Clinical trial NCT03506360
Conditions: Recurrent Plasma Cell Myeloma
Sponsor: Mayo Clinic
Start date: 2018-06-19; Completion date: 2020-12-10
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well pembrolizumab works when given together with ixazomib citrate and dexamethasone in treating patients with multiple myeloma that has come back (relapsed). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ixazomib citrate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pembrolizumab together with ixazomib citrate and dexamethasone may work better in treating patients with multiple myeloma.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the overall response rate (\>= partial response \[PR\]) of pembrolizumab in combination with standard doses of ixazomib citrate (ixazomib) and dexamethasone, in patients with relapsed symptomatic multiple myeloma (MM).

SECONDARY OBJECTIVES:

I. To determine the \>= very good partial response (VGPR) and complete response (CR) rate of pembrolizumab added to standard doses of ixazomib and dexamethasone in relapsed myeloma.

II. To determine the progression free survival and overall survival among patients with relapsed MM following treatment with the combination of pembrolizumab, ixazomib and dexamethasone.

III. To determine the toxicities associated with pembrolizumab added to standard doses of ixazomib and dexamethasone in patients with relapsed MM.

CORRELATIVE RESEARCH:

I. PDL-1 expression on myeloma cells and non-tumor cell compartments from the bone marrow will be assessed at baseline.

II. Measures of T-cell activation/exhaustion will be assessed at baseline and after cycle 1 and cycle 3.

III. Natural killer (NK) cell function and numbers will be evaluated at baseline and after cycle 1 and cycle 3.

OUTLINE:

Patients receive ixazomib citrate orally (PO) on days 1, 8, 15, 29, 36, 43, 57, 64, and 71 and pembrolizumab intravenously (IV) over 30 minutes on days 1, 22, 43, 64. Patients also receive dexamethasone PO on days 1, 8, 15, 29, 36, 43, 57, 64, and 71. Cycles with dexamethasone repeat every 84 days for up to 1 year and cycles with ixazomib citrate and pembrolizumab repeat every 84 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months until progressive disease, and then every 6 months for up to 2 years.

Arms: arm 1: Patients receive ixazomib citrate PO on days 1, 8, 15, 29, 36, 43, 57, 64, and 71 and pembrolizumab IV over 30 minutes on days 1, 22, 43, 64. Patients also receive dexamethasone PO on days 1, 8, 15, 29, 36, 43, 57, 64, and 71. Cycles with dexamethasone repeat every 84 days for up to 1 year and cycles with ixazomib citrate and pembrolizumab repeat every 84 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Dexamethasone intervention 2: Ixazomib Citrate intervention 3: Laboratory Biomarker Analysis intervention 4: Pembrolizumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies intervention 4: Given IV

Protocol documents:
Prot_SAP_000.pdf: 




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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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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. 
 


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 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) 


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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. 
 


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 
 
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
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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
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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
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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
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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. 
 
 


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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
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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
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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. 
 


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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 


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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. 




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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 




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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 






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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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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; 


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•  
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 


M C 1 7 8 2
 5 6
 
 
 
 
Pr ot oc ol versi o n date:  2 8 Oct 2 0 2 0 
 
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 


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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
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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 


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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 


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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
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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
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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
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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
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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