Phase 2 Trial of Pembrolizumab, Ixazomib, and Dexamethasone for Relapsed Multiple Myeloma
Phase: PHASE2
Conditions: Recurrent Plasma Cell Myeloma
Sponsor: Mayo Clinic



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T a ble of C o nte nts 
P hase 2 Trial of Pe m br oliz u ma b, I xaz o mi b a n d De xa met has o ne f or Rela pse d M ulti ple M y el o ma ............. 1  
Pr ot oc ol Res o urces ............................................................................................................ ............................ 2 
Ta ble of C o nte nts ............................................................................................................. ............................. 3 
Sc he ma ........................................................................................................................ .................................. 4 
1. 0  
Bac k gr o u n d .................................................................................................................... ............... 5 
2. 0  
G oals ......................................................................................................................... ................... 1 6 
3. 0  
Patie nt Eli gi bilit y ........................................................................................................... .............. 1 6 
4. 0  
Test Sc he d ule.................................................................................................................. ............. 2 0 
5. 0  
Gr o u pi n g Fact or:  N o ne ................................................................................................................ 2 3  
6. 0  
Re gistrati o n Pr oce d ures ....................................................................................................... ........ 2 3 
7. 0  
Pr ot oc ol Treat me nt ............................................................................................................ .......... 2 5 
8. 0  
D osa ge M o dificati o n Base d o n A d verse E ve nts ......................................................................... 2 6  
9. 0  
A ncillar y Treat me nt/ S u p p orti ve Care ......................................................................................... 3 1  
1 0. 0  
A d verse E ve nt ( A E) M o nit ori n g a n d Re p orti n g .......................................................................... 4 0  
1 1. 0  
Treat me nt E val uati o n .......................................................................................................... ........ 5 4 
1 2. 0  
Descri pti ve Fact ors ........................................................................................................... ........... 5 9 
1 3. 0  
Treat me nt/ F oll o w – u p Decisi o n at E val uati o n of Patie nt............................................................. 6 0  
1 4. 0  
B o d y Fl ui d Bi os peci me ns ....................................................................................................... ..... 6 2 
1 5. 0  
Dr u g I nf or mati o n .............................................................................................................. ........... 6 5 
1 6. 0  
Statistical C o nsi derati o ns a n d Met h o d ol o g y ........................................................................... 7 4  
1 7. 0  
Pat h ol o g y C o nsi derati o ns/ Ti ss ue Bi os peci me ns: N o ne .......................................................... 8 0 
1 8. 0  
Rec or ds a n d Data C ollecti o n Pr oce d ures .................................................................................... 8 0  
1 9. 0  
B u d get ........................................................................................................................ ............. 8 1 
A p pe n di x I  
E C O G Perf or ma nce Stat us .................................................................................................. 8 2  
A p pe n di x II  P A TI E N T M E DI C A TI O N DI A R Y ....................................................................................... 8 3  
 
 

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1. 0
 B ac k gr o u n d
 
1. 1
 M ulti ple
 
M y el o ma
 
M ulti ple m y el o ma is a mali g na nc y of t he differe ntiate d plas ma cells, t hat affect t he ol der 
patie nt wit h a me dia n a ge at o nset of 6 5- 7 0 y ears a n d a sli g ht male pre d o mi na nce. Nearl y 
2 0, 0 0 0 patie nts wit h m y el o ma are dia g n ose d i n  t he U nite d States eac h y ear, a n d des pite 
c o nsi dera ble i m pr o ve me nts i n t hera p y re ma i ns i nc ura ble a n d u nif or ml y fatal wit h a 
me dia n o verall s ur vi val of ar o u n d 8 y ears.  Rece nt i m pr o ve me nts i n t hera pies ha ve 
si g nifica ntl y i m pr o ve d t he s ur vi val o utc o mes, b ut gi ve n t he i ne vita ble rela pses see n i n 
t hese patie nts, ne w a p pr oac hes t o t hera p y are clearl y nee de d. T he hi g hl y effecti ve dr u g 
c o m bi nati o ns c urre ntl y use d are beset wit h a de gree of t o xicit y t hat precl u des l o n g-ter m 
t hera p y a n d als o ca n affect t he q ualit y of life metrics. Fi nall y, s o me of t hese re gi me ns 
re q uire I V or s u bc uta ne o us a d mi nistrati o n, w hic h ca n re q uire fre q ue nt cli nic, visits f or 
patie nts. T he hi g hl y effecti ve m ulti- dr u g re gi me ns c urre ntl y i n use t y picall y i ncl u de a 
pr oteas o me i n hi bit or, eit her b ortez o mi b gi ve n I V or S Q or carfilz o mi b gi ve n I V. 
1. 2
 I xaz o mi b:
  
I xaz o mi b, w hic h has bee n f or m ulate d f or b ot h i ntra ve n o us (I V) a n d oral ( P O) 
a d mi nistrati o n, is a s mall m olec ule pr oteas o me i n hi bit or. I xaz o mi b citrate ( M L N 9 7 0 8) is 
t he citrate ester of t he bi ol o gicall y acti ve b or o nic aci d f or m, i xaz o mi b M L N 2 2 3 8, w hic h 
is str uct urall y si milar t o b ortez o mi b.  I n water or a q ue o us s yste ms, i xaz o mi b citrate 
ra pi dl y h y dr ol y zes t o M L N 2 2 3 8, t heref ore all d oses a n d c o nce ntrati o ns are e x presse d as 
M L N 2 2 3 8.  N o ncli nical st u dies were c o n d ucte d wit h a s ol uti o n of eit her M L N 2 2 3 8 or 
M L N 2 2 3 8 i n e q uili bri u m wit h i xaz o mi b citr ate.  Si milar t o b ortez o mi b, M L N 2 2 3 8 
p ote ntl y, re versi bl y, a n d selecti vel y i n hi bits t he 2 0 S pr oteas o me.  H o we ver, i n c o ntrast t o 
b ortez o mi b, it has a s h orter diss ociati o n half-life (t 1/ 2) t hat ma y c o ntri b ute t o i ncrease d 
tiss ue distri b uti o n.  B ortez o mi b has a sl o wl y re versi ble diss ociati o n rate fr o m t h e re d 
bl o o d cell pr oteas o me, w hile M L N 2 2 3 8 de m o nstrates a m ore ra pi dl y re versi ble 
diss ociati o n rate fr o m t he bl o o d b ut s ustai ne d effects o n b o ne marr o w a n d t u m or 
pr oteas o mes s u g gesti n g better tiss ue distri b uti o n.  T he p har mac ol o gic i m plicati o ns of t his 
differe nce i n bi n di n g ki netics a n d tiss ue distri b uti o n ma y i n t ur n res ult i n differe nces i n 
safet y a n d efficac y pr ofiles i n a br oa der ra n ge of t u m ors.  I n xe n o graft- beari n g mice, t he 
m ore ra pi d diss ociati o n rate c orrelates wit h a n i ncrease d rati o of t u m or pr oteas o me 
i n hi biti o n t o bl o o d pr oteas o me i n hi biti o n, a n d i xaz o mi b s h o ws greater a ntit u m or acti vit y 
i n se veral xe n o graft m o dels, b ot h s oli d t u m or a n d b ortez o mi b-resista nt xe n o grafts, t ha n 
b ortez o mi b.   
 
N o ncli nic al P h ar m ac ol o gy : M L N 2 2 3 8 citrate refers t o t he bi ol o gicall y acti ve, b or o nic 
aci d f or m of t he dr u g s u bsta nce, i xaz o mi b citrate.  I xaz o mi b citrate  refers t o t he citrate 
ester of M L N 2 2 3 8.  I n water or a q ue o us s yst e ms, t he e q uili bri u m s hifts fr o m i xaz o mi b 
citrate t o t he bi ol o gicall y acti ve b or o nic aci d f or m M L N 2 2 3 8.  All d oses a n d 
c o nce ntrati o ns are e x presse d as t he b or o nic aci d, M L N 2 2 3 8. 
 
I n Vitr o P h ar m ac ol o gy: M L N 2 2 3 8 prefere ntiall y bi n ds t he β 5 site of t he 2 0 S pr oteas o me; 
at hi g her c o nce ntrati o ns, it als o i n hi bits t he acti vit y of t he β 1 a n d β 2 sites.  M L N 2 2 3 8 
i n hi bits ß 5 site 2 0 S pr oteas o me acti vit y i n vitr o, wit h a half- ma xi mal i n hi bit or y 
c o nce ntrati o n (I C 5 0) of 3. 4 n M.  P ote nc y is re d uce d r o u g hl y 1 0-f ol d vers us ß 1 (I C 5 0  3 1 
n M) a n d 1, 0 0 0-f ol d vers us ß 2 (I C 5 0 = 3 5 0 0 n M).  M L N 2 2 3 8 was als o teste d f or 
i n hi biti o n a gai nst a pa nel of 1 0 3 ki nases, 1 8 rece pt ors ( ne ur otra ns mitter, i o n c ha n nel, 
brai n a n d g ut rece pt ors), a n d 9 seri ne pr oteases.  I n all cases, t he I C 5 0 val ues were > 1 0 

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μ M.  M L N 2 2 3 8 a n d b ortez o mi b ha ve differe nt β 5 pr oteas o me diss ociati o n half-li ves 
(t 1/ 2), reflecti n g differe nces i n t heir o n- off bi n din g ki netics (t he β 5 pr oteas o me 
diss ociati o n t 1/ 2 f or M L N 2 2 3 8 a n d b ortez o mi b are 1 8 a n d 1 1 0 mi n utes, res pecti vel y).  
Base d o n t hese fa v ora ble c haracteristics, i xaz o mi b is a ntici pate d t o be effecti ve a gai nst 
m ulti ple m y el o ma. (I xaz o mi b I n vesti gat or’s Br oc h ure (I B)). Pr oteas o me i n hi biti o n 
res ults i n t he acc u m ulati o n of p ol y- u bi q uiti nate d s u bstrates wit hi n t he cell a n d lea ds t o 
cell c y cle disr u pti o n, wit h c o nc o mita nt acti va ti o n of a p o pt otic pat h wa ys a n d cell deat h.  
C o nsiste nt wit h i n hi biti o n of ß 5 2 0 S acti v it y, M L N 2 2 3 8 de m o nstrate d p ote nt acti vit y 
a gai nst c ult ure d M D A- M B 2 3 1 h u ma n breast ca n cer cells i n t he W S T cell via bilit y assa y.  
I n n o ncli nical m o dels M L N 2 2 3 8 has acti vit y a gai nst b ot h s oli d t u m or a n d b ortez o mi b-
resista nt xe n o grafts 
 
I n Viv o P h ar m ac ol o gy: T o deter mi ne t he acti vit y of M L N 2 2 3 8 i n vi v o, 
p har mac o d y na mic st u dies were perf or me d i n i m m u n oc o m pr o mise d mice beari n g eit her 
C W R 2 2 h u ma n pr ostate or W S U- D L C L 2 ( h u ma n diff use lar ge B-cell l y m p h o ma 
[ D L B C L]) t u m ors.  P har mac o d y na mic res p o nses i n xe n o graft t u m ors were a nal y ze d b y 
assessi n g 2 0 S pr oteas o me i n hi biti o n a n d b y e v al uati n g le vels of acc u m ulate d pr otei n 
mar kers s uc h as de o x yri b o n ucleic aci d ( D N A)  da ma g e-i n d uci ble pr otei n 3 4 ( G A D D 3 4) 
a n d acti vati n g tra nscri pti o n fact or- 3 ( A T F- 3) as well as meas uri n g gr o wt h arrest.  
I ncrease d e x pressi o n of G A D D 3 4 a n d A T F- 3 is i n dicati ve of a d o w nstrea m bi ol o gical 
res p o nse t o pr oteas o me i n hi biti o n.  After a si n gle d ose of M L N 2 2 3 8, a clear d ose 
res p o nse was o bser ve d i n C W R 2 2 xe n o grafts as see n i n b ot h t u m or 2 0 S pr oteas o me 
i n hi biti o n a n d i n c ha n ges i n G A D D 3 4 a n d A T F- 3 e x pressi o n.  I n W S U- D L C L 2 
xe n o grafts, greater t u m or pr oteas o me i n hi biti o n was o bser ve d wit h M L N 2 2 3 8 c o m pare d 
t o b ortez o mi b a n d res ulte d i n i ncrease d e x pressi o n of G A D D 3 4 a n d A T F- 3. M L N 2 2 3 8 
efficac y e x peri me nts de m o nstrate d str o n g a ntit u m or acti vit y i n 4 xe n o graft m o dels: 
C W R 2 2 (a h u ma n pr ostate ca ncer cell li ne) a n d 3 h u ma n l y m p h o ma cell li nes ( W S U-
D L C L 2, O CI- L y 7- 7 D 1-l uc, a n d P H T X- 2 2 L).  I n t he case of t he C W R 2 2 xe n o graft 
m o del, si g nifica nt a ntit u m or acti vit y w as see n wit h b ot h I V a n d P O d osi n g, 
de m o nstrati n g t hat t his m olec ule has a ntit u m or acti vit y w he n a d mi nistere d via differe nt 
d osi n g r o utes.  I n all 3 l y m p h o ma li nes, M L N 2 2 3 8 de m o nstrate d str o n ger a ntit u m or 
acti vit y t ha n di d b ortez o mi b. I n s u m mar y, M L N 2 2 3 8, si milar t o b ortez o mi b, is a 
di pe pti de b or o nic aci d pr oteas o me i n hi bit or t hat p ote ntl y, re versi bl y, a n d selecti vel y 
i n hi bits t he pr oteas o me.  T here are se veral feat ures, s u c h as s ustai ne d p har mac o d y na mic 
effects a n d acti vit y i n a b ortez o mi b-refract or y l y m p h o ma xe n o graft m o del, t hat s u g gest 
t hat it ma y ha ve acti vit y t hat e xte n ds be y o n d t hat see n wit h b ortez o mi b. 
 
N o ncli nic al P h ar m ac oki netics a n d P h ar m ac o dy n a mics : N o ncli nical P har mac o ki netics: 
T he p har mac o ki netic ( P K) pr o perties of M L N 2 2 3 8 were st u die d i n se vere c o m bi ne d 
i m m u n o deficie nt ( S CI D) mice beari n g h u ma n C W R 2 2 t u m or xe n o grafts, S pra g ue-
Da wle y rats, bea gle d o gs, a n d c y n o m ol g us m o n ke ys.  Beca use of t he e xte nsi ve re d bl o o d 
cell ( R B C) partiti o ni n g of M L N 2 2 3 8, b ot h bl o o d a n d plas ma P K p ara meters were 
deter mi ne d i n t hese st u dies.  M L N 2 2 3 8 ha d a ver y l o w bl o o d cleara nce ( C L b) a n d a 
m o derate bl o o d v ol u me of distri b uti o n at stea d y-state ( Vss, b) after I V a d mi nistrati o n.  
T he c o nce ntrati o n- vers us-ti me c ur ve of M L N 2 2 3 8 dis pla y e d a disti nct bi-e x p o ne ntial 
pr ofile wit h a stee p i nitial distri b uti o n p hase a n d a l o n g ter mi nal t 1/ 2 ( > 2 4 hr) i n all 
s pecies teste d.  M L N 2 2 3 8 ha d hi g her plas ma cleara n ce ( C L p) a n d a lar ger plas ma 
v ol u me of distri b uti o n at stea d y-state ( Vss, p) t ha n i n bl o o d, lar gel y beca use of t he 
e xte nsi ve R B C partiti o ni n g. T he P K pr o perties of M L N 2 2 3 8 after oral a d mi nistrati o n 
were st u die d i n rats a n d d o gs.  T he plas ma oral bi oa vaila bilit y ( F) was 4 1 % i n rats a n d 
nearl y 1 0 0 % i n d o gs.  A cli nical pr ot ot y pe f or m ulati o n of t he i xaz o mi b ca ps ule 

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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
de m o nstrate d t hat M L N 2 2 3 8 ha d e xcelle nt oral  F a n d a n e xcelle nt a bs or pti o n pr ofile i n 
d o gs.  I n a d diti o n, i nteri n di vi d ual varia bilit y, as meas ure d b y % C V, i n C ma x  a n d A U C0- 2 4 hr 
after oral a d mi nistrati o n was l o w t o m o derate, si milar t o t hat after I V a d mi nistrati o n.  T he 
ter mi nal t1/ 2 after oral a d mi nistrati o n was als o si milar t o t hat after I V a d mi nistrati o n.  
C o m paris o n of t he P K pr ofiles after I V or P O a d mi nistrati o n i n t he d o g is re p orte d i n 
f urt her detail i n t he I B. M L N 2 2 3 8 is pre dicted t o ha ve ver y l o w C L b ( 0. 0 0 4 5 L/ hr/ k g) 
a n d a m o derate Vss, b ( 0. 7 9 L/ k g) wit h a l o n g ter mi nal t 1/ 2 ( > 2 4 h o urs) i n h u ma ns.  T he 
h u ma n efficaci o us I V d ose of M L N 2 2 3 8 is pre dicte d t o be 2. 0 m g/ m 2 ( 0. 0 5 4 m g/ k g) 
t wice wee kl y. T he h u ma n efficaci o us oral d ose is pre dicte d t o be bet wee n 2 a n d 5 m g/ m2 
t wice wee kl y, base d o n a pre dicte d oral F of bet wee n 4 1 % (as see n i n rats) a n d 1 0 0 % (as 
see n i n d o gs).  T he efficaci o us d ose pr ojecti o n f or o nce wee kl y oral w o ul d be hi g her t ha n 
t wice wee kl y oral ( data n ot pr o vi de d). 
 
Meta b olis m a p pears t o be a maj or r o ute of eli mi nati o n f or M L N 2 2 3 8 a n d uri nar y 
e xcreti o n of t he pare nt dr u g was ne gli gi ble ( < 5 % of d ose). I n vitr o i n li ver micr os o mes, 
t he meta b olis m of M L N 2 2 3 8 was hi g h i n mice a n d l o w t o m o derate i n all ot her s pecies 
st u die d.  M L N 2 2 3 8 is meta b olize d b y m ulti ple c yt oc hr o me P 4 5 0 ( C Y P) is oz y mes a n d 
n o n- C Y P e nz y mes a n d pr otei ns.  At hi g her t ha n cli nical c o nce ntrati o ns, i xaz o mi b was 
meta b olize d b y m ulti ple C Y P is of or ms wit h  esti mate d relati ve c o ntri b uti o ns of 3 A 4 
( 4 2 %), 1 A 2 ( 2 6 %), 2 B 6 ( 1 6 %), 2 C 8 ( 6 %), 2 D 6 ( 5 %), 2 C 1 9 ( 5 %) a n d 2 C 9 ( < 1 %).  
M L N 2 2 3 8 is neit her a n i n hi bit or of C Y P is oz y mes 1 A 2, 2 C 9, 2 C 1 9, 2 D 6, or 3 A 4 (I C 5 0 
> 3 0 μ M, wit h a n esti mate d i n hi biti o n diss ociati o n c o nsta nt [ Ki] > 1 5 μ M) n or a ti me 
de pe n de nt i n hi bit or of C Y P 3 A 4/ 5 ( u p t o 3 0 μ M).  T he p ote ntial f or i xaz o mi b treat me nt t o 
pr o d uce D DIs via C Y P i n hi biti o n is i nferre d t o be l o w. 
 
I n a Cac o- 2 cell assa y, M L N 2 2 3 8 s h o we d me di u m per mea bilit y wit h a B-t o- A/ A-t o- B 
per mea bilit y rati o of 2. 9.  M L N 2 2 3 8 ma y be a l o w-affi nit y s u bstrate of para- gl yc o pr otei n 
( P- g p), breast ca ncer resista nce pr otei n ( B C R P), a n d m ulti dr u g resista nce pr otei n 2 
( M R P 2) effl u x p u m p tra ns p orters.  M L N 2 2 3 8 is n ot a n i n hi bit or of P- g p, B C R P, a n d 
M R P 2 (I C 5 0 > 1 0 0 μ M).  C o nse q ue ntl y, t he p ote ntial f or M L N 2 2 3 8 t o ca use D DIs wit h 
s u bstrates or i n hi bit ors of P- g p, B C R P, a n d M R P 2 is l o w.   
 
See t he I B f or f urt her details. 
 
S afety P h ar m ac ol o gy : I n e x pl orat or y safet y p har mac ol o g y st u dies, M L N 2 2 3 8 was a 
wea k i n hi bit or of t he cl o ne d car diac p otassi u m ( K +) h u ma n et her à- g o- g o relate d ge ne 
( h E R G) c ha n nel, wit h a n I C 5 0 of 5 9. 6 μ M, w hic h e xcee ds, b y a p pr o xi matel y 2 0 0-f ol d, 
t he plas ma C ma x ( 1 1 1 n g/ m L [ 0. 3 μ M]) pre dicte d t o occ ur i n h u ma ns at t he o pti mall y 
efficaci o us d ose after I V a d mi nistrati o n. 
 
I n t he G L P-c o m plia nt, 1-c y cle, re peat- d ose, P O t o xic ol o g y st u d y i n bea gle d o gs, a n 
i ncrease i n Q Tc was see n i n male d o gs at n o n-t olerate d d oses, a n d a p ote ntial i ncrease i n 
Q Tc was see n i n male d o gs at t olerate d d o ses.  H o we ver, i ncrease d Q Tc was n ot see n i n 
fe male d o gs at a n y d ose, des pite t he fact t hat fe male d o gs ha d plas ma Cma x val ues si milar 
t o t h ose of male d o gs.  A d diti o nall y, i n a G L P-c o m plia nt, 2-c y cle, re peat- d ose, I V 
t o xic ol o g y st u d y i n bea gle d o gs, n o i ncrease i n Q Tc was see n i n eit her male or fe male 
d o gs at a n y d ose, e ve n t h o u g h d o gs i n t he I V st u d y ha d hi g her M L N 2 2 3 8 plas ma C ma x  
val ues t ha n di d t he male d o gs i n t he P O st u d y.  T hese data s u g gest t hat M L N 2 2 3 8 has a 
l o w p ote ntial f or pr ol o n gi n g t he Q T i nter val i n vi v o. 
 

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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
T oxic ol o gy : All st u dies disc usse d i n t his secti o n were c o n d ucte d wit h a s ol uti o n of eit her 
M L N 2 2 3 8 or M L N 2 2 3 8 i n e q uili bri u m wit h i xaz o mi b citrate.  Beca use i xaz o mi b citrate 
was s h o w n t o diss ociate i m me diatel y t o M L N 2 2 3 8 u p o n e x p os ure t o plas ma i n vitr o a n d 
t heref ore c o ul d n ot be detecte d i n plas ma sa m ples i n vitr o all d oses, c o nce ntrati o ns, a n d 
P K para meters n ote d, here a n d i n t he I B, are e x presse d as t he b or o nic aci d, M L N 2 2 3 8. 
 
T he t o xic ol o g y st u dies of M L N 2 2 3 8 were st u die d i n S CI D mice beari n g h u ma n C W R 2 2 
t u m or xe n o grafts, S pra g ue- Da wle y rats, bea gle d o gs, a n d c y n o m ol g us m o n ke ys.  Details 
of t hese st u dies are i ncl u de d i n t he I B. 
 
I n Vitr o T o xic ol o g y: M L N 2 2 3 8 was n ot m uta ge nic i n a G o o d La b orat or y Practice 
( G L P)-c o m plia nt bacterial re verse m utati o n assa y ( A mes assa y).  
 
I n Vi v o T o xic ol o g y: Details of t he i n vi v o t o xic ol o g y I V d osi n g a n d oral d osi n g st u dies 
are pr o vi de d i n t he I B.  T o s u m marize, t he t o xic ol o gic effects see n i n t he I V a n d P O 
st u dies are q ualitati vel y si milar t o w hat was pre vi o usl y o bser ve d i n r o de nts d ose d wit h 
b ortez o mi b, f or w hic h i xaz o mi b is t he ne xt- ge nerati o n m olec ule.  M L N 2 2 3 8 di d n ot 
ca use si g nifica nt t o xicities t hat ha ve n ot bee n pre vi o usl y o bser ve d after d osi n g wit h 
b ortez o mi b.  T heref ore, o n t he basis of t he si milarit y i n t he t o xicit y pr ofile i n rats 
bet wee n M L N 2 2 3 3 8 a n d b ortez o mi b, M L N 2 2 3 8 is  n ot k n o w n t o prese nt a n y a d diti o nal 
safet y ris ks be y o n d t h ose t hat occ ur after treatme nt wit h b ortez o mi b.  I n a d diti o n, t here 
were n o si g nifica nt fi n di n gs at t olerate d e x p os ures i n d o gs o bser ve d after P O 
a d mi nistrati o n t hat were n ot see n after I V a d mi nistrati o n, a n d si milar e x p os ures were 
t olerate d re gar dless of t he r o ute of a d mi nistrati o n. 
 
T he p ote ntial ris ks i de ntifie d fr o m n o ncli nical st u dies i n d o gs a n d rats i ncl u de: 
•  
GI t o xicit y t hat c o ul d res ult i n na usea, v o miti n g, diarr hea, de h y drati o n, electr ol yte 
i m bala nce, blee di n g, b o wel o bstr ucti o n i ncl u di n g ile us a n d i nt uss usce pti o n, a n d 
se psis. 
•  
Re d uce d bl o o d c o u nts ma nifest as t hr o m b oc yt o pe nia, ne utr o pe nia, a n d a ne mia.  
Retic ul oc yt o pe nia was descri be d i n a ni mals a n d ma y be ass ociate d wit h a ne mia.  
Re d ucti o ns i n bl o o d c o u nts ma y pre dis p ose t o a n i ncrease d s usce pti bilit y t o i nfecti o n, 
blee di n g, a n d a ne mia. 
•  
Peri p heral ner ve ga n glia effects t hat ma y be ass ociate d wit h peri p heral ne ur o pat h y 
t hat i ncl u des pai n, b ur ni n g se nsati o n, a n d n u m b ness.  A ut o n o mic a n d m ot or 
ne ur o pat h y ma y be o bser ve d, as b ot h ha ve bee n re p orte d f or b ortez o mi b. 
•  
L y m p h oi d cell de pleti o n t hat ma y be ass ocia te d wit h i ncrease d ris k of i nfecti o n, 
i ncl u di n g re-acti vati o n of her pes z oster. 
•  
Ac ute p hase res p o nse t hat ma y res ult i n fe ver a n d meta b olic c ha n ges. 
 
All of t he effects see n i n t he G L P-c o m plia nt P O t o xic ol o g y st u dies i n b ot h d o gs a n d rats 
at t olerate d d oses were re v ersi ble/re versi n g a n d ca n be m o nit ore d i n t he cli nic wit h 
r o uti ne cli nical o bser vati o ns ( GI dist ur ba nces a n d i nfecti o ns sec o n dar y t o l y m p h oi d 
c o m pr o mise), cli nical pat h ol o g y assess me nts (i n hi biti o n of er yt hr o p oiesis, 
t hr o m b oc yt o pe nia, a n d i nfla m mat or y le u k o gra m), a n d ne ur ol o gic assess me nt, as are 
c o m m o nl y d o ne f or patie nts treate d wit h b ort ez o mi b.  T he ne ur ol o gic lesi o ns i n t hese 
st u dies are si milar t o w hat has bee n descri be d after treat me nt wit h b ortez o mi b a n d are 
belie ve d t o be t he ca use of t he peri p heral ne ur o pat h y o bser ve d i n patie nts treate d wit h 
b ortez o mi b. 
F urt her details are prese nte d i n t he I B. 

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1. 3  
Cli nical E x perie nce wit h I xaz o mi b 
I xaz o mi b has bee n st u die d i n se veral p hase 1 a n d p hase 1/ 2 st u dies e val uati n g b ot h t wice-
wee kl y a n d wee kl y d osi n g sc he d ules.  I xaz o mi b is a vaila ble as a n i ntra ve n o us a n d oral 
f or m ulati o n. Re gar dless of t he r o ute of a d mi nistrati o n i n t he t wice- wee kl y d osi n g 
sc he d ule, i xaz o mi b is gi ve n o n Da ys 1, 4, 8, a n d 1 1 of a 2 1- da y c ycle; i n t he wee kl y 
d osi n g sc he d ule, t he dr u g is gi ve n o n Da ys 1, 8, a n d 1 5 of a 2 8- da y c y cle. T o date, t he 
de vel o p me nt of oral i xaz o mi b has f oc use d o n m ulti ple m y el o ma [rela pse d a n d/ or 
refract or y a n d ne wl y dia g n ose d] a n d a differe nt y et relate d plas ma cell d yscrasia, 
s yste mic li g ht c hai n ( A L) a m yl oi d osis.   Details of t hese trials ca n be f o u n d i n 
Cli nical Trials. g o v a n d t he i xaz o mi b I B.   
P har mac o ki netics a n d Dr u g Meta b olis m: After oral d osi n g, a bs or pti o n of i xaz o mi b is 
ra pi d wit h a me dia n first ti me t o ma xi m u m o bser ve d plas ma c o nce ntrati o n ( T ma x) of 
a p pr o xi matel y 1 h o ur p ost d ose. T he plas ma e x p os ure ( A U C) of i xaz o mi b i ncreases i n a 
d ose- pr o p orti o nal ma n ner o ver a d ose ra n ge of 0. 2 t o 1 0. 6 m g base d o n p o p ulati o n P K 
a nal ysis. T he a bs ol ute oral bi oa vaila bilit y ( F ) of i xaz o mi b is esti mate d t o be 5 8 % base d 
o n p o p ulati o n P K a nal ysis.  A hi g h-fat meal re d uce d i xaz o mi b C ma x b y 6 9 % a n d 
A U C 0- 2 1 6 b y 2 8 %.  T his i n dicates t hat a hi g h-fa t meal decreases b ot h t he rate a n d e xte nt 
of a bs or pti o n of i xaz o mi b. T heref ore, i xaz o mi b s h o ul d be d ose d at least 2 h o urs after 
f o o d or 1 h o ur bef ore f o o d. 
T he stea d y-state v ol u me of distri b uti o n of i xaz o mi b is lar ge a n d is esti mate d t o be 5 4 3 L 
base d o n a p o p ulati o n P K m o del. Base d o n i n vitr o plas ma pr otei n bi n di n g meas ure me nts 
o n sa m ples fr o m cli nical st u dies ( St u dies C 1 6 0 1 5 a n d C 1 6 0 1 8), i xaz o mi b is hi g hl y b o u n d 
t o plas ma pr otei ns ( 9 9 %). I xaz o mi b c o nce ntrati o ns are hi g her i n w h ole bl o o d t ha n i n 
plas ma, i n dicati n g e xte nsi ve partiti o ni n g of  i xaz o mi b i nt o re d bl o o d cells, w hic h are 
k n o w n t o c o ntai n hi g h c o nce ntrati o ns of t he 2 0 S pr oteas o me. 
Meta b olis m a p pears t o be t he maj or r o ute of  eli mi nati o n f or i xaz o mi b. I n vitr o st u dies 
i n dicate t hat i xaz o mi b is meta b olize d b y m ulti ple c yt oc hr o me P 4 5 0 ( C Y P) a n d n o n- C Y P 
pr otei ns. At c o nce ntrati o ns e xcee di n g t h ose o bser ve d cli nicall y ( 1 0 µ M), i xaz o mi b was 
meta b olize d b y m ulti ple C Y P is of or ms wit h  esti mate d relati ve c o ntri b uti o ns of 3 A 4 
( 4 2. 3 %), 1 A 2 ( 2 6. 1 %), 2 B 6 ( 1 6. 0 %), 2 C 8 ( 6. 0 %), 2 D 6 ( 4. 8 %), 2 C 1 9 ( 4. 8 %), a n d 2 C 9 
(≤1 %). At 0. 1 a n d 0. 5 µ M s u bstrate c o nce n trati o ns, w hic h are cl oser t o cli nical 
c o nce ntrati o ns of i xaz o mi b f oll o wi n g oral a d mi nistrati o n of 4 m g i xaz o mi b, n o n- C Y P 
me diate d cleara nce was o bser ve d a n d see me d t o  pla y a maj or r ole i n i xaz o mi b cleara nce 
i n vitr o.  T hese data i n dicate t hat at cli nicall y rele va nt c o nce ntrati o ns of i xaz o mi b, n o n-
C Y P pr otei ns c o ntri b ute t o t he cleara nce of i xaz o mi b a n d n o s pecific C Y P is oz y me 
pre d o mi na ntl y c o ntri b utes t o t he cleara nce of i x az o mi b. T heref ore, at cli nicall y rele va nt 
c o nce ntrati o ns of i xaz o mi b, mi ni mal C Y P- me diate d D DIs wit h a selecti ve C Y P i n hi bit or 
w o ul d be e x pecte d. 
I xaz o mi b is neit her a ti me- de pe n de nt i n hi bit or n or a re versi ble i n hi bit or of C Y Ps 1 A 2, 
2 B 6, 2 C 8, 2 C 9, 2 C 1 9, 2 D 6, or 3 A 4/ 5.  I xaz o mi b di d n ot i n d uce C Y Ps 1 A 2, 2 B 6, a n d 
3 A 4/ 5 acti vit y or c orres p o n di n g i m m u n oreacti ve pr otei n le vels. T h us, t he p ote ntial f or 
i xaz o mi b t o pr o d uce D DIs via C Y P is oz y me i n d ucti o n or i n hi biti o n is l o w. 
I xaz o mi b is n ot a s u bstrate of B C R P, M R P 2 a n d O A T Ps. I xaz o mi b is n ot a n i n hi bit or of 
P- g p, B C R P, M R P 2, O A T P 1 B 1, O A T P 1 B 3, O A T 1, O A T 3, O C T 2, M A T E 1 a n d 
M A T E 2- K. I xaz o mi b is u nli kel y t o ca use or be s usce pti ble t o cli nical D DIs wit h 
s u bstrates or i n hi bit ors of cli nicall y rele va nt dr u g tra ns p orters. 

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
T he ge o metric mea n ter mi nal half-life (t 1/ 2) of i xaz o mi b is 9. 5 da ys base d o n p o p ulati o n 
P K a nal ysis. F or b ot h I V a n d oral d osi n g, t here is a n a p pr o xi matel y a vera ge 3-f ol d 
acc u m ulati o n ( base d o n A U C) f oll o wi n g t he Da y 1 1 d ose f or t he t wice- wee kl y sc he d ule 
a n d a 2-f ol d acc u m ulati o n ( base d o n A U C ) f oll o wi n g t he Da y 1 5 d ose f or t he 
o nce- wee kl y sc he d ule. 
Mea n plas ma cleara nce ( C L) of i xaz o mi b is 1. 8 6 L/ hr base d o n t he res ults of a p o p ulati o n 
P K a nal ysis. Ta ke n t o get her wit h t he bl o o d-t o- plas ma A U C rati o of a p pr o xi matel y 1 0, it 
ca n be i nferre d t hat i xaz o mi b is a l o w cleara nce dr u g. Usi n g t he a bs ol ute oral 
bi oa vaila bilit y ( F) esti mate of 5 8 % (als o fr o m a p o p ulati o n P K m o del), t his tra nslates t o 
a n a p pare nt oral plas ma cleara nce ( C L/ F) of 3. 2 1 L/ hr. T he ge o metric mea n re nal 
cleara nce f or i xaz o mi b is 0. 1 1 9 L/ hr, w hic h is 3. 7 % of C L/ F a n d 6. 4 % of C L esti mate d i n 
a p o p ulati o n P K a nal ysis. T heref ore, re nal cleara nce d oes n ot mea ni n gf ull y c o ntri b ute t o 
i xaz o mi b cleara nce i n h u ma ns. A p pr o xi matel y 6 2 % of t he a d mi nistere d ra di oacti vit y i n 
t he A D M E st u d y ( St u d y C 1 6 0 1 6) was rec o vere d i n t he uri ne a n d 2 2 % of t he t otal 
ra di oacti vit y was rec o vere d i n t he feces after oral a d mi nistrati o n. O nl y 3. 2 % of t he 
a d mi nistere d i xaz o mi b d ose was rec o vere d i n t he uri ne as u nc ha n ge d i xaz o mi b u p t o 
1 6 8 h o urs after oral d osi n g, s u g gesti n g t hat m ost of t he t otal ra di oacti vit y i n uri ne was 
attri b uta ble t o meta b olites.  
T he P K of i xaz o mi b was si milar wit h a n d wit h o ut c o-a d mi nistrati o n of clarit hr o m y ci n, a 
str o n g C Y P 3 A i n hi bit or, a n d he nce n o d ose a dj ust me nt is necessar y w he n i xaz o mi b is 
a d mi nistere d wit h str o n g C Y P 3 A i n hi bit ors. C o nsiste ntl y, i n a p o p ulati o n P K a nal ysis, 
c o-a d mi nistrati o n of str o n g C Y P 1 A 2 i n hi bit ors di d n ot affect i xaz o mi b cleara n ce. 
T heref ore, n o d ose a dj ust me nt is re q uire d f or patie nts recei vi n g str o n g i n hi bit ors of 
C Y P 1 A 2. Base d o n i nf or mati o n fr o m t he cli ni cal rifa m pi n D DI st u d y, i xaz o mi b C ma x 
a n d A U C 0-last were re d uce d i n t he prese nce of rifa m pi n b y a p pr o xi matel y 5 4 % a n d 
7 4 %, res pecti vel y. T heref ore, t he c o-a d mi nistrati o n of str o n g C Y P 3 A i n d ucers wit h 
i xaz o mi b is n ot rec o m me n de d.  
Mil d or m o derate re nal i m p air me nt ( Cr C L ≥3 0 m L/ mi n) di d n ot alter t he P K of i xaz o mi b 
base d o n t he res ults fr o m a p o p ulati o n P K a nal ysis. As a res ult, n o d ose a dj ust me nt is 
re q uire d f or patie nts wit h mil d or m o derate re nal i m p air me nt.  I n a de dicate d re nal 
i m pair me nt st u d y ( C 1 6 0 1 5), u n b o u n d A U C 0-last was 3 8 % hi g her i n patie nts wit h se vere 
re nal i m pair me nt or E S R D patie nts re q uiri n g dial ysis as c o m pare d t o patie nts wit h 
n or mal re nal f u ncti o n.  Acc or di n gl y, a re d uce d starti n g d ose of i xaz o mi b is a p pr o priate i n 
patie nts wit h se vere re nal i m p air me nt or E S R D re q uiri n g dial ysis.  Pre- a n d p ost- dial y zer 
c o nce ntrati o ns of i xaz o mi b meas ure d d uri n g t he he m o dial ysis sessi o n were si milar, 
s u g gesti n g t hat i xaz o mi b is n ot rea dil y dial yza ble, c o nsiste nt wit h its hi g h plas ma pr otei n 
bi n di n g ( 9 9 %). 
T he P K of i xaz o mi b is si milar i n patie nts w it h n or mal he patic f u ncti o n a n d i n patie nts 
wit h mil d he patic i m pair me nt, as defi ne d b y t he Nati o nal Ca ncer I nstit ute Or ga n 
D ysf u ncti o n W or ki n g Gr o u p (t otal bilir u bi n < 1. 5 ti mes t he u p per li mit of n or mal [ U L N]), 
base d o n t he res ults fr o m a p o p ulati o n P K a nal ysis. C o nse q ue ntl y, n o d ose a dj ust me nt is 
re q uire d f or patie nts wit h mil d he patic i m p airme nt. I n a de dicate d P K st u d y i n patie nts 
wit h m o derate (t otal bilir u bi n > 1. 5 t o 3 ti m es t he U L N) or se vere (t otal bilir u bi n > 3 ti mes 
t he U L N) he patic i m pair me nt ( St u d y C 16 0 1 8), u n b o u n d d ose- n or malize d A U C 0-last was 
2 7 % hi g her i n patie nts wit h m o derate or se vere he patic i m pair me nt as c o m pare d t o 
patie nts wit h n or mal he patic f u ncti o n. T heref or e, a re d uce d starti n g d ose of i xaz o mi b is 
a p pr o priate i n patie nts wit h m o derate or se vere he patic i m pair me nt.  

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
T here was n o statisticall y si g nifica nt effect of a ge ( 2 3- 9 1 y ears), se x, b o d y s urface area 
( 1. 2- 2. 7 m 2), or race o n t he cleara nce of i xaz o mi b base d o n t he res ults fr o m a p o p ulati o n 
P K a nal ysis. 
F urt her details o n t hese st u dies are pr o vi de d i n t he I B. 
1. 4  
O ver vie w of t he Oral F or m ulati o n of i xaz o mi b 
T he safet y pr ofile i n dicates t hat oral i xaz o mi b is ge nerall y well t olerate d wit h 
pre d o mi na nt t o xicities lar gel y re versi ble, a b le t o be m o nit ore d b y r o uti ne cli nical 
e xa mi nati o ns a n d ma n a gea ble b y d ose re d ucti o ns, disc o nti n uati o n, or sta n dar d s u p p orti ve 
care. Fr o m e x perie nce fr o m p hase 1 t hr o u g h 3 st u dies t he maj or t o xicities ca n be 
ma na ge d t o all o w re peat treat me nt c y cles o ver peri o ds e xte n di n g be y o n d 2 4 m o nt hs.  
Rel a pse d M M: Si n gle- a ge nt, Weekly ix az o mi b ( St u dy C 1 6 0 0 4) :  
St u d y C 1 6 0 0 4 is a n o pe n-la bel, d ose-escalati o n, p hase 1 st u d y of i xaz o mi b a d mi nistere d 
wee kl y o n Da ys 1, 8, a n d 1 5 of a 2 8- da y c y cle i n a d ult patie nts wit h R R M M. Patie nts 
wit h M M e nr olle d i n t he d ose-escalati o n c o m p o ne nt of t he st u d y ha ve rela pse d f oll o wi n g 
at least 2 li nes of t hera p y, w hic h m ust h a ve i ncl u de d b ortez o mi b, t hali d o mi de ( or 
le nali d o mi de), a n d c ortic oster oi ds. I n t his st u d y, 2 of 3 patie nts e x perie nce d pr ot oc ol-
defi ne d D L Ts ( Gra de 3 ras h a n d Gra de 3 na usea, v o miti n g, a n d diarr hea) at a d ose of 
3. 9 5 m g/ m 2. As per pr ot oc ol, s u bse q ue nt patie nts were treate d at 1 d ose le vel bel o w 
( 2. 9 7 m g/ m2) w here 1 of 6 patie nts e x perie nce d a D L T ( Gra de 3 na usea, v o miti n g, a n d 
diarr hea). T he M T D of wee kl y oral i xaz o mi b was deter mi ne d t o be 2. 9 7 m g/ m 2. 
O nce t he M T D was esta blis he d, c o h orts of  patie nts re prese nti n g t he heter o ge ne o us 
patie nt p o p ulati o n c urre ntl y see n  i n cli nical practice were e nr olle d i n or der t o f urt her 
e val uate t he safet y, t olera bilit y, efficac y , P K, a n d p har mac o d y na mics of oral i xaz o mi b 
a n d i ncl u de d: 
 
1. Rela pse d a n d Refract or y e x pa nsi o n c o h ort [refract or y is defi ne d as disease pr o gressi o n   
w hile o n t hera p y or wit hi n 6 0 da ys after t he last d ose of t hera p y]; 
2. Carfilz o mi b e x pa nsi o n c o h ort 
3. Pr oteas o me I n hi bit or- Naï ve e x pa nsi o n c o h ort 
4. V E L C A D E- Rela pse d e x pa nsi o n c o h ort 
Si xt y patie nts wit h rela pse d a n d/ or refract or y m ulti ple m y el o ma were e nr olle d. T he M T D 
was deter mi n e d t o be 2. 9 7 m g/ m 2. D ose-li miti n g t o xicities were gra de 3 na usea, 
v o miti n g, a n d diarr hea i n 2 patie nts, a n d gra de 3 s ki n ras h i n 1 patie nt. C o m m o n dr u g-
relate d a d verse e ve nts were t hr o m b oc yt o pe nia ( 4 3 %), diarr hea ( 3 8 %), na usea ( 3 8 %), 
fati g ue ( 3 7 %), a n d v o miti n g ( 3 5 %). T he o bser ve d rate of peri p heral ne ur o pat h y was 
2 0 %, wit h o nl y 1 gra de 3 e ve nt re p orte d. Ni ne ( 1 8 %) patie nts ac hie ve d a partial res p o nse 
or better, i ncl u di n g 8 of 3 0 ( 2 7 %) e val ua ble patie nts treate d at t he M T D. 
P har mac o ki netic st u dies s u g geste d a l o n g ter mi nal h alf-life of 3. 6 t o 1 1. 3 da ys, 
s u p p orti n g o nce- wee kl y d osi n g.  
Ne wly Di a g n ose d M ulti ple Myel o m a ( C 1 6 0 0 5):   
I n St u d y C 1 6 0 0 5, i xaz o mi b is gi ve n wee kl y ( Da ys 1, 8, a n d 1 5), i n c o m bi nati o n wit h 
le nali d o mi de ( Da ys 1- 2 1), a n d de xa met has o ne ( Da ys 1, 8, 1 5, a n d 2 2) i n a 2 8- da y 
c y cle. 1 3 Patie nts wit h ne wl y dia g n ose d M M were e nr olle d a n d treate d wit h oral i xaz o mi b 
( da ys 1, 8, a n d 1 5) pl us le nali d o mi de 2 5 m g ( da ys 1- 2 1) a n d de xa met has o ne 4 0 m g ( da ys 
1, 8, 1 5, 2 2) f or u p t o t wel ve 2 8- da y c y cles, t he n mai nte na nce t hera p y wit h i xaz o mi b 
(sa me sc he d ule) e ver y 2 8 da ys u ntil pr o gressi o n. Patie nts were all o we d t o u n der g o ste m 
cell c ollecti o n after 3 c y cles a n d disc o nti n ue f or a ut ol o g o us ste m cell tra ns pla nt ( A S C T) 

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
after 6 c y cles. O verall, 6 5 patie nts were e nr olle d, 1 5 i n P hase 1 a n d 5 0 i n P hase 2. 
Patie nts recei ve d a me dia n of 6 c y cles (ra n ge 1- 1 9) wit h 2 7 ( 4 2 %) re mai ni n g o n 
treat me nt as of N o ve m ber 2 0 1 2. Of t h ose w h o ha ve u n der g o ne ste m cell m o bilizati o n, a 
me dia n yiel d was 1 1. 3 x 1 0 6 C D 3 4 + cells/ K g (ra n ge 5- 2 8). I xaz o mi b M T D was 
esta blis he d as 2. 9 7 m g/ m 2 a n d R P 2 D was selecte d as 2. 2 3 m g/ m2; R P 2 D tra nslates t o a 4 
m g fi xe d d ose base d o n p o p ulati o n P K res ults . A m o n g t he 6 4 e val ua ble patie nts, t he 
o verall res p o nse rate was 9 2 %, i ncl u di n g 5 5 % V G P R a n d 2 3 % C R.  Me dia n ti me t o first 
res p o nse was 0. 9 2 m o nt hs (ra n ge 0. 8 9- 6. 4 4).  
 
Rel a pse d M ulti ple Myel o m a ( T o ur m ali ne M M 0 1): T his i nter nati o nal p hase 3 trial 
e nr olle d a d ults wit h R R M M w h o ha d recei ve d 1 – 3 pri or li nes of t hera p y a n d w h o were 
n ot refract or y t o pri or le nali d o mi de or PI- base d  t hera p y. Patie nts were ra n d o mize d 1: 1 t o 
recei ve i xaz o mi b 4 m g or matc hi n g place b o wee kl y o n d 1, 8, a n d 1 5, pl us le nali d o mi de 
2 5 m g P O o n d 1 – 2 1 a n d de xa met has o ne 4 0 m g P O o n d 1, 8, 1 5, a n d 2 2, i n 2 8- da y 
c y cles. 7 2 2 patie nts were ra n d o mize d ( 3 6 0 I R d; 3 6 2 R d); 1 9 % ha d hi g h-ris k c yt o ge netics 
b y FI S H ( del( 1 7), t( 4; 1 4), or t( 1 4; 1 6)), i n cl u di n g 1 0 % del( 1 7). T he st u d y de m o nstrate d 
si g nifica ntl y better P F S wit h I R d ( 2 0. 6 m o nt hs) c o m pare d wit h R d ( 1 4. 7 m o nt hs); a 3 5 % 
i m pr o ve me nt i n P F S ( H R 0. 7 4 2; p = 0. 0 1 2). T he P F S i m pr o ve me nt was see n i n all patie nt 
s u b gr o u ps, es peciall y i n patie nts wit h del 1 7 p, w here t he i m pr o ve me nt wit h t he 
c o m bi nati o n was q uite stri ki n g. 
P ote nti al Ris ks a n d Be nefits of i x az o mi b :  
Please refer t o t he c urre nt i xaz o mi b I n vesti gat or’s Br oc h ure (I B).   
1. 5
 Pe m br oliz u ma b:
 
T he i m p orta n ce of i ntact i m m u ne s ur veilla n ce i n c o ntr olli n g o ut gr o wt h of ne o plastic 
tra nsf or mati o n has bee n k n o w n f or deca des.  Acc u m ulati n g e vi de nce s h o ws a c orrelati o n 
bet wee n t u m or-i nfiltrati n g l y m p h oc ytes ( TI Ls) i n ca ncer tiss ue a n d fa v ora ble pr o g n osis 
i n vari o us mali g na ncies.  I n partic ular, t he prese nce of C D 8 + T-cells a n d t he rati o of 
C D 8 + effect or T-cells / F o x P 3 + re g ulat or y T-cells see ms t o c orrelate wit h i m pr o ve d 
pr o g n osis a n d l o n g-ter m s ur vi val i n ma n y s oli d t u m ors. 
T he P D- 1 rece pt or-li ga n d i nteracti o n is a ma j or pat h wa y hijac ke d b y t u m ors t o s u p press 
i m m u ne c o ntr ol.  T he n or mal f u ncti o n of P D- 1, e x presse d o n t he cell s urface of acti vate d 
T-cells u n der healt h y c o n diti o ns, is t o d o w n- m o d ulate u n wa nte d or e xcessi ve i m m u ne 
res p o nses, i ncl u di n g a ut oi m m u ne reacti o ns.  P D- 1 (e nc o de d b y t he ge ne P dc d 1) is a n I g 
s u perfa mil y me m b er relate d t o C D 2 8 a n d CT L A- 4, w hic h has bee n s h o w n t o ne gati vel y 
re g ulate a nti ge n rece pt or si g nali n g u p o n e n gage me nt of its li ga n ds ( P D- L 1 a n d/ or 
P D- L 2).  T he str uct ure of m uri ne P D- 1 has b ee n res ol ve d.  P D- 1 a n d fa mil y me m b ers are 
t y pe I tra ns me m bra ne gl y c o pr otei ns c o ntai ni n g a n I g Varia ble-t y pe ( V-t y pe) d o mai n 
res p o nsi ble f or li ga n d bi n di n g a n d a c yt o plas mic tail w hic h is res p o nsi ble f or t he bi n di n g 
of si g nali n g m olec ules.  T he c yt o plas mic tail of P D- 1 c o ntai ns 2 t yr osi ne- base d si g nali n g 
m otifs, a n i m m u n orece pt or t yr osi ne- base d i n hi biti o n m otif (I TI M) a n d a n 
i m m u n orece pt or t yr osi ne- base d s witc h m otif (I T S M).  F oll o wi n g T-cell sti m ulati o n, 
P D- 1 recr uits t he t yr osi ne p h os p hatases S H P- 1 a n d S H P- 2 t o t he I T S M m otif wit hi n its 
c yt o plas mic tail, lea di n g t o t he de p h os p h or ylati o n of effect or m olec ules s uc h as C D 3 ζ, 
P K C θ  a n d Z A P 7 0 w hic h are i n v ol ve d i n t he C D 3 T-cell si g nali n g casca de.  T he 
mec ha nis m b y w hic h P D- 1 d o w n m o d ulates T-ce ll res p o nses is si milar t o, b ut disti nct 
fr o m t hat of C T L A- 4 as b ot h m olec ules re g ulate a n o verla p pi n g set of si g nali n g pr otei ns.  
P D- 1 was s h o w n t o be e x presse d o n acti vat e d l y m p h oc ytes i ncl u di n g peri p heral C D 4 + 
a n d C D 8 + T-cells, B-cells, T re gs a n d Nat u ral Killer cells.  E x pressi o n has als o bee n 

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s h o w n d uri n g t h y mic de vel o p me nt o n C D 4-C D 8- ( d o u ble ne gati ve) T-cells as well as 
s u bsets of macr o p ha ges a n d de n dritic cells.  T he li ga n ds f or P D- 1 ( P D- L 1 a n d P D- L 2) 
are c o nstit uti vel y e x presse d or ca n be i n d uce d i n a variet y of cell t y pes, i ncl u di n g n o n-
he mat o p oietic tiss ues as well as i n vari o us t u m ors.  B ot h li ga n ds are t y pe I 
tra ns me m bra ne rece pt ors c o ntai ni n g b ot h I g V- a n d I g C-li ke d o mai ns i n t he e xtracell ular 
re gi o n a n d c o ntai n s h ort c yt o plas mic re gi o ns wit h n o k n o w n si g nali n g m otifs.  Bi n di n g of 
eit her P D- 1 li ga n d t o P D- 1 i n hi bits T-cell ac ti vati o n tri g gere d t hr o u g h t he T-cell rece pt or.  
P D- L 1 is e x presse d at l o w le vels o n vari o us n o n- he mat o p oietic tiss ues, m ost n ota bl y o n 
vasc ular e n d ot heli u m, w hereas P D- L 2 pr otei n is o nl y detecta bl y e x presse d o n a nti ge n-
prese nti n g cells f o u n d i n l y m p h oi d tiss ue or c hr o nic i nfla m mat or y e n vir o n me nts.  P D- L 2 
is t h o u g ht t o c o ntr ol i m m u ne T-cell acti vati o n i n l y m p h oi d or ga ns, w hereas P D- L 1 ser ves 
t o da m pe n u n warra nte d T-cell f u ncti o n i n peri p heral tiss ues.  Alt h o u g h healt h y or ga ns 
e x press little (if a n y) P D- L 1, a variet y of ca n cers were de m o nstrate d t o e x press a b u n da nt 
le vels of t his T-cell i n hi bit or.  P D- 1 has bee n s u g geste d t o re g ulate t u m or-s pecific T-cell 
e x pa nsi o n i n s u bjects wit h mela n o ma ( M E L).  T his s u g gests t hat t he P D- 1/ P D- L 1 
pat h wa y pla ys a critical r ole i n t u m or i m m u ne e v asi o n a n d s h o ul d be c o nsi dere d as a n 
attracti ve tar g et f or t hera pe utic i nter ve nti o n. 
Pe m br oliz u ma b is a p ote nt a n d hi g hl y sel ecti ve h u ma nize d m o n ocl o nal a nti b o d y ( m A b) 
of t he I g G 4/ ka p pa is ot y pe desi g ne d t o directl y  bl oc k t he i nteracti o n bet wee n P D- 1 a n d its 
li ga n ds, P D- L 1 a n d P D- L 2.  Ke ytr u da® ( pe m br oliz u ma b) has rece ntl y bee n a p pr o ve d i n 
t he U nite d State d f or t he treat me nt of patie nts wit h u nresecta ble or metastatic mela n o ma 
a n d disease pr o gressi o n f oll o wi n g i pil u m u ma b a n d, if B R A F V 6 0 0 m utati o n p ositi ve, a 
B R A F i n hi bit or. 
A n o pe n-la bel P hase I trial ( Pr ot oc ol 0 0 1) is bei n g c o n d ucte d t o e val uate t he safet y a n d 
cli nical acti vit y of si n gle a ge nt M K- 3 4 7 5.  T he d ose escalati o n p orti o n of t his trial 
e val uate d t hree d ose le vels, 1 m g/ k g, 3 m g/ k g, a n d 1 0 m g/ k g, a d mi nistere d e ver y 2 wee ks 
( Q 2 W) i n s u bjects wit h a d va nce d s oli d t u m ors.  All t hree d ose le vels were well t olerate d 
a n d n o d ose-li miti n g t o xicities were o bser ve d.  T his first i n h u ma n st u d y of M K- 3 4 7 5 
s h o we d e vi de nce of tar get e n ga ge me nt a n d o bjecti ve e vi de nce of t u m or size re d ucti o n at 
all d ose le vels ( 1 m g/ k g, 3 m g/ k g a n d 1 0 m g/ k g Q 2 W).  N o M T D has bee n i de ntifie d t o 
date.  1 0 m g/ k g Q 2 W, t he hi g hest d ose teste d i n P N 0 0 1, will be t he d ose a n d sc he d ule 
utilize d i n C o h orts A, B, C a n d D of t his pr ot oc ol t o test f or i nitial t u m or acti vit y.  Rece nt 
data fr o m ot her cli nical st u dies wit hi n t he M K- 3 4 7 5 pr o gra m has s h o w n t hat a l o wer d ose 
of M K- 3 4 7 5 a n d a less fre q ue nt sc he d ule ma y be s ufficie nt f or tar get e n ga ge me nt a n d 
cli nical acti vit y. 
P K data a nal ysis of M K- 3 4 7 5 a d mi nister e d Q 2 W a n d Q 3 W s h o we d sl o w s yste mic 
cleara nce, li mite d v ol u me of distri b uti o n, a n d a l o n g half-life (refer t o I B).  
P har mac o d y na mic data (I L- 2 release assa y) s u g g este d t hat peri p heral tar get e n ga ge me nt 
is d ura ble ( > 2 1 da ys).  T his earl y P K a n d p har mac o d y na mic data pr o vi des scie ntific 
rati o nale f or testi n g a Q 2 W a n d Q 3 W d osi n g sc he d ule.   
A p o p ulati o n p har mac o ki netic a nal ysis has b ee n perf or me d usi n g ser u m c o nce ntrati o n 
ti me data fr o m 4 7 6 patie nts. Wit hi n t he res ulti n g p o p ulati o n P K m o del, cleara nce a n d 
v ol u me para meters of M K- 3 4 7 5 were f o u n d t o be de pe n de nt o n b o d y wei g ht. T he 
relati o ns hi p bet wee n cleara nce a n d b o d y wei g ht, wit h a n all o metric e x p o ne nt of 0. 5 9, is 
wit hi n t he ra n ge o bser ve d f or ot her a nti b o dies a n d w o ul d s u p p ort b ot h b o d y wei g ht 
n or malize d d osi n g or a fi xe d d ose acr oss all b o d y wei g hts.  M K- 3 4 7 5 has bee n f o u n d t o 
ha ve a wi de t hera pe utic ra n ge base d o n t he mela n o ma i n dicati o n.  T he differe nces i n 
e x p os ure f or a 2 0 0 m g fi xe d d ose re gi me n rela ti ve t o a 2 m g/ k g Q 3 W b o d y wei g ht base d 
re gi me n are a ntici pate d t o re mai n well wit hi n t he esta blis he d e x p os ure mar gi ns of 0. 5 – 

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5. 0 f or M K- 3 4 7 5 i n t he mela n o ma i n dicati o n. T he e x p os ure mar gi ns are base d o n t he 
n oti o n of si milar efficac y a n d safet y i n mela n o ma at 1 0 m g/ k g Q 3 W vs. t he pr o p ose d 
d ose re gi me n of 2 m g/ k g Q 3 W (i.e. 5-f ol d hi g her d ose a n d e x p os ure). T he p o p ulati o n P K 
e val uati o n re veale d t hat t here was n o si g nifica nt i m p act of t u m or b ur de n o n e x p os ure. I n 
a d diti o n, e x p os ure was si milar bet wee n  t he N S C L C a n d mela n o ma i n dicati o ns. 
T heref ore, t here are n o a ntici pate d c ha n ges i n e x p os ure bet wee n differe nt i n dicati o n 
setti n gs. 
T he rati o nale f or f urt her e x pl orati o n of 2 m g/ k g a n d c o m para ble d oses of pe m br oliz u ma b 
i n s oli d t u m ors is base d o n: 1) si milar efficac y a n d safet y of pe m br oliz u ma b w he n d ose d 
at eit her 2 m g/ k g or 1 0 m g/ k g Q 3 W i n mela n o ma patie nts, 2) t he flat e x p os ure-res p o nse 
relati o ns hi ps of pe m br oliz u ma b f or b ot h efficac y a n d safet y i n t he d ose ra n ges of 2 
m g/ k g Q 3 W t o 1 0 m g/ k g Q 3 W, 3) t he lac k of effect of t u m or b ur de n or i n dicati o n o n 
distri b uti o n be ha vi or of pe m br oliz u ma b (as assesse d b y t he p o p ulati o n P K m o del) a n d 4) 
t he ass u m pti o n t hat t he d y na mics of pe m br oliz u ma b tar get e n ga ge me nt will n ot var y 
mea ni n gf ull y wit h t u m or t y pe. 
T he c h oice of t he 2 0 0 m g Q 3 W as a n a p pr o priate d ose f or t he s witc h t o fi xe d d osi n g is 
base d o n si m ulati o ns perf or me d usi n g t h e p o p ulati o n P K m o del of pe m br oliz u ma b 
s h o wi n g t hat t he fi xe d d ose of 2 0 0 m g e ver y 3 wee ks will pr o vi de e x p os ures t hat 1) are 
o pti mall y c o nsiste nt wit h t h ose o btai ne d wit h t he 2 m g/ k g d ose e ver y 3 wee ks, 2) will 
mai ntai n i n di vi d ual patie nt e x p os ures i n t h e e x p os ure ra n ge esta blis he d i n mela n o ma as 
ass ociate d wit h ma xi mal efficac y res p o nse a n d 3) will mai ntai n  i n di vi d ual patie nts 
e x p os ure i n t he e x p os ure ra n ge esta blis he d i n me la n o ma t hat are well t olerate d a n d safe.  
A fi xe d d ose re gi me n will si m plif y t he d osi n g re gi me n t o be m ore c o n ve nie nt f or 
p h ysicia ns a n d t o re d uce p ote ntial f or d osi n g err ors.  A fi xe d d osi n g sc he me will als o 
re d uce c o m ple xit y i n t he l o gistical c hai n at treat me nt facilities a n d re d uce wasta ge. 
Pe m br oliz u m a b e x perie nce i n m ulti ple myel o m a : T he ke y n ote- 2 3 trial e nr olle d patie nts 
wit h R R M M w h o ha ve faile d ≥2 pri or t hera pies i ncl u di n g a pr oteas o me i n hi bit or a n d a n 
I Mi D. D uri n g t he d ose deter mi nati o n p hase, co h orts of 3- 6 patie nts were e nr olle d at 2 
m g/ k g of pe m br oliz u ma b e ver y 2 wee ks ( Q 2 W) i n c o m bi nati o n wit h 1 0 m g or 2 5 m g of 
le nali d o mi de o n da ys 1- 2 1 a n d 4 0 m g l o w- d ose de xa met has o ne wee kl y, t o be re peate d 
e ver y 2 8 da ys. After a n M T D was i de ntifie d, a d diti o nal patie nts were e nr olle d at a fi xe d 
d ose of 2 0 0 m g of pe m br oliz u ma b i n c o m bi n ati o n wit h le nali d o mi d e a n d de xa met has o ne. 
O verall, 5 1 patie nts wit h a me dia n of 4 pri or li nes of t hera p y were e nr olle d, 7 8 % of w h o 
were refract or y t o t he last li ne of t hera p y. M ost c o m m o n A Es n ote d i ncl u de d c yt o pe nias, 
fati g ue a n d gastr oi ntesti nal si de effects. DL Ts see n i ncl u de d t u m or l ysis, ne utr o pe nia a n d 
p ne u m o nia. O verall res p o nse rate was 5 0 % i ncl u di n g 1 6 % wit h V G P R or better; t he 
c orres p o n di n g n u m bers were 3 8 % a n d 1 3 % a m o n g t he patie nts w h o were refract or y t o 
le nali d o mi de. 
  

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I n a si milar p hase II st u d y, 2 4 patie nts wit h R R M M recei ve d 2 8- da y c y cles of 
pe m br oliz u ma b (at a d ose of 2 0 0 m g I V) e ver y 2 wee ks (i n a r u n off p hase, first 6 
patie nts recei ve d 2 0 0 m g I V e ver y 4 wee ks) pl us p o mali d o mi de ( 4 m g dail y x 2 1 da ys) 
a n d de xa met has o ne 4 0 m g wee kl y. Patie nts w it h rela pse d a n d/ or refract or y m y el o ma 
wit h t w o or m ore li nes of pri or t hera p y t hat  i ncl u de d a n I Mi d a n d a pr oteas o me i n hi bit or 
were eli gi ble f or t his trial. T hirt y-t hree patie nts, m ost refract or y t o pr oteas o me i n hi bit ors 
a n d I Mi Ds ( 7 0 % d o u ble refract or y), were e n r olle d. T he o verall res p o nse rate was 6 0 % 
a m o n g t he 2 7 patie nts e val ua ble f or res p o nse, i ncl u di n g 5 patie nts wit h a V G P R or better.  
 
1. 6  
Rati o nale f or t he c urre nt trial:  
C urre ntl y, t here is c o nsi dera ble a m o u nt of w or k is bei n g d o ne t o e n ha nce t his re gi me n. 
Bi n di n g of t he P D- 1 li ga n ds, P D- L 1 a n d P D- L 2, t o t he P D- 1 rece pt or f o u n d o n T cells, 
i n hi bits T cell pr oliferati o n a n d c yt o ki ne pro d ucti o n. U p re g ulati o n of P D- 1 li ga n ds occ ur 
i n s o me t u m ors a n d si g nali n g t hr o u g h t his pat h wa y ca n c o ntri b ute t o i n hi biti o n of acti ve 
T-cell i m m u n e s ur veilla nce of t u m ors. Pe m b r oliz u ma b is a m o n ocl o nal a nti b o d y t hat 
bi n ds t o t he P D- 1 rece pt or a n d bl oc ks its i nteracti o n wit h P D- L 1 a n d P D- L 2, releasi n g 
P D- 1 pat h wa y- me diate d i n hi biti o n of t he i m m u ne res p o nse, i ncl u di n g t he a nti-t u m or 
i m m u ne res p o nse. I n s y n ge neic m o use t u m or m o dels, bl oc ki n g P D- 1 acti vit y res ulte d i n 
decrease d t u m or gr o wt h. I n t he setti n g of m y el o ma, B-cell res p o nses are altere d t o a state 
of f u ncti o nal h y p o ga m ma gl o b uli ne mia, lea di n g t o  a n i ncrease d ris k f or i nfecti o ns. T-cell-
me diate d i m m u nit y is als o se verel y i m paire d i n M M wit h T- hel per ( T h) 1/ T h 2 i m b ala nce 
lea di n g t o i m m u ne d ysf u ncti o n. Se veral stu dies ha ve s h o w n t hat P D- L 1 is a bse nt fr o m 
n or mal plas ma cells, w hereas it is e x presse d o n m y el o ma cell li nes a n d pri mar y m y el o ma 
t u m or cells fr o m patie nts wit h M M. It has bee n de m o nstrate d t hat P D- 1 e x pressi o n is u p 
re g ulate d o n T cells is olate d fr o m patie nts wit h M M, s u g gesti n g t hat t his pat h wa y is of 
i m p orta nce i n me diati n g t he i m m u n os u p pressi ve state i n t his patie nt p o p ulati o n. Be ns o n 
et al. ha ve s h o w n t hat N K cells fr o m M M patie nts e x press P D- 1 a n d s u g geste d t hat P D-
1/ P D- L 1 i nteracti o ns u n der mi ne t he i m m u n ol o g ical c o ntr ol of M M b y N K cells. T he y 
ha ve als o de m o nstrate d t hat t he a p pli cati o n of a n a nti- P D- 1 m o n ocl o nal a nti b o d y 
e n ha nces t he c yt ol ytic acti vit y of N K cells  a gai nst a ut ol o g o us, pri mar y M M cells. 
Preli mi nar y res ults fr o m o n g oi n g trials of pe m br oliz u ma b wit h le nali d o mi de or 
p o mali d o mi d e ha ve de m o nstrate d e vi de nce of acti vit y. I xaz o mi b has e xcelle nt acti vit y i n 
M M, a n d pr oteas o me i n hi bit ors ha ve bee n s h o w n t o be acti ve i n c o m bi nati o n wit h ot her 
i m m u n ot hera p y a p pr oac hes s uc h as el ot uz u ma b a n d darat u m u ma b.  Gi ve n t hese fi n di n gs, 
it is rati o nal t o e val uate t he c o m bi nati o n of pe m br oliz u ma b i n c o m bi nati o n wit h i xaz o mi b 
a n d de xa met has o ne i n rela pse d m y el o ma. 
 

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2. 0
 G o als
 
2. 1
 Pri mar y
 
T o deter mi ne t he o verall res p o nse rate ( > = P R)  of pe m br oliz u ma b i n c o m bi nati o n wit h 
sta n dar d d oses of i xaz o mi b a n d de xa met has o ne, i n patie nts wit h rela pse d s y m pt o matic 
M M.  
2. 2
 Sec o n dar y
 
2. 2 1   
T o deter mi ne t he ≥ ver y g o o d partial res p o nse ( V G P R) a n d c o m plete res p o nse 
( C R) rate of pe m br oliz u ma b a d de d t o sta n dar d d oses of i xaz o mi b a n d 
de xa met has o ne i n rela pse d m y el o ma. 
2. 2 2   
T o deter mi ne t he pr o gressi o n free s ur v i val a n d o verall s ur vi val a m o n g patie nts 
wit h rela pse d M M f oll o wi n g treat me nt w it h t he c o m bi nati o n of pe m br oliz u ma b, 
i xaz o mi b a n d de xa met has o ne. 
2. 2 3   
T o deter mi ne t he t o xicities ass ociate d  wit h pe m br oliz u ma b a d de d t o sta n dar d 
d oses of i xaz o mi b a n d de xa met has o ne i n patie nts wit h rela pse d M M. 
 
2. 3
 C orrelati ve
 
Researc h
 
2. 3 1  
P D L- 1 e x pressi o n o n m y el o ma cells a n d n o n-t u m or cell c o m part me nts fr o m t he 
b o ne marr o w will be assesse d at baseli ne  
 
2. 3 2  
Meas ures of T-cell acti vati o n / e x ha us ti o n will be assesse d at baseli ne a n d after 
C y cle 1 a n d C y cle 3.  
 
2. 3 3  
N K cell f u ncti o n a n d n u m bers will be e v al uate d at baseli ne a n d after C y cle 1 a n d 
C y cle  3. 
 
3. 0
 P atie nt
 
Eli gi bilit y
 
3. 1
 I ncl usi o n
 
Criteri a   
3. 1 1  
Dia g n osis of rela pse d, s y m pt o matic  m ulti ple m y el o ma b y I M W G dia g n ostic 
criteria f or m ulti ple m y el o ma. 
3. 1 2   
A ge ≥1 8 y ears 
3. 1 3  
T he f oll o wi n g la b orat or y val ues o btai ne d ≤1 4 da ys pri or t o re gistrati o n.  
•  
Calc ulate d creati ni ne cleara nce ( usi n g C oc kcr oft- Ga ult e q uati o n bel o w) *  
≥3 0 m L/ mi n   
•  
A bs ol ute ne utr o p hil c o u nt ( A N C) ≥1 0 0 0/ m m 3 
•  
Pl at el et c o u nt ≥7 5 0 0 0/ m m 3   N ote:  Platelet tra nsf usi o n is n ot all o we d ≤3 
da ys pri or t o re gistrati o n. 
•  
He m o gl o bi n ≥8. 0 g/ d L 
•  
T otal bilir u bi n ≤ 1. 5 x U L N 
•  
A L T a n d A S T ≤ 2. 5 x U L N 
* C oc kcr oft- Ga ult E q uati o n: 
Creati ni ne cleara nce f or males = ( 1 4 0 - a ge)(act ual b o d y wei g ht i n k g)  
( 7 2)(ser u m creati ni ne i n m g/ d L) 
Creati ni ne cleara nce f or fe males = ( 1 4 0 - a ge)(act ual b o d y wei g ht i n k g)( 0. 8 5) 
( 7 2)(ser u m creati ni ne i n m g/ d L) 
 

M C 1 7 8 2
 1 7
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
3. 1 4  
M ust ha ve rela pse d or refract or y disease after treat me nts i ncl u di n g t hree 
t hera pies: pr oteas o me i n hi bit ors, I Mi D S, a n d a nti- C D 3 8 a nti b o d y. 
 
 3. 1 5  
Meas ura ble disease of m ulti ple m y el o ma as defi ne d b y at least O N E of t he 
f oll o wi n g: 
•  
Ser u m m o n ocl o nal pr otei n ≥1. 0 g/ d L (see Secti o n 1 1. 1 f or defi niti o n) 
•  
≥2 0 0 m g of m o n ocl o nal pr otei n i n t he uri ne o n 2 4 h o ur electr o p h oresis  
•  
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 t o la m b da free li g ht c hai n rati o. 
3. 1 6  
E C O G perf or ma nce stat us ( P S) 0, or 1 ( A p pe n di x I). 
3. 1 7  
Pr o vi de i nf or me d writte n c o nse nt. 
3. 1 8  
Ne gati ve pre g na nc y test d o ne ≤7 da ys pri or t o re gistrati o n, f or w o me n of 
c hil d beari n g p ote ntial o nl y. 
3. 1 9a  
Willi n g t o f oll o w strict birt h c o ntr ol meas ures as detaile d i n Secti o n 9. 9i. 
Fe male patie nts: If t he y are of c hil d b eari n g p ote ntial, a gree t o o ne of t he 
f oll o wi n g: 
•  
Practice 2 effecti ve met h o ds of c o ntrace pti o n, at t he sa me ti me, fr o m t he 
ti me of si g ni n g t he i nf or me d c o nse nt f or m t hr o u g h 1 2 0 da ys after t he last 
d ose of st u d y dr u g, A N D m ust als o a d here t o t he g ui deli nes of a n y 
treat me nt-s pecific pre g na nc y pre ve nti o n pr o gra m, if a p plica ble, O R  
•  
A gree t o practice tr ue a bsti ne nce w he n t his is i n li ne wit h t he preferre d 
a n d us ual lifest yle of t he s u bject.  ( Peri o dic a bsti ne nce [e g, cale n dar, 
o v ulati o n, s y m pt ot her mal, p ost- o v ul ati o n met h o ds] a n d wit h dra wal are 
n ot acce pta ble met h o ds of c o ntrace pti o n.) 
 
Male patie nts: e ve n if s ur gicall y sterilize d (i.e., stat us p ost- vasect o m y), m ust 
a gree t o o ne of t he f oll o wi n g: 
•  
A gree t o practice effecti ve barrier c o ntrace pti o n d uri n g t he e ntire st u d y 
treat me nt peri o d a n d t hr o u g h 1 2 0 da ys after t he last d ose of st u d y dr u g, 
O R 
•  
M ust als o a d here t o t he g ui deli nes of a n y treat me nt-s pecific pre g na nc y 
pre ve nti o n pr o gra m, if a p plica ble, O R 
•  
A gre e t o practice tr ue a bsti ne nce w he n t his is i n li ne wit h t he preferre d 
a n d us ual lifest yle of t he s u bject.  ( Peri o dic a bsti ne nce (e g, cale n dar, 
o v ulati o n, s y m pt ot her mal, p ost- o v ul ati o n met h o ds] a n d wit h dra wal are 
n ot acce pta ble met h o ds of c o ntrace pti o n.) 
3. 1 9 b  
Willi n g t o ret ur n t o e nr olli n g i ns tit uti o n f or f oll o w- u p ( d uri n g t he Acti ve 
M o nit ori n g P hase of t he st u d y). 
3. 1 9c  
Willi n g t o pr o vi de b o ne  marr o w a n d bl o o d sa m ples f or pla n ne d researc h (see 
Sec. 1 4. 1). 
3. 2
 E xcl usi o n
 
Criteri a
 
3. 2 1   
M y el o ma disease t hat is refract or y t o i xaz o mi b treat me nt. 
3. 2 2  
Has a k n o w n a d diti o nal mali g na nc y t hat is pr o gressi n g or re q uires acti ve 
treat me nt.  E xce pti o ns i ncl u de earl y sta ge ca ncers (carci n o ma i n sit u or Sta ge 1) 
treate d wit h c urati ve i nte nt, basal cell carci n o ma of t he s ki n, s q ua m o us cell 

M C 1 7 8 2
 1 8
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
carci n o ma of t he s ki n, i n sit u cer vical ca ncer, or i n sit u breast ca ncer t hat has 
u n der g o ne p ote ntiall y c urati ve t hera p y. 
3. 2 3  
A n y of t he f oll o wi n g beca use t his st u d y i n v ol ves a n i n vesti gati o nal a ge nt w h ose 
ge n ot o xic, m uta ge nic a n d terat o ge nic effects o n t he de vel o pi n g fet us a n d 
ne w b or n are u n k n o w n: 
•  
Pre g na nt w o me n 
•  
N ursi n g w o me n  
•  
Me n or w o me n of c hil d beari n g p ote ntial w h o are u n willi n g t o e m pl o y 
a de q uate c o ntrace pti o n 
3. 2 4  
Ot her c o- m or bi dit y w hic h w o ul d i nterfere  wit h patie nt's a bilit y t o partici pate i n 
trial, e. g. u nc o ntr olle d i nfecti o n, u nc o m pe nsate d heart or l u n g disease. 
3. 2 5  
Ot her c o nc urre nt c he m ot hera p y, or a n y a ncillar y t hera p y c o nsi dere d 
I n vesti gati o nal ≤1 4 da ys pri or t o st u d y re gistrati o n.  
N O T E:  Bis p h os p h o nates are c o nsi dere d t o be s u p p orti ve care rat h er t ha n 
t hera p y, a n d are t h us all o we d w hile o n pr ot oc ol treat me nt. 
3. 2 6
 Peri p heral
 
ne ur o pat h y
 
≥Gra de 3 o n cli nical e xa mi nati o n or Gra de 2 wit h pai n 
d uri n g t he scree ni n g peri o d. 
3. 2 7
 Maj or
 
s ur ger y
 
≤1 4 da ys pri or t o st u d y re gistrati o n. 
3. 2 8
 Ra di ot hera p y
  
≤1 4 da ys pri or t o re gistrati o n. N O T E: If t he i n v ol ve d fiel d is 
s mall, 7 da ys will be c o nsi dere d a s ufficie nt i nter val bet wee n treat me nt a n d 
a d mi nistrati o n of st u d y dr u gs 
3. 2 9a  Partici pati o n i n a n y ot her cli nical tr ials wit h ot her i n vesti gati o nal a ge nts n ot 
i ncl u de d i n t his trial ≤2 1 da ys pri or t o re gistrati o n.  
3. 2 9 b  Has acti ve a ut oi m m u ne disease t hat has re q uire d s yste mic treat me nt ≤2 y ears  
pri or t o st u d y re gistrati o n  (i.e. wit h use of disease m o dif yi n g a ge nts, 
c ortic oster oi ds or i m m u n os u p pressi ve dr u gs).  
N O T E: Re place me nt t hera p y (e. g., t h yr o xi ne, i ns uli n, or p h ysi ol o gic 
c ortic oster oi d re place me nt t hera p y f or a dre nal or pit uitar y i ns ufficie nc y, etc.) is 
n ot c o nsi dere d a f or m of s yste mic treat me nt.  
3. 2 9c  Has a hist or y of ( n o n-i nfecti o us) p ne u m o nitis t hat re q uire d ster oi ds or c urre nt 
p ne u m o nitis. 
3. 2 9 d  Has a k n o w n hist or y of i nterstitial l u n g disease. 
3. 2 9e  Has a n acti ve i nfecti o n re q uiri n g s yste mic t hera p y. 
3. 2 9f  
Has a hist or y of c urre nt e vi de nce of a n y c o n diti o n, t hera p y, or la b orat or y 
a b n or malit y t hat mi g ht c o nf o u n d t he res ults of t he trial, i nterfere wit h t he 
s u bject’s partici pati o n f or t he f ull d urati o n of t he trial, or is n ot i n t he best i nterest 
of t he s u bject t o partici pate, i n t he o pi ni o n of t he treati n g i n vesti gat or.   
3. 2 9 g  Has k n o w n ps y c hiatric or s u bsta nce a b use dis or ders t hat w o ul d i nterfere wit h 
c o o perati o n wit h t he re q uire me nts of t he trial. 
3. 2 9 h  Is pre g na nt or breastfee di n g, or e x pec ti n g t o c o ncei ve or fat her c hil dre n wit hi n 
t he pr ojecte d d urati o n of t he trial, starti n g wit h t he pre-scree ni n g or scree ni n g 
visit t hr o u g h 1 2 0 da ys after t he last d ose of trial treat me nt. 
3. 2 9i  
Has recei ve d pri or t hera p y wit h a n a n ti- P D- 1, a nti- P D- L 1, or a nti- P D- L 2 a ge nt. 

M C 1 7 8 2
 1 9
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
3. 2 9j  
Has a k n o w n hist or y of H u ma n I m m u n o deficie nc y Vir us ( HI V) ( HI V 1/ 2 
a nti b o dies). 
3. 2 9 k  Has k n o w n acti ve He patitis B (e. g., H Bs A g reacti ve) or He patitis C (e. g., H C V 
R N A [ q ualitati ve] is detecte d). 
3. 2 9l  
Has a k n o w n hist or y of acti ve T B ( Bacill us T u berc ul osis) 
3. 2 9 m  Has recei ve d a li ve vacci ne ≤3 0 da ys pri or t o st u d y re gistrati o n. 
3. 2 9 n  Has k n o w n acti ve ce ntral ner v o us s yste m ( C N S) metastases a n d/ or 
carci n o mat o us me ni n gitis. 
3. 2 9 o  All o ge neic  he mat o p oie tic ste m cell tra ns pla nt. 
3. 2 9 p  S yste mic treat me nt wit h str o n g C Y P 3 A i n d ucers (rifa m pi n, rifa pe nti ne, rifa b uti n, 
car ba maze pi ne, p he n yt oi n, p he n o bar bital) , or use of St. J o h n’s w ort ≤1 4 da ys 
pri or t o re gistrati o n.  
3. 2 9 q  K n o w n GI disease or GI pr oce d ure t hat  c o ul d i nterfere wit h t he oral a bs or pti o n 
or t olera nce of i xaz o mi b i n cl u di n g diffic ult y s wall o wi n g. 
 
 

M C 1 7 8 2
 2 0
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
4. 0  
Test Sc h e d ule  
4. 1  
Sc he d ule of assess me nts  
 
D ays Pri or t o Re gistr ati o n  
 
Every cycle  
 
Tests a n d Pr oce d ures 
≤3 0 d ays 
≤1 4 d ays 
Weekly 
(f or first 
cycle) 1 
D ay 1,  
Pre-tre at me nt 
 (± 4 da ys) 
D ay 2 2, 4 3, 6 4 
Pre-tre at me nt 
(± 1 da y) 
E n d of 
tre at me nt 
C o m plete me dical hist or y 
X 
 
 
 
 
 
A d verse E ve nt m o nit ori n g 
 
X  
  
X 
X  
X 
P h ysical e xa m, i ncl u di n g wei g ht a n d vital si g ns 
 
X  
  
X 
X 1 1 X
 
Hei g ht
 
 
X
 
 
 
 
 
Perf or ma nce stat us ( E C O G scale)  
 
X  
  
X 
 
X 
C B C wit h diff. 
 
X  
X  
X 1 0 X
 X
 
Pr ot hr o m bi n ti me ( P T) 
X 
 
 
 
 
 
C he mistr y gr o u p t o i ncl u de s o di u m, p otassi u m, gl uc ose, 
al kali ne p h os p hatase; T otal a n d Direct bilir u bi n; S G O T 
( A S T); S G P T ( A L T), ser u m creati ni ne, calci u m 
 X
 X
 X
1 0 X
 X
 
T h yr oi d f u ncti o n casca de ( T S H, T 3, T 4, T P O a nti b o d y)   
X 
 
  
X 
X 
 
L D H, Beta 2- micr o gl o b uli n, C-reacti ve pr otei n, Plas ma 
cell assess me nt 
X
 
 
 
 
 
 
 
 
Electr o p h oresis of ser u m a n d uri ne 
 
X  
  
X 1 3 
X1 3 X
 
Affecte d I m m u n o gl o b uli n  
 X
 
 X
7 
X 7 
X 7 
I m m u n ofi xati o n ser u m a n d uri ne 
X 
 
  
X2 
X2 
X2 
I m m u n o gl o b uli n free li g ht c hai n 
 
X  
  
X 4 
X4 
X4 
X-ra y s keletal s ur ve y or l o w d ose w h ole b o d y C T 
X 
 
 
 
 
 
B o ne marr o w as pirate a n d bi o ps y 9  
X 
 
  
X5 
X5 
X5 
Researc h b o ne marr o w R 
 
 
 
X5 
X5 
X5 
Researc h bl o o d sa m ple R  
 
 
 
X 8 
X8 
X8 
C hest x-ra y 
X 
 
 
 
 
 
P E T C T 1 2      
 
 
  
X1 2 
  
 
Pre g na nc y test 3 
 
X 3 
 
 
 
 
 
 
 

M C 1 7 8 2
 2 1
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
 
D ays Pri or t o Re gistr ati o n  
 
Every cycle  
 
Tests a n d Pr oce d ures 
≤3 0 d ays 
≤1 4 d ays 
Weekly 
(f or first 
cycle) 1 
D ay 1,  
Pre-tre at me nt 
 (± 4 da ys) 
D ay 2 2, 4 3, 6 4 
Pre-tre at me nt 
(± 1 da y) 
E n d of 
tre at me nt 
Patie nt Me dicati o n Diar y ( A p pe n di x II) 6 
 
 
 
X
 
 
X
 
1)  All sc he d ule d visits will ha ve a wi n d o w of ± 4 da ys u nless ot her wise state d 
2)  I m m u n ofi xati o n (I F) nee de d o nl y i n t he a bse nce of M-s pi ke t o d oc u me nt C R or s C R. 
3)  F or pers o ns of c hil d beari n g p ote ntial o nl y. M ust be d o ne ≤7 da ys pri or t o re gistrati o n a n d ≤7 2 h o urs pri or t o recei vi n g t he first d ose of st u d y 
dr u g. If t he uri ne test is p ositi ve or ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y test will be re q uire d.  
4)  F L C is re q uire d o nl y if use d t o assess disease res p o nse d uri n g acti ve p hase  
5)  C ollecte d pri or t o C 1 D 1 treat me nt; at t he e n d of 2 c ycles, a n d t o d oc u me nt pr o gressi o n or  C R at a n y ti me p oi nt.  
6)  T he diar y m ust be gi n t he da y t he patie nt starts ta ki n g t he me di cati o n a n d m ust be c o m plete d per pr ot oc ol a n d ret ur ne d t o t he treati n g 
i nstit uti o n. 
7)  Affecte d i m m u n o gl o b uli n refers t o t he baseli ne M- pr otei n t y pe, t h at is, I g G, I g A, I g D, or I g M .  N ot a p plica ble if patie nt “ n o n-
secret or y ” or if patie nt has n o hea v y c hai n, i.e. li g ht c hai n m y el o ma. 
8)  C ollecte d pri or t o C 1 D 1 a n d C 1 D 2 2; t he n e ve y c y cle pri or t o D 1 treat me nt; a n d t o d oc u me nt pr o gressi o n or C R at a n y ti me p oi nt.  
9)   T he f oll o wi n g testi n g ma y be d o ne if cli nicall y i n dicate d: M y el o ma FI S H, plas ma cell pr oliferati o n, a n d fl o w c yt o metr y ( M R D )  
1 0) D oes n ot nee d t o be re peate d at C y cle 1 Da y 1. Baseli ne val ues ca n be use d f or C y cle 1. 
1 1) If patie nt is sta ble after 2 c y cles, p h ysical e xa m  ca n be decrease d t o Wee ks 1 a n d 7 of eac h c y cle.  
1 2) O nl y if cli nicall y i n dicate d f or M R D ne gati ve patie nts  e ver y 1 2 wee ks. 
1 3) Uri ne Electr o p h oresis re q uire d o nl y if use d t o assess disease res p o nse. 
R)  Researc h f u n de d (see Secti o n 1 9. 0).  Will be  c har ge d t o st u d y a n d n ot t o patie nt’s acc o u nt. 
 
 
 

M C 1 7 8 2
 2 2
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
4. 2  
E ve nt M o nit ori n g/ S ur vi val F oll o w- u p  
 
  
  
E ve nt M o nit ori n g P hase1 
 
q. 3 m o nt hs 
u ntil P D or 
s u bse q ue nt 
treat me nt f or 
m y el o ma 
At P D or 
s u bse q ue nt 
treat me nt 
f or 
m y el o ma 
After P D or 
s u bse q ue nt 
treat me nt f or 
m y el o ma 
q. 6 m o nt hs 
Deat h
 Ne w
 
Pri mar y
 
E ve nt M o nit ori n g   
X  
X  
X  
X  
At eac h occ urre nce 
1. If a patie nt is still ali ve 2 y ears after re gistrati o n, n o f urt her f oll o w- u p is re q uire d.  
 

M C 1 7 8 2
 2 3
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
5. 0
 Gr o u pi n g
 
F act or:  N o ne 
 
6. 0   
Re gistr ati o n Pr oce d ures 
6. 1
 Re gistrati o n
 
Pr oce d ures
 
6. 1 1  
T o re gister a patie nt, access t he Ma y o Cli nic Ca ncer Ce nter 
( M C C C) we b pa ge a n d e nter t he re m ote 
re gistrati o n/ra n d o mizati o n a p plicati o n.  T he 
re gistrati o n/ra n d o mizati o n a p plicati o n is a vaila ble 2 4 h o urs a 
da y, 7 da ys a wee k.  Bac k u p a n d/ or s yste m s u p p ort c o ntact 
i nf or mati o n is a vaila ble o n t he We b site.  If u na ble t o access t he 
We b site, call t he M C C C Re gistrati o n Office at 
 
bet wee n t he h o urs of 8 a. m. a n d 5: 0 0 p. m. Ce ntral Ti me 
( M o n da y t hr o u g h Fri da y). 
 
T he i nstr ucti o ns f or t he re gistrati o n/ra n d o mizati o n a p plicati o n are a vaila ble o n 
t he M C C C we b pa ge 
a n d detail t he 
pr ocess f or c o m pleti n g a n d c o nfir mi n g patie nt  re gistrati o n.  Pri or t o i nitiati o n of 
pr ot oc ol treat me nt, t his pr ocess m ust be  c om plete d i n its e ntiret y a n d a M C C C 
s u bject I D n u m b er m ust be a vaila ble as n ote d i n t he i nstr ucti o ns.  It is t he 
res p o nsi bilit y of t he i n di vi d ual a n d i nstit uti o n re gisteri n g t he patie nt t o c o nfir m 
t he pr ocess has bee n s uccessf ull y c o m plete d pri or t o release of t he st u d y a ge nt.  
Patie nt re gistrati o n via t he re gistra ti o n/ra n d o mizati o n a p plicati o n ca n be 
c o nfir me d i n a n y of t he f oll o wi n g wa ys: 
•  
C o ntact t he M C C C Re gistrati o n Office 
If t he 
patie nt was f ull y re gistere d, t he M C C C Re gistrati o n Office staff ca n 
access t he i nf or mati o n fr o m t he ce ntralize d data base a n d c o nfir m t he 
re gistrati o n. 
•  
Refer t o “I nstr ucti o ns f or Re m ote Re gistrati o n” i n secti o n 
“ Fi n di n g/ Dis pla yi n g I nf or mati o n a b o ut A Re gistere d S u bject.” 
 
6. 1 2  
C orrelati ve Researc h: ( See Secti o n 1 4.) 
A ma n dat or y  c orrelati ve researc h c o m p o ne nt is part of t his st u d y, t he patie nt will 
be a ut o maticall y re gistere d o nt o t his c o m p o ne nt (see Secti o ns 3. 1 9c  a n d 1 4. 1). 
 
6. 1 3  
Pri or t o acce pti n g t he re gistrati o n, re gistrati o n/ra n d o mizati o n a p plicati o n will 
verif y t he f oll o wi n g: 
•  
I R B a p pr o val at t he re gisteri n g i nstit uti o n 
•  
Patie nt eli gi bilit y 
•  
E xiste nce of a si g ne d c o nse nt f or m 
•  
E xiste nce of a si g ne d a ut h orizati o n f or use a n d discl os ure of pr otecte d healt h 
i nf or mati o n  
 
6. 1 4  
D oc u me ntati o n of I R B a p pr o val m ust be o n file i n t he Re gistrati o n Office bef ore 
a n i n vesti gat or ma y re gister a n y patie nts.   
I n a d diti o n t o s u b mitti n g i nitial I R B ap pr o val d oc u me nts, o n g oi n g I R B a p pr o val 
d oc u me ntati o n m ust be o n file ( n o less t ha n a n n uall y) at t he Re gistrati o n Office 
  If t he necessar y d oc u me ntati o n is n ot s u b mitte d i n a d va nce 

M C 1 7 8 2
 2 4
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
of atte m pti n g patie nt re gistrati o n, t he re gistrati o n will n ot be acce pte d a n d t he 
patie nt ma y n ot be e nr olle d i n t he pr ot oc ol u ntil t he sit uati o n is res ol ve d. 
 
W he n t he st u d y has bee n pe r ma ne ntl y cl ose d t o patie nt e nr oll me nt, s u b missi o n of 
a n n ual I R B a p pr o vals t o t he Re gistrati o n Office is n o l o n ger necessar y.  
 
6. 1 5  
At t he ti me of re gistrati o n, t he f oll o wi n g will be rec or de d: 
•  
Patie nt has/ has n ot gi ve n per missi o n t o st ore a n d use his/ her sa m ple(s) f or 
f ut ure researc h of M ulti ple M y el o ma at Ma y o. 
•  
Patie nt has/ has n ot gi ve n per missi o n t o st ore a n d use his/ her sa m ple(s) f or 
f ut ure researc h t o lear n, pre ve nt, or treat ot her healt h pr o ble ms. 
•  
Patie nt has/ has n ot gi ve n per missi o n f or M C C C t o gi ve his/ her sa m ple(s) t o 
researc hers at ot her i nstit uti o ns. 
 
6. 1 6  
Treat me nt o n t his pr ot oc ol m ust c o m me nce at a Ma y o Cli nic I nstit uti o n, u n der 
t he s u per visi o n of a he mat ol o gist. 
 
6. 1 7  
Treat me nt ca n n ot be gi n pri or t o re gistrati o n a n d m ust be gi n ≤ 1 4 da ys after 
re gistrati o n. 
 
6. 1 8  
Pretreat me nt tests/ pr oce d ures (see Secti o n 4. 0) m ust be c o m plete d wit hi n t he 
g ui deli nes s pecifie d o n t he test sc he d ule. 
 
6. 1 9  
All re q uire d baseli ne s y m pt o ms (see Secti o n 1 0. 6 1) m ust be d oc u me nte d a n d 
gra de d. 
 
6. 1 9a  Bl o o d dra w kit is a vaila ble o n s ite, if a p plica ble (see Secti o n 1 4). 
 
6. 2
 St u d y
 
C o n d uct
 
T he cli nical trial will be c o n d ucte d i n c o m p lia n ce wit h re g ulati o ns ( 2 1 C F R 3 1 2, 5 0, a n d 
5 6), g ui deli nes f or G o o d Cli nical Practice (I C H G ui da nce E 6), a n d i n acc or da nce wit h 
ge neral et hical pri nci ples o utli ne d i n t he Decl arati o n of Helsi n ki; i nf or me d c o nse nt will 
be o btai ne d fr o m all partici pati n g patie nts;  t he pr ot oc ol a n d a n y a me n d me nts will be 
s u bject t o a p pr o val b y t he desi g nate d I R B pri or t o i m ple me ntati o n, i n acc or da nce wit h 2 1 
C F R 5 6. 1 0 3(a); a n d s u bject rec or ds will be st ore d i n a sec ure l ocati o n a n d s u bject 
c o nfi de ntialit y will be mai ntai ne d. T he i n vesti gat or will be t h or o u g hl y fa miliar wit h t he 
a p pr o priate use of t he st u d y dr u g as descri b e d i n t he pr ot oc ol a n d I n vesti gat or’s 
Br oc h ure.  Esse ntial cli nical d oc u me nts will be  mai ntai ne d t o de m o nstrate t he vali dit y of 
t he st u d y a n d t he i nte grit y of t he data c ollecte d.  Master files s h o ul d be esta blis he d at t he 
be gi n ni n g of t he st u d y, mai ntai ne d f or t he d urati o n of t he st u d y a n d retai ne d acc or di n g t o 
t he a p pr o priate re g ulati o ns.   
 
 

M C 1 7 8 2
 2 5
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
7. 0
 Pr ot oc ol
 
Tre at me nt
 
7. 1
 Treat me nt
 
Sc he d ule
  
C y cle le n gt h: 8 4 da ys.  
A ge nt
 R o ute
 
D ose 
D a y
 Retre at me nt
 
I xaz o mi b
 P O
 
4
 
m g
 
1, 8, 1 5,   
2 9, 3 6, 4 3,  
5 7, 6 4, 7 1 
E ver y 8 4 
da ys 
Pe m br oliz u ma b  
I V  
2 0 0 m g   
Da y 1, 2 2, 4 3, 6 4 
E ver y 8 4 
da ys 
De xa met has o ne 
P O
 4 0
 
m g
 
1, 8, 1 5, 
2 9, 3 6, 4 3 
5 7, 6 4, 7 1 
E ver y 8 4 
da ys 
 
7. 2  
F or t his pr ot oc ol, t he patie nt m ust ret u r n t o t he c o nse nti n g i nstit uti o n ( Ma y o Cli nic) f or 
e val uati o n at least e ver y 2 1 da ys (±  1 da y).  Treat me nt b y a l ocal me dical d oct or ( L M D) is 
n ot all o we d. N ote:  If patie nt is sta ble after 2 c y cles, p h ysical e xa m ca n be re d uce d t o 
Wee ks 1 a n d 7 of eac h c y cle. 
 
7. 3  
Patie nts are all o we d t o c ollect ste m cells afte r 1 c y cle of i nitial t hera p y. Ste m cells ca n be 
c ollecte d usi n g sta n dar d i nstit uti o nal pr ot oc ols. A n y dela y be y o n d 4 wee ks s h o ul d be 
disc usse d wit h t he st u d y PI pri or t o  rei nitiati n g pr ot oc ol t hera p y. 
 
7. 4  
Patie nts s h o ul d be i nstr ucte d t o s wall o w i x az o mi b ca ps ules w h ole, wit h water, a n d n ot t o 
brea k, c he w, or o pe n t he ca ps ules T he i xaz o mi b s h o ul d be ta ke n o n a n e m pt y st o mac h 
( n o f o o d or dri n k a part fr o m 2 4 0 m L of water), at least 1 h o ur bef ore or n o s o o ner t ha n 
2 h o urs after f o o d. Eac h ca ps ule s h o ul d be s wall o we d se paratel y wit h a si p of water. A 
t otal of a p pr o xi matel y 2 4 0 m L (a b o ut 1 c u p/8 oz) of water s h o ul d be ta ke n wit h t he 
ca ps ules. 
Misse d d oses ca n be ta ke n as s o o n as t he patie nt  re me m b ers as l o n g as t he ne xt sc he d ule d 
d ose is 7 2 h o urs or m ore a wa y. Patie nts w h o v o mit a d ose after i n gesti o n will n ot recei ve 
a n a d diti o nal d ose, b ut s h o ul d res u me d osi n g at t he ti me of t he ne xt sc he d ule d d ose. 
Dr u g will be a d mi nistere d o nl y t o eli gi b le patie nts u n der t he s u per visi o n of t he 
i n vesti gat or or i de ntifie d s u b-i n vesti gator(s). T he dr u g will be pre pare d u n der t he 
s u per visi o n of a p har macist, or a p pr o priatel y q ualifie d a n d trai ne d pers o n nel. 
 
7. 5  
De xa met has o ne ( C y cles 1- 4, ma xi m u m of 1 y ear) 
•  
De xa met has o ne ma y be self-a d mi nistere d b y t he s u bject o n a n o ut patie nt basis. 
•  
Misse d d oses of de xa met h as o ne will n ot be ma de u p. Pr oce d ures f or d ose re d ucti o ns 
a n d dela ys are s u m marize d i n Secti o n 8. 0. 
•  
De xa met has o ne is c o m merciall y a vaila ble. Acc urate rec or ds will be ke pt i n t he 
s o urce d oc u me nts of all dr u g a d mi nistrati o n (i ncl u di n g dis pe nsi n g a n d d osi n g).  

M C 1 7 8 2
 2 6
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
8. 0  
D os a ge M o dific ati o n B ase d o n A d verse E ve nts  
I n di vi d ual dr u gs ca n be d ose re d uce d as per t he ta ble bel o w de pe n di n g o n t he a d verse e ve nt 
attri b uti o n of p ossi ble, pr o ba ble, or defi nite. If m ulti ple a d verse e ve nts are see n, a d mi nister d ose 
base d o n greatest re d ucti o n re q uire d f or a n y si n gle a d verse e ve nt o bser ve d. Re d ucti o ns a p pl y t o 
treat me nt gi ve n i n t he prece di n g c y cle a n d are base d o n a d verse e ve nts o bser ve d si nce t he pri or 
d ose.  
A L E R T: 
A D R re p orti n g m ay be re q uire d f or s o me a dverse eve nts ( See Secti o n 1 0) 
8. 1   
D ose Le vels f or eac h dr u g i n t he c o m bi nati o n.  
 
I x az o mi b 
( D a ys 1, 8, 1 5, ,  
2 9, 3 6, 4 3,  
5 7, 6 4, 7 1) 
Pe m br oliz u m a b 
( 2 0 0 m g/ d ose) 
De x a met h as o ne 
( D a ys 1, 8, 1 5,  
2 9, 3 6, 4 3,  
5 7, 6 4, 7 1) 
Starti n g 
d ose  
4 m g  
Da y 1, 2 2, 4 3, 6 4   
4 0 m g 
- 1 
3 m g  
Da y 1 a n d 4 3   
2 0 m g 
- 2  
2. 3 m g    
Disc o nti n ue 
1 2 m g 
* See Ta ble 8. 2 bel o w  
N ote:  If i x az o mi b is disc o nti n ue d, t he p atie nt will disc o nti n ue pe m br oliz u m a b a n d 
de x a met h as o ne a n d g o t o e ve nt m o nit ori n g. 
8. 1 1   I nstr ucti o n f or i nitiati o n of a ne w c y cle of t hera p y  
A ne w c y cle of treat me nt ma y be gi n o n t he sc he d ule d Da y 1 of a ne w c y cle if: 
•  
T he A N C is ≥1 0 0 0/ μ L 
•  
T he platelet c o u nt is ≥7 5, 0 0 0/ μ L 
•  
A n y ot her n o n- he mat ol o gic dr u g-relate d ( p ossi ble, pr o ba ble, or defi nite) 
a d verse e ve nt t hat ma y ha ve  occ urre d has res ol ve d t o ≤Gra de 1 or 
baseli ne se verit y. 
If  t hese  c o n diti o ns  are  n ot  met  o n  Da y  1  of  a  ne w  c y cle,  d osi n g  s h o ul d  be  
dela y e d f or 1 wee k. At t he e n d of t hat ti me, t he patie nt s h o ul d be re-e val uate d t o 
deter mi ne w h et her t he criteria ha ve bee n met. If t he patie nt c o nti n ues t o fail t o 
meet t he a b o ve-cite d criteria, dela y t h era p y a n d c o nti n ue t o re-e val uate. 
If a n y dr u g d osi n g was halte d d uri n g t he pre vi o us c ycle a n d was restarte d wit h a 
o ne-le vel d ose re d ucti o n wit h o ut re q uiri n g a n i nterr u pti o n f or t he re mai n der of 
t he c y cle, t he n t hat re d uce d d ose le vel will be i nitiate d o n Da y 1 of t he ne w 
c y cle. 
If a n y dr u g d osi n g was o mitte d f or t he re mai n der of t he pre vi o us c y cle or if t he 
ne w c y cle is hel d d ue t o k n o w n he mat ol o gic t o xicit y ne wl y e nc o u ntere d o n t he 
sc he d ule d  Da y  1,  t he n  t he  ne w  c y cle  will  be  starte d  wit h  a  o ne-le vel  d ose  
re d ucti o n.  If a ne w c y cle of t hera p y ca n n ot be restarte d wit hi n 4 wee ks of t he 
sc he d ule d Da y 1 d ue t o n o n-res ol uti o n of dru g relate d t o xicities, t he patie nt will 
be re m o ve d fr o m pr ot oc ol t hera p y a n d will g o t o e ve nt m o nit ori n g. 
 
 

M C 1 7 8 2
 2 7
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
8. 2  
D ose m o dific ati o ns f or pe m br oliz u m a b b ase d o n a d verse e ve nts d uri n g a c ycle 
C T C A E 
S yste m/ Or g a n/ Cl ass 
( S O C)
 A d verse
 
E ve nt 
O mit 
Tre at me nt 
f or Gr a de 
Ti mi n g f or Rest arti n g 
Tre at me nt  
Tre at me nt Disc o nti n u ati o n  
E n d ocri ne dis or ders 
E n d ocri ne 
dis or ders – Ot her, 
s pecif y: 
H y p o p h ysitis 
2- 4 
A E res ol ves t o  
Gra de 0- 1. T hera p y wit h 
pe m br oliz u ma b ca n be 
c o nti n ue d w hile 
e n d ocri ne re place me nt 
t hera p y is i nstit ute d 
A E d oes n ot res ol ve wit hi n  
1 2 wee ks of last d ose or 
i na bilit y t o re d uce c ortic oster oi d 
t o 1 0 m g or less of pre d nis o ne 
or e q ui vale nt per da y wit hi n 1 2 
wee ks 
E n d ocri ne dis or ders  
H y pert h yr oi dis m  
3 
A E res ol ves t o  
Gra de 0- 1 
A E d oes n ot res ol ve wit hi n  
1 2 wee ks of last d ose or 
i na bilit y t o re d uce c ortic oster oi d 
t o 1 0 m g or less of pre d nis o ne 
or e q ui vale nt per da y wit hi n 1 2 
wee ks 
 
 
4  
Per ma ne ntl y disc o nti n ue  Per ma ne ntl y disc o nti n ue 
E n d ocri ne dis or ders  
H y p ot h yr oi dis m  
2 
T hera p y wit h 
pe m br oliz u ma b ca n be 
c o nti n ue d w hile t h yr oi d 
re place me nt t hera p y is 
i nstit ute d 
T hera p y wit h pe m br oliz u ma b 
ca n be c o nti n ue d w hile t h yr oi d 
re place me nt t hera p y is i nstit ute d 
Gastr oi ntesti nal 
dis or ders 
Diarr hea or C olitis  
2- 3 
A E res ol ves t o  
Gra de 0- 1 
A E d oes n ot res ol ve wit hi n 
 1 2 wee ks of last d ose or 
i na bilit y t o re d uce c ortic oster oi d 
t o 1 0 m g or less of pre d nis o ne 
or e q ui vale nt per da y wit hi n 1 2 
wee ks 
 
 
4  
Per ma ne ntl y disc o nti n ue  Per ma ne ntl y disc o nti n ue 
Ge neral dis or ders a n d 
a d mi nistrati o n site 
c o n diti o ns 
I nf usi o n relate d 
reacti o n 
2 b 
A E res ol ves t o  
Gra de 0- 1 
Per ma ne ntl y disc o nti n ue if A E 
de vel o ps des pite a de q uate 
pre me dicati o n  
 
 
3- 4  
Per ma ne ntl y disc o nti n ue  Per ma ne ntl y disc o nti n ue 
I n vesti gati o ns 
As partate 
a mi n otra nsferase 
( A S T) i ncrease d or 
Ala ni ne 
a mi n otra nsferase 
( A L T) i ncrease d or 
Bl o o d bilir u bi n 
i ncrease d 
2 
A E res ol ves t o  
Gra de 0- 1 
A E d oes n ot res ol ve wit hi n 
1 2 wee ks of last d ose 
 3- 4
 
Per ma ne ntl y disc o nti n ue 
(see e xce pti o n bel o w)a 
Per ma ne ntl y disc o nti n ue 
Meta b olis m a n d 
n utriti o n dis or ders 
Gl uc ose 
i nt olera nce ( T y pe 1 
dia betes mellit us 
[if ne w o nset]) or 
H y per gl yce mi a 
3- 4 
O mit pe m br oliz u ma b f or 
ne w o nset T y pe 1 
dia betes mellit us or 
Gra de 3- 4 h y per gl yce mia 
ass ociate d wit h e vi de nce 
of beta cell fail ure 
Res u me pe m br oliz u ma b w he n 
patie nts are cli nicall y a n d 
meta b olicall y sta ble 

M C 1 7 8 2
 2 8
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
C T C A E 
S yste m/ Or g a n/ Cl ass 
( S O C)
 A d verse
 
E ve nt 
O mit 
Tre at me nt 
f or Gr a de 
Ti mi n g f or Rest arti n g 
Tre at me nt  
Tre at me nt Disc o nti n u ati o n  
Re nal a n d uri nar y 
dis or ders 
Ac ute ki d ne y 
i nj ur y or C hr o nic 
ki d ne y disease  
(e. g., Re nal fail ure 
or Ne p hritis) 
2 
A E res ol ves t o  
Gra de 0- 1 
A E d oes n ot res ol ve wit hi n  
1 2 wee ks of last d ose or 
i na bilit y t o re d uce c ortic oster oi d 
t o 1 0 m g or less of pre d nis o ne 
or e q ui vale nt per da y wit hi n 1 2 
wee ks 
 
 
3- 4  
Per ma ne ntl y disc o nti n ue  Per ma ne ntl y disc o nti n ue 
Res pirat or y, t h oracic 
a n d me diasti nal 
dis or ders 
P ne u m o nitis
 2
 
H ol d pe m br oliz u ma b 
u ntil A E res ol ves t o 
 Gra de 0- 1  
 
A E d oes n ot res ol ve wit hi n  
1 2 wee ks of last d ose or 
i na bilit y t o re d uce c ortic oster oi d 
t o 1 0 m g or less of pre d nis o ne 
or e q ui vale nt per da y wit hi n 1 2 
wee ks  
 
 
3- 4 or  
Rec urre nt 2 Per ma ne ntl y disc o nti n ue  Per ma ne ntl y disc o nti n ue 
Car diac dis or ders   
M y ocar ditis  
1- 2 
H ol d pe m br oliz u ma b 
u ntil A E res ol ves t o 
Gra de 0- 1 
Base d o n se verit y of A E 
a d mi nister c ortic oster oi ds 
3- 4  
Per ma ne ntl y disc o nti n ue  Per ma ne ntl y disc o nti n ue 
 
All Ot her Dr u g-
Relate d A d verse 
E ve nts c 
3 
A E res ol ves t o  
Gra de 0- 1 
A E d oes n ot res ol ve wit hi n  
1 2 wee ks of last d ose or 
i na bilit y t o re d uce c ortic oster oi d 
t o 1 0 m g or less of pre d nis o ne 
or e q ui vale nt per da y wit hi n 1 2 
wee ks 
 
 
4  
Per ma ne ntl y disc o nti n ue  Per ma ne ntl y disc o nti n ue 
N ote: Per m a ne ntl y disc o nti n ue f or a n y se vere or Gr a de 3 dr u g-rel ate d A E t h at rec urs or a n y life-t hre ate ni n g 
e ve nt. 
a F or patie nts wit h li ver met astasis w h o be gi n treat me nt wit h Gra de 2 A S T or A L T, if  A S T or A L T i ncreases b y 
greater t ha n or e q ual t o 5 0 % relati ve t o baseli ne a n d lasts f or at least 1 wee k t he n patie nts s h o ul d be disc o nti n ue d. 
b If s y m pt o ms res ol ve wit hi n o ne h o ur of st o p pi n g dr u g i nf usi o n, t he i nf usi o n ma y be restarte d at 5 0 % of t he 
ori gi nal i nf usi o n rate   (e. g., fr o m 1 0 0 m L/ hr t o 5 0 m L/ hr). Ot her wise d osi n g will be hel d u ntil s y m pt o ms res ol ve 
a n d t he s u bject s h o ul d be pre me dicate d f or t he ne xt sc he d ule d d ose. 
c Patie nts wit h i nt olera ble or persiste nt Gra de 2 dr u g-relate d A E ma y h ol d st u d y me dicati o n at p h ysicia n discreti o n. 
Per ma ne ntl y disc o nti n ue st u d y dr u g f or persiste nt Gra de 2 a d verse reacti o ns f or w hic h treat me nt wit h st u d y dr u g 
has bee n hel d, t hat d o n ot rec o ver t o Gra de 0- 1 wit hi n 1 2 wee ks of t he last d ose. 
*
 L ocate d
 at
 
* *   Use t he f oll o wi n g t o descri be acti o ns i n t he Acti o n c ol u m n: 
 O mit = T he c u rre nt d ose(s) f or t he s pecifie d dru g(s) d uri n g a c y cle is s ki p pe d. T he patie nt 
d oes n ot ma k e u p t he o mitte d d ose(s) at a later ti me 
 H ol d/ Dela y = T he c urre nt d ose(s) of all dr u gs d uri n g a c y cle is dela y e d. T he patie nt d oes 
ma ke u p t he dela y e d d ose(s) w he n t he patie nt meets t he pr ot oc ol criteria t o restart dr u gs. 
 Disc o nti n ue = T he s pecifie d dr u g(s) are t otall y st o p pe d. 
 
 

M C 1 7 8 2
 2 9
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
8. 3   
D ose m o dific ati o ns f or I x az o mi b b ase d o n a d verse e ve nts d uri n g a c ycle 
C T C A E 
S yste m/ Or g a n/
Cl ass ( S O C) *  
A D V E R S E E V E N T  
A C TI O N * * 
I n vesti gati o ns  
Ne utr o p hil c o u nt decrease d < 1. 0 x 
1 0 9/ L or 
Ne utr o p hil c o u nt decrease d > 1. 0 ×  
1 0 9/ L ( u p t o L L N) a n d Fe ver 
(te m perat ure > 3 8. 5° C) or Platelet 
c o u nt decrease d ˂ 3 0 ×  1 09/ L  
Da ys 2- 8 4: I xaz o mi b d ose s h o ul d be o mitte d o n 
Da ys 1, 8, 1 5, 2 9, 3 6, 4 3, 5 7, 6 4, 7 1 as a p plica ble 
C o m plete bl o o d c o u nt ( C B C) wit h differe ntial 
s h o ul d be f oll o we d wee kl y  
If A N C is > 1. 0 ×  1 09/ L a n d/ or  
platelet c o u nts > 3 0 ×  1 09/ L, i xaz o mi b ma y be 
rei nitiate d wit h 1 d ose le vel re d ucti o n. T he 
s u bse q ue nt c ycle will use t he re d uce d d ose.  
Ner v o us S yste m 
Dis or ders 
Ne wl y de vel o pe d peri p heral se ns or y 
ne ur o pat h y Gra de 1 wit h pai n or  
Peri p heral se ns or y ne ur o pat h y 
Gra de 2 
O mit u ntil res ol uti o n t o Gra de < 1 or baseli ne  
N o d ose re d ucti o n necessar y f or t his gra de 
 
Peri p heral se ns or y ne ur o pat h y wit h 
pai n  Gra de 2 or 
Peri p heral se ns or y ne ur o pat h y 
Gra de 3  
O mit i xaz o mi b u ntil t o xicit y res ol ves or ret ur ns t o 
baseli ne. W he n t o xicit y res ol ves, re-i nitiate i xaz o mi b 
at t he ne xt l o wer d ose le vel. 
 
Peri p heral se ns or y ne ur o pat h y 
Gra de 4  
Disc o nti n ue i xaz o mi b. 
Peri p heral ne ur o pat h y s h o ul d be m o nit ore d u ntil 
t o xicit y res ol ves or ret ur ns t o baseli ne.  
S ki n a n d 
s u bc uta ne o us 
tiss ue dis or ders 
Ras h, mac ul o- pa p ular,  
≥Gra de 2 
O mit i xaz o mi b u ntil ras h res ol ves t o ≤Gra de 1  
( See Secti o n 9. 9a ). Restart at sa me d ose. If t he ras h 
rec urs, re d uce d ose b y o ne d ose le vel. 
 
A n y ot her s ki n A E, Gra de 4  
Disc o nti n ue i xaz o mi b a n d re m o ve patie nt fr o m all 
st u d y treat me nt 
 
A n y ot her Gra de 3 attri b uta ble 
a d verse e ve nt e xce pt: 
O mit i xaz o mi b de pe n di n g o n t he attri b uti o n, u ntil 
res ol uti o n t o Gra de ≤1 or baseli ne 
Restart at ne xt l o wer d ose. If a patie nt is alrea d y at 
t he l o west dr u g le vel, g o t o e ve nt m o nit ori n g 
•  
Na usea a n d/ or V o miti n g Gra de 
3 i n t he a bse nce of o pti mal a nti-
e metic pr o p h yla xis  
•  
Diarr hea Gra de 3 t hat occ urs i n 
t he a bse nce of o pti mal 
s u p p orti ve t hera p y 
•  
Fati g ue Gra de 3  
•  
A ne mia  
•  
W hite bl o o d cell decrease d  
•  
L y m p h oc yte c o u nt decrease d  
 
A n y ot her A d verse E ve nts Gra de 4  
C o nsi der per ma ne ntl y disc o nti n ui n g i xaz o mi b –
E xce pti o n if t he i n vesti gat or deter mi nes t he patie nt 
is o btai ni n g a cli nical be nefit 
 
*
 L ocate d
 at
 
* *   Use t he f oll o wi n g t o descri be acti o ns i n t he Acti o n c ol u m n: 

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
 O mit = T he c urre nt d ose(s) f or t he s pecifie d dr u g( s) d uri n g a c y cle is s ki p pe d.  T he patie nt 
d oes n ot ma k e u p t he o mitte d d ose(s) at a later ti me 
 H ol d/ Dela y = T he c urre nt d ose(s) of all dr u gs d uri n g a c y cle is dela y e d. T he patie nt d oes 
ma ke u p t he dela y e d d ose(s) w he n t he patie nt meets t he pr ot oc ol criteria t o restart dr u gs. 
 Disc o nti n ue = T he s pecifie d dr u g(s) are t otall y st o p pe d. 
 
8. 4  
D ose m o dific ati o ns f or de x a met h as o ne b ase d o n a d verse e ve nts d uri n g a c ycle 
C T C A E 
S yste m/ Or g a n/ Cl ass 
( S O C)
 A D V E R S E
 
E V E N T
 A G E N T
  
A C TI O N * *
 
Gastr oi ntesti nal 
dis or ders 
D ys pe psia Gra de 1 or 2  or  
D u o de nal ulcer Gra de 1 or 2 
or 
Gastric ulcer Gra de 1 or 2 
or Gastritis Gra de 1 or 2 
De xa met has o ne  
Treat wit h H 2 bl oc kers, s ucralfate, or 
o me praz ole. If s y m pt o ms persist 
des pite a b o ve meas ures, decrease 
de xa met has o ne d ose b y 1 d ose le vel.  
D ys pe psia ≥Gra de 3 
 or  
D u o de nal ulcer ≥Gra de 3 
or Gastric ulcer ≥Gra de 3 or 
Gastritis ≥Gra de 3 
De xa met has o ne  
O mit de xa met has o ne u ntil s y m pt o ms 
a de q uatel y c o ntr olle d. Restart o ne 
d ose le vel bel o w al o n g wit h 
c o nc urre nt t hera p y wit h H 2 bl oc kers, 
s ucralfate, or o me praz ole  
If s y m pt o ms persist des pite a b o ve 
meas ures, disc o nti n ue 
de xa met has o ne a n d d o n ot res u me  
Pa ncreatitis ≥Gra de 3   
De xa met has o ne  
Disc o nti n ue de xa met has o ne a n d d o 
n ot res u me 
Ge neral dis or ders a n d 
a d mi nistrati o n site 
c o n diti o ns 
E de ma li m bs 
≥Gra de 3 or  
E de ma tr u n k ≥Gra de 3 
De xa met has o ne  
Di uretics as nee de d, a n d decrease 
de xa met has o ne d ose b y 1 d ose le vel; 
if e de ma persists des pite a b o ve 
meas ures, decrease d ose a n ot her d ose 
le vel  
Disc o nti n ue de xa met has o ne a n d d o 
n ot res u me if s y m pt o ms persist 
des pite sec o n d re d ucti o n 
Meta b olis m a n d 
n utriti o n dis or ders 
H y per gl yce mi a ≥Gra de 3  
De xa met has o ne  
Treat me nt wit h i ns uli n or oral 
h y p o gl yce mics as nee de d.  
If u nc o ntr olle d des pite a b o ve 
meas ures, decrease d ose b y o ne d ose 
le vel at a ti me u ntil le vels are 
satisfact or y. 
M usc ul os keletal a n d 
c o n necti ve tiss ue 
dis or ders 
Ge neralize d m uscle 
wea k ness ≥Gra de 2   
De xa met has o ne  
Decrease de xa met has o ne d ose b y 
o ne d ose le vel; if wea k ness persists 
des pite a b o ve meas ures decrease 
d ose b y o ne a d diti o nal d ose le vel. 
Disc o nti n ue de xa met has o ne a n d d o 
n ot res u me if s y m pt o ms c o nti n ue t o 
persist 
Ps yc hiatric dis or ders  C o nf usi o n Gra de ≥2 
O R/ A n d A n xiet y Gra de ≥2  
De xa met has o ne  
O mit de xa met has o ne u ntil s y m pt o ms 
res ol ve. Restart wit h o ne d ose le vel 
re d ucti o n. If s y m pt o ms persist 
des pite a b o ve meas ures, disc o nti n ue 
de xa met has o ne a n d d o n ot res u me. 

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
*
 L ocate d at
 
* *   
Use t he f oll o wi n g t o descri be acti o ns i n t he Acti o n c ol u m n: 
 O mit = T he c u rre nt d ose(s) f or t he s pecifie d dr u g(s) d uri n g a c y cle is s ki p pe d.  T he patie nt 
d oes n ot ma k e u p t he o mitte d d ose(s) at a later ti me 
 H ol d/ Dela y = T he c urre nt d ose(s) of all dr u gs d uri n g a c y cle is dela y e d. T he patie nt d oes 
ma ke u p t he dela y e d d ose(s) w he n t he patie nt meets t he pr ot oc ol criteria t o restart dr u gs. 
 Disc o nti n ue = T he s pecifie d dr u g(s) are t otall y st o p pe d. 
 
9. 0
 A ncill ar y
 
Tre at m e nt/ S u p p orti ve C are 
Me dicati o ns or vacci nati o ns s pecificall y pr o hi b ite d i n t he e xcl usi o n criteria are n ot all o we d 
d uri n g t he o n g oi n g trial.  If t here is a cli nical i n dicati o n f or o ne of t hese or ot her me dicati o ns or 
vacci nati o ns s pecificall y pr o hi bite d d uri n g t he trial, disc o nti n uati o n fr o m trial t hera p y or 
vacci nati o n ma y be re q uire d.  T he i n vesti gat or s h o ul d disc uss a n y q uesti o ns re gar di n g t his wit h 
t he Merc k Cli nical tea m.  T he fi nal decisi o n o n a n y s u p p orti ve t hera p y or vacci nati o n rests wit h 
t he i n vesti gat or a n d/ or t he s u bject's pri mar y p h ysicia n.  
All  treat me nts  t hat  t he  i n vesti gat or  c o nsi d ers  necessar y  f or  a  s u bject’s  welfare  ma y  be  
a d mi nistere d at t he discreti o n of t he i n vesti gat or i n kee pi n g wit h t he c o m m u nit y sta n dar ds of 
me dical  care.  All  c o nc o mita nt  me dicati o n  will  be  rec or de d  o n  t he  case  re p ort  f or m  ( C R F)  
i ncl u di n g all prescri pti o n, o ver-t he-c o u nter ( O T C), her bal s u p ple me nts, a n d I V me dicati o ns a n d 
fl ui ds.  If c ha n ges occ ur d uri n g t he trial peri o d, d oc u me ntati o n of dr u g d osa ge, fre q ue nc y, r o ute, 
a n d date ma y als o be i ncl u de d o n t he C R F. 
All c o nc o mita nt me dicati o ns recei ve d wit hi n 2 8 da ys bef ore t he first d ose of trial treat me nt a n d 
3 0  da ys  after  t he  last  d ose  of  trial  treat me nt  s h o ul d  be  rec or de d.  C o nc o mita nt  me dicati o ns  
a d mi nistere d after 3 0 da ys after t he last d ose of trial treat me nt s h o ul d be rec or de d f or S A Es a n d 
E CIs as defi n e d i n Secti o n 1 0. 1. 
9. 1
 Oral
 
h y drati o n
 
Patie nts are e nc o ura ge d t o dri n k at l east 6 t o 8 c u ps of li q ui d per da y. 
 
9. 2  
Disall o we d c o nc urre nt treat me nt 
T he f oll o wi n g treat me nts are n ot per mitte d d uri n g t he trial: 
•  
A n y ot her i n vesti gati o nal treat me nt  
•  
A n y ot her s yste mic a nti- ne o plastic t h era p y i ncl u di n g, b ut n ot li mite d t o, 
i m m u n ot hera p y, h or m o nal t hera p y or m o n ocl o nal a nti b o d y t hera p y. 
•  
A n y e xter nal bea m ra di ot hera p y 
•  
Platelet tra nsf usi o ns t o hel p patie nts meet  eli gi bilit y criteria are n ot all o we d wit hi n 
3 da ys pri or t o st u d y dr u g d osi n g f or a n y d osi n g da y 
 
 

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9. 3  
Na usea a n d/ or v o miti n g 
Sta n dar d a nti-e metics i ncl u di n g 5- h y dr o x ytr y pta mi n e 3 ser ot o ni n rece pt or a nta g o nists are 
rec o m me n de d f or e mesis if it occ urs o nce treatme nt is i nitiate d; pr o p h ylactic a nti-e metics 
ma y als o be c o nsi dere d at t he p h ysicia n’ s discreti o n. De xa met has o ne s h o ul d n ot be 
a d mi nistere d as a n a nti-e metic. Fl ui d deficit s h o ul d be c orrecte d bef ore i nitiati o n of st u d y 
dr u g a n d d uri n g treat me nt. 
 
9. 4  
Bl o o d pr o d ucts a n d gr o wt h fact ors 
Bl o o d pr o d ucts a n d gr o wt h fact ors s h o ul d be  utilize d as cli nicall y warra nte d a n d 
f oll o wi n g i nstit uti o nal p olicies a n d rec o m me n dati o ns.  T he use of gr o wt h fact ors s h o ul d 
f oll o w p u blis he d g ui deli nes of t he J o ur nal of Cli nical O nc ol o g y, V ol 2 4, N o 1 8 (J u ne 
2 0), 2 0 0 6: p p. 2 9 3 2- 2 9 4 7. 
 
9. 5
 Diarr hea
 
a n d
 
I xaz o mi b
 
Pr o p h ylactic a nti diarr heals s h o ul d be use d i n t his pr ot oc ol. Diarr hea occ urri n g des pite t he 
pr o p h yla xis s h o ul d be ma n a ge d acc or di n g t o cli nical practice, i ncl u di n g t he 
a d mi nistrati o n of a nti diarr heals s uc h as l o pe ra mi de o nce i nfecti o us ca uses are e x cl u de d. 
Fl ui d i nta ke s h o ul d be mai ntai ne d t o a v oi d de h y drati o n. Fl ui d deficit s h o ul d be c orrecte d 
bef ore i nitiati o n of treat me nt a n d d uri n g tr eat me nt. A d diti o nal d oses of l o pera mi d e at 2 
m g e ver y 2- 4 h o urs u ntil diarr hea free ( ma xi m u m 1 6 m g/ da y). 
I n t he e ve nt of Gra de 3 or 4 diarr hea, t he f oll o wi n g s u p p orti ve meas ures are all o we d: 
h y drati o n, octre oti de, a n d a nti diarr heals. 
If diarr hea is se vere (re q uiri n g i ntra ve n o us re h y drati o n) a n d/ or ass ociate d wit h fe ver or 
se vere ne utr o pe nia ( Gra de 3 or 4), br oa d-s pectr u m a nti bi otics m ust be prescri be d. 
Patie nts wit h se vere diarr h ea or a n y diarr hea ass ociate d wit h se vere na usea or v o miti n g 
s h o ul d be h os pit alize d f or i ntra ve n o us h y drati o n a n d c orrecti o n of electr ol yte 
i m bala nces. 
Please m o nit or patie nts caref ull y f or de vel o p me nt of ile us. 
 
9. 6   
Re nal fail ure a n d I xaz o mi b 
T w o cases of ac ute re nal fail ure ha ve bee n re p orte d i n patie nts treate d at or a b o ve t he 
M T D f or i ntra ve n o us i xaz o mi b. V ol u me de pl eti o n s h o ul d be c orrecte d bef ore i nitiati o n 
of st u d y dr u g. U ntil f urt her i nf or mati o n is a vaila ble, i nta ke of n o nster oi dal a nti-
i nfla m mat or y dr u gs i m me diatel y pri or t o t he a d mi nistrati o n of i xaz o mi b s h o ul d be 
disc o ura ge d a n d re q uires c o ns ultati o n wit h t he pri nci pal i n vesti gat or. All necessar y 
s u p p orti ve care c o nsiste nt wit h o pti mal patient care s hall be a vaila ble t o patie nts as 
necessar y. 
 
9. 7  
Her pes Z oster pr o p h yla xis 
Patie nts ma y be at a n i ncrease d ris k of i nfecti o n i ncl u di n g reacti vati o n of her pes z oster 
a n d her pes si m ple x vir uses. Pr o p h yla xis wit h  ac y cl o vir 4 0 0 m g P O BI D is rec o m me n de d 
w hile o n st u d y t hera p y a n d f or 1 m o nt h be y o n d t he e n d of t hera p y. 
 

M C 1 7 8 2
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9. 8
 Pr o hi bite d
 
me dicati o ns
 
9. 8 1  
Pr o hi bite d e nz y me i n d ucers 
S yste mic treat me nt wit h a n y of t he f oll o wi n g meta b olizi n g e nz y me i n d ucers 
s h o ul d be a v oi de d, u nless t here is n o a p pro priate alter nati ve me dicati o n f or t he 
patie nt’s use. ( Rati o nale: If t here were t o be a dr u g- dr u g i nteracti o n wit h a n 
i n d ucer, i xaz o mi b e x p os ure w o ul d be less - s o t here is a re d uce d c ha nce of a n 
a d verse e ve nt. H o we ver, t here ma y be less c ha nce f or a n a ntit u m or effect, b ut 
t hat is n ot a n a bs ol ute reas o n t o be ta ke n off st u d y):  
Str o n g C Y P 3 A i n d ucers: rifa m pi n, rifa pe nti ne, rifa b uti n, car ba maze pi ne, 
p he n yt oi n, a n d p he n o bar bital.  
9. 8 2  
E xcl u de d f o o ds a n d dietar y s u p ple me nts i ncl u de St. J o h n’s w ort. 
9. 8 3   
S u bjects are pr o hi bite d fr o m recei vi n g t he f oll o wi n g t hera pies d uri n g t he 
Scree ni n g a n d Treat me nt P hase    of t his trial: 
•  
A nti ne o plastic s yste mic c h e m ot hera p y or bi ol o gical t hera p y  
•  
I m m u n ot hera p y n ot s pecifie d i n t his pr ot oc ol 
•  
C he m ot hera p y n ot s pecifie d i n t his pr ot oc ol 
•  
Ra diati o n t hera p y  
o  N ote:  Ra diati o n t hera p y t o a s y m pt o matic s olitar y lesi o n or t o t he brai n 
ma y be all o we d at t he i n vesti gat or’s discreti o n. 
•  
Li ve vacci nes wit hi n 3 0 da ys pri or t o  t he first d ose of trial treat me nt a n d 
w hile partici pati n g i n t he trial.  E xa m ples of li ve vacci nes i ncl u de, b ut are n ot 
li mite d t o, t he f oll o wi n g: measles, m u m ps, r u bella, varicella/z oster, y ell o w 
fe ver, ra bies, B C G, a n d t y p h oi d vacci ne.  
S u bjects w h o, i n t he assess me nt b y t he i n v esti gat or, re q uire t he use of a n y of t he 
af ore me nti o ne d treat me nts f or cli nical ma na ge me nt s h o ul d be re m o ve d fr o m t he 
trial.  S u bjects ma y recei v e ot her me dicati o ns t hat t he i n vesti gat or dee ms t o be 
me dicall y necessar y. 
T he E xcl usi o n Criteria descri bes ot her me di cati o ns w hic h are pr o hi bite d i n t his 
trial. 
T here are n o pr o hi bite d t hera pies d uri n g t he P ost- Treat me nt F oll o w- u p P hase. 
9. 9a  
Er yt he mat o us Ras h wit h or wit h o ut Pr urit us 
Ras h wit h or wit h o ut pr urit us has bee n re p orte d wit h i xaz o mi b, pri maril y at t he hi g her 
d oses teste d a n d w he n gi ve n wit h a ge nts w here ras h is a n o verla p pi n g t o xicit y. T he ras h 
ma y ra n ge fr o m li mite d er yt he mat o us areas, mac ular a n d/ or s mall pa p ular b u m ps t hat 
ma y or ma y n ot be pr uritic o ver a fe w areas of t he b o d y, t o a m ore ge neralize d er u pti o n 
t hat is pre d o mi natel y o n t he tr u n k or e xtre mities. Ras h has bee n m ost c o m m o nl y 
c haracterize d as mac ul o pa p ular or mac ular. T o  date, w he n it d oes occ ur, ras h is m ost 
c o m m o nl y re p orte d wit hi n t he first 3 c ycles of t hera p y. T he ras h is ofte n tra nsie nt, self-
li miti n g, a n d is t y picall y Gra de 1 t o 2 i n se verit y.  
S y m pt o matic meas ures s uc h as a nti hista mi nes or  c ortic oster oi ds ( oral or t o pical) ha ve 
bee n s uccessf ull y use d t o ma na ge ras h a n d ha ve bee n use d pr o p h ylac ticall y i n s u bse q ue nt 
c y cles. T he use of a t o pical, I V, or oral ster oi d (e. g., pre d nis o ne ≤1 0 m g per da y or 
e q ui vale nt) is per mitte d. Ma na ge me nt of a Gra de 3 ras h ma y re q uire i ntra ve n o us 
a nti hista mi nes or c ortic oster oi ds. A d mi ni strati o n of i xaz o mi b (a n d/ or ot her ca usati ve 

M C 1 7 8 2
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a ge nt if gi ve n i n c o m bi nati o n) s h o ul d be  m o difie d per pr ot oc ol secti o n 8. 3 a n d re-
i nitiate d at a re d uce d le vel fr o m w here ras h was n ote d (als o, per pr ot oc ol). 
I n li ne wit h cli nical practice, der mat ol o g y c o ns ult a n d bi o ps y of Gra de 3 or hi g her ras h or 
a n y S A E i n v ol vi n g ras h is rec o m me n de d. Pr o p h ylactic meas ures s h o ul d als o be 
c o nsi dere d if a patie nt has pre vi o usl y de vel o pe d a ras h (e. g., usi n g a t hic k, alc o h ol-free 
e m ollie nt crea m o n dr y areas of t he b o d y or oral or t o pical a nti hista mi nes). A rare ris k is 
Ste ve ns-J o h ns o n S y n dr o me, a se vere a n d p ote ntiall y life-t hreate ni n g ras h wit h s ki n 
peeli n g a n d m o ut h s ores, w hic h s h o ul d be  ma na ge d s y m pt o maticall y acc or di n g t o 
sta n dar d me dical practice. P u nc h bi o psies f or hist o pat h ol o gical a nal ysis are e nc o ura ge d 
at t he discreti o n of t he i n vesti gat or. 
 
9. 9 b
 T hr o m b oc yt o pe nia
 
Bl o o d c o u nts s h o ul d be m o nit ore d re g ularl y as o utli ne d i n t he pr ot oc ol wit h a d diti o nal 
testi n g o btai ne d acc or di n g t o sta n dar d cli nical practice. T hr o m b oc yt o pe nia ma y be se vere 
b ut has bee n ma na gea ble wit h platelet tr a nsf usi o ns acc or di n g t o sta n dar d cli nical 
practice. I xaz o mi b a d mi nistrati o n s h o ul d be m o difie d as n ote d as per d ose m o dificati o n 
rec o m me n dati o ns i n t he pr ot oc ol w he n t hr o m b oc yt o pe nia occ urs (see Secti o n 8). 
T hera p y ca n be rei nitiate d at a re d uce d le vel u p o n rec o ver y of platelet c o u nts. A rare ris k 
is t hr o m b otic t hr o m b oc yt o pe nic p ur p ura ( T T P), a rare bl o o d dis or der w here bl o o d cl ots 
f or m i n s mall bl o o d vessels t hr o u g h o ut t he b o d y c haracterize d b y t hr o m b oc yt o pe nia, 
petec hiae, fe v er, or p ossi bl y m ore seri o us  si g ns a n d s y m pt o ms. T T P s h o ul d be ma na ge d 
s y m pt o maticall y acc or di n g t o sta n dar d me dical practice. 
 
9. 9c
 Ne utr o pe nia
 
Bl o o d c o u nts s h o ul d be m o nit ore d re g ularl y as o utli ne d i n t he pr ot oc ol secti o n 4. 0 wit h 
a d diti o nal testi n g o btai ne d acc or di n g t o sta n da r d cli nical practice. Ne utr o pe nia ma y be 
se vere b ut has bee n ma na g ea ble. Gr o wt h fact or s u p p ort is n ot re q uire d b ut ma y be 
c o nsi dere d acc or di n g t o sta n dar d cli nical practice. I xaz o mi b a d mi nistrati o n s h o ul d be 
m o difie d as n ote d as per d ose m o dificati o n rec o m me n dati o ns i n t he pr ot oc ol w he n 
ne utr o pe nia occ urs (see Secti o n 8). T hera p y ca n be rei nitiate d at a re d uce d le vel u p o n 
rec o ver y of A N Cs. 
 
9. 9 d
 Fl ui d
 
Deficit
 
Vitals s h o ul d be assesse d pri or t o start of eac h c y cle as per Ta ble 4. 1. De h y drati o n s h o ul d 
be a v oi de d si nce i xaz o mi b ma y ca use v o miti n g,  diarr hea, a n d de h y drati o n. Patie nts 
s h o ul d be e nc o ura ge d t o mai ntai n a de q uate fl ui d i nta ke. Ac ute re nal fail ure has bee n 
re p orte d i n patie nts treate d wit h i xaz o mi b, c o m m o nl y i n t he setti n g of t he pre vi o usl y 
n ote d gastr oi ntesti nal t o xicities a n d de h y drati o n. Fl ui d deficit s h o ul d be c orrecte d bef ore 
i nitiati o n of st u d y dr u g a n d as nee de d d uri n g treat me nt t o a v oi d de h y drati o n. 
 
9. 9e
 H y p ote nsi o n
 
S y m pt o matic h y p ote nsi o n a n d ort h ostatic h y p ote n si o n wit h or wit h o ut s y nc o pe ha ve bee n 
re p orte d wit h i xaz o mi b. Bl o o d press ure s h o ul d be cl osel y m o nit ore d w hile t he patie nt is 
o n st u d y treat me nt a n d fl ui d deficit s h o ul d be c orrecte d as nee de d , es peciall y i n t he 

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setti n g of c o nc o mita nt s y m pt o ms s uc h as na usea, v o miti n g, diarr hea, or a n ore xia. 
Patie nts ta ki n g me dicati o ns a n d/ or di uretics t o ma na ge t heir bl o o d press ure (f or eit her 
h y p o- or h y perte nsi o n) s h o ul d be ma na ge d acc or di n g t o sta n dar d cli nical practice, 
i ncl u di n g c o nsi derati o ns f or d ose a dj ust me nts of t heir c o nc o mita nt me dicati o ns d uri n g 
t he c o urse of t he trial. Fl ui d deficit s h o ul d be c orrecte d bef ore i nitiati o n of st u d y dr u g a n d 
as nee de d d uri n g treat me nt t o a v oi d de h y drati o n. 
 
9. 9f  
P osteri or Re versi ble E nce p hal o pat h y S y n dr o me 
O ne case of p osteri or re versi ble e nce p hal o pat h y s y n dr o me, w hic h ulti matel y res ol ve d, 
has bee n re p orte d wit h i xaz o mi b. T his c o n d iti o n is c haracterize d b y hea dac he, seiz ures 
a n d vis ual l oss, as well as a br u pt i ncrease i n  bl o o d press ure. Dia g n osis ma y be c o nfir me d 
b y ma g netic res o na nce i ma gi n g ( M RI). If t he s y n dr o me is dia g n ose d or s us pecte d, 
s y m pt o m- directe d treat me nt s h o ul d be mai ntai ne d u ntil t he c o n diti o n is re verse d b y 
c o ntr ol of h y perte nsi o n or ot her i nsti gati n g fact ors. 
 
9. 9 g
 Tra ns verse
 M y elitis
 
Tra ns verse m y elitis has als o bee n re p orte d wit h i xaz o mi b. It is n ot k n o w n if i xaz o mi b 
ca uses tra ns verse m y elitis; h o we ver, beca use it ha p pe ne d t o a patie nt recei vi n g i xaz o mi b, 
t he p ossi bilit y t hat i xaz o mi b ma y ha ve c o ntri b ute d t o tra ns verse m y elitis ca n n ot be 
e xcl u de d. 
 
9. 9 h
 S u p p orti ve
 
Care
 
S u bjects s h o ul d recei ve a p pr o priate s u p p orti ve care meas ures as dee me d necessar y b y t he 
treati n g i n vesti gat or.  S u g geste d s u p p orti ve care meas ures f or t he ma na ge me nt of a d verse 
e ve nts wit h p ote ntial i m m u n ol o gic eti ol o g y are o utli ne d bel o w. W here a p pr o priate, t hese 
g ui deli nes i ncl u de t he use of oral or i ntra ve n o us treat me nt wit h c ortic oster oi ds as well as 
a d diti o nal a nti-i nfla m mat or y a ge nts if s y m p t o ms d o n ot i m pr o ve wit h a d mi nistrati o n of 
c ortic oster oi ds.   N ote t hat se veral c o urses of ster oi d ta peri n g ma y be necessar y as 
s y m pt o ms ma y w orse n w he n t he ster oi d d ose is decrease d. F or eac h dis or der, atte m pts 
s h o ul d be ma de t o r ule o ut ot her ca uses s uc h as metastatic disease or bacterial or viral 
i nfecti o n, w hic h mi g ht re q uire a d diti o nal s u p p orti ve care. T he treat me nt g ui deli nes are 
i nte n de d t o be a p plie d w he n t he i n vesti gat or deter mi nes t he e ve nts t o be relate d t o 
pe m br oliz u ma b.  
N ote: if after t he e val uati o n t he e ve nt is dete r mi ne d n ot t o be relate d, t he i n vesti gat or 
d oes n ot nee d t o f oll o w t he treat me nt g ui da nce (as o utli ne d bel o w). Refer t o Ta ble 8. 2 f or 
d ose m o dificati o n.  
It ma y be necessar y t o perf or m c o n diti o nal pr oce d ures s uc h as br o nc h osc o p y, e n d osc o p y, 
or s ki n p h ot o gra p h y as part of e val uati o n of t he e ve nt.  
 
•  
P ne u m o nitis :  
o  F or Gr a de 2 e ve nts , treat wit h s yste mic c ortic oster oi ds. W he n s y m pt o ms i m pr o ve t o 
Gra de 1 or less, ster oi d ta per s h o ul d be star te d a n d c o nti n ue d o ver n o less t ha n 4 wee ks. 
o  F or Gr a de 3- 4 e ve nts , i m me diatel y treat wit h i ntra ve n o us ster oi ds.  A d mi nister 
a d diti o nal a nti-i nfla m mat or y meas ures, as nee de d. 

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o  A d d pr o p h ylactic a nti bi otics f o r o p p ort u nistic i nfecti o ns i n t he case of pr ol o n ge d ster oi d 
a d mi nistrati o n. 
 
•  
Di arr he a/ C olitis :  
S u bjects s h o ul d be caref ull y m o nit ore d f or si g ns a n d s y m pt o ms of e nter oc olitis (s uc h as diarr hea, 
a b d o mi nal pai n, bl o o d or m u c us i n st o ol, wit h or wit h o ut fe ver) a n d of b o wel perf orati o n (s uc h as 
perit o neal si g ns a n d ile us).   
o  All s u bjects w h o e x perie nce diarr hea/c olitis s h o ul d be a d vise d t o dri n k li beral q ua ntities 
of clear fl ui ds.  If s ufficie nt oral fl ui d i nta ke is n ot feasi ble, fl ui d a n d electr ol ytes s h o ul d 
be s u bstit ute d via I V i nf usi o n.  F or Gra de 2 or hi g her diarr hea, c o nsi der GI c o ns ultati o n 
a n d e n d osc o p y t o c o nfir m or r ule o ut c olitis. 
o  F or Gr a de 2 di arr he a/c olitis,  a d mi nister oral c ortic oster oi ds.  
o  F or Gr a de 3 or 4 di arr he a/c olitis,  treat wit h i ntra ve n o us ster oi ds f oll o we d b y hi g h d ose 
oral ster oi ds.   
o  W he n  s y m pt o ms  i m pr o ve  t o  Gra de  1  or  less,  ster oi d  ta per  s h o ul d  be  starte d  a n d  
c o nti n ue d o ver n o less t ha n 4 wee ks. 
•  
T y pe 1 di a betes mellit us (if ne w o nset, i ncl u di n g di a betic ket o aci d osis [ D K A]) or ≥ Gr a de 3 
H y per gl yce mi a, if ass oci ate d wit h ket osi s ( ket o n uri a) or met a b olic aci d osis ( D K A) 
o  F or T 1 D M  or Gr a de 3- 4  H y per gl y ce mia 
 
I ns uli n re place me nt t hera py is rec o m me n de d f or T y pe I dia betes mellit us a n d f or 
Gra de 3- 4 h y per gl y ce mia ass ociate d wit h meta b olic aci d osis or ket o n uria.  
 
E val uate  patie nts  wit h  ser u m  gl uc ose  a n d  a  meta b olic  pa nel,  uri ne  ket o nes,  
gl y c os ylate d he m o gl o bi n, a n d C- pe pti de.  
•  
H y p o p h ysitis : 
o  F or Gr a de 2  e ve nts, treat wit h c ortic oster oi ds. W he n s y m pt o ms i m pr o ve t o Gra de 1 or 
less,  ster oi d  ta per  s h o ul d  be  starte d  an d  c o nti n ue d  o ver  n o  less  t ha n  4  wee ks.  
Re place me nt of a p pr o priate h or m o nes ma y be  re q uire d as t he ster oi d d ose is ta pere d. 
o  F or Gr a de 3- 4  e ve nts, treat wit h a n i nitial d ose of I V c ortic oster oi ds f oll o we d b y oral 
c ortic oster oi ds. W he n s y m pt o ms i m pr o ve t o  Gra de 1 or less, ster oi d ta per s h o ul d be 
starte d a n d c o nti n ue d o ver n o less t ha n 4 wee ks. Re place me nt of a p pr o priate h or m o nes 
ma y be re q uire d as t he ster oi d d ose is ta pere d. 
 
•  
H y pert h yr oi dis m or H y p ot h yr oi dis m :  
T h yr oi d dis or ders ca n occ ur at a n y ti me d uri n g tr eat me nt. M o nit or patie nts f or c ha n ges i n t h yr oi d 
f u ncti o n (at t he start of treat me nt, peri o dicall y d uri n g treat me nt, a n d as i n dicate d base d o n cli nical 
e val uati o n) a n d f or cli nical si g ns a n d s y m pt o ms of t h yr oi d dis or ders. 
o  Gr a de 2  h y pert h yr oi dis m e ve nts (a n d Gr a de 2- 4  hy p ot h y r oi dis m): 
 
I n h y pert h yr oi dis m, n o n-selecti ve beta- bl oc kers (e. g. pr o pra n ol ol) are s u g geste d 
as i nitial t hera p y. 
 
I n h y p ot h yr oi dis m, t h yr oi d h or m o ne re place me nt t hera p y, wit h le v ot h yr o xi ne or 
li ot h yr oi ni ne, is i n dicate d per sta n dar d of care. 
o  Gr a de 3- 4  h y pert h yr oi dis m  

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 
Treat wit h a n i nitial d ose of I V c ortic oste r oi d f oll o we d b y oral c ortic oster oi ds. 
W he n s y m pt o ms i m pr o ve t o Gra de 1 or less, ster oi d ta per s h o ul d be starte d a n d 
c o nti n ue d o ver n o less t ha n 4 wee ks. Re place me nt of a p pr o priate h or m o nes ma y 
be re q uire d as t he ster oi d d ose is ta pere d. 
•  
He p atic : 
o  F or Gr a de  2  e ve nts,  m o nit or  li ver  f u ncti o n  tests  m ore  fre q ue ntl y  u ntil  ret ur ne d  t o  
baseli ne val ues (c o nsi der wee kl y). 
 
Treat wit h I V or oral c ortic oster oi ds 
o  F or Gr a de 3- 4  e ve nts, treat wit h i ntra ve n o us c ortic oster oi ds f or 2 4 t o 4 8 h o urs.  
o  W he n  s y m pt o ms  i m pr o ve  t o  Gra de  1  or  le ss,  a  ster oi d  ta per  s h o ul d  be  starte d  a n d  
c o nti n ue d o ver n o less t ha n 4 wee ks. 
•  
Re n al F ail ure or Ne p hritis : 
o  F or Gr a de 2  e ve nts, treat wit h c ortic oster oi ds. 
o  F or Gr a de 3- 4  e ve nts, treat wit h s yste mic c ortic oster oi ds. 
o  W he n  s y m pt o ms  i m pr o ve  t o  Gra de  1  or  less,  ster oi d  ta per  s h o ul d  be  starte d  a n d  
c o nti n ue d o ver n o less t ha n 4 wee ks.  
•  
M a n a ge me nt of I nf usi o n Re acti o ns : Si g ns a n d s y m pt o ms us u all y de vel o p d uri n g or s h ortl y 
after dr u g i nf usi o n a n d ge nerall y res ol ve c o m pletel y  wit hi n 2 4 h o urs of c o m pleti o n of i nf usi o n.  
Ta ble 9. 1. bel o w  s h o ws treat me nt g ui deli nes f or s u bjects w h o e x perie nce a n i nf usi o n reacti o n 
ass ociate d wit h a d mi nistrati o n of pe m br oliz u ma b ( M K- 3 4 7 5). 
T a ble 9. 9 h 1 I nf usi o n Re acti o n Tre at me nt G ui deli n es 
N CI C T C A E Gr a de 
Tre at me nt 
Pre me dic ati o n at 
s u bse q ue nt d osi n g 
Gra de 1 
Mil d reacti o n; i nf usi o n 
i nterr u pti o n n ot i n dicate d; 
i nter ve nti o n n ot i n dicate d 
I ncrease m o nit ori n g of vital si g ns as 
me dicall y i n dicate d u ntil t he s u bject 
is dee me d me dicall y sta ble i n t he 
o pi ni o n of t he i n vesti gat or. 
N o ne 
Gra de 2 
Re q uires i nf usi o n 
i nterr u pti o n b ut res p o n ds 
pr o m ptl y t o s y m pt o matic 
treat me nt (e. g., 
a nti hista mi nes, N S AI D S, 
narc otics, I V fl ui ds); 
pr o p h ylactic me dicati o ns 
i n dicate d f or < = 2 4 hrs 
St o p I nf usi o n a n d m o nit or 
s y m pt o ms. 
A d diti o nal a p pr o priate me dical 
t hera p y ma y i ncl u de b ut is n ot 
li mite d t o: 
I V fl ui ds 
A nti hista mi nes 
N S AI D S 
Aceta mi n o p he n 
Narc otics 
I ncrease m o nit ori n g of vital si g ns as 
me dicall y i n dicate d u ntil t he s u bject 
is dee me d me dicall y sta ble i n t he 
o pi ni o n of t he i n vesti gat or. 
If s y m pt o ms res ol ve wit hi n o ne 
h o ur of st o p pi n g dr u g i nf usi o n, t he 
i nf usi o n ma y be restarte d at 5 0 % of 
S u bject ma y be 
pre me dicate d 1. 5 h ( ± 3 0 
mi n utes) pri or t o i nf usi o n 
of pe m br oliz u ma b ( M K-
3 4 7 5) wit h: 
 
Di p he n h y dra mi ne 5 0 m g 
p o ( or e q ui vale nt d ose of 
a nti hista mi ne). 
 
Aceta mi n o p he n 5 0 0- 1 0 0 0 
m g p o ( or e q ui vale nt d ose 
of a nti p yretic). 

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N CI C T C A E Gr a de 
Tre at me nt 
Pre me dic ati o n at 
s u bse q ue nt d osi n g 
t he ori gi nal i nf usi o n rate (e. g., fr o m 
1 0 0 m L/ hr t o 5 0 m L/ hr).  Ot her wise 
d osi n g will be hel d u ntil s y m pt o ms 
res ol ve a n d t he s u bject s h o ul d be 
pre me dicate d f or t he ne xt sc he d ule d 
d ose. 
S u bjects w h o de vel o p Gr a de 2 
t o xicit y des pite a de q u ate 
pre me dic ati o n s h o ul d be 
per m a ne ntl y disc o nti n ue d fr o m 
f urt her tri al tre at me nt 
a d mi nistr ati o n.  
Gra des 3 or 4 
Gra de 3: 
Pr ol o n ge d (i.e., n ot ra pi dl y 
res p o nsi ve t o s y m pt o matic 
me dicati o n a n d/ or brief 
i nterr u pti o n of i nf usi o n); 
rec urre nce of s y m pt o ms 
f oll o wi n g i nitial 
i m pr o ve me nt; 
h os pitalizati o n i n dicate d f or 
ot her cli nical se q uelae (e. g., 
re nal i m pair me nt, 
p ul m o nar y i nfiltrates) 
Gra de 4: 
Life-t hreate ni n g; press or or 
ve ntilat or y s u p p ort 
i n dicate d 
St o p I nf usi o n. 
A d diti o nal a p pr o priate me dical 
t hera p y ma y i ncl u de b ut is n ot 
li mite d t o: 
I V fl ui ds 
A nti hista mi nes 
N S AI D S 
Aceta mi n o p he n 
Narc otics 
O x y ge n 
Press ors 
C ortic oster oi ds 
E pi ne p hri ne 
 
I ncrease m o nit ori n g of vital si g ns as 
me dicall y i n dicate d u ntil t he s u bject 
is dee me d me dicall y sta ble i n t he 
o pi ni o n of t he i n vesti gat or. 
H os pitalizati o n ma y be i n dicate d. 
S u bject is per m a ne ntl y 
disc o nti n ue d fr o m f urt her tri al 
tre at me nt a d mi nistr ati o n. 
N o s u bse q ue nt d osi n g 
A p pr o priate res uscitati o n e q ui p me nt s h o ul d be a v aila ble i n t he r o o m a n d a p h ysicia n rea dil y 
a vaila ble d uri n g t he peri o d of dr u g a d mi nistrati o n. 
 
 
9. 9i   Pe m br oliz u ma b ma y ha ve a d verse effects o n a fet us i n uter o.  F urt her m ore, it is n ot k n o w n 
if pe m br oliz u ma b has tra nsie nt a d verse effects o n t he c o m p ositi o n of s per m.   
F or t his trial, male s u bjects will be c o nsi der e d t o be of n o n-re pr o d ucti ve p ote ntial if t he y 
ha ve az o os per mia ( w het her d ue t o ha vi n g  ha d a vasect o m y or d ue t o a n u n derl yi n g 
me dical c o n diti o n).   
Fe male s u bjects will be c o nsi dere d of n o n -re pr o d ucti ve p ote ntial if t he y are eit her:  
( 1) p ost me n o pa usal ( defi ne d as at least 1 2 m o nt hs wit h n o me nses wit h o ut a n alter nati ve 
me dical ca use; i n w o me n < 4 5 y ears of a ge 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 

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w o me n n ot usi n g h or m o nal c o ntrace pti o n or h or m o nal re place me nt t hera p y. I n t he 
a bse nce of 1 2 m o nt hs of a me n orr hea, a si n gl e F S H meas ure me nt is i ns ufficie nt.);  
O R  
( 2) ha ve ha d a h ysterect o m y a n d/ or bilateral o o p h orect o m y, bilateral sal pi n gect o m y or 
bilateral t u bal li gati o n/ occl usi o n, at least 6 wee ks pri or t o scree ni n g;  
O R  
( 3) has a c o n ge nital or ac q uire d c o n diti o n t hat pre ve nts c hil d beari n g. 
Fe male a n d male s u bjects of  re pr o d ucti ve p ote ntial m ust a gree t o a v oi d bec o mi n g 
pre g na nt or i m pre g nati n g a part ner, res pec ti vel y, w hile recei vi n g st u d y dr u g a n d f or 1 2 0 
da ys after t he last d ose of st u d y dr u g b y c o m pl yi n g wit h o ne of t he f oll o wi n g:   
( 1) practice a bsti ne nce † fr o m heter ose x ual acti vit y;  
O R   
( 2) use ( or ha ve t heir part ner use) acce pta ble c o ntrace pti o n d uri n g heter ose x ual acti vit y.   
 
Acce pta ble met h o ds of c o ntrace pti o n are ‡: 
Si n gle met h o d ( o ne of t he f oll o wi n g is acce pta ble): 
• i ntra uteri ne de vice (I U D) 
• vasect o m y of a fe male s u bject’s male part ner  
• c o ntrace pti ve r o d i m pla nte d i nt o t he s ki n 
  
C o m bi nati o n met h o d (re q uires use of t w o of t he f oll o wi n g): 
• dia p hra g m wit h s per mici de (ca n n ot be use d i n c o nj u ncti o n wit h cer vical ca p/s p er mici de) 
• cer vical ca p wit h s per mici de ( n ulli par o us w o me n o nl y)   
• c o ntrace pti ve s p o n ge ( n ulli par o us w o me n o nl y)  
• male c o n d o m or fe male c o n d o m (ca n n ot be use d t o get her) 
• h or m o nal c o ntrace pti ve: oral c o ntrace pti ve pill (estr o ge n/ pr o gesti n pill or pr o gesti n- o nl y 
pill), c o ntrace pti ve s ki n patc h, va gi nal c o nt race pti ve ri n g, or s u bc uta ne o us c o ntrace pti ve 
i njecti o n 
  
† A bsti ne nce (relati ve t o heter ose x ual acti vit y) ca n be use d as t he s ole met h o d of 
c o ntrace pti o n if it is c o nsiste ntl y e m pl o ye d as t he s u bject’s preferre d a n d us ual lifest yle 
a n d if c o nsi dere d acce pta ble b y l ocal re g ulat or y a ge ncies a n d E R Cs/I R Bs.  Peri o dic 
a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt o -t her mal, p ost- o v ulati o n met h o ds, etc.) a n d 
wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n.  
  
‡If a c o ntrace pti ve met h o d liste d a b o ve is rest ricte d b y l ocal re g ulati o ns/ g ui deli nes, t he n it 
d oes n ot q ualif y as a n acce pta ble met h o d of c o ntrace pti o n f or s u bjects partici pati n g at sites 
i n t his c o u ntr y/re gi o n. 
 
S u bjects s h o ul d be i nf or me d t hat ta ki n g t he st u d y me dicati o n ma y i n v ol ve u n k n o w n ris ks 
t o t he fet us ( u n b or n ba b y) if pre g na nc y were t o occ ur d uri n g t he st u d y.  I n or der t o 
partici pate i n t he st u d y s u bjects of c hil d beari n g p ote ntial m ust a d here t o t he c o ntrace pti o n 
re q uire me nt ( descri be d a b o ve) fr o m t he da y of st u d y me dicati o n i nitiati o n ( or 1 4 da ys 
pri or t o t he i nitiati o n of st u d y me dicati o n f or oral c o ntrace pti o n) t hr o u g h o ut t he st u d y 
peri o d u p t o 1 2 0 da ys after t he last d ose of trial t hera p y.  If t here is a n y q uesti o n t hat a 
s u bject of c hil d beari n g p ote ntial will n ot relia bl y c o m pl y wit h t he re q uire me nts f or 
c o ntrace pti o n, t hat s u bject s h o ul d n ot be e ntere d i nt o t he st u d y. 
 
 
 
 

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Eve nts of I nterest 
E ve nts t hat w o ul d n ot t y picall y be c o nsi dere d t o meet t he criteria f or e x pe dite d re p orti n g, b ut t hat 
f or a s pecific pr ot oc ol are bei n g re p orte d via e x pe dite d mea ns i n or der t o facilitate t he re vie w of 
safet y data ( ma y be re q ueste d b y t he F D A or t he s p o ns or).  
U n a ntici p ate d A dverse Device Eve nt ( U A D E) 
A n y seri o us a d verse effect o n healt h or safet y or  a n y life-t hreate ni n g pr o ble m or deat h ca use d b y, 
or ass ociate d wit h, a de vice, if t hat effect, pr o ble m, or deat h was n ot pre vi o usl y i de ntifie d i n 
nat ure, se verit y, or de gree of i nci de nce i n t he i n vesti gati o nal pla n or a p plicati o n (i ncl u di n g a 
s u p ple me ntar y pla n or a p plicati o n), or a n y ot her u na ntici pate d seri o us pr o ble m ass ociate d wit h a 
de vice t hat relates t o t he ri g hts, safet y, or welfare of s u bjects 
1 0. 1  
A d verse E ve nt C haracteristics 
C T C A E ter m ( A E descri pti o n) a n d gr a de: T he descri pti o ns a n d gra di n g scales f o u n d 
i n t he re vise d 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) versi o n 
4. 0 will be utilize d f or A E re p orti n g. All a p pr o priate treat me nt areas s h o ul d ha ve access 
t o a c o p y of t he C T C A E versi o n 4. 0. A c o p y of t he C T C A E versi o n 4. 0 ca n be 
d o w nl oa de d fr o m t he C T E P we b site: 
 
a. I de ntify t he gra de a n d se verit y of t he e ve nt usi n g t he C T C A E versi o n 4. 0. 
b.  Deter m i ne whet her t he e ve nt is e x pecte d or u ne x pecte d (see Secti o n 1 0. 2). 
c. Deter mi ne if t he a d verse e ve nt is relate d t o  t he st u d y i nter ve nti o n (a ge nt, treat me nt or 
pr oce d ure) (see Secti o n 1 0. 3). 
d.  Deter mi ne w het her t he e ve nt m ust be re p orte d as a n e x pe dite d re p ort. If y es, 
deter mi ne t he ti mefra me/ mec ha n is m (see Secti o n 1 0. 4).  
e. Deter mi ne if ot her re p orti n g is  re q uire d (see Secti o n 1 0. 5). 
f. N ote: All A Es re p orte d via e x pe dite d mec h a nis ms m ust als o be re p orte d via t he 
r o uti ne data re p orti n g mec ha nis ms defi ne d b y t he pr ot oc ol (see Secti o ns 1 0. 6 a n d 
1 8. 0). 
N O T E: A se v ere A E is N O T t he sa me as a seri o us A E, w hic h is defi ne d i n Secti o n 1 0. 4. 
1 0. 2  
E x pecte d vs. U ne x pecte d E ve nts  
Ex pecte d eve nts  - are t h ose descri be d wit hi n t he Secti o n 1 5. 0 of t he pr ot oc ol, t he st u d y 
s pecific c o nse nt f or m, pac ka ge i nsert (if a p plica ble), a n d/ or t he i n vesti gat or br oc h ure, (if 
a n i n vesti gat or br oc h ure is n ot re q uire d, ot her wise descri be d i n t he ge neral 
i n vesti gati o nal pla n).  
U nex pecte d a dverse eve nts  or s us pecte d a d verse reacti o ns are t h ose n ot liste d i n Secti o n 
1 5. 0 of t he pr ot oc ol, t he st u d y s pecific c o nse nt f or m, pac ka ge i nsert (if a p plica ble), or i n 
t he i n vesti gat or br oc h ure ( or are n ot liste d at t he s pecificit y or se verit y t hat has bee n 
o bser ve d); if a n i n vesti gat or br oc h ure is n ot re q uire d or a vaila ble, is n ot c o nsiste nt wit h 
t he ris k i nf or mati o n descri be d i n t he ge neral i n vesti gati o nal pla n. 
U nex pecte d  als o refers t o a d verse e ve nts or s us pecte d a d verse reacti o ns t hat are 
me nti o ne d i n t he i n vesti gat or br oc h ure as occ urri n g wit h a class of dr u gs b ut ha ve n ot 
bee n o bser ve d wit h t he dr u g u n der i n vesti gati o n. 
A n i n vesti gati o nal a ge nt/i nter v e nti o n mi g ht e xacer bate t he e x pecte d A Es ass ociate d wit h a 
c o m mercial a ge nt. T heref ore, if a n e x pecte d A E (f or t he c o m m ercial a ge nt) occ urs wit h a 
hi g her de gree of se verit y or s pecificit y, e x pe dite d re p orti n g is re q uire d. 

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 0. 3 2 
E X P E C T E D Seri o us A d verse E ve nts: Pr ot oc ol S pecific E xce pti o ns t o 
E x pe dite d Re p orti n g  
F or t his pr ot oc ol o nl y, t he f oll o wi n g A d verse E ve nts/ Gra des are e x pecte d t o occ ur 
wit hi n t his p o p ulati o n a n d d o n ot re q uire E x pe dite d Re p orti n g. T hese e ve nts m ust still 
be re p orte d via R o uti ne Re p orti n g (see Secti o n 1 0. 6). * 
* Re p ort a n y cli nicall y i m p orta nt i ncrease i n t he rate of a seri o us s us pecte d 
a d verse reacti o n (at y o ur st u d y site) o ver t h at w hic h is liste d i n t he pr ot oc ol or 
i n vesti gat or br oc h ure as a n e x pe dite d e ve nt.  
* Re p ort a n e x pecte d e ve nt t hat is greater i n se verit y or s pecificit y t ha n e x pecte d 
as a n e x pe dite d e ve nt.   
C T C A E 
S yste m Or ga n Class 
( S O C) 
A d verse e ve nt/ 
S y m pt o ms 
C T C A E Gra de at 
w hic h t he e ve nt 
will n ot be 
e x pe dite dl y 
re p orte d. 
Bl o o d a n d l y m p hatic 
s yste m dis or ders 
A ne mia 
≤ Gra de 4 
Gastr oi ntesti nal
 Diarr hea
 
≤ Gra de 3 
 Na usea
 
≤ Gra de 3 
 V o miti n g
 
≤ Gra de 3 
Ge neral dis or ders a n d 
a d mi nistrati o ns site 
c o n diti o ns 
Fati g ue  
≤ Gra de 3 
 
 
I n vesti gati o ns
 L y m p h oc yte
 
c o u nt
 
decrease d 
≤ Gra de 4 
Ne utr o p hil c o u nt 
decrease d 
≤ Gra de 4 
Platelet c o u nt 
decrease d 
≤ Gra de 4 
 
W hite bl o o d cell c o u nt 
decrease d 
≤ Gra de 4 
1 T hese e xce pti o ns o nl y a p pl y if t he a d verse e ve nt d oes n ot res ult i n h os pitalizati o n. If t he a d verse 
e ve nt res ults i n h os pitalizati o n, t he n t he sta n dar d e x pe dite d a d verse e ve nts re p orti n g 
re q uire me nts m ust be f oll o we d.  
S pecific pr ot oc ol e xce pti o ns t o e x pe dite d re p orti n g s h o ul d be re p orte d e x pe diti o usl y b y 
i n vesti gat ors O N L Y  if t he y e xcee d t he e x pecte d gra de of t he e ve nt. 
 
T he f oll o wi n g h os pitalizati o ns are n ot c o nsi dere d t o be S A Es beca use t here is n o “a d verse e v e nt” 
(i.e., t here is n o u nt o war d me dical occ urre nce) ass ociate d wit h t he h os pitalizati o n: 
● H os pitalizati o ns f or res pite care 
● Pla n ne d h os pitalizati o ns re q uire d b y t he pr ot oc ol 
● H os pitalizati o n pla n ne d bef ore i nf or me d c o nse nt ( w here t he c o n diti o n re q uiri n g t he 
h os pitalizati o n has n ot c ha n ge d p ost st u d y dr u g a d mi nistrati o n) 
● H os pitalizati o n f or electi ve pr oce d ures u nrelate d t o t he c urre nt disease a n d/ or treat me nt o n t his 
trial 
● H os pitalizati o n f or a d mi nistrati o n of st u d y dr u g or i nserti o n of access f or a d mi nistrati o n of 
st u d y dr u g 
● H os pitalizati o n f or r o uti ne mai nte na nce of a de vice (e. g., batter y re place me nt) t hat was i n place 
bef ore st u d y e ntr y 

M C 1 7 8 2
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1 0. 4 2  Ge neral re p orti n g i nstr ucti o ns 
T he Ma y o I N D C o or di nat or will assist t he s p o ns or-i n vesti gat or i n t he pr ocessi n g 
of e x pe dite d a d verse e ve nts a n d f or w ar di n g of s us pecte d u ne x pecte d seri o us 
a d verse reacti o ns ( S U S A Rs) t o t he F D A a n d I R B. 
Use Ma y o E x pe dite d E ve nt Re p ort f or m 
i n vesti gati o nal a ge nts or 
c o m mercial/i n vesti gati o nal a ge nts o n t he sa me ar m.  
  
1 0. 4 3   Re p orti n g of re- occ urri n g S A Es 
A L L S E RI O U S a d verse e ve nts t hat meet  t he criteria o utli ne d i n ta ble 1 0. 4 1 
M U S T be i m me diatel y re p orte d t o t he s p o ns or wit hi n t he ti mefra mes detaile d i n 
t he c orres p o n di n g ta ble. T his re p orti n g i ncl u des, b ut is n ot li mite d t o S A Es t hat 
re- occ ur a gai n after res ol uti o n. 
1 0. 5  
Ot her Re q uire d Re p orti n g 
1 0. 5 1  U na ntici pate d Pr o ble ms I n v ol vi n g Ris ks t o S u bjects or Ot hers ( U PI R T S O S)  
U na ntici pate d Pr o ble ms I n v ol vi n g Ris ks t o S u bjects or Ot hers ( U PI R T S O S) i n 
ge neral, i ncl u de a n y i nci de nt, e x perie nce, or o utc o me t hat meets all  of t he 
f oll o wi n g criteria: 
1.  U ne x pecte d (i n ter ms of nat ure, se verit y , or fre q ue nc y) gi ve n (a) t he researc h 
pr oce d ures t hat are descri be d i n t he pr ot oc ol-relate d d oc u me nts, s uc h as t he 
I R B-a p pr o ve d researc h pr ot oc ol a n d i nf or me d c o nse nt d oc u me nt; a n d ( b) t he 
c haracteristics of t he s u bject p o p ulati o n bei n g st u die d; 
2.  Relate d or p ossi bl y relate d t o partici p ati o n i n t he researc h (i n t his g ui da nce 
d oc u me nt, p ossi bl y relate d mea ns t here is a reas o na ble p ossi bilit y t hat t he 
i nci de nt, e x perie nce, or o utc o me ma y ha ve bee n ca use d b y t he pr oce d ures 
i n v ol ve d i n t he researc h); a n d 
3.  S u g gests t hat t he researc h places s u bjects or ot hers at a greater ris k of har m 
(i ncl u di n g p h ysical, ps y c h ol o gical, ec o n o mic, or s ocial har m) t ha n was 
pre vi o usl y k n o w n or rec o g nize d. 
S o me u na ntici pate d pr o ble ms i n v ol ve s oci al or ec o n o mic har m i nstea d of t he 
p h ysical or ps y c h ol o gical har m ass ociate d wit h a d verse e ve nts. I n ot her cases, 
u na ntici pate d pr o ble ms place s u bjects or ot hers at i ncrease d risk of har m, b ut n o 
har m occ urs. 
N ote: If t here is n o la n g ua ge i n t he pr ot oc ol i n dicati n g t hat pre g na nc y is n ot 
c o nsi dere d a n a d verse e x perie nce f or t his trial, a n d if t he c o nse nt f or m d oes n ot 
i n dicate t hat s u bjects s h o ul d n ot get pre g na nt/i m pre g n ate ot hers, t he n a n y 
pre g na nc y i n a s u bject/ patie nt or a male patie nt’s part ner (s p o nta ne o usl y 
re p orte d) w hic h occ urs d uri n g t he st u d y or wit hi n 1 2 0 da ys of c o m pleti n g t he 
st u d y s h o ul d be re p orte d as a U PI R T S O. 
M a y o Cli nic C a ncer Ce nter ( M C C C) I nstit uti o ns: 
If t he e ve nt meets t he criteria f or I R B s u b missi o n as a Re p orta ble 
E ve nt/ U PI R T S O, pr o vi de t he Re p orta ble E ve nt Re p ort F or m 

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 0. 6  
Re q uire d R o uti ne Re p orti n g  
1 0. 6 1  Baseli ne a n d A d verse E ve nts E val uati o ns 
Pretreat me nt s y m pt o ms/c o n diti o ns t o be gr a de d at baseli ne a n d a d verse e ve nts t o 
be gra de d at eac h e val uati o n.  
Gra di n g is per C T C A E v 4. 0 u nless  alter nate gra di n g is i n dicate d i n t he ta ble 
bel o w: 
C T C A E 
S Y S T E M/ O R G A N/ C L A S S
 A d verse
 
e ve nt/ S y m pt o ms
  Baseli ne
 
Eac h 
e val uati o n 
Bl o o d a n d l y m p hatic s yste m 
dis or ders 
Fe brile ne utr o pe nia  
X  
X 
Gastr oi ntesti nal Dis or ders  
Baseli ne # of st o ols 
X  
 
 C o nsti pati o n
 
 
 
X
 Diarr hea
 
 
 
X
 Na usea
  
X
 
X
 V o miti n g
  
X
 
X
Ge neral dis or ders a n d 
a d mi nistrati o n site 
c o n diti o ns 
Fati g ue   
X  
X 
I nfecti o ns a n d i nfestati o ns  
Se psis 
X  
X 
I n vesti gati o ns
 Creati ni ne
 
i ncrease d
  
X
 
X
 
 
Ne utr o p hil c o u nt decrease d 
X  
X 
 
Platelet c o u nt decrease d 
X  
X 
S ki n a n d s u bc uta ne o us tiss ue 
dis or ders 
Ras h, mac ul o- pa p ular  
X  
X 
1 0. 6 2  S u b mit via a p pr o priate M C C C Case Re p ort F or ms (i.e., pa per or electr o nic, as 
a p plica ble) t he f oll o wi n g A Es e x perie nce d b y a patie nt a n d n ot s pecifie d i n 
Secti o n 1 0. 6: 
1 0. 6 2 1  Gra de 2 A Es dee me d p ossi bly, pr o b a bly, or defi nitely  relate d t o t he st u d y 
treat me nt or pr oce d ure. 
1 0. 6 2 2  Gra de 3 a n d 4 A Es re gar dless of attri b uti o n t o t he st u d y treat me nt or 
pr oce d ure. 
1 0. 6 2 3  Gra de 5 A Es ( Deat hs) 
1 0. 6 2 3 1 A n y deat h wit hi n 3 0 da ys of t he patie nt’s last st u d y treat me nt or 
pr oce d ure re gar dless of attri b uti o n t o t he st u d y treat me nt or pr oce d ure. 
1 0. 6 2 3 2 A n y deat h m ore t ha n 3 0 da ys after t he patie nt’s last st u d y treat me nt or 
pr oce d ure t hat is felt t o be at least p ossi bl y treat me nt relate d m ust als o be 
s u b mitte d as a Gra de 5 A E, wit h a C TC A E t y pe a n d attri b uti o n assi g ne d. 
1 0. 7  
Late Occ urri n g A d verse E ve nts 
Refer t o t he i nstr ucti o ns i n t he F or ms Pa c ket ( or electr o nic data e ntr y scree ns, as 
a p plica ble) re gar di n g t he s u b missi o n of la te occ urri n g A Es f oll o wi n g c o m pleti o n of t he 
Acti ve M o nit ori n g P hase (i.e., c o m plia n ce w it h Test Sc he d ule i n Secti o n 4. 0). 
 
 

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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 0. 8  
A d diti o nal E ve nt Re p orti n g I nstr ucti o ns  
1 0. 8 1  Merc k  
All a d verse e ve nts will be rec or de d fr o m t he ti me t he c o nse nt f or m is si g ne d t hr o u g h 3 0 
da ys f oll o wi n g cessati o n of treat me nt a n d at eac h e xa mi nati o n o n t he A d verse E ve nt case 
re p ort f or ms/ w or ks heets. T he re p orti n g ti mefra me f or a d verse e ve nts meeti n g a n y seri o us 
criteria is descri be d a b o ve. 
Defi niti o n of a n O ver d ose f or T his Pr ot oc ol a n d Re p orti n g of O ver d ose t o t he 
S p o ns or a n d t o Merc k 
F or p ur p oses of t his trial, a n o ver d ose of pe m br oliz u ma b will be defi ne d as a n y d ose of 
1, 0 0 0 m g or greater ( ≥5 ti mes t he i n dicate d d ose).  N o s pecific i nf or mati o n is a vaila ble 
o n t he treat me nt of o ver d ose of pe m br oliz u m a b. A p pr o priate s u p p orti ve treat me nt s h o ul d 
be pr o vi de d if cli nicall y i n dicate d. I n t he e ve nt of o ver d ose, t he s u bject s h o ul d be 
o bser ve d cl osel y f or si g ns of t o xicit y.  A p pr o priate s u p p orti ve treat me nt s h o ul d be 
pr o vi de d if cli nicall y i n dicate d. 
 
If a n a d verse e ve nt(s) is ass ociate d wit h (“res ults fr o m”) t he o ver d ose of a Merc k 
pr o d uct, t he a d verse e ve nt(s) is re p orte d as a seri o us a d verse e ve nt, e ve n if n o ot her 
seri o us ness criteria are met. 
If a d ose of Merc k’s pr o d uct meeti n g t he pr ot ocol defi niti o n of o ver d ose is ta ke n wit h o ut 
a n y ass ociate d cli nical s y m pt o ms or a b n or mal la b orat or y res ults, t he o ver d ose is re p orte d 
as a n o n-seri o us E ve nt of Cli nical I nterest ( E CI), usi n g t he ter mi n ol o g y “acci de ntal or 
i nte nti o nal o ver d ose wit h o ut a d verse effect.” 
All re p orts of o ver d ose wit h a n d wit h o ut a n  a d verse e ve nt m ust be re p orte d wit hi n 2 4 
h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g da ys h o u
 
 
 
Re p orti n g of Pre g n a nc y a n d L act ati o n t o Merc k 
Alt h o u g h pre g na nc y a n d lactati o n are n ot c o nsi dere d a d verse e ve nts, it is t he 
res p o nsi bilit y of i n vesti gat ors or t heir desi g nees t o re p ort a n y pre g na nc y or lactati o n i n a 
s u bject (s p o nta ne o usl y re p orte d t o t he m), i ncl u di n g t he pre g na nc y of a male s u bject's 
fe male part ner t hat occ urs d uri n g t he trial or wit hi n 1 2 0 da ys of c o m pleti n g t he trial 
c o m pleti n g t he trial, or 3 0 da ys f oll o wi n g cessati o n of treat me nt if t he s u bject i nitiates 
ne w a ntica ncer t hera p y, w hic he ver is earlier.  All s u bjects a n d fe male part ners of male 
s u bjects w h o bec o me pre g na nt m ust be f oll o we d t o t he c o m pleti o n/ter mi nati o n of t he 
pre g na nc y.  Pre g na nc y o utc o mes of s p o nt a ne o us a b orti o n, misse d a b orti o n, be ni g n 
h y dati dif or m m ole, bli g hte d o v u m, fetal deat h, i ntra uteri ne deat h, miscarria ge a n d 
still birt h m ust be re p orte d as seri o us e ve nts (I m p orta nt Me dical E ve nts).  If t he pre g na nc y 
c o nti n ues t o ter m, t he o utc o me ( healt h of i nfa nt) m ust als o be re p orte d.  
S uc h e ve nts m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g da ys 
t o Merc k Gl o bal Safet y. 
 
 
I m me di ate Re p orti n g of A d verse E ve nts t o Merc k 
Seri o us A d verse E ve nts 
A seri o us a d verse e ve nt is a n y a d verse e ve nt occ urri n g at a n y d ose or d uri n g a n y use of 
Merc k’s pr o d uct t hat: 
•  
Res ults i n deat h; 
•  
Is life t hreate ni n g; 
•  
Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y; 
•  
Res ults i n or pr ol o n gs a n e x isti n g i n patie nt h os pitalizati o n; 

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
•  
Is a c o n ge nital a n o mal y/ birt h defect; 
•  
Is a ne w ca ncer (t hat is n ot a c o n diti o n of t he st u d y); 
•  
Is ass ociate d wit h a n o ver d ose; 
•  
Is a n ot her i m p orta nt me dical e ve nt  
 
A n y seri o us a d verse e ve nt, or f oll o w u p t o a seri o us a d verse e ve nt, i ncl u di n g deat h d ue t o 
a n y ca use ot her t ha n pr o gressi o n of t he ca ncer u n der st u d y t hat occ urs t o a n y s u bject 
fr o m t he ti me t he c o nse nt is si g ne d t hr o u g h 9 0 da ys f oll o wi n g cessati o n of treat me nt, or 
t he i nitiati o n of ne w a nti-ca ncer t hera p y, w hic hever is earlier, w het her or n ot relate d t o 
Merc k pr o d uct, m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g 
da ys t o Merc k Gl o bal Safet y.  
 
N o n-seri o us E ve nts of Cli nical I nterest w ill be f or war de d t o Merc k Gl o bal Safet y a n d 
will be ha n dle d i n t he sa me ma n ner as S A Es.  
 
A d diti o nall y, a n y seri o us a d verse e ve nt, c o nsi d ere d b y a n i n vesti gat or w h o is a q ualifie d 
p h ysicia n t o be relate d t o Merc k pr o d uct t hat is br o u g ht t o t he atte nti o n of t he 
i n vesti gat or at a n y ti me o utsi de of t he ti me peri o d s pecifie d i n t he pre vi o us para gra p h 
als o m ust be re p orte d i m me diatel y t o t he S p o ns or a n d t o Merc k. 
 
S A E re p orts a n d a n y ot her rele v a nt s afet y i nf or m ati o n are t o be f or w ar de d t o t he 
Merc k Gl o b al S afet y f acsi mile n u m b er:  
 
 
A c o p y of all 1 5 Da y Re p orts a n d A n n ual Pr o gress Re p orts is s u b mitte d as re q uire d b y 
F D A, or ot her l ocal re g ulat ors. I n vesti gat ors will cr oss refere nce t his s u b missi o n 
acc or di n g t o l ocal re g ulati o ns t o t he Merc k I n vesti gati o nal C o m p o u n d N u m ber (I N D, 
C S A, etc.) at t he ti me of s u b missi o n.  A d diti o nall y i n vesti gat ors will s u b mit a c o p y of 
t hese re p orts t o Merc k & C o., 
 
at t he ti me of s u b missi o n t o F D A. 
 
All s u bjects wit h seri o us a d verse e ve nts m ust be f oll o we d u p f or o utc o me. 
 
E ve nts of Cli nic al I nterest 
Selecte d n o n-seri o us a n d seri o us a d verse e ve nts are als o k n o w n as E ve nts of Cli nical 
I nterest ( E CI) a n d m ust be rec or de d as s uc h o n t he A d verse E ve nt case re p ort 
f or ms/ w or ks heets a n d re p orte d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g da ys 
t o Merc k Gl o bal Safet y. 
E ve nts of 
cli nical i nterest f or t his trial i ncl u de: 
1.  A n o ver d ose of Merc k pr o d uct, as defi ne d a b o ve - Defi niti o n of a n O ver d ose f or T his 
Pr ot oc ol a n d Re p orti n g of O ver d ose t o t he S p o ns or, t hat is n ot ass ociate d wit h cli nical 
s y m pt o ms or a b n or mal la b orat or y res ults.  
2.  A n ele vate d A S T or A L T la b val ue t hat is greater t ha n or e q ual t o 3 X t he u p per li mit 
of n or mal a n d a n ele vate d t otal bilir u bi n la b va l ue t hat is greater t ha n or e q ual t o 2 X t he 
u p per li mit of n or mal a n d, at t he sa me ti me, a n  al kali ne p h os p hatase la b val ue t hat is less 
t ha n 2 X t he u p per li mit of n or mal, as deter mi ne d b y wa y of pr ot oc ol-s pecifie d la b orat or y 
testi n g or u nsc he d ule d la b orat or y testi n g. * 
 
* N ote:  T hese criteria are base d u p o n a vaila ble re g ulat or y g ui da nce d oc u me nts. T he 
p ur p ose of t he criteria is t o s pecif y a t hres h ol d of a b n or mal he patic tests t hat ma y re q uire 
a n a d diti o nal e val uati o n f or a n u n derl yi n g eti ol o g y.   

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E CIs ( b ot h n o n-seri o us a n d seri o us a d verse e ve nts) i de ntifie d i n t his g ui da nce d oc u me nt 
fr o m t he date of first d ose t hr o u g h 9 0 da ys f oll o wi n g cessati o n of treat me nt, or 3 0 da ys 
after t he i nitiati o n of a ne w a ntica ncer t hera p y,  w hic he ver is earlier, nee d t o be re p orte d 
wit hi n 2 w or ki n g da ys t o Merc k Gl o bal Sa fet y. ( Att n: W orl d wi de Pr o d uct Safet y;  
 
re gar dless of attri b uti o n t o stu d y treat me nt, c o nsiste nt wit h sta n dar d S A E 
re p orti n g g ui deli nes. 
 
S u bjects s h o ul d be assesse d f or p ossi ble E CIs pri or t o eac h d ose.  La b res ults s h o ul d be 
e val uate d a n d s u bjects s h o ul d be as ke d f o r si g ns a n d s y m pt o ms s u g gesti ve of a n 
i m m u ne-relate d e ve nt.  S u bjects w h o de velo p a n E CI t h o u g ht t o be i m m u ne-relate d 
s h o ul d ha ve a d diti o nal testi n g t o r ule o ut ot her eti ol o gic ca uses.  If la b res ults or 
s y m pt o ms i n dicate a p ossi ble i m m u ne-relate d E CI, t he n a d diti o nal testi n g s h o ul d be 
perf or me d t o r ule o ut ot her eti ol o gic ca uses.  If n o ot her ca use is f o u n d, t he n it is 
ass u me d t o be i m m u ne-relate d. 
 
1 0. 8 2  T a ke d a  
A Es ma y be s p o nta ne o usl y re p orte d b y t he patie nt a n d/ or i n res p o nse t o a n o pe n q uesti o n 
fr o m st u d y pers o n nel or re veale d b y o bser vati o n, p h ysical e xa mi nati o n, or ot her 
dia g n ostic pr oce d ures. A n y cli n icall y rele va nt deteri oratio n i n la b orat or y assess me nts or 
ot her cli nical fi n di n g is c o nsi dere d a n A E. W he n p ossi ble, si g ns a n d s y m pt o ms i n dicati n g 
a c o m m o n u n derl yi n g pat h ol o g y s h o ul d be n ote d as o ne c o m pre he nsi ve e ve nt. F or 
seri o us A Es, t he i n vesti gat or m ust deter mi ne b ot h t he i nte nsit y of t he e ve nt a n d t he 
relati o ns hi p of t he e ve nt t o st u d y dr u g a d mi nistrati o n.  
A Es w hic h are seri o us m ust be re p orte d t o Ta ke da P har mac o vi gila nce ( or desi g nee) fr o m 
t he first d ose of st u d y dr u g t hr o u g h 3 0 da ys after a d mi nistrati o n of t he last d ose of 
i xaz o mi b. A n y S A E t hat occ urs at a n y ti me after c o m pleti o n of i xaz o mi b treat me nt or 
after t he desi g nate d f oll o w- u p peri o d t hat t he s p o ns or-i n vesti gat or a n d/ or s u b-i n vesti gat or 
c o nsi ders t o be relate d t o a n y st u d y dr u g m ust be re p orte d t o Ta ke da P har mac o vi gila nce 
( or desi g nee). I n a d diti o n, ne w pri mar y mali g na ncies t hat occ ur d uri n g t he f oll o w- u p 
peri o ds m ust be re p orte d, re gar dless of ca u salit y t o st u d y re gi me n, f or a mi ni m u m of 
t hree y ears after t he last d ose of t he i n vesti gati o nal pr o d uct, starti n g fr o m t he first d ose of 
st u d y dr u g. All ne w cases of pri mar y mali g na nc y m ust be re p orte d t o Ta ke da 
P har mac o vi gila nce ( or desi g nee). 
Pla n ne d h os pital a d missi o ns or s ur gical pr oce d ures f or a n ill ness or disease t hat e xiste d 
bef ore t he patie nt was e nr olle d i n t he tria l are n ot t o be c o nsi dere d A Es u nless t he 
c o n diti o n deteri orate d i n a n u ne x pecte d ma n ner d uri n g t he trial (e. g., s ur ger y was 
perf or me d earlier or later t ha n pla n ne d). All S A Es s h o ul d be m o nit ore d u ntil t he y are 
res ol ve d or are clearl y deter mi ne d t o be d ue t o a patie nt’s sta ble or c hr o nic c o n diti o n or 
i nterc urre nt ill ness(es). 
Si nce t his is a n i n vesti gat or-i nitiate d st u d y, t he pri nci pal i n vesti gat or, Yi Li n, M D, als o 
referre d t o as t he s p o ns or-i n vesti gat or, is resp o nsi ble f or re p orti n g seri o us a d verse e ve nts 
( S A Es) t o a n y re g ulat or y a ge nc y a n d t o t he s p o ns or- i n vesti gat or’s E C or I R B. 
Re gar dless of e x pecte d ness or ca usalit y, all S A Es (i ncl u di n g seri o us pretreat me nt e ve nts) 
m ust als o be re p orte d i n E n glis h t o Ta ke da P har mac o vi gila nce ( or desi g nee): 
F at al a n d Life T hre ate ni n g S A Es wit hi n 2 4 h o urs of t he s p o ns or-i n vesti gat or’s 
o bser vati o n or a ware ness of t he e ve nt 

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All ot her seri o us ( n o n-f at al/ n o n-life-t hre ate ni n g) e ve nts wit hi n 4 cale n dar da ys of t he 
s p o ns or-i n vesti gat or’s o bser vati o n or a ware ness of t he e ve nt 
See bel o w f or c o ntact i nf or mati o n f or t he re p orti n g of S A Es t o Ta ke da 
P har mac o vi gila nce. 
T he s p o ns or-i n vesti gat or m ust fa x or e ma il t he S A E F or m per t he ti meli nes a b o ve. A 
sa m ple of a n S A E F or m will be pr o vi de d. 
T he S A E re p ort m ust i ncl u de at mi ni m u m: 
•  E ve nt ter m(s) 
•  Seri o us criteri a  
•  I nte nsit y of t he e ve nt(s): S p o ns or-i n vesti gat or’s or s u b-i n vesti gat or’s deter mi n ati o n. 
I nte nsit y f or eac h S A E, i ncl u di n g a n y la b ab n or malities, will be deter mi ne d b y usi n g 
t he N CI C T C A E versi o n s pecifie d i n t he pr ot oc ol, as a g ui deli ne, w he ne ver p ossi ble. 
T he criteria are a vaila ble o nli ne at 
 
•  C a us alit y of t he e ve nt(s): S p o ns or-i n v esti gat or’s or s u b- i n vesti gat or’s deter mi n ati o n 
of t he relati o ns hi p of t he e ve nt(s) t o st u d y dr u g a d mi nistrati o n.  
  F oll o w- u p i nf or mati o n o n t he S A E ma y be re q ueste d b y Ta ke da. 
I nte nsit y f or eac h S A E, i ncl u di n g a n y la b a b n ormalities, will be deter mi ne d b y usi n g t he 
N CI C T C A E versi o n use d at y o ur i nstit uti o n, as a g ui deli ne, w he ne ver p ossi ble. T he 
criteria are a vaila ble o nli ne at 
 
I n t he e ve nt t hat t his is a m ultisite st u d y, t he s p o ns or-i n vesti gat or is res p o nsi ble t o e ns ure 
t hat t he S A E re p orts are se nt t o Ta ke da P h ar mac o vi gila nce ( or desi g nee) fr o m all sites 
partici pati n g i n t he st u d y. S u b-i n vesti gat ors m ust re p ort all S A Es t o t he s p o ns or-
i n vesti gat or s o t hat t he s po ns or-i n vesti gat or ca n meet his/ her f ore g oi n g re p orti n g 
o bli gati o ns t o t he re q uire d re g ulat or y a ge ncies a n d t o Ta ke da P har mac o vi gila nce, u nless 
ot her wise a gree d bet wee n t he s p o ns or-i n vesti gat or a n d s u b-i n vesti gat or(s). 
Relati o ns hi p t o all st u d y dr u gs  f or eac h S A E will be deter mi ne d b y t he i n vesti gat or or 
s u b-i n vesti gat or b y res p o n di n g y es or n o t o t he q uesti o n: Is t here a reas o na ble p ossi bilit y 
t hat t he A E is ass ociate d wit h t he st u d y dr u g(s)? 
S p o ns or-i n vesti gat or m ust als o pr o vi de Ta ke da P har mac o vi gila nce wit h a c o p y of all 
c o m m u nicati o ns wit h a p plica ble re g ulat or y a u t h orities relate d t o t he st u d y pr o d uct(s), as 
s o o n as p ossi ble b ut n o later t ha n 4 cale n dar da ys of s uc h c o m m u nicati o n. 
  
  
  S A E a n d Pre g n a nc y Re p orti n g C o nt act I nf or m ati o n 
 
 
 
 
 
  
 
 
 
S u g geste d
 
Re p orti n g
 
F or m:
 
•  
S A E Re p ort F or m  ( pr o vi de d b y Ta ke da) 
•  
U S F D A Me d Watc h 3 5 0 0 A: 
 
•  
A n y  ot her f or m dee me d a p pr o priate b y the s p o ns or-i n vesti gat or 
 
 
 
Pr o d uct
 
C o m pl ai nts
 
A pr o d uct c o m plai nt is a ver bal, writte n, or electr o nic e x pressi o n t hat i m plies 

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dissatisfacti o n re gar di n g t he i de ntit y, stre n gt h, p urit y, q ualit y, or sta bilit y of a dr u g 
pr o d uct. I n di vi d uals w h o i de ntif y a p ote ntia l pr o d uct c o m plai nt sit uati o n s h o ul d 
i m me diatel y c o ntact Ta ke da  a n d re p ort t he e ve nt. W he ne ver p ossible, t he ass ociate d 
pr o d uct s h o ul d be mai ntai n e d i n acc or da nce w it h t he la bel i nstr ucti o ns pe n di n g f urt her 
g ui da nce fr o m a Ta ke da Q ualit y re prese ntati ve. 
F or Pr o d uct C o m pl ai nts 
•  
 
•  
E- mail: 
 
•  
F A X: 
 
•  
H o urs: M o n- Fri, 9 a. m . – 7 p. m. E T 
    
Pr o d uct c o m plai nts i n a n d of t he msel ves are n ot A Es. If a pr o d uct c o m plai nt res ults 
i n a n S A E, a n S A E f or m s h o ul d be c o m plete d a n d se nt t o Ta ke da P har mac o vi gila nce 
Pr oce d ures f or Re p orti n g Dr u g E x p os ure D uri n g Pre g na nc y a n d Birt h E ve nts 
If a w o ma n bec o mes pre g na nt or s us pects t hat s he is pre g na nt w hile partici pati n g i n t his 
st u d y or wit hi n 9 0 da ys after t he last d ose, s he m ust i nf or m t he i n vesti gat or i m me diatel y 
a n d per ma ne ntl y disc o nti n ue st u d y dr u g.  T h e s p o ns or-i n vesti gat or m ust i m me diatel y fa x 
a c o m plete d Pre g na nc y F or m t o t he Ta ke da  De part me nt of P har mac o vi gila nce or 
desi g nee (see Secti o n 8. 2) .  T he pre g na nc y m ust be f oll o we d f or t he fi nal pre g na nc y 
o utc o me. 
If a fe male part ner of a male patie nt bec o mes pre g na nt d uri n g t he male patie nt’s 
partici pati o n i n t his st u d y, t he s p o ns or-i n vesti gat or m ust als o i m me diatel y fa x a 
c o m plete d Pre g na nc y F or m t o t he Ta ke da De part me nt of P har mac o vi gila nce or desi g nee 
(see Secti o n 8. 2).  E ver y eff ort s h o ul d be ma de t o f oll o w t he pre g na nc y f or t he fi nal 
pre g na nc y o utc o me. 
S u g geste d Pre g na nc y Re p orti n g F or m: 
Pre g na nc y Re p ort F or m ( pr o vi de d b y Ta ke da) 
 
 

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1 1. 0
 Tre at me nt
 
E v al u ati o n
 
T he I nter nati o nal M y el o ma W or ki n g Gr o u p (I M W G) u nif or m res p o nse criteria ( K u mar et al, 
2 0 1 6) will be use d t o assess res p o nse t o t hera p y  
1 1. 1   
Ter ms a n d defi niti o ns 
•  
M- pr otei n: s y n o n y ms i ncl u de M-s pi ke, m o n ocl o nal pr otei n a n d m yel o ma pr otei n, 
para pr otei n, M-c o m p o ne nt. 
 
Ser u m M- pr otei n le vel is q ua ntitate d usi n g de nsit o metr y o n S P E P e xce pt i n cases 
w here t he S P E P is felt t o be u nrelia ble.   
•  M- pr otei ns mi grati n g i n t he β -re gi o n ( us uall y I g A M- pr otei ns)  
•  Cases i n w hic h t he M- pr otei n is s o  lar ge a n d narr o w o n a gar ose (s o me 
s peci me ns > 4 g/ d L) t hat t he y u n deresti mate t he act ual i m m u n o gl o b uli n le vel 
( b y greater t ha n 1 5 0 0 m g/ d L) d ue t o tec h nical stai ni n g pr o perties of t he 
a gar ose gel. 
•  Cases i n w hic h t here are m ulti ple pea k s of sa me M- pr otei n (a g gre gates or 
di mers) 
 
If S P E P is n ot a vaila ble or felt t o be u nrelia ble (a b o ve e xa m ples) f or r o uti ne M-
pr otei n q ua ntitati o n, t he n q ua ntitati ve i m m u n o gl o b uli n le vels deri ve d fr o m 
ne p hel o metr y or t ur bi d o metr y ca n be acce p te d, wit h t he e xce pti o n t hat q ua ntitati ve 
I g G ma y n ot be use d.  H o we ver, t his m ust be e x plicitl y re p orte d at baseli ne, a n d o nl y 
ne p hel o metr y ca n be use d f or t hat patie nt t o assess res p o nse. S P E P deri ve d M- pr otei n 
val ues a n d q ua ntitati ve ne p hel o metric i m m u n o gl o b uli n val ues ca n n ot be use d 
i nterc ha n gea bl y.   
 
Uri ne M- pr otei n meas ure me nt is esti mate d usi n g 2 4- h U P E P o nl y.  Ra n d o m or 2 4 h 
uri ne tests meas uri n g ka p pa a n d la m b da li g ht c hai n le vels are n ot relia ble a n d are n ot 
rec o m me n de d. 
 
F L C esti m ati o n  is c urre ntl y carrie d o ut usi n g t he ser u m F L C assa y ( Freelite, T he 
Bi n di n g Site Li mite d, U K).  Patie nts wit h ka p pa/la m b da F L C rati o < 0. 2 6 are defi ne d 
as ha vi n g m o n ocl o nal la m b da F L C a n d t h ose wit h rati os > 1. 6 5 as ha vi n g a 
m o n ocl o nal ka p pa F L C.  T he m o n ocl o nal li g ht c hai n is ot y pe is c o nsi dere d t he 
i n v ol ve d F L C is ot y pe, a n d t he o p p osite li g ht c hai n t y pe as t he u ni n v ol ve d F L C t y pe.  
 
•  
Res p o nse ter ms:  T he f oll o wi n g res p o nse ter ms will be use d: stri n ge nt C o m plete 
Res p o nse (s C R), c o m plete res p o nse ( C R), ve r y g o o d partial res p o nse ( V G P R), partial 
res p o nse ( P R), Mi ni mal Res p o nse ( M R), sta ble disease ( S D), a n d pr o gressi ve disease 
( P D).  
 
I n a d diti o n, f or eac h res p o nse cate g or y, t here will be a n “ u nc o nfir me d” res p o nse 
cate g or y, w hic h will be f or i nter nal use, f or t he p ur p ose of g ui di n g decisi o n ma ki n g 
a n d test or deri n g. T hese desi g nati o ns will be a p plie d at t he ti me of t he first 
meas ure me nt at w hic h t he q ua ntitati ve as p ect of t he res p o nse cate g or y has bee n 
satisfie d wit h o ut t he c o nfir mati o n ste p ha vi n g bee n satisfie d. T he desi g nati o n “ u” 
will prece de t he sta n dar d a b bre viati o ns, a n d will i ncl u de us C R, u C R, u V G P R, u P R, 
u M R, u P D.  
 
•  
Me as ur a ble dise ase:  Patie nts w h o ha ve a meas ura ble ser u m or uri ne M- pr otei n.  

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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
 
o  Ser u m M- pr otei n ≥1 g/ dl  
N O T E:  Q ua ntitati ve I g G ma y n ot be us e d f or defi ni n g meas ura ble disease 
o  Uri ne M- pr otei n ≥ 2 0 0 m g/ 2 4 h 
o  Ser u m F L C assa y: I n v ol ve d F L C le vel ≥  1 0 m g/ dl pr o vi de d ser u m F L C rati o is 
a b n or mal 
 
T he ser u m free li g ht c hai n ( F L C) assa y is of partic ular use i n m o nit ori n g res p o nse t o 
t hera p y i n patie nts w h o ha ve oli g o-secret or y or n o n-secret or y disease a n d s h o ul d be use d 
i n assessi n g res p o nse o nl y if t he b aseli ne ser u m a n d/ or uri ne M pr otei ns are n ot 
“ me as ur a ble ” as a b o ve, a n d t he b aseli ne le vel of t he i n v ol ve d F L C is “ me as ur a ble. ”  
W he n usi n g t his assa y, it is i m p orta nt t o n ote t h at t he F L C le vels var y c o nsi dera bl y wit h 
c ha n ges i n re nal f u ncti o n a n d i n patie nts wit h  re nal i ns ufficie nc y, t he le vels of b ot h t he 
ka p pa a n d la m b da ma y re mai n ele vate d, b ut t he rati o n or malizes wit h ac hie ve me nt of 
C R.  T h us, b ot h t he le vel of t he i n v ol ve d a n d t he u ni n v ol ve d F L C is ot y pe (i.e., t he 
i n v ol ve d/ u ni n v ol ve d rati o or i n v ol ve d- u ni n v olve d differe nce) s h o ul d be c o nsi dere d i n 
assessi n g res p o nse.  P atie nts i ncl u de d o n t he st u dy o n t he b asis of F L C al o ne (i.e., n o 
me as ur a ble ser u m/ uri ne M- pr otei n) s h o ul d be t he o nly o nes w h o are ev al u ate d usi n g 
F L C res p o nse criteri a.  T he ot hers s h o ul d f oll o w us u al criteri a a n d i g n ore F L C res ults 
wit h t he e xce pti o n of defi ni n g stri n ge nt c o m plete res p o nse. 
 
•  
E v al u a ble dise ase : Patie nts w h o d o n ot ha ve a “ meas ura ble” ser u m M- pr otei n, 
ser u m free li g ht c hai n, or uri ne M- pr otei n. 
 
•  
Oli g osecret or y m yel o m a:  Patie nt wit h m ulti ple m y el o ma w h o has N E V E R ha d 
“ meas ura ble” ser u m M- pr otei n or uri ne M- pr otei n, b ut has ha d a detecta ble M-
pr otei n i n his/ her ser u m a n d/ or uri ne a n d/ or meas ura ble ser u m free li g ht c hai n.  
 
•  
N o n-secret or y m yel o m a:  Patie nt wit h m ulti ple m y el o ma w h o has N E V E R ha d a 
detecta ble M- pr otei n i n his/ her ser u m a n d/ or uri ne. 
 
1 1. 2   
Clarificati o n of test i n dicati o ns 
Liste d bel o w are t he mi ni mal re q uire d t ests re q uire d t o assess res p o nse base d o n t he 
c haracteristics of t heir disease at o n st u d y.   
Tests Re q uire d T o Assess Res p o nse ( M ust Be D o ne At E ac h Dise ase M e as ure me nt Visit 
e xce pt as i n dic ate d 1, 2) 
O n St u d y B aseli ne V al ue 
S P E P 4 
2 4 hr 
U P E P 2 
I g 
F L C
 B M
 
B x
 
Ser u m M- pr otei n ≥1 g/ dl, a n d uri ne M- pr otei n ≥ 
2 0 0 m g/ 2 4 hrs 
X
 X
 
 
 
 
Ser u m M- pr otei n ≥ 1 g/ dl, b ut uri ne M- pr otei n < 
2 0 0 m g/ 2 4 hrs 
X
 
 
 
 
 
Ser u m M- pr otei n < 1 g/ dl, a n d uri ne M- pr otei n ≥ 
2 0 0 m g/ 2 4 hrs 
 X
 
 
 
Ser u m M- pr otei n < 1 g/ dl, uri ne M- pr otei n < 2 0 0 
m g/ 2 4 hrs, b ut i n v ol ve d I g F L C is ≥1 0 m g/ d L 
 
 X
 
 
Ser u m M- pr otei n < 1 g/ dl, uri ne M- pr otei n < 2 0 0 
m g/ 2 4 hrs, i n v ol ve d I g F L C is < 1 0 m g/ d L, b o ne 
 
 
 
X3 

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Tests Re q uire d T o Assess Res p o nse ( M ust Be D o ne At E ac h Dise ase M e as ure me nt Visit 
e xce pt as i n dic ate d 1, 2) 
O n St u d y B aseli ne V al ue 
S P E P 4 
2 4 hr 
U P E P 2 
I g 
F L C
 B M
 
B x
 
marr o w ≥3 0 % plas ma cells 
1  S P E P, U P E P, I m m u n ofi x ati o n st u dies of b ot h ser u m a n d uri ne, a n d B o ne m arr o w 
bi o psy  are re q uire d t o d oc u me nt C R re g ar dless of re gistr ati o n v al ues, a n d i n a d diti o n 
F L C  me as ure me nt a n d b o ne m arr o w i m m u n o p he n oty pi n g  is re q uire d t o d oc u me nt 
s C R.  S P E P a n d U P E P are re q uire d t o d oc u me nt V G P R re g ar dless of re gistr ati o n 
v al ues. 
2  F or ser u m me as ur a ble p atie nts, 2 4 h o ur uri ne d oes n ot nee d t o be c o nfir me d (i.e. 
re pe ate d after d oc u me nte d res p o nse) f or a ny res p o nse c ate g ory 
3  At a mi ni m u m, a  b o ne m arr o w bi o psy s h o ul d be re pe ate d every 3 m o nt hs u ntil 
d oc u me nte d res p o nse.  B o ne m arr o w bi o psy res u lts d o n ot nee d t o be re pe ate d after 
d oc u me nte d res p o nse.  
4    If ser u m M- pr otei n is bei n g f oll o we d by q u a ntit ative i m m u n o gl o b uli n levels derive d 
fr o m ne p hel o metry or t ur bi d o metry, q u antit ative i m m u n o gl o b uli ns are re q uire d.  S P E P 
is o nly re q uire d t o d oc u me nt C R or V G P R.  
 
1 1. 3  
C o nfir me d res p o nse  
I n or der t o be classifie d as a he mat ol o gic res p o nse, c o nfir mati o n of ser u m M- pr otei n, 
ser u m i m m u n o gl o b uli n free li g ht c hai n ( w hen pri mar y deter mi na nt of res p o nse) a n d 
uri ne M- pr otei n ( w he n pri mar y deter mi na n t of res p o nse) res ults m ust be ma de b y 
verificati o n o n t w o c o nsec uti ve deter mi nati o ns.   
•  
B o ne marr o w as pirate a n d bi o ps y are o nl y  re q uire d t o d oc u me nt C R or s C R, 
e xce pt f or patie nts wit h e val ua ble disease o nl y , w here a b o ne marr o w is re q uire d 
t o d oc u me nt all res p o nse cate g ories i ncl u di n g pr o gressi o n. H o we ver, a sec o n d 
c o nfir mat or y b o ne marr o w is n ot  re q uire d t o c o nfir m res p o nse i n a n y case. 
•  
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; 
h o we ver, if ra di o gra p hic st u dies were perf o r me d t here s h o ul d be n o e vi de nce of 
pr o gressi ve or ne w b o ne lesi o ns. 
 
A p pr o priate tests re q uire d t o d oc u me nt a n d c o nfir m res p o nse are liste d i n Ta ble 1 1. 2 
 
1 1. 4
 B o ne
 
pr o gressi o n
  
Ca uti o n m ust be e xercise d t o a v oi d rati n g pr o gressi o n o n t he basis of variati o n of 
ra di ol o gic tec h ni q ue al o ne.  C o m pressi o n fract ure d oes n ot e xcl u de c o nti n ue d res p o nse 
a n d ma y n ot i n dicate pr o gressi o n.  W he n pr o gr essi o n is base d o n s keletal disease al o ne, it 
s h o ul d be disc usse d wit h t he St u d y C hair bef ore re m o vi n g t he patie nt fr o m t he st u d y.  
 
1 1. 5  
 Res p o nse a n d Pr o gressi o n 
Criteria f or res p o nse a n d pr o gressi o n are liste d i n Ta ble 1 1. 5. Pr o gressive disease f or all 
patie nts as defi ne d i n Ta ble 1 1. 5.  
I M W G M R D 
N E G A TI VI T Y 
C A T E G O R Y  
 R E S P O N S E C RI T E RI A a 
S ustai ne d M R D  
M R D ne gati vit y i n t he marr o w ( Ne xt Ge nerati o n Fl o w ( N G F) or Ne xt 

M C 1 7 8 2
 5 7
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
I M W G M R D 
N E G A TI VI T Y 
C A T E G O R Y  
 R E S P O N S E C RI T E RI A a 
Ge nerati o n Se q ue nci n g ( N G S), or b ot h) a n d b y i ma gi n g as defi ne d 
bel o w, c o nfir me d mi ni m u m of 1 y ear a part. S u bse q ue nt e val uati o ns 
ca n be use d t o f urt her s pecif y t he d urati o n of ne gati vit y (e g, M R D-
ne gati ve at 5 y ears) 
Fl o w M R D k 
A bse nce of p he n ot y picall y a berra nt cl o nal plas ma cells b y N G F o n 
b o ne marr o w as pirates usi n g t he E ur o Fl o w sta n dar d o perati o n 
pr oce d ure f or M R D detecti o n i n m ulti ple m y el o ma ( or vali date d 
e q ui vale nt met h o d) wit h a mi ni m u m se nsiti vit y of 1 i n 1 0 5 n ucleate d 
cells or hi g her 
Se q ue nci n g M R D k  
A bse nce of cl o nal plas ma cells b y N G S o n b o ne marr o w as pirates i n 
w hic h prese nce of a cl o ne is defi ne d as less t ha n t w o i de ntical 
se q ue nci n g rea ds o btai ne d after D N A se q ue nci n g of b o ne marr o w 
as pirates usi n g t he L y m p h o SI G H T platf or m ( or vali date d e q ui vale nt 
met h o d) wit h a mi ni m u m se nsiti vit y of 1 i n 1 0 5 n ucleate d cells or 
hi g her 
I ma gi n g Pl us M R D k  
M R D ne gati vit y as defi ne d b y N G F or N G S pl us disa p peara nce of 
e ver y area of i ncrease d tracer u pta ke f o u n d at baseli ne or a prece di n g 
P E T/ C T or decrease t o less t ha n me diasti nal bl o o d p o ol S U V or 
decrease t o less t ha n t hat of s urr o u n di n g n or mal tiss ue 
S T A N D A R D I M W G 
R E S P O N S E 
C A T E G O R Y 
R E S P O N S E C RI T E RI A a 
Stri n ge nt C o m plete 
Res p o nse (s C R)  b 
C R as defi ne d pl us  
N or mal F L C rati o a n d  
•  A bse nce of cl o nal P Cs b y i m m u n o hist oc he mistr y or 2- t o 4- c ol or 
fl o w c yt o metr y i 
C o m plete Res p o nse ( C R) 
b  
•  Ne gati ve i m m u n ofi xati o n of ser u m a n d uri ne c a n d  
•  Disa p peara nce of a n y s oft tiss ue plas mac yt o ma a n d  
•  < 5 % P Cs i n B o ne Marr o w a n d  
•  If t he o nl y meas ura ble disease is F L C, a n or mal F L C rati o d  
Ver y G o o d Partial 
Res p o nse ( V G P R)  
•  Ser u m a n d uri ne M- pr otei n detecta ble b y i m m u n ofi xati o n b ut n ot o n 
electr o p h oresis c or  
•  ≥9 0 % re d ucti o n i n ser u m M- pr otei n a n d uri ne M- pr otei n < 1 0 0 
m g/ 2 4 h  c 
•  If t he o nl y meas ura ble disease is F L C, a > 9 0 % re d ucti o n 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 
Partial Res p o nse ( P R) 
•  If prese nt at baseli ne, ≥ 5 0 % re d ucti o n of ser u m M- pr otei n a n d 
re d ucti o n i n 2 4- h o ur uri nar y M- pr otei n b y ≥9 0 % or t o < 2 0 0 
m g/ 2 4 hrs  c 
•  If t he o nl y meas ura ble disease is F L C, a ≥5 0 % re d ucti o n 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 
•  If t he o nl y meas ura ble disease is B M, a ≥ 5 0 % re d ucti o n i n B M P Cs 
( pr o vi de d t he baseli ne P Cs was ≥ 3 0 %) 
•  If prese nt at baseli ne, ≥ 5 0 % re d ucti o n i n t he size ( S P D) of s oft 
tiss ue plas mac yt o mas j 
Mi n or Res p o nse ( M R)  
•  If prese nt at baseli ne, ≥2 5 % b ut ≤ 4 9 % re d ucti o n of ser u m M 
pr otei n a n d  re d ucti o n i n 2 4- h o ur uri ne M- pr otei n b y 5 0- 8 9 % w hic h 

M C 1 7 8 2
 5 8
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
I M W G M R D 
N E G A TI VI T Y 
C A T E G O R Y  
 R E S P O N S E C RI T E RI A a 
still e xcee ds 2 0 0 m g/ 2 4 h o urs  c a n d  
•  If prese nt at baseli ne, ≥5 0 % re d ucti o n i n t he size ( S P D) of s oft 
tiss ue plas mac yt o ma j  
Sta ble Disease ( S D) 
•  N ot meeti n g criteria f or s C R, C R, V G P R, P R, M R or P D 
Pr o gressi ve Disease ( P D) 
b, h 
 
I ncrease of 2 5 % fr o m l o west val ue i n a n y of t he f oll o wi n g f, g: 
•  
Ser u m M- pr otei n (a bs ol ute i ncrease m ust be ≥ 0. 5 g/ d L) a n d/ or 
•  
Uri ne M- pr otei n (a bs ol ute i ncrease m ust be ≥ 2 0 0 m g/ 2 4 hrs) 
a n d/ or  
•  
If t he o nl y meas ura ble disease is F L C, 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 (a bs ol ute i ncrease m ust be 
> 1 0 m g/ d L)  a n d/ or  
•  
If t he o nl y meas ura ble disease is B M, b o ne marr o w P C perce nta g e 
(a bs ol ute i ncrease m ust be ≥ 1 0 %) e  
Or a n y o ne or m ore of t he f oll o wi n g: 
•  
De vel o p me nt of ne w b o ne lesi o n or s oft tiss ue plas mac yt o ma or 
≥5 0 % i ncrease fr o m na dir i n t he size ( S P D) of  e xisti n g b o ne 
lesi o ns or s oft tiss ue plas mac yt o ma or ≥ 5 0 % i ncrease i n t he 
l o n gest dia meter of a pre vi o us lesi o n > 1 c m i n s h ort a xis j 
•  
5 0 % i ncrease i n circ ulati n g plas ma cells ( mi ni m u m of 2 0 0 cells per 
L) if t his is t he o nl y meas ure of disease 
Cli nical Rela pse 
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 
a n d/ or e n d- or ga n d ysf u ncti o n t hat are c o nsi dere d relate d t o t he 
u n derl yi n g plas ma cell pr oliferati ve dis or der: 
1.   De vel o p me nt of ne w s oft tiss ue plas mac yt o mas or b o ne lesi o ns o n 
s keletal s ur ve y, ma g netic res o nance i ma gi n g, or ot her i ma gi n g 
2.   Defi nite i ncrease i n t he size of e xisti n g plas mac yt 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 
3.   H y percalce mia ( > 1 1. 5 m g/ d L; > 2. 8 7 5 m M/ L) 
4.   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) or t o less 
t ha n 1 0 g/ d L 
5.   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 
(≥1 7 7 m M/ L) 
6.   H y per visc osit y 
 
 
a All res p o nse cate g ories re q uire t w o c o nsec uti ve assess me nts (s C R, C R, V G P R, P R, M R, P D) 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.  M R D tests s h o ul d be i nitiate d o nl y at t he ti me of 
s us pecte d c o m plete res p o nse. s C R, C R, V G P R, P R, M R a n d S D cate g ories a n d M R D re q uire n o k n o w n 
e vi de nce of pr o gressi ve or ne w b o ne lesi o ns or e x tra me d ullar y plas mac yt o mas if ra di o gra p hic st u dies 
were perf or me d. H o we ver, 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 
e xce pt f or t he re q uire me nt of F D G P E T if i ma gi n g M R D- ne gati ve stat us is re p orte d. B o ne marr o w 
assess me nts nee d n ot be c o nfir me d. Eac h cate g or y, e xce pt f or sta ble disease, will ha ve a w or ki n g 
s u bcate g or y of “ u nc o nfir me d” [ prefi x ‘ u ”] t o desi g nate first ti me p oi nt at w hic h res p o nse cate g or y M A Y 
ha ve bee n ac hie ve d if c o nfir me d. T he date of t he i nitial test is c o nsi dere d as t he date of res p o nse f or 
e val uati o n of ti me de pe n de nt o utc o mes s uc h as d urati o n of res p o nse. 

M C 1 7 8 2
 5 9
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
 
b C R patie nt will nee d t o pr o gress at t he sa me le vel as V G P R a n d P R patie nts t o be c o nsi dere d a P D.  A 
p ositi ve i m m u n ofi xati o n al o ne is n ot s ufficie nt. 
 
c If m ore t ha n o ne M pr otei n s pi ke meets t he criteria f or meas ura ble disease at baseli ne, t he n b ot h nee d t o 
be f oll o we d f or res p o nse.  Ot her wise, o nl y f oll o w  t he meas ura ble M pr otei n s pi ke f or res p o nse.   
 
d I n patie nts i n w h o m t he o nl y meas ura ble disease is b y ser u m F L C le vels: C R i n s uc h patie nts i n dicates a 
n or mal F L C rati o of 0. 2 6- 1. 6 5 i n a d d iti o n t o t he C R criteria liste d a b o ve. 
 
e B o ne marr o w criteria f or P D are o nl y t o be use d i n  patie nts wit h o ut meas ura ble disease b y M pr otei n a n d 
b y F L C;  
 
f A " 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 ma or h y percalce mia.  T he l o west val ue d oes n ot nee d t o be a c o nfir me d val ue.  If 
t he l o west ser u m M- pr otei n is ≥ 5 g/ d L, a n i ncrease i n ser u m M- pr otei n of ≥ 1 g/ d L is s ufficie nt t o defi ne 
disease pr o gressi o n. 
 
g I n t he case w here a val ue is felt t o be a s p uri o us res ult per p h ysicia n discreti o n (f or e xa m ple, a p ossi ble 
la b err or), t hat val ue will n ot be c o nsi dere d w he n deter mi ni n g t he l o west val ue. 
 
h Pr o gressi ve disease s h o ul d be c o nfir me d o n t w o c o nsec uti ve e val uati o ns, w here t he ti mi n g of 
c o nfir mati o n is per t he treati n g p h ysicia n a n d ca n be  d o ne i m me diatel y wit hi n t he sa me c y cle or o n t he 
ne xt c y cle.  H o we ver, treat me nt ma y be disc o n ti n ue d f or pr o gressi ve disease t hat is u nc o nfir me d per 
p h ysicia n discreti o n.  I n t his case, a n o bjecti ve stat us of P D s h o ul d be e ntere d o n t he meas ure me nt f or m 
a n d pr o gressi ve disease s h o ul d be re p orte d o n t he e ve nt m o nit ori n g f or m. 
 
i Prese nce/a bse nce of cl o nal cells is base d u p o n t he k/l rati o. A n a b n or mal k/l rati o b y 
i m m u n o hist oc he mistr y 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 k/l of 4: 1 or 1: 2.  
 
j Plas mac yt o ma meas ure me nts s h o ul d be ta ke n fr o m t he C T p orti o n of t he P E T/ C T, or M RI sca ns, or 
de dicate d C T sca ns w here a p plica ble. F or patie nts w it h o nl y s ki n i n v ol ve me nt, s ki n lesi o ns s h o ul d be 
meas ure d wit h a r uler. Meas ure me nt of t u m or size wi ll be deter mi ne d b y t he s u m of t he pr o d ucts of t he 
ma xi mal per pe n dic ular dia meters of meas ure d lesi o ns ( S P D). 
 
k Re q uires a c o m plete res p o nse as defi ne d i n t he ta ble.  M R D tests s h o ul d be i nitiate d o nl y at t he ti me of 
s us pecte d c o m plete res p o nse. M R D re q uires n o k n o wn e vi de nce of pr o gressi ve or ne w b o ne lesi o ns if 
ra di o gra p hic st u dies were perf or me d. H o we ver, 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 e xce pt f or t he re q uire me nt of F D G P E T if i ma gi n g M R D- ne gati ve stat us is 
re p orte d. 
 
1 2. 0
 Descri pti ve
 
F act ors
 
 
1 2. 1  
Para meters f oll o we d f or he mat ol o gic res p o nse ( pic k o ne):.ser u m m o n ocl o nal pr otei n ≥ 1 
g/ d L a n d uri ne M-s pi ke ≥2 0 0 m g/ 2 4 h o urs vs. ser u m m o n ocl o nal pr otei n ≥1 g/ d L o nl y vs. 
uri ne M-s pi ke ≥2 0 0 m g/ 2 4 h o urs o nl y vs. 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. Disti n g uis h bet wee n S P E P meas ur e me nt vers us q ua ntitati ve I g A a n d I g D 
meas ure me nts f or ser u m m o n ocl o nal pr otei n.   
1 2. 2  
N u m ber of li nes of pri or t hera p y:  1 vs. 2 vs. ≥ 3 

M C 1 7 8 2
 6 0
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 2. 3  
Pri or S C T:  yes vs. n o  
1 3. 0  
Tre at me nt/ F oll o w – u p Decisi o n at E v al u ati o n of P atie nt   
 
1 3. 1  
Patie nts w h o are s C R, C R, V G P R, P R, M R ( or us C R, u C R, u V G P R, u P R, u M R), or S D 
will c o nti n ue treat me nt per pr ot oc ol. 
 
1 3. 2  
Patie nts w h o de vel o p pr o gressi ve disease or start alter nate t hera p y w hile recei vi n g 
t hera p y will g o t o t he e ve nt- mo nit ori n g p hase per Secti o n 4. 2. 
 
1 3. 3  
Patie nts w h o g o off pr ot oc ol treat me nt f or reas o ns ot her t ha n P D will g o t o t he e ve nt-
m o nit ori n g p hase per Secti o n 4. 2. 
 
1 3. 4  
Patie nts w h o are disc o nti n ue d fr o m t hera p y f or a n u nacce pta ble a d verse e ve nt(s) will be 
f oll o we d u ntil res ol uti o n or sta bilizati o n of t he A E(s). 
1 3. 5  
Criteria f or Patie nt Wit h dra wal fr o m St u d y Treat me nt 
Patie nts ma y be wit h dra w n fr o m t he st u d y f or t he f oll o wi n g reas o ns: 
•  Pr o gressi ve
 m ulti ple
 m y el o ma
 
•   
Patie nt ref uses f urt her treat me nt o n t he trial 
•   
Patie nt de vel o ps a n i nterc urre nt ill ness t hat precl u des f urt her partici pati o n, or 
re q uires a pr o hi bite d c o nc o mita nt treat me nt 
•   
T he I n vesti gat or wit h dra ws t he patient i n t he patie nt’s best i nterests 
•   
Patie nt is l ost t o f oll o w- u p ( defi ne d as t he i na bilit y t o c o ntact t he patie nt o n 3 
se parate occasi o ns     at least 1 m o nt h a part).   
•   
A d mi nistrati ve reas o ns (e. g., t he patie nt is tra nsferre d t o h os pice care) 
•   
A n a d verse e ve nt, w hic h i n t he o pi ni o n of t he I n vesti gat or, precl u des f urt her trial 
partici pati o n  
 
All atte m pts s h o ul d be ma d e t o c o m plete t he E n d of St u d y pr oce d ures if a patie nt 
wit h dra ws fr o m t he trial earl y. 
1 3. 6  
Criteria f or St u d y Disc o nti n uati o n 
T he st u d y ma y be te m p oraril y or per ma n e ntl y disc o nti n ue d at a n y site a n d at a n y ti me.  
Reas o ns f or st u d y disc o nti n uati o n ma y i ncl u de , b ut are n ot li mite d t o, t he f oll o wi n g: 
•  Safet y
 c o ncer ns
 
•  P o or
 e nr oll me nt
 
•   
N o n-c o m plia nce wit h t he pr ot oc ol, G o o d Cli nical Practice g ui da nces or ot her 
re g ulat or y re q uire me nts b y t he I n vesti gat or(s) 
•   
Re q uest t o disc o nti n ue t he trial b y a reg ulat or y or healt h a ut h orit y or a n I R B 
•  Ma n ufact uri n g
 diffic ulties/c o ncer ns
 
All I n vesti gat ors a n d t he re q uisite re g ulat or y a ut h orities will be n otifie d if t he st u d y is 
s us pe n de d or ter mi nate d f or safet y reas o ns.  I n t he case of s uc h ter mi nati o n, t he 
I n vesti gat or will n otif y t he I R B. 
1 3. 7
 I neli gi ble
 
A patie nt is dee me d i neli gi ble if after re gistrati o n, it is deter mi ne d t hat at t he ti me of 
re gistrati o n, t he patie nt di d n ot satisf y eac h an d e ver y eli gi bilit y criteria f or st u d y e ntr y.  
T he patie nt ma y c o nti n ue treat me nt off- pr ot oc ol at t he discreti o n of t he p h ysicia n as l o n g 

M C 1 7 8 2
 6 1
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
as t here are n o safet y c o ncer ns, a n d t he patie nt  was pr o perl y re gistere d. T he patie nt will 
g o directl y t o t he e ve nt- m o nit ori n g p hase of t he st u d y ( or off st u d y, if a p plica ble).  
•  
If t he patie nt recei ve d treat me nt, all data u p u ntil t he p oi nt of c o nfir mati o n of 
i neli gi bilit y m ust be s u b mitte d.  E ve nt m o nit ori n g will be re q uire d per Secti o n 4. 2 of 
t he pr ot oc ol.  
•  
If t he patie nt ne ver recei ve d treat me nt, o n-st u d y material a n d t he E n d of Acti ve 
Treat me nt/ Ca ncel N otificati o n F or m m ust be s u b mitte d.  N o f urt her data s u b missi o n 
is necessar y. 
1 3. 8
 Maj or
 
vi olati o n
 
A patie nt is dee me d a m aj or vi ol ati o n , if pr ot oc ol re q uire me nts re gar di n g treat me nt i n 
c y cle 1 of t he i nitial t hera p y are se verel y vi olate d t hat e val ua bilit y f or pri mar y e n d p oi nt 
is q uesti o na ble.  All data u p u ntil t he p oi nt of c o nfir mati o n of a maj or vi olati o n m ust be 
s u b mitte d.  T he patie nt will g o directl y t o t he e ve nt- m o nit ori n g p hase of t he st u d y.  T he 
patie nt ma y c o nti n ue treat me nt off- pr ot oc ol at t he discreti o n of t he p h ysicia n as l o n g as 
t here are n o safet y c o ncer ns, a n d t he patie nt was pr o perl y re gistere d.  E ve nt m o nit ori n g 
will be re q uire d per Secti o n 4. 2 of t he pr ot oc ol. 
1 3. 9
 Ca ncel
 
A patie nt is dee me d a c a ncel  if he/s he is re m o ve d fr o m t he st u d y f or a n y reas o n bef ore 
a n y st u d y treat me nt is gi ve n.  O n-st u d y ma terial a n d t he E n d of Acti ve Treat me nt/ Ca ncel 
N otificati o n F or m m ust be s u b mitte d.  N o  f urt her data s u b missi o n is necessar y. 
 

M C 1 7 8 2
 6 2
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 4. 0  
B o d y Fl ui d Bi os peci me ns   
1 4. 1   
S u m mar y Ta ble of Researc h Bl o o d a n d B o d y Fl ui d S peci me ns t o be c ollecte d f or t his Pr ot oc ol:  
B o ne m arr o w c ollecti o n sc he d ule:  
C orrelati ve 
St u d y 
( Secti o n f or 
m ore 
i nf or mati o n) 
Ma n dat or y 
or 
O pti o nal 
Bl o o d or 
B o d y 
Fl ui d 
bei n g 
C ollecte d 
T y pe of 
C ollecti o n 
T u be 
(c ol or of 
t u be t o p) 
V ol u me 
t o c ollect 
per t u be 
( # of 
t u bes t o 
be 
c ollecte d) 
Baseli ne 
( Pri or t o c y cle 
1) 
  
C y cle 
2   
Da y 
1   
 At 
Pr o gressi o n  
D oc u me nt 
C R 
Pr ocess 
at site? 
 
 
Te m perat ure/ 
C o n diti o ns 
( Yes or 
N o) 
f or St ora ge 
/ S hi p pi n g 
  
I m m u ne 
mar kers  
Ma n dat or y
 Marr o w
 
A C D 
( y ell o w) 
6 ml     
( 3) 
X
 X
 X  
X
 N o
 K o ol- Pa k
 
 I m m u ne 
mar kers  
Ma n dat or y   
Marr o w 
E D T A  
( p ur ple) 
4 ml 
( 1) 
X
 X
 X 
X
 N o
  K o ol- Pa k
 
 
Bl o o d c ollecti o n sc he d ule:  
C orrelati ve 
St u d y 
( Secti o n f or 
m ore 
i nf or mati o n) 
Ma n dat or y 
or O pti o nal 
Bl o o d or 
B o d y 
Fl ui d 
bei n g 
C ollecte d 
T y pe of 
C ollecti o n 
T u be 
(c ol or of 
t u be t o p) 
V ol u me 
t o c ollect 
per t u be 
( # of 
t u bes t o 
be 
c ollecte d) 
C y cle 1 
Da ys 1, 2 2 
( pre d ose) 
E ver y 
C y cle   
Da y 
1 
( pre 
d ose) 
 At 
pr o gressi o n  
D oc u me nt 
C R 
Pr ocess 
at site? 
Te m perat ure/ 
C o n diti o ns 
( Yes or 
N o) 
f or St ora ge 
/ S hi p pi n g 
I m m u ne 
mar kers 
Ma n dat or y
 Bl o o d
 
He pari n 
( gree n) 
1 0 ml 
( 5) 
X
 X
 X
  X
 N o
 K o ol- Pa k
 
I m m u ne 
mar kers 
Ma n dat or y
 Bl o o d
 
E D T A 
( p ur ple) 
6 ml or 
( 1) 
X
 X
 X
  X
 N o
 K o ol- Pa k
 

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 4. 4  
Bac k gr o u n d a n d Met h o d ol o g y 
1 4. 4 1  P D L 1  e x pressi o n  
P D L 1 e x pressi o n will be meas ure d o n t he m y el o ma cells i n t he b o ne marr o w 
( C D 1 3 8, 3 8 p ositi ve) b y usi n g fl o w c yt o metr y. T he e x pressi o n will als o be 
deter mi ne d o n ot her cell t y pes i n t he b o ne marr o w.  
1 4. 4 2   Meas ures of i m m u ne acti v ati o n 
T he “ gl o bal” i m pact of t hera p y o n i m m u ne cell s u bsets will be ascertai ne d b y 
i m m u n o p he n ot y pic a nal ysis of P B M Cs f or s u bsets of T, B, N K cells, m o n oc ytes 
a n d de n dritic cells ( D C) a n d t heir acti vati o n stat us usi n g c o m merciall y a vaila ble 
m o n ocl o nal a nti b o dies directe d at t he f oll o wi n g a nti ge ns: C D 3, C D 4, C D 8, 
C D 1 1c, C D 1 4, C 1 6, C D 1 9, C D 2 0, C D 2 5, C D 4 5 R A/ R O, C D 5 6, C D 6 9, C D 6 3 L, 
C D 8 0, C D 8 3, C D 8 6, C D 1 2 3, D R.  T he fl o w  c yt o metric a nal ysis will als o be 
perf or me d o n t he b o ne marr o w sa m ples. 
 
Acti vati o n of D C a n d s u bse q ue nt m o d ula ti o n of t he i m m u ne res p o nse ca use d b y 
treat me nt wit h I xaz o mi b ma y directl y or i n directl y alter t he c yt o ki nes prese nt i n 
plas ma. T he Bi o Ra d h u ma n 2 7- ple x c yt o ki ne pa nel will be use d f or t he 
meas ure me nts of plas ma c o nce ntrati o ns of I L- 1 β , I L- 1rα , I L- 2, I L- 4, I L- 5, I L- 6, 
I L- 7, I L- 8, I L- 9, I L- 1 0, I L- 1 2( p 7 0), I L- 1 3, I L- 1 5, I L- 1 7, basic F G F, e ota xi n, G-
C S F, G M- C S F, I F N- γ, I P- 1 0, M C P- 1, MI P- 1α , MI P- 1β , P D G F, R A N T E S, T N F-
α , a n d V E G F. 
 
1 4. 4 3  Sa m ples f or f ut ure st u dies 
A n ali q u ot of C D 1 3 8 s orte d M M cells a n d C D 1 3 8 ne gati ve cells will be st ore d i n 
D M S O f or f ut ure st u dies. A n ali q u ot of peri p heral bl o o d plas ma as well as 
P B M C will be st ore d f or p ote ntial st u dies i n f ut ure. 
 
 
 

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 5. 0
 Dr u g
 
I nf or m ati o n
 
1 5. 1  
I xaz o mi b ( M L N 9 7 0 8, Ni nlar o ® ) 
1 5. 1 1 
B ac k gr o u n d : I xaz o mi b ( M L N 9 7 0 8) is a sec o n d- ge nerati o n s mall m olec ule 
i n hi bit or of t he 2 0 S pr oteas o me t hat is u n der de vel o p me nt f or t he treat me nt of 
n o n- he mat ol o gic mali g na ncies, l y m p h o ma, a n d m ulti ple m y el o ma.   
I xaz o mi b ( M L N 2 2 3 8) refers t o t he bi ol o gicall y acti ve, b or o nic aci d f or m of t he 
dr u g s u bsta nce, i xaz o mi b citrate ( M L N 9 7 0 8).  T he tra nsiti o n t o M L N 2 2 3 8 
occ urs i n a n y a q ue o us s yste m. 
 
1 5. 1 2 
F or m ul ati o n : T he i xaz o mi b ( M L N 9 7 0 8) ca ps ule dr u g pr o d uct f or m ulati o n 
c o nsists of dr u g s u bsta nce, micr ocr y stalli ne cell ul ose, talc, a n d ma g nesi u m 
stearate.  Se ve n differe nt ca ps ule stre n gt hs are ma n ufact ure d: 0. 2, 0. 5, 2. 0, 2. 3, 
3. 0, 4. 0, a n d 5. 5 m g; eac h ca ps ule stre n g t h has a u ni q ue c ol or. D osa ge stre n gt h is 
state d as i xaz o mi b (t he acti ve b or o nic aci d). I xaz o mi b ( M L N 9 7 0 8) ca ps ules are 
i n di vi d uall y pac ka ge d i n blisters. 
 
1 5. 1 3 
Pre p ar ati o n a n d st or a ge : I xaz o mi b ca ps ules ( 0. 2 m g, 0. 5 m g,  
2 m g), i n di vi d uall y pac ka ge d i n blisters, ca n be st ore d at 2º C t o 8º C   
or “ D o n ot st ore a b o ve 2 5° C. D o n ot freeze." I xaz o mi b ca ps ules ( 2. 3 m g, 3 m g, 4 
m g, a n d 5. 5 m g), i n di vi d uall y pac ka ge d i n blisters ca n be st ore d at “ 2° C - 8° C” 
or “ D o n ot st ore a b o ve 3 0° C. D o n ot freeze." 
I xaz o mi b t hat is dis pe nse d t o t he patie nt f or ta ke- h o me d osi n g s h o ul d re mai n i n 
t he blister pac ka gi n g u ntil t he p oi nt of use. T he i n vesti gati ve site is res p o nsi ble 
f or pr o vi di n g t he me dicati o n t o t he patie nt i n u nits t hat c o m prise t he c orrect dail y 
d ose c o nfi g urati o ns.  Ca ps ules s h o ul d re mai n i n t he blisters u ntil t he p oi nt of use.  
I xaz o mi b ca ps ules m ust be a d mi nistere d as i ntact ca ps ules a n d m ust n ot be 
o pe ne d or ma ni p ulate d i n a n y wa y.  C o m pre he nsi ve i nstr ucti o ns s h o ul d be 
pr o vi de d t o t he patie nt i n or der t o e ns ure c o m plia nce wit h d osi n g pr oce d ures.  
Patie nts will be i nstr ucte d t o st ore t he me dicati o n i n t he refri gerat or u ntil t he ti me 
of use. Rec o nciliati o n will occ ur acc or di n gl y w he n t he patie nt ret ur ns f or t heir 
ne xt c y cle of t hera p y. A n y e xtre mes i n te m perat ure s h o ul d be re p orte d as a n 
e xc ursi o n a n d will be ma na ge d o n a case b y case basis.  Ret ur ne d u n use d 
ca ps ules s h o ul d be discar de d i n a pr o per bi o hazar d c o ntai ner. 
I xaz o mi b is a n a ntica ncer dr u g. As wit h ot her p ote ntiall y t o xic c o m p o u n ds, 
ca uti o n s h o ul d be e xercise d w he n ha n dli n g i xaz o mi b.  It is rec o m me n de d t o wear 
gl o ves a n d pr otecti ve gar me nts d uri n g pr e parati o n w he n dis pe nse d i n cli nic. 
Please refer t o p u blis he d g ui deli nes re gar di n g t he pr o per ha n dli n g a n d dis p osal of 
a ntica ncer a g e nts. 
 
1 5. 1 4 
A d mi nistr ati o n:   I xaz o mi b ( M L N 9 7 0 8) ca ps ules m ust be a d mi nistere d as i ntact 
ca ps ules a n d are n ot i nte n de d t o be o pe ne d  or ma ni p ulate d i n a n y wa y.  Ca ps ules 
s h o ul d be ta ke n o n a n e m pt y st o mac h wit h ap pr o xi matel y 8 oz ( 1 c u p) of water at 
least 1 h o ur bef ore or at least 2 h o urs after f o o d. 
 
I xaz o mi b s h o ul d n ot be ta ke n if t he patie nt has ha d a seri o us aller gic reacti o n t o 
b or o n or b or o n c o ntai ni n g pr o d ucts. 
 
1 5. 1 5 
P h ar m ac o ki netic ( P K) i nf or m ati o n :   

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
a) A bs or pti o n:  After oral d osi n g, i xaz o mi b is ra pi dl y a bs or be d wit h a me dia n 
T ma x of 1 h o ur.  T he lac k of a discer ni ble relati o ns hi p bet wee n B S A a n d i xaz o mi b 
cleara nce o ver a relati vel y wi de B S A ra n ge ( 1. 4- 2. 6 m 2) i n dicates t hat t otal 
s yste mic e x p os ure ( A U C) f oll o wi n g fi xe d d osi n g s h o ul d be i n de pe n de nt of t he 
i n di vi d ual patie nt’s B S A.  A hi g h-fat meal decrease d b ot h t he rate a n d e xte nt of 
a bs or pti o n.  T heref ore, i xaz o mi b s h o ul d be  a d mi nistere d o n a n e m pt y st o mac h.   
b) Distri b uti o n: T he stea d y state v ol u me of distri b uti o n is lar ge a n d is esti mate d 
t o be 5 4 3 L. I xaz o mi b is 8 8- 9 4 % pr otei n b o u n d. 
c) Meta b olis m:  Meta b olis m is t he pri mar y r o ute f or eli mi nati o n of i xaz o mi b b y 
b ot h C Y P a n d n o n- C Y P e nz y mes. C Y P 3 A 4 a n d 1 A 2 c o m prise t he maj or C Y P 
is oz y mes t hat c o ntri b ute t o i xaz o mi b meta b olis m. 
d) E xcreti o n: T he mea n ter mi nal half-lif e is 9. 5 da ys.  Re nal eli mi n ati o n is a 
mi n or cleara n ce pat h wa y f or i xaz o mi b.  D osi n g a dj ust me nt is n ot re q uire d i n 
patie nts wit h mil d a n d m o derate re nal i m pair me nt i n st u dies. H o we ver, i n a 
de dicate d re nal i m pair me nt st u d y ( C 1 6 0 1 5), u n b o u n d A U C 0-last was 3 8 % hi g her 
i n patie nts wit h se vere re nal i m pair me nt or 
e n d-sta ge re nal disease ( E S R D) re q uiri n g dial ysis as c o m pare d t o patie nts wit h 
n or mal re nal f u ncti o n.  Acc or di n gl y, a re d uce d starti n g d ose of i xaz o mi b is 
rec o m me n de d i n patie nts wit h se vere re nal i m pair me nt a n d E S R D re q uiri n g 
dial ysis.  U n b o u n d s yste mic e x p os ures of i xaz o mi b are 2 7 % hi g her i n patie nts 
wit h m o derate or se vere he patic i m pair me nt as c o m pare d t o patie nts wit h n or mal 
he patic f u ncti o n.  A re d uce d starti n g d ose of i xaz o mi b is rec o m me n de d f or 
patie nts wit h m o derate or se vere he patic i m pair me nt. 
 
1 5. 1 6 
P ote nti al Dr u g I nter acti o ns :   
T he P K of i xaz o mi b was si milar wit h a n d wit h o ut c oa d mi nistrati o n of 
clarit hr o m y ci n, a str o n g C Y P 3 A i n hi bit or, a n d t heref ore n o d ose a dj ust me nt is 
necessar y w he n i xaz o mi b is a d mi nistere d wit h C Y P 3 A 
i n hi bit ors. I n t he p o p ulati o n P K a nal ysis, c oa d mi nistrati o n of str o n g C Y P 1 A 2 
i n hi bit ors di d n ot affect i xaz o mi b cleara nce. T h us, n o d ose a dj ust me nt is re q uire d 
f or patie nts recei vi n g str o n g C Y P 1 A 2 i n hibit ors. I n a cli nical rifa m pi n D DI 
st u d y, i xaz o mi b C ma x  a n d A U C0-last were re d uce d i n t he prese nce of rifa m pi n b y 
a p pr o xi matel y 5 4 % a n d 7 4 %, res pecti vel y. As a res ult, t he c oa d mi nistrati o n of 
str o n g C Y P 3 A i n d ucers wit h i xaz o mi b s h o ul d be a v oi de d.  I xaz o mi b is neit her a 
ti me- de pe n de nt n or re versi ble i n hi bit or of C Y Ps 1 A 2, 2 B 6, 2 C 8, 2 C 9, 2 C 1 9, 
2 D 6, or 3 A 4/ 5, t heref ore t he p ote ntial f or i xaz o mi b t o pr o d uce D DIs via C Y P 
is oz y me i n hi biti o n is l o w.  I xaz o mi b di d n ot i n d uce C Y P 1 A 2, C Y P 2 B 6, a n d 
C Y P 3 A 4/ 5 acti vit y.  T he p ote ntial f or i x az o mi b t o ca use D DIs wit h s u bstrates or 
i n hi bit ors of P- g p, B C R P, M R P 2, M A T E- 1, M A T E 2- K, O C T 2, O A T 1, O A T 3, 
a n d O A T Ps is l o w. 
P har mac o ki netic para meters f or i xaz o mi b c oa d mi nistere d wit h 
le nali d o mi de a n d de xa met has o ne ( Le n Dex) are si milar t o t h ose o bser ve d 
w he n i xaz o mi b is a d mi nistere d as a si n g le a ge nt. T his s u g gests t hat t here 
is n o rea dil y a p pare nt effect of c oa dmi nistrati o n of Le n De x o n t he cli nical 
P K of i xaz o mi b. 
I xaz o mi b s h o ul d n ot be ta ke n if t he patie nt has ha d a seri o us aller gic 
reacti o n t o b or o n or b or o n c o ntai ni n g pr o d ucts. 
 

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 5. 1 7 
K n o w n p ote nti al t o xicities :  See t he c urre nt versi o n of t he I n vesti gat or’s 
Br oc h ure f or m ore c o m plete i nf or mati o n i ncl u di n g p ote ntial ris ks, as well as 
rec o m me n dati o ns f or cli nical m o nit ori n g a n d me dical ma na ge me nt of t o xicit y. 
 
Ver y c o m m o n ( ≥1 0 %):  a ne mia, ne utr o pe nia, t hr o m b oc yt o pe nia, 
c o nsti pati o n, diarr hea, na usea, v o miti n g, fati g ue, decrease d a p petite, 
peri p heral ne ur o pat h y 
C o m m o n ( ≥1 % t o < 1 0 %):  Her pes z oster, peri p heral se ns or y ne ur o pat h y, 
er yt he ma, ras h, er yt he mat o us ras h, pr uritic ras h, mac ular ras h, peri p heral 
e de ma, u p per res pirat or y tract i nfecti o n, bac k pai n, mac ul o- pa p ular ras h, 
pa p ular ras h 
U nc o m m o n ( ≥0. 1 % t o < 1 %): ge neralize d pr uritis, ge neralize d ras h 
Her p es z oster  – a nti viral pr o p h yla xis s h o ul d be c o nsi dere d i n patie nts 
bei n g treate d wit h i xaz o mi b t o d ecrease t he ris k of her pes z oster 
reacti vati o n. 
R are b ut seri o us ris ks – i ntesti nal o bstr ucti o n, p ne u m o nia, life-
t hreate ni n g se vere s ki n ras h ( Ste ve n J o h ns o n s y n dr o me, T E N, D R E S S 
s y n dr o me), t hr o m b otic t hr o m b oc yt o pe nic p ur p ura, t u m or l ysis s y n dr o me, 
re nal fail ure, p osteri or re versi ble e nce p hal o pat h y s y n dr o me, tra ns verse 
m y elitis, pr o gressi ve m ultif o cal le u k oe nce p hal o pat h y. 
O ver d ose –  T here is n o k n o w n s pecific a nti d ote f or i xaz o mi b o ver d ose.  
I n t he e ve nt of a n o ver d ose i n bli n de d st u dies, st u d y me dicati o n 
assi g n me nt s h o ul d be u n bli n de d i m me diatel y.  T he cli nicia n s h o ul d 
c o nsi der a d mitti n g t he patie nt t o t he h o s pital f or I V h y drati o n, m o nit ori n g 
f or a d verse dr u g reacti o ns, m o nit ori n g of vital si g ns, a n d a p pr o priate 
s u p p orti ve care.  Ga va ge ma y be c o nsi dere d, b ut it s h o ul d be ke pt i n mi n d 
t hat i xaz o mi b a bs or pti o n is ra pi d.  I xaz o mi b is n ot rea dil y dial y za ble.   
  
1 5. 1 8 
Dr u g pr oc ure me nt:   I n vesti gati o nal pr o d uct will be s u p plie d free of c har ge t o 
trial partici pa nts b y Millen ni u m P har mace uticals, I nc. 
 
1 5. 1 9 
N ursi n g g ui deli nes 
1 5. 1 9 1  
Ca ps ules m ust be a d mi nistere d i ntact a n d s h o ul d n ot be o pe ne d or 
ma ni p ulate d i n a n y wa y. A d diti o nall y, ca ps ules s h o ul d re mai n i n t he 
blister pac ks u ntil t he y are rea d y t o be ta ke n. It is rec o m me n de d t o 
wear gl o ves a n d pr otecti ve gar me nts d uri n g pre parati o n w he n 
dis pe nse d i n cli nic. 
1 5. 1 9 2  
Ca ps ules s h o ul d be ta ke n o n a n e m pt y st o mac h (eit her 1 h o urs bef ore 
or 2 h o urs after meals) wit h 8 oz of water. 
1 5. 1 9 3  
C yt o pe nias ha ve bee n o bser ve d. M o nit or C B C w/ diff. I nstr uct patie nt 
t o re p ort a n y si g ns or s y m pt o ms of i nfecti o n or blee di n g t o t he st u d y 
tea m. 
1 5. 1 9 4  
GI si de effects ha ve bee n see n ( na usea, diarr hea, v o miti n g), treat 
s y m pt o maticall y a n d m o nit or f or effecti ve ness of i nter ve nti o n. 
1 5. 1 9 5  
Ras h has bee n see n. Rarel y Ste v e n J o h ns o n s y n dr o me ( SJ S) has bee n 
see n wit h t his a ge nt. I nstr uct patie nts t o re p ort a n y ras h t o st u d y tea m. 
1 5. 1 9 6  
Assess patie nts c o nc o mita nt me dicati o ns, i ncl u di n g o ver t he c o u nter 
a n d s u p ple me nts. M L N 9 7 0 8 is meta b olize d t hr o u g h b ot h C Y P a n d 

M C 1 7 8 2
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Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
n o n- C Y P e nz y mes, a n d dr u g t o dr u g i nteracti o ns e xist. I nstr uct patie nts 
n ot t o start a n y ne w me dicati o ns or s u p ple me nts wit h o ut c hec ki n g wit h 
t he st u d y tea m first.  
1 5. 1 9 7  
Fati g ue has bee n see n. I nstr uct patie nt i n e ner g y c o nser vi n g lifest yle. 
1 5. 1 9 8  
I ns o m nia ca n be see n. Treat s y m pt o maticall y a n d m o nit or f or 
effecti ve ness. 
1 5. 1 9 9a  Patie nts w h o ha ve ha d a n aller g ic reacti o n t o b or o n or b or o n c o ntai ni n g 
pr o d ucts s h o ul d n ot ta ke M L N 9 7 0 8. 
1 5. 1 9 9 b  T he f oll o wi n g rare b ut life t hreate ni n g c o n diti o ns ha ve bee n see n wit h 
a ge nt: C H F, li ver fail ure, T T P, T L S, re nal fail ure, b o wel o bstr ucti o n, 
a n d R P L S, tra ns verse m y elitis, pr o gressi ve m ultif ocal 
le u k oe nce p hal o pat h y.  M o nit or la bs cl osel y, i nstr uct patie nt t o re p ort 
a n y ne w or w orse ni n g s y m pt o ms t o t he st u d y tea m a n d pr o vi de f urt her 
assess me nt base d o n s y m pt o ms. 
 
1 5. 2  
Pe m br oliz u m a b ( M K- 3 4 7 5, S C H 9 0 0 4 7 5, Ke ytr u d a ®) 
1 5. 2 1 
B ac k gr o u n d :  Pe m br oliz u ma b is a p ote nt h u ma nize d I g G 4 m o n ocl o nal a nti b o d y 
wit h hi g h s pecificit y of bi n di n g t o t he P D- 1 rece pt or, t h us i n hi biti n g its 
i nteracti o n wit h P D- L 1 a n d P D- L 2. Base d o n precli nical i n vitr o data, 
pe m br oliz u ma b has hi g h affi nit y a n d p ot e nt rece pt or bl oc ki n g acti vit y f or P D- 1. 
 
1 5. 2 2 
F or m ul ati o n     
 Pe m br oliz u ma b is a vaila ble as a li q ui d 2 5 m g/ m L, 1 0 0 m g/ vial.  
  
1 5. 2 3   Pre p ar ati o n a n d st or a ge:  
Dr u g c o nce ntrate is f urt her dil ute d wit h n or mal sali ne ( or 5 % de xtr ose) i n   
Vials s h o ul d be st ore d i n t he refri gerat or at te m perat ures bet wee n 2- 8° C.   
Dr u g c o nce ntrate is f urt her dil ute d wit h n or mal sali ne ( or 5 % de xtr ose) i n 
t he c o nce ntrati o n ra n ge of 1 t o 1 0 m g/ m L i T he i nf usi o n s ol uti o n i n t he I V 
ba g s h o ul d be i m me diatel y a d mi nistere d.  Dil ute d pe m br oliz u ma b 
s ol uti o ns ma y be st ore d at r o o m te m p erat ure f or a c u m ulati ve peri o d of u p 
t o 6 h o urs. T his i ncl u des r o o m te m p erat ure st ora ge of a d mi xt ur e  s ol uti o ns 
i n t he I V ba gs a n d t he d urati o n of i nf usi o n. T he pr o d uct ca n als o be st ore d 
u n der refri gerati o n at 2° C t o 8° C f or n o m ore t ha n 9 6 h o urs fr o m t he ti me 
of dil uti o n. If refri gerate d, t he dil ute d s ol uti o n m ust be all o we d t o c o me t o 
r o o m te m p erat ure pri or t o a d mi nistrati o n. T he s ol uti o n m ust be discar de d 
after 6 h o urs at r o o m te m p erat ure or 9 6 h o urs u n der refri gerati o n.   
  
1 5. 2 4 
A d mi nistr ati o n:   Pe m br oliz u ma b is a d mi nistere d b y i ntra ve n o us i nf usi o n o ver 
3 0 mi n utes via a 0. 2 2 micr o n i n-li ne filter. T he fi nal i nf usi o n v ol u me m ust be 
bet wee n 1 a n d 1 0 m g/ m L. Ma xi m u m rate  of i nf usi o n s h o ul d n ot e xcee d 6. 7 
m L/ mi n ute t hr o u g h a peri p heral or i n d welli n g cat heter. Fl us h t he li ne wit h 0. 9 % 
Na C L f oll o wi n g t he c o m pleti o n of t he i nf usi o n. 
 
1 5. 2 5 
P h ar m ac o ki netic i nf or m ati o n : 
a)  A bs or pti o n – Beca use pe m br oliz u ma b is a d mi nistere d i ntra ve n o usl y, it 
is i m me diatel y a n d c o m pletel y bi oa vaila ble. Stea d y-state c o nce ntrati o ns of 

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pe m br oliz u ma b are reac he d b y 1 6 wee ks of re peate d d osi n g wit h a Q 3 W 
re gi me n a n d t he s yste mic acc u m ulati o n is 2. 1 f ol d. T he pea k 
c o nce ntrati o n, tr o u g h c o nce ntrati o n, a n d area u n der t he plas ma 
c o nce ntrati o n vers us ti me c ur ve at stea d y state of pe m br oliz u ma b 
i ncrease d d ose pr o p orti o nall y i n t he d ose ra n ge of 2 t o 1 0 m g/ k g Q 3 W. 
b)  Distri b uti o n – Pe m br oliz u ma b has a li mite d v ol u me of distri b uti o n.  
c)  E xcreti o n -  is a p pr o xi matel y 2 3 % l o wer after ac hie vi n g ma xi mal 
c ha n ge at stea d y state c o m pare d wit h t he first d ose T he ter mi nal 
eli mi nati o n half-life (t ½) is esti mate d t o be ~ 2 6 da ys at stea d y state. 
d)  Meta b olis m - P e m br oliz u ma b is cata b olize d  t hr o u g h n o n-s pecific pat h wa ys; 
meta b olis m d oes n ot c o ntri b ute t o its C L. 
 
1 5. 2 6 
P ote nti al Dr u g I nter acti o ns:  T here are n o k n o w n si g nifica nt dr u g 
i nteracti o ns.  
 
1 5. 2 7 
K n o w n p ote nti al t o xicities :   
Ver y c o m m o n k n o w n p ote nti al t o xicities, ≥ 1 0 %: 
Gastr oi ntesti nal dis or ders: diarr hea, na usea, a b d o mi nal pai n 
S ki n a n d s u bc uta ne o us tiss ue dis or ders: ras h, pr uritis 
Ge neral dis or ders a n d a d mi nistrati o n site c o n diti o ns: fati g ue 
 
C o m m o n k n o w n p ote nti al t o xicities, ≥1 % t o < 1 0 % :   
Bl o o d a n d l y m p hatic s yste m dis or der: a ne mia 
I m m u ne s yste m dis or ders: i nf usi o n relate d reacti o n 
E n d ocri ne dis or ders: h y pert h yr oi dis m, h y p ot h yr oi dis m 
Meta b olis m a n d n utriti o n dis o r ders: decrease d a p petite 
Ner v o us s yste m dis or ders: hea dac he, dizzi ness, d ys ge usia 
Res pirat or y, t h oracic, a n d me diasti nal dis or ders: p ne u m o nitis, d ys p nea, c o u g h 
 
Gastr oi ntesti nal dis or ders: c olitis, v o miti n g, c o nsti pati o n, dr y m o ut h 
S ki n a n d s u bc uta ne o us tiss ue dis or ders: se vere s ki n reacti o ns, vitili g o, dr y s ki n, 
er yt he ma  
M usc ul os keletal a n d c o n necti ve dis use dis or ders: art hral gia, j y ositis, 
m usc ul os keletal pai n, art hritis, pai n i n e xtre mit y 
 
Ge neral dis or ders a n d a d mi nistrati o n site  c o n diti o ns: ast he nia, e de ma, p yre xia, 
i nfl ue nza li ke ill ness, c hills 
I n vesti gati o ns: ala ni ne a mi n otra nsferase i ncrease d, as partate a mi n otra nsferase 
i ncrease d, bl o o d al kali ne p h os p hatase i ncrease d, bl o o d creati ni ne i ncrease d 
 
Less c o m m o n k n o w n p ote nti al t o xicities, ≥0. 1 % t o < 1 %: 
I nf usi o n rel ate d re acti o ns 
Bl o o d a n d l y m p hatic s yste m dis or ders: ne utr o pe nia, t hr o m b oc yt o pe nia, 
le u k o pe nia, l y m p h o pe nia, e osi n o p hilia 
E n d ocri ne dis or ders: h y p o p h ysitis, a dre nal i ns ufficie nc y, t h yr oi ditis, 
h y p o pit uitaris m 
 
Meta b olis m a n d n utriti o n dis or ders: t y pe I dia betes mellit us, h y p o natre mia, 
h y p o kale mia, h y p ocalce mia 
Ps y c hiatric dis or ders: i ns o m nia, c o nf usi o nal state 
Ner v o us s yste m dis or ders; e pile ps y, let har g y, peri p heral ne ur o pat h y 

M C 1 7 8 2
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E y e dis or ders: u veitis, dr y e y e 
Car diac dis or ders: m y ocar ditis, atrial fi brillati o n 
Vasc ular dis or ders: h y perte nsi o n 
Gastr oi ntesti nal dis or ders: pa ncreatitis, d ys p ha gia 
He pat o biliar y dis or ders: he patitis 
S ki n a n d s u bc uta ne o us tiss ue dis or ders: lic he n oi d kerat osis, ps oriasis, al o pecia, 
der matic, der matitis  ac neif or m, ecze ma, hair c ol or c ha n ges, pa p ule 
M usc ul os keletal a n d c o n necti ve tiss ue dis or ders: te n os y n o vitis, m y elitis 
Re nal a n d uri nar y dis or ders: ne p hritis, ac ute ki d ne y i nj ur y 
I n vesti gati o ns: bl o o d bilir u bi n i ncreased, a m ylase i ncrease d, h y percalce mia 
 
R are k n o w n p ote nti al t o xicities, < 0. 1 % ( Li mite d t o i m p ort a nt or life-
t hre ate ni n g): 
Bl o o d a n d l y m p hatic s yste m dis or ders: i m m u ne t hr o m b oc yt o pe nic 
p ur p ura, he m ol ytic a ne mia  
I m m u ne s yste m dis or ders: sarc oi d osis 
Ner v o us s yste m dis or ders: G uillai n- Barre s y n dr o me, m y ast he nic 
s y n dr o me 
Gastr oi ntesti nal dis or ders: s mall i ntesti nal perf orati o n 
S ki n a n d s u bc uta ne o us tiss ue dis or d ers: t o xic e pi der mal necr ol ysis, 
Ste ve ns-J o h ns o n s y n dr o me, er yt he ma n o d os u m 
 
T he ris k pr ofile f or pe m br oliz u ma b als o i ncl u des t w o i m p orta nt p ote ntial ris ks: a) 
m y ast he nic s y n dr o me, a n d b) a n i ncrease d ris k of se vere c o m plicati o ns (s uc h as 
earl y se vere graft vers us h ost disease a n d ve n o occl usi ve disease) of all o ge neic 
tra ns pla nt i n patie nts wit h he mat ol o gic mali g na ncies w h o ha ve pre vi o usl y bee n 
treate d wit h P D- 1 i n hi bit ors.  
 
Patie nts wit h m ulti ple m y el o ma w h o were treate d wit h pe m br oliz u ma b i n 
c o m bi nati o n wit h eit her p o mali d o mi de or Le nali d o mi de a n d de xa met has o ne, ha d 
a n i ncrease d n u m ber of seri o us si de effects a n d deat hs as c o m pare d t o patie nts 
w h o recei ve d o nl y de xa met has o ne a n d e it her p o mali d o mi de or Le n ali d o mi de. 
T he be nefit-ris k pr ofile is u nfa v ora ble  f or t he c o m bi nati o n of pe m br oliz u ma b, 
p o mali d o mi d e, a n d de xa met has o ne i n rela pse d refract or y m ulti ple m y el o ma, a n d 
t he c o m bi nati o n of pe m br oliz u ma b, Le nali d o mi de, a n d de xa met has o ne i n ne wl y 
dia g n ose d treat me nt- naï ve m ulti ple m y el o ma. 
 
P ost mar keti n g re p orts i de ntifie d V o gt- K o y a na gi- Hara da s y n dr o me a n d 
he m o p ha g oc ytic l y m p h o histi oc yt osis. 
 
1 5. 2 8 
Dr u g pr oc ure me nt:   Pe m br oliz u ma b will be pr o vi de d free of c har ge t o st u d y 
partici pa nts b y Merc k. 
 
1 5. 2 9  N ursi n g  g ui deli nes  
1 5. 2 9 1  Pe m br oliz u ma b si de effects var y greatl y fr o m t h ose of tra diti o nal 
c he m ot hera p y a n d ca n var y i n se verit y fr o m mil d t o life t hreate ni n g. 
I nstr uct patie nts t o re p ort a n y si de effects t o t he st u d y tea m i m me diatel y. 
Si de effects ma y be i m me diate or dela ye d u p t o m o nt hs after 
disc o nti n uati o n of t hera p y. M ost si de effects are re versi ble wit h pr o m pt 
i nter ve nti o n of c ortic oster oi ds. 

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1 5. 2 9 2  Diarr hea ca n be see n h o we ver is less c o m m o n t ha n t hat see n wit h a nti-
C T L A- 4 a ge nts. H o we ver it ca n be se vere, lea di n g t o c ol o nic 
perf orati o n. I nstr uct patie nts t o re p ort A N Y i ncrease i n t he n u m ber of 
st o ols a n d/ or c ha n ge i n baseli ne, bl o o d i n t he st o ol, a b d o mi nal pai n t o t he 
st u d y tea m i m me diatel y.  
1 5. 2 9 3  Ras h/ pr uirits/ der matitis  is see n. Patie nts s h o ul d re p ort a n y ras h t o t he 
st u d y tea m. Treat per secti o n 9. 0 a n d m o nit or f or effecti ve ness.  
1 5. 2 9 4  M o nit or L F T’s cl osel y as ele vati o ns  i n t hese le vels c o ul d i n dicate earl y 
o nset a ut oi m m u ne he patitis. Patie nts s h o ul d als o be i nstr ucte d t o re p ort 
a n y ja u n dice, or ri g ht u p per q ua dra nt pai n t o t he st u d y tea m i m me diatel y. 
1 5. 2 9 5  P ne u m o nitis ca n be see n a n d ma y be mil d ( o nl y see n o n i ma gi n g) t o 
se vere. Patie nts s h o ul d be i nstr ucte d t o re p ort a n y S O B, d ys p nea, c o u g h, 
c hest pai n, etc. t o t he st u d y tea m i m me diatel y. Patie nts re p orti n g t hese 
s y m pt o ms s h o ul d ha ve a p ulse o x c hec ke d a n d c o nsi der i m me diate 
i ma gi n g per t he treati n g M D. 
1 5. 2 9 6  E n d ocri n o pat hies (i ncl u di n g h y p o pit uitaris m, h y p ot h yr oi dis m, 
h y p o p h ysistis, a n d a dre nal i ns ufficie n c y) are see n wit h t his a ge nt. 
Patie nts ma y prese nt o nl y wit h t he va g ue se nse of  fati g ue a n d “ n ot 
feeli n g well” . A d diti o nal s y m pt o ms ma y be t hat of na usea, s weati n g a n d 
decrease d acti vit y t olera nce. I nstr u ct patie nts t o re p ort t hese si g ns or 
s y m pt o ms i m me diatel y a n d o btai n a p pr o priate la bs as or dere d b y M D.  
1 5. 1 9 7  Patie nts w h o are starte d o n ster oi d t hera p y f or a n y si de effects of 
pe m br olizi ma b t o xicit y s h o ul d be i nstr ucte d t o ta ke t he ster oi ds as 
or dere d, a n d n ot t o disc o nti n ue a br u ptl y as s y m pt o ms ma y ret ur n a n d be 
se vere. Patie nts ma y be o n ster oi d t hera p y f or wee ks. I nstr uct patie nts t o 
re p ort a n y i ncrease or c ha n ge i n si de effects wit h a n y d osa ge decrease as 
patie nts ma y nee d a sl o wer ta per.  
1 5. 2 9 8  Fati g ue is c o m m o n a n d ma y or ma y n ot be ass ociate d wit h i m m u ne 
relate d si de effects. Assess patie nt’s fati g ue le vel pri or t o eac h c y cle of 
t hera p y a n d re p ort a n y c ha n ges t o t he st u d y tea m. 
1 5. 2 9 9a  Patie nts s h o ul d a v oi d recei vi n g li ve vacci nes wit hi n 3 0 da ys of st u d y 
dr u g a d mi nistrati o n or per ot her st u d y g ui deli nes.  
1 5. 2 9 9 b Patie nts w h o ha ve u n der g o ne a n a ll o ge nic b o ne marr o w tra ns pla nt, ha ve 
a n i ncrease d ris k of se vere c o m plicati o ns i ncl u di n g earl y G V H D, a n d 
ve n o occl usi ve disease, if t he y ha ve pre vi o usl y bee n treate d wit h 
pe m br oliz u ma b 
1 5. 2 9 9c M y ocar ditis has bee n re p orte d a n d ass ociate d wit h pe m br oliz u ma b. 
I nstr uct patie nts t o re p ort c hest pai n, S O B, or d ys p nea t o st u d y tea m 
i m me diatel y a n d/ or see k e mer ge nc y me dical atte nti o n. 
1 5. 2 9 9 d A ut oi m m u ne he mat ol o gic dis or ders i ncl u di n g I T P a n d he m ol ytic a ne mia 
ha ve bee n re p orte d. M o nit or bl o o d c o u nts cl osel y a n d re p ort a n y 
a b n or malities t o t he st u d y tea m. 

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1 5. 2 9 9e Rare ne ur ol o gic dis or ders i ncl u di n g G uillia n- Barre s y n dr o me a n d 
m y ast he nia gra vis ha ve bee n re p orte d. I nstr uct patie nts t o re p ort a n y 
ne ur ol o gic s y m pt o ms i ncl u di n g wea k ness, parast hesias or n u m b ness, 
ti n gli n g t o t he st u d y tea m i m me diatel y. 
1 5. 3  
De x a met h as o ne f or Or al A d mi nistr ati o n ( D X M) 
1 5. 3 1 
B ac k gr o u n d : De xa met has o ne is a n a dre nal c ortic oster oi d c o m p o u n d. 
De xa met has o ne decreases i nfla m mati o n b y s u p pressi o n of ne utr o p hil mi grati o n, 
decrease d pr o d ucti o n of i nfla m mat or y me diat ors, a n d re versal of i ncrease d 
ca pillar y per mea bilit y; s u p presses n or mal i m m u ne res p o nse. De xa met has o ne’s 
mec ha nis m of a ntie metic acti vit y is u n k n o w n. 
 
1 5. 3 2 
F or m ul ati o n : C o m merciall y a vaila ble f or oral a d mi nistrati o n as:  
Ta blets [sc ore d]: 0. 5 m g, 0. 7 5 m g, 1 m g, 1. 5 m g, 2 m g, 4 m g, a n d 6 m g 
S ol uti o n, oral: 0. 5 m g/ m L ( 5 0 0 m L) 
S ol uti o n, oral c o nce ntrate: De xa met has o ne I nte ns ol: 1 m g/ m L ( 3 0 m L) 
 
1 5. 3 3 
Pre p ar ati o n, st or a ge, a n d st a bilit y : Refer t o pac ka ge i nsert f or c o m plete 
pre parati o n a n d dis pe nsi n g i nstr ucti o ns. St ore oral ta blets at r o o m 
te m perat ure b et wee n 2 0º C t o 2 5º C ( 6 0º F t o 7 7º F). Pr otect fr o m m oist ure. 
Dis pe nse i n a well-cl ose d, li g ht-resista nt c o ntai ner as defi ne d i n t he 
U S P/ N F. St ore oral li q ui d at r o o m te m p erat ure, d o n ot freeze. D o n ot use 
if s ol uti o n c o ntai ns a preci pitate. Refer t o c o m mercial pac ka ge f or dr u g 
e x pirati o n date. 
1 5. 3 4 
A d mi nistr ati o n:   Refer t o t he treat me nt secti o n f or s pecific a d mi nistrati o n 
i nstr ucti o ns. Ma y be ta ke n wit h meals t o decrease GI u pset.  
 
1 5. 3 5 
P h ar m ac o ki netic i nf or m ati o n : 
O nset of acti o n: Pr o m pt 
D ur ati o n of met a b olic effect: 7 2 h o urs 
Met a b olis m:  He patic 
H alf-life eli mi n ati o n: N or mal re nal f u ncti o n: 1. 8- 3. 5 h o urs; Bi ol o gic al 
h alf-life:  3 6- 5 4 h o urs 
Ti me t o pe a k, ser u m:  Oral: 1- 2 h o urs 
E xcreti o n : Uri ne a n d feces 
 
1 5. 3 6 
P ote nti al Dr u g I nter acti o ns : 
C yt oc hr o me P 4 5 0 Effect: S u bstr ate of C Y P 3 A 4 ( maj or); I n d uces 
C Y P 2 A 6 ( wea k), 2 B 6 ( wea k), 2 C 8 ( wea k), 2 C 9 ( wea k), 3 A 4 (str o n g) 
I ncre ase d Effect/ T o xicit y: A pre pita nt, az ole a ntif u n gals, calci u m c ha n nel 
bl oc kers, c y cl os p ori ne, estr o ge ns, a n d macr oli des ma y i ncrease t he ser u m 
le vels of c ortic oster oi ds. C ortic oster oi ds ma y i ncrease t he h y p o kale mic 
effects of a m p h oterici n B or p otassi u m- wasti n g di uretics (l o o p or 
t hiazi de); m o nit or. Refer t o t he pac ka ge i nsert f or a listi n g of ot her dr u gs. 
Decre ase d Effect:  A ntaci ds a n d bile aci d se q uestra nts ma y re d uce t he 
a bs or pti o n of c ortic oster oi ds; ma y re d u ce t he a bs or pti o n of c ortic oster oi ds; 
se parate a d mi nistrati o n b y 2 h o urs. A mi n o gl utet hi mi de, bar bit urates, a n d 
C Y P 3 A 4 i n d ucers ma y re d uce t he ser u m le vels/effects of de xa met has o ne 
a n d de xa met has o ne ma y decrease t he le vels/effects of ot her C Y P 3 A 4 
s u bstrates. Ser u m c o nce ntrati o ns of is o niazi d ma y be decrease d b y 

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c ortic oster oi ds. C ortic oster oi ds ma y l ea d t o a re d ucti o n i n warfari n effect. 
C ortic oster oi ds ma y s u p press t he res p o nse t o vacci nati o ns. 
Et h a n ol/ N utriti o n/ Her b I nter acti o ns :  
Et ha n ol: A v oi d et ha n ol ( ma y e n ha nce gastric m uc osal irritati o n). 
F o o d: De xa met has o ne i nterferes wit h calci u m a bs or pti o n. Li mit caffei ne. 
Her b/ N utrace utical: A v oi d cat’s cla w, Ec hi nacea ( ha ve i m m u n osti m ula nt 
pr o perties) 
 
1 5. 3 7 
K n o w n p ote nti al a d verse e ve nts:  C o ns ult t he pac ka ge i nsert f or t he m ost 
c urre nt a n d c o m plete i nf or mati o n.  
C o m m o n k n o w n p ote nti al t o xicities, fre q ue nc y n ot defi ne d:   
Fl ui d a n d electr ol yte dist ur ba nces, c o n gesti ve heart fail ure i n s usce pti ble 
pers o ns, h y perte nsi o n, e u p h oria, pers o nalit y c ha n ges, i ns o m nia, 
e xacer bati o n of i nfecti o n, e xacer bati o n or s y m pt o ms of dia betes, 
ps y c h osis, m uscle wea k ness, oste o p or osis, verte bral c o m pressi o n 
fract ures, pa n creatitis, es o p ha gitis, pe ptic ulcer, der mat ol o gic dist ur ba nces, 
c o n v ulsi o ns, verti g o a n d hea dac he, e n d ocri ne a b n or malities, o p ht hal mic 
c ha n ges, a n d meta b olic c ha n ges. S o me p atie nts ha ve e x perie nce d itc hi n g 
a n d ot her aller gic, a na p h ylactic or h y perse nsiti vit y reacti o ns. Wit h dra wal 
fr o m pr ol o n ge d t hera p y ma y res ult i n s y m pt o ms i ncl u di n g fe ver, m y al gia 
a n d art hral gia. 
 
1 5. 3 8 
Dr u g pr oc ure me nt:   C o m mercial s u p plies. P har macies or cli nics s hall o btai n 
s u p plies fr o m n or mal c o m mercial s u p pl y c hai n or w h olesaler. 
1 5. 3 9 
N ursi n g g ui deli nes  
 
1 5. 3 9 1  M o nit or re g ularl y f or h y perte nsi o n, C H F a n d ot her e vi de nce of fl ui d 
rete nti o n. 
 
1 5. 3 9 2  A d vise patie nt of p ossi ble m o o d or be ha vi oral c ha n ges, i.e., de pressi o n, 
e u p h oria, i ns o m nia, e ve n ps y c h osis.  I nstr uct patie nt t o re p ort a n y 
s us pecte d c ha n ges t o healt hcare tea m. 
 
1 5. 3 9 3  Assess f or s y m pt o ms of gastric ulcer, heart b ur n, or gastritis.  S u g gest 
a ntaci ds.  I nstr uct patie nt t o re p ort s y m pt o ms t o healt hcare tea m if u na ble 
t o c o ntr ol. 
 
1 5. 3 9 4  E val uate si g ns of i nfecti o n, par tic ularl y l ocal ca n di dal i nfecti o ns a n d 
treat a p pr o priatel y. 
 
1 5. 3 9 5  M o nit or bl o o d gl uc ose fre q ue ntl y. 
 
1 5. 3 9 6  I nstr uct patie nt t o re p ort fre q ue nt, u nrele nti n g hea dac hes or vis ual 
c ha n ges t o healt hcare tea m. 
 
1 5. 3 9 7  A d vise patie nt t hat eas y br uisi n g is a si de effect. 
 
 
 

M C 1 7 8 2
 7 4
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 6. 0   
St atistic al C o nsi der ati o ns a n d Met h o d ol o g y  
1 6. 1
 O ver vie w
 
T his is a p hase II st u d y of a n o vel re gi me n of Pe m br oliz u ma b wit h i xaz o mi b a n d 
de xa met has o ne f or treat me nt of rela pse d m u lti ple m y el o ma patie nts re q uiri n g t hera p y.  
T his st u d y is desi g ne d t o assess t he o verall r es p o nse rate ass ociate d wit h t hera p y wit h 
pe m br oliz u ma b a d de d t o sta n dar d d oses of i x az o mi b a n d de xa met has o ne i n patie nts wit h 
rela pse d m ulti ple m y el o ma usi n g a si n gle sta ge p hase II st u d y desi g n wit h a n i nteri m 
a nal ysis.   
 
1 6. 1 1  
E n d p oi nt: T he pri mar y e n d p oi nt of t he trial is t he o verall res p o nse rate.  A 
s uccess will be defi ne d as a P R or better n ote d as t he o bjecti ve stat us o n t w o 
c o nsec uti ve e val uati o ns.  Res p o nse will be e val uate d usi n g all c y cles.  
T hr o u g h o ut Secti o n 1 6. 0, res p o nse will be c o nsi dere d s y n o n y m o us wit h 
“s uccess”, u nless s pecifie d ot her wise.   
 
1 6. 1 2  
Sa m ple Size:  T he si n gle-sta ge st u d y desi g n wit h a n i nteri m a nal ysis t o be use d is 
f ull y descri be d bel o w.  A mi ni m u m of 1 4 a n d a ma xi m u m of 3 7 e val ua ble 
patie nts will be accr ue d i n t he p hase II st u d y u nless u n d ue t o xicit y is 
e nc o u ntere d.  We a ntici pate accr ui n g a n a d diti o nal 4 patie nts t o acc o u nt f or 
i neli gi bilit y, ca ncellati o n, maj or treat me nt vi olati o n, or ot her reas o ns f or a 
ma xi m u m of 4 1 patie nts. All patie nts meeti n g t he eli gi bilit y criteria w h o ha ve 
si g ne d c o nse nt a n d recei ve d at least o ne d ose of treat me nt will be c o nsi dere d 
e val ua ble f or res p o nse, wit h t he e xce pti o n of patie nts w h o are deter mi ne d t o be a 
maj or vi olati o n.  
 
1 6. 1 3  
Accr ual Rate a n d St u d y D urati o n:  T he a ntici pate d accr ual rate is 2- 3 e val ua ble 
m ulti ple m y el o ma patie nts per m o nt h.  At t his rate, it will li kel y ta ke a b o ut 1. 5 
y ears t o e nr oll t he patie nts. T he ma xi m u m t otal st u d y d urati o n is e x pecte d t o be 
a p pr o xi matel y 4. 5 y ears, or u ntil t he last patie nt accr ue d has bee n o bser ve d f or at 
least 3 y ears.  T he earliest date a ntici pate d f or prese ntati o n of res ults is at 
a p pr o xi matel y 2 y ears, or w he n t he last patie nt accr ue d has bee n o bser ve d f or at 
least 6 m o nt hs. 
 
1 6. 2   
Statistical Desi g n: 
1 6. 2 1  Decisi o n R ule:   
A c o m bi nati o n of i xaz o mi b pl us de xa met has o ne, a n oral re gi me n, is effecti ve f or 
t he treat me nt of rela pse d m ulti ple m y el o ma, wit h a res p o nse rate of 3 1 % see n i n 
a pre vi o us st u d y t hat i ncl u de d 3 5 patie nts treate d at t he sta n dar d d oses. A n 
i ncrease i n t he o verall res p o nse rate wit h t he a d diti o n of pe m br oliz u ma b t o 
I xaz o mi b pl us de xa met has o ne w o ul d be of i nterest.    
T he lar gest s uccess pr o p orti o n w here t he pr o p ose d treat me nt re gi me n w o ul d be 
c o nsi dere d i neffecti ve i n t his p o p ul ati o n is 3 0 %, a n d t he s mallest s uccess 
pr o p orti o n t hat w o ul d warra nt s u bse q ue nt st u dies wit h t he pr o p ose d re gi me n i n 
t his patie nt p o p ulati o n is 5 0 %. T he f oll o wi n g o ne-sta ge desi g n wit h a n i nteri m 
a nal ysis is base d o n a Si m o n o pti m u m desi g n a n d re q uires 3 7 e val ua ble patie nts 
t o test t he n ull h y p ot hesis t hat t he tr ue s uccess pr o p orti o n i n t his patie nt 
p o p ulati o n is at m ost 3 0 %.  
 

M C 1 7 8 2
 7 5
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 6. 2 1 1  
I nteri m A nal ysis:  E nter 1 4 e val ua ble patie nts i nt o t he st u d y. If 4 or 
fe wer s uccesses are o bser v e d i n t he first 1 4 e val ua ble patie nts, we will 
c o nsi der t his re gi me n i neffecti v e i n t his patie nt p o p ulati o n a n d 
ter mi nate t his st u d y. Ot her wise, if t he n u m ber of s uccesses is at least 5, 
we will c o nti n ue accr ual. 
 
1 6. 2 1 2  
Fi nal Decisi o n R ule:  E nter a n a d diti o nal 2 3 e val ua ble patie nts i nt o t he 
st u d y.  If 1 4 or fe wer s uccesses are o bser ve d i n t he first 3 7 e val ua ble 
patie nts, we will c o nsi der t his re gi me n i neffecti ve i n t his patie nt 
p o p ulati o n. Ot her wise, if t he n u m ber of s uccesses is at least 1 5, t his 
will be c o nsi dere d e vi de nce of pr o misi n g acti vit y a n d t he treat me nt 
ma y be rec o m me n de d f or f urt her testi n g i n s u bse q ue nt st u dies. 
 
1 6. 2 1 3  
O ver Accr u al: If m ore t ha n t he tar get n u m b er of patie nts are accr ue d, 
t he a d diti o nal patie nts will n ot be use d t o e val uate t he st o p pi n g r ule or 
use d i n a n y decisi o n ma ki n g pr ocess.  A nal yses i n v ol vi n g o ver accr ue d 
patie nts are disc usse d i n Secti o n 1 6. 3 4. 
 
1 6. 2 1 4   
N O T E: We will n ot s us pe n d accr ual at t he i nteri m a nal ysis t o all o w t he 
first 1 4 patie nts t o bec o me e val ua ble, u nless u n d ue t o xicit y is 
o bser ve d. Gi ve n t he li mite d o verall sa m ple size a n d t he i ncl usi o n of a n 
a d verse e ve nts st o p pi n g r ule, we feel it is et hical t o n ot halt accr ual f or 
t he i nteri m a n al ysis. H o we ver, if accr ual is e xtre mel y ra pi d, we ma y 
te m p oraril y s us pe n d accr ual i n or der t o o btai n safet y data o n t hese 
patie nts bef ore re- o pe ni n g accr ual t o f urt her patie nts 
 
1 6. 2 2  P o wer a n d Si g nifica nce Le vel:  Ass u mi n g t hat t he n u m b er of s uccesses is 
bi n o miall y distri b ute d, t he si g nifica nce le vel is . 0 9 5, i.e. t here is a 9. 5 % c ha nce 
of fi n di n g t he dr u g t o be effecti ve w he n it tr ul y is n ot.  T he pr o ba bilit y of 
declari n g t hat t his re gi me n warra nts f urt her st u d y (i.e. statistical p o wer) a n d t he 
pr o ba bilit y of st o p pi n g after t he i nteri m a nal ysis u n der vari o us s uccess 
pr o p orti o ns ca n be ta b ulate d as a f u ncti o n of t he tr ue s uccess pr o p orti o n as 
s h o w n i n t he f oll o wi n g ta ble. 
 
If t he tr ue s uccess pr o p orti o n is... 
0. 3 0
 0. 3 5
 0. 4 0
 0. 4 5
 0. 5 0
 
T he n t he pr o ba bilit y of declari n g 
t hat t he re gi me n warra nts f urt her 
st u d y is … 
0. 0 9 5
 0. 2 5 3
 0. 4 7 4
 0. 6 9 4
 0. 8 5 3
 
A n d t he pr o ba bilit y of st o p pi n g 
after t he i nteri m a nal ysis is … 
0. 5 8 4
 0. 4 2 3
 0. 2 7 9
 0. 1 6 7
 0. 0 9 0
 
 
1 6. 2 3  Ot her c o nsi derati o ns:  A d verse e ve nts, q ualit y/ d urati o n of res p o nse, a n d patter ns 
of treat me nt fail ure o bser ve d i n t his st u d y, as well as scie ntific disc o veries or 
c ha n ges i n sta n dar d care will be ta ke n i n t o acc o u nt i n a n y decisi o n t o ter mi nate 
t he st u d y 
 
 
 

M C 1 7 8 2
 7 6
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 6. 3
 A nal ysis
 
Pla n
 
1 6. 3 1  Pri mar y O utc o me A nal yses: 
1 6. 3 1 1  Defi niti o n:  T he pri mar y e n d p oi nt i n t his trial is t he o verall res p o nse rate.  
A s uccess is defi ne d as a P R or better n ote d as t he o bjecti ve stat us o n 
t w o c o nsec uti ve e val uati o ns.  Resp o nse will be e val uate d usi n g all 
c y cles. All patie nts meeti n g t he eli gi bilit y criteria w h o ha ve si g ne d a 
c o nse nt f or m a n d ha ve be g u n treat me nt will be e val ua ble f or res p o nse, 
wit h t he e xce pti o n of patie nts deter m i ne d t o be a maj or vi olati o n. 
 
1 6. 3 1 2  Esti mati o n:  T he pr o p orti o n of s uccesses will be esti mate d b y t he n u m ber 
of s uccesses di vi de d b y t he t otal n u m ber of e val ua ble patie nts. 
C o nfi de nce i nter vals f or t he tr ue s uccess pr o p orti o n will be calc ulate d 
acc or di n g t o t he a p pr oac h of D uff y a n d Sa nt ner. 
 
1 6. 3 2  Sec o n dar y O utc o me A nal yses 
 
1 6. 3 2 1  T he  ≥V G P R res p o nse rate wit h pe m br oliz u ma b a d de d t o I xaz o mi b a n d 
de xa met has o ne will be esti mate d b y t he n u m ber of patie nts w h o ac hie ve 
a V G P R, C R, or s C R at a n y ti me di vi de d b y t he t otal n u m ber of 
e val ua ble patie nts. E xact bi n o mial 9 5 % c o nfi de nce i nter vals f or t he tr ue 
s uccess rate will be calc ulate d. 
 
1 6. 3 2 2  T he c o m plete res p o nse rate wit h  pe m br oliz u ma b a d de d t o I xaz o mi b a n d 
de xa met has o ne will be esti mate d b y t he n u m ber of patie nts w h o ac hie ve 
a C R or s C R at a n y ti me di vi de d b y t he t otal n u m ber of e val ua ble 
patie nts. E xact bi n o mial 9 5 % c o nfi de nce i nter vals f or t he tr ue s uccess 
rate will be calc ulate d.   
 
1 6. 3 2 3  S ur vi val ti me is defi ne d as t he ti me fr o m date of first treat me nt t o deat h 
d ue t o a n y ca use. T he distri b uti o n of s ur vi val ti me will be esti mate d 
usi n g t he met h o d of Ka pla n- Meier 7.  
 
1 6. 3 2 4  Pr o gressi o n-free s ur vi val is defi ne d as t he ti me fr o m date of first 
treat me nt t o t he earliest date of d oc u me ntati o n of disease pr o gressi o n or 
deat h d ue t o a n y ca use. Patie nts w h o recei ve s u bse q ue nt treat me nt f or 
m y el o ma bef ore disease pr o gressi o n will be ce ns ore d o n t he date of 
t heir last disease assess me nt pri or t o i nitiati o n of t he s u bse q ue nt 
treat me nt.   Tra ns pla nt will n ot be c o nsi dere d s u bse q ue nt treat me nt.  
T he distri b uti o n of pr o gressi o n-free s ur vi val will be esti mate d usi n g t he 
met h o d of Ka pla n- Meier 
 
1 6. 3 2 5  A d verse E ve nts:  All eli gi ble patie nt s t hat ha ve i nitiate d treat me nt will be 
c o nsi dere d e val ua ble f or assessi n g a d verse e ve nt rate(s).  T he ma xi m u m 
gra de f or eac h t y pe of a d verse e ve nt will be rec or de d f or eac h patie nt, 
a n d fre q ue nc y ta bles will be re vie we d t o deter mi ne p atter ns.  
A d diti o nall y, t he relati o ns hi p of t he a d verse e ve nt(s) t o t he st u d y 
treat me nt will be ta ke n i nt o c o nsi derati o n. 
 
 

M C 1 7 8 2
 7 7
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 6. 3 3   C orrelati ve A nal yses 
1 6. 3 3 1  P D L- 1 e x pressi o n o n m y el o ma cells a n d n o n-t u m or cell c o m part me nts 
fr o m t he b o ne marr o w will be assesse d at baseli ne.  Eac h meas ure will be 
s u m marize d descri pti vel y b y me dia n, mi n, ma x a n d i nter q uartile ra n ge.   
 
1 6. 3 3 2  Mar kers of T-cell acti vati o n a n d e x ha usti o n will be s u m marize d 
descri pti vel y b y me dia n, mi n, ma x, a n d i nter q uartile ra n ge at eac h ti me 
p oi nt. Patter ns o ver ti me will be s u m ma rize d b y a bs ol ute differe nce or 
relati ve c ha n ge. C ha n ges acr oss ti me will be assesse d usi n g paire d 
a nal yses, i ncl u di n g Wilc o x o n si g ne d ra n k tests. Jit pl ots will be use d t o 
vis uall y e xa mi ne differe nces bet w ee n gr o u ps f or c o nti n u o us fact ors. 
 
1 6. 3 3 3  N K cell f u ncti o n a n d n u m bers will be s u m marize d descri pti vel y b y 
me dia n, mi n, ma x, a n d i nter q uartile ra n ge at eac h ti me p oi nt. Patter ns 
o ver ti me will be s u m marize d b y a bs ol u te differe nce or relati ve c ha n ge. 
C ha n ges acr oss ti me will be assesse d usi n g paire d a nal yses, i ncl u di n g 
Wilc o x o n si g ne d ra n k tests. Jit pl ots will be use d t o vis uall y e xa mi n e 
differe nces b et wee n gr o u ps f or c o nti n u o us fact ors. 
 
1 6. 3 4  O ver Accr u al: If m ore t ha n t he tar get n u m b er of patie nts are accr ue d, t he 
a d diti o nal patie nts will n ot be use d t o e v al uate t he st o p pi n g r ule or use d i n a n y 
decisi o n ma ki n g pr ocesses; h o we ver, t he y will be i ncl u de d i n fi nal e n d p oi nt 
esti mates a n d c o nfi de nce i nter vals. 
1 6. 4
 Earl y
 
Safet y
 
A nal ysis
 
A n earl y safet y a nal ysis will be perf or me d afte r t he first 6 patie nts ha ve bee n accr ue d t o 
t he st u d y a n d o bser ve d f or at least 4 2 da ys. Accr ual will be te m p oraril y halte d w hile 
t hese patie nts are e val uate d. If 2 or m ore of t he first 6 patie nts e x perie nce a D L T as 
defi ne d bel o w, t he n accr ual t o t he st u d y will c o nti n ue t o be te m p oraril y halte d w hile t he 
st u d y tea m deter mi nes if c h a n ges t o t he d osi n g sc he d ule are warra nte d. 
T o xicit y will be meas ure d per N CI- C T C A E versi o n 4. D L T is defi ne d as a n a d verse 
e ve nt occ urri n g d uri n g t he first c y cle of treat me nt t hat is p ossi bl y, pr o ba bl y, or defi nitel y 
relate d t o st u d y treat me nt a n d t hat meets o ne of t he f oll o wi n g: 
•  
A n y ≥Gra de 4 ne utr o p hil c o u nt decrease or platelet c o u nt decrease t hat persists 
> 7 da ys 
•  
A n y ≥G gra de 3 i nfecti o ns 
•  
≥Gra de 3 er yt he ma m ultif or me, ulcerati o n, or urticarial t hat d oes n ot res ol ve t o 
≤Gra de 2 wit hi n 3 wee ks 
•  
≥Gra de 3 br o nc hial o bstr ucti o n, p ne u m o nitis, or w heezi n g 
•  
≥Gra de 3 aller gic reacti o n or a ut oi m m u nit y 
•  
All ot her ≥Gra de 3 n o n- he mat ol o gic t o xicities ( w it h t he e xce pti o n of electr ol yte 
a b n or malities t hat are re versi ble a n d as y m pt o matic) t hat d oes n ot res ol ve t o ≤Gra de 2 
i n ≤7 2 h o urs des pite o pti mal s u p p orti ve me dicati o ns 
1 6. 5  
Data & Safet y M o nit ori n g: 
1 6. 5 1  T he pri nci pal i n vesti gat or(s) a n d t he st u d y statisticia n will re vie w t he st u d y at 
least t wice a y ear t o i de ntif y accr ual, a d verse e ve nt, a n d a n y e n d p oi nt pr o ble ms 
t hat mi g ht be de vel o pi n g. T he Ma y o Cli nic Ca ncer Ce nter ( M C C C) Data Safet y 

M C 1 7 8 2
 7 8
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
M o nit ori n g B oar d ( D S M B) is res p o nsi ble  f or re vie wi n g accr ual a n d safet y data 
f or t his trial at least t wice a y ear, base d o n re p orts pr o vi de d b y t he M C C C 
Statistical Office. 
 
1 6. 5 2  A d verse E ve nt St o p pi n g R ules 
T he st o p pi n g r ules s pecifie d bel o w are b ase d o n t he k n o wle d ge a vaila ble at st u d y 
de vel o p me nt.  We n ote t hat t he A d verse E ve nt St o p pi n g R ule ma y be a dj uste d i n 
t he e ve nt of eit her ( 1) t he st u d y re- o peni n g t o accr ual or ( 2) at a n y ti me d uri n g 
t he c o n d uct of t he trial a n d i n c o nsi derati o n of ne wl y ac q uire d i nf or mati o n 
re gar di n g t he a d verse e ve nt pr ofile of t he treat me nt(s) u n der i n vesti gati o n.  T he 
st u d y tea m ma y c h o ose t o s us pe n d accr ual beca use of u ne x pecte d a d verse e ve nt 
pr ofiles t hat ha ve n ot cr osse d t he s pecifie d r ule bel o w. 
 
Accr ual will be te m p oraril y s us pe n de d t o t his st u d y if at a n y ti me we o bser ve 
e ve nts c o nsi dere d at least p ossi bl y relate d t o st u d y treat me nt (i.e. a n a d verse 
e ve nt wit h attri b ute s pecifie d as  “ p ossi ble,” “ pr o ba ble,” or “ defi nite”) t hat 
satisf y o ne of t he f oll o wi n g: 
 
•  
if 2 or m ore patie nts i n t he first 6 treate d patie nts e x perie nce a gra de 4 or 
hi g her n o n- he mat ol o gic a d verse e ve nt at  least p ossi bl y relate d t o treat me nt. 
 
•  
if after t he first 6 patie nts ha ve bee n treate d, 4 0 % of all patie nts e x perie nce a 
gra de 4 or hi g her n o n- he mat ol o gic a d verse e ve nt at least p ossi bl y relate d t o 
treat me nt.  
 
We n ote t hat we will re vie w Gra de 4 a n d 5 a d verse e ve nts dee me d “ u nrelate d” or 
“ u nli kel y t o be relate d”, t o verif y t hei r attri b uti o n a n d t o m o nit or t he e mer ge nce 
of a pre vi o usl y u nrec o g nize d treat me nt-relate d a d verse e ve nt. 
 
1 6. 6  
Res ults Re p orti n g o n Cli nical Trials. g o v:  
At st u d y acti vati o n, t his st u d y will ha ve bee n  re gistere d wit hi n t he 
 
we bsite. T he Pri mar y a n d Sec o n dar y E n d p oi nts al o n g wit h ot her re q uire d i nf or mati o n f or 
t his st u d y will be re p orte d o n 
 F or p ur p oses of ti mi n g of t he 
Res ults Re p orti n g, t he i nitial esti mate d c o m p leti o n date f or t he Pri mar y E n d p oi nt of t his 
st u d y is 3 y ears after t he st u d y o pe ns t o accr ual. T he defi niti o n of “ Pri mar y E n d p oi nt 
C o m pleti o n Date” ( P E C D) f or t his st u d y is at  t he ti me all patie nts re gistere d ha ve bee n 
o bser ve d f or 1 2 m o nt hs. 
 
1 6. 7  
I ncl usi o n of W o me n a n d Mi n orities 
1 6. 7 1  T his st u d y will be a vaila ble t o all eli gi b le patie nts, re gar dless of race, ge n der, or 
et h nic ori gi n. 
 
1 6. 7 2  T here is n o i nf or mati o n c urre ntl y a vaila ble re gar di n g differe ntial effects of t his 
re gi me n i n s u bsets defi ne d b y race, ge n der, or et h nicit y, a n d t here is n o reas o n t o 
e x pect s uc h differe nces t o e xist. T heref ore, alt h o u g h t he pla n ne d a nal ysis will, as 
al wa ys, l o o k f or differe nces i n treat me nt effect base d o n racial a n d ge n der 
gr o u pi n gs, t he sa m ple size is n ot i ncrease d i n or der t o pr o vi de a d diti o nal p o wer 
f or s u bset a nal yses. 

M C 1 7 8 2
 7 9
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
 
1 6. 7 3  T he ge o gra p hical re gi o n ser ve d b y M C C C has a p o p ulati o n w hic h i ncl u des 
a p pr o xi matel y 3 % mi n orities.  Base d o n pri or M C C C st u dies i n v ol vi n g si milar 
disease sites, we e x pect a b o ut 3- 5 % of patie nts will be classifie d as mi n orities b y 
race a n d a b o ut 3 3 % of patie nts will be w o me n. E x pecte d sizes of racial b y 
ge n der s u bsets are s h o w n i n t he f oll o wi n g ta ble: 
 
Accr u al Esti m ates b y Ge n der/ Et h nicit y/ R ace  
Et h nic C ate g or y 
Se x/ Ge n der 
Fe m ales
 M ales
  U n k n o w n
  
T ot al
 
His pa nic or Lati n o 
0  
1  
0 
1 
N ot His pa nic or Lati n o 
1 4  
2 6  
0 
4 0 
Et h nic C ate g or y: T ot al of all s u bjects *  
1 4  
2 7  
0 
4 1 
R aci al C ate g or y 
 
A merica n I n dia n or Alas ka n Nati ve 
0  
0  
0 
0 
Asia n
 0
 
0
 
0
0
Blac k or Africa n A merica n 
1  
1  
0 
2 
Nati ve Ha waiia n or ot her Pacific Isla n der  
0  
0  
0 
0 
W hite
 1 3
 
2 6
 
0
3 9
R aci al C ate g or y: T ot al of all s u bjects *  
1 4
 2 7
  0
  
4 1
 
 
Et h nic 
C ate g ories:  
His p a nic or L ati n o – a pers o n of C u ba n, Me xica n, P uert o Ric o, S o ut h or Ce ntral 
A merica n, or ot her S pa nis h c ult ure or ori g i n, re gar dless of race. T he ter m “ S pa nis h 
ori gi n” ca n als o be use d i n a d diti o n t o “ His pa nic or Lati n o.” 
N ot His p a nic or L ati n o 
R aci al 
C ate g ories: 
A meric a n I n di a n or Al as k a n N ati ve –  a pers o n ha vi n g ori gi ns i n a n y of t he ori gi nal 
pe o ples of N ort h, Ce ntral, or S o ut h A merica,  a n d w h o mai ntai ns tri bal affiliati o ns or 
c o m m u nit y attac h me nt.  
Asi a n –  a pers o n ha vi n g ori gi ns i n a n y of t he ori gi nal pe o ples of t he Far East, 
S o ut heast Asia, or t he I n dia n s u bc o nti ne nt i ncl u di n g, f or e xa m ple, Ca m b o dia, C hi na, 
I n dia, Ja pa n, K orea, Mala ysia, Pa kista n, t he P hili p pi ne Isla n ds, T haila n d, a n d 
Viet na m. ( N ote: I n di vi d uals fr o m t he P hili p pi ne Isla n ds ha ve bee n rec or de d as P acific 
Isla n ders i n pre vi o us data c ollecti o n strate gies.)  
Bl ac k or Afric a n A meric a n – a pers o n ha vi n g ori gi ns i n a n y of t he blac k racial 
gr o u ps of Africa.  Ter ms s uc h as “ Haitia n” or “ Ne gr o” ca n be use d i n a d diti o n t o 
“ Blac k or Africa n A merica n.”  
N ati ve H a w aii a n or ot her P acific Isl a n der – a pers o n ha vi n g ori gi ns i n a n y of t he 
ori gi nal pe o ples of Ha waii, G ua m, Sa m o a, or ot her Pacific Isla n ds.  
W hite – a pers o n ha vi n g ori gi ns i n a n y of t he ori gi nal pe o ples of E ur o pe, t he Mi d dle 
East, or N ort h Africa. 
 

M C 1 7 8 2
 8 0
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 7. 0  
P at h ol o g y C o nsi der ati o ns/ Tiss ue Bi os peci me ns: N o ne 
 
1 8. 0  
Rec or ds a n d D at a C ollecti o n Pr oce d ures 
1 8. 1
 S u b missi o n
 
Ti met a ble
 
Data s u b missi o n i nstr ucti o ns f or t his st u d y ca n be f o u n d i n t he Data S u b missi o n 
Sc he d ule. 
1 8. 2
 E ve nt
 m o nit ori n g
 
See Secti o n 4. 0  a n d data s u b missi o n ta ble f or t he e ve nt m o nit ori n g sc he d ule. 
1 8. 3
 C R F
 
c o m pleti o n
 
T his st u d y will use Me di data Ra ve f or re m o te data ca pt ure (r dc) of all st u d y data. 
1 8. 4  
Site res p o nsi bilities 
Eac h site will be res p o nsi ble f or i ns uri n g t h at all materials c o ntai n t he patie nt’s i nitials, 
M C C C re gistrati o n n u m ber, a n d M C C C pr ot oc ol n u m b er. Patie nt’s na me m ust be 
re m o ve d. 
1 8. 5
 S u p p orti n g
 
d oc u me nt ati o n
 
T his st u d y re q uires s u p p orti n g d oc u me ntati o n f or e vi de nce of res p o nse t o st u d y t hera p y 
a n d pr o gressi o n after st u d y t hera p y (s C R, M R D ne gati ve, P D).  
1 8. 6  
L a belli n g of m ateri als 
Eac h site will be res p o nsi ble f or i ns uri n g t h at all materials c o ntai n t he patie nt’s i nitials, 
M C C C re gistrati o n n u m ber, a n d M C C C pr ot oc ol n u m b er. Patie nt’s na me m ust be 
re m o ve d. 
1 8. 7
 I nc o m plete
 m ateri als
 
A n y data e ntere d i nt o a f or m will res ult i n  t hat f or m bei n g mar k e d as “recei ve d. ” 
H o we ver, missi n g data will be fla g ge d b y e dit c hec ks i n t he data base. 
1 8. 8
 O ver d ue
 
lists
 
A list of o ver d ue materials is a ut o maticall y a vaila ble t o eac h site at a n y ti me. T he 
a p pr o priate c o-s p o ns or/ partici pa nt will be r es p o nsi ble t o s u b mit t he o ver d ue material. 
1 8. 9  
C orrecti o ns f or ms 
If a c orrecti o n is necessar y t he Q A S will q uer y t he site. T he q uer y will be se nt t o t he 
a p pr o priate site t o ma ke t he c orrecti o n i n t he data base a n d res p o n d bac k t o t he Q A S.  
 
 

M C 1 7 8 2
 8 1
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
1 9. 0   
B u d get 
1 9. 1  
C osts c har ge d t o patie nt:  r o uti ne cli nical care, a n d de xa met has o ne 
1 9. 2  
Tests t o be researc h f u n de d: N o ne  
1 9. 3  
Ot her b u d get c o ncer ns:  I xaz o mi b t o be pr o vi de d t o t he patie nt b y Ta ke da free of c har ge. 
Pe m br oliz u ma b t o be pr o vi de d t o t he patie nt b y Merc k free of c har ge. 
 
2 0. 0  
Refere nces 
 
1.  Ric har ds o n P, Ja ga n nat h S, Sc hl oss ma n R, et al. A M ulti-ce nter, Ra n d o mize d, P hase 2 St u d y 
t o E val uate t he Efficac y a n d Safet y of 2 C DC- 5 0 1 3 D ose Re gi me ns W he n Use d Al o ne or i n 
C o m bi nati o n wit h De xa met has o ne ( De x) f or t he Treat me nt of Rela pse d or Refract or y 
M ulti ple M y el o ma ( M M). Bl o o d . 2 0 0 3; 1 0 2: 2 3 5a. 
2.  Lac y M, Gertz M, Dis pe nzieri A, et al. I xaz o mi b Pl us De xa met has o ne ( Re v/ De x) i n Ne wl y 
Dia g n ose d M y el o ma: Res p o nse t o T hera p y, Ti me t o Pr o gressi o n, a n d S ur vi val. Bl o o d . 
2 0 0 6; 1 0 8( 1 1): 7 9 8-. 
3.  Raj k u mar S V, Jac o b us S, Calla n der N, et al . P hase III trial of I xaz o mi b pl us hi g h- d ose 
de xa met has o ne vers us I xaz o mi b pl us l o w- d ose de xa met has o ne i n ne wl y dia g n ose d m ulti ple 
m y el o ma ( E 4 A 0 3): a trial c o or di nate d b y t he Easter n C o o perati ve O nc ol o g y Gr o u p. J Cli n 
O nc ol 2 0 0 7 A S C O A n n u al Meeti n g A bstr acts 2 0 0 7; 2 5 ( 1 8 S): L B A 8 0 2 5. 
4.  We ber D M, C he n C, Nies viz k y R, et al. I x az o mi b pl us de xa met has o ne f or rela pse d m ulti ple 
m y el o ma i n N ort h A merica. N E n gl J Me d . 2 0 0 7; 3 5 7( 2 1): 2 1 3 3- 2 1 4 2. 
5.  Di m o p o ul os M, S pe ncer A, Attal M, et al. I xaz o mi b pl us de xa met has o ne f or rela pse d or 
refract or y m ulti ple m y el o ma. N E n gl J Me d . 2 0 0 7; 3 5 7( 2 1): 2 1 2 3- 2 1 3 2. 
6.  Raj k u mar S V, Jac o b us S, Calla n der N S, et  al. I xaz o mi b pl us hi g h- d ose de xa met has o ne 
vers us I xaz o mi b pl us l o w- d ose de xa met has o ne as i nitial t hera p y f or ne wl y dia g n ose d 
m ulti ple m y el o ma: a n o pe n-la be l ra n d o mise d c o ntr olle d trial. L a ncet O nc ol . 2 0 1 0; 1 1( 1): 2 9-
3 7. 
7.  Ka pla n E, Meier P. N o n para metric esti mati o n fr o m i nc o m plete o bser vati o ns. J A m St at 
Ass oc . 1 9 5 8; 5 3: 4 5 7- 4 8 1. 

M C 1 7 8 2
 8 2
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
  
A p pe n di x I  
E C O G Perf o r m a nce St at us 
 
E C O G P E R F O R M A N C E S T A T U S *  
Gr a de 
E C O G 
0 
F ull y acti ve, a ble t o carr y o n all pre- disease perf or ma nce wit h o ut restricti o n 
1 
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a li g ht 
or se de ntar y nat ure, e. g., li g ht h o use w or k, office w or k 
2 
A m b ulat or y a n d ca pa ble of all selfcare b ut u na bl e t o carr y o ut a n y w or k acti vities. U p a n d 
a b o ut m ore t ha n 5 0 % of wa ki n g h o urs 
3 
Ca pa ble of o nl y li mite d selfcare, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g h o urs. 
4 
C o m pletel y disa ble d. Ca n n ot carr y o n a n y selfcare. T otall y c o nfi ne d t o be d or c hair. 
5 
Dea d 
* As p u blis he d i n A m. J. Cli n. O nc ol.: 
Oke n, M. M., Creec h, R. H., T or mey, D. C., H ort o n, J., D avis, T. E., Mc F a d de n, E. T., C ar b o ne, P. P.: 
T oxicity A n d Res p o nse Criteri a Of T he E aster n C o o per ative O nc ol o gy Gr o u p. A m J Cli n O nc ol 5: 6 4 9-
6 5 5, 1 9 8 2.  
T he E C O G Perf or ma nce Stat us is i n t he p u blic d o mai n t heref ore a vaila ble f or p u blic use. T o d u plicate 
t he scale, please cite t he refere nce a b o ve a n d cre dit t he 
 
 
Fr o m