , a n 
I Mi D a n d a n a nti-C D 3 8 m A b a n d ha ve di sease pr o gressi o n d uri n g or wit hi n 6 0 da ys 
of c o m pleti n g of t he m ost rece nt re gi me n or w h o are refract or y  t o a n I Mi D a n d / or a 
PI  a ge nt acc or di n g t o t he IM W G criteria a n d f or w h o m n o effecti ve sta n dar d t hera p y 
e xists or w h o d o n ot t olerate a n y of t he sta ndar d treat me nt. Mai nte na nce 
is n ot 
c o nsi dere d t o be a se parate li ne of t hera p y. 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
8 1 / 1 5 5

Partici pa nt m ust ha ve d oc u me nte d e vi de nce o f pr o gressi ve disease as defi ne d b y  the 
I M W G criteria eit her o n or after t heir last re gi me n (Ta ble 1 6) .

Partici pa nt m ust ha ve meas ura ble disease of M M
as me nti o ne d a b o ve. 
5. 1
I ncl usi o n Criteri a
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y onl y  if t he a b o ve criteria f or st u d y 
p o p ulati o n are met at S cree ni n g a n d c o nfir me d at D a y 1 C y cle 1 a n d all t he f oll o wi n g criteria 
a p pl y:
I nf or me d C o nse nt
1.
Ca n gi ve si g ne d i nf or me d c o nse nt, as i n dicate d i n A p pe n di x 2 w hic h i ncl u des 
c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n t he i nf or me d c o nse nt f or m 
(IC F) a n d t his pr ot oc ol.
P art A a n d B
A ge
2.
Are partici pa nt s ≥ 1 8 y ears of a ge, at t he ti me of si g ni n g t he i nf or me d c o nse nt.
Wei g ht
N o criteri o n f or wei g ht.
Se x
3.
Are male or fe male.
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
4.
E C O G Perf or ma nce Stat us ≤ 1 
5.
A de q uate he mat ol o gic f u ncti o n as i n dicate d:
a.
Platelet c o u nt ≥ 7 5, 0 0 0/ m m 3
N ote: Tra nsf usi o n or use of gr o wt h -fact ors per mitte d u ntil 5 da ys bef ore first d ose of 
st u d y i nter ve nti o n
b.
H e m o gl o bi n ≥ 8. 0 g/ d L 
N ote: Tra nsf usi o ns are per mitte d u ntil 1 wee k bef ore first d ose of st u d y 
i nter ve nti o n. At Da y 1 C y cle 1 t he he m o gl o bi n le vel s h o ul d meet i ncl usi o n 
criteri o n wit h o ut tra nsf usi o n > 7 da y s was h-o ut wi n d o w. 
c.
A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1 0 0 0/ μ L  
N ote: Use of gr o wt h -fact ors per mitte d u ntil 5 da ys bef ore first d ose of st u d y 
i nter ve nti o n.
6.
A de q uate he patic f u ncti o n defi ne d: b y  a total bilir u bi n le vel ≤ 1. 5 × u p per li mit of 
n or mal ( U L N), a n as partate a mi n otra nsferase (A S T ) le vel ≤ 3. 0 × U L N, a n d a n 
ala ni ne a mi n otra nsferase ( A L T ) le vel ≤ 3. 0 × U L N
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
8 2 / 1 5 5
o
F or d oc u me nte d Gil bert's S y n dr o me a t otal bilir u bi n < 3 x U L N is acce pte d .
7.
Creati ni ne cleara nce m ust be ≥ 3 0 m L/ mi n b y  calc ulati o n usi n g t he C oc kcr oft- Ga ult 
f or m ula:
8.
Male partici pa nts :
A gree t o t he f oll o wi n g d uri n g t he st u d y i nter ve nti o n peri o d a n d f or at least 9 0 da y s, 
after t he last d ose of st u d y i nter ve nti o n:
Refrai n fr o m d o nati n g s per m
P L U S eit her
a.
A bstai n fr o m i nterc o urse wit h a fe male
or
b.
Use male c o n d o ms
o
W he n ha vi n g se x ual i nterc o urse wit h a w o ma n of c hil d -beari n g p ote ntial 
( W O C B P), w h o is n ot c urre ntl y pre g na nt, a n d a d vise her t o use a hi g hl y 
effecti ve c o ntrace pti ve met h o d wit h a fail ure rate of < 1 % per ye ar, as 
descri be d i n  A p pe n di x 3 , si nce a c o n d o m ma y brea k or lea k.
o
W he n e n ga gi n g i n a n y acti vit y t hat all o ws f or e x p os ure t o ejac ulate. 
9.
Fe male Partici pa nts :
Are n ot pre g na nt or breastfee di n g, a n d at least o ne of t he f oll o wi n g c o n di ti o ns 
a p plies:
N ot a W O C B P
or
If a W O C B P , use a hi g hl y effecti ve c o ntrace pti ve met h o d (i.e., wit h a fail ure rate 
of < 1 % per ye ar), prefera bl y wit h l o w user de pe n de nc y , as descri be d i n
A p pe n di x 3 f or t he f oll o win g ti me peri o ds:
o
Bef ore
t he first d ose of t he st u d y inter ve nti o n(s), if usi n g h or m o nal 
c o ntrace pti o n :
o
Has c o m plete d at least o ne 4- wee k c ycle of a n oral c o ntrace pti o n pill 
a n d eit her ha d or has be g u n her me nses
or
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
8 3 / 1 5 5
Has use d a de p ot c o ntrace pti ve or e xte n de d-c ycle oral c o ntrace pti ve f or least at 
2 8 d a y s a n d has a d oc u me nte d ne gati ve ser u m pre g na nc y  test usi n g a hi g hl y 
se nsiti ve assa y.
o
D uri n g t he i nter ve nti o n peri o d
o
After t he st u d y i nter ve nti o n peri o d f or at least 9 0 d a y s after t he last d ose 
of st u d y inter ve nti o n 
A gree n ot t o d o nate e g gs ( o va, o oc y tes) f or re pr o d ucti o n d uri n g t his peri o d.
T he I n vesti gat or e val uates t he effecti ve ness of t he c o ntrace pti ve met h o d 
i n 
relati o ns hi p t o t he first d ose of st u d y i nter ve nti o n.
Ha ve a ne gati ve ser u m/ uri ne pre g na nc y  test, as re q uire d b y l ocal re g ulati o ns, wit hi n 
2 4 h o urs bef ore t he first d ose of st u d y  i nter ve nti o n.
A d diti o nal re q uire me nts f or pre g na nc y  testi n g d uri n g a n d after st u d y inter ve nti o n 
are i n Secti o n 8. 3. 5 .
T he I n vesti gat or re vie ws t he me dical hist or y , me nstr ual hist or y , a n d rece nt se x ual 
acti vit y t o decrease t he ris k f or i ncl usi o n of a fe male wit h a n earl y un detecte d 
pre g na nc y
1 0. Willi n g ness 
a nd a bilit y to c o m pl y wit h st u d y pr oce d ures i ncl u di n g b o ne marr o w 
bi o ps y  at D a y 1 C y cle 1 a n d at ti me of res p o nse ( Part A a n d Part B ma n dat or y )
1 1. F or partici pa nt s e x perie nci n g t o xicities res ulti n g fr o m pre vi o us t hera py (i ncl u di n g 
peri p heral ne ur o pat h y) , t he t o xicities m ust be res ol ve d or sta bilize d t o ≤ Gra de 1.
P art A 
1 2. Partici pa nt m ust ha ve recei ve d > 3 pri or li nes of t hera p y for M M i ncl u di n g a PI , a n 
I Mi D a n d a n a nti-C D 3 8 m A b a n d ha ve disease pr o gressi o n d uri n g or wit hi n 6 0 da ys 
of c o m pleti n g of t he m ost rece nt re gi me n or w h o are refract or y to a n I Mi D a n d / or 
a PI  age nt acc or di n g t o t he I MW G 
criteria a n d f or w h o m n o effecti ve sta n dar d 
t hera py e xists or w h o d o n o t t olerate a n y of t he sta n dar d treat me nt. Mai nte na nce is 
n ot c o nsi dere d t o be a se parate li ne of t hera p y. 
1 3. Partici pa nt m ust ha ve d oc u me nte d e vi de nce pr o gressi ve disease as defi ne d b y  th e 
I M W G criteria eit her o n or after t heir last re gi me n (Ta ble 1 6 ).
1 4. Partici pa nts m ust ha ve meas ura ble disease of M M as defi n e d a b o ve.
P art B
1 5. Partici pa nt m ust ha ve recei ve d > 3 pri or li nes of t hera p y for M M i ncl u di n g a PI , a n 
I Mi D a n d a n a nti-C D 3 8 m A b a n d ha ve disease pr o gressi o n d uri n g or wit hi n 6 0 da ys 
of c o m pleti n g of t he m ost rece nt re gi me n or w h o are refract or y to a n I Mi D a n d / or 
a PI  age n t acc or di n g t o t he I MW G 
criteria a n d f or w h o m n o effecti ve sta n dar d 
t hera py e xists or w h o d o n ot t olerate a n y of t he sta n dar d treat me nt. Mai nte na nce is 
n ot c o nsi dere d t o be a se parate li ne of t hera p y. 
1 6. Partici pa nt m ust ha ve d oc u me nte d e vi de nce o f pr o gressi ve disease as defi ne d b y t he 
I M W G criteria eit her o n or after t heir last re gi me n (Ta ble 1 6 ).
1 7. Partici pa nts m ust ha ve meas ura ble disease of M M as defi ne d a b o ve.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
8 4 / 1 5 5
5. 2
E xcl usi o n Criteri a
Partici pa nts are e xcl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:
Me dic al
C o n diti o ns
1.
A n y  co n diti o n, i ncl u di n g a n y u nc o ntr olle d disease state t hat i n t he I nvesti gat or’s 
o pi ni o n c o nstit utes a n i na p pr o priate ris k or a c o ntrai n dicati o n f or partici pati o n i n t he 
st u d y or t hat c o ul d i nterfere wit h t he st u d y o bjecti ves, c o n d uct, or e val uati o n.
2.
A n acti ve sec o n d mali g na nc y
or e vi de nce of disease of ca ncer ( ot her t ha n M M ) 
bef ore t he date of e nr oll me nt (e xce pti o ns are s q ua m o us a n d basal cell carci n o mas of 
t he s ki n a n d carci n o ma i n sit u of t he cer vi x, or mali g na nc y t hat i n t he o pi ni o n of t he 
I n vesti gat or, wit h c o nc urre nce wit h t he S p o ns or's M e dical M o nit or, is c o nsi dere d 
c ure d wit h mi ni mal ris k of rec urre nce wit hi n 3 ye ars).
3.
Cere br o vasc ular acci de nt/str o ke ( < 6 m o nt hs 
pri or e nr oll me nt) or ne ur ol o gic 
i nsta bilit y per cli nical e val uati o n d ue t o t u m or i n v ol ve me nt of t he C N S. 
4.
Dia g n osis of fe ver wit hi n 1 wee k pri or t o st u d y i nter ve nti o n a d mi nistrati o n.
5.
U nc o ntr olle d c o nc urre nt ill ness (e. g., seri o us u nc o ntr olle d dia betes [ bl o o d gl uc ose 
> 2 5 0 m g/ d L ], or ps yc hi atric ill ness/s ocial sit uati o ns t hat w o ul d li mit c o m plia nce 
wit h t he st u d y  re q uire me nts).
6.
Acti ve s ym pt o matic f u n gal, bacterial a n d/ or viral i nfecti o n. I n di vi d uals wit h k n o w n 
or ser o p ositi ve testi n g f or h u ma n i m m u n o deficie nc y vir us ( HI V) or acti vel y i nfecte d 
viral he patitis ( B or C) are e xcl u de d. H o we ver, i n di vi d ual wit h He patitis C treate d 
wit h c urati ve t hera p y are n ot c o nsi dere d acti vel y i nfecte d.
7.
P las ma cell le u ke mia ( > 2. 0 × 1 0 9/ L circ ulati n g plas ma cells b y  sta n dar d differe ntial), 
acti ve 
C N S 
M M 
or 
P O E M S 
s yn dr o me 
( p ol yne ur o pat h y , or ga n o me gal y , 
e n d ocri n o pat h y, m o n ocl o nal pr otei n, a n d s ki n c ha n ges) or a m yl oi d osis.
8. I m paire d car diac f u ncti o n
o
Left ve ntric ular ejecti o n fracti o n < 4 5 % defi ne d b y  ec h ocar di o gra p h y (at 
Scree ni n g )
o
Seri o us arr h yt h mia
o
U nsta ble a n gi na pect oris
o
Ne w Y or k Heart Ass ociati o n heart fail ure Class III a n d I V
o
M y ocar dial i nfarcti o n wit hi n t he last 1 2 m o nt hs pri or t o st u d y e ntr y
o
S y m pt o matic pericar dial eff usi o n
9.
P eri p heral ne ur o pat h y of Gra de ≥ 2 wit h pai n
1 0. Acti ve graft vers us h ost disease
1 1. Life e x pecta nc y  of < 4 m o nt hs.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
8 5 / 1 5 5
1 2. C urre nt si g nifica nt car diac c o n d ucti o n a b n or malities, i ncl u di n g c orrecte d Q T i nter val 
( Q Tc) pr ol o n gati o n of > 4 5 0 m s f or males a n d > 4 7 0 ms f or fe males m ust
be 
c o nfir me d o n D a y 1 C y cle 1. 
Pri or/ C o nc o mit a nt T her a p y
1 3. Partici pa nt w h o recei ve d c he m ot hera p y, e xte nsi ve ra diati o n t hera p y (i n v ol vi n g 
≥3 0 % of b o ne marr o w), verte br o plast y , k y p h o plast y  or bi ol o gical t hera p y (e. g.,
a nti b o dies, er yt hr o p oieti n) wit hi n 2 wee ks ( 6 wee ks f or nitr os o urea, mit o m y ci n-C) 
or 5 half -li ves pri or t o d osi n g or w h o ha ve bee n treate d wit h s mall m olec ule 
t hera pe utics or i n vesti gati o nal a ge nts wit hi n 4 wee ks pri or t o starti n g st u d y 
i nter ve nti o n wit h M 3 2 5 8 or w h o ha ve n ot rec o vere d fr o m t he si de effects of s uc h 
t hera py t o Baseli ne or Gra de 1 (e xce pt f or al o pecia or p ote ntiall y ne ur o pat h y).
1 4. H or m o nal 
t hera pies acti n g o n t he h y p ot hala mic -pit uitar y -g o na dal a xis (i.e., 
l utei nizi n g h or m o ne-releasi n g h or m o ne a g o nist/a nta g o nists).
1 5. Ster oi d t hera py f or a nti ne o plastic i nte nt ta ke n < 7 da ys pri or t o t he first d ose of st u d y 
i nter ve nti o n. I ncl u des
partici pa nt s w h o 
ha ve recei ve d a c u m ulati ve d ose of 
c ortic oster oi d greater t ha n or e q ual t o t he e q ui vale nce of 1 4 0 m g  pre d nis o ne or a 
si n gle d ose of c ortic oster oi d greater t ha n or e q ual t o t he e q ui vale nce of 2 0 m g/ da y 
de xa met has o ne wit hi n t he 2- wee k peri o d bef ore first d ose of st u d y  i nter ve nti o n.
1 6. Partici pa nt c urre ntl y recei vi n g ( or u na ble t o st o p usi n g pri or t o recei vi n g t he first 
d ose of st u d y i nter ve nti o n) me dicati o ns k n o w n t o be str o n g i n hi bit ors or i n d ucers of 
C Y P 3 A or a n y her bal s u p ple me nts k n o w n t o i n hi bit or i n d uce C Y P 3 A. C o me dicati o n
a n d her bal s u p ple me nts m ust sto p at least 7 da y s bef ore t he first a d mi nistrati o n of t he 
st u d y i nter ve nti o n (f or details see Secti o n 6. 5. 3 ).
1 7. Partici pa nt c urre ntl y recei vi n g ( or u na ble t o st o p usi n g pri or t o recei vi n g t he first 
d ose of st u d y inter ve nti o n) me dicati o ns or her bal s u p ple me nts k n o w n t o be i n hi bit ors 
of P -g p . C o me dicati o n m ust st o p at least 7 da ys bef ore t he first a d mi nistrati o n of t he 
st u d y i nter ve nti o n (f or details see Secti o n 6. 5. 3 ).
1 8. Partici pa nt c urre ntl y recei vi n g ( or u na ble t o st o p usi n g pri or t o recei vi n g t he first 
d ose of st u d y inter ve nti o n) me dicati o ns k n o w n to pr ol o n g t he Q T/ Q Tc i nter val. 
C o me dicati o n m ust st o p at least 7 d a y s bef ore t he first a d mi nistrati o n of t he st u d y 
i nter ve nti o n (a list of me dicati o n is attac he d i n t he A p pe n di x 4:
Pr o hi bite d 
C o m e dicati o n Pr ol o n gi n g t he Q T/ Q Tc I nter val ).
1 9. Partici pa nt has recei ve d a ut ol o g o us ste m cell tra ns pla nt wit hi n 1 2 wee ks bef ore t he 
first d ose of st u d y inter ve nti o n, or t he partici pa nt has pre vi o usl y recei ve d a n all o ge nic 
ste m cell tra ns pla nt (re gar dless of ti mi n g).
Di a g n ostic Assess me nts
N ot a p plica ble
Ot her E xcl usi o ns
P art B o nl y:
2 0. Partici pa nt s pla n ni n g t o u n der g o a ste m cell tra ns pla nt s h o ul d n ot be e nr olle d t o 
re d uce disease b ur de n pri or t o tra ns pla nt.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
8 6 / 1 5 5
5. 3
Lifest yle C o nsi der ati o ns
5. 3. 1
Me als a n d Diet ar y Restricti o ns
Partici pa nts will
be i nstr ucte d t o refrai n fr o m c o ns u m pti o n of gra pefr uit, gra pefr uit j uice, 
Se ville ora n ges, Se ville ora n ge mar mala de, or ot her pr o d ucts c o ntai ni n g gra pefr uit or Se ville 
ora n ges , St. J o h n’s w ort as well as a n y ot her C Y P 3 A i n hi biti n g/i n d uci n g or P- g p i n hi biti n g 
her bal s u p ple me nts starti n g at least 7 da y s bef ore t he first a d mi nistrati o n of t he st u d y 
i nter ve nti o n a n d d uri n g t he st u d y i nter ve nti o n a d mi nistrati o n.
P art A a n d P art B
Partici pa nts will recei ve st u d y i nter ve nti o n dail y  wit h restricti o n of f o od f or 1 h o ur bef ore a n d 
2 h o urs after d ose a d mi nistrati o n e xce pt f or t he f o o d effect e val uati o n o n Part B Da y  1 C y cle 2.
P art B D a y 1 C ycle 2 – F o o d E ffect E v al u ati o n
D a y  1 Cycl e 2 will be a n e val uati o n of a p ossi ble effect of f o o d o n t he P K. All partici pa nts will 
be all ocate d t o 1 of 2 treat me nt sc he d ule c o h ort s (as l o n g as safety of t he partici pa nt is n ot 
e n da n gere d [i.e., dia betic partici pa nt]). T he first 9 partici pa nts i n P art B will be all ocate d t o 
S c he d ule A (st u d y treat me nt wit h o ut f o o d) a n d s u bse q ue nt 9 partici pa nts will recei ve S c he d ule 
B ( st u d y treat me nt wit h f o o d), u nless t here has bee n a c ha n ge i n d ose. At t he i nteri m a nal ys is, 
t he nee d f or a d diti o nal partici pa nts f or f o o d effect will be deter mi ne d wit h o ut affectin g t he 
o verall n u m ber of partici pa nts i n t he st u d y. The n all ocati o n will be alter nati n g A B A B, etc.
U p o n e nr ol lme nt , t he site will recei ve t he f o o d-sc he d ule assi g n me nt f or t he partici pa nt fr o m 
t he me dical m o nit or or a desi g nee.

Sc he d ule A : all partici pa nts of t his c o h ort will recei ve t he re g ular d ose a n d re gi me n
of M 3 2 5 8 wit h o ut f o o d. T he y  will fast f or 1 0 h o urs (i.e., n o f o o d [e xce pt as n ote d 
bel o w] fr o m mi d ni g ht o n war ds) bef ore a d mi nistrati o n of st u d y inter ve nti o n u ntil at 
least 4 h o urs after d osi n g. 

Sc he d ule B : all partici pa nts of t his c o h ort will recei ve t he re g ular d ose a n d re gi me n
of M 3 2 5 8 wit h f o o d. T he y will recei ve a re g ular brea kfast ; 3 0 mi n utes after start of 
t he brea kfast all partici pa nt s will recei ve a re g ular d ose of M 3 2 5 8.
T he re g ular 
brea kfast 
c o ntai ns 
a p pr o xi matel y 
40 0- 5 0 0 
kcal 
wit h 
fat c o ntri b uti n g 
t o 
a p pr o xi matel y 1 5 0 kcal. M 3 2 5 8 
will be ta ke n wit h 2 0 0 m L  of water. After 
a d mi nistrati o n of st u d y  i nter ve nti o n, t he partici pa nts will fast f or at least 4 h o urs. 
D uri n g t he P K sa m pli n g, partici pa nts wi ll be all o we d t o dri n k water as t he y desire e xce pt 1 
h o ur bef ore a n d after a d mi nistrati o n of st u d y  i nter ve nti o n. 
M 3 2 5 8 will be ta ke n wit h 2 0 0 m L  of water.
5. 3. 2
C affei ne, Alc o h ol, a n d T o b acc o
N o restricti o ns are a p plica ble. 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
8 7 / 1 5 5
5. 3. 3
Acti vit y
Partici pa nts will a bstai n fr o m stre n u o us e xercise f or 4 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. Partici pa nts ma y  partici pate i n li g ht recreati o nal acti vities (e. g., 
watc hi n g tele visi o n or rea di n g).
5. 4
Scree n F ail ures
I n di vi d uals i n Part A w h o d o n ot meet t he he mat ol o gical a n d/ or re nal criteria f or partici pati o n 
i n t his st u d y (scree n fail ure) ma y be rescree ne d o nce. Rescree ne d partici pa nts will be assi g ne d 
a ne w partici pa nt n u m ber. Rescree ni n g d oes n ot a p pl y  t o partici pa nts i nte n de d f or Part B.
6
St u d y I nter ve nti o n(s)
St u d y  inter ve nti o n is a n y i n vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s), place b o, or 
me dical de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y  partici pa nt per t he st u d y pr ot oc ol.
6. 1
St u d y I nter ve nti o n(s) A d mi nistr ati o n
St u d y I nter ve nti o n N a me:
M 3 2 5 8 Pi Cs
D ose F or m ul ati o n:
P o w der i n Ca ps ules ( Pi Cs)
U nit D ose Stre n gt h(s)/
D os a ge Le vel(s):
1 m g, 5 m g, 3 0 m g
R o ute of A d mi nistr ati o n:
Oral
D osi n g I nstr ucti o ns:
See Secti o n  6. 6 ( D ose Selecti o n a n d M o dificati o n).
S u p plier/ M a n uf act urer:
T he S p o ns or will s u p pl y  t he st u d y i nter ve nti o n.
P ac k a gi n g a n d L a beli n g
Pi Cs will be s u p plie d i n 
 pac ks. Eac h
 
pac k will be pac ka ge d a n d la bele d per all a p plica ble 
re g ulat or y re q uire me nts 
a n d 
G o o d 
Ma n ufact uri n g 
Practice G ui deli nes.
I n ad diti o n, c o m merciall y availa ble de xa met has o ne t o be gi ve n at t he re gi me n pr o p ose d i n 
S ecti o n 4. 1 f or oral a d mi nistrati o n will be pr o vi de d l ocally b y  the site as per l ocal a vaila ble 
d osa ge .
6. 1. 1
Me dic al De vice(s) Use
N ot a p plica ble. 
6. 2
St u d y I nter ve nti o n(s) Pre p ar ati o n, H a n dli n g, St or a ge, a n d 
Acc o u nt a bilit y
T he In vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y i nter ve nti o n acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (i.e., 
recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds).

U p o n recei pt of t he st u d y inter ve nti o n(s), t he In vesti gat or or desi g nee m ust c o nfir m 
a p pr o priate te m perat ure c o n diti o ns ha ve bee n mai ntai ne d 
d uri n g tra nsit a n d a n y 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
8 8 / 1 5 5
discre pa ncies are re p orte d a n d res ol ve d bef ore use. Als o, t he res p o nsi ble pers o n will c hec k 
f or acc urate deli ver y  an d ac k n o wle d ge recei pt b y  si gni n g or i nitiali n g a n d dati n g t he 
a p pr o priate d oc u me nt a n d ret ur ni n g it t o t he l ocati o n s pecifie d. A c o p y will be arc hi ve d f or 
t he In vesti gat or Site File.

O nl y  partici pa nts e nr olle d i n t he st u d y 
ma y recei ve st u d y inter ve nti o n(s) a n d o nl y 
a ut h orize d site staff ma y s u p pl y it. All st u d y inter ve nti o n(s) m ust be st ore d i n a sec ure, 
e n vir o n me ntall y-c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area , i n acc or da nce wit h 
t he la bele d st ora ge c o n diti o ns, a n d wit h access li mite d t o t he In vesti gat or a n d a ut h orize d 
site staff.

Dis pe nsi n g will be rec or de d o n t he a p pr o priate acc o u 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 e ac h m o nit ori n g visit.

St u d y  i nter ve nti o n(s) acc o u nta bilit y rec or ds at t he st u d y site will i ncl u de t he f oll o wi n g:
o
C o nfir mati o n of recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m perat ure ra n ge.
o
T he i n ve nt or y  pr o vi de d f or t he cli nical st u d y a n d pre pare d at t he site.
o
T he d ose(s) eac h partici pa nt use d d uri n g t he st u d y.
o
T he dis p ositi o n (i ncl u di n g ret ur n, if a p plica ble) of a n y  u n use d st u d y i nter ve nti o n(s).
o
Dates, q ua ntities, batc h n u m bers, kit n u m bers, e x pir y dates, a n d t he partici pa nt 
n u m bers.

T he I n vesti gat or site will mai ntai n rec or ds, w hic h a de q uatel y d oc u me nts t hat partici pa nts 
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 inter ve nti o n(s) pr o vi de d 
were f ull y  rec o ncile d.

U n use d st u d y inter ve nti o n(s) m ust n ot be discar de d or u se d f or a n y pur p ose ot her t ha n t he 
prese nt st u d y. N o st u d y i nter ve nti o n t hat is dis pe nse d t o a partici pa nt ma y be re-dis pe nse d 
t o a differe nt partici pa nt.

A St u d y  M o nit or will peri o dicall y c ollect t he st u d y i nter ve nti o n(s) acc o u nta bilit y f or ms.

F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y inter ve nti o n(s) 
are pr o vi de d i n t he O perati o ns Ma n ual.
6. 3
Me as ures t o Mi ni mize Bi as: St u d y I nter ve nti o n Assi g n me nt 
a n d Bli n di n g
6. 3. 1
St u d y I nter ve nti o n Assi g n me nt
N ot a p plica ble. 
6. 3. 2
Bli n di n g
N ot a p plica ble. 
6. 3. 3
E mer ge nc y U n bli n di n g
N ot a p plica ble. 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
8 9 / 1 5 5
6. 4
St u d y I nter ve nti o n C o m pli a nce
I n t his st u d y, partici pa nts will recei ve st u d y inter ve nti o n at t he i n vesti gati o nal site o n visit da y s. 
T rai ne d me dical staff will m o nit or a n d/ or perf or m t he o n- site st u d y i nter ve nti o n a d mi nistrati o n. 
Partici pa nts 
will 
be i nstr ucte d b y  the I n vesti gat or/ desi g nee re gar di n g off -site self-
a d mi nistrati o n of M 3 2 5 8, a n d c o m plia nce c hec ks perf or me d at all st u d y visits. T he i nf or mati o n 
of eac h st u d y inter ve nti o n a d mi nistrati o n ( date a n d d ose of st u d y inter ve nti o n ) will be rec or de d 
i n t he partic ipa nt n otes a n d electr o nic C ase R e p ort F or m (e C R F). O n d a y s prece di n g P K ,
sa m pli n g ti me of dr u g i nta ke will als o be rec or de d. T he I n vesti gat or will e ns ure t hat t he 
i nf or mati o n e ntere d i nt o t he e C R F re gar di n g dr u g a d mi nistrati o n is acc urate f or eac h 
partici pa nt. A n y  reas o n f or n o nc o m plia nce s h o ul d be d oc u me nte d . I n the sit uati o n w here
partici pa nts disc o nti n ue st u d y inter ve nti o n f or m ore t ha n 5 d a y s per c ycle, or if ≥ 6 c o nsec uti ve 
pla n ne d d oses of M 3 2 5 8 are misse d f or reas o ns ot her t ha n t o xicit y unless, u p o n c o ns ultati o n 
wit h t he S p o ns or a n d t he re vie w of safet y  an d efficac y, c o n ti n uati o n is a gree d u p o n ( Secti o ns 
7. 1 a n d 8. 4 ).
6. 5
C o nc o mit a nt T her a p y
Rec or d i n t he e C R F all c o nc o mita nt t hera pies ( e. g., me dici nes or n o n dr u g i nter ve nti o ns) use d 
fr o m t he ti me t he partici pa nt si g ns t he i nf or me d c o nse nt u ntil c o m pleti o n of t he st u d y, 
i ncl u di n g a n y c ha n ges. F or prescri pti o n a n d o ver -t he-c o u nter me dici nes, vacci nes, vita mi ns, 
a n d her bal s u p ple me nts, rec or d t he na me, reas o n f or use, dates a d mi nistere d, a n d d osi n g 
i nf or mati o n.
C o ntact t he Me dical M o nit or f or a n y q uesti o ns o n c o nc o mita nt or pri or t hera p y.
Partici pa nts m ust a bstai n fro m ta ki n g prescri pti o n or n o n prescri pti o n dr u gs (i ncl u di n g vita mi ns 
a n d dietar y  or her bal s u p ple me nts) wit hi n 7 d a y s (als o f or p ote ntial e nz yme i n d ucers) or 5 half -
li ves ( w hic he ver is l o n ger) bef ore t he start of st u d y inter ve nti o n u ntil c o m pleti o n of t he st u d y 
i nter ve nti o n a d mi nistrati o n , u nless, i n t he o pi ni o n of t he I nvesti gat or a n d S p o ns or, t he 
me dicati o n will n ot i nterfere wit h t he st u d y (see Secti o n 6. 5. 2 f or per mitte d me dici nes; Secti o n 
6. 5. 3 f or pr o hi bite d me dici nes) . 
A nti viral pr o p h y la xis f or Her pes z oster (e. g., ac ycl o vir, valac ycl o vir) is per mitte d.
A ntie metic a n d a nti diarr heal me dicati o ns ma y  be re q uire d a n d will be a d mi nistere d acc or di n g 
t o i nstit uti o nal g ui deli nes. A mi ni mal oral h y drati o n of 2 liters/ da y  is rec o m me n de d f or
pa rtici pa nts t o pre ve nt de h ydrati o n a n d h y per visc osit y .
Paraceta m ol/ aceta mi n o p he n , at d oses of ≤ 2 gra ms/ 2 4 h o urs, is per mitte d f or use a n y ti me 
d uri n g t he st u dy;  Ot her c o nc o mita nt me dicati o n ma y be c o nsi dere d o n a case-b y -case basis b y 
t he In vesti gat or i n c o ns ultati o n wit h t he Me dical M o nit or if re q uire d.
6. 5. 1
Resc ue Me dic i ne
N ot a p plica ble. 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
9 0 / 1 5 5
6. 5. 2
Per mitte d Me dici nes
A n y  me dici nes t hat are c o nsi dere d necessar y  to pr otect t he partici pa nt’s welfare i n e mer ge ncies
ma y  be gi ve n at t he I n vesti gat or’s discreti o n , re gar dless if it res ults i n a pr ot oc ol de viati o n. All 
per mitte d dr u gs ne e d t o be e ntere d i n t he e C R F.
Sta n dar d s u p p orti ve care f or M M s uc h as tra nsf usi o ns, i ntra ve n o us I g, p ne u m o nia pr o p h y la xis, 
fl u a n d p ne u m o nia vacci nes are all o we d d uri n g treat me nt. H o we ver, 
treat me nt wit h 
tra nsf usi o ns or gr o wt h fact ors (e. g., gra n ul oc y t e-c ol o n y sti m ulati n g fact or [ G-C S F], 
er yt hr o p o ieti n) is n ot per mitte d d uri n g t he D L T peri o d. 
Bis p h os p h o nates s h o ul d be c o nsi dere d i n all partici pa nt s wit h m y el o ma -relate d b o ne disease. 
I ntra ve n o us z ole dr o nic aci d or pa mi dr o nate are t he rec o m me nde d bis p h os p h o nates ca n be use d 
at t he I nvesti gat or ’s discreti o n. N o nster oi dal a nti-i nfla m mat or y dr u gs (N S AI Ds , i ncl u di n g 
as piri n/acet yl salic ylic aci d) use is n ot pr o hi bite d; alt h o u g h t heir use is ge nerall y disc o ura ge d 
i n t he setti n g of acti ve re nal disease.
6. 5. 3
Pr o hi bite d Me dici nes
A d diti o nal de xa met has o ne wit h t he i nte nti o n t o treat t he u n derl yi n g disease.
Str o n g C Y P 3 A i n hi bit ors/i n d ucers m ust st o p at least 7 d a y s bef ore t he first a d mi nistrati o n of 
t he st u d y inter ve nti o n a n d d uri n g t he st u d y inter ve nti o n a d mi nistrati o n (i.e., clarit hr o m yci n, 
itrac o naz ole, ket oc o naz ole, 
nefaz o d o ne, 
nelfi na vir, 
rit o na vir
b oce pre vir, 
c o bicistat, 
c o ni va pta n, da n o pre vir a n d rit o na vir, el vite gra vir a n d rit o na vir, i n di na vir a n d rit o na vir, 
l o pi na vir a n d rit o na vir, parita pre vir a nd rit o na vir a n d ( o m bitas vir a n d/ or dasa b u vir), 
p osac o naz ole, rit o na vir, sa q ui na vir a n d rit o na vir, tela pre vir, ti pra na vir a n d rit o na vir, 
tr olea n d o m yci n, v oric o naz ole, diltiaze m, i delalisi b, as well as car ba maze pi ne, e nzal uta mi de, 
mit ota ne, p he n yt oi n, rifa m pi n. F or f urt her details a n d u p date refer t o t he F o o d a n d Dr u g 
A d mi nistrati o n Dr u g De vel o p me nt a n d Dr u g I nteracti o ns we bsite a n d t he Dr u g I nteracti o ns 
Ta ble ™ we bsite. 
All her bal s u p ple me nts k n o w n t o i n hi bit o r i n d uce C Y P 3 A are pr o hi bite d. Partici pa nt s will be 
i nstr ucte d t o a v oi d a n y i nta ke of gra pefr uit, gra pefr uit j uice, Se ville ora n ges, Se ville ora n ge 
mar mala de, or ot her pr o d ucts c o ntai ni n g gra pefr uit or Se ville ora n ges , St. J o h n’s w ort as well 
as a n y ot her C Y P 3 A i n hi biti n g or i n d uci n g her bal s u p ple me nts starti n g at least 7 d a y s bef ore 
t he first a d mi nistrati o n of t he st u d y inter ve nti o n
a n d d uri n g t he st u d y inter ve nti o n
a d mi nistrati o n.
A n y  P-g p i n hi bit ors (i ncl u di n g her bal s u p ple me nts) m ust st o p at least 7 da y s bef ore t he first 
a d mi nistrati o n of t he st u d y inter ve nti o n a n d d uri n g t he st u d y i nter ve nti o n a d mi nistrati o n (i.e.,
a mi o dar o ne, car ve dil ol, clarit hr o m yci n, dr o ne dar o ne, itrac o naz ole, la pati ni b, l o pi na vir a n d 
rit o na vir, pr o pafe n o ne, q ui ni di ne, ra n olazi ne, rit o na vir, sa q ui na vir a n d rit o na vir, tela pre vir, 
ti pra na vir a n d rit o na vir, vera pa mil). F or f urt her details a n d u p date refer t o t he F o o d a n d Dr u g 
A d mi nistrati o n Dr u g De vel o p me nt a n d Dr u g I nteracti o ns we bsite a n d t he Dr u g I nteracti o ns 
Ta ble ™ we bsite.
Me dicati o ns k n o w n t o pr ol o n g t he Q T/ Q Tc i nter val m ust st o p at least 7 da y s bef ore t he first 
a d mi nistrati o n of t he st u d y inter ve nti o n a n d are n ot all o we d d uri n g t he st u d y inter ve nti o n 
a d mi nistrati o n . Alist of me dicati o n is attac he d i n t he A p pe n di x 4 , for f urt her details a n d u p date 
refer t o we bsite at w w w.cre di ble me ds. or g.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
9 1 / 1 5 5
6. 5. 4
Ot her I nter ve nti o ns
N ot a p plica ble. 
6. 6
D ose Selecti o n a n d M o dific ati o n
D ose escalati o n will pr ocee d acc or di n g t o t he S M C rec o m me n dati o n u ntil t he 5 0 m g d ose le vel 
or t he M T D is reac he d ( w hic he ver is l o wer). F or f urt her d ose c o h orts, a S M C will meet a n d 
re vie w all a vaila ble data t o pr o vi de rec o m me n dati o ns o n t he ne xt d ose le vel. I n case escalati o n 
s h o ul d pr ocee d t o d oses hi g her t ha n 5 0 m g, a pr ot oc ol a me n d me nt will be s u b mitte d. Details 
are descri be d i n t he S M C c harter. T he S M C recei ves o ut p uts of a Ba yesia n d ose -t o xicit y mo del 
esti mate d D L T pr o ba bilities f or p ote ntial ne xt d ose le vels. T he Ba yesia n m o del will be base d 
o n pri or , o bser ve d n u m ber of e val ua ble partici pa nt s a n d n u m ber of partici pa nt s wit h D L T. 
F urt her details o n t he Ba yesia n m o del are pr o vi de d i n Secti o n  9. 4. 2. F urt her details o n t he S M C 
are pr o vi de d i n Secti o n 1 0.
A D L T is defi ne d as a n y of t he A Es liste d bel o w as assesse d b y  the I n vesti gat or a n d/ or t he 
S p o ns or at a n y d ose a n d re gi me n , a n d j u d ge d n ot t o be relate d t o t he u n derl yi n g disease or a n y 
pre vi o us or c o nc o mita nt me dicati o n
or c o nc urre nt c o n diti o n occ urri n g d uri n g t he D L T 
o bser vati o n peri o d (first treat me nt c ycle), acc or di n g t o t he N CI -C T C A E v 5. 0 .  A n y  DL T m ust
be c o nfir me d b y t he S M C. 
D uri n g t he D L T assess me nt peri o d : Tre a t me nt wit h tr a nsf usi o ns or gr o wt h f act ors (e. g., G-
C S F, er yt hr o p o ieti n) is n ot per mitte d. Tr a nsf usi o ns are o nl y per mitte d if cle arl y rel ate d 
t o m ulti ple m yel o m a.
Partici pa nts w h o de vel o p a D L T will per ma ne ntl y  disc o nti n ue treat me nt. 
Partici pa nts w h o di d n ot recei ve ≥ 8 0 % of t he pla n ne d c u m ulati ve d ose or misse d m ore t ha n 
2 0 % of d os es i n t he D L T peri o d will n ot be c o nsi dere d i n t he D L T a nal ysis set u nless t he y 
e x perie nce d a D L T.
A Es j u d ge d as D L T will i ncl u de:

A n y  Gra de ≥ 3 n o n he m at ol o gic A E wit h e xce pti o n of: 
o
Si n gle la b orat or y val ues o ut of a b n or mal ra n ge t hat ha ve n o cli nical c orrelate, a n d res ol ve 
t o Gra de ≤ 1 or t o Baseli ne wit hi n 7 da y s wit h a de q uate me dical ma na ge me nt
o
Gra de 3 diarr hea persisti n g ≤ 7 2 h o urs after i nitiati o n of me dical ma na ge me nt 
o
Na us ea a n d v o miti n g of ≤ 7 2 h d urati o n wit h a de q uate a n d o pti mal t hera p y
o
Tra nsie nt ( < 1 wee k ) Gra de 3 fati g ue, l ocal reacti o ns, fl u-li ke s ym pt o ms, f or fe ver, a n d 
hea dac he (≤ 7 2 h) t hat res ol ves t o Gra de ≤ 1 wit h a de q uate treat me nt 
o
Gra de 3 n o nrec urre nt s ki n t o xicit y t hat res ol ves t o Gra de ≤ 1 i n less t ha n 7 da y s after 
i nitiati o n of me dical ma na ge me nt
o
As y m pt o matic Gra de
≥ 3 li pase or a m yl ase ele vati o n n ot ass ociate d wit h cli nical 
ma nifestati o ns of pa ncreatitis .

H y ’s la w: E vi de nce of he pat ocell ular t o xicit y with o ut clear alter nati ve reas o n t o e x plai n t he 
o bser ve d li ver-relate d la b orat or y ab n or malities, s uc h as i ncrease i n A S T or A L T of ≥ 3 x 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
9 2 / 1 5 5
U L N ele vati o n a n d ele vati o n of ser u m t otal bilir u bi n ≥ 2 x U L N, wit h o ut i nitial fi n di n gs of 
c h olestasis (ele vate d ser u m A L P) or ot her a p pare nt cli nical ca usalit y (e g viral he patitis A, 
B, C or c o -me dicati o n)

A n y  deat h n ot clearl y d ue t o t he u n derl yi n g disease or e xtra ne o us ca uses

A n y  Gra de ≥ 4 he m at ol o gic A E, a n d: 
o
Gra de ≥3 fe brile ne utr o pe nia wit h A N C < 1 0 0 0/ m m 3 a n d a si n gle te m perat ure of > 3 8. 3 ° C 
( 1 0 1° F) or a s ustai ne d te m perat ure of ≥ 3 8° C ( 1 0 0. 4° F) f or m ore t ha n 1 h
o
Gra de ≥ 3 t hr o m b oc y t o pe nia wit h me dically c o ncer ni n g blee di n g
o
Gra de 4 t hr o m b oc y t o pe nia lasti n g > 7 da ys, or platelets < 1 0 ,0 0 0/ m m 3 at a n y ti me
E xce pt :

Is olate d Gra de 4 l y m p h o pe nia wit h o ut cli nical c orrelate 

A n y  Gra de 4 ne utr o pe nia of < 7 da y s d urati o n n ot ass ociate d wit h a n y cli nical 
s ym pt o ms .

Ne ur o pat hic Pai n or Peri p heral Se ns or y  or M ot or Ne ur o pat hy:
o
A n y  ag gra vati o n b y  2 gra des or a n y Gra de
≥3 (se vere s ym pt o ms: li miti n g self-care 
Acti vit y  of Dail y Life [A D L ]).

A n y  TE A E t he S M C dee ms cli nicall y  rele va nt, t hat i m pairs dail y  fu ncti o n or a b n or malit y 
occ urri n g i n partici pa nts treate d wit h M 3 2 5 8 -/ + c o m bi nati o n wit h de xa met has o ne at a n y 
ti me i n C ycle 1 a n d a n y t o xicit y  at a ny ti me i n C ycle 1

A st u d y inter ve nti o n -relate d T E A E ( o bser ve d i n s u bse q ue nt c ycles) t hat i n t he o pi ni o n of 
t he S M C is of p ote ntial cli nical si g nifica nce s uc h t hat f urt her d ose escalati o n w o ul d e x p ose 
partici pa nts t o u nacce pta ble ris k.
A n y  D L T will be c o nfir me d b y t he S M C.
Ta ble 1 1 descri bes t he rec o m me n de d i n di vi d ual d ose m o dificati o ns relate d t o M 3 2 5 8 -relate d 
n e ur o pat hic p ai n or p eri p heral se ns or y or m ot or n e ur o pat h y w he n e x perie nce d b y partici pa nts 
o utsi de of D L T p eri o d. Ta ble 1 2 descri bes t he i n di vi d ual d ose m o dificati o ns a n d te m p orar y or 
per ma ne nt treat me nt disc o nti n uati o ns f or M 3 2 5 8 -relate d he mat ol o gic t o xicities w he n 
e x perie nce d b y  partici pa nts o utsi de of D L T peri o d. Ta ble 1 3 descri bes t he i n di vi d ual 
rec o m me n de d te m p orar y treat me nt disc o nti n uati o ns f or M 3 2 5 8 -relate d ge neral t o xicities w he n 
e x perie nce d b y partici pa nts o utsi de of D L T peri o d. 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
9 3 / 1 5 5
T a ble 1 1
Rec o m me n de d D ose M o dific ati o n 
f or N e w O nset or W orse ni n g 
Ne ur o p at hic P ai n a n d/ or Peri p her al Se ns or y or M ot or Ne ur o p at h y 
( o utsi de of D L T Peri o d)
S e v erit y of P eri p h er al N e ur o p at h y  Si g n s a n d 
S y m pt o m s 
a
M o difi c ati o n of D o s e a n d R e gi m e n
Gr a d e 1 ( a s y m pt o m ati c: l o s s of d e e p t e n d o n 
r efl e x e s or p ar e st h e si a) wit h o ut p ai n or l o s s of 
f u n cti o n
N o a cti o n
Gr a d e 1 wit h p ai n or Gr a d e 2 ( m o d er at e 
s y m pt o m s: li miti n g i n str u m e nt al A D L b )
R e d u c e M 3 2 5 8 d o s e b y o n e d o s e l e v el ( b a s e d o n 
d o s e e s c al ati o n p art) or at l e a st b y 5 0 % if n o l o w er 
d o s e l e v el i s a v ail a bl e
Gr a d e 2 wit h p ai n or Gr a d e 3 ( s e v er e s y m pt o m s: 
li miti n g s elf-c ar e A D L c)
Wi t h h ol d M 3 2 5 8 t h er a p y u ntil t o xi cit y r e s ol v e s t o 
B a s eli n e or Gr a d e 1 wit h o ut p ai n , t h e n r ei niti at e 
wit h a r e d u c e d d o s e of M 3 2 5 8 b y o n e d o s e l e v el
( b a s e d o n d o s e e s c al ati o n p art) or at l e a st b y 5 0 % 
if n o l o w er d o s e l e v el i s a v ail a bl e
If r e c urr e n c e t o G r a d e 2 wit h p ai n or hi g h er, 
p er m a n e ntl y di s c o nti n u e M 3 2 5 8.
Gr a d e 4 (lif e -t hr e at e ni n g c o n s e q u e n c e s: ur g e nt 
i nt er v e nti o n i n di c at e d)
P er m a n e ntl y d i s c o nti n u e M 3 2 5 8.
A D L = Acti vities of dail y li vi n g; D L T = D ose -li miti n g t o xicit y; N CI = Nati o nal Ca ncer I nstit ute. 
a  
Gra di n g base d o n N CI C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) v 5. 0.
b
I nstr u me ntal A D L: refers t o pre pari n g me als, s h o p pi n g f or gr oceries or cl ot hes, usi n g tele p h o ne, ma na gi n g m o ne y etc.
c
Self -care A D L: refers t o bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he t oilet, ta ki n g me d icati o ns, a n d n ot  
be dri d de n.
T a ble 1 2
D ose 
M o dific ati o ns 
a n d 
Te m p or ar y /Per m a ne nt 
Tre at me nt 
Disc o nti n u ati o n f or He m at ol o gic T o xicit y ( o utsi de of D L T Peri o d)
H e m at ol o gi c T o xi cit y
D o s e M o difi c ati o n
N e utr o p e ni a Gr a d e 3 ( wit h o ut c o m pli c ati o n s)
N o d o s e r e d u cti o n , c o n si d er tr e at m e nt wit h G -C S F
Gr a d e 3 N e utr o p e ni a a s s o ci at e d wit h f e v er ( ≥3 8. 5 ° C)
or n e utr o p e ni a Gr a d e 4
H ol d M 3 2 5 8 u ntil r e c o v er y t o B a s eli n e O R ≤ Gr a d e 2. 
U p o n r e c o v er y, r e st art M 3 2 5 8 at c urr e nt d o s e a n d 
c o n si d er G -C S F s u p p ort. 
If r e c urr e n c e i s s e e n, r e d u c e M 3 2 5 8 b y o n e d o s e l e v el 
( b a s e d o n d o s e e s c al ati o n p art) or at l e a st b y 5 0 % if n o 
l o w er d o s e l e v el i s a v ail a bl e. 
If s e c o n d o c c urr e n c e, p er m a n e ntl y di s c o nti n u e d o si n g
T hr o m b o c yt o p e ni a Gr a d e 3 ( wit h o ut c o m pli c ati o n s)
N o d o s e r e d u cti o n r e q uir e d
Pl at el et c o u nt < 2 5, 0 0 0 / μ L (i . e., Gr a d e 4) or Gr a d e 3 
t hr o m b o c yt o p e ni a wit h bl e e di n g
H ol d M 3 2 5 8 
u ntil r e c o v er y t o B a s eli n e
Or 
≤ Gr a d e 2. 
U p o n r e c o v er y, r e st art at a d o s e w hi c h i s o n e d o s e l e v el 
l o w er ( b a s e d o n d o s e e s c al ati o n p art) or at l e a st b y 5 0 % 
if n o l o w er d o s e l e v el i s a v ail a bl e.
D L T = D ose li miti n g t o xicit y; G-C S F = gra n ul oc yte - c ol o n y sti m ulati n g fact or.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
9 4 / 1 5 5
T a ble 1 3
Rec o m me n de d Te m p or ar y Tre at me nt Disc o nti n u ati o n f or G e ner al 
T o xicit y ( o utsi de of D L T Peri o d)
Or g a n i n v ol v e d
S p e cifi c s
T o xi cit y  
N CI -C T C A E 
5. 0 Gr a d e
M a n a g e m e nt of T o xi cit y  wit h p er m a n e nt 
Di s c o nti n u ati o n or D o s e I nt err u pti o n a n d 
M o difi c ati o n
R e n al
Cr e ati ni n e 
i n cr e a s e d 
Gr a d e 3
H ol d t h e M 3 2 5 8 u ntil r e c o v er y t o Gr a d e ≤ 1 or 
B a s eli n e . 
U p o n r e c o v er y or r et ur ni n g t o b a s eli n e, d o si n g m a y 
c o nti n u e at s a m e or l o w er l e v el b a s e d o n cli ni c al 
j u d g m e nt.
H e p ati c
I n cr e a s e d A S T 
/ A L T
Gr a d e 3
I s ol at e d o c c urr e n c e; r e p e at t e st wit hi n 7 2 h o ur s; 
p er si st e nt or w or s e ni n g, m a y h ol d off t h e M 3 2 5 8 u ntil 
r e c o v er y t o Gr a d e ≤ 1 or B a s eli n e , b a s e d o n 
I n v e sti g at or’ s cli ni c al j u d g e m e nt.
I n cr e a s e d t ot al 
bilir u bi n
Gr a d e 2 +
I s ol at e d o c c urr e n c e; r e p e at t e st wit hi n 7 2 h o ur s; 
p er si st e nt or w or s e ni n g, m a y h ol d off t h e M 3 2 5 8 u ntil 
r e c o v er y t o Gr a d e ≤ 1 or B a s eli n e , b a s e d o n 
I n v e sti g at or’ s cli ni c al j u d g e m e nt.
Ot h er 
n o n h e m at ol o gi c al 
t o xi citi e s
i. e., di arr h e a, 
v o miti n g; GI 
h e m orr h a g e
Gr a d e 2 +
Wi t h h ol d M 3 2 5 8 a d mi ni str ati o n u ntil r e c o v er y t o 
Gr a d e ≤1; or t o B a s eli n e .
s y m pt o m ati c tr e at m e nt i n a c c or d a n c e t o st a n d ar d 
m e di c al pr a cti c e 
Ot h er 
Gr a d e 3 +
H ol d M 3 2 5 8 b a s e d o n I n v e sti g at or ’s cli ni c al 
j u d g e m e nt.
A L T = Al a ni ne a mi n otra nsferase ; A S T = As partate a mi n otra nsferase; D L T = D ose -li miti n g t o xicit y; G-C S F = gra n ul oc yte -
c ol o n y sti m ulati n g fact or; GI = Gastr oi ntesti nal .
D ose re d ucti o n of M 3 2 5 8 f or safet y  an d t olera bilit y  reas o ns b y  o ne d ose le vel ( base d o n d ose 
escalati o n part) or at least b y  50 % if n o l o wer d ose le vel is a vaila ble or deci de d b y  SM C
is 
per mitte d f or i n di vi d ual st u d y  partici pa nt at a n y ti me d uri n g t he st u d y i nter ve nti o n, e xce pt f or 
partici pa nts i n t he first c o h ort. M 3 2 5 8
d ose escalati o n s h o ul d n ot be c o nsi dere d f or a n 
i n di vi d ual partici pa nt o nce d ose m o dificati o n has bee n a p plie d f or safety or t olera bilit y reas o ns.
If M 3 2 5 8 d osi n g were wit h hel d f or m ore t ha n 2 wee ks f or sc he d ule d d ose f or a n y reas o n, 
partici pa nt s h o ul d di sc o nti n ue t he st u d y inter ve nti o n per ma ne ntl y. T he st u d y partici pa nt s h o ul d 
c o m plete E n d- of-Treat me nt visit a n d t he n s h o ul d c o m plete t he re mi n der of t he st u d y peri o d as 
F oll o w - U p peri o d per t he S o A (Ta ble 1 a n d Ta ble 2 f or Part A;  Ta ble 3 a n d Ta ble 4 f or Part 
B) . 
D ose m o dificati o n 
or deferral
s h o ul d al wa ys be disc usse d wit h
t he S p o ns or
Me dical 
Res p o nsi ble .
De x a met h as o ne
De xa met has o ne ma y  be d ose re d uce d acc or di n g t o Ta ble 1 4 A a n d Ta ble 1 4 B or i nstit uti o nal 
g ui deli nes , if a p plica ble , f or t o xicities assesse d as strictl y relate d t o de xa met has o ne. I n t h ose 
cases, w here t he t o xicit y ca n n ot be attri b ute d t o de xa met has o ne, t he d ose of M 3 25 8 s h o ul d be 
re d uce d first (see S ecti o n 6. 9. 1) .
D ose m o dificati o n 
or deferral s h o ul d al wa ys be disc usse d wit h
t he S p o ns or
Me dical 
Res p o nsi ble.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
9 5 / 1 5 5
T a ble 1 4 A
Rec o m me n de d 
D ose 
M o dific ati o n 
( Del a ys, 
R e d ucti o ns 
a n d 
D isc o nti n u ati o ns) d ue t o D e x a met h as o ne-rel ate d A d verse E ve nts 
( Outsi de t he D L T P eri o d)
M o difie d fr o m  Pal u m b o a n d Ga y, 2 0 0 9
Or g a n i n v ol v e d
S p e cifi c s
T o xi cit y
N CI -C T C A E 
v 5. 0 Gr a d e
M a n a g e m e nt of T o xi cit y  wit h p er m a n e nt 
Di s c o nti n u ati o n or D o s e I nt err u pti o n a n d 
M o difi c ati o n
A c ut e p a n cr e atiti s
P er m a n e ntl y di s c o nti n u e d e x a m et h a s o n e.
G a str oi nt e sti n al
D y s p e p si a, 
g a stri c, or 
d u o d e n al ul c er,
G a striti s 
(r e q uiri n g 
m e di c al 
m a n a g e m e nt)
Gr a d e 1 - 2
I n stit ut e pr ot o n p u m p i n hi bit or . 
If s y m pt o m s p er si st or w or s e n d e s pit e m e a s ur e s, r e d u c e 
d e x a m et h a s o n e b y 5 0 % ( e g., 2 0 m g p er w e e k t o 1 0 m g
p er w e e k ).
R e q uiri n g 
h o s pit ali z ati o n or 
s ur g er y
Gr a d e ≥ 3
H ol d 
d e x a m et h a s o n e 
u ntil 
s y m pt o m s 
a d e q u at el y 
c o ntr oll e d. R e st art a n d r e d u c e d e x a m et h a s o n e b y 5 0 % 
fr o m i niti al d o s e al o n g wit h t h e u s e of pr ot o n p u m p 
i n hi bit or s. 
M et a b oli c
H y p er gl y c e mi a 
Gr a d e ≥ 2
Gr a d e ≥ 3
Di et c o ntr ol a n d m o nit or cl o s el y.
Tr e at wit h i n s uli n or or al h y p o gl y c e mi c s a s n e e d e d. 
If u n c o ntr oll e d 
d e s pit e 
t h e s e m e a s ur e s, 
r e d u c e 
d e x a m et h a s o n e b y 5 0 % fr o m i niti al d o s e. 
C ar di o v a s c ul ar
E d e m a (li miti n g 
f u n cti o n a n d 
u nr e s p o n si v e t o 
t h er a p y or 
a n a s ar c a)
Gr a d e > 2  
Di ur eti c s a s n e e d e d a n d d o s e r e d u cti o n b y 5 0 % s h o ul d 
b e 
c o n si d er e d . If e d e m a 
p er si st s 
d e s pit e 
t h e s e 
m e a s ur e s, c o n si d er r e d u ci n g d e x a m et h a s o n e d o s e fr o m 
1 0 m g t o 5
m g .
M o nit or cl o s el y ( w e e kl y w ei g ht, r e stri ct
h y dr ati o n).
M u s c ul o s k el et a l
M u s cl e 
w e a k n e s s 
(i nt erf eri n g wit h 
f u n cti o n 
a n d/ or 
i nt erf eri n g 
wit h 
a cti viti e s of d ail y 
li vi n g)
Gr a d e > 2
R e d u c e d e x a m et h a s o n e b y 5 0 % . 
I n c a s e of n o i m pr o v e m e nt or w or s e ni n g, f urt h er ( 5 0 %) 
d o s e r e d u cti o n i s r e c o m m e n d e d.  If w e a k n e s s p er si st s 
d e s pit e 
t h e s e m e a s ur e s, 
p er m a n e ntl y 
di s c o nti n u e 
d e x a m et h a s o n e.
N e ur ol o gi c al
C o nf u si o n or 
m o o d alt er ati o n 
Gr a d e > 2
H ol d d e x a m et h a s o n e u ntil s y m pt o m s r e s ol v e. R e st art 
a n d r e d u c e d e x a m et h a s o n e b y 5 0 % . U p o n w or s e ni n g or 
n o i m pr o v e m e nt, c o n si d er f urt h er r e d u cti o n of d o s e t o 5
m g . 
P er m a n e ntl y 
di s c o nti n u e 
d e x a m et h a s o n e 
if 
s y m pt o m s r e c ur. 
C o n stit uti o n al
I n s o m ni a
Gr a d e ≥ 2
A d vi s e
d e x a m et h a s o n e a d mi ni str ati o n i n t h e m or ni n g 
o nl y.
If s y m pt o m s p er si st, r e d u c e t h e d o s e b y 5 0 % ( e g., 2 0 m g 
t o 1 0 m g
t o 5 m g ).
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
9 6 / 1 5 5
T a ble 1 4 B  
Rec o m me n de d D ose Re d ucti o n f or De x a met h as o ne
Fir st D o s e R e d u cti o n
S e c o n d D o s e R e d u cti o n
T hir d D o s e R e d u cti o n
R e d u c e d e x a m et h a s o n e b y 5 0 % fr o m 
st arti n g d o s e
Gi v e d e x a m et h a s o n e o nl y o n D a y 
8, 1 5, 2 1
Di s c o nti n u e d e x a m et h a s o n e
Refer t o  Pal u m b o a n d Ga y, 2 0 0 9.
P art B
I n t he e x pa nsi o n c o h orts, t he S M C will als o m o nit or t he safety of t he partici pa nts treate d wit h 
M 3 2 5 8 at R D E i n c o m bi nati o n wit h 2 0 m g / da y de xa met has o ne a n d will meet after 3 , 6, a n d 
s u bse q ue ntl y ever y  6 partici pa nts ha ve fi nis he d t he D L T peri o d or d isc o nti n ue d, u nless a 
c ha n ge i n d osi n g has occ urre d. I n case d osi n g i n t he e x pa nsi o n c o h ort was c ha n ge d, t he ne xt 
S M C will be hel d after 3 partici pa nts ha ve fi nis he d t he D L T peri o d or d isc o nti n ue d. T hereafter 
t he S M C will e val uate t he safety after e ver y 6 partici pa nts (see S ecti o n 1 0) . T he S M C ca n 
rec o m me n d c o nti n ui n g e nr oll me nt at t he R D E, c ha n gi n g t he d ose, or st o ppi n g t he e x pa nsi o n
part of t he st u d y. T he S M C decisi o ns i n t he e x pa nsi o n p hase will als o be s u p p orte d b y  Ba yesia n 
m o deli n g . St u d y  I nter ve nti o n after t he 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 ad diti o nal care t o partici pa nts after t he y lea ve t he st u d y 
beca use s uc h care w o ul d n ot differ fr o m w hat is n or mall y e x pecte d f or partici pa nt s wit h M M.
P art A a n d B
If a partici pa nt receives M 3 2 5 8 Q D a n d misses ta ki n g a sc he d ule d d ose of M 3 2 5 8, t he n wit hi n 
a wi n d o w of 1 2 h o urs it is acce pta ble t o re place t he misse d d ose. If i n t he Q D d osi n g re gi me n 
t he wi n d o w is m ore t ha n 1 2 h o urs after t he sc he d ule d d ose ti me, t he n t he misse d d ose s h o ul d 
n ot be ta ke n, a n d partici pa nts s h o ul d be i nstr ucte d t o ta ke t he ne xt sc he d ule d d ose.
If a partici pa nt recei ves M 3 2 5 8 t wice-per -wee k a n d misses ta ki n g a sc he d ule d d ose wit hi n a 
wi n d o w of 2 4 h o urs, t he n it is acce pta ble t o re place t he misse d d ose.   F or t he t wice-per -wee k 
d osi n g re gi me ns i n case of a dela y  of the sc he d ule d d ose , t he misse d d ose s h o ul d be ta ke n as 
s o o n as p ossi ble, b ut at least t w o da ys ( mi ni m u m 3 6 h) bef ore t he ne xt sc he d ule d d ose.
If a partici pa nt v o mits after ta ki n g M 3 2 5 8, t he partici pa nt s h o ul d n ot re peat t he d ose, b ut 
res u me d osi n g at t he ti me of t he ne xt sc he d ule d d ose.
6. 7
St u d y I nter ve nti o n at t he E n d of t he St u d y
N ot a p plica ble .
6. 8
S peci al Prec a uti o ns
M o nit ori n g of ne ur o pat hic pai n a n d/ or peri p heral se ns or y or m ot or ne ur o pat h y  b e y o n d D L T 
peri o d i n escalati o n p hase a n d c o nti n u o usl y  i n e x pa nsi o n p hase.
6. 9
M a n a ge me nt of A d verse E ve nts of S peci al I nterest
A n A E SI (seri o us or n o nseri o us reacti o n) is o ne of t he scie ntific a n d me dical c o ncer n s pecific 
t o t he st u d y inter ve nti o n , f or w hic h o n g oi n g m o n it ori n g a n d ra pi d c o m m u nicati o n b y  the 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
9 7 / 1 5 5
I n vesti gat or t o t he S p o ns or will be e nc o ura ge d. S uc h e ve nts of i nterest ma y  re q uire f urt her 
i n vesti gati o n or i n-de pt h e val uati o ns t o better c haracterize a n d u n dersta n d t he ass ociati o n 
bet wee n t he a d verse e ve nt a n d M 3 2 5 8. Base d o n n o n cli nical data, f oll o wi n g A Es will be 
c o nsi dere d A E SI (Ta ble 1 5) . 
T a ble 1 5
A d verse E ve nts of S peci al I nterest
A E 
M a n a g e m e nt 
M y el o s u p pr e s si o n ( Gr a d e > 3) wit h 
c o m pli c ati o n s i. e. , c yt o p e ni a, f e bril e 
n e utr o p e ni a, t hr o m b o c yt o p e ni a wit h 
cli ni c all y si g nifi c a nt bl e e di n g 
R e p e at bl o o d t e st wit hi n 7 2 h o ur s 
S e e T a bl e 1 2 f or g ui d a n c e o n d o s e m o difi c ati o n. 
Cli ni c all y si g nifi c a nt GI H e m orr h a g e 
R o uti n e m o nit ori n g of cli ni c al si g n s a n d s y m pt o m s 
S y m pt o m ati c tr e at m e nt at I n v e sti g at or’ s di s cr eti o n 
S e e T a bl e 1 3 f or g ui d a n c e o n d o s e m o difi c ati o n 
GI M u c o siti s ( Di arr h e a, v o miti n g)
M o nit or si g n s a n d s y m pt o m s .
S y m pt o m ati c tr e at m e nt at I n v e sti g at or ’ s di s creti o n i s all o w e d
S e e T a bl e 1 3 f or f urt h er g ui d a n c e.
O p p ort u ni sti c i nf e cti o n s i n clu di n g C O VI D -
1 9
M o nit or si g n s a n d s y m pt o m s; T e st i n g f or C O VI D-1 9 a c c or di n g t o l o c al 
m e di c al pr a cti c e
S y m pt o m ati c tr e at m e nt p er l o c al m e di c al pr a cti c e .
All er gi c/ H y p er s e n siti vit y R e a cti o n / S ki n 
R a s h
A d vi s e d t o m a n a g e p arti ci p a nt i n a c c or d a n c e t o s t a n d ar d lo c al p r a cti c e.
Pr e m e di c ati o n ( a nti hi st a mi n e /c orti c o st er oi d) f or t h e s a m e a n d/or 
s u b s e q u e nt p arti ci p a nt s m a y b e c o n si d er e d if a p pr o pri at e b a s e d o n 
I n v e sti g at or’ s cli ni c al j u d g e m e nt li miti n g d e x a m et h a s o n e t o d o s e s n ot 
r e a c hi n g t h e l e v el r e q uir e d f or t h e tr e at m e nt of m ulti pl e m y el o m a.
A E = A d verse e ve nt, GI = Gastr oi nte sti nal.
I n vesti gat or m ust c o m plete t he A E SI  Re p ort F or m a n d c o m m u nicate wit h t he S p o ns or wit hi n 
2 4 h o urs of occ urre nce of A E SI. Seri o us A E SI ( base d o n S A E re p orti n g criteria) s h o ul d al wa ys 
be re p orte d as S A E as o utli ne d i n Secti o n  8. 2.
6. 9. 1
M o nit ori n g 
a n d M a n a ge me nt 
of O t her T o xicities (e. g.,
O ver -Arc hi n g T o xicities i n P art B ) 
C ortic oster oi d t hera py is k n o w n t o ca use mil d t o se vere A Es
t hat affect al m ost all b o d y 
s yste ms; h o we ver, t he i nci de nce of t o xicit y is de pe n de nt o n m ulti ple fact ors i ncl u di n g t he d ose 
le vel a n d d urati o n of treat me nt. M ost c o m m o n A Es k n o w n t o occ ur wit h d e xa met has o ne (l o w 
d ose) m a y  incl u de he mat ol o gical t o xicit y, i.e., a ne mia, t hr o m b oc yt o pe nia, ne utr o pe nia
( m yel os u p pressi o n). A m o n g n o n he mat ol o gical t o xicit y, i.e., diarr hea, na usea, v o miti n g, 
fati g ue; s yste mic i nfecti o n (s pecificall y o p p ort u nistic); t hr o m b oe m b olic e ve nts i ncl u di n g dee p 
vei n t hr o m b osis a n d p ul m o nar y e m b olis m; a n d c uta ne o us ras h ha ve bee n re p orte d; 
I n vesti gat ors will be a d vise d t o refer t o t he l ocal pr o d uct la bel. T o xicities ma nifeste d b y  
a d mi nistrati o n of d e xa met has o ne i n t he e x pa nsi o n part of t he st u d y will be ma na ge d i n 
acc or da nce wit h t he l ocal me dical practices a n d l ocal la bels; a g ui da nce o n t he d ose re d ucti o n 
d uri n g t he st u d y inter ve nti o n peri o d is pr o vi de d (Ta ble 1 4 A a n d Ta ble 1 4 B) .
Al beit, d ose 
re d ucti o n f or t o xicit y dee me d t o be attri b ute d t o de xa met has o ne al o ne m ust be perf or me d as 
cli nicall y in dicate d. A de viati o n fr o m t he rec o m me n de d d ose re d ucti o n ma y  be perf or me d 
base d o n t he cli nical j u d ge me nt of t he st u d y i n vesti gat or a n d after disc ussi o n wit h t he S p o ns or 
M e dical M o nit or .
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
9 8 / 1 5 5
Si nce re nal i m pair me nt is a c o m m o n c o m plicati o n of M M , a b n or malities i n re nal f u ncti o ns 
( ne w or w orse ni n g fr o m Baseli ne ) will be caref ull y mo nit ore d t hr o u g ho ut t he st u d y. If decrease 
i n esti mate d gl o mer ular filtrati o n rate is > 2 5 % fr o m Baseli ne or d o u bli n g of ser u m creati ni ne 
is o bser ve d , la b orat or y c he mistr y tests will be re peate d wit hi n 7 2 h o urs fr o m t he i nitial fi n di n g 
i n or der t o c o nfir m t he a b n or mal fi n di n gs. T he st u d y partici pa nt will be e val uate d t h or o u g hl y 
b y  the I n vesti gat or, i.e., p h y sical e xa mi nati o n, re vie w of c o nc o mita nt me dicati o n , etc. U p o n 
rec o ver y to ≤ Gra de 1 or pretreat me nt le vels, st u d y i nter ve nti o n m a y  be res u me d at t he sa me 
or a l o wer d ose, if a p pr o priate, base d o n I n vesti gat or’s cli nical j u d ge me nt a n d after disc ussi o n 
wit h t he S p o ns or Me dical M o nit or . A d diti o nall y, beca use of t he c o m m o n occ urre nce of re nal 
i n v ol ve me nt i n M M , t he use of ne p hr ot o xic a ge nts (e. g., N S AI Ds) s h o ul d be a v oi de d 
t hr o u g h o ut t he st u dy. 
Gr a de 3 or 4 ( He m at ol o gic al or N o n h e m at ol o gic al ) T o xicities 
If a p plica ble, re peat la b orat or y tests i n t he l ocal la borat or y wit hi n 7 2 h o urs a n d t he n re peat 
tests t wice a wee k u ntil rec o ver y t o Gra de 2 is o bser ve d. T hereafter, re peat la b orat or y  tests as 
a p pr o priate base d o n I n vesti gat or’s cli nical j u d ge me nt.
F or cli nicall y e vi de nt Gra de 4 t o xicities occ urri n g after D L T peri o d, disc o nti n uati o n of M 3 2 5 8 
a d mi nistrati o n is a d vise d. A decisi o n o n re-i nitiati o n of M 3 2 5 8 s h o ul d o nl y  be c o nsi dere d after 
rec o ver y of t o xicit y i n q uesti o n t o ≤ Gra de 1 is o bser ve d wit hi n t w o wee ks of disc o nti n uati o n 
of M 3 2 5 8 treat me nt (if a la b orat or y  para meter, rec o ver y s h o ul d be c o nfir me d b y a re peat test), 
a n d t he d ose of M 3 2 5 8
s h o ul d be re d uce d b y  at least 1 d ose le vel. W he n a d ose re d ucti o n is 
re q uire d, n o r e-escalati o n of t he d ose will be all o we d. If Gra de 4 t o xicit y rec urs u p o n res u mi n g 
M 3 2 5 8, 
t he n a d mi nistrati o n of st u d y treat me nt s h o ul d i m me diatel y be disc o nti n ue d. T he 
dec isi o n t o c o nti n ue treat me nt s h o ul d be disc usse d wit h t he Me dical M o nit or a n d d oc u me nte d 
i n t he st u d y rec or ds. I n case of t he occ urre nce of o verla p pi n g t o xicities of M 3 2 5 8 
a n d 
d e xa met has o ne, t he d ose re d ucti o n of M 3 2 5 8 will occ ur first (see Ta ble 1 1 , Ta ble 1 2,  a n d Ta ble 
1 3 ). D e xa met has o ne d ose s h o ul d be re d uce d base d o n l ocal pr o d uct la bel or i nstit uti o nal 
g ui deli nes o nl y f or t o xicities w hic h are dee me d relate d t o de xa met has o ne (f or relate d t o xicities 
a n d g ui da nce o n d ose re d ucti o n , see Ta ble 1 4 A a n d Ta ble 1 4 B.   
I n t he e ve nt of ne w or w orse ni n g p ul m o nar y  sy m pt o ms, a pr o m pt dia g n ostic e val uati o n a nd 
i n v ol ve me nt of a p ul m o n ol o gist s h o ul d be c o nsi dere d . Partici pa nts will be treate d acc or di n g t o 
i nstit uti o nal sta n dar ds. Si nce l o w-gra de p ul m o nar y t o xicities ( Gra de 1- 2) , s uc h as d y s p nea a n d
c o u g h, ma nifest as s ym pt o ms of di verse u n derl yi n g eti ol o gies, t he st u d y in vesti gat ors s h o ul d 
bear hi g h s us pici o n f or st u d y  treat me nt-i n d uce d p ul m o nar y i nj ur y. T he st u d y  i n vesti gat or will 
als o be re q uire d t o disc uss a n y gra de p ul m o nar y  to xicit y  
wit h t he S p o ns or me dical 
re prese ntati ve. Re -i nitiati o n of M 3 2 5 8 
m ust 
be disc usse d wit h 
t he S p o ns or me dical 
re prese ntati ve. T he be nefit/ris k bala nce s h o ul d be c o nsi dere d pri or t o c o nti n ui n g M 3 2 5 8 
t hera py.
T he a d verse e ve nts s u g gesti ve of l u n g t o xicit y wit h Gra de ≥3 irres pecti ve of attri b uta bilit y 
will be re p orte d as S A Es t hr o u g h o ut t he st u d y. 
Gra de 4 t o xicit y sh o ul d al wa ys be re p orte d t o t he S p o ns or as a S A E i n e x pe dite d ma n ner, 
wit hi n 2 4 h o urs of a ware ness.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
9 9 / 1 5 5
Treat me nt c y cles wit h M 3 2 5 8 -/ + c o m bi nati o n wit h de xa met has o ne will be re peate d e ver y  2 1
or 2 8 d a y s; he nce, f or a c ycle of treat me nt t o be gi n, t he partici pa nt’s bl o o d A N C m ust be ≥ 
1, 0 0 0 m m 3 a n d t he platelet c o u nt m ust be ≥ 7 5, 0 0 0 m m 3. A d diti o nall y , all ot her t o xicities 
c o nsi dere d t o be relate d t o st u d y inter ve nti o n m ust ha ve res ol ve d t o ≤ Gra de
1 or t o t he 
partici pa nt’s Baseli ne val ue. 
If t he partici pa nt fails t o meet t he a b o ve-cite d criteria f or treat me nt, re-i nitiati o n of t he ne xt 
c ycle of treat me nt s h o ul d be dela ye d f or o ne wee k. At t he e n d of w hic h, t he partici pa nt s h o ul d 
be re-e val uate d t o deter mi ne w het her t he criteria f or re -treat me nt ha ve bee n met. If a dela y  i n 
t he i nitiati o n of t he ne xt c ycle of m ore t ha n t w o wee ks is re q uire d beca use of i nc o m plete 
rec o ver y fr o m t o xicit y, t he n t his e ve nt s h o ul d be c o nsi dere d a D L T. If t o xicit y d oes n ot res ol ve 
b y  tw o wee ks, t he n t he partici pa nt s h o ul d be disc o nti n ue d fr o m t he st u d y. T his decisi o n will 
be ma de i n t he c o nte xt of e mer gi n g cli nical data a n d i n c o ns ultati o n wit h S p o ns or M e dical 
R es p o nsi ble. If, i n t he o pi ni o n of t he I n vesti gat or a n d t he S p o ns or M e dical R es p o nsi ble, it is 
i n t he partici pa nt’s best i nterest t o c o nti n ue t he treat me nt wit h M 3 2 5 8 -/ + c o m bi nati o n wit h 
de xa met has o ne, t he st u d y inter ve nti o n will o nl y  be res u me d after rec o ver y fr o m t o xicit y to ≤ 
Gra de 1 or Baseli ne val ues. A d diti o nall y , t he d ose of st u d y i nter ve nti o n s h o ul d be re d uce d b y 
at least 1 d ose le vels. If t he D L T rec urs u p o n res u mi n g st u d y i nter ve nti o n at a l o wer d ose, t he 
st u d y i nter ve nti o n s h o ul d i m me diatel y be disc o nti n ue d. F or t he first st u d y co h ort, n o d ose 
re d ucti o n will be all o we d.
7
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al
7. 1
Disc o nti n u ati o n of St u d y I nter ve nti o n
St o p pi n g R ules f or In di vi d u al P artici p a nts: 
T he I n vesti gat or m ust c o nsi der disc o nti n uati o n of st u d y inter ve nti o n f or a b n or mal li ver 
f u ncti o n w he n a pa rtici pa nt meets o ne of t he c o n diti o ns o utli ne d i n Secti o n 6. 6 or if t he 
I n vesti gat or belie ves t hat it is i n best i nterest of t he partici pa nt.
All e ve nts of A L T ≥3 × U L N a n d bilir u bi n ≥2 × U L N ( > 3 5 % direct bilir u bi n) or A L T > 3 × 
U L N a n d i nter nati o nal n or malize d rati o (I N R) > 1. 5, if I NR meas ure d, ma y  in dicate p ote ntial 
se vere li ver i nj ur y ( p ossi ble H y’s La w) a n d m ust be re p orte d as a n A E a n d S A E.
If a cli nicall y si g nifica nt fi n di n g i n E C G rec or di n g is i de ntifie d (i ncl u di n g, b ut n ot li mite d t o 
c ha n ges fr o m Baseli ne
i n Q T i nter val c orrecte d usi n g Fri dericia’s f or m ula [Q Tc F ]) after 
e nr oll me nt, t he I n vesti gat or or q ualifie d desi g nee will deter mi ne if t he partici pa nt ca n c o nti n ue 
i n t he st u d y an d if a n y c ha n ge i n partici pa nt ma na ge me nt is nee de d. T his re view of t he E C G 
pri nte d at t he ti me of c ollecti o n m ust be d oc u me nte d. A n y  ne w cli nicall y rele va nt fi n di n g 
s h o ul d be re p orte d as a n A E.
T he S o A (Ta ble 1 a n d Ta ble 2 f or Part A; Ta ble 3 a n d Ta ble 4 f or Part B) s pecifies t he data t o 
c ollect at st u d y inter ve nti o n disc o nti n uati o n a n d F oll o w -U p , a n d a n y a d diti o nal e val uati o ns 
t hat nee d t o be c o m plete d.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 0 / 1 5 5
If a partici pa nt 's st u d y i nter ve nti o n m ust be disc o nti n ue d, t his will n ot res ult i n a ut o matic 
wit h dra wal of t he partici pa nt fr o m t he st u dy a n d t he partici pa nt s h o ul d be assesse d at t he E n d-
of- Treat me nt v isit a n d Safet y  F oll o w -U p visit.
A partici pa nt 's st u dy i nter ve nti o n s h o ul d be disc o nti n ue d if:

T he I n vesti gat or belie ves t hat f or safet y  reas o ns (e g, A E ) it is i n t he best i nterest of t he 
partici pa nt t o disc o nti n ue st u d y i nter ve nti o n.

T he partici pa nt bec o mes pre g na nt.

T he partici pa nt ( or t he partici pa nt ’s le gally a ut h orize d re prese ntati ve) wit h dra ws 
c o nse nt f or a d mi nistrati o n of st u d y i nter ve nti o n.

T he partici pa nt ’s d ose is hel d f or m ore t ha n 5 da y s per c ycle, or if ≥6 c o nsec uti ve 
pla n ne d d oses of M 3 2 5 8 are misse d f or reas o ns ot her t ha n t o xicit y unless, u p o n 
c o ns ultati o n wit h t he S p o ns or a n d t he re vie w of safety a n d efficac y, c o nti n uati o n is 
a gree d u p o n.

T he partici pa nt e x perie nces disease pr o gressi o n.
S afet y St o p pi n g R ules f or S t u d y Inter ve nti o n i n P art B:
U nacce pta ble t o xicit y i n t he e x pa nsi o n c o h ort is defi ne d as A Es t hat meet t he D L T criteria
re gar dless of w he n t he y occ ur d uri n g treat me nt (as defi ne d i n Secti o n 6. 6 ). T he f oll o wi n g 
st o p pi n g r ules f or u nacce pta ble t o xicit y a p ply:

≥5 partici pa nts wit h o bser ve d D L T criteria o ut of 1 2 e val ua ble partici pa nts treate d o n 
t he sa me d ose.

≥ 7 partici pa nts wit h o bse r ve d D L T criteria o ut of 1 8 e val ua ble partici pa nts treate d o n 
t he sa me d ose.

≥ 9 partici pa nts wit h o bser ve d D L T criteria o ut of 2 4 e val ua ble partici pa nts treate d o n 
t he sa me d ose.

T he c ha nce is > 8 0 % t hat t he tr ue D L T rate is ≥ 3 0 % ( base d o n Ba yes m o del).
If at a n y ti me i n t he e x pa nsi o n c o h ort, t he n u m ber of u nacce pta ble t o xicit y e ve nts i n dicate t hat 
t here is a ris k of safety t o t he partici pa nts (i.e., if a n y of t he a b o ve b o u n dar y is met) , accr ual t o 
t he c o h ort will be pa use d a n d t he S M C will meet t o deter mi ne w het her f urt her e nr oll me nt 
s h o ul d be halte d ta ki n g i nt o acc o u nt fee d bac k fr o m st u d y In vesti gat ors. I n t his case, t he S M C 
will deci de w het her partici pa nts still o n treat me nt a n d t olerati n g t he treat me nt ca n sta y on 
treat me nt or w het her treat me nt nee ds t o be d ose re d uce d or wit h dra w n . T he H A will be n otifie d 
of t he S M C decisi o n.
7. 1. 1
Te m p or ar y Disc o nti n u ati o n
See t o Secti o n  6. 6 .
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 1 / 1 5 5
7. 1. 2
Rec h alle n ge
See t o Secti o n  6. 6 .
7. 2
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y
A partici pa nt ma y  wit h dra w fr o m t he st u d y at a n y t i me, at his/ her o w n re q uest (i.e., wit h dra wal 
of c o nse nt), a n d wit h o ut gi vi n g a reas o n .
T he partici pa nt ma y  be wit h dra w n b y  the I n vesti gat or d ue t o partici pati o n i n a n ot her cli nical 
st u d y. Partici pa nt s h o ul d ha ve E n d of St u d y assess me nt per st u d y pr ot oc ol. 
T he partici pa nt m a y  be wit h dra w n at a n y ti me at t he discreti o n of t he I n vesti gat or for safety,  
be ha vi oral, c o m plia nce, or a d mi nistrati ve reas o ns.
T he S o A (Ta ble 1 a n d Ta ble 2 f or Part A; Ta ble 3 a n d Ta ble 4 f or Part B) s pecifies t he data t o 
c ollect at st u d y disc o nti n uati o n a n d F oll o w -U p , a n d a n y a d diti o nal e val uati o ns t hat nee d t o be 
c o m plete d.
7. 3
L ost t o F oll o w -U p
A partici pa nt will be c o nsi dere d l ost t o F oll o w -U p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d by t he st u d y  site.
T he f oll o wi n g acti o ns will be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d 
st u d y visit:

T he site will atte m pt t o c o ntact t he partici pa nt a n d resc he d 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 In 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 ho 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 will 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.
8
St u d y Assess me nts a n d Pr oce d ures

St u d y  assess me nts a n d pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A s (Ta ble 
1 a n d Ta ble 2 f or Part A; Ta ble 3 a n d Ta ble 4 f or Part B).

N o pr ot oc ol wai vers or e xe m pti o ns are all o we d.

I m me diate safety c o ncer ns are disc usse d wit h t he S p o ns or i m me diatel y u p o n occ urre nce 
or a ware ness t o deter mi ne if t he partici pa nt s ho ul d c o nti n ue or disc o nti n ue st u d y 
i nter ve nti o n.

A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is 
esse ntial a n d re q uire d f or st u d y c o n d uct.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 2 / 1 5 5

All Scree ni n g e val uati o ns will be c o m plete d a n d re vie we d b y  the I n vesti gat or t o c o nfir m 
t hat p ote ntial partici pa nts meet all i ncl usi o n a n d e xcl usi o n criteria bef ore s u b mitti n g 
eli gi bilit y criteria. T he eli gi bilit y will be c o nfir me d at Da y  1 C y cle 1. T he In vesti gat or 
will mai ntai n a Scree ni n g l o g t o rec or d details of all partici pa nts scree ne d, t o c o nfir m 
eli gi bilit y, a n d if a p plica ble, rec or d reas o ns f or Scree ni n g fail ure.

Pri or t o perf or mi n g a n y st u d y assess me nts t hat are n ot part of t he partici pa nt’s r o uti ne 
me dical care, t he I nvesti gat or wi ll o btai n writte n i nf or me d c o nse nt as s pecifie d i n 
A p pe n di x 2 .

Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne me dical care (e. g., bl o o d c o u nt) 
a n d o btai ne d bef ore si g ni n g of t he I CF m a y  be use d f or scree ni n g or baseli ne p ur p oses 
pr o vi de d t he pr oce d ures met t he pr ot oc ol -s pecifie d criteria a n d were pref or me d wit hi n 
t he ti me fra me defi ne d i n t he S o A.

Re peat or u nsc he d ule d sa m ples ma y  be ta ke n f or safety reas o ns or f or tec h nical iss ues
wit h t he sa m ples.

U nsc he d ule d visits nee d t o be d oc u me nte d i n t he e C R F.
8. 1
Effic ac y Assess me nts a n d Pr oce d ures

Efficac y  assess me nts a n d pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o As (Ta ble 
1 a n d Ta ble 2 f or Part A; Ta ble 3 a n d Ta ble 4 f or Part B).

De m o gra p h y:  date of birt h, se x ( ge n der), race, a n d et h nicit y

Me dical hist or y : pre vi o us ill ness a n d s ur geries (e. g., all d uri n g t he past year a n d o nl y 
maj or o nes pri or t o t hat), c onc o mita nt ill ness, aller gies, pri or t hera pies f or t he tar get 
i n dicati o n (i.e., rele va nt pre vi o us me dicati o ns), t hera pies st o p pe d or c ha n ge d at e ntr y int o 
t he st u d y, t o bacc o use, alc o h ol use, s pecial diets a n d, f or w o me n, me nstr ual stat us a n d 
date of last m e nstr ual peri o d.

Disease fact ors

A n y  as pects of t he s c he d ule n ot c o vere d i n t he S o A (e. g., ti mi n g relati ve t o meals or 
st u d y i nter ve nti o n a d mi nistrati o n).

A n y  necessar y co n diti o ns (e. g., pre parati o n of partici pa nts or materials, la b orat ory 
s u p pl y, a d diti ves i n test s yste ms, sa m ple ori gi n, safet y meas ures bef ore, d uri n g, a n d after 
t he pr oce d ure, a n d sa m ple la beli n g, pr ocessi n g, st ora ge, a n d tra nsfer).

A n y  e val uati o n criteria.

If assess me nts/ pr oce d ures var y fr o m o ne ti me p oi nt t o a n ot her.

A n y  q ualitati ve or e xit i nter vie w e val uati o ns.

Efficac y  assess me nts per I M W G res p o nse criteria (K u mar et al, 2 0 1 6).
Assess me nt of t u m or res p o nse a n d disease pr o gressi o n will be c o n d ucte d i n acc or da nce 
wit h t he I MW G res p o nse criteria (K u mar et al, 2 0 1 6 ). Disease e val uati o ns will i ncl u de 
meas ure me nts of m y el o ma pr otei ns, b o ne marr o w e xa mi nati o ns (bi o ps y  an d / or as pirate 
[as pirate preferre d ] re q uire d pri or t o d osi n g D a y 1 C y cle 1 a n d at t he ti me of c o nfir mati o n 
of C R ), assess me nt of b o ne lesi o ns, assess me nt of e xtra me d ullar y plas mac yt o mas, a n d 
meas ure me nts of ser u m calci u m c orrecte d f or al b u mi n (see S o As : Ta ble 1 a n d Ta ble 2
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 3 / 1 5 5
f or Part A; Ta ble 3 a n d Ta ble 4 f or Part B). Ser u m a n d uri ne tests are t o be perf or me d as 
i n dicate d i n t he S o As : Ta ble 1 a n d Ta ble 2 f or Part A;  Ta ble 3 a n d Ta ble 4 f or Part B . 
After C y cle 1, i m m u n ofi xati o n electr o p h oresis (I F E) s h o ul d o nl y be d o ne w he n M-
pr otei n is 0 or n o n q ua ntifia ble. After C y cle 6, disease assess me nts ser u m pr otei n 
electr o p h oresis ( S P E P), uri ne pr otei n electr o p h oresis ( U P E P), a n d ser u m calci u m 
c orrecte d f or al b u mi n, s h o ul d be c ollecte d e ver y c ycle u ntil e n d of st u d y i nter ve nti o n. 
All res p o nses (i ncl u di n g P d base d o n bi oc he mical i n vesti gati o ns) re q uire 2 c o nsec uti ve 
assess me nts wit h t he sa me , w orse, or be tter o utc o me.

Disease state

S ur vi val stat us a n d s u bse q ue nt a ntica ncer treat me nt data ( wit hi n t he O S F oll o w -U p of 
t his st u d y) will be c ollecte d i n Part B ce ns ore d at t he E n d of S t u d y (Secti o n  9. 4. 1).
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 4 / 1 5 5
T a ble 1 6
I nter n ati o n al 
U nif or m 
Res p o nse 
Criteri a 
C o nse ns us 
Rec o m me n d ati o ns
R e s p o n s e
R e s p o n s e Crit eri a
s C R

C R a s d efi n e d b el o w, pl u s

N or m al F L C r ati o, a n d

A b s e n c e of cl o n al P C s b y i m m u n o hi st o c h e mi str y, 
i m m u n ofl u or e s c e n c e or 2 t o 4 c ol or fl o w c yt o m etr y
C R a

N e g ati v e i m m u n ofi x ati o n o n t h e s er u m a n d uri n e, a n d d i s a p p e ar a n c e 
of a n y s oft ti s s u e pl a s m a c yt o m a s, a n d < 5 % P C s i n b o n e m arr o w
V G P R a

S er u m a n d uri n e M -pr ot ei n d et e ct a bl e b y i m m u n ofi x ati o n, b ut n ot o n 
el e ctr o p h or e si s or 

≥9 0 % r e d u cti o n i n s er u m M -pr ot ei n pl u s 2 4 -h o ur uri n e M -pr ot ei n 
< 1 0 0 m g/ 2 4 h o ur s
P R

≥5 0 % r e d u cti o n of s er u m M -pr ot ei n a n d r e d u cti o n i n 2 4 -h o ur uri n ar y 
M- pr ot ei n b y ≥9 0 % or t o < 2 0 0 m g/ 2 4 h o ur s

If t h e s er u m a n d uri n e M -pr ot ei n ar e n ot m e a s ur a bl e, a d e cr e a s e of 
≥5 0 % i n t h e diff er e n c e b et w e e n i n v ol v e d a n d u ni n v ol v e d F L C l e v el s 
i s r e q uir e d i n pl a c e of t h e M-pr ot ei n crit eri a

I n a d diti o n t o t h e a b o v e crit eri a, if pr e s e nt at b a s eli n e, ≥5 0 % 
r e d u cti o n i n t h e si z e ( S P D) of s oft ti s s u e pl a s m a c yt o m a i s al s o 
r e q uir e d
M R

I n p arti ci p a nt s wit h r el a p s e d r efr a ct or y m y el o m a a d o pt e d fr o m t h e 
E B M T crit eri a ( Bl a d e 1 9 9 8): ≥2 5 % b ut ≤4 9 % r e d u cti o n of s er u m M-
pr ot ei n a n d r e d u cti o n i n 2 4 -h o ur uri n e M -pr ot ei n b y 5 0 % t o 8 9 %

I n a d diti o n t o t h e a b o v e crit eri a, if pr e s e nt at B a s eli n e , ≥5 0 %
r e d u cti o n i n t h e si z e ( S P D) of s oft ti s s u e pl a s m a c yt o m a s i s al s o 
r e q uir e d
S D

N ot m e eti n g crit eri a f or C R, V G P R, P R, M R, or P D

N o i n cr e a s e i n si z e or n u m b er of l yti c b o n e l e si o n s ( d e v el o p m e nt of 
c o m pr e s si o n fr a ct ur e d o e s n ot e x cl u d e r e s p o n s e)
P D b

I n cr e a s e of 2 5 % fr o m l o w e st r e s p o n s e v al u e i n a n y o n e of t h e 
f oll o wi n g:

S er u m M -c o m p o n e nt ( a b s ol ut e i n cr e a s e m u st b e ≥0. 5 g/ d L),

Uri n e M -c o m p o n e nt ( a b s ol ut e i n cr e a s e m u st b e ≥2 0 0 m g/ 2 4 h o ur s),

O nl y i n p arti ci p a nt s wit h o ut m e a s ur a bl e s er u m a n d uri n e M -pr ot ei n 
l e v el s: t h e diff er e n c e b et w e e n i n v ol v e d a n d u ni n v ol v e d F L C l e v el s 
( a b s ol ut e i n cr e a s e m u st b e > 1 0 m g/ d L)

D efi nit e d e v el o p m e nt of n e w b o n e l e si o n s or s oft ti s s u e 
pl a s m a c yt o m a s or d efi nit e i n cr e a s e i n t h e si z e of e xi sti n g b o n e 
l e si o n s or s oft ti s s u e pl a s m a c yt o m a s

D e v el o p m e nt of h y p er c al c e mi a ( c orr e ct e d s er u m c al ci u m > 1 1. 5 
m g/ d L) t h at c a n b e attri b ut e d s ol el y t o t h e P C pr olif er ati v e di s or d er
C R = C o m plete res p o nse, E B M T = E ur o pea n Gr o u p f or Bl o o d a n d Marr o w  Tra ns pla ntati o n; F L C = free li g ht 
c hai n; M R = Mi ni mal res p o nse, P C = plas ma cell, P D = Pr o gressi ve disease, P R = Partial res p o nse, s C R = 
Stri n ge nt c o mplete res p o nse, S D = Sta ble disease, S P D = S u m of t he pr o d ucts of t he ma xi mal per pe n dic ular 
dia m eters of meas ure d lesi o ns, V G P R = Ver y g o o d partial res p o nse .
All res p o nse cate g ories ( C R, s C R, V G P R, P R, M R, a n d P D) re q uire 2 c o nsec uti ve assess me nts ma de at a n y ti me 
bef ore t he i nstit uti o n of  an y ne w t hera p y; C R, s C R, V G P R, P R, a n d S D cate g ories als o re q uire n o k n o w n e vi de nce 
of pr o gressi ve or ne w  bo ne lesi o ns if ra di o gra p hic st u dies we re perf or me d. V G P R a n d C R cate g ories re q uire 
ser u m a n d uri ne st u dies re gar dless of w het her disease at Baseli ne wa s meas ura ble o n ser u m, uri ne, b ot h, or neit her. 
Ra di o gra p hic st u dies are n ot re q uire d t o satisf y t hese res p o nse re q uire me nts. B o ne marr o w assess me nts nee d n ot 
be c o nfir me d.
F or P D, ser u m M -c o mp o ne nt i ncreases of m o re t ha n or e q ual t o 1 g/ d L are s ufficie nt t o defi ne rela pse if starti n g 
M- c o mp o ne nt is ≥5 g/ d L.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 5 / 1 5 5
a
Clarificati o ns t o I M W G criteria f or c o di n g C R a n d V G P R i n partici pa nt s i n w h o m t he o nl y  meas ura ble disease 
is by ser u m  F L C le vels: C R i n s uc h partici pa nt s i n dicates a n or mal F L C rati o of 0. 2 6 t o 1. 6 5 i n a d diti o n t o C R 
criteria liste d a b o ve. V G P R i n s uc h partici pa nt s re q uires a > 9 0 % decrease i n t he differe nce bet wee n i n v ol ve d 
a n d u ni n v ol ve d F L C le vels.
b
Clarificati o ns t o I M W G criteria f or c o di n g P D: B o ne marr o w criteria f or P D are t o be use d o nl y i n partici pa nt s 
wit h o ut m eas ura ble disease b y  M pr otei n a n d b y  FL C le vels; “ 2 5 % i ncrease” refers t o M pr otei n, F L C, a n d 
b o ne marr o w res ults, a n d d oes n ot refer t o b o ne lesi o ns, s oft tiss ue plas mac yt o mas, or h y percalce mia a n d t he 
“l o west res p o nse val ue” d oes n ot nee d t o be a c o nfir me d val ue.
c
Prese nce/a bse nce of cl o nal cells is base d u p o n t he ka p pa/la m b da rati o. A n a b n or mal ka p pa/la m b da rati o b y 
i m m u n o hist oc he mistr y or i m m u n ofl u oresce nce re q uires a mi ni m u m of 1 0 0 plas ma cells f or a nal ysis. A n 
a b n or mal rati o reflecti n g prese nce of a n a b n or mal cl o ne is ka p pa/la m b da of > 4: 1 or < 1: 2.
F or t he i nteri m a nal ysis t he f oll o wi n g res ults are c o nsi dere d a res p o nse: P R, V G P R, C R, s C R.
Cli nic al Rel a pse
Cli nical rela pse is defi ne d usi n g t he defi niti o n of cli nical rela pse i n t he I M W G criteria (K u mar
et al, 2 0 1 6; Raj k u mar et al, 2 0 1 1 ). It is defi ne d as re q uiri n g o ne or m ore of t he f oll o wi n g direct 
i n dicat ors of i ncreasi n g disease or e n d-or ga n d y sf u ncti o n t hat are c o nsi dere d relate d t o t he 
u n derl y i n g plas ma cell pr oliferati ve dis or der:

De vel o p me nt of ne w s oft tiss ue plas mac y t o mas or b o ne lesi o ns o n s keletal s ur ve y, 
ma g netic res o na nce i ma gi n g, or ot her i ma gi n g

Defi nite i ncrease i n t he size of e xisti n g plas mac y t o mas or b o ne lesi o ns. A defi nite 
i ncrease is defi ne d as a 5 0 % (a n d at least 1 c m) i ncrease as meas ure d seriall y b y t he 
s u m of t he pr o d ucts of t he cr oss-dia meters of t he meas ura ble lesi o n

H y percalce mia ( > 1 1. 5 m g / d L)

Decrease i n he m o gl o bi n of m ore t ha n 2 g/ d L ( 1. 2 5 m M) 

Rise i n ser u m creati ni ne b y  m ore t ha n or e q ual t o 2 m g/ d L 

H y per visc osit y
I n s o me partici pa nt s, b o ne pai n ma y be t he i nitial s ym pt o m of rela pse i n t he a bse nce of a n y of 
t he a b o ve feat ures. H o we ver, b o ne pai n wit h o ut i ma gi n g c o nfir mati o n is n ot a de q uate t o meet 
t hese criteria i n st u dies.
M yel o m a Pr otei n Me as ure me nts i n Ser u m a n d Uri ne
Bl o o d a n d 2 4- h o ur uri ne sa m ples f or M -pr otei n meas ure me nts will be a nal yze d acc or di n g t o 
t he L a borat or y M a n ual a n d as o utli ne d i n t he S o As (Ta ble 1 a n d Ta ble 2 f or Part A;  Ta ble 3
a n d Ta ble 4 f or Part B) . O nl y  1 ser u m a n d o ne 2 4- h o ur uri ne sa m ple per ti me p oi nt are re q uire d 
t o perf or m t he f oll o wi n g tests:

Ser u m a n d uri ne q ua ntitati ve i m m u n o gl o b uli ns (I g G, I g A, I g M, I g E, a n d I g D) at 
Scree ni n g a n d t hereafter w he n C R is s us pecte d a n d w he n n o M-pr otei n is detecta ble 
i n ser u m

Ser u m M -pr otei n q ua ntitati o n b y  electr o p h oresis ( S P E P)

Uri ne M -pr otei n q ua ntitati o n b y  electr o p h oresis ( U P E P)
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 6 / 1 5 5

Ser u m a n d uri ne free li g ht c hai n assa y at Scree ni n g a n d t hereafter w he n C R is 
s us pecte d. I n case of free li g ht c hai n disease, free li g ht c hai n assa y in ser u m at 
Scree ni n g, Da y  1 of e ver y c ycle a n d w he n C R is s us pecte d. 
Ser u m C alci u m C orrecte d f or Al b u mi n
Bl o o d sa m ples f or calc ulati n g ser u m calci u m c orrecte d f or al b u mi n will be c ollecte d as 
i n dicate d i n t he S o As : Ta ble 1 a n d Ta ble 2 f or Part A;  Ta ble 3 a n d Ta ble 4 f or Part B a n d 
a nal yz e d ce ntrall y u ntil t he de vel o p me nt of c o nfir me d disease pr o gressi o n. De vel o p me nt of 
h y percalce mia (c orrecte d ser u m calci u m > 1 1. 5 m g/ d L) ca n i n dicate disease pr o gressi o n or 
rela pse if it is n ot attri b utable t o a n y ot her ca use. Calci u m bi n ds t o al b u mi n a n d o nl y t he 
u n b o u n d (free) calci u m is bi ol o gicall y acti ve; t heref ore, t he ser u m calci u m le vel m ust be 
a dj uste d f or a b n or mal al b u mi n le vels (“c orrecte d ser u m calci u m”). Ca lci u m will als o be 
a nal yz e d l ocall y f or i m me diate ma na ge me nt of partici pa nt safety.
Ser u m β 2 -mi cr o gl o b uli n 
Bl o o d sa m ples f or β 2 micr o gl o b uli n a n d al b u mi n are t o be c ollecte d as i n dicate d i n t he S o As :
Ta ble 1 a n d Ta ble 2 f or Part A;  Ta ble 3 a n d Ta ble 4 f or Part B a n d will be a nal yz e d b y  the 
ce ntral la b orat or y.
B o ne M arr o w E x a mi n ati o n
B o ne marr o w as pirate a n d/or bi o ps y  (as pirate preferre d) will be perf or me d b y  the l ocal 
la b orat or y at D a y 1 C ycl e 1 (see S o A s: Ta ble 1 a n d Ta ble 2 f or Part A; Ta ble 3 a n d Ta ble 4 f or 
Part B ) f or cli nical sta gi n g ( m or p h ol o g y, c yt o ge netics, a n d eit her i m m u n o hist oc he mistr y or 
i m m u n ofl u oresce nce or fl o w c yt o metr y) a n d assess me nt of M R D
( b o ne marr o w as pirate). 
B o ne marr o w e xa mi nati o n f or M R D
( b o ne marr o w as pirate)
will als o be perf or me d after 
treat me nt t o c o nfir m C R (i ncl u di n g s C R). If t he partici pa nt meets criteria f or C R a n d has a 
n or malize d free li g ht c hai n (F L C ) rati o, a n a d diti o nal b o ne marr o w as pirate sa m ple will be 
re q uire d t o c o nfir m s C R. F or b o ne marr o w ha n dli n g at C R , refer t o t he L a borat or y M a n ual.
Assess me nt of L ytic Dise ase
A c o m plete s keletal s ur ve y (i ncl u di n g s k ull, e ntire verte bral c ol u m n, pel vis, c hest, h u meri, 
fe m ora, a n d a n y ot her b o nes f or w hic h t he I n vesti gat or s us pects i n v ol ve me nt b y disease) is t o 
be perf or me d a n d e val uate d b y  the l ocal la b orat or y by r oe nt ge n o gra p hy as i n dicate d i n t he 
S o As : Ta ble 1 a n d Ta ble 2 f or Part A; Ta ble 3 a n d Ta ble 4 f or Part B . B o ne lesi o ns ca n als o be 
assesse d b y  C T, l o w-d ose w h ole- b o d y  CT, P E T -C T, w h ole- b o d y  CT, F D G -P E T/ C T, a n d M RI . 
If perf or me d b y  PE T/ C T or M RI , oste ol y tic lesi o ns a n d e xtra me d ullar y disease ca n be 
e val uate d wit hi n t he sa me i ma gi n g d uri n g scree ni n g. A F oll o w -U p d uri n g t he Treat me nt P hase 
wit h x- ra ys s h o ul d be perf or me d w he ne ver cli nicall y in dicate d base d o n s ym pt o ms, t o 
d oc u me nt res p o nse or pr o gressi o n.
8. 2
S afet y Assess me nts a n d Pr oce d ures
T he safety pr ofile of t he st u dy i nter ve nti o n will be assesse d t hr o u g h t he rec or di n g, re p orti n g 
a n d a nal ysis of Baseli ne me dical c o n diti o ns, A Es, p h y sical e xa mi nati o n fi n di n gs, vital si g ns, 
E C Gs , a n d la b orat or y tests.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 7 / 1 5 5
C o m pre he nsi ve assess me nt of a n y p ote ntial t o xicit y ex perie nce d b y  each partici pa nt will be 
c o n d ucte d starti n g w he n t he partici pa nts gi ve i nf or me d c o nse nt a n d t hr o u g h o ut t he st u d y . T he 
In vesti gat or will re p ort a n y AEs, 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; t he re p orti n g peri o d is s pecifie d i n S ecti o n 8. 3. 1 .
8. 2. 1
P h ysic al E x a mi n ati o ns

A c o m plete p h y sical e xa mi nati o n will be c o n d ucte d as o utli ne d i n t he S o A (Ta ble 1
a n d Ta ble 2 f or Part A;  Ta ble 3 a n d Ta ble 4 f or Part B ). It will i ncl u de, at a mi ni m u m, 
assess me nts of t he s ki n, ears, n ose, t hr oat, l u ngs, heart, a b d o me n, e xtre mities, 
m usc ul os keletal s yste m, l ym p hatic s yste m, a n d ner v o us s yste ms of a partici pa nt. 
Wei g ht will als o be meas ure d a n d rec or de d. Hei g ht will be meas ure d a n d rec or de d at 
Scree ni n g o nl y.

A brief p h y sical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, 
l u n gs, car di o vasc ular s yste m, a b d o me n (li ver a n d s plee n) a n d peri p heral m ot or a n d 
se ns or y ner v o us s yste m. Brief e xa mi nati o n ma y 
als o i ncl u de tar gete d s yste m 
e xa mi nati o n as a p pr o priate. F or i nsta nce, In vesti gat or m a y  ex a mi ne t he partici pa nt 
wit h a me dical hist or y  of peri p heral ne ur o pat hy f or w orse ni n g. 

I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses.
8. 2. 2
Vit al Si g ns

B o d y te m perat ure (use o ne met h o d f or a partici pa nt [ oral preferre d]) , p ulse rate, 
res pirat or y rate, a n d bl o o d press ure will be assesse d as o utli ne d i n t he S o A (Ta ble 1
a n d Ta ble 2 f or Part A; Ta ble 3 a n d Ta ble 4 f or Part B). 

Bl o o d press ure a n d p ulse meas ure me nts will be assesse d i n t he sitti n g p ositi o n wit h 
a c o m pletel y a ut o mate d de vice. Ma n ual tec h ni q ues will be use d o nl y  if a n a ut o mate d 
de vice is n ot a vaila ble.

Bl o o d press ure a n d p ulse meas ure me nts s h o ul d be prece de d b y  at least 5 mi n utes of 
rest f or t he partici pa nt i n a sitti n g p ositi o n a n d i n a q uiet setti n g wit h o ut distracti o ns 
(e. g., tele visi o n, cell p h o nes).

Vital si g ns (t o be ta ke n bef ore bl o o d c ollecti o n f or la b orat or y tests) will c o nsist of 
p ulse rate a n d bl o o d press ure meas ure me nts . T he rea di n gs will be rec or de d o n t he 
e C R F.
8. 2. 3
Electr oc ar di o gr a ms
S afet y E C Gs
Safet y  E C Gs are sta n dar d si n gle 1 2- lea d E C G s o btai ne d f or safety m o nit ori n g acc or di n g t o t he 
S o As (Ta ble 1 a n d Ta ble 2 f or Part A , Ta ble 3 a n d Ta ble 4 f or Part B ). Partici pa nts will rest i n 
rec u m be nt p ositi o n f or at least 1 0 mi n utes . Safet y  EC Gs will be rea d l ocall y an d all E C Gs 
s h o ul d be assesse d o n t he d a y  of c ollecti o n t o deter mi ne c o nti n ue d eli gi bilit y. T he calc ulate d 
Q Tc a vera ge of 1 2- lea d E C Gs m ust be ≤ 4 5 0 ms f or males a n d ≤ 4 7 0 ms f or fe male
partici pa nt s’ eli gi bilit y. Partici pants , i n w h o m t he calc ulate d Q Tc a vera ge i ncreases t o > 5 0 0 
ms or > 6 0 ms c ha n ge o ver baseli ne d uri n g treat me nt wit h M 3 2 5 8, m ust
i nterr u pt st u d y 
treat me nt u ntil f urt her cli nical e val uati o n. E C Gs s h o ul d be re peate d if Q Tc is o utsi de t he ra n ge 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 8 / 1 5 5
u ntil res ol uti o n. T o assess t he safet y a n d t olera bilit y of t he st u d y i nter ve nti o n, a n E C G ca n be 
re peate d at t he I n vesti gat or’s discreti o n at u nsc he d ule d visits. Start a n d e n d of resti n g ti me a n d 
E C G ti me will be rec or de d i n t he e C R F . 
Q T/ Q Tc E v al u ati o n
Tri ple E C G m o nit ori n g will be perf or me d wit h a pr o vi de d H olter E C G at t he ti me p oi nts 
s pecifie d i n t he S o As (Ta ble 1/ Ta ble 2 a n d Ta ble 5 f or Part A a n d Ta ble 3 /Ta ble 4 a n d Ta ble 
6 f or Part B). Partici pa nts will rest i n rec u m be nt p ositi o n f or at least 1 0 mi n. Start a n d e n d of 
resti n g ti me will be d oc u me nte d i n t he e C R F.
E C Gs will be st ore d di gitall y f or a later i n de pe n de nt a nal ys is: E C G e xtracti o ns will be ma de 
b y  the ce ntral E C G la borat or y a n d o ver-rea d of i nter val meas ure me nts will be pr o vi de d b y  
e x perie nce d, q ualifie d, a n d certifie d car diac safet y specialists. T he ce ntral rea ders will be 
bli n de d t o partici pa nt details, treat me nt, visit da y , a n d ti me p oi nts of t he E C G rec or di n g, a n d a 
si n gle rea der will rea d all E C Gs of a gi ve n partici pa nt. 
8. 2. 4
C hest X -R a y at Pretre at me nt
A pretreat me nt (scree ni n g)
c hest ra di o gra p h ser ves t o i de ntif y pne u m o nitis, i nterstitial 
p ne u m o nia a n d l u n g i nfiltrati o n f or eli gi bilit y of par tici pants a n d as a baseli ne f or p ote ntial 
p ost -treat me nt p ul m o nar y c ha n ges. 
I n t he e ve nt of ne w or w orse ni n g p ul m o nar y  sy m pt o ms (e. g., c o u g h, d ys p nea ), a pr o m pt 
dia g n ostic e val uati o n a n d i n v ol ve me nt of a p ne u m ol o gist s h o ul d be c o nsi dere d. Partici pa nts
treate d acc or di n g t o i nstit uti o nal sta ndar ds . T he st u d y in vesti gat or will als o be re q uire d t o 
disc uss a n y gra de p ul m o nar y to xicit y  wit h t he S p o ns or me dical re prese ntati ve. Re-i nitiati o n of 
M 3 2 5 8 m ust be disc usse d wit h t he S p o ns or me dical re prese ntati ve. T he be nefit/ris k bala nce
s h o ul d be c o nsi dere d pri or t o c o nti n ui n g M 3 2 5 8 t hera p y.
8. 2. 5
Cli nic al S afet y L a b or at or y Assess me nts

A p pe n di x 7 lists t he la b orat or y tests t hat will be a nal yze d f or t he st u d y for eac h pa nel 
(e. g., he mat ol o g y, c he mistr y, uri nal ysis).

He mat ol o g y  incl u des c o m plete bl o o d c o u nt wit h differe ntial a n d platelet c o u nts. 
Bl o o d sa m ples f or he mat ol o g y will be o btai ne d pri or t o a d mi nistrati o n of st u d y 
i nter ve nti o n. 

U ri nal ysis assess me nts are liste d i n A p pe n di x 7 a n d are re q uire d at t he ti me p oi nts 
liste d i n t he S o As (Ta ble 1 a n d Ta ble 2 f or Part A; Ta ble 3 a n d Ta ble 4 f or Part B).

β- h u ma n c h ori o n g o na d otr o pi n m ust be deter mi ne d fr o m ser u m at Scree ni n g a n d 
fr o m uri ne t hereafter i n W O C B P
(Ta ble 1 a n d Ta ble 2 f or Part A; Ta ble 3 a n d Ta ble 
4 f or Part B). A p pr o priate me n o pa usal stat us of w o me n ca n be c o nfir me d b y testi n g 
f or i ncreased F S H le vels at Scree ni n g. A ne gati ve uri ne pre g na nc y  test o n Da y  1 of 
eac h c ycle pri or t o st u d y i nter ve nti o n a d mi nistrati o n nee ds t o be a vaila ble. Res ults of 
t he m ost rece nt pre g na nc y test ( wit hi n t he last 7 da ys) m ust be a vaila ble pri or t o ne xt 
a d mi nistrati o n of t he st u d y dr u g.

Bl o o d a n d uri ne sa m ples will be c ollecte d f or t he cli nical la b orat or y tests liste d i n 
A p pe n di x 7,  at t he ti me p oi nts liste d i n t he S o A (Ta ble 1 a n d Ta ble 2 f or Part A; 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 9 / 1 5 5
Ta ble 3 a n d Ta ble 4 f or Part B ). Bl o o d sa m ples f or P K will be o btai ne d pri or t o t he 
a d mi nistrati o n of t he st u d y i nter ve nti o n. All sa m ples s h o ul d be clearly i de ntifie d. 

A d diti o nal tests ma y  be perf or me d at a n y ti me d uri n g t he st u d y, as deter mi ne d 
necessar y  b y t he I n vesti gat or or re q uire d by l ocal re g ulati o ns.

T he tests will be perf or me d b y  the l ocal la b orat or y. T he S p o ns or m ust recei ve a list 
of t he l ocal la b orat or y nor mal ra n ges bef ore s hi p me nt of st u d y inter ve nti o n(s). A n y 
c ha n ges t o t he ra n ges d uri n g t he st u d y must be f or war de d t o t he desi g nate d 
or ga nizati o n.

T he I n vesti gat or m ust re vie w eac h la b orat or y re p ort, d oc u me nt t heir re vie w, a n d 
rec or d a n y cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y in t he A E secti o n 
of t he eC R F. T he la b orat or y  re p orts m ust be file d wit h t he s o urce d oc u me nts.
8. 2. 6
S uici d al I de atio n a n d Be h a vi or al Ris k M o nit ori n g
N ot a p plica ble. 
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts
T he defi niti o ns of a n A E a n d a S A E are i n A p pe n di x 5.
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A d verse E ve nt 
a n d Seri o us A d v erse E ve nt I nf or m ati o n
T he A E re p orti n g peri o d f or safety 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 3 0- Da y  F oll o w -U p Safet y  Visit.
A n y  S A E assesse d as relate d t o st u d y i nter ve nti o n m ust be rec or de d a n d re p orte d, as i n dicate d 
i n A p pe n di x 5 , 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  i nter ve nti o n.
T he met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y of A Es (i ncl u di n g S A Es) a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are i n  A p pe n di x 5 .
8. 3. 2
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts
At eac h st u d y visit, t he partici pa nt will be q uerie d o n c ha n ges i n his or her c o n diti o n. 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 p orte d b y  t he partici pa nt or o bser ve d b y t he In vesti 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 
e C R F. All S A Es a n d all n o nseri o us A E SI s 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 s pecifie d i n A p pe n di x 5 .
8. 3. 3
F oll o w -U p of A d verse E ve nts a n d Seri o us A d verse E ve nts
A Es are rec or de d a n d assesse d c o nti n u o usl y t hr o u g h o ut t he st u d y, as s pecifie d i n Secti o n  8. 3. 1
a n d are assesse d f or t heir o utc o me at t he 3 0 -Da y  F oll o w- U p Safet y Visit. All S A Es o n g oi n g at 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 0 / 1 5 5
t he 3 0 -D a y  F oll o w -U p Safet y Visit m ust be m o nit ore d a n d f oll o we d u p b y t he 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 mpts 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. F urt her i nf or mati o n o n 
F oll o w -U p pr oce d ures i s gi ve n i n A p pe n di x 5 .
Base d o n t he n o n cli nical t o xic ol o g y st u dies, a d verse e ve nts of m yel os u p pressi o n, GI t o xicit y, 
o p p ort u nistic i nfecti o ns a n d aller gic reacti o ns are c o nsi dere d A E SI ( Secti o n  6. 9 ). T hese e ve nts 
m ust be re p orte d o n A E S I F or ms t o Merc k Healt hcare Gl o bal Patie nt Safet y  thr o u g h o ut t he 
st u d y u ntil res ol uti o n or per ma ne nt o utc o me of t he e ve nt.
8. 3. 4
Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us A d verse 
E ve nts
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 a n y a p plica ble site-s pecific re q uire me nts relate d t o t he 
re p orti n g of S A Es ( partic ularl y deat hs) i n v ol vi n g st u d y partici pa nts t o t he I n de pe n de nt Et hics 
C o m mittee/I nstit uti o nal Re vie w B oar d ( I E C/IR B ) t hat a p pr o ve d t he st u dy.
I n acc or da nce wit h I C H G o o d Cli nical Practice ( 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 nts, 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 li ne wit h res pecti ve r eg ulati o ns, t he S p o ns or/ desi g nee will i nf or m t he I n vesti 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 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 opies of Safet y  Re p orts i n t he I nvesti gat or Site File. Nati o nal re g ulati o ns re gar di n g Safet y 
Re p ort n otificati o ns t o I n vesti gat ors 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 Sa fety 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 n a ti o nal or site-s pecific 
re g ulati o ns, t he In vesti gat or will be res p o nsi ble f or pr o m ptl y  n otifyi n g t he c o n cer ne d I E C/I R 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.
8. 3. 5
Pre g n a nc y
O nl y  pre g na ncies t he I nvesti gat or c o nsi ders t o be relate d t o t he st u d y inter ve nti o n (e. g., 
res ulti n g fr om a dr u g i nteracti o n wit h a c o ntrace pti ve met h o d) are A Es. H o we ver, all 
pre g na ncies wit h a n esti mate d c o nce pti o n date d uri n g t he peri o d defi ne d i n Secti o n  8. 3. 1 ( Ti me 
Peri o d a n d Fre q ue nc y  for C ollecti n g A d verse E ve nt a n d Seri o us A d verse E ve nt I nf or mati o n) 
m ust be rec or de d i n t he A E pa ge/secti o n of t he e C 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 nvesti 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 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 1 / 1 5 5
Re p ort F or m, w hic h m ust be tra ns mitte d b y  the sa me pr ocess s pecifie d f or S A E re p orti n g i n
A p pe n di x 5 , secti o n o n Re p orti n g Seri o us A d verse E ve nts .
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  the 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  ab 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 n ge 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  8. 3. 1 , w hile n or mal o utc o mes m ust be re p orte d wit hi n 4 5 d a y s after 
deli ver y .
I n t he e ve nt of a pre g na nc y i n 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 i nter 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  
a n d t he partici pa nt m ust be f oll o we d as i n dicate d a b o ve.
8. 4
Tre at me nt of O ver d ose
F or t his st u d y, a n y d ose hi g her t ha n t he calc ulate d d ose f or t hat partic ular a d mi nistrati o n wit hi n 
a 1 2- h o ur ti me peri o d is c o nsi dere d a n o ver d ose. 
T he S p o ns or d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose , b ut t he I n vesti gat or 
s h o ul d use his or her cli nical j u d g me nt w he n treati n g a n o ver d ose of t he st u d y inter ve nti o n
c o nsi deri n g the prese nti n g s y m pt o ms a n d sta n dar d e val uati o n res ults. 
F or m o nit ori n g p ur p oses, a n y case of o ver d ose, e ve n if it n ot ass ociate d wit h a n A E or a S A E, 
a n y over d ose is rec or de d i n t he e C R F a n d re p orte d t o dr u g safety i n a n e x pe dite d ma n ner. 
O ver d oses are rep orte d o n a S A E Re p ort F or m, f oll o wi n g t he pr oce d ure i n A p pe n di x 5,  secti o n 
o n re p orti n g S A Es. 
8. 5
P h ar m ac o k i netics
Sa m pli n g ti me sc he d ules f or deter mi nati o n of M 3 2 5 8 ca n be f o u n d i n Ta ble 5 f or Part A a n d 
f or M 3 2 5 8 a n d de xa met has o ne i n Ta ble 6 f or Part B. W h ole bl o o d sa m ples of a p pr o xi matel y 
4 0 m L  in C y cle 1 of Part A will be c ollecte d f or meas ure me nt of plas ma c o nce ntrati o ns of 
M 3 2 5 8 ; w h ole bl o o d sa m ple of a p pr o xi matel y 30 m L i n C y cle 1 a n d 3 0 m L o n C y cle 2 of Part 
B will be c ollecte d f or meas ure me nt of p las ma c o nce ntrati o ns of M 3 2 5 8
a n d de xa met has o ne.
T he act ual date a n d ti me ( 2 4-h o ur cl oc k ti me) of eac h sa m ple will be rec or de d t o calc ulate 
act ual ti me ela pse d si nce t he pri or d ose a d mi nistrati o n . Details o n pr ocesses f or c ollecti o n a n d 
s hi p me nt of t hese sa m ples are i n La b orat or y Ma n ual.
T he q ua ntificati o n of M 3 2 5 8 a n d de xa met has o ne i n plas ma will be perf or me d usi n g a vali date d 
assa y met h o d. C o nce ntrati o ns will be use d t o e val uate t he P K of st u d y  i nter ve nti o n. 
Re mai ni n g sa m ples c ollecte d f or a nal yses of pl as ma co nce ntrati o n m a y  als o be use d t o e val uate 
meta b olites safety or efficac y as pects relate d t o c o ncer ns arisi n g d uri n g or after t he st u d y.
T he defi niti o ns f or P K para meters are liste d i n  A p pe n di x 8 .
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 2 / 1 5 5
Details o n pr ocesses f or c ollecti o n a n d s hi p me nt of t hese sa m ples are i n t he La b orat or y Ma n ual.
Rete nti o n ti me a n d p ossi ble a nal ys es of sa m ples after t he e n d of st u d y are s pecifie d i n t he 
res pecti ve I CF.
8. 6
P h ar m ac o d y n a mics
P har mac o d y na mic mar ker s are descri be d i n Secti o n 8. 8 , a n d details o n pr ocesses f or c ollecti o n 
a n d s hi p me nt of t hese sa m ples are i n t he La b orat or y  Ma n ual.
 
 
 
 
 
 
 
8. 8
Bi o m ar k ers

C ollecti o n of partici pa nt sa m ples f or bi o mar ker researc h is als o part of t his st u d y an d 
is g o ver ne d by t he a p pr o priate I C F.

T he f oll o wi n g partici pa nt sa m ples f or bi o mar ker researc h are re q uire d a n d will be 
c ollecte d fr o m all partici pa nts i n t his st u d y, as s pecifie d i n t he S o A s (Ta ble 1 a n d 
Ta ble 2 f or Part A; Ta ble 3 a n d Ta ble 4 f or Part B):
o
Bl o o d sa m ples f or a nal ysis of L- citr ulli ne, β 5c acti vit y i n w h ole bl o o d a n d 
L M P 7 acti vit y i n P B M Cs.
o
B o ne marr o w sa m ple f or deter mi n i n g c yt o ge netic ris k fact ors a n d mi ni mal 
resi d ual disease ( M R D).

Baseli ne b o ne marr o w sa m ple s t o i de ntif y c yt o ge netic ris k fact ors i n
or der t o e val uate ass ociati o ns wit h dr u g res p o nse.

Baseli ne b o ne marr o w sa m ples t o deter mi ne M M cl o nalit y bef ore 
treat me nt, w hic h is nee de d as a refere nce w he n e val uati n g M R D (i.e. 
disease b ur de n)
usi n g
ne xt ge nerati o n se q ue nci n g ( N G S) f or 
partici pa nts t hat e x perie nce a C R or s C R.

O n -st u d y bo ne marr o w as pirate t o deter mi ne M R D i n partici pa nts 
e x perie nci n g C R
or s CR
usi n g N G S a n d/ or ne xt ge nerati o n fl o w 
c yt o metr y. Of n ote, o nl y partici pa nts t hat e x perie nce a C R or s CR
will ha ve t heir baseli ne sa m ple a nal yz e d usi n g N G S , w hereas ne xt 
ge nerati o n fl o w c y t o metr y d oes n ot re q uire a baseli ne sa m ple.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 3 / 1 5 5
A p orti o n of t he b o ne marr o w sa m ple t o c o nfir m C R (i ncl u di n g s C R), as descri be d i n Secti o n 
8. 1 , will be se nt t o a la borat or y f or M R D
assess me nt b y  ne xt ge nerati o n fl o w c yt o metr y a n d/ or
ne xt ge nerati o n se q ue nci n g.
I n a d diti o n , partici pa nt sa m ples ma y be use d f or a d diti o nal researc h, as s pecifie d i n t he I C F.
Details o n pr ocesses f or c ollecti o n a n d s hi p me nt of t hese sa m ples are i n La b orat or y  Ma n ual. 
T he S p o ns or will st ore t he sa m ples i n a sec ure st ora ge s pace wit h a de q uate meas ures t o pr otect 
c o nfi de ntialit y. Rete nti o n ti me a n d p ossi ble a nal yses of sa m ples after t he e n d of st u d y are 
s pecifie d i n t he res pecti ve IC F.
8. 9
He alt h Ec o n o mics
N ot a p plica ble. 
8. 1 0
I m m u n o ge nicit y Assess me nts
N ot a p plica ble. 
9
St atistic al C o nsi der ati o ns
9. 1
St atistic al H y p ot hes es
T his is a n e x pl orat or y  st u d y. N o f or mal statistical h yp ot hesis will be teste d.
9. 2
S a m ple Size Deter mi n ati o n
D ose E sc al ati o n P art A
T he pla n ne d c o h ort size is 3 partici pa nts at a gi ve n d ose. Parallel scree ni n g a n d e nr oll me nt of 
partici pa nts will all o w eli gi ble partici pa nts t o e nr oll , t he c o h ort size m a y  t heref ore i ncrease t o 
a ma xi m u m of 4 partici pa nts. A n y a d diti o nal partici pa nts e nr olle d i n t he st u d y at a gi ve n d ose, 
will c o m plete all st u d y pr oce d ures a n d assess me nts as per pr ot oc ol a n d are c o nsi dere d i n t he 
Ba yesia n m o del if t he y f ulfill t he criteria f or i ncl usi o n i n t he D LT set .
T he t otal sa m ple size will de pe n d o n t he n u m ber of c o h orts a n d re gi me ns t o be e val uate d. It is 
a ntici pate d t hat 1 5 t o 2 1 partici pa nts ( 4 pr ojecte d d ose le vels wit h 3 t o 9 partici pa nts eac h) ma y 
be nee de d. If c ha n ge(s) i n re gi me n w o ul d occ ur, t he sa m ple size ma y  i ncrease.
T he f oll o wi n g sce nari o is a ntici pate d :
2 d ose le vels wit h 3 partici pa nts eac h a n d 2 d ose le vels wit h 6 partici pa nts eac h, res ulti n g i n 
1 8 partici pa nt s.
C o nsi deri n g f or e xa m ple o ne c ha n ge i n re gi me n after t he first d ose le vel, t he sa m ple size ma y 
i ncrease by 3 if i n t he ne w re gi me n, t he a b o ve sce nari o h ol ds. 
D ose E x p a nsi o n P art B
Part B be gi ns wit h a safet y r u n-i n of 6 partici pa nts . D ose a dj ust me nts d uri n g P art B m a y  occ ur . 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 4 / 1 5 5
Part B will i ncl u de 3 0 partici pa nts treate d at t he sa me d ose w h o are e val ua ble f or res p o nse i n 
a t w o-sta ge desi g n . T his sa m ple size will gi ve a p osteri or pr o ba bilit y  of 8 5 % t hat t he O R R ≥ 
2 0 % if 8/ 3 0 res p o nses are see n at t he fi nal a nal ys is. 
A n i nteri m a nalys is will occ ur after e nr oll me nt of 1 5 partici pa nts treate d at t he sa me d ose are 
e val ua ble f or res p o nse. T he c ut-off f or t he i nteri m a nal ysis was c h ose n t o bala nce s ufficie nt 
i nf or mati o n f or decisi o n wit h t he p ote ntial of s pari n g partici pa nt s a n i nefficie nt treat me nt. T he 
b o u n dar y  a n d o perati o nal c haracteristics are descri be d i n Secti o n 9. 4. 1 .
If i n t he c o urse of t he e x pa nsi o n a n d/or at t he i nteri m a nal ysis, t he M 3 2 5 8 d ose is m o difie d, 
t he n o nl y  partici pa nts treate d at t he sa me d ose will be c o nsi dere d i n t he t w o-sta ge desi g n. 
T heref ore , t he n u m ber of partici pa nts i n t he e x pa nsi o n c o h ort mi g ht i ncrease b y  a p pr o xi mately 
3 t o 2 1 partici pa nts t o reac h t he re q uire d n u m ber of 3 0 partic i pa nts treate d o n t he sa me d ose
w h o are e val ua ble f or res p o nse acc or di n g t o I M W G .
A d diti o nall y , i n P art B (as well as i n P art A) t he S M C ma y  rec o m me n d t o e n d t he e nr oll me nt 
i n t he e x pa nsi o n c o h ort d ue t o safet y c o ncer ns.
9. 3
P o p ul ati o ns f or A n al yses
T he a nal ys is p o p ulati o ns are s pecifie d bel o w. T he fi nal decisi o n t o e x cl u de partici pa nts fr o m 
a n y a nalys is p o p ulati o n will be ma de d uri n g a data re vie w meeti n g pri or t o data base l oc k.
D L T = D ose -li miti n g t o xicit y; P d = P har mac o d y na mics; P K = P har mac o ki netics .
9. 4
St atistic al A n al yses
T here is n o f or mal si g nifica nce le vel f or t his st u d y, a n d all a nal ys es are c o nsi dere d descri pti ve.
9. 4. 1
Effic ac y A n al yses
E n d p oi nt
St ati sti c al A n al y si s M et h o d s
Pri m ar y
N o pri m ar y effi c a c y e n d p oi nt i s s p e cifi e d
A n al y s i s S et
D e s cri pti o n
S cr e e ni n g ( S C R) 
All p arti ci p a nt s, w h o pr o vi d e d i nf or m e d c o n s e nt, r e g ar dl e s s of t h e p arti ci p a nt’ s 
r a n d o mi z ati o n a n d st u d y i nt er v e nti o n st at u s i n t h e st u d y.
S af et y ( S A F)
All p arti ci p a nt s, w h o w er e a d mi ni st er e d a n y d o s e of a n y st u d y i nt er v e nti o n. 
A n al y s e s will c o n si d er p arti ci p a nt s a s tr e at e d.
D L T
T h e D o s e E s c al ati o n S et will i n cl u d e 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 st u d y i nt er v e nti o n a n d m e et at l e a st o n e of t h e f oll o wi n g crit eri a:

E x p eri e n c e d at l e a st o n e D L T d uri n g t h e D L T p eri o d, r e g ar dl e s s of t h e 
a d mi ni st er e d n u m b er of d o s e s of st u d y i nt er v e nti o n / c o m pl eti o n of t h e D L T 
p eri o d

R e c ei v e d at l e a st 8 0 % of t h e pl a n n e d c u m ul ati v e d o s e a n d 8 0 % of 
pl a n n e d a d mi ni str ati o n s of e a c h tr e at m e nt d uri n g t h e D L T p eri o d a n d 
c o m pl et e d t h e D L T p er i o d.
P K
All p arti ci p a nt s, w h o r e c ei v e at l e a st o n e d o s e of st u d y i nt er v e nti o n, h a v e n o 
cli ni c all y i m p ort a nt pr ot o c ol d e vi ati o n s or i m p ort a nt e v e nt s aff e cti n g P K, a n d pr o vi d e 
at l e a st o n e m e a s ur a bl e p o st d o s e c o n c e ntr ati o n. P arti ci p a nt s will b e a n al y z e d p er
t h e a ct u al st u d y i nt er v e nti o n t h e y r e c ei v e d.
P d
All p arti ci p a nt s, w h o r e c ei v e at l e a st o n e d o s e of st u d y i nt er v e nti o n, h a v e n o 
cli ni c all y i m p ort a nt pr ot o c ol d e vi ati o n s or i m p ort a nt e v e nt s aff e cti n g P d, a n d pr o vi d e 
at l e a st o n e m e a s ur a bl e P d e n d p oi nt p o st d o s e.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 5 / 1 5 5
S e c o n d ar y
Wi ll b e s p e cifi e d i n t h e I nt e gr at e d A n al y si s Pl a n fi n ali z e d b ef or e d at a b a s e l o c k.
I n g e n er al, c o nti n u o u s v ari a bl e s will b e s u m m ari z e d u si n g n u m b er of p arti ci p a nt s 
( n); m e a n, st a n d ar d d e vi ati o n; m e di a n, 2 5 t h P er c e ntil e t o 7 5 t h P er c e ntil e ( Q 1 -Q 3), 
mi ni m u m, a n d m a xi m u m. If t h er e ar e l e s s t h a n 5 o b s er v ati o n s a v ail a bl e, o nl y 
m e a n a n d t h e o b s er v e d d at a will b e gi v e n.
C at e g ori c al v ari a bl e s will b e s u m m ari z e d u si n g fr e q u e n c y c o u nt s a n d 
p er c e nt a g e s.
T h e c al c ul ati o n of pr o p orti o n s will b e b a s e d o n t h e n u m b er of p arti ci p a nt s i n t h e 
a n al y si s s et of i nt er e st, u nl e s s ot h er wi s e s p e cifi e d i n t h e st u d y I nt e gr at e d A n al y si s 
Pl a n.
K a pl a n -M ei er e sti m at e s ( pr o d u ct -li mit e sti m at e s) will b e pr e s e nt e d f or t h e an al y si s 
of P F S a n d O S t o g et h er wit h a s u m m ar y of a s s o ci at e d st ati sti c s ( m e di a n s ur vi v al 
ti m e, 6-, 1 2-m o nt h s ur vi v al r at e e sti m at e s a n d e sti m at e s f or e v er y 6 m o nt h s 
t h er e aft er if a p pli c a bl e) i n cl u di n g t h e c orr e s p o n di n g 2-si d e d 9 5 % CI s.
T erti ar y/ E x pl or at or y
Wi ll b e s p e cifi e d i n t h e I nt e gr at e d A n al y si s Pl a n fi n ali z e d b ef or e d at a b a s e l o c k.
CI = C o nfi d e n c e I nt er v al; P F S = Pr o gr e s si o n -Fr e e S ur vi v al; O S = O v er all S ur vi v al .
I n Part B, a t w o-sta ge desi g n wit h a n i nteri m a nal ysis after 1 5 partici pa nts treate d o n t he sa me 
d ose a n d e val ua ble f or res p o nse is f oresee n. If less t ha n 3 res p o nses are see n o ut of 1 5 
partici pa nts e val ua ble f or res p o nse, t he e x pa nsi o n c o h ort is st o p pe d f or f utilit y or d ose is 
i ncrease d. T his gi ves a pr o ba bilit y  of falsely st o p pi n g t he st u d y if t he dr u g were effecti ve 
(ass u mi n g a n O R R of 3 5 %) of 6 %, w hile alrea dy c orrectl y st o p pi n g t he st u d y if t he dr u g is n ot 
s ufficie ntl y effecti ve (ass u mi n g a n O R R of 1 5 %) of 6 0 %. Else t he st u d y co nti n ues, u ntil 3 0 
partici pa nts are e val ua ble f or res p o nse.
At t his i nteri m a nal ysis t here is t he p ossi bilit y t o:

If ≥3 res p o n ders are see n (i n partici pa nts treate d o n t he sa me d ose) a n d t here are n o 
safety c o ncer ns , c o nti n ue t he st u d y o n t he sa me d ose u ntil 1 5 a d diti o nal partici pa nts 
are treate d at t he sa me d ose w h o are e val ua ble f or res p o nse acc or di n g t o I M W G, or

If < 3 res p o n ders are see n, eit her:
o
St o p t he st u d y  f or f utilit y, or
o
I ncrease t he d ose (wit hi n t he li mits s pecifie d i n Secti o n 4. 1 a n d o nl y  t o d oses 
wit h a n esti mate d 7 5 % perce ntile of t he D L T rate bel o w 3 0 % fr o m t he
Ba yesia n m o del i n c o m bi nati o n will be c o nsi dere d ). E nr oll partici pa nts at t he 
ne w d ose u ntil 1 5 partici pa n ts treate d at t he ne w d ose are e val ua ble f or res p o nse 
acc or di n g t o I MW G. S u bse q ue ntl y  a ne w i nteri m a nal ysis is perf or me d . T he 
f oll o wi n g o pti o ns at t hat sec o n d i nteri m a nal ysis are p ossi ble (t he sa me f utilit y 
r ule as f or t he first i nteri m a p plies after 1 5 partici pa nts treate d o n t he sa me d ose 
w h o are e val ua ble f or res p o nse ):

If ≥3 res p o n ders (i n partici pa nts treate d o n t he sa me d ose) are see n a n d 
t here are n o safet y c o ncer ns: C o nti n ue at t he sa me d ose u ntil a d diti o nal 
1 5 partici pa nts are e val ua ble f or res p onse
(t o reac h o verall 3 0 
partici pa nts o n t he c ha n ge d d ose e val ua ble f or res p o nse), or

If < 3 res p o n ders are see n, st o p t he st u d y f or f utilit y.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 6 / 1 5 5
If a ny ot her o pti o n is dee me d necessar y , a pr ot oc ol a me n d me nt will be s u b mitte d.  
N o m ore t ha n 2 s uc h i nteri m a nal ys es will be perf or me d, u nless a pr ot oc ol a me n d me nt is 
s u b mitte d.
Treate d o n t he sa me d ose i ncl u des all partici pa nts w h o were pla n ne d t o recei ve t he sa me d ose.
9. 4. 2
S afet y A n al yses
A nal y ses t o deci de o n d ose escalati o n will be base d o n safety, P K, a n d P d da ta.
T o s u p p ort t he decisi o n o n d ose escalati o n, t he S M C will recei ve res ults of a Ba yesia n d ose -
t o xicit y m o del, i ncl u di n g t he rec o m me n dati o n of ne xt d ose le vel fr o m t he m o del.
T he Ba y esia n d ose -t o xicit y a nal ysis will be perf or me d o n t he d ose escalati o n set.
M ore details of t his Ba yesia n t w o -para meter l o gistic re gressi o n m o del (Ne ue nsc h wa n der et al. 
2 0 0 8 ) are f urt her s pecifie d i n A p pe n di x 1 0 . 
F or eac h S M C meeti n g, t he m o del will be u p date d wit h t he n u m ber of D L Ts a n d e val ua ble 
partici pa nts per d ose le vel. Base d o n t he o bser ve d data t he m o del will s u g gest t he ne xt d ose 
le vel. T he f oll o wi n g d ose le vels are f oresee n: 1 0 m g, 2 0 m g, 3 5 m g, a n d 5 0 m g . H o we ver, t he 
S M C ma y  deci de t o ha ve differe nt or a d diti o nal d ose le vels or s ki p d ose le vels, e xce pt 
escalati o n m a y  not pr ocee d t o a n y d ose hi g her t ha n 5 0 m g. I n case escalati o n s h o ul d pr ocee d 
t o d oses hi g her t ha n 5 0 m g, a n a me n d me nt will be s u b mitte d. 
T he d ose s u g geste d b y  the m o del f or t he ne xt c o h ort will be t he d ose wit h mi ni mal Ba yesia n 
Ris k (a m o n g all c o nsi dere d d oses).
T he tar get D L T t o xicit y  f or t he M T D is 2 5 %.
T he S M C ma y  ch o ose a differe nt d ose t ha n s u g geste d b y  the B a y esia n escalati o n a p pr oac h ( n ot 
hi g her t ha n 5 0 m g ). Als o, t he S M C ma y  deci de t o c ha n ge t he d osi n g re gi me n as s pecifie d i n 
S ecti o n 4. 1.  I n suc h a case t he d ose t o xicit y mo del will be e xte n de d, or a se parate m o del will 
be set u p.
Us uall y  decisi o ns o n d ose escalati o n are ta ke n o nce all partici pa nts of t he m ost rece nt c o h ort 
ha ve c o m plete d t he D L T peri o d or d isc o nti n ue d. I n e xce pti o nal cases, h o we ver, t he S M C ma y 
rec o m me n d o n t he ne xt c o h ort earlier, i.e., bef ore t he last partici pa nt of a c o h ort has fi nis he d 
t he D L T peri o d (c o nsi deri n g t he a vaila ble data fr o m t he c urre nt a n d pre vi o us c o h orts as well 
as m o del rec o m me n dati o n). Per defi niti o n of t he D ose Escalati o n set, partici pa nts w h o ha ve 
n ot c o m plete d t he D L T peri o d are n ot i ncl u de d f or u p date of t he m o del, u nless t he y ex perie nce d 
a D L T. H o we ver, data of s uc h partici pa nts will be i ncl u de d at ne xt S M C (if criteria f or t he 
D ose Escalati o n set are t he n f ulfille d).
Bef ore first d osi n g, t he ass u me d relati o ns hi p bet wee n d ose le vel a n d t o xicit y is s pecifie d 
t hr o u g h t he pri or distri b uti o n. T he pri or distri b uti o n c h ose n f or t his st u d y c orres p o n d t o t he 
f oll o wi n g mea n/ me dia n esti mates of D LT pr o ba bilit y :
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 7 / 1 5 5
Pr o b a bilit y  f or D L T
1 0 m g 
2 0 m g 
3 5 m g
5 0 m g
Pri or m e a n
1 5 %  
1 9 %  
2 4 %  
2 8 % 
Pri or m e di a n
8 % 
1 3 % 
1 8 % 
2 2 %
D L T = D ose -li miti n g t o xicit y.
Details of t he m o del, i ncl u di n g t he pri or distri b uti o n ca n be f o u n d i n  A p pe n di x 1 0 .
Decisi o ns of t he S M C i n t he e x pa nsi o n c o h ort will als o be ai de d b y a Ba ye sia n t w o-para meter 
l o gistic re gressi o n m o del wit h t he sa me s pecificati o ns as f or t he d ose escalati o n, e xce pt t he 
pri or. T he p ri or will be base d o n t he data see n i n t he m o n ot hera p y d ose escalati o n a n d s pecifie d 
in t he S M C c harter bef ore t he first S M C f or t he e x pa nsi o n c o h ort occ urs . T he m o del will be 
u p date d at ti mes of S M Cs i n t he e x pa nsi o n c o h ort. A d diti o nal st o p pi n g r ules i n P art B a p pl y 
(see S ecti o n 7. 1) .
Ot her s pecificati o ns are as f or d ose escalati o n a n d ca n be f o u n d i n  A p pe n di x 1 0 .
Details o n a nal ys es f or S M Cs will be descri be d i n t he S M C I nte grate d A nal y sis Pla n.
All ot her safet y a nal ys es will be perf or me d o n t he Safet y  A nalys is p o p ulati o n.
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
( D L T s)
A ft er e n d of d o s e e s c al ati o n a n d m ai n a n al y si s, th e n u m b er a n d pr o p orti o n of 
p arti ci p a nt s e x p eri e n ci n g D L T s will b e r e p ort e d b y d o s e l e v el, b a s e d o n 
o b s er v ati o n s d uri n g t h e fir st st u d y i nt er v e nti o n c y cl e. P o st eri or pr o b a biliti e s ( 2. 5 %, 
2 5 %, 5 0 %, 7 5 %, a n d 9 7. 5 % q u a ntil e s) f or D L T pr o b a biliti e s at s el e ct e d d o s e s will 
b e e sti m at e d fr o m t h e B a y e si a n l o gi sti c r e gr e s si o n m o d el. A s e n siti vit y a n al y si s 
will b e p erf or m e d u si n g fr e q u e nti st m o d eli n g ( wit h o ut pri or).
S e c o n d ar y
I n g e n er al, c o nti n u o u s v ari a bl e s will b e s u m m ari z e d u si n g n u m b er of p arti ci p a nt s 
( n); m e a n, st a n d ar d d e vi ati o n; m e di a n, 2 5t h P er c e ntil e t o 7 5 t h P er c e ntil e ( Q 1 -Q 3), 
mi ni m u m, a n d m a xi m u m. If t h er e ar e l e s s t h a n 5 o b s er v ati o n s a v ail a bl e o nl y m e a n 
a n d t h e o b s er v e d d at a will b e gi v e n.
C at e g ori c al v ari a bl e s will b e s u m m ari z e d u si n g fr e q u e n c y c o u nt s a n d 
p er c e nt a g e s.
T h e c al c ul ati o n of pr o p orti o n s will b e b a s e d o n t h e n u m b er of p arti ci p a nt s i n t h e 
a n al y si s s et of i nt er e st, u nl e s s ot h er wi s e s p e cifi e d i n t h e st u d y I nt e gr at e d A n al y si s 
Pl a n .
D et ail s w ill b e s p e cifi e d i n t h e I nt e gr at e d A n al y si s Pl a n fi n ali z e d b ef or e d at a b a s e 
l o c k.
T erti ar y/ E x pl or at or y
D et ail s w ill b e s p e cifi e d i n t h e I nt e gr at e d A n al y si s Pl a n fi n ali z e d b ef or e d at a b a s e 
l o c k.
D L T = D o s e -li miti n g t o xi cit y.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 8 / 1 5 5
Q T/ Q Tc A n al ysis
T he E C G para meter will be s u m marize d b y  descri pti ve statistics per ti me p oi nt; c ha n ges fr o m 
Baseli ne will be calc ulate d.
Ti me -matc he d, re plicate E C Gs a n d P K sa m ples c ollecte d i n t he d ose escalati o n p hase will be 
use d t o a nal yze f or c Q Tc res p o nses usi n g sl o pe a nal ys is of e x p os ure/res p o nse. T his a nal ysis 
ma y  be re p orte d se paratel y.
9. 4. 3
Ot her A n al yses
P K, P d, a n d bi o mar ker e x pl orator y  anal ys es will be s pecifie d i n t he I nte grate d A nal ys is Pla n 
fi nalize d bef ore data base l oc k. I nte grate d a nal yses acr oss st u dies, s uc h as t he p o p ulati o n P K 
a nal ys is a n d P d a nalys es will be prese nte d se paratel y  fr o m t he mai n cli nical st u d y re p ort.
9. 4. 4
Se q ue nce of A n al yses
T his is a n e x pl orat or y  st u d y.
T he S M C will re vie w a vaila ble data d uri n g st u d y co n d uct. T he c ut off f or d ose escalati o n 
assess me nts i n P art A b y  the S M C will be tri g gere d b y  the c o m pleti o n of t he D L T peri o d ( or
disc o nti n uati o n ) of t he last part ici pa nt i n t he res pecti ve d ose escalati o n c o h ort. If e nr ollme nt of 
t he last partici pa nt i n a d osi n g c o h ort is dela y e d, t he S M C ma y  deci de o n a vaila ble data f or 
e nr oll me nt a n d d ose of t he ne xt d osi n g c o h ort bef ore all partici pa nts i n a c o h ort ha ve c o m plete d
C y cle 1. I n these cases, c ut-off ca n be ea rlier (after D L T peri o d of t he first 2 partici pa nts is 
fi nis he d or t he y e x perie nce d a D L T).
F or Part A, t he c ut off f or a n e x pl orat or y i nteri m a nal ysis of t he safet y, a v aila ble P K, a vaila ble 
P d a n d preli mi nar y a nt it u m or acti vit y data fr o m t he c o m plete d ose escalati o n will be tri g gere d 
w he n all partici pa nts e nr olle d i n t he d ose escalati o n:

Ha d t he first o n -st u d y i nter ve nti o n t u m or assess me nt or

E x perie nce d deat h or

Wit h dre w f or a n y reas o n
w hic he ver c o mes first.
I n Part B, a n i nteri m a nal y sis will be c o n d ucte d after 1 5 partici pa nts w h o are treate d at t he 
sa me d ose are e val ua ble f or res p o nse. If at t his i nteri m a nalys is, t he d ose is i ncrease d, o ne 
a d diti o nal i nteri m a nal ysis ma y occ ur after 1 5 p artici pa nts are treate d o n t he ne w d ose a n d 
are e val ua ble f or res p o nse. A d diti o nall y , t here are S M Cs pla n ne d after 3, 6, a n d i n t he 
f oll o wi n g e ver y 6 partici pa nts ha ve fi nis he d t he D L T peri o d . For all S M Cs t he a nalys es 
necessar y  f or t hese S M Cs will be c o n d ucte d (as descri be d i n t he i nte grate d a nalys is pla n f or 
S M Cs) .
A d diti o nal a nal y sis d uri n g t he st u d y mi g ht be c o n d ucte d, e. g., f or p u blicati o n p ur p oses.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 9 / 1 5 5
T he pri mar y  a nalys is will be perf or me d o nce all partici pa nts ha ve c o m plete d t he sec o n d 
res p o nse e val uati o n ( or disc o nti n ue d pre mat urely) .
F oll o w - Up a nal ys es t o f urt her efficac y a n d safety data will be d o ne o nce t he E n d of St u d y  
has bee n reac he d.
T he preli mi nar y  f o o d effect will be e val uate d at t he ti me of interi m a nal ys is i n t he a vaila ble 
partici pa nts i n Part B. T he res ults will be i n dicati ve of w het her t o e val uate f urt her 
partici pa nts o n f o o d effect or st o p t he f o o d effect e val uati o n.
M ore details will be descri be d i n t he I nte grate d A nal y sis Pla n.
1 0
S afet y M o nit ori n g C o m mittee
T he S M C c o nsists of c ore (i nter nal a n d e xter nal v oti n g) me m bers f or t he S p o ns or ( Gl o bal 
Patie nt Safet y  Pr o d uct Lea der [ C hair], Me dical Res p o nsi ble, Cli nical P har mac ol o gist a n d 
Bi ostatisticia n), t he C o or di nati n g I n vesti gat or, a n d t he Me di cal M o nit or 
of t he C o ntract 
Researc h Or ga nizati o n. A d h oc me m bers ma y  be i n vite d as nee de d. 
D uri n g t he d ose -escalati o n P art A of t he st u d y, t he S M C will e val uate t he safet y data (i ncl u di n g 
D L Ts) a n d a vaila ble P K a n d P d data, as defi ne d i n t he S M C c harter , i n or der t o ma ke 
rec o m me n dati o ns o n t he d osi n g of t he ne xt partici pa nt c o h ort.
A B a y esia n t w o-para meter l o gistic re gressi o n m o del (Ne ue nsc h wa n der et al. 2 0 0 8 ) will be 
use d t o assist t he S M C wit h d ose selecti o n. F urt h er details o n t he Ba yesia n m o del are pr o vi de d 
i n Secti o n 9. 4. 2 a n d A p pe n di x 1 0
Descri pti o n of t h e Ba yesia n D ose Escalati o n M o del 0.  
T he S M C ma y  ch o ose a differe nt d ose t ha n s u g geste d b y  the B a y esia n escalati o n m o del 
(h o we ver , n ot hi g her t ha n 5 0 m g) .
Base d o n t he o bser ve d t o xicit y  pr ofile a n d a vaila ble P K a n d P d, d ose le vel(s) t hat are differe nt 
t ha n t he pres pecifie d d oses ma y  be rec o m me n de d b y  the S M C. H o we ver, escalati o n m a y  not 
pr ocee d t o a n y d ose hi g her t ha n 5 0 m g. I n case escalati o n s h o ul d pr ocee d t o d oses hi g her t ha n 
5 0 m g , a n a me n d me nt will be s u b mitte d . Base d o n o bser ve d t o xicit y pr ofile, P K a n d P d data,
t he S M C ma y rec o m me n d c ha n gi n g t he d osi n g re gi me n as s pecifie d i n S ecti o n 4. 1.
T he pla n ne d c o h ort size is 3 partici pa nts at a gi ve n d ose. Parallel scree ni n g a n d e nr oll me nt of 
partici pa nts will all o w eli gi ble partici pa nts t o e nr oll, t he c o h ort size ma y  t heref ore i ncrease t o 
4 partici pa nts . A n y ad diti o nal partici pa nts e nr olle d i n t he st u d y at a gi ve n d ose, will c o m plete 
all st u d y pr oce d ures a n d assess me nts as per pr ot oc ol . Base d o n t he safet y , P K a n d P d data (if 
a vaila ble) c ollecte d fr o m t he partici pa nts i n a c o h ort, t he S MC ma y  rec o m me n d t hat n o f urt her 
partici pa nts are re q uire d i n a c o h ort bef ore t he pla n ne d c o h ort size is reac he d. I n cases w here 
e nr oll me nt of t he last partici pa nt i n a d osi n g c o h ort was dela ye d, t he S M C ma y deci de ( base d 
o n a vaila ble data) u p o n e nr ol lme nt a n d d ose f or t he ne xt d osi n g c o h ort bef ore all partici pa nts 
i n a c o h ort ha ve c o m plete d t he D L T peri o d. F or t his partici pa nt, t he S M C will c o nsi der all 
a vaila ble data (a n d a n y s u bse q ue nt e mer gi n g data at a s u bse q ue nt meeti n g). A n a d-h oc meeti n g 
will be c o n v e ne d if t his partici pa nt e x perie nces a D L T.
Partici pa nts w h o di d n ot e x perie nce a D L T a n d w h o eit her di d n ot recei ve at least 8 0 % of t he 
pla n ne d c u m ulati ve d ose of treat me nt d uri n g t he D L T peri o d , or at least 8 0 % of t he pla n ne d 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 0 / 1 5 5
a d mi nistrati o ns, or di d n ot c o m plete t he D L T o bser vati o n peri o d will n ot be c o nsi dere d f or 
D L T e val uati o n a n d i n t he Ba ye sia n m o del. A n S M C meeti n g wit h selecti o n of d ose f or ne xt 
c o h ort will als o be hel d if n ot all partici pa nts i n a c o h ort are e val ua ble (e. g., if a parti ci pa nt
misse d m ore t ha n 2 0 % of treat me nt i n t he first c y cle f or a n y reas o n ot her t ha n a D L T). 
T he S M C mi g ht m o dif y  the sc he d ule of P K a n d P d sa m pli n g base d o n e mer ge nt data. H o we ver, 
t he t otal bl o o d v ol u me ta ke n f or P K a n d P d sa m ples will n ot e xcee d bl o o d v ol u me descri be d 
i n t his pr ot oc ol or t he L a b orat or y Ma n ual . 
F or t he e x pa nsi o n part of t he st u d y, t he S M C will m o nit or t he safet y of M 3 2 5 8 
at t he 
rec o m me n de d d ose wit h de xa met has o ne a n d ma y rec o m me n d b y c o nse ns us o n c o nti n uati o n at
t he sa me d ose , c ha n ge in d ose (o nl y  to d oses declare d safe b y  SM C 
i n m o n ot hera p y ),
m o dificati o ns of t he st u d y pr ot oc ol , or st o p of e x pa nsi o n c o h ort . T he sa me D L T criteria as f or 
t he m o n ot hera p y d ose escalati o n will a p pl y. A d diti o nal safet y st o p pi n g r ules a p pl y as o utli ne d 
i n Sec ti o n 7. 1 .
T he S M C will e val uate t he safet y of t he c o m bi nati o n t hera py after 3, 6, (safety r u n-i n) a n d 
s u bse q ue ntl y ever y  6 partici pa nt s fi nis he d t heir D L T peri o d or disc o nti n ue d , u nless a c ha n ge 
i n d osin g has occ urre d. I n case t he d osi n g i n t he e x pa nsi o n c o h ort was c ha n ge d, t he ne xt S M C 
will be hel d after t he ne xt 3 partici pa nts ha ve fi nis he d t he D L T peri o d or disc o nti n ue d a n d t he n 
t he S M Cs are sc he d ule d e ver y 6 partici pa nts ha vi n g fi nis he d t he D L T peri od or disc o nti n ue d.
F or S M Cs i n t he safety r u n-i n a n d t he first S M C after a d ose c ha n ge, d osi n g of ne w par tici pa nts 
ca n o nl y start after S M C has deci de d t o pr ocee d (i nclu di n g o n w hat d ose). F or all ot her S M Cs 
t here is n o pa use i n e nr oll me nt.
T he S M C decisi o ns i n e x pa nsi o n c o h ort will als o be s u p p orte d b y  a tw o -para meter Ba ye sia n 
l o gistic re gressi o n m o del. F or details o n t he m o del , see S ecti o n 9. 4. 2.
T he S M C ma y  m o dif y t he fre q ue nc y of meeti n gs as dee me d a p pr o priate d uri n g t he st u d y.
After t he e val uati o n of t he f o o d effect i n 1 5 partici pa nts i n Part B, t he S M C will ta ke t he 
decisi o n w het her t o i ncrease t he n u m ber of partici pa nts w hic h are t o be i ncl u de d i n t he f o o d 
effect e val uati o n. 
T he s pecific w or ki n g pr oce d ures will be descri be d i n a n S M C c harter, w hic h will be esta blis he d 
pri or t o t he start of d osi n g.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 1 / 1 5 5
1 1
Refere nces 
Bra ye r J a n d Baz R. T he p ote ntial of i xaz o mi b, a sec o n d-ge nerati o n pr oteas o me i n hi bit or, i n 
t he treat me nt of m ulti ple m yel o ma. T her A d v He mat ol. 2 0 1 7 J ul; 8( 7): 2 0 9 - 2 0. 
B ust or os M, M o u hie d di ne T H, Deta p pe A, et al. Esta blis he d a n d N o vel Pr o g n ostic Bi o mar kers 
i n M ulti ple M yel o ma. A m S oc Cli n O nc ol E d uc B o o k. 2 0 1 7; 3 7: 5 4 8 - 6 0. 
Ca v o M, Tacc hetti P, Patriarca F et al. La ncet. 2 0 1 0; 3 7 6: 2 0 7 5 - 8 5. Errat u m i n: La ncet. 2 0 1 1; 
3 7 8: 1 8 4 6.
Ce n giz Se val G
a n d Be ksac M. 
T he safety of b ortez o mi b f or t he treat me nt of m ulti ple 
m y el o ma. E x pert O pi n Dr u g Saf. 2 0 1 8 Se p; 1 7( 9): 9 5 3 - 6 2.
Di m o p o ul os M A, 
Orl o ws ki R Z, Fac o n T et al. Retr os pecti ve matc he d -pairs a nal ys is of 
b ortez o mi b pl us de xa met has o ne vers us b ortez o mi b m o n ot hera p y  in rela pse d m ulti ple 
m y el o ma. Hae mat ol o gica. 2 0 1 5 Ja n; 1 0 0( 1): 1 0 0 – 6. 
Ettari R, Za p palà M, Grass o S, M us oli n o C, I n na o V, Alle gra A. I m m u n o pr oteas o me -selecti ve 
a n d n o n- selecti ve i n hi bit ors: A pr o misi n g a p pr oac h f or t he treat me nt of m ulti ple m y el o ma. 
P har mac ol T her. 2 0 1 8 Fe b; 1 8 2: 1 7 6 - 9 2.
F o o d a n d Dr u g A d mi nistrati o n Dr u g De vel o p me nt a n d Dr u g I nteracti o ns. Dr u g I nteracti o ns & 
La beli n g > Dr u g De vel o p me nt a n d Dr u g I nteracti o ns. Ta ble of S u bstrates, I n hi bit ors a n d 
I n d ucers/ 
Ta ble 
2- 2, 
Accesse d 
N o ve m ber 
2 9,  
2 0 1 8. 
A vaila ble 
at: 
w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI nteracti o ns
La beli n g/ uc m 0 9 3 6 6 4. ht m #ta ble 2 - 2.
F o o d a n d Dr u g A d mi nistrati o n Dr u g De vel o p me nt a n d Dr u g I nteracti o ns. Ta ble 3- 2, Accesse d 
N o ve m ber 
2 9, 
2 0 1 8. 
A vaila ble 
at: 
w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI nteracti o ns
La beli n g/ uc m 0 9 3 6 6 4. ht m #ta ble 3 -2. 
F o o d a n d Dr u g A d mi nistrati o n Dr u g I nteracti o ns Ta ble, Accesse d N o ve m ber 2 9, 2 0 1 8. 
A vaila ble at: // dr u g -i nteracti o ns. me dici ne.i u.e d u/ Mai n-Ta ble.as p x
Haller mal m K, Se ki K, Wei C, et al. T u m or necr osis fact or -al p ha i n d uces c o or di nate d c ha n ges 
i n maj or hist oc o m pati bilit y  class I prese ntati o n pat h wa y , res ulti n g i n i ncrease d sta bilit y of class 
I c o m ple xes at t he cell s urface. Bl o o d. 2 0 0 1 A u g 1 5; 9 8( 4): 1 1 0 8 - 1 5.
Harris o n SJ, Ha n g Q uac h H, S pe ncer A, Pri nce H M. C o m me nt o n “ Retr os pecti ve matc he d -
pairs anal ys is of b ortez o mi b pl us de xa met has o ne vers us b ortez o mi b m o n ot hera p y  i n rela pse d 
m ulti ple m y el o ma”. Hae mat ol o gica. 2 0 1 5 Se p; 1 0 0( 9):e 3 7 9.
K u bicz k o va L, P o ur L, Se dlari k o va L et al. Pr oteas o me i n hi bit ors - m olec ular basis a n d c urre nt 
pers pecti ves i n m ulti p le m yel o ma. J Cell M ol Me d. 2 0 1 4 J u n; 1 8( 6): 9 4 7 -6 1. 
K u mar S K, Dis pe nzieri A, Fraser R et al. Earl y rela pse after a ut ol o g o us he mat o p oietic cell 
tra ns pla ntati o n re mai ns a p o or pr o g n ostic fact or i n m ulti ple m y el o ma b ut o utc o mes ha ve 
i m pr o ve d o ver ti me. Le u ke mia. 2 0 1 8 A pr; 3 2( 4): 9 8 6- 9 5.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 2 / 1 5 5
K u mar S K, Pai va B, A n ders o n K C et al. I nter nati o nal M y el o ma W or ki n g Gr o u p c o nse ns us 
criteria f or res p o nse a n d mi ni mal resi d ual disease assess me nt i n m ulti ple m y el o ma. La ncet 
O nc ol. 2 0 1 6 A u g; 1 7:e 3 2 8 - 4 6.
L o nial S, Waller E K, Ric har ds o n P G, et al. Ris k fact ors a n d ki nectics of t hr o m b oc yt o pe nia 
ass ociate d wit h b orte x o mi n f or rela pse d, refract or y multi ple m y el o ma. Bl o o d. 2 0 0 5 Dec 1 ; 
1 0 6( 1 2) : 3 7 7 7- 8 4.
L o nial S, Di m o p o ul os M, Pal u m b o A et al. El ot uz u ma b. T hera p y f or Rela pse d or Refract o r y 
M ulti ple M y el o ma. N E n gl J Me d. 2 0 1 5 A u g 1 3; 3 7 3( 7): 6 2 1- 3 1. 
Mc Bri de A
a n d R y a n P Y. Pr oteas o me i n hi bit ors i n t he treat me nt of m ulti ple m yel o ma. E x pert 
Re v A ntica ncer T her. 2 0 1 3 Mar; 1 3( 3): 3 3 9- 5 8.
Micale N, Scar baci K, Tr oia n o V et al. Pe pti de -base d pr otea s o me i n hi bit ors i n a ntica ncer dr u g 
desi g n. Me d Res Re v. 2 0 1 4 Se p; 3 4( 5): 1 0 0 1 - 6 9.
Miller Z,  Lee W, Ki m K B. T he i m m u n o pr oteas o me as a t hera pe utic tar get f or he mat ol o gical 
mali g na ncies. C urr Ca ncer Dr u g Tar gets. 2 0 1 4; 1 4( 6): 5 3 7 - 4 8. 
Ne ue nsc h wa n der B, Bra ns o n M, Gs p o ner T. Critical as pects of t he Ba ye sia n a p pr oac h t o p hase 
I ca ncer trials. Stat Me d 2 0 0 8; 2 7( 1 3): 2 4 2 0 - 3 9.
O ke n 
M M. 
M ulti ple 
m y el o ma: pr o g n osis 
a n d sta n dar d treat me nt. Ca ncer I n vest. 
1 9 9 7; 1 5( 1): 5 7 - 6 4.
Pal u m b o A a n d G a y  F. H o w t o treat el derl y patie nts wi t h m ulti ple m y el o ma: c o m bi nati o n of 
t hera py or se q ue nci n g. He mat ol o g y , 2 0 0 9 b; 1: 5 6 6- 7 7.
Raj k u mar S V, Ga hrt o n G, Leif Ber gsa gel P. A p pr oac h t o t he treat me nt of m ulti ple m y el o ma: 
a clas h of p hil os o p hies. Bl o o d. 2 0 1 1 Se p 2 2; 1 1 8( 1 2): 3 2 0 5 – 1 1.
Ric har ds o n P, Hi d es hi ma T, A n ders o n K. T hali d o mi de i n m ulti ple 
m y el o ma. Bi o me d 
P har mac ot her 2 0 0 2; 5 6: 1 1 5- 2 8. 
S o n ne vel d P, Sc h mi dt -W olf I G, va n der H olt B et al. B ortez o mi b i n d ucti o n a n d mai nte na nce 
treat me nt i n patie nts wit h ne wl y d ia g n ose d m ulti ple m y el o ma: res ults of t he ra n d o mize d p hase 
III H O V O N-6 5/ G M M G -H D 4 trial. J Cli n O nc ol. 2 0 1 2 A u g 2 0; 3 0( 2 4): 2 9 4 6 -5 5.
S o n ne vel d P. S h o ul d mi ni mal resi d ual disease ne gati vit y  not be t he e n d p oi nt of m y el o ma 
t hera py?  Bl o o d A d v. 2 0 1 7 Mar 1 4; 1( 8): 5 2 2- 5.
Ste wart A K, Jac o b us S, F o nseca R et al. Mel p hala n, pre d nis o ne, a n d t hali d o mi de vs mel p hala n, 
pre d nis o ne, a n d le nali d o mi de ( E C O G E 1 A 0 6) i n u ntreate d m ulti ple m y el o ma. Bl o o d. 2 0 1 5 
Se p 1 0; 1 2 6( 1 1): 1 2 9 4 -3 0 1.
S weeti n g M, Ma n der A, Sa bi n T . bcr m: Ba ye sia n C o nti n ual Reassess me nt Met h o d Desi g ns f or 
P hase I D ose -Fi n di n g Trials. J Stat S oft ware . A u g ust 2 0 1 3; 5 4:( 1 3); 1 - 2 6.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 3 / 1 5 5
1 2
A p pe n dices
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 4 / 1 5 5
A p pe n di x 1
A b bre vi ati o ns 
A D L
Acti vit y  of Dail y Life
A E
A d verse E ve nt
A E SI
A d verse E ve nts of S pecial I nterest
A L T
Ala ni ne A mi n otra nsferase 
A N C
A bs ol ute Ne utr o p hil C o u nt
A S T
As partate A mi n otra nsferase
A U C
Area u n der t he C o nce ntrati o n - Ti me C ur ve
B E D
Bi ol o gicall y  Effecti ve D ose 
C L/ f  
Ap pare nt T otal B o d y  C leara nce
C L ss
Cleara nce at Stea d y State
C ma x
M a xi m u m O bser ve d C o nce ntrati o n 
C R
C o m plete Res p o nse 
C S R
Cli nical St u d y  Re p ort
(e) C R F
(electr o nic) Case Re p ort F or m
C T
C o m p ute d T o m o gra p h y
C V
C oefficie nt of Variati o n
D L T
D ose -Li miti n g T o xicit y
D O R
D urati o n of Res p o nse
E C G
Electr ocar di o gra m
E C O G
Easter n C o -o perati ve O nc ol o g y Gr o u p
E D C
Ele ctr o nic Data C a pt ure
F D A
F o o d a n d Dr u g A d mi nistrati o n
Fi H
First i n H u ma n
F L C
Free Li g ht C hai n 
F S H
F ollicle -Sti m ulati n g H or m o ne
G C P
G o o d Cli nical Practice
G- C S F
Gra n ul oc y te-C ol o n y  Sti m ulati n g Fact or 
GI
Gastr oi ntesti nal
H A
Healt h A ut h orities
HI V
H u ma n I m m u n o deficie nc y  Vir us
H R
Hazar d Rati o
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 5 / 1 5 5
H R T
H or m o ne Re place me nt T hera p y
I B
I n vesti gat or’s 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 nisati o n
I E C
I n de pe n de nt Et hics C o m mittee
I F E
I m m u n ofi xati o n Electr o p h oresis
I Mi D
I m m u n o m o d ulat or y Imi de Dr u g
I M W G
I nter nati o nal Myel o ma W or ki n g Gr o u p
I N R
I nter nati o nal N or malize d Rati o
I RB 
I nstit uti o nal Re vie w B oar d
L M P 7
Lar ge M ultif u ncti o nal Pr otease 7 
M M
M ulti ple M y el o ma
M- pr otei n
M o n ocl o nal Para pr otei n
M R
Mi ni mal Res p o nse
M R D
Mi ni mal Resi d ual Disease 
M RI
Ma g netic Res o na nce I ma gi n g
M T D  
Ma xi m u m T olerate d D ose
M U G A
M ulti gate d A c q uisiti o n
N A
N ot A p plica ble
N CI -
C T C A E
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
N G S
N e xt- Ge nerati o n- Se q ue nci n g
N S AI Ds  
N o n ster oi dal A nti- i nfla m mat or y Dr u gs
O R
O verall Res p o nse
O R R
O verall Res p o nse Rate
O S
O verall S ur vi val
P B M C
Peri p heral Bl o o d M o n o n uclear Cell
P C
P las ma C ell
P d
P har mac o d y na mics
P D
Pr o gressi ve Disease
P F S
Pr o gressi o n -Free S ur vi val
PI
Pr oteas o me I n hi bit ors
Pi C
P o w der i n Ca ps ule
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 6 / 1 5 5
P K
P har mac o ki netics
P R
Partial Res p o nse
Q D
O nce Dail y
Q Tc
Q T I nter val C orrecte d
Q Tc F
Q T I nter val C orrecte d usi n g Fri dericia’s F or m ula 
R D E
Rec o m me n de d D ose a n d Re gi me n f or E x pa nsi o n
R R M M
Rela pse d Refract or y  M ulti ple M yel o ma
S A E
Seri o us A d verse E ve nt
s C R
Stri n ge nt C o m plete Res p o nse
S M C
Safet y  M o nit ori n g C o m mittee
S o A
Sc he d ule of Acti vities
S P D
S u m of t he P r o d ucts of t he M a xi mal P er pe n dic ular D ia meters of M eas ure d 
L esi o ns
S P E P
Ser u m Pr otei n Electr o p h oresis 
S T D
Se verel y T o xic D ose 
S U S A R
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns
T E A E
Treat me nt -E mer ge nt A d verse E ve nt
T R A E
Treat me nt - Relate d A d verse E ve nt
U L N
U p per Li mit of N or mal
U P E P
Uri ne Pr otei n Electr o p h oresis
U S
U nite d States
V G P R
Ver y  G o o d Partial Res p o nse 
W O C B P
W o ma n/ W o me n of C hil d beari n g P ote ntial
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 7 / 1 5 5
A p pe n di x 2
St u d y G o ver n a nce
Fi n a nci al Discl os ure
I n vesti gat ors a n d S u b -I n vesti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate 
fi na ncial i nf or mati o n, as re q ueste d, f or t he S p o ns or t o s u b mit c o m plete a n d acc urate 
fi na ncial certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y aut h o rities. T his 
i nf or mati o n is re q uire d d uri n g t he st u dy a n d f or 1 year after c o m pleti o n of t he st u d y.
I nf or me d C o nse nt Pr ocess

T he I n vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y to t he 
partici pa nt or his/ her le gall y aut h orize d represe ntati ve a n d a ns wer all q uesti o ns o n 
t he st u d y.

Partici pa nts will be i nf or me d t hat t heir partici pati o n is v ol u ntar y .

Partici pa nts or t heir le gall y-a ut h orize d re prese ntati ve will be re q uire d t o si g n a 
state me nt of i nf or me d c o nse nt t hat meets t he re q uireme nts of 2 1 C F R 5 0; t he 
Ja pa nese mi nisterial or di na nce o n G C P; l ocal re g ulati o ns; I CH g ui deli nes; Healt h 
I ns ura nce P orta bilit y  an d Acc o u nta bilit y  
Act ( HI P A A) re q uire me nts, w here 
a p plica ble; a n d t he I RB/I E C or st u d y  ce nter.

T he me dical rec or d will
i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was 
o btai ne d bef ore t he partici pa nt was e nr olle d i n t he st u d y an d t he date t he writte n 
c o nse nt was o btai ne d. T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt will
als o si g n t he I C F.

If t he I CF is u p date d d uri n g t heir partici pati o n i n t he st u d y, partici pa nts will be re-
c o nse nte d t o t he m ost c urre nt, a p pr o ve d versi o n.

A c o p y of t he I CF(s) will be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gally 
a ut h orize d re prese ntati ve.

T he ori gi nal si g ne d a n d date d c o nse nt will re mai n at t he I nvesti gat or’s site a n d will
be safel y a rc hi ve d s o t hat it ca n be retrie ve d at a ny ti me f or m o nit ori n g, a u diti n g a n d 
i ns pecti o n p ur p oses.
D at a Pr otecti o n

T he S p o ns or will assi g n a u ni q ue i de ntifier t o parti ci pa nts after o btai ni n g t heir 
i nf or me d c o nse nt. A n y partici pa nt rec or ds or datasets t hat are tra nsferre d t o t he 
S p o ns or will c o ntai n t he i de ntifier o nl y;  partici pa nt na mes or a n y i de ntifia ble 
i nf or mati o n will n ot be tra nsferre d.

T he S p o ns or will i nf or m par tici pa nts t hat t heir pers o nal st u d y-relate d data will be 
use d per l ocal data pr otecti o n a n d pri vac y  la ws. T he le vel of discl os ure will als o be 
e x plai ne d t o t he partici pa nt a n d pre g na nt part ners (if a p plica ble), w h o will be 
re q uire d t o gi ve c o nse nt f or t heir data t o be use d, as s pecifie d i n t he i nf or me d c o nse nt.

T he partici pa nt will be i nf or me d t hat his/ her me dical rec or ds m a y  be e xa mi ne d b y  
Cli nical 
Q ualit y  
Ass ura nce a u dit ors or ot her S p o ns or -a p p oi nte d, a ut h orize d 
pers o n nel, b y a p p r o priate IR B/I E C me m bers, a n d b y re g ulat or y a ut h orit y i ns pect ors. 
All s uc h pers o ns will strictl y  mai ntai n partici pa nts’ c o nfi de ntiality.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 8 / 1 5 5

T he I nvesti gat or will c o m plete t he partici pa nt re gistrati o n f or m a n d fa x it t o t he 
me dical m o nit or . If t he partici pa nt meets all i ncl usi o n criteria a n d d oes n ot meet a ny 
of t he e xcl usi o n criteria, t he me dical m o nit or
will i nf or m t he I n vesti gat or a n d t he 
S p o ns or of t he re gistrati o n n u m ber b y e mail or fa x. If t he partici pa nt is i neli gi ble f or 
t he st u d y, a partici pa nt n u m ber will be all ocate d a n d d oc ume nte d.
St u d y A d mi nistr ati ve
T he
C o or di nati n g I n vesti gat or liste d o n t he title pa ge re prese nts all I n vesti gat ors f or 
decisi o ns a n d disc ussi o ns o n t his st u d y, per I C H G C P. T he C o or di nati n g I n vesti gat or will 
pr o vi de e x pert me dical i n p ut a n d a d vice o n t he st ud 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 (C S R ).
T he st u d y will a p pear i n t he f oll o wi n g cli nical st u dies re gistries: E u dra C T 2 0 1 9- 0 0 0 9 4 7-
2 8 ; Cli nical Trail. g o v
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 O perati o ns a n d
St u d y  Refere nce Ma n ual.
Re g ul at or y a n d Et hic al C o nsi der ati o ns

T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d t he f oll o wi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes, i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces ( CI O M S) I nter nati o nal Et hical G ui deli nes

A p plica ble I C H G o o d Cli nical Practice ( G C P) G ui deli nes

A p plica ble la ws a n d re g ulati o ns

T he I nvesti gat or will s u b mit t he pr ot oc ol, pr ot oc ol a me n d me nts (if a p plica ble), I C F, 
I B, a n d ot her rele va nt d oc u me nts (e. g., a d vertise me nts) t o a n I RB/I E C a n d t he I RB/I E C 
will re vie w a n d a p pr o ve t he m bef ore t he st u d y is i nitiate d.

A n y  pr ot oc ol a me n d me nts (i.e., c ha n ges t o t he pr ot oc ol) will be d oc u me nte d i n writi n g 
a n d re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of c ha n ges, e xce pt f or c ha n ges 
necessar y  to eli mi nate a n i m me diate hazar d t o st u d y partici pa nts. W he n a p plica ble, 
a me n d me nt s will be s u b mitte d t o t he a p pr o priate Healt h A ut h orities.

T he I n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:

Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y to t he I R B/I E C a n n uall y or m ore 
fre q ue ntly per t he I R B’s/I E C’s re q uire me nts, p olicies, a n d pr oce d ures.

N otif y i n g t he I RB/I E C of S A Es or ot her si g nifica nt safety fi n di n gs, as re q uire d b y  
I RB/I E C pr oce d ures

Pr o vi di n g o versi g ht of t he st u d y co n d uct at t he site a n d a d here nce t o re q uire me nts of 
2 1 C F R, I CH g ui deli nes, t he I RB/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical 
st u dies (if a p plica ble), a n d all ot her a p plica ble l ocal re g ulati o ns

T he pr ot oc ol a n d a n y ap plica ble d oc u me ntati o n will be s u b mitte d or n otifie d t o t he 
Healt h A ut h orities i n acc or da nce wit h all l ocal a n d nati o nal re g ulati o ns f or eac h site.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 9 / 1 5 5
E mer ge nc y Me dic al S u p p ort

T he S p o ns or or desi g nee will pr o vi de E mer ge nc y  
Me dical S u p p ort car ds t o 
partici pa nts f or use d uri n g t he st u d y. T hese pr o vi de t he mea ns f or partici pa nts t o 
i de ntif y the msel ves as partici pati n g i n a cli nical st u d y. Als o , t hese gi ve healt h care 
pr o vi ders access t o a n y i nf or mati o n a b o ut t his partici pati o n t hat ma y  be nee de d t o 
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 o n t he 
E mer ge nc y  Me dical S u p p ort car d m a y  incl u de t he pr ocess f or e me r ge nc y un 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 In vesti gat or 
cari n g f or t he partici pa nt. C o nse q ue ntl y, 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. If t he I n vesti gat or is a vaila ble w he n a n 
e ve nt occ urs, t he y 
will a ns wer a n y q uesti o ns. A n y  su bse q ue nt acti o n (e. g., 
u n bli n di n g) will f oll o w t he sta n dar d pr ocess esta blis he d f or I n vesti gat ors.
W he n 
t he I n vesti gat or is n ot a vaila ble, t he S p o ns or pr o vi des t he a ppr o priate mea ns t o 
c o ntact t he me dical m o nit or . T his i ncl u des pr o visi o n of a 2 4- h o ur c o ntact n u m ber at a call 
ce nter, w here b y t he healt h care pr o vi ders will be gi ve n access t o t he a p pr o priate me dical 
m o nit or t o assist wit h t he me dical e mer ge nc y an d t o pr o v i 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.
Cli nic al St u d y I ns ur a nce a n d C o m pe ns ati o n t o P artici p a nts
I ns ura nce c o vera ge will be pr o vi de d f or eac h c o u ntr y partici pati n g i n 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.
Cli nic al St u d y Re p ort
After st u d y c o m pleti o n, t he S p o ns or will write a C S R i n c o ns ultati o n wit h t he C o or di nati n g 
I n vesti gat or.
P u blic ati o n

T he res ults of t his st u d y  ma y be p u 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 Healt hcare 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 nter st u dies o nl y  in t heir e ntiret y a n d n o t as i n di vi d ual site data. I n this 
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  agree 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.
Disse mi n ati o n of C li nic al St u d y D at a

After c o m pleti o n of t he st u d y , a C S R will be writte n b y  t he S p o ns or i n c o ns ultati o n 
wit h t he C o or di nati n g I n vesti gat or f oll o wi n g t he g ui da nce i n I C H T o pic E 3 a n d will 
be s u b mitte d i n acc or da nce wit h l ocal re g ulati o ns.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 0 / 1 5 5

A n y  an d all scie ntific, c o m mercial, a n d tec h nical i nf or mati o n discl ose d b y  the 
S p o ns or i n t his pr ot oc ol or else w here s h o ul d b e c o nsi dere d t he c o nfi de ntial a n d 
pr o prietar y  pr o perty of t he S p o ns or. T he I n vesti gat or s hall h ol d s uc h i nf or mati o n i n 
c o nfi de nce a n d s hall n ot discl o se t he i nf or mati o n t o a n y thir d part y  exce pt t o s uc h 
of t he I n vesti gat or’s e m pl o yees a n d staff w h o ha d bee n ma de a ware t hat t he 
i nf or mati o n is c o nfi de ntial a n d w h o are b o u n d t o treat it as s uc h a n d t o w h o m 
discl os ure is necessar y  to e val uate t hat i nf or matio n. T he I n vesti gat or s hall n ot use 
s uc h i nf or mati o n f or a n y pur p ose ot her t ha n f or deter mi ni n g m ut ual i nterest i n 
perf or mi n g t he st u d y an d, if t he parties deci de t o pr ocee d wit h t he st u d y, f or t he 
p ur p ose of c o n d ucti n g t he st u d y .

T he I n vesti gat or u n dersta n ds t hat t he i nf or mati o n de vel o pe d fr o m t his cli nical st u dy 
will be use d b y  the S p o ns or i n c o n necti o n wit h t he de vel o p me nt of t he st u d y 
i nter ve nti o n a n d t heref ore m a y  be
discl ose d as re q uire d t o ot her cli nical 
I n vesti gat ors, t o t he U S F o o d a n d Dr u g A d mi nist rati o n, a n d t o ot her g o ver n me nt 
a ge ncies. T he I n vesti gat or als o u n dersta n ds t hat, t o all o w f or t he use of t he
i nf or mati o n deri ve d fr o m t he cli nical st u d y, t he I nvesti gat or has t he o bli gati o n t o 
pr o vi de t he S p o ns or wit h c o m plete test res ults a n d all data de vel o pe d i n t he st u d y.
N o p u blicati o n or discl os ure of st u d y res ults will be per mitte d e xce pt u n der t he ter ms 
a n d c o n diti o ns of a se parate writte n a gree me nt.
D at a Q u alit y Ass ur a nce

All partici pa nt st u d y data will be rec or de d o n pri nte d or electr o nic C R Fs or
tra ns mitte d t o t he S p o ns or or desi g nee electr o nicall y (e. g., la b orat or y data). T he 
I n vesti gat or is res p o nsi ble f or verif y i n g t hat data e ntries are c o m plete, acc urate, 
le gi ble, a n d ti mely b y  ph y sically or electr o nicall y si gni n g t he C R F. Details f or 
ma na gi n g C R Fs are i n t he O perati o ns Ma n ual.

T he I n vesti gat or will mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n i n t he C R F.

T he I n vesti gat or will
per mit st u d y-relate d m o nit ori n g, q ualit y  ass ura nce a u dits, 
I RB/I E C re vie w, a n d re g ulat or y age nc y i ns pecti o ns a n d pr o vi de direct access t o t he 
st u d y file a n d s o urce data.

M o nit ori n g details descri bi n g strate g y (e g, ris k-base d i nitiati ves i n o perati o ns a n d 
q ualit y  suc h as Ris k Ma na ge me nt a n d Miti gati o n Strate gies a n d A nal yt ical Ris k -
Ba se d M o nit ori n g), met h o ds, res p o nsi bilities a n d re q uire me nts, i ncl u di n g ha n dli n g 
of n o nc o m plia nce iss ues a n d m o nit ori n g tec h ni q ues (ce ntral, re m ote, or o n- site 
m o nit ori n g) are i n t he M o nit ori n g Pla n or c o ntracts.

T he S p o ns or or desi g nee is res p o nsi ble f or d ata ma na ge me nt of t his st u d y, i ncl u di n g 
q ualit y  chec ki n g of t he data a n d mai ntai ni n g a vali date d data base. 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. 
Details will be o utli ne d i n Data Ma na ge me nt d oc u m e nts a n d pr oce d ures.

St u d y  M o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data i n 
t he C R F are acc urate, c o m plete, a n d verifia ble; t hat t he safet y an d ri g hts of 
partici pa nts are bei n g pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d per t he 
c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her st u d y agree me nts, I C H G C P , a n d all 
a p plica ble re g ulat or y re q uire me nts.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 1 / 1 5 5

T he I n vesti gat or will retai n rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I CFs, pertai ni n g 
t o t he c o n d uct of t his st u d y for 1 5 ye ars after st u d y co m pleti o n, u nless l ocal 
re g ulati o ns, i nstit uti o nal p olicies, or t he S p o ns or re q uires a l o n ger rete nti o n. N o 
rec or ds m a y  be destr o ye d d uri n g t he rete nti o n peri o d wit h o ut t he S p o ns or’s writte n 
a p pr o val. N o rec or ds ma y  be tra nsferre d t o a n ot her l ocati o n or part y  wit h o ut t he 
S p o ns or’s writte n n otificati o n.
S o urce D oc u me nts

S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d 
s u bsta ntiate t he i nte grit y of t he data c ollecte d.

T he I n vesti gat or will kee p a pa per or electr o nic file ( me dical file a n d ori gi nal me dical 
rec or ds) at t he site f or eac h st u d y partici pa nt. T he file will i de ntif y eac h partici pa nt, 
c o ntai n t he f oll o wi n g de m o gra p hic a n d me dical i nf or mati o n f or t he partici pa nt, a n d 
will be as c o m plete as p ossi ble:

Partici pa nt’s f ull na me, date of birt h, se x, hei g ht, a n d 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  i de ntifier (i.e., t he S p o ns or’s st u d y n u m ber) a n d partici pa nt’s st u d y n u m ber.

Dates of e ntr y int o t he st u d y (i.e., si g nat ure date o n t he i nf or me d c o nse nt) a n d eac h 
visit t o t he site

A n y  me dical e xa mi nati o ns a n d cli nical fi n di n gs pre defi ne d i n t he pr ot oc ol

All A Es

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 i nter ve nti o n, if a p plica ble.

All s o urce data will be file d (e. g., C T or M RI  sca n i ma ges, E C G rec or di n gs, a n d 
la b orat or y res ults). Eac h d oc u me nt will
ha ve t he partici pa nt n u m ber a n d t he 
pr oce d ure date; i deall y, pri nte d b y  the i nstr u me nt u se d f or t he pr oce d ure. As 
necessar y , me dical e val uati o n of t hese rec or ds will
be perf or me d, d oc u me nte d, 
si g ne d a n d date d by t he I n vesti gat or. 

Data rec or de d o n pri nte d or electr o nic C R Fs t hat are tra nscri be d fr o m s o urce 
d oc u me nts will be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies will be 
e x plai ne d. T he I n vesti gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer 
rec or ds, de pe n di n g o n t he st u d y. Als o, c urre nt me dical rec or ds will be a vaila ble.

T he S t u d y M o nit ors w ill use pri nt o uts of electr o nic files f or s o urce data verificati o n. 
T hese pri nt o uts will be si g ne d a n d date d b y  the I n vesti gat or a n d ke pt i n t he st u d y file.

S o urce d oc u me nts are st ore d at t he site f or t he l o n gest p ossi ble ti me per mitte d b y t he 
a p plica ble re g ulati o ns, a n d/ or as per I C H G C P g ui deli nes, w hic he ver is l o n ger. T he 
I n vesti gat or e ns ures 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 
S p o ns or’s writte n a p pr o val.

Defi niti o n of w hat c o nstit utes s o urce data is fo u n d i n e C R F g ui deli nes.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 2 / 1 5 5
St u d y a n d Site St art a n d Cl os ure
First Act of Recr uit me nt

T he st u d y  start date is t he date w he n t he cli nical st u d y will be o pe n f or recr uit me nt.

T he first act of recr uit me nt is w he n t he first site is o pe ne d a n d will be t he st u d y start 
date.
St u d y  Cl os ure a n d Site Ter mi nati o n

T he S p o ns or reser ves t he ri g ht t o cl ose t he st u d y site or ter mi nate t he st u d y at a n y 
ti me a n d f or a n y reas o n. St u d y  sites will be cl ose d u p o n st u d y co m pleti o n. A st u d y 
site is c o nsi dere d cl ose d w he n all re q uire d d oc u me nts a n d st u d y s u pplies ha ve bee n 
c ollecte d a n d a site cl os ure visit has bee n c o m plete d.

T he I nvesti gat or m a y  initiate site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble 
ca use a n d e n o u g h n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n.
o
Reas o ns f or t he earl y cl os ure of a st u d y site b y  the S p o ns or or I n vesti gat or 
ma y  i ncl u de:
o
Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of 
t he I RB/ I E C or l ocal healt h a ut h orities, t he S p o ns or's pr oce d ures, or G C P 
g ui deli nes
o
I na de q uate recr uit me nt of partici pa nts b y t he I n vesti gat or
o
Disc o nti n uati o n of f urt her de vel o p me nt of t he S p o ns or’s c o m p o u n d .

If t he st u d y is pre mat urel y  ter mi nate d or s us pe n de d, t he S p o ns or will pr o m ptl y  
i nf or m t he I n vesti gat ors, t he I E Cs/IR Bs, t he re g ulat or y  aut h orities, a n d a n y c o ntract 
researc h or ga nizati o n(s) use d i n t he st u d y of t he reas o n f or ter mi nati o n or s us pe nsi o n, 
as s pecifie d b y  the a p plica ble re g ulat or y re q uire me nts. T he I n vesti gat or will 
pr o m ptl y  inf or m t he partici pa nts a n d ass ure a p pr o priate partici pa nt t hera p y an d/ or
f oll o w- u p.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 3 / 1 5 5
A p pe n di x 3
C o ntr ace pti o n
Defi niti o ns :
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma ne ntl y sterile, as s pecifie d bel o w.
If fertilit y is u nclear (e. g. , a men 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 C B P is n ot:
1.
Pre me narc hal
2.
A pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:
•
D oc u me nte d h y sterect o m y
•
D oc u me nte d bilateral sal pi n gect o m y
•
D oc u me nte d bilateral o o p h orect o m y
D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t 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), I n vesti gat or discreti o n a p plies t o deter mi ne 
st u d y e ntr y.
3.
A p ost me n o pa usal fe male
•
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 ollicle -sti m ulati n g h or m o ne ( 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 py ( 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.
•
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 nestr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if s he wis hes t o c o nti n ue 
her H R T d uri n g t he st u d y. Ot her wise, s he m ust disc o nti n ue H R T t o all o w c o nfir mati o n of 
p ost me n o pa usal stat us bef ore st u d y e nr oll me nt.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 4 / 1 5 5
C o ntr ace pti o n G ui d a nce:
C O N T R A C E P TI V E S A L L O W E D D U RI N G T H E S T U D Y I N C L U D E:
Hi g hl y  Eff e cti v e M et h o d s T h at H a v e L o w U s er D e p e n d e n c y

I m pl a nt a bl e pr o g e st o g e n-o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n

I ntr a ut eri n e d e vi c e (I U D)

I ntr a ut eri n e h or m o n e-r el e a si n g s y st e m (I U S)

Bil at er al t u b al o c cl u si o n

V a s e ct o mi z e d p art n er: a hi g hl y eff e cti v e c o ntr a c e pti v e m et h o d pr o vi d e d t h at t h e p art n er i s t h e s ol e s e x u al 
p art n er of a W O C B P a n d t h e a b s e n c e of s p er m h a s b e e n c o nfir m e d. Ot h er wi s e, u s e a n a d diti o n al hi g hl y 
eff e cti v e m et h o d of c o ntr a c e pti o n. T h e s p er m at o g e n e si s c y cl e i s a p pr o xi m at el y 9 0 d a y s.
Hi g hl y  Eff e cti v e M et h o d s T h at Ar e U s er D e p e n d e nt

C o m bi n e d ( e str o g e n- a n d pr o g e st o g e n -c o nt ai ni n g) h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of 
o v ul ati o n

Or al

I ntr a v a gi n al

Tr a n s d er m al

I nj e ct a bl e

Pr o g e st o g e n -o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n

Or al

I nj e ct a bl e

S e x u al a b sti n e n c e: a hi g hl y eff e cti v e m et h o d o nl y if d efi n e d a s r efr ai ni n g fr o m i nt er c o ur s e d uri n g t h e e ntir e 
p eri o d of ri s k a s s o ci at e d wit h t h e st u d y i nt er v e nti o n. T h e r eli a bilit y of s e x u al a b sti n e n c e n e e d s t o b e 
e v al u at e d i n r el ati o n t o t h e d ur ati o n of t h e st u d y.
N ot e s:
C o ntr a c e pti v e u s e b y m e n or w o m e n i s c o n si st e nt wit h l o c al r e g ul ati o n s o n t h e u s e of c o ntr a c e pti v e m et h o d s 
f or cli ni c al st u d y p arti ci p a nt s.
Hi g hl y eff e cti v e m et h o d s ar e t h o s e wit h a f ail ur e r at e of < 1 % p er y e ar w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. 
T y pi c al u s e f ail ur e r at e s diff er fr o m t h o s e w h e n u s e d c o n si st e ntl y a n d c orr e ctl y.
H or m o n al c o ntr a c e pti o n m a y b e s u s c e pti bl e t o i nt er a cti o n wit h t h e st u d y i nt er v e nti o n( s), w hi c h m a y r e d u c e t h e 
effi c a c y of t h e c o ntr a c e pti v e m et h o d. A s s u c h, m al e c o n d o m s m u st b e u s e d i n a d diti o n t o h or m o n al 
c o ntr a c e pti o n. If l o c all y r e q uir e d, i n a c c or d a n c e wit h Cli ni c al Tri al F a cilit ati o n Gr o u p ( C T F G) g ui d eli n e s, 
a c c e pt a bl e c o ntr a c e pti v e m et h o d s a r e li mit e d t o t h o s e w hi c h i n hi bit o v ul ati o n a s t h e pri m ar y m o d e of a cti o n.
P eri o di c a b sti n e n c e ( c al e n d ar, s y m pt ot h er m al, p o st o v ul ati o n m et h o d s), wit h dr a w al ( c oit u s i nt err u pt u s), 
s p er mi ci d e s o nl y, a n d l a ct ati o n al a m e n orr h e a m et h o d ( L A M) ar e n ot a c c e pt a bl e m et h o d s of c o ntr a c e pti o n f or 
t hi s st u d y. M al e c o n d o m a n d f e m al e c o n d o m c a n n ot b e u s e d t o g et h er ( d u e t o ri s k of f ail ur e wit h fri cti o n).
All st u d y partici pa nts will be pr o vi de d wit h t he i nf or mati o n o n acce pta ble met h o ds of 
c o ntrace pti o n as part of t he i nf or me d C o nse nt F or m (I C F) pr ocess . Eac h st u d y partici pa nt will 
be as ke d t o rea d a n d si g n I CF stati n g t hat t he y un dersta n d t he re q uire me nts f or a v oi da nce of 
pre g na nc y , d o nati o n of o va or s per m d uri n g t he st u d y  u ntil 9 0 da ys after t he last d ose of st u d y 
i nter ve nti o n.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 5 / 1 5 5
A p pe n di x 4: 
Pr o hi bite d C o m e dic ati o n Pr ol o n gi n g t he Q T/ Q Tc I nter v al
Me dicati o ns k n o w n t o pr ol o n g t he Q T/ Q Tc i nter val m ust st o p at least 7 da y s bef ore t he first 
a d mi nistrati o n of t he st u d y inter ve nti o n a n d are n ot all o we d d uri n g t he st u d y i nter ve nti o n 
a d mi nistrati o n:
Ge neric Na mes: Aclar u bici n ( O nl y on N o n U S Mar ket) , A mi o dar o ne , A na greli de , Arse nic 
tri o xi de, Aste miz ole ( Re m o ve d fr o m U S Mar ket) , Azit hr o m y ci n, Be pri di ( Re m o ve d fr o m U S 
Mar ket) , C hl or o q ui ne , C hl or pr o mazi ne , Cil ostaz ol , Ci pr of l o xaci n, Cisa pri de ( Re m o ve d fr o m 
U S Mar ket) , Cital o pra m , Clarit hr o m y ci n, C ocai ne , Dis o p y ra mi de, D ofetili de , D o m peri d o ne 
( O nl y o n N o n U S Mar ket) , D o ne pezil , Dr o ne dar o ne , Dr o peri d ol, Er y t hr o myci n , Escital o pra m , 
Flecai ni de , Fl uc o naz ole , Gatifl o xaci n (Re m o ve d fr o m U S Mar ket) , Gre pafl o xaci n (Re m o ve d 
fr o m U S Mar ket) , Hal ofa ntri ne ( O nl y o n N o n U S Mar ket) , Hal o peri d ol , H y dr o q ui ni di ne, 
di h y dr o q ui ni di ne (O nl y  on N o n U S Mar ket) , I b o gai ne (O nl y o n N o n U S Mar ket) , I b utili de, 
Le v ofl o xaci n , Le v o me pr o mazi ne 
( met h otri me prazi ne) ( O nly 
o n 
N o n 
U S 
Mar ket) , 
Le v o met ha d yl  acetate (Re m o ve d fr o m U S Mar ket) , Le v os ul piri de (O nl y o n N o n U S Mar ket) , 
Mes ori dazi ne
(Re m o ve d 
fr o m U S 
Mar ket) , Met ha d o ne , M o xifl o xaci n , 
O n da nsetr o n, 
O xali plati n, Pa pa veri ne H Cl (Intra - c or o nar y), Pe nta mi di ne, Pi m ozi de, Pr o b uc ol (Re m o ve d 
fr o m U S Mar ket), 
Pr ocai na mi de, Pr o p of ol, Q ui ni di ne, R o xit hr o m y ci n (O nl y  on N o n U S 
Mar ket), Se v ofl ura ne, S otal ol, S parfl o xaci n ( Re m o ve d fr o m U S Mar ket), S ul piri de (O nl y  on 
N o n U S Mar ket), S ult o pri de (O nl y o n N o n U S Mar ket), Terfe na di ne (Re m o ve d fr o m U S 
Mar ket), 
Terli pressi n (O nl y  on N o n U S Mar ket), Ter o dili ne
(O nl y  on N o n U S Mar ket), 
T hi ori dazi ne, Va n deta ni b.
F or 
f urt her 
details 
a n d 
u p date 
refer 
t o 
t he 
we bsite 
“cre di ble me ds. or g ”
( w w w.cre di ble me ds. or g). 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 6 / 1 5 5
A p pe n di x 5
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -U p , a n d Re p orti n g
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 utical 
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 verit y or t o xicit y  of eac h A E.
I n vesti gat ors will reference t he Nati o nal Ca ncer I nstit ute - C o m m o n Ter mi n ol o g y  Criteria 
f or A Es (N CI -C T C A E), versi o n 5. 0 ( p u blicati o n date: 2 7 N o v 2 0 1 7 ), a descri pti ve 
ter mi n ol o g y t hat ca n be use d f or A E re p orti n g.
A ge neral gra di n g (se verit y/i nte nsity;  hereafter referre d t o as se verit y) scale is pr o vi de d at 
t he be gi n ni n g of t he a b o ve refere 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 defi niti o ns of Gra de 1 t hr o u g h Gra de 5, usi n g his or her best 
me dical j u d g me nt.
T he 5 ge neral gra 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 of Gra de 4, s uc h as a ne mia or ne utr o pe nia, is c o nsi dere d seri o us 
o nl y  if t he c o n diti o n meets o ne of t he seri o us criteria 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 lea di n g t o death 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 his 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 assess t he se verity of A Es per t he Q ualitati ve T o xicit y Scale, as f oll o ws:
Mil d:
T he partici pa nt is a ware of t he e ve nt or s ym pt o m, b ut t he e ve nt or s ym pt o m
is easil y 
t olerate d.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 7 / 1 5 5
M o derate:
T he partici pa nt e x perie nces s ufficie nt disc o mf ort t o i nterfere wit h or re d uce his or her us ual 
le vel of acti vity.
Se vere:
Si g nifica nt i m pair me nt of f u ncti o ni n g: t he partici pa nt is u na ble t o carr y  o ut his or her us ual 
acti vities.
I n vesti gat ors m ust als o s yste matically assess t he ca usal relati o ns hi p of A Es t o st u d y 
i nter ve nti o n (i ncl u di n g a n y ot her n o n-st u d y i nter ve nti o ns, ra diati o n t hera p y, etc.) usi n g t he 
f oll o wi n g defi niti o ns. Decisi ve fact ors f or t he assess me nt of ca usal relati ons hi p of a n A E t o 
t he M 3 2 5 8 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 M 3 2 5 8, k n o w n si de effects of M 3 2 5 8
or d e xa met has o ne , me dical hist or y, c o nc o mita nt 
me dicati o n, c o urse of t he u n derl y i n g disease, a n d 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 inter ve nti o n. 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 inter ve nti o n 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 bl e.
Rel ate d:
Reas o na bl y relate d t o t he st u d y inter ve nti o n. 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 inter ve nti o n u n der 
st u 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 a l 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 ym pt o ms, lea d t o st u d y inter ve nti o n disc o nti n uati o n or are c o nsi dere d ot her wise me dicall y 
i m p orta nt b y  the I n vesti gat or. If a la b orat or y ab n or malit y  fulfills 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 nts
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h

Is life-t hreate ni n g. 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 g ht ha ve 
ca use d 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 gs a n e xisti n g h os pitalizati o n

Res ults i n persiste nt or si g nifica nt disa bilit y  or i nca pacity

Is a c o n ge nital a n o maly or birt h defect

Is ot her wise c o nsi dere d t o be me dicall y i m 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 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 8 / 1 5 5
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 
i nter ve nti o n is als o c o nsi dere d a n S A E, as s pecifie d bel o w f or re p orti n g S A Es, A E SI s a n d 
D L Ts.
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 n t o o bser ve, a d mi nister or si m plif y st u d y inter ve nti o n or st u d y
pr oce d ure (f or i nsta nce, a n o ver ni g ht sta y to facilitate c he m ot hera p y a n d relate d h y drati o n 
t hera py a p plicati o n) are n ot c o nsi dere d S A Es. H o we ver, all e ve nts lea di n g t o u n pla n ne d 
h os pitalizati o ns or u n pla n ne d pr ol o n gati o n of a n electi ve h os pitalizati o n (i.e., u n desira ble 
effects of a n y a d mi nistere d treat me nt) m ust be d oc u me nte d a n d re p orte d as S A E.
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 duri 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 gre ssi 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 partici pa nt’ s 
ge neral c o n diti o n is m ore se vere t ha n e x pecte d f or t he 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 8. 3. 2.
A d verse E ve nts of S peci al I nterest
Base d o n t he oretical safet y  co ncer ns relate d t o a M 3 2 5 8, I n vesti gat or s h o ul d re p ort A E SIs 
( Secti o n 6. 9 ) t o t he S p o ns or i n a n e x pe dite d ma n ner, re gar dless if t he y satisf y t he sta n dar d 
defi niti o n of a n S A E. A Es of s pecial i nterest f or m o nit ori n g are t he n re p orte d f oll o wi n g t he 
pr oce d ure f or a n S A E s pecifie d bel o w f or re p orti n g S A Es, A E SI, a n d D L Ts.
Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E
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, w het her re p orte d b y  t he partici pa nt or o bser ve d b y t he I n vesti gat or.
It is i m p orta nt t hat eac h A E re p ort i ncl u de a descri pti o n of t he e ve nt, its d urati o n ( o nset a n d 
res ol uti o n dates a n d 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 st u d y i nter ve nti o n a d mi nistrati o n ti me), its se verit y , its 
ca usal relati o ns hi p wit h t he st u d y inter ve nti o n, 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 i nter ve nti o n, 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 is i n t he C R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns pr o vi de d b y  th e 
S p o ns or.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 9 / 1 5 5
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 m iti 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 nvesti 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 usi n g t he electr o nic S A E re p ort f or m i n t he Electr o nic Data 
Ca pt ure ( E D C) s ys te m.
Re p orti n g of S A Es usi n g a pa per re p ort f or m is re q uire d as a bac k -u p met h o d o nl y  for a n 
E D C s y ste m fail ure. Na mes, a d dresses, a n d tele p h o ne a n d fa x n u m bers will be i ncl u de d o n 
t he pa per f or m. All i nf or mati o n fr o m t he pa per f or m m ust be tra nscri be d i nt o t he electr onic 
f or m as s o o n as t he sys te m bec o mes a vaila ble.
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 n electr o nic S A E re p ort f or m m ust be c o m plete d i m me diatel y 
t hereafter.
Rele va nt pa ges fr o m t he C R F m a y  be pr o vi de d i n parallel (e. g., 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 
(e. g., la b orat or y res ults, h os pital re p ort, a ut o psy re p ort). 
T he I n vesti gat or m ust res p o n d t o a n y re q uest f or F oll o w -U p i nf or mati o n (e. g., a d diti o nal 
i nf or mati o n, o utc o me, fi nal e val uati o n, ot her rec or ds w here nee de d) or t o a n y q uesti o n t he 
S p o ns or/ desi g nee m a y  ha ve 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 t o e ns ure pr o m pt assess me nt of t he e ve nt b y t he 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 safet y 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 st u dy m o nit or , alt h o u g h i n e xce pti o nal 
circ u msta nces t he dr u g safety de part me nt m a y  co ntact t he I n vesti gat or directl y  to o btai n 
f urt her i nf or mati o n or t o disc uss t he e ve nt.
A d verse E ve nts of S peci al I nterest
I n t he e ve nt of a n o nseri o us A E SI , t he I n vesti gat or will n otif y  the S p o ns or/ desi g nee b y  
c o m pleti n g t he electr o nic A E SI Re p ort F or m i n t he E D C s yste m wit hi n 2 4 h o urs of 
occ urre nce of a n e ve nt . Seri o us A E SI s 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.
Re p orti n g of n o n -seri o us A E SIs usi n g a pa per re p ort f or m is re q uire d as a bac k-u p met h o d 
o nl y  for a n E D C s y ste m fail ure. Na mes, a d dresses, a n d tele p h o ne a n d fa x n u m bers will be 
i ncl u de d o n t he pa per re p ort f or m. All i nf or mati o n fr o m t he pa per f or m m ust be tra nscri be d 
i nt o t he electr o nic f or m as s o o n as t he s yste m bec o mes a vaila ble.
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, as s pecifie d i n Secti o n 6. 6 , m ust be rec or de d i n 
t he C R F wit hi n 2 4 H O U R S after bec o mi n g a ware of t he e ve nt. Seri o us D L Ts m ust be 
re p orte d i n a n e x pe dite d ma n ner as S A Es, as o utli ne d a b o ve.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 0 / 1 5 5
A p pe n di x 6
Li ver 
S afet y: 
S u g geste d 
Acti o ns 
a n d 
F oll o w -U p
Assess me nts
If a st u d y partici pa nt is n ote d t o ha ve A LT or A S T ele vate d > 3 x U L N ( ne w or w orse ni n g of 
pree xisti n g), t he a b n or malit y  s h o ul d be rec or de d as a n A E, re gar dless if cli nical s y m pt o ms are 
prese nt or n ot. If a st u d y partici pa nt is n ote d t o ha ve A L T or A S T > 3 ti mes U L N a n d t otal 
bilir u bi n > 2 U L N f or w hic h a n alter nati ve eti ol o g y has n ot bee n i de ntifie d, t he e ve nt s h o ul d 
be re p orte d as a S A E. T he I n vesti gat or m ust c o ntact t he S p o ns or Me dical Res p o nsi ble f or 
disc ussi o n.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 1 / 1 5 5
A p pe n di x 7
L a b or at or y Tests
Assess me nts i n A p pe n di x 7 t o be perf or me d by t he l ocal la b orat or y.
S er u m C h e mi str y
H e m at ol o g y
C o a g ul ati o n
Al b u mi n
A b s ol ut e l y m p h o c yt e c o u nt
A cti v at e d p arti al t hr o m b o pl a sti n ti m e
Al k ali n e p h o s p h at a s e
A b s ol ut e n e utr o p hil c o u nt
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 ( Q ui c k, I N R)
Al a ni n e a mi n otr a n sf er a s e
H e m at o crit
A m yl a s e
H e m o gl o bi n
A s p art at e a mi n otr a n sf er a s e
Pl at el et c o u nt
G a m m a gl ut a m yltr a n sf er a s e
R e d bl o o d c ell c o u nt
Bl o o d ur e a nitr o g e n/t ot al 
ur e a
W h it e bl o o d c ell c o u nt a n d 
diff er e nti al c o u nt
C al ci u m 
R e d bl o o d c ell m or p h ol o g y
C hl ori d e
R eti c ul o c yt e s
Cr e ati ni n e a
M e a n c or p u s c ul ar h e m o gl o bi n
C- r e a cti v e pr ot ei n
M e a n c or p u s c ul ar v ol u m e
F erriti 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
Gl u c o s e
L a ct at e d e h y dr o g e n a s e
S er u m q u a ntit ati v e 
i m m u n o gl o b uli n s f or I g G, I g A, 
I g M, I g D,I g E
Uri n e q u a ntit ati v e i m m u n o gl o b uli n s 
f or M- pr ot ei n
Li p a s e
S er u m M - pr ot ei n q u a ntit ati o n b y 
el e ctr o p h or e si s ( S P E P) e v er y c y cl e
( P art A o nl y)
2 4 -h o ur uri n e M -pr ot ei n q u a ntit ati o n b y 
el e ctr o p h or e si s ( U P E P) e v er y c y cl e
( P art A o nl y)
P h o s p h or u s/ p h o s p h at e s
M a g n e si u m
P ot a s si u m
S er ol o g y ( at S cr e e ni n g o nl y )
S er u m a n d uri n e pr e g n a n c y  t e st
S o di u m
H B s A g, H B c A b 
S er u m pr e g n a n c y t e st at S cr e e ni n g
T ot al bilir u bi n/i n dir e ct 
bilir u bi n
H B V D N A ( q u a ntit ati v e P C R)
Uri n e pr e g n a n c y t e st at F oll o w - U p
T ot al pr ot ei n
H C V A b, H C V R N A ( q u a ntit ati v e 
P C R)
Uri c a ci d
HI V t e st
H B c A b = H e p atiti s B c or e a nti b o d y; H B s A g = H e p atiti s B s urf a c e a nti g e n; H B V = H e p atiti s B vir u s; H C V = 
H e p atiti s C vir u s; H C V A b = H e p atiti s C vir u s a nti b o d y; HI V = H u m a n i m m u n o d efi ci e n c y vir u s. 
F ull h e m at ol o g y, s er u m c h e mi str y a n d c o a g ul ati o n will b e p erf or m e d at S cr e e ni n g, o n e v er y ti m e p oi nt of S o A s 
(Ta ble 1 a n d Ta ble 2 f or Part A; Ta ble 3 a n d Ta ble 4 f or Part B) i n cl u di n g at t h e E n d -of -Tr e at m e nt a n d S af et y 
F oll o w -U p v i sit s.
a Creati ni ne clear a nce will be calc ulate d usi n g t he C oc kcr oft-Ga ult f or m ula .
. 
D et ail s of li v er c h e mi str y st o p pi n g crit eri a a n d r e q uir e d a cti o n s a n d F oll o w -U p a s s e s s m e nt s aft er li v er st o p pi n g 
or m o nit ori n g e v e nt ar e gi v e n i n S e cti o n  7. 1 a n d  A p p e n di x 6 .
R o uti n e Uri n al y si s

S p e cifi c gr a vit y

p H, gl u c o s e, pr ot ei n, bl o o d, k et o n e s, bilir u bi n, ur o bili n o g e n, nitrit e, l e u k o c yt e 
e st er a s e s p e cifi c gr a vit y, pr ot ei n, bl o o d, a n d gl u c o s e a n d a b a si c uri n al y si s ( pr ot ei n 
c o nt e nt o nl y) e st er a s e b y di p sti c k

Mi cr o s c o pi c e x a mi n ati o n (if bl o o d or pr ot ei n i s a b n o r m al). 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 2 / 1 5 5
A p pe n di x 8
P h ar m ac o ki netic P ar a meters
Si n gle D ose P ar a meters
S y m b ol
Defi niti o n
A U C 0-t
T he area u n der t he c o nce ntrati o n-ti me c ur ve ( A U C) fr o m ti me zer o ( = d osi n g 
ti me) t o t he last sa m pli n g ti me (tlast) at w hic h t he c o nce ntrati o n is at or a b o ve 
t he l o wer li mit of q ua ntificati o n. Calc ulate d usi n g t he mi xe d 
l o g-li near 
tra pez oi dal r ule (li near u p, l o g d o w n).
A U C 0- t 
/ D ose
T he D ose n or malize d A U C fr o m ti me zer o t o t he last sa m pli n g ti me (tlast) at 
w hic h t he c o nce ntrati o n is at or a b o ve t he l o wer li mit o f q ua ntificati o n. 
N or malize d usi n g t he act ual d ose, usi n g t he f or m ula A U C 0 -t / D ose.
A U C 0-
(Pre d )
T he A U C fr o m ti me zer o ( d osi n g ti me) e xtra p olate d t o i nfi nit y, base d o n t he 
pre dicte d val ue f or t he c o nce ntrati o n at tlast, A U C 0- ∞= A U C 0-t+ C last o bs/ λ z
Pre dicte d/ o bser ve d A U C 0- ∞s h o ul d be selecte d as a p pr o priate.
A U C 0- ∞ 
/ D ose
T he D ose n or malize d A U C fr o m ti me zer o e xtra p olate d t o i nfi nit y . N or malize d 
usi n g act ual d ose, usi n g t he f or m ula A U C 0- ∞ / D ose.
A U C e xtra %
T he A U C fr o m ti me t last e xtra p olate d t o i nf i nit y gi ve n as perce nta ge of A U C0- 
. A U Ce xtra = (e xtra p olate d area/ A U C0- ∞) * 1 0 0. 
C L /f
T he a p pare nt t otal b o d y c leara nce of st u d y i nter ve nti o n f oll o wi n g e xtra vasc ular 
a d mi nistrati o n, 
ta ki n g i nt o acc o u nt 
t he fracti o n of 
d ose 
a bs or be d. 
C L /f = D ose p. o. / A U C0- ∞. Eit her t he o bser ve d or pre dicte d A U C 0- ∞ s h o ul d be 
use d, de pe n di n g o n t he st u d y s pecific re q uire me nts.
C last
T he o bser ve d c o nce ntrati o n at t he last sa m pli n g ti me (tlast) at w hic h t he 
c o nce ntrati o n is at or a b o ve t he l o wer li mit of q ua ntificati o n
C ma x
Ma xi m u m o bser ve d c o nce ntrati o n 
C ma x
/ D ose
T he D ose n or malize d ma xi m u m c o nce ntrati o n. N or malize d usi n g t he act ual 
d ose, a n d t he f or m ula C ma x / D ose.
C mi n
T he mi ni m u m o bser ve d c o nce ntrati o n d uri n g a c o m plete d osi n g i nter val 
t1/ 2
A p pare nt ter mi nal half -life. t1/ 2 = l n ( 2)/ λ z
tla g
T he 
ti me pri or t o t he first meas ura ble 
( n o n-zer o) c o nce ntrati o n (f or 
e xtra vasc ular i n p ut o nl y)
tlast
T he last sa m pli n g ti me at w hic h t he c o nce ntrati o n is at or a b o ve t he l o wer li mit 
of q ua ntificati o n
tma x
T he ti me t o reac h t he ma xi m u m o bser ve d c o nce ntrati o n c ollecte d d uri n g a 
d osi n g i nter val ( u nless ot her wise defi ne d, ta ke t he 1 st occ urre nce i n case of 
m ulti ple/i de ntical C ma x val ues)
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 3 / 1 5 5
S y m b ol
Defi niti o n
V Z/f
T he a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase f oll o wi n g 
e xtra vasc ular a d mi nistrati o n, base d o n t he fracti o n of d ose a bs or be d. V z/f = 
D ose/( A U C 0- ∞* λ z) f oll o wi n g si n gle d ose. V z/f = D ose/( A U C * λ z) f oll o wi n g 
m ulti ple d ose.
z
Ter mi nal first or der (eli mi nati o n) rate c o nsta nt. Deter mi ne d fr o m t he ter mi nal 
sl o pe of t he l o g-tra nsf or me d c o nce ntrati o n c ur ve usi n g li near re gressi o n o n 
ter mi nal data p oi nts of t he c ur ve
M ulti ple D ose P ar a meter of M 3 2 5 8 a n d De x a met h as o ne
S y m b ol
Defi nit i o n
A U C 
T he area u n der t he c o nce ntrati o n-ti me c ur ve ( A U C) o ver t he d osi n g i nter val 
fr o m T 1= 0 h t o T 2=τ h. Calc ulate d usi n g t he mi xe d l o g-li near tra pez oi dal r ule 
(li near u p, l o g d o w n). F or si n gle d ose, A U Cτ is calc ulate d as a partial area wit h 
t he defi ne d ti me ra n ge. I n m ulti ple d ose pr ofiles A U C is calc ulate d at stea d y 
state fr o m o ne pre d ose ti me p oi nt t o t he d osi n g i nter val ti me. I n cases w here t he 
act ual o bser vati o n ti me is n ot e q ual t o t he sc he d ule d o bs er vati o n ti me A U C 
will be calc ulate d base d o n t he esti mate d c o nce ntrati o n at τ h o urs, a n d n ot t he 
c o nce ntrati o n at t he act ual o bser vati o n ti me.
A U C τ 
/ D ose
T he D ose n or malize d A U C o ver t he i nter val fr o m T 1= 0 h t o T 2=τ h. N or malize d 
usi n g act ual d ose, usi n g t he f or m ula A U C τ / D ose.
C L S S/f
T he a p pare nt t otal b o d y  cleara nce of st u d y inter ve nti o n at stea d y state f oll o wi n g 
e xtra vasc ular a d mi nistrati o n, ta ki n g i nt o acc o u nt t he fracti o n of d ose a bs or be d. 
C L ss/f = D ose p. o. / A U C.
C ma x
Ma xi m u m o bser ve d c o nce ntrati o n 
C ma x
/ D ose
T he d ose n or malize d ma xi m u m c o nce ntrati o n. N or malize d usi n g t he act ual 
d ose, a n d t he f or m ula C ma x / D ose.
C tr o u g h
T he c o nce ntrati o n o bser ve d i m me diatel y bef ore ne xt d osi n g (c orres p o n di n g t o 
pre d ose or tr o u g h c o nce ntrati o n f or m ulti ple d osi n g)
R acc( A U C )
T he acc u m ulati o n fact or t o assess t he i ncrease i n e x p os ure u ntil stea dy state is 
reac he d. R acc( A U C )= ( A U Cafter m ulti ple d ose (at stea d y state)) / ( A U Cafter 
si n gle d ose)
R acc( C ma x)
T he acc u m ulati o n fact or t o assess t he i ncrease i n ma xi m u m c o nce ntrati o n u ntil 
stea d y state is reac he d. R acc( C ma x) = ( Cma x after m ulti ple d ose (at stea d y state) )/ 
( Cma x after si n gle d ose)
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 4 / 1 5 5
S y m b ol
Defi nit i o n
R acc( A U C 0 -∞)
T he acc u m ulati o n fact or t o assess t he i ncrease i n e x p os ure via A U C 0- ∞. 
R acc( A U C 0 -∞) = ( A U Cafter m ulti ple d ose (at stea d y state)) / ( A U C0- ∞ after si n gle 
d ose)
t1/ 2
A p pare nt ter mi nal half -life. t1/ 2 = l n ( 2)/ λ z
tma x
T he ti me t o reac h t he ma xi m u m o bser ve d c o nce ntrati o n c ollecte d d uri n g a 
d osi n g i nter val ( u nless ot her wise defi ne d, ta ke t he 1 st occ urre nce i n case of 
m ulti ple/i de ntical C ma x val ues)
z
Ter mi nal first or der (eli mi nati o n) rate c o nsta nt. Deter mi ne d fr o m t he ter mi nal 
sl o pe of t he l o g-tra nsf or me d c o nce ntrati o n c ur ve usi n g li near re gressi o n o n 
ter mi nal data p oi nts of t he c ur ve

D osi n g i nter val
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 5 / 1 5 5
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI




M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 7 / 1 5 5
I n case i nf or mati o n arises fr o m ot her st u dies t hat c ha n ges c urre nt k n o wle d ge o n t he d ose 
t o xicit y relati o ns hi p, t he pri or distri b uti o n ca n be u p date d pri or t o t he first partici pa nt bei n g 
treate d i n t his st u d y. If a c ha n ge i n re gi me n occ urs, a se parate m o del will be set u p f or eac h 
re gi me n. A n y c ha n ge i n pri or a n d t he pri ors f or c ha n ge d re gi me ns will be d oc u me nte d i n t he 
S M C c harter.
Decisi o ns of t he S M C i n t he e x pa nsi o n c o h ort will als o be ai de d b y a B a yesia n t w o-para meter 
l o gistic re gressi o n m o del wit h t he sa me s pecificati o ns as f or t he d ose escalati o n, e xce pt t he 
pri or. T he pri or will be base d o n t he data see n i n t he d ose escalati o n a n d be s pecifie d i n t he 
S M C c harter . T he m o del will be u p date d at ti mes of S M Cs i n t he e x pa nsi o n c o h ort.
P osteri or distri b uti o n a n d t he rec o m me n de d ne xt d ose le vel s u g geste d b y  the m o del will be 
calc ulate d usi n g E A S T versi o n 6. 4 or hi g her/ R versi o n 3. 4. 2 or hi g her wit h li brar y pac ka ge 
bcr m (S w eeti n g et al, 2 0 1 3 ) or pac ka ge C R M pac k or S A S versi o n 9. 4 ( or hi g her) pr oc M C M C.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 8 / 1 5 5
A p pe n di x 1 1
Pr ot oc ol A me n d me nt Hist or y
Pr ot oc ol Versi o n 3. 0 ( 1 2 - Se p- 2 0 1 9)
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
Re visi o n of t he ori gi nal pr ot oc ol is t o i ncl u de c ha n ges re q ueste d b y  AN S M . C ha n ges t o t he 
pr ot oc ol; t he rati o nale f or t he c ha n ges are liste d i n t he ta ble bel o w. 
S e cti o n N u m b er a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
1. 3 S c h e d ul e of A cti viti e s T a bl e s 1 
a n d 2 
I n cl u si o n of 
m o nt hl y 
pr e g n a n c y 
t e st s aft er C y cl e 6.
R e q u e st b y r e g ul at or y a g e n c y i n or d er t o 
all o w f or e arl y d et e cti o n w hil e a p arti ci p a nt 
i s r e c ei vi n g st u d y i nt er v e nti o n. 
E x p a n si o n 
of 
c h e st 
X- r a y 
e x a mi n ati o n t o e x cl u d e n ot o nl y 
i nf e cti o n 
b ut 
al s o 
i nt er stiti al 
p n e u m o niti s a n d l u n g i nf e cti o n. 
R e q u e st b y r e g ul at or y a g e n c y b e c a u s e of 
m e c h a ni s m 
of 
a cti o n 
b et w e e n 
p a n -
pr ot e a s o m e i n hi bit or s a n d M 3 2 5 8 . 
A d diti o n of a - 3- da y wi n d o w f or 
a s s e s s m e nt 
f or M R D 
i n b o n e 
m arr o w , d i s e a s e s t a gi n g i n b o n e 
m arr o w , a n d s k el et al s ur v e y
at 
s cr e e ni n g.
Cl arifi c ati o n
A d diti o n al 
g ui d a n c e 
a d d e d 
f or 
e v al u ati o n of o st e ol yti c l e si o n s a n d 
e xtr a m e d ull ar y di s e a s e f or t h e M RI 
or C T s c a n a s s e s s m e nt s.
Cl arifi c ati o n
6. 6 
D o s e 
S el e cti o n 
a n d 
M o difi c ati o n
D e s cri pti o n 
of Gr a d e 
≥3 f e bril e 
n e utr o p e ni a c h a n g e d t o Gr a d e ≥ 3 
f e bril e 
n e utr o p e ni a 
wit h 
A N C 
< 1 0 0 0/ m m 3
a n d 
a 
si n gl e 
t e m p er at ur e of > 3 8. 3° C ( 1 0 1° F) or 
a s u st ai n e d t e m p er at ur e of ≥ 3 8° C 
( 1 0 0. 4° F) f or m or e t h a n 1 h.
Cl arifi c ati o n. R e vi s e d d e s cri pti o n of Gr a d e 
≥3 f e bril e n e utr o p e ni a t o ali g n wit h C T C A E 
v 5. 0
E x p a n d e d 
t h e 
g ui d a n c e
o n 
d e x a m et h a s o n e d o s e a dj u st m e nt s, 
A d d e d t a bl e. 
R e q u e st b y r e g ul at or y a g e n c y t o pr o vi d e a 
g e n er al g ui d a n c e o n d e x a m et h a s o n e d o s e 
r e d u cti o n a n d t o cl arif y o n s e q u e n c e of 
d o s e r e d u cti o n of d e x a m et h a s o n e v er s u s 
M 3 2 5 8 
u p o n o b s er v ati o n of o v erl a p pi n g 
t o xi citie s.  
6. 9. 1. M o nit ori n g a n d M a n a g e m e nt 
of Ot h er 
T o xi citi e s ( e. g., O v er -
Ar c hi n g T o xi citi e s i n P art B)
E x p a n d e d 
t h e 
g ui d a n c e 
o n 
d e x a m et h a s o n e d o s e a dj u st m e nt s. 
R e q u e st 
b y r e g ul at or y a g e n c y t o gi v e 
g e n er al 
g ui d a n c e 
d o s e 
r e d u cti o n 
of 
d e x a m et h a s o n e a n d t o cl arif y o n s e q u e n c e 
of d o s e r e d u cti o n of d e x a m et h a s o n e v s 
M 3 2 5 8 w h e n o v erl a p pi n g t o xi citi e s of t h e s e 
c o m p o u n d s o c c ur. 
8. 9. 1 Effi c a c y 
A s s e s s m e nt s 
a n d 
Pr o c e d ur e s
A d diti o n al 
g ui d a n c e 
a d d e d 
f or 
e v al u ati o n of o st e ol yti c l e si o n s a n d 
e xtr a m e d ull ar y di s e a s e f or t h e M RI 
or C T s c a n a s s e s s m e nt s.
Cl arifi c ati o n. 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 9 / 1 5 5
8. 2. 4 C h e st X -R a y at Pr etr e at m e nt
N e w s e cti o n a d d e d t o d e s cri b e a n d 
pr o vi d e r ati o n al e f or c h e st X- r a y at 
s cr e e ni n g a s b a s eli n e t o e x cl u d e 
i nf e cti o n 
a n d 
ot h er 
a c ut e 
p ul m o n ar y a b n or m aliti e s . 
C o n si d eri n g 
t h e 
r e q u e st 
fr o m 
t h e 
r e g ul at or y a g e n c y, t h e r ol e a n d r el e v a n c e 
of t h e c h e st X- r a y at pr etr e at m e nt a n d 
i nf or m ati o n f or t h e i n v e sti g at or r e g ar di n g 
t h e p ot e nti al 
o c c urr e n c e 
of 
p ul m o n ar y 
t o xi cit y i s i n cl u d e d. 
8. 2. 5 Cli ni c al 
S af et y 
L a b or at or y 
A s s e s s m e nt s
A dj u st e d 
w or di n g 
t o all o w 
f or 
m o nt hl y pr e g n a n c y t e sti n g. 
R e q u e st b y r e g ul at or y a g e n c y i n or d er t o 
all o w f or e arl y d et e cti o n of pr e g n a n c y w hil e 
a p arti ci p a nt i s r e c ei vi n g st u d y i nt er v e nti o n.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 0 / 1 5 5
Pr ot oc ol Versi o n 2. 0 ( 0 1 -J ul - 2 0 1 9)
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
Re visi o n of t he ori gi nal pr ot oc ol is mai nl y  to i ncl u de c ha n ges re q ueste d b y  US F D A . Maj or 
c ha n ges t o t he pr ot oc ol a n d t he rati o nale f or t he c ha n ges are liste d i n t he ta ble bel o w. 
S e cti o n N u m b er 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
M ulti pl e s e cti o n s
D e x a m et h a s o n e 
w a s 
r e m o v e d 
fr o m t h e d o si n g r e gi m e n i n P art A 
D o s e E s c al ati o n. 
At t h e r e q u e st of U S F D A, p arti ci p a nt s i n 
t h e d o s e -e s c al ati o n p h a s e will 
r e c ei v e 
M 3 2 5 8 m o n ot h er a p y. 
M ulti pl e s e cti o n s
A s af et y r u n-i n f or t h e c o m bi n ati o n 
of M 3 2 5 8 a n d d e x a m et h a s o n e w a s 
a d d e d t o P art B D o s e E x p a n si o n. 
B e c a u s e 
t h e 
c o m bi n ati o n 
wit h 
d e x a m et h a s o n e w a s r e m o v e d fr o m P art A, 
a s af et y r u n-i n wit h t h e c o m bi n ati o n wit h 
d e x a m et h a s o n e w a s a d d e d t o P art B. 
M ulti pl e s e cti o n s
A d diti o n of st o p pi n g r ul e s f or P art B 
a n d 
d efi niti o n 
of 
u n a c c e pt a bl e 
t o xi cit y f or P art B. 
At t h e r e q u e st of U S F D A.  
M ulti pl e s e cti o n s
D et ail s 
a d d e d 
of 
t h e m e eti n g 
s c h e d ul e f or t h e S af et y M o nit ori n g 
C o m mitt e e ( S M C) i n P art B.
Wi t h t h e a d diti o n of t h e s af et y r u n-i n, 
cl arifi c ati o n of t h e S M C 
s c h e d ul e w a s 
n e c e s s ar y. 
M ulti pl e s e cti o n s
I n or d er t o d o s e i n P art A a b o v e 
5 0 m g 
M 3 2 5 8 
Q D, 
a 
pr ot o c ol 
a m e n d m e nt m u st b e s u b mitt e d. 
At t h e r e q u e st of U S F D A. 
M ulti pl e s e cti o n s 
I nt eri m a n a l y si s f or P art B w a s 
a d a pt e d t o c h a n g e s i n st u d y d e si g n 
a n d d e s cri b e d wit h m or e d et ail. 
T o a c c o m m o d at e t h e c h a n g e s r e q u e st e d i n 
P art s A a n d B.  
M ulti pl e s e cti o n s 
P h ar m a c o ki n eti c a n al y si s a dj u st e d 
i n P art s A a n d B t o a c c o m m o d at e 
t h e c h a n g e i n d o si n g r e gi m e n s i n 
P art s A a n d B a n d i n cl u si o n of t h e 
P art B s af et y r u n -i n.
T o a c c o m m o d at e t h e c h a n g e s r e q u e st e d i n 
P art s A a n d B.  
M ulti pl e s e cti o n s
T h e 
a p pr o xi m at e 
n u m b er 
of 
p arti ci p a nt s i n P art s A a n d B a n d 
g ui d a n c e f or e nr olli n g w a s a dj u st e d 
t o a c c o m m o d at e t h e c h a n g e i n 
st u d y d e si g n. 
T o a c c o m m o d at e t h e c h a n g e s r e q u e st e d i n 
P art s A a n d B.
M ulti pl e s e cti o n s
T h e t ar g et e d D L T r at e f or d efi ni n g 
t h e M T D w a s c h a n g e d fr o m 3 0 % t o 
2 5 %. 
At t h e r e q u e st of U S F D A.
M ulti pl e s e cti o n s
T h e f o o d-eff e ct a s s e s s m e nt will b e 
c o n d u ct e d d uri n g P art B D a y 1 
C y cl e 2, r at h er t h a n D a y 1 C y cl e 1 
i n or d er 
t o a c c o m m o d at e 
t h e 
c h a n g e i n d o si n g r e gi m e n i n t h e 
st u d y. 
T o a c c o m m o d at e t h e r e q u e st e d c h a n g e i n 
P art B. 
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 1 / 1 5 5
1. 1 
S y n o p si s, 
O bj e cti v e s 
a n d 
E n d p oi nt s,
St u d y O bj e cti v e s 
a n d 
E n d p oi nt s – D o s e E s c al ati o n – P art 
A
3 O bj e cti v e s a n d E n d p oi nt s, T a bl e 
5 St u d y O bj e cti v e s a n d E n d p oi nt -
D o s e E s c al ati o n – P art A
“t ol er a bilit y a n d P K” a d d e d t o P art 
A 
s e c o n d ar y  
o bj e cti v e 
t o 
i n v e sti g at e t h e r e c o m m e n d e d d o s e 
f or e x p a n sio n. 
R efl e ct s t h e c h a n g e i n st u d y d e si g n a n d 
cl arifi c ati o n of e n d p oi nt s t o o bj e cti v e s. 
1. 1 
S y n o p si s, 
O bj e cti v e s 
a n d 
E n d p oi nt s, St u d y O bj e cti v e s 
a n d 
E n d p oi nt s – D o s e E x p a n si o n – P art 
B
3 O bj e cti v e s a n d E n d p oi nt s, T a bl e 
6 St u d y O bj e cti v e s a n d E n d p oi nt -
D o s e E x p a n si o n – P art B
Pri m ar y 
s af et y 
o bj e cti v e 
a d d e d 
( ori gi n all y a s e c o n d ar y o bj e cti v e) 
wit h 
t h e 
a d diti o n 
of 
s af et y 
e n d p oi nt s.
R efl e ct s 
st art 
of 
c o m bi n ati o n 
wit h 
d e x a m et h a s o n e i n e x p a n si o n c o h ort w h er e 
s af et y of c o m bi n ati o n b e c o m e s a pri m ar y 
o bj e cti v e. 
P ri m ar y 
o bj e cti v e 
a n d 
c orr e s p o n di n g e n d p oi nt s a d d e d t o 
d et er mi n e 
t h e 
r e c o m m e n d e d 
P h a s e II d o s e of M 3 2 5 8 w h e n c o -
a d mi ni st er e d wit h d e x a m et h a s o n e.
R efl e ct s t h e c h a n g e i n st u d y d e si g n f or P art 
B. 
E n d p oi nt 
f or d et er mi ni n g o v er all 
r e s p o n s e, d ur ati o n of r e s p o n s e, 
a n d ti m e t o r e s p o n s e a d d e d f or 
s e c o n d ar y effi c a c y o bj e cti v e 
Cl arifi c ati o n of e n d p oi nt s t o o bj e cti v e. 
R e vi s e d 
s e c o n d ar y P K o bj e cti v e 
f or P art B. 
R efl e ct s t h e c h a n g e i n st u d y d e si g n. 
3 O bj e cti v e s a n d E n d p oi nt s, T a bl e 
5 St u d y O bj e cti v e s a n d E n d p oi nt s 
–
D o s e 
e s c al ati o n 
–
P art 
A, 
E x pl or at or y 
A d d e d a n o bj e cti v e a n d e n d p oi nt 
f or 
i n v e sti g ati n g 
t h e 
g e n eti c 
v ari ati o n s t h at m a y aff e ct M 3 2 5 8 a s 
a si n gl e a g e nt. 
A d d e d i n or d er t o a s s e s s g e n eti c v ari ati o n s 
t h at aff e ct dr u g m et a b oli s m a n d 
dr u g 
tr a n s p ort of M 3 2 5 8 
a n d ot h er p ot e nti al 
g e n e s t h at m a y a c c o u nt f or diff er e n c e s i n 
t h e P K pr ofil e.
3 O bj e cti v e s a n d E n d p oi nt s, T a bl e 
6 St u d y O bj e cti v e s a n d E n d p oi nt -
D o s e 
E x p a n si o n 
–
P art 
B, 
E x pl or at or y
A d d e d 
P K 
o bj e cti v e 
( a n d 
e n d p oi nt s) i n or d er t o e v al u ati o n 
f urt h er P K p ar a m et er s i n a d diti o n t o 
t h o s e i n v e sti g at e d i n t h e s e c o n d ar y 
o bj e cti v e. 
A d d e d t o all o w f or a m or e c o m pl et e P K 
pr ofil e of M 3 2 5 8 w h e n a d mi ni st er e d wit h 
d e x a m et h a s o n e. 
Cl arifi e d t h e e n d p oi nt f or t h e Q T c 
e x pl or at or y o bj e cti v e
R efl e ct s t h e c h a n g e i n st u d y d e si g n. 
A d d e d a n o bj e cti v e ( a n d e n d p oi nt s) 
f or t h e i n v e sti g ati o n of t h e P K 
pr ofil e f or d e x a m et h a s o n e w h e n 
gi v e n wit h M 3 2 5 8.
R efl e ct s 
t h e c h a n g e i n st u d y d e si g n: 
D e x a m et h a s o n e 
P K 
e v al u at e d 
i n
e x p a n si o n p h a s e.
A d d e d a n o bj e cti v e ( a n d e n d p oi nt) 
t o 
e x pl or e 
L- citr ulli n e
a s 
a n 
e x pl or at or y bi o m ar k er
A d d e d t o i n v e sti g at e L-citr ulli n e c orr el ati o n 
wit h e arl y cli ni c al si g n s of g a str oi nt e sti n al 
t o xi cit y.
5. 1 I n cl u si o n Crit eri o n 7
D el eti o n of s er u m cr e ati ni n e ≤ 1. 5 x 
U L N.
R e q u e st e d b y U S F D A. 
D el eti o n t h at cr e ati ni n e cl e ar a n c e 
c o ul d b e c al c ul at e d u si n g t h e 2 4 -
h o ur uri n e c oll e cti o n.
Cl arifi c ati o n 
t h at o nl y s er u m cr e ati ni n e 
w o ul d 
b e u s e d t o c al c ul at e cr e ati ni n e 
cl e ar a n c e.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 2 / 1 5 5
5. 2 E x cl u si o n Crit eri o n 1 2
A d d e d 
e x cl u si o n 
f or 
c urr e nt 
si g nifi c a nt 
c ar di a c 
c o n d u cti o n 
a b n or m aliti e s .
R e q u e st e d b y U S F D A.
5. 2 E x cl u si o n Crit eri a 1 6 a n d 1 7
Str e n gt h e n e d 
t h e 
r e stri cti o n s 
c o n c er ni n g 
h er b al 
s u p pl e m e nt s, 
C Y P 3 A 
i n hi bit or s a n d i n d u c er s, 
a n d P -g p i n hi bit or s. 
R e q u e st e d b y U S F D A.
5. 2 E x cl u si o n Crit eri o n 1 8
A d d e d e x cl u si o n f or m e di c ati o n s 
k n o w n 
t o pr ol o n g 
t h e Q T/ Q T c 
i nt er v al. 
R e q u e st e d b y U S F D A.
5. 3. 1 
M e al s 
a n d 
Di et ar y 
R e stri cti o n s
A d diti o n al di et ar y r e stri cti o n s f or 
C Y P 3 A 
i n hi bit or s a n d 
i n d u c er s 
a d d e d. 
R e q u e st e d b y U S F D A.
6. 5. 3 Pr o hi bit e d M e di ci n e s
R e vi s e d t o i n di c at e t h at b ot h str o n g 
i n hi bit or s a n d i n d u c er s of C Y P 3 A 
m u st b e st o p p e d at l e a st 7 d a y s 
b ef or e 
i niti ati o n 
of 
st u d y 
i nt er v e nti o n. 
R e q u e st e d b y U S F D A.
A d diti o n t h at h er b al s u p pl e m e nt s 
t h at ar e k n o w n t o i n hi bit or i n d u c e 
C Y P 3 A ar e pr o hi bit e d. 
R e q u e st e d b y U S F D A.
A d diti o n t h at all P- g p i n hi bit or s ar e 
pr o hi bit e d at l e a st 7 d a y s b ef or e t h e 
fir st a d mi ni str ati o n of t h e st u d y 
i nt er v e nti o n a n d 
t hr o u g h o ut t h e
st u d y.
R e q u e st e d b y U S F D A.
A d diti o n t h at m e di c ati o n s k n o w n t o 
pr ol o n g t h e Q T/ Q T c 
i nt er v al ar e 
pr o hi bit e d at l e a st 7 d a y s b ef or e t h e 
fir st a d mi ni str ati o n of t h e st u d y 
i nt er v e nti o n a n d 
t hr o u g h o ut t h e 
st u d y. 
R e q u e st e d b y U S F D A.
6. 6 
D o s e 
S el e cti o n 
a n d 
M o difi c ati o n
H y’ s L a w w a s a d d e d t o t h e li st of 
A E s j u d g e d a s D L T s.
R e q u e st e d b y U S F D A.
A p p e n di x 
4: 
Pr o hi bit e d 
C o m e di c ati o n 
Pr ol o n gi n g 
t h e 
Q T/ Q T c I nt er v al
A d d e d a p p e n di x w hi c h li st s a n d 
gi v e s r ef er e n c e f or m e di c ati o n s 
k n o w n 
t o pr ol o n g 
t h e Q T/ Q T c 
i nt er v al.
R e q u e st e d b y U S F D A.
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 3 / 1 5 5
A p pe n di x 1 2
S p o ns or Si g n at ure P a ge
St u d y Title:
A P hase I O pe n La bel First i n H u ma n D ose Escalati o n 
of t he I mm u n o pr oteas o me I n hi bit or M 3 2 5 8
as a Si n gle 
A ge nt a n d E x pa nsi o n St u d y  of M 3 2 5 8 i n C o m bi nati o n 
wit h De xa met has o ne i n Partici p a nts wit h Rela pse d 
Refract or y  M ulti ple M yel o ma
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:
I ND 
E u dra C T 2 0 1 9 - 0 0 0 9 4 7-2 8
Cli nic al 
St u d y 
Pr ot oc ol 
Versi o n:
1 1
M a y 2 0 2 0 / Versi o n 4 . 0
I a p pr o ve t he desi g n of t he cli nical st u d y :
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
F u ncti o n/ Title:
Me dical Res p o nsi ble
I nstit uti o n:
Merc k Healt hcare K Ga A
A d dress:
Fra n kf urter Str . 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
F a x n u m ber:
E- m ail a d dress:
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D
P P D
P P D
P P D
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 4 / 1 5 5
A p pe n di x 1 3
C o or di n ati n g I n vesti g at or Si g n at ure P a ge
St u d y Title:
A P hase I O pe n La bel First i n H u ma n D ose Escalati o n 
of t he I mm u n o pr oteas o me I n hi bit or M 3 2 5 8
as a Si n gle 
A ge nt a n d E x pa nsi o n St u d y  of M 3 2 5 8 i n C o m bi nati o n 
wit h De xa met has o ne i n Partici pa nts wit h Rela pse d 
Refract or y  M ulti ple M yel o ma
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:
I ND 
 
E u dra C T 2 0 1 9 - 0 0 0 9 4 7-2 8
Cli nic al 
St u d y 
Pr ot oc ol 
Versi o n:
1 1 Ma y 2 0 2 0 / Versi o n 4 . 0
Site N u m ber:
I a p pr o ve t he desi g n of t he cli nical st u d y, a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his 
site, a n d u n dersta n d a n d will c o n d uct it per t he cli nical st u d y pr ot oc ol, a n y 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 G o o d Cli nica l Practice ( T o pic E 6) a n d 
all a p plica ble Healt h A ut h orit y re q uire me nts a n d nati o nal la ws.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
F u ncti o n/ Title:
C o or di nati n g I n vesti gat or
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
F a x n u m ber:
 
E- m ail a d dress:
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n
of  
M3 2 5 8 as a Si n gle A ge nt
a n d 
E x p a nsi o n St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 5 / 1 5 5
A p pe n di x 1 4
Pri nci p al I n vesti g at or Si g n at ure P a ge
St u d y Title:
A P hase I O pe n La bel First i n H u ma n D ose Escalati o n 
of t he I m m u n o pr oteas o me I n hi bit or M 3 2 5 8
as a Si n gle 
A ge nt a n d E x pa nsi o n St u d y  of M 3 2 5 8 i n C o m bi nati o n 
wit h De xa met has o ne i n Partici pa nts wit h Rela pse d
Refract or y  M ulti ple M yel o ma
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:
I ND
E u dra C T 2 0 1 9 - 0 0 0 9 4 7-2 8
Cli nic al 
St u d y 
Pr ot oc ol 
Versi o n:
1 1 Ma y 2 0 2 0 / Versi o n 4 . 0
Site N u m ber:
I a m res p o nsi ble f or t he c o n d uct of t he st u dy at t his site a n d u n dersta n d a n d will c o n d uct it per 
t he cli nical st u d y pr ot oc ol, a n y 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 G o o d Cli nical Practice ( T o pic E 6) a n d all a p plica ble Healt h A ut h orit y 
re q uire me nts a n d nati o nal la ws.
I als o u n derstan 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 suc h 
i nf or mati o n s olel y for c o m pl yi n g wit h t he re g ulat or y re q uire me nts. T heref ore, I a gree t o s u p pl y 
t he S p o ns or wit h a n y necessar y  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 m y  sp 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  to 
meet Healt h A ut h orit y re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
F u ncti o n/ Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
F a x n u m ber:
E- m ail a d dress:
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

SAP_001.pdf: 
M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
1/ 8 7
I nte gr ate d A n al ysis Pl a n
Cli nic al St u d y Pr ot oc ol 
I de ntific ati o n N o.
M S 2 0 1 8 1 4 - 0 0 1 0
Title
A P hase I O pe n La bel First i n H u ma n D ose Escalati o n of t he 
I m m u n o pr oteas o me I n hi bit or M 3 2 5 8 
as a Si n gle A ge nt a n d 
E x pa nsi o n  
St u d y   
of 
M 3 2 5 8  
i n 
C o m bi nati o n  
wit h 
De xa met has o ne 
i n Partici pa nts 
wit h 
Rela pse d 
Refract or y 
M ulti ple M y el o ma
St u d y P h ase
P hase I ( d ose escalati o n a n d e x pa nsi o n)
I n vesti g ati o n al Me dici n al 
Pr o d uct(s)
M 3 2 5 8
Cli nic al St u d y Pr ot oc ol 
Versi o n
1 2 Se pte m ber 2 0 1 9/ Versi o n 3. 0
I nte gr ate d A n al ysis Pl a n 
A ut h or
C o or di n ati n g A ut h or
 M er c k
F u n cti o n
A ut h or( s) / D at a A n al y s t( s)
 
, 
M er c k
 M er c k
 
I nte gr ate d A n al ysis Pl a n
D ate a n d Versi o n
1 6 Ma y  2 0 2 1 / Versi o n 2 .0
I nte gr ate d A n al ysis Pl a n 
Re vie wers
F u n cti o n
N a m e
, M er c k
, 
M er c k
 
, M er c k
 , 
M er c k
C o nfi de nti al
T his d oc u me nt is t he pr o pert y of Merc k Healt hcare K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or 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 Healt hcare K Ga A, Dar msta dt, Ger ma n y or its affiliate. 
C o p yri g ht © 2 0 2 1 b y Merc k He alt hc are K G a A, D ar mst a dt, Ger m a n y or its affili ate. All ri g hts reser ve d.
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
P P D
C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
2/ 8 7
A p pr o v al P a ge
I nte gr ate d A n al ysis Pl a n: M S 2 0 1 8 1 4 - 0 0 1 0
A P hase I O pe n La bel First i n H u ma n D ose Escalati o n of t he I m m u n o pr oteas o me I n hi bit or M 3 2 5 8 
as a Si n gle A ge nt a n d E x pa nsi o n St u d y  of M 3 2 5 8 
i n C o m bi nati o n wit h De xa met has o ne i n 
Partici pa nts wit h Rela pse d Refract or y M ulti ple M y el o ma
A p pr ov al of t he I A P by all Merck D at a A n alysis Res p o nsi ble s h as t o be d oc u me nte d wit hi n 
E L D O R A D O vi a e Si g n at ure. Wi t h t he a p pr ov al, t he Merck res p o nsi ble f or e ac h of t he a n alysis 
als o t akes res p o nsi bility t h at all revie wers’ c o m me nts are a d dresse d a de q u ately.
By usi n g e Si g n at ure, all si g n at ures will a p pe ar at t he e n d of t he d oc u me nt.
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
3/ 8 7
1
T a ble of C o nte nts
I nte grate d A nalys is Pla n ...................................................................................................... 1
A p pr o val Pa ge 
2
1
Ta ble of C o nte nts .................................................................................. 3
2
List of A b bre viati o ns a n d Defi niti o n of Ter m s .................................... 6
3
M o dificati o n Hist or y
............................................................................ 8
4
P ur p ose of t he I nte grate d A nal y sis Pla n ............................................... 8
5
O bjecti ves a n d E n d p oi nts ..................................................................... 9
6
O ver vie w of Pla n ne d A nal y ses........................................................... 1 3
6. 1
A nal y ses f or S M C meeti n gs ...............................................................1 4
7
C ha n ges t o t he Pla n ne d A nal y ses i n t he Cli nical St u d y  Pr ot oc ol ...... 1 4
8
A nal y sis P o p ulati o ns a n d S u b gr o u ps.................................................. 1 4
8. 1
Defi niti o n of A nal ys is P o p ulati o ns..................................................... 1 4
9
Ge neral S pecificati o ns f or Data A nal y ses .......................................... 1 6
9. 1
Defi niti o n of baseli ne a n d c ha n ge fr o m baseli ne ............................... 1 8
9. 2
Defi niti o n of D urati o n a n d ‘ti me si nce’ Varia bles ............................. 1 8
9. 3
C o n versi o n fact ors .............................................................................. 1 9
9. 4
Defi ni ti o n of O n-treat me nt Peri o d...................................................... 1 9
9. 5
I m p utati o n of missi n g data ................................................................. 1 9
9. 6
St u d y  D a y / St u d y Treat me nt Da y defi niti o n..................................... 2 1
1 0
St u d y  Partici pa nts............................................................................... 2 2
1 0. 1
Dis p osi ti o n of Partici pa nts a n d Disc o nti n uati o ns............................... 2 2
1 0. 2
Pr ot oc ol De viati o ns / E xcl usi o n fr o m A nal ys is P o p ulati o n ...............2 2
1 0. 2. 1
I m p orta nt Pr ot oc ol De viati o ns............................................................ 2 2
1 0. 2. 2
Reas o ns Lea di n g t o t he E xcl usi o n fr o m a n A nal y sis P o p ulati o n ....... 2 3
1 1
De m o gra p hics a n d Ot her Baseli ne C haracteristics ............................. 2 3
1 1. 1
De m o gra p hics ..................................................................................... 2 3
1 1. 2
Me dical Hist or y ..................................................................................2 4
1 1. 3
Ot her Baseli ne C haracteristics ............................................................ 2 5
1 1. 4
Pri or A nti -ca ncer T hera p y..................................................................2 5
1 2
Pre vi o us or c o nc o mita nt me dicati o ns/i nter ve nti o ns........................... 2 6
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
4/ 8 7
1 3
St u d y  i nter ve nti o n C o m plia nce a n d E x p os ure ................................... 2 7
1 4
Efficac y  A nalys es ............................................................................... 2 8
1 4. 1
O verall Res p o nse ................................................................................ 2 8
1 4. 2
D urati o n of treat me nt .......................................................................... 2 9
1 4. 3
M -pr otei n a n d F L C............................................................................. 2 9
1 5
Safet y  A nalys es .................................................................................. 3 0
1 5. 1
D L T a nal ys is....................................................................................... 3 0
1 5. 2
A d verse E ve nts ................................................................................... 3 2
1 5. 2. 1
All A d verse E ve nts ............................................................................. 3 3
1 5. 2. 2
A d verse E ve nts Lea di n g t o St u d y  Inter ve nti o n Disc o nti n uati o n ....... 3 4
1 5. 3
Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt 
A d ver se E ve nts ...................................................................................3 4
1 5. 3. 1
Deat hs ................................................................................................. 3 4
1 5. 3. 2
Seri o us A d verse E ve nts ...................................................................... 3 4
1 5. 3. 3
Ot her Si g nifica nt A d verse E ve nts ...................................................... 3 4
1 5. 4
Cli nical L a b orat or y E val uati o n........................................................... 3 5
1 5. 5
Vital Si g ns .......................................................................................... 3 9
1 5. 6
Ot her Safet y or T olera bilit y  E val uati o ns ............................................3 9
1 6
A nal y ses of Ot her E n d p oi nts ..............................................................4 0
1 6. 1
P har mac o ki netics ................................................................................ 4 0
1 6. 1. 1
P har m ac o ki netic A nal ysis .................................................................. 4 0
1 6. 1. 1. 1 
Criteria f or Ha n dli n g C o nce ntrati o ns Bel o w t he Li mit of 
Q ua ntificati o n i n P har mac o ki netic A nal ys is ...................................... 4 2
1 6. 1. 1. 2 
Criteria f or t he Calc ulati o n of a n A p pare nt Ter mi nal Eli mi nati o n 
Half -Life ............................................................................................. 4 2
1 6. 1. 1. 3 
Calc ulati o n of Area U n der t he C o nce ntrati o n- ti me C ur ve................. 4 2
1 6. 1. 1. 4 
A n o mal o us Val ues ..............................................................................4 3
1 6. 1. 2
Prese ntati o n of P har mac o ki netic Data................................ ................4 3
1 6. 2
P har mac o d y na mics .............................................................................4 5
1 6. 2. 1
Ba yesia n m o deli n g c o nsi deri n g t o xicit y a n d p har mac o d y na mics ......4 6
1 6. 3
P har mac o metric m o deli n g a nal ys is.................................................... 4 7
1 7
Refere nces ........................................................................................... 4 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
5/ 8 7
1 8
A p pe n dices ......................................................................................... 4 9
1 8. 1
I nte grate d A nalys is Pla n f or S M C ...................................................... 4 9
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
6/ 8 7
2
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms
A E
A d verse E ve nt
A E SI
A d verse E ve nt of S pecial I nterest
A T C
A nat o mical T hera pe utic C he mical classificati o n 
C DI S C 
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m
C H M P 
C o m mittee f or Me dici nal Pr o d ucts f or H u ma n Use
CI
C o nfi de nce I nter val
C R
C o m plete Res p o nse
(e) C R F 
(electr o nic) Case Re p ort F or m
C S R
Cli nical St u d y  Re p ort
D L T
D ose L i miti n g T o xicit y
D O R
D urati o n of Re p o nse
E C G
Electr ocar di o gra m
E C O G 
Easter n C o -o perati ve O nc ol o g y Gr o u p
F L C
Free Li g ht C hai n
I C H
I nter nati o nal C o nfere nce o n Har m o nizati o n
IA P
I nte grate d A nalys is Pla n
I M W G 
I nter nati o nal M y el o ma W or ki n g Gr o u p
Me d D R A 
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
M- pr otei n  
M- pr otei n M o n ocl o nal Para pr otei n
M R D
Mi ni mal Resi d ual Disease
M RI
Ma g netic Res o na nce I ma gi n g
M T D  
Ma xi m u m T olerate d D ose
N A
N ot A p plica ble
N CI -C T C A E 
Nati o nal Ca ncer I nstit ute – C o m m o n Ter mi n ol o g y  Criteria f or A d verse 
E ve nts
N L M E 
O R
N o n -li near Mi xe d Effects
O verall Res p o nse
O R R
O verall Res p o nse Rate
P D
Pr o gressi ve Disease 
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
7/ 8 7
P d 
P har mac o d y na mics
P R
Partial res p o nse
P T
Preferre d Ter m
P K
P har mac o ki netics
P P
Per Pr ot oc ol
Q D
O nce Dail y
P R
Partial Res p o nse
R D E
Rec o m me n de d D ose f or E x pa nsi o n
R R M M 
Rela pse d Refract or y  M ulti ple M yel o ma
S A E
Seri o us A d verse E ve nt
S A F
Safet y
s C R
Stri n ge nt C o m plete Res p o nse
S C R
Scree ni n g a nal y sis p o p ulati o n
S D
Sta ble Disease or Sta n dar d De viati o n
S D T M 
St u d y  Data Ta b ulati o n M o del
S M C
Safet y  M o nit ori n g C o m mittee
S O C
S y ste m Or ga n Class
T E A E 
Treat me nt -E mer ge nt A d verse E ve nt
T R A E 
Treat me nt -Relate d A d verse E ve nt
T L F
Ta bles, L isti n gs, a n d Fi g ures
T T R
Ti me t o Res p o nse
V G P R 
Ver y  G o o d Partial Res p o nse
W H O -D D 
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. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
8/ 8 7
3
M o dific ati o n Hist or y
U ni q u e
I d e ntifi er f or
V er si o n
D at e of
I A P V er si o n
A ut h or
C h a n g e s fr o m t h e Pr e vi o u s V er si o n
0. 1 
0 6 D E C 2 0 1 9
I niti al dr aft
1. 0 
0 7 M A Y 2 0 2 0
Fi n al v er si o n
2. 0 
1 6 M a y 2 0 2 1
A d d e d a d diti o n al a n al y si s n e e d e d f or pri m ar y
a n al y si s A d a pt e d i A P t o t h e pr e m at ur e st o p of t h e 
tri al wit h o ut e x p a n si o n c o h ort , e. g. r e m o v e d 
a n al y s e s t h at ar e n o l o n g er n e e d e d
4
P ur p ose of t he I ntegr ate d A n al ysis Pl a n
T he p ur p ose of t his I nte grate d A nal ys is Pla n (I A P) is t o d oc u me nt tec h nical a n d detaile d 
s pecificati o ns f or t he pri mar y  a nalys is a n d ot her a nal yses of pr ot oc ol M S 2 0 1 8 1 4 - 0 0 1 0. 
T he c urre nt versi o n s pecifies t he a nal ys es t hat will be perf or me d at t he e n d of t he trial ( pri mar y 
a nal ys is). 
Res ults of t he a nal y ses descri be d i n t his I A P will be i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R), 
e xce pt f or

citr ulli ne res ults a nal ys is, 

Ba yes ia n m o delli n g c o nsi deri n g t o xicit y a n d p har mac o d yna mics ( secti o n 1 6. 2. 1)). 
Citr ulli ne a nal ysis a n d Ba y esia n m o delli n g c o nsi deri n g t o xicit y an d P har mac o d y na mics m a y  be 
perf or me d i nter nally a t Merc k at a later p oi nt i n ti me. T he res ults of t hese a nal yses are n ot re p orte d 
i n t he C S R.
A d diti o nall y , t he pla n ne d a nal ys es i de ntifie d i n t his I AP ma y  be i ncl u de d i n re g ulat or y 
s u b missi o ns or f ut ure ma n uscri pts. A n y  post -h oc, or u n pla n ne d a nal yses perf or me d t o pr o vi de 
res ults f or i ncl usi o n i n t he C S R b ut n ot i de ntifie d i n t his pr os pecti ve IA P will be clearl y i de ntifie d 
i n t he C S R.
T he I A P is base d u p o n secti o n 9 ( Statistical c o nsi derati o ns) of t he st u d y pr ot oc ol a n d pr ot oc ol 
a me n d me nts a n d is pre pare d i n c o m plia nce wit h I C H E 9. I t descri bes a nal yses pla n ne d i n t he 
pr o t oc ol a n d pr ot oc ol a me n d me nts. Details of t he Safet y M o nit ori n g C o m mittee ( S M C) a nal yses 
f or re g ular re vie w of t he partici pa nts’ safety are pr o vi de d i n a p pe n di x.
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
P P D
P P D
P P D


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
9/ 8 7
5
O bjecti ves a n d E n d p oi nts
P art A
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
I A P s e cti o n
Pri m ar y
 
T o d et er mi n e s af et y, t ol er a bilit y 
a n d t h e M T D 
(if o b s er v e d) of 
M 3 2 5 8  a s a si n gl e a g e nt i n 
p arti ci p a nt s wit h R R M M
 
O c c urr e n c e of D L T s i n p arti ci p a nt s wit h 
R R M M r e c ei vi n g M 3 2 5 8 a s a si n gl e a g e nt 
d uri n g t h e fir st 2 8 -d a y tr e at m e nt c y cl e 
 
O c c urr e n c e of a n y A E s r e p ort e d ( s eri o u s 
or n o n s eri o u s) will b e c o n si d er e d T E A E s 
a n d T R A E s (i n cl u di n g T E A E s l e a di n g t o 
d e at h or di s c o nti n u ati o n of tr e at m e nt) i n 
p arti ci p a nt s r e c ei vi n g M 3 2 5 8 a s a si n gl e 
a g e nt fr o m st art of st u d y i nt er v e nti o n t o 
3 0 d a y s aft er e n d of st u d y i nt er v e nti o n 
 
O c c urr e n c e of T E A E s o ut si d e of t h e D L T 
p eri o d t h at S M C 
d e e m s r el e v a nt f or 
d et er mi n ati o n of t h e M T D
 
St u d y 
tr e at m e nt-e m er g e nt c h a n g e s i n 
cli ni c al  
l a b or at or y  
m e a s ur e s  
fr o m 
B a s eli n e,  
s af et y  
El e ctr o c ar di o gr a m s
(E C G s ) m e a s ur e s,  vit al si g n s, E C O G 
p erf or m a n c e  
st at u s  
i n  p arti ci p a nt s 
r e c ei vi n g M 3 2 5 8 a s a si n gl e a g e nt fr o m 
st art of st u d y i nt er v e nti o n t o 3 0 d a y s aft er 
e n d of st u d y i nt er v e nti o n
 
S e cti o n  
1 5  
S af et y 
A n al y s e s
S e c o n d ar y
 
T o i n v e sti g at e t h e P K pr ofil e of 
M 3 2 5 8 ( si n gl e a n d m ulti pl e d o s e 
e x p o s ur e) i n p arti ci p a nt s wit h 
R R M M
 
P K pr ofil e of M 3 2 5 8 
i n t er m s of C m a x, 
A U C 0-t , A U C0- 2 4 at D a y 1, C y cl e 1, ( si n gl e 
d o s e): pr e d o s e, 1, 2, 3, 4, 5, 6, 8 a n d 2 4 
h aft er a d mi ni str ati o n
 
P K pr ofil e of M 3 2 5 8 
i n t er m s of C m a x, 
A U C 0- 2 4 at D a y 
1 5 C y cl e 
1, ( m ulti pl e 
d o s e): pr e d o s e, 1, 2, 3, 4, 5, 6, a n d 8 h 
aft er a d mi ni str ati o n
 
S e cti o n 
1 6. 1 
P h ar m a c o ki n eti c s
 
T o  i n v e sti g at e t h e R D E  
i n 
p arti ci p a nt s wit h R R M M
 
I n a d diti o n t o s af et y, t ol er a bilit y a n d P K, 
f or s el e cti o n of R D E, 
c h a n g e s i n P d 
( L M P 7 a cti vit y) i n pr e a n d p o st st u d y 
i nt er v e nti o n s a m pl e s o n D a y 1 C y cl e 1 
pr e a n d p o st d o s e, D a y 2 C y cl e 1 pr e d o s e 
a n d D a y 1 5 C y cl e 1 pr e a n d p o st d o s e 
 
C h a n g e s 
fr o m B a s eli n e 
i n s er u m M-
pr ot ei n, uri n e M- pr ot ei n, or fr e e li g ht c h ai n 
pr ot ei n l e v el s (f or fr e e li g ht c h ai n di s e a s e)  
o n D a y 1 of e v er y c y cl e

 
T o e v al u at e pr eli mi n ar y cli ni c al 
a cti vit y u si n g I M W G  crit eri a
 
O v er all  
R e s p o n s e  (O R ), D ur ati o n  of 
R e s p o n s e (D O R ), Ti m e t o R e s p o n s e u ntil 
C o m pl et e  
R e s p o n s e  
(C R ), str i n g e nt 
C o m pl et e R e s p o n s e (s C R ), V er y G o o d 
 
S e cti o n  
1 4  
Effi c a c y 
A n al y s e s
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
1 0 /8 7
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
I A P s e cti o n
P arti al  R e s p o n s e  (V G P R ) or 
P arti al 
R e s p o n s e ( P R ) a c c or di n g t o I M W G
E x pl or at or y
 
T o i n v e sti g at e t h e c h a n g e s i n 
t h e P d m ar k er of M 3 2 5 8 a s a 
si n gl e a g e nt i n p arti ci p a nt s wit h 
R R M M
 
C h a n g e s i n P d ( L M P 7 a cti vit y) i n pr e a n d 
p o st st u d y i nt er v e nti o n s a m pl e s o n D a y 1 
C y cl e 1 pr e a n d p o st d o s e, D a y 2 C y cl e 1 
pr e d o s e a n d D a y 1 5 C y cl e 1 pr e a n d 
p o st d o s e
 
S e cti o n 
1 6. 2
P h ar m a c o d y n a mi c s
 
S e cti o n 1 6. 3. 2. 1 L M P 7 
R e si d u al A cti vit y
 
T o  
i n v e sti g at e  
f urt h er  
P K 
p ar a m et er s of M 3 2 5 8 ( si n gl e a n d 
m ulti pl e  
d o s e  
e x p o s ur e)  
i n 
p arti ci p a nt s wit h R R M M
 
P K pr ofil e of M 3 2 5 8 i n t er m s of tm a x , tl a g, 
t1/ 2 , C L/ F, V z/ F at D a y 1 C y cl e 1, ( si n gl e 
d o s e): pr e d o s e, 1, 2, 3, 4, 5, 6, 8 a n d 2 4 
h aft er a d mi ni str ati o n
 
P K pr ofil e of M 3 2 5 8 i n t er m s of A U C 0 →∞
(if c al c ul a bl e), t m a x, tl a g, t1/ 2 , C Ls s/ F, at D a y 
1 5 C y cl e 1, ( m ulti pl e d o s e): pr e d o s e, 1, 2,  
3, 4, 5, 6 a n d 8 h aft er a d mi ni str ati o n
 
P K pr ofil e of M 3 2 5 8 i n t er m s of C tr o u g h at  
D a y 8 a n d D a y 2 2: pr e d o s e, C y cl e 1 a n d  
pr e d o s e, D a y 1 C y cl e 2
 
P K pr ofil e of M 3 2 5 8 i n t er m s of R a c c ( A U C)
a n d R a c c ( C m a x) aft er D a y 1 ( si n gl e d o s e) 
a n d D a y 1 5 ( m ulti pl e d o s e), C y cl e 1 a n d 
d o s e -n or m ali z e d C m a x, A U C 0-t , A U C 0- 2 4 f or 
si n gl e a n d m ulti pl e d o s e
 
S e cti o n 
1 6. 1
P h ar m a c o ki n eti c s
 
T o i n v e sti g at e t h e r el ati o n s hi p 
b et w e e n e x p o s ur e of M 3 2 5 8 a s 
a 
si n gl e a g e nt 
a n d 
Q T c  i n 
p arti ci p a nt s wit h R R M M
 
R el ati v e c h a n g e s fr o m B a s eli n e i n E C G 
p ar a m et er Q T c  i n r el ati o n t o M 3 2 5 8 
pl a s m a c o n c e ntr ati o n: all ti m e s aft er 
si n gl e  
a n d  
m ulti pl e  
d o si n g  
wit h 
c o n c urr e nt  
Q T c  
a n d  
pl a s m a 
c o n c e ntr ati o n a s s e s s m e nt s
 
N ot  i n s c o p e of t h e 
C T R, will b e r e p ort e d 
s e p ar at el y.
 
T o i n v e sti g at e g e n eti c v ari ati o n s 
t h at m a y aff e ct P K of M 3 2 5 8 a s 
a si n gl e a g e nt
 
A s s e s s m e nt of g e n eti c v ari ati o n s t h at 
aff e ct  
dr u g  
m et a b oli s m  
a n d  
dr u g 
tr a n s p ort of M 3 2 5 8 a n d ot h er p ot e nti al 
g e n e s t h at m a y a c c o u nt f or diff er e n c e s i n 
t h e P K pr ofil e 
 
N ot  i n s c o p e of t h e 
C T R, will b e r e p ort e d 
s e p ar at el y.
 
T o e x pl or e p ot e nti al m et a b olit e s 
of  
M 3 2 5 8  
i n  pl a s m a  
i n 
p arti ci p a nt s wit h R R M M
 
A s s e s s m e nt of p ot e nti al m et a b olit e s of 
M 3 2 5 8 i n
pl a s m a 
 
N ot  i n s c o p e of t h e 
C T R, will b e r e p ort e d 
s e p ar at el y.
 
T o 
e x pl or e L- citr ulli n e a s a n 
e x pl or at or y bi o m ar k er 
 
C h a n g e s i n t h e L- citr ulli n e bl o o d l e v el s 
d uri n g t h e st u d y at D a y 1 pr e d o s e a n d 
D a y 1 5 pr e d o s e, C y cl e 1, a n d D a y 1 
pr e d o s e, C y cl e s 2 – 6 pr e d o s e a n d e v er y 
t hir d c y cl e aft er C y cl e 6 pr e d o s e, a n d at 
E n d of St u d y Vi sit
 
S e cti o n 1 6. 2
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
1 1 /8 7
 
T o 
i n v e sti g at e r el ati o n s hi p of 
dr u g  tr e at m e nt a n d  Mi ni m al 
R e si d u al  
Di s e a s e  
( M R D) i n 
p arti ci p a nt s wit h R R M M
 
A s s e s s m e nt of M R D u p o n C R or s C R 
 
S e cti o n 1 6. 7 M R D
P art B ( will n ot be d o ne d ue t o st o p of st u d y)
O bj e cti v e s
E n d p oi nt s
I A P s e cti o n
Pri m ar y
 
T o  
d et er mi n e  
s af et y  
a n d 
t ol er a bilit y of M 3 2 5 8  at R D E 
w h e n  
c o -a d mi ni st er e d  
wit h 
d e x a m et h a s o n e i n p arti ci p a nt s 
wit h R R M M 
 
O c c urr e n c e  
of  
d o s e -li miti n g 
t o xi citi e s ( D L T s) i n p arti ci p a nt s 
r e c ei vi n g M 3 2 5 8  
i n c o m bi n ati o n 
wit h d e x a m et h a s o n e d uri n g t h e fir st 
2 8 -d a y tr e at m e nt c y cl e)
 
O c c urr e n c e  
of  st u d y 
tr e at m e nt-
e m er g e nt S A E s i n cl u di n g 
d e at h s 
fr o m fir st d o s e of st u d y i nt er v e nti o n 
t o 3 0 d a y s aft er e n d of st u d y 
i nt er v e nti o n
 
O c c urr e n c e of T E A E s a n d T R A E s 
(i n cl u di n g d e at h s) fr o m st art of 
st u d y i nt er v e nti o n u p t o 3 0 d a y s 
aft er e n d of st u d y i nt er v e nti o n
 
St u d y tr e at m e nt-e m er g e nt cli ni c all y 
r el e v a nt  a b n or m al  
c h a n g e s  
i n 
cli ni c al l a b or at or y m e a s ur e s  fr o m 
B a s eli n e,  E C G s  m e a s ur e s,  
vit a l 
si g n s, E C O G p erf or m a n c e st at u s 
fr o m st art of st u d y i nt er v e nti o n t o 3 0 
d a y s aft er e n d of st u d y i nt er v e nti o n
 
T b d i n l at er v er si o n
 
T o  
d et er mi n e  
r e c o m m e n d e d 
P h a s e II d o s e of M 3 2 5 8 w h e n 
c o -a d mi ni st er e d 
wit h 
d e x a m et h a s o n e i n p arti ci p a nt s 
wit h  R R M M  b a s e d 
o n 
e arl y 
si g n s of s af et y a n d effi c a c y i n 
t h e e x p a n si o n p h a s e
 
O c c urr e n c e of T E A E s a n d T R A E s 
(i n cl u di n g d e at h s) i n p arti ci p a nt s 
r e c ei vi n g M 3 2 5 8  
w h e n  gi v e n i n 
c o m bi n ati o n wit h  d e x a m et h a s o n e 
fr o m st art of st u d y i nt er v e nti o n t o 3 0 
d a y s aft er e n d of st u d y i nt er v e nt i o n
 
O R, D O R. Ti m e t o R e s p o n s e u ntil 
C R, s C R, V G P R, or P R a c c or di n g t o 
I MW G
 
T b d i n l at er v er si o n
S e c o n d ar y
 
T o c oll e ct pr eli mi n ar y effi c a c y 
d at a i n p arti ci p a nt s wit h R R M M 
u n d er tr e at m e nt wit h  M 3 2 5 8, 
w h e n  
c o -a d mi ni st er e d  
wit h 
d e x a m et h a s o n e
 
O R, D O R. Ti m e t o R e s p o n s e u ntil 
C R, s C R, V G P R, or P R a c c or di n g t o 
I MW G  
 
Pr o gr e s si o n -Fr e e  S ur vi v al  
( P F S) 
p er I n v e sti g at or
 
O v er all S ur vi v al ( O S) c e n s or e d at 
E n d of St u d y
 
T b d i n l at er v er si o n
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
1 2 /8 7
O bj e cti v e s
E n d p oi nt s
I A P s e cti o n
 
T o i n v e sti g at e t h e P K pr ofil e of 
M 3 2 5 8 ( si n gl e a n d m ulti pl e d o s e 
e x p o s ur e)  
w h e n  
c o -
a d mi ni st er e d 
wit h 
d e x a m et h a s o n e i n p arti ci p a nt s 
wit h R R M M
 
P K pr ofil e of M 3 2 5 8 i n t er m s of C m a x, 
A U C 0-t at D a y 1 C y cl e 1, ( si n gl e 
d o s e): pr e d o s e, 1, 2, 3, 4, 5, a n d 6 h 
aft er a d mi ni str ati o n
 
P K pr ofil e of M 3 2 5 8 i n t er m s of C m a x, 
A U C 0- 2 4 at D a y 1 5 C y cl e 1, ( m ulti pl e 
d o s e): pr e d o s e, 2, 4, a n d 6 h aft er  
a d mi ni str ati o n
 
T b d i n l at er v er si o n
E x pl or at or y
 
T o i n v e sti g at e t h e c h a n g e s i n 
t h e p h ar m a c o d y n a mi c m ar k er of 
M 3 2 5 8  
w h e n  c o -a d mi ni st er e d 
wit h  
d e x a m et h a s o n e  
i n 
p arti ci p a nt s wit h R R M M 
 
C h a n g e s i n L M P 7 a cti vit y o n D a y 1 
C y cl e 1 pr e a n d p o st d o s e a n d D a y 
1 5 C y cl e 1 pr e a n d p o st d o s e 
 
T b d i n l at er v er si o n
 
T o  
i n v e sti g at e  f urt h er  
P K 
p ar a m et er s of M 3 2 5 8  ( si n gl e 
a n d 
m ulti pl e  
d o s e 
e x p o s ur e) 
w h e n  
c o -a d mi ni st er e d  
wit h 
d e x a m et h a s o n e i n p arti ci p a nt s 
wit h R R M M 
 
P K pr ofil e of M 3 2 5 8 i n t er m s of t m a x, 
tl a g, t1/ 2 , C L/ F, Vz/ F at D a y 1 C y cl e 1, 
( si n gl e d o s e): pr e d o s e, 1, 2, 3, 4, 5, 
a n d 6 h aft er a d mi ni str ati o n
 
P K pr ofil e of M 3 2 5 8 
i n t er m s of 
A U C 0 →∞, tm a x, tl a g, t1/ 2 , C L s s/ F, at D a y 
1 5  
C y cl e  
1,  
( m ulti pl e  d o s e): 
pr e d o s e, 
2, 
4, 
a n d 
6 
h 
aft er 
a d mi ni str ati o n
 
P K pr ofil e of M 3 2 5 8 
i n t er m s of 
d o s e -n or m ali z e d  
C m a x, 
A U C 0-t , 
A U C 0- 2 4 f or si n gl e a n d m ulti pl e d o s e
 
T b d i n l at er v er si o n
 
T o i n v e sti g at e t h e f o o d eff e ct o n 
t h e P K 
of M 3 2 5 8  w h e n  c o -
a d mi ni st er e d 
wit h 
d e x a m et h a s o n e i n p arti ci p a nt s 
wit h R R M M
 
Ar e a  
u n d er  
t h e  
pl a s m a 
c o n c e ntr ati o n -ti m e c ur v e ( A U C0- 8 h ) 
wit h a n d wit h o ut f o o d fr o m ti m e z er o 
( = d o si n g ti m e) t o 8 h a n d C m a x of 
M 3 2 5 8 o b s er v e d o n D a y 1 C y cl e 2:  
pr e d o s e, 1, 2, 3, 4, 5, 6 a n d 8 h 
p o st d o s e 
 
T b d i n l at er v er si o n
 
T o i n v e sti g at e t h e r el ati o n s hi p 
b et w e e n e x p o s ur e wit h M 3 2 5 8 
a n d Q T c, w h e n c o -a d mi ni st er e d 
wit h  
d e x a m et h a s o n e  
i n 
p arti ci p a nt s wit h R R M M 
 
R el ati v e c h a n g e s fr o m B a s eli n e i n 
E C G p ar a m et er s ( Q T c) i n r el ati o n t o 
M 3 2 5 8  pl a s m a c o n c e ntr ati o n: all 
ti m e s aft er 
si n gl e 
a n d 
m ulti pl e 
d o si n g wit h 
c o n c urr e nt Q T c  a n d 
pl a s m a c o n c e ntr ati o n a s s e s s m e nt s
 
N ot i n s c o p e of t h e C T R, will 
b e r e p ort e d s e p ar at el y.
 
T o i n v e sti g at e g e n eti c v ari ati o n s 
t h at m a y 
aff e ct P K of M 3 2 5 8, 
w h e n  
c o -a d mi ni st er e d  
wit h 
d e x a m et h a s o n e i n p arti ci p a nt s 
wit h R R M M
 
A s s e s s m e nt of g e n eti c v ari ati o n s 
t h at aff e ct dr u g m et a b oli s m  a n d 
dr u g tr a n s p ort of M 3 2 5 8 a n d ot h er 
p ot e nti al g e n e s t h at m a y a c c o u nt f or 
diff er e n c e s i n t h e P K pr ofil e 
 
N ot i n s c o p e of t h e C T R, will 
b e r e p ort e d s e p ar at el y.
 
T o e x pl or e p ot e nti al m et a b olit e s 
of M 3 2 5 8 i n pl a s m a, w h e n c o -
a d mi ni st er e d 
wit h 
d e x a m et h a s o n e i n p arti ci p a nt s 
wit h R R M M
 
A s s e s s m e nt of p ot e nti al m et a b olit e s 
of M 3 2 5 8 
 
N ot i n s c o p e of t h e C T R, will 
b e r e p ort e d s e p ar at el y.
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
1 3 /8 7
O bj e cti v e s
E n d p oi nt s
I A P s e cti o n
 
T o i n v e sti g at e t h e P K pr ofil e of 
d e x a m et h a s o n e  
w h e n  
c o -
a d mi ni st er e d  wit h  
M 3 2 5 8  
i n 
p arti ci p a nt s wit h R R M M
 
Ar e a  
u n d er  
t h e  
pl a s m a 
c o n c e ntr ati o n -ti m e c ur v e ( A U C0- 8 h ) 
fr o m ti m e z er o ( = d o si n g ti m e) t o 8 h 
a n d  
C m a x
of  
d e x a m et h a s o n e 
o b s er v e d  o n  D a y  
1,  C y cl e  
2: 
pr e d o s e, 1, 2, 3, 4, a n d 6 h p o st d o s e
 
T b d i n l at e r v er si o n
 
T o e x pl or e L- citr ulli n e a s a n 
e x pl or at or y bi o m ar k er 
 
C h a n g e s 
i n t h e L- citr ulli n e bl o o d  
l e v el s d uri n g t h e st u d y at D a y 1 
pr e d o s e a n d D a y 1 5 pr e d o s e, C y cl e 
1, a n d D a y 1 pr e d o s e, C y cl e s 2 – 6 
pr e d o s e a n d e v er y t hir d c y cl e aft er 
C y cl e 6 pr e d o s e, a n d
at E n d of 
St u d y Vi sit
 
T b d i n l at er v er si o n
 
T o  
i n v e sti g at e c h a n g e  β 5 c 
a cti vit y aft er M 3 2 5 8, w h e n c o -
a d mi ni st er e d 
wit h 
d e x a m et h a s o n e i n p arti ci p a nt s 
wit h R R M M
 
C h a n g e s i n β 5 c a cti vit y o n D a y 1 
C y cl e 1 pr e a n d p o st d o s e a n d D a y 
1 5 C y cl e 1 pr e a n d p o st d o s e
 
T b d i n l at er v er si o n
 
T o 
i n v e sti g at e r el ati o n s hi p of 
dr u g tr e at m e nt a n d M R D, w h e n 
M 3 2 5 8 i s c o -a d mi ni st er e d wit h 
d e x a m et h a s o n e i n p arti ci p a nt s 
wit h R R M M
 
A s s e s s m e nt of M R D u p o n C R or 
s C R
 
T b d i n l at er v er si o n
6
O ver vie w of Pl a n ne d A n al yses
T he f oll o wi n g a nal ys es are pla n ne d f or t his trial:

S M C a nal y ses (See I A P f or S M C i n  A p pe n di x 1 8. 1 )

Pri mar y  a nalys is of trial
Statistical a nal yses (e xce pt f or S M Cs ) will be perf or me d o n t he basis of C DI S C S D T M data. T hese 
S D T M data c o ntai n as clea n as p ossi ble e C R F data as well as e xter nal data f or ce ntral la b orat or y
a n d D L T decisi o ns fr o m S M C .
A data re vie w meeti n g will be hel d pri or t o a n y data base l oc k. I n a d diti o n, n o data base ca n be 
l oc ke d u ntil t his IA P has bee n a p pr o ve d (e xce pt f or e mer ge nc y).
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
1 4 /8 7
6. 1
A n al yses f or S M C meeti n gs
Details of a nal ys es f or S M C meeti n gs are s pecifie d i n a se parate I A P, pr o vi de d i n A p pe n di x 1 8. 1 .
7
C h a n ges 
t o t he Pl a n ne d A n al yses 
i n t he Cli nic al 
St u d y
Pr ot oc ol
T he st u d y was st o p pe d d ue t o lac k of e nr oll me nt bef ore part B was starte d a n d bef ore part A 
reac he d its pri mar y  objecti ve . T heref ore, a d diti o nal t o t he S M C a nal ys es t here is o nl y o ne pri mar y  
a nal ys is (t his i ncl u des t he e n d of d ose escalati o n a naly sis).
T here is o ne c ha n ge i n t he defi niti o n of t he D L T a nal ys is set c o m pare d t o t he pr ot oc ol . T he 
f oll o wi n g is a d de d: 
“A d diti o nall y , partici pa nts t hat di d n ot recei ve at least 8 0 % of t he pla n ne d t otal d ose of st u d y 
treat me nt, b ut at least 8 0 % d osi n g of a differe nt (l o wer) d ose le vel, di d n ot miss m ore t ha n 2 0 % of 
pla n ne d a d mi nistrati o ns , a n d fi nis he d t he D L T peri o d are eli gi ble f or t he D L T a nal ys is set t o be 
a nal yz e d i n t he hi g hest d ose le vel t he y recei ve d 8 0 % of d osi n g. ”
T he pr ot oc ol o nl y m e nti o ne d β 5c as a n e n d p oi nt f or part B, h o we ver, data a nal yses f or t his mar ker 
are pla n ne d f or t he d ose escalati o n part A , t o o. 
I n case t he recei ve d c u m ulati ve d ose is hi g her t ha n pla n ne d d ose (a n d all ot her criteria f or i ncl usi o n 
i n D L T a nal ysis set are f ulfille d) the pa rtici pa nt will still be a nal yz e d i n t he pla n ne d d ose le vel F or 
a nal ys is of p har mac o d y na mic mar kers a n d efficac y an al y sis t he partici pa nt will be s h o w n i n 
listi n gs a n d fi g ures s h o wi n g data o n i n di vi d ual le vel. A f o ot n ote will e x plai n t he c u m ulati ve d os i n g 
t he s u bject recei ve d. I n s u m mar y a nalys is of p har mac o dy na mic mar kers a n d efficac y a nal ysis t he 
partici pa nt’s data will n ot be i ncl u de d.
8
A n al ysis P o p ul ati o ns a n d S u b gr o u ps
8. 1
Defi niti o n of A n al ysis P o p ul ati o ns
T he a nal ys is p o p ulati o ns are s pecifie d bel o w. T he fi nal decisi o n t o e xcl u de partici pa nts fr o m a ny 
a nal ys is p o p ulati o n will be ma de d uri n g a data re vie w meeti n g pri or t o data base l oc k e xce pt f or 
t he D L T a nalys is p o p ulati o ns. F or t he D L T a nal ys is p o p ulati o ns, decisi o ns f or D L Ts are ta ke n b y 
t he S M C.
Scree ni n g A n al ysis P o p ul ati o n ( S C R)
T he Scree ni n g a nal ys is p o p ulati o n i ncl u des all partici pa nts w h o si g ne d t he i nf or me d c o nse nt.
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
1 5 /8 7
S afet y A n al ysis P o p ul ati o n ( S A F)
T he Safet y a nal ys is set will i ncl u de all partici pa nts w h o were a d mi nistere d a n y d ose of a n y st u d y 
i nter ve nti o n. A nal ys es will co nsi der partici pa nts as treate d, mea ni n g t hat p artici pa nts will be 
classifie d acc or di n g t o t he st u d y i nter ve nti o n act uall y recei ve d (re gar di n g d ose le vel, see secti o n 
9 Ge ner al S pecificati o ns f or Data A nal ys es i ncl u di n g e x pla nati o n o n h o w t o deal wit h partici pa nts
t hat di d recei ve a d ose differe nt t o t he pla n ne d d ose).
D ose Li miti n g T o xicit y A n al ysis P o p ul ati o n ( D L T) 
T he D ose Li miti n g T o xicit y  a nalys is p o p ulati o n ( D LT) will i ncl u de all partici pa nts w h o recei ve d 
at least o ne d ose of st u d y i nter ve nti o n a n d meet at least o ne of t he f oll o wi n g criteria:

E x perie nce d at least o ne D L T d uri n g t he D L T peri o d, re gar dless of t he a d mi nistere d 
n u m ber of d oses of st u d y i nter ve nti o n/c o m pleti o n of t he D L T peri o d

Recei ve d at least 8 0 % of t he pla n ne d c u m ulati ve d ose a n d at least 8 0 % of pla n ne d 
a d mi nistrati o ns (e g.: 4 a d mi nistrati o ns b y c ycle, 2 a d mi nistrati o ns b y wee k …etc.) of eac h 
treat me nt d uri n g t he D L T peri o d a n d c o m plete d t he D L T peri o d. 

A d diti o nall y ,partici pa nts t hat di d n ot recei ve at least 8 0 % of t he pla n ne d t otal d ose of 
st u d y treat me nt, b ut at least 8 0 % d osi n g of a differe nt (l o wer) d ose le vel, di d n ot miss 
m ore t ha n 2 0 % of d osi n g, a n d fi nis he d t he D L T peri o d are eli gi ble f or t he D L T a nal ys is 
set t o be a nalyz e d i n t he hi g hest d ose le vel t he y recei ve d 8 0 % of d osi n g of.   
I n case t he recei ve d c u m ulati ve d ose is hi g her t ha n pla n ne d d ose (a n d all ot her criteria f or 
i ncl usi o n i n D LT a nal y sis set are f ulfille d) t he partici pa nt will still be a nal yze d i n t he pla n ne d 
d ose le vel
P h ar m ac o ki netics P o p ul a ti o n ( P K)
T he p har mac o ki netics p o p ulati o n ( P K) will i ncl u de all partici pa nts, w h o recei ved at least o ne d ose 
of st u d y inter ve nti o n, ha ve n o cli nicall y i m p orta nt pr ot oc ol de viati o ns or i m p orta nt e ve nts 
affecti n g P K, a n d pr o vi de at least o ne meas ura ble p ost d ose c o nce ntrati o n. Partici pa nts will be 
a nal yz e d per t he act ual st u d y i nter ve nti o n t he y recei ve d.
P h ar m ac o d y n a mics P o p ul ati o n ( P d)
T he p har mac o d y n a mics p o p ulati o n ( P d) will i ncl u de all, w h o recei ved at least o ne d ose of st u d y 
i nter ve nti o n, ha ve n o cli nicall y im p orta nt pr ot oc ol de viati o ns or i m p orta nt e ve nts affecti n g P d, a n d 
pr o vi de at least o ne meas ura ble P d e n d p oi nt p ost d ose . I n case t he recei ve d c u m ulati ve d ose of a 
partici pa nt is hi g her t ha n t he pla n ne d d ose, t he partici pa nt ’s data will be i ncl u de d i n listi n gs a n d 
fi g ures s h o wi n g data o n i n di vi d ual le vel. A f o ot n ote will e x plai n t he c u m ulati ve d os e t he s u bject 
recei ve d. I n su m mar y  anal y sis of p har mac o d y n a mic mar kers t he partici pa nt’s data will n ot be 
i ncl u de d.
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
1 6 /8 7
A n al yses per A n al ysis P o p ul ati o n
T he f oll o wi n g ta ble s u m marizes t he use of t he a nal ysis sets i n t he differe nt a nal ys es. 
A n al y s i s P o p ul ati o n
A n al y s e s
S A F
D L T
P K
P d
D L T


S af et y a n d T ol er a bilit y


P K




P d








Effi c a c y

E x pl or at or y b i o m ar k er s ( M R D)

B a s eli n e C h ar a ct eri sti c s


Pr e vi o u s a n d C o n c o mit a nt T h er a pi e s


C o m pli a n c e a n d E x p o s ur e


N ote: 
Safet y , P K, will be descri be d b y act ual d ose.
Baseli ne c haracteristics a n d c o m plia nce a n d e x p os ure will be descri be d f or b ot h ( b y pla n ne d d ose 
a n d act ual d ose) if differe nt.
All ot her a nal ys es will be descri be d b y pla n ne d d ose, acc or di n g t o I nte nti o n T o Treat pri nci ple.
F or m ore details see  secti on 9 Ge neral S pecificati o ns f or Data A nal ys es i ncl u di n g.
9
Ge ner al S pecific ati o ns f or D at a A n al yses
T his secti o n descri bes a n y ge neral s pecificati o ns n ot i ncl u de d i n s u bse q ue nt secti o ns. 
St u d y  i nter ve nti o n is defi ne d a n d la belle d as “M 3 2 5 8 ”.
A nal y ses will b e dis pla ye d se parately b y  re gi me n ( or dere d b y  dose i nte nsit y starti n g fr o m m ost 
i nte nsi ve re gi me n ( Q D)), d ose (i n i ncreasi n g or der a n d n ot e val ua ble at t he fi nal) a n d s u m marize d.
T he pla n ne d re gi me n a n d d ose le vel will be ta ke n fr o m t he C R F “ C o h ort Assi g n m e nt”. 
Ge neral r ule f or act ual d ose if act ual d ose differs fr o m pla n ne d d ose ( deter mi ned d uri n g t he D L T 
peri o d) :
-
Pla n ne d d ose > d ose rece i ve d

If t he partici pa nt recei ves at least 8 0 % of his c u m ulati ve pla n ne d d ose or has D L T 
d uri n g D L T peri o d , t he n his act ual d ose will be his pla n ne d d ose
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
1 7 /8 7

If t he partici pa nt recei ves less t ha n 8 0 % of his c u m ulati ve pla n ne d d ose a n d has n o
D L T d uri n g D L T peri o d b ut recei ve d at least 8 0 % of a c u m ulati ve l o wer teste d d ose , 
t he n his act ual d ose will be t he l o wer d ose le vel he recei ve d at least 8 0 % of c u m ulati ve 
d ose f or safet y a nal yses a n d t he pla n ne d d ose is use d f or all ot her a nalys es.

If t he partici pa nt recei ves less t ha n 8 0 % of t he c u m ulati ve of a n y teste d d ose or less 
t ha n 8 0 % of t he pla n ne d a d mi nistrati o ns or di d n ot fi nis h t he D L T peri o d t he partici pa nt
is n ot e val ua ble f or t he D L T a nal ys is set (t his cate g or y will be prese nte d i n t he ta bles 
f or D L T a nal ys is set), b ut f or ot her safet y anal y ses. F or ot her safet y anal y ses i n t his 
case t he partici pa nt will be a nal yz e d wit h t he 
o
pla n ne d d ose i n case he di d recei ve less t ha n 8 0 % c u m ulati ve d ose of a n y t este d 
d ose
o
C u m ulati ve d ose he recei ve d 8 0 % of (i n case he misse d t o o ma n y  dosi n gs or 
di d n ot fi nis h t he D L T peri o d)
-
Pl a n ne d d ose < d ose recei v e d:

Act ual d ose will be t he pla n ne d d ose (i n D L T a nal ysis set)

F or a nal ys is of p har mac o d y na mic mar kers a n d efficac y anal ys is t he data of s uc h a 
partici pa nt will be s h o w n i n listi n gs a n d fi g ures s h o wi n g data o n i n di vi d ual le vel. A 
f oot n ote will e x plai n t he c u m ulati ve d osi n g t he s u bject recei ve d. I n s u m mar y anal ys is 
of p har mac o d y na mic mar kers a n d efficac y anal ys is t he data of s uc h a partici pa nt will 
n ot be i ncl u de d.
T he “start date” f or t his st u d y  is t he date of first st u d y  dr u g a d mi nistrati o n ( M 3 2 5 8).
All a nal yses will be perf or me d usi n g S A S ® S oft ware versi o n 9. 2 or hi g her, a n d ot her wise as 
s pecifie d (e. g. f or Ba ye s m o deli n g)
Si g nific a nce le vel:
T here is n o f or mal si g nifica nce le vel f or t his st u d y, a n d al l a nalys es are c o nsi dere d descri pti ve .
T here will be n o statistical tests perf or me d. If c o nfi de nce or cre di bilit y inter vals are me nti o ne d, 
t he le vel will be 9 5 % u nless ot her wise s pecifie d.
Prese nt ati o n of c o nti n u o us a n d q u alit ati ve v ari a bles:
C o nti n u o us v aria bles will be s u m marize d usi n g descri pti ve statistics, i.e. 

n u m ber of partici pa nts wit h n o n -missi n g val ues ( n)

mea n, sta n dar d de viati o n ( S D)
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
1 8 /8 7

me dia n, 2 5t h Perce n tile - 7 5t h Perce ntile ( Q 1 -Q 3)

mi ni m u m, ma xi m u m
If t here are fe wer t ha n 5 o bser vati o ns s u m marize d, o nl y  the n u m ber of partici pa nts wit h n o n-
missi n g val ues, t he mea n, a n d t he mi ni m u m a n d ma xi m u m will be gi ve n.
Q ualitati ve varia bles will be s u m marize d b y  c o u nts a n d perce nta ges.               
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 n u m ber of partici pa nts 
i n t he a nal ysis set of i nterest. T heref ore , 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 .
De viati o ns fr o m t his defi niti o n mi g ht a p pl y  t o t he P K a nal ysis (see secti o n 1 6. 1 f or defi niti o ns).
Descri pti ve statistics will be c o m p ute d b y  treat me nt da y  (C 1 D 1, C 1 D 2, C 1 D 8,
…, 
E O T) . 
U nsc he d ule d visits will be i ncl u de d i n t he deri vati o n of baseli ne (if occ urre d wit hi n t he all o we d 
scree ni n g peri o d) or w orst o n -treat me nt val ues an d i n a n y  a nal ysis usi n g treat me nt da y (e. g. pl ots 
of la b data) .
9. 1
Defi niti o n of b aseli ne a n d c h a n ge fr o m b aseli ne
I n ge neral, t he last n o n- missi n g meas ure me nt pri or t o t he first st u d y dr u g a d mi nistrati o n will be 
use d as t he baseli ne meas ure me nt.
If a n assess me nt t hat is pla n ne d t o be perf or me d bef ore treat me nt per pr ot oc ol is perf or me d o n t he 
sa me da y as t he start of treat me nt, res pecti vel y, b ut t he assess me nt ti me is n ot a vaila ble, it will be 
ass u me d t hat it was perf or me d pri or a n d will be c o nsi dere d as baseli ne.
If a sc he d ule d pre -d ose meas ure me nt 
act uall y occ urre d p ost -d ose, t he n t he c orres p o n di n g 
meas ure me nt will be a nal y ze d si milar t o a n u nsc he d ule d p ost -d ose meas ure me nt.
A bs ol ute a n d perce nt c ha n ges fr o m baseli ne are defi ne d as 
a bs ol ute c ha n ge = p ost baseli ne val ue – baseli ne val ue
perce nt c ha n ge = 1 0 0 * ( p ost baseli ne val ue – baseli ne val ue) / baseli n e val ue
9. 2
Defi niti o n of D ur ati o n a n d ‘ti me si nce’ V ari a bles
If n ot ot her wise s pecifie d, d urati o n will be calc ulate d b y  the differe nce of start a n d st o p date + 1 
(e. g. s ur vi val ti me ( da ys) = date of deat h – date of first st u d y dr u g a d mi nistrati o n + 1). 
T he ti me si nce a n e ve nt (e. g. ti me si nce first dia g n osis) will be calc ulate d as refere nce date mi n us 
date of e ve nt.  
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
1 9 /8 7
9. 3
C o n versi o n f act ors
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert da y s i nt o m o nt hs or ye ars: 1 m o nt h = 
3 0. 4 3 7 5 da y s, 1 year = 3 6 5. 2 5 da y s.
9. 4
Defi niti o n of O n -tre at me nt Peri o d
T he o n -treat me nt peri o d is defi ne d as t he ti me fr o m first d ose of st u d y i nter ve nti o n t o 3 0 da ys 
after e n d of st u d y i nter ve nti o n , or t he c ut-off date, w hic he ver occ urs first.
9. 5
I m p ut ati o n of missi n g d at a
U nless ot her wise s pecifie d all data will be e val uate d as o bser ve d, a n d n o i m p utati o n met h o d f or 
missi n g val ues will be use d.
I n all partici pa nt data listi n gs, i m p ute d val ues will be prese nte d a n d i m p ute d i nf or mati o n will be 
fla g ge d, if i m p utati o n was d o ne.
Missi n g statistics, e. g. w he n t he y  ca n n ot be calc ulate d, s h o ul d be prese nte d as “ n d”.  
W here 
ta bles are prese nte d o ver differe nt ti me p oi nts, t he t otal of missi n g a n d n o n- missi n g 
o bser vati o ns at eac h ti me-p oi nt s h o ul d reflect t he p o p ulati o n still i n t he trial at t hat ti me. T his d oes 
n ot a p pl y w he n i m p utati o ns are ma de be y o n d trial wit h dra wal. F or e xa m ple, if a partici pa nt is still 
i n t he trial at t he ti me-p oi nt b ut wit h missi n g data, t he y sh o ul d be c o u nte d i n t he n u m ber of missi n g 
o bser vati o ns.
T he f oll o wi n g ta ble f or i m p utati o n r ules will be c o nsi dere d:
A d verse e ve nts 
I nc o m plete A E -relate d dates will be i m p ute d as f oll o ws:

If t he o nset date is missi n g c o m pletel y or missi n g partiall y – b ut t he 
o nset m o nt h a n d ye ar, or ye ar, are e q ual t o t hat of t he st u d y treat me nt 
start – t he n t he o nset date will be re place d b y t he mi ni m u m of t he start 
of st u d y  treat me nt a n d t he A E res ol uti o n date.

I n all ot her cases, t he missi n g o nset da y or m o nt h will be re place d b y 1.

I nc o m plete st o p dates will be re place d b y  the last da y  of t he m o nt h (if 
da y  is missi n g o nl y ), if n ot res ulti n g i n a date later t ha n t he date of 
partici pa nt’s deat h. I n t he latter case, t he date of deat h will be use d t o 
i m p ute t he i nc o m plete st o p date.
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
2 0 /8 7

I n all ot her cases t he i nc o m plete st o p date will n ot be i m p ute d. If t he 
st o p date of a n A E is after t he date of c ut-off, t he o utc o me of t he A E is 
o n g oi n g at c ut -off.

F urt her i nf or mati o n after c ut-off (s uc h as fatal o utc o me) mi g ht be ta ke n 
fr o m t he Safety data base a n d re p orte d se paratel y.
Pre vi o us  
a n d 
c o nc o mita nt 
me dicati o n
F or i de ntificati o n of pre vi o us or c o nc o mita nt me dicati o ns/ pr oce d ures, n o 
f or mal i m p utati o n will be perf or me d o n missi n g or i nc o m plete dates. 
R ules prese nte d i n  Ta ble 2 will be use d t o defi ne if a 
me dicati o n/ pr oce d ure is c o nsi dere d as a pre vi o us, c o nc o mita nt or b ot h 
pre vi o us a n d c o nc o mita nt me dicati o n/ pr oce d ure.
T a ble 1
I m p ut ati o n r ules f or me dic ati o n/ pr oce d ure e n d d ates
E n d d at e of m e di c ati o n/ pr o c e d ur e
i m p ut ati o n r ul e
D a y 
M o nt h
Y e ar
U N K   
U N K   
U N K
Aft er tr e at m e nt st art ( o n g oi n g)
U N K   
U N K 
< Tr e at m e nt st art ( y e ar)
B ef or e tr e at m e nt st art
U N K   
U N K 
> = Tr e at m e nt st art ( y e ar)
Aft er tr e at m e nt st art
U N K 
< Tr e at m e nt st art ( m o nt h a n d y e ar)
B ef or e tr e at m e nt st art
U N K 
> = Tr e at m e nt st art ( m o nt h a n d y e ar)
Aft er tr e at m e nt st art
< Tr e at m e nt st art ( c o m pl et e d at e)
B ef or e tr e at m e nt st art
> = Tr e at m e nt st art ( c o m pl et e d at e)
Aft er tr e at m e nt st art
U N K = U n k n o w n
T a ble 2
R ules t o defi ne pre vi o us a n d/ or c o nc o mit a nt me dic ati o n
St art d at e of m e di c ati o n/ pr o c e d ur e
i m p ut ati o r ul e 
( s e e T a bl e 1)
M e di c ati o n/ pr o c e d ur e
D a y 
M o nt h
Y e ar
U N K   
U N K   
U N K
B ef or e tr e at m e nt 
st art
Pr e vi o u s
U N K   
U N K   
U N K
Aft er tr e at m e nt 
st art
Pr e vi o u s a n d c o n c o mit a nt
U N K   
U N K
< = Tr e at m e nt st art 
( y e ar)
B ef or e tr e at m e nt 
st art
Pr e vi o u s
U N K   
U N K
< = Tr e at m e nt st art 
( y e ar)
Aft er tr e at m e nt 
st art
Pr e vi o u s a n d c o n c o mit a nt
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
2 1 /8 7
St art d at e of m e di c ati o n/ pr o c e d ur e
i m p ut ati o r ul e 
( s e e T a bl e 1)
M e di c ati o n/ pr o c e d ur e
D a y 
M o nt h
Y e ar
U N K   
U N K
> Tr e at m e nt st art ( y e ar) 
a n d < = Tr e at m e nt e n d 
+ 3 0 d a y s ( y e ar)
Aft er tr e at m e nt 
st art
C o n c o mit a nt
U N K
< = Tr e at m e nt st art ( m o nt h a n d 
y e ar)
B ef or e tr e at m e nt 
st art
Pr e vi o u s
U N K
< = Tr e at m e nt st art ( m o nt h a n d 
y e ar)
Aft er tr e at m e nt 
st art
Pr e vi o u s a n d c o n c o mit a nt
U N K
> Tr e at m e nt st art ( m o nt h a n d 
y e ar) a n d < = Tr e at m e nt e n d + 3 0 
d a y s ( m o nt h a n d y e ar)
Aft er tr e at m e nt 
st art
C o n c o mit a nt
< = Tr e at m e nt st art ( d at e)
B ef or e tr e at m e nt 
st art
Pr e vi o u s
< = Tr e at m e nt st art ( d at e)
Aft er tr e at m e nt 
st art
Pr e vi o u s a n d c o n c o mit a nt
> Tr e at m e nt st art ( d at e) a n d < = Tr e at m e nt 
e n d + 3 0 d a y s ( d at e)
Aft er tr e at m e nt 
st art
C o n c o mit a nt
U N K = U n k n o w n
Deat h date
N ote: F or partici pa nt s w h o 
die d a n d f or w h o m n o 
c o m plete deat h date is 
a vaila ble us uall y t he deat h date 
is n ot i m p ute d. J ust f or s ur vi val 
a nal ys es i m p utati o n r ules are 
a p plie d, i n deat h listi n gs n o n -
i m p ute d data will be prese nte d.
F or t he p ur p ose of s ur vi val a nal ys es partiall y  missi n g 
deat h dates will be i m p ute d as f oll o ws:
If o nl y t he da y  is missi n g, t he deat h date will be i m p ute d 
t o t he ma xi m u m of t he ( n o n-i m p ute d) da y after t he date 
of last c o ntact a n d t he 1 5t h da y  of t he m o nt h. 
Ot her wise it will n ot be i m p ute d.
9. 6
St u d y D a y / St u d y Tre at me nt D a y defi niti o n
Treat me nt d a y i s defi ne d relati ve t o t he date of first st u d y dr u g a d mi nistrati o n ( M 3 2 5 8). Treat me nt 
Da y  1 is treat me nt start date of first a dmi nistrati o n of t he st u d y dr u g; t he da y bef ore is defi ne d as 
Treat me nt Da y  -1 ( n o Treat me nt Da y  0 is defi ne d).
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
2 2 /8 7
1 0
St u d y P artici p a nt s
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or re p orti n g partici pa nt dis p ositi o n a n d 
st u d y inter ve nti o n /st u d y disc o nti n uati o ns. A d diti o nall y , pr oce d ures f or re p orti n g pr ot oc ol 
de viati o ns are pr o vi de d.
1 0. 1
Dis p ositi o n of P artici p a nts a n d Disc o nti n u ati o ns
A ta ble will dis pla y  t he f oll o wi n g ( per re gi me n a n d d ose le vel a n d o verall):

N u m ber of partici pa nts i n eac h a nalys is p o p ulati o n ( S C R, S A F, D LT, P K, P d )

N u m ber of partici pa nts w h o disc o nti n ue d fr o m t he st u d y pri or t o treat me nt o verall a n d gr o u pe d 
b y  t he mai n reas o n (partici pa nts di d n ot meet eli gi bilit y  criteria, wit h dre w c o nse nt, ot her)
T his ta ble will be pr o d uce d t wice if t here are partici pa nts wit h differi n g pla n ne d d ose a n d act ual 
d ose , o ne by pl a n ne d d ose (i ncl u di n g S C R, S A F, P d , P K) a n d o ne by a ct ual d ose (i ncl u di n g S C R, 
S A F, D L T, P K).
T his ta ble will a d diti o nall y  be dis pla ye d b y site.
A n ot her ta ble of dis p ositi o n will pr o vi d e t he f oll o wi n g, a m o n g partici pa nts i n S A F:

N u m ber a n d perce nta ge of partici pa nts still i n trial

N u m ber a n d perce nta ge of partici pa nts wit h dra w n fr o m trial 

N u m ber of partici pa nts b y  reas o n f or wit h dra wal
A d d iti o nall y a listi n g will dis pla y  all disc o nti n ue d patie nts i ncl u di n g pla n ne d re gi me n a n d d ose, 
t he reas o n f or disc o nti n uati o n fr o m treat me nt a n d reas o n f or disc o nti n uati o n fr o m st u d y an d 
treat me nt start a n d e n d date.
1 0. 2
Pr ot oc ol De vi ati o ns / E xcl usi o n fr o m A n al ysis P o p ul ati o n
1 0. 2. 1 
I m p ort a nt Pr ot oc ol De vi ati o ns
I m p orta nt pr ot oc ol de viati o ns (IP Ds) are pr ot oc ol de viati o ns t hat mi g ht si g nifica ntly affect t he 
c o m plete ness, acc urac y, a n d/ or relia bilit y of t he st u d y data or t hat mi g ht si g nifica ntl y affect a 
partici pa nt 's ri g hts, safet y, or well-bei n g. 
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
2 3 /8 7
T he I P Ds will be i de ntifie d f or all partici pa nts b y eit her site m o nit ori n g, me dical re vie w pr ocesses 
or pr o gra m mi n g a n d c o nfir me d pri or t o or at t he Data Re vie w Meeti n g at t he latest.
All i m p orta nt pr ot oc ol de viati o ns are d oc u me nte d i n S D T M datasets w het her i de ntifie d t hr o u g h 
site m o nit ori n g, me dical re vie w or pr o gra m mi n g.
A f ull list of p ote ntial pr ot oc ol de viati o ns i ncl u di n g defi niti o n a n d cate g orizati o n is mai ntai ne d b y 
C o va nce i n t he “ St u d y Specific Pr ot oc ol De viati o n Li st” attac he d t o t he Pr ot oc ol De viat i o n 
Ma na ge me nt Pla n .
A fre q ue nc y ta ble f or i m p orta nt, se parate d f or s uc h pre -/ p ost i ncl usi o n de viati o ns, as well as a 
listi n g ( b y partici pa nt) of i m p orta nt pr ot oc ol de viati o ns, will be pr o vi de d base d o n t he Safet y 
a nal ys is set.
Referri n g t o F D A, a listi n g of all partici pa nts affecte d b y  t he C O VID- 1 9 relate d st u d y  disr u pti o n 
will be pr o d uce b y  u ni q ue s u bject n u m ber i de ntifier a n d b y  i n vesti gati o nal site, a n d a descri pti o n 
of h o w t he i n di vi d ual’s partici pati o n was altere d .
T he pr ot oc ol de viati o ns are detaile d i n t he d oc u me nt M S 2 0 1 8 1 4 - 0 0 1 0 Pr ot oc ol De viati o n 
Listi n g _ 1 4 N o v 2 0 1 9 _ v 1. 0. xls x or a n u p date d versi o n.
1 0. 2. 2 
Re as o ns 
Le a di n g 
t o t he E xcl usi o n 
fr o m a n 
A n al ysis 
P o p ul ati o n
A listi n g of reas o ns f or e xcl usi o n fr o m D LT a nal ysis p o p ulati o n will be pr o vi de d.
A d diti o nall y  a listi n g of s u bjects e xcl u de d fr o m a nal ysis sets ( D L T, S A F, P K, P d) wit h reas o n f or 
e xcl usi o n will be pr o vi de d ( f or secti o n 9. 2. 3).
Of n ote, par tici pa nts w h o di d n ot recei ve at least 8 0 % of t he pla n ne d d ose are e xcl u de d fr o m t he 
D L T a nal ys is set u nless t he y ca n be c o nsi dere d i n a n ot her d ose le vel as descri be d i n Secti o ns 8
a nd  1 0. 2. 1.
1 1
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics
If n ot state d ot her wise, t he f oll o wi n g a nal ys es will be perf or me d base d o n t he S A F, b y  re gi me n 
a n d d ose, a n d o verall.
1 1. 1
De m o gr a p hics 
De m o gra p hic c haracteristics a n d p h y sical meas ure me nts will be s u m marize d descri pti vel y  usi n g 
t he f oll o wi n g i nf or mati o n fr o m t he Scree ni n g/C y cle 1 Da y 1 e C R F pa ges.
T he f oll o wi n g de m o gra p hic c haracteristics will be i ncl u de d: 
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI




M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
2 5 /8 7
1 1. 3
Ot her B aseli ne C h ar acteristics
Inf or mati o n o n disease c hara cteristics c ollecte d at baseli ne will be s u m marize d. S u m mar y 
statistics will be prese nte d f or (as a p plica ble)

Pri or tra ns pla nt:
o
Ste m cell tra ns pla nt ( Yes, N o)
o
Ste m cell t y pe ( B o ne marr o w, Peri p heral bl o o d ste m cell)
o
Si n gle or Ta n de m tra ns pla nt
o
T y pe of tra ns pla nt ( A ut ol o g o us Ste m Cell Tra ns pla nt, All o ge nic Ste m Cell 
Tra ns pla nt)
o
C h em ot hera p y ( Yes, N o)
o
T otal B o d y Irra diati o n ( Yes, N o)

Hist or y  of disease u n der st u d y: 
o
Ti me si nce i nitial dia g n osis
o
T y pe of m yel o ma at dia g n osis (I g G, I g M, I g A, I gD, I g E)
o
Li g ht c hai n of m yel o ma at dia g n osis ( La m b da, Ka p pa)
o
I S S sta ge at dia g n osis (I, II, III)

Disease c haracteristics at st u d y  e ntr y: 
o
T y pe of m yel o ma at (I g G, I g M, I g A, I g D, I g E)
o
Li g ht c hai n of m y el o ma ( La m b da, Ka p pa)
o
I S S sta ge (I, II, III)

Prese nce of b o ne lesi o ns a t C y cle 1 Da y 1 ( base d o n pa ge “ Oste ol yt ic b o ne lesi o n assess me nt”)
All t hese ot her baseli ne c haracteristics al o n g wit h su bsta nce usa ge ( Dr u g, alc o h ol, nic oti ne a n d 
caffei ne c o ns u m pti o n) a n d fa mil y hist or y of pre mat ure car di o vasc ular disease will be liste d f or 
pri mar y  a nalys is
Baseli ne  
c haracteristics 
wit h  
res pect 
t o 
vital 
si g ns 
a n d 
la b orat or y 
(i ncl ud i n g 
he mat ol o g y / bi oc he mistr y) will be part of Secti o n Err or! Refere nce s o urce n ot f o u n d. ( Safet y E
val uati o n).
1 1. 4
Pri or A nti -c a ncer T her a p y
T he pri or a nti-ca ncer t hera pies are c ollecte d u n der t he “ Pri or A nti- Ca ncer Dr u g T hera pies 
Details”, “ Pri or A nti- Ca ncer Ra di ot hera p y Details” a n d “ Pri or A nti- Ca ncer S ur geries Details” 
e C R F pa ges.
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
2 6 /8 7
T he n u m ber a n d perce nta ge of partici pa nts i n eac h of t he f oll o wi n g a nti -ca ncer t hera p y cate g ories 
will be ta b ulate d:

Partici pa nts wit h at least o ne pri or a nti -ca ncer dr u g t hera p y

Partici pa nts wit h at least o ne pri or a nti -ca ncer ra di ot hera p y

Partici pa nts wit h at least o ne pri or a nti -ca ncer s ur ger y
T his ta ble will als o ta b ulate t he n u m ber of pri or a ntica ncer t hera pies, pri or a ntica ncer dr u g 
t hera pies, pri or a nti-ca ncer ra di ot hera pies a n d n u m ber of pri or a nti -ca ncer s ur geries.
T he listi n g of pri or a nti -ca ncer treat me nts a n d pr oce d ures will als o be pr o vi de d as f oll o ws. T hese 
will i ncl u de t he partici pa nt i de ntificati o n n u m ber, a n d all t he rele va nt c ollecte d data -fiel ds o n t he 
c orres p o n di n g e C R F pa ges (i ncl u di n g if c he m ot hera p y was ass ociated t o a ste m cell tra ns pla nt) .

Listi n g of pri or a nti -ca ncer dr u g t hera pies 

Listi n g of pri or a nti -ca ncer ra di ot hera p y 

Listi n g of pri or a nti -ca ncer s ur geries
1 2
Pre vi o us or c o nc o mit a nt me dic ati o ns/i nter ve nti o ns
T he f oll o wi n g a nal ys es will be perf or me d base d o n t he S A F a nal ys is set, b y  re gi me n a n d b y  d ose 
(i n i ncreasi n g or der) a n d s u m marize d 
C o nc o mit a nt tre at me nts are me dicati o ns, ot her t ha n st u d y treat me nt, w hic h are ta ke n b y  
partici pa nts a n y ti me d uri n g t he o n -treat me nt peri o d, see secti o n 9. 4.
Pre vi o us me dic ati o ns are me dicati o ns, ot her t ha n st u d y treat me nt a n d pre-me dicati o ns f or st u d y 
treat me nts, w hic h starte d bef ore first a d mi nistrati o n of st u d y treat me nts.
A me dicati o n m a y  be classifie d as b ot h c o nc o mita nt a n d pre vi o us. T he res pecti ve fla gs will be 
deri ve d base d o n start a n d e n d date. 
C o nc o mita nt a n d pre vi o us treat me nt eac h will be s u m marize d b y  nu m ber a n d perce nta ge of 
partici pa nts fr o m t he “Rele va nt Pre vi o us me dicati o ns”
a n d “ C o nc o mita nt me dicati o n s” e C R F. 
A T C -2 n d le vel a n d preferre d ter m will be ta b ulate d as gi ve n fr o m t he W H O -D D dicti o nar y  m ost 
c urre nt versi o n. If a n y p re vi o us or c o nc o mita nt me dicati o n is classifie d i nt o m ulti ple A T C classes, 
t he me dicati o n will be s u m marize d se parately u n der eac h of t hese A T C classes. T he s u m mar y 
ta bles will be s orte d b y  decreasi n g fre q ue nc y of dr u g class a n d decreasi n g fre q ue nc y of dr u g na me 
i n a gi ve n dr u g class. I n case of e qual fre q ue nc y re gar di n g dr u g class (res pecti vely dr u g na me), 
al p ha betical or der will be use d. I n case a n y s pecific me dicati o n d oes n ot ha ve a n A T C 
classificati o n le vel 2 c o de d ter m, it will be s u m marize d u n der “ U na vaila ble A T C classificati o n” 
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
2 7 /8 7
cate g or y. Each partici pa nt will o nl y  be c o u nte d o nce, e ve n if he/s he recei ve d t he sa me me dicati o n 
at differe nt ti mes.
All c o nc o mita nt treat me nts, pre vi o us me dicati o ns a n d c o nc o mit a nt pr oce d ures , w hic h were 
u n derta ke n d uri n g t he o n- treat me nt peri o d will be liste d. C o nc o mita nt pr oce d ures acc or di n g t o t he 
C R F pa ge “ C o nc o mita nt Pr oce d ures”.
1 3
St u d y i nter ve nti o n C o m pli a nce a n d E x p os ure
T he f oll o wi n g a nal ys es will be perf or me d base d o n t he S A F a nal ysis set, b y  re gi me n a n d d ose (i n 
i ncreasi n g or der) a n d s u m marize d 
All d osi n g calc ulati o ns a n d s u m maries will be base d o n C R F “ M 3 2 5 8 A d mi nistrati o n Details ”, , 
i n partic ular f or first st u d y dr u g a d mi nistrati o n.
T he date of last st u d y dr u g a d mi nistrati o n will be defi ne d as t he last date i n t he “M 3 2 5 8 
A d mi nistrati o n Details” , wit h d ose > 0 .
N o i m p utati o n of missi n g start dates of st u d y treat me nts will be d o ne.
I n case t he last date of st u d y dr u g is i nc o m plete t he date of last st u d y dr u g a d mi nistrati o n will be 
ta ke n fr o m t he E n d of Treat me nt pa ge.
I nterr u pti o n of treat me nt will be i de ntifie d i n t he “M 3 2 5 8 A d mi nistrati o n Details”, wit h n o d ose.
Eac h st u d y dr u g ( M 3 2 5 8
a n d de xa met has o ne) will be a nal yz e d se parately.
.A d ose is re gar de d t o be a d mi nistere d, if t he act ual d ose recei ve d (“D ose per a d mi nistrati o n”) is 
> 0
F or t he e n d of d ose escalati o n a nal ys is, the s u m mar y of treat me nt e x p os ure will i ncl u de t he 
f oll o wi n g i nf or mati o n:

E x p os ure d urati o n (i n wee ks) as defi ne d b y  (date of last d ose of st u d y dr u g– date of first d ose 
of st u d y  dr u g + 1)/ 7

N u m ber of d osi n g d a y s (i n da y s) as def i ne d b y  (date of last d ose of st u d y dr u g– date of first d ose 
of st u d y  dr u g–s u m of d a y s wit h d ose i nterr u pti o n + 1)

T otal n u m ber of c ycles recei ve d at least 8 0 % of pla n ne d d ose as defi ne d s u m of c ycles wit h 
recei ve d d ose > = 8 0 % of pla n ne d d ose

N u m ber a n d p e rce nta ge of partici pa nts wit h at least o ne d ose re d ucti o n will be prese nte d.
A listi n g will be pr o vi de d f or all a d mi nistrati o ns of partici pa nts ( date a n d d ose of a d mi nistrati o n)
i ncl u di n g pla n ne d re gi me n a n d d ose.
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
2 8 /8 7
1 4
Effic ac y A n al yses
T he f oll o wi n g a nal ys es will be perf or me d base d o n t he S A F a nal ysis set , b y  re gi me n a n d d ose (i n 
i ncreasi n g or der) a n d s u m marize d I n case t he recei ve d c u m ulati ve d ose of a partici pa nt is hi g her 
t ha n pla n ne d c u m ulati ve d ose t he partici pa nt will n ot be c o nsi dere d i n efficac y a nal yses.
1 4. 1
O ver all R es p o nse
O verall res p o nse ( O R) will be assesse d base d o n re p orte d o verall res p o nses at differe nt e val uati o n 
ti me p oi nts fr o m t he treat me nt start date i n acc or da nce t o I MW G 
res p o nse criteria, ta ki n g 
re q uire me nts f or c o nfir mati o n i nt o acc o u nt as detaile d bel o w. 
O R is defi ne d as a c o nfir me d ( 2 c o nsec uti ve assess me nts ma de at a n y ti me bef ore t he i nstit uti o n 
of a n y ne w t hera p y) Best O verall Res p o nse of sC R , C R, V G P R , or P R acc or di n g t o I M W G
res p o nse criteria.
Partici pa nts wil l be c o nsi dere d e val ua ble f or res p o nse i n t he a nal ysis set if t he y ha ve at least t w o 
o n-treat me nt assess me nt of I M W G res p o nse criteria ot her t ha n N ot E val ua ble ( N E).
E xce pt f or p artici pa nts w h o ha ve at least o ne o n -treat me nt assess me nt of I M W G res p o nse criteria
a n d w h o recei ve a nti-t u m or treat me nts ot her t ha n t he st u d y treat me nt, die, pr o gress or wit h dra w 
f or a n y reas o n pri or t o reac hi n g c o nfir me d s C R, C R, V G P R or P R . T hese will be c o nsi dere d as 
n o n-res p o n ders i n t he assess me nt of O R.
Eac h e val ua ble partici pa nt will ha ve a n o bjecti ve res p o nse stat us ( 0: ‘ n o O R’; 1: ‘ O R’)  T he 
partici pa nt s w h o are n ot e val ua ble will be c o nsi der e d N ot E val u y ble ( NE ).
O R rate ( O R R) is t he pr o p orti o n of partici pa nts wit h O R i n t he partici pa nt s e val ua ble f or res p o nse 
i n t he a nal ys is set.
T he O R R b y re gi me n a n d d ose a n d i n s u m mar y will be calc ulate d al o n g wit h t he t w o -si de d 9 5 % 
CI  usi n g t he Cl o p per-Pears o n met h o d (e xact CI f or a bi n o mial pr o p orti o n as c o m p ute d b y  defa ult 
b y  t he S A S F R E Q pr oce d ure usi n g t he E X A C T o pti o n). 
A
ta ble will dis pla y  the n u m ber a n d perce nta ge of partici pa nt s e val ua ble f or res p o nse, t he 
partici pa nt s wit h o verall res p o nse, i ncl u di n g t he c o nfir me d I M W G res p o nse criteria
M ore o ver, t his descri pti ve ta ble will be i ncl u de eac h cate g or y of Best O verall R es p o nse (s C R, C R, 
V G P R, P R, M R, S D, P D, N E) acc or di n g t he c o nfir me d a n d n ot c o nfir me d I MW G 
res p o nse 
criteria.  
A listi n g will be als o be pr o vi de d wit h all I MW G
assess me nts, s pecif yi n g als o t he i n dicat ors f or 
pr o gressi ve disease a n d i n dicat ors f or cli nical rela pse, as c ollecte d i n t he C R F.
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
2 9 /8 7
1 4. 2
D ur ati o n of tre at me nt
A d urati o n of treat me nt pl ot b y  act ual ti me gr o u pe d b y d ose le vel will be pl otte d . T he pl ot will be 
i n i ncreasi n g or der of dr u g i nte nsity ( 1 0 m g Q D at t he b ott o m, t he 1 0 m g BI W i n t he mi d dle a n d 
t he 2 0 m g BIW at t he t o p) T u m or assess me nts will be dis pla y e d wit h o utc o me (e. g. P D or S D)
M olec ular i nf or mati o n o n c yt o ge netic a b n or malit y (if a vaila ble) will be s pecifie d at t he e n d of 
eac h bar.
A n arr o w at t he e n d of t he bar pl ot will i de ntif y t he patie nt wit h treat me nt o n g oi n g at t he data c ut 
off ..
T he s C R a n d C R will be gr o u pe d a n d N E n ot prese nte d.
1 4. 3
M -pr otei n a n d F L C
Ser u m a n d uri ne M- pr otei n (i n g/ d L a n d m g / 2 4 h res pecti vely) a n d F L C rati o a n d F L C val ues 
( ka p pa a n d la m b da) will be liste d f or all c ycles. C ha n ges fr o m baseli ne will be a d de d t o t he listi n g
I n all f urt her a nalys is t he affecte d li g ht c hai n o nly will be c o nsi dere d (as per “t y pe of li g ht c hai n” 
fr o m e C R F, or if i nf or mati o n n ot a vaila ble, li g ht c hai n t ype wit h > 1 0 m g/ L = 1 m g/ d L at baseli ne)
T he val ues f or ser u m a n d uri ne m pr otei n, F L C rati o a n d affecte d li g ht c hai n will be s u m marize d 
usi n g descri pti ve statistics of relati ve c ha n ges fr o m baseli ne f or eac h c ycle. E n d of treat me nt visit 
will be s u m marize d se paratel y.
Fi g ures
T he f oll o wi n g gra p hics will be pl otte d:

A waterfall pl ot de picti n g t he best % c ha n ge fr o m baseli ne bet wee n ser u m M -pr otei n, uri ne M -
pr otei n a n d affecte d free li g ht c hai n. O nl y t he best c ha n ge fr o m t he t hree differe nt bi o mar kers 
will be de picte d . Dis pla ys of ser u m M- pr otei n will be i de ntifie d b y  a circle, t he uri ne M- pr otei n 
b y  a tria n gle, t he affecte d free li g ht c hai n b y  a cr oss. T he bar pl ot will be fille d wit h differe nt 
c ol or de pe n di n g of t he d ose le vel. If a vaila ble, fille d b o xes bel o w t he waterfall pl ot will si g nif y 
w het her a hi g h c yt o ge netic a b n or malit y (del( 1 7 p), t ( 4; 1 4) t ( 1 4; 1 6)) was detecte d i n t he 
patie nt . S u bject I D will be a vaila ble bel o w t he bars.

A s pi der pl ot b y  act ual ti me f or c ha n ge fr o m baseli ne f or ser u m M- pr otei n. T he li ne will be 
dra w n wit h differe nt li ne t ypes de pe n di n g of t he d ose le vel. C ol or will be use d t o se parate 
i n di vi d ual partici pa nts. T he % c ha n ge e xcee di n g 1 0 0 % will be i de ntifie d wit h gra y s q uares f or 
act ual val ues b y  treat me nt da y

A s pi der pl ot b y act ual ti me f or c ha n ge fr o m baseli ne f or affecte d free li g ht c hai n. T he li ne will 
be dra w n wit h differe nt li ne t ypes de pe n di n g of t he d ose le vel. C ol or will be use d t o se parate 
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
3 0 /8 7
i n di vi d ual partici pa nts. T he % c ha n ge e xcee di n g 1 0 0 % will be i de ntifie d wit h gra y s q uares f or 
act ual val ues b y  treat me nt da y
1 5
S afet y A n al yses
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or s u m marizi n g safet y en d p oi nts t hat are 
c o m m o n acr oss cli nical stu dies s uc h as a d verse e ve nts, la b orat or y tests a n d vital si g ns.
T he pri mar y  en d p oi nt d uri n g d ose escalati o n is t he occ urre nce of D L Ts, A Es a n d ot her safety 
relate d meas ure me nts.
T he a nal ys is p o p ulati o n f or t he D L T a nal ys is will be t he D L T a nal ys is set, f or all ot her safet y 
a nal ys es it will be t he S A F a nal ys is set.
1 5. 1
D L T a n al ysis
Of N ote, D L T as per S M C decisi o n will be a vaila ble i n t he ta ble “ Re vie w of data” i n t he S M C 
mi n utes.
I n case of ne w D L T a p pears after D L T peri o d, t he mi n utes will be u p date d.
A ta ble of will dis pla y  the f oll o wi n g ( per re gi me n a n d d ose le vel a n d i n t otal) f or t he D L T a nal ys is 
set:

N u m ber a n d perce nta ge of partici pa n ts wit h a D L T per i n vesti gat or’s j u d ge me nt as rec or de d i n 
e C R F ( usi n g D L T fla g fr o m t he A E C R F pa ge)
N u m ber a n d perc e nta ge of partici pa nt s wit h a D L T per S M C decisi o n
A listi n g of D L Ts (per i n vesti gat or a nd/ or per S M C) will be pr o vi de d b y  dose le vel a n d partici pa nt , 
i ncl u di n g w het her it was j u d ge d t o be a D L T by i n vesti gat or a n d/ or b y S M C)
T his listi n g will a d diti o nall y co ntai n a ge, se x, t ype of m y el o ma, S O C, P T, gra de, S A E ( yes/ n o), 
relate d ness t o M 3 2 5 8 ( yes/ n o), start date ( +treat me nt da y ), st o p date ( +treat me nt da y ), acti o n ta ke n 
wit h M 3 2 5 8, if treat me nt was st o p pe d bef ore start of A E: da y s si nce st o p of treat me nt, a n d 
o utc o me.
I n a d diti o n, t he f oll o wi n g will be prese nte d:

Q ua ntiles ( 2. 5 %, 2 5 %, 5 0 %, 7 5 % a n d 9 7. 5 %) f or t he p osteri or pr o ba bilit y  of a partici pa nt
e x perie nci n g a D L T at eac h of t he d ose le vels use d i n t he st u d y acc or di n g t o t he sa me 
Ba yesia n L o gistic M o del ( B LM) as descri b e d i n t he S M C I AP (see A p pe n di x 1 8. 1 ) or 
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
3 1 /8 7
S M C c harter (if c ha n ge occ urre d) . F or t his a nal ysis eit her S A S or R ( usi n g t he pac ka ge 
bcr m or cr m Pac k) will be use d.
M T D
s u g gesti o n fr o m t he Ba yesi a n l o gistic re gressi o n m o del
T he M T D as s u g geste d fr o m t he m o deli n g will be deri ve d as f oll o ws:
1)
T he B L R M will be u p date d wit h all D L T data ( S M C decisio n) fr o m t he d ose escalati o n.
2)
T he d ose wit h tar gete d t o xicit y  pr o ba bility of 2 5 % will be i de ntifie d.
3)
T he ne xt l o wer teste d d ose wit h t he u p per b o u n d of t he 9 5 % cre di ble i nter val of a p ote ntial 
M T D bel o w or e q ual 4 0 % a n d wit h esti mate d D L T pr o ba bilit y a b o v e or e q ual t o 1 7 % will 
be selecte d.
4)
T he cre di bilit y  i nter val will be pr o vi de d.
5)
If t he M T D esti mate of all teste d d oses is bel o w 1 7 % , t here is n o M T D s u g gesti o n fr o m 
t he m o del.
T his i nf or mati o n will be f or war de d t o t he S M C t hat will deci de o n t he deter mi nati o n of t he M T D. 
A d diti o nall y , t he S M C will recei ve t he esti mate d D L T pr o ba bilit y  an d ass ociate d pr o ba bilit y 
q ua ntiles f or all ot her d oses teste d.
F or a b o ve a nal ys is eit her S A S or R ( usi n g t he pac ka ge bcr m or cr m Pac k) will be use d.
Fre q ue ntist M T D s u g gesti o n
As sec o n d a p pr oac h, t he M T D as s u g geste d b y t he fre q ue ntist esti mati o n will als o be deri ve d:
1)
All D L T data fr o m t he d ose escalati o n will be i ncl u de d i n a t w o-para meter l o gistic 
re gressi o n m o del (i nterce pt a n d sl o p o ver l o g of t he scale d d ose, n o pri or; if t he m o del d oes 
n ot c o n ver ge, it will be re p orte d as n ot calc ula ble; t he pr o gra m c o de f or t his a nal ys is ca n 
be f o u n d i n t he T L F s hells).
2)
T he d ose wit h tar gete d t o xicit y  pr o babilit y of 2 5 % will be i de ntifie d.
3)
T he ne xt l o wer teste d d ose will be selecte d.
T he t w o-si de d c o nfi de nce i nter val f or t he D L T pr o ba bilit y  will be pr o vi de d.
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
3 2 /8 7
1 5. 2
A d verse E ve nts
A Es will be a nal yze d a m o n g t he S A F a nal ys is set a n d prese nte d b y  re gi me n a n d d ose (i n i ncreasi n g 
or der) a n d s u m marize d . O nl y  partici pa nts c o u nts will be prese nte d wit h fre q ue nc y .
Treat me nt -e mer ge nt a d verse e ve nts ( T E A E) are t h ose e ve nts wit h o nset dates occ urri n g wit hi n t he 
o n- treat me nt peri o ds as defi ne d i n secti o n 9. 4.

Rel ate d A d verse E ve nts : A Es wit h relati o ns hi p missi n g, u n k n o w n or yes . Relati o ns hi p is 
j u d ge d se parately f or M 3 2 5 8 , a n d de xa met has o ne.

S A Es : Seri o us a d verse e ve nts (as rec or de d o n t he A E e C R F pa ge, Seri o us A d verse E ve nt 
= ‘ Yes’).

A Es Le a di n g t o Tre at me nt Disc o nti n u ati o n : A Es lea di n g t o per ma ne nt disc o nti n uati o n 
of st u d y treat me nt (as rec or de d o n t he A E e C R F pa ge, Acti o n ta ke n wit h st u d y treat me nt 
= ‘ Dr u g wit h dra w n’). Treat me nt disc o nti n uati o n is rec or de d se parately f or M 3 2 5 8, a n d 
de xa met has o ne .

A Es Le a di n g t o De at h : A Es lea di n g t o deat h (as rec or de d o n t he A E e C R F pa ge, O utc o me 
= ‘ Fatal’).
All a nal yses descri be d i n Secti o n  1 5. 2 will be base d o n T E A Es if n ot ot her wise s pecifie d. 
T E A Es will be s u m marize d b y  nu m ber a n d perce nta ge of partici pa nts wit h at least o ne T E A E i n 
t he cate g or y of i nterest, b y  pri mar y  Me d D R A a n d P T ( b ot h s orte d al p ha beticall y), u nless ot her wise 
state d. Eac h partici pa nt will be c o u nte d o nl y  once wit hi n eac h S O C or P T. If a partici pa nt 
e x perie nces m ore t ha n o ne A E wit hi n a S O C or P T f or t he sa me s u m mar y peri o d, o nl y t he A E 
wit h t he str o n gest relati o ns hi p or t he w orst se verit y, as a p pr o priate, will be i ncl u de d i n t he 
s u m maries of relati o ns hi p a n d se verity. 
T he se verity of a d verse e ve nts will be gra de d usi n g t he N CI -C T C A E versi o n 5. 0, e xce pt w here 
C T C A E gra des are missi n g. N o i m p utati o n of missi n g gra des will be perf or me d. 
A d verse e ve nts will be c o de d acc or di n g t o t he latest Me d D R A versi o n at t he ti me of t he data c ut -
off.
I nc o m plete A E -relate d dates will be ha n dle d as defi ne d i n secti o n  9. 5.
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
3 3 /8 7
1 5. 2. 1 
All A d verse E ve nts
T he o verall s u m mar y of A Es ta ble will i ncl u de t he fre q ue nc y (n u m ber a n d perce nta ge) of 
partici pa nts wit h eac h of t he f oll o wi n g, ta bul at e d b y d ose le vel a n d o verall:

T E A Es

T E A Es wit h N CI -C T C A E Gra de ≥ 3

T E A Es wit h N CI -C T C A E Gra de ≥ 4 

Relate d wit h M 3 2 5 8 T E A Es

Relate d wit h M 3 2 5 8 T E A Es wit h N CI -C T C A E Gra de ≥ 3

Relate d wit h M 3 2 5 8 T E A Es wit h N CI -C T C A E Gra de ≥ 4 

T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of M 3 2 5 8

Relate d wit h M 3 2 5 8 T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of M 3 2 5 8

Seri o us T E A Es

Relate d wit h M 3 2 5 8 Seri o us T E A Es 

T E A Es lea di n g t o deat h ( A Es wit h Gra de 5 or o utc o me “fatal” if gra de 5 n ot a p plica ble)

Relate d wit h M 3 2 5 8 T E A Es lea di n g t o deat h
Ta bles b y  SO C a n d P T will be ta bul ate d b y  re gi me n, d ose le vel a n d o verall i n a ta ble dis pla y i n g 
i n se parate c ol u m ns a n d s h o wi n g t he inci de nce of T E A Es, b y  SO C a n d P T ( b ot h s orte d 
al p ha beticall y) . T his t ype of t a ble b y S O C a n d P T will be d o ne f or:

All T E A Es

relate d  T E A Es 

Gra de ≥3 T E A Es 

Relate d Gra de ≥3 T E A Es

T E A Es e xcl u di n g S A Es ( Cli nical trial. g o v a n d E u dra C T -re q uire me nt)

Als o, T E A Es will be s u m marize d b y  worst t o xicit y (acc or di n g t o N CI -C T C A E versi o n 5 . 0) 
per partici pa nt, usi n g preferre d ter m as e ve nt cate g or y an d pri mar y  s yste m or ga n class ( S O C).
A nal y sis b y w orst t o xicit y will be pr o vi de d b y re gi me n, d ose le vel a n d o verall.
If a n a d verse e ve nt is re p orte d f or a gi ve n partici pa nt m ore t ha n o nce d uri n g st u d y inter ve nti o n, 
t he w orst t o xicit y an d t he w orst relati o ns hi p to st u d y inter ve nti o n will be ta b ulate d. I n case a 
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
3 4 /8 7
partici pa nt ha d e ve nts wit h missi n g a n d n o n- missi n g gra des, t he ma xi m u m of t he n o n- missi n g 
gra des will be dis pla y e d.
A listi n g of all A Es will be pr o vi de d . T his listi n g will be s orte d b y st u d y part, re gi me n, d ose le vel 
a n d partici pa nt . T his listi n g will a d diti o nally c o ntai n a ge, se x, t ype of m y el o ma, S O C, P T, gra de, 
S A E ( yes/ n o), D L T per i n vesti gat or ( yes/ n o), D L T per S M C, relate d ness t o M3 2 5 8 ( yes/ n o), start 
date ( +treat me nt da y ), st o p date ( +treat me nt da y), d urati o n (i n da y s), acti o n ta ke n wit h M 3 2 5 8, if 
treat me nt was st o p pe d bef ore start of A E: da ys si nce st o p of treat me nt, a n d o utc o me.
Si milarl y , listi n g of all a d verse e ve nts gra de > = 3 (i ncl n o n T E A Es) a n d S A Es will be pr o vi de d.
1 5. 2. 2 
A d verse  
E ve nts  
Le a di n g  
t o 
St u d y  
I nter ve nti o n 
Disc o nti n u ati o n
A listi n g of T E A Es lea di n g t o treat me nt disc o nti n uati o n, i nterr u pti o n, or d ose re d ucti o n of eac h
st u d y dr u g will be pr o vi de d . T his listi n g, s orte d b y  dose le vel a n d partici pa nt I D, will i ncl u de: 
d ose le vel, partici pa nt I D, a ge, se x, site of pri mar y t u m or, A E i n vesti gat or ter m, S O C, P T, 
relati o ns hi p t o M 3 2 5 8 a n d de xa met has o ne (as a p plica ble), seri o us ness, acti o n ta ke n wit h M 3 2 5 8   
(dis pla y e d as: Disc/I R/ D R), start date ( +treat me nt da y ), st o p date ( +treat me nt da y ), d urati o n (i n 
da y s), if treat me nt was st o p pe d bef ore start of A E: da ys si nce st o p of treat me nt, a n d o utc o me.
1 5. 3
De at hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt 
A d verse E ve nts
1 5. 3. 1 
De at hs
A listi n g of Deat hs will be pr o vi de d, defi ne d as a n y  A E wit h Gra de 5, or o utc o me “fatal” if gra de 
5 n ot a p plica ble. T his will be s orte d b y  st u d y part, re gi me n, d ose le vel a n d partici pa nt . T his listi n g 
will a d diti o nall y co ntai n a ge, se x, t ype of m y el o ma, SO C, P T, gra de, S A E ( yes/ n o), D L T per 
i n vesti gat or ( yes/ n o), relate d ness t o M 3 2 5 8 
( yes/ n o),  start date ( +treat me nt da y ), st o p date 
( +treat me nt d a y ), d urati o n (i n d a y s), acti o n ta ke n wit h M 3 2 5 8, if treat me nt was st o p pe d bef ore 
start of A E: da ys si nce st o p of treat me nt, a n d o utc o me.
1 5. 3. 2 
Seri o us A d verse E ve nts
T he listi n g of S A Es will als o be pr o vi de d wit h t he rele va nt i nf or mati o n wit h a fla g f or S A Es wit h 
o nset o utsi de of t he o n -treat me nt peri o d.
1 5. 3. 3 
Ot her Si g nific a nt A d verse E ve nts
A listi n g of A Es of s pecial i ntere st ( A E SI) will be pr o vi de d. T his will be s orte d b y d ose le vel a n d 
partici pa nt . T his listi n g will a d diti o nall y co ntai n a ge, se x, , S O C, P T, gra de, S A E ( yes/ n o), D L T 
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
3 5 /8 7
per i n vesti gat or/ S M C ( yes/ n o), relate d ness t o M 3 2 5 8 ( yes/ n o),), start date ( +treat me nt d a y ), st o p 
date ( +treat me nt d a y ), d urati o n (i n d a y s), acti o n ta ke n wit h M 3 2 5 8, if treat me nt was st o p pe d bef ore 
start of A E: da ys si nce st o p of treat me nt, a n d o utc o me.
1 5. 4
Cli nic al L a b or at or y E v al u ati o n
La b orat or y  val ues (i ncl u di n g c orres p o n di n g n or mal ra n ges) fr o m t he l ocal la borat or ies will be 
use d B f or s u m mar y statistics a n d s hift ta bles.
La b orat or y  res ults will be classifie d acc or di n g t o t he N CI -C T C A E criteria versi o n 5. 0. S o me of 
t he t o xicit y gra di ngs are base d o n la b orat or y  meas ure me nts i n c o nj u ncti o n wit h cli nical fi n di n gs. 
N o n -n u merical q ualifiers ( wit h t he e xce pti o n of fasti n g fla gs) will n ot be ta ke n i nt o c o nsi derati o n 
i n t he deri vati o n of C T C A E criteria (e. g., h y p o kale mia Gra de 1 a n d Gra de 2 are o nl y d isti n g uis he d 
b y  a n o n- n u merical q ualifier a n d t heref ore Gra de 2 will n ot be deri ve d).
A d diti o nal la b orat or y res ults t hat are n ot part of N CI -C T C A E will be prese nte d acc or di n g t o t he 
cate g ories: bel o w n or mal li mit, wit hi n n or mal li mits a n d a b o ve n or mal li mit (acc or di n g t o t he 
la b orat or y n or mal ra n ges).
P ar a meters wit h N CI -C T C gr a des a v ail a ble:
He mat ol o g y : 
He m o gl o bi n ( H B), Le u k oc y tes ( w hite bl o o d cell decrease d), L y m p h oc y tes (l ym p h oc y te 
c o u nt i ncrease d/ decrease d), Ne utr o p hils / A bs ol ute Ne utr o p hils C o u nt ( A N C) ( ne utr o p hil 
c o u nt decrease d), Platelet C o u nt ( P L T) ( platelet c o u nt decrease d).
Ser u m C he mistr y :
Al b u mi n ( h yp oal b u mi ne mia), Al kali ne P h os p hatase (al kali ne p h os p hatase i ncrease d), 
Ala ni ne A mi n otra nsferase ( A L T) ( A L T i ncrease d), As partate A mi n otra n sferase ( A S T) 
( A S T i ncrease d), T otal Bilir u bi n ( bl o o d bilir u bi n i ncrease d, C h olester ol (c h olester ol hi g h), 
Creati ni ne 
(creati ni ne i ncrease d), P otassi u m ( h yp o kale mia/ h y per kale mia), S o di u m 
( h yp o natre mia/ 
h y per natre mia), 
Ma g nesi u m  
( h yp o ma g nese mia/ h y per ma g nes e mia), 
Calci u m 
( h yp ocalce mia/ 
h y percalce mia), 
Gl uc ose 
( hy p o gl yc e mia/ h yper gl y ce mia), 
Ga m ma 
Gl uta m y l Tra nsferase ( G G T) ( G G T i ncrease d), Li pase (li pase i ncrease d), 
P h os p hates ( h y p o p h os p hate mia)
P ar a meters wit h N CI -C T C gr a des n ot a v ail a ble:
He mat ol o g y : 
He mat ocrit, Re d Bl o o d Cell ( R B C), Retic ul oc ytes, Mea n 
C or p usc ular He m o gl o bi n 
( M C H), Mea n  
C or p usc ular 
V ol u me 
( M C V), Mea n  
C or p usc ular 
He m o gl o bi n 
C o nce ntrati o n ( M C H C ).
Ser u m C he mistr y : 
C- Reacti ve Pr otei n, Lactate De h y dr o ge nase ( L D H), T otal Pr otei n, T otal Ure a, Uric Aci d . 
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
3 6 /8 7
C oa g ulati o n: acti vate d partial t hr o m b o plasti n ti me (a P T T), Pr ot hr o m bi n ti me ( P T) a n d 
pr ot hr o m bi n ti me (I N R).
Uri nal y sis a n d micr osc o pic uri nal ysis: all uri nalys is para meters
Pre g na nc y  test ( n ot nee de d f or e n d of d ose escalati o n a nal ysis)
T he last meas ure me nt bef ore st u d y t reat me nt (i ncl u di n g u nsc he d ule d meas ure me nts) will ser ve as 
t he baseli ne meas ure me nt.
Val ues bel o w t he detecti o n li mit will be i m p ute d b y  half of t he detecti o n li mit. 
I n case j ust a te xt val ue wit h a n “ > x” is re p orte d it will be a nal yze d as + 1 si g nifica nt di git, e. g. “ > 
7. 2 m m ol” will be a nal y ze d as 7. 3.
F or W B C differe nti al c o u nts (t otal ne utr o p hil, l y mp h oc y te, m o n oc y te, e osi n o p hil, a n d bas o p hil 
c o u nts), t he a bs ol ute val ue will be use d w he n re p orte d.  W he n o nl y perce nta ges are a vaila ble (t his 
is mai nl y i m p orta nt f or ne utr o p hils a n d l ym p h oc y tes, beca use t he C T C A E gra di n g is base d o n t he 
a bs ol ute c o u nts), t he a bs ol ute val ue is deri ve d as f oll o ws: 
Deri ve d differe ntial a bs ol ute c o u nt = ( W B C c o u nt) * ( Differe ntial % val ue / 1 0 0)
If t he ra n ge f or t he differe ntial a bs ol ute c o u nt is n ot a vaila ble ( o nly ra n ge f or val ue i n % is 
a vaila ble) t he n Gra de 1 will be attri b ute d t o as f oll o ws: 

L y m p h oc y te c o u nt decrease d:  
-
deri ve d a bs ol ute c o u nt d oes n ot meet Gra de 2 -4 criteria, a n d
-
% val u e < % L L N val ue, a n d
-
deri ve d a bs ol ute c o u nt ≥ 8 0 0/ m m 3

Ne utr o p hil c o u nt decrease d 
-
deri ve d a bs ol ute c o u nt d oes n ot meet Gra de 2 -4 criteria, a n d
- 
% val ue < % L L N val ue, a n d
-
deri ve d a bs ol ute c o u nt ≥ 1 5 0 0/ m m 3
F or c alci u m, C T C A E gra di n g is base d o n C orrecte d Calci u m a n d I o nize d Calci u m ( C A L CI O), if 
a vaila ble. C orrecte d Calci u m is calc ulate d fr o m Al b u mi n a n d Calci u m as f oll o ws
C orrecte d calci u m ( m m ol/ L ) =  
meas ure d t otal Calci u m ( m m ol/ L) + 0. 0 2 ( 4 0 - ser u m 
al b u mi n [ g/ L])
T he ti me wi n d o ws gi ve n i n Ta ble 4 will b e a p plie d t o all ocate meas ure me nts t o treat me nt da y . I n 
case of m ulti ple bl o o d sa m ples are c ollecte d i n t he sa me wi n d o w, t he val ue cl osest t o t he tar get 
da y  will be use d f or a nal ysis. If t here are t w o val ues wit h t he sa me ti me bef ore a n d after t he tar get 
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
3 7 /8 7
d a y, t he earlier val ue will be use d f or a nal ysis. Wi n d o ws o nl y  t o be use d f or s u m mar y ta bles, n ot 
fi g ures or listi n gs
T a ble 4
Ti me wi n d o ws f or s afet y l a b or at or y a n al ysis 
Tr e at m e nt d a y
Wi n d o w D efi niti o n
C 1 D 1
N o ti m e wi n d o w
C 1 D 2
± 1 d a y
C 1 D 8
C 1 D 1 5
C 1 D 2 2
C 1 D 1
C 1 D 8
C 1 D 1 5
C 1 D 2 2
C 3 D 1
C 3 D 1 5
C 4 D 1
± 3 d a y s
C 5 D 1
C 6 D 1
C X D 1 ( aft er c y cl e 6)
± 7 d a y s
E n d of St u d y I nt er v e nti o n ( wit hi n 7 d a y s aft er l a st 
i nt er v e nti o n/i nt a k e)
± 3 d a y s
F oll o w -u p/ Di s c o nti n u ati o n ( 3 0 d a y s aft er l a st d o s e)
± 7 d a y s
Si nce t he n u m ber of partici pa nts will decrease o ver ti me, ti me wi n d o ws will n ot be a p plie d f or t he 
c o m plete treat me nt peri o d (st o p pe d after C 6 D 1) . F or s u m maries b y  treat me nt da y , t he last 
a vaila ble la b orat or y meas ure me nt will be prese nte d i n a d diti o n t o t he treat me nt da y defi ne d a b o ve.
Q ua ntitati ve data will be s u m marize d  for act ual val ues a n d a bs ol ute c ha n ges fr o m baseli ne t o eac h  
treat me nt da y. T he E n d of treat me nt visit will be s u m marize d se parately. 
Q ualitati ve data base d o n refere nce ra n ges will be descri be d acc or di n g t o t he cate g ories (i.e. L o w, 
N or mal, a n d Hi g h). A b n or malities classifie d acc or di n g t o N CI -C T C A E t o xicit y gra di n g versi o n 
will be descri be d usi n g t he w orst o n -treat me nt gra de. F or t h ose para meters w hic h are gra de d wit h 
t w o directi o ns of t o xicities s uc h as p otassi u m ( h y p o kale mia/ h yper kale mia), t he t o xicities will be 
s u m marize d se parately. L o w directi o n t o xicit y (e. g., h y p o kale mia) gra des at baseli ne a n d p ost 
baseli ne will be set t o 0 w he n t he varia bles are deri ve d f or s u m marizi n g hi g h directi o n t o xicit y 
(e. g., hy per kale mia), a n d vice versa.   
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
3 8 /8 7
P ar a meters wit h N CI -C T C gr a des a v ail a ble:
T he la b orat or y t o xicities will be ta b ulate d usi n g descri pti ve statistics ( n u m ber of partici pa nts a n d 
perce nta ges) d uri n g t he o n- treat me nt peri o d.  The de n o mi nat or t o calc ulate perce nta ges f or eac h 
la b orat or y para meter is t he n u m ber of partici pa nts e val ua ble f or C T C A E gra di n g (i.e. t h ose 
partici pa nts f or w h o m a Gra de 0, 1, 2, 3 or 4 ca n be deri ve d).
T he s u m mar y of la b orat or y para meters b y  CT C A E gra de ta ble will i ncl u de n u m ber a n d perce nta ge 
of partici pa nts wit h Gra de 1, 2, 3, 4, 3/ 4, a n d a n y gra de ( 1 t o 4), la b orat or y a b n or malities d uri n g 
t he o n-treat me nt peri o d.  
T he s hift ta ble will s u m marize baseli ne C T C A E gra de vers us t he w orst o n- treat me nt C T C A E 
gra de. T he hi g hest C T C A E gra de d uri n g t he o n -treat me nt peri o d is c o nsi dere d as t he w orst gra de 
f or t he s u m mar y.
P ar a meters wit h N CI -C T C gr a des n ot a v ail a ble:
He mat ol o g y  an d c he mistr y eval uati o ns w hic h ca n n ot be gra de d per C T C A E criteria will be 
s u m marize d as fre q ue nc y ( n u m ber a n d r o w perce nta ge) of partici pa nts wit h: 
-
s hifts fr o m baseli ne n or mal t o at least o ne res ult a b o ve n or mal d uri n g o n-treat me nt peri o d 
-
s hifts fr o m baseli ne n or mal t o at least o ne res ult bel o w n or mal d uri n g o n-treat me nt peri o d
T he c oa g ulati o n para meters, uri nal ys is para meters, micr osc o pic 
uri nal y sis para meters a n d 
pre g na nc y  test will be liste d i n de dicate d listi n gs prese nti n g
all c orres p o n di n g c ollecte d 
i nf or mati o n o n t he e C R F.
T he listi n gs of la b orat or y res ults will be pr o vi de d f or all la b orat or y para meters ,. T he listi n gs will 
be s orte d b y para meters a n d assess me nt dates or visits f or eac h partici pa nt. La b orat or y val ues t hat 
are o utsi de t he n or mal ra n ge will als o be fla g ge d i n t he data listi n gs, al o n g wit h c orres p o n di n g 
n or mal ra n ges a n d C T C A E gra des..
T he la b a b n or malities   > = gra de 3 will be als o prese nte d i n a se parate listi n g .
Li ne pl ots f or He m at ol o g y
Gra p hical dis pla y  (li ne pl ots) of ne utr o p hils, platelets, l ym p h oc y tes a n d he m o gl o bi n will be 
pr o vi de d b y  act ual ti me i n d a y s f or all a nal ys es. ( wit h x- a xis ti me, y- a xis la b val ue ), usi n g differe nt 
c ol ors per re gi me n, d ose le vel a n d differe nt li ne t y pes t o i de ntif y partici pa nts
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
3 9 /8 7
If a vaila ble (a n d feasi ble d ue t o p ote ntial differe nces bet wee n la bs) refere nce li nes f or U L N a n d 
L L N s h o ul d be a d de d t o t he pl ots. A d diti o nall y  treat me nt a d mi nistrati o n will be s h o w n o n t he pl ot.
He p at ot o xicit y assess me nt
A pl ot of pea k A L T vers us pea k t otal bilir u bi n, b ot h relati ve t o t he u p per li mit of n or mal ( U L N)
will be pr o vi de d. T his e DI S H pl ot (e v al uati o n of dr u g -i n d uce d seri o us he pat ot o xicit y) will ha ve
refere nce li nes at 3 × U L N f or A L T a n d at 2 × U L N f or t otal bilir u bi n. S u bjects o utsi de t he l o wer
left b o x will be i de ntifie d b y s u bject-I D.
1 5. 5
Vit al Si g ns
Vital si g n s u m maries will i ncl u de vital si g n assess me nts fr o m t he o n- treat me nt peri o d. All vital 
si g n assess me nts will be liste d a n d t h ose c ollecte d o utsi de t he o n-treat me nt peri o d will be fla g ge d 
i n t he listi n g.
All vital si g n para meters will be s u m marize d usi n g descri pti ve statistics of t he ma xi m u m c ha n ge 
fr o m baseli ne.
1 5. 6
Ot her S afet y or T oler a bilit y E v al u ati o ns
E C O G
A fre q ue nc y ta ble will be pr o vi de d wit h t he n u m ber a n d perce nta ge of partici pa n ts i n eac h E C O G 
stat us cate g or y a n d c ha n ge of cate g or y fr o m baseli ne b y  visit, b y re gi me n, d ose le vel a n d o verall. 
C orres p o n di n g listi n g will be pr o vi de d.
E C G res ults
T he E C G para meter s ( H R, a n d Q T, Q Tc, Q R S, P R i nter vals) will be s u m marize d b y  descri pti ve 
statistics per treat me nt da y , wit h c ha n ges fr o m Baseli ne, b y re gi me n, d ose le vel gr o u p a n d o v erall.
E C G s u m maries will i ncl u de all E C G assess me nts fr o m t he o n- treat me nt peri o d as c ollecte d i n t he 
C R F.
U nsc he d ule d E C G meas ure me nts will n ot be use d i n c o m p uti n g t he descri pti ve statistics f or 
c ha n ge fr o m baseli ne at eac h p ost -baseli ne ti me p oi nt. H o we ver, t he y  will be use d i n t he a nal ysis 
of n ota ble E C G c ha n ges.
Fre q ue nc y  (n u m ber a n d perce nta ge) of partici pa nts wit h n ota ble E C G val ues acc or di n g t o t he 
f oll o wi n g cate g ories, b y  visit. T he de n o mi nat or t o calc ulate perce nta ges f or eac h cate g or y is t he
n u m ber of partici pa nts e val ua ble f or t he cate g or y .
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
4 0 /8 7

Q Tc F i ncrease fr o m baseli ne > 3 0 ms, > 6 0 ms

Q Tc F > 4 5 0 ms, > 4 8 0 ms, > 5 0 0 ms

H R ≤ 5 0 b p m a n d decrease fr o m baseli ne ≥ 2 0 b p m

H R ≥ 1 2 0 b p m a n d i ncrease fr o m baseli ne ≥ 2 0 b p m

P R ≥ 2 2 0 ms a n d i ncrease fr o m baseli ne ≥ 2 0 ms

Q R S ≥ 1 2 0 ms 
Fre q ue nc y  (n u m ber a n d perce nta ge)
of partici pa nts wit h 
p ost -baseli ne q ualitati ve E C G 
a b n or malities (m or p h ol o g y ) ( E C G res ult =a b n or mal” i n t he E C G f or m of t he e C R F) will be 
s u m marize d.
All E C G assess me nts will be liste d, a n d t h ose c ollecte d o utsi de t he o n- treat me nt peri o d will be 
fla g ge d i n t he listi n g as well as a n y ab n or malities a n d val ues t hat fall i nt o a b o ve s pecifie d 
cate g ories .
H olter E C Gs mi g ht be a nal yze d i n de pe n de ntl y a n d at a later ti me b y  a ce ntral la b orat or y. Data are 
n ot pla n ne d t o be part of t his C T R a n d ma y  be re p orte d se parately.
1 6
A n al yses of Ot her E n d p oi nts
1 6. 1
P h ar m ac o k i netics
1 6. 1. 1 
P h ar m ac o k i netic A n al ysis
P har mac o ki netic para meters f or M 3 2 5 8 i n Plas m a will be calc ulate d b y  C o va nce, usi n g sta n dar d 
n o n- c o m part me ntal met h o ds a n d t he act ual a d mi nistere d d ose. P K para meters will be calc ulate d 
usi n g t he act ual ela pse d ti me si nce d osi n g.  I n cases w here t he act ual sa m pli n g ti me is missi n g, 
calc ulati o ns will be perf or me d usi n g t he sc he d ule d ti me. 
N o n -c o m part me ntal c o m p utati o n of p har mac o ki netic para meters will be perf or me d usi n g t he 
c o m p uter pr o gra m P h oe ni x ® Wi n N o nli n ® versi o n 6. 4, or hi g her ( Certara, L. P., 1 6 9 9 S Ha nle y 
R oa d, St L o uis, M O 6 3 1 4 4, U S A). 
T he f oll o wi n g P K par ameters will be c alc ulate d, w here a p plica ble:
P ar a meter
Defi niti o n
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
4 1 /8 7
A U C e xtra %
perce nta ge of A U C t hat is d ue t o e xtra p olati o n fr o m t he last meas ura ble 
c o nce ntrati o n t o i nfi nit y(si n gle d ose o nly)
A U C 0-t
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he ti me of last 
q ua ntifia ble c o nce ntrati o n (t last) (si n gle d ose o nl y) 
A U C 0- 8
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 8 h p ost d ose 
tla g
ti me i m me diatel y pri or t o t he first q ua ntifia ble c o nce ntrati o n
C ma x
ma xi m u m o bser ve d plas ma c o nce ntrati o n
tma x
ti me of ma xi m u m o bser ve d plas ma c o nce ntrati o n
tlast
ti me of last q ua ntifia ble plas ma c o nce ntrati o n
C tr o u g h
T he c o nce ntrati o n o bser ve d i m me diatel y bef ore ne xt d osi n g (c orres p o n di n g t o 
pre d ose or tr o u g h c o nce ntrati o n f or m ulti ple d osi n g)
t1/ 2
a p pare nt plas ma ter mi nal eli mi nati o n half-life
z
a p pare nt ter mi nal eli mi nati o n rate c o nsta nt
Racc ( C ma x)
acc u m ulati o n rati o base d u p o n C ma x ( M 3 2 5 8 m ulti ple d ose o nl y)
Racc A U C 
acc u m ulati o n rati o base d u p o n A U C 0- 8 ( M 3 2 5 8 m ulti ple d ose o nl y)
A d diti o nal para meters ma y  be calc ulate d w here a p pr o priate
D ose n or malize d para meters, C ma x / D, A U C0-t/ D, a n d A U C 0- 8/ D, will be calc ulate d by di vi di n g t he 
ori gi nal para meter b y d ose i n m g.
C ma x a n d t ma x will be o btai ne d directl y fr o m t he plas ma c o nce ntrati o n -ti me pr ofiles.  
F or m ulti ple pea ks, t he hi g hest p ost d ose c o nce ntrati o n will be re p orte d as C ma x . I n the case t hat 
m ulti ple pea ks are of e q ual ma g nit u de, t he earliest T
ma x will be re p orte d.
Acc u m ulati o n rati os will be deter mi ne d fr o m si n gle d ose a n d m ulti ple d ose (at stea dy state) C ma x , 
a n d A U C 0 - 8as f oll o ws
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI






M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
4 4 /8 7
( Ma x).  Phar mac o ki netic para meters will be s u m marize d a d diti o nall y, usi n g t he ge o metric mea n 
( Ge o Mea n), t he ge o metric c oefficie nt of variati o n ( Ge o C V) a n d t he t w o-si de d 9 5 % c o nfi de nce 
i nter val f or t he Ge o Mea n ( LCI  95 % G M, U CI 9 5 % G M). F o r ti me t o reac h ma xi m u m o bser ve d 
c o nce ntrati o n (t ma x ), o nl y n, Mi n, Me dia n, a n d Ma x will be re p orte d. 
Descri pti ve statistics of P K c o nce ntrati o n data will be calc ulate d usi n g val ues wit h t he sa me 
precisi o n as t he s o urce data a n d r o u n de d f or re p orti n g p ur p oses o nl y. Descri pti ve statistics will 
o nl y  be calc ulate d f or N > 2 i n w hic h a meas ure me nt of < L L O Q re prese nts a vali d meas ure me nt.
Descri pti ve statistics will be calc ulate d f or p har mac o ki netic para meter w here N > 2. All n o res ult 
( N R) a n d n ot d o ne ( n d) val ues will be set t o missi n g.
P K para meters rea d directl y  fr o m t he meas ure me nts (i.e. C ma x ) will be re p orte d wit h t he sa me 
precisi o n as t he s o urce data. All ot her P K para meters will be re p orte d t o 3 si g nifica nt fi g ures.
T he f oll o wi n g c o n ve nti o ns will be a p plie d w he n re p orti n g descri pti ve statistics of P K data: 
Mea n, Mi n, Me dia n, Ma x, Ge o Mea n, t w o-si de d 9 5 % CI : 3 si g nifica nt di gits 
S D 4 si g nifica nt di gits 
C V %, Ge o C V %: 1 deci mal place
I n di vi d ual M 3 2 5 8 plas ma c o nce ntrati o ns will be pl otte d b y  st u d y da y, a nal yte a n d sc he d ule d 
c ollecti o n ti me, i ncl u di n g s u m mar y  statistics w here data all o ws. 
B ot h i n di vi d ual a n d arit h metic mea n c o nce ntrati o n-ti me pr ofiles , will be pl otte d o n li near a n d 
se mi-l o garit h mic scales as f oll o ws: 

S pa g hetti pl ots s h o wi n g M 3 2 5 8 plas ma c o nce ntrati o n vs act ual ti me all i n di vi d uals per
re gi me n a n d d ose gr o u p; Da y 1 C y cle 1 a n d Da y 1 5 C ycle 1

I n di vi d ual per partici pa nt pl ots s h o wi n g M 3 2 5 8 o verla y i n g Da y  1 Cycle 1 a n d Da y  15, 
C y cle 1 c o nce ntrati o n pr ofiles 

Arit h metic mea n c o nce ntrati o n-ti me pr ofil e s h o wi n g M 3 2 5 8 per re gi me n a n d d ose gr o u p 
wit h Da y  1, Cycl e 1 a n d Da y 1 5, C ycle 1 o verlai d.  O n li near pl ots ± S D will be i ncl u de d.  

Arit h metic mea n c o nce ntrati o n-ti me pr ofiles per Da y , o verla y i n g Si n gle a n d M ulti ple D ose 
Da y  1 a n d Da y 1 5.  O n li near pl ots ± S D will be i ncl u de d.  
T he f oll o wi n g pl ots will als o be pr o vi de d, f or ke y  P K para meters: 
• D ose N or malize d C ma x , , A U C 0- 8 a n d A U C 0 -tlast f or Da y  1vers us D ose le vel as a scatter pl ot
A n y  re gressi o n li ne s h o ul d n ot be fi xe d t hr o u g h t he ori gi n. 
F or all li near P K pl ots, t he x a n d y  a xes s h o ul d b ot h be gi n at ( 0, 0).
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
4 5 /8 7
.
1 6. 2
P h ar m ac o d y n a mics
T he p har mac o d y na mic para meter a nal yz e d are t he res ults fr o m t he L M P 7 β 5i assa y a n d b 5c assa y. 
Sa m ple c ollecti o n f or L M P 7 is o n Da y 1 ( pre d ose, 2 h, 6 h a n d 2 4 h a n d o n da y 1 5 ( pre d ose, 2 h a n d 
6 h). If d a y  15 is n o l o n ger sa m ple d, t his will be da y  8. O n t he plate f or t he assa y there will t w o 
wells f or eac h sa m ple a n d bla n k wells (sa m ple wit h o ut s u bstrate ). Bef ore usi n g t he data, t he mea n 
of t he bla n k wells nee ds t o be s u btracte d fr o m t he mea n of t he t w o wells per treat me nt da y a n d 
ti me p oi nt. It is ass u me d t hat t his c orrecti o n will alrea d y be d o ne at t he la b a n d o nl y  correcte d 
val ues will be deli vere d.
T he pre pr ocesse d data will be a nal yz e d as rati o t o t he pre pr ocesse d baseli ne val ue (“resi d ual 
acti vit y”).
If t he x- a xes i n li ne pl ots f or P D data is ti me, all data will be use d ( wit h res pecti ve da y  of a nal ys is), 
a nal ys is is n ot visit base d.
Li ne pl ots will s ho w t he i n di vi d ual resi d ual acti vit y o ver ti me ( wit h x- a x is ti me, y- a xis L M P 7 
resi d ual acti vit y), usi n g differe nt c ol ors per re gi me n a n d per d ose le vel a n d differe nt li ne t y pes t o 
i de ntif y partici pa nts. If p ossi ble (s ufficie nt data i n a d ose le vel), L O E S S li nes per re gi me n a n d per 
d ose le vel ca n be pl otte d.
S u m mar y  li ne pl ots will s h o w t he mea n per re gi me n a n d per d ose le vel
D ot pl ots will s h o w data of i n di vi d ual partici pa nts at s pecific selecte d treat me nt da y vers us d ose 
( x-a xis d ose, y-a xis LM P 7 resi d ual acti vit y ). Selecte d treat me nt da y are: 

Da y  1 2 4 h = C 1 D 2 pre d ose

Da y  1 5 pre d ose (If da y 1 5 is n o l o n ger sa m ple d, t his will be da y 8)
T he off -tar get β 5c assa y will be be ha n dle d i n t he sa me wa y as t he L M P 7 β 5i assa y , i.e. usi n g t he 
sa me pl ots. T he e x pectati o n is t o see o nl y  mi ni mal i n hi biti o n i n t his assa y ( n o c ha n ges fr o m 
baseli ne acti vit y t o resi d ual acti vit y after d osi n g).
Citr ulli ne data a nal ys is will n ot be part of t he C S R a n d will be perf or me d f or i nter nal i nsi g ht b y  
Merc k i nter nally. Citr ulli ne meas ure me nts will be pl otte d i n s u bject li ne pl ots (ti me x -a xis, y- a xis: 
citr ulli ne val ues, differe nt s ha pe f or differe nt d osi n g /re gi me n, differe nt c ol or f or eac h partici pa nt ).
Parallel pl o t bel o w will s h o w t he c orres p o n di n g dr u g a d mi nistrati o ns a n d d urati o n of A E i n S O C: 
“ gastr oi ntesti nal”, usi n g t he sa me c ol or c o de f or partici pa nts. 
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI






M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
4 8 /8 7
5 
Fri ber g L. E, He n ni n gss o n A, Maas H, N g u ye n  L & Karlss o n M. O ( 2 0 0 2). M o del of 
c he m ot hera p y- i n d uce d m yel os u p pressi o n wit h para meter c o nsiste nc y acr oss dr u gs. J Cli n 
O nc ol, 2 0 4 7 1 3 - 4 7 2 1.
6 
Beal S L . ( 2 0 0 1) W a y s t o fit a P K m o del wit h s o me data bel o w t he q ua nt ificati o n li mit. J 
P h ar m ac oki net P h ar m ac o dy n. 2 8 ( 5): 4 8 1– 5 0
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
4 9 /8 7
1 8
A p pe n dices
1 8. 1
I nte gr ate d A n al ysis Pl a n f or S M C
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
5 0 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
5 1 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
5 2 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
5 3 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
5 4 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
5 5 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
P P D
P P D


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
5 6 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
5 7 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
5 8 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
5 9 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
6 0 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
6 1 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
6 2 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
6 3 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
6 4 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
6 5 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
6 6 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
6 7 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
6 8 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
6 9 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
7 0 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
7 1 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
7 2 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
7 3 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
7 4 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
7 5 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
7 6 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
7 7 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
7 8 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
7 9 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
8 0 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
8 1 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
8 2 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
8 3 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
8 4 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
8 5 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
8 6 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 2 5 8
First i n H u m a n D ose Esc al ati o n of  M 3 2 5 8 as a Si n gle A ge nt a n d E x p a nsi o n 
St u d y of M 3 2 5 8 i n C o m bi n ati o n wit h De x a met h as o ne
M S 2 0 1 8 1 4- 0 0 1 0 
       
v 2. 0
8 7 /8 7
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
P P D


E L E C T R O NI C SI G N A T U R E S
D oc u me nt: i nte gr ate d a n al ysis pl a n m 3 2 5 8 v 2 - m ai n te xt b o d y
Si g ne d B y
E ve nt N a me 
Me a ni n g of Si g n at ure
Ser ver D ate
( d d- M M M- y y y y
H H: m m ‘ G M T’ Z)
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
B usi ness A p pr o val 
1 7- Ma y- 2 0 2 1 0 6: 0 9
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
B usi ness A p pr o val 
1 7- Ma y- 2 0 2 1 1 3: 3 9
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
Tec h nical A p pr o val 
1 8- Ma y- 2 0 2 1 1 5: 0 7
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
B usi ness A p pr o val 
1 8- Ma y- 2 0 2 1 1 5: 4 5
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
B usi ness A p pr o val 
1 9- Ma y- 2 0 2 1 1 6: 4 9
D oc u me nt N o.
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
P P D