Clinical trial NCT03269136
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma relapse/ refractory multiple myeloma bispecific antibody bispecific BCMA BCMA- CD3 bispecific Phase 1 PF-06863135 dexamethasone lenalidomide pomalidomide
Sponsor: Pfizer
Start date: 2017-11-29; Completion date: 2024-01-19
Enrollment: 101 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
To assess the safety and tolerability at increasing dose levels of PF-06863135 in patients with relapse/ refractory multiple myeloma in order to determine the maximum tolerated dose and select the recommended Phase 2 dose.

Detailed description:
Study C1071001 is a Phase 1, open label, multi dose, multi center, dose escalation, safety, pharmacokinetic (PK) and pharmacodynamic study of PF-06863135 in adult patients with advanced multiple myeloma who have relapsed from or are refractory to standard therapy. This is a two part study; Part 1 will assess the safety and tolerability of increasing dose levels of PF-06863135 and Part 2 will evaluate safety and anti-myeloma activity of PF-06863135 at the RP2Ds determined in Part 1.

Arms: arm 1: BCMA-CD3 bispecific antibody arm 2: BCMA-CD3 bispecific antibody + dexamethasone arm 3: BCMA-CD3 bispecific antibody + lenalidomide arm 4: BCMA-CD3 bispecific antibody + pomalidomide
Interventions: intervention 1: PF-06863135 monotherapy IV or SC intervention 2: PF-06863135 + dexamethasone intervention 3: PF-06863135 + lenalidomide intervention 4: PF-06863135 + pomalidomide
Intervention descriptions: intervention 1: PF-06863135 will be administered intravenously or subcutaneously. intervention 2: PF-06863135 will be administered intravenously or subcutaneously and dexamethasone orally. intervention 3: PF-06863135 will be administered intravenously or subcutaneously and lenalidomide orally intervention 4: PF-06863135 will be administered intravenously or subcutaneously and pomalidomide orally

Protocol documents:
Prot_000.pdf: 
P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
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P FI Z E R C O N FI D E N TI A L
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M A G N E TI S M M - 1
A P H A S E I, O P E N L A B E L S T U D Y T O E V A L U A T E T H E S A F E T Y, 
P H A R M A C O KI N E TI C, P H A R M A C O D Y N A MI C A N D C LI NI C A L A C TI VI T Y O F 
E L R A N A T A M A B ( P F -0 6 8 6 3 1 3 5 ), A B-C E L L M A T U R A TI O N A N TI G E N 
( B C M A) - C D 3 BI S P E CI FI C A N TI B O D Y, A S A SI N G L E A G E N T A N D I N 
C O M BI N A TI O N WI T H I M M U N O M O D U L A T O R Y A G EN T S I N P A TI E N T S WI T H 
R E L A P S E D/ R E F R A C T O R Y A D V A N C E D M U L TI P L E M Y E L O M A ( M M )
I n vesti g ati o n al Pr o d uct N u m ber:
P F -0 6 8 6 3 1 3 5
I n vesti g ati o n al Pr o d uct N a me:
Elra nata ma b 
U nite d S t ates ( U S) I n vesti g ati o n al Ne w 
Dr u g ( I N D) N u m ber:
1 3 3 ,9 4 0
E ur o pe a n Cli nic al Tri al s D at a b ase 
( E u dr a C T) N u m ber:
2 0 1 9 -0 0 0 8 2 2 -2 4
Cli nic al Tri als. g o v N C T :
N C T 0 3 2 6 9 1 3 6
Pr ot oc ol N u m ber:
C 1 0 7 1 0 0 1
P h ase:
1
T his d oc u me nt a n d acc o m pa n yi n g materials c o ntai n c o nfi de ntial i nf or mati o n bel o n gi n g t o Pfizer.  E xce pt as 
ot her wise a gree d t o i n writi n g, b y acce pti n g or re vie wi n g t h ese d oc u me nt s, yo u  a gree t o h ol d t his 
i nf or mati o n i n c o nfi de nce a n d n ot c o p y or discl ose it t o ot hers (e xce pt w here re q uire d b y a p plica ble la w) or 
use it f or u na ut h orize d p ur p oses.  I n t he e ve nt of a n y act ual or s us pecte d breac h of t his o bli gati o n, Pfizer 
m ust be pr o m ptl y n otifie d .
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E T M F C o py of:
 
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P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2
D oc u me nt Hist or y
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
Ori gi nal 
pr ot oc ol
1 0 Ma y
2 0 1 7  
N/ A
A me n d me nt 1
2 8 Se pte m ber 2 0 1 7
1. S u m mar y , Secti o ns 3. 1, 3. 3, a n d 9. 2. 1: 
Re vise d D L T rate t o 2 5 % wit h a n acce pta ble 
e q ui vale nce i nter val of ( 2 0%- 3 0 %) f oll o wi n g 
fee d bac k fr o m t he F D A. 
2. S u m mar y , Secti o n 3. 1: Re m o ve d Part 2 B 
c o m bi nati o n t hera p y secti o n si nc e details of 
c o m bi nati o n p orti o n will o nl y be pr o vi de d i n a 
f ut ure a me n d me nt.
3. Sc he d ule of acti vities: Clarifie d t hat res ults 
fr o m t he patie nt’s last b o ne marr o w 
assess me nts ma y be utilize d f or scree ni n g if t he 
res ults were c ollecte d wit hi n 3 m o nt hs fr o m
pla n ne d st u d y  dr u g treat me nt.
4. Sc he d ule of acti vities a n d Secti o n 3. 1: A d de d 
7 2 hr h os pitalizati o n o n C y cle 1 Da y 1 ( C 1 D 1) 
f or patie nts i n Part 1 a n d 7 2 hr h os pitalizati o n 
o n C y cle 1 Da y 8 ( C 1 D 8) f or patie nts i n Part 
1 A , per re q uest fr o m t he F D A .
5 . Secti o n 3. 1. 4. a n d A p pe n di x 8 : D ose decisi o n 
r ules ha ve bee n re vise d f oll o wi n g a c ha n ge i n 
D L T tar get rate.
6. Secti o n 3. 2: D ose li miti n g t o xicit y  ( D L T) 
criteria ha ve bee n re vise d f oll o wi n g F D A’s 
rec o m me n dati o ns. 
7. Secti o n 3. 5: A ne w st o p pi n g criteria sect i o n 
has bee n i ncl u de d t o pr o vi de r ules f or st o p pi n g 
t he st u d y i n Part 2 d ose e x pa nsi o n.
8. Secti o n 4. 1: A d mi nistrati ve e dits were ma de 
t o clarif y i ncl usi o n criteria # 1 t o e ns ure t hat 
o nl y  patie nts wit h meas ura ble disease a n d eit her 
a bi o ps y pr o ve n plas mac yt o ma or b o ne marr o w 
plas ma cells > 2 0 % will be i ncl u de d. Criteria 
f or pri or t hera p y ha ve bee n m o ve d t o criteria # 2 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
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P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 3
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
s o t hat all patie nts are n o w re q uire d t o meet 
t hese criteria.
9. Secti o n 5. 5. 3 Ta ble 3 : Re vise d d ose 
m o dificati o n criteria f or n o n -he mat ol o gi cal 
t o xicities gra des 3 a n d 4 s uc h t hat a gra de 3 
e ve nt w o ul d re q uire d ose - de- escalati o n a n d 
gra de 4 e ve nts will re q uire disc o nti n uati o n, per 
g ui da nce fr o m t he F D A.
1 0. Secti o n 7. 1. 2: A d de d treat me nt g ui da nce f or 
patie nts w h o ha ve recei ve d a n all o ge neic b o ne 
marr o w tra ns pla nt.
1 1. Secti o n 7. 1. 3: A d de d o pti o n f or sites t o 
a nal yz e c yt o ki nes l ocally s h o ul d t his be 
re q uire d f or patie nt ma na ge me nt. 
1 2. Secti o n 7. 2. 1: Pr o vi de d i nf or mati o n 
re gar di n g p ote ntial darat u m u ma b i nterfere nce 
i nf or mati o n a n d clarifie d t hat t he F L C assa y 
s h o ul d be utilize d if darat u m u ma b treat me nt 
was gi ve n < 1 1 4 da y s pri or t o pla n ne d treat me nt 
da y  ( C 1 D 1). 
A me n d me nt 2
2 5 A pril 2 0 1 8
1. Pr ot oc ol S u m mar y  a n d Secti o n 3: A d diti o n 
of s u bc uta ne o us ( S C) c o h orts i n Part 1 a n d Part 
1 A t o all o w f or e val uati o n of S C d osi n g. 
E val uati o n of 1 hr i nf usi o n has bee n re vise d 
s uc h t hat it will n o w occ ur i n Part 2 as a lea d-i n 
c o h ort. 
2. Pr ot oc ol S u m mar y  a n d Sectio n 2:
A d mi nistrati ve c ha n ges ha ve bee n ma de t o t he 
w or di n g i n e x pl orat or y  bi o mar ker e n d p oi nts.
3. Sc he d ule of assess m e nt A a n d B a n d Secti o n 
5. 8. 6: A d diti o n of l ocal site i njecti o n 
t olera bilit y assess me nt t o e val uate i njecti o n site 
reacti o ns (IS R).
4. Sc he d ule of assess me nt A a n d B : Re visi o n of 
bi oc he mical disease assess me nts fr o m wee kl y 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 4
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
t o per c ycle ti mefra me t o acc o u nt f or half -life
of M -pr otei ns a n d t o re d uce b ur de n o n sites.
5. Sc he d ule of assess me nt A a n d B a n d Secti o n 
7. 1. 5: Tri plicate E C Gs will o nl y  be ta ke n o n 
C 1 D 1 u ntil C 2 D 1 5. All ot her assess me nts will 
be base d o n a si n gle E C G.
6. Sc he d ule of assess me nt A a n d B a n d 
Secti o n 7. 2. 2: A d mi nistrati ve e dits t o b o ne 
marr o w c ollecti o n a n d assess me nt t o e ns ure 
ali g n me nt bet wee n t he sc he d ule of assess me nts 
an d S ecti o n 7. 2. 2. 
7. Sc he d ule of assess me nt A a n d B: Re d uce d 
n u m ber of uri nal ys is assess me nts s uc h t hat it
will o nl y  be perf or me d w he n cli nicall y 
i n dicate d.
8. Sc he d ule of assess me nt B : Re m o val of 
wee kl y wei g ht assess me nt i n Sc he d ule of 
assess me nt B t o al i gn wit h Sc he d ule of 
assess me nt A a n d Secti o n 5. 4. 1 w here wei g ht is 
e val uate d o n Da y 1 of eac h c ycle.
9. Secti o n 1. 2. 4: S C n o n -cli nical safet y 
i nf or mati o n has bee n a d de d t o j ustif y 
i nc or p orati o n of S C d osi n g i n t his st u d y.
1 0. Secti o n 1. 2. 6. 2: S C starti n g d ose rati o nale 
has bee n a d de d t o s u p p ort t he a d diti o n of S C 
a d mi nistrati o n. 
1 1. Secti o n 4: I ncl usi o n criteria has bee n 
re vise d s uc h t hat bi o psy pr o ve n plas mac y t o ma 
a n d ≥2 0 % plas ma cells i n b o ne marr o w is n o
l o n ger a re q uire me nt si nce t his will e x pa n d t he 
n u m ber of p ote ntial rela pse/ refract or y  m ulti ple 
m y el o ma patie nts t hat ma y be e nr olle d.
1 2 . Secti o n 4 a n d Secti o n 5. 8. 1 4 : I ncl usi o n 
criteria ha ve bee n re vise d s uc h t hat tra nsf usi o n 
s u p p ort will be all o we d d uri n g scree ni n g.  
S pecificall y, Secti o n 5. 8. 1 4 has bee n a d de d t o 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
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P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
clarif y w he n tra nsf usi o n s u p p ort will be 
all o we d. 
1 1. Secti o n 4: Clarificati o n has bee n ma de t o 
patie nts treate d wit h el ot uz u ma b or ot her 
a nti-S L A M F 7 rece pt or (als o k n o w n as 
a nti-C D 3 1 9 ) t hera py s uc h t hat t he y  will o nly be 
e xcl u de d if last d ose of t hera p y is less t ha n 3 0 
da y s fr o m e nr oll me nt i nt o st u d y.
1 2. Secti o n 4: E xcl usi o n criteria f or pri or 
B C M A t hera pies has bee n clarifie d f or Part 1 
a n d Part 1 A s uc h t hat k n o w n B C M A ne gati ve 
patie n ts will n ot be eli gi ble b ut patie nts wit h 
B C M A p ositi ve rela pse ma y  be all o we d 
f oll o wi n g disc ussi o n wit h t he s p o ns or. F or Part 
2, t he e xcl usi o n criteria ha ve bee n clarifie d t o 
all B C M A tar gete d t hera p y.
1 3 . Secti o n 7. 1. 3 a n d 7. 5. 4: Tar gete d pa nel f or 
a d hoc ce ntral c yt o ki ne pa nel has bee n re place d 
wit h t he f ull pa nel t o ali g n wit h t he ce ntral 
assess me nts t hat will be c o m plete d.
1 4 . A p pe n di x 9: Ad de d : t o pr o vi de g ui da nce o n 
s u bc uta ne o us i njecti o ns.
A me n d me nt 3
0 7 Fe br uar y  2 0 1 9 
1. E u dra C T n u m ber 2 0 1 9- 0 0 0 8 2 2 - 2 4 was 
a d de d t o t he c o ver pa ge
2.
Pr ot oc ol S u m mar y : F or t he p ur p ose of 
clarit y, refere nce t o Secti o n 3. 1. 1. 3 (I V 
Pri mi n g a n d Mai nte na nce D ose Escalati o n) 
is n o w liste d wit h eac h s u m mar y descri bi n g 
d osi n g gr o u ps.
3.
Pr ot oc ol S u m mar y : F or t he p ur p ose of
clarit y, t he P art 2 e x pa nsi o n para gra p h ha d 
la n g ua ge re m o ve d w hic h was re peate d i n 
Secti o n 3. 1. 2.
4.
Pr ot oc ol S u m m ar y a n d T a ble 1 i n Secti o n 
3. 1. 4: A d diti o n of 9 0 a n d 2 7 0 µ g/ k g d oses 
f or t he I V c o h orts ( Part 1) b ase d o n 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
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P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
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2 0 2 3
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D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
e mer gi n g data t hat T B D ha ve bee n 
i de ntifie d.
5.
Secti o n 1. 2. 6: Title was u p date d t o Starti n g 
D ose Rati o nale t o clarif y t he c o nte nt of t he 
secti o n.
6.
Pr ot oc ol s u m mar y  a n d Secti o n 1. 2. 6. 2: 
C larifie d la n g ua ge f or s u bc uta ne o us starti n g 
d ose rati o nale e x plai ne d i n detail i n S ecti o n 
3. 1. 1. 2. 
7.
Secti o n 1. 2. 6. 3: U p date d title a n d m o difie d 
la n g ua ge t o clarif y se nte nce t hat t he pri mi n g 
a n d mai nte na nce p art ma y be e val uate d 
pri or t o reac hi n g M T D.
8.
Secti o n 3. 1: U p date d st u d y  sc he ma t o 
reflect st u d y desi g n a n d a d de d f o ot n ote t o 
s pecif y t hat t he n o lea d-i n c o h ort will be 
c o n d ucte d if t he s u bc uta ne o us r o ute is 
selecte d f or Part 2.
9.
Secti o n 3. 1. 1. 3 : A d de d g ui da nce f or 
pri mi n g a n d mai nte na nce d ose f or P art 1 A 
I V c o h orts.
1 0. Pr ot oc ol S u m mar y , Secti o n 1. 2. 6. 2 Secti o n 
1. 2. 6. 3, Secti o n 3. 1. 1. 1, Secti o n 3. 1. 1. 2, 
Secti o n 3. 2 a n d A p pe n di x 5: Clarifie d 
la n g ua ge t o re m o ve tociliz u ma b a n d/ or 
vas o press ors fr o m t he ma na ge me nt of C R S 
a n d re place d ( w here a p pr o priate) wit h 
la n g ua ge t hat w o ul d e na ble t he treat me nt 
wit h sta n dar d of care per t he i nstit uti o n’s, 
i n vesti gat or’s or treati n g ph y sicia n’s 
g ui deli nes.
1 1. Pr ot oc ol S u m mar y  Sc he d ule of Acti vities 
B: F o ot n ote # 2 1 was c orrecte d fr o m C y cle 1 
Da y  1 t o C ycle 1 Da y 8 f or t he mai nte na nce 
d ose.
1 2. Secti o n 3. 1. 1. 1: C ha n ge d la n g ua ge t o clarif y  
t hat d oses a b o ve 2 7 0 µ g/ K g will be 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 7
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
e x pl ore d a n d a d de d lan g ua ge t hat P art 1 
s u bc uta ne o us or I V mai nte na nce ma y be 
i nitiate d.
1 3. Secti o n 3. 1. 1. 2: M o difie d la n g ua ge t o start 
t he s u bc uta ne o us part i n de pe n de nt of G ra de 
3 C R S a n d all o w S C starti n g d ose at hi g her 
d ose le vel base d o n c urre nt I V preli mi nar y  
safety, P K , a n d C R S data.
1 4. Secti o n 3. 1. 1. 3: Re vise d te xt t o lea ve o nl y  
Pri mi n g a n d Mai nte na nce f or Part 1 A I V.
1 5. Secti o n 3. 1. 1. 4: Delete d secti o n f or Part 1 A 
s u bc uta ne o us a d mi nistrati o n.
1 6. Secti o n 3. 1. 1. 5: Delete d secti o n f or Part 1 A 
I V a d mi nistrati o n.
1 7. Secti o n 3. 1. 4: M o di fie d la n g ua ge s o t hat 
hi g her d oses i n t he I V a d mi nistrati o n 
c o h orts ca n be e val uate d.
1 8. Secti o n 3. 1. 2: A d de d a state me nt t hat , base d 
o n e mer gi n g cli nical data fr o m t he Part 1 
d ose escalati o n, eit her I V or S C 
a d mi nistrati o n , i ncl u di n g pri mi n g a n d 
mai nte na nce d ose , will be selecte d f or t he 
Part 2 d ose e x pa nsi o n.  A d diti o nall y , a 
se nte nce was a d de d t hat n o lea d -i n c o h ort 
will be c o n d ucte d if s u bc uta ne o us r o ute is 
selecte d f or Part 2 e x pa nsi o n.
1 9. Secti o n 3. 2: T he D ose Li miti n g T o xicit y  
Defi niti o n was u p date d f or Gr a de 4 
thr o m b oc y t o pe nia t o acc o u nt f or s u bjects 
t hat ha ve a platelet c o u nt bet wee n 2 5, 0 0 0 
a n d 5 0, 0 0 0 a n d a d de d for Gra de 4 
t hr o m b oc yt o pe nia wit h ≥
Gra de 2 
blee di n g .
2 0. Secti o n 4. 1: Reflect t he f oll o wi n g 
clarificati o ns: 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 8
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
2 1. I ncl usi o n criteri o n # 1a a n d A p pe n di x 2: 
L o were d t he M- pr otei n t o greater t ha n or 
e q ual t o 0. 5 g/ d L f or Part 1 a n d greater t ha n 
or e q ual t o 1. 0 g/ d L f or Part 2.
2 2. I ncl usi o n criteri o n # 1c: Up date d t o reflect 
meas ura ble disease f or F L C.
2 3. I ncl usi o n criteri o n # 2 a n d Secti o n 3. 1. 1. 1:
C larifie d t hat patie nts m ust ha ve recei ve d 
pri or t hera pies wit h pr oteas o me i n hi bit ors, 
I Mi D dr u gs , a n d a nti -C D 3 8 m o n ocl o nal 
a nti b o dies, w here a p pr o ve d a n d a vaila ble. 
2 4. I ncl usi o n criteri o n # 2: Re vise d t o s pecif y 
t hat patie nts m ust ha ve pr o gresse d o n or are 
i nt olera nt of esta blis he d t hera pies k n o w n t o 
pr o vi de cli nical be nefit i n m ulti ple 
m y el o ma.
2 5. I ncl usi o n criteri o n # 5: L o were d t he platelet 
c o u nt t o 2 5, 0 0 0/ m m 3, clarifie d t hat 
he m o gl o bi n ma y  be greater t ha n or e q ual t o 
8 g/ d L, tra nsf usi o n s u p p ort is all o we d f or 
b ot h sit uati o ns if c o m plete d pri or t o pla n ne d 
C 1 D 1. 
2 6. I ncl usi o n criteri o n # 6:
Mo difie d t he 
creati ni ne cleara nce t o ≥3 0 m L / mi n a n d 
ser u m creati ni ne t o ≤2. 5 m g/ d L.
2 7. E xcl usi o n criteri o n # 6:  M o difie d t o i ncl u de 
a d diti o nal ≥
Gra de 3 i m m u ne -me diate d 
a d verse e ve nt s a n d a d de d e xce pti o ns f or 
i m m u ne-relate d a d verse e ve nts 
a p pr o priatel y ma na ge d b y c hec k p oi nt 
i n hi bit ors.
2 8. E xcl usi o n criteri o n # 1 4: C larifie d t o reflect 
t he la n g ua ge re gar di n g patie nts wit h rela pse 
f oll o wi n g B C M A tar gete d t hera py 
eli gi bilit y. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 9
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
2 9. E xcl usi o n criteri o n # 1 5: E li mi nate d t he 
re q uire me nt f or pri or B C M A t hera pies i n 
Part 2 o nl y . 
3 0. Secti o n 5. 3. 1: D osa ge F or m(s) a n d 
Pac ka gi n g:  title was re vise d t o reflect t he 
P har mace utical f or m a n d refer t o t he 
I n vesti gati o nal Pr o d uct Ma n ual a n d 
I n vesti gat or’s Br oc h ure f or a d diti o nal 
details re gar di n g P F -0 6 8 6 3 1 3 5.
3 1. Secti o n 5. 3. 2: Re m o ve d t he p hr ase 
“I n vesti gati o nal Pr o d uct Ma n ual” a n d 
a b bre viate d t he na me as it was pre vi o usl y 
s pelle d i n t he pri or para gra p h.
3 2. Secti o n 5. 5. 2: Clarifie d sit uati o n i n w hic h 
patie nts re q uire disc o nti n uati o n of t he st u d y 
dr u g f or m ore t ha n 4 2 da ys, clarifie d t hat it 
w o ul d be fr o m Da y  1 of t he c urre nt c ycle.
3 3. Secti o n 5. 5. 3: A d de d > 4 2 da y s f or patie nts 
e x perie nci n g a D L T of pr ol o n ge d 
m y el os u p pressi o n.
3 4. A p pe n di x 2: ( See i ncl usi o n criteria f or 
m o dificati o ns) was a d de d i n t he I M W G 
res p o nse criteria f or ser u m M -pr otei n.
3 5. A d diti o nal a d mi nistrati ve c ha n ges a n d 
clarificati o ns were ma de t h ro u g h o ut t he 
pr ot oc ol.
A me n d me nt 4
3 1 Oct o ber 2 0 1 9
T he p ur p ose of t his a me n d me nt is pri maril y  t o 
e na ble e val uati o n of c o m bi nati o ns of 
P F - 0 6 8 6 3 1 3 5 wit h a nti-P D 1 a nti b o d y  
P F - 0 6 8 0 1 5 9 1 or wit h le nali d o mi de a n d all o w 
t he o pti o n of s u bc uta ne o us e ver y 2 wee k d osi n g 
of P F - 0 6 8 6 3 1 3 5. I n a d diti o n, clarificati o ns, 
a d mi nistrati ve a n d t yp o gra p hical m o dificati o ns 
were ma d e.
1.
Pr ot oc ol S u m mar y , bac k gr o u n d a n d 
rati o nale: A d de d la n g ua ge t o i n dicate t he 
c o m bi nati o n of P F-0 6 8 6 3 1 3 5 wit h a n 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
a nti-P D -1 a nti b o d y  or a n I Mi D will be 
i n vesti gate d.
2.
Pr ot oc ol S u m mar y , st u d y desi g n, St u d y 
O bjecti ves a n d E n d p oi nts, Sc he d ule of 
Acti vities B, Secti o ns 2, 3. 1. 1, 3. 1. 1. 2, 
3. 1. 1. 3, 3. 1. 1. 4, 5. 4. 1, 9. 6 a n d Fi g ure 6: 
re na me d Part 1 A Pri mi n g a n d Mai nte na nce 
D ose Escalati o n t o Part 1. 1 Pri mi n g a n d 
Mai nte na nce D os e Escalati o n.
3.
Pr ot oc ol S u m mar y , st u d y desi g n a n d 
Secti o n 3 a n d Fi g ure 6: A d de d la n g ua ge t o 
s pecif y w hat eac h Part of t he st u d y will 
eac h i n vesti gate a n d t he n u m ber of patie nt s
t hat eac h Part will e nr oll.
4.
Pr ot oc ol S u m mar y , st u d y desi g n a n d Fi g ure 
6: Clarifie d t he d ose escalati n g d oses of P F-
0 6 8 6 3 1 3 5 f or Parts 1 I V a n d S C .
5.
Pr ot oc ol S u m mar y , st u d y desi g n: A d de d a 
state me nt t hat clarifies t he 7 2- h o ur
h os pitalizati o n peri o d o n C 1 D 1 f or all 
m o n ot hera p y d ose escalati o n c o h orts a n d t o 
f urt her e val uate t he h os pitalizati o n peri o d i n 
t he e x pa nsi o n c o h orts.
6.
Pr ot oc ol S u m mar y , st u d y desi g n: A d de d 
la n g ua ge f or Part 1 m o n ot hera py t o s pecif y 
D L T peri o d a n d s pecif y  peri o d f or i ntra-
patie nt d ose escalati o n a n d restricti o ns t o 
e nr oll t he sa me patie nt i nt o differe nt Parts 
of t he st u d y.
7.
Pr ot oc ol S u m mar y , St u d y Desi g n, Sc he d ule 
of Acti vities B , secti o ns 3. 1. 1. 3: M o difie d 
t he pri mi n g sc he d ule t o start o n C 0 D 1 a n d 
mai nte na nce o n C 1 D 1.
I n a d diti o n, a n 
alter nati ve ste p -u p re gi me n a n d 
pr o p h y lactic ster oi d o pti o ns were a d de d t o 
t he sc hed ule.
8.
Pr ot oc ol S u m mar y , st u d y desi g n, sc he d ule 
of acti vities B , secti o ns 3. 1. 1. 3, 5. 4. 2: a d de d 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
s u bc uta ne o us r o ute f or pri mi n g a n d 
mai nte na nce . I ncl u de d le nali d o mi de a n d 
P F -0 6 8 0 1 5 9 1 i n t his Part . Ad de d t w o wee k 
sc he d ule o pti o n f or m o n ot hera py, 
le nali d o mi de a n d P F- 0 6 8 0 1 5 9 1. Re m o ve d 
da y s 9 a n d 1 0 fr o m c ycle 1, c ha n ge d 
sc he d ule t o a 4 wee k c ycle.
9.
Pr ot oc ol S u m mar y , st u d y o bjecti ves a n d 
e n d p oi nts a n d Secti o n 2: A d de d la n g ua ge 
t hat defi nes t he o bjecti ves a n d e n d p oi nts f or 
eac h c o m bi nati o n d ose fi n di n g a n d 
e x pa nsi o n Part s of t he st u d y .
1 0. Pr ot oc ol S u m mar y , Sc he d ule of acti vities 
A: Re na me d s o t hat all wee kl y i ntra ve n o us 
a n d s u bc uta ne o us m o n ot hera p y d ose 
escalati o n sc he d ules f oll o w eit her S O A A or 
B, rearra n ge d t he pr oce d ures b y sect i o n, 
clarifie d t he visit wi n d o w i n t he 
p har mac o ki netic, s ol u ble fact or a n d 
c yt o ki ne acti vities.
1 1. Pr ot oc ol S u m mar y , Sc he d ule of acti vities C: 
Was create d t o reflect ne w c o m bi nati o n 
d ose fi n di n g, e x pa nsi o n m o n ot hera p y a n d 
c o m bi nati o n c o h orts, clarifie d t o c he c k f or 
M R D w he n a patie nt ac hie ves c o m plete 
res p o nse.
1 2. Pr ot oc ol S u m mar y , Sc he d ule of acti vities 
A, B, C, Secti o ns 5. 9 . 3, 5.9 . 4, A p pe n di x 5, 
Ta bles 1 2, 1 4: A d de d ne w A S T C T 
c o nse ns us criteria f or C R S a n d I C A N S 
ma na ge me nt of c y t o ki ne release s yn dr o me 
( C R S) a n d i m m u ne effect or cell ass ociate d 
ne ur ot o xicit y  sy n dr o me (I C A N S).
1 3. St u d y  desi g n, sc he d ule of acti vities A, B 
a n d C: Clarifie d t hr o u g h o ut t he 
p har mac o d y n a mic, p har mac o ki netic, 
s ol u ble fact or a n d c yt o ki ne assess me nts 
ta bles w he n b o ne marr o w s h o ul d be 
c ollecte d f or t he i ntra ve n o us r o ute a n d 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
a d de d clarificati o n o n w he n t hese 
pr oce d ures s h o ul d be ta ke n relati ve t o 
C 1 D 1.
1 4. Secti o ns 1 I ntr o d ucti o n: U p date d t o a d d 
s u p p orti n g bac k gr o u n d pre-cli nical 
i nf or mati o n a n d cli nical data re gar di n g 
c o m bi nati o n of C D 3 bis pecifics a n d 
a nti-P D 1/ L 1 or le nali d o mi de.
1 5. Secti o ns 1. 2. 8. 1, 1. 2. 8. 4, 3. 1. 1. 4, 3. 1. 2 a n d
3. 1. 4, 5. 4. 3: U p date d t o i n dicate t hat a fi xe d 
d ose a p pr oac h will be use d f or 
P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n d ose fi n di n g 
i n all e x pa nsi o n c o h orts. 
1 6. Secti o n 1. 2. 8. 3: A d de d t o s pecify t he 
starti n g d oses f or all c o m bi nati o n Parts.
1 7. Secti o n 1. 2. 8. 5: A d de d t o all o w a Q 2 W 
d osi n g i nter val o pti o n f or patie nts treate d 
wit h wee kl y d osi n g at least 6 m o nt hs . 
1 8. Secti o n 3: St u d y  desi g n sc he me was create d 
t hat reflects all ne w c o m bi nati o n d ose 
fi n din g a n d e x pa nsi o n c o h orts.
1 9. Secti o n 3. 1. 1. 2: U p date d t o reflect act ual 
starti n g d ose of Part 1 s u bc uta ne o us 
m o n ot hera p y.
2 0. Secti o n 3. 1. 1. 4 descri bes c o m bi nati o n d ose 
fi n di n g c o h orts.
2 1. Secti o n 3. 1. 2: Was u p date d t o descri be t he 
c o m bi nati o n e x pa nsi o n c o h orts.
2 2. Sec ti o n 3. 1. 4: Ta ble 1 was u p dated t o 
i ncl u de d oses use d i n t he i ntra ve n o us d ose 
escalati o n. Ta ble 2 was a d de d t o i ncl u de 
s u bc uta ne o us pla n ne d d oses a n d la n g ua ge 
was a d de d t o clarif y  wee kl y a n d e ver y t w o 
wee k d osi n g i nter vals. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
2 3. Secti o n 3. 2: T he D L T defi niti o n was 
u p date d t o s pecif y  D L T peri o ds f or 3 a n d 4 
wee k c ycles. D L T defi niti o ns were re vise d 
t o pr o vi de clarity f or Gra de 4 ne utr o pe nia, 
fe brile ne utr o pe nia a n d is olate d Gra de 3 
la b orat or y a b n or malities. 
2 4. Secti o n 3. 2. 1: L ate t o xicit y e val uati o n 
sc he d ules were clarifie d f or c o m bi nati o n 
a n d m o n ot hera p y d ose escalati o n c o h orts. 
2 5. Secti o n 3. 4: Re vise d t o pr o vi de clarit y 
re gar di n g deter mi nati o n of t he 
rec o m me n de d p hase 2 d ose of P F- 0 6 8 6 3 1 3 5 
i n c o m bi nati o n c o h orts.
2 6. Secti o ns 4. 1 was a n d 4. 2 were re vise d as 
f oll o ws:

I ncl usi o n Criteria # 1a: Re vise d t o ha ve a 
ser u m M-pr otei n of 0. 5 g/ d L f or b ot h, 
Part 1 a n d 2.

I ncl usi o n Criteria # 5: Re vise d t o clarif y  
t he re q uire me nts f or a de q uate 
he mat ol o gical f u ncti o n f or A N C a n d 
platelet c o u nt f or Part 1 C a n d 2 C of t he 
st u d y. 

I ncl usi o n Criteria # 6 : Re vise d t o 
s pecif y t he creati ne cleara nce f or Part 
1 C a n d 2 C of t he st u d y .

I ncl usi o n Criteria # 8: Re vise d t o 
pr o vi de clarit y f or he patitis B a n d C 
testi n g.

I ncl usi o n Criteria # 1 2: La n g ua ge was 
u p date d t o reflect ne w te m plate pr ot oc ol 
i nf or mati o n re gar di n g i nf or me d c o nse nt 
re q uire me nts.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges

I ncl usi o n Criteria 1 4: A d de d T S H, T 3 
a n d T 4 f or patie nts e nr olle d i n Part 1 B 
a n d 2 B.

E xcl usi o n criteria # 1 1: Pr o vi de d clarit y 
f or a nti b o dy base d t hera pies.

E xcl usi o n Criteria # 1 4: Clarifie d 
re q uire me nts f or patie nts t hat ha ve 
recei ve d pri or B C M A t hera py.

E xcl usi o n Criteria # 1 6: A d de d ne w 
te m plate la n g ua ge f or re q uire me nts o n 
E C G res ults.

E xcl usi o n Criteria # 2 0: Re vise d t o 
i ncl u de re q uire me nts f or P F- 0 6 8 0 1 5 9 1. 

E xcl usi o n Criteria # 2 3: A d de d disease 
restricti o ns f or patie nts e nr olle d i nt o 
Part s 1 B a n d 2 B.

E xcl usi o n Criteria # 2 4: A d de d 
restricti o n re gar di n g t he use of 
c ortic oster oi ds a n d 
i m m u n os u p pressa nts.

E xcl usi o n Criteria # 2 5: A d de d t o 
e xcl u de patie nts wit h Gra de ≥3 
a na p h yl actic reacti o ns t o a nti b o dies .

E xcl usi o n Criteria # 2 6: A d de d a 
restricti o n f or Parts 1C a n d 2 C f or 
patie nts w h o ha d pre vi o us le nali d o mi de 
d ose re d ucti o ns.
2 7. Secti o n 4. 3: A d de d t hat 2 hi g hl y effecti ve 
met h o ds of c o ntrace pti o n are re q uire d f or 
Parts 1 C a n d 2 C.
2 8. Secti o n 5. 3. 3 : Re vise d la n g ua ge t o 
refere nce t he I P ma n ual a n d I B f or 
P F -0 6 8 6 3 1 3 5.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
2 9. Secti o n 5. 3. 2: Clarifie d t he pre parati o n a n d 
dis pe nsi n g f or b ot h, P F -0 6 8 6 3 1 3 5 a n d P F -
0 6 8 0 1 5 9 1. 
3 0. Secti o n 5. 3: A d de d le nali d o mi de as a n
i n vesti gati o nal pr o d uct. 
3 1. Secti o n 5. 4. 1: A d de d clarit y  t o w he n a n d 
h o w t he o pti o n of 2 wee k i nter val d osi n g 
ca n be d o ne f or P F -0 6 8 6 3 1 3 5 I V 
a d mi nistrati o n.
3 2. Secti o n 5. 4. 2: A d de d clarit y  t o w he n a n d 
h o w o pti o n of 2 wee k i nter val d osi n g ca n be 
d o ne f or P F -0 6 8 6 3 1 3 5 S C a d mi nistrati o n.
3 3. Secti o n 5. 4. 3: A d de d i nstr ucti o ns o n t he 
a dmi nistrati o n of P F -0 6 8 0 1 5 9 1.
3 4. Secti o n 5. 5: A d de d d ose m o dificati o ns t hat 
ca n occ ur f or P F- 0 6 8 0 1 5 9 1 a n d 
le nali d o mi de. 
3 5. Secti o n 5. 7 a n d 5. 7. 1: Re vise d titles t o 
i ncl u de n o n-i n vesti gati o nal pr o d ucts.
3 6. Secti o n 5. 9 . 1 0: Re m o ve d restricti o n o n t he 
use of he mat o p oietic gr o wt h fact ors o nl y at 
c ycle 2 a n d be yo n d.
3 7. Secti o n 5. 9 . 1 5: Re m o ve d restricti o n o n 
tra nsf usi o n s u p p ort d uri n g c ycle 1 a n d 
wit hi n 1 4 da y s pri or t o c ycle 1.
3 8. Secti o n 6. 4: A d de d re q uire me nt f or f oll o w-
u p of late i m m u ne relate d a d verse e ve nts i n 
Pa rts 1 B a n d 2 B.
3 9. Secti o n 7. 1. 3: Delete d d u plicate d 
i nf or mati o n. Clarifie d he patitis tests, a d de d 
T S H, T 4 re q uire me nts i n ta ble 8. 
4 0. Secti o n 7. 1. 5: All o we d disc ussi o n wit h 
s p o ns or f or c o nti n uati o n of st u d y treat me nt 
f or patie nts t hat e x perie nce tra nsie nt 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
pr ol o n ge d Q Tc F if t he i n vesti gat or belie ves 
it is i n t he best i nterest of t he patie nt.
4 1. Secti o n 7. 1. 7 a n d a p pe n di x 9: Pr o vi de d 
i nf or mati o n o n t he use of a b d o mi nal 
q ua dra nts f or t he s u bc uta ne o us 
a d mi nistrati o n of P F -0 6 8 6 3 1 3 5 a n d 
P F - 0 6 8 0 1 5 9 1.
4 2. Secti o n 7. 2. 2: Clarif ie d assa ys t o be use d 
f or M R D testi n g.
4 3. Secti o n 7. 3: A d de d a bl o o d 
p har mac o ki netics sa m ple c ollecti o n f or P F-
0 6 8 0 1 5 9 1.
4 4. Secti o n 7. 4: A d de d a nti -dr u g a nti b o d y  
a nal ys is f or P F-0 6 8 0 1 5 9 1. 
4 5. Secti o n 7. 5: A d de d clarificati o n f or b o ne 
marr o w sa m ples at 6 a n d 9 m o nt h
ti me p oi nts.
4 6. Secti o n 7. 5. 2: A d de d t hat P D- 1 rece pt or 
occ u pa nc y  will be e val uate d i n Parts 1 B a n d 
2 B.
4 7. Secti o n 7. 5. 4: Re vise d la n g ua ge t o pr o vi de 
clarit y o n c ollecti o n of sa m ples f or C R S 
assess me nt.
4 8. Secti o n 8. 1. 4: A d de d la n g ua ge t o s pecif y  
a d verse e ve nt c oll ecti o n peri o d f or 
P F -0 6 8 0 1 5 9 1 i n Parts 1 B a n d 2 B. 
4 9. Secti o n 9. 1: A d de d defi niti o n f or 
p har mac o ki netic a n d i m m u n o ge nicit y tests 
i n Parts 1 B a n d 2 B.
5 0. Secti o n 9. 3: A d de d clarificati o n t o s u p p ort 
t he calc ulati o n of sa m ple sizes f or 
c o m bi nati o n d ose escalati o n a n d e x pa nsi o n 
c o h orts.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
5 1. Secti o n 9. 5. 1 a n d 9. 5. 2: A d de d 
p har mac o ki netic a nal ys is f or Parts 1 B an d 
2 B. 
5 2. A p pe n di x 1 0: A d de d ma na ge me nt f or 
i m m u ne-relate d a d verse e ve nts i n Parts 1 B 
a n d 2 B.
A me n d me nt 5
1 3 J ul y 2 0 2 0
T he pri mar y  p ur p ose of t his a me n d me nt is t o 
a d d p o mali d o mi de as a c o m bi nati o n t hera p y  
wit h P F - 0 6 8 6 3 1 3 5.  I n a d diti o n, clarificati o ns, 
a d mi nistrati ve, a n d t yp o gra p hical m o dificati o ns 
were ma de.
1.
C orrecte d ite m 3 0 i n list of S u m mar y  of 
C ha n ges f or A me n d me nt 4. T he c orrect 
secti o n n u m ber s h o ul d be 5. 3 a n d 
le nali d o mi de s h o ul d ha ve bee n liste d as 
i n vesti gati o nal pr o d uct.
2.
Gl o bal: Re place d P F -0 6 8 0 1 5 9 1 wit h 
sasa nli ma b. W here nee de d f or clarit y  a d de d 
t he f oll o wi n g “sasa nli ma b (f or merly 
P F -0 6 8 0 1 5 9 1)”.
3.
Pr ot oc ol S u m mar y Sc he d ules of Acti vities 
A, B, a n d C f o ot n ote # 3 7, Secti o ns 3. 1, 6. 3, 
a n d 6. 6: I ncrease d treat me nt d urati o n/f oll o w 
u p wit h P F -0 6 8 6 3 1 3 5 fr o m 1 2 u p t o 
2 4 m o nt hs after t he last patie nt first d ose as 
ot her B C M A -tar geti n g a ge nts ha ve see n 
re p orte d res p o nse d urati o n be yo n d 1 ye ar. 
4.
Pr ot oc ol S u m mar y a n d Gl o ball y ( where 
a p plica ble, i ncl u di n g st u d y O bjecti ves
Secti o n 2 ): A d de d p o mali d o mi de t o list of 
c o m bi nati o n a ge nts ( Part 1 D a n d Part 2 D).
5.
Pr ot oc ol S u m mar y  a n d Gl o ball y ( w here 
i n dicate d f or clarity): S pecifie d Par ts 1 B 
a n d 2 B will be c o n d ucte d e x -U S o nl y .
6.
Pr ot oc ol S u m mar y  a n d Gl o bal Secti o ns (as 
a p plica ble, i ncl u di n g Sc he ma): A d de d 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
Parts 1 D a n d 2 D ( p o mali d o mi de 
c o m bi nati o n c o h orts) .
7.
Pr ot oc ol S u m mar y  a n d Gl o ball y ( where 
a p plica ble), i ncl u de d “ or ma xi m u m 
a d mi nistere d d ose ( M A D) ” or “/ M A D”
after ma xi m u m t olerate d d ose ( M T D).
8.
Pr ot oc ol S u m mar y  a n d Gl o ball y: Re vise d 
d oses f or Part 1 s u bc uta ne o us ( S C)
a d mi nistrati o n (c ha n ge d 2 0 0 t o 2 1 5 µ g/ k g, 
c ha n ge d 3 0 0 t o 3 6 0 µ g/ k g, a n d a d de d d oses 
of 6 0 0 a n d 1 0 0 0 µ g/ k g ).
9.
Pr ot oc ol S u m mar y a n d Secti o n 3. 1 : A d de d: 
U p o n reac hi n g M T D/ M A D, u p t o 
a p pr o xi matel y 6 - 1 2 patie nts t otal at selecte d 
le vel(s) bel o w t he M T D/ M A D wee kly a n d 
Q 2 W d osi n g u p t o t he sa me d ose i nte nsit y  
as t he M T D/ M A D wee kl y re gi me n ma y be 
e val uate d f urt her t o s u p p ort t he R P 2 D 
d ecisi o n.
1 0. Pr ot oc ol S u m mar y : S pecifie d t hat t he safet y 
c o h ort f or Part 1 B will use a 
d ose -escalati o n/ de -escalati o n a p pr oac h f or 
P F -0 6 8 6 3 1 3 5 starti n g at least 1 d ose le vel 
bel o w t he m o n ot hera p y M T D/ M A D or t he 
R P 2 D, w hic he ver is l o wer a n d will be 
c o m bi ne d with a fi xe d S C d ose of 3 0 0 m g 
sasa nli ma b. 
1 1. Pr ot oc ol S u m mar y , Secti o n 3. 1 , a n d 9. 3: 
U p date d patie nt n u m bers. A p pr o xi matel y  
1 0 0 patie nts are e x pecte d t o be e nr olle d i nt o 
Parts 1/ 1. 1/ 1 B, 1 C, a n d 1 D. Parts 2 A, 2 B, 
2 C, a n d 2 D will e nr oll a p pr o xi matel y  
2 0 patie nts eac h. U p date d sa m ple size 
calc ulati o n secti o n. 
1 2. Pr ot oc ol S u m mar y  a n d Secti o n 2 : A d de d 
“a n d b o ne marr o w b y fl o w c yt o metr y 
a nal ys is” t o t he t hir d Tertiar y/ E x pl orat or y 
E n d p oi nt b ullet.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
1 3. Sc he d ules of Acti vities: A d de d refere nce t o 
A p pe n di x 1 1 f or alter nati ve meas ure 
g ui deli nes d ue t o C O VI D - 1 9.
1 4. Clarifie d d osi n g i n Sc he d ule of Acti vities
C f o ot n ote # 7 f or Part 1 S C Q 2 W.
1 5. Clarifie d h os pitalizati o n as o pti o nal i n 
Sc he d ule s of Acti vities B f o ot n ote # 7 f or 
Parts 2 A, 2 B, 2 C , a n d 2 D at C 1 D 1.
1 6. Clarifie d ti mi n g of pre g na nc y testi n g f or 
patie nts i n Parts 1 C, 1 D, 2 C, a n d 2 D i n 
Sc he d ule of Acti vities B, a n d C 
f o ot n ote # 2 0 a n d Secti o n 7. 1. 1 per 
le nali d o mi de a n d p o mali d o mi de 
re q uire me nts f or pre g na nc y testi n g. 
1 7. Sc he d ules of Acti vities A, B, a n d C 
f o ot n ote # 2 4, Secti o n 7. 2. 2, a n d A p pe n di x 
3: C larifie d patie nt stat us f or assess me nt of 
M R D ( mi ni mal resi d ual disease)
a n d a d de d 
clarif yi n g la n g ua ge f or ce ntral a n d l ocal 
assess me nt f or M R D.
1 8. Sc he d ule s of A cti vities A, B, a n d C
f o ot n ote # 2 5 , re vise d te xt re gar di n g ti mi n g 
of assess me nts f or fl u or o de o x ygl uc ose 
( F D G) p ositr o n e missi o n t o m o gra p hy 
( P E T)/c o m p uterize d t o m o gra p hy ( C T).
Delete d “as cli nicall y i n dicate d” i n t he 
Sc he d ule of Acti vities Visit I de ntifier 
c ol u m n.
Ali g ne d Secti o n 7. 2. 3.
1 9. A d de d la n g ua ge t o Sc he d ules of Acti vities 
A, B, a n d C f o ot n ote # 2 8 a n d Secti o n 7. 6. 2 
re gar di n g ge netic a nalys is; a d de d b o ne 
marr o w as pirates will be e val uate d at t he 
l ocal la b, a n d i nstr ucti o ns f or w he n 
assess me nts ca n n ot be d o ne . Clarifie d 
ti mi n g. 
2 0. A d de d clarif yi n g la n g ua ge t o f o ot n ote # 3 5 
i n Sc he d ule of Acti vities B t o i ncl u de 
Part s 1 a n d 2 B as part of t he o ne -m o nt h 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
f oll o w-u p a n d late f oll o w - u p f or late 
i m m u ne-relate d a d verse e ve nts. A d de d 
“ 2 B” t o f o ot n ote # 3 5 i n Sc he d ule of 
Acti vities C. 
2 1. Sc he d ule of Acti vities C: A d de d Parts 1 D 
a n d 2 D t o t he title an d descri pti o n , a d de d 
r o w f or p o mali d o mi de a d mi nistrati o n 
( Parts 1 D a n d 2 D) a n d a d de d a f o ot n ote 
wit h a d diti o nal details (i ncl u di n g d ose). 
2 2. Sc he d ule of P har mac o ki netic, S ol u ble 
Fact or a n d C yt o ki ne Acti vities C: A d de d 
Parts 1 D a n d 2 D t o title a n d descri pti o n, 
a d de d r o ws f or sa m ple c ollecti o n f or 
le nali d o mi de a n d p o mali d o mi de P K
(ali g ne d Secti o n 7. 3). Ali g ne d s B C M A 
sa m ple c ollecti o n f or Part 2 wit h P K 
c ollecti o n f or Part 2.
2 3. T o e ns ure c o nsiste nc y  wit h ti mi n g of 
sa m ples i n Part 2, ad de d C y cles 1 a n d 2
Da y 2 2 0 hr ti me p oi nts f or t he c ollectio n of
sa m ples f or P F-0 6 8 6 3 1 3 5 a n d s ol u ble 
B C M A i n t he Sc he d ule of 
P har mac o ki netics, S ol u ble fact or , a n d 
C y t o ki ne Assess me nts A cti vities B. 
2 4. C orrecti o n t o t he li n ks of t he Sc he d ule of 
P har mac o ki netic, S ol u ble Fact or a n d 
C y t o ki ne Assess me nts s o t he y c orrectly li n k 
t o t heir res pecti ve Sc he d ule of Acti vities B 
or C.
2 5. Secti o ns 1. 2. 3. 1. 1. 2. 3. 1. 1, 1. 2. 3. 1. 2, a n d 
1. 2. 3. 2 : A d de d safety a n d efficac y data as of 
1 5 A pril 2 0 2 0 f or patie nts i n Part 1 treate d 
wit h P F - 0 6 8 6 3 1 3 5.
2 6. Secti o n 1. 2. 7: A d de d e x -U S s o urces f or 
le nali d o mi de pr o d uct i nf or mati o n (a n d 
a d de d t o refere nce list). A d de d rati o nal e f or 
w h y  de xa met has o ne will n ot be 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
a d mi nistere d wit h le nali d o mi de i n Parts 1 C 
a n d 2 C.
2 7. Secti o n 1. 2. 8: A d de d descri pti o n of 
p o ma li d o mi de a n d refere nces f or c o m plete 
i nf or mati o n.
2 8. Secti o n 1. 2. 9. 1: A d de d li n k t o 
Secti o n 1. 2. 9. 4 f or a d diti o nal details of t he 
fi xe d-d osi n g a p pr oac h. 
2 9. Secti o n 1. 2. 9. 3: A d de d Parts 1 C a n d 1 D 
pr o vi de d details o n p o mali d o mi de d ose. 
3 0. Secti o n 1. 2. 9. 4: A d de d preli mi nar y  
p o p ulati o n P K data f or P F -0 6 8 6 3 1 3 5 t o 
s u p p ort fi xe d d osi n g a p pr oac h. 
3 1. Secti o n 3. 1. 1: A d de d la n g ua ge f or t he 
e val uati o n of u p t o 6-1 2 patie nts t otal at 
selecte d le vel(s) bel o w t he M T D/ M A D 
wee kl y a n d Q 2 W d osi n g u p t o t he sa me 
d ose i nte nsit y  as t he M T D/ M A D wee kly 
re gi men ma y  be e val uate d f urt her t o s u p p ort 
t he R P 2 D decisi o n.
3 2. Secti o n 3. 1. 1. 3: C orrecte d err or (see 
stri ket hr o u g h te xt): T he 4 8 hr o bser vati o n 
peri o d f or t he first patie nt i n eac h d ose le vel 
i n Part 1. 1 will be gi n o n C 1 0 D 1 d uri n g t he 
sec o n d h os pitalizati o n peri o d.
3 3. Secti o n 3. 1. 1. 4: Re vise d Part 1 c o m bi nati o n 
d ose fi n di n g te xt re gar di n g M A D a n d R P 2 D 
starti n g d ose a n d de-escalati o n, clarifie d 
t hat t he fi xe d d ose of 3 0 0 m g w o ul d be 
a d mi nistere d S C , a n d a d de d a para gra p h f or 
Part 1 D.
3 4. Secti o n 3. 1. 2: A d de d te xt re gar di n g 
s u bc uta ne o us fi xe d d ose of P F- 0 6 8 6 3 1 3 5 
f or patie nts i n Part 2 A, a d de d para gra p h f or 
Part 2 D , a n d re m o ve d para gra p h f or 
i ntra ve n o us a d mi nistrati o n si nce I V is n o 
l o n ger c o nsi dere d f or d ose e x pa nsi o n. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
Re m o ve d refere nce t o “I V o nl y” fr o m 
S C H E D U L E O F P H A R M A C O KI N E TI C, 
S O L U B L E F A C T O R A N D C Y T O KI N E 
A C TI VI TI E S C (i ncl u di n g f o ot n ote * ) t o 
ali g n. 
3 5. Secti o n 3. 1. 4 : Delete d last r o w of Ta ble 1 
( d ose le vel 8 a n d u p, d ose T B D), m o difie d 
Ta ble 2 d oses f or d ose le vels 3, 4, a n d 5 a n d 
a d de d a 6 t h d ose le vel, delete d 
n o na p plica ble para gra p h. Clarifie d t hat i n 
Part 1. 1, t he starti n g mai nte na nce d ose will 
be n o m ore t ha n 2- f ol d a b o ve t he pri mi n g 
d ose esta blis he d fr o m Part 1. 
3 6. Secti o n 3. 2. 1: Clarifie d start of late 
t o xicities. 
3 7. Secti o n 3. 3: A d de d Ma xi m u m A d mi nistere d
D ose t o secti o n title, a d de d defi niti o n of 
M A D.
3 8. Secti o n 4. 1: I ncl usi o n criteri o n # 5 , a d de d 
platelet c o u nt f or Parts 1 D a n d 2 D, 
c orrecti o n ma de t o i ncl usi o n criterio n # 8 t o 
e xcl u de patie nts wit h acti ve he patitis B or
C.
3 9. Secti o n 4. 2: E xcl usi o n criteri o n # 4, a d de d 
refere nce t o A p pe n di x 1 1 f or a d diti o nal 
clarificati o n as it relates t o S A R S -C o V 2 
i nfecti o n, # 2 0, a d de d re q uire me nt f or 
c o ntrace pti o n d urati o n f oll o wi n g t he last 
d ose of le nali d o mi de a n d p o mali d o mi de .
4 0. Secti o n 4. 2: A d de d criteria # 2 7, 2 8, a n d 2 9 
descri bi n g e xcl usi o ns f or patie nts e nr olli n g 
i n p o mali d o mi de c o m bi nati o n c o h orts 
Parts 1 D a n d 2 D ( patie nts pre vi o usl y  
recei ve d p o mali d o mi de, patie nts recei vi n g 
str o n g C Y P 1 A 2 i n hi bit ors, a n d patie nts wit h 
a n y le vel of he patic i m pair me nt t hat w o ul d 
re q uire d ose re d ucti o n of p o mali d o mi de, 
res pecti vely) .
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
4 1. Secti o n 4. 3: U p date d c o ntrace pti o n f or 
fe males of c hil d beari n g p ote ntial t o i ncl u de 
a list of hi g hl y effecti ve met h o ds a n d 
i nc or p orate d p o mali d o mi de a n d 
le nali d o mi de w here ap pr o priate. A d de d 
t hat a n y ris k a n d e val uati o n a n d miti gati o n 
strate g y re q uire d by l oca l re g ulati o ns f or 
le nali d o mi de a n d p o mali d o mi de m ust be 
f oll o we d. 
4 2. Secti o n 4. 1: T he last I ncl usi o n Criteri o n ha d 
bee n mer ge d i nt o t he hea der f or t he 
E xcl usi o n Criteria secti o n. It n o w rea ds as 
I ncl usi o n criteria # 1 4.
4 3. Secti o n 5. 3. 1: Re vise d le nali d o mi de 
para gra p h, a d de d para gra p h f or 
p o mali d o mi de.  
4 4. Secti o n 5. 4. 2: Delete d para gra p h descri bi n g 
d urati o n of a d mi nistrati o n of sasa nli ma b.
4 5. Secti o n 5. 5. 2: A d de d A N C a n d platelet
val ues f or p o mali d o mi de, a d de d refere nce 
t o A p pe n di x 1 1 f or g ui deli nes f or d ose 
dela y s of P F-0 6 8 6 3 1 3 5 f or partici pa nts wit h 
acti ve or pres u me d S A R S -C o V 2 i nfecti o n. 
4 6. Secti o n 5. 5. 3: M o difie d Ta ble 4. 
L y m p h o pe nia will n ot be i ncl u de d i n 
he mat ol o gical t o xici t y as t his e x pecte d as 
part of P F - 0 6 8 6 3 1 3 5 mec ha nis m of acti o n .  
A d de d te xt a n d T a ble 8 f or d ose 
m o dificati o ns f or p o mali d o mi de.
4 7. Secti o n 5. 9 : A d de d dr u g-dr u g i nteracti o n 
( D DI) te xt f or le nali d o mi de a n d 
p o mali d o mi de. Secti o n 5. 9 a n d 
A p pe n di x 1 2: A d de d D DI te xt f or 
P F - 0 6 8 6 3 1 3 5.
4 8. Secti o n 5. 9. 1 0: A d de d ca uti o nar y  te xt f or 
t he use of a ge nts t hat ma y i ncrease t he ris k 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 4
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
of t hr o m b osis i n patie nts recei vi n g 
le nali d o mi de. 
4 9. Secti o n 6. 4: Re place d “st u d y dr u g” wit h 
sasa nli ma b.
5 0. Secti o n 7. 2: A d de d te xt descri bi n g t he 
d isease res p o nse assess me nt. 
5 1. Secti o n 7. 2. 1: A d de d te xt t o free li g ht c hai n 
a nal ys is descri bi n g ti mi n g f or patie nts 
treate d wit h darat u m u ma b. A d de d t his te xt 
t o f o ot n ote # 2 2 of Sc he d ules of 
Acti vities A, B, a n d C t o ali g n. Delete d 
“ o nl y” fr o m Beta -2 micr o gl o b uli n b ullet f or 
clarit y. 
5 2. Secti o n 7. 2. 2: A d de d t hat I n case of 
s us pecte d stri n ge nt C o m plete Res p o nse 
(s C R), t he prese nce/a bse nce of cl o nal cells 
o n i m m u n o hist oc he mistr y s h o ul d als o be 
e val uate d t o b o ne marr o w bi o ps y  para gra p h.
5 3. Secti o n 8. 1. 4. 2: A d de d te xt s pecif y i n g t he 
start of t he c ollecti o n peri o d f or n o nseri o us 
A Es a n d S A Es. A d de d i nstr ucti o nal te xt f or 
patie nts e x perie nci n g c y t o ki ne release 
s yn dr o me.
5 4. Secti o n 8. 4. 3. 1: Re place d i nsta nce of 
“ partici pa nt” wit h patie nt t o ali g n wit h 
pr ot oc ol ter mi n ol o g y . 
5 5. Secti o n 9. 2. 1: A d de d “If t he M T D is n ot 
reac he d, t he n t he M A D will be ma xi m u m 
d ose t hat is e val uate d i n t he st u d y ” f or 
clarit y. 
5 6. Secti o n 9. 3: U p date d sa m ple size 
deter mi nati o n secti o n f or a d diti o nal c o h orts.
5 7. Secti o n 9. 5. 1: A d de d Parts 1 D a n d 2 D t o 
a nal y sis of P F-0 6 8 6 3 1 3 5, re place d i nsta nce 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
of “ partici pa nts” wit h patie nts t o ali g n wit h 
ot her pr ot oc ol secti o ns. 
5 8. Secti o n 9. 5. 2: A d de d le nali d o mi de a n d 
p o mali d o mi de , 1 C a n d 2 C a n d 1 D a n d 2 D 
as a p pr o priate t o t he secti o n title. A d de d 
le nali d o mi de a n d p o mali d o mi de t o t he 
a nal ys is of c o nce ntrati o n-ti me data. 
5 9. Secti o n 9. 5. 6: Delete d first para gra p h 
descri bi n g a nal ys is of bl o o d a n d b o ne 
marr o w bi o mar ker sa m ples. A d de d 
para gra p h f or a nal ys is a n d re p orti n g of 
tertiar y/e x pl orat or y a nalyses.
6 0. Secti o n 9. 6. 2. 1: A d de d t hat t he se verity of 
I m m u ne Effect or Cell-Ass ociate d 
Ne ur ot o xicit y  Sy n dr o me ( I CA N S ) s h o ul d 
be gra de d acc or di n g t o t he A merica n 
S ociet y  f or Tra ns pla ntati o n a n d Cell ular 
T hera p y ( A S T C T ) c o nse ns us criteria.
6 1. Secti o n 1 3. 1: A d de d refere nce t o 
Secti o n 6. 6 f o r m ore i nf or mati o n o n h o w 
e n d of st u d y is deter mi ne d. 
6 2. A p pe n di x 2: Re m o ve d re d u n da nt te xt i n 
I M W G criteria c ol u m n i n Pr o gressi ve 
Disease ( P D) r o w a n d ad de d clarif y i n g 
la n g ua ge pri or t o b ullete d list. C orrecte d 
f o ot n ote n u m ber refere nce i n t hir d b ullet i n 
Cli nical Rela pse r o w . 
6 3. A p pe n di x 1 1: A d de d a p pe n di x t o pr o vi de 
g ui da nce f or alter nati ve meas ures d uri n g 
p u blic e mer ge ncies.
6 4. A p pe n di x 1 2: A d de d dr u g- dr u g i nteracti o n 
a p pe n di x.
A me n d me nt 6
( C o u ntr y 
s pecific 
1 7 Dece m ber 2 0 2 0
T he pri mar y  p ur p ose of t his a me n d me nt is t o 
a d dress re q uests recei ve d fr o m re g ulat or y  
a ge nc y Pa ul -E hrlic h -I nstit ut
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 6
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
A me n d me nt, 
Ger ma n y)
( P EI). T he c ha n ges f or A me n d me nt 6 are 
s pecific o nly t o Ger ma n y.
1. Re m o ve d Parts 1 B a n d 2 B (c o m bi nati o n wit h 
Sasa nli ma b) t hr o u g h o ut t he pr ot oc ol.
2. Secti o n 3. 2: Re m o ve d last b ullet i n dicati n g 
t hat Inf usi o n Relate d Reacti o ns (I R Rs) a n d 
I njecti o n Site Reacti o ns (I S Rs) will n ot be 
a dj u dicate d as D L Ts.
3 . Secti o n 3. 4: Secti o n was u p date d wit h 
Rec o m me n de d P hase 2 D ose f or m o n ot hera p y 
a n d fi xe d (flat) d ose a d diti o nal details .
4. Secti o n 5. 5. 3: P o mali d o mi de disc o nti n uati o n 
criteria ha ve bee n u p date d t o i ncl u de  
a na p h yl actic reacti o ns, a n gi oe de ma, 
pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y 
( P M L), or ras h ( Gra de 4 or blisteri n g).
5 . Secti o n 5. 9. 6: Re m o ve d last para gra p h 
i n dicati n g t hat I nf usi o n Relate d Reacti o ns 
(IR Rs) will n ot be c o nsi dere d as D L Ts .
6. Secti o n 5. 9. 7: Re m o ve d last para gra p h 
i n dicati n g t hat I njecti o n Site Reacti o ns (IS Rs)
will n ot be c o nsi dere d as D LTs .
A me n d me nt 7
1 5 Ja n uar y 2 0 2 1
T he pri mar y  p ur p ose of t his a me n d me nt is t o 
i nc or p orate c ha n ges pre vi o usl y i ncl u de d i n 
c o u ntr y s pecific A me n d me nt 6 ( Ger ma n y). I n 
a d diti o n, b eca use de xa met has o ne is a ke y 
c o m p o ne nt of sta n dar d a nti-m y el o ma t hera pies 
a n d its effect o n t he safet y  a n d efficacy of T-
cell e n ga gi n g bis pecific a ge nts is n ot k n o w n, 
P F - 0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h 
de xa met has o ne will be i n vesti gate d i n Part s 1 E
a n d 2 E.
Clarificati o ns, a d mi nistrati ve, a n d 
t yp o gra p hical m o dificati o ns were ma de. 
1.
C ha n ges pre vi o usl y i ncl u de d i n c o u ntr y  
s pecific A me n d me nt 6 ( Ger ma ny) as descri be d 
a b o ve.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 7
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
2.
Pr ot oc ol S u m mar y  (St u d y  desi g n) a n d 
Secti o n 3. 1: A d de d la n g ua ge t o e na ble P F -
0 6 8 6 3 1 3 5 c o m bi nati o n wit h de xa met has o ne i n 
Part 1 E a n d e x pa nsi o n Part 2 E , t o e val uate its 
p ote ntial t o miti gate i m m u ne effect or cell -
ass ociate d t o xicities a n d m o d ulate efficac y  of 
P F -0 6 8 6 3 1 3 5. Part 1 E will e nr oll ~ 9 - 1 6 
patie nts . If t he c o m bi nati o n re gi me n wit h 
de xa met has o ne i n Part 1 E is well t olerate d, Part 
2 E will e nr oll ~ 2 0 patie nts.
3.
St u d y  O bjecti ves a n d E n d p oi nts 
( Pr ot oc ol S u m mar y a n d Secti o n 2. 1): U p date 
la n g ua ge t o i ncl u de e val uati o n P F- 0 6 8 6 3 1 3 5 
c o m bi nati o n wit h de xa met has o ne a n d t o clarif y  
t hat plas ma will be c ollecte d f or P K a nalys is. 
4.
Pr ot oc ol S u m mar y  (St u d y  Desi g n),
Secti o n 3. 1 . 1, Secti o n 3.1 . 1. 3 a n d Secti o n 
3. 1. 1. 4 : F or t he p ur p ose of clarity, a d de d 
la n g ua ge t o s pecif y t hat patie nts will be 
h os pitalize d o n C 1 D 1 a n d re m o ve d 7 2 hrs, as 
h os pitalizati o n re q uire me nts are descri be d i n 
detail i n S c he d ule o f A cti vities f or s pecific Parts 
of t he st u d y .
5.
Secti o n 3. 1. 1: U p date d t o clarif y  D L T 
o bser vati o n peri o d ta ki n g i nt o acc o u nt d osi n g 
sc he d ule f or c o h orts t hat i m ple me nt 4 wee ks 
c ycle wit h pri mi n g.
6.
Pr ot oc ol S u m mar y  (St u d y  Desi g n), 
Secti o n 3. 1 a n d Secti o n 3. 1 . 1. 4: U p date t o 
i n dicate t hat if t he c o m bi nati o n re gi me n wit h 
de xa met has o ne i n Part 1 E is well t olerate d as 
g ui de d b y m T PI, Part 2 E ma y be i nitiate d .
7.
Pr ot oc ol S u m mar y , Secti o n 3. 1 ( St u d y 
desi g n) Secti o n 3. 1. 1. 4 a n d Secti o n 9. 3: 
U p date d t otal patie nt n u m bers f or t he st u d y, t o 
acc o u nt f or a d diti o n of de xa met has o ne c o h ort s
Part 1 E a n d 2 E. A p pr o xi matel y  1 2 0 patie nts are 
e x pecte d t o be e nr olle d i nt o Parts 1/ 1. 1, 1 C, 1 D , 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 8
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
a n d 1 E a n d a p pr o xi matel y 8 0 i n c o m bi nati o n 
c o h orts of Part 2.
8. 
Sc he d ule of Acti vities A, B, C: A d de d 
“ De m o gra p h y”  as re q uire d assess me nt a n d 
pr o vi de d a d diti o nal i nf or mati o n re gar di n g M R D 
assess me nt re q uire me nts f or clarit y.
9.
Sc he d ule of Acti vities A, B, C: F or t he 
p ur p ose of clarit y , f o ot n ote 2 4 u p date d t o 
i ncl u de a d diti o nal i nf or mati o n re gar di n g M R D
assess me nt re q uire me nts f or clarit y.
1 0. 
Sc he d ule of Acti vities A, B, a n d C: 
F o ot n ote 2 5 u p date d t o i ncl u de t hat o nl y  M RI is 
all o we d t o be use d as i ma gi n g m o dalit y f or 
patie nts b y  sites i n Ger ma n y.
1 1.
Sc he d ule of Acti vities B: U p date d t o 
i ncl u de de xa met has o ne i n c o m bi nati o n wit h 
P F -0 6 8 6 3 1 3 5 i n Parts 1 E a n d 2 E .
1 2.
Sc he d ule of Acti vities B a n d f o ot n ote 7: 
U p date d t o i n dicate t hat all patie nts recei vi n g a 
pri mi n g d ose will be h os pitalize d f or at least 
2 4 hrs o n C 0 D 1 a n d f or at least 2 4 hrs o n C 1 D 1.
H os pitalizati o n o n C 1 D 2 a n d C 1 D 3 a n d C 1 D 4 
visits (i ncl u di n g assess me nts) ha ve bee n 
re m o ve d fr o m Part 1. 1 a n d a n y part usi n g 
pri mi n g d ose, f oll o we d b y mai nte na nce.
1 3.
Sc he d ule of Acti vities B (f o ot n ote 4 1): 
A d de d la n g ua ge t o e na ble de xa met has o ne 
a d mi nistrati o n f or Parts 1 E a n d 2 E as nee de d 
a n d pr o vi de f urt her i nf or mati o n re gar di n g 
d osi n g, disc o nti n uati o n , a n d d urati o n of 
treat me nt.
1 4.
Sc he d ule of P har mac o ki netic, S ol u ble 
Fact or a n d C yt o ki ne Acti vities B (f o ot n ote 2): 
U p date d t o i n dicate t hat P K sa m ple s h o ul d be
c ollecte d if t he h os pitalizati o n peri o d is 
e xte n de d be y o n d 2 4 h o urs o n C 0 D 1 or C 1 D 1.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 9
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
1 5.
Sc he d ule of P har mac o ki netic, S ol u ble 
Fact or a n d C yt o ki ne Acti vities B: U p date d t o 
i n dicate t hat C 1 D4 a n d C 2 D 4 visits (i ncl u di n g 
assess me nts) ha ve bee n re m o ve d .
1 6.
Sc he d ul e of P har mac o ki netic, S ol u ble 
Fact or a n d C yt o ki ne Acti vities B ( i ncl u di n g 
f o ot n ote 5): U p date d t o pr o vi de i nstr ucti o ns a n d 
clarificati o n a b o ut bl o o d sa m ple c ollecti o n f or 
le nali d o mi de a n d p o mali d o mi de c o nce ntrati o n 
a nal ys is. 
1 7. 
Sc he d ule of P har mac o ki netic, S ol u ble 
Fact or a n d C yt o ki ne Acti vities B (i ncl u di n g 
f o ot n ote 6): U p date d t o pr o vi de i nstr ucti o ns f or 
bl o o d sa m ple c ollecti o n f or de xa met has o ne 
c o nce ntrati o n a nal ys is.
1 8.
Sc he d ule of P har mac o ki netic, S ol u ble 
Fact or a n d C yt o ki ne Acti vities C (f o ot n ote 3): 
Clar ificati o n pr o vi de d a b o ut bl o o d sa m ple 
c ollecti o n f or le nali d o mi de a n d p o mali d o mi de 
c o nce ntrati o n a nal ys is.
1 9.
Secti o n 1. 2. 3. 1: U p date d base d o n 
c urre nt safet y data. Safet y  data f or b ot h I V a n d 
S C c o h orts c o ns oli date d u n der Secti o n 1. 2. 3. 1.
2 0.
Secti o n 1. 2. 3. 2: U p date d base d o n 
c urre nt efficac y data. Efficac y  data f or b ot h I V 
a n d S C c o h orts c o ns oli date d u n der Secti o n 
1. 2. 3. 2.
2 1.
Secti o n 1. 2. 6: U p date d t o i n dicate t hat 
le nali d o mi de ca n ca use e m br yo- fetal t o xicit y. 
Re m o ve d refere nce t o de xa met has o ne, as 
de xa met has o ne is e na ble d i n Parts 1 E a n d 2 E t o 
u n dersta n d its effects o n t he safet y a n d efficac y 
of P F - 0 6 8 6 3 1 3 5.
2 2.
Secti o n 1. 2. 7: U p date d t o i n dicate t hat 
p o mali d o mi de ca n ca use e m br y o- fetal t o xicit y. 
Re m o ve d refere nce t o de xa met has o ne, as 
de xa met has o ne is e na ble d i n Part E t o 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 3 0
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
u n dersta n d effects of t his bac k b o ne a nti -
m y el o ma a ge nt o n t he safet y a n d efficac y of 
P F - 0 6 8 6 3 1 3 5
2 3.
Secti o n 1. 2. 8: I ntr o d uce d secti o n t o 
descri be t he rati o nale f or c o m bi ni n g P F -
0 6 8 6 3 1 3 5 wit h de xa met has o ne.
2 4.
Secti o n 1. 2. 9. 3: U p date d secti o n t o 
i n dicate t hat Part 1 E will e val uate t he R P 2 D 
d ose le vel of P F 0 6 8 6 3 1 3 5 wit h
de xa met has o ne. 
2 5.
Secti o n 3. 1 ( St u d y  Sc he ma/ Fi g ure 4): 
U p date d t o i ncl u de c o m bi nati o n wit h 
de xa met has o ne, Part 1 E (≈9- 1 6 patie nts) a n d 
Part 2 E (≈2 0 patie nts).
2 6.
Secti o n 3. 1 ( St u d y  Sc he ma/ Fi g ure 4): 
U p date d t o descri be Part 1. 1 pri mi n g c o h orts, 
i ncl u di n g pri mi n g a n d mai nte na nce ( Q 1 W a n d 
Q 2 W ).
2 7.
Secti o n 3. 1. 1: U p date d hea di n g wit h 
pri mi n g a n d mai nte na nce c o h orts f or clarit y.
2 8.
Secti o n 3. 1. 1. 4: U p date d t o i ncl u de 
R P 2 D f or P F -0 6 8 6 3 1 3 5 as a si n gle a ge nt a n d a 
ta ble detaili n g p ote ntial fi xe d d oses t o be 
a d mi nistere d i n m o n ot hera p y a n d c o m bi nati o n 
ar ms wit h p o mali d o mi de, le nali d o mi de a n d 
de xa met has o ne. Pr o vi de detaile d i nf or mati o n 
f or P F-0 6 8 6 3 1 3 5 a d mi nistrati o n i n c o m bi nati o n 
wit h de xa met has o ne.
2 9. 
Secti o n 3. 1. 2 a n d 3. 1. 4: A d de d la n g ua ge 
t o i ntr o d uce Part 1 E a n d 2 E as nee de d a n d 
pr o vi de f urt her i nf or mati o n re gar di n g d osi n g 
a n d de-escalati o n. 
3 0. 
Secti o n 3. 1. 1, 3. 1. 1. 3, 3. 2 a n d 3. 2. 1: 
Base d o n e mer gi n g data t hat t here was n o 
si g nifica nt late t o xicit y, late t o xicit y e val uati o n 
of patie nts f or a mi ni m u m of 6 0 da y s was 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 3 1
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
rem o ve d as re q uire me nt f or t he p ur p ose of 
M T D/ M A D deter mi nati o n.
3 1. 
Secti o n 3. 1. 1. 3: U p date d hea di n g wit h 
pri mi n g a n d mai nte na nce c o h orts a n d re m o ve d 
d ose escalati o n f or clarit y. 
3 2.
Secti o n 3. 4 : U p date d t o i ncl u de R P 2 D 
f or P F-0 6 8 6 3 1 3 5 as a si n gle a ge nt a n d 
prel i mi nar y data s u g gesti n g t hat a d mi nistrati o n 
of pri mi n g d ose re d uces d urati o n of C R S.
3 3.
Secti o n 4. 1: Restricte d Easter n 
C o o perati ve O nc ol o g y  Gr o u p ( E C O G) 
Perf or ma nce Stat us ( P S) t o 0- 1 f or Part 2 A a n d 
t o 0-2 f or all ot her c o h orts (i ncl usi o n 4).
3 4.
Secti o n 4. 1: Clarifie d i ncl usi o n criteria 
f or platelet c o u nts f or b ot h Part 1 E a n d Part 2 E 
(i ncl usi o n 5).
3 5.
Secti o n 4. 2: Pr o vi de d clarit y  f or 
re q uire me nt f or sys te mic i m m u ne s u p pressi ve 
me dicati o n i n (e xcl usi o n 1 2).
3 6.
Secti o n 4. 2: Pr o vi de d clarit y  re gar di n g 
p ote ntial C O VI D vacci nati o n (e xcl usi o n 1 8).
3 7. 
Secti o n 4. 3: Pr o vi de d a d diti o nal clarit y  
re gar di n g pre g na nc y pre ve nti o n pr o gra m f or 
le nali d o mi de a n d p o mali d o mi de.
3 8.
Secti o n 5 (st u d y  treat me nts), Secti o n 
5. 2 a n d Secti o n 5. 3. 1: I ncl u de d de xa met has o ne 
as i n vesti gati o nal m e dici nal pr o d uct.
3 9.
Secti o n 5. 5: U p date d t o i ncl u de 
de xa met has o ne a n d clarif y  t hat if a d ose of P F-
0 6 8 6 3 1 3 5 is dela y e d or i nterr u pte d, t he n 
de xa met has o ne s h o ul d n ot be a d mi nistere d u ntil 
P F -0 6 8 6 3 1 3 5 a d mi nistrati o n is restarte d .
4 0.
Secti o n 5. 5. 2 ( D ose dela ys): U p date d t o 
i ncl u de de xa met has o ne. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 3 2
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
4 1.
Secti o n 5. 5. 3 ( D ose re d ucti o ns): 
U p date d t o i ncl u de g ui da nce f or d ose dela y s f or 
de xa met has o ne relate d t o xicities, i ncl u di n g 
Ta ble 1 0. U p date d t o i ncl u de g ui da nce f or d ose 
m o dificati o n f or P F -0 6 8 6 3 1 3 5 relate d t o xicities. 
S pecificall y, f or a n y patie nt w h o recei ves fi xe d 
d oses of P F -0 6 8 6 3 1 3 5, t he ne xt d ose le vel of 
P F -0 6 8 6 3 1 3 5 will be 2 5 % l o wer .
4 2.
Secti o n 5. 9: U p date d t o i ntr o d uce 
de xa met has o ne as m o derate i n d ucer of C Y P 
3 A 4.
4 3.
Secti o n 5. 9. 1 3: U p date d t o i n dicate t hat , 
e xce pt as s pecifie d i n t he pr ot oc ol,
c ortic oster oi ds f or palliati ve or s u p p orti ve 
p ur p oses are per mitte d o nl y  f oll o wi n g 
disc ussi o n a n d a gree me nt bet wee n t he 
i n vesti gat or a n d s p o ns or.
4 4.
Secti o n 7. 2. 2: U p date d t o f urt her clarif y  
M R D assess me nt pr ocess a n d re q uire me nts.
4 5.
Secti o n 7. 2. 3: U p date d t o i ncl u de t hat 
o nl y  M RI is all o we d t o be use d as i ma gi n g 
m o dalit y  b y sites i n Ger ma n y.
4 6. 
Secti o n 9 . 3: U p date d t o i ncl u de Part 1 E 
a n d 2 E i n t he sa m ple size deter mi nati o n.
4 7.
Secti o n 9. 4: U p date d t o e na ble 
i n de pe n de nt ce ntral re vie w f or efficac y 
e n d p oi nts as nee de d. Secti o n u p date d t o clarif y 
t hat c o nfir me d res p o nses are re q uire d, mi ni mal 
res p o nse ( M R) is n ot i ncl u de d i n t he O R R 
res p o nse defi niti o n a n d sta ble disease ( S D) is 
n ot i ncl u de d i n c li nical be nefit ( C B) defi niti o n.
4 8.
S ecti o n 9. 5. 1: U p date d t o i ncl u de bl o o d 
sa m ple c ollecti o n f or P F - 0 6 8 6 3 1 3 5 i n Part 1 E 
a n d 2 E.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 3 3
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
4 9.
Secti o n 9. 5. 2: U p date d t o i ncl u de bl o o d 
sa m ple c ollecti o n f or de xa met has o ne i n Part 1 E 
a n d 2 E.
5 0.
Secti o n 1 6: U p date d Refere nces as 
nee de d .
5 1.  
A p pe n di x 1: U p date d a b bre viati o ns as 
nee de d .
A me n d me nt 8
0 6 J u ne 2 0 2 1
T he pri mar y  p ur p ose of t his a me n d me nt is t o 
i nc or p orate c ha n ges relate d t o peri p heral 
ne ur o pat h y, i ncl u di n g miti gati o n meas ures.
1.
Pr ot oc ol S u m mar y  ( St u d y Desi g n) a n d 
St u d y  O ver vie w ( St u d y Desi g n): U p date d t o 
clarif y t hat e nr ollme nt i n st u d y  C 1 0 7 1 0 0 1 
has bee n c o m plete d, as cli nical de vel o p me nt 
pr o gra m f or P F- 0 6 8 6 3 1 3 5 has bee n 
e x pa n de d wit h de dicate d st u dies t hat will 
f urt her i n vesti gate b ot h m o n ot hera py a n d 
c o m bi nati o n t hera p y. 
2.
Beca use le nali d o mi de bel o n gs t o t he sa me 
dr u g class as p o mali d o mi de, t he ma xi m u m 
d ose of le nali do mi de was re d uce d t o 1 5 m g, 
as descri be d t hr o u g h o ut t he d oc u me nt. T he 
d ose a dj ust me nt ta bles (Ta ble 6 a n d 
Ta ble 7 ) i n Secti o n 5. 5. 3 w ere m o difie d
acc or di n gl y.
3.
I n or der t o f oc us o n t he data m ost i m p orta nt 
f or i n vesti gat ors, Secti o n 1. 2. 3. 1 a n d 
Secti o n 1. 2. 3. 2 were u p date d wit h safety 
a n d efficac y data, res pecti vel y.
4.
Clarifie d t hat n e urol o gical assess me nts 
occ ur at eac h p h ys ical e xa mi nati o n i n t he 
S o As a n d Secti o n 7. 1. 4 .
5.
Sc he d ule of P har mac o ki netic, S ol u ble 
Fact or a n d C yt o ki ne Acti vities B (f o ot n ote 
5): Pr o vi de d g ui da nce a b o ut bl o o d sa m ple 
c ollecti o n f or le nali d o mi de a n d 
p o mali d o mi de c o nce ntrati o n a nal y sis f or 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 3 4
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
patie nts tra nsiti o ne d t o m o n ot hera p y wit h 
P F - 0 6 8 6 3 1 3 5.
6.
Clarifi cati o n a d de d f or d ose dela y s i n 
Secti o n 5. 5. 2 a n d 5. 5. 3 .
7.
D ose m o dificati o ns of P F - 0 6 8 6 3 1 3 5 f or 
peri p heral ne u r o pat hy were a d de d t o 
Ta ble 5 i n Secti o n 5. 5. 3 .
8.
C o nsi derati o ns re gar di n g c o nc o mita nt 
me dicati o ns wer e i ncl u de d i n Secti o n 5. 9 .
9.
Secti o n 5. 9. 1 a n d 5. 9. 4 : U p date d t o descri be
pre me dicati o n f or C R S.
1 0. Rec o m me n de d e val uati o n f or peri p heral 
ne ur o pat h y was a d de d t o Secti o n 8. 4. 4 .
1 1. Criteria f or i nterr u pti o n of st u d y  treat me nt 
were a d de d i n Secti o n 9. 7 .
1 2. Bi o mar ke r c ollecti o ns f or M R D assess me nt 
b y  N G S were clarifie d i n t he t he S o A.
1 3. Pre g na nc y tests a n d c o ntrace pti o n c hec ks, 
al o n g wit h A E assess me nts were e xte n d e d 
t o 9 0 da ys after t he last d ose of 
i n vesti gati o nal pr o d uct.
1 4. T he Title Pa ge was u p date d t o i ncl u de t he 
ne w Pfizer l o g o, t he st u d y na me
( MA G N E TI S M M - 1), t he ge neric na me
(elra n ata ma b), a n d t he N C T n u m ber.
1 5. U p date d refere nces as nee de d i n Secti o n 1 6 .
1 6. F or c o nsiste nc y  bet wee n A p pe n di x 5 , 
Secti o n 5. 9. 4 a n d rest of t he pr ot oc ol, it has 
bee n c larifie d t hr o u g h o ut t he d oc u me nt t hat 
C R S will be assesse d acc or di n g t o t he 
gra di n g descri be d b y Lee et al. 2 0 1 4 a n d 
2 0 1 9 (see A p pe n di x 5 ) as i nitiall y descri be d 
i n pr ot oc ol a me n d me nt 7.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 3 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
1 7. Ge neral f or matti n g a n d c o p y e diti n g were
perf or me d t hr o u g h o ut t he d oc u me nt .
A me n d me nt 9
2 8 Marc h 2 0 2 3
T he pri mar y  p ur p ose of t his a me n d me nt is t o 
e xte n d t he d urati o n of t he st u d y b y  ~ 6 m o nt hs, 
re d uce sa m ple c ollecti o ns f or e x pl orat or y 
e n d p oi nts, a n d e xte n d c o ntrace pti o n peri o d p ost 
last d ose.
1. S o A A (f o ot n ote # 3 7), S o A B (f o ot n ote # 3 7) ,
S o A C (f o ot n ote # 3 6 ), Secti o n 3. 1 ( St u d y 
O ver vie w), Secti o n 6. 3 ( F oll o w -u p), Secti o n 
6. 5 ( E n d of St u d y ): E n d of st u d y  f or all patie nts 
will be deat h or u p t o a p pr o xi matel y  3 0 m o nt hs 
after last patie nt first d ose, f oll o we d b y a n y 
re q uire d f oll o w-u p visits ; S ur vi val f oll o w- u p 
has bee n u p date d acc or di n gl y. B y  re visi n g e n d 
of st u d y , acti ve patie nts will c o nti n ue recei vi n g 
si g nifica nt cli nical be nefit fr o m t hera py wit h 
elra nata ma b. 2 2 Fe br uar y  2 0 2 3 P A C L
2. S o A A (f o ot n ote # 2 0 ), S o A B (f o ot n ote # 20 ),
S o A C (f o ot n ote # 1 9 ), Secti o n 4. 2 ( E xcl usi o n 
Criteria ), Secti o n 4. 3 ( Lifest y le Re q uire me nts): 
Re vise d c o ntrace pti o n re q uire me nts base d o n 
rece ntly u p date d P K data as descri be d i n I B.
3 . S o A A (f o ot n ote # 2 1), S o A B (f o ot n ote # 2 1) ,
S o A C (f o ot n ote # 2 0 ), Secti o n 1. 2. 9. 5 ( D osi n g 
I nter val), Secti o n 3. 1. 1. 4 ( Part 1 C o m bi nati o n 
D ose Fi n di n g), Secti o n 5. 4 ( A d mi nistrati o n): I n 
or der t o re d uce partici pa nt b ur de n of fre q ue nt 
visits, d osi n g o nce per c ycle ( C X D 1) is all o we d 
u p o n c o ns ultati o n wit h t he s p o ns or .
4 . S o A A (i ncl u di n g f o ot n otes #2 9, 3 1- 3 3 ), S o A 
B (i ncl u di n g f o ot n otes # 2 9, 3 1 - 3 3), S o A C 
(i ncl u di n g f o ot n otes #2 8, 3 0- 3 2 ), Secti o n 1. 2. 1 0 
( Bi o mar kers), Secti o n 2 ( St u d y O bjecti ves a n d 
E n d p oi nts ), Secti o n 7. 5 (Bi o mar kers a n d 
P har mac o d y na mics Assess me nt; Ta ble 1 2) : I n 
or der t o li mit t he b ur de n of fre q ue nt sa m ple 
c ollecti o ns, bl o o d sa m ple a n d b o ne marr o w 
as pirate c ollecti o ns are re d uce d (e x pl orat or y 
e n d p oi nts ). 1 9 A u g ust 2 0 2 1 P A C L
5 . I n or der t o f oc us o n t he data m ost i m p orta nt 
f or i n vesti gat ors, Secti o n 1. 2. 3. 1 a n d Secti o n 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 3 6
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
1. 2. 3. 2 were u p date d wit h safet y a n d efficac y 
data, res pecti vel y.
6. I n or der t o ali g n wit h Pfizer pr ocesse s a n d 
pr ot oc ol te m plate re q uire me nts, Secti o n s 1 1. 1, 
1 1. 3, 1 2. 1, 1 5. 1 a n d 1 5. 2 were u p date d.
T his a me n d me nt i nc or p orates all re visi o ns t o date, i ncl u di n g a me n d me nts ma de at t he 
re q uest of c o u ntr y healt h a ut h orities a n d i nstit uti o nal re vie w b oar ds (IR Bs)/et hics c o m mittees 
(E Cs) a n d a n y pr ot oc ol a d mi nistrati ve c ha n ge letter(s) .
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 3 7
T A B L E O F C O N T E N T S
LI S T O F T A B L E S ...................................................................................................................4 4
LI S T O F FI G U R E S ................................................................................................................. 4 4
A P P E N DI C E S ......................................................................................................................... 4 5
S C H E D U L E O F A C TI VI TI E S A: P A R T 1 I V A N D S C W E E K L Y M O N O T H E R A P Y 
( N O P RIMI N G D O S E) ....................................................................................................... 5 4
S C H E D U L E O F P H A R M A C O KI N E TI C, S O L U B L E F A C T O R A N D C Y T O KI N E 
A C TI VI TI E S A: P A R T 1 I V A N D S C W E E K L Y M ON O T H E R A P Y ( N O 
P RI MI N G D O S E) ............................................................................................................... 6 2
S C H E D U L E O F A C TI VI TI E S B: P A R T 1. 1 A N D A N Y P A R T U SI N G P RI MI N G 
D O S E A N D M AI N T E N A N C E .......................................................................................... 6 5
S C H E D U L E O F P H A R M A C O KI N E TI C, S O L U B L E F A C T O R A N D C Y T O KI N E 
A C TI VI TI E S B: P A R T 1 . 1 A N D A N Y O T H E R P A RT U SI N G P RI MI N G D O S E
A N D M AI N T E N A N C E ...................................................................................................... 7 6
S C H E D U L E O F A C TI VI TI E S C: P A R T S 1 S C Q 2 W , 1 C, A N D 1 D ( D O S E 
E S C A L A TI O N C O M BI N A TI O N) A N D 2 A, 2 C A N D 2 D ( D O S E E X P A N SI O N 
C O H O R T S) WI T H O U T P RI MI N G D O S E ........................................................................ 8 0
S C H E D U L E O F P H A R M A C O KI N E TI C, S O L U B L E F A C T O R A N D C Y T O KI N E 
A C TI VI TI E S C: P A R T S 1 S C Q 2 W, 1 C A N D 1 D ( D O S E E S C A LA T I O N 
C O M BI N A T I O N) A N D 2 A, 2 C A N D 2 D ( D O S E E X P A N SI O N C O H O R T S) 
WI T H O U T P RI MI N G D O S E ............................................................................................. 9 0
1. I N T R O D U C TI O N ............................................................................................................... 9 4
1. 1. Mec ha nis m of Acti o n/I n dicati o n ............................................................................. 9 4
1. 2. Bac k gr o u n d a n d Rati o nale ...................................................................................... 9 4
1. 2. 1. M ulti ple M y el o ma ...................................................................................... 9 4
1. 2. 2. Bis pecific A nti b o dies .................................................................................. 9 5
1. 2. 3. P F -0 6 8 6 3 1 3 5............................................................................................... 9 6
1. 2. 3. 1. Safet y ......................................................................................... 9 6
1. 2. 3. 2. Efficac y ..................................................................................... 9 7
1. 2. 3. 3. M o n ocl o nal A nti b o d y  Interfere nce of La b orat or y  
E val uati o n of M y el o ma ..................................................................... 9 7
1. 2. 4. N o ncli nical Safet y I nf or mati o n .................................................................. 9 7
1. 2. 5. P F -0 6 8 6 3 1 3 5 Precli nical Efficac y ..............................................................9 8
1. 2. 5. 1. I n Vitr o Acti vit y  of P F-0 6 8 6 3 1 3 5............................................. 9 8
1. 2. 5. 2. Si n gle A ge nt A nti -t u m or Efficac y of P F-0 6 8 6 3 1 3 5 i n 
Ort h ot o pic M ulti ple M y el o ma M o dels T u m or M o dels ..................... 9 8
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 3 8
1. 2. 5. 3. A nti- t u m or Efficac y of P F-0 6 8 6 3 1 3 5 i n C o m bi nati o n wit h 
t he Im m u n o m o d ulat or y  Dr u g Le nali d o mi de i n Ort h ot o pic a n d 
S u bc uta ne o us M y el o ma M o dels ........................................................ 9 9
1. 2. 6. L e nali d o mi de ............................................................................................ 1 0 0
1. 2. 7. P o mali d o mi de ........................................................................................... 1 0 1
1. 2. 8. De xa met has o ne ......................................................................................... 1 0 1
1. 2. 9. Starti n g D ose Rati o nale ............................................................................ 1 0 2
1. 2. 9. 1. I ntra ve n o us (I V) Starti n g D ose Rati o nale ............................... 1 0 2
1. 2. 9. 2. S u bc uta ne o us ( S C) Starti n g D ose Rati o nale ........................... 1 0 3
1. 2. 9. 3. Starti n g D ose f or C o m bi nati o n Safet y  C o h orts ( Parts 1 C, 
1 D a n d 1 E) ....................................................................................... 1 0 3
1. 2. 9. 4. Fi xe d D osi n g A p pr oac h .......................................................... 1 0 4
1. 2. 9. 5. D osi n g I nter val ........................................................................ 1 0 4
1. 2. 9. 6. Pri mi n g a n d Mai nte na nce D ose Rati o nale .............................. 1 0 5
1. 2. 1 0. Bi o mar ker Rati o nale ............................................................................... 1 0 5
1. 2. 1 0. 1. Ba n ke d Bi os peci me ns ........................................................... 1 0 6
2. S T U D Y O BJ E C TI V E S A N D E N D P OI N T S ..................................................................... 1 0 7
2. 1. Part 1 I V a n d S C m o n ot hera p y D ose Escalati o n, Part 1. 1 Pri mi n g a n d 
Mai nte na nce D ose Escalati o n a n d Parts 1 C, 1 D a n d 1 E D ose 
Escalati o n/ Fi n di n g ...................................................................................................1 0 7
2. 2. Part 2 D ose E x pa nsi o n .......................................................................................... 1 0 9
3. S T U D Y D E SI G N ............................................................................................................... 1 1 0
3. 1. St u d y  O ver vie w..................................................................................................... 1 1 0
3. 1. 1. Part 1 M o n ot hera p y  D ose Escalati o n a n d Part 1. 1 Pri mi n g a n d 
Mai nte na nce C o h orts ..................................................................................... 1 1 2
3. 1. 1. 1. Part 1 I ntra ve n o us (I V) A d mi nistrati o n .................................. 1 1 3
3. 1. 1. 2. Part 1 S u bc uta ne o us ( S C) A d mi nistrati o n .............................. 1 1 3
3. 1. 1. 3. Part 1. 1 Pri mi n g a n d Mai nte na nce C o h orts ............................ 1 1 4
3. 1. 1. 4. Part 1 C o m bi nati o n D ose Fi n di n g ........................................... 1 1 5
3. 1. 2. Part 2 D ose E x pa nsi o n .............................................................................. 1 1 7
3. 1. 3. Starti n g D ose ............................................................................................ 1 1 8
3. 1. 4. Criteria f or D ose Escalati o n/ De -Escalati o n .............................................. 1 1 8
3. 1. 4. 1. Criteria f or I ntra patie nt D ose Escalati o n ................................. 1 2 0
3. 2. D ose L i miti n g T o xicit y ( D L T) Defi niti o n............................................................ 1 2 1
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 3 9
3. 2. 1. L ate T o xicities .......................................................................................... 1 2 3
3. 3. Ma xi m u m T olerate d a n d Ma xi m u m A d mi nistere d D ose ( M T D a n d M A D) 
Defi niti o ns ............................................................................................................... 1 2 3
3. 4. Rec o m me n de d P hase 2 D ose ( R P 2 D) Defi niti o n ................................................. 1 2 4
3. 5. St o p pi n g Criteria i n Part 2 D ose E x pa nsi o n .......................................................... 1 2 4
4. P A TI E N T E LI GI BI LI T Y C RI T E RI A ............................................................................... 1 2 5
4. 1. I ncl usi o n Criteria ................................................................................................... 1 2 5
4. 2. E xcl usi o n Criteria .................................................................................................. 1 2 7
4. 3. L ifest yle Re q uire me nts ......................................................................................... 1 3 0
4. 4. S p o ns or’s Q ualifie d Me dical Pers o n nel ................................................................ 1 3 1
5. S T U D Y T R E A T M E N T S ................................................................................................... 1 3 2
5. 1. All ocati o n t o Treat me nt ........................................................................................ 1 3 2
5. 2. Patie nt C o m plia nce ...............................................................................................1 3 2
5. 3. I nvesti gati o nal Pr o d uct S u p plies ........................................................................... 1 3 3
5. 3. 1. P har mace utical F or m(s) a n d Pac ka gi n g ................................................... 1 3 3
5. 3. 2. Pre parati o n a n d Dis pe nsi n g ...................................................................... 1 3 3
5. 4. A d mi nistrati o n .......................................................................................................1 3 3
5. 4. 1. I V A d mi nistrati o n P F - 0 6 8 6 3 1 3 5.............................................................. 1 3 3
5. 4. 2. S C A d mi nistrati o n P F -0 6 8 6 3 1 3 5 ............................................................. 1 3 4
5. 5. Rec o m me n de d D ose M o difica ti o ns ...................................................................... 1 3 5
5. 5. 1. D osi n g I nterr u pti o ns ................................................................................. 1 3 6
5. 5. 2. D ose Dela y s ..............................................................................................1 3 7
5. 5. 3. D ose Re d ucti o ns ....................................................................................... 1 3 7
5. 5. 4. I ntra - Patie nt D ose Escalati o n f or P F-0 6 8 6 3 1 3 5 ....................................... 1 4 3
5. 6. Per ma ne nt Disc o nti n uati o n ................................................................................... 1 4 4
5. 7. I n vesti gati o nal Pr o d uct St ora ge ............................................................................ 1 4 4
5. 8. I n vesti gati o nal a n d N o n -I n vesti gati o nal Pr o d uct Acc o u nta bility......................... 1 4 5
5. 8. 1. Destr ucti o n of I n vesti gati o nal a n d N o n -I n vesti gati onal Pr o d uct 
S u p plies .......................................................................................................... 1 4 5
5. 9. C o nc o mita nt Treat me nt(s) ..................................................................................... 1 4 5
5. 9. 1. Pre me dicati o n Re q uire d f or C yt o ki ne Release S y n dr o me Pr o p h yl a xis ... 1 4 6
5. 9. 2. Ot her A nti -t u m or/ A nti-ca ncer or E x peri me ntal Dr u gs .............................1 4 7
5. 9. 3. S u p p orti ve Care ........................................................................................ 1 4 7
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 4 0
5. 9. 4. C y t o ki ne Release S yn dr o me ..................................................................... 1 4 7
5. 9. 5. I m m u ne Effect or Cell -Ass ociate d Ne ur ot o xicit y  S yn dr o me I C A N S ....... 1 4 7
5. 9. 6. T u m or L y sis Sy n dr o m e ( T L S) .................................................................. 1 4 8
5. 9. 7. I nf usi o n Relate d Reacti o ns (I R R) .............................................................1 4 8
5. 9. 8. I njecti o n Site Reacti o ns (I S R) .................................................................. 1 4 9
5. 9. 9. H y perse nsiti vit y  T ypes 1 a n d 3 ................................................................ 1 4 9
5. 9. 1 0. E xtra vasati o n .......................................................................................... 1 4 9
5. 9. 1 1. He mat o p oietic Gr o wt h Fact ors ...............................................................1 4 9
5. 9. 1 2. A nti -Diarr heal, A nti -E metic T hera p y..................................................... 1 5 0
5. 9. 1 3. A nti- I nfla m mat or y T hera p y.................................................................... 1 5 0
5. 9. 1 4. C ortic oster oi ds ........................................................................................ 1 5 0
5. 9. 1 5. S ur ger y .................................................................................................... 1 5 0
5. 9. 1 6. Tra nsf usi o n S u p p ort ................................................................................ 1 5 0
6. S T U D Y P R O C E D U R E S ................................................................................................... 1 5 0
6. 1. Scree ni n g ............................................................................................................... 1 5 0
6. 2. St u d y  Peri o d .......................................................................................................... 1 5 1
6. 3. F oll o w -u p.............................................................................................................. 1 5 1
6. 4. E n d of Treat me nt ................................................................................................... 1 5 1
6. 5. E n d of St u d y .......................................................................................................... 1 5 1
6. 6. Patie nt Wit h dra wal ................................................................................................ 1 5 2
7. A S S E S S M E N T S ................................................................................................................ 1 5 3
7. 1. Safet y Assess me nt ................................................................................................. 1 5 4
7. 1. 1. Pre g na nc y  Testi n g .................................................................................... 1 5 4
7. 1. 2. A d verse E ve nts ......................................................................................... 1 5 4
7. 1. 3. La b orat or y  Safety Assess me nt ................................................................. 1 5 5
7. 1. 4. Vital Si g ns a n d P h ysical E xa mi nati o n ...................................................... 1 5 6
7. 1. 5. ( 1 2 -Lea d) Electr ocar di o gra m ....................................................................1 5 6
7. 1. 6. Ec h ocar di o gra m ( Ec h o) or M ulti gate d Ac q uisiti o n Sca n ( M U G A)......... 1 5 7
7. 1. 7. L ocal Site I njecti o n T olera bilit y  Assess me nt ( S C O nl y) ......................... 1 5 7
7. 2. Disease Res p o nse Assess me nt .............................................................................. 1 5 8
7. 2. 1. L a b orat or y E val uati o n of Disease Res p o nse............................................ 1 5 8
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 4 1
7. 2. 2. B o ne Marr o w Plas ma Cell E val uati o n a n d B o ne Marr o w Sa m ple 
C ollecti o n .......................................................................................................1 5 9
7. 2. 3. Fl u or o de o x y gl uc ose ( F D G) P ositr o n E missi o n T o m o gra p h y 
( P E T)/ C o m p ute d T o m o gra p hy ( C T) I ma gi n g ............................................... 1 6 1
7. 3. P har mac o ki netics Assess me nts ............................................................................. 1 6 2
7. 4. I m m u n o ge nicit y A nal yses ..................................................................................... 1 6 3
7. 5. Bi o mar ker a n d P har mac o d y na mic Assess me nts ................................................... 1 6 3
7. 5. 1. B o ne Marr o w Bi o mar kers ........................................................................ 1 6 5
7. 5. 2. W h ole Bl o o d P har mac o d y na mic Mar kers ................................................ 1 6 5
7. 5. 3. S hi p me nt of P har mac o d y na mic Sa m ples ................................................. 1 6 5
7. 5. 4. C y t o ki ne Assess me nts .............................................................................. 1 6 5
7. 5. 5. S ol u ble B C M A Assess me nts .................................................................... 1 6 6
7. 6. P har mac o ge n o mics ................................................................................................ 1 6 6
7. 6. 1. Ge n ot y pi n g A nal ysis ................................................................................ 1 6 6
7. 6. 2. Ge netic A nal y sis ....................................................................................... 1 6 7
7. 7. Ba n ke d Bi os peci me ns ........................................................................................... 1 6 7
7. 7. 1. A d diti o nal Researc h .................................................................................. 1 6 8
8. A D V E R S E E V E N T R E P O R TI N G .................................................................................... 1 6 8
8. 1. Re q uire me nts ......................................................................................................... 1 6 8
8. 1. 1. A d d iti o nal Details O n Rec or di n g A d verse E ve nts o n t he C R F................ 1 6 9
8. 1. 2. Eliciti n g A d verse E ve nt I nf or mati o n ........................................................ 1 6 9
8. 1. 3. Wit h dra wal Fr o m t he St u d y  D ue t o A d verse E ve nts................................ 1 6 9
8. 1. 4. Ti me Peri o d f or C ollecti n g A E/ S A E I nf or mati o n .................................... 1 7 0
8. 1. 4. 1. Re p orti n g S A Es t o Pfizer Safet y ............................................. 1 7 0
8. 1. 4. 2. Rec or di n g N o n -seri o us A Es a n d S A Es o n t he C R F ............... 1 7 0
8. 1. 5. Ca usalit y  Assess me nt ............................................................................... 1 7 1
8. 1. 6. S p o ns or’s Re p orti n g Re q uire me nts t o Re g ulat or y  A ut h orities................1 7 1
8. 2. Defi niti o ns............................................................................................................. 1 7 1
8. 2. 1. A d v erse E ve nts ......................................................................................... 1 7 1
8. 2. 2. A b n or mal Test Fi n di n gs ........................................................................... 1 7 2
8. 2. 3. Seri o us A d verse E ve nts ............................................................................ 1 7 3
8. 2. 4. H os pitalizati o n .......................................................................................... 1 7 3
8. 3. Se verit y  Assess me nt..............................................................................................1 7 5
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 4 2
8. 4. S pecial Sit uati o ns ..................................................................................................1 7 5
8. 4. 1. P ote ntial Cases of Dr u g -I n d uce d Li ver I nj ur y.......................................... 1 7 5
8. 4. 2. E x p os ure t o t he I n vesti gati o nal Pr o d uct D uri n g Pre g na nc y  or 
Breastfee di n g, a n d Occ u pati o nal E x p os ure ................................................... 1 7 7
8. 4. 2. 1. E x p os ure D uri n g Pre g na nc y  ( E D P) ........................................ 1 7 7
8. 4. 2. 2. E x p os ure D uri n g Breastfee di n g .............................................. 1 7 8
8. 4. 2. 3. Occ u pati o nal E x p os ure ........................................................... 1 7 8
8. 4. 3. Me dicati o n Err ors ..................................................................................... 1 7 8
8. 4. 3. 1. Me dicati o n Err ors .................................................................... 1 7 9
8. 4. 4. Peri p heral ne ur o p at h y ............................................................................... 1 7 9
9. D A T A A N A L Y SI S/ S T A TI S TI C A L  M E T H O D S.............................................................1 8 0
9. 1. A nal y sis Sets ......................................................................................................... 1 8 0
9. 2. Statistical Met h o ds a n d Pr o perties ........................................................................ 1 8 1
9. 2. 1. Statistical Met h o ds f or D ose Escalati o n/ De -Escalati o n ........................... 1 8 1
9. 2. 2. Statistical Met h o d f or Esti mati n g t he M T D/ M A D ................................... 1 8 2
9. 3. Sa m ple Size Deter mi nati o n ................................................................................... 1 8 3
9. 4. Efficac y  A nalys is .................................................................................................. 1 8 3
9. 5. A nal y sis of P har mac o ki netics a n d P har mac o d yna mics ........................................ 1 8 5
9. 5. 1. P F -0 6 8 6 3 1 3 5 P K A nal y sis ....................................................................... 1 8 5
9. 5. 2. L e nali d o mi de, P o mali d o mi de, a n d De xa met has o ne P har mac o ki netic 
A nal y sis ( Parts 1 C a n d 2 C, Parts 1 D a n d 2 D, Parts 1 E a n d 2 E as 
a p pr o priate) .................................................................................................... 1 8 5
9. 5. 3. P o p ulati o n P har mac o ki netic A nal ys is of P har mac o ki netics 
( P K)/ P har mac o dy n a mic M o deli n g ................................................................ 1 8 5
9. 5. 4. A nal y sis of Im m u n o ge nicit y ..................................................................... 1 8 5
9. 5. 5. A nal y sis of P har mac o d yna mics ................................................................ 1 8 6
9. 5. 6. A nal y sis of Bi o mar ker E n d p oi nts .............................................................1 8 6
9. 6. Safet y A nal ys is...................................................................................................... 1 8 6
9. 6. 1. A nal y sis of t he Pri mar y E n d p oi nt f or Part 1 ............................................ 1 8 6
9. 6. 2. A nal y sis of Sec o n dar y Safety E n d p oi nts .................................................. 1 8 6
9. 6. 2. 1. A d verse E ve nts ........................................................................ 1 8 6
9. 6. 2. 2. La b orat or y  Test A b n or malities ............................................... 1 8 7
9. 6. 2. 3. Electr ocar di o gra m ................................................................... 1 8 7
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 4 3
9. 7. I nteri m A nal ys is.................................................................................................... 1 8 8
9. 8. D ata M o nit ori n g C o m mittee ................................................................................. 1 8 9
1 0. Q U A LI T Y C O N T R O L  A N D Q U A LI T Y A S S U R A N C E ............................................... 1 8 9
1 1. D A T A H A N D LI N G A N D R E C O R D K E E PI N G ........................................................... 1 8 9
1 1. 1. Case Re p ort F or ms/ Electr o nic Data Rec or d ....................................................... 1 8 9
1 1. 2. Rec or d Rete nti o n ................................................................................................. 1 9 0
1 1. 3. Data Pr otecti o n .................................................................................................... 1 9 0
1 2. E T HI C S ............................................................................................................................ 1 9 1
1 2. 1. Re g ulat or y  a n d Et hical C o nsi derati o ns...............................................................1 9 1
1 2. 2. Patie nt I nf or mati o n a n d C o nse nt ......................................................................... 1 9 2
1 2. 3. Re p orti n g of Safet y I ss ues a n d Seri o us Breac hes of t he Pr ot oc ol or I CH 
G C P ......................................................................................................................... 1 9 2
1 3. D E FI NI TI O N O F E N D O F T RI A L ................................................................................. 1 9 3
1 3. 1. E n d of Trial i n All Partici pati n g C o u ntries ......................................................... 1 9 3
1 4. S P O N S O R DI S C O N TI N U A TI O N C RI T E RI A ..............................................................1 9 3
1 5. P U B LI C A TI O N O F S T U D Y R E S U L T S ........................................................................ 1 9 3
1 5. 1. Disse mi nati o n of Cli nical St u d y  Data................................................................. 1 9 3
1 5. 2. P u blicati o n P olic y ...............................................................................................1 9 4
1 6 . R E F E R E N C E S ................................................................................................................1 9 6
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 4 4
LI S T O F T A B L E S
Ta ble 1.
Ta ble of P ote ntial Fi xe d D ose Le vels .....................................................1 1 6
Ta ble 2.
Ta ble of P ote ntial D ose Le vels i n Part 1 I V A d mi nistrati o n .................. 1 1 9
Ta ble 3.
Ta ble of P ote ntial D ose Le vels i n Part 1 S C A d mi nistrati o n ................. 1 1 9
Ta ble 4.
Decisi o n R ules ........................................................................................ 1 2 0
Ta ble 5.
D ose M o dificati o ns f or P F -0 6 8 6 3 1 3 5 Pr o d uct -Relate d T o xicit y  an d 
f or Peri p heral Se ns or y or M ot or Ne ur o pat hy * * * ................................... 1 3 8
Ta ble 6.
Le nali d o mi de D ose A dj ust me nt f or T hr o m b oc y t o pe nia........................ 1 4 0
Ta ble 7.
Le nali d o mi de D ose A dj ust me nt f or Ne utr o pe nia................................... 1 4 0
Ta ble 8.
Le nali d o mi de D ose A dj ust me nt f or Re nal I m pair me nt .......................... 1 4 1
Ta ble 9.
D ose M o dificati o n I nstr ucti o ns f or P o mali d o mi de f or He mat ol o gic 
T o xicities ................................................................................................1 4 1
Ta ble 1 0.
D ose M o dificati o n I nstr ucti o ns f or De xa met has o ne T o xicities ............. 1 4 2
Ta ble 1 1.
Safet y  La b orat or y Tests.......................................................................... 1 5 5
Ta ble 1 2.
Bi o mar ker Assa y s a n d Sa m ple S o urces ................................................. 1 6 4
Ta ble 1 3.
Lee et al 2 0 1 4 C R S re vise d gra di n g s ys te m2 .......................................... 2 1 4
Ta ble 1 4.
Defi niti o n of Hi g h D ose Vas o press or ..................................................... 2 1 5
Ta ble 1 5.
A S T C T C R S re vise d gra di n g s ys te m3 .................................................... 2 1 5
Ta ble 1 6.
I m m u ne Effect or Cell-Ass ociate d E nce p hal o pat h y  (IC E) Sc ore ........... 2 1 8
Ta ble 1 7.
A S T C T I C A N S Gra di n g ......................................................................... 2 1 9
LI S T O F FI G U R E S
Fi g ure 1.
P F -0 6 8 6 3 1 3 5 Acti vit y  In Vitr o ................................................................. 9 8
Fi g ure 2.
P F -0 6 8 6 3 1 3 5 Acti vit y  i n a n O P M-2 M M Ort h otr o pi c T u m or M o del .....9 9
Fi g ure 3.
Efficac y  of P F-0 6 8 6 3 1 3 5 i n C o m bi nati o n wit h L e nali d o mi de i n 
M M. 1 S a n d M O L P- 8 Ort h ot o pic T u m or M o dels ................................... 1 0 0
Fi g ure 4.
C 1 0 7 1 0 0 1 St u d y  Desi g n.........................................................................1 1 0
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 4 5
A P P E N DI C E S
A p pe n di x 1. A B B R E VI A TI O N S ...........................................................................................2 0 1
A p pe n di x 2. T H E I N T E R N A TI O N A L M Y E L O M A W O R KI N G G R O U P (I M W G) 
R E S P O N S E C RI T E RI A F O R M U L TI P L E M Y E L O M A ...................... 2 0 9
A p pe n di x 3. I M W G MI NI M A L  R E SI D U A L DI S E A S E ( M R D) Criteria............................ 2 1 2
A p pe n di x 4. E C O G P E R F O R M A N C E S T A T U S ................................................................. 2 1 3
A p pe n di x 5. C R S A N D I C A N S MI TI G A TI O N A N D M A N A G E M E N T ............................ 2 1 4
A p pe n di x 6. I N T E R N A TI O N A L M Y E L O M A W O R KI N G G R O U P (I M W G) 
M U L TI P L E M Y E L O M A DI A G N O SI S C RI T E RI A 4 5 .......................... 2 2 4
A p pe n di x 7. M A N A G E M E N T O F I N F U SI O N R E L A T E D R E A C TI O N S, 
I N CL U DI N G A L L E R GI C R E A C TI O N S O R A N A P H Y L A XI S .......... 2 2 5
A p pe n di x 8. D E T AI L E D D O S E E S C A L A TI O N/ D E -E S C A L A TI O N S C H E M E F O R 
m T PI  D E SI G N........................................................................................ 2 2 7
A p pe n di x 9. S U B C U T A N E O U S I NJ E C TI O N SI T E L O C A TI O N S .................................... 2 3 0
A p pe n di x 1 0. Alter nati ve Meas ures D uri n g P u blic E mer ge ncie s ......................................... 2 3 1
A p pe n di x 1 1. Pr o hi bite d C o nc o mita nt Me dicati o ns w hic h ma y  Res ult i n Dr u g-Dr u g 
I nteracti o n ( D DI) ....................................................................................2 3 4
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 4 6
P R O T O C O L S U M M A R Y
B ac k gr o u n d a n d R ati o n ale
Des pite a n u m ber of rece nt treat me nt a d va nces f or M ulti ple M y el o ma ( M M), m ost patie nts 
are e x pecte d t o rela pse.  M M is n ot c o nsi dere d c ura ble a n d e ac h li ne of t hera p y re n ders t he 
patie nt m ore refract or y  t o treat me nt.  F or e xa m ple , t he me dia n o verall s ur vi val of patie nts 
wit h M M w h o rela pse d f oll o wi n g i m m u n o m o d ulat or y dr u g (IMi D ) a n d b ortez o mi b 
(Velca de ) t hera pies is 9 m o nt hs .1 It is t heref ore clear t hat a d diti o nal treat me nt a p pr oac hes 
are re q uire d f or rela pse d/refract or y  M M.
B y  directl y tar geti n g c yt ot o xic T-cells t o t u m ors, bis pecific a nti b o dies offer a n o vel 
i m m u n ot hera pe utic a p pr oac h f or ca ncer.  T hese a nti b o dies ha ve t w o se parate a nti ge n 
rec o g niti o n d o mai ns: a d o mai n t hat rec o g nizes a t u m or a nti ge n a n d a n ot her t hat rec o g nizes 
cl uster of differe ntiati o n ( C D ) 3 e x presse d o n T -cells.  Bis pecific a nti b o dies are t heref ore 
a ble t o si m ulta ne o usl y bi n d t o C D 3 a n d t he t u m or a nti ge n at t he sa me ti me, t here b y i nitiati n g 
a c yt ot o xic res p o nse t o war ds t he b o u n d t u m or cell.  P F-0 6 8 6 3 1 3 5 is a heter o di mer ic 
h u ma nize d f ull -le n gt h bis pecific a nti b o dy c o m prise d of o ne B -cell Mat urati o n A nti ge n 
( B C M A) bi n di n g ar m a n d o ne C D3 bi n di n g ar m paire d t hr o u g h hi n ge m utati o n tec h n ol o g y . 
Strate gies t o f urt her e n ha nce t he i m m u ne effects of P F- 0 6 8 6 3 1 3 5 ha ve bee n s u p p orte d b y  
pre -cli nical data s h o wi n g e n ha nce d t u m or gr o wt h i n hi biti o n b y c o m bi ni n g P F-0 6 8 6 3 1 3 5 wit h 
a n i m m u n o m o d ulat or y dr u g (I Mi D).
I n t his first i n patie nt ( FI P) cli nical st u d y, P F-0 6 8 6 3 1 3 5 will be e val uate d f or t he treat me nt of 
a d ult patie nts wit h rela pse d /refract ory m ulti ple m y el o ma, w h o ha ve recei ve d a pr oteas o me 
i n hi bit or, a n IMi D a n d a n a nti C D 3 8 m o n ocl o nal a nti b o d y ( m A b) eit her i n c o m bi nati o n wit h
le nali d o mi de, p o mali d o mi de , de xa met has o ne, or as a si n gle a ge nt.
St u d y Desi g n:
T his is a P hase 1 o pe n -la bel, m ulti -d ose, m ulti -ce nter, d ose escalati o n, safet y, 
p har mac o ki netic ( P K) a n d p har mac o d y n a mic st u d y of P F- 0 6 8 6 3 1 3 5 as m o n ot hera p y a n d i n 
c o m bi nati o n wit h le nali d o mi de , p o mali d o mi de or de xa met has o ne i n a d ult patie nts wit h 
a d va nce d M M
w h o ha ve rela pse d fr o m or are refract or y t o sta n dar d t hera p y.  T his st u d y  will 
be di vi de d i nt o d ose escalati o n /fi n di n g part ( Part 1) a n d d ose e x pa nsi o n part ( Part 2). 
Part 1 d ose escalati o n /fi n di n g ( wit h eit her m o n ot hera py or c o m b inati o n t hera pies) i n or der t o 
deter mi ne t he rec om me n de d P hase 2 d ose (R P 2 D ) is f urt her di vi de d i nt o :

Part 1 i ntra ve n o us (I V) m o n ot hera p y a n d Part 1 s u bc uta ne o us ( S C) m o n ot hera p y 
c o h orts as well as Part 1. 1 pri mi n g a n d mai nte na nce c o h ort s .

Part 1 C le nali d o mi de c o m bi nati o n, Part 1 D p o mali d o mi de c o m bi nati o n a n d Part 1 E 
de xa met has o ne c o m bi nati o n c o h orts. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 4 7
Part 2 d ose e x pa nsi o n p hase will be di vi de d i nt o 4 c o h orts as f oll o ws: 

Part 2 A ( P F -0 6 8 6 3 1 3 5 as m o n ot hera p y).

Part 2 C ( P F - 0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h le nali d o mi de).

Part 2 D ( P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h p o mali d o mi de) .

Part 2 E ( P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h de xa met has o ne).
After t he si n gle -a ge nt P F -0 6 8 6 3 1 3 5 ma xi m u m t olerate d d ose ( M T D) or ma xi m u m 
a d mi nistere d d ose ( M A D) a n d R P 2 D as well as prefer re d r o ute of a d mi nistrati o n has bee n 
dete r mi ne d i n t he Part 1 m o n ot hera p y  d ose escalati o n, safet y c o h orts e val uati n g 
c o m bi nati o ns of P F -0 6 8 6 3 1 3 5 wit h eit her le nali d o mi de, p o mali d o mi de or de xa met has o ne 
ma y  be i nitiate d i n Parts 1 C, 1 D or Part 1 E res pecti vel y.  F oll o wi n g i de ntificati o n of t he 
M T D / M A D a n d R P 2 D as m o n ot hera p y a n d i n eac h c o m bi nati o n c o h ort, d ose e x pa nsi o n
c o h orts testi n g m o n ot hera p y  a n d c o m bi nati o n s wit h le nali d o mi de , p o mali d o mi de or 
de xa met has o ne will be i nitiate d (e x pa nsi o n c o h orts Parts 2 A, 2 C , 2 D, or 2 E res pecti vely ).
I V a n d S C a d mi nistrati o n of P F - 0 6 8 6 3 1 3 5 will be e val uate d d uri n g t he Part 1 d ose 
escalati o n. A n alter nati ve mai nte na nce d ose escalati o n p hase ( Part 1. 1), w hic h i nc or p orates 
t he usa ge of a pri mi n g d ose d uri n g C y cle 0 D a y 1 ( C0 D 1) f oll o we d by a mai nte na nce d ose 
1 wee k later at C 1 D 1 f or all s u bse q ue nt d oses, ma y als o be i nitiate d. Part 1 will be 
i m ple me nte d as f oll o ws:

Part 1 I V st u dies escalati n g d oses of P F -0 6 8 6 3 1 3 5 a d mi nistere d i ntra ve n o usl y  
( 0. 1, 0. 3, 1, 3, 1 0, 3 0, 5 0 µ g/ k g or hi g her if i n dicate d ) wee kl y  (see Secti o n 3. 1. 1. 3 ).  
A d diti o nal d ose le vels (l o wer, i nter me diate or hi g her ) m a y  be e val uate d [see 
Secti o n 3. 1. 4 ].

After Part 1 I V 5 0 µ g/ k g d ose was cleare d , Part 1 S C a d mi nistrati o n (8 0, 1 3 0, 2 1 5, 
3 6 0, 6 0 0, a n d 1 0 0 0 µ g/ k g ) wee kly w as o pe ne d base d o n t he e mer gi n g cli nical a n d P K 
data fr o m Part 1 I V c o h orts (see Secti o n 3. 1. 1. 3 ). U p o n reac hi n g M T D/ M A D, u p t o 
6- 1 2 patie nts t otal at selecte d le vel(s) bel o w t he M T D/ M A D wee kly a n d Q 2 W d osi n g 
u p t o t he sa me d ose i nte nsit y as t he M T D/ M A D
wee kl y re gi me n m a y  be e val uate d 
f urt her t o s u p p ort t he R P 2 D decisi o n.

A n alter nati ve Part 1 . 1 pri mi n g a n d mai nte na nce d os i n g f or m o n ot hera p y  I V or S C
a d mi nistrati o n ma y be tri g gere d if ≥Gra de 3 c yt o ki ne release sy n dr o me ( C R S ) e ve nts
(lasti n g f or > 2 4 h o urs des pite treat me nt wit h sta n dar d of care per t he i nstit uti o n’s, 
I n vesti gat or’s, or treati n g p h ysicia n’s g ui deli nes f or t he ma na ge me nt of C R S) are
o bser ve d (see Secti o n 3. 1. 1. 3 ). A p ri mi n g d ose (C yc le 0) w o ul d be gi ve n o ne wee k 
pri or t o C ycle 1 of mai nte na nce d osi n g a n d i ncl u de a ma n dat or y o ver ni g ht 
h os pitalizati o n o n C 0 D 1. Alter nati ve strate g ies f or i ncreasi n g d osi n g s uc h as a 
ste p-u p re gi me n or pr o p h y lactic ster oi ds m a y  als o be c o nsi dere d a n d i m ple me nte d t o 
f urt her i m pr o ve t olera bilit y if nee de d.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 4 8

F or all patie nts i n m o n ot hera p y Part 1 c o h orts, t o cl osel y  ma na ge a n d m o nit or ac ute 
t o xicities, patie nts will be h os pitalize d o n C 1 D 1. T he nee d f or ma n dat or y  
h os pitalizati o n as well as its le n gt h will be re -assesse d f or patie nts e nr olle d i n Part 2 A 
base d o n safet y data fr o m Part 1 after a gree me nt of s p o ns or a n d i n vesti gat ors at t he 
ti me of m o n ot hera py M T D/ M A D a n d R P 2 D
deter mi nati o n .

A sta g gere d e nr oll me nt strate g y will be a p plie d f or all patie nts i n t he m o n ot hera p y 
Part 1 c o h ort at eac h d ose le vel: whe n a d ose le vel o pe ns f or e nr ol l me nt, t he 
first patie nt will be d ose d a n d o bser ve d f or 4 8 h o urs.   I n Part 1, if n o safety c o ncer ns 
arise d uri n g t his 4 8 hr peri o d fr o m start of treat me nt, t he n s u bse q ue nt patie nts will be 
e nr olle d i nt o t he sa me d ose le vel. I n Part 1. 1, if n o safety c o nce r ns arise 4 8 hrs after 
recei vi n g t he mai nte na nce d ose o n C 1 D1 , s u bse q ue nt patie nts will be e nr olle d i nt o 
t he sa me mai nte na nce d ose le vel.

All patie nts i n t he m o n ot hera py c o h orts of Part 1 will be m o nit ore d cl osel y f or d ose 
li miti n g t o xicities ( D LTs, see Secti o n 3. 2 ), u ntil t he e n d of C ycle 1 .  
Eit her I V or S C a d mi nistrati o n of P F - 0 6 8 6 3 1 3 5 eit her wit h or wit h o ut a pri mi n g d ose will be 
selecte d t o m o ve f or war d i n c o m bi nati o ns wit h le nali d o mi de, p o mali d o mi de , or 
de xa met has o ne.

Part 1 C will i n vesti gate P F- 0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h le nali d o mi de , Part 1 D will 
i n vesti gate P F-0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h p o mali d o mi de .

T h ese safety c o h ort s ( Parts 1 C a n d 1 D) will use a d ose -escalati o n/ de -escalati o n 
a p pr oac h f or P F -0 6 8 6 3 1 3 5 starti n g wit h t he d ose le vel M T D -1/ M A D -1 or R P 2 D 
( w hic he ver is l o wer) of P F-0 6 8 6 3 1 3 5 fr o m Part 1 d ose escalati o n c o m bi ne d wit h 
1 5 m g le nali d o mi de , or 4 mg p o mali d o mi de .  If safe a n d well t olerate d 
P F -0 6 8 6 3 1 3 5 will t he n be escalate d t o t he m o n ot hera p y M T D/ R P 2 D , if 
a p plica ble, a gai n i n c o m bi nati o n wit h 1 5 m g le nali d o mi de , or 4 m g p o mali d o mi de
i n or der t o select t he c o m bi nati o n R P 2 D.  I f t he c o m bi nati o n re gi me n is n ot well 
t olerate d d ue t o P F-0 6 8 6 3 1 3 5, P F - 0 6 8 6 3 1 3 5 m a y  be de -escalate d i n c o m bi nati o n 
acc or di n g t o m T PI desi g n.  Eac h c y cle of t he c o m bi nati o n of P F-0 6 8 6 3 1 3 5 a n d 
le nali d o mi de or p o mali d o mi de starti n g wit h C yc le 1 will be 2 8 d a y s. 

T o cl osel y  ma na ge ac ute t o xicities, patie nts will be h os pitalize d o n C 1 D 1.
T he 
nee d f or ma n dat or y  h os pitalizati o n as well as its le n gt h will be re -assesse d f or 
patie nts e nr olle d i n Parts 2 C a n d 2 D base d o n safet y  data fr o m Parts 1 C a n d 1 D, 
res pecti vely.

A sta g gere d e nr oll me nt strate g y  will be a p plie d f or Parts 1 C a n d 1 D: w he n a d ose 
le vel o pe ns f or e nr oll me nt, t he first patie nt wi ll be d ose d, a n d o bser ve d f or 
9 6 h o urs after C 1 D 1.  If n o safet y c o ncer ns arise d uri n g t his 9 6 hr peri o d fr o m 
C 1 D 1 , s u bse q ue nt patie nts will be e nr olle d i nt o t he sa me d ose le vel a n d 
c o m bi nati o n .
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 4 9

U p o n reac hi n g M T D/ M A D, u p t o a p pr o xi matel y 6- 1 2 patie nts t otal at selecte d 
le vel(s) bel o w t he M T D/ M A D ma y be e val uate d f urt her t o s u p p ort t he R P 2 D 
decisi o n .

Part 1 E will i n vesti gate P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h de xa met has o ne.  
De xa met has o ne w o ul d be gi n o n C 0 D 1 a n d it will be d ose d as pre me dicati o n pri or t o 
P F -0 6 8 6 3 1 3 5 a d mi nistrati o n .

T his safet y c o h ort will e val uate t he R P 2 D of P F -0 6 8 6 3 1 3 5 wit h de xa met has o ne at 
a d ose of 4 0 m g. F or s u bjects ol der t ha n 7 5 ye ars or u n der wei g ht ( b o d y mass 
i n de x [ B MI] < 1 8. 5), de xa met has o ne pre me dicati o n ma y be gi ve n pri or t o 
P F - 0 6 8 6 3 1 3 5 at a d ose of 2 0 m g. P F - 0 6 8 6 3 1 3 5 ma y  be de- escalate d acc or di n g t o 
m o difie d t o xicit y  pr o ba bilit y i nter val ( m T PI) desi g n. If t he c o m bi nati o n re gi me n 
is n ot well t olerate d as g ui de d b y m T PI, Part 2 E ma y n ot be i nitiate d. Eac h c y cle 
of t he c o m bi nati o n of P F -0 6 8 6 3 1 3 5 a n d de xa met has o ne starti n g wit h C ycle 1 will 
be 2 8 d a y s. 

T o cl osel y  ma na ge ac ute t o xicities, patie nts i n Part 1E will be h os pi talize d o n
C 1 D 1. T he nee d f or h os pitalizati o n as well as its le n gt h will be re- assesse d f or 
patie nts e nr olle d i n Part 2 E base d o n safet y data fr o m Part 1 E after a gree me nt of 
s p o ns or a n d i n vesti gat ors.

F or Part 1 E or Part 2 E , patie nts wit hi n t hese parts ma y  e nr oll c o nc urre ntl y.

It is e x pecte d t hat Part 1 E will e nr oll a p pr o xi matel y 9-1 6 patie nts .
A m o difie d t o xicit y  pr o ba bilit y i nter val ( m T PI) met h o d, tar getin g a D L T rate of 2 5 % a n d a n 
acce pta ble e q ui vale nce i nter val of 2 0 % - 3 0 % will be utilize d f or d ose escalati o n i n Part 1.  
All patie nts will als o be m o nit ore d cl osel y f or D L Ts u ntil t he e n d of C ycle 1. All patie nts 
will be m o nit ore d f or late t o xicities f oll owi n g t he i nitial D L T peri o d u p t o Da y 6 0 fr o m first 
d ose (see Secti o n 3. 2. 1 ).  O nce a d ose le vel has bee n declare d safe, patie nts at l o wer d ose 
le vels w h o ha ve c o m plete d t he 6 0 d a y  late t o xicit y o bser vati o n peri o d ma y escalate t o t he 
ne xt hi g her d ose le vel, if criteria o utli ne d i n Secti o n 3. 1. 4. 1 Criteria f or I ntra patie nt D ose
Escalati o n ha ve bee n met .  A d diti o nal i ntra -patie nt d ose escalati o ns will als o be per mitte d 
after a mi ni mal i nter val of 6 0 d a y s.  N o cr oss o ver is all o we d, h o we ver, bet wee n patie nts 
assi g ne d t o m o n ot hera p y P F - 0 6 8 6 3 1 3 5 a n d t he differe nt c o m bi nati o n re gi me ns.
F oll o wi n g t he deter mi nati o n s of t he R P 2 D of m o n ot hera p y a n d c o m bi nati o ns wit h 
le nali d o mi de or p o mali d o mi de i n Part 1, t he res pecti ve e x pa nsi o n c o h orts i n Part 2 will 
c o m me nce. I n a d diti o n, if t he c o m bi nati o n wit h de xa met has o ne i n Part 1 E is well t olerate d as 
g ui de d b y m T PI, Part 2 E ma y be i nitiate d.
Part 2 d ose e x pa nsi o n p hase will be di vi de d i nt o 4 c o h orts as f oll o ws: Part 2 A ( P F - 0 6 8 6 3 1 3 5 
as m o n ot hera p y), Part 2 C ( P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h le nali d o mi de) , Part 2 D 
( P F-0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h p o mali d o mi de ) a n d Part 2 E ( P F -0 6 8 6 3 1 3 5 i n 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 5 0
c o m bi nati o n wit h de xa met has o ne) w hic h will e val uate safet y a n d a nti -m y el o ma acti vit y of 
P F -0 6 8 6 3 1 3 5 at R P 2 Ds deter mi ne d i n Part 1 .
A p pr o xi matel y  1 2 0 patie nts ha d bee n pla n ne d t o e nr oll i nt o Parts 1/ 1 . 1, 1 C, 1 D, 1 E wit h
a p pr o xi matel y 8 0 patie nts pla n ne d t o e nr oll i nt o Part 2. Parts 1 C, 1 D a n d 1 E were pla n ne d t o 
e nr oll a p pr o xi matel y 9- 1 6 patie nts wit h P arts 2 A, 2 C , 2 D a n d 2 E pla n ne d t o e nr oll 
a p pr o xi matel y 2 0 patie nts eac h.
T he cli nical de vel o p me nt pr o gra m f or P F - 0 6 8 6 3 1 3 5 has bee n e x pa n de d wit h de dicate d 
st u dies t hat will f urt her i n vesti gate b ot h m o n ot hera p y a n d c o m bi nati o n t hera p y. Theref ore, 
t he S p o ns or has deter mi ne d t hat e nr ollme nt i n st u d y  C 1 0 7 1 0 0 1 has bee n c o m plete d.
St u d y O bjecti ves a n d E n d p oi nts
P art 1 I V a n d S C m o n ot her a p y D ose Esc al ati o n , P art 1 . 1 Pri mi n g a n d M ai nte n a nce 
D ose Esc al ati o n a n d P art s 1 C, 1 D a n d 1 E C o m bi n ati o n D ose Esc al ati o n/ Fi n di n g
Pri m ar y O bjecti ves: 
Pri m ar y E n d p oi nts: 

T o assess safet y a n d t olera bilit y at i ncreasi n g 
d ose le vels of P F -0 6 8 6 3 1 3 5 as m o n ot hera p y 
a n d i n c o m bi nati o n wit h le nali d o mi de,
p o m ali d o mi de, or d e xa met has o ne i n 
s uccessi ve c o h orts of patie nts wit h m ulti ple 
m yel o ma i n or der t o esti mate t he Ma xi m u m 
T ol erate d D ose ( M T D) or Ma xi m u m 
A d mi nistere d D ose ( M A D) a n d select t he 
Rec o m me n de d P hase 2 D ose ( R P 2 D).

N u m ber of D L Ts f oll o wi n g treat me nt wit h 
escalati n g d oses of P F -0 6 8 6 3 1 3 5 as 
m o n ot hera p y a n d i n c o m bi nati o n wit h 
le nali d o mi de, p o m ali d o mi de , or de xa met has o ne .
Sec o n d ar y O bjecti ves: 
Sec o n d ar y E n d p oi nts: 

T o e val uate t he o verall safet y pr ofile. 

A d verse E ve nts as c haracterize d b y t y pe, 
fre q ue nc y, se verit y as gra de d b y Nati o nal 
Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts ( N CI C T C A E) versi o n 4. 0 3, 
ti mi n g, seri o us ness, a n d relati o ns hi p t o 
P F -0 6 8 6 3 1 3 5 as m o n ot hera p y a n d i n 
c o m bi nati o n wit h le nali d o mi de, p o m ali d o mi de ,
or de xa met has o ne .  T he se verit y of c yt o ki ne 
release s y n dr o me ( C R S) will be assesse d 
acc or di n g t o t he gra di n g descri be d b y Lee et al. 
( 2 0 1 4 a n d 2 0 1 9 ,2 ,3 See A p pe n di x 5 );

La b orat or y a b n or malities as c haracterize d b y 
t ype, fre q ue nc y, se verit y (as gra de d b y N CI 
C T C A E versi o n 4. 0 3), a n d ti mi n g.

T o e val uate a nti -m yel o ma acti vit y of  
P F -0 6 8 6 3 1 3 5 as m o n ot hera p y a n d i n 
c o m bi nati o n wit h le nali d o mi de,
p o m ali d o mi de, or d e xa met has o ne.

O bjecti ve res p o nse rate ( O R R) usi n g t he 
i nter nati o nal m yel o ma w or ki n g gr o u p (I M W G) 
res p o nse criteria f or m ulti ple m yel o ma4 ,5 (see 
A p pe n di x 2 );

Ti m e t o e ve nt e n d p oi nts: ti me t o res p o nse 
(T T R ), c o m plete res p o nse rate ( C R R), d urati o n 
of res p o nse (D O R ), d urati o n of c o m plete 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 5 1
res p o nse ( D o C R), d urati o n of sta ble disease 
(D O S D ), pr o gressi o n -free s ur vi val (P F S ), 
o verall s ur vi val ( O S ), as assesse d b y I M W G 
criteria f or res p o nse 4 ,5 (see A p pe n di x 2 );

Rate of patie nts wit h n o mi ni mal resi d ual disease 
( M R D) after treat me nt wit h P F-0 6 8 6 3 1 3 5 usi n g 
I M W G M R D criteria5 (see A p pe n di x 3 ).

T o e val uate si n gle d ose a n d m ulti ple d ose P K 
of P F -0 6 8 6 3 1 3 5 gi ve n as m o n ot hera p y a n d i n 
c o m bi nati o n wit h le nali d o mi de ,p o m ali d o mi de,
a n d de xa met has o ne . A d diti o nall y, P K of 
le nali d o mi de, p o m ali d o mi de, a n d 
de xa met has o ne will be e val uate d w he n 
c o m bi ne d wit h P F -0 6 8 6 3 1 3 5 ( Parts 1 C , 1 D ,
a n d 1 E , res pecti vel y).

P har m ac o ki netic para meters of P F -0 6 8 6 3 1 3 5 : 
C y cle 1 Da y 1 d ose a n d C ycle 2 Da y 1 d ose 
ma xi m u m c o nce ntrati o n ( C ma x ), area u n der t he 
c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o 
t o t he last q ua ntifia ble ti me p oi nt pri or t o t he 
ne xt d ose ( A U C last) a n d if data per mit, cleara nce 
( C L) or cleara nce after n o n -i ntra ve n o us 
a d mi nistrati o n ( C L/ F ), v ol u me of distri b uti o n at 
stea d y state ( Vss) or a p pare nt v ol u me of 
distri b uti o n after o n -i ntra ve n o us a d mi nistrati o n 
(Vss/ F ), a n d ter mi nal eli mi nati o n t 1/ 2.

P las ma le nali d o mi de, p o mali d o mi de, a n d 
de xa met has o ne c o nce ntrati o ns at selecte d ti me 
p oi nts ( Parts 1 C, 1 D, a n d 1 E , res pecti vel y).

T o e val uate i m m u n o ge nicit y of  P F -0 6 8 6 3 1 3 5
as m o n ot hera p y a n d i n c o m bi nati o n wit h 
le nali d o mi de,  p o m ali d o mi de , or 
de xa met has o ne, .

I nci de nce a n d titers of a nti-dr u g a nti b o dies 
( A D A) a n d ne utralizi n g a nti b o dies ( Na b ) a gai nst 
P F -0 6 8 6 3 1 3 5 .

T o c haracterize t he i m pact of P F -0 6 8 6 3 1 3 5 as 
a mo n ot hera p y a n d i n c o m bi nati o n wit h 
le nali d o mi de, p o m ali d o mi de, or 
de xa met has o ne o n s yste mic s ol u ble i m m u ne 
fact ors.

Pre - a n d p ost-d ose q ua ntificati o n of s ol u ble 
c yt o ki nes i n ser u m.
Terti ar y/ E x pl or at or y O bjecti ves: 
Terti ar y/ E x pl or at or y E n d p oi nts: 

E val uate t he effect of P F -0 6 8 6 3 1 3 5 as a 
m o n o t hera p y a n d i n c o mbi n ati o n wit h 
le nali d o mi de, p o m ali d o mi de, or 
de xa met has o ne o n plas ma cell, T a n d B cell 
c o m part me nts.

B C M A e x pressi o n o n plas ma cell s i n b o ne 
marr o w , as assesse d b y m ulti para meter fl o w 
c yt o metr y a n d i m m u n o hist oc he mistr y;

Pre - a n d p ost-d ose le vels of s ol u ble B C M A;

E n u merati o n of T, B, a n d nat ural killer ( N K )
s u bt y pes i n w h ole bl o o d a n d b o ne marr o w b y 
fl o w c yt o metr y a nal ysis;

T- cell i m m u n o p he n ot y pi n g, i ncl u di n g b ut n ot 
li mite d t o pr oliferati o n a n d acti vati o n mar kers i n 
w h ole bl o o d a n d b o ne marr o w b y fl o w 
c yt o metr y a nal ysis;

T- cell e n ga ge me nt, i ncl u di n g b ut n ot li mite d t o 
pr oliferati o n a n d acti vati o n mar kers i n b o ne 
marr o w  b y i m m u n o hist oc he mistr y;

T he relati ve e x pressi o n of (ri b o n ucleic aci d) 
R N A tra nscri pts, i ncl u di n g b ut n ot li mite d t o, 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 5 2
t h ose ass ociate d wit h i mm u ne acti vati o n a n d 
i m m u ne re g ulati o n i n b o ne marr o w;

T he a b u n da nce a n d di versit y of T -cell cl o nes i n 
b o ne marr o w .

T o c ollect ba n ke d bi os peci me ns f or 
e x pl orat or y researc h, u nless pr o hi bite d b y 
l ocal re g ulati o ns or et hics c o m mittee decisi o n.  

C ollecti o n of ba n ke d bi os peci me ns u nless 
pr o hi bite d b y l ocal re g ulati o ns or et hics 
c o m mittee decisi o n.  A d diti o nal i nf or mati o n o n 
c ollecti o n a n d p ote ntial use is pr o vi de d i n t he 
Ba n ke d Bi os peci me ns Secti o n 7. 7 .
P art 2 D ose E x p a nsi o n
Pri m ar y O bjecti ves: 
Pri m ar y E n d p oi nts: 

T o assess preli mi nar y cli nical efficac y at 
R P 2 D f or P F-0 6 8 6 3 1 3 5 as m o n ot hera p y a n d
i n c o m bi nati o n wit h le nali d o mi de,  
p o m ali d o mi de, or de xa met has o ne .

O R R a n d D O R , as assesse d b y I M W G criteria 
f or res p o nse4 ,5 (see A p pe n di x 2 )
Sec o n d ar y O bjecti ves: 
Sec o n d ar y E n d p oi nts: 

T o f urt her c haracterize t he safet y a n d 
t olera bilit y of P F-0 6 8 6 3 1 3 5 as m o n ot hera p y 
a n d i n c o m bi nati o n wit h le nali d o mi de, 
p o m ali d o mi de, or de xa met has o ne .

A d verse E ve nts as c haracterize d b y t y pe, 
fre q ue nc y, se verit y (as gra de d b y N CI C T C A E 
versi o n 4. 0 3), ti mi n g, seri o us ness, a n d 
relati o ns hi p t o P F -0 6 8 6 3 1 3 5 as m o n ot hera p y a n d 
i n c o m bi nati o n wit h le nali d o mi de, 
p o m ali d o mi de, or de xa met has o ne . T he se verit y 
of C R S will be assesse d acc or di n g t o t he gra di n g 
descri be d b y Lee et al. ( 2 0 1 4 a n d 2 0 1 9 ,2 ,3 See 
A p pe n di x 5 );

La b orat or y a b n or malities as c haracterize d b y 
t ype, fre q ue nc y, se verit y (as gra de d b y N CI 
C T C A E versi o n 4. 0 3), a n d ti mi n g.

T o f urt her e val uate a nti -m yel o ma efficac y of 
P F -0 6 8 6 3 1 3 5 as m o n ot hera p y a n d i n 
c o m bi nati o n wit h le nali d o mi de, 
p o m ali d o mi de, or de xa met has o ne .

Ti m e t o e ve nt e n d p oi nts: C R R, D o C R, T T R, 
D O S D, P F S, O S, as assesse d b y I M W G criteria 
f or res p o nse4 ,5 (see A p pe n di x 2 );

Rate of patie nts wit h n o mi ni mal resi d ual diseas e 
( M R D) after treat me nt wit h P F-0 6 8 6 3 1 3 5 usi n g 
I M W G M R D criteria5 (see A p pe n di x 3 ).

T o e val uate P K of P F -0 6 8 6 3 1 3 5 at R P 2 D as 
m o n ot hera p y a n d i n c o mbi nati o n wit h 
le nali d o mi de, p o mali d o mi de, or 
de xa met has o ne . A d diti o nall y, t o c ollect 
le nali d o mi de, p o mali d o mi de, or 
de xa met has o ne c o nce ntrati o n data whe n 
c o m bi ne d wit h P F -0 6 8 6 3 1 3 5.

C o nce ntrati o ns of P F -0 6 8 6 3 1 3 5 , le nali d o mi de, 
p o m ali d o mi de, or de xa met has o ne f or selecte d 
ti me p oi nts. 

T o e val uate i m m u n o ge nicit y of  P F -0 6 8 6 3 1 3 5
as m o n ot hera p y a n d i n c o mbi nati o n wit h 

I nci de nce a n d titers of a nti-dr u g a nti b o dies 
( A D A a n d ne utralizi n g a nti b o dies ( Na b ) a gai nst 
P F -0 6 8 6 3 1 3 5 .
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 5 3
le nali d o mi de, p o mali d o mi de, or 
de xa met has o ne .

T o c haracterize t he i m pact of P F -0 6 8 6 3 1 3 5 as 
m o n ot hera p y a n d i n c o m bi nati o n wit h 
le nali d o mi de, p o m ali d o mi de or 
de xa met has o ne o n s yste mic s ol u ble i m m u ne 
fact ors.

Pre - a n d p ost-d ose q ua ntificati o n of s ol u ble 
c yt o ki nes i n ser u m.
Terti ar y/ E x pl or at or y O bjecti ves: 
Terti ar y/ E x pl or at or y E n d p oi nts: 

E val uate t he effect of P F -0 6 8 6 3 1 3 5 as 
m o n ot hera p y a n d i n c o m bi nati o n wit h 
le nali d o mi de, p o m ali d o mi de, or 
de xa met has o ne o n plas ma cell, T a n d B cell 
c o m part me nts.

B C M A e x pressi o n o n plas ma cells i n b o ne 
marr o w , as assesse d b y m ulti para meter fl o w 
c yt o metr y a n d i m m u n o hist oc he mistr y;

Pre - a n d p ost-d ose le vels of s ol u ble B C M A;

E n u merati o n of T, B, a n d N K s u bt y pes i n w h ole 
bl o o d a n d b o ne marr o w b y fl o w c yt o metr y 
a nal ysis ;

T- cell i m m u n o p he n ot y pi n g, i ncl u di n g b ut n ot 
li mite d t o pr oliferati o n a n d acti vati o n mar kers i n 
w h ole bl o o d a n d b o ne marr o w b y fl o w 
c yt o metr y a nal ysis;

T- cell e n ga ge me nt, i ncl u di n g b ut n ot li mite d t o 
pr oliferati o n a n d acti vati o n mar kers i n b o ne 
marr o w  b y i m m u n o hist oc he mistr y;

T he relati ve e x pressi o n of R N A tra nscri pts, 
i ncl u di n g b ut n ot li mite d t o, t h ose ass ociate d 
wit h i m m u ne acti vati o n a n d i m m u ne re g ulati o n 
i n b o ne marr o w;

T he a b u n da nce a n d di versit y of T -cell cl o nes i n 
b o ne marr o w .

T o c ollect ba n ke d bi os peci me ns f or 
e x pl orat or y researc h, u nless pr o hi bite d b y 
l ocal re g ulati o ns or et hics c o m mittee decisi o n.  

C ollecti o n of ba n ke d bi os peci me ns u nless 
pr o hi bite d b y l ocal re g ulati o ns or et hics 
c o m mittee decisi o n.  A d diti o nal i nf or mati o n o n 
c ollecti o n a n d p ote ntial use is pr o vi de d i n t he 
Ba n ke d Bi os peci me ns Secti o n 7. 7 .
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M








P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 5 7
Sc he d ule of Acti vities A
Visit I de ntifier
Scree ni n g 1
D a ys pri or t o 
e nr oll me nt
Tre at m e nt Peri o d
1 m o nt h 
F oll o w -u p 3 5
S ur vi v al 
F oll o w -u p 3 7
C ycle 1
( 1 C ycle = 3 
wee ks)
C ycle 2
C ycle 3 
o n w ar ds
E O T 3 6
St u d y D a y
-2 8 t o - 1 
-1 4 
t o - 1
1
2
3
4 * 8
1 5 1
4 * 8
1 5 1
8
1 5
Visit Wi n d o w ( d a ys)
± 1 ± 1 ± 1 ± 1
± 1 ± 2 ± 2 ± 2 ± 2
+ 7
± 1 4
p ol y merase c hai n reacti o n; R N A = ri b o n ucleic aci d; SI F E = ser u m i m m u n ofi xati o n electr o p h oresis; S P E P = ser u m pr otei n electr o p h oresis; T C R = T-cell 
rece pt or; T B N K = T, B, a n d N K l y m p h oc ytes; UI F E = 2 4 hr uri ne i m m u n ofi xati o n electr o p h oresis ; U P E P = 2 4 hr uri ne pr otei n electr o p h oresis.
* P lease see Sc he d ule o f P har mac o ki netic, S ol u ble Fact or a n d C yt o ki ne Assess me nts A f or a d diti o nal assess me nts o n C ycle 1 Da y 4 ( C 1 D 4) a n d C ycle 2 Da y 4 
( C 2 D 4).
F o ot n otes f or Sc he d ule of Acti vities A
1.
Scree ni n g: T o be c o m plete d wit hi n 2 8 da ys pri or t o start of st u d y treat me nt.
2.
I nf or me d C o nse nt: M ust be o btai ne d pri or t o u n der g oi n g a n y st u d y s pecific pr oce d ures, a n d be c o m plete d wit hi n 2 8 da ys pri or t o start of st u d y treat me nt.
3.
M y el o m a H ist or y: wi ll be c ollecte d wit hi n 2 8 da ys d uri n g scree ni n g pri or t o start of st u d y treat me nt.  I ncl u des hist or y of disease u n der st u d y i ncl u di n g 
details of pri mar y dia g n osis, bi o ps y i nf or mati o n, a n d treat me nt hist or y.
4.
Me dic al Hist or y:
I ncl u des hist or y of disease pr ocess ot her t ha n t he ca ncer u n der st u d y (acti ve or res ol ve d) a n d c o nc urre nt ill ness.  I ncl u des pri or 
treat me nts a n d a n y c urre nt me dical treat me nts f or a n y c o n diti o n.
5.
B aseli ne Si g ns & S y m pt o ms: Patie nts will be as ke d a b o ut a n y si g ns a n d s y m pt o ms e x perie nce d w it hi n t he 2 8 da ys pri or t o C 1 D 1.  D uri n g t he st u d y, a n y 
ne w or w orse ne d c o n diti o ns s i nce baseli ne will be rec or de d o n t he A d verse E ve nts ( A E) case re p ort f or m ( C R F) pa ge. 
6.
Re gistr ati o n : Patie nt n u m ber a n d d ose le vel all ocati o n assi g ne d b y Pfizer I nc. 
7.
P atie nt h os pit aliz ati o n: All patie nts i n Part 1 I V or S C m o n ot hera p y d ose escalati o n wil l be h os pitalize d f or 7 2 hrs fr o m C ycle 1 Da y 1 ( C 1 D 1).  
H os pitalizati o n peri o d ma y be e xte n de d if t he patie nt e x perie nces a b n or mal la b orat or y fi n di n gs or o n g oi n g a d verse e ve nts t hat
re q uire f urt her 
h os pitalizati o n.
8.
P h ysic al e x a mi n ati o n ( P E): P h y sical e xa mi nati o n i ncl u des ne ur ol o gical assess me nt a n d, at scree ni n g , will als o i ncl u de hei g ht.
9.
Wei g ht:
Wei g ht will be meas ure d pri or t o d osi n g.
1 0. Vit al Si g ns: I ncl u des te m perat ure ( oral, t y m pa nic, te m p oral or a xillar y), bl o o d press ure ( B P), a n d p ulse rate t o be rec orde d i n t he sitti n g p ositi o n after 
5 mi n utes of rest.
1 1. Perf or m a nce St at us: Use Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) – see A p pe n di x 4 .
1 2. 1 2 -Le a d el ectr oc ar di o gr a m ( E C G): At scree ni n g, si n gle 1 2-lea d E C G will be perf or me d.  O n C 1 D 1 u ntil C 2 D 1 5, tri plicate 1 2-lea d E C Gs will be 
perf or me d t o deter mi ne mea n Q Tc F i nter val.  O n Da y 1, 8 , a n d 1 5 of C ycles 1 a n d 2, E C Gs will be perf or me d pri or t o i n vesti gati o nal pr o d uct 
a d mi nistrati o n ( u p t o 6 0 mi n utes bef ore d osi n g), a n d t he e n d of i nf usi o n or s u bc uta ne o us i njecti o n.  F or s u bc uta ne o us a d mi nistrati o n o nl y, tri plicate 1 2 -lea d 
E C Gs will als o be perf or me d o n Da y 4 of C ycles 1 a n d 2.  Fr o m C ycle 3 o n war ds, si n gle 1 2 -lea d E C G will be perf or me d o n Da y 1 of eac h c ycle pri or t o 
i n vesti gati o nal pr o d uct a d mi nistrati o n ( u p t o 6 0 mi n utes bef ore d osi n g).  W he n c oi nci di n g wit h bl o o d sa m ple dra ws f or p har maco ki netics ( P K), E C G 
assess me nt s h o ul d be perf or me d pri or t o bl o o d sa m ple c ollecti o n, s uc h t hat t he bl o o d sa m ple is c ollecte d at t he n o mi nal ti me.  If t he mea n Q Tc F is 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 5 8
Sc he d ule of Acti vities A
Visit I de ntifier
Scree ni n g 1
D a ys pri or t o 
e nr oll me nt
Tre at m e nt Peri o d
1 m o nt h 
F oll o w -u p 3 5
S ur vi v al 
F oll o w -u p 3 7
C ycle 1
( 1 C ycle = 3 
wee ks)
C ycle 2
C ycle 3 
o n w ar ds
E O T 3 6
St u d y D a y
-2 8 t o - 1 
-1 4 
t o - 1
1
2
3
4 * 8
1 5 1
4 * 8
1 5 1
8
1 5
Visit Wi n d o w ( d a ys)
± 1 ± 1 ± 1 ± 1
± 1 ± 2 ± 2 ± 2 ± 2
+ 7
± 1 4
pr ol o n ge d ( > 5 0 0 msec), t he E C Gs s h o ul d be re -e val uate d b y a q ualifie d pers o n at t he i nstit uti o n f or c o nfir mati o n.  A d diti o nal tri plicate E C Gs ma y be 
perf or me d as cli nicall y i n dicate d. 
1 3. Ec h oc ar di o gr a m  ( Ec h o) or m ulti g ate d ac q uisiti o n sc a n ( M U G A): Ec h o or M U G A will be e val uate d i n patie nts wit h pre vi o us hist or y of car diac e ve nts.  
F or t hese patie nts, a n Ec h o or M U G A will be perf or me d at scree ni n g, w he n cli nicall y i n dicate d a n d at t he e n d of treat me nt ( E O T) visit.
1 4. H e m at ol o g y : N o nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 3 d a y s pri or t o t hat date.  All sa m ples will be c ollecte d pri or t o 
i n vesti gati o nal pr o d uct a d mi nistrati o n o n da ys w here b y i n vesti gati o nal pr o d uct is t o be a d mi nistere d.  See Assess me nts Secti o n 7. 1. 3 f or La b orat or y Tests 
list.
1 5. Bl o o d C he m istr y: N o nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 3 da ys pri or t o t hat date.  All sa m ples will be c ollecte d pri or t o 
i n vesti gati o nal pr o d uct a d mi nistrati o n o n da ys w here b y i n vesti gati o nal pr o d uct is t o be a d mi nistere d.  See Assess me nts Secti o n 7. 1. 3 f or La b orat or y Tests 
list.
1 6. C o a g ul ati o n : N o nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 3 d a y s pri or t o t hat date.  All sa m ples will be c ollecte d pri or t o 
i n vesti gati o nal pr o d uct a d mi nistrati o n o n da ys w here b y i n vesti gati o nal pr o d uct is t o be a d mi nistere d.  See Assess me nts Secti o n 7. 1. 3 f or La b orat or y Tests 
list.
1 7. He p atitis assess me nt : Scree ni n g tests f or he patitis B ( H B V) a n d C ( H C V) s h o ul d be perf or me d i ncl u di n g he patitis B s urface a nti ge n ( H Bs A g), he patiti s B 
c ore a nti b o d y ( H Bc A b), a n d he patitis C vir us ( H C V) a nti b o d y.  I n t he case of a p pare nt o n g oi n g H B V or H C V i nfecti o n, refle x ser u m D N A or R N A viral 
l oa d testi n g, res pecti vel y, will be perf or me d.  See Assess me nts Secti o n 7. 1. 3 f or La b orat or y Tests list.
1 8. M ulti ple x c yt o ki ne ass a ys : see S C H E D U L E O F P H A R M A C O KI N E TI C, S O L U B L E F A C T O R A N D C Y T O KI N E acti vities A ta ble.  See assess me nts
Secti o n 7. 5. 4 f or la b orat or y tests list.
1 9. Uri n al ysis : Di pstic k is acce pta ble.  Micr osc o pic a nal yses if di pstic k a b n or mal.  N o nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 3 da ys 
pri or t o t hat date.  F oll o wi n g C 1 D 1, o nl y o btai n as cli nicall y i n dicate d u ntil E O T.  See Assess me nts Secti o n 7. 1. 3 f or La b orat or y Tests list.
2 0. Pre g n a nc y Test a n d c o ntr ace pti o n c hec k :  Ser u m pre g na nc y test f or fe males of c hil d beari n g p ote ntial (see Pre g na nc y Testi n g Secti o n 7. 1. 1 ).  
C o ntrace pti o n use will be c hec ke d t o c o nfir m t hat c o ntrace pti o n is use d t hr o u g h o ut t he st u d y a n d f or 5 m o nt hs after t he last d ose of st u d y treat me nt 
c o nsiste ntl y a n d c orrectl y. C o ntrace pti o n o nl y re q uire d f or W O C B P.
2 1. Tre at m e nt wit h i n vesti g ati o n al pr o d uct P F -0 6 8 6 3 1 3 5 : I n vesti gati o nal pr o d uct will be a d mi nistere d o n Da y 1, 8 a n d 1 5 of eac h c ycle (see A d mi nistrati o n 
Secti o n 5. 4 ). If a patie nt has recei ve d treat me nt wit h e ver y wee k d osi n g ( Q 1 W) P F-0 6 8 6 3 1 3 5 f or at least 6 m o nt hs, a n d disease assess me nts ha ve re mai ne d 
sta ble o ver at least 2 m o nt hs, c o nsi derati o n may be gi ve n t o i ncreasi n g d ose i nter vals fr o m wee kl y t o e ver y 2 w ee ks or o nce e ver y t hree wee ks ( o nce per 
c ycle; o nl y C X D 1 d osi n g a n d acti vities a p plica ble) after c o ns ultati o n wit h s p o ns or.  C ycles wo ul d re m ai n t he sa me le n gt h wit h a n y s ki p pe d w ee kl y d oses 
n ote d.  If t he patie nt s u bse q ue ntl y be gi ns t o ha ve i ncrease of disease b ur de n, d ose i nter vals s h o ul d ret ur n t o wee kl y d osi n g.
2 2. Ser u m i m m u n ofi x ati o n electr o p h oresis ( SI F E), ser u m  pr otei n electr o p h oresis ( S P E P), ser u m free li g ht c h ai n a n al ysis ( F L C) tests a n d bet a -2 
mi cr o gl o b uli n tests : N o nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 3 da ys pri or t o t hat date.  See Assess me nts Secti o n 7. 2. 1 f or 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 5 9
Sc he d ule of Acti vities A
Visit I de ntifier
Scree ni n g 1
D a ys pri or t o 
e nr oll me nt
Tre at m e nt Peri o d
1 m o nt h 
F oll o w -u p 3 5
S ur vi v al 
F oll o w -u p 3 7
C ycle 1
( 1 C ycle = 3 
wee ks)
C ycle 2
C ycle 3 
o n w ar ds
E O T 3 6
St u d y D a y
-2 8 t o - 1 
-1 4 
t o - 1
1
2
3
4 * 8
1 5 1
4 * 8
1 5 1
8
1 5
Visit Wi n d o w ( d a ys)
± 1 ± 1 ± 1 ± 1
± 1 ± 2 ± 2 ± 2 ± 2
+ 7
± 1 4
la b orat or y disease assess me nt tests list.  Beta 2 micr o gl o b uli n will be c ollecte d o n C 1 D 1 ( ot her ti me p oi nts are o pti o nal).  N ote t hat SI F E will o nl y be 
c o m plete d at baseli ne w he n electr o p h oresis s h o ws n o meas ura bl e pr otei n, at s us pecte d C R, a n d at s us pecte d pr o gressi o n (cli nical or bi oc he mical).  W he n a 
c o m plete res p o nse ( C R) or a cli nical or bi oc he mical pr o gressi o n is s us pecte d, S P E P, SI F E, a n d ser u m free li g ht c hai n a nal ysis ( F L C) tests will be re peate d 
wit hi n 1 t o 4 we e ks.  F or patie nts sc he d ule d t o be d ose escalate d, sa m ples will als o be c ollecte d w it hi n 1 wee k pri or t o recei vi n g t he firs t hi g her d ose.  All 
sa m ples will be c ollecte d pri or t o i n vesti gati o nal pr o d uct a d mi nistrati o n o n da ys w here b y i n vesti gati o nal pr o d uct is t o be a d mi nistere d.   If patie nts were 
treate d wit h darat u m u ma b less t ha n 1 1 4 da ys pri or t o pla n ne d treat me nt da y, darat u m u ma b will i nterfere wit h S P E P, U P E P, SI F E a n d UI F E assa ys.  
T heref ore, f or t hese patie nts, F L C assa y s h o ul d be c o m plete d at scree ni n g, C 1 D 1, a n d all s u bse q ue nt disease assess me nts. I n t hese patie nts w h o pre vi o usl y 
recei ve d darat u m u ma b ser u m a n d uri ne M-s pi ke if meas ura ble at baseli ne i n t hese patie nts s h o ul d als o be f oll o we d at t he sa me ti me p oi nts as F L C wit h t he 
m o st re prese ntati ve mar ker of disease stat us use d f or deter mi nati o n I M W G assess me nt.
2 3. 2 4 hr uri ne i m m u n ofi x ati o n electr o p h oresis ( UI F E), 2 4 hr uri ne pr otei n electr o p h oresis ( U P E P) : N o nee d t o re peat o n C 1 D 1 if baseli ne assess me nt 
perf or me d wit hi n 3 d a y s pri or t o t hat date.  See Assess me nts Secti o n 7. 2. 1 f or la b orat or y disease assess me nt tests list.  N ote t hat UI F E will o nl y be 
c o m plete d at baseli ne w he n electr o p h oresis s h o ws n o meas ura ble pr otei n, at s us pecte d C R, a n d at s us pecte d pr o gres si o n (cli nical or bi oc he mical).  W he n a 
C R or a cli nical or bi oc he mical pr o gressi o n is s us pecte d, U P E P a n d UI F E will be re peate d wit hi n 1 t o 4 w ee ks.  F or patie nts s c he d ule d t o be d ose escalate d, 
sa m ples will als o be c ollecte d wit hi n 1 wee k pri or t o recei v i n g t he first hi g her d ose.  If sa m ples c ollecti o n da y c oi nci des wit h da ys w here b y i n vesti gati o nal 
pr o d uct is t o be a d mi nistere d, sa m ples will be c ollecte d pri or t o i n vesti gati o nal pr o d uct a d mi nistrati o n.
2 4. B o ne M arr o w C ollecti o n a n d Assess me nts : F or C 1 D 1 a n d o n treat me nt b o ne marr o w c ollecti o ns a n d assess me nts, see- Secti o n 7. 2. 2 .  Sa m ple f or C ycle 1 
D a y 1 ( C 1 D 1) ma y be ta ke n u p t o 7 da ys bef ore st u d y treat me nt.   B o ne marr o w  c ollecti o ns a n d l ocal plas ma cell assess me nts s h o ul d be fi xe d acc or di n g t o 
t he cale n dar, re gar dless of treat me nt dela ys.  B o ne marr o w  e val uati o n c o nsisti n g of b o ne marr o w as pirate a n d/ or b o ne marr o w bi o psies will be perf or me d t o 
f oll o w disease res p o nse.  W he n b o ne marr o w plas macell i nfiltrati o n is assesse d b y b ot h b o ne marr o w as pirate a n d b y b o ne marr o w bi o ps y, t he hi g hest 
val ue of b o ne marr o w  -plas macell i nfiltrati o n s h o ul d be utilize d f or res p o nse e val uati o n.  B o ne marr o w  as pirates will als o be c ollecte d a n d plas ma cells will 
be e val uate d at ti me of s us pecte d c o m plete res p o nse ( C R) a n d o pti o nal at ti me of s us pecte d disease pr o gressi o n.  B o ne marr o w  bi o ps y will als o be c ollecte d 
a n d plas ma cells will be e val uate d w he n c o nfir mati o n of stri n ge nt c o m plete res p o nse (s C R -) is re q uire d.  F or patie nts w h o e x perie nce a platea u or C R, 
a d diti o nal B M as pirates at 9 m o nt hs after C 1 D 1 a n d o n war ds w ill be o pti o nal.  O pti o nal b o ne marr o w as pirate a n d bi o ps y sa m ples will als o be ta ke n at 
disease pr o gressi o n if a sa m ple w as n ot ta ke n wit hi n t he past 4 wee ks.  If a patie nt is sc he d ule d f or escalati o n t o t he ne xt hi g hest d ose le vel c o h ort f oll o w i n g 
6 0 da y late t o xicit y e val uati o n, a b o ne marr o w as pirate will be c ollecte d w it hi n 1 wee k bef ore d ose escalati o n, u nless a n -o ntreat me nt - sa m ple was c ollecte d 
wit hi n t he past 2 8 da ys or t he i n vesti gat or assesses t hat t here i n a n u nj ustifia ble ris k f or t he patie nt, a n d/ or t he patie nt ref uses t o u n der g o a b o ne marr o w 
pr oce d ure.  A b o ne marr o w as pirate sa m ple will be c ollecte d f or ce ntral M R D assess me nt usi n g t he ne xt ge nerati o n se q ue nci n g ( N G S) assa y w he n patie nt 
is i n s us pecte d C R or act ual C R. A C 1 D 1 b o ne marr o w  as pirate m ust als o be c ollecte d i n all patie nts as t he baseli ne M R D
refere nce sa m ple. Sa m ples f or
M R D assess me nts s h o ul d be ali q u ote d fr o m t he first b o ne marr o w as pirate p ull. S a mples at 1 a n d 3 m o nt hs after C 1 D 1 will be c ollecte d 7 da ys; sa m ples 
at 9 m o nt hs after C 1 D 1 a n d later will be c ollecte d 1 4 da ys .  
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 6 0
Sc he d ule of Acti vities A
Visit I de ntifier
Scree ni n g 1
D a ys pri or t o 
e nr oll me nt
Tre at m e nt Peri o d
1 m o nt h 
F oll o w -u p 3 5
S ur vi v al 
F oll o w -u p 3 7
C ycle 1
( 1 C ycle = 3 
wee ks)
C ycle 2
C ycle 3 
o n w ar ds
E O T 3 6
St u d y D a y
-2 8 t o - 1 
-1 4 
t o - 1
1
2
3
4 * 8
1 5 1
4 * 8
1 5 1
8
1 5
Visit Wi n d o w ( d a ys)
± 1 ± 1 ± 1 ± 1
± 1 ± 2 ± 2 ± 2 ± 2
+ 7
± 1 4
2 5. Dise ase asse ss me nts b y fl u or o de o x y gl uc ose ( F D G) p ositr o n e missi o n t o m o gr a p h y ( P E T)/ c o m p uterize d t o mo gr a p h y ( C T): See Assess me nts 
Secti o n 7. 2. 3 .  Ra di o gra p hic assess me nts o btai ne d per t he patie nt’s sta n dar d of care pri or t o e nr oll me nt i nt o t he st u d y d o n ot nee d t o be re peate d a n d are 
acce pta ble t o be use d as baseli ne e val uati o n, if, ( 1) o btai ne d wit hi n 2 8 da ys bef ore C 1 D 1 , ( 2) t he sa me tec h ni q ue/ m o dalit y ca n be use d t o f oll o w i de ntifie d 
lesi o ns t hr o u g h o ut t he trial f or a gi ve n patie nt, a n d ( 3) a p pr o priate d oc u me ntati o n i n dicati n g t hat t hese ra di o gra p hic t u m or assess me nts were perf or me d as 
sta n dar d of care is a vaila ble i n the patie nt’s s o urce n otes.  F or all patie nts, i ma ges are re q uire d at scree ni n g, s us pecte d C R, w he n disease pr o gressi o n is 
s us pecte d (e g, s y m pt o matic deteri orati o n), e n d of treat me nt visit (if n ot d o ne i n pre vi o us 4 w ee ks) a n d w he n ot her wise cli nicall y i n di cate d.   I n patie nts wit h 
meas ura ble tar get lesi o ns at scree ni n g, i ma ges at 1 a n d 3 m o nt hs after C 1 D 1 will be c ollecte d ± 7 da ys; i ma ges at 9 m o nt hs after C 1 D 1 a n d e ver y 6 m o nt hs 
t hereafter will be c ollecte d ± 1 4 da ys . F or sites i n Ger ma n y: O nl y M RI is all o wed t o be use d as i ma gi n g m o dalit y f or partici pa nts.
2 6. A d verse E ve nt ( A E) Assess me nts : A Es s h o ul d be d oc u me nte d a n d rec or de d at eac h visit usi n g t he Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E ve nts ( N CI C T C A E) versi o n 4. 0 3.  H o w e ver, t he se verit y of c yt o ki ne release s y n dr o me ( C R S) will be assesse d acc or di n g t o t he 
gra di n g descri be d b y Lee et al. ( 2 0 1 4 a n d 2 0 1 9 2 ,3 See A p pe n di x 5 ) i nstea d of C T C A E. I n a d diti o n, A merica n S ociet y f or Tra ns pla ntati o n a n d Cell ular 
T hera p y ( A S T C T) c o nse ns us gra di n g of C R S a n d i m m u ne effect or cell -ass ociate d ne ur ot o xicit y (I C A N S) 3will be ca pt ure d se paratel y fr o m t he A E 
assess me nts ( See A p pe n di x 5 ). T he ti me peri o d f or acti vel y eliciti n g a n d c ollecti n g A Es a n d S A Es ( “acti ve c ollecti o n peri o d”) f or eac h patie nt be gi ns fr o m 
t he ti me t he patie nt pr o vi des i nf or me d c o nse nt t hr o u g h a n d i ncl u di n g a mi ni m u m of 9 0 cale n dar da ys after t he last i n vesti gati o nal pr o d uct a d mi nistrati o n.  
If t he patie nt be gi ns a ne w a ntica ncer t her a p y, t he peri o d f or rec or di n g n o n-seri o us A Es o n t he case re p ort f or m ( C R F) e n ds at t he ti me t he ne w treat me nt is 
starte d.  H o we ver, a n y S A Es occ urri n g d uri n g t he acti ve c ollecti o n peri o d m ust still be re p orte d t o Pfizer Safet y a n d rec or de d o n t he C R F, ir res pecti ve of 
a n y i nter ve ni n g treat me nt.
2 7. C o nc o m it a nt Tre at me nts: all c o nc o mita nt me dicati o ns a n d N o n dr u g S u p p orti ve I nter ve nti o ns s h o ul d be rec or de d o n t he C R F.
2 8. Ge netic A n al ysis : B o ne marr o w as pirates ta ke n o n C 1 D 1 will be e val uate d at l ocal la b f or t( 4; 1 4)( p 1 6; q 3 2), t( 1 4; 1 6)( q 3 2; q 2 3), 1 7 p 1 3 deleti o ns, 
t( 1 1; 1 4)( q 1 3; q 3 2), c hr o m os o me 1 3 deleti o n, pl oi d y cate g or y, a n d c hr o m os o me 1 a b n or malities . If s o me of t hese c yt o ge netic assess me nts ca n n ot be d o ne, 
site s h o ul d pr o vi de patie nt’s m ost rece nt c yt o ge netic testi n g res ults a n d e nter i nt o e C R F.  Sa m ple m a y be ta ke n u p t o 7 da ys bef ore t he start of st u d y 
treat me nt.
2 9. B C M A + e x pressi o n o n m ulti ple m y el o m a cells i n b o ne m arr o w: E x pressi o n of B C M A will be e val uate d o n fres h b o ne marr o w  as pirates ( b y fl o w 
c yt o metr y) a n d bio psies ( b y I H C).  E x pressi o n of a d diti o nal mar kers i ncl u di n g C D 1 3 8 will als o be e val uate d.  A d diti o nal a nal yses ma y be perf or me d o n 
b o ne marr o w  bi o psies, i ncl u di n g i m m u n o p he n ot y pi n g of i nfiltrati n g i m m u ne cells a n d e x pl orat or y m olec ular a nal yses. If t he sa mple c ollecti o n da y 
c oi nci des wit h da ys w here b y i n vesti gati o nal pr o d uct is t o be a d mi nistere d, sa m ples will be c ollecte d pri or t o i n vesti gati o nal pr o d uct a d mi nistrati o n .  Sa m ple 
f or C ycle 1 Da y 1 ( C 1 D 1) ma y be ta ke n u p t o 7 da ys bef ore st u d y treat me nt ; sa m p les at 1 a n d 3 m o nt hs after C 1 D 1 will be c ollecte d pre -d ose 7 da ys; 
sa m ples at 9 m o nt hs after C 1 D 1 will be c ollecte d pre -d ose 1 4 da ys.  .
3 0. S ol u ble B C M A : See Sc he d ule of P har mac o ki netic, S ol u ble Fact or a n d C yt o ki ne Acti viti es A.  S ol u ble B C M A will be meas ure d i n plas ma b y mass 
s pectr o metr y. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 6 1
Sc he d ule of Acti vities A
Visit I de ntifier
Scree ni n g 1
D a ys pri or t o 
e nr oll me nt
Tre at m e nt Peri o d
1 m o nt h 
F oll o w -u p 3 5
S ur vi v al 
F oll o w -u p 3 7
C ycle 1
( 1 C ycle = 3 
wee ks)
C ycle 2
C ycle 3 
o n w ar ds
E O T 3 6
St u d y D a y
-2 8 t o - 1 
-1 4 
t o - 1
1
2
3
4 * 8
1 5 1
4 * 8
1 5 1
8
1 5
Visit Wi n d o w ( d a ys)
± 1 ± 1 ± 1 ± 1
± 1 ± 2 ± 2 ± 2 ± 2
+ 7
± 1 4
3 1. T B N K a n d I m m u n o p he n ot y pi n g: e n u merati o n a n d p he n ot y pes of T -cell s u bsets b y m ulti para meter fl o w c yt o metr y.  If sa m ple c ollecti o n da y c oi nci des 
wit h da ys w here b y i n vesti gati o nal pr o d uct is t o be a d mi nistere d, sa m ples will be c ollecte d pri or t o i n vesti gati o nal pr o d uct a d m i nistrati o n.  B o ne marr o w  
sa mple f or C ycle 1 Da y 1 ( C 1 D 1) ma y be ta ke n u p t o 7 da ys bef ore st u d y treat me nt ; sa m ples at 1 m o nt h or 3 m o nt hs after C 1 D 1 will be c ollecte d 7 da ys.  
. 
3 2. Ge ne e x pressi o n ri b o n ucleic aci d ( R N A) pr ofile: ge ne e x pressi o n ass ociate d wit h acti vati o n state a n d a nti -t u mor acti vit y will be meas ure d b y  R N A 
se q ue nci n g i n b o ne marr o w.  If sa m ple c ollecti o n da y c oi nci des wit h da ys w here b y i n vesti gati o nal pr o d uct is t o be a d mi nistered, sa m ples will be c ollecte d 
pri or t o i n vesti gati o nal pr o d uct a d mi nistrati o n.  B o ne marr o w sa m ple f or C ycle 1 Da y 1 ( C 1 D 1) ma y be ta ke n u p t o 7 d a y s bef ore st u d y treat me nt; sa m ples 
at 1 m o nt h or 3 m o nt hs after C 1 D 1 will be c ollecte d 7 da ys; sa m ples at 9 m o nt hs after C 1 D 1 will be c ollecte d 1 4 da ys.  W he n b o ne marr o w as pirate 
sa m ples are ta ke n f or disease res p o nse e val uati o n,  sa m ples f or ge ne e x pressi o n a nal ysis will als o be ac q uire d.
3 3. T -cell rece pt or ( T C R) se q ue nci n g : cl o nal e x pa nsi o n, c o ntracti o n a n d di versit y a n d its ass ociati o n wit h acti vit y a n d d ura bilit y will be assesse d b y 
de o x yri b o n ucleic aci d ( D N A) se q ue nci n g of T C R i n b o ne marr o w .  If sa m ple c ollecti o n da y c oi nci des wit h da ys w here b y i n vesti gati o nal pr o d uct is t o be 
a d mi nistere d, sa m ples will be c ollecte d pri or t o i n vesti gati o nal pr o d uct a d mi nistrati o n.  B o ne marr o w sa m ple f or C ycle 1 Da y 1 ( C 1 D 1) ma y be ta ke n u p t o 
7 da ys bef ore s t u d y treat me nt; sa m ples at 1 m o nt h or 3 m o nt hs after C 1 D 1 will be c ollecte d 7 da ys; sa m ples at 9 m o nt hs after C 1 D 1 will be c ollecte d
1 4 da ys.  W he n b o ne marr o w as pirate sa m ples are ta ke n f or disease res p o nse e val uati o n, sa m ples f or T C R se q u e nci n g will als o be ac q uire d.
3 4. Ge n o mic b a n ke d bi os peci me ns Pre p D 1: If n ot c ollecte d o n C 1 D 1, c ollect at t he ne xt a vaila ble ti me p oi nt w he n bi os peci me ns are bei n g c ollecte d i n 
c o nj u ncti o n wit h a patie nt visit.
3 5. O ne m o nt h f oll o w -u p: At least 2 8 cale n dar da ys, a n d n o m ore t ha n 3 5 cale n dar da ys, after disc o nti n uati o n of treat me nt, patie nts will ret ur n t o u n der g o 
re vie w of c o nc o mita nt treat me nts, vital si g ns, a n d assess me nt f or res ol uti o n of a n y treat me nt-relate d t o xicit y.  Patie nts c o nti n ui n g t o e xperie nce t o xicit y at 
t his p oi nt f oll o wi n g disc o nti n uati o n of treat me nt will c o nti n ue t o be f oll o we d at least e ver y 4 we e ks u ntil res ol uti o n or deter mi nati o n, i n t he cli nical 
j u d g me nt of t he i n vesti gat or, t hat n o f urt her i m pr o ve me nt is e x pecte d.  If t he patie nt c o m pletes t he f oll o w-u p visit pri or t o c o m pleti o n of t he 6 0 d a y  l o n g 
ter m d ose li miti n g t o xicit y ( D L T) o bser vati o n peri o d, a f oll o w u p p h o ne call will be c o m plete d o n at least Da y 6 0, a n d n o m ore t ha n Da y 6 5.
3 6. E n d of Tre at me nt ( E O T) Visit: O btai n t hese assess me nts if n ot c o m plete d i n t he last wee k (last 4 wee ks f or disease assess me nts).
3 7. S ur vi v al f oll o w u p: F oll o w i n g disc o nti n uati o n of st u d y treat me nt ( u nless patie nts are l ost t o f oll o w u p, c o nse nt is wit h dra w n, or st u d y is disc o nti n ue d b y 
t he s p o ns or), s ur vi val stat us will be c ollecte d b y tele p h o ne e ver y 3 m o nt hs u ntil deat h, or u p t o a p pr o xi matel y 3 0 m o nt hs after last patie nt first d ose, 
w hic he ver c o mes first.  S u bse q ue nt a nti -ca ncer t hera pies a n d rele va nt tra ns pla nt i nf or mati o n will als o be c ollecte d. A n y sta n dar d of care ( S O C) disease 
assess me nts o btai ne d bet wee n E O T a n d s u bse q ue nt a nti -ca ncer t hera p y will be c ollecte d. 
3 8. L oc al Site I njecti o n T oler a bilit y Assess me nt ( S C A d mi nistr ati o n C o h ort O nl y): Assess me nt of i njecti o n site s h o ul d be c o n d ucte d at 1 t o 4 h o urs 
f oll o wi n g treat me nt a d mi nistrati o n o n Da y 1, 8 a n d 1 5 f or t he first c ycle.  If i njecti o n site pai n or i njecti o n site reacti o n (I S R) c haracteristics c o nti n ue t o 
persist after t he first c ycle, l ocal site i njecti o n t olera bilit y assess me nts s h o ul d c o nti n ue u ntil t he s y m pt o ms res ol ve.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 6 2
S C H E D U L E O F P H A R M A C O KI N E TI C, S O L U B L E F A C T O R A N D C Y T O KI N E A C T I VI TI E S A: P A R T 1 I V A N D S C 
W E E K L Y M O N O T H E R A P Y ( N O P RI MI N G D O S E )
T he sc he d ule of p har mac o ki netic, s ol u ble fact or a n d c y t o ki ne acti vities ta ble pr o vi des a n o ver vie w of t he pr ot oc ol visits a n d 
pr oce d ures.  T his sc he d ule of acti vities is a p plica ble t o Part 1 I V a n d S C m o n ot hera py d ose escalati o n c o h orts .  T he i n vesti gat or ma y  
sc he d ule visits ( u n pla n ne d visits) i n a d diti o n t o t h ose liste d i n t he sc he d ule of activities ta ble i n or der t o c o n d uct e val uati o ns or 
assess me nts re q uire d t o pr otect t he well -bei n g of t he patie nt.   See A p pe n di x 1 0 f or alter nati ve meas ure g ui deli nes d ue t o C O VI D- 1 9.
Visit 
I de ntifier
U p t o 7 
d a ys 
pri or t o 
C 1 D 1
Tre at m e nt Peri o d
E O T
C ycle 1
C ycle 2
C ycle 3 o n w ar ds
St u d y D a y
D 1  
D 2  
D 4  
D 8
D 1 5
D 1  
D 4  
D 8
D 1 5
D 1
H o urs Pre/ 
after d osi n g †
0 
2 *
4 *
8
2 4 
7 2
0 
2 *
4 *
0 
2 *
0 
2 *
4 *
7 2
0 
2 *
0 
2 *
0 
2 *
Visit wi n d o w
0. 5 
hr
1 
hr
3 
hrs
2 4 
hrs
0. 5 
hr
1 hr
2 4 
hrs
C y t o ki ne 
e val uati o n i n 
ser u m1
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
3 ( 7 da ys) 
a n d 
9 m o nt hs 
(1 4 da ys) 
after C 1 D 1
Sa m ples f or 
P F - 0 6 8 6 3 1 3 5 
bl o o d le vel 2
X  
X  
X  
X  
X  
X  
X
(I V 
o nl y)
X
(I V 
o nl y)
X  
X
(I V 
o nl y)
X  
X
(I V 
o nl y)
X
(I V 
o nl y)
X  
X  
X
(I V 
o nl y)
X  
X
(I V 
o nl y)
X 2
X 2
(I V 
o nl y
)
X
Bl o o d sa m ples 
f or A D A a n d 
N A b a gai nst 
P F -0 6 8 6 3 1 3 5 3
X
X  
X
X 3
X
S ol u ble B C M A 
a n d ot her 
fact ors4
X  
X  
X  
X  
X  
X  
X  
X
(I V 
o nl y)
X
(I V 
o nl y)
X  
X
(I V 
o nl y)
X  
X
(I V 
o nl y)
X
(I V 
o nl y)
X  
X  
X
(I V 
o nl y)
X  
X
(I V 
o nl y)
X 4
X 4
(I V 
o nl y
)
X
A b bre viati o ns: A nti -P F -0 6 8 6 3 1 3 5 a nti b o dies = A D A; B C M A = B -cell mat urati o n a nti ge n; D = Da y; E O T = e n d of treat me nt; ne utralizi n g a nti b o dies = N A b.
* F or i ntra ve n o us (I V) a d mi nistrati o n, t he 2-h o ur sa m ple s h o ul d be ta ke n i m me diatel y ( u p t o 1 5 mi n utes bef ore) bef ore t he e n d of P F -0 6 8 6 3 1 3 5 i nf usi o n; if 
t he i nf usi o n is l o n ger t ha n 2 h o urs ( or s h orter if a 1 h o ur i nf usi o n is teste d), t he c ollecti o n ti me of t his sa m ple s h o ul d be a dj uste d acc or di n gl y f or t he sa m ple t o 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 6 3
Visit 
I de ntifier
U p t o 7 
d a ys 
pri or t o 
C 1 D 1
Tre at m e nt Peri o d
E O T
C ycle 1
C ycle 2
C ycle 3 o n w ar ds
St u d y D a y
D 1  
D 2  
D 4  
D 8
D 1 5
D 1  
D 4  
D 8
D 1 5
D 1
H o urs Pre/ 
after d osi n g †
0 
2 *
4 *
8
2 4 
7 2
0 
2 *
4 *
0 
2 *
0 
2 *
4 *
7 2
0 
2 *
0 
2 *
0 
2 *
be c ollecte d i m me diatel y bef ore t he act ual e n d of P F -0 6 8 6 3 1 3 5 i nf usi o n.  F or s u bc uta ne o us a d mi nistrati o n, t he 2-h o ur sa m ple s h o ul d be ta ke n at 2 h o urs 
p ost -i njecti o n 1 2 mi n utes ; als o f or S C a d mi nistrati o n, wit h t he e xce pti o n of c yt o ki ne sa m ples, 2 a n d 4 hr sa m ples are n ot nee de d ot her t ha n o n C ycle 1 D 1 .  
† Sa m pli n g ti mes are relate d t o t he start of t he i nf usi o n.  All eff orts will be ma de t o o btai n t he p har mac o ki netic ( P K) sa m ples at t he e xact n o mi nal ti me 
relati ve t o d osi n g.  H o we ver, sa m ples o btai ne d wit hi n t he wi n d o w s pecifie d will be c o nsi dere d acce pta ble.  
F o ot n otes f or Sc he d ule of P h ar m ac o ki netic, S ol u ble F act ors a n d C yt o ki ne Acti vities A
1.
C yt o ki ne e v al u ati o n i n ser u m: See C yt o ki ne Assess me nts Secti o n 7. 5. 4 f or a f ull list of c yt o ki ne assess me nts.  All sa m ples will be a nal yze d ce ntrall y.  
All 0 h o ur sa m ples will be c ollecte d pri or t o i n vesti gati o nal pr o d uct a d mi nistrati o n o n da ys w here b y i n ves ti gati o nal pr o d uct is t o be a d mi nistere d.  If C R S 
is s us pecte d, a n a d h oc c yt o ki ne sa m ple will be c ollecte d(see Secti o n 7. 1. 3 La b orat or y Safet y Assess me nts).  S h o ul d t he site re q uire c yt o ki ne i nf or mati o n 
f or patie nt ma na ge me nt, t he site will ha ve t he o pti o n of c ollecti n g a n a d diti o nal sa m ple f or l ocal a nal ysis. If a sa m ple f or c yt o ki ne pa nel e val uati o n is d ue 
t o be c ollecte d o n t he sa me da y as t he da y a s us pecte d C R S e ve nt occ urs, t he n a n a d h oc sa m ple f or ce ntral a nal ysis is n ot req uire d/c ollecte d. H o w e ver, 
a n a d h oc sa m ple f or l ocal a nal ysis ma y still be c oll ecte d f or patie nt ma na ge me nt.  
2.
Bl o o d s a m ple f or P F -0 6 8 6 3 1 3 5 bl o o d le vel: A p pr o xi matel y 5 m L sa m ple of w h ole bl o o d (t o pr o vi de a p pr o xi matel y 2 m L of ser u m) will be c ollecte d at 
eac h ti me p oi nt f or P K a nal ysis of P F -0 6 8 6 3 1 3 5.  After C ycle 8, pre - a n d p ost- dose P K sa m ples will be c ollecte d o nl y o n e ver y 4 t h c ycle ( C ycle 8, 
C y cle 1 2, C ycle 1 6, etc.).  A n a d diti o nal P K sa m ple s h o ul d als o be ta ke n if C R S is s us pecte d, a n d a P K sa m ple is n ot alrea d y sc he d ule d t o be ta ke n 
(e g, C ycle 3 o n war ds).
3.
A nti P F -0 6 8 6 3 1 3 5 A n ti b o dies ( A D A) a n d Ne utr alizi n g A nti b o dies ( N A b): C ollecti o n of t w o 1 m L pre -d ose ser u m sa m ples (fr o m 5 m L t otal w h ole 
bl o o d) t o detect t he prese nce of a nti b o dies t o P F -0 6 8 6 3 1 3 5 is t o be o btai ne d pri or t o t he start of treat me nt.  Patie nts ha vi n g a n u nres ol ve d a d verse e ve nt 
t hat is p ossi bl y relate d t o a nti-P F -0 6 8 6 3 1 3 5 a nti b o dies at t heir last assess me nt will be as ke d t o ret ur n t o t he cli nic f or A D A a n d dr u g c o nce ntrati o n bl o o d 
sa m pli n g at a p pr o xi matel y 3-m o nt h i nter vals u ntil t he a d verse e ve nt or its se q uela e res ol ve or sta bilize at a le vel acce pta ble t o t he i n vesti gat or a n d 
s p o ns or.  After C ycle 4, pre -d ose A D A a n d N A b sa m ples will be c ollecte d o nl y o n C ycles 6, 8, a n d e ver y 4 t h c ycle t hereafter ( C ycle 8, C ycle 1 2, 
C y cle 1 6, etc.).
4.
S ol u ble B C M A a n d ot her f ac t ors: A p pr o xi matel y 3 m L sa m ple of w h ole bl o o d (t o pr o vi de a p pr o xi matel y 1
m L of plas ma) will be c ollecte d at eac h 
ti me p oi nt f or a nal ysis of s ol u ble B C M A a n d ot her fact ors b y mass s pectr o metr y.  All 0 h o ur sa m ples will be c ollecte d pri or t o i n vesti gati o na l pr o d uct 
a d mi nistrati o n o n da ys w here b y i n vesti gati o nal pr o d uct is t o be a d mi nistere d.  After C ycle 8, pre - a n d p ost-d ose P K sa m ples will be c ollecte d o nl y o n 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 6 4
Visit 
I de ntifier
U p t o 7 
d a ys 
pri or t o 
C 1 D 1
Tre at m e nt Peri o d
E O T
C ycle 1
C ycle 2
C ycle 3 o n w ar ds
St u d y D a y
D 1  
D 2  
D 4  
D 8
D 1 5
D 1  
D 4  
D 8
D 1 5
D 1
H o urs Pre/ 
after d osi n g †
0 
2 *
4 *
8
2 4 
7 2
0 
2 *
4 *
0 
2 *
0 
2 *
4 *
7 2
0 
2 *
0 
2 *
0 
2 *
e ver y 4 t h c ycle ( C ycle 8, C ycle 1 2, C ycle 1 6, etc.).  A n a d diti o nal s ol u ble B C M A/ ot her fact or sa m p le s h o ul d als o be ta ke n if C R S is s us pecte d, a n d a 
sa m ple is n ot alrea d y sc he d ule d t o be ta ke n (e g, C ycle 3 o n war ds).
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M




























































P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 9 4
1. I N T R O D U C TI O N
1. 1.
Mec h a nis m of Acti o n/ I n dic ati o n
P F -0 6 8 6 3 1 3 5 is a bis pecific m o n ocl o nal a nti b o d y  a gai nst B-cell mat urati o n a nti ge n ( B C M A, 
als o k n o w n as t u m or necr osis fact or rece pt or s u perfa mil y  me m ber 1 7 [ T N F R S F 1 7] or cl uster 
of differe ntiati o n [ C D] 2 6 9) a n d C D 3.  Tar gete d T- cell me diate d c yt ot o xicit y f oll o ws t he 
bi n di n g of o ne e pit o pe of P F -0 6 8 6 3 1 3 5 t o C D 3 e x pressi n g T -cells, a n d a sec o n d e pit o pe t o 
B C M A e x pressi n g m ulti ple m y el o ma cells.  I n t his cli nical st u d y , P F-0 6 8 6 3 1 3 5 will be 
e val uate d f or t he treat me nt of a d ult patie nts wit h rela pse d or refract or y m ulti ple m y el o ma as 
m o n ot hera p y a n d i n c o m bi nati o n wit h le nali d o mi de, p o mali d o mi de , or de xa met has o ne .
1. 2. B ac k gr o u n d a n d R ati o n ale
1. 2. 1. M ulti ple M yel o m a
M ulti ple m y el o ma ( M M) is a he mat ol o gical mali g na nc y  t hat is c haracterize d b y u nc o ntr olle d 
e x pa nsi o n of b o ne marr o w plas ma cells.  A p pr o xi matel y  1 1 4, 0 0 0 ne w cases of M M are 
dia g n ose d w orl d wi de eac h y ear, a n d 8 0, 0 0 0 patie nts will die fr o m t heir disease. 6 I n t he U S, 
t he i nci de nce of M M has i ncrease d fr om 4. 9 1 per 1 0 0, 0 0 0 i n 1 9 7 5, t o 6. 7 9 per 1 0 0, 0 0 0 i n 
2 0 1 3. 7  M ore patie nts are dia g n ose d at a n ol der a ge; 3 4. 4 per 1 0 0, 0 0 0
dia g n ose d at 
a ge 6 5 a n d o ver, w hilst 2. 4 per 1 0 0, 0 0 0 are dia g n ose d u n der t he a ge of 6 5.
M M is a disease t hat e v ol ves fr o m a pre- mali g na nt sta ge of m o n ocl o nal ga m m o pat h y  of 
u n deter mi ne d cli nical si g nifica nce ( M G U S), t o as y m pt o matic s m ol deri n g m y el o ma, t o 
s ym pt o matic acti ve m yel o ma .8 D uri n g t he acti ve sta ge of disease, a maj orit y  of patie nts 
de vel o p pai nf ul b o ne lesi o ns a n d or ga n d ys f u ncti o n, lea di n g t o a ne mia, re nal i ns ufficie nc y 
a n d h y percalce mia.  W hilst patie nts wit h s m ol deri n g m yel o ma d o n ot re q uire pri mar y 
t hera py, t he treat me nt re gi me n f or patie nts wit h acti ve disease is c urre ntl y de pe n de nt o n t he 
patie nt’s eli gi bilit y  t o recei ve a n a ut ol o g o us ste m cell tra ns pla nt ( A S C T).  F or patie nts 
< 7 0 ye ars ol d wit h n o c o m or bi dities, i n d ucti o n t hera p y (eit her pr oteas o me i n hi bit or- base d or 
i m m u n o m o d ulati o n-base d re gi me ns) c o m bi ne d wit h a n A S C T is t he s u g geste d a p pr oac h, 
wit h 2 -ye ar s ur vi val ac hie ve d i n 8 0 % of patie nts. 8 ,9 Still, e ve n i n t his y o u n ger a ge gr o u p, t he 
rate of t o xicit y f oll o wi n g tra ns pla nt is hi g h, wit h 5 % m ortalit y d ue t o a d verse e ve nts re p orte d 
i n cli nical st u dies.1 0  I n ol der patie nts ie, t h ose > 7 0 ye ars, a d verse e ve nt relate d m ortalities 
f oll o wi n g A S C T is a sta g geri n g 1 9 %.1 0 T h o u g h i n t he or y all o ge neic ste m cell tra ns pla nt has 
a c urati ve p ote ntial, it is n ot a rec o m me n de d re gi me n f or t his p o p ulati o n as n o s ur vi val 
a d va nta ges ha ve bee n de m o nstrate d i n ra n d o mize d st u dies d ue t o i ncrease d t o xicities .1 1 F or 
tra ns pla nt i neli gi ble patie nts, i m m u n o m o d ulati o n base d re gi me n of b ortez o mi b, 
le nali d o mi de, a n d de xa met has o ne is t he pri mar y preferre d treat me nt o pti on as it was 
de m o nstrate d i n t he P hase III S o ut h west O nc ol o g y  Gr o u p (S W O G ) S 0 7 7 7 st u d y  t hat a n 
o bjecti ve res p o nse rate ( O R R), of 7 1 %, a n d pr o gressi o n free s ur vi val of 4 3 m o nt hs ca n be 
ac hie ve d .9 ,1 2 H o we ver, t o xicit y  re mai ns t o be a c o ncer n, wit h Gra de 3 or hi g her ne ur o pat h y  
re p orte d i n 2 4 % of patie nts. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 9 5
Des pite a n u m ber of rece nt a d va nces, t he maj orit y of patie nts are e x pecte d t o rela pse, e ve n 
f or t h ose w h o res p o n d i nitiall y t o treat me nt.  E ve n f or patie nts w h o are eli gi ble t o recei ve 
a ut ol o g o us ste m cell tra ns pla nts, t he me dia n ti me t o rela pse was 1 7. 2 m o nt hs .1 3 Si milarl y , 
f or patie nts t hat are treate d wit h n o vel pr oteas o me i n hi bit or-base d or
i m m u n o m o d ulati o n-base d c o m bi nati o n re gi me ns as fr o nt li ne treat me nt, t he me dia n ti me t o 
rela pse is 1 6. 4 m o nt hs .1 4
Patie nts wit h rela pse d refract or y  m ulti ple m yel o ma w h o res p o n d p o orl y t o pr oteas o me 
i n hi bit or- base d or i m m u n o m o d ulati o n-base d re gi me ns s h o w a me dia n o verall s ur vi val of 
o nl y  1. 5 ye ars.1 5 I n t his rela pse d setti n g, a p pr o xi matel y 5 0 % treat me nt-relate d a d verse 
e ve nts ( A E) a n d 2 0 % seri o us a d verse e ve nts ( S A E) ha ve bee n re p orte d .1 6 F urt her m ore, eac h 
s u bse q ue nt li ne of t hera p y re n ders t he patie nt m ore refract or y t o treat me nt.  F or e xa m ple, 
patie nts w h o are d o u ble -refract or y t o pr oteas o me i n hi bit or- base d or i m m u n o m o d ulati o n 
re gi me ns ha ve a me dia n o verall s ur vi val of 9 a n d 5 m o nt hs .1 7 It is t heref ore clear t hat 
a d diti o nal treat me nt a p pr oac hes are re q uire d f or rela pse d/ refract or y  M M.
1. 2. 2. Bis pecific A nti b o dies
F u ncti o nal l ocal a n d s y ste mic i m m u nit y is ofte n s u p presse d i n a M M patie nt.  Im paire d 
i m m u nit y res ults fr o m t he disr u pti o n of n or mal he mat o p oiesis f oll o wi n g b o ne marr o w 
i n vasi o n b y plas ma cl o nes.  T he p ote ntial f or T-cell base d i m m u n ot hera p y f or M M has bee n 
hi g hli g hte d b y t he a bilit y f or graft i m m u ne reacti ve T -cells t o era dicate m yel o ma cells 
f oll o wi n g all o ge neic ste m cell tra ns pla ntati o n.1 8 It ma y t heref ore be p ossi ble t o rest ore 
i m m u ne-reacti ve T- cells, pre ve nt mali g na nt cell gr o wt h a n d decrease disease rec urre nce wit h 
i m m u n ot hera pe utic a p pr oac hes.
Bis pecific a nti b o dies offer a n o vel i m m u n ot hera pe utic a p pr oac h t hat all o ws t he direct 
tar geti n g of c yt ot o xic T- cells t o t u m or cells.  T hese a nti b o dies are e n gi neere d wit h t w o 
se parate a nti ge n rec o g niti o n d o mai ns; o ne t hat rec o g nizes a t u m or a nti ge n a n d a n ot her t hat 
rec o g nizes C D 3 e x presse d o n T- cells.  Si m ulta ne o us bi n di n g of C D 3 a n d t he t u m or a nti ge n 
i nitiates a c yt ot o xic res p o nse t o war ds t he b o u n d t u m or cell.  U nli ke n or mal T- cell
c yt ot o xicit y, bis pecific a nti b o d y me diate d c yt ot o xicit y is i n de pe n de nt t o t he prese nce of 
a nti ge n prese nti n g cells ( A P Cs), e x pre ssi o n of maj or hist oc o m pati bilit y c o m ple x ( M H C) 
I m olec ules b y  t he t u m or, a n d t he prese nce of c osti m ulat or y m olec ules.  Bli nat u m o ma b, a 
C D 1 9/ C D 3 bis pecific a nti b o d y , was t he first bis pecific a nti b o d y t o be a p pr o ve d b y t he 
U nite d States ( U S) F o o d a n d Dr u g A d mi nistrati o n ( F D A) .1 9 I n a P hase 2 trial of rela pse or 
refract or y B cell ac ute l y m p h o blastic le u ke mia ( A L L) patie nts, 3 3 % ac hie ve d c o m plete 
res p o nse ( C R) a n d 1 0 % ac hie ve d C R wit h i nc o m plete he mat ol o gical rec o ver y.1 9 It ma y 
t heref ore be p ossi ble t o use t he sa me a p pr oac h f or M M wit h a m yel o ma-restricte d a nti ge n.
B- cell mat urati o n a nti ge n ( B C M A, als o k n o w n as T N F R S F 1 7 a n d C D 2 6 9) is a ca n di date f or 
bis pecific a nti b o d y base d i m m u n ot hera p y.  B C M A e x pressi o n is u pre g ulate d d uri n g B-cell 
mat urati o n i nt o plas ma blasts a n d plas ma cells, b ut it is n ot e x presse d o n naï ve B cells, 
he mat o p oietic ste m cells or n or mal tiss ues s uc h as t he heart, l u n g, ki d ne y , or t o nsil.2 0 ,2 1
B C M A k n oc k o ut mice s h o w n or mal de vel o p me nt, a n d are a ble t o elicit a n or mal h u m oral 
i m m u ne res p o nse.2 2 ,2 3 I n m ulti ple m yel o ma, B C M A e x pressi o n was i de ntifie d at eac h 
disease sta ge, a n d o n patie nts wit h differi n g c y t o ge netic ris ks.2 0 F urt her m ore, B C M A 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 9 6
e x pressi o n was n ot i nfl ue nce d b y treat me nt wit h a ut ol o g o us ste m cell tra ns pla nt ( A S C T) or 
c he m ot hera p y. 2 0 ,2 1 I n vi v o, bis pecific a nti b o dies a gai nst B C M A ha ve bee n s h o w n t o i n d uce 
T- cell acti vati o n, re d uce t u m or b ur de n a n d pr ol o n g s ur vi v al.2 4 -2 6 A P hase 1 d ose escalati o n 
st u d y wit h a B C M A bis pecific a nti b o dy ( BI 8 3 6 9 0 9) has bee n i nitiate d.  As of A u g ust 2 0 1 9, 
4 3 patie nts ha ve bee n e n r olle d.2 6
1. 2. 3. P F -0 6 8 6 3 1 3 5
P F -0 6 8 6 3 1 3 5 is a heter o di meric h u ma nize d f ull -le n gt h bis pecific a nti b o dy c o m prise d of o ne 
B -cell Mat urati o n A nti ge n ( B C M A) bi n di n g ar m a n d o ne cl uste r of differe ntiati o n ( C D 3) 
bi n di n g ar m paire d t hr o u g h hi n ge m utati o n tec h n ol o g y .  It utilizes a m o difie d h u ma n I g G 2 Da 
fra g me nt cr ystalliza ble ( Fc) re gi o n.  T he half-life of P F-0 6 8 6 3 1 3 5 was 3 d a y s i n a 
n o n- h u ma n pri mate m o del , a n d P F-0 6 8 6 3 1 3 5 has a pr ojecte d ter mi nal half -life of 1 0 d a y s i n 
h u ma ns. 
1. 2. 3. 1. S afet y
T he safet y, efficac y, a n d P K of elra nata ma b were i nitiall y e val uate d i n P hase 1 st u d y 
( C 1 0 7 1 0 0 1) as m o n ot hera p y (IV a n d S C) or i n c o m bi nati o n wit h le nali d o mi de or 
p o mali d o mi de. 
As of t he 2 2 J u ne 2 0 2 2 data c ut off date, 1 0 1 partici pa nts ha ve bee n e nr olle d i n t he st u d y  as 
f oll o ws: 2 3 i n Part 1 IV d ose escalati o n, 3 0 i n Part 1 S C d ose escalati o n, 2 0 i n Part 1. 1 S C 
pri mi n g d ose c o h orts, 1 5 i n Part 2 A: S C d ose d ose e x pa nsi o n, 4 i n Part 1 C: elra nata ma b + 
le nali d o mi de a n d 9 i n Part 1 D: elra nata ma b + p o mali d o mi de. In Part 1. 1, t o miti gate t he ris k 
of C R S a n d I C A N S, partici pa nts recei ve d a pri mi n g d ose of 6 0 0 µ g/ k g elra nata ma b 
(e q ui vale nt t o 4 4 m g) o n Da y 1 pri or t o t he first f ull d ose of 1 0 0 0 µ g/ k g (e q ui valent t o 7 6 
m g) o n Da y  8. I n Part 2 A, i n a d diti o n t o t he pri mi n g d ose of elra nata ma b, partici pa nts 
recei ve d pre-me dicati o n wit h de xa met has o ne, aceta mi n o p he n a n d di p he n h y dra mi ne pri or t o 
t he first 2 d oses, pri mi n g d ose a n d first f ull d ose res pecti vel y. 
Base d o n t he data fr o m t his st u d y , 7 6 m g Q W a d mi nistere d S C was selecte d as t he R P 2 D of 
elra nata ma b f or f ut ure st u dies. T his secti o n will f oc us o n safet y data fr o m partici pa nts w h o 
recei ve d elra nata ma b m o n ot hera py at t he f ull 1 0 0 0 μ g/ k g or 7 6 m g [ Q W or Q 2 W] d osi n g 
re gi me n ( N = 4 1) re gar dless of pri mi n g d ose or pre me dicati o n.
I n t he 4 1 partici pa nts w h o recei ve d elra nata ma b m o n ot hera py at t he f ull 1 0 0 0 μ g/ k g or 7 6 m g 
[ Q W or Q 2 W] d osi n g re gi me n , t he m ost c o m m o n all ca usalit y T E A Es (fre q ue nc y ≥2 0 %) 
were C R S ( 8 7. 8 %), n e utr o pe nia ( 7 8. 0 %), a ne mia ( 6 3. 4 %), I S R ( 5 6. 1 %), t hr o m b oc y t o pe nia 
a n d fati g ue (eac h 4 8. 8 %), diarr hea, h y p o p h os p hate mia a n d l y m p h o pe nia (eac h 3 9. 0 %), 
decrease d a p petite a n d dr y s ki n (eac h 3 6. 6 %), bac k pai n ( 3 4. 1 %), na usea a n d 
h y p o ma g nesae mia (eac h 3 1. 7 %), A S T i ncrease d a n d le u k o pe nia (eac h 2 6. 8 %), A L T 
i ncrease d, fall, hy p o kale mia, p yre xia, v o miti n g, pai n i n e xtre mit y a n d wei g ht decrease d (eac h 
2 4. 4 %), art hral gia, c o u g h, d y s p n oea, hea dac he a n d p ne u m o nia (eac h 2 2. 0 %).
F or a d diti o nal i nf or mati o n , refer t o t he si n gle refere nce safety d oc u me nt ( S R S D), w hic h f or 
t his st u d y is t he In vesti gat or’s B r oc h ure. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 9 7
1. 2. 3. 2. Effic ac y
Cli nical acti vit y  has bee n o bser ve d i n St u d y C 1 0 7 1 0 0 1. As of t he 2 2 J u ne 2 0 2 2 data c ut off 
date , t he c o nfir me d o bjecti ve res p o nse rate at t he f ull 1 0 0 0 μ g/ k g or 7 6 m g [ Q W or Q 2 W 
d osi n g re gi me n ( N = 4 1)] was 6 3. 4 % ( 9 5 % CI, 4 8. 1, 7 6. 4), p er I M W G criteria . Res p o nses 
were d ura ble a n d dee pe ne d o ver ti me. Me dia n d urati o n of f oll o w -u p f or all 4 1 patie nts 
treate d at t he f ull 1 0 0 0 μ g/ k g or 7 6 m g ( Q W or Q 2 W d osi n g re gime n) was 1 0. 9 4 m o nt hs 
( 0. 3 0, 2 4. 4 1). F or res p o n di n g partici pa nts, t he me dia n d urati o n of res p o nse ( 9 5 % CI) was 
1 1. 6 ( 7. 2, N E) m o nt hs. T he me dia n pr o gressi o n -free s ur vi val ( 9 5 % CI) was 1 0. 4 ( 4. 7, 1 5. 2) 
m o nt hs .
A d diti o nal i nf or mati o n f or t his c o m p o u n d ma y  be f o u n d i n t he si n gle refere nce safet y 
d oc u me nt ( S R S D), w hic h f or t his st u d y  is t he In vesti gat or’s B r oc h ure. 
1. 2. 3. 3. M o n ocl o n al A nti b o d y I nterfere nce of L a b or at or y E v al u ati o n of M yel o m a
Wit h t he i ncreasi n g use of t hera pe utic i m m u n o gl o b uli n G ka p pa (I g Gk) m A bs , eit her as a 
treat me nt f or m ulti ple m yel o ma itself, or f or ot her reas o ns, t he iss ue of m A b i nterfere nce a n d 
ass ociate d false-p ositi ve res ults i n t he m o n ocl o nal s pi ke (M- s pi ke) assa y f or patie nts wit h 
I g Gk m ulti ple m y el o mas has bee n n ote d. O n b ot h ser u m pr otei n electr o p h oresis (S P E P ) a n d 
ser u m i m m u n ofi xati o n electr o p h oresis (SI F E ) met h o ds, a visi ble a n d q ua ntifia ble m y el o ma 
pr otei n ( M- pr otei n ) c orres p o n di n g t o t he t hera pe utic a nti b o d y  ma y mi grate wit h si milar 
c haracteristics t o t he patie nt’s o w n M -s pi ke. T his has pr o m pte d t he i nter nati o nal m yel o ma 
w or ki n g gr o u p (I M W G) t o iss ue a n u p date d defi niti o n of C R t hat w he n l o o ki n g at detecta ble 
m y el o ma pr otei n ( M- pr otei n ) i n peri p heral bl o o d, t he prese nce or a bse nce of m o n ocl o nal
ba n ds b y  S P E P a n d SI F E m ust be ma de o nl y  i n refere nce t o t he patie nt’s ori gi nal M-pr otei n 
secrete d by pat h ol o gic plas ma cells .2 7  T his s pea ks t o t he i m p orta nce of ha vi n g a baseli ne 
sa m ple fr o m t he patie nt’s ori gi nal disease cl o ne a n d als o t he nee d f or e x perie nce d rea ders 
w h o ca n rec o g nize c haracteristic mi grati o n patter ns of cert ai n t hera pe utic m A bs. St u dies 
re p ort t he detecti o n li mit i n S P E P a n d SI F E assa ys usi n g sa m ples s pi ke d wit h t hera pe utic 
m A bs t o be 1 0 0 g/ ml; a c o nce ntrati o n t hat is well e xcee de d i n t he circ ulati o n at t hera pe utic 
d oses .2 8  P F -0 6 8 6 3 1 3 5, h o we ver, is pre dicte d t o reac h a ma xi mal ser u m c o nce ntrati o n of 
1 0 0 µ g/ ml o nl y  at d oses of 2 5 0 0 μ g/ k g a n d a b o ve; he nce t here is n o e x pectati o n of 
t hera pe utic m A b i nterfere nce i n t he M-s pi ke assa y i n t his i nsta nce.
1. 2. 4. N o ncli nic al S afet y I nf or m ati o n
I n n o ncli nical safet y st u dies c o n d ucte d i n c yn o m ol g us m o n ke y s wit h P F-0 6 8 6 3 1 3 5 
a d mi nistere d b y eit her t he I V or S C r o ute f or u p t o 1 -m o nt h i n d urati o n, t he ke y  effects were 
c yt o ki ne ele vati o ns t hat were occasi o nall y acc o m pa nie d b y e mesis d uri n g t he first 6 h o urs 
after t he first dr u g a d mi nistrati o n a n d mi ni mal t o m o derate i nfla m mati o n at t he i njecti o n 
site. Decreases i n B cells a n d plas ma cells as well as fl uct uati o ns i n peri p heral T- cell
n u m bers were o bser ve d i n I V st u dies w here i m m u n o p he n ot y pi n g meas ure me nts were 
i ncl u de d. All of t hese effects were c o nsi dere d relate d t o t he mec ha nis m of acti o n.
I n 
a d diti o n, re d s ki n disc ol orati o n was n ote d i n a s u bset of a ni mals a d mi nistere d P F - 0 6 8 6 3 1 3 5 
b y  t he I V r o ute. N o ne of t he effects were c o nsi dere d a d verse.
T h us, t he n o o b ser ve d a d verse 
effect le vel ( N O A E L) i n t he pi v otal t o xicit y  st u d y was 0. 3 m g/ k g i n m o n ke y s [ hi g hest d ose 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M




P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 9 9
M O L P- 8 (a m ulti ple m yel o ma cell li ne wit h t( 1 1; 1 4)( q 1 3; q 3 2) c hr o m os o mal a b n or malit y  
a n d ne gati ve f or C D 2 8) t u m or m o dels. 
Fi g ure 2.
P F- 0 6 8 6 3 1 3 5 Acti vit y i n a n O P M -2 M M Ort h otr o pic T u m or M o del
1. 2. 5. 3. A nti -tu m or Effic ac y of P F -0 6 8 6 3 1 3 5 i n C o m bi n ati o n wit h t he 
I m m u n o m o d ul at or y Dr u g Le n ali d o mi de i n Ort h ot o pic a n d S u bc ut a ne o us M yel o m a 
M o dels 
I n vi v o st u dies were perf or me d i n T cell e n grafte d h u ma n m yel o ma ort h ot o pic t u m or -beari n g 
mice t o e val uate t he c o m bi nati o n of P F -0 6 8 6 3 1 3 5 wit h t he i m m u n o m o d ulat or y  dr u g (I Mi D) 
le nali d o mi de (P F -0 6 8 6 3 1 3 5 _ 2 9 A pr 1 9 _ 0 9 3 4 0 4) .
I n t he hi g h B C M A e x pressi n g M M. 1 S m o del, P F -0 6 8 6 3 1 3 5 treat me nt res ulte d i n s u peri or 
a nti-t u m or res p o nse vers us le nali d o mi de al o ne. T u m or gr o wt h i n hi biti o n i n d uce d b y  
P F -0 6 8 6 3 1 3 5 was e n ha nce d w he n gi ve n i n c o m bi nati o n wit h le nali d o mi de c o m pare d t o 
si n gle a ge nt treat me nts, alt h o u g h it was n ot sta tisticall y si g nifica nt (Fi g ure 3 A) . Usi n g b o d y 
wei g ht as a meas ure me nt of p ote ntial f or t o xicit y , t here were n o i n dicati o ns t hat t he 
si n gle-a ge nt or c o m bi nati o ns t hera p ies ha d ne gati ve effects o n t he ge neral healt h of t he 
a ni mals d uri n g t he st u d y.   I n t he M O LP - 8 m o del, w hic h e x presses l o w le vels of B C M A, 
tu m or gr o wt h i n hi biti o n was statisticall y si g nifica ntl y e n ha nce d i n t he P F-0 6 8 6 3 1 3 5 + 
le nali d o mi de c o m bi nati o n c o m pare d t o ot her treat me nts (Fi g ure 3 B) .  T he h u ma n T cell 
e n grafte d m yel o ma m o dels ha ve a li mite d re pert oire of h u ma n i m m u ne cells e n grafte d a n d 
t heref ore t he y ca n n ot be use d t o c o m pre he nsi vely reca pit ulate all p ote ntial mec ha nis ms of 
acti o n of le nali d o mi de.  Per ha ps beca use of t his, t he e n ha nce me nt i n a nti -t u m or acti vit y was 
n ot statisticall y  si g nifica nt i n t he M M. 1 S m o del c o m pare d to si n gle a ge nt P F - 0 6 8 6 3 1 3 5 
treat me nt gr o u ps. E ve n s o, e n ha nce d t u m or acti vit y  of t he c o m bi nati o n of P F- 0 6 86 3 1 3 5 a n d 
le nali d o mi de was o bser ve d i n b ot h t he M M. 1 S a n d M O LP - 8 m o dels, s u g gesti n g t he p ote ntial 
f or sy ner g y i n t he h u ma n setti n g.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M




P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 1
i nfecti o n, d ys p nea, dizzi ness, t hr o m b oc yt o pe nia, tre m or a n d ras h. Le nali d o mi de, a 
t hali d o mi de a nal o g ue, ca n ca use e m br y o-fetal t o xicit y.
Le nali d o mi de will be d ose d at 1 5 m g orall y dail y da y s 1-2 1 of e ver y  2 8 da ys starti n g C 1 D 1. 
C o m plete i nf or mati o n f or t his c o m p o u n d ca n be f o u n d i n t he Cel ge ne U S PI, Re vli mi d®
(le nali d o mi de), S u m mit, Ne w Jerse y w hic h is t he S R S D f or t his st u d y .3 0 I n t he E U, 
Re vli mi d ® ca n be f o u n d at t he E ur o pea n Me dici nes A ge nc y  S P C.3 1 I n Ca na da t his 
c o m p o u n d ca n be f o u n d i n t he Cel ge ne Pr o d uct M o n o gra p h, R e vli mi d ® (le nali d o mi de) 
Mississa u ga, O ntari o .3 2
1. 2. 7. P o m ali d o mi de
P o mali d o mi de ( P o mal y st ® i n t he U S a n d I m n o vi d i n t he E U) is a t hali d o mi de a nal o g ue 
w hic h has direct a nti -m y el o ma t u m orici dal acti vit y, i n hi bits str o ma l cell s u p p ort f or M M 
t u m or cell gr o wt h a n d has i m m u n o m o d ulat or y acti vities.3 3  A d diti o nall y , p o mali d o mi de 
i n d uces t u m or cell deat h i n b ot h, le nali d o mi de-se nsiti ve a n d le nali d o mi de-resista nt cell li nes.  
P o mali d o mi de is i n dicate d i n c o m bi nati o n wit h de xa met has o ne f or patie nts wit h M M w h o 
ha ve recei ve d at least 2 pri or t hera pies i ncl u di n g le nali d o mi de a n d a pr oteas o me i n hi bit or 
a n d ha ve de m o nstrate d disease pr o gressi o n o n or wit hi n 6 0 da y s of c o m pleti o n of t he last 
t hera py. M ost c o m m o n si de effects i ncl u de fati g ue a n d ast he nia, ne utr o pe nia, a ne mia, 
c o nsti pati o n, na usea, diarr hea, d ys p nea, u p per -res pirat or y tract i nfecti o ns, bac k pai n, a n d 
p y re xia. Ras h, c o u g h, peri p heral e de ma, m uscle s pas ms, a n d h y p ot h y r oi dis m ca n als o be 
c o m m o n si de effects.  P o mali d o mi de, a t hali d o mi de a nal o g ue, ca n ca use e m br y o -fetal t o xicit y. 
A d ose of 4 m g  of p o mali d o mi de will be a d mi nistere d orall y o n Da ys 1- 2 1 of e ver y  2 8 d a y s
starti n g C 1 D 1. C o m plete i nf or mati o n f or t his c o m p o u n d ca n be f o u n d i n t he Cel ge ne U S PI, 
P o mal y st® ( p o mali d o mi de), S u m mit, Ne w Jerse y (t he S R S D f or t his st u d y).3 4 I n t he E U, 
I m n o vi d® ca n be f o u n d at t he E ur o pea n Me dici nes A ge nc y  S P C.3 5  I n Ca na da t his c o m p o u n d 
ca n be f o u n d i n t he Cel ge ne Pr o d uct M o n o gra p h, P o mal y st® ( p o mali d o mi de), Mississa u ga, 
O ntari o .3 6
1. 2. 8. De x a met h as o ne
De xa met has o ne is a c ortic oster oi d w hic h has i m m u n o m o d ulat or y  pr o perties a n d a nti-
ne o plastic acti vit y  a gai nst l ym p h oi d mali g na ncies i ncl u di n g m ulti ple m y el o ma. 3 7
De xa met has o ne has bee n use d i n t he pre ve nti o n a n d treat me nt of i m m u ne effect or cell -
ass ociate d t o xicities i ncl u di n g c y t o ki ne release sy n dr o me .3 8 ,3 9 I n a d diti o n t o its 
i m m u n o m o d ulat or y pr o perties, de xa met has o ne e x hi bits a nti-m y el o ma acti vit y a n d has bee n 
i nte grate d i nt o sta n dar d c o m bi nati o n re gi me ns s uc h as
b ortez o mi b/le nali d o mi de/ de xa met has o ne a n d
darat u m u ma b/le nali d o mi de/ de xa met has o ne. 4 0 ,4 1  Beca use t he effect of de xa met has o ne o n t he 
safety a n d efficac y of T -cell e n ga gi n g bis pecific a ge nts is n ot k n o w n, t he a d diti o n of 
de xa met has o ne t o P F -0 6 8 6 3 1 3 5 will be i n vesti gate d i n Part 1 E a n d P art 2 E .  T he m ost 
c o m m o n a d verse reacti o ns are car di o vasc ular, der mat ol o gic, e n d ocri ne, fl ui d a n d electr ol yt e 
dist ur ba nces, gastr oi ntesti nal, meta b olic, m usc ul os keletal, ne ur ol o gical/ ps yc hiatric, 
o p ht hal mic, a b n or mal fat de p osits, decrease d resista nce t o i nfecti o n, hicc u ps, i ncrease d or 
decrease d m otilit y  a n d n u m ber of s per mat oz oa, malaise, m o o n face, a n d wei g ht gai n.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 2
De xa met has o ne will be d ose d as pre me dicati o n at 4 0 m g orall y  6 0 ± 3 0 mi n utes pri or t o P F-
0 6 8 6 3 1 3 5 a d mi nistrati o n.  F or s u bjects ol der t ha n 7 5 ye ars or u n der wei g ht ( b o d y  mass i n de x 
[ B MI] < 1 8. 5), de xa met has o ne ma y be d ose d as pre me dicati o n at 2 0 m g  orall y 6 0 ± 3 0 
mi n utes pri or t o P F -0 6 8 6 3 1 3 5 a d mi nistrati o n. If a d ose of P F-0 6 8 6 3 1 3 5 is hel d or s ki p pe d, 
t he n de xa met has o ne s h o ul d n ot be a d mi nistere d. F or patie nts recei vi n g de xa met has o ne
pre me dicati o n, de xa met has o ne s h o ul d be disc o nti n ue d after 6 m o nt hs u nless cli nical 
rati o nale t o c o nti n ue de xa met has o ne is pr o vi de d b y i n vesti gat or a n d a p pr o ve d b y s p o ns or.
1. 2. 9. St arti n g D ose R ati o n ale
1. 2. 9. 1. I ntr a ve n o us (I V) St ar ti n g D ose R ati o n ale
T he selecti o n of t he starti n g d ose f or t his first -i n-patie nt ( FI P) st u d y  was base d o n t he 
mi ni m u m a ntici pate d bi ol o gical effect le vel ( M A B E L) i n acc or da nce wit h t he I nter nati o nal 
C o nfere nce o n Har m o nizati o n (I C H) S 9 G ui da nce, gi ve n t hat P F -0 6 8 6 3 1 3 5 is a bi -s pecific 
T- cell-e n ga gi n g a ge nt wit h i m m u ne a g o nistic pr o perties.  T he i n vitr o bi ol o gical acti vities f or 
P F -0 6 8 6 3 1 3 5 were deter mi ne d via T- cell acti vati o n, c yt o ki ne release, a n d c yt ot o xicit y 
e x peri me nts.  Base d o n e x p os ure -res p o nse a nal yses, ei g ht o ut of te n assa y meas ures ac hie ve d 
2 0 % ma xi mal effect (effecti ve c o nce ntrati o n [ E C] 2 0) a b o ve 1. 9 n g/ m L.  All te n assa y  
meas ures als o ac hie ve d 5 0 % ma xi mal effect ( E C 5 0) a b o ve 1. 9 n g/ m L.  T his E C 2 0 val ue i n 
c o m bi nati o n wit h t he pr ojecte d P F - 0 6 8 63 1 3 5 h u ma n p har mac o ki netics ( P K) base d o n 
all o metric scali n g of m o n ke y P K data were use d f or pr ojecti n g t he M A B E L d ose.  
S pecificall y, t he M A B E L d ose was calc ulate d b y setti n g t he ma xi m u m ( or pea k) ser u m 
c o nce ntrati o n ( C ma x ) less t ha n or e q ual t o t he 1. 9 n g/ m L t hres h ol d (ass u mi n g pea k c y t o ki ne 
release a n d C D 3 + T- cell acti vati o n is dri ve n b y ma xi m u m dr u g e x p os ure).  I n a d diti o n, 
rece pt or occ u pa nc y ( R O) was calc ulate d base d o n i n vitr o bi n di n g affi nities (e q uili bri u m 
diss ociati o n c o nsta nt or K D ) of P F- 0 6 8 6 3 1 35 ( 3 8 p M a gai nst B C M A a n d 1 7 n M a gai nst 
C D 3) t o f urt her e ns ure t hat t he rec o m me n de d M A B E L starti n g d ose will res ult i n mi ni m u m 
rece pt or bi n di n g.
Base d o n t his M A B E L a p pr oac h, t he cli nical starti n g d ose selecte d f or t he st u d y  is 0. 1 μ g/ k g 
gi ve n as a 2 - h o ur i ntra ve n o us i nf usi o n gi ve n wee kl y i n 3 wee k c y cles.  As P F -0 6 8 6 3 1 3 5 has 
a pr ojecte d half -life of 3. 5 da y s i n h u ma ns, a wee kl y re gi me n, wit h a pr ojecte d < 1. 3 3 -f ol d 
e x p os ure acc u m ulati o n rati o at stea d y state acr oss t he pla n ne d d ose escalati o n ra n ge was 
c hose n t o mai ntai n a hi g her a vera ge c o nce ntrati o n o ver t he d osi n g i nter val (a p ote ntial dri ver 
of efficac y ) relati ve t o Cma x .  T he h u ma n C ma x f or u n b o u n d P F -0 6 8 6 3 1 3 5 at t he starti n g d ose 
of 0. 1 μ g/ k g is pr ojecte d t o be a p pr o xi matel y 1. 1 n g/ m L, w hic h is e x pec te d t o res ult i n 
mi ni mal bi ol o gical effec t.  T his free c o nce ntrati o n pr ojecti o n acc o u nts f or bi n di n g t o t y pical 
le vels of ser u m s ol u ble B C M A ( 2. 5 7 n g/ m L) i n healt h y  h u ma ns.  Beca use t he ser u m s ol u ble 
B C M A le vels are ele vate d i n rela pse d/refract or y  M M patients, t he u n b o u n d P F -0 6 8 6 3 1 3 5 
c o nce ntrati o ns at C ma x ma y  be l o wer.  I n a d diti o n, t he rec o m me n de d starti n g d ose of 
0. 1 g/ k g is e x pecte d t o res ult i n mi ni m u m rece pt or bi n di n g, as t he t he oretical rece pt or 
occ u pa nc y  (R O ) val ues at t he pr ojecte d Cma x are less t ha n 1 7 % f or B C M A a n d 0. 0 5 % C D 3.
A b o d y  wei g ht-base d d osi n g a p pr oac h (g/ k g ) will be a p plie d f or t he d ose -escalati o n part 
( Part 1) of FI P st u d y  of P F-0 6 8 6 3 1 3 5 wit h t he g oal t o re d uce i nter -i n di vi d ual variati o ns i n 
P K e x p os ure.  Fi xe d -d osi n g a p pr oac h will be a p plie d i n d ose -fi n di n g f or c o m bi nati o n a n d
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 3
als o i n all e x pa nsi o n parts of t he st u d y (see Secti o n 1. 2. 9. 4 f or m ore details). Pfizer i nte n ds 
t o c o n d uct p o p ulati o n P K a nalys is of P F- 0 6 8 6 3 1 3 5 after s ufficie nt data ha ve bee n c ollecte d 
t o i nf or m o pti mal d osi n g a p pr oac h f or f ut ure st u dies.
1. 2. 9. 2. S u bc ut a ne o us ( S C) St arti n g D ose R ati o n ale
T he pr o p ose d starti n g d ose f or S C a d mi nistrati o n is 8 0 µ g/ k g, o ne d ose le vel hi g her (“ D ose 
I V + 1”) t ha n t he pre vi o usl y teste d I V d ose le vel ( 5 0 µ g/ k g) i n Part 1 I V a d mi nistrati o n t hat is 
dee me d safe.   Ta ki n g e x pecte d bi oa vaila bilit y  f or S C vers us IV i nt o c o nsi derati o n, t he 
8 0 µ g/ k g S C d ose is e x pecte d t o ha ve l o wer e x p os ure t ha n 5 0 µ g/ k g I V. A vaila ble a n d 
e mer gi n g safet y data fr o m c o m plete d a n d i nitiate d I V a d mi nistrati o n c o h orts i n t he d ose 
escalati o n Part 1 I V i nf or me d a n d s u p p orte d t he decisi o n t o i nitiate S C a d mi nistrati o n.
Base d o n a n ass u me d bi oa vaila bilit y  ≤1 0 0 % a n d sl o we d u pta ke t o t he s ys te mic circ ulati o n 
wit h S C a d mi nistrati o n, t he s y ste mic e x p os ure Cma x a n d area u n der t he c ur ve ( A U C ) after S C 
a d mi nistrati o n at t he starti n g d ose di d n ot e xcee d e x p os ures of “ D ose I V - + 1” f or S C d ose
escalati o n.  C o nse q ue ntl y, relati ve t o t he ne xt pr o p ose d d ose le vel i n Part 1 I V, t he S C 
starti n g d ose c o h ort is e x pecte d t o e x hi bit c o m para ble or less se vere sys te mic a d verse e ve nts, 
i ncl u di n g C R S.  T his s h o ul d re d uce t he p ote ntial f or t o xicit y wit h t he i nitial tra nsiti o n fr o m 
I V t o S C d osi n g. T he s p o ns or ma y  deci de t o disc o nti n ue or pa use t he I V d ose escalati o n a n d 
o nl y  deter mi ne an M T D / M A D f or t he S C r o ute. 
I n c yn o m ol g us m o n ke y s, P F- 0 6 8 6 3 1 3 5 was well t olerate d f oll o wi n g re peate d I V d oses u p t o 
3 0 0 µ g/ k g or f oll o wi n g re peate d S C d oses u p t o 3 0 0 µ g/ k g. F or refere nce, f oll o wi n g S C 
a d mi nistrati o n of P F -0 6 8 6 3 1 3 5 at 1 0 0 µ g/ k g wee kl y  i n h u ma ns a n d ass u mi n g 
1 0 0 % bi oa vaila bilit y , t he s yste mic ma xi m u m c o nce ntrati o n ( C ma x ) is pre dicte d t o be 
a p pr o xi matel y 3 3. 4 % a n d 5 7. 0 % of t he Cma x o bser ve d f oll o wi n g a d mi nistrati o n of 3 0 0 µ g/ k g 
I V a n d 3 0 0 µ g / k g S C, res pecti vel y i n c yn o m ol g us m o n ke y s.  Si milarl y, t he area u n der t he 
c o nce ntrati o n-ti me c ur ve f or the first d osi n g i nter val ( A U C 0 - 1 6 8) f oll o wi n g si n gle S C 
a d mi nistrati o n of P F -0 6 8 6 3 1 3 5 at 1 0 0 µ g/ k g wee kl y  i n h u ma ns is pre dicte d t o be 
a p pr o xi matel y 5 7. 6 % a n d 4 9. 8 % of t he A U C deter mi ne d f oll o wi n g t he a d mi nistrati o n of 
3 0 0 µ g/ k g I V a n d 3 0 0 µ g/ k g S C, res pec ti vel y, i n c yn o m ol g us m o n ke y s. T h us, e x p os ures of 
P F -0 6 8 6 3 1 3 5 f oll o wi n g S C a d mi nistrati o n u p t o 1 0 0 µ g/ k g are pr ojecte d t o be l o wer t ha n 
t h ose o bser ve d to be well t olerate d i n c y n o m ol g us m o n ke y .
1. 2. 9. 3. St arti n g D ose f or C o m bi n ati o n S afet y C o h orts ( P arts 1 C, 1 D a n d 1 E ) 
T he d ose fi n di n g e val uati o n wit h P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h le nali d o mi de or 
p o mali d o mi de is pla n ne d t o be i nitiate d after t he P F-0 6 8 6 3 1 3 5 m o n ot hera p y  d ose escalati o n, 
a n d t he M T D/ M A D a n d R P 2 D
of P F -0 6 8 6 3 1 3 5 m o n ot hera p y has bee n deter mi ne d .  T he 
starti n g d ose of P F-0 6 8 6 3 1 3 5 f or t he c o m bi nati o n wit h le nali d o mi de or p o mali d o mi de 
t hera py will be 1 d ose le vel bel o w t he M T D / M A D if t he M T D/ M A D a n d R P 2 D of 
m o n ot hera p y P F -0 6 8 6 3 1 3 5 are e q ual, a n d t he d ose of P F -0 6 8 6 3 1 3 5 will be d ose escalate d t o 
t he m o n ot hera p y M T D/ M A D or R P 2 D . If t he m o n ot hera py R P 2 D is alrea d y at least 1 d ose 
le vel bel o w t he M T D/ M A D, t he n t he R P 2 D will be use d as t he starti n g d ose of P F- 0 6 8 6 3 1 3 5 
i n c o m bi nati o n wit h le nali d o mi de or p o mali d o mi de , a n d n o d ose escalati o n will be pla n ne d.
Le nali d o mi de will be d ose d at 1 5 m g orall y dail y da y s 1-2 1 of e ver y  2 8 da y s starti n g C 1 D 1. 
P o mali d o mi de will be d ose d at 4 m g orall y dail y D a ys 1-2 1 of e ver y  2 8 da ys starti n g C 1 D 1.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 4
Part 1 E will i n vesti gate P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h de xa met has o ne .  De xa met has o ne 
w o ul d be gi n o n C 0 D 1 a n d it will be d ose d as pre me dicati o n pri or t o P F - 0 6 8 6 3 1 3 5
a d mi nistrati o n. D ue t o n o n -o verla p pi n g t o xicit y  bet wee n P F - 0 6 8 6 3 1 3 5 a n d de xa met has o ne,
this safet y  c o h ort will e val uate t he R P 2 D of P F-0 6 8 6 3 1 3 5 m o n ot hera p y a n d a fi xe d d ose of 
de xa met has o ne, at a d ose of 4 0 m g. F or s u bjects ol der t ha n 7 5 years or u n der wei g ht ( b o d y 
mass i n de x [ B MI] < 1 8. 5), de xa met has o ne pre me dicati o n ma y  be gi ve n pri or t o P F - 0 6 8 6 3 1 3 5
at a fi xe d d ose of 2 0 m g. If a d ose of P F-0 6 8 6 3 1 3 5 is hel d or s ki p pe d, t he n de xa met has o ne 
s h o ul d n ot be a d mi nistere d. F or patie nts recei vi n g de xa met has o ne pre me dicati o n, 
de xa met has o ne s h o ul d be disc o nti n ue d after 6 m o nt hs u nless cli nical rati o nale t o c o nti n ue 
de xa met has o ne is pr o vi de d b y i n vesti gat or a n d a p pr o ve d b y  s p o ns or.
1. 2. 9. 4. Fi xe d D osi n g A p pr o ac h 
A fi xe d-d ose a p pr oac h will be a p plie d f or P F -0 6 8 6 3 1 3 5 i n Part s 1 C, 1 D a n d 1 E a n d Part 2 
gi ve n t hat a fi xe d d osi n g a p pr oac h was s h o w n t o pr o vi de si milar P K varia bilit y c o m pare d t o 
b o d y - wei g ht a dj uste d d osi n g w he n e val uate d f or m o n ocl o nal a nti b o dies, t hera pe utic 
pe pti des, a n d pr otei ns. 4 2 ,4 3 I n a d diti o n, fi xe d d osi n g offers ease of pre parati o n a n d less 
c ha nce of d osi n g err ors. Base d o n t he preli mi nar y p o p ulati o n P K a nal y sis of P F- 0 6 8 6 3 1 3 5 
i n 4 1 patie nts u p t o 3 6 0 µ g/ k g d ose, t here is n o cli nicall y mea ni n gf ul effect of b o d y wei g ht 
(ra n ge: 4 7. 9 t o 1 2 0 k g) or b o d y  s urface area (ra n ge: 1. 3 7 t o 2. 3 6 m 2), o n t he P F- 0 6 8 6 3 1 3 5 
cleara nce a n d f urt her j ustifies fi xe d d osi n g a p pr oac h f or e x pa nsi o n parts of t he o n g oi n g 
st u d y. Als o, a ge (ra n ge: 4 7 t o 8 2 years) or se x ( 2 0 males vs 2 1 fe males) were n ot cli nicall y 
mea ni n gf ul c o variate s o n P F -0 6 8 6 3 1 3 5 e x p os ure .
1. 2. 9. 5. D osi n g I nter v al
T he i nitial Q 1 W d osi n g fre q ue nc y of P F -0 6 8 6 3 1 3 5 i n t hi s st u d y was selecte d base d o n t he 
pr ojecte d t1/ 2 of 4- 8 da y s in h u ma ns . Base d o n e mer gi n g P K, P D, a n d safet y data, re gi me ns 
wit h alter nati ve d osi n g fre q ue ncies (e g, Q 2 W or Q 4 W) ma y  als o be c o nsi dere d. I n or der t o 
re d uce t he b ur de n of wee kl y visits, if a patie nt has recei ve d treat me nt wit h Q 1 W 
P F - 0 6 8 6 3 1 3 5 f or at least 6 m o nt hs, a n d disease assess me nts ha ve re mai ne d sta ble o ver at 
least 2 m o nt hs, c o nsi derati o n ma y be gi ve n t o i ncreasi n g d ose i nter vals fr o m wee kly t o e ver y 
2 wee ks or o nce per c y cle ( C X D 1) after c o ns ultati o n wit h t he s p o ns or. C y cles w o ul d re mai n 
t he sa me le n gt h. It w o ul d be prefera ble t o s ki p d osi n g of P F-0 6 8 6 3 1 3 5 o n da y s 8 a n d 2 2 of 
eac h c ycle if c ycles are 4 wee ks i n le n gt h . If t he patie nt s u bse q ue ntl y be gi ns t o ha ve a n 
i ncrease of disease b ur de n, d ose i nter vals s h o ul d ret ur n t o wee kl y d osi n g.
I n a d diti o n, if P K data at a n y p oi nt d uri n g S C Q 1 W d ose escalati o n s u g gests t hat a Q 2 W 
d ose sc he d ule ma y  be a ble t o ac hie ve s ufficie nt tr o u g h c o nce ntrati o ns a n d pr o vi de a de q uate 
s yste mic e x p os ure, a Q 2 W d osi n g sc he d ule w o ul d re place Q 1 W at the ne xt hi g her d ose le vel
if M T D or M A D ha ve n ot bee n reac he d. If it is p ossi ble a n d warra nte d t o c o nti n ue d ose 
escalati o n wit h S C Q 2 W e ve n if M T D / M A D has bee n reac he d f or S C Q 1 W, Part 1. 1 ma y  be 
use d wit h pri mi n g d ose at t he M T D / M A D of S C Q 1 W a n d s u bse q u e nt escalati o n t o ne xt 
hi g her d ose le vel wit h S C Q 2 W d osi n g as mai nte na nce, pr o vi de d t hat t he ne xt hi g her d ose 
le vel gi ve n Q 2 W w o ul d n ot e xcee d t he o verall e x p os ure t hat ha d bee n ac hie ve d at 
M T D / M A D of S C Q 1 W.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 5
C y cles f or Q 2 W d osi n g w o ul d be 4 wee ks. B ot h Q 1 W a n d Q 2 W d osi n g will be c o nsi dere d 
f or R P 2 D deter mi nati o n fr o m Part 1.
1. 2. 9. 6. Pri mi n g a n d M ai nte n a nce D ose R ati o n ale
I n a P hase 2 trial of bli nat u m o ma b i n a d ults patie nts wit h rela pse/refract or y ac ute 
l ym p h o blastic le u ke mia ( A L L), d ose li miti n g t o xicities of Gra de 4 c yt o ki ne release 
s yn dr o me ( C R S) were re p orte d i n 2 o ut of 7 patie nts treate d at 1 5 g/ m 2/ da y .4 4 It was f o u n d 
t hat if treat me nt was i nterr u pte d f or 1- 2 wee ks, patie nts rec o vere d s ufficie ntl y  f or treat me nt 
t o res u me.  T his le d t o t he i m ple me ntati o n of a l o wer starti n g d ose ( pri mi n g d ose) of 
5 g / m 2/da y  f or t he first wee k, escalati n g t o 1 5 a n d 3 0 g/ m 2 per da y s u bse q ue ntl y.  Of t he 
1 1 patie nts treate d wit h t his a p pr oac h wit hi n t he sa me st u d y , 2 patie nts de vel o pe d Gra de 3 
C R S , b ut n o d ose li miti n g Gra de 4 or 5 C R S was o bser ve d. 4 4 W he n t his
ste p wise a p pr oac h 
was a p plie d t o a sec o n d P hase 2 st u d y , o nl y 3 patie nts o ut of 1 8 9 treate d e x perie nce d C R S
( Gra de 3) b ut n o Gra de 4 or 5 C R S was o bser ve d .1 8 T h us, it was c o ncl u de d t hat t he 
i m ple me ntati o n of a pri mi n g d ose a p pr oac h is effecti ve i n a meli orati n g C R S t hr o u g h 
b uil di n g t olera nce , a n d it has bec o me t he rec o m me n de d treat me nt re gi me n f or A L L patie nts.  
Base d o n pri mi n g f oll o we d b y  mai nte na nce bei n g de m o nstrate d t o be p ote ntiall y s uccessf ul 
i n re d uci n g C R S, t his a p pr oac h ma y be e val uate d pri or t o reac hi n g an M T D / M A D (see 
Secti o n 3. 1. 1. 3 ). T his a p pr oac h ma y  be i m ple me nte d t o re d uce C R S relate d t o xicities if 
i n dicate d f or patie nt safet y.
1. 2. 1 0. Bi o m ar ker R ati o n ale
T he o bjecti ves of t he bi o mar ker assess me nts will be t o u n dersta n d t he relati o ns hi p bet wee n 
t he p har mac o ki netics ( P K), tar get l oa d, i m m u ne cell p he n oty pes, a n d p har mac o d y na mic 
acti vit y of P F- 0 6 8 6 3 1 3 5, wit h a n d wit h o ut c o m bi nati o n part ners, a n d its a nti-t u m or acti vit y 
a n d safet y pr ofile.  T his u n dersta n di n g will i n t ur n i nf or m t he selecti o n of a t hera pe utic d ose, 
as well as p ote ntiall y i de ntif y a p he n ot y pic pr ofile t hat ma xi mizes a nti -t u m or acti vit y w hile 
mi ni mizi n g t he ris k of t o xicit y . 
Tar get l oa d will be assesse d usi n g a fl o w c y t o metr y assa y t o meas ure cell s urface B C M A o n 
m ulti ple m y el o ma cells i n fres h b o ne marr o w as pirates at baseli ne.  Le vels of circ ulati n g 
s ol u ble B C M A will be meas ure d fr o m plas ma sa m ples bef ore a n d after P F-0 6 8 6 3 1 3 5 usi n g 
mass s pectr o metr y .  T he relati o ns hi p bet wee n tar get l oa d a n d t he p har mac o ki netics of 
P F -0 6 8 6 3 1 3 5 will pr o vi de g ui da nce f or d ose selecti o n f or P F -0 6 8 6 3 1 3 5.  T he g oal of t his 
a nal ys is will be t o select d oses t hat e x hi bit a n acce pta ble safety pr ofile, a n d p ote ntiall y  
pr o vi d e e vi de nce of a nti -t u m or acti vit y.  T he p har mac o d yna mic effect of B C M A: C D 3 
e n ga ge me nt b y P F -0 6 8 6 3 1 3 5 will b e i n vesti gate d i n t he b o ne marr o w f or all patie nts.  
P ote ntial effects of P F- 0 6 8 6 3 1 3 5 o n T- cell s u bset perce nta ges , pr oliferati o n a n d s ur vi val, a n d 
acti vati o n mar kers will be assesse d b y fl o w c yt o metr y.  I n a d diti o n t o t hese fl o w c yt o metr y 
a nal ys es, b o ne m arr o w bi o ps y tiss ue sa m ples will be assesse d f or si milar e n d p oi nts i ncl u di n g 
B C M A e x pressi o n a n d T- cell s u bset i m m u n o p he n ot ypi n g b y  i m m u n o hist oc he mistr y (I H C).  
T he s patial relati o ns hi p of m y el o ma cells a n d T- cells ma y be i nterr o gate d .  T hereafter, 
material a n d assa y  per mitti n g, a d diti o nal e x pl orat or y a nalys es ma y be u n derta ke n t o f urt her 
e val uate mec ha nis m of acti o n a n d/ or resista nce. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 6
T o m o nit or f or p ote ntial i m m u ne acti vati o n or i nfla m mati o n res ulti n g fr o m t he 
i m m u n osti m ulat or y effects of d osi n g wit h P F -0 6 8 6 3 1 3 5, ser u m will be c ollecte d t o meas ure 
c yt o ki nes a n d c he m o ki nes, a n d w h ole bl o o d a bs ol ute cell c o u nts (T, B, a n d N K [ nat ural 
killer] l ym p h oc y tes or T B N K) will be meas ure d. 
T he m ost c halle n gi n g o bjecti ve of t he bi o mar ker pla n wi ll be t o disc o ver mar kers t hat 
i de ntif y patie nts at baseli ne m ost li kel y t o res p o n d t o P F-0 6 8 6 3 1 3 5 t hera p y wit h mi ni mal ris k 
of t o xicit y .  E x pl orat or y a nalys es ma y be u n derta ke n t o u n dersta n d t he bi ol o gical basis f or 
res p o nse t o B C M A: C D 3 e n ga ge me nt.  T hese meas ures will atte m pt t o a d dress w het her 
baseli ne le vels or c ha n ges i n b o ne marr o w ri b o n ucleic aci d ( R N A) e x pressi o n, a n d T- cell
cl o nal di versit y c orrelate wit h t u m or res p o nse.  B o ne marr o w sa m ple ma y  be s u b mitte d t o 
R N A pr ofili n g a nal ys is t o i nterr o gate t he bala nce bet wee n i m m u ne tra nscri pts ass ociate d 
wit h i m m u ne acti vati o n a n d i m m u ne re g ulati o n.  T -cell re pert oire di versit y ma y be assesse d 
b y  hi g h t hr o u g h p ut se q ue nci n g of T-cells fr o m b o ne marr o w tiss ue a n d/ or peri p heral bl o o d.  
W h ole bl o o d a n d, s a m ple per mitti n g, a p orti o n of t he b o ne marr o w sa m ple ma y  be use d f or 
de o x yri b o n ucleic aci d (D N A ) is olati o n f or e x pl orat or y a nalys es s uc h as p har mac o ge n o mics.  
T hese assess me nts ma y  be a nalyz e d i n t he c o nte xt of cli nical res p o nse data t o p ote ntiall y  
i de ntif y patie nts wit h t he hi g hest pr o ba bilit y of res p o n di n g t o B C M A: C D 3 e n ga ge me nt.  All 
of t hese meas ures will be c orrelate d wit h meas ures of t o xicit y  a n d a nti-t u m or acti vit y t o 
ascertai n t heir usef ul ness as p ote ntial bi o mar kers of cli nical be nefit.
1. 2. 1 0. 1. B a n ke d Bi os pec i me ns
Ba n ke d b i os peci me ns will be c ollecte d f or t he p ur p ose of c o n d ucti n g researc h; s pecific uses 
are descri be d i n t he B a n ke d B i os peci me ns Secti o n 7. 7 .  C o m pari n g t he D N A, R N A, pr otei n, 
a n d meta b olite variati o n patter ns of patie nts w h o res p o n d well a n d t h ose w h o res p o n d p o orl y 
t o treat me nt ma y hel p t o better defi ne t he m ost a p pr o priate gr o u p of patie nts i n w hic h t o 
tar get a gi ve n treat me nt.  C ollecti n g bi os peci me ns f or e x pl orat or y 
p har mac o ge n o mic/ ge n o mic/ bi o mar ker a nal yses a n d retai ni n g t he m i n t he Bi os peci me n 
Ba n ki n g S ys te m ( B B S) ma ke it p ossi ble t o better u n dersta n d t he i n vesti gati o nal pr o d uct’s 
mec ha nis m of acti o n a n d t o see k e x pla nati o ns f or differe nces i n, f or e xa m ple, e x p os ure, 
t olera bilit y, safety, a n d/ or efficac y n ot a ntici pate d pri or t o t he be gi n ni n g of t he st u d y .
Ba n ke d b i os peci me ns retai ne d i n t he B B S als o ca n be use d i n research o n M M .
Pr o vi di n g t hese bi os peci me ns is a re q uire d st u d y acti vit y f or st u d y sites a n d patie nts, u nless 
pr o hi bite d b y  l ocal re g ulati o ns or et hics c o m mittee ( E C) decisi o n.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 7
2. S T U D Y O B J E C TI V E S A N D E N D P OI N T S
2. 1. P art 1 I V a n d S C m o n ot her a p y D ose Esc al ati o n , P art 1 . 1 Pri mi n g a n d M ai nte n a nce D ose Esc al ati o n
a n d P art s 1 C, 1 D a n d 
1 E D ose Esc al ati o n/ Fi n di n g
Pri m ar y O bjecti ves: 
Pri m ar y E n d p oi nts: 

T o assess safet y a n d t olera bilit y at i ncreasi n g d ose 
le vels of P F-0 6 8 6 3 1 3 5 as m o n ot hera p y a n d i n 
c o m bi nati o n wit h le nali d o mi de, p o mali d o mi de, or 
de xa met has o ne i n s uccessi ve c o h orts of patie nts wit h 
m ulti ple m yel o ma i n or der t o esti mate t he Ma xi m u m 
T olerate d D ose ( M T D) or Ma xi m u m A d mi nistere d 
D ose ( M A D) a n d select t he Rec o m me n de d P hase 2 
D ose ( R P 2 D).

N u m ber of D L Ts f oll o wi n g treat me nt wit h escalati n g d oses of P F -0 6 8 6 3 1 3 5 as 
m o n ot hera p y a n d i n c o m bi nati o n wit h le nali d o mi de, p o mali d o mi de, or de xa met has o ne .
Sec o n d ar y O bjecti ves: 
Sec o n d ar y E n d p oi nts: 

T o e val uate t he o verall safet y pr ofile. 

A d verse E ve nts as c haracterize d b y t y pe, fre q ue nc y, se verit y as gra de d b y N CI C T C A E 
versi o n 4. 0 3, ti mi n g, seri o us ness, a n d relati o ns hi p t o P F -0 6 8 6 3 1 3 5 treat me nt as 
m o n ot hera p y a n d i n c o m bi nati o n wit h le nali d o mi de, p o m ali d o mi de, or de xa met has o ne .  
T he se verit y of C R S will be assesse d acc or di n g t o t he gra di n g descri be d b y Lee et al. ( 2 0 1 4
a n d 2 0 1 9 ,2 ,3 See A p pe n di x 5 );

La b orat or y a b n or malities as c haracterize d b y t y pe, fre q ue nc y, se verit y (as gra de d b y N CI 
C T C A E versi o n 4. 0 3), a n d ti mi n g.

T o e val uate a nti -m yel o ma acti vit y of  P F-0 6 8 6 3 1 3 5 as 
m o n ot hera p y an d i n c o m bi nati o n wit h le nali d o mi de, 
p o m ali d o mi de, or de xa met has o ne .

O bjecti ve res p o nse rate ( O R R) usi n g t he i nter nati o nal m yel o ma w or ki n g gr o u p (I M W G) 
res p o nse criteria f or m ulti ple m yel o ma4 ,5 (see A p pe n di x 2 );

Ti m e t o e ve nt e n d p oi nts: ti me t o res p o nse ( T T R), c o m plete res p o nse rate ( C R R), d urati o n 
of res p o nse ( D O R), d urati o n of c o m plete res p o nse ( D o C R), d ur ati o n of sta ble dise ase 
( D O S D), pr o gressi o n -free s ur vi val ( P F S), o verall s ur vi val ( O S), as assesse d b y I M W G 
criteria f or res p o nse 4 ,5 (see A p pe n di x 2 );

Rate of patie nts wit h n o M R D after treat me nt wit h P F -0 6 8 6 3 1 3 5 usi n g I M W G M R D 
criteria 5 (see A p pe n di x 3 ).

T o e val uate si n gle d ose a n d m ulti ple d ose P K of 
P F -0 6 8 6 3 1 3 5 gi ve n as m o n ot hera p y a n d i n 
c o m bi nati o n wit h le nali d o mi de or p o mali d o mi de.
A d diti o nall y, P K of le nali d o mi de, p o mali d o mi de, a n d 

P har m ac o ki netic para meters of P F -0 6 8 6 3 1 3 5 : C y cle 1 Da y 1 d ose a n d C ycle 2 D a y 1 d ose 
ma xi m u m c o nce ntrati o n ( C ma x ), area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me 
zer o t o t he last q ua ntifia ble ti me p oi nt pri or t o t he ne xt d ose ( A U C last) a n d if data per mit, 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 8
de xa met has o ne will be e val uate d w he n c o m bi ne d wit h 
P F -0 6 8 6 3 1 3 5 ( Parts 1 C, 1 D , a n d 1 E, res pecti vel y).
cleara nce ( C L or C L/ F ), v ol u me of distri b uti o n at stea d y state ( Vss or Vss/ F ), a n d ter mi nal 
eli mi nati o n t 1/ 2..

P las ma le nali d o mi de, p o mali d o mi de, a n d de xa met has o ne c o nce ntrati o ns at selecte d ti me 
p oi nts ( Parts 1 C, 1 D , a n d 1 E , res pecti vel y). 

T o e val uate i m m u n o ge nicit y of  P F -0 6 8 6 3 1 3 5 as 
m o n ot hera p y a n d i n c o m bi nati o n wit h , le nali d o mi de,
p o m ali d o mi de. or de xa met has o ne .  

I nci de nce a n d titers of a nti-dr u g a nti b o dies (A D A ) a n d ne utralizi n g a nti b o dies ( Na b) 
a gai nst P F -0 6 8 6 3 1 3 5 .

T o c haracterize t he i m pact of P F -0 6 8 6 3 1 3 5 as 
m o n ot hera p y a n d i n c o m bi nati o n wit h le nali d o mi de, 
p o m ali d o m i de, or de xa met has o ne, o n s yste mic s ol u ble 
i m m u ne fact ors.

Pre - a n d p ost-d ose q ua ntificati o n of s ol u ble c yt o ki nes i n ser u m .
Terti ar y/ E x pl or at or y O bjecti ves: 
Terti ar y/ E x pl or at or y E n d p oi nts: 

E val uate t he effect of P F -0 6 8 6 3 1 3 5 as a m o n ot hera p y 
a n d i n c o m bi nati o n wit h le nali d o mi de, p o mali d o mi de,
or  de xa met has o ne o n plas ma cell, T a n d B cell 
c o m part me nts.

B C M A e x pressi o n o n plas ma cells i n b o ne marr o w , as assesse d b y m ulti para meter fl o w 
c yt o metr y a n d i m m u n o hist oc he mistr y;

Pre - a n d p ost-d ose le vels of s ol u ble B C M A;

E n u merati o n of T, B, a n d N K s u bt y pes i n w h ole bl o o d a n d b o ne marr o w b y  fl o w 
c yt o metr y a nal ysis;

T- cell i m m u n o p he n ot y pi n g, i ncl u di n g b ut n ot li mite d t o pr oliferati o n a n d acti vati o n 
mar kers i n w h ole bl o o d a n d b o ne marr o w  b y fl o w c yt o metr y a nal ysis;

T- cell e n ga ge me nt, i ncl u di n g b ut n ot li mite d t o pr oliferati o n a n d acti vati o n mar kers i n 
b o ne marr o w  b y i m m u n o hist oc he mistr y;

T he relati ve e x pressi o n of R N A tra nscri pts, i ncl u di n g b ut n ot li mite d t o, t h ose ass ociate d 
wit h i m m u ne acti vati o n a n d i m m u ne re g ulati o n i n b o ne marr o w;

T he a b u n da nce a n d di versit y of T- cell cl o nes i n b o ne ma rr o w.

T o c ollect ba n ke d bi os peci me ns f or e x pl orat or y 
researc h, u nless pr o hi bite d b y l ocal re g ulati o ns or 
et hics c o m mittee decisi o n.  

C ollecti o n of ba n ke d bi os peci me ns u nless pr o hi bite d b y l ocal re g ulati o ns or et hics 
c o m mittee decisi o n.  A d diti o nal i nf or mati o n o n c ollecti o n a n d p ote ntial use is pr o vi de d i n 
t he Ba n ke d Bi os peci me ns Secti o n 7. 7 .
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 9
2. 2. P art 2 D ose E x p a nsi o n
Pri m ar y O bjecti ves: 
Pri m ar y E n d p oi nts: 

T o assess preli mi nar y cli nical efficac y at 
R P 2 D f or P F-0 6 8 6 3 1 3 5 as m o n ot hera p y a n d
i n c o m bi nati o n wit h le nali d o mi de, 
p o m ali d o mi de, or de xa met has o ne .

O R R a n d D o R , as assesse d b y I M W G criteria f or 
res p o nse4 ,5 (see A p pe n di x 2 ).
Sec o n d ar y O bjecti v es: 
Sec o n d ar y E n d p oi nts: 

T o f urt her c haracterize t he safet y a n d 
t olera bilit y of P F-0 6 8 6 3 1 3 5 as m o n ot hera p y 
a n d i n c o m bi nati o n wit h le nali d o mi de, 
p o m ali d o mi de, or de xa met has o ne .

A d verse E ve nts as c haracterize d b y t y pe, 
fre q ue nc y, se verit y (as gra de d b y N CI C T C A E 
versi o n 4. 0 3), ti mi n g, seri o us ness, a n d 
relati o ns hi p t o P F -0 6 8 6 3 1 3 5 treat me nt as 
m o n ot hera p y a n d i n c o m bi nati o n wit h 
p o m ali d o mi de, le nali d o mi de, or de xa met has o ne .  
T he se verit y of C R S will be assesse d acc or di n g 
t o t he gra di n g descri be d b y Lee et al. ( 2 0 1 4 a n d 
2 0 1 9 ,2 ,3 See A p pe n di x 5 );

La b orat or y a b n or malities as c haracterize d b y 
t ype, fre q ue nc y, se verit y (as gra de d b y N CI 
C T C A E versi o n 4. 0 3), a n d ti mi n g.

T o f urt her e val uate a nti -m yel o ma efficac y of 
P F -0 6 8 6 3 1 3 5 as m o n ot hera p y a n d i n 
c o m bi nati o n wit h le nali d o mi de, 
p o m ali d o mi de, or de xa met has o ne .

Ti m e t o e ve nt e n d p oi nts: C R R, D o C R, T T R, 
D O S D, P F S, O S, as assesse d b y I M W G criteria 
f or res p o nse4 ,5 (see A p pe n di x 2 );

Rate of patie nts wit h n o M R D after treat me nt 
wit h P F -0 6 8 6 3 1 3 5 usi n g I M W G M R D criteria 5
(see A p pe n di x 3 ).

E val uate P K of P F -0 6 8 6 3 1 3 5 at R P 2 D as 
m o n ot hera p y a n d i n c o m bi nati o n wit h 
le nali d o mi de, p o mali d o mi de, or 
de xa met has o ne . A d diti o nall y, t o c ollect
le nali d o mi de, p o mali d o mi de, a n d 
de xa met has o ne c o nce ntrati o n data whe n 
c o m bi ne d wit h P F -0 6 8 6 3 1 3 5.

C o nce ntrati o ns of P F -0 6 8 6 3 1 3 5 , le nali d o mi de, 
p o m ali d o mi de, a n d de xa met has o ne at selecte d 
ti me p oi nts.

T o e val uate i m m u n o ge nicit y of  P F -0 6 8 6 3 1 3 5
as m o n ot hera p y a n d i n c o m bi nati o n wit h 
le nali d o mi de, p o m ali d o mi de, or
de xa met has o ne . 

I nci de nce a n d titers of a nti-dr u g a nti b o dies 
(A D A ) a n d ne utralizi n g a nti b o dies ( Na b ) a gai nst 
P F -0 6 8 6 3 1 3 5.

T o c haracterize t he i m pact of P F -0 6 8 6 3 1 3 5 as 
m o n ot hera p y a n d i n c o m bi nati o n wit h 
le nali d o mi de, p o mali d o mi de, or 
de xa met has o ne o n s yste mic s ol u ble i m m u ne 
fact ors.

Pre - a n d p ost-d ose q ua ntificati o n of s ol u ble 
c yt o ki nes i n ser u m.
Terti ar y/ E x pl or at or y O bjecti ves: 
Terti ar y/ E x pl or at or y E n d p oi nt): 

E val uate t he effect of P F -0 6 8 6 3 1 3 5 as 
m o n ot hera p y a n d i n c o m bi nati o n wit h 
le nali d o mi de, p o mali d o mi de, or 

B C M A e x pressi o n o n plas ma cells i n b o ne 
marr o w , as assesse d b y m ulti para meter fl o w 
c yt o metr y a n d i m m u n o hist oc he mistr y;
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 0
de xa met has o ne o n plas ma cell, T a n d B cell 
c o m part me nts.

Pre - a n d p ost-d ose le vels of s ol u ble B C M A;

E n u merati o n of T, B, a n d N K s u bt y pes i n w h ole 
bl o o d a n d b o ne marr o w b y fl o w c yt o metr y 
a nal ysis ;

T- cell i m m u n o p he n ot y pi n g, i ncl u di n g b ut n ot 
li mite d t o pr oliferati o n a n d acti vati o n mar kers i n 
w h ole bl o o d a n d b o ne marr o w b y fl o w 
c yt o metr y a nal ysis;

T- cell e n ga ge me nt, i ncl u di n g b ut n ot li mite d t o 
pr oliferati o n a n d acti vati o n mar kers i n b o ne 
marr o w  b y i m m u n o hist oc he mistr y;

T he relati ve e x pressi o n of R N A tra nscri pts, 
i ncl u di n g b ut n ot li mite d t o, t h ose ass ociate d 
wit h i m m u ne acti vati o n a n d i m m u ne re g ulati o n 
i n b o ne marr o w;

T he a b u n da nce a n d di versit y of T- cell cl o nes i n 
b o ne marr o w .

T o c ollect ba n ke d bi os peci me ns f or 
e x pl orat or y researc h, u nless pr o hi bite d b y 
l ocal re g ulati o ns or et hics c o m mittee decisi o n.  

C ollecti o n of ba n ke d bi os peci me ns u nless 
pr o hi bite d b y l ocal re g ulati o ns or et hics 
c o m mittee decisi o n.  A d diti o nal i nf or mati o n o n 
c ollecti o n a n d p ote ntial use is pr o vi de d i n t he 
Ba n ke d Bi os peci me ns Secti o n 7. 7 .
3. S T U D Y D E SI G N
3. 1. St u d y O ver vie w
Fi g ure 4.
C 1 0 7 1 0 0 1 St u d y Desi g n
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 1
T his is a P hase 1, o pe n -la bel, m ulti-d ose, m ulti -ce nter, d ose escalati o n, safet y, 
p har mac o ki netic ( P K) a n d p har mac o d y n a mic ( P D) st u d y of P F- 0 6 8 6 3 1 3 5 as m o n ot hera p y 
a n d i n c o m bi nati o n wit h le nali d o mi de , p o mali d o mi de or de xa met has o ne i n a d ult patie nts 
wit h a d va nce d m ulti ple m y el o ma w h o ha ve rela pse d fr o m or are refract or y  t o sta n dar d 
t hera py.  T his st u d y will be di vi de d i nt o d ose escalati o n /fi n di n g ( Part 1) a n d d ose e x pa nsi o n 
( Part 2) . Intra ve n o us (I V) a n d s u bc uta ne o us ( S C) a d mi nistrati o n of P F-0 6 8 6 3 1 3 5 will be 
e val uate d d uri n g t he Part 1 d ose escalati o n.   A n alter nati ve mai nte na nce d ose escalati o n 
p hase ( Part 1. 1), w hic h i nc or p orates t he usa ge of a pri mi n g d ose d uri n g C y cle 0 D a y 1 
( C0 D 1) 1 wee k pri or t o a mai nte na nce d ose f or all s u bse q ue nt d oses ma y  als o be i nitiate d if 
e xcessi ve t o xicit y occ urs or t he M T D / M A D is reac he d earlier t ha n desire d (see 
Secti o n 3. 1. 1. 3 ). U p o n reac hi n g M T D/ M A D, u p t o a p pr o xi matel y 6 - 1 2 patie nts t otal at 
selecte d le vel(s) bel o w t he M T D/ M A D wee kly a n d Q 2 W d osi n g u p t o t he sa me d ose 
i nte nsit y as t he M T D/ M A D wee kl y re gi me n m a y be e val uate d f urt her t o s u p p ort t he R P 2 D 
decisi o n. T he r o ute of P F -0 6 8 6 3 1 3 5 a d mi nistrati o n f or Parts 1 C, 1 D a n d Part 1 E a n d Part 2
will be deci de d o nce t he I V a n d S C d ose escalati o ns ha ve bee n c o m plete d, a n d a n R P 2 D has 
bee n selecte d.
F oll o wi n g t he deter mi nati o ns of t he R P 2 D of m o n ot hera p y a n d c o m bi nati o ns wit h 
le nali d o mi de or p o mali d o mi de i n Part 1, t he res pecti ve e x pa nsi o n c o h orts i n Part 2 will 
c o m me nce. I n a d diti o n, if t he c o m bi nati o n re gi me n wit h de xa met has o ne is well t olerate d as 
g ui de d b y m T PI i n Part 1 E , Part 2 E ma y be i nitiate d.
T he Part 2 d ose e x pa nsi o n p hase will be di vi de d i nt o 4 c o h orts as f oll o ws: Part 2 A 
(P F - 0 6 8 6 3 1 3 5 as m o n ot hera p y), Part 2 C ( P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h le nali d o mi de) ,
Part 2 D ( P F - 0 6 8 6 3 1 3 5 i n c o m bi natio n wit h p o mali d o mi de) , a n d Part 2 E (P F -0 6 8 6 3 1 3 5 i n 
c o m bi nati o n wit h de xa met has o ne), w hic h will e val uate safet y a n d a nti -m y el o ma acti vit y of 
P F -0 6 8 6 3 1 3 5 at t he R P 2 Ds deter mi ne d i n Part 1 (see Secti o n 3. 1. 1 , 3. 1. 1. 3 a n d 3. 1. 2 ).
A p pr o xi matel y 1 2 0 patie nts ha d bee n pla n ne d t o e nr oll i nt o Parts 1/ 1 . 1, 1 C, 1 D a n d 1E wit h
a p pr o xi matel y 8 0 patie nts pla n ne d t o e nr oll i nt o Part 2. Parts 1 C ,1 D a n d 1 E were pla n ne d t o
e nr ol l a p pr o xi matel y 9-1 6 patie nts wit h Part s 2 A, 2 C , 2 D a n d 2E pla n ne d t o e nr oll 
a p pr o xi matel y 2 0 patie nts eac h .
T he cli nical de vel o p me nt pr o gra m f or P F - 0 6 8 6 3 1 3 5 has bee n e x pa n de d wit h de dicate d 
st u dies t hat will f urt her i n vesti gate b ot h m o n ot hera p y a n d c o m bi nati o n t hera p y. T heref ore, 
t he S p o ns or has deter mi ne d t hat e nr ollme nt i n st u d y  C 1 0 7 1 0 0 1 has bee n c o m plete d.
All patie nts will c o m plete u p t o 4 wee ks of scree ni n g f or all Parts. 
F oll o wi n g t he i nitial d ose, treat me nt wit h i n vesti gati o nal pr o d uct will c o nti n ue u ntil disease 
pr o gressi o n, patie nt wit h dra wal of c o nse nt or u nacce pta ble t o xicit y  occ urs.  A f oll o w-u p visit 
a p pr o xi matel y 4 wee ks after t he last d ose f or a d verse e ve nt ( A E) a n d seri o us A E ( S A E) 
c ollecti o n will be c o n d ucte d.  If t he patie nt c o m plet es t he 1 m o nt h f oll o w- u p visit pri or t o 
c o m pleti o n of t he 6 0 da y l o n g ter m D L T o bser vati o n peri o d (see Secti o n 3. 2. 1 ), a f oll o w u p 
p h o ne call will be c o m plete d o n at least Da y 6 0, a n d n o m ore t ha n Da y 6 5. Patie nts f o u n d t o 
ha ve a nti -dr u g a nti b o dies ( A D A) at t heir fi nal st u d y  visit a n d a n o n g oi n g A E p ossi bl y relate d 
t o A D A will be as ke d t o ret ur n t o t he cli nic f or A D A assess me nt at a p pr o xi matel y 3 m o nt h 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 2
i nter vals (if feasi ble gi ve n t he u n derlyi n g disease) u ntil t he a d verse e ve nt or its se q uelae 
ret ur n t o baseli ne or sta bilize at a le vel acce pta ble t o t he i n vesti gat or a n d s p o ns or.
F oll o wi n g disc o nti n uati o n of st u d y  treat me nt ( u nless patie nts are l ost t o f oll o w u p, c o nse nt is 
wit h dra w n, or st u d y is disc o nti n ue d b y t he s p o ns or), s ur vi val stat us will be c ollecte d b y 
tele p h o ne e ver y 3 m o nt hs u ntil deat h, or u p t o a p pr o xi matel y 3 0 m o nt hs after first treat me nt 
of t he last patie nt, w hic he ver c o mes first.  S u bse q ue nt a nti -ca ncer t hera pies a n d rele va nt 
tra ns pla nt i nf or mati o n will als o be c ollecte d.
Treat me nt wit h i n vesti gati o nal pr o d uct will c o nti n ue u ntil disease p r o gressi o n, patie nt ref usal 
or u nacce pta ble t o xicit y  occ urs.  T he last st u d y treat me nt will be u p t o a p pr o xi matel y 
3 0 m o nt hs after first treat me nt of t he last patie nt , a n d t he st u d y w o ul d t he n e n d after a ny 
a d diti o nal f oll o w -u p visits re q uire d after t he l ast st u d y treat me nt.
3. 1. 1. P art 1 M o n ot her a p y D ose Esc al ati o n a n d P art 1. 1 Pri mi n g a n d M ai nte n a nce 
C o h orts
S C H E D U L E O F A C TI VI TI E S A a n d S C H E D U L E O F P H A R M A C O KI N E TI C, S O L U B L E 
F A C T O R A N D C Y T O KI N E acti vities A will be utilize d i n Part 1. 
T o cl osel y  ma na ge ac ute t o xicities, all patie nts e nr olle d i nt o Part 1 d ose escalati o n p hase will 
be h os pitalize d o n C 1 D 1 ( Als o f or at least 2 4 hrs if a pri mi n g d ose is gi ve n o n C 0 D 1). T he 
h os pitalizati o n peri o d ma y be e xte n de d if t he patie nt e x perie nces a b n or mal la b orat or y  
fi n di n gs or o n g oi n g a d verse e ve nts t hat re q uire f urt her h os pitalizati o n.  T he nee d f or 
ma n dat or y  h os pitalizati o n as well as its le n gt h will be re-assesse d f or patie nts e nr olle d i n 
Part s 2 A, 2 C , a n d 2 D base d o n safet y data fr o m Part 1 after a gree me nt of s p o ns or a n d 
i n vesti gat ors at t he ti me of m o n ot hera py M T D / M A D/ a n d R P 2 D deter mi nati o n
F or safet y reas o ns, a sta g gere d e nr oll me nt strate g y will be a p plie d f or Parts 1 a n d 1. 1 at eac h 
d ose le vel ; t he first patie nt will be d ose d a n d o bser ve d f or 4 8 h o urs. If n o safety c o ncer ns 
arise d uri n g t his 4 8 hr peri o d fr o m start of treat me nt, t he n s u bse q ue nt patie nts will be 
e nr olle d i nt o t he sa me d ose le vel. All patie nts i n Part 1 a n d Part 1. 1 will be m o n it ore d 
cl osel y f or d ose li miti n g t o xicities ( D LTs, see Secti o n 3. 2 ).  Decisi o ns f or d ose escalati o n
will be ma de ba se d o n D L Ts o bser ve d wit hi n t he D L T o bser vati o n peri o d . A m o difie d 
t o xicit y pr o ba bilit y i nter val ( m T PI) met h o d, tar geti n g a D L T rate of 2 5 % a n d a n acce pta ble 
e q ui vale nce i nter val of 2 0 % -3 0 % will be utilize d f or d ose escalati o n Part 1 (see 
Secti o n 3. 1. 4 ).  At least 6, u p t o 1 6 patie nts m ust be e nr olle d i nt o a d ose le vel t hat is 
deter mi ne d t o be M T D / M A D. U p o n reac hi n g M T D/ M A D, u p t o a p pr o xi matel y 
6- 1 2 patie nts t otal at selecte d le vel(s) bel o w t he M T D/ M A D wee kl y a n d Q 2 W d osi n g u p t o 
t he sa me d ose i nte nsit y as t he M T D/ M A D wee kl y re gi me n m a y  be e val uate d f urt her t o 
s u p p ort t he R P 2 D decisi o n.
Assess me nt of late t o xicities will als o be c o m plete d after t he D L T o bser vati o n peri o d t o 
6 0 da y s after C 1 D 1 f or all patie nts. O nce a d ose le vel has bee n declare d safe, patie nts at 
l o wer d ose le vels w h o ha ve c o m plete d t he 6 0 d a y  late t o xicit y o bser vati o n peri o d ma y  
escalate t o t he ne xt hi g her d ose le vel, if criteria o utli ne d i n Secti o n 3. 1. 4. 1 Criteria f or
I ntra patie nt D ose Escalati o n ha ve bee n met .  A d diti o nal i ntra -patie nt d ose escalati o ns will 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 3
als o be per mitte d after a mi ni mal i nter val of 6 0 da ys.  N o cr oss o ver is all o we d, h o we ver, 
bet wee n m o n ot hera p y P F -0 6 8 6 3 1 3 5 a n d t he differe nt c o m bi nati o n re gi me ns.
3. 1. 1. 1. P art 1 I ntr a ve n o us (I V) A d mi nistr ati o n
I n Part 1, P F -0 6 8 6 3 1 3 5 will i nitiall y be st u die d as a n I V f or m ulati o n i n se q ue ntial d ose le vels 
( 0. 1, 0. 3, 1, 3, 1 0, 3 0, 5 0 g/ k g or hi g her if i n dicate d ) i n a d ult patie nts wit h 
rela psed /refract ory m ulti ple m y el o ma, w h o ha ve recei ve d a pr oteas o me i n hi bit or, a n 
i m m u n o m o d ulat or y dr u g (IMi D ) a n d a n a nti C D 3 8 m o n ocl o nal a nti b o d y ( m A b) w here 
a p pr o ve d a n d a vaila ble eit her i n c o m bi nati o n or as a si n gle a ge nt.  A d diti o nal d ose le vels 
(l o wer, i nter me diate or hi g her) m a y  be e val uate d.  If t o xicit y is o bser ve d at t he starti n g d ose 
le vel of 0. 1 g/ k g, 0. 0 3 g/ k g will be e val uate d .  S u bse q ue nt t o t he starti n g d ose le vel, if 
d ose de -escalati o n is rec o m me n de d b y  t he m T PI m o del after D L T e val uati o n, i nter me diate 
d ose le vels bet wee n t he pre vi o us d ose a n d c urre nt d ose ma y  be st u die d.  De pe n di n g o n t he 
o bser ve d safet y a n d t olera bilit y pr ofile of P F -0 6 8 6 3 1 3 5, d ose le vels a b o ve 5 0 g/ k g or 
hi g her if i n dicate d m a y  be e x pl ore d.  All patie nts will als o be m o nit ore d fr o m Da y 2 2 t o 
Da y 6 0 f or late t o xicities (see Secti o n 3. 2. 1 ).
If wit hi n 2 1 d a y s after t he i nitial i nf usi o n a d ose le vel i n d uces sy m pt o ms c o nsiste nt wit h
Gra de 3 C R S a n d lasts f or > 2 4 h o urs des pite sta n dar d of care treat me nt f or t he 
ma na ge me nt of C R S per t he g ui deli nes of t he i nstit uti o n, I n vesti gat or, or treati n g p h ys icia n, 
a n d it is c o nsi dere d n ot t o be d ue t o a n I R R, aller gic reacti o n, a na p h yl a xis or ot her ca uses, 
e val uati o n of Part 1 S C or Part 1 . 1 I V Mai nte na nce a d mi nistrati o n ma y be i nitiate d.
3. 1. 1. 2. P art 1 S u bc ut a ne o us ( S C) A d mi nistr ati o n
Part 1 S C a d mi nistrati o n has be e n tri g gere d base d o n t he e mer gi n g cli nical a n d P K data fr o m 
I V c o h orts at 8 0 µ g/ k g, o ne d ose le vel hi g her (“ D ose I V + 1”) t ha n t he teste d I V d ose le vel of 
5 0 µ g/ k g i n Part 1 I V a d mi nistrati o n t hat is dee me d safe a n d has n ot e x perie nce d a G ra de 3 
C R S e ve nt.
De pe n di n g o n t he o bser ve d safet y a n d t olera bilit y pr ofile of P F- 0 6 8 6 3 1 3 5, eac h d ose le vel 
f or S C a d mi nistrati o n will be i ncrease d by a ma xi m u m of 3- f ol d. 
De pe n di n g o n e val uati o n of i m m u n o ge nicit y, safet y , efficac y, P K a n d/ or P D data t he S C 
a d mi nistrati o n p orti o n ma y be place d o n h ol d or disc o nti n ue d a n d Part 1. 1 Pri mi n g a n d 
Mai nte na nce D ose Escalati o n a d mi nistrati o n ma y be re-i nitiate d if a p pr o priate. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 4
3. 1. 1. 3. P art 1 . 1 Pri mi n g a n d M ai nte n a nce C o h orts
Part 1 . 1 is a n alter nati ve d osi n g re gi me n t hat will be i nitiate d o nl y if a pri mi n g d ose f or I V or 
S C has bee n declar e d i n Part 1.  T he decisi o n t o e val uate a re gi me n t hat i ncl u des a pri mi n g 
d ose ma y  be ma de b y t he i n vesti gat ors a n d s p o ns or pri or t o reac hi n g an M T D / M A D usi n g 
t he f oll o wi n g criteria as g ui da nce:

If a d ose le vel i n d uces sy m pt o ms c o nsiste nt ≥ Gra de 3 C R S lasti n g f or > 2 4 h o urs 
(des pite treat me nt wit h sta n dar d of care per t he i nstit uti o n’s, I n vesti gat or’s , or 
treati n g p hys icia n’s g ui deli nes f or t he ma na ge me nt of C R S) c o nsi dere d n ot t o be d ue 
t o a n i nf usi o n relate d reacti o n (IR R), aller gic reacti o n, a na p h y la xis or ot her ca uses, 
t he n a l o wer d ose, w hic h has bee n e val uate d i n at least 2-4 patie nts, will be c h ose n as 
a pri mi n g d ose ( D ose Pri me) f or s u bse q ue nt c o h orts. 

If a D ose Pri me is selecte d, d ose escalati o n will c o nti n ue t o deter mi ne t he 
M T D / M A D of a d ose re gi me n t hat i ncl u des a pri mi n g d ose. 

If a d ose le vel i n d uces c o nfir me d C R S of Gra de 4 c o nsi dere d n ot t o be d ue t o a n IR R, 
aller gic reacti o n, a na p h yl a xis or ot her ca uses, t he n a l o wer d ose, w hic h has bee n 
e val uate d i n at least 2 - 4 patie nts, will be c h ose n as a pri mi n g d ose ( D ose Pri me) f or 
s u bse q ue nt c o h orts.

I n a d diti o n, o bser vati o n of a c o nfir me d C R S eve nt t hat meets t he a b o ve q ualificati o ns 
f oll o wi n g later i nf usi o ns (ie, after C ycle 1 Da y 1) or C R S e ve nts t hat are a p pr oac hi n g 
t he li mit of t olera bilit y ma y pr o m pt t he i n vesti gat ors a n d s p o ns or t o i ncl u de 
e val uati o n of a D ose Pri me f or s u bse q ue nt c o h orts.
After c o nfir mati o n of t he safet y of D ose Pri me, t he treat me nt sc he d ule will i m ple me nt t he 
i ncl usi o n of t he fi xe d pri mi n g d ose as t he first d ose ( C0 D 1) f oll o we d b y a mai nte na nce d ose
1 wee k later ( C 1 D1 ) t hat will c o nti n ue t o be escalate d i n s u bse q ue nt c o h orts f oll o wi n g a n 
m T PI  met h o d.  T he starti n g mai nte na nce d ose le vel will be n o greater t ha n 2 -f ol d a b o ve t he 
pri mi n g d ose (see Secti o n 3. 1. 4 ). De pe n di n g o n t he o bser ve d safet y a n d t olera bilit y pr ofile 
of P F -0 6 8 6 3 1 3 5, eac h mai nte na nce d ose le vel a d mi nistrati o n will be i ncrease d b y  a 
ma xi m u m of 2 -f ol d. After t he M T D / M A D h a s bee n esta blis he d, t he pri mi n g d ose ma y 
p ote ntiall y  be f urt her verifie d i n c o n necti o n t o t he esta blis he d M T D/M A D/ R P 2 D, i ncl u di n g 
c o nsi derati o n of m ore t ha n o ne pri mi n g ste p, if i n dicate d, usi n g i nf or mati o n fr o m all patie nts 
w h o were i ncl u de d i n t he i nitia l pri mi n g d ose deter mi nati o n as well as t h ose e nr olle d i n 
s u bse q ue nt d osi n g c o h orts.
S C H E D U L E O F A C TI VI TI E S B: WI T H P RI MI N G D O S E A N D S C H E D U L E O F 
P H A R M A C O KI N E TI C , S O L U B L E F A C T O R A N D C Y T O KI N E A C TI VI TI E S B will t he n 
be utilize d i n Part 1 . 1.  I n Part 1 . 1, patie nts will recei ve t he pri mi n g d ose o n C0 D 1 d uri n g t he 
pr i mi n g d ose p orti o n of C ycle 0. T he pri mi n g d ose will re mai n t he sa me f or all d ose le vel 
c o h orts. T he mai n te na nce d ose will be a d mi nistere d o ne wee k later o n C 1 D 1 a n d f or 
s u bse q ue nt c ycles. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 5
T o cl osel y  ma na ge ac ute t o xicities, all patie nts recei vi n g a pri mi n g d ose will be h os pitalize d 
f or at least 2 4 hrs o n b ot h C 0 D 1, a n d C 1 D 1.  T he h os pitalizati o n peri o d ma y be e xte n de d if 
t he patie nt e x perie nces a b n or mal la b orat or y fi n di n gs or o n g oi n g a d verse e ve nts t hat re q uire 
f urt her h os pitalizati o n. 
F or safet y reas o ns, a sta g gere d start will be e m pl o ye d at eac h d ose le vel; t he first pati e nt will 
be d ose d, a n d o bser ve d f or 4 8 h o urs. T he 4 8 hr o bser vati o n peri o d f or t he first patie nt i n 
eac h d ose le vel i n Part 1 . 1 will be gi n o n C 1 D 1 d uri n g t he sec o n d h os pitalizati o n peri o d. If 
n o safet y c o ncer ns arise d uri n g t his 4 8 hr peri o d fr o m start of treat me nt, t he n s u bse q ue nt 
patie nts will be e nr olle d i nt o t he sa me mai nte na nce d ose le vel. 
Decisi o ns f or mai nte na nce d ose escalati o n will be ma de base d o n t o xicities o bser ve d wit hi n 
t he D L T o bser vati o n peri o d ( C ycles 0 a n d 1) .  S u bse q ue nt t o starti n g t h e mai nte na nce d ose 
le vel, if d ose de-escalati o n is rec o m me n de d b y t he m T PI  m o del after e val uati o n, i nter me diate 
d ose le vels bet wee n t he pre vi o us d ose a n d c urre nt d ose ma y  be st u die d.  At least 6, u p t o 
a p pr o xi matel y 1 6 patie nts m ust be e nr olle d i nt o a mai n te na nce d ose le vel t hat is deter mi ne d 
t o be t he ma xi m u m t olerate d d ose ( M T D)/M A D . 
O nce a d ose le vel has bee n declare d safe, patie nts at l o wer d ose le vels w h o ha ve c o m plete d 
6 0 da y  late t o xicit y o bser vati o n peri o d ma y  escalate t o t he ne xt hi g her d ose le vel, if criteria 
o utli ne d i n Secti o n 3. 1. 4. 1 Criteria f or I ntra patie nt D ose Escalati o n ha ve bee n met .  
A d diti o nal i ntra -patie nt mai nte na nce d ose escalati o ns will als o be per mitte d after a mi ni mal 
i nter val of 6 0 d a y s fr o m first a d mi nistrati o n of mai nte na nce d ose.  
Alter nati ve strate gies f or i ncreasi n g d osi n g s uc h as a ste p -u p re gi me n or pr o p h y lactic ster oi ds 
ma y als o be c o nsi dere d a n d i m ple me nte d t o f urt her i m pr o ve t olera bilit y  if nee de d.
3. 1. 1. 4. P art 1 C o m bi n ati o n D ose Fi n di n g
Parts 1 C, 1 D a n d 1E , are d ose fi n di n g safety c o h orts f or P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h 
le nali d o mi de, p o mali d o mi de or de xa met has o ne , res pecti vely.  U p o n deter mi ni n g t he 
P F - 0 6 8 6 3 1 3 5 R P 2 D/ M T D / M A D a n d r o ute of a d mi nistrati o n as m o n ot hera p y eit her wit h or 
wit h o ut pri mi n g d ose i n Part 1, Parts 1 C, 1 D a n d 1E will be i nitiate d t o st u d y t he safety of
P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h le nali d o mi de , p o mali d o mi de , or de xa met has o ne .  Parts 1 C
a n d 1 D will be starte d wit h P F -0 6 8 6 3 1 3 5 o ne d ose le vel bel o w t he M T D / M A D a n d escalate d 
o ne d ose le vel u nless t he R P 2 D is bel o w t he M T D / M A D i n w hic h case t he R P 2 D will be 
use d as t he starti n g d ose of P F- 0 6 8 6 3 1 3 5 . If i n Parts 1 C, or 1 D, t he c o m bi nati o n is n ot well 
t olerate d, d oses of P F -0 6 8 6 3 1 3 5 ma y  be de- escalate d t o a l o wer d ose le vel bel o w t he starti n g 
d ose of P F -0 6 8 6 3 1 3 5 use d i n c o m bi nati o n . Part 1 E will be a c o m bi nati o n of P F -0 6 8 6 3 1 3 5 at 
R P 2 D/ M T D/ M A D a n d de xa met has o ne. If t his c o m bi nati o n is n ot well t olerate d, Part 2 E ma y 
n ot be i nitiate d.  
As descri be d i n Secti o n 3. 4 , a d ose of 1 0 0 0 µ g/ k g S C wee kl y has bee n selecte d as t he R P 2 D 
f or P F-0 6 8 6 3 1 3 5 as a si n gle a ge nt. T his si n gle a ge nt R P 2 D will be a d mi nistere d as a fi xe d 
d ose of 7 6 m g ( a fi xe d d ose e q ui vale nt of 1 0 0 0 µ g/ k g; see Secti o n 1. 2. 9. 4 f or rati o nale) 
f oll o wi n g a pri mi n g d ose of 4 4 m g (a fi xe d d ose e q ui vale nt of 6 0 0 µ g/ k g) a d mi nistere d o ne 
wee k earlier. Si milarl y, Part 1 c o m bi nati o n d ose fi n di n g ( Part 1 C a n d Part 1 D) will be 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 6
a d mi nistere d as fi xe d d oses f or P F- 0 6 8 6 3 1 3 5 wit h mai nte na nce d os es starte d o ne wee k after 
t he pri mi n g d ose; t he starti n g d ose is o ne d ose le vel bel o w t he si n gle a ge nt R P 2 D as 
descri be d i n Ta ble 1:
T a ble 1. 
T a ble of P ote nti al Fi xe d D ose Le vels 
D ose le vel a
Pri mi n g D ose
(m g )
M ai nte n ace D ose
( mg)
0
2 4
3 2
1 (starti n g)
3 2
4 4
2 b
4 4
7 6
a. D ose le vel refers t o desi g nate d d ose le vels f or Part 1 C a n d Part 1 D
b. Desi g nate d d ose le vel f or Part 1 E
Part 1 C will i n vesti gate P F- 0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h le nali d o mi de i n se q ue ntiall y 
escalati n g d oses of P F- 0 6 8 6 3 1 3 5 . T his safet y c o h ort will start wit h t he d ose le vel 
M T D- 1 / M A D- 1 or R P 2 D ( w hic he ver is l o wer) of P F -0 6 8 6 3 1 3 5 fr o m t he Part 1 d ose
escalati on a n d 1 5 m g d ose of le nali d o mi de i n or der t o select t he c o m bi nati o n R P 2 D. If t he 
c o m bi nati o n re gi me n is n ot well t olerate d, a d ose t hat is l o wer t ha n t he R P 2 D deter mi ne d f or 
si n gle-a ge nt P F-0 6 8 6 3 1 3 5 ma y  be e val uate d i n c o m bi nati o n bef ore pr ocee di n g t o Par t 2. If 
necessar y , de-escalati o n will be g ui de d b y a n m T PI desi g n . P F - 0 6 8 6 3 1 3 5 will be 
a d mi nistere d o n C 1 D 1 a n d wee kl y or e ver y  2 wee ks or o nce per c y cle ( C X D 1) t hereafter
wit h or wit h o ut a pri mi n g d ose . A d ose of 1 5 m g of le nali d o mi de will be a d mi niste re d orally 
o n Da y s 1- 2 1. P F -0 6 8 6 3 1 3 5 a n d le nali d o mi de will be a d mi nistere d o ver a c y cle of 2 8 d a y s.
A sta g gere d e nr oll me nt strate g y  will be a p plie d at eac h d ose le vel: w he n a d ose le vel o pe ns 
f or e nr oll me nt, t he first patie nt wi ll be d ose d, a n d o bser ve d f or 9 6 h o urs be y o n d C 1 D 1 .  If n o 
safet y c o ncer ns arise d uri n g t his 9 6 hr peri o d fr o m C 1 D 1 of P F - 0 6 8 6 3 1 3 5 a n d le nali d o mi de, 
s u bse q ue nt patie nts will be e nr olle d i nt o t he sa me d ose le vel.  T o cl osel y ma na ge ac ute 
t o xicities, patie nts will be h os pitalize d o n C 1 D 1.   It is e x pecte d t hat Part 1 C will e nr oll 
a p pr o xi matel y 9- 1 6 patie nts.
Part 1 D will i n vesti gate P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h p o mali d o mi de i n de -escalati o n 
d oses.  T his safet y c o h ort will e val uate t he M T D -1/ M A D - 1 or R P 2 D d ose le vel ( w hic he ver 
is l o wer) of P F - 0 6 8 6 3 1 3 5 fr o m Part 1 d ose escalati o n a n d a sta n dar d of care d ose of 
p o mali d o mi de i n or der t o select t he c o m bi nati o n R P 2 D.  I f t he c o m bi nati o n re gi me n is n ot 
well t olerate d, a d ose t hat is l o wer t ha n t he R P 2 D deter mi ne d f or si n gle -a ge nt P F- 0 6 8 6 3 1 3 5 
ma y  be e val uate d i n c o m bi nati o n bef ore pr ocee di n g t o Part 2.  If necessar y, de-escalati o n 
will be g ui de d b y m T PI.  T he first d ose of P F -0 6 8 6 3 1 3 5 will be a d mi nistere d o n C 1 D 1 a n d 
wee kl y t hereafter.  A d ose of 4 m g of p o mali d o mi de will be a d mi nistere d oral l y o n 
D a y s 1-2 1.  P F -0 6 8 6 3 1 3 5 a n d p o mali d o mi de will be a d mi nistere d o ver a c y cle of 2 8 d a y s.  A 
sta g gere d e nr oll me nt strate g y will be a p plie d at eac h d ose le vel: w he n a d ose le vel o pe ns f or 
e nr oll me nt, t he first patie nt will be d ose d, a n d o bser ve d f or 9 6 h o urs.  If n o safet y c o ncer ns 
arise d uri n g t his 9 6 hr peri o d fr o m C 1 D 1 of P F -0 6 8 6 3 1 3 5 a n d p o mali d o mi de, s u bse q ue nt 
patie nts will be e nr olle d i nt o t he sa me d ose le vel.  T o cl osel y ma na ge ac ute t o xicities, 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 7
patie nts will be h os pitalize d o n C 1 D 1.  It is e x pected t hat Part 1 D will e nr oll a p pr o xi matel y  
9 - 1 6 patie nts.
Part 1 E will i n vesti gate P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h de xa met has o ne. T his safet y c o h ort 
will e val uate t he R P 2 D fi xe d d ose le vel of P F -0 6 8 6 3 1 3 5 m o n ot hera p y a n d a fi xe d d ose of 
de xa met has o ne , at a d ose of 4 0 m g .  F or s u bjects ol der t ha n 7 5 years or u n der wei g ht ( b o d y 
mass i n de x [ B MI] < 1 8. 5), de xa met has o ne pre me dicati o n ma y  be gi ve n pri or t o P F - 0 6 8 6 3 1 3 5
at a d ose of 2 0 m g. If t he c o m bi nati o n re gi me n is n ot well t olerate d d ue t o P F- 0 6 8 6 3 1 3 5, 
P F - 0 6 8 6 3 1 35 ma y  be de-escalate d i n c o m bi nati o n acc or di n g t o m o difie d t o xicit y  pr o ba bility 
i nter val ( m T PI) desi g n. Eac h c ycle of t he c o m bi nati o n of P F-0 6 8 6 3 1 3 5 a n d de xa met has o ne 
starti n g wit h C ycle 1 will be 2 8 d a y s. If t he c o m bi nati o n re gi me n is n ot well t olerate d as 
g ui de d b y m T PI, Part 2 E ma y  n ot be i nitiate d. De xa met has o ne w o ul d be gi n o n C 0 D 1 a n d it 
will be d ose d as pre me dicati o n pri or t o P F -0 6 8 6 3 1 3 5 a d mi nistrati o n. If a patie nt has recei ve d 
de xa met has o ne f or 6 m o nt hs or P F -0 6 8 6 3 1 3 5 is disc o nti n ue d, t he n de xa met ha s o ne s h o ul d be 
disc o nti n ue d u nless cli nical rati o nale t o c o nti n ue de xa met has o ne is pr o vi de d b y  i n vesti gat or 
a n d a p pr o ve d b y s p o ns or . Patie nts w h o nee d t o disc o nti n ue treat me nt wit h de xa met has o ne 
ma y  c o nti n ue t o recei ve treat me nt wit h P F -0 6 8 6 3 1 3 5 . If a d ose of P F -0 6 8 6 3 1 3 5 is hel d or 
s ki p pe d, t he n de xa met has o ne s h o ul d n ot be a d mi nistere d u ntil P F- 0 6 8 6 3 1 3 5 is restarte d. It is 
e x pecte d t hat Part 1 E will e nr oll a p pr o xi matel y  9- 1 6 patie nts.
3. 1. 2. P art 2 D ose E x p a nsi o n 
Part 2 d ose e x pa nsi o n p hase will be di vi de d i nt o 4 c o h orts as f oll o ws: Part 2 A ( P F -0 6 8 6 3 1 3 5 
as m o n ot hera p y), Part 2 C ( P F - 0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h le nali d o mi de), Part 2 D 
(P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h p o mali d o mi de), a n d Part 2 E (P F -0 6 8 6 3 1 3 5 i n 
c o m bi nati o n wit h d e xa met has o ne) w hic h will e val uate safety a n d a nti -m y el o ma acti vit y of 
P F -0 6 8 6 3 1 3 5 at t he m o n ot hera p y /c o m bi nati o n R P 2 D .
Base d o n e mer gi n g cli nical data fr o m t he Part 1 d ose escalati o n, eit her I V or S C 
a d mi nistrati o n i ncl u di n g pri mi n g a n d mai nte na nce d ose Q 1 W or Q 2 W will be selecte d f or 
t he Part 2 d ose e x pa nsi o n.
If t he S C a d mi nistrati o n is selecte d f or Part 2 d ose e x pa nsi o n, all patie nts i n 2 C, 2 D a n d 2 E 
will recei ve a s u bc uta ne o us fi xe d d ose of P F -0 6 8 6 3 1 3 5 at t he Q 1 W R P 2 D ( wit h or wit h o ut a 
pri mi n g d ose gi ve n at C 0 D 1 1 wee k pri or t o C 1 D 1). Part 2 A patie nts will als o recei ve a 
s u bc uta ne o us fi xe d d ose of P F- 0 6 8 6 3 1 3 5 at eit her t he R P 2 D Q 1 W or Q 2 W sc he d ule, 
de pe n di n g o n e mer gi n g cli nical data i n Part 1. 
F or le nali d o mi de, Part 2 C, 1 5 m g orall y ( P O ) will be a d mi nistere d dail y o n da y s 1– 2 1 o f a
2 8 da y  c ycle starti n g C 1 D 1 i n c o m bi nati o n wit h t he M T D/M A D
or R P 2 D of P F - 0 6 8 6 3 1 3 5 
deter mi ne d i n Part 1 C ( wit h or wit h o ut a pri mi n g d ose of P F-0 6 8 6 3 1 3 5 gi ve n at C 0 D 1 ,
1 wee k pri or t o C 1 D 1) .
F or p o mali d o mi de , Part 2 D, 4 m g P O will be a d mi nistere d dail y  o n days  1– 2 1 of a 2 8-d a y  
c ycle starti n g C 1 D 1 i n c o m bi nati o n wit h t he M T D/M A D
or R P 2 D of P F -0 6 8 6 3 1 3 5 
deter mi ne d i n Part 1 D ( wit h or wit h o ut a pri mi n g d ose of P F -0 6 8 6 3 1 3 5 gi ve n at C 0 D 1 
1 wee k pri or t o C 1 D 1).
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 8
F or de xa met has o ne, Part 2 E, 4 0 m g P O will be a d mi nister e d as pre me dicati o n 6 0 ± 3 0 
mi n utes pri or t o P F - 0 6 8 6 3 1 3 5 starti n g C 0 D 1 i n c o m bi nati o n wit h t he M T D/ M A D/ R P 2 D 
fi xe d d ose of P F-0 6 8 6 3 1 3 5 deter mi ne d i n Part 1. F or s u bjects ol der t ha n 7 5 y ears or 
u n der wei g ht ( b o d y mass i n de x [ B MI ] < 1 8. 5), de xa met has o ne pre me dicati o n ma y be gi ve n 
6 0 ± 3 0 mi n utes pri or t o P F - 0 6 8 6 3 1 3 5 at a d ose of 2 0 m g.
T he R P 2 D selecte d will be base d o n t he M T D or t he M A D , a n d f urt her e val uati o n of ot her 
c o variates s uc h as disease b ur de n, s ol u ble plas ma B C M A le vel, a n d b o d y s ize i nf or mati o n
will als o be utilize d .  S electi o n of 1 hr or 2 hr i ntra ve n o us a d mi nistrati o n (if utilize d i n 
P art 2) will be base d o n t he i nci de nce of I R Rs.  A p pr o xi mat el y 8 0 patie nts ma y be e nr olle d 
i nt o Part 2 (see Secti o n 9. 3 Sa m ple Size Deter mi nati o n ) wit h a p pr o xi matel y 2 0 patie nts i n 
Part s 2 A, 2 C , 2 D, a n d 2 E. Patie nts fr o m t he d ose fi n di n g c o m bi nati o n c o h orts of Parts 1 C, 
a n d 1 D treate d at t he d ose le vels selecte d f or Part 2 ma y be c o u nte d t o war ds sa m ple size of 
t he c orres p o n di n g c o h orts of Part 2.
P reli mi nar y data fr o m t he Part 2 d ose e x pa nsi o n ma y  pr o vi de g ui da nce i n t he S p o ns or’s 
decisi o n t o a dj ust t he sa m ple size of eac h ar m, t o a d d ot her a vaila ble treat me nt c o m bi nati o ns
i n a f ut ure a me n d me nt, or t o i nitiate a d diti o nal cli nical st u dies.
3. 1. 3. St arti n g D ose
T he starti n g d ose f or Part 1 I V a d mi nistrati o n will be 0. 1 g/ k g gi ve n wee kl y  i n 3 wee k
c ycles. 
3. 1. 4. Criteri a f or D ose Esc al ati o n / De- Esc al ati o n
T he st u d y  has bee n desi g ne d t o esta blis h t he M T D / M A D defi ne d as t he d ose t hat y iel ds 
a p pr o xi matel y 2 5% pr o ba bilit y  of D L T a n d c o nsi ders e q ui vale nt d oses t hat yiel d pr o ba bility 
of D L T i n t he i nter val ( E q ui vale nce I nter val) 2 0 % t o 3 0 %. 
All d ose escalati o n/ de -escalati o ns will be g ui de d b y t he m T PI desi g n a n d t heref ore 
2- 4 patie nts will be e nr olle d i n eac h c o h ort (see Secti o n 3. 1 St u d y  O ver vie w).
T he p ote ntial d ose le vels t o be e val uate d f or Part 1 I V a d mi nistrati o n are liste d i n Ta ble 2 .  
T he p ote ntial d ose le vels t o be e val uate d f or Part 1 S C a d mi nistrati o n are liste d i n Ta ble 3 . 
D ose esc alati o n f or Part 1 I V a n d S C will start at d ose le vel 1 f or eac h (Ta ble 2 a n d Ta ble 3 ).
I n Part 1, f or b ot h I V a n d S C a d mi nistrati o n, t he ma xi m u m d ose i ncrease will be 
a p pr o xi matel y 3 f ol d if n o D LTs are o bser ve d; per m T PI , i nter me diate or hi g her d oses ma y  
be e val uat e d base d o n cli nical fi n di n gs.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 9
T a ble 2.
T a ble of P ote nti al D ose Le vels i n P art 1 I V A d mi nistr ati o n
D ose le vel
D ose
( μ g/ k g)
1
0. 1
2
0. 3
3
1. 0
4
3. 0
5
1 0. 0
6
3 0. 0
7
5 0. 0
T a ble 3 .
T a ble of P ote nti al D ose Le vels i n P art 1 S C A d mi nistr ati o n
D ose le vel
D ose
( μ g/ k g)
0
5 0
1
8 0
2
1 3 0
3
2 1 5
4
3 6 0
5
6 0 0
6
1 0 0 0
I n Part 1 . 1, t he starti n g mai nte na nce d ose will be n o m ore t ha n 2-f ol d a b o ve t he pri mi n g d ose 
esta blis he d fr o m Part 1. Ma xi m u m mai nte na nce d ose i ncreases will be 2 -f ol d ( 1 0 0 %).
Q 2 W d osi n g w o ul d be e val uate d u p o n reac hi n g M T D/ M A D. C y cles f or Q 2 W d osi n g w o ul d 
be 4 wee ks rat her t ha n t he 3 wee ks wit h Q 1 W d osi n g. B ot h Q 1 W a n d Q 2 W d osi n g ma y  be 
c o nsi dere d f or Part 2 A e x pa nsi o n fr o m Part 1.
O nce t he first D L T is o bser ve d, t he ma xi m u m i ncrease w o ul d i ncrease n o m ore t ha n 2- f ol d
u p t o 3 µ g/ k g , a n d n o m ore t ha n 6 7 % b e y o n d 3 µ g/ k g .
Part s 1 C, a n d 1 D will c o m bi ne escalati n g d oses of P F -0 6 8 6 3 1 3 5 starti n g at t he m o n ot hera p y 
M T D- 1 /M A D - 1 or R P 2 D ( w hic he ver is l o wer) d ose le vel a n d i ncreasi n g t o t he m o n ot hera py 
R P 2 D / M T D, if a p plica ble, i n c o m bi nati o n wit h a sta n dar d d ose of le nalid o mi de or 
p o mali d o mi de, res pecti vel y. D e -escalati o n of P F -0 6 8 6 3 1 3 5 t o a l o wer d ose le vel ma y  occ ur 
if necessar y.
I n Part 1 E, t he c o h ort t hat i ncl u des de xa met has o ne will e val uate P F-0 6 8 6 3 1 3 5 at a pri mi n g 
d ose of 4 4 m g f oll o we d b y a mai nte na nce d ose of 7 6 m g a d mi nistere d.  De -escalati o n of 
P F -0 6 8 6 3 1 3 5 t o a l o wer d ose le vel ma y  occ ur if necessar y.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M




P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 1
a n d/ or t he patie nt ref uses t o u n der g o a b o ne marr o w pr oce d ure ; if a b o ne marr o w 
as pirate or bi o ps y was perf or me d wit hi n t he past 2 8 da y s pri or t o pla n ne d start of 
escalate d d ose, o nly disease sta gi n g l a b tests m ust be perf or me d );
4.
A disc ussi o n bet wee n t he i n vesti gat or a n d s p o ns or has bee n c o m plete d, a n d it is 
a gree d t hat t his will be i n t he patie nt’s best i nterest .
A patie nt w h ose d ose has bee n escalate d will n ot c o ntri b ute t o t he assess me nt of t he n u m ber 
of D L Ts at t he escalate d d ose le vel.
3. 2. D ose Li miti n g T o xicit y ( D L T ) Defi niti o n
M o nit ori n g f or D L Ts
will occ ur d uri n g Part 1. Se verit y  of a d verse e ve nts ( A Es) will be 
gra de d acc or di n g t o Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts ( C T C A E ) versi o n 4. 0 3.  T he se verit y  of c yt o ki ne release s yn dr o me ( C R S) will be 
assesse d acc or di n g t o t he gra di n g descri be d b y Lee et al. ( 2 0 14 a n d 2 0 1 9 ,2 ,3 See A p pe n di x 5 ).
F or t he p ur p ose of d ose escalati o n, t he D L T o bser vati o n peri o d will be u p t o t he e n d of C ycle 
1 i n eac h patie nt. F or t h ose patie nts recei vi n g a pri mi n g d ose, C ycle 0 a n d C y cle 1 w o ul d be 
i ncl u de d i n t he D L T o bser vati o n peri o d.  D L T e val ua ble patie nts will i ncl u de patie nts t hat 
ha ve e x perie nce d a D L T i n t he D LT o bser vati o n peri o d or . D L T e val ua ble patie nts will als o 
i ncl u de t h ose w h o recei ve d all of t heir pla n ne d d oses of P F - 0 6 8 63 1 3 5 i n t he i nitial D LT 
o bser vati o n peri o d if Q 2W d osi n g is bei n g e val uate d or at least all b ut o ne of t heir pla n ne d 
d oses of P F -0 6 8 6 1 3 5 if Q 1 W d osi n g is bei n g e val uate d , pr o vi de d a d ose was n ot misse d d ue 
t o t o xicit y attri b ute d t o st u d y dr u g. Safet y i nf or mati o n fr o m a n y patie nts t hat d o n ot meet 
D L T e val ua ble criteria c o ul d still be c o nsi dere d f or o verall d ose escalati o n decisi o ns 
alt h o u g h t he y w o ul d n ot fact or i nt o m T PI decisi o n r ules.
A n y  of t he f oll o wi n g a d verse e ve nts o bser ve d wit hi n t he D LT o bser vati o n peri o d c o nsi dere d 
relate d t o P F- 0 6 8 63 1 3 5 or P F -0 6 8 6 3 1 3 5 i n c o m bi nati o n wit h
le nali d o mi de, p o mali d o mi de, 
de xa met has o ne, will be classifie d as D L Ts: 
He m at ol o gic al:

Gra de 4 ne utr o pe nia lasti n g > 5 d a y s. E xce pt i n le nali d o mi de c o m bi nati o n c o h ort 
w here it ca n be ma na ge d b y  d ose re d ucti o n of le nali d o mi de i n t he ne xt c ycle.

Fe brile ne utr o pe nia ( defi ne d as a n a bs ol ute ne utr o p hil c o u nt [ A N C] < 1 0 0 0/ m m 3 wit h 
a si n gle te m perat ure of > 3 8. 3 C [ 1 0 1 F] , or a s ustai ne d te m perat ure of 3 8 C
[ 1 0 0. 4F] f or m ore t ha n o ne h o ur). If fe ver is d eter mi ne d t o be a s y m pt o m of C R S 
c o nfir me d b y cli nical c o urse a n d c yt o ki ne le vels a n d res ol ves i n a ma n ner c o nsiste nt 
wit h C R S, t his w o ul d n o l o n ger be c o nsi dere d a D L T, a n d t he patie nt ma y  res u me 
treat me nt.

Gra de 3 ne utr o pe nia wit h i nfecti o n . 

Gra de 4 t h r o m b oc yt o pe nia ( u nless t he st u d y e ntr y baseli ne c o u nt was ≥2 5, 0 0 0 a n d 
< 5 0, 0 0 0 t o ta ke i nt o acc o u nt b o ne marr o w s u p pressi o n d ue t o m ulti ple m yel o ma, i n 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 2
t his case gra de 4 t hr o m b oc yt o pe nia nee ds t o be acc o m pa nie d b y ≥Gra de 2 blee di n g 
t o be a D L T).  For su bjects w h o e x perie nce a platelet c o u nt < 1 0 , 0 0 0/ m m3, t his is 
c o nsi dere d a D L T irres pecti ve of ot her fact ors wit h t he e xce pti o n of le nali d o mi de-
relate d Gra de 4 t hr o m b oc yt o pe nia ma na gea ble b y platelet tra nsf usi o ns a n d 
le nali d o mi de d ose re d ucti o n i n t he ne xt c ycle. 

Gra de 3 t hr o m b oc y t o pe nia wit h ≥Gra de 2 blee di n g.
N o n -he m at ol o gic al:

Gra de 4 A d verse E ve nts ( A Es).

Gra de 3 A E lasti n g ≥5 d a y s des pite o pti mal s u p p orti ve care, wit h t he e xce pti o n of A E 
attri b ute d t o a C R S e ve nt (i e, Gra de 3 tra nsa mi nitis).

Gra de 3 C R S , e xce pt t h ose C R S t hat ha ve i) n ot bee n ma xi mall y  treate d (ie, lac k of
a d mi nistrati o n of sta n dar d of care treat me nt per t he i nstit uti o n’s, I n vesti gat or’s, or 
treati n g p hys icia n’s g ui deli nes f or t he ma na ge me nt of C R S) or ii) i m pr o ve d t o 
≤Gra de 1 wit hi n 4 8 h o urs .

Gra de 4 C R S.

C o nfir me d dr u g -i n d uce d li ver i nj ur y ( DI LI) meeti n g H y’s la w criteria o utli ne d i n 
Secti o n 8. 4. 1 .

Gra de 4 la b orat or y  a b n or malities dee me d cli nicall y si g nifica nt b y  t he i n vesti gat or 
s hall be re p orte d as Gra de 4 A E as descri be d i n Secti o n 8. 2. 2 .

Cli nicall y  i m p orta nt or persiste nt t o xicities (e g, t o xicities res p o nsi ble f or si g nifica nt 
d ose dela y ) t hat are n ot i ncl u de d i n t he a b o ve criteria ma y als o be c o nsi dere d a D L T 
f oll o wi n g re vie w b y t he i n vesti gat ors a n d t he S p o ns or.  All D L Ts nee d t o re prese nt a 
cli nicall y si g nifica nt s hift fr o m baseli ne.
T he f oll o wi n g A Es will n ot be a dj u dicate d as D L Ts:

Is olate d Gra de 3 la b orat or y  a b n or malities t hat are n ot ass ociate d wit h cli nical 
se q uelae a n d are c orrecte d wit h s u p ple me ntati o n/a p pr o priate ma na ge me nt wit hi n 
7 2 h o urs of t heir o nset or dee me d cli nicall y i nsi g nifica nt b y  t he i n vesti gat or.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 3
3. 2. 1. L ate T o xicities
Late t o xicities are A Es t hat meet t he sa me gra di n g criteria as D L T criteria a n d occ ur fr o m 
C y cle 2 Da y 1 t hr o u g h t he 6 0 d a y  assess me nt peri o d.  If late t o xicities occ ur t h ose m a y be 
i nc or p orate d i n t he m T PI a p pr oac h a n d e nr oll me nt i nt o a n y hi g her d ose le vel c o h orts ma y be 
place d o n te m p oraril y h ol d.  All safet y data will be re vie we d, a n d a decisi o n will be ma de t o 
eit her:

C o nti n ue e nr oll me nt i n hi g her d ose le vel c o h orts.

I ncrease t he n u m ber of patie nts at t he d ose le vel i n w hic h t he late t o xicities occ urre d 
t o satisf y t he m T PI decisi o n r ules (Secti o n 3. 1. 4 ).  All patie nts will be f oll o we d f or at 
least 6 0 d a y s t o assess safet y at t his d ose le vel.  If t he m T PI decisi o n r ule of 
d ose -escalati o n is reac he d, e nr oll me nt i n hi g her d ose le vel c o h orts ma y  res u me.  If 
after t he e nr oll me nt of a d diti o nal s u bjects t he m T PI rec o m me n ds t o de -escalate t he 
d ose, t he o pti o n t o de-escalate t he d ose will be disc usse d.

Per ma ne ntl y  st o p e nr oll me nt i n hi gher d ose le vel c o h orts, a n d declare t he d ose le vel 
t o be a b o ve M T D/ M A D.  Increase t he n u m ber of patie nts at t he d ose le vel i n w hic h 
t he late t o xicities occ urre d t o satisf y t he m T PI decisi o n r ules (Secti o n 3. 1. 4 ).

St o p t he st u d y . 
F or a n y gi ve n patie nt t hat is o n -treat me nt at d ose le vels t hat are s u bse q ue ntl y c o nsi dere d t o 
be a b o ve t he M T D / M A D, t he o pti o n t o d ose re d uce will be disc usse d.  If a patie nt t olerate d 
t he a b o ve M T D/ M A D d ose le vel well a n d is be nefiti n g, c o nti n uati o n of treat me nt at t he 
a b o ve M T D/ M A D d ose le vel will re q uire re -c o nse nti n g.
3. 3. M a xi m u m T oler ate d a n d M a xi m u m A d mi nistere d D ose ( M T D
a n d M A D )
Defi niti o n s
T he M T D is defi ne d as t he hi g hest d ose wit h tr ue t o xicit y pr o ba bilities i n t he e q ui vale nce 
i nter val (EI ) w here t he EI is defi ne d as 2 0 %- 3 0 %.
E ve n t h o u g h t he m T PI m o del ma y  select a n M T D wit h a n i nci de nce of D L Ts t hat is hi g her 
t ha n 3 0 % si nce m T PI decisi on r ules are base d o n u nit pr o ba bilit y  mass ( U P M) a n d n ot o n 
p oi nt esti mates of t he D L T rate (see Secti o n 9. 2. 1 ), d oses wit h a n i nci de nce of D L T 
> 3 0 % (e g, 3 o ut of 9) ca n n ot be declare d as t he M T D.   I n practice, m o del rec o m me n dati o ns 
ma y  be o verri d de n b y cli nical j u d g me nt, a n d M T D wit h a n i nci de nce of D L Ts t hat is hi g her 
t ha n 3 0 % will n ot be c o nsi dere d acce pta ble t o be selecte d as M T D.  T he M T D will be t he 
hi g hest d ose ass ociate d wit h t he occ urre nce of D L Ts ≤3 0 % (e g, < 3 of 9 e val ua ble patie nts 
e x perie nce a D L T).
If t he M T D is n ot reac he d, t he n t he M A D will be ma xi m u m d ose t hat is e val uate d i n t he 
st u d y.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 4
3. 4. Rec o m me n de d P h ase 2 D ose ( R P 2 D) Defi niti o n
B ase d o n preli mi nar y  safet y, efficac y, P K, a n d p har mac o d y n a mics data fr o m Part 1 
( m o n ot hera py d ose escalati o n) , a d ose of 1 0 0 0 µ g/ k g S C wee kl y has bee n selecte d as t he 
R P 2 D f or P F - 0 6 8 6 3 1 3 5 as a si n gle a ge nt . Briefl y , si n gle-a ge nt a nti-m y el o ma acti vit y has 
bee n o bser ve d at d oses ≥2 1 5 µ g/ k g S C wit h a n acce pta ble safet y pr ofile acr oss all d ose 
le vels. T he o verall res p o nse rate ( O R R) f or t he 2 1 5, 3 6 0, 6 0 0, a n d 1 0 0 0 µ g/ k g S C d ose le vels 
w as 7 5 % ( 3 / 4), 7 5 % (3/ 4 ), 6 6. 7 % (4/ 6 ) a n d 8 3 % (5/ 6 ), res pecti vely. I n a d diti o n, p reli mi nar y 
e x p os ure -efficac y a nalys es i n dicate d t hat hi g her P F - 0 6 8 6 3 1 3 5 e x p os ure (a vera ge 
c o nce ntrati o n at stea d y state ) m a y  be ass ociate d wit h hi g her pr o ba bilit y of o bjecti ve 
res p o nse, es pecially i n patie nts wit h hi g h baseli ne s ol u ble B C M A . O verall, t he data s up p ort
1 0 0 0 µ g/ k g S C wee kl y as a t olera ble d ose t hat pr o vi de s cli nical be nefit f or t he maj orit y of 
patie nts wit h rela pse d or refract or y M M , i ncl u di n g t h ose wit h hi g h baseli ne sol u ble B C M A .
Alt h o u g h o nl y Gra de 1 or Gra de 2 C R S was re p orte d d uri n g d ose escalati o n , 2 of 6 patie nts 
e x perie nce d Gra de 1 C R S e ve nts t hat laste d f or 9 da ys wit h t he first d ose of 1 0 0 0 µ g/ k g . T he 
l o n gest d urati o n of C R S i n t he 6 0 0 µ g/ k g S C c o h ort was 4 da ys, w hic h occ urre d i n 1 patie nt 
a n d was Gra de 1. T heref ore, Part 1. 1 of t his st u d y e val uat es w het her t he d urati o n of C R S ca n
be miti gate d b y a si n gle pri mi n g d ose of 6 0 0 µ g/ k g gi ve n o ne wee k pri or t o 1 0 0 0 µ g/ k g 
mai nte na nce d osi n g (see Secti o n 1. 2. 9. 6 f or rati o nale). Base d o n preli mi nar y safety data fr o m 
Part 1. 1, a d mi nistrati o n of a pri mi n g d ose ( 6 0 0 µ g/ k g) re d uces d urati o n of C R S ass ociate d 
wit h s u bse q ue nt mai nte na nce d osi n g (1 0 0 0 µ g / k g). Theref ore , a pri mi n g strate g y will be 
a d o pte d for b ot h P F -0 6 8 6 3 1 3 5 m o n ot hera p y  a n d c o m bi nati o n t hera py i n t his st u d y as well as
ot her st u dies .
F or m o n ot hera p y d osi n g wit h P F - 0 6 8 6 3 1 3 5, the R P 2 D of 1 0 0 0 µ g/ k g will be a d mi nistere d as 
a fi xe d d ose of 7 6 m g S C wee kl y (see Secti o n 1. 2. 9. 4 f or rati o nale) f oll o wi n g a si n gle 
pri mi n g d ose of 4 4 m g (fi xe d d ose e q ui vale nt of 6 0 0 µ g/ k g ) a d mi nistere d o ne wee k bef ore 
i nitiati o n of mai nte na nce d osi n g .
T he c o m bi nati o n R P 2 D f or P F -0 6 8 6 3 1 3 5 will be deter mi ne d se paratel y f or eac h c o m bi nati o n 
t hera py .
3. 5. St o p pi n g Criteri a i n P art 2 D ose E x p a nsi o n
If t he f oll o wi n g criteria liste d bel o w are met i n a n y of t he c o h orts i n Part 2 d ose e x pa nsi o n , 
f urt her e nr oll me nt i nt o t he c o h ort meeti n g t he criteria will be place d o n h ol d , a n d a decisi o n 
t o st o p t he c o h ort ma y be ma de f oll o wi n g a re vie w of all safet y i nf or mati o n:

Gra de 5 treat me nt -relate d A E ≥1 0 %; or

Gra de 4 - 5 treat me nt-relate d n o n-he mat ol o gica l A E > 2 5 %.
A d verse e ve nt i nf or mati o n c ollecte d d uri n g d ose escalati o n of patie nts treate d at t he sa me 
d ose le vels will be i ncl u de d i n t he e val uati o n.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 5
4. P A TI E N T E LI GI BI LI T Y C RI T E RI A
T his st u d y  ca n f ulfill its o bjecti ves o nl y if a p pr o priate patie nts are e nr olle d.  T he f oll o wi n g 
eli gi bilit y criteria are desi g ne d t o select patie nts f or w h o m partici pati o n i n t he st u d y is 
c o nsi dere d a p pr o priate.  All rele va nt me dical a n d n o n me dical c o n diti o ns s h o ul d be ta ke n i nt o 
c o nsi derati o n w he n deci di n g w het her a partic ular pat ie nt is s uita ble f or t his pr ot oc ol.
4. 1. I ncl usi o n Criteri a
Patie nts m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or e nr oll me nt i n t he 
st u d y:
1.
Patie nts wit h rela pse d or refract or y  m ulti ple m yel o ma, as defi ne d b y 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 p date d criteria 2 0 1 44 5 (see A p pe n di x 6 ), a n d 
meas ura ble disease o n e nr oll me nt (st u d y  e ntr y) as defi ne d b y o ne or m ore of t he 
a b n or malities liste d i n a t o c bel o w:
a.
Ser u m m y el o ma ( M)-pr otei n greater t ha n or e q ual t o 0. 5 g/ d L ( 5 g/ L).   
b.
Uri ne M -pr otei n greater or e q ual t o 2 0 0 m g/ 2 4 h.
c.
F or patie nts wit h o ut meas ura ble ser u m a n d uri ne M- pr otei n le vels or if t he ser u m 
a n d uri ne M -pr otei n le vels are u ni nter preta ble d ue t o assa y  i nterfere nce b y pri or 
treat me nt wit h darat u m u ma b o nl y : free li g ht c hai n (F L C ) is co nsi dere d t o be 
meas ura ble i n patie nts w h ose i n v ol ve d li g ht c hai n (eit her ka p pa or la m b da) 
is  > 1 0 0  m g/ L ( 1 0  m g/ d L) a n d w h o ha ve a n a b n or mal ka p pa:la m b da rati o 
(a b n or mal is o utsi de t he ra n ge . 2 6 t o 1. 6 5).
2.
Patie nts m ust ha ve pr o gresse d o n or are i nt olera nt o f esta blis he d t hera pies k n o w n t o 
pr o vi de cli nical be nefit i n m ulti ple m y el o ma i ncl u di n g pr oteas o me i n hi bit or, a n IMi D 
dr u g a n d a n a nti -C D 3 8 m A b, w here a p pr o ve d a n d a vaila ble , eit her i n c o m bi nati o n or 
as a si n gle a ge nt.  Patie nts m ust n ot be ca n di date f or r e gi me ns k n o w n t o pr o vi de 
cli nical be nefit i n rela pse or refract or y  m ulti ple m yel o ma base d o n t he i n vesti gat or’s 
j u d g me nt.  If a patie nt decli nes s uc h t hera py, t his m ust be rec or de d i n t he st u d y  files.
3.
Fe male or male patie nts a ge 1 8 years. 
4.
Easter n C o o pera ti ve O nc ol o g y Gr o u p ( E CO G) Perf or ma nce Stat us ( P S) (see
A p pe n di x 4 ).

F or Part 2 A: Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce Stat us 
( P S) 0- 1.

F or all ot her Parts: Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce 
Stat us ( P S) 0 - 1. P S -2 is per mitte d if P S is d ue t o u n derl yi n g m yel o ma.  
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 6
5.
A de q uate he mat ol o gical f u ncti o n i ncl u di n g:

A bs ol ute ne utr o p hil c o u nt ( A N C) 1, 0 0 0/ m m 3 .

F or P F - 0 6 8 6 3 13 5 m o n ot hera p y , Part 1 E a n d 2 E : Platelet c o u nt ≥2 5 , 0 0 0/ m m3
(tra nsf usi o n s u p p ort is per mitte d if c o m plete d pri or t o pla n ne d start of d osi n g ).
F or Parts 1 C a n d 2 C platelet c o u nt ≥3 0 , 0 0 0/ m m3. F or Parts 1 D a n d 2 D platelet 
c o u nt ≥5 0 , 0 0 0/ m m3.

He m o gl o bi n ≥8. 0 g/ d L (tra nsf usi o n s u p p ort is per mitte d if c o m plete d pri or t o 
pla n ne d start of d osi n g) .
6.
A de q uate Re nal F u ncti o n, i ncl u di n g:

F or n o n -le nali d o mi de parts of t he st u d y: Esti mate d creati ni ne cleara nce
3 0 m L / mi n as calc ulate d usi n g t he met ho d sta n dar d f or t he i nstit uti o n.  (If a n 
esti mate d creati ni ne cleara nce [ C r Cl] is belie ve d t o be i nacc urate f or a patie nt, 
2 4- h o ur uri ne c ollecti o n wit h act ual assess me nt of Cr Cl is all o we d); F or Parts 1 C 
a n d 2C , esti mate d creati ni ne cleara nce 6 0 m L / mi n.

Ser u m creati ni ne ≤2. 5 m g/ d L;

N ot dial y sis- de pe n de nt.
7.
A de q uate Li ver F u ncti o n, i ncl u di n g:

As partate a n d ala ni ne a mi n otra nsferase ( A S T a n d A L T) ≤2. 5 x u p per li mit of 
n or mal ( U L N ); ≤5. 0 x U L N if t here is li ver i n v ol ve me nt b y  t he t u m or. 

Al kali ne p h os p hatase ≤2. 5 x U L N (5 x U L N i n case of b o ne metastasis). 

T otal bilir u bi n ≤2. 0 m g/ d L, e x ce pt i n patie nts wit h Gil bert S y n dr o me w h o m ust 
ha ve a t otal bilir u bi n less t ha n 3. 0 m g/ d L.
8.
N o acti ve he patitis B ( H B V) or he patitis C ( H C V) i nfecti o n.
9.
Res ol ve d ac ute effects of a n y  pri or t hera py t o baseli ne se verit y or C T C A E Gra de ≤1, 
wit h t he e xce pti o n of peri p heral ne ur o pat h y attri b uta ble t o b ortez o mi b i n t he li mit of 
Gra de ≤2.
1 0. Ser u m pre g na nc y  test (f or fe males of c hil d beari n g p ote ntial) ne gati ve at scree ni n g.
1 1. Fe male patie nts of n o n -c hil d beari n g p ote ntial m ust meet at least 1 of t he f oll o wi n g 
criteria:

Ac hie ve d p ost me n o pa usal stat us, defi ne d as f oll o ws: cessati o n of re g ular me nses 
f or at least 1 2 c o nsec uti ve m o nt hs wit h n o alter nati ve pat h ol o gical or 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 7
p h y si ol o gical ca use; stat us ma y be c o nfir me d wit h a ser u m f ollicle sti m ulati n g 
h or m o ne ( F S H) le vel c o nfir mi n g t he p ost me n o pa usal state.

Ha ve u n der g o ne a d oc u me nte d h y sterect o m y a n d/ or bilateral o o p h orect o m y. 

Ha ve me dicall y  c o nfir me d o varia n fail ure. 

All ot her fe male patie nts (i ncl u di n g fe male pat ie nts wit h t u bal li gati o ns) are 
c o nsi dere d t o be of c hil d beari n g p ote ntial. 
1 2. Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as descri be d i n A p pe n di x 1 , w hic h 
i ncl u des c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n t he inf or me d 
c o nse nt d oc u me nt (I C D) a n d i n t his pr ot oc ol.
1 3. Willi n g a n d a ble t o c o m pl y  wit h sc he d ule d visits, treat me nt pla n, la b orat or y tests, a n d 
ot her pr oce d ures.
4. 2. E xcl usi o n Criteri a
Patie nts wit h a n y  of t he f oll o wi n g c haracteristics/c o n diti o ns will n ot be i ncl u de d i n t he st u d y:
1.
Patie nts wit h ot her mali g na ncies i n a d diti o n t o m ulti ple m y el o ma are n ot eli gi ble if 
t he ot her mali g na nc y has re q uire d treat me nt wit hi n t he past 3 ye ars or is n ot i n 
c o m plete re missi o n wit h t he e xce pti o ns of s uccessf ull y  treate d n o n-metastatic basal 
cell or s q ua m o us cell s ki n carci n o ma.
2.
Hist or y  of acti ve a ut oi m m u ne dis or ders (i ncl u di n g b ut n ot li mite d t o: Cr o h n’s 
disease, r he u mat oi d art hritis, scler o der ma, s ys te mic l u p us er yt he mat os us, Gra ve’s 
disease) a n d ot her c o n diti o ns t hat c o m pr o mise or i m pair t he i m m u ne s y ste m.
3.
A n y  f or m of pri mar y i m m u n o deficie nc y (s uc h as Se vere C o m bi ne d 
I m m u n o deficie nc y Disease).
4.
Patie nts wit h acti ve u nc o ntr olle d bacterial, f u n gal or viral i nfecti o n, i ncl u di n g k n o w n 
h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n or ac q uire d i m m u n o deficie nc y  
s yn dr o me ( AI D S) relate d ill ness. See A p pe n di x 1 0 f or a d diti o nal clarificati o n as it 
relates t o S A R S -C o V 2 i nfecti o n .  
5.
Patie nts wit h e vi de nce of acti ve m uc osal or i nter nal blee di n g.
6.
Hist or y  of C T C A E Gra de ≥3 i m m u ne -me diate d a d verse e ve nt (i ncl u di n g he patitis,
pa ncreatitis, c olitis, p ne u m o nitis, car ditis, a n d c yt o ki ne release sy n dr o me) t hat was 
c o nsi dere d relate d t o pri or i m m u ne -m o d ulat or y  t hera p y (e xce pti o ns: i m m u ne-relate d 
a d verse e ve nts sec o n dar y t o c hec k p oi nt i n hi bit ors t hat ha ve bee n a p pr o priatel y 
ma na ge d or res ol ve d s uc h as h y p o p h y sitis a n d h y p ot h y r oi dis m).
7.
Maj or s ur ger y  wit hi n 4 wee ks pri or t o st u d y e ntr y.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 8
8.
Ra diati o n t hera p y wit hi n 2 wee ks pri or t o st u d y e ntr y ( b o ne lesi o ns re q uiri n g 
ra diati o n ma y be treate d wit h li mite d [ie, ≤2 5 % of b o ne marr o w i n fiel d] ra diati o n 
t hera py d uri n g t his peri o d).
9.
Patie nts wit h a hist or y  of ste m cell tra ns pla nt (a ut ol o g o us or all o ge neic) wit hi n 
1 0 0 da y s pri or t o st u d y  e nr oll me nt.
1 0. D o n or L y m p h oc y te I nf usi o n ( D LI) wit hin 3 0 d a y s pri or t o st u d y e ntr y.
1 1. Ti me bet wee n t he last d oses of pre vi o us s ys te mic a nti-ca ncer t hera p y is less t ha n 
5 ti mes t he eli mi nati o n half-life of pre vi o us t hera p y or less t ha n 3 0 d a y s after last 
d ose of a nti b o d y  base d t hera pies (e g, el ot uz u ma b, darat u m u ma b).
1 2. Re q uire me nt f or s ys te mic i m m u ne s u p pressi ve me dicati o n e xce pt as per mitte d i n t he 
st u d y pr ot oc ol.
1 3. C urre nt re q uire me nt f or c hr o nic bl o o d pr o d uct s u p p ort.
1 4. Patie nts wi t h k n o w n rela pse f oll o wi n g B C M A tar gete d t hera py (e xce pt f or 
P F -0 6 8 6 3 1 3 5) m a y be eli gi ble f oll o wi n g disc ussi o n wit h t he s p o ns or. H o we ver, 
patie nts w h o ha d recei ve d ale mt uz u ma b pre vi o usl y or w h o ha ve n ot rec o vere d w hite 
bl o o d cell c o u nts t o baseli ne after c o n diti o ni n g c he m ot hera p y f or pri or c hi meric 
a nti ge n rece pt or ( C A R) T cell t hera p y are e xcl u de d.
1 5. Patie nt k n o w n t o be refract or y  t o platelet or re d bl o o d cell tra nsf usi o ns.
1 6. Baseli ne 1 2 -lea d electr ocar di o gra m ( E C G) t hat de m o nstrates cli nicall y rele va nt 
a b n or malities t hat ma y affect patie nt safety or i nter pretati o n of st u d y res ults 
(e g, baseli ne c orrecte d Q T [ Q Tc] i nter val > 4 7 0 msec, c o m plete left b u n dle bra nc h 
bl oc k [ L B B B], si g ns of a n ac ute or i n deter mi nate -a ge m y ocar dial i nfarcti o n , S T-T 
i nter val c ha n ges s u g gesti ve of acti ve my o car dial isc he mia, sec o n d - or t hir d -de gree 
atri o ve ntric ular [ A V] bl oc k, or seri o us bra d yarr h yt h mias or tac h yarr h yt h mias). If t he 
baseli ne u nc orrecte d Q T i nter val is > 4 7 0 msec, t his i nter val s h o ul d be rate- c orrecte d 
usi n g t he Fri dericia met h o d a n d t he res ulti n g C orrecte d Q T i nter val b y  Fre dericia
(Q Tc F ) s h o ul d be use d f or decisi o n ma ki n g a n d re p orti n g.  If Q Tc e xcee ds 4 7 0 msec, 
or Q R S e xcee ds 1 2 0 msec, t he E C G s h o ul d be re peate d 2 m ore ti mes a n d t he a vera ge 
of t he 3 Q Tc or Q R S val ues s h o ul d be use d t o deter mi ne t he patie nts eli gi bilit y. 
C o m p uter -i nter prete d E C Gs s h o ul d be o verrea d by a p h ysicia n e x perie nce d i n 
rea di n g E C Gs bef ore e xcl u di n g partici pa nts.  Cases m ust be disc usse d i n detail wit h 
s p o ns or’s me dical m o nit or t o j u d ge eli gi bilit y .
A n y  of t he f oll o wi n g i n t he pre vi o us 6 m o nt hs: m yocar dial i nfarcti o n, l o n g Q T 
s yn dr o me, T orsa de de P oi ntes, arr h y t h mias (i ncl u di n g s ustai ne d ve ntric ular 
tac hyarr h yt h mia a n d ve ntric ular fi brillati o n), seri o us c o n d ucti o n s y ste m a b n or malities 
(e g, left a nteri or he mi bl oc k, left b u n dle bra nc h bl oc k), u nsta ble a n gi na, 
c or o nar y/ peri p heral arter y b y pass graft, s y m pt o matic c o n gesti ve heart fail ure ( C H F, 
Ne w Y or k Heart Ass ociati o n class III or I V), cere br o vasc ular acci de nt, tra nsie nt 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 9
ische mic attac k, s y m pt o matic p ul m o nar y  e m b olis m, a n d/ or ot her cli nical si g nifica nt 
e pis o de of t hr o m b oe m b olic disease, o n g oi n g car diac d ys r hyt h mias of Nati o nal 
Ca ncer I nstit ute ( N CI) C T C A E > Gra de 2, atrial fi brillati o n of a n y  gra de ( > Gra de 2 
i n t he case of as ym pt o matic l o ne atrial fi brillati o n). If a partici pa nt has a car diac 
r h yt h m de vice/ pace ma ker place d a n d Q Tc F > 4 7 0 msec, t he partici pa nt ca n be 
c o nsi dere d eli gi ble.  S u bjects wit h car diac r h yt h m de vice/ pace ma ker m ust be 
disc usse d i n detail wit h s p o ns or’s me dical m o nit or t o j u d ge eli gi bilit y .
1 7. H y perte nsi o n t hat ca n n ot be c o ntr olle d b y  me dicati o ns ( > 1 5 0/ 1 0 0 m m H g des pite 
o pti mal me dical t hera p y).
1 8. Partici pati o n i n ot her st u dies i n v ol vi n g i n vesti gati o nal dr u g(s) wit hi n 4 wee ks pri or t o 
st u d y e ntr y.  Patie nt m a y  be i ncl u de d if 5 ti mes eli mi nati o n half-life of dr u g has 
passe d. N ote: C O VI D -1 9 vacci nati o n ma y  be c o nsi dere d a n e xce pti o n a n d s h o ul d be 
disc usse d wit h t he s p o ns or o n a n i n di vi d ual basis.
1 9. K n o w n or s us pecte d h y p erse nsiti vit y t o m uri ne a n d b o vi ne pr o d ucts. 
2 0. Fe rtile male patie nts a n d fe male patie nt s of c hil d beari n g p ote ntial w h o are u n willi n g 
or u na ble t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n as o utli ne d i n t his 
pr ot oc ol . 
2 1. Ot her ac ute or c hr o nic me dical or ps yc hi atric c o n diti o n, i ncl u di n g rece nt ( wit hi n t he 
past y ear) or acti ve s uici dal i deati o n or be ha vi or or la b orat or y  a b n or malit y t hat ma y 
i ncrease t he ris k ass ociate d wit h st u d y partici pati o n or i n vesti gati o nal pr o d uct 
a d mi nistrati o n or ma y i nterfere wit h t he i nter pretati o n of st u d y res ults a n d, i n t he 
j u d g me nt of t he i n vesti gat or, w o ul d ma ke t he patie nt i na p pr o priate f or e ntr y i nt o t his 
st u d y.
2 2. I n vesti gat or site staff me m bers directly i n v ol ve d i n t he c o n d uct of t he st u d y a n d t heir 
fa mil y me m bers , site staff me m bers ot her wise s u per vise d b y t he i n vesti gat or, or 
patie nts w h o are Pfizer e m pl o y ees, i ncl u di n g t heir fa mil y me m bers, directl y i n v ol ve d 
i n t he c o n d uct of t he st u d y.
2 3. F or e nr oll me nt i n le nali d o mi de c o m bi nati o n c o h orts Parts 1 C a n d 2 C , patie nts w h o 
ha d pre vi o usl y recei ve d le nali d o mi de a n d were d ose re d uce d t o less t ha n 2 5 m g dail y 
f or t hr o m b oc yt o pe nia, ne utr o pe nia or re nal i m pair me nt.
2 4. F or e nr oll me nt i n p o mali d o mi de c o m bi nati o n c o h orts Parts 1 D a n d 2 D, patie nts w h o 
ha d pre vi o usl y recei v e d p o mali d o mi de a n d were d ose re d uce d t o less t ha n 4 m g dail y 
f or t hr o m b oc yt o pe nia, ne utr o pe nia, se vere re nal i m pair me nt, or he patic i m pair me nt.
2 5. F or e nr oll me nt i n p o mali d o mi de c o m bi nati o n c o h orts Parts 1 D a n d 2 D, patie nts w h o 
are recei vi n g str o n g C Y P 1 A 2 i n hi bit ors ( eg, ci pr ofl o xaci n a n d fl u v o xa mi ne ).
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 0
2 6. F or patie nts o n p o mali d o mi de c o m bi nati o n Parts 1 D a n d 2 D, patie nts w h o ha ve a n y 
le vel of he patic i m pair me nt ( C hil d-P u g h A -C) t hat w o ul d re q uire d ose re d ucti o n of 
p o mali d o mi de.
4. 3. Life st yle Re q uire me nts
All fertil e fe male patie nts w h o are of c hil d beari n g p ote ntial w h o are, i n t he o pi ni o n of t he 
i n vesti gat or, se x uall y acti ve a n d at ris k f or pre g na nc y wit h t heir part ner(s) m ust a gree t o use 
a hi g hl y effecti ve met h o d of c o ntrace pti o n c o nsiste ntl y  a n d c orrectly f or t he d urati o n of t he 
acti ve treat me nt peri o d a n d f or at least 5 m o nt hs after t he last d ose of P F -0 6 8 6 3 1 3 5 .
N o c o ntrace pti o n met h o ds are re q uire d f or male partici pa nts w h o recei ve P F - 0 6 8 6 3 1 3 5 i n 
t his st u d y, as t he calc ulate d safety mar gi n is ≥1 0 0 ‑f ol d bet wee n t he esti mate d mater nal 
e x p os ure d ue t o se mi nal tra nsfer a n d t he esti mate d M A B E L ( mi ni mal a ntici pate d bi ol o gical 
effect le vel) use d as c o nser vati ve esti mate of e x p os ure t hat ma y  res ult i n seri o us 
ma nifestati o ns of de vel o p me ntal t o xicit y .
I n a d diti o n t o c o ntrace pti o n re q uire me nts t o P F-0 6 8 6 3 1 3 5, f or Parts 1 C , 2 C, 1 D a n d 2 D , t he 
ma n ufact urer’s ( Brist ol Me y ers S q ui b b’s) pre g na nc y pre ve nti o n pr o gra ms ( P P P) f or 
le nali d o mi de a n d p o mali d o mi de m ust be f oll o we d. All fe males of c hil d beari n g p ote ntial , as 
defi ne d p er P P P, m ust use at least 2 acce pta ble met h o d s of c o ntrace pti o n as s pecifie d i n t he 
P P P i ncl u di n g at least o ne hi g hly effecti ve met h o d (t u bal li gati o n, I U D, h or m o nal [ birt h 
c o ntr ol pills, h or m o nal patc hes, i njecti o ns, va gi nal ri n gs, or i m pla nts], or part ner’s
vasect o m y) a n d at least o ne a d diti o nal effecti ve met h o d of birt h c o ntr ol ( male late x or 
s ynt hetic c o n d o m, dia p hra g m, or cer vical ca p e ver y  ti me t he y ha ve se x wit h a male, or 
a bstai ni n g fr o m se x wit h a male) f or at least 4 wee ks bef ore le nali d o mi de or p o ma li d o mi de 
t hera py (i ncl u di n g d uri n g d osi n g i nterr u pti o ns) , d uri n g le nali d o mi de or p o mali d o mi de 
t hera py, a n d u ntil at least 4 wee ks after t he last d ose of le nali d o mi de or p o mali d o mi de 
t hera py, a n d me n m ust al wa y s use a late x or s ynt hetic c o n d o m d uri n g a n y  sex ual c o ntact 
wit h fe males of c hil d beari n g p ote ntial d uri n g le nali d o mi de or p o mali d o mi de t hera py
(i ncl u di n g d uri n g d osi n g i nterr u pti o ns) a n d u ntil at least 4 wee ks after disc o nti n ui n g 
le nali d o mi de or p o mali d o mi de . I n a d diti o n, P P P re q uire me nts relate d t o pr o hi biti o n of bl o o d, 
se me n, a n d s per m d o nati o n d uri n g le nali d o mi de a n d p o mali d o mi de treat me nt a n d f or at least 
4 wee ks after disc o nti n ui n g treat me nt m ust be f oll o we d.
T he i n vesti gat or or his or her desi g nee, i n c o ns ultati o n wit h t he patie nt , will c o nfir m t hat t he 
patie nt has selecte d a n a p pr o priate met h o d of c o ntrace pti o n f or t he i n di vi d ual patie n t a n d his 
or her part ner(s) fr o m t he per mitte d list of c o ntrace pti o n met h o ds (see bel o w) a n d will 
c o nfir m t hat t he patie nt has bee n i nstr ucte d i n its c o nsiste nt a n d c orrect use.  At ti me p oi nts 
i n dicate d i n t he S C H E D U L E O F A C TI VI TI E S (i ncl u di n g t he re q uire d c o ntrace pti o n peri o d 
[t hr o u g h 5 m o nt hs p ost last d ose of P F - 0 6 8 6 3 1 3 5 f or W O C B P]), t he i n vesti gat or or desi g nee 
will i nf or m t he patie nt o f t he nee d t o use hi g hly effecti ve c o ntrace pti o n c o nsiste ntl y  a n d 
c orrectl y a n d d oc u me nt t he c o n versati o n a n d t he patie nt ’s affir mati o n i n t he patie nt ’s c hart 
(patie nts nee d t o affir m t heir c o nsiste nt a n d c orrect use of t he selecte d met h o ds of 
c o ntrace pti on).  I n a d diti o n, t he i n vesti gat or or desi g nee will i nstr uct t he patie nt t o call 
i m me diatel y if t he selecte d c o ntrace pti o n met h o d is disc o nti n ue d or if pre g na nc y  is k n o w n or 
s us pecte d i n t he patie nt or part ner. I n a d diti o n t o re p orti n g re q uire me nts o utli ne d i n Secti o ns
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 1
8. 4. 2 a n d 8. 4. 2. 1 , f or Parts 1 C, 2 C, 1 D a n d 2 D, a d diti o nal re p orti n g re q uire me nts as defi ne d 
i n t he P P P f or le nali do mi de a n d p o mali d o mi de m ust be f oll o we d, i ncl u di n g i m me diate 
re p orti n g of p ote ntial pre g na nc y e x p os ure t o t he ma n ufact urer, f oll o w-u p re p orti n g t o t he 
ma n ufact urer eac h tri mester u ntil o utc o me, a n d i nfa nt f oll o w- u p t o t he ma n ufact urer e ver y  
q uarter f or 1 year after birt h ( pe n di n g c o nse nt of t he fe male partici pa nt or fe male part ner).
Hi g hl y effecti ve met h o ds of c o ntrace pti o n are t h ose t hat, al o ne or i n c o m bi nati o n, res ult i n a 
fail ure rate of less t ha n 1 % per ye ar w he n use d c o nsiste ntl y a n d c orrectl y (ie, perfect use) a n d 
i ncl u de t he f oll o wi n g:
1.
Esta blis he d use of h or m o nal met h o ds of c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n (e g, oral, i nserte d, i n jecte d, i m pla nte d, tra ns der mal), pr o vi de d t he patie nt or 
male patie nt ’s fe male part ner pla ns t o re mai n o n t he sa me treat me nt t hr o u g h o ut t he 
e ntire st u d y a n d has bee n usi n g t hat h or m o nal c o ntrace pti ve f or a n a de q uate peri o d of 
ti me t o e ns ure effecti ve ness. 
2.
C orrectl y place d c o p per -c o ntai ni n g i ntra uteri ne de vice (I U D).
3.
Male c o n d o m or fe male c o n d o m use d WI T H a se parate s per mici de pr o d uct (ie, f oa m, 
gel, fil m, crea m, or s u p p osit or y ).  F or c o u ntries w here s per mici de is n ot a vaila ble or 
c o n d o m pl us s per mici de is n ot acce pte d as hi g hl y effecti ve c o ntrace pti o n, t his o pti o n 
is n ot a ppr o priate.
4.
Male sterilizati o n wit h a bse nce of s per m i n t he p ost vasect o m y ejac ulate.
5.
Bilateral t u bal li gati o n/ bilateral sal pi n gect o m y or bilateral t u bal occl usi ve pr oce d ure 
( pr o vi de d t hat occl usi o n has bee n c o nfir me d i n acc or da nce wit h t he de vice’s la bel).
N O T E: Se x ual a bsti ne nce, defi ne d as c o m pletel y a n d persiste ntl y refrai ni n g fr o m all 
heter ose x ual i nterc o urse (i ncl u di n g d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y 
treat me nts) ma y o b viate t he nee d f or c o ntrace pti o n O N L Y if t his is t he preferre d a n d us ual 
lifest yle of t he patie nt .
4. 4. S p o ns or ’s Q u alifie d Me dic al Pers o n nel
T he c o ntact i nf or mati o n f or t he s p o ns or's a p pr o priatel y q ualifie d me dical pers o n nel f or t he 
st u d y is d oc u me nte d i n t he st u d y c o ntact list l ocate d i n t he s u p p orti n g st u d y d oc u me ntati o n . 
T o facilitate access t o a p pr o priatel y q ualifie d me dical pers o n nel o n st u d y- relate d me dical 
q uesti o ns or pr o ble ms, patie nts are pr o vi de d wit h a c o ntact car d. T he c o ntact car d c o ntai ns, 
at a mi ni m u m, pr ot oc ol a n d i n vesti gati o nal pr o d uct i de ntifiers, patie nt st u d y n u m bers, 
c o ntact i nf or mati o n f or t he i n vesti gator site, a n d c o ntact details f or a c o ntact ce nter i n t he 
e ve nt t hat t he i n vesti gator site staff ca n n ot be reac he d t o pr o vi de a d vice o n a me dical 
q uesti o n or pr o ble m ori gi nati n g fr o m a n ot her healt hcare pr ofessi o nal n ot i n v ol ve d i n t he 
patie nt’s partici pati o n i n t he st u d y . T he c o ntact n u m ber ca n als o be use d b y  i n vesti gator staff 
if t he y are see ki n g a d vice o n me dical q uesti o ns or pr o ble ms; h o we ver, it s h o ul d be use d o nl y  
i n t he e ve nt t hat t he esta blis he d c o m m u nicati o n pat h wa ys bet wee n t he i n vesti gator site a n d 
t he st u d y tea m are n ot a vaila ble. It is t heref ore i nte n de d t o a u g me nt, b ut n ot re place, t he 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 2
esta blis he d c o m m u nicati o n pat h wa y s bet wee n t he i n vesti gator site a n d t he st u d y tea m f or 
a dvice o n me dical q uesti o ns or pr o ble ms t hat ma y arise d uri n g t he st u d y .  T he c o ntact 
n u m ber is n ot i nte n de d f or use b y t he patie nt directl y, a n d if a patie nt calls t hat n u m ber, he or 
s he will be directe d bac k t o t he i n vesti gator site.
5. S T U D Y T R E A T M E N T S
F or t he p ur p oses of t his st u d y , a n d per I nter nati o nal C o nfere nce o n Har m o nizati o n (IC H) 
g ui deli nes, i n vesti gati o nal pr o d uct is defi ne d as a p har mace utical f or m of a n acti ve 
i n gre die nt or place b o bei n g teste d or use d as a refere nce/c o m parat or i n a cli nical trial, 
i ncl u di n g a pr o d uct wit h a mar keti n g a ut h orizati o n w he n use d or asse m ble d (f or m ulate d or 
pac ka ge d) i n a wa y  differe nt fr o m t he a p pr o ve d f or m, or w he n use d f or a n u na p pr o ve d 
i n dicati o n, or w he n use d t o gai n f urt her i nf or mati o n a b o ut a n a p pr o ve d use (IC H E 6 1. 3 3).
F or t his st u d y , t he i n vesti gati o nal me dici nal pr o d uct s i ncl u de P F - 0 6 8 6 3 1 3 5, le nali d o mi de,
p o mali d o mi de a n d de xa met has o ne.  F or d ose le vel i nf or mati o n, please see Secti o n 3. 1 .
5. 1. All oc ati o n t o Tre at me nt
D ose le vel all ocati o n will be perf or me d b y t he s p o ns or after patie nts ha ve gi ve n t heir writte n 
i nf or me d c o nse nt a n d ha ve c o m plete d t he necessar y baseli ne assess me nts. T he site staff will
e-mail a c o m plete Re gistrati o n F or m t o t he desi g nate d s p o ns or st u d y  tea m me m ber or 
desi g nee .  T he s p o ns or will assi g n a patie nt i de ntificati o n n u m ber a n d s u p pl y t his n u m ber t o 
t he site.  T he patie nt i de ntificati o n n u m ber will be use d o n all st u d y -relate d d oc u me ntati o n at 
t he site.
N o patie nt s hall recei ve i n vesti gati o nal pr o d uct u ntil t he i n vesti gat or or desi g nee has recei ve d 
t he f oll o wi n g i nf or mati o n i n writi n g fr o m t he s p o ns or:

C o nfir mati o n of t he patie nt’s e nr oll me nt;

S pecificati o n of t he d ose le vel f or t hat patie nt a n d ;

P er missi o n t o pr ocee d wit h d osi n g t he patie nt .
T he s p o ns or or desi g nee will n otif y  t he ot her sites of t he i ncl usi o n of a ne w patie nt, a n d will 
i nf or m st u d y sites a b o ut t he ne xt p ossi ble e nr oll me nt date.
5. 2. P atie nt C o m pli a nce
All d oses of P F -0 6 8 6 3 1 3 5 will be a d mi nistere d b y t he a p pr o priatel y desi g nate d st u d y staff at 
t he i n vesti gati o nal site. Oral me dicati o ns le nali d o mi de ,p o mali d o mi de , a n d de xa met has o ne, 
if a p plica ble, will be ta ke n b y t he patie nt eit her at t he site or at h o me.
T he site will c o m plete re q uire d d osa ge Pre parati o n R ec or d l ocate d i n t he I n vesti gati o nal 
Pr o d uct ma n ual (I P ma n ual).  T he use of t he Pre parati o n Rec or d is preferre d b ut it d oes n ot 
precl u de t he use of a n e xisti n g a p pr o priate cli nical site d oc u me ntati o n s y ste m.  T he e xisti n g 
cli nical site's d oc u me ntati o n s y ste m s h o ul d ca pt ure all perti ne nt/re q uire d i nf or mati o n o n t he 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 3
pr e parati o n a n d a d mi nistrati o n of t he d ose.  T his ma y  be use d i n place of t he Pre parati o n 
Rec or d after a p pr o val fr o m t he s p o ns or a n d/ or desi g nee. 
5. 3. I n vesti g ati o n al Pr o d uct S u p plies
5. 3. 1. P h ar m ace utic al F o r m(s) a n d P ac k a gi n g
P F - 0 6 8 6 3 1 3 5 is prese nte d as a sterile a q ue o us b uffere d s ol uti o n f or 
i ntra ve n o us/s u bc uta ne o us a d mi nistrati o n .  Please c o ns ult t he In vesti gati o nal Pr o d uct Ma n ual
(IP ma n ual) a n d I n vesti gat or’s Br oc h ure f or f urt her details.
Le nali d o mi de ( Re vli mi d ® ) is a n oral me dicati o n a p pr o ve d i n t he U S, E U, a n d Ca na da f or t he 
treat me nt of m ulti ple m yel o ma. Please c o ns ult t he Re vli mi d ® U S pac ka ge I nsert ( U S PI) or 
E U Pac ka ge I nsert or S P C f or f urt her details.3 0 -3 2
P o mali d o mi de ( U S P o mal y st® , E U a n d Ca na da I mn o vi d ® ) is a n oral me dicati o n a p pr o ve d i n 
t he U S, E U, a n d Ca na da f or t he treat me nt of m ulti ple m y el o ma. Please c o ns ult t he 
P o mal y st® U S pac ka ge I nsert ( U S PI) or E U pac ka ge i nsert or S P C f or f urt her details.3 4 -3 6
De xa met has o ne is a n oral me dicati o n a p pr o ve d i n t he U S, E U, a n d Ca na da.3 7
5. 3. 2. Pre p ar ati o n a n d Dis pe nsi n g
F or P F -0 6 8 6 3 1 3 5 , see t he I P man ual f or i nstr ucti o ns o n h o w t o pre pare t he i n vesti gati o nal 
pr o d uct f or a d mi nistrati o n.  I n vesti gati o nal pr o d uct s h o ul d be pre pare d a n d dis pe nse d b y a n 
a p pr o priatel y q ualifie d a n d e x perie nce d me m ber of t he st u d y  staff (e g, p h y sicia n, n urse, 
p h y sicia n’s assista nt, n urse practiti o ner, p har mac y assista nt/tec h nicia n, or p har macist) as 
all o we d b y l ocal, state, a n d i nstit uti o na l g ui da nce.
O nl y  q ualifie d pers o n nel w h o are fa miliar wit h pr oce d ures t hat mi ni mize u n d ue e x p os ure t o 
t he msel ves a n d t o t he e n vir o n me nt s h o ul d u n derta ke t he pre parati o n, ha n dli n g, a n d safe 
dis p osal of bi ot hera p y a ge nts.
5. 4. A d mi nistr ati o n
5. 4. 1. I V A d mi nistr ati o n P F -0 6 8 6 3 1 3 5
P F - 0 6 8 6 3 1 3 5 will be a d mi nistere d o n Da y 1, 8 a n d 1 5 of eac h c y cle per t he IP ma n ual as a n 
i ntra ve n o us (I V) i nf usi o n o ver 2 hrs (1 5 mi n utes).   If t he patie nt is assi g ne d t o t he lea d-i n 
c o h ort i n Part 2 t hat is s pecifically desi g ne d t o e val uate re d uce d i nf usi o n ti me, P F- 0 6 8 6 3 1 3 5
ma y  be a d mi nistere d as a n I V i nf usi o n o ver 1 hr (1 0 mi n utes) .  F or m o n ot hera p y, eac h 
c ycle will be 3 wee ks i n d urati o n, a n d eac h patie nt will be treate d 3 ti mes d uri n g eac h c ycle, 
u nless d ose dela y s or i nterr u pti o ns occ ur (see Secti o ns 5. 5. 1 a n d 5. 5. 2 ).  O n C 1 D 1 f or all 
patie nts, a n d o n C 0 D 1 f or patie nts recei vi n g a pri mi n g d ose, P F-0 6 8 6 3 1 3 5 will be 
a d mi nistere d o n a n i n patie nt basis.  O n all ot her da ys, P F -0 6 8 6 3 1 3 5 will be a d mi nistere d o n 
a n o ut patie nt basis. ).  O n C 1 D 1 f or all patie nts, a n d o n C 0 D 1 f or patie nts recei vi n g a pri mi n g 
d ose , P F- 0 6 8 6 3 1 3 5 will be a d mi nistere d o n a n i n patie nt basis.  O n all ot her da y s, 
P F -0 6 8 6 3 1 3 5 will be a d mi nistere d o n a n o ut patie nt basis.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 4
Details f or P F - 0 6 8 6 3 1 3 5 i nf usi o n are pr o vi de d i n t he c urre nt P F - 0 6 8 6 3 1 3 5 I P Ma n ual . T he 
d ose le vel will be assi g ne d b y  t he s p o ns or (see Secti o n 5. 1 All ocati o n t o Treat me nt).   F or 
m o n ot hera p y Part 1, all patie nts s h o ul d be wei g he d wit hi n 7 2 h o urs pri or t o Da y 1 of eac h 
c ycle t o e ns ure t he y di d n ot e x perie nce eit her a wei g ht l oss or gai n >1 0 % fr o m t he pri or 
wei g ht use d t o calc ulate t he a m o u nt of P F -0 6 8 6 3 1 3 5 re q uire d f or d ose pre parati o n. If t he 
patie nt e x perie nce d eit her a wei g ht l oss or g ai n > 1 0 % c o m pare d t o t he pri or wei g ht use d t o 
calc ulate t he i nitial d ose or d ose i n t he pre vi o us c ycle , t he a m o u nt of P F -0 6 8 6 3 1 3 5 re q uire d 
f or pre parati o n a n d a d mi nistrati o n f or t he c urre nt c ycle m ust be recalc ulate d usi n g t hi s m ost 
rece nt wei g ht o btai ne d. S h o ul d t he i nstit uti o nal p olic y  be s uc h t hat t he d ose is re q uire d t o be 
calc ulate d if a patie nt e x perie nces a wei g ht gai n of < 1 0 %, t his will be all o we d. Fi xe d d osi n g 
a p pr oac h will be a p plie d i n d ose -fi n di n g f or c o m bi nati o n a n d als o-d osi n g a p pr oac h will be 
a p plie d i n d ose- fi n di n g f or c o m bi nati o n a n d als o i n all e x pa nsi o n parts of t he st u d y ( See 
Secti o n 1. 2. 9. 4 ).
T he use of a n i nf usi o n or s y ri n ge p u m p is t he preferre d met h o d of a d mi nistrati o n t o e ns ure 
acc urate deli ver y of t he i n vesti gati o nal pr o d uct.  Please refer t o t he I P ma n ual f or i nf usi o n 
rate a n d d urati o n.
Eac h patie nt ma y  recei ve P F-0 6 8 6 3 1 3 5 u ntil disease pr o gressi o n, u nacce pta b le t o xicit y, 
wit h dra wal of c o nse nt, or st u d y  ter mi nati o n. If a patie nt has recei ve d treat me nt wit h Q 1 W 
P F -0 6 8 6 3 1 3 5 f or at least 6 m o nt hs , a n d disease assess me nts ha ve re mai ne d sta ble o ver at 
least 2 m o nt hs, c o nsi derati o n ma y  be gi ve n t o i ncreasi n g d ose i nter vals fr o m wee kly t o e ver y 
2 wee ks or o nce per c y cle ( o nl y C X D 1 d osi n g a n d acti vities a p plica ble) after c o ns ultati o n 
wit h s p o ns or . C y cles w o ul d re mai n t he sa me le n gt h wit h a n y  s ki p pe d wee kl y d oses n ote d. If 
t he patie nt s u bse q ue ntly be gi ns t o ha ve i ncr ease of disease b ur de n, d ose i nter vals s h o ul d
ret ur n t o wee kl y d osi n g.
5. 4. 2. S C A d mi nistr ati o n P F - 0 6 8 6 3 1 3 5
Q ualifie d a n d trai ne d i n vesti gat or site pers o n nel will a d mi nister P F - 0 6 8 6 3 1 3 5 t o patie nts b y 
S C i njecti o n.  I deall y, eac h i njecti o n m a y be u p t o 2 m L  i n v ol u me. H o we ver, if t he 
ma xi m u m v ol u me all o we d per i nstit uti o n’s p olic y  is l o wer, t he n u m ber of i njecti o ns ma y 
i ncrease t o acc o m m o date t his differe nce i n v ol u me t o e ns ure t he c orrect fi nal d ose is 
deli vere d .
St u d y  dr u g s h o ul d be a d mi nistere d t o t he a b d o me n ( wit h prefere nce gi ve n t o t he l o wer 
q ua dra nts w he n p ossi ble). Refer t o A p pe n di x 9 for details o n a d mi nistrati o n of m ulti ple 
i njecti o ns t o t he a b d o me n.  St u d y staff s h o ul d refer t o t he I P Ma n ual f or s pecific i nstr ucti o ns 
o n t he ha n dli n g a n d pre parati o n of st u d y  dr u g.
Si mila r t o I V d osi n g, d uri n g m o n ot hera p y d ose escalati o n wit h Q 1 W S C P F - 0 6 8 6 3 1 3 5 o nl y
eac h c ycle will be 3 wee ks i n d urati o n, a n d eac h patie nt will be treate d 3 ti mes d uri n g eac h 
c ycle, u nless d ose dela ys or i nterr u pti o ns occ ur (see Secti o ns 5. 5. 1 a n d 5. 5. 2 .  If patie nts are 
e nr olle d i nt o Q 2 W S C d osi n g c o h orts d uri n g d ose escalati o n, eac h c y cle will be 4 wee ks i n 
d urati o n, a n d eac h patie nt will be tre ate d t wice d uri n g eac h c y cle. O n C 1 D 1 f or all patie nts, 
a n d o n C 0 D 1 f or patie nts recei vi n g a pri mi n g d ose, P F- 0 6 8 6 3 1 3 5 will be a d mi nistere d o n a n 
i n patie nt basis.  O n all ot her da ys, P F-0 6 8 6 3 1 3 5 will be a d mi nistere d o n a n o ut patie nt basis ).  
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 5
If patie nts are e nr olle d i nt o Q 2 W S C d osi n g c o h orts d uri n g d ose escalati o n, eac h c ycle will 
be 4 wee ks i n d urati o n, a n d eac h patie nt will be treate d t wice d uri n g eac h c ycle. O n C 1 D 1 
f or all patie nts, a n d o n C0 D 1 f or patie nts recei vi n g a pri mi n g d ose, P F 0 6 8 6 3 1 3 5 will be 
a d mi nistere d o n a n i n patie nt basis.  O n all ot her da ys, P F 0 6 8 6 3 1 3 5 will be a d mi nistere d o n 
a n o ut patie nt basis.
Details f or P F - 0 6 8 6 3 1 3 5 i njecti o ns are pr o vi de d i n t he c urre nt P F -0 6 8 6 3 1 3 5 I P Ma n ual. T he 
d ose le vel will be assi g ne d b y  t he s p o ns or (see Secti o n 5. 1 All ocati o n t o Treat me nt).  F or 
m o n ot hera p y Part 1, all patie nts s h o ul d be wei g he d wit hi n 7 2 h o urs pri o r t o Da y 1 of eac h 
c ycle t o e ns ure t he y di d n ot e x perie nce eit her a wei g ht l oss or gai n > 1 0 % fr o m t he pri or 
wei g ht use d t o calc ulate t he a m o u nt of P F -0 6 8 6 3 1 3 5 re q uire d f or d ose pre parati o n.  If t he 
patie nt e x perie nce d eit her a wei g ht l oss or gai n > 1 0 % c o m pare d t o t he pri or wei g ht use d t o 
calc ulate t he i nitial d ose or d ose i n t he pre vi o us c ycle , t he a m o u nt of P F -0 6 8 6 3 1 3 5 re q uire d 
f or pre parati o n a n d a d mi nistrati o n f or t he c urre nt c ycle m ust be recalc ulate d usi n g t his m ost 
rece nt wei g ht o btai ne d. S h o ul d t he i nstit uti o nal p olic y be s uc h t hat t he d ose is re q uire d t o be 
calc ulate d if a patie nt e x perie nces a wei g ht gai n of < 1 0 %, t his will be all o we d. Fi xe d -d osi n g 
a p pr oac h will be a p plie d i n d ose -fi n di n g f or c o m bi nati o n a n d als o i n all e x pa nsi o n parts of 
t he st u d y ( See Secti o n 1. 2. 9. 4 ).
Eac h patie nt ma y  recei ve P F- 0 6 8 6 3 1 3 5 u ntil disease pr o gressi o n, u nacce pta ble t o xicit y , 
wit h dra wal of c o nse nt, patie nt n o l o n ger willi n g t o partici pate i n trial, or st u d y  ter mi nati o n.
If a patie nt has recei ve d treat me nt wit h Q 1 W P F - 0 6 8 6 3 1 3 5 f or at least 6 m o nt hs, a n d disease 
assess me nts ha ve re mai ne d sta ble o ver at lea st 2 m o nt hs, c o nsi derati o n ma y be gi ve n t o 
i ncreasi n g d ose i nter vals fr o m wee kly t o e ver y 2 wee ks or o nce per c y cle ( o nl y C X D 1 d osi n g 
a n d acti vities a p plica ble) after c o ns ultati o n wit h s p o ns or . C y cles w o ul d re mai n t he sa me 
le n gt h wit h a ny s ki p pe d wee kl y d oses n ote d. If t he patie nt s u bse q ue ntly be gi ns t o ha ve 
i ncrease of disease b ur de n, d ose i nter vals s h o ul d ret ur n t o wee kly d osi n g.
F or Parts 1 C, 1 D, 1 E a n d Part 2 d ose e x pa nsi o n : P F - 0 6 8 6 3 1 3 5 will be a d mi nistere d as 
descri be d f or m o n ot hera p y  P F- 0 6 8 6 3 1 3 5, a n d e ac h c ycle will be 4 wee ks i n d urati o n.  O n 
C 1 D 1 f or all patie nts a n d C 0 D 1 f or patie nts recei vi n g a pri mi n g d ose, P F -0 6 8 6 3 1 3 5 will be 
a d mi nistere d o n a n i n patie nt basis.  O n all ot her da ys, P F- 0 6 8 6 3 1 3 5 will be a d mi nistere d o n 
a n o ut patie nt basis.
If a patie nt has recei ve d treat me nt wit h Q 1 W P F -0 6 8 6 3 1 3 5 f or at least 6 m o nt hs, a n d disease 
assess me nts ha ve re mai ne d sta ble o ver at least 2 m o nt hs, c o nsi derati o n ma y be gi ve n t o 
i ncreasi n g d ose i nter vals fr o m wee kly t o e ver y 2 wee ks or o nce per c y cle ( o nl y CX D 1 d osi n g 
a n d acti vities a p plica ble) after c o ns ultati o n wit h s p o ns or . C y cles w o ul d re mai n t he sa me 
le n gt h wit h a ny s ki p pe d wee kl y d oses n ote d. F or e ver y  2 wee k d osi n g, it w o ul d be 
prefera ble t o s ki p d osi n g of P F -0 6 8 6 3 1 3 5 o n da y s 8 a n d 2 2 of eac h c ycle. If t he patie nt 
s u bse q ue ntl y be gi ns t o ha ve i ncrease of disease b ur de n, d ose i nter vals s h o ul d ret ur n t o 
wee kl y d osi n g.
5. 5. Rec o m me n de d D ose M o dific ati o ns
E ver y  eff ort s h o ul d be ma de t o a d mi nister i n vesti gati o nal pr o d uct o n t he pla n ne d d ose a n d 
sc he d ule.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 6
I n t he e ve nt of si g nifica nt t o xicit y, d osi n g ma y  be dela ye d a n d/ or re d uce d as descri be d 
bel o w.  I n t he e ve nt of m ulti ple t o xicities, d ose m o dificati o n s h o ul d be base d o n t he w orst 
t o xicit y o bser ve d.  Patie nts are t o be i nstr ucte d t o n otif y i n vesti gat ors at t he first occ urre nce 
of a n y a d verse s y m pt o m.
D ose m o dificati o ns of P F - 0 6 8 6 3 1 3 5, le nali d o mi de, p o mali d o mi de a n d de xa met has o ne, m a y  
occ ur i n o ne of t hree wa ys:

Wit hi n a c y cle: d osi n g i nterr u pti o n u ntil a de q uate rec o ver y a n d d ose re d ucti o n, if 
re q uire d, d uri n g a gi ve n treat me nt c ycle; 

Bet wee n c y cles: ne xt c ycle a d mi nistrati o n ma y be dela ye d d ue t o persisti n g t o xicit y 
w he n a ne w c y cle is d ue t o start;

I n t he ne xt c ycle: d ose re d ucti o n ma y be re q uire d i n a s u bse q ue nt c ycle base d o n 
t o xicit y e x perie nce d i n t he pre vi o us c y cle.
I n Parts 1 E a n d 2 E, if a d ose of P F-0 6 8 6 3 1 3 5 is dela y e d or i nterr u pte d, t he n de xa met has o ne 
s h o ul d n ot be a d mi nistere d u ntil P F-0 6 8 6 3 1 3 5 a d mi nistrati o n is restarte d.
5. 5. 1. D os i n g I nterr u pti o ns
Patie nts e x perie nci n g Gra de 3 or 4 p ote ntiall y treat me nt -relate d t o xicit y or i nt olera ble 
dr u g -relate d Gra de 2 t o xicit y  des pite s u p p orti ve care s h o ul d ha ve t heir treat me nt i nterr u pte d. 
A p pr o priate f oll o w- u p assess me nts s h o ul d be d o ne u ntil a de q uate rec o ver y occ urs as 
assesse d b y t he i n vesti gat or.  Criteria re q uire d bef ore treat me nt ca n res u me are descri be d i n 
t he D ose Dela y s Secti o n 5. 5. 2 .
D oses ma y  be hel d as nee de d u ntil t o xicit y res ol uti o n.  De pe n di n g o n w he n t he a d verse e ve nt 
res ol ve d, a treat me nt i nterr u pti o n ma y lea d t o t he patie nt missi n g all s u bse q ue nt pla n ne d 
d oses wit hi n t hat sa me c y cle or e ve n t o dela y t he i nitiati o n of t he s u bse q ue nt c ycle. 
If t he a d verse e ve nt t hat le d t o t he treat me nt i nterr u pti o n rec o vers wit hi n t he sa me c ycle, t he n 
re-d osi n g i n t hat c y cle is all o we d.  D oses o mitte d f or t o xicit y are n ot re place d wit hi n t he 
sa me c ycle. T he nee d f or a d ose re d ucti o n at t he ti me of treat me nt res u m pti o n s h o ul d be 
base d o n t he criteria defi ne d i n t he D ose Re d ucti o ns Secti o n 5. 5. 3 , u nless e x pressl y a gree d 
ot her wise f oll o wi n g disc ussi o n bet wee n t he i n vesti gat or a n d t he s p o ns or. 
I n t he e ve nt of a treat me nt i nterr u pti o n f or reas o ns ot her t ha n treat me nt-relate d t o xicit y 
(e g, electi ve s ur ger y) lasti n g > 3 wee ks, treat me nt res u m pti o n will be deci de d i n c o ns ultati o n 
wit h t he s p o ns or.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 7
5. 5. 2. D ose Del a ys
Re -treat me nt f oll o wi n g treat me nt i nterr u pti o n f or treat me nt-relate d t o xicit y or at t he start of 
a n y ne w c ycle s h o ul d n ot occ ur u ntil all of t he f oll o wi n g para meters ha ve bee n met:

A N C ≥1, 0 0 0/ m m 3 f or P F- 0 6 8 6 3 1 3 5, de xa met has o ne, a n d le nali d o mi de; ≥5 0 0/ m m 3
f or p o mali d o mi de;

Platelets c o u nt ≥2 5 , 0 0 0/m m 3 f or P F - 0 6 8 6 3 1 3 5 a n d de xa met has o ne; ≥3 0, 0 0 0/ m m3 f or 
le nali d o mi de; ≥5 0, 0 0 0/ m m3 f or p o mali d o mi de ;

N o n -he mat ol o gic t o xicities ha ve ret ur ne d t o baseli ne or Gra de 1 se verit y  ( or, at t he 
i n vesti gat or’s discreti o n, Gra de 2 if n ot c o nsi dere d a safet y ris k f or t he patie nt).

Rec o ver y  of treat me nt-e mer ge nt peri p heral ne ur o pat h y t o Gra de ≤1 se verit y .
If a treat me nt dela y  res ults fr o m w orse ni n g of he mat ol o gic or bi oc he mical para meters, t he 
fre q ue nc y of rele va nt bl o o d tests s h o ul d be i ncrease d as cli nically i n dicate d.
If t hese c o n diti o ns are met wit hi n 3 wee ks of treat me nt i nterr u pti o n or c y cle dela y, st u d y 
treat me nt m a y  be res u me d.  R efer t o t he D ose Re d ucti o ns Secti o n 5. 5. 3 f or a d verse e ve nts 
re q uiri n g d ose re d ucti o n at t he ti me of treat me nt res u m pti o n. 
If t hese c o n diti o ns are n ot met, treat me nt res u m pti o n m ust be dela y e d u p t o a ma xi m u m of 
3 wee ks .  If patie nts re q uire disc o nti n uati o n of st u d y treat me nt f or m ore t ha n 4 2 da y s of 
D a y 1 of t he c urre nt c ycle, t he n st u d y treat me nt s h o ul d be per ma ne ntly disc o nti n ue d, u nless 
t he i n vesti gat or’s be nefit/ris k assess me nt s u g gests ot her wise after disc ussi o n wit h t he 
S p o ns or’s me dical m o nit or.
If a treat me nt i nterr u pti o n c o nti n ues be yo n d t he last da y of t he c urre nt c y cle, t he n t he da y 
w he n treat me nt is restarte d will be c o u nte d as Da y 1 of t he ne xt c y cle. 
Rec o m me n de d g ui deli nes f or d ose dela y s of P F -0 6 8 6 3 1 3 5 f or partici pa nts w h o ha ve acti ve 
[c o nfir me d ( p ositi ve b y re g ulat or y a ut h ority- a p pr o ve d test) or pres u me d (test 
pe n di n g/cli nical s us pici o n)] S A R S -C o V 2 i nfecti o n ca n be f o u n d i n A p pe n di x 1 0 .
5. 5. 3. D ose Re d ucti o ns
F oll o wi n g d os i n g i nterr u pti o n or c ycle dela y d ue t o t o xicit y, t he P F -0 6 8 6 3 1 3 5 d ose ma y  nee d 
t o be re d uce d w he n treat me nt is res u me d.
N o s peci fic d ose a dj ust me nts f or P F- 0 6 8 6 3 1 3 5 are rec o m me n de d f or Gra de 1/ 2 
treat me nt-relate d t o xicit y.  H o we ver, i n vesti gat ors s h o ul d al wa ys ma na ge t heir patie nts 
acc or di n g t o t heir me dical j u d g me nt base d o n t he partic ular cli nical circ u msta nces.
Patie nts e x perie nci n g rec urre nt a n d i nt olera ble Gra de 2 t o xicit y  m a y res u me d osi n g at t he 
ne xt l o wer d ose le vel of P F - 0 6 8 6 3 1 3 5 o nce rec o ver y  t o Gra de 1 or baseli ne is ac hie ve d.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 8
D ose re d ucti o n of P F -0 6 8 6 3 1 3 5 b y  1 a n d, if nee de d, 2 d ose le vels will be all o we d de pe n d i n g 
o n t he t y pe a n d se verit y  of t o xicit y e nc o u ntere d.  Patie nts e nr olle d i n t he first ( 0. 1 g/ k g ) 
c o h ort will be all o we d 1 d ose re d ucti o n if re q uire d.  Patie nts re q uiri n g m ore t ha n 2 d ose 
re d ucti o ns ( or 1 d ose re d ucti o n f or t he first c o h ort) will be disc o nti n ue d fr o m t he treat me nt 
a n d e ntere d i nt o t he f oll o w -u p p hase, u nless ot her wise a gree d bet wee n t he i n vesti gat or a n d 
t he s p o ns or. If d ose re d ucti o n of P F - 0 6 8 6 3 1 3 5 is nee de d for a n y patie nt w h o recei ve s fi xe d 
d oses of P F - 0 6 8 6 3 1 3 5 ( Parts 1 C, 1 D, 1 E, 2 A, 2 C, 2 D, 2 E), t he ne xt d ose le vel of 
P F -0 6 8 6 3 1 3 5 will be 2 5 % l o wer t ha n t he c urre nt d ose le vel (e g, fr o m 3 2 m g t o 2 4 m g, or 
fr o m 2 4 m g t o 1 6 m g). All d ose m o dificati o ns/a dj ust me nts m ust be clearl y d oc u me nte d i n 
t he patie nt's s o urce n otes a n d case re p ort f or m ( C R F ). 
O nce a d ose has bee n re d uce d f or a gi ve n patie nt, all s u bse q ue nt c y cles s h o ul d be 
a d mi nistere d at t hat d ose le vel, u nless f urt her d ose re d ucti o n is re q uire d.  I ntra patie nt dose 
re-escalati o n is n ot all o we d.
Patie nts e x perie nci n g a D L T m a y  res u me d osin g at t he ne xt l o wer d ose le vel (if a p plica ble) 
o nce a de q uate rec o ver y  is ac hie ve d.  Patie nts e x perie nci n g a D L T of pr ol o n ge d 
m y el os u p pressi o n ( > 4 2 da ys) m a y  n ot res u me treat me nt e ve n if a de q uate rec o ver y is 
ac hie ve d.  N o d ose re d ucti o ns are pla n ne d f or pa tie nts e x perie nci n g t o xicities ot her t ha n 
t h ose liste d as D LTs.  H o we ver, patie nts e x perie nci n g rec urre nt a n d i nt olera ble Gra de 2 
t o xicit y ma y res u me d osi n g at t he ne xt l o wer d ose le vel o nce rec o ver y t o Gra de 1 or 
baseli ne is ac hie ve d.  Patie nts w h ose he mat ol o gic i n dices i m pr o ve pri or t o meeti n g t he 
criteria f or pr ol o n ge d m yel os u p pressi o n > 4 2 d a y s ma y res u me d osi n g at t he ne xt l o wer d ose 
le vel or per ma ne ntl y disc o nti n ue fr o m treat me nt at t he discreti o n of t he i n vesti gat or.
Rec o m me n de d d ose re d ucti o ns f or P F- 0 6 8 6 3 1 3 5 are descri be d i n Ta ble 5.
T a ble 5.
D ose M o dific ati o ns f or P F -0 6 8 6 3 1 3 5 Pr o d uct -Rel ate d T o xicit y a n d f or 
Peri p her al Se ns or y or M ot or Ne ur o p at h y * * *
T o xicit y
Gr a de 1
Gr a de 2
Gr a de 3
Gr a de 4
N o n -he mat ol o gic 
(e xcl u di n g peri p heral 
ne ur o pat h y -see bel o w)
C o nti n ue at t he 
sa me d ose 
le vel.
C o nti n ue at t he sa me 
d ose le vel. 
Wit h h ol d d ose u ntil 
t o xicit y is 
G ra de ≤1, or has 
ret ur ne d t o 
baseli ne, t he n 
re d uce t he d ose b y 
1 le vel.*
Per m a ne ntl y 
disc o nti n ue .*
H e m at ol o gic e xce pt f or 
l y m p h o pe nia, w hic h is 
e x pecte d as part of 
P F -0 6 8 6 3 1 3 5 
mec ha nis m of acti o n
C o nti n ue at t he 
sa me d ose 
le vel.
C o nti n ue at t he sa me 
d ose le vel.
Wit h h ol d d ose u ntil 
t o xicit y is 
G ra de ≤2, or has 
ret ur ne d t o 
baseli ne, t he n 
res u me treat me nt at 
t he sa me d ose 
le vel.* *   If t o xicit y 
re occ urs, d osi n g 
ma y be re d uce d b y 
1 d ose le vel.   If 
Wit h h ol d d ose u ntil 
t o xicit y is G ra de ≤2, 
or has ret ur ne d t o 
baseli ne, t he n 
re d uce t he d ose b y 
1 le vel a n d res u me 
treat me nt.* *   If 
t o xicit y re occ urs 
des pite d ose 
re d ucti o n, d osi n g 
ma y be re d uce d b y 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 9
T a ble 5.
D ose M o dific ati o ns f or P F -0 6 8 6 3 1 3 5 Pr o d uct -Rel ate d T o xicit y a n d f or 
Peri p her al Se ns or y or M ot or Ne ur o p at h y * * *
T o xicit y
Gr a de 1
Gr a de 2
Gr a de 3
Gr a de 4
t o xicit y re occ urs 
after a ma xi m u m of 
2 d ose le vel 
re d ucti o ns ( 1 f or 
patie nts i n first 
c o h ort), patie nt 
ma y be 
per ma ne ntl y 
disc o nti n ue d fr o m 
treat me nt.
F or platelets, 
wit h h ol d d ose if 
t o xicit y 
≤2 5, 0 0 0 m m 3 a n d 
re-start w he n 
platelets ha ve 
ret ur ne d t o 
≥2 5, 0 0 0 m m 3 or 
baseli ne
1 m o re d ose le vel.  
If t o xicit y re occ urs, 
patie nt ma y be 
per ma ne ntl y 
disc o nti n ue d fr o m 
treat me nt.
Peri p heral se ns or y or 
m o t or ne ur o pat h y (all 
ca usalit y)
See 
Secti o n 8. 4. 4 f or 
rec o m me n de d wor k - u p.
C o nti n ue at t he 
sa me d ose 
le vel.
C o nti n ue t o 
m o nit or t he 
partici pa nt f or 
si g ns of 
w orse ni n g 
ne ur o pat h y
Wit h h ol d d ose u ntil 
res ol uti o n t o Gra de ≤1, 
t he n res u me at a 
re d uce d d ose le vel. 
C o nti n ue t o m o nit or t he 
partici pa nt s f or si g ns of 
w orse ni n g ne ur o pat h y.
If G ra de ≥2 ne ur o pat h y
reocc urs , per ma ne ntl y 
disc o nti n ue 
elra nata ma b.
P er ma ne ntl y 
disc o nti n ue 
elra nata ma b.
Per m a ne ntl y 
disc o nti n ue 
elra nata ma b
* Na usea, v o miti n g, or diarr hea m ust persist at Gra de 3 or 4 des pite ma xi mal me dical t hera p y t o re q uire d ose 
m o dificati o n.
* * C ycle will n ot be e xte n de d t o c o ver f or t he missi n g d os es.
* * * D ose re d ucti o ns f or le n ali do mi de s h o ul d als o f oll o w t he rec o m me n dati o ns i n t his ta ble.
D oses ma y  be hel d as nee de d u ntil t o xicit y res ol uti o n. A p pr o priate f oll o w-u p assess me nts 
s h o ul d be d o ne u ntil a de q uate rec o ver y occ urs as assesse d b y t he i n vesti gat or.
D ose m o dificati o ns f or le nali d o mi de (ie, f or ne utr o pe nia, t hr o m b oc yt o pe nia, re nal 
i m pair me nt, gra de 3 or 4 t o xicities j u d ge d t o be relate d t o le nali d o mi de) per ma n ufact urer’s 
g ui deli nes is per mitte d. Please see , Ta ble 7 a n d Ta ble 8 he mat ol o gic t o xicities a n d re nal 
i m pair me nt f or d ose m o dificati o ns. Please c o ns ult t he Re vli mi d ® U S pac ka ge I nsert ( U S PI) 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 0
f or f urt her details.3 0 F or E ur o pe, please c o ns ult t he Re vli mi d ® S u m mar y  of Pr o d uct 
C haracteristics ( S P C) f or f urt her details. 3 1  F or Ca na da, please c o ns ult t he Re vli mi d ® Pr o d uct 
M o n o gra p h f or f urt her details.
3 2
T a ble 6.
Le n ali d o mi de D ose A dj ust me nt f or T hr o m b oc yt o pe ni a
Pl atelet C o u nt
Rec o m me n de d C o urse of Acti o n

W he n c o u nt first falls t o < 3 0 , 0 0 0 mc L.

W he n c o u nt ret ur ns t o ≥3 0, 0 0 0 mc L .

I nterr u pt le nali d o mi de treat me nt, f oll o w c o m plete
bl o o d c o u nt ( C B C) wee kl y .

Res u me le nali d o mi de at 1 0 m g .

F or eac h s u bse q ue nt dr o p i n c o u nt t o < 3 0, 0 0 0 mc L .

W he n c o u nt ret ur ns t o ≥3 0, 0 0 0 mc L .

I nterr u pt le nali d o mi de treat me nt.

Res u me le nali d o mi de at t he ne xt l o wer d ose le vel 
( 5 m g) o nce dail y. D o n ot dec rease d ose bel o w 5 
m g o nce dail y .
T a ble 7. 
Le n ali d o mi de D ose A dj ust me nt f or Ne utr o pe ni a
Ne utr o p hil C o u nt
Rec o m me n de d C o urse of Acti o n

W he n c o u nt first falls t o < 1, 0 0 0/ mc L .

W he n c o u nt ret ur ns t o ≥1, 0 0 0/ mc L a n d ne utr o pe nia 
is t he o nl y  o bser ve d t o xicit y.

W he n c o u nt ret ur ns t o ≥1, 0 0 0/ mc L a n d ot her 
t o xicit y is o bser ve d.

I nterr u pt le nali d o mi de treat me nt, start G-C S F 
treat me nt, f oll o w C B C wee kl y .

Res u me le nali d o mi de at 1 5 m g o nce dail y .

Res u me le nali d o mi de at 1 0 m g o nce dail y.

F or eac h s u bse q ue nt dr o p i n c o u nt t o < 1, 0 0 0/ mc L .

W he n c o u nt ret ur ns t o ≥1, 0 0 0/ mc L .

I nterr u pt le nali d o mi de treat me nt.

Res u me le nali d o mi de at t he ne xt l o wer d ose le vel 
( 1 0 m g or 5 m g) o nce dail y. D o n ot decrease d ose 
bel o w  5 m g o nce dail y.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 1
T a ble 8. 
Le n ali d o mi de D ose A dj ust me nt f or Re n al I m p air me nt
C ate g or y
Re n al F u ncti o n
D ose
M o derate re nal i m pair me nt
Cr Cl a 3 0 -6 0 m L/ mi n
1 0 m g e ver y o nce dail y
Se vere re nal i m pair me nt
Cr Cl a < 3 0 m L/ mi n ( n ot re q uiri n g 
dial ysis)
1 5 m g e ver y ot her da y
E n d -sta ge re nal disease
Cr Cl a < 3 0 m L/ mi n (re q uiri n g 
dial ysis)
5 m g o nce dail y. O n dial ysis da ys, 
a d mi nister t he d ose after dial ysis
Ke y: Cr Cl = creati ni ne cleara nce.
a Esti mate d b y creati ni ne cleara nce as calc ulate d b y t he C oc kcr oft -Ga ult e q uati o n.
F or r ec o m me n de d le nali d o mi de d ose m o dificati o ns f or peri p heral ne ur o pat h y (all ca usality) , 
refer t o Ta ble 5 .
D ose m o dificati o ns f or p o mali d o mi de (ie, f or ne utr o pe nia, t hr o m b oc y t o pe nia, str o n g 
C Y P 1 A 2 i n hi bit ors, se vere re nal i m pair me nt, or he patic i m pair me nt) per ma n ufact urer’s 
g ui deli nes is per mitte d.  Please see Ta ble 9 he mat ol o gic t o xicities f or d ose m o dificati o ns.  
Please c o ns ult t he P o mal yst ® U S pac ka ge I nsert ( U S PI ) f or f urt her details.3 4  F or E ur o pe, 
please c o ns ult t he I m n o vi d ® S u m mar y  of Pr o d uct C haracteristics ( S P C) f or f urt her details.3 5
F or Ca na da, please c o ns ult t he P o mal y st ® Pr o d uct M o n o gra p h f or f urt her details. 3 6
T a ble 9 .  
D ose M o dific ati o n I nstr ucti o ns f or P o m ali d o mi de f or He m at ol o gic T o xicities
I nterr u pti o n/res u m pti o n t hres h ol d
D ose M o dific ati o n
Ne utr o pe nia
A N C * < 5 0 0 per mc L or Fe brile ne utr o pe nia (fe ver ≥ t o 
3 8. 5° C a n d A N C < 1, 0 0 0 per mc L)
A N C ret ur n t o ≥5 0 0/ mc L
I nterr u pt p o mali d o mi de treat me nt, f oll o w C B C wee kl y.  
Res u me p o mali d o mi de at 3 m g dail y.
F or eac h s u bse q ue nt dr o p < 5 0 0/ mc L
Ret ur n t o ≥5 0 0/ mc L
I nterr u pt p o mali d o mi de treat me nt.
Res u me p o mali d o mi de at 1 m g less t ha n t he pre vi o us 
d ose
T hr o m b oc yt o pe nia
Platelets < 2 5, 0 0 0/ mc L
Platelets ret ur n t o > 5 0, 0 0 0/ mc L
I nterr u pt p o mali d o mi de treat me nt, f oll o w C B C wee kl y. 
Res u me p o mali d o mi de treat me nt at 3 m g dail y.
F or eac h s u bse q ue nt dr o p < 2 5, 0 0 0/ mc L
Ret ur n t o m ore t ha n or e q ual t o 5 0, 0 0 0/ mc L
I nterr u pt p o mali d o mi de treat me nt.
Res u me p o mali d o mi de at 1 m g less t ha n pre vi o us d ose.
* N ote: A N C = A bs ol ute Ne utr o p hil C o u nt
F or ot her Gra de 3 or 4 t o xicities (e xce pt as n ote d bel o w), h ol d treat me nt a n d restart treat me nt 
at 1 m g less t ha n t he pre vi o us d ose w he n t o xicit y  has res ol ve d t o less t ha n or e q ual t o Gra de 
2 at t he p h y sicia n’s discreti o n. F or a na p h ylactic reacti o ns, a n gi oe de ma, pr o gressi ve 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 2
m ultif ocal le u k oe nce p hal o pat h y  ( P M L), or ras h ( Gra de 4 or blisteri n g), p o mali d o mi de s h o ul d 
be per ma ne ntl y  disc o nti n ue d.
T o i nitiate a ne w c y cle of p o mali d o mi de, t he ne utr o p hil c o u nt m ust be at least 5 0 0 per mc L, 
t he platelet c o u nt m ust be at least 5 0, 0 0 0 per mc L.  If t o xicities occ ur after d ose re d ucti o ns t o 
1 m g, t he n disc o nti n ue p o mali d o mi de.

D osa ge A dj ust me nt f or Str o n g C Y P 1 A 2 I n hi bit ors:

A v oi d c o nc o mita nt use of p o mali d o mi de wit h str o n g i n hi bit ors of C Y P 1 A 2. 
C o nsi der alter nati ve treat me nts. If a str o n g C Y P 1 A 2 i n hi bit or m ust be use d, 
re d uce p o mali d o mi de d ose b y 5 0 %.

D osa ge A dj ust me nt f or Patie nts wit h Se vere Re nal I m pair me nt o n He m o dial y sis:

F or patie nts wit h se vere re nal i m pair me nt re q uiri n g dial ys is, t he rec o m me n de d 
starti n g d ose is 3 m g dail y ( 2 5 % d ose re d ucti o n).  Ta ke p o mali d o mi de after 
c o m pleti o n of dial ysis pr oce d ure o n he m o dialys is da ys.

D osa ge A dj ust me nt f or Patie nts wit h He patic I m pair me nt:

F or patie nts wit h mil d or m o derate he patic i m pair me nt ( C hil d- P u g h classes A or 
B), t he rec o m me n de d starti n g d ose is 3 m g dail y ( 2 5 % d ose re d ucti o n). F or 
patie nts wit h se vere he patic i m pair me nt ( C hil d -P u g h class C), t he rec o m me n de d 
d ose is 2 m g ( 5 0 % d ose re d ucti o n).
De xa met has o ne will be a d mi nistere d at a d ose of 4 0 m g wee kl y. F or s u bjects ol der t ha n 7 5 
ye ars or u n der wei g ht ( b o d y mass i n de x [ B MI ] < 1 8. 5), t he de xa met has o ne d ose ma y be 
a d mi nistere d at a d ose of 2 0 m g wee kl y. De xa met has o ne ma y  be re d uce d, if necessar y, 
acc or di n g t o Ta ble 1 0.
T a ble 1 0.
D ose M o dific ati o n I nstr ucti o ns f or De x a met h as o ne T o xicities
C T A C A E C ate g or y
T o xicit y
D ose M o dific ati o n
Gastr oi ntesti nal
Gra de 1 -2 D ys pe psia, gastric or d u o de nal
ulcer, gastritis re q uiri n g me dical 
ma na ge me nt
Treat w it h H 2 bl oc kers, s ucralfate, or 
o m e praz ole. If
s y m pt o ms persist des pite a b o ve 
meas ure, decrease
de xa met has o ne d ose b y 5 0 %.
≥Gra de 3 re q uiri n g
h os pitalizati o n or s ur ger y
H ol d 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 at 5 0 % 
of c urre nt d ose 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 m e praz ole. If s y m pt o ms persist 
des pite a b o ve meas ure, disc o nti n ue 
de xa met has o ne a n d d o n ot res u me.
Ac ute pa ncreatitis
Disc o nti n ue de xa met has o ne a n d d o 
n ot res u me
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 3
T a ble 1 0.
D ose M o dific ati o n I nstr ucti o ns f or De x a met h as o ne T o xicities
C T A C A E C ate g or y
T o xicit y
D ose M o dific ati o n
Car di o vasc ular
≥Gra de 3 E de ma li miti n g f u ncti o n a n d
u nres p o nsi ve t o t hera p y or a nasarca
Di uretics as nee de d a n d decrease 
de xa met has o ne d ose b y 2 5 %; if e de ma 
persists des pite a b o ve meas ures, 
decrease d ose t o 5 0 % of i nitial d ose; 
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 
5 0 % re d ucti o n
Ne ur ol o g y/ Ps yc hiatric
≥Gra de 2 i nterferi n g wit h f u ncti o n b ut n ot
i nterferi n g wit h acti vities of dail y li vi n g
H ol d 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 at 5 0 % 
of c urre nt d ose. If s y m pt o ms persist 
des pite a b o ve meas ure, disc o nti n ue 
de xa met has o ne a n d d o n ot res u me
M usc ul os keletal
≥Gra de 2 M uscle w ea k ness S y m pt o matic
a n d i nterferi n g wit h f u ncti o n b ut n ot
i nterferi n g wit h acti vities of dail y li vi n g
Decrease de xa met has o ne d ose b y 
2 5 %; if wea k ness persists des pite 
a b o ve meas ures, decrease d ose t o 5 0 % 
of i nitial d ose; 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 5 0 %
Meta b olic
≥Gra de 3 H y per gl yce mia
Treat me nt wit h i ns uli n or oral 
h y p o gl yce mic a ge nts as nee de d. If 
u nc o ntr olle d des pite a b o ve meas ure, 
decrease d ose b y 2 5 % decre me nts 
u ntil le vels are satisfact or y
5. 5. 4. I ntr a-P atie nt D ose Esc al ati o n f or P F- 0 6 8 6 3 1 3 5
O nce a patie nt c o m pletes t heir 6 0 d a y  late t o xicit y o bser vati o n peri o d , if t he patie nt di d n ot 
e x perie nce a n y ≥Gra de 3 dr u g relate d t o xicities, t he patie nt ma y  escalate t o t he ne xt hi g her 
d ose le vel if t he hi g her d ose le vel is alrea d y bee n declare d safe f oll o wi n g 6 0-d a y  late t o xicit y 
e val uati o n, a n d criteria o utli ne d i n Secti o n 3. 1. 4. 1 Criteria f or I ntra patie nt D ose Escalati o n
ha ve bee n met .
A d diti o nal i ntra -patie nt d ose escalati o ns will als o be per mitte d o nce a d diti o nal 6 0 d a y  late 
t o xicit y e val uati o n has bee n c o m plete d , a n d if t he patie nt di d n ot e x perie nce a n y ≥Gra de 3 
dr u g relate d t o xicities.  N o cr oss o ver is all o we d, h o we ver, bet wee n m o n ot hera p y  
P F - 0 6 8 6 3 1 3 5 a n d t he differe nt c o m bi nati o n re gi me ns.
A mai nte na nce d ose le vel will be declare d safe f oll o wi n g D L T e val uati o n of patie nts f or a 
mi ni m u m of 6 0 da y s.  O nce a mai nte na nce d ose le vel has bee n declare d safe, patie nts at 
l o wer d ose le vels w h o ha ve c o m plete d t he 6 0 d a y  late t o xicit y o bser vati o n peri o d ma y  
escalate t o t he ne xt hi g her d ose le vel, if criteria o utli ne d i n Secti o n 3. 1. 4. 1 Criteria f or 
I ntra patie nt D ose Escalati o n ha ve bee n met .  N o cr oss o ver is all o we d, h o we ver, bet wee n 
m o n ot hera p y P F -0 6 8 6 3 1 3 5 a n d t he differe nt c o m bi nati o n re gi me ns.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 4
5. 6. Per m a ne nt Disc o nti n u ati o n
T he st u d y will st o p if all d oses e x pl ore d a p pear t o be o verl y t o xic as deter mi ne d b y st u d y 
s p o ns or a n d i n vesti gat ors.  F or ot her s p o ns or disc o nti n uati o n criteria, please refer t o 
Secti o n 1 4 .  F or patie nt wit h dra wal criteria, please refer t o Secti o n 6. 6 .
N ote t hat disease pr o gressi o n as deter mi ne d b y la b orat or y  assess me nts c o m plete d wit hi n t he 
first c ycle ca n n ot be a reas o n f or st u d y wit h dra wal.
D ose escalati o n ma y  als o st o p if:

T he ma xi m u m sa m ple size has bee n ac hie ve d;

A p pr o xi matel y 6 - 1 6 patie nts ha ve bee n e nr olle d at a d ose t hat is pre dicte d t o be t he 
M T D / M A D;

All d oses e x pl ore d a p pear t o be o verl y t o xic a n d t he M T D / M A D ca n n ot be 
deter mi ne d. 
5. 7. I n vesti g ati o n al P r o d uct St or a ge 
T he i n vesti gat or, or a n a p pr o ve d re prese ntati ve, e g, p har macist will e ns ure t hat all 
i n vesti gati o nal pr o d ucts are st ore d i n a sec ure d area wit h c o ntr olle d access u n der re q uire d 
st ora ge c o n diti o ns a n d i n acc or da nce wit h a p plica ble re g ulat or y re q uire me nts.
In vesti gati o nal pr o d uct s s h o ul d be st ore d i n t heir ori gi nal c o ntai ner s a n d i n acc or da nce wit h 
t he la bels. 
See t he I P m a n ual f or st ora ge c o n diti o ns of t he pr o d uct o nce rec o nstit ute d.
A n y  st ora ge co n diti o ns state d i n t he S R S D will be s u perse de d b y t he st ora ge c o n diti o ns 
state d o n t he pr o d uct la bel. 
Site s y ste ms m ust be ca pa ble of meas uri n g a n d d oc u me nti n g (f or e xa m ple, via a l o g), at a 
mi ni m u m, dail y  mi ni m u m a n d ma xi m u m te m perat ures f or all site st ora ge l ocati o ns (as 
a p plica ble, i ncl u di n g fr oze n, refri gerate d , a n d/ or r o o m -te m perat ure pr o d ucts).  T his s h o ul d 
be ca pt ure d fr o m t he ti me of i n vesti gati o nal pr o d uct recei pt t hr o u g h o ut t he st u d y.  E ve n f or 
c o nti n u o us-m o nit ori n g s y ste ms, a l o g or site pr oce d ure t hat e ns ures acti ve e val uati o n f or 
e xc ursi o ns s h o ul d be a vaila ble.  T he i nte nt is t o e ns ure t hat t he mi ni m u m a n d ma xi m u m 
te m perat ure is c hec ke d eac h b usi ness da y t o c o nfir m t hat n o e xc ursi o n occ urre d si nce t he l ast 
e val uati o n a n d t o pr o vi de t he site wit h t he ca pa bilit y t o st ore or vie w t he mi ni m u m/ ma xi m u m
te m perat ure f or all n o n w or ki n g da ys u p o n ret ur n t o n or mal o perati o ns.  T he o perati o n of t he 
te m perat ure m o nit ori n g de vice a n d st ora ge u nit (f or e xa m ple, refri gerat or), as a p plica ble, 
s h o ul d be re g ularly i ns pecte d t o e ns ure t h e y are mai ntai ne d i n w or ki n g or der.
A n y  e xc ursi o ns fr o m t he pr o d uct la bel st ora ge c o n diti o ns s h o ul d be re p orte d t o Pfizer u p o n 
disc o ver y .  T he site s h o ul d acti vel y  p urs ue o pti o ns f or ret ur ni ng t he pr o d uct t o t he st ora ge 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 5
c o n diti o ns descri be d i n t he la beli n g , as s o o n as p ossi ble.  De viati o ns fr o m t he st ora ge 
re q uire me nts, i ncl u di n g a n y acti o ns ta ke n, m ust be d oc u me nte d a n d re p orte d t o Pfizer .
O nce a n e xc ursi o n is i de ntifie d, t he i n vesti gati o nal pr o d uct m ust be q uara nti ne d a n d n ot use d 
u ntil t he Pfizer pr o vi des per missi o n t o use t he i n vesti gati o nal pr o d uct. It will n ot be 
c o nsi dere d a pr ot oc ol de viati o n if Pfizer a p pr o ves t he use of t he i n vesti gati o nal pr o d uct after 
t he te m perat ure e xc ursi o n.  Us e of t he i n vesti gati o nal pr o d uct pri or t o Pfizer a p pr o val will be 
c o nsi dere d a pr ot oc ol de viati o n. 
S pecific details re gar di n g i nf or mati o n t he site s h o ul d re p ort f or eac h e xc ursi o n will be 
pr o vi de d t o t he site. 
Recei pt of materials, d o or o pe ni n g a n d cl osi n g, a n d ot her r o uti ne ha n dli n g o perati o ns w here 
t he pr o d ucts are briefly o ut of t he te m perat ure ra n ge descri be d i n t he la beli n g are n ot 
c o nsi dere d e xc ursi o ns. 
5. 8. I n vesti gati o n al a n d N o n -I n vesti g ati o n al Pr o d uct Acc o u nt a bilit y 
T he i n vesti gat or site m ust mai ntai n a de q uate rec or ds d oc u me nti n g t he recei pt, use, l oss, or 
ot her dis p ositi o n of t he i n vesti gati o nal a n d n o n -i n vesti gati o nal pr o d uct s u p plies.  All 
i n vesti gati o nal a n d n o n -i n vesti gati o nal pr o d ucts will be acc o u nte d f or usi n g a dr u g 
acc o u ntabilit y  f or m/rec or d.
5. 8. 1. Destr ucti o n of I n vesti g ati o n al a n d N o n -I n vesti g ati o n al Pr o d uct S u p plies 
T he s p o ns or or desi g nee will pr o vi de g ui da nce o n t he destr ucti o n of u n use d i n vesti gati o nal 
a n d n o n -i n vesti gati o nal pr o d uct (e g, at t he site).  If destr ucti o n is a ut h orize d t o ta ke place at 
t he i n vesti gat or site, t he i n vesti gat or m ust e ns ure t hat t he materials are destr o ye d i n 
c o m plia nce wit h a p plica ble e n vir o n me ntal re g ulati o ns, i nstit uti o nal p olic y , a n d a n y s pecial 
i nstr ucti o ns pr o vi de d b y Pfizer, a n d all destr ucti o n m ust be a de q uatel y d oc u me nte d.
5. 9. C o nc o mit a nt Tre at me nt (s)
C o nc o mita nt treat me nt c o nsi dere d necessar y  f or t he patie nt’s well -bei n g m a y  be gi ve n at 
discreti o n of t he treati n g p h y sicia n.
All c o nc o mita nt treat me nts, bl o o d pr o d ucts, as well as n o n dr u g i nter ve nti o ns recei ve d by 
patie nts fr o m scree ni n g u ntil t he e n d of st u d y  visit will be rec or de d o n t he C R F.
P F - 0 6 8 6 3 1 3 5 has bee n de m o nstrate d t o tra nsie ntl y i ncrease c yt o ki ne le vels (e g, I L- 6) i n vi v o 
i n m o n ke ys a n d h u ma n s (als o de m o nstrate d via i n vitr o assa ys) w hic h is e x pecte d wit h 
C D 3 -tar gete d bis pecifics. C y t o ki nes ha ve bee n s h o w n t o res ult i n m o dest i n hi biti o n of s o me 
c yt oc hr o me P 4 5 0 e nz ymes. T heref ore, treat me nt wit h P F- 0 6 8 6 3 1 3 5 has a p ote ntialt o
i ncrease t he e x p os ure of c o nc o mita nt me dicati o ns t hat are s u bstrates f or t hese e nz ymes. 
Ca uti o n s h o ul d be use d u p o n c o nc o mita nt use of se nsiti ve s u bstrates of c yt oc hr o me P 4 5 0 
e nz ymes wit h narr o w t hera pe utic i n de x (e g , C Y P 3 A 4: alfe nta nil, c y cl os p ori ne, 
di h y dr oer g ota mi ne, er g ota mi ne, fe nta n yl , pi m ozi de, q ui ni di ne, sir oli m us a n d tacr oli m us; 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 6
C Y P 2 C 9: p he n y t oi n, warfari n) es pecially d uri n g t he i nitial treat me nt c y cle. A d diti o nal 
details are pr o vi de d i n A p pe n di x 1 1 .
Le nali d o mi d e w he n c o -a d mi nistere d wit h di g o xi n has de m o nstrate d a n i ncrease i n di g o xi n 
C ma x a n d A U C i nf b y  1 4 %.3 0 Le v els of di g o xi n f or patie nts recei vi n g b ot h dr u gs m ust be 
m o nit ore d i n Parts 1 C a n d 2 C i n acc or da nce wit h cli nical j u d g me nt a n d base d o n sta n da r d 
cli nical practice i n patie nts recei vi n g di g o xi n . Refer t o le nali d o mi de la bel re gar di n g dr u gs 
t hat are pr o hi bite d f or use c o nc o mita ntly. 
P o mali d o mi de e x p os ure ma y  be i ncrease d b y str o n g C Y P 1 A 2 i n hi bit ors (e g, ci pr ofl o xaci n 
a n d fl u v o xa mi ne). If c o-a d ministrati o n is u na v oi da ble i n Parts 1 D a n d 2 D, re d uce t he 
p o mali d o mi de d ose per i nstr ucti o ns i n P o mal y st la bel3 4 a n d Secti o n 5. 5. 3 .
Dr u gs w hic h i n d uce C Y P 3 A 4 e nz y me acti vit y  (e. g., bar bit urates, p he nyt oi n, car ba maze pi ne, 
rifa m pi n) ma y e n ha nce t he meta b olis m of c ortic oster oi ds a n d re q uire t hat t he d osa ge of t he 
c ortic oster oi d be i ncrease d. Dr u gs w hic h i n hi bit C Y P 3 A 4 (e. g., ket oc o naz ole, macr oli de 
a nti bi otics s uc h as er yt hr o m yci n) ha ve t he p ote ntial t o res ult i n i ncrease d plas ma 
c o nce ntrati o ns of c ortic oster oi ds. De xa met has o ne is a m o derate i n d ucer of C Y P 3 A 4. C o -
a d mi nstrati o n wit h ot her dr u gs t hat are meta b olize d b y C Y P 3 A 4 (e. g., i n di na vir, 
er yt hr o m y ci n) ma y i ncrease t heir cleara nce, res ulti n g i n decrease d plas ma c o nce ntrati o n.
All C O VI D - 1 9 vacci nes are per mitte d a n d s h o ul d be rec or de d as c o nc o mita nt me dicati o ns 
(sta n dar d A E c ollecti o n a n d re p orti n g pr ocesses s h o uld be f oll o we d) .  T he ti mi n g of 
C O VI D - 1 9 vacci ne a d mi nistrati o n relati ve t o st u d y i nter ve nti o n is at t he discreti o n of t he 
i n vesti gat or, alt h o u g h, if p ossi ble, it is best t o a v oi d vacci ne a d mi nistrati o n wit hi n 4 8 h o urs 
bef ore or after t he first a n d sec o n d d oses of st u d y i nter ve nti o n.
T he a d mi nistrati o n of dr u gs k n o w n t o ca use peri p heral ne ur o pat h y  s h o ul d be caref ully 
c o nsi dere d, a n d if p ossi ble, a v oi de d b y t he i n vesti gat or.
5. 9. 1. Pre me dic ati o n Re q uire d f or C yt o ki ne Rele ase S y n dr o me Pr o p h yl a xis
F or b ot h t he pri mi n g d oses a n d first f ull d ose ( 7 6 m g), a d mi nister t hese me dicati o ns 
6 0 mi n utes ( ± 1 5 mi n utes) pri or t o elra nata ma b d ose:   

aceta mi n o p he n 6 5 0 m g ( or paraceta m ol 5 0 0 m g) *

di p he n h y dra mi ne 2 5 m g ( or e q ui vale nt) *, oral or I V

de xa met has o ne 2 0 m g ( or e q ui vale nt), oral or I V
* Differe nt b ut c o m para ble d oses d ue t o l ocal stre n gt h variati o ns are per missi ble.
Si milar pre me dicati o ns f or d oses at ot her ti me p oi nts ma y  be gi ve n at t he discreti o n of  t he 
i n vesti gat or.
See A p pe n di x 5 f or ma na ge me nt of C R S a n d IC A N S .
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 7
5. 9. 2. Ot her A nti -t u m or/A nti - ca ncer or E x peri me nt al Dr u gs
N o a d diti o nal a nti -ca ncer t hera p y will be per mitte d w hile patie nts are recei vi n g st u d y 
treat me nt.  A d diti o nall y , t he c o nc urre nt use of select vita mi ns or her bal s u p ple me nts is n ot 
per mitte d . Palliati ve ra di ot hera p y o n st u d y is per mitte d f or t he treat me nt of pai nf ul b o n y 
lesi o ns pr o vi de d t hat t he lesi o ns were k n o w n at t he ti me of st u d y e ntr y a n d t he i n vesti gat or 
clearl y i n dicates t hat t he nee d f or palliati ve ra di ot hera p y is n ot i n dicati ve of disease 
pr o gressi o n.  I n vie w of t he c urre nt lac k of data a b o ut t he i nteracti o n of P F - 0 6 8 6 3 1 3 5 wit h
ra di ot hera py, P F -0 6 8 6 3 1 3 5 treat me nt s h o ul d be i nterr u pte d d uri n g palliati ve ra di ot hera p y , 
st o p pi n g 7 d a y s bef ore a n d res u mi n g treat me nt after 7 d a y s.
5. 9. 3. S u p p orti ve C are 
Palliati ve a n d s u p p orti ve care f or disease relate d s y m pt o ms ma y  be a d mi nistere d at t he 
i n vesti gat or’s discreti o n a n d acc or di n g t o a ny a vaila ble A merica n S ociet y  of Cli nical 
O nc ol o g y ( A S C O) g ui deli nes. 
All o p uri n ol/ras b uricase ma y  be a d mi nistere d as nee de d f or t u m or l ysis pr o p h yla xis or 
treat me nt. 
5. 9. 4. C yt o ki ne Rele ase S y n dr o me
S y m pt o ms ass ociate d wit h C R S var y  greatl y a n d ma y be diffic ult t o disti n g uis h fr o m ot her 
c o n diti o ns.  T he m ore c o m m o n s y m pt o ms i ncl u de fe ver, na usea, hea dac he, tac h y car dia, 
h y p ote nsi o n, ras h a n d s h ort ness of breat h.  T he se verit y  of s ym pt o ms ca n be mil d t o life 
t hreate ni n g a n d t h us t here s h o ul d be a hi g h s us pici o n f or C R S if t hese s ym pt o ms occ ur.   If 
C R S is s us pecte d, c yt o ki nes will be a nal yz e d at ce ntral la b orat ories t o deter mi ne if c yt o ki ne 
ele vati o n c o nsiste nt wit h C R S is o bser ve d (see Secti o n 7. 1. 3 ).  T he se verit y of c y t o ki ne 
release s yn dr o me ( C R S) will be assesse d acc or di n g t o t he m o difie d gra di n g descri be d b y  Lee 
et al. i n 2 0 1 4 2 as well as t he m ore rece nt c o nse ns us gra din g fr o m t he A merica n S ociet y f or 
Tra ns pla ntati o n a n d Cell ular T hera p y ( A S T C T )3 b ut o nl y A S T C T will be use d f or 
ma na ge me nt of C R S 3 8 ,3 9 (A p pe n di x 5 ). 
F or C R S D L T criteria, please see Secti o n 3. 2 .
5. 9. 5. I m m u ne Effect or Cell-Ass oci ate d Ne ur ot o xicit y S y n dr o me I C A N S
I C A N S is defi ne d as “a dis or der c haracterize d by a pat h ol o gic pr ocess i n v ol vi n g t he ce ntral 
ner v o us s ys te m f oll o wi n g a ny i m m u ne t hera p y t hat res ults i n t he acti vati o n or e n ga ge me nt of 
e n d o ge n o us or i nf use d T cells a n d/ or ot her i m m u ne effect or cells. S y m pt o ms or si g ns ca n be 
pr o gressi ve a n d ma y  i ncl u de a p hasia, altere d le vel of c o nsci o us ness, i m pair me nt of c o g niti ve 
s kills, m ot or wea k ness, seiz ures, a n d cere bral e de ma. 3 It has bee n o bser ve d f oll o wi n g 
a d mi nistrati o n of s o me c hi meric a nti b o d y rece pt or ( C A R) T cells a n d bis pecific a nti b o dies
a n d ca n occ ur i n de pe n de ntl y  of C R S. T he se verit y of I CA N S s h o ul d be gra de d acc or di n g t o 
t he A S T C T c o nse ns us criteria,3 a n d ma na ge me nt g ui deli nes are pr o vi de d i n A p pe n di x 5 .3 8 ,3 9
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 8
5. 9. 6. T u m or L ysis S y n dr o me ( T L S)
T u m or l y sis is a gr o u p of meta b olic c o m plicati o ns t hat ca n occ ur after treat me nt of ca ncer.  
T u m or l y sis s yn dr o me ( T L S) occ urs w he n t u m or cells release t heir c o nte nts i nt o t he 
bl o o dstrea m, eit her s p o nta ne o usl y or i n res p o nse t o t hera p y , lea di n g t o t he c haracteristic 
fi n di n gs of hy p er urice mia, h yper kale mia, h y p o p h os p hate mia , a n d hy p ocalce mia.   T hese 
electr ol yt e a n d meta b olic dist ur ba nces ca n pr o gress t o cli nical t o xic effects, i ncl u di n g re nal 
i ns ufficie nc y, car diac arr h yt h mias, seiz ures, a n d deat h d ue t o m ulti -or ga n fail ure.  T he 
i nci de nce a n d se verit y of t he T LS de pe n d o n t he ca ncer mass, t he p ote ntial f or l y sis of t u m or
cells, t he c haracteristics of t he patie nt, a n d s u p p orti ve care.
O pti mal m a na ge me nt of T LS s h o ul d i n v ol ve preser vati o n of re nal f u ncti o n.   Ma na ge me nt 
s h o ul d als o i ncl u de pre ve nti o n of d ysr hyt h mias a n d ne ur o m usc ular irrita bilit y .  All patie nts 
w h o are at ris k f or T L S s h o ul d recei ve i ntra ve n o us h y drati o n t o ra pi dl y  i m pr o ve re nal 
p erf usi o n a n d gl o mer ular filtrati o n a n d t o mi ni mize aci d osis.   Re d uci n g t he le vel of uric aci d, 
wit h t he use of all o p uri n ol a n d partic ularl y wit h t he use of ras b uricase, ca n preser ve or 
i m pr o ve re nal f u ncti o n a n d re d uce ser u m p h os p h or us le vels as a sec o n dary be neficial effect. 
H y per kale mia re mai ns t he m ost da n ger o us c o m p o ne nt of T L S beca use it ca n ca use s u d de n 
deat h d ue t o car diac d ys r h yt h mia.  Patie nts s h o ul d li mit p otassi u m a n d p h os p h or us i nta ke 
d uri n g t he ris k peri o d f or T L S.   Fre q ue nt meas ure me nt of p otassi u m le vels (e ver y 4 t o 
6 h o urs), c o nti n u o us car diac m o nit ori n g, a n d t he a d mi nistrati o n of oral s o di u m p ol y st yre ne 
s ulf o nate are rec o m me n de d i n patie nts wit h T LS a n d ac ute ki d ne y  i nj ur y.  H y p ocalcae mia 
ca n als o lea d t o life-t hreate ni n g d ysr hyt h mias a n d n e ur o m usc ular irrita bilit y; c o ntr olli n g t he 
ser u m p h os p h or us le vel ma y pre ve nt h yp ocalce mia.   S y m pt o matic h y p ocalce mia s h o ul d be 
treate d wit h calci u m at t he l o west d ose re q uire d t o relie ve sy m pt o ms.   H y p ocalce mia n ot 
acc o m pa nie d b y si g ns or s y m pt o ms d oes n o t re q uire treat me nt.
5. 9. 7. I nf usi o n Rel ate d Re acti o ns (I R R)
F oll o wi n g t he first i nf usi o n of s o me m o n ocl o nal a nti b o d y  t hera pe utics, s o me patie nts 
e x perie nce fe ver, hea dac he, na usea, v o miti n g or h y p ote nsi o n.  T hese a d verse e ve nts ( A Es) 
are ge nerall y ascri be d t o l ysis of cell ular tar gets, c yt o ki ne release, or c o m ple me nt acti vati o n. 
Inf usi o n relate d reacti o n is c haracterize d b y  fe ver a n d c hills, a n d less c o m m o nl y 
h y p ote nsi o n, eit her e x perie nce d b y  a partic ular patie nt or if see n i n ot her patie nts, 
pretreat me nt me dic ati o n s h o ul d be a d mi nistere d t o re d uce t he i nci de nce a n d se verit y.  A 
re gi me n is s u g geste d here; h o we ver, if l ocal sta n dar d of care is a differe nt re gi me n, t his will 
be all o we d.  I n cases of i nf usi o n reacti o ns, patie nts s h o ul d be pretreate d wit h aceta mi n o p he n 
a n d di p he n h y dra mi ne ( or ot her a nti hista mi ne) a p pr o xi matel y  0. 5 t o 2 h o urs bef ore 
i n vesti gati o nal pr o d uct a d mi nistrati o n.  T he pretreat me nt me dicati o ns will n ot be s u p plie d b y 
Pfizer.  S u g geste d starti n g d oses are 6 5 0 t o 1 0 0 0 m g aceta mi n o p he n a n d 5 0 m g 
di p he n h y dra mi ne ( or e q ui vale nt f or ot her a nti hista mi nes) eit her I V or oral.  T w o ( 2) 
a d diti o nal d oses of aceta mi n o p he n ma y  be a d mi nistere d a p pr o xi matel y e ver y 4- 6 h o urs after 
t he i nitial pretreat me nt or as nee de d.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 9
Detaile d g ui da nce o n treat me nt, d ose i nter r u pti o ns a n d p ote ntial retreat me nt is pr o vi de d i n 
A p pe n di x 7 .
5. 9. 8. I njecti o n Site Re acti o ns (I S R)
I S R is a ty pe of h y p erse nsiti vit y reacti o n t hat ma y be i m me diate, alt h o u g h it us uall y a p pears 
wit hi n 2 4 -4 8 hrs after i njecti o n. I S R, b y  defi niti o n, i ncl u des t he f oll o wi n g er yt he ma, pr urit us , 
pai n, i nfla m mati o n, ras h, i n d urati o n, itc hi n g a n d e de ma at t he i njec ti o n site. T o e val uate 
I S Rs, site t olera bilit y assess me nts will be perf or me d per S C H E D U L E O F A C TI VI TI E S .
5. 9. 9. H y perse nsiti vit y T y pes 1 a n d 3
T y pe 1 h y perse nsiti vit y  or aller gic (e g, s h ort ness of breat h, urticaria, a na p h yla xis, 
a n gi oe de ma) reacti o ns are t he oreticall y  p ossi ble i n res p o nse t o a n y i njecte d pr otei n.  Im m u ne 
c o m ple x me diate d T ype 3 h y perse nsiti vit y  reacti o ns are si milar t o t he a d verse e ve nts ( A Es) 
of T y p e 1 reacti o n s b ut are li kel y t o be dela ye d fr o m t he ti me of i nf usi o n a n d ma y  i ncl u de 
s ym pt o ms s uc h as ras h, urticaria, p ol ya rt hritis, m y al gia, p olys y n o vitis, fe ver, a n d, if se vere, 
gl o mer ul o ne p hritis. 
All patie nts s h o ul d be cl osel y  o bser ve d w hile recei vi n g i n vesti gati o nal pr o d uct i nf usi o ns a n d 
m o nit ori n g f or cli nical si g ns of a s ys te mic reacti o n will c o nti n ue t hereafter f or cli nical si g ns 
of aller gic reacti o ns/ h y perse nsiti vit y . 
I n t he case of a hy p erse nsiti vit y reacti o n, t he s u bject will be treate d sy m pt o maticall y  wit h 
s u p p orti ve care, f urt her m o nit ori n g, a n d treat me nt wit h a nti-hista mi nes a n d/ or 
c ortic oster oi ds.  St u d y i nf usi o ns ma y be st o p pe d a n d t he s u bject will be f oll o we d u ntil t he 
e n d of t he st u d y. 
Detaile d g ui da nce o n treat me nt, d ose i nterr u pti o ns a n d p ote ntia l retreat me nt is pr o vi de d i n 
A p pe n di x 7 .
5. 9. 1 0. E xtr a v as ati o n
I n t he e ve nt of e xtra vasati o n, i nf usi o n s h o ul d be st o p pe d i m me diatel y a n d t he i n vesti gat or 
n ee ds t o be c o ns ulte d i m me diatel y .  Treat me nt of e xtra vasati o n s h o ul d f oll o w l ocal sta n dar d 
of care. 
5. 9. 1 1. He m at o p oietic Gr o wt h F act ors
Pri mar y  pr o p h ylactic use of gra n ul oc yte-c ol o n y sti m ulati n g fact ors is n ot per mitte d d uri n g 
C ycle 1, b ut t he y  ma y be use d t o treat treat me nt e mer ge nt ne utr o pe nia as i n dicate d b y t he 
c urre nt A merica n S ociet y of Cli nical O nc ol o g y  g ui deli nes.4 6  
Use of er yt hr o p oieti n gr o wt h fact ors is all o we d as nee de d t o treat a ne mia.  Er y t hr o p oietic 
a ge nts or ot her a ge nts t hat ma y  i ncrease t he ris k of t hr o m b osis s h o ul d be use d wit h ca uti o n 
after ma ki n g a be nefit -ris k assess me nt i n patie nts recei vi n g le nali d o mi de.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 0
5. 9. 1 2. A nti -Di arr he a l, A nti-E metic T her a p y
Pri mar y  pr o p h y la xis of diarr hea, na usea a n d v o miti n g is per mitte d i n t he first c y cle. Pri mar y  
pr o p h y la xis i n s u bse q ue nt c ycles is at t he i n vesti gat or’s discreti o n. T he c h oice of t he 
pr o p h y lactic dr u g as well as t he d urati o n of treat me nt is u p t o t he i n vesti gat or wit h s p o ns or 
a p pr o val ass u mi n g t here is n o k n o w n or e x pecte d dr u g - dr u g i nteracti o n a n d ass u mi n g t he 
dr u g is n ot i ncl u de d i n t he C o nc o mita nt Treat me nt(s) Secti o n 5. 9 .
5. 9. 1 3. A nti -Infl a m m at or y T her a p y
A nti- i nfla m mat or y or narc otic a nal gesic ma y be offere d as nee de d ass u mi n g t here is n o 
k n o w n or e x pecte d dr u g- dr u g i nteracti o n a n d ass u mi n g t he dr u g is n ot i ncl u de d i n t he 
C o nc o mita nt Treat me nt (s) Secti o n 5. 9 . 
5. 9. 1 4. C ortic oster oi ds 
C hr o nic s y ste mic c ortic oster oi d use f or palliati ve or s u p p orti ve p ur p oses, e xce pt as s pecifie d 
i n t he pr ot oc ol, is per mitte d o nl y  f oll o wi n g disc ussi o n a n d a gree me nt bet wee n t he 
i n vesti gat or a n d s p o ns or. Ac ute e mer ge nc y  a d mi nistrati o n, t o pical a p plicati o ns, i n hale d 
s pra ys, e ye dr o ps , or l ocal i njecti o ns of c ortic oster oi ds are all o we d.
5. 9. 1 5. S ur ger y 
Ca uti o n is a d vise d o n t he oretical gr o u n ds f or a n y s ur gical pr oce d ures d uri n g t he st u d y.  T he 
a p pr o priate i nter val of ti me bet wee n s ur ger y  a n d P F - 0 6 8 6 3 1 3 5 re q uire d t o mi ni mize t he ris k 
of i m paire d w o u n d heali n g a n d blee di n g has n ot bee n deter mi ne d.  St o p pi n g P F - 0 6 8 6 3 1 3 5 is 
rec o m me n de d at least 7 d a y s pri or t o s ur ger y.  P ost o perati vely, t he decisi o n t o rei nitiate 
P F - 0 6 8 6 3 1 3 5 treat me nt s h o ul d be base d o n a cli nical assess me nt of satisfact or y  w o u n d 
heali n g a n d rec o ver y  fr o m s ur ger y.
5. 9. 1 6. Tr a nsf usi o n S u p p ort
Pri mar y  pr o p h ylactic use of tra nsf usi o n s u p p ort f or a ne mia is all o we d t o treat a ne mia, as 
i n dicate d by t he c urre nt A merica n S ociet y of Cli nical O nc ol o g y  a n d A merica n Ass ociati o n 
of Bl o o d Ba n ks ( A A B B) g ui deli nes .4 7
Pri mar y  pr o p h y lactic use of tra nsf usi o n s u p p ort f or t hr o m b oc y t o pe nia is all o we d d uri n g 
scree ni n g if t he tra nsf usi o n is c o m plete d pri or t o pla n ne d st u d y treat me nt start. Pri mar y  
pr o p h y lactic use of tra nsf usi o n s u p p ort f or t hr o m b oc yt o pe nia is all o we d t o treat 
t hr o m b oc yt o pe nia, as i n dicate d b y t he c urre nt A merican S ociet y of Cli nical O nc ol o g y. 4 8
6. S T U D Y P R O C E D U R E S 
6. 1. Scree ni n g
F or scree ni n g pr oce d ures see t he S C H E D U L E O F A C TI VI TI E S a n d Assess me nts Secti o n 7 .
All patie nts bei n g c o nsi dere d f or t he st u d y a n d eli gi ble f or scree ni n g m ust si g n a n i nf or me d 
c o nse nt f or t he st u d y bef ore c o m pleti n g a n y st u d y-s pecific pr oce d ures.  A patie nt 
i de ntificati o n n u m ber will be assi g ne d.  T he i n vesti gat or ( or a p pr o priate dele gate at t he site) 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 1
will o btai n i nf or me d c o nse nt fr o m eac h patie nt i n acc or da nce wit h t he pr oce d ures descri be d 
i n t he S C H E D U L E O F A C TI VI TI E S a n d o n I nf or me d C o nse nt.
All patie nts will be scree ne d wit hi n 2 8 da y s pri or t o a d mi nistrati o n of t he first d ose  t o 
c o nfir m t hat t he y meet t he patie nt selecti o n criteria f or t he st u d y.
T he re q uire d scree ni n g assess me nts a n d la b orat or y tests are s u m marize d i n t he S C H E D U L E 
O F A C TI VI TI E S a n d Secti o n 7. 1. 3 .  F ollo wi n g c o m pleti o n of t he scree ni n g assess me nts a n d 
c o nfir mati o n of eli gi bilit y, patie nts ma y be e nr olle d.
6. 2. St u d y Peri o d
F or t he treat me nt peri o d pr oce d ures, see t he S C H E D U L E O F A C TI VI TI E S a n d Secti o n 7 .
6. 3. F oll o w -u p 
F or f oll o w -u p pr oce d ures see t he S C H E D U L E O F A C TI VI TI E S a n d Assess me nts Secti o n 7 .
At least 2 8 cale n dar d a y s, a n d n o m ore t ha n 3 5 cale n dar da ys, after disc o nti n uati o n of 
treat me nt, patie nts will ret ur n t o u n der g o re vie w of c o nc o mita nt treat me nts, vital si g ns, a n d 
assess me nt f or res ol uti o n of a n y treat me nt relate d t o xicit y .  Patie nts c o nti n ui n g t o e x perie nce 
t o xicit y at t his p oi nt f oll o wi n g disc o nti n uati o n of treat me nt will c o nti n ue to be f oll o we d at 
least e ver y 4 wee ks u ntil res ol uti o n or deter mi nati o n, i n t he cli nical j u d g me nt of t he 
i n vesti gat or, t hat n o f urt her i m pr o ve me nt is e x pecte d.  Patie nts f o u n d t o ha ve A D A at t heir 
fi nal st u d y visit a n d a n o n g oi n g A E p ossi bly relate d t o A D A will be as ke d t o ret ur n t o t he 
cli nic f or A D A assess me nt at a p pr o xi matel y  3 m o nt h i nter vals (if feasi ble gi ve n t he 
u n derl y i n g disease) u ntil t he a d verse e ve nt or its se q uelae ret ur n t o baseli ne or sta bilize at a 
le vel acce pta ble t o t he i n vesti gat or a n d s p o ns or. If t he patie nt c o m pletes t he 1 m o nt h f oll o w 
u p visit pri or t o c o m pleti o n of t he 6 0 d a y  l o n g ter m D LT o bser vati o n peri o d, a f oll o w u p 
p h o ne call will be c o m plete d o n Da y 6 0 a n d n o m ore t ha n Da y 6 5.
F oll o wi n g disc o nti n uati o n of st u d y  treat me nt ( u nless patie nts are l ost t o f oll o w u p, c o nse nt is 
wit h dra w n, or st u d y is disc o nti n ue d b y t he s p o ns or), s ur vi val stat us will be c ollecte d b y 
tele p h o ne e ver y 3 m o nt hs u ntil deat h, or u p t o a p pr o xi matel y 3 0 m o nt hs after first treat me nt 
of t he last patie nt, w hic he ver c o mes first.  S u bse q ue nt a nti -ca ncer t hera pies a n d rele va nt 
tra ns pla nt i nf or mati o n will als o be c ollecte d.
6. 4. E n d of Tre at me nt
E n d of treat me nt is defi ne d as t he date i n w hic h t he patie nt c o m pletes t he e n d of treat me nt 
( E O T) visit ( u nless patie nts are l ost t o f oll o w u p, c o nse nt is wit h dra w n, or st u d y is 
disc o nti n ue d b y  t he s p o ns or). N ote t hat t he patie nt ma y  c o nti n ue o n t he st u d y f or t heir 
f oll o w u p a n d s ur vi val f oll o w u p visits.
6. 5. E n d of St u d y 
E n d of st u d y  f or all patie nts will be deat h or u p t o a p pr o xi matel y 3 0 m o nt hs after last patie nt 
first d ose, f oll o we d by a n y re q uire d f oll o w -u p visits.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 2
6. 6. P atie nt Wit h dr a w al
Wit h dr a w al of co nse nt: 
Patie nts w h o re q uest t o disc o nti n ue recei pt of st u d y treat me nt will re mai n i n t he st u d y a n d 
m ust c o nti n ue t o be f oll o we d f or pr ot oc ol s pecifie d f oll o w- u p pr oce d ures. T he o nl y  
e xce pti o n t o t his is w he n a patie nt s pecificall y wit h dra ws c o nse nt f or a n y f urt her c o ntact wit h 
hi m or her or pers o n s pre vi o usl y a ut h orize d b y t he patie nt t o pr o vi de t his i nf or mati o n. 
Patie nts s h o ul d n otif y t he i n vesti gat or i n writi n g of t he decisi o n t o wit h dra w c o nse nt fr o m 
f ut ure f oll o w-u p, w he ne ver p ossi ble. T he wit h dra wal of c o nse nt s h o ul d be e x plai ne d i n 
detail i n t he me dical rec or ds b y  t he i n vesti gat or, as t o w het her t he wit h dra wal is o nl y  fr o m 
f urt her recei pt of i n vesti gati o nal pr o d uct or als o fr o m st u d y  pr oce d ures a n d/ or p ost treat me nt
st u d y f oll o w- u p, a n d e ntere d o n t he a p pr o priate case re p ort f or m ( C R F ) pa ge. I n t he e ve nt 
t hat vital stat us ( w het her t he patie nt is ali ve or dea d) is bei n g meas ure d, p u blicl y a vaila ble 
i nf or mati o n s h o ul d be use d t o deter mi ne vital stat us o nl y as a p pr o priately directe d i n 
acc or da nce wit h l ocal la w.
L ost t o foll o w - up: 
All reas o na ble eff orts m ust be ma de t o l ocate patie nts t o deter mi ne a n d re p ort t heir o n g oi n g 
stat us. T his i ncl u des f oll o w- u p wit h pers o ns a ut h orize d b y  t he patie nt as n ote d a b o ve. L ost 
t o f oll o w-u p is defi ne d b y  t he i na bility t o reac h t he patie nt after a mi ni m u m of 2 d oc u me nte d 
p h o ne calls, fa xes, or e - mails as well as lac k of res p o nse by t he patie nt t o 1 re gistere d mail 
letter. All atte m pts s h o ul d be d oc u me nte d i n t he patie nt’s me dical rec or ds.
If it is 
deter mi ne d t hat t he patie nt has die d, t he site wi ll use l ocall y per missi ble met h o ds t o o btai n 
t he date a n d ca use of deat h. If t he i n vesti gat or’s use of a t hir d-part y re prese ntati ve t o assist 
i n t he f oll o w-u p p orti o n of t he st u d y  has bee n i ncl u de d i n t he patie nt’s i nf or me d c o nse nt, 
t he n t he i n vesti gat or ma y use a sp o ns or -retai ne d t hir d-part y re prese ntati ve t o assist site staff 
wit h o btai ni n g t he patie nt’s c o ntact i nf or mati o n or ot her p u blic vital stat us data necessar y  t o 
c o m plete t he f oll o w-u p p orti o n of t he st u d y . T he site staff a n d re prese ntati ve will c o ns ult 
p u blicl y  a vaila ble s o urces, s uc h as p u blic healt h re gistries a n d data bases, i n or der t o o btai n 
u p date d c o ntact i nf or mati o n. If, after all atte m pts, t he patie nt re mai ns l ost t o f oll o w-u p, t he n 
t he last-k n o w n -ali ve date as deter mi ne d b y t he i n vesti gat or s h o ul d be re p orte d a n d 
d oc u me nte d i n t he patie nt’s me dical rec or ds.
Patie nts ma y  wit h dra w fr o m treat me nt at a ny ti me at t heir o w n re q uest, or t he y  m a y be 
wit h dra w n at a n y ti me at t he discreti o n of t he i n vesti gat or or s p o ns or f or safet y (see als o t he 
Wit h dra wal Fr o m t he St u d y  D ue t o A d verse E ve nts secti o n) or be ha vi oral reas o ns, or t he 
i na bilit y of t he patie nt t o c o m pl y wit h t he pr ot oc ol -re q uire d sc he d ule of st u d y visits or
pr oce d ures at a gi ve n i n vesti gat or site. 
Reas o ns f or wit h dra wal of st u d y  treat me nt ma y i ncl u de:

O bjecti ve disease pr o gressi o n ( n ote t hat disease pr o gressi o n as deter mi ne d b y 
la b orat or y assess me nts c o m plete d wit hi n t he first c ycle ca n n ot be a reas o n f or st u d y 
wit h dra wal) ;
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 3

Gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n;

U nacce pta ble t o xicit y ;

Pre g na nc y ;

Si g nifica nt pr ot oc ol vi olati o n;

L ost t o f oll o w - u p;

Patie nt ref use d f urt her treat me nt;

St u d y  ter mi nate d b y s p o ns or;

Deat h.
Reas o ns f or wit h dra wal fr o m st u d y f oll o w-u p ma y i ncl u de:

C o m plete d st u d y  f oll o w- u p;

St u d y  ter mi nate d b y s p o ns or;

L ost t o f oll o w - u p;

Ref us e d f urt her f oll o w-u p;

Deat h.
N ote t hat disc o nti n uati o n of st u d y treat me nt d oes n ot re prese nt wit h dra wal fr o m t he st u d y .  If 
st u d y treat me nt is defi niti vel y disc o nti n ue d, t he partici pa nt will re mai n i n t he st u d y If a 
patie nt d oes n ot ret ur n f or a sc he d ule d vi sit, e ver y eff ort s h o ul d be ma de t o c o ntact t he 
patie nt.  All atte m pts t o c o ntact t he patie nt a n d i nf or mati o n recei ve d d uri n g c o ntact atte m pts 
m ust be d oc u me nte d i n t he patie nt’s me dical rec or d.
I n a ny circ u msta nce, e ver y  eff ort 
s h o ul d be ma de t o d oc u me nt patie nt o utc o me, if p ossi ble.  T he i n vesti gat or s h o ul d i n q uire 
a b o ut t he reas o n f or wit h dra wal, re q uest t hat t he patie nt ret ur n f or a fi nal visit, if a p plica ble, 
a n d f oll o w u p wit h t he patie nt re gar di n g a n y u nres ol ve d A Es .
If t he patie nt ref uses f urt her visits, t he patie nt s h o ul d c o nti n ue t o be f oll o we d f or s ur vi val 
u nless t he patie nt wit h dra ws c o nse nt f or discl os ure of f ut ure i nf or mati o n or f or f urt her 
c o ntact.  I n t his case, n o f urt her st u d y-s pecific e val uati o ns s h o ul d be perf or me d a n d n o 
a d diti o nal data s h o ul d be c ollecte d.  T he s p o ns or ma y  retai n a n d c o nti n ue t o use a n y data 
c ollecte d bef ore s uc h wit h dra wal of c o nse nt.
7. A S S E S S M E N T S
E ver y  eff ort s h o ul d be ma de t o e ns ure t hat t he pr ot oc ol -re q uire d tests a n d pr oce d ures are 
c o m plete d as descri be d. H o we ver , it is a ntici pate d t hat fr o m ti me t o ti me t here ma y be 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 4
circ u msta nces o utsi de of t he c o ntr ol of t he i n vesti gat or t hat ma y  ma ke it u nfeasi ble t o 
perf or m t he test. I n t hese cases t he i n vesti gat or will ta ke all ste ps necessar y t o e ns ure t he 
safety a n d well - bei n g of t he patie nt . W he n a pr ot oc ol
-re q uire d test ca n n ot be perf or me d, t he 
i n vesti gat or will d oc u me nt t he reas o n f or t his a n d a n y c orrecti ve a n d pre ve nti ve acti o ns t hat 
he or s he has ta ke n t o e ns ure t hat n or mal pr ocesses are a d here d t o as s o o n as p ossi b le. T he 
st u d y tea m will be i nf or me d of t hese i nci de nts i n a ti mel y ma n ner .
F or sa m ples bei n g c ollecte d a n d s hi p pe d, detaile d c ollecti o n, pr ocessi n g, st ora ge, s hi p me nt 
i nstr ucti o ns a n d c o ntact i nf or mati o n will be pr o vi de d t o t he i n vesti gat or site pri or t o i nitiati o n 
of t he st u d y .
7. 1. S afet y Assess me nt
Safet y  assess me nts will i ncl u de c ollecti o n of A Es, seri o us a d verse e ve nts (S A Es ), vital si g ns 
a n d p h ysical e xa mi nati o n, electr ocar di o gra m (E C G [1 2- lea d]), la b orat or y assess me nts, 
i ncl u di n g pre g na nc y tests a n d verificati o n of c o nc o mita nt treat me nts.  See A p pe n di x 1 0 f or 
alter nati ve meas ure g ui deli nes d ue t o C O VI D -1 9. 
7. 1. 1. Pre g n a nc y Testi n g
F or fe male patie nts of c hil d beari n g p ote ntial, a ser u m pre g na nc y  test, wit h se nsiti vit y of at 
least 2 5 mI U/ m L , will be perf or me d at scree ni n g a n d o n Da y 1 of eac h c y cle.
A ne gati ve pre g na nc y  test res ult is re q uire d bef ore t he patie nt m a y  recei ve t he i n vesti gati o nal 
pr o d uct .  Pre g na nc y tests will als o be d o ne w he ne ver 1 me nstr ual c y cle is misse d d uri n g t he 
acti ve treat me nt peri o d ( or w he n p ote ntial pre g na nc y  is ot her wise s us pecte d).  Pre g na nc y 
tests ma y als o be re peate d if re q ueste d by i nstit uti o nal re vie w b oar ds (I R Bs)/et hics 
c o m mittees ( E Cs) or if re q uire d b y  l ocal re g ulati o ns.
I n a d diti o n, f or P arts 1 C, 1 D, 2 C, a n d 2 D, pre g na nc y  testi n g s h o ul d occ ur at C 1 D 1 a n d 
wee kl y d uri n g first c ycle, a n d if me nstr ual c ycles are irre g ular s h o ul d occ ur e ver y 2 wee ks
t hereafter. I n a d diti o n, pre g na nc y  pre venti o n pr o gra ms ( P P P) f or le nali d o mi de a n d 
p o mali d o mi de m ust be f oll o we d.  
7. 1. 2. A d verse E ve nts
Assess me nt of a d verse e ve nts will i ncl u de t he t y pe, i nci de nce, se verit y  ( gra de d b y t he 
Nati o nal Ca ncer I nstit ute [ N CI ] C T C A E versi o n 4. 0 3 ) ti mi n g, seri o us ness, a n d relate d ness.  
T he se verit y of c y t o ki ne release s yn dr o me ( C R S) will be assesse d acc or di n g t o t he gra di n g 
descri be d b y Lee et al. ( 2 0 1 4 a n d 2 0 1 9 ,2 ,3 see A p pe n di x 5 ).
Patie nts w h o ha ve u n der g o ne all o ge neic ste m cell tra ns pla nt > 1 0 0 da y s bef ore t he first d ose 
of st u d y  treat me nt will be m o nit ore d f or c hr o nic graft -vers us -h ost disease ( G v H D ) acc or di n g 
t o i nstit uti o nal g ui deli nes.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 5
7. 1. 3. L a b or at or y S afet y Assess me nt
He mat ol o g y , bl o o d c he mistr y , viral, c oa g ulati o n a n d pre g na nc y  assess me nts will be dra w n at 
t he ti me p oi nts descri be d i n t he S C H E D U L E O F A C TI VI TI E S a n d a nal yz e d at l ocal 
la b orat ories.  If C R S is s us pecte d, a n a d h oc c yt o ki ne sa m ple will be c ollecte d a n d e val uate d 
ce ntrall y ( See Secti o n 7. 5. 4 ).  S h o ul d t he site re q uire c y t o ki ne i nf or mati o n f or patie nt 
ma na ge me nt, t he site will ha ve t he o pti o n of c ollecti n g a n a d diti o nal sa m ple f or l ocal 
a nal ys is. If a sa m ple f or p har mac o d y n a mic c yt o ki ne pa nel e val uati o n is d ue t o be c ollecte d 
o n t he sa me da y  as a s us pecte d C R S e ve nt occ urs , t he n a n a d h oc sa m ple f or ce ntral a nalys is 
is n ot re q uire d/c ollecte d. H o we ver, a n a d h oc sa m ple f or l ocal a nal ys is ma y still be c ollecte d 
f or patie nt ma na ge me nt .  L o cal c yt o ki ne a nalys is ma y i ncl u de i nterle u ki n (I L)-6, I L -1 , 
t u m or necr osis fact or –al p ha ( T N F ), a n d/ or I L-1 0 or ot her c y t o ki nes t hat will hel p t he 
i n vesti gat or wit h patie nt ma na ge me nt.
If T L S is s us pecte d, a s u b-set of c he mistr y tests will be c o m plete d (ie, t otal calci u m, 
creati ni ne, p h os p h or us or p h os p hate, p otassi u m a n d uric aci d) t o c o nfir m dia g n osis if t he 
tests were n ot perf or me d wit hi n t he last 2 4 hrs.
T a ble 1 1.
S afet y L a b or at or y Tests
He m at ol o g y
C he mi str y
Vir al
C o a g ul ati o n
Uri n al ysis
Pre g n a nc y 
Test
A d h oc C e ntr al 
L a b C yt o ki ne 
A n al ysis †
He m o gl o bi n
A L T
H Bs A g 
a n d 
H Bc A b) 
wit h 
refle xi ve 
D N A 
testi n g
P T  or I N R
Uri ne 
di pstic k f or 
uri ne 
pr otei n: If 
p ositi ve, 
c ollect 2 4 -hr 
a n d 
micr osc o pic 
( Refle x 
Testi n g)
F or fe male 
patie nts of 
c hil d beari n g 
p ote ntial, 
ser u m.
I L-6, I L -1 0, 
I L-2, sI L 2 R, 
I L-1 2, I L -4, 
I L-5, I L --1 3, 
I L-1 7, I L -1 b, 
I L-8, I F N , a n d 
T N F -
Platelets
A S T
H C V 
a nti b o d y 
wit h 
refle xi ve 
R N A 
testi n g.
P T T
W B C
bicar b o nate
A bs ol ute 
Ne utr o p hils
C R P
A bs ol ute 
L y m p h oc ytes
Al k P h os
A bs ol ute 
M o n oc ytes
S o di u m
A bs ol ute 
E osi n o p hils
P otassi u m
O pti o n al A d 
h oc L oc al L a b 
C yt o ki ne 
A n al ysis †
A bs ol ute 
Bas o p hils
Ma g nesi u m
Uri ne 
di pstic k f or 
uri ne bl o o d: 
If p ositi ve, 
c ollect a 
micr osc o pic 
( Refle x 
Testi n g)
C hl ori de
I L-6
T otal calci u m
I L-1 
T otal 
bilir u bi n * * *
I L-1 0
T otal Pr otei n
T N F 
B U N or Urea
Ot her c yt o ki nes
Creati ni ne
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 6
T a ble 1 1.
S afet y L a b or at or y Tests
He m at ol o g y
C he mi str y
Vir al
C o a g ul ati o n
Uri n al ysis
Pre g n a nc y 
Test
A d h oc C e ntr al 
L a b C yt o ki ne 
A n al ysis †
Uric Aci d
Gl uc ose 
( n o nfaste d)
L D H
Al b u mi n
P h os p h or us or 
P h os p hate
A b bre viati o ns: A l kali ne p h os p hatase = Al k P h os; ala ni ne A mi n otra nsferase = A L T; as partate 
a mi n otra nsferase = A S T; bl o o d urea nitr o ge n = B U N; C -reacti ve pr otei n = C R P; he patitis B = H B V; 
he patitis C = H C V; i nterfer o n-ga m ma = I F N ; I L = i nterle u ki n; I nter nati o nal N or malize d = I N R; lactate 
de h y dr o ge nase = L D H; partial t hr o m b o plasti n ti me = P T T; ; T N F = T u m or necr osis fact or - al p ha; w hite 
bl o o d cells = W B C .
* * * F or p ote ntial H y's La w cases, i n a d diti o n t o re peati n g A S T a n d A L T, la b orat or y tests s h o ul d i ncl u de 
al b u mi n, creati ne ki nase, t otal bilir u bi n, direct a n d i n direct bilir u bi n, ga m ma -gl uta m yl tra nsferase, 
pr ot hr o m bi n ti me ( P T)/I N R, al kali ne p h os p hatase, t otal bile aci ds a n d aceta mi n o p he n dr u g a n d/ or pr otei n 
a d d uct le vels. 
† A d h oc c yt o ki nes f or ce ntral la b e val uati o n will be c ollecte d if C R S is s us pecte d a n d c oi nci des wit h a da y 
p har mac o d y na mic sa m ples are n ot c ollecte d per t he Sc he d ule of Acti vities .  L ocal la b e val uati o n of 
c yt o ki ne is o nl y  re q uire d if t he site re q uire t his i nf or mati o n f or patie nt ma na ge me nt.
7. 1. 4. Vit al Si g ns a n d P h ysic al E x a mi n ati o n
Patie nts will ha ve a p h y sical e xa mi nati o n t o i ncl u de ne ur ol o gical assess me nt, wei g ht, vital 
si g ns, p ulse rate, assess me nt of E C O G perf or ma nce stat us (A p pe n di x 4 ) a n d hei g ht; hei g ht 
will be meas ure d at scree ni n g o nl y.
7. 1. 5. ( 1 2-Le a d) E lectr oc ar di o gr a m
Electr ocar di o gra m ( E C G): Tri plicate 1 2 -lea d (wit h a 1 0 -sec o n d r h yt h m stri p) traci n g will be 
use d f or E C Gs c ollecte d i n C ycles 1 a n d 2 .  Si n gle E C Gs will be c ollecte d at scree ni n g a n d 
fr o m C ycle 3 o n war ds. It is prefera ble t hat t he mac hi ne use d has a ca pacity t o calc ulate t he 
sta n dar d i nter vals a ut o maticall y.  At eac h ti me p oi nt i n C ycles 1 a n d 2 (see t he S C H E D U L E 
O F A C TI VI TI E S ), 3 c o nsec uti ve E C Gs will be perf or me d at a p pr o xi matel y 2 mi n utes a part 
t o deter mi ne t he mea n Q Tc F i nter val.  If t he mea n Q Tc F is pr ol o n ge d ( >5 0 0 msec, 
ie, C T C A E Gra de 3), t he n t he E C Gs s h o ul d be re- e val uate d b y a q ualifie d pers o n at t he site 
f or c o nfir mati o n as s o o n as t he fi n di n g is ma de, i ncl u di n g verificati on t hat t he mac hi ne 
rea di n g is acc urate.  If ma n ual rea di n g verifies a Q Tc F of > 5 0 0 msec , i m me diate c orrecti o n 
f or re versi ble ca uses (i ncl u di n g electr ol yte a b n or malities, h yp o xia a n d c o nc o mita nt 
me dicati o ns f or dr u gs wit h t he p ote ntial t o pr ol o n g t he Q Tc F i nter val) s h o ul d be perf or me d.  
I n a d diti o n, re peat E C Gs s h o ul d be i m me diatel y perf or me d h o urly f or at least 3 h o urs u ntil 
t he Q Tc F i nter val falls bel o w 5 0 0 msec.  If Q Tc F i nter val re verts t o less t ha n 4 8 0 msec, a n d 
i n t he j u d g me nt of t he i n vesti gat or(s) an d s p o ns or is deter mi ne d t o be d ue t o ca use(s) ot her 
t ha n i n vesti gati o nal pr o d uct, treat me nt ma y be c o nti n ue d wit h re g ular E C G m o nit ori n g.  If i n 
t hat ti mefra me t he Q Tc F i nter vals rise a b o ve 5 0 0 msec t he i n vesti gati o nal pr o d uct will be 
hel d u ntil t he Q Tc F i nter val decreases t o 4 8 0 msec.  Patie nts will t he n restart t he 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 7
i n vesti gati o nal pr o d uct at t he ne xt l o west d ose le vel.  If t he Q Tc F i nter val has still n ot 
decrease d t o ≤4 8 0 msec after 2 wee ks, or if at a n y ti me a patie nt has a Q Tc F i nter val 
> 5 1 5 msec or b ec o mes s ym pt o matic, t he patie nt will be re m o ve d fr o m t he st u d y u nless t he 
i n vesti gat or belie ves t hat it is i n t he best i nterest of t he patie nt t o c o nti n ue a n d it has bee n 
a gree d u p o n after disc ussi o n wit h t he s p o ns or.  A d diti o nal tri plicate E C Gs ma y  be perf or me d 
as cli nicall y i n dicate d. 
Pri or t o c o ncl u di n g t hat a n e pis o de of pr ol o n gati o n of t he Q Tc F i nter val is d ue t o 
i n vesti gati o nal pr o d uct, t h or o u g h c o nsi derati o n s h o ul d be gi ve n t o p ote ntial preci pitati n g 
fact ors (e g, c ha n ge i n patie nt cli nical c o n diti o n, effect of c o nc urre nt me dicati o n, electr olyt e 
dist ur ba nce) a n d p ossi ble e val uati o n b y s pecialist.
If a patie nt e x perie nces a car diac or ne ur ol o gic A E (s pecificall y  sy n c o pe, dizzi ness, seiz ures, 
or str o ke), a n E C G (tri plicate) s h o ul d be o btai ne d at t he ti m e of t he e ve nt. 
W he n matc he d wit h P K sa m pli n g, t he E C G s h o ul d be carrie d o ut bef ore eac h P K sa m ple 
dra wi n g s uc h t hat t he P K sa m ple is c ollecte d at t he n o mi nal ti me (ie, t he ti mi n g of t he P K 
c ollecti o ns o verri des t he ti mi n g of t he E C G c ollecti o ns). 
7. 1. 6. Ec h oc ar di o gr a m ( Ec h o) or M ulti g ate d Ac q uisiti o n Sc a n ( M U G A)
Ec h ocar di o gra m ( Ec h o) or m ulti gate d ac q uisiti o n sca n ( M U G A) will be e val uate d i n patie nts 
wit h pre vi o us hist or y  of car diac e ve nts.  F or t hese patie nts, a n ec h ocar di o gra m or M U G A
will be perf or me d at scree ni n g, w he n cli nicall y i n dicate d, a n d at t he e n d of treat me nt ( E O T) 
visit.  T he f oll o wi n g para meters will be e val uate d: ve ntric ular f u ncti o n (i ncl u di n g left 
ve ntric ular ejecti o n fracti o n [ L V E F], e n d s ys t olic v ol u me [ E S V] a n d e n d diast olic v ol u me 
[ E DV]), q ualitati ve e val uati o n of c ha m ber size, a n d wall m oti o n.  A D o p pler e xa mi nati o n 
will be c o m plete d a n d s h o ul d i ncl u de a n assess me nt of mitral val ve, atria, ri g ht ve ntricle, 
tric us pi d val ve, a ortic val ve, p ul m o nic val ve, great vessels, a n d pericar di u m. 
7. 1. 7. L oc al Site I njecti o n T oler a bilit y Assess me nt ( S C O nl y)
Assess me nts ma de of t he i njecti o n sites i n t he a b d o mi nal fat f ol d t o m o nit or l ocal t olera bilit y 
t o P F- 0 6 8 6 3 1 3 5 S C i njecti o ns will be perf or me d 1 t o 4 h o urs f oll o wi n g st u d y dr u g 
a d mi nistrati o n, as per t he S C H E D U L E O F A C TI VI TI E S .  If S C i njecti o ns i n t he a b d o mi nal 
l ocati o n are n ot p ossi ble, S C i njecti o ns ca n be a d mi nistere d i n a distri b ute d ma n ner i n t he 
t hi g hs.  S C i njecti o ns i n t he u p per e xtre mities (e g, delt oi d, u p per a n d lo wer ar m) are n ot 
per mitte d.  Refer t o A p pe n di x 9 f or m ore details.
Site t olera bilit y  assess me nts s h o ul d c o nti n ue at re g ularl y s c he d ule d visits if i njecti o n site 
pai n or i njecti o n site reacti o n (I S R) c haracteristics c o nti n ue t o persist.  T he assess me nts 
s h o ul d c o nti n ue u ntil t he s ym pt o ms res ol ve.  T he i njecti o n sites will be assesse d f or 
er yt he ma, i n d urati o n, ecc h y m osis, i njecti o n site pai n, i njecti o n site pr urit us, or ot her 
o bser ve d c haracteristics after st u d y dr u g d osi n g.  T he dia meter of t he affecte d area will be 
meas ure d a n d t he c o n diti o n of t he i njecti o n site will be rec or de d o n t he S C I njecti o n Site 
Assess me nt C R F.  A n y o bser ve d a b n or malit y at t he i njecti o n site will be j u d ge d b y t he 
i n vesti gat or t o deter mi ne w het her a c orres p o n di n g A E s h o ul d be re p orte d.  I S Rs s h o ul d be 
i m me diatel y p h ot o gra p he d i n c ol or, wit h scale d r uler place d by t he reacti o n, a n d t hese 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 8
p h ot o gra p hs s h o ul d be i ncl u de d i n t he pa tie nt’s s o urce d oc u me ntati o n.  W he n a p pr o priate, at 
t he discreti o n of t he i n vesti gat or, a patie nt wit h a n IS R ma y  be referre d f or a der mat ol o gical 
c o ns ultati o n a n d s ki n bi o ps y  ma y be o btai ne d f or f ut ure e xa mi nati o n of t he IS R.  T he 
der mat ol o g y  c o ns ultati o n is e x pecte d t o ta ke place at t he der mat ol o gist’s practice l ocati o n, or 
ma y  occ ur wit hi n t he sa me i nstit uti o n w here t his st u d y is c o n d ucte d.
7. 2. Dise ase Res p o nse Assess me nt 
A nti- ca ncer assess me nts a n d res p o nse will be assesse d acc or di n g t o t he I nter nati o nal 
M yel o ma W or ki n g Gr o u p (I M W G) res p o nse criteria f or m ulti ple m yel o ma 4 ,5 ( M M, See 
A p pe n di x 2 ).  Disease res p o nse assess me nt s h o ul d be c o nti n ue d t o e n d of treat me nt if e n d of 
treat me nt reas o n is disease pr o gressi o n. Patie nts t hat e n d treat me nt wit h o ut pr o gressi o n a n d 
re mai n i n f oll o w-u p o n st u d y  s h o ul d c o nti n ue t o ha ve disease res p o nse assess me nts t hat are 
o btai ne d per sta n dar d of care re p orte d u ntil disease pr o gressi o n , start of ne w a nti-m y el o ma 
t hera py, or e n d of f oll o w -u p o n st u d y wit h res p o nse assess me nts rec or de d i n t he st u d y  
data base .
7. 2. 1. L a b or at or y E v al u ati o n of Dise ase Res p o nse
La b orat or y  tests f or disease res p o nse will be use d t o e x pl ore early si g nals of a nti-ca ncer 
acti vit y (see A p pe n di x 2 ).4 ,5 T he se la b orat or y tests will be c o m plete d per S C H E D U L E O F 
A C TI VI TI E S , i ncl u di n g assess me nts at s us pecte d C R, w he ne ver disease pr o gressi o n is 
s us pecte d (e g, s ym pt o matic deteri orati o n), a n d at wit h dra wal fr o m treat me nt if n ot d o ne i n 
t he pre vi o us 4 wee ks.  F or patie nts sc he d ule d t o be d ose escalate d, sa m ples will als o be 
c ollecte d wit hi n 1 wee k b ef ore t he pla n ne d start of t he escalate d d ose .  Assess me nts will 
i ncl u de: 

Ser u m pr otei n electr o p h oresis ( S P E P) f or t he meas ure me nt of ser u m al b u mi n a n d 
M -pr otei ns ( al p ha 1 gl o b uli ns, al p ha 2 gl o b uli ns, beta 1 gl o b uli ns, beta 2 gl o b uli ns [beta 
gl o b uli ns if la b is u na ble t o se parate beta 1 a n d beta 2 gl o b uli ns ], a n d/ or ga m ma 
gl o b uli ns ).

Ser u m i m m u n ofi xati o n electr o p h oresis ( SI F E) f or defi niti ve i de ntificati o n of s pecific 
M- pr otei ns (i ncl u di n g i m m u n o gl o b uli n [I g]G, I g A, I g M, a n d t w o li g ht c hai ns ka p pa 
a n d la m da).  SI F E will o nl y  be c o m plete d at baseli ne w he n electr o p h oresis s h o ws n o 
meas ura ble pr otei n at s us pecte d C R, a n d at s us pecte d pr o gressi o n (cli nical or 
bi oc he mical) .

2 4 hr uri ne pr otei n electr o p h oresis ( U P E P) f or t he meas ure me nt of uri ne al b u mi n a n d 
M - pr otei ns ( al p ha 1 gl o b uli ns, al p ha 2 gl o b uli ns, beta 1 gl o b uli ns, beta 2 gl o b uli ns, 
[ beta gl o b uli ns if la b is u na ble t o se parate beta 1 a n d beta 2 gl o b uli ns], a n d/ or ga m ma 
gl o b uli ns ).

2 4 hr uri ne i m m u n ofi xati o n electr o p h oresis ( UI F E) f or defi niti ve i de ntificati o n of 
s pecific M- pr otei ns (i ncl u di n g I g G, I g A, I g M, a n d t w o li g ht c hai ns ka p pa a n d la m da).  
UI F E will o nl y be c o m plete d at baseli ne w he n electr o p h oresis s h o ws n o meas ura ble 
pr otei n at s us pecte d C R, a n d at s us pecte d pr o gressi o n (cli nical or bi oc he mical).
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 9

I n v ol ve d a n d u ni n v ol ve d ser u m free li g ht c hai n a nal ysis ( F L C) o nly w he n b ot h ser u m 
a n d uri ne M -c o m p o ne nts are dee me d n o n -meas ura ble (i ncl u di n g at s us pecte d C R).
Ser u m free ka p pa, free l a m b da a n d free ka p pa/la m b da rati o s h o ul d be rec or de d. 

If patie nts were treate d wit h darat u m u ma b less t ha n 1 1 4 da y s pri or t o pla n ne d 
treat me nt da y, darat u m u ma b will i nterfere wit h S P E P, U P E P, SIF E a n d UI F E 
assa ys.  T heref ore, f or t hese patie nts, F L C assa y  s h o ul d be c o m plete d at 
scree ni n g, C 1 D 1, a n d all s u bse q ue nt disease assess me nts. I n t hese patie nts w h o 
pre vi o usl y  recei ve d darat u m u ma b ser u m a n d uri ne M- s pi ke if meas ura ble at 
baseli ne i n t hese patie nts s h o ul d als o be f oll o we d at t he sa me ti me p oi nts as F L C
wit h t he m ost re prese ntati ve mar ker of disease stat us use d f or deter mi nati o n 
I M W G assess me nt.

Beta -2 micr o gl o b uli n . T his will be c ollecte d o n t he first da y of treat me nt.
All sa m ples will be c ollecte d pri or t o i n vesti gati o nal pr o d uct a d mi nistrati o n o n da y s w here b y 
i n vesti gati o nal pr o d uct is t o be a d mi nistere d.  I n patie nts wit h t w o M-pr otei n ba n ds at t he 
start of t hera py, u nless t he sec o n d ba n d is d ue t o darat u m u ma b or ot her t hera pe utic m A b
i nterfere nce, t he s u m of t he t w o s pi kes s h o ul d be use d f or m o nit ori n g of disease.  W he n a 
c o m plete res p o nse ( C R) , or a cli nical or bi oc he mical pr o gressi o n is s us pecte d, S P E P, ser u m 
SI F E, U P E P, UI F E a n d F L C tests will be re peate d wit hi n 1 t o 4 wee ks . 
N ote t hat if a patie nt ha d meas ura ble ser u m or uri ne M-s pi ke at baseli ne, u nless t he ba n d is 
d ue t o darat u m u ma b or meas ure me nt of M -s pi ke is c o nf o u n de d b y t he prese nce of 
darat u m u ma b or ot her t hera pe utic m A b , pr o gressi o n ca n n ot be defi ne d b y  i ncreases i n ser u m 
F L C al o ne.   Ser u m F L C le vels s h o ul d o nl y  be use d f or res p o nse assess me nt w he n b ot h t he 
ser u m a n d uri ne M-c o m p o ne nt le vels are dee me d n ot meas ura ble or u ni nter preta ble.  
F urt her m ore, caref ul atte nti o n s h o ul d be gi ve n t o ne w p ositi ve i m m u n ofi xati o n res ults 
a p peari n g i n patie nts w h o ha ve ac hie ve d a C R, w he n t he is ot ype is differe nt.   T his ma y  
re prese nt oli g ocl o nal i m m u ne rec o nstit uti o n a n d s h o ul d n ot be c o nf use d wit h rela pse; t hese 
ba n ds t y picall y  disa p pear o ver ti me.
7. 2. 2. B o ne M arr o w Pl as m a Cell E v al u ati o n a n d B o ne M arr o w S a m ple C ollecti o n
B o ne marr o w e val uati o n of plas ma cells i n b o ne marr o w as pirate a n d/ or b o ne marr o w 
bi o psies will be perf or me d t o f oll o w disease res p o nse. 
U nilateral b o ne marr o w as pirate sa m ples will be c ollecte d a n d t he perce nta ge of plas ma cells
will be e val uate d at t he f oll o wi n g ti mes: 
a.
First p re-d ose f irst da y of st u d y treat me nt or u p t o 7 da y s bef ore st u d y treat me nt);
b.
At 1 m o nt h after C 1 D 1 ± 7 da y s; 
c.
At 3 m o nt h s after C 1 D 1 ± 7 da y s;
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 0
d.
W he n s u bject is f o u n d i m m u n ofi xati o n ne gati ve i n b ot h ser u m a n d uri ne t o c o nf ir m 
a n y c o m plete res p o nse ( C R);
e.
At ti me of s us pecte d disease pr o gressi o n ( o pti o nal) ; 
f.
Wit hi n 1 wee k p ri or t o escalati n g t o t he ne xt hi g her d ose le vel c o h ort f oll o wi n g 
6 0- d a y  late t o xicit y e val uati o n ( u nless t he i n vesti gat or assesses t hat t her e i n a n 
u nj ustifia ble ris k f or it a n d/ or t he patie nt ref uses t o u n der g o a b o ne marr o w 
pr oce d ure ; if a b o ne marr o w as pirate or bi o ps y  was perf or me d wit hi n t he past 
4 wee ks pri or t o pla n ne d start of escalate d d ose, o nl y  disease sta gi n g la b tests m ust be 
perf or me d );
g.
At 9 m o nt hs after C 1 D 1 a n d e ver y 6 m o nt hs t hereafter u nless a platea u or C R is 
o bser ve d.   F or patie nts w h o e x perie nce a platea u or C R, a d diti o nal sa m ples at 9 
m o nt hs after C 1 D 1 a n d o n war ds will be o pti o nal. A ± 1 4 da y  wi n d o w a p plies f or 
t hese c ollecti o ns.
B o ne marr o w bi o psies will als o be c ollecte d a n d t he perce nta ge of plas ma cells wit hi n t he 
bi o ps y  sa m ples will als o be e val uate d at t he f oll o wi n g ti mes .  I n case of s us pecte d stri n ge nt 
C o m plete Res p o nse (s C R), t he prese nce/a bse nce of cl o nal cells o n i m m u n o hist oc he mistr y  
s h o ul d als o be e val uate d.
a.
First da y  of st u d y treat me nt ( or u p t o 7 d a y s bef ore st u d y treat me nt); 
b.
At 1 m o nt h after C 1 D 1 ± 7 da y s;
c.
At 3 m o nt hs (o pti o nal) after C 1 D 1 ± 7 da y s;
d.
At 9 m o nt hs ± 1 4 da y s ( o pti o nal) after C 1 D 1 a n d e ver y 6 m o nt hs ± 1 4 da y s t hereafter 
( o pti o nal);
e.
At s us pecte d stri n ge nt C o m plete Res p o nse (s C R) ;
f.
At ti me of s us pecte d disease pr o gressi o n ( o pti o nal). 
Assess me nts s h o ul d be fi xe d acc or di n g t o t he cale n dar, re gar dless of treat me nt dela ys.  W he n 
b o ne marr o w plas ma cell i nfiltrati o n is assesse d b y b ot h b o ne marr o w as pirate a n d b y b o ne 
marr o w bi o ps y, t he hi g hest val ue of b o ne marr o w plas ma cell i nfiltrati o n s h o ul d be utilize d 
f or res p o nse e val uati o n.
T he sa me b o ne marr o w l ocati o n use d f or c haracterizati o n at baseli ne s h o ul d be e m pl o y e d i n 
p ost -baseli ne b o ne marr o w sa m pli n g if cli nicall y feasi ble . 
W he n b o ne marr o w as pirate a n d bi o ps y sa m ples are ta ke n f or disease res p o nse e val uati o n, 
sa m ples f or bi o mar ker a nal ysis will als o be ac q uire d (see B o ne Marr o w Bi o mar kers 
Secti o n 7. 5. 1 ).  I n a d diti o n, if a s u bject is i m m u n ofi xati o n ne gati ve i n b ot h ser u m a n d uri ne 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 1
a n d fl o w c yt o metr y is n ot a vaila ble, bi o ps y sa m ple will be re q uire d f or I H C stai ni n g t o assess 
cl o nalit y. 
B o ne marr o w as pirates will als o be e val uate d ce ntrall y f or mi ni mal resi d ual disease ( M R D,
see A p pe n di x 3 )5 usi n g a ne xt ge nerati o n se q ue nci n g ( N G S) assa y w he n a patie nt is i n 
s us pecte d C R or act ual C R. B o ne marr o w as pirates will be c ollecte d f oll o wi n g t he sa m ple 
c ollecti o n sc he d ule descri be d i n Sc he d ule of Acti vities A, B, a n d C. A C 1 D 1 ( patie nts 
wit h o ut pri mi n g d ose ) or C 0 D 1 ( patie nts wit h pri mi n g d ose) b o ne marr o w as pirate m ust als o 
be c ollecte d a n d s u b mitte d f or all patie nts as t he baseli ne refere nce of t he N G S M R D test.
Sa m ples f or M R D assess me nts s h o ul d be ali q u ote d fr o m t he first b o ne marr o w as pirate p ull.
L ocal M R D testi n g is n ot e nc o ura ge d. I n t he case t hat M R D assess me nt is perf or me d l ocall y 
usi n g a n a nal yt ically vali date d fl o w c yt o metr y M R D assa y  t hat meets t he I M W G se nsiti vit y 
criteria (i.e. se nsiti vit y of o ne i n 1 05 n ucleate d cells), res ults of s uc h test s h o ul d be pr o vi de d 
t o t he s p o ns or b y rec or di n g i n t he st u d y data base. N G S M R D testi n g s h o ul d n ot be 
perf or me d l ocall y. .
7. 2. 3. Fl u or o de o x y gl uc ose ( F D G) P ositr o n E missi o n T o m o gr a p h y ( P E T)/ C o m p ute d 
T o m o gr a p h y ( C T) Im a gi n g 
Fl u or o de o x y gl uc ose -P E T/ C T ( 1 8F- F D G -P E T/ C T) i ma gi n g will be use d t o e x pl ore early 
si g nals of a nti-ca ncer acti vit y.  F D G -P E T/ C T is a f u ncti o nal i ma gi n g met h o d i n w hic h t he 
u pta ke of 1 8 F -F D G b y  cells reflects t he tiss ue u pta ke of gl uc ose, t h us re veali n g s pecific 
t ypes of tiss ue meta b olis m.   I n M M, f u ncti o nal i ma gi n g o n hy bri d sca n ners (c o m bi nati o n of 
P E T a n d C T i ma gi n g) rat her t ha n o n P E T sca n ners al o ne are re q uire d.  T he ass ociati o n of 
a b n ormal F D G u pta ke pr o vi de d b y  P E T i ma gi n g a n d t he assess me nt of b o ne str uct ure 
pr o vi de d b y C T i ma gi n g lea ds t o a n o pti mal e val uati o n of disease.
I ma gi n g st u dies will be c ollecte d per S C H E D U L E O F A C TI VI TI E S . F or all patie nts, 
i ma ges are re q uire d at scree ni n g, s us pecte d C R, w he n disease pr o gressi o n is s us pecte d 
(e g, s ym pt o matic deteri orati o n), e n d of treat me nt visit (if n ot d o ne i n pre vi o us 4 wee ks) a n d 
w he n ot her wise cli nicall y  i n dicate d.  I n patie nts wit h meas ura ble tar get lesi o ns at scree ni n g, 
i ma ges are re q uire d at 1, 3, a n d 9 m o nt hs after C 1 D 1 a n d e ver y 6 m o nt hs t hereafter.
T he scree ni n g P E T/ C T will be use d t o deter mi ne e val ua ble tar get lesi o ns f or eac h patie nt.  
T u m or bac k gr o u n d rati os ( T B Rs ) a n d de vel o p me nt of ne w sites of a b n or malit y will be 
rec or de d. 
If i ma gi n g is use d i n disease assess me nt, t he sa me i ma gi n g tec h ni q ue use d t o c haracterize 
eac h i de ntifie d a n d re p orte d lesi o n at baseli ne will be e m pl o y e d i n p ost -baseli ne disease 
assess me nts.  A n y s oft tiss ue plas mac y t o ma d oc u me nte d at baseli ne m ust u n der g o serial 
m o nit ori n g ; ot her wise, t he patie nt will be classifie d as u ne v al ua ble.  Plas mac y t o ma t hat has 
bee n irra diate d will n ot be s uita ble f or res p o nse assess me nt; h o we ver, it m ust be m o nit o re d 
f or pr o gressi ve disease.
Ra di o gra p hic st u dies are n ot re q uire d t o satisf y  res p o nse a n d M R D re q uire me nts, e xce pt if 
C R or i ma gi n g M R D - ne gati ve stat us is s us pecte d (see A p pe n di x 3 ). 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 2
Disease res p o nse assess me nts will be base d u p o n I M W G criteria
4 ,5 (see A p pe n di x 2 ). 
All patie nts’ files a n d ra di ol o gic i ma ges a n d pat h ol o g y  sa m ples m ust be a vaila ble f or s o urce 
verificati o n a n d f or p ote ntial peer re vie w or i n de pe n de nt ce ntral re vie w . 
Ra di o gra p hic assess me nts o btai ne d per t he patie nt’s sta n dar d of care pri or t o e nr oll me nt i nt o 
t he st u d y d o n ot nee d t o be re peate d a n d are acce pta ble t o be use d as baseli ne e val uati o n, if, 
( 1) o btai ne d wit hi n 2 8 da y s bef ore start of st u d y treat me nt, ( 2) t he sa me tec h ni q ue/ m o dalit y 
ca n be u se d t o f oll o w i de ntifie d lesi o ns t hr o u g h o ut t he trial f or a gi ve n patie nt, a n d ( 3) 
a p pr o priate d oc u me ntati o n i n dicati n g t hat t hese ra di o gra p hic t u m or assess me nts were 
perf or me d as sta n dar d of care is a vaila ble i n t he patie nt’s s o urce n otes.
N ote: F or sites i n Ger ma n y, o nly M RI is all o we d t o be use d as i ma gi n g m o dalit y f or 
partici pa nts wit h e xtra me d ullar y  disease.
7. 3. P h ar m ac o ki netics Assess me nts
Bl o o d sa m ples f or t he a nal y sis of P F-0 6 8 6 3 1 3 5 c o nce ntrati o ns will be c ollecte d i nt o 
a p pr o priatel y la bele d t u bes at t he ti mes s pecifie d i n t he S C H E D U L E O F A C TI VI TI E S of t he 
pr ot oc ol.   If C R S is s us pecte d, a n d if a P K sa m ple is n ot alrea dy sc he d ule d t o be ta ke n 
(eg, fr o m C ycle 3 o n war ds), a P K sa m ple s h o ul d als o be ta ke n.  F or eac h a nal y sis, 
a p pr o xi m atel y 5 m L  of bl o o d sa m ples will be c ollecte d t o pr o vi de a p pr o xi matel y 2 m L  
ser u m.  T he P K sa m pli n g sc he d ule ma y  be m o difie d base d o n e mer gi n g P K data. Bl o o d 
sa m ples (a p pr o xi matel y 3 m L ) t o pr o vi de a p pr o xi matel y 1. 5 m L  plas ma f or t he a nalys is of
le nali d o mi de, p o mali d o mi de , a n d de xa met has o ne co nce ntrati o ns will be c ollecte d i n Parts 1 C
a n d 2C , Parts 1 D a n d 2 D, a n d Parts 1 E a n d 2 E, res pecti vel y, of t he st u d y as o utli ne d i n t he
S C H E D U L E O F A C TI VI TI E S .
I n a d diti o n t o sa m ples c ollecte d at t he sc he d ule d ti mes, a n a d diti o nal bl o o d sa m ple f or 
P F - 0 6 8 6 3 1 3 5 s h o ul d be c ollecte d fr o m patie nts e x perie nci n g u ne x pecte d a n d/ or seri o us A Es 
a n d t he date a n d ti me of bl o o d sa m ple c ollecti o n a n d of last d osi n g pri or t o P K c ollecti o n 
s h o ul d be d oc u me nte d i n t he C R F.   W here n ote d i n t he S C H E D U L E O F A C TI VI TI E S , 
bl o o d sa m ples f or P F -0 6 8 6 3 1 3 5 c o nce ntrati o ns will be c ollecte d at a p pr o xi matel y  t he sa me 
ti me as ot her assess me nts s uc h as p har mac o dy na mic sa m ples w he ne ver p ossi ble.
All eff orts will be ma de t o o btai n t he p har mac o ki netic sa m ples at t he e xact n o mi nal ti me 
relati ve t o d osi n g.  All bl o o d sa m ples s h o ul d be ta ke n fr o m t he c o ntralateral i nf usi o n ar m o n 
d osi n g da y s.  H o we ver, t he e xact ti me of t he sa m ple c ollecti o n will al wa y s be n ote d o n t he 
C R F.   Sa m ples o btai ne d wit hi n t he s pecifie d visit wi n d o w will be n ot be ca pt ure d as a 
pr ot oc ol de viati o n.   T he 2 hr sa m ples s h o ul d be c ollecte d i m me diatel y  bef ore t he i nf usi o n 
e n ds ( n ot m ore t ha n 1 5 mi n utes pri or) fr o m t he c o ntra -lateral ar m of t he i nf usi o n.  If a 
sc he d ule d bl o o d sa m ple c ollecti o n ca n n ot be c o m plete d f or a ny reas o n, t he misse d sa m ple 
ti me ma y be re-sc he d ule d wit h a gree me nt of cli nical i n vesti gat ors, patie nt a n d S p o ns or.  
A d diti o nal i nstr ucti o ns f or sa m ple c ollecti o n, pr ocessi n g, st ora ge a n d s hi p pi n g will be 
pr o vi de d i n t he la b ma n ual.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 3
P K sa m ples will be assa ye d f or P F- 0 6 8 6 3 1 3 5, le nali d o mi de, a n d p o mali d o mi de usi n g a 
vali date d a nal yt ical met h o d i n c o m plia nce wit h Pfizer sta n dar d o perati n g pr oce d ures.  Details 
re gar di n g t he collecti o n, pr ocessi n g, st ora ge a n d s hi p pi n g of t he bl o o d sa m ples will be 
pr o vi de d i n t he st u d y  ma n ual.
As part of u n dersta n di n g t he p har mac o ki netics of t he i n vesti gati o nal pr o d uct sa m ples ma y  be 
use d f or e val uati o n of t he bi oa nal y tical met h o d, as well as for ot her i nter nal e x pl orat or y  
p ur p oses.   T hese data will n ot be i ncl u de d i n t he cli nical st u d y re p ort. 
7. 4. I m m u n o ge nicit y A n al yses
Bi oa nal ys is t o assess f or a nti-dr u g ( P F - 0 6 8 6 3 1 3 5) a nti b o dies ( A D A) will be perf or me d.  
Sa m ples will be a nal y ze d usi n g a vali date d a nal yt ical met h o d i n c o m plia nce wit h Pfizer
sta n dar d o perati n g pr oce d ures (S O Ps ).  All sa m ples t hat are p ositi ve i n a scree ni n g assa y  will 
be f urt her c haracterize d i n ter ms of a nti b o d y  s pecificit y.  A tiere d a p pr oac h t o scree ni n g, 
c o nfir mati o n a n d titer/ q ua ntitati o n will be utilize d. A scree ni n g assa y wit h c o m petiti ve 
c o nfir mat or y ste ps f oll o we d b y a titer assa y will be use d.  Sa m ples ma y  als o be a nalyz e d i n 
ne utralizi n g a nti b o d y ( N A b) assa ys.  Patie nts f o u n d t o ha ve a nti - dr u g a nti b o dies at t heir fi nal 
st u d y visit a n d a n o n g oi n g A E p ossi bly relate d t o A D A will be as ke d t o ret ur n t o t he cli nic 
f or A D A a n d dr u g c o nce ntrati o n bl o o d sa m pli n g at a p pr o xi matel y 3 m o nt h i nter vals u ntil t he 
a d verse e ve nt or it s se q uelae res ol ve or sta bilize at a le vel acce pta ble t o t he i n vesti gat or a n d 
s p o ns or.
Bl o o d sa m ples (a p pr o xi matel y  5 m L ) t o pr o vi de a p pr o xi matel y 1 m L  of ser u m eac h f or A D A 
a n d N A b a gai nst P F-0 6 8 6 3 1 3 5 a nal ys is will be c ollecte d i nt o a p pr o priately la bele d t u bes at 
ti mes s pecifie d i n t he sc he d ule of acti vities of t his pr ot oc ol.  A d diti o nal i nstr ucti o ns f or 
sa m ple c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p pi n g will be pr o vi de d i n t he la b ma n ual.
T he i m m u n o ge nicit y sa m ples m ust be pr ocesse d a n d s hi p pe d as i n dicate d i n t he i nstr ucti o ns 
pr o vi de d t o t he i n vesti gat or site t o mai ntai n sa m ple i nte grit y . A n y de viati o ns fr o m t he 
i m m u n o ge nicity sa m ple ha n dli n g pr oce d ure (e g, sa m ple c ollecti o n a n d pr ocessi n g ste ps, 
i nteri m st ora ge or s hi p pi n g c o n diti o ns), i ncl u di n g a n y acti o ns ta ke n, m ust be d oc u me nte d a n d 
re p orte d t o t he s p o ns or.  O n a case-b y -case basis, t he s p o ns or ma y  ma ke a deter mi nati o n as 
t o w het her sa m ple i nte grit y has bee n c o m pr o mise d.  A n y  de viati o n fr o m t he s pecifie d sa m ple 
ha n dli n g pr oce d ure res ulti n g i n c o m pr o mise d sa m ple i nte grit y will be c o nsi dere d a pr ot oc ol 
de viati o n.
As part of u n dersta n di n g t he i m m u n o ge nicit y of t he i n vesti gati o nal pr o d uct, sa m ples ma y be 
use d f or e val uati o n of t he bi oa nal y tical met h o d a n d/ or a d diti o nal c haracterizati o n of a n 
o bser ve d i m m u n o ge nicit y  res p o nse.  T hese data will be use d f or i nter nal e x pl orat or y  
p ur p oses a n d will n ot be i ncl u de d i n t he cli nical st u d y re p ort (C S R ).  Sa m ples c ollecte d f or 
t his p ur p ose will be retai ne d i n acc or da nce t o l ocal re g ulati o ns a n d if n ot use d wit hi n t his 
ti mefra me, will be destr o ye d.
7. 5. Bi o m ar ker a n d P h ar m ac o d y n a mic Assess me nts
O ne of t he ke y  ele me nts of t his st u d y is t he p ossi bilit y t o e val uate p ote ntial m olec ular tar gets 
t hat c o ul d be m o difie d b y P F-0 6 8 6 3 1 3 5 , as a m o n ot hera py a n d i n c o m bi nati o n.  Tiss ue 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 4
sa m ples (i ncl u di n g b ut n ot li mite d t o b o ne marr o w bi o ps y, b o ne marr o w as pirate, peri p heral 
bl o o d, ser u m a n d plas ma) will be c ollecte d bef ore a n d after P F-0 6 8 6 3 1 3 5 d osi n g f or 
bi o mar ker e val uati o n a n d p har mac o d y n a mic assess me nts.  Sa m ples o btai ne d pre a n d p ost 
P F -0 6 8 6 3 1 3 5 a d mi nistrati o n will be ma n dat or y f or all patie nts (e xce pt f or b o ne marr o w 
bi o ps y  sa m ples c ollecte d at 1, 3 a n d 9 m o nt hs after C 1 D 1( o pti o nal) a n d e ver y 6 m o nt hs 
t hereafter ( o pti o nal), or f or b o ne marr o w as pirate sa m ples fr o m 9 m o nt hs after C 1 D 1 a n d 
e ver y 6 m o nt hs t hereafter f or patie nts w h o e x perie nce a platea u or C R). If t he c ollecti o n of a 
b o ne marr o w bi o ps y is n ot re q uire d f or disease res p o nse assess me nt, a n d t he i n vesti gat or 
deter mi nes t hat t he ris k ass ociate d wit h t he b o ne marr o w bi o psy is n ot a p pr o priate f or a 
researc h setti n g e g, base d o n c o m plicati o ns d uri n g a pre vi o us pr oce d ure, after c o ns ultati o n 
wit h t he s p o ns or’s me dical m o nit or , t he c ollecti o n of a n y i m pe n di n g b o ne marr o w bi o psies 
ma y  be o mitte d. 
Ta ble 1 2 s u m marizes re prese ntati ve assa ys t o be use d a n d t he sa m ple s o urce.  Refer t o t he 
S C H E D U L E O F A C TI VI TI E S   f or details pertai ni n g t o s pecific da ys a n d ti mes of sa m ple 
c ollecti o n a n d t o t he La b Ma n ual f or details of sa m ple pre parati o n, st ora ge, a n d s hi p me nt.  
T he bi o mar ker st u dies will be use d t o hel p u n dersta n d t he mec ha nis m of acti o n of 
P F -0 6 8 6 3 1 3 5 al o ne a n d i n c o m bi nati o n as well as p ote n tial mec ha nis ms of resista nce.  T he 
st u dies ma y hel p i n t he f ut ure de vel o p me nt of P F-0 6 8 6 3 1 3 5.
T a ble 1 2.
Bi o m ar ker Ass a ys a n d S a m ple S o urces
Bi o m ar ker
M atri x
Ass a y
S ol u ble i m m u ne fact ors
S er u m
I m m u n oassa y
S ol u ble B C M A/relate d fact ors
Plas ma
Mass s pectr o metr y
B C M A e x pressi o n
B M as pirate 
Fl o w  c yt o metr y 
B M bi o ps y
I H C
T B N K
W h ole bl o o d 
Fl o w  c yt o metr y 
B M as pirate 
Fl o w  c yt o metr y
I m m u ne cell p he n ot y pi n g
W h ole bl o o d 
Fl o w  C yt o metr y 
B M as pirate 
Fl o w  C yt o metr y 
B M bi o ps y 
I H C
R N A pr ofili n g
B M as pirate a n d/ or 
bi o ps y ( p ossi ble)
R N A Se q ue nci n g
T- cell re pert oire a nal ysis
W h ole bl o o d 
D N A Se q ue nci n g 
B M as pirate a n d/ or 
Bi o ps y ( p ossi ble)
D N A Se q ue nci n g
A b bre viati o ns: B C M A = B -cell mat urati o n a nti ge n; B M = b o ne marr o w ; de o x yri b o n ucleic aci d = D N A; 
T, B, a n d N K cells = T B N K 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 5
7. 5. 1. B o ne M arr o w Bi o m ar kers
Patie nts will be re q uire d t o pr o vi de b o ne marr o w bi o ps y  a n d as pirate sa m ples f or bi o mar ker 
a nal ys is at ti mes s pecifie d i n t he S C H E D U L E O F A C TI VI TI E S (see als o Secti o n 7. 2. 2 B o ne 
Marr o w E val uati o n ). 
W he n b o ne marr o w as pirate a n d bi o psy sa m ples are ta ke n f or disease 
res p o nse e val uati o n, sa m ples f or bi o mar ker a nalys is will als o be ac q uire d. T his i ncl u des 
b o ne marr o w t a ke n f oll o wi n g a C R, s C R or f oll o wi n g disease pr o gressi o n .
A nal y ses will be c o n d ucte d at fl o w c yt o metr y a n d I H C refere nce la bs t o assess tar get 
e x pressi o n a n d e n u merati o n a n d p he n ot y pi n g of plas ma cells, i nfiltrati n g T- cell s u bsets a n d 
a d diti o nal i m m u ne cells.  F urt her I H C, i m m u n ofl u oresce nce or m ulti ple x i ma gi n g assa ys f or 
a d diti o nal i m m u ne cell p o p ulati o ns a n d/ or i m m u ne acti vati o n a n d re g ulati o n mar kers, a n d/ or 
e pi ge netic assa ys f or i m m u ne cell q ua ntificati o n ma y  be perf orme d t o assess a d diti o nal 
p har mac o d y n a mic effects, if bi o ps y materials s uffice.  T u m or tiss ue ma y als o be s u b mitte d t o 
R N A, T-cell rece pt or ( T C R ), a n d ot her m olec ular pr ofili n g of dr u g res p o nse b y n ucle oti de 
se q ue nci n g. 
I nstr ucti o ns f or sa m ple c ollecti o n, pr ocessi n g, st ora ge a n d s hi p me nt will be pr o vi de d i n t he 
la b orat or y ma n ual.
7. 5. 2. W h ole Bl o o d P h ar m ac o d y n a mic M ar kers
W h ole bl o o d sa m ples f or circ ulati n g T, B, N K l y m p h oc yte assa y ( T B N K), a n d T- cell
i m m u n o p he n ot ypi n g will be c ollecte d at ti mes s pecifie d i n t he S C H E D U L E O F 
A C TI VI TI E S of t his pr ot oc ol.  T he T B N K assa y  deter mi nes t he a bs ol ute c o u nts a n d 
perce nta ges f or T, B, N K l y m p h oc y te p o p ulati o ns as well as C D 4 + a n d C D 8 + T- cell s u bset 
rati os i n peri p heral bl o o d.  T-cell i m m u n o p he n ot y pi n g will use m ulti para meter fl o w 
c yt o metr y t o e val uate mar kers s uc h as pr oliferati o n a n d s ur vi val, acti vati o n, a n d e x ha usti o n 
i n C D 4 + a n d C D 8 + naï ve a n d me m or y T-cell s u bsets.  
W h ole bl o o d sa m ples f or e x pl orat or y  m olec ular a nal ysis a n d bi o ba n ki n g will be c ollecte d at 
ti mes s pecifie d i n t he S C H E D U L E O F A C TI VI TI E S of t his pr ot oc ol.
I nstr ucti o ns f or sa m ple c ollecti o n, pr ocessi n g, st ora ge a n d s hi p me nt will be pr o vi de d i n t he 
la b orat or y ma n ual.
Sa m ples ma y  be use d f or fl o w assa y de vel o p me nt.  Sa m ples c ollecte d f or t his p ur p ose will be 
retai ne d i n acc or da nce t o l ocal re g ulati o ns a n d if n ot use d wit hi n t his ti mefra me, will be 
destr o y e d.
7. 5. 3. S hi p me nt of P h ar m ac o d y n a mic S a m ples
T he s hi p me nt a d dress a n d assa y  la b c o ntact i nf or mati o n are pr o vi de d i n t he la b orat or y 
ma n ual .
7. 5. 4. C yt o ki ne Assess me nts
Sa m ples will be c ollecte d f or ce ntral e val uati o n of c y t o ki nes at t he ti me p oi nts s pecifie d i n 
t he S C H E D U L E O F A C TI VI TI E S a n d Secti o n 7. 1. 3 .  I nstr ucti o ns f or sa m ple c ollecti o n, 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 6
pr ocessi n g, st ora ge a n d s hi p me nt will be pr o vi de d i n t he st u d y  ma n ual.  All sa m ples will be 
a nal yz e d ce ntrall y.  If C R S is s us pected a nd c oi nci des wit h a da y  p har mac o d yna mic sa m ples 
are n ot c ollecte d per t he Sc he d ule of Acti vities , a n a d h oc c y t o ki ne sa m ple s h o ul d be 
c ollecte d (see Secti o n 7. 1. 3 La b orat or y Safet y Assess me nts ).  I n a d diti o n, sh o ul d t he site 
re q uire c yt o ki ne i nf or matio n f or patie nt ma na ge me nt, t he site will ha ve t he o pti o n of 
c ollecti n g a n a d diti o nal sa m ple f or l ocal a nal ys is. 
7. 5. 5. S ol u ble B C M A Assess me nts
W h ole bl o o d sa m ples (a p pr o xi matel y  3 m L ) t o pr o vi de a p pr o xi matel y 1 m L plas ma f or 
s ol u ble B C M A assess me nt will be c ollecte d at t he ti mes s pecifie d i n t he S C H E D U L E O F 
A C TI VI TI E S of t his pr ot oc ol.   A n a d diti o nal s ol u ble B C M A/ ot her fact or sa m ple s h o ul d als o 
be ta ke n if C R S is s us pecte d, a n d a sa m ple is n ot alrea d y  sc he d ule d t o be ta ke n (eg, fr o m 
C ycle 3 o n war ds).   I nstr ucti o ns f or sa m ple c ollecti o n, pr ocessi n g, st ora ge a n d s hi p me nt will 
be pr o vi de d i n t he st u d y ma n ual.
S ol u ble B C M A le vels will be deter mi ne d b y a mass s pectr o metr y assa y, a n d sa m ples ma y b e 
use d f or f urt her e val uati o n of t he bi oa nal yt ical met h o d, as well as f or ot her i nter nal 
e x pl orat or y p ur p oses i ncl u di n g deter mi nati o n of relate d s ol u ble fact ors s uc h as A 
Pr oliferati o n -In d uci n g L i ga n d (A P RI L ).  T hese data will n ot be i ncl u de d i n t he cli nic al 
re p ort.  Sa m ples c ollecte d f or t his p ur p ose will be retai ne d i n acc or da nce t o l ocal re g ulati o ns 
a n d if n ot use d wit hi n t his ti mefra me, will be destr o y e d.
7. 6. P h ar m ac o ge n o mics
7. 6. 1. Ge n ot y pi n g A n al ysis 
Bl o o d sa m ples f or ge n ot y pi n g m a y  be e xa mi ne d t o assess t he i m pact of allelic varia nts of 
ge nes pr o p ose d t o i m pact res p o nse t o P F -0 6 8 6 3 1 3 5, as well as mec ha nis ms of acti o n a n d/ or 
resista nce.  A d diti o nall y, t hese sa m ples ma y als o be use d f or retr os pecti ve e val uati o n of 
a d diti o nal ge netic varia nts ass ociate d wit h variati o n i n P K or t o e x pl ore A Es s h o ul d t hese be 
o bser ve d.  Sa m ples will be retai ne d f or a peri o d of u p t o 3 ye ars after re g ulat or y a p pr o val.
A 4 -m L  bl o o d sa m ple will be c ollecte d fr o m eac h patie nt i nt o a plastic di p otassi u m e detic
aci d et h yl e ne dia mi netetraacetic aci d ( K 2E D T A) t u be at ti mes s pecifie d i n t he S C H E D U L E 
O F A C TI VI TI E S secti o n of t he pr ot oc ol. 
Sa m ples will be a nal y ze d usi n g a n o n- c haracterize d assa y ( n o n-vali date d ).  T hese data will 
be use d f or i nt er nal e x pl orat or y p ur p oses a n d will n ot be i ncl u de d i n t he C S R .
T he p har mac o ge n o mic ( P G x ) sa m ples m ust be pr ocesse d a n d s hi p pe d as i n dicate d i n t he 
i nstr ucti o ns pr o vi de d t o t he i n vesti gat or site t o mai ntai n sa m ple i nte grit y. A n y  de viati o ns 
fr o m t he P G x processi n g ste ps, i ncl u di n g a n y acti o ns ta ke n, m ust be d oc u me nte d a n d 
re p orte d t o t he s p o ns or. O n a case -b y -case basis, t he s p o ns or ma y  ma ke a deter mi nati o n as 
t o w het her sa m ple i nte grit y has bee n c o m pr o mise d. A n y  sa m ple dee me d o utsi de of 
esta blis he d sta bi lit y, or of q uesti o na ble i nte grity, will be c o nsi dere d a pr ot oc ol de viati o n.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 7
7. 6. 2. Ge netic A n al ysis 
B o ne marr o w as pirates ta ke n bef ore t he start of st u d y treat me nt will be e val uate d at l ocal la b 
f or t( 4; 1 4)( p 1 6; q 3 2), t( 1 4; 1 6)( q 3 2; q 2 3), 1 7 p 1 3 deleti o ns, t( 1 1; 1 4)( q 1 3; q 3 2), c hr o m os o me 
1 3 deleti o n, pl oi d y  cate g or y, a n d c hr o m os o me 1 a b n or malities . If s o me of t hese c yt o ge netic 
assess me nts ca n n ot be d o ne, site s h o ul d pr o vi de patie nt’s m ost rece nt c y t o ge netic testi n g 
res ults a n d e nter i nt o e C R F. Sa m ple s ma y  be ta ke n u p t o 7 d a y s bef ore t he start of st u d y 
treat me nt.
7. 7. B a n ke d Bi os peci me ns 
Ba n ke d b i os peci me ns will be c ollecte d fr o m patie nts f or e x pl orat or y researc h relati n g t o t he 
dr u g res p o nse a n d M M .  T hese c ollecti o ns are n ot t ypicall y ass ociate d wit h a pla n ne d 
assess me nt descri be d i n t he pr ot oc ol.  T he y  will be ha n dle d i n a ma n ner t hat pr otects eac h 
patie nt’s pri vac y  a n d c o nfi de ntialit y.  Ba n ke d b i os peci me ns will be assi g ne d t he patie nt’s 
st u d y i de ntificati o n c o de (I D) at t he site.  T he data ge nerated fr o m t hese b a n ke d 
b i os peci me ns will als o be i n de xe d b y t his I D.  Bi os peci me ns will be ke pt u ntil destr ucti o n i n 
facilities wit h access li mite d t o a ut h orize d pers o n nel, a n d bi os peci me n-deri ve d data will be 
st ore d o n pass w or d-pr otecte d c o m p uter s ys te ms.  The ke y  bet wee n t he patie nt’s I D a n d t he 
patie nt’s direct pers o nall y  i de ntif yi n g i nf or mati o n (e g, na me, a d dress) will be hel d at t he 
st u d y site.  Bi os peci me ns will be use d o nl y f or t he p ur p oses descri be d i n t he pr ot oc ol a n d 
i nf or me d c o nse nt d oc u me nt; a n y other uses re q uire a d diti o nal et hical a p pr o val.  U nless a 
ti me li mitati o n is re q uire d b y l ocal re g ulati o ns or et hical re q uire me nts, bi os peci me ns will be 
st ore d f or ma ny ye ars ( n o ti me li mit) t o all o w f or researc h i n t he f ut ure, i ncl u di n g researc h 
c o n d ucte d d uri n g t he le n gt h y dr u g -de vel o p me nt pr ocess a n d als o p ost -mar keti n g researc h.  
Patie nts ma y  wit h dra w t heir c o nse nt f or t he use of t heir ba n ke d b i os peci me ns at a n y ti me b y 
ma ki n g a re q uest t o t he i n vesti gat or; i n t his case, a n y re mai ni n g bi os peci me ns will be
destr o ye d, b ut data alrea d y  ge nerate d fr o m t he bi os peci me ns will c o nti n ue t o be a vaila ble t o 
pr otect t he i nte grit y of e xisti n g a nal ys es. 
U nless pr o hi bite d b y  l ocal re g ulati o ns or et hics c o m mittee decisi o n, a 4- m L bl o o d ge n o mic 
b a n ke d b i os peci me n Pre p D 1 (di p ot assi u m e detic aci d [et h yle ne di a mi netetr a acetic aci d] 
[ K2E D T A] w h ole -bl o o d c ollecti o n o pti mize d f or D N A a n al ysis) will be c ollecte d at t he 
ti me s pecifie d i n t he S C H E D U L E O F A C TI VI TI E S secti o n of t he pr ot oc ol t o be retai ne d f or 
p ote ntial p har mac o ge n o mic/ ge n o mic/ bi o mar ker a nal ys es relate d t o dr u g res p o nse a n d M M .  
F or e xa m ple, p utati ve safet y  bi o mar kers, dr u g-meta b olizi n g e nz y me ge nes, dr u g -tra ns p ort 
pr otei n ge nes, or ge nes t h o u g ht t o be relate d t o t he mec ha nis m of dr u g acti o n ma y be 
e xa mi ne d.  T he pri mar y p ur p ose is t o e xa mi ne D N A; h o we ver, t he bi os peci me n ma y als o be 
use d t o st u d y  ot her m olec ules (e g, R N A, pr otei ns, a n d meta b olites).
T he b a n ke d b i os peci me ns will be c ollecte d fr o m all patie nts u nless pr o hi bite d b y l ocal 
re g ulati o ns or I R B/ E C decisi o n.
It is p ossi ble t hat t he use of t hese bi os peci me ns ma y res ult i n c o m merciall y via ble pr o d ucts.  
Patie nts will be a d vise d i n t he i nf or me d c o nse nt d oc u me nt t hat t he y  will n ot be c o m pe nsate d 
i n this e ve nt.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 8
7. 7. 1. A d diti o n al Rese arc h
U nless pr o hi bite d b y  l ocal re g ulati o ns or I R B/ E C decisi o n, patie nts will be as ke d t o i n dicate 
o n t he c o nse nt f or m w het her t he y will all o w b a n ke d b i os peci me ns t o als o be use d t o desi g n 
a n d c o n d uct researc h i n or der t o gai n a f urt her u n dersta n di n g of ot her diseases a n d t o 
a d va nce scie nce, i ncl u di n g de vel o p me nt of ot her me dici nes f or patie nts.
Patie nts nee d n ot pr o vi de a d diti o nal bi os peci me ns f or t he uses descri be d i n t his secti o n; t he 
bi os peci me ns s pecifie d i n t he B a n ke d B i os peci me ns Secti o n 7. 7 will be use d.  Patie nts ma y  
still partici pate i n t he st u d y if t he y elect n ot t o all o w t heir b a n ke d b i os peci me ns t o be use d 
f or t he a d diti o nal p ur p oses descri be d i n t his secti o n.
8. A D V E R S E E V E N T R E P O R TI N G
8. 1. Re q uire me nts
T he ta ble bel o w s u m marizes t he re q uire me nts f or rec or di n g safet y e ve nts o n t he C R F a n d f or 
re p orti n g safet y e ve nts o n t he Cli nical Trial ( C T) Seri o us A d verse E ve nt ( S A E) Re p ort F or m 
t o Pfizer Safet y.  T hese re q uire me nts are deli neate d f or 3 t ypes of e ve nts: 1) S A Es; 
2) n o n- seri o us a d verse eve nts ( A Es); a n d 3) e x p os ure t o t he i n vesti gati o nal pr o d uct u n der 
st u d y d uri n g pre g na nc y or breastfee di n g, a n d occ u pati o nal e x p os ure. 
S afet y E ve nt
Rec or de d o n t he C R F
Re p orte d o n t he C T 
S A E Re p ort F or m t o 
Pfizer S afet y Wit hi n 
2 4 H o urs of A w are ness
S A E
All
All
N o n -seri o us A E
All
N o ne
E x p os ure t o t he 
i n vesti gati o nal pr o d uct u n der 
st u d y d uri n g pre g na nc y or 
breastfee di n g, a n d 
occ u pati o nal e x p os ure
All (re gar dless of w het her 
ass ociate d wit h a n A E), 
e xce pt occ u p ati o n al 
e x p os ure
E x p os ure d uri n g 
pre g na nc y , e x p os ure via 
breastfee di n g, 
occ u pati o nal e x p os ure 
(re gar dless of w het her 
ass ociate d wit h a n A E)
All o bser ve d or v ol u nteere d e ve nts re gar dless of tre at me nt gr o u p or s us pecte d ca usal 
relati o ns hi p t o t he i n vesti gati o nal pr o d uct(s) will be re p orte d as descri be d i n t he f oll o wi n g 
para gra p hs.
E ve nts liste d i n t he ta ble a b o ve t hat re q uire re p orti n g t o Pfizer Safet y o n t he cli nical trial 
seri o us a d verse e ve nt (C T S A E ) Re p ort F or m wit hi n 2 4 h o urs of a ware ness of t he e ve nt b y 
t he i n vesti gat or are t o be re p orte d re g ar dless of w het her t he e ve nt is deter mi ne d b y t he 
i n vesti g at or t o be rel ate d t o a n i n vesti g ati o n al pr o d uct u n der st u d y.  In partic ular, if t he 
S A E is f atal or life-t hreate ni n g, n otificati o n t o Pfizer Safety m ust be ma de i m me diatel y, 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 9
irres pecti ve of t he e xte nt of a vaila ble e ve nt i nf or mati o n.  T his ti me fra me als o a p plies t o 
a d diti o nal ne w (f oll o w-u p) i nf or mati o n o n pre vi o usl y  f or war de d re p orts.  I n t he rare sit uati o n 
t hat t he i n vesti gat or d oes n ot bec o me i m me diately a ware of t he occ urre nce of a n e ve nt, t he 
i n vesti gat or m ust re p ort t he e ve nt wit hi n 2 4 h o urs after lear ni n g of it a n d d oc u me nt t he ti me 
of his/ her first a ware ness of t he e ve nt.
F or eac h e ve nt, t he i n vesti gat or m ust p urs ue a n d o btai n a de q uate i nf or mati o n b ot h t o 
deter mi ne t he o utc o me a n d t o assess w het her it meets t he criteria f or classificati o n as a n S A E 
(see t he Seri o us A d verse E ve nts Secti o n 8. 2. 3 bel o w).  I n a d diti o n, t he i n vesti gat or ma y  be 
re q ueste d by Pfizer Safet y t o o btai n s pecific f oll o w -u p i nf or mati o n i n a n e x pe dite d fas hi o n.  
T his i nf or mati o n is m ore detaile d t ha n t hat rec or de d o n t he C R F .  I n ge neral, t his will i ncl u de 
a descri pti o n of t he e ve nt i n s ufficie nt detail t o all o w f or a c o m plete me dical assess me nt of 
t he case a n d i n de pe n de nt deter mi nati o n of p ossi ble ca usalit y.  A n y i nf or mati o n rele va nt t o 
t he e ve nt, s uc h as c o nc o mita nt me dicati o ns a n d ill nesses, m ust be pr o vi de d.  In t he case of a 
patie nt deat h, a s u m mar y of a vaila ble a ut o ps y fi n di n gs m ust be s u b mitte d as s o o n as p ossi ble 
t o Pfizer Safet y .  A ny perti ne nt a d diti o nal i nf or mati o n m ust be re p orte d o n t he C T S A E 
Re p ort F or m; a d diti o nal s o urce d oc u me nts (e g, me dical rec or ds, C R F, la b orat or y  data) are t o 
be se nt t o Pfizer Safet y O N L Y u p o n re q uest.
As part of o n g oi n g safet y re vie ws c o n d ucte d b y  t he s p o ns or, a n y n o n-seri o us A E t hat is 
deter mi ne d b y t he s p o ns or t o be seri o us will be re p orte d b y t he s p o ns or as a n S A E.  T o assist 
i n t he deter mi nati o n of case seri o us ness, f urt her i nf or mati o n ma y be re q ueste d fr o m t he 
i n vesti gat or t o pr o vi de clarit y a n d u n dersta n di n g of t he e ve nt i n t he c o nte xt of t he cli nical 
st u d y.
8. 1. 1. A d diti o n al Det ails O n Rec or di n g A d verse E ve nts o n t he C R F
All e ve nts detaile d i n t he ta ble a b o ve will be rec or de d o n t he A E pa ge(s) of t he C R F .  It 
s h o ul d be n ote d t hat t he C T S A E Re p ort F or m f or re p orti n g of S A E i nf or mati o n is n ot t he 
sa me as t he A E pa ge of t he C R F.  W he n t he sa me data are c ollecte d, t he f or ms m ust be 
c o m plete d i n a c o nsiste nt ma n ner.   A Es s h o ul d be rec or de d usi n g c o ncise me dic al 
ter mi n ol o g y a n d t he sa me A E ter m s h o ul d be use d o n b ot h t he C R F a n d t he C T S A E Re p ort 
F or m f or re p orti n g of S A E i nf or mati o n.
8. 1. 2. Eliciti n g A d verse E ve nt I nf or m ati o n
T he i n vesti gat or is t o rec or d o n t he C R F all directl y  o bser ve d A Es a n d all A Es s p o nta ne o usl y
re p orte d by t he st u d y patie nt.  I n a d diti o n, eac h st u d y  patie nt will be q uesti o ne d a b o ut t he 
occ urre nce of A Es i n a n o n -lea di n g ma n ner.
8. 1. 3. Wit h dr a w al Fr o m t he St u d y D ue t o A d verse E ve nts 
S ee als o t he Patie nt Wit h dra wal
Secti o n 6. 6 .
Wit h dra wal d ue t o A Es s h o ul d be disti n g uis he d fr o m wit h dra wal d ue t o ot her ca uses, 
acc or di n g t o t he defi niti o n of A E n ote d bel o w, a n d rec or de d o n t he C R F. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 0
W he n a patie nt wit h dra ws fr o m t he st u d y  beca use of a n S A E, t he S A E m ust be rec or de d o n 
t he C R F a n d re p orte d, as a p pr o priate, o n t he C T S A E Re p ort F or m, i n acc or da nce wit h t he 
Re q uire me nts secti o n a b o ve.
8. 1. 4. Ti me Peri o d f or C ollecti n g A E/ S A E I nf or m ati o n
T he ti me peri o d f or acti vel y  eliciti n g a n d c ollecti n g A Es a n d S A Es (“acti ve c ollecti o n 
peri o d”) f or eac h patie nt be gi ns fr o m t he ti me t he patie nt pr o vi des i nf or me d c o nse nt, w hic h 
is o btai ne d bef ore t he patie nt’s partici pati o n i n t he st u d y (ie, bef ore u n der g oi n g a ny 
st u d y-relate d pr oce d ure a n d/ or recei vi n g i n vesti gati o nal pr o d uct), t hr o u g h a n d i ncl u di n g a 
mi ni m u m of 9 0 cale n dar da ys after t he last a d mi nistrati o n of P F - 0 6 8 6 3 1 3 5.  If t he 1-m o nt h 
f oll o w u p visit is c o m plete d bef ore t he 6 0 d a y  late t o xicit y e val uati o n peri o d is c o m plete d, 
the A E / S A E c ollecti o n peri o d will be e xte n de d u ntil t he late t o xicit y e val uati o n is c o m plete d.
F or patie nts w h o are scree n fail ures, t he acti ve c ollecti o n peri o d e n ds w he n scree n fail ure 
stat us is deter mi ne d.
8. 1. 4. 1. Re p orti n g S A Es t o Pfizer S afet y
All S A Es occ urri n g i n a patie nt d uri n g t he acti ve c ollecti o n peri o d are re p orte d t o Pfizer 
Safet y  o n t he C T S A E Re p ort F or m.
S A Es occ urri n g i n a patie nt after t he acti ve c ollecti o n peri o d has e n de d are re p orte d t o Pfizer 
Safet y  if t he i n vesti gat or bec o mes a ware of t he m; at a mi ni m u m, all S A Es t hat t he 
i n vesti gat or belie ves ha ve at least a reas o na ble p ossi bilit y of bei n g relate d t o i n vesti gati o nal 
pr o d uct m ust be re p orte d t o Pfizer Safet y .
F oll o w u p b y  t he i n vesti gat or c o nti n ues t hr o u g h o ut a n d after t he acti ve c ollecti o n peri o d a n d 
u ntil t he e ve nt or its se q uelae res ol ve or sta bilize at a le vel acce pta ble t o t he i n vesti gat or, a n d 
Pfizer c o nc u rs wit h t hat assess me nt.
If a patie nt be gi ns a ne w a ntica ncer t hera p y, S A Es occ urri n g d uri n g t he a b o ve-i n dicate d 
acti ve c ollecti o n peri o d m ust still be re p orte d t o Pfizer Safet y  irres pecti ve of a n y i nter ve ni n g 
treat me nt.
8. 1. 4. 2. Rec or di n g N o n -seri o us A Es a n d S A Es o n t he C R F
All n o nseri o us A Es a n d S A Es occ urri n g i n a patie nt d uri n g t he acti ve c ollecti o n peri o d, 
w hic h be gi ns after o btai ni n g i nf or me d c o nse nt as descri be d i n Secti o n 8. 1. 4 , will be rec or de d 
o n t he A E secti o n of t he C R F. A n y  si g ns a n d sy m pt o ms e ntirel y  d ue t o C R S (e g, fe ver, 
h y p o xia, h y p ote nsi o n) s h o ul d be rec or de d wit hi n t he C R S assess me nt C R F . A si n gle ter m of 
C y t o ki ne release s yn dr o me gra de d b y m o difie d Lee et al 2 0 1 4 criteria 2 s h o ul d t he n be 
rec or de d i n t he A E C R F. A n y  si g ns a n d sy m pt o ms e ntirel y  d ue t o I C A N S (e g, c o nf usi o n, 
seiz ure) s h o ul d be rec or de d wit hi n t he IC A N S assess me nt C R F. A si n gle ter m of I m m u ne 
cell- ass ociate d ne ur ot o xicit y gra de d by A S T C T criteria 3 s h o ul d t he n be rec or de d i n t he A E 
C R F. I njecti o n site assess me nts c o ntai ni n g A Es s h o ul d ha ve t he ter m of I njecti o n site 
reacti o n rec or de d wit h C T C A E 4. 0 3 gra di n g i n t he A E C R F.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 1
F oll o w -u p b y  t he i n vesti gat or ma y be re q uire d u ntil t he e ve nt or its se q uelae res ol ve or 
sta bilize at a le vel acce ptable t o t he i n vesti gat or, a n d Pfizer c o nc urs wit h t hat assess me nt.
If a patie nt be gi ns a ne w a ntica ncer t hera py, t he rec or di n g peri o d f or n o n -seri o us A Es e n ds at 
t he ti me t he ne w treat me nt is starte d; h o we ver, S A Es m ust c o nti n ue t o be rec or de d o n t he 
C R F d u ri n g t he a b o ve -i n dicate d acti ve c ollecti o n peri o d.
8. 1. 5. C a us alit y Assess me nt
T he i n vesti gat or’s assess me nt of ca usalit y m ust be pr o vi de d f or all A Es (seri o us a n d 
n o n-seri o us); t he i n vesti gat or m ust rec or d t he ca usal relati o ns hi p o n t he C R F, a n d re p ort s uc h 
a n assess me nt i n acc or da nce wit h t he S A E re p orti n g re q uire me nts, if a p plica ble.  A n 
i n vesti gat or’s ca usality assess me nt is t he deter mi nati o n of w het her t here e xists a reas o na ble 
p ossi bilit y  t hat t he i n vesti gati o nal pr o d uct ca use d or c o ntri b ute d t o a n A E; ge nerally t he facts 
(e vi de nce) or ar g u me nts t o s u g gest a ca usal relati o ns hi p s h o ul d be pr o vi de d.  If t he 
i n vesti gat or d oes n ot k n o w w het her or n ot t he i n vesti gati o nal pr o d uct ca use d t he e ve nt, t he n 
t he e ve nt will be ha n dle d as “relate d t o i n vesti gati o nal pr o d uct” f or re p orti n g p ur p oses, as 
defi ne d b y t he s p o ns or.  If t he i n vesti gat or's ca usalit y assess me nt is “ u n k n o w n b ut n ot 
relate d” t o i n vesti gati o nal pr o d uct, t his s h o ul d be clearly d oc u me nte d o n st u d y  rec or ds. 
I n a d diti o n, if t he i n vesti gat or deter mi nes t hat a n S A E is ass ociate d wit h st u d y pr oce d ures, 
t he i n vesti gat or m ust rec or d t his ca usal relati o ns hi p i n t he s o urce d oc u me nts a n d C R F, a n d 
re p ort s uc h a n assess me nt i n t he de dicate d secti o n of t he C T S A E Re p ort F or m a n d i n 
acc or da nce wit h t he S A E re p orti n g re q uire me nts.
8. 1. 6. S p o ns or’s Re p orti n g Re q uire me nts t o Re g ul at or y A ut h orities
A E re p orti n g, i ncl u di n g s us pecte d u ne x pecte d seri o us a d verse reacti o ns, will be carrie d o ut 
i n acc or da nce wit h a p plica ble l ocal re g ulati o ns.
8. 2. Defi niti o ns
8. 2. 1. A d verse E ve nts
A n A E is a n y u nt o war d me dical occ urre nce i n a st u d y  patie nt a d mi nistere d a pr o d uct or 
me dical de vice; t he e ve nt nee d n ot necessaril y ha ve a ca usal relati o ns hi p wit h t he treat me nt 
or usa ge.  E xa m ples of A Es i ncl u de, b ut are n ot li mite d t o: 

A b n or mal test fi n di n gs;

Cli n icall y si g nifica nt si g ns a n d s ym pt o ms;

C ha n ges i n p h ys ical e xa mi nati o n fi n di n gs;

H y perse nsiti vit y ;

Dr u g a b use;

Dr u g de pe n de nc y .
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 2
A d diti o nall y , A Es ma y i ncl u de si g ns a n d sy m pt o ms res ulti n g fr o m:

Dr u g o ver d ose;

Dr u g wit h dra wal;

Dr u g mis use; 

Dr u g i nteracti o ns;

E xtra vasati o n;

E x p os ure d uri n g pre g na nc y  ( E D P);

E x p os ure via breastfee di n g;

Me dicati o n err or;

Occ u pati o nal e x p os ure.
W orse ni n g of si g ns a n d s y m pt o ms of t he mali g na nc y  u n der st u d y s h o ul d be rec or de d as A Es 
i n t he a p pr o priate secti o n of t he C R F.  Disease pr o gressi o n assesse d by meas ure me nt of 
mali g na nt lesi o ns o n ra di o gra p hs or ot her met h o ds s h o ul d n ot be re p orte d as A Es.
8. 2. 2. A b n or m al Test Fi n di n gs
A b n or mal o bjecti ve test fi n di n gs s h o ul d be rec or de d as A Es w he n a n y of t he f oll o wi n g 
c o n diti o ns are met: 

Test res ult is ass ociate d wit h acc o m pa nyi n g s y m pt o ms; a n d/ or

Test res ult re q uires a d diti o nal dia g n ostic testi n g or me dical/s ur gical i nter ve nti o n; 
a n d/ or

Test res ult lea ds t o a c ha n ge i n st u d y d osi n g ( o utsi de of a n y pr ot oc ol -s pecifie d d ose 
a dj ust me nts) or disc o n ti n uati o n fr o m t he st u d y, si g nifica nt a d diti o nal c o nc o mita nt 
dr u g treat me nt, or ot her t hera p y;  a n d/ or

Test res ult is c o nsi dere d t o be a n A E b y t he i n vesti gat or or s p o ns or.
Merel y re peati n g a n a b n or mal test, i n t he a bse nce of a n y of t he a b o ve c o n diti o ns, d o es n ot 
c o nstit ute a n A E.  A n y a b n or mal test res ult t hat is deter mi ne d t o be a n err or d oes n ot re q uire 
rec or di n g as a n A E.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 3
8. 2. 3. Seri o us A d verse E ve nts
A seri o us a d verse e ve nt is a n y  u nt o war d me dical occ urre nce at a n y d ose t hat:

Res ults i n deat h;

Is life-t hreate ni n g (i m me diate ris k of deat h);

Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n;

Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y (s u bsta ntial disr u pti o n of t he 
a bilit y t o c o n d uct n or mal life f u ncti o ns);

Res ults i n c o n ge nital a n o mal y/ birt h defect.
Or t hat is c o nsi dere d t o be:

A n i m p orta nt me dical e ve nt.
Me dical a n d scie ntific j u d g me nt is e xercise d i n deter mi ni n g w het her a n e ve nt is a n i m p orta nt 
me dical e ve nt.  A n i m p orta nt me dical e ve nt ma y  n ot be i m me diatel y life-threate ni n g a n d/ or 
res ult i n deat h or h os pitalizati o n.  H o we ver, if it is deter mi ne d t hat t he e ve nt ma y je o par dize 
t he patie nt or ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her A E o utc o mes, t he 
i m p orta nt me dical e ve nt s h o ul d be re p orte d as seri o us.
E x a m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or 
aller gic br o nc h os pas m; bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n; 
or de vel o p me nt of dr u g de pe n de nc y  or dr u g a b use.
Pr o gressi o n of t he mali g na nc y  un der st u d y (i ncl u di n g si g ns a n d sy m pt o ms of pr o gressi o n) 
s h o ul d n ot be re p orte d as a n S A E u nless t he o utc o me is fatal wit hi n t he acti ve c ollecti o n
peri o d.  H os pitalizati o n d ue t o si g ns a n d s y m pt o ms of disease pr o gressi o n s h o ul d n ot be 
re p orte d as a n S A E.  If t he mali g na nc y has a fatal o utc o me d uri n g t he st u d y or wit hi n t he 
acti ve c ollecti o n peri o d, t he n t he e ve nt lea di n g t o deat h m ust be rec or de d as a n A E o n t he 
C R F, a n d as a n S A E wit h C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E) 
Gra de 5 (see t he Secti o n 8. 3 Se verit y  Assess me nt).
8. 2. 4. H os pit aliz ati o n
H os pitalizati o n is defi ne d as a n y i nitial a d missi o n (e ve n less t ha n 2 4 h o urs) i n a h os pital or 
e q ui vale nt healt hcare facilit y, or a n y pr ol o n gati o n of a n e xisti n g a d missi o n.  A d missi o n als o 
i ncl u des tra nsfer wit hi n t he h os pital t o a n ac ute/i nte nsi ve care u nit (e g, fr o m t he ps yc hiatric 
wi n g t o a me dical fl o or, me dical fl o or t o a c or o nar y  care u nit, or ne ur ol o gical fl o or t o a 
t u berc ul osis u nit).  A n e mer gen c y  r o o m visit d oes n ot necessaril y c o nstit ute a h os pitalizati o n; 
h o we ver, t he e ve nt lea di n g t o t he e mer ge nc y  r o o m visit is assesse d f or me dical i m p orta nce.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 4
H os pitalizati o n d oes n ot i ncl u de t he f oll o wi n g:

Re ha bilitati o n facilities;

H os pice facilities;

Res pite care (e g, care gi ver relief);

S kille d n ursi n g facilities;

N ursi n g h o mes;

Sa me -d a y  s ur geries (as o ut patie nt/sa me-d a y /a m b ulat or y pr oce d ures).
H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n t he a bse nce of a preci pitati n g cli nical 
A E is n ot i n it self a n S A E.  E xa m ples i ncl u de: 

A d missi o n f or treat me nt of a pree xisti n g c o n diti o n n ot ass ociate d wit h t he 
de vel o p me nt of a ne w A E or wit h a w orse ni n g of t he pree xisti n g c o n diti o n (e g, f or 
w or k u p of a persiste nt pretreat me nt la b orat or y  a b n or malit y);

S ocia l a d missi o n (e g, patie nt has n o place t o slee p);

A d mi nistrati ve a d missi o n (e g, f or ye arl y p h ys ical e xa mi nati o n);

Pr ot oc ol -s pecifie d a d missi o n d uri n g a st u dy (e g, f or a pr oce d ure re q uire d b y t he st u d y 
pr ot oc ol);

O pti o nal a d missi o n n ot ass ociate d wit h a prec i pitati n g cli nical A E (e g, f or electi ve 
c os metic s ur ger y);

H os pitalizati o n f or o bser vati o n wit h o ut a me dical A E;

Pre pla n ne d treat me nts or s ur gical pr oce d ures.  T hese s h o ul d be n ote d i n t he baseli ne 
d oc u me ntati o n f or t he e ntire pr ot oc ol a n d/ or f or t he i n di vi d ual patie nt;

A d missi o n e xcl usi vel y  f or t he a d mi nistrati o n of bl o o d pr o d ucts.
Dia g n ostic a n d t hera pe utic n o ni n vasi ve a n d i n vasi ve pr oce d ures, s uc h as s ur ger y , s h o ul d n ot 
be re p orte d as S A Es.  H o we ver, t he me dical c o n diti o n f or w hic h t he pr oce d ure was 
perf or me d s h o ul d be re p orte d if it meets t he defi niti o n of a n S A E.  F or e xa m ple, a n ac ute 
a p pe n dicitis t hat be gi ns d uri n g t he re p orti n g peri o d s h o ul d be re p orte d if t he S A E 
re q uire me nts are met, a n d t he res ulti n g a p pe n dect o m y s h o ul d be rec or de d as treat me nt of t he 
A E.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 5
8. 3. Se verit y Assess me nt
G R A D E
Cli nical Descri pti o n of Se verit y
0  
N o c ha n ge fr o m n or mal or refere nce ra n ge ( T his gra de is n ot i ncl u de d i n t he 
Versi o n 4. 0 3 C T C A E d oc u me nt b ut ma y  be use d i n certai n circ u msta nces.)
1
MI L D a d verse e ve nt
2
M O D E R A T E a d verse e ve nt
3
S E V E R E a d verse e ve nt
4
LI F E -T H R E A T E NI N G c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d
5
D E A T H R E L A T E D T O a d verse e ve nt
N ote t he disti ncti o n bet wee n t he se verit y a n d t he seri o us ness of a n A E.  A se vere e ve nt is n ot necessaril y 
a n S A E.  F or e xa m ple, a hea dac he ma y be se vere (i nterferes si g nifica ntl y wit h t he patie nt’s us ual f u ncti o n) 
b ut w o ul d n ot be classifie d as seri o us u n less it met o ne of t he criteria f or S A Es, liste d a b o ve.
8. 4. S peci al Sit u ati o ns
8. 4. 1. P ote nti al C ases of Dr u g -I n d uce d Li ver I nj ur y
H u ma ns e x p ose d t o a dr u g w h o s h o w n o si g n of li ver i nj ur y  (as deter mi ne d b y ele vati o ns i n 
tra nsa mi nases) are ter me d “t olerat ors,” w hile t h ose w h o s h o w tra nsie nt li ver i nj ur y, b ut a da pt 
are ter me d “a da pt ors.”  I n s o me patie nts, tra nsa mi nase ele vati o ns are a har bi n ger of a m ore 
seri o us p ote ntial o utc o me.  T hese patie nts fail t o a da pt a n d t heref ore are "s usce pti ble" t o 
pr o gressi ve a n d seri o u s li ver i nj ur y, c o m m o nl y referre d t o as dr u g-i n d uce d li ver i nj ur y 
( DI LI).  Patie nts w h o e x perie nce a tra nsa mi nase ele vati o n a b o ve 3 ti mes t he u p per li mit of 
n or mal ( × U L N) s h o ul d be m o nit ore d m ore fre q ue ntl y  t o deter mi ne if t he y are a n “a da pt or” 
or are “s usce pti ble.”
I n t he maj orit y of DI LI cases, ele vati o ns i n as partate a mi n otra nsferase ( A S T) a n d/ or ala ni ne 
a mi n otra nsferase ( A L T) prece de t otal bilir u bi n ( T Bili) ele vati o ns ( > 2 × U L N) b y  se veral 
da y s or wee ks.  T he i ncrease i n T Bili t ypicall y occ urs w hile A S T/ A L T is/are still ele vate d 
a b o ve 3 × U L N (ie, A S T/ A L T a n d T Bili val ues will be ele vate d wit hi n t he sa me la b sa m ple).  
I n rare i nsta nces, by t he ti me T Bili ele vati o ns are detecte d, A S T/ A L T val ues mi g ht ha ve 
decrease d.  T his occ urre nce is still re gar de d as a p ote ntial DI LI.  T heref ore, a b n or mal 
ele vati o ns i n eit her A S T O R A L T i n a d diti o n t o T Bili t hat meet t he criteria o utli ne d bel o w 
are c o nsi dere d p ote ntial DI LI (assesse d per H y ’s la w criteria) cases a n d s h o ul d al wa ys be 
c o nsi dere d i m p orta nt me dical e ve n ts, e ve n bef ore all ot her p ossi ble ca uses of li ver i nj ur y 
ha ve bee n e xcl u de d.
T he t hres h ol d of la b orat or y  a b n or malities f or a p ote ntial DI LI case de pe n ds o n t he patie nt’s 
i n di vi d ual baseli ne val ues a n d u n derlyi n g c o n diti o ns.  Patie nts w h o prese nt wit h t he 
f oll o wi n g la b orat or y a b n or malities s h o ul d be e val uate d f urt her as p ote ntial DI LI ( H y’s la w) 
cases t o defi niti vel y deter mi ne t he eti ol o g y of t he a b n or mal la b orat or y  val ues:

Patie nts wit h A S T/ A L T a n d T Bili baseli ne val ues wit hi n t he n or mal ra n ge w h o 
s u bse q uentl y  prese nt wit h A S T O R A LT val ues > 3 × U L N A N D a T Bili val ue 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 6
> 2 × U L N wit h n o e vi de nce of he m ol ys is a n d a n al kali ne p h os p hatase val ue 
< 2 × U L N or n ot a vaila ble;

F or patie nts wit h baseli ne A S T O R A L T O R T Bili val ues a b o ve t he U L N, t he 
f oll o wi n g t hres h ol d val ues are use d i n t he defi niti o n me nti o ne d a b o ve, as nee de d, 
de pe n di n g o n w hic h val ues are a b o ve t he U L N at baseli ne:

Pree xisti n g A S T or A L T baseli ne val ues a b o ve t he n or mal ra n ge: A S T or A L T 
val ues > 2 ti mes t he baseli ne val ues A N D > 3 × U L N; or > 8 × U L N ( w hic he ver is 
s maller).

Pree xisti n g val ues of T Bili a b o ve t he n or mal ra n ge: T Bili le vel i ncrease d fr o m 
baseli ne val ue b y a n a m o u nt of at least 1 × U L N o r if t he val ue reac hes 
> 3 × U L N ( w hic he ver is s maller).
Rises i n A S T/ A L T a n d T Bili se parate d b y m ore t ha n a fe w wee ks s h o ul d be assesse d 
i n di vi d uall y base d o n cli nical j u d g me nt; a n y case w here u ncertai nt y re mai ns as t o w het her it 
re prese nts a p ote ntial H y’s la w case s h o ul d be re vie we d wit h t he s p o ns or. 
T he patie nt s h o ul d ret ur n t o t he i n vesti gat or site a n d b e e val uate d as s o o n as p ossi ble, 
prefera bl y wit hi n 4 8 h o urs fr o m a ware ness of t he a b n or mal res ults.  T his e val uati o n s h o ul d 
i ncl u de la b orat or y tests, detaile d hist or y, a n d p h ysical assess me nt. 
I n a d diti o n t o re peati n g meas ure me nts of A S T a n d A LT a n d T Bili , la b orat or y tests s h o ul d 
i ncl u de al b u mi n, creati ne ki nase ( C K), direct a n d i n direct bilir u bi n, ga m ma-gl uta m yl  
tra nsferase ( G G T), pr ot hr o m bi n ti me ( P T)/i nter nati o nal n or malize d rati o (I N R), t otal bile 
aci ds, al kali ne p h os p hatase a n d aceta mi n o p he n dr u g a n d/ or pr otei n a d d uct le vels.  
C o nsi derati o n s h o ul d als o be gi ve n t o dra wi n g a se parate t u be of cl otte d bl o o d a n d a n 
a ntic oa g ulate d t u be of bl o o d f or f urt her testi n g, as nee de d, f or f urt her c o nte m p ora ne o us 
a nal ys es at t he ti me of t he rec o g nize d i nitial a b n or ma lities t o deter mi ne eti ol o g y.  A detaile d 
hist or y , i ncl u di n g rele va nt i nf or mati o n, s uc h as re vie w of et ha n ol, aceta mi n o p he n (eit her b y 
itself or as a c of or m ulate d pr o d uct i n prescri pti o n or o ver-t he-c o u nter me dicati o ns) , 
recreati o nal dr u g, s u p ple me nt ( her bal) use a n d c o ns u m pti o n, fa mil y hist or y, se x ual hist or y, 
tra vel hist or y, hist or y of c o ntact wit h a ja u n dice d pers o n, s ur ger y, bl o o d tra nsf usi o n, hist or y 
of li ver or aller gic disease, a n d p ote ntial occ u pati o nal e x p os ure t o c he micals, s h o ul d be 
c ollecte d.  F urt her testi n g f or ac ute he patitis A, B, C, D, a n d E i nfecti o n a n d li ver i ma gi n g 
(e g, biliar y tract) ma y be warra nte d. 
All cases de m o nstrate d o n re peat testi n g as meeti n g t he la b orat or y  criteria of A S T/ A LT a n d 
T Bili ele vati o n defi ne d a b o ve s h o ul d be c o nsi dere d p ote ntial DI LI ( H y ’s la w) cases if n o 
ot her reas o n f or t he li ver f u ncti o n tests (L F T ) a b n or malities has yet bee n f o u n d.  S uc h 
p ote nti al DI LI ( H y’s l a w) c ases are t o be re p orte d as S A Es, irres pecti ve of a v ail a bilit y 
of all t he res ults of t he i n vesti g a ti o ns perf or me d t o deter mi ne eti ol o g y of t he L F T 
a b n or m alities.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 7
A p ote ntial DI LI ( H y ’s la w) case bec o mes a c o nfir me d case o nly after all res ults of 
reas o na ble i n vesti gati o ns ha ve bee n recei ve d a n d ha ve e xcl u de d a n alter nati ve eti ol o g y.
8. 4. 2. E x p os ure t o t he I n vesti g ati o n al Pr o d uct D uri n g Pre g n a nc y or Bre astfee di n g, a n d 
Occ u p ati o n al E x p os ure
E x p os ure t o t he i n vesti gati o nal pr o d uct u n der st u d y  d uri n g pre g na nc y or breastfee di n g a n d 
occ u pati o nal e x p os ure are re p orta ble t o Pfizer Safet y  wit hi n 2 4 h o urs of i n vesti gat or 
a ware ness.
8. 4. 2. 1. E x p os ure D uri n g Pre g n a nc y ( E D P)
F or b ot h u na p pr o ve d/ u nlice nse d pr o d ucts a n d f or mar kete d pr o d ucts, a n E D P occ urs if:

A fe male bec o mes, or is f o u n d t o be, pre g na nt eit her w hile recei vi n g or ha vi n g bee n 
e x p ose d (e g, beca use of treat me nt or e n vir o n me ntal e x p os ure) t o t he i n vesti gati o nal 
pr o d uct; or t he fe male bec o mes or is f o u n d t o be pre g na nt after disc o nti n ui n g a n d/ or 
bei n g e x p ose d t o t he i n vesti gati o nal pr o d uct;

A n e xa m ple of e n vir o n me ntal e x p os ure w o ul d be a case i n v ol vi n g direct c o ntact 
wi t h a Pfizer pr o d uct i n a pre g na nt w o ma n (e g, a n urse re p orts t hat s he is pre g na nt 
a n d has bee n e x p ose d t o c he m ot hera pe utic pr o d ucts).

A male has bee n e x p ose d (e g, beca use of treat me nt or e n vir o n me ntal e x p os ure) t o t he 
i n vesti gati o nal pr o d uct pri or t o or aro u n d t he ti me of c o nce pti o n a n d/ or is e x p ose d 
d uri n g his part ner’s pre g na nc y .
If a patie nt or patie nt’s part ner bec o mes or is f o u n d t o be pre g na nt d uri n g t he patie nt’s 
treat me nt wit h t he i n vesti gati o nal pr o d uct, t he i n vesti gat or m ust re p ort t his i nf or mati on t o 
Pfizer Safet y  o n t he C T S A E Re p ort F or m a n d a n E D P s u p ple me ntal f or m, re gar dless of 
w het her a n S A E has occ urre d.  I n a d diti o n, t he i n vesti gat or m ust s u b mit i nf or mati o n 
re gar di n g e n vir o n me ntal e x p os ure t o a Pfizer pr o d uct i n a pre g na nt w o ma n (e g, a patie nt 
re p orts t hat s he is pre g na nt a n d has bee n e x p ose d t o a c yt ot o xic pr o d uct b y i n halati o n or 
s pilla ge) t o Pfizer Safet y usi n g t he E D P s u p ple me ntal f or m.  T his m ust be d o ne irres pecti ve 
of w het her a n A E has occ urre d a n d wit hi n 2 4 h o urs of a ware ness of t he e x p os ure.  T he 
i nf or mati o n s u b mitte d s h o ul d i ncl u de t he a ntici pate d date of deli ver y (see bel o w f or 
i nf or mati o n relate d t o ter mi nati o n of pre g na nc y).
F oll o w -u p is c o n d ucte d t o o btai n ge neral i nf or mati o n o n t he pre g na nc y  a n d its o utc o me f or 
all E D P re p orts wit h a n u n k n o w n o utc o me.  T he i n vesti gat or will f oll o w t he pre g na nc y  u ntil 
c o m pleti o n ( or u ntil pre g na nc y  ter mi nati o n) a n d n otif y Pfizer Safety of t he o utc o me as a 
f oll o w- u p t o t he i nitial E D P s u p ple me ntal f or m.  I n t he case of a li ve birt h, t he str uct ural 
i nte grity of t he ne o nate ca n be assesse d at t he ti me of birt h.  I n t he e ve nt of a ter mi nati o n, t he 
reas o n(s) f or ter mi nati o n s h o ul d be s pecifie d a n d, if cli nicall y p ossi ble, t he str uct ural 
i nte grity of t he ter mi nate d fet us s h o ul d be assesse d b y gr oss vis ual i ns pecti o n ( u nless 
pre -pr oce d ure test fi n di n gs are c o ncl usi ve f or a c o n ge nital a n o mal y a n d t he fi n di n gs are 
re p orte d).
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 8
If t he o utc o me of t he pre g na nc y meets t he criteria f or a n S A E (ie, ect o pic pre g na nc y, 
s p o nta ne o us a b orti o n, i ntra uteri ne fetal de mise, ne o natal deat h, or c o n ge nital a n o maly [i n a 
li ve-b or n ba b y, a ter mi nate d fet us, a n i ntra uteri ne fetal de mise, or a ne o natal deat h]), t he 
i n vesti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g S A Es.
A d diti o nal i nf or mati o n a b o ut pre g na nc y  o utc o mes t hat are re p orte d t o Pfizer Safet y as S A Es 
f oll o ws: 

S p o nta ne o us a b orti o n i ncl u des miscarria ge a n d misse d a b orti o n;

Ne o natal deat hs t hat occ ur wit hi n 1 m o nt h of birt h s h o ul d be re p orte d, wit h o ut re gar d 
t o ca usalit y, as S A Es.  I n a d diti o n, i nfa nt deat hs after 1 m o nt h s h o ul d be re p orte d as 
S A Es w he n t he i n vesti gat or assesses t he i nfa nt deat h as relate d or p ossi bl y  relate d t o 
e x p os ure t o t he i n vesti gati o nal pr o d uct. 
A d diti o nal i nf or mati o n re gar di n g t he E D P ma y  be re q ueste d b y t he s p o ns or.  F urt her 
f oll o w-u p of birt h o utc o mes will be ha n dle d o n a case- b y -case basis (e g, f oll o w- u p o n 
preter m i nfa nts t o i de ntif y de vel o p me ntal dela y s).  In t he case of pater nal e x p os ure, t he 
i n vesti gat or will pr o vi de t he patie nt wit h t he Pre g na nt Part ner Release of I nf or mati o n F or m 
t o deli ver t o his part ner.  T he i n vesti gat or m ust d oc u me nt i n t he s o urce d oc u me nts t hat t he 
patie nt was gi ve n t he Pre g na nt Part ner Release of I nf or mati o n F or m t o pr o vi de t o his part ner.
8. 4. 2. 2. E x p os ure D uri n g Bre astfee di n g
Sce nar i os of e x p os ure d uri n g breastfee di n g m ust be re p orte d, irres pecti ve of t he prese nce of 
a n ass ociate d S A E, t o Pfizer Safet y wit hi n 2 4 h o urs of t he i n vesti gat or’s a ware ness, usi n g t he 
C T S A E Re p ort F or m.  A n e x p os ure d uri n g breastfee di n g re p ort is n ot create d w he n a Pfizer 
dr u g s pecificall y  a p pr o ve d f or use i n breastfee di n g w o me n (e g, vita mi ns) is a d mi nistere d i n 
acc or d wit h a ut h orize d use.  H o we ver, if t he i nfa nt e x perie nces a n S A E ass ociate d wit h s uc h 
a dr u g’s a d mi nistrati o n, t he S A E is re p orte d t o get her wi t h t he e x p os ure d uri n g breastfee di n g.
8. 4. 2. 3. Occ u p ati o n al E x p os ure
A n occ u pati o nal e x p os ure occ urs w he n, d uri n g t he perf or ma nce of j o b d uties, a pers o n 
( w het her a healt hcare pr ofessi o nal or ot her wise) gets i n u n pla n ne d direct c o ntact wit h t he 
pr o d uct, w hic h ma y  or ma y n ot lea d t o t he occ urre nce of a n A E.
A n occ u pati o nal e x p os ure is re p orte d t o Pfizer Safet y  wit hi n 2 4 h o urs of t he i n vesti gat or’s 
a ware ness, usi n g t he C T S A E Re p ort F or m, re gar dless of w het her t here is a n ass ociate d 
S A E.  Si nce t he i nf or mati o n d oes n o t pertai n t o a patie nt e nr olle d i n t he st u d y, t he 
i nf or mati o n is n ot rec or de d o n a C R F; h o we ver, a c o p y of t he c o m plete d C T S A E Re p ort 
F or m is mai ntai ne d i n t he i n vesti gat or site file.
8. 4. 3. Me dic ati o n Err ors
Ot her e x p os ures t o t he i n vesti gati o nal pr o d uct u n der st u d y m a y occ ur i n cli nical trial setti n gs, 
s uc h as me dicati o n err ors .
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 9
S afet y E ve nt
Rec or de d o n t he C R F
Re p orte d o n t he C T 
S A E Re p ort F or m t o 
Pfizer S afet y Wit hi n 
2 4 H o urs of A w are ness
Me dicati o n err ors
All (re gar dless of w het her 
ass ociate d wit h a n A E)
O nl y  if ass ociate d wit h 
a n S A E
8. 4. 3. 1. Me dic ati o n Err ors
Me dicati o n err ors ma y  res ult fr o m t he a d mi nistrati o n or c o ns u m pti o n of t he i n vesti gati o nal 
pr o d uct b y t he wr o n g patie nt, or at t he wr o n g ti me, or at t he wr o n g d osa ge stre n gt h. 
Me dicati o n err ors i ncl u de :

Me dicati o n err ors i n v ol vi n g patie nt e x p os ure t o t he i n vesti gati o nal pr o d uct;

P ote ntial me dicati o n err ors or uses o utsi de of w hat is f oresee n i n t he pr ot oc ol t hat d o 
or d o n ot i n v ol ve t he partici pati n g patie nt.
S uc h me dicati o n err ors occ urri n g t o a st u d y pa tie nt are t o be ca pt ure d o n t he me dicati o n err or 
pa ge of t he C R F, w hic h is a s pecific versi o n of t he A E pa ge.
I n t he e ve nt of me dicati o n d osi n g err or, t he s p o ns or s h o ul d be n otifie d i m me diatel y.
W het her or n ot t he me dicati o n err or is acc o m pa nie d b y  a n A E, as deter mi ne d b y t he 
i n vesti gat or, t he me dicati o n err or is rec or de d o n t he me dicati o n err or pa ge of t he C R F a n d, if 
a p plica ble, a n y ass ociate d A E(s), seri o us a n d n o n -seri o us, are rec or de d o n a n A E pa ge of t he 
C R F. 
Me dicati o n err ors s h o ul d be re p orte d t o Pfizer Safet y  wit hi n 2 4 h o urs o n a C T S A E Re p ort 
F or m o nl y w he n ass oci ate d wit h a n S A E .
8. 4. 4. Peri p her al ne ur o p at h y
Peri p heral ne ur o pat h y is a c o m m o n c o m plicati o n of M M a n d its treat me nt. Peri p heral 
ne ur o pat h y ca n be ca use d b y M M itself, eit her b y t he para ne o pl astic effects of t he 
m o n ocl o nal pr otei n ( p ol y ne ur o pat h y is a n esse ntial feat ure of P O E M S s y n dr o me) or i n t he 
f or m of ra dic ul o pat hy fr o m direct c o m pressi o n, a n d partic ularl y b y certai n t hera pies, 
i ncl u di n g I Mi Ds a n d pr oteas o me i n hi bit ors. S y m pt o ms are us ua ll y sy m metric a n d i ncl u de 
parest hesias, n u m b ness, b ur ni n g se nsati o n a n d m uscle wea k ness; t hese are ge nerall y mil d, 
b ut i n rare cases ca n be disa bli n g or e ve n life -t hreate ni n g. Treat me nt -e mer ge nt peri p heral 
ne ur o pat h y s y m pt o ms are us uall y  sy m metric, distal a n d pr o gressi ve. 4 9 Rece ntl y , peri p heral 
ne ur o pat h y has bee n descri be d f oll o wi n g a d mi nistrati o n of B C M A -directe d bis pecifi c T-cell 
e n ga gers. 5 0  
Peri p heral ne ur o pat h y (i ncl u di n g G B S) is c o nsi dere d a n i m p orta n t p ote ntial ris k of 
elra nata ma b.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 0
W or k -u p f or ne w or w orse ni n g Gra de ≥2 peri p heral ne ur o pat h y  s h o ul d i ncl u de a ne ur ol o g y 
c o ns ult, i ma gi n g (e g, M RI  of t he s pi ne), N C V/ E M Gs, a n d l u m bar p u nct ure t o assess C S F.  I n 
c o ns ultati o n wit h a ne ur ol o gist, a p pr o priate t hera p y f or peri p heral ne ur o pat h y (e g, ster oi ds 
a n d/ or I V i m m u n o gl o b uli n) s h o ul d be c o nsi dere d.
Cl osel y  m o nit or partici pa nts f or si g ns a n d sy m pt o ms of ne ur o pat h y  f oll o wi n g i nfecti o ns or 
f oll o wi n g t he a d mi nistrati o n of a ny vacci ne. 
F or rec o m me n de d d ose m o d ificati o ns f or peri p heral ne ur o pat h y (all ca usalit y), refer t o 
Ta ble 5 .
9. D A T A A N A L Y SI S/ S T A TI S TI C A L M E T H O D S
Detaile d met h o d ol o g y  f or s u m mar y a n d statistical a nalys es of t he data c ollecte d i n t his st u d y 
is o utli ne d here a n d f urt her detaile d i n a statistical a nalys is pla n ( S A P), w hic h will be 
mai ntai ne d b y  t he s p o ns or.  T he S A P ma y  m o dif y w hat is o utli ne d i n t he pr ot oc ol w here 
a p pr o priate; h o we ver, a n y maj or m o dificati o ns of t he pri mar y  e n d p oi nt defi niti o ns or t heir
a nal ys es will als o be reflecte d i n a pr ot oc ol a me n d me nt.
9. 1. A n al ysis S ets 
Treate d patie nt safety a nal ysis set:
T he safet y a nal ys is set i ncl u des all e nr olle d patie nts w h o recei ve at least o ne d ose of 
st u d y treat me nt.
F ull a nal ys is set:
T he f ull a nal ys is set i ncl u des all e nr olle d patie nts.
Per- pr ot oc ol a nal ysis set (e val ua ble f or M T D/ M A D):
T he per -pr ot oc ol a nal y sis set i ncl u des all e nr olle d patie nts w h o recei ve at least o ne 
d ose of st u d y  treat me nt a n d w h o d o n ot ha ve maj or treat me nt de viati o ns d uri n g D L T 
o bser vati o n peri o d.  Patie nts wit h maj or treat me nt de viati o ns d uri n g D L T o bser vati o n 
peri o d are n ot e val ua ble f or t he M T D / M A D assess me nt a n d will be re place d as nee de d 
t o per mit M T D/ M A D esti mati o n. 
P F - 0 6 8 6 3 1 3 5 P K a nal ys is sets:
T he P K para meter a nal ys is p o p ulati o n is defi ne d as all e nr olle d patie nts treate d w h o 
ha ve s ufficie nt i nf or mati o n t o esti mate at least 1 of t he P K para meters of i nterest.
T he P K c o nce ntrati o n p o p ulati o n is defi ne d as all e nr olle d patie nts w h o are t reate d 
wit h P F -0 6 8 6 3 1 3 5, ha ve n o pr ot oc ol de viati o ns affecti n g t he P K assess me nt, a n d ha ve 
at least 1 p ost-d ose c o nce ntrati o n meas ure me nt.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 1
Bi o mar ker a nal ys is set(s):
T he bi o mar ker a nal ys is set i ncl u des all e nr olle d patie nts wit h at least o ne of t he 
p har mac o d y n a mic/ bi o mar ker para meters e val uate d at pre- or p ost -d ose.
Ef ficac y mo difie d i nte nt t o treat (I T T) a nal ys is set:
I ncl u des all Patie nts w h o ha ve recei ve d at least o ne d ose of st u d y  treat me nt.
Efficac y  Per-Pr ot oc ol a nal y sis set:
T he efficac y  per -pr ot oc ol a nal ys is set i ncl u des all treate d patie nts w h o d o n ot ha ve 
maj or treat me nt de viati o ns a n d are e val ua ble at least f or t he first t u m or assess me nt. 
P F -0 6 8 6 3 1 3 5 I m m u n o ge nicit y a nal ysis set:
T he i m m u n o ge nicit y a nal y sis set is defi ne d as patie nts w h o recei ve at least 1 d ose of 
st u d y treat me nt a n d ha ve at least 1 A D A sa m ple c ollecte d.
9. 2. St atistic al Met h o ds a n d Pr o perties
9. 2. 1. St atistic al Met h o ds f or D ose Esc al ati o n/ De- Esc al ati o n
T his st u d y  has bee n desi g ne d t o esta blis h t he Ma xi m u m T olerate d D ose ( M T D)/ M A D.  T he 
M T D is
defi ne d as t he d ose t hat y iel ds a p pr o xi matel y 2 5% pr o ba bilit y  of D L T a n d c o nsi ders 
e q ui vale nt d oses t hat yi el d pr o ba bilit y of D L T i n t he i nter val ( E q ui vale nce I nter val) 2 0 % t o 
3 0 %.  T he 2 5 % tar get was c h ose n base d o n safet y c o nsi derati o ns a n d is c o nsi dere d 
a p pr o priate base d o n si m ulati o ns a n d e x pert i n p ut. 
T he m T PI  desi g n5 1 -5 3 uses a B a y esia n statistics fra me w or k a n d a beta/ bi n o mial hierarc hical 
m o del t o c o m p ute t he p osteri or pr o ba bilit y  of 3 d osi n g i nter vals t hat reflect t he relati ve 
differe nce bet wee n t he t o xicit y  rate of eac h d ose le vel t o t he tar get rate (tar get pr o ba bilit y 
[ p T] = 0. 2 5).  If t he t o xicit y rate of t he c urre ntly use d d ose le vel is far s maller t ha n p T, t he 
m T PI  will rec o m me n d escalati n g t he d ose le vel; if it is cl ose t o p T, t he m T PI will 
rec o m me n d c o nti n ui n g at t he c urre nt d ose; if it is far greater t ha n p T, t he m T PI will 
rec o m me n d de-escalati n g t he d ose le vel.  T hese r ules are c o nce pt uall y  si milar t o t h ose use d 
b y  t he 3 + 3 desi g n, e xce pt t he decisi o ns of a n m T PI desi g n are base d o n p osteri or 
pr o ba bilities calc ulate d u n der a c o here nt pr o ba bilit y  m o del. 
Bei n g a m o del -base d desi g n, m T PI a ut o maticall y a n d a p pr o priatel y tail ors d ose -escalati o n 
a n d de-escalati o n decisi o ns f or differe nt st u dies wit h differe nt t o xicit y  para meters.  M ore 
i m p orta ntl y, all t he d ose-escalati o n decisi o ns f or a gi ve n st u d y ca n be pre -calc ulate d u n der 
t he m T PI desi g n a n d prese nte d i n a t w o-w a y  ta ble (see A p pe n di x 8 ).  T h us, c o m pare d t o 
ot her a d va nce d m o del -base d desi g ns p u blis he d i n t he literat ure, t he m T PI desi g n is 
l o gisticall y less c o m plicate d a n d easier t o i m ple me nt. 
Decisi o n r ules are base d o n calc ulati n g u nit pr o ba bilit y  mass ( U P M) of 3 d osi n g i nter vals 
c orres p o n di n g t o u n der, pr o per, a n d o ver d osi n g i n ter ms of t o xicit y.  S pecificall y , t he 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 2
u n der d osi n g i nter val is defi ne d as ( 0; p T -e1), t he o ver-d osi n g i nter val ( p T +e 2, 1), a n d t he 
pr o per -d osi n g i nter val ( p T - e1, p T + e2), w here e1 a n d e 2 are s mall fracti o ns.  In st u d y , e1 a n d 
e 2 are selecte d as 0. 0 5, t h eref ore, t he tar get i nter val f or t he D L T rate is ( 0. 2 0, 0. 3 0 ).  T he 
2 5 % tar get, t he s y m metr y  of t he E q ui vale nce I nter val a n d its u p per li mit were c h ose n base d 
o n safet y c o nsi derati o ns.  T he pri or distri b uti o n of D L T is set as a beta ( 0. 5, 0. 5), a n d t he 
t hres h ol d pr o ba bilit y f or early ter mi nati o n a n d d ose e xcl usi o n is set t o 0. 9 5. 
T he 3 d osi n g i nter vals are ass ociate d wit h 3 differe nt d ose -escalati o n decisi o ns.  T he 
u n der d osi n g i nter val c orres p o n ds t o a d ose -escalati o n ( E), o ver d osi n g c orres p o n ds t o a d ose 
de-escalati o n ( D), a n d pr o per d osi n g c orres p o n ds t o re mai ni n g at t he c urre nt d ose ( R).  Gi ve n 
a d osi n g i nter val a n d a pr o ba bilit y  distri b uti o n, t he u nit pr o ba bilit y mass ( U P M) of t hat 
d osi n g i nter val is defi ne d as t he pr o ba bilit y of a patie nt bel o n gi n g t o t hat d osi n g i nter val 
di vi de d b y  t he le n gt h of t he d osi n g i nter val.  E ve n t h o u g h t he m T PI ma y select a n 
M T D / M A D wit h a n i nci de nce of D L Ts t hat is hi g her t ha n 3 0 %, d oses wit h a n i nci de nce of 
D L T > 3 0 % (e g, 4 o ut of 9) ca n n ot be declare d as t he M T D / M A D. 
If t he M T D is n ot reac he d, t he n t he M A D will be ma xi m u m d ose t hat is e val uate d i n t he 
st u d y.
9. 2. 2. St atistic al Met h o d f or Esti m ati n g t he M T D / M A D
As pre vi o usl y  descri be d, t he esti mate d M T D is t he hi g hest teste d d ose le vel wit h D LT rate
0. 3 0 i n at least 6 D L T -e val ua ble patie nts (ie, per pr ot oc ol a nal ys is set).  It is ass u me d t hat 
hi g her d oses res ult i n hi g her t o xicit y  rates.  B ut, d ue t o t he relati vely l o w n u m ber of patie nts 
t hat ma y be p ote ntiall y all ocate d t o a ny d ose, t his ass u m pti o n ma y  be vi olate d.
T o est i mate t he M T D/ M A D the st u d y  will c o nti n ue accr ui n g u ntil o ne of t he t hree st o p pi n g 
c o n diti o ns bel o w is tri g gere d:
1.
T he ma xi m u m sa m ple size has bee n ac hie ve d.
2.
M T D / M A D has bee n i de ntifie d wit h s ufficie nt acc urac y : 6 t o 1 6 patie nts ha ve bee n 
acc u m ulate d o n a dose t hat is c urre ntl y esti mate d t o be t he M T D / M A D; or
3.
All d oses e x pl ore d a p pear t o be o verl y t o xic a n d t he M T D / M A D ca n n ot be 
deter mi ne d. 
Cli nical j u d g me nt will be e xercise d i n ta ki n g f or war d d oses t o t he e x pa nsi o n c o h ort(s), i n 
case n o clear c h oice e xists bet wee n m ore t ha n 1 c o m peti n g M T D/ M A D.  T his decisi o n will 
be base d u p o n t he c o m bi nati o n of data relate d t o safet y, a nti -t u m or acti vit y, a n d cli nical 
j u d g me nt of t he i n vesti gat ors a n d t he s p o ns or.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 3
9. 3. S a m ple Size Deter mi n ati o n
D ue t o t he d y na mic nat ure of t he Ba yesia n all ocati o n pr oce d ure, t he sa m ple size of t he m T PI  
a p pr oac h ca n n ot be deter mi ne d i n a d va nce.  It is esti mate d a p pr o xi matel y 1 0 0 D L T e val ua ble 
patie nts ma y  be e nr olle d i n t he d ose escalati o n sta ge i n or der t o ha ve a relia ble a n d acc urate 
esti mate of t he M T D/ M A D a n d R P 2 D .  At least 6 a n d u p t o 16 patie nts s h o ul d be e nr olle d at 
a d ose le vel t hat is pre dicte d t o be t he M T D / M A D as per t he m T PI met h o d. H o we ver, 
a d diti o nal c o h orts bel o w M T D/ M A D ma y  als o be c o nsi dere d f or e nr oll me nt u p t o 
a p pr o xi matel y 6- 1 2 patie nts f or t he p ur p ose of c o nfir mi n g t he R P 2 D.
It is a ntici pate d t hat Parts 1 C, 1 D a n d 1 E will eac h ha ve a p pr o xi matel y 9-1 6 patie nts 
e nr olle d. H o we ver, t he t otal n u m ber of patie nts will de pe n d o n t he n u m ber of d ose le vels 
nee de d t o deter mi ne t he M T D / M A D f or eac h c o m bi nati o n a n d n u m ber of patie nts e val ua ble 
f or D L T at eac h c o h ort.
S u bse q ue nt patie nts will e nter a n e x pa nsi o n c o m p o ne nt, Part 2, ai me d at e val uati n g safet y 
a n d a nti -m y el o ma acti vit y of P F-0 6 8 6 3 1 3 5 at t he R P 2 D i n m o n ot hera p y (Part 2 A ) a n d i n 
c o m bi nati o n wit h le nali d o mi de , p o mali do mi de , or de xa met has o ne (Parts 2 C, 2 D a n d 2E,
c orres p o n di n gl y) .  A p pr o xi matel y 2 0 patie nts are e x pecte d t o be e nr olle d i nt o eac h of 
Parts 2 A, 2 C, 2 D a n d 2 E, b ut e nr oll me nt of patie nts ma y be disc o nti n ue d earlier if mi ni mal 
or n o a nti -t u m or acti vit y is o bser ve d.
C o h ort sa m ple size is deter mi ne d as f oll o ws.
Part 2 A - m o n ot hera p y : Ass u mi n g a n o n-i nf or mati ve pri or (ie, Jeffre y’s pri or) if 1 2 o ut of 
2 0 partici pa nts ha ve t u m or res p o nse, t his w o ul d pre dict a p osteri or pr o ba bilit y 
( Beta Bi n o mial) e q ual t o 0. 8 1 4 t hat tr ue res p o nse rate is n ot i nferior t o tar get res p o nse rate of 
5 0 % a n d a p oste ri or pr o ba bilit y e q ual t o 0. 0 0 3 t hat tr ue res p o nse rate is i nferi or t o 
be nc h mar k rat e of 3 0 %.  
Part s 2 C, 2 D , a n d 2 E – c o m bi nati o n wit h le nali d o mi de, p o mali d o mi de, a n d de xa met has o ne
res pecti vely : Ass u mi n g a n o n-i nf or mati ve pri or (ie, Jeffre y’s pri or) if 1 4 o ut of 2 0
partici pa nts ha ve t u m or res p o nse, t his w o ul d pre dict a p osteri or pr o ba bil it y ( Beta Bi n o mial) 
e q ual t o 0. 8 1 8 t hat tr ue res p o nse rate is n ot i nferi or t o t he tar get res p o nse rate of 6 0 % a n d a 
p oste ri or pr o ba bilit y e q ual t o 0. 0 0 0 1 t hat tr ue res p o nse rate is i nferi or t o be nc h mar k rate of 
3 0 %.
9. 4. Effic ac y A n al ysis
I n t his First i n Patie nt st u d y , a nti-m y el o ma acti vit y is a sec o n dar y o bjecti ve i n Part 1 d ose 
escalati o n.  O bjecti ve res p o nse rate ( OR R) a n d d urati o n of res p o nse ( D OR) are pri mar y 
o bjecti ves i n Part 2 d ose e x pa nsi o n .  Ot her efficac y e n d p oi nts are sec o n dar y o bjecti ves i n 
Pa rt 2.  T he a nal ys is p o p ulati o n is defi ne d i n Secti o n 9. 1 A nal y sis Sets.
I ma gi n g st u dies, rele va nt la b orat or y assess me nts, a n d b o ne marr o w pat h ol o g y  ma y be 
c ollecte d t o s u p p ort i n de pe n de nt ce ntral re vie w f or efficac y e n d p oi nts.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 4
Disease res p o nse will be prese nte d i n t he f or m of patie nt data listi n gs t hat i ncl u de, b ut are n ot 
li mite d t o starti n g d ose, disease res p o nse at eac h visit, a n d best o verall res p o nse.  I n a d diti o n, 
pr o gressi o n date, deat h date, date of first res p o nse a n d last disease assess me nt date, a n d date 
of last c o ntact will be liste d.
Best o ver all res p o nse ( B O R) will be assesse d base d o n re p o rte d o verall res p o nses at 
differe nt e val uati o n ti me p oi nts usi n g I M W G res p o nse criteria (see A p pe n di x 2 ).4 ,5

C o m plete Res p o nse will e nc o m pass c o nfir me d stri n ge nt C o m plete Res p o nse (s C R) 
a n d C o m plete Res p o nse ( C R).

O ver all Res p o nse ( O R) will e nc o m pass c o nfir me d s C R, C R, V G P R ( ver y g o o d 
partial res p o nse ) a n d partial res p o nse ( P R ).

Cli nic al Be nefit ( C B) will e nc o m pass c o nfir me d s C R, C R, VG P R, P R a n d M R.
Pr o gressi o n -free s ur vi v al ( P F S) is t he ti me fr o m start date of st u d y  treat me nt t o date of 
first d oc u me ntati o n of pr o gressi o n, or deat h d ue t o a n y ca use.  Pr o gressi o n is defi ne d as t he 
a p peara nce of l ocal, re gi o nal or dista nt disease of t he sa me t ype after c o m plete res p o nse or 
pr o gressi o n of pre -e xisti n g lesi o ns.  It d oes n ot i ncl u de sec o n d pri mar y  mali g na ncies of 
u nrelate d t y pes. 
O ver all s ur vi v al ( O S) is t he ti me fr o m start date of st u d y  treat me nt t o date of deat h d ue t o 
a n y ca use.
D ur ati o n of C o m plete Re missi o n is defi ne d f or patie nts wit h c o nfir me d c o m plete res p o nse 
(s C R, C R) as t he ti me fr o m t he first d oc u me ntati o n of c o m plete res p o nse t o t he first 
d oc u me ntati o n of o bjecti ve t u m or pr o gressi o n or t o deat h d ue t o a n y ca use, w hic he ve r occ urs 
first.
D ur ati o n of Res p o nse ( D O R) is defi ne d f or patie nts wit h c o nfir me d o bjecti ve res p o nse (as 
defi ne d a b o ve i n o verall res p o nse) as t he ti me fr o m t he first d oc u me ntati o n of o bjecti ve 
t u m or res p o nse t o t he first d oc u me ntati o n of o bjecti ve t u m or pr o gressi o n or t o deat h d ue t o 
a n y ca use, w hic he ver occ urs first.
D ur ati o n of St a ble Dise ase ( D O S D) is defi ne d f or patie nts wit h c o nfir me d sta ble disease as 
t he ti me fr o m t he first d oc u me ntati o n of o bjecti ve sta ble disease t o t he first d oc u me ntati o n of 
o bje cti ve t u m or pr o gressi o n or t o deat h d ue t o a n y ca use, w hic he ver occ urs first.
Ti me t o Res p o nse ( T T R) is defi ne d f or patie nts wit h c o nfir me d o bjecti ve res p o nse (as 
defi ne d a b o ve i n o verall res p o nse) as t he ti me fr o m t he first d oc u me ntati o n of o bjecti ve 
t u m or res p o nse.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 5
9. 5. A n al ysis of P h ar m ac o ki netics a n d P h ar m ac o d y n a mics 
9. 5. 1. P F -0 6 8 6 3 1 3 5 P K A n al ysis
T he c o nce ntrati o ns of P F -0 6 8 6 3 1 3 5 will be s u m marize d b y  descri pti ve statistics ( n, mea n, 
sta n dar d de viati o n, c oefficie nt of variati o n, me dia n, mi ni m u m ma xi m u m, a n d ge o metric 
mea n) b y d osi n g c o h ort, c ycle, a n d n o mi nal ti me.   I ndi vi d ual patie nt a n d me dia n pr ofiles of 
t he c o nce ntrati o n-ti me data will be pl otte d b y d osi n g c o h ort a n d c ycle usi n g n o mi nal ti mes.   
Me dia n pr ofiles will be prese nte d o n b ot h li near-li near a n d l o g -li near scales.
F or patie nts fr o m Parts 1, 1. 1 , 1 C, 1 D, a n d 1 E, i n di vi d ual c o nce ntrati o n-ti me data of 
P F -0 6 8 6 3 1 3 5 f oll o wi n g t he C y cle 0 Da y 1 d ose (o nl y  f or patie nts recei v i n g pri mi n g d ose),
C y cle 1 Da y 1 d ose a n d C y cle 2 Da y 1 d ose (I V o nl y) will be a nal yz e d se paratel y usi n g 
n o n- c o m part me ntal a nal ysis t o esti mate t he P K para meters.  T he P K para meters esti mate d 
will i ncl u de C ma x , ti me t o ma xi m u m c o nce ntrati o n ( Tma x ), a n d c o nce ntrati o n vers us ti me 
c ur ve (A U C last).  If data per mit or if c o nsi dere d a p pr o priate, mi ni m u m c o nce ntrati o n ( C mi n ), 
ter mi nal eli mi nati o n half-life (t1/ 2), cleara nce (C L or C L / F), vol u me of distri b uti o n at stea d y 
state (V ss or V ss/ F), a n d acc u m ulati o n rati o ( Rac) will be als o esti mate d f or C ycle 1 Da y 1 a n d 
C y cle 2 Da y 1.  Act ual sa m ple c ollecti o n ti mes will be use d f or t he para meter calc ulati o ns.   
T he P K para meters will be s u m marize d descri pti vel y  b y d osi n g c o h ort, a n d c ycle.
F or patie nts e nr olle d i n Part s 2 A, 2 C , 2 D, a n d 2 E of t he st u d y , tr o u g h P F-0 6 8 6 3 1 3 5
c o nce ntrati o ns w ill be s u m marize d descri pti vel y b y c ycle.
9. 5. 2. Le n ali d o mi de , P o m ali d o mi de , a n d De x a met h as o ne P h ar m ac o ki netic A n al ysis
( P arts 1 C a n d 2 C, P arts 1 D a n d 2 D , P arts 1 E a n d 2 E as a p pr o pri ate )
T he c o nce ntrati o n -ti me data of le nali d o mi de, p o mali d o mi de, a n d de xa met has o ne will be 
s u m marize d b y descri pti ve statistics ( n, mea n, sta n dar d de viati o n, c oefficie nt of variati o n, 
me dia n, mi ni m u m, ma xi m u m, a n d ge o metric mea n) acc or di n g t o d osi n g c o h ort a n d ti me f or 
eac h part of t he st u d y.  
9. 5. 3. P o p ul ati o n P h ar m ac o ki netic A n al ysis of P h a r m ac o ki netics 
( P K)/ P h ar m ac o d y n a mic M o deli n g
P K a n d p har mac o d y na mic data fr o m t his st u d y  ma y be a nalyz e d usi n g m o deli n g a p pr oac hes 
a n d ma y als o be p o ole d wit h data fr o m ot her st u dies t o i n vesti gate a n y ass ociati o n bet wee n 
P F -0 6 8 6 3 1 3 5 e x p os ure a n d bi o mar kers or si g nifica nt safet y a n d/ or efficac y e n d p oi nts.  T he 
res ults of t hese a nal yses, if perf or me d, ma y be re p orte d se parately fr o m t he cli nical st u d y 
re p ort.
9. 5. 4. A n al ysis of I m m u n o ge nicit y
F or t he i m m u n o ge nicit y data, t he perce nta ge of patie nts wit h A D A will be s u m marize d.   
Listi n gs a n d s u m mar y  ta b ulati o ns of t he A D A data at baseli ne a n d p ost-ra n d o mizati o n will 
be ge nerate d.   Sa m ples ma y  als o be a nalyz e d f or t he prese nce of N A b, a n d a n y  data will be 
si milarl y s u m marize d.  F or patie nts wit h p ositi ve A D A or N A b, t he ma g nit u de (titer), ti me of 
o nset, a n d d urati o n of A D A or N A b res p o nse will als o be descri be d, if data per mit.   T he 
p o te ntial i m pact of i m m u n o ge nicit y o n P K a n d cli nical res p o nse i ncl u di n g p har mac o dy n a mic 
mar kers, safet y/ t olera bilit y a n d efficac y of A D A will be e x pl ore d, if warra nte d b y t he data.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 6
9. 5. 5. A n al ysis of P h ar m ac o d y n a mics
P har mac o d y na mic e n d p oi nts bei n g meas ure d i ncl u de cell ular B C M A e x pressi o n, plas ma
s ol u ble B C M A, e n d o ge n o us patie nt i m m u ne cell p o p ulati o ns, peri p heral bl o o d ge ne 
e x pressi o n pr ofiles a n d T- cell rece pt or ( T C R) cl o nalit y.  T hese e n d p oi nts will be s u bject t o 
a nal ys is b y s u m mar y statistics of val ues at baseli ne as well as c ha n ge fr o m baseli ne o n st u d y.  
Ge ne e x pressi o n pr ofili n g a n d T C R cl o nal a nal ys is will als o be s u bject t o s pecialize d, 
fit-f or-p ur p ose a nal y sis al g orit h ms use d t o i nterr o gate hi g h di me nsi o nal data sets.
9. 5. 6. A n al ysis of Bi o m ar ker E n d p oi nts
Data fr o m bi o mar ker assa y s ma y be a nal yze d usi n g gra p hical met h o ds a n d descri pti ve 
statistics s uc h as li near re gressi o n, t-test, a n d a nalysis o f varia nce.  T he statistical a p pr oac h 
will e xa mi ne c orrelati o ns of bi o mar ker res ults wit h P K para meters a n d meas ures of 
a nti-ca ncer efficac y.
Res ults fr o m tertiar y /e x pl orat or y a nalys es will be re p orte d i n t he C S R w here p ossi ble.  
H o we ver, gi ve n t he e x pl ora t or y nat ure of e x pl orat or y o bjecti ves a n d e n d p oi nts, t he a nal yses 
ma y  n ot be c o m plete at t he ti me of t he C S R.  Res ults fr o m e x pl orat or y a nal yses t hat are n ot 
i ncl u de d i n t he C S R will be s hare d wit h t he scie ntific c o m m u nit y t hr o u g h p u blicati o n at a 
scie ntific c o nfere nce a n d/ or i n a peer-re vie we d scie ntific j o ur nal. Detaile d a nal ys is f or t he 
tertiar y a n d e x pl orat or y e n d p oi nts will be s pecifie d i n a se parate tec h nical d oc u me nt o utsi de 
of t he S A P.
9. 6. S afet y A n al ysis
S u m maries a n d a nal ys es of safet y para meters will i ncl u de all patie nts i n t he Safet y  A nalys is 
Set.  F or patie nts w h o u n der g o i ntra -patie nt d ose escalati o n, safet y a nal ys is of t heir i nitial 
assi g ne d d ose will be ce ns ore d at ti me of i ntra -patie nt d ose escalati o n ( or mai nte na nce d ose 
escalati o n f or Part 1. 1 ).  T his will all o w at least 6 0 da y s of safet y a nalys is f or all patie nts at 
t heir i nitial assi g ne d d ose le vels.
9. 6. 1. A n al ysis of t he Pri m ar y E n d p oi nt f or P art 1
D L T is t he pri mar y  e n d p oi nt of t he d ose escalati o n c o m p o ne nt of t he st u d y.  T he occ urre nce 
of D L Ts o bser ve d i n t he d osi n g c o h orts is use d t o esti mate t he M T D / M A D as descri be d i n 
t he St u d y Desi g n Secti o n 3 .  A d verse E ve nts c o nstit uti n g D L Ts will be liste d per d ose le vel.
9. 6. 2. A n al ysis of Sec o n d ar y S afet y E n d p oi nts
9. 6. 2. 1. A d verse E ve nts
A Es (e xce pt C R S) will be gra de d b y t he i n vesti gat or acc or di n g t o t he C T C A E versi o n 4. 0 3 
a n d c o de d usi n g t he Me dical Dicti o nar y  f or Re g ulat or y Acti vities ( Me d D R A).  C R S will be 
assesse d acc or di n g t o t he gra di n g descri be d b y Lee et al. ( 2 0 1 4 a n d 2 0 1 9 ,2 ,3 See 
A p pe n di x 5 )a n d c o de d usi n g Me d D R A.  T he se verit y  of I C A N S s h o ul d be gra de d acc or di n g 
t o t he A S T C T c o nse ns us criteria3 (A p pe n di x 5 ).  T he f oc us of A E s u m maries will be o n 
Treat me nt E mer ge nt A d verse E ve nts, t h ose wit h i nitial o nset or i ncreasi n g i n se verit y  after 
t he first d ose of st u dy treat me nt.  T he n u m ber a n d perce nta ge of patie nts w h o e x perie nce d 
a n y A E, S A E, treat me nt relate d A E, a nd treat me nt relate d S A E will be s u m marize d 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 7
acc or di n g t o w orst t o xicit y  gra des.  T he s u m maries will prese nt A Es b ot h o n t he e ntire st u d y 
peri o d a n d b y c ycl e ( C yc le 1 a n d C y cles be yo n d 1). 
9. 6. 2. 2. L a b or at or y Test A b n or m alities
T he n u m ber a n d perce nta ge of patie nts w h o e x perie nce d la b orat or y  test a b n or malities will be 
s u m marize d acc or di n g t o w orst t o xicit y gra de o bser ve d f or eac h la b orat or y assa y.  T he 
a nal ys es will s u m marize la b orat or y  tests b ot h o n t he e ntire st u d y peri o d a n d b y c ycle 
( C ycle 1 a n d C ycles be y o n d 1).   S hift ta bles will be pr o vi de d t o e xa mi ne t he distri b uti o n of 
la b orat or y t o xicities.
F or la b orat or y  tests wit h o ut C T C A E gra de defi niti o ns, res ults will be cate g orize d as n or mal, 
a b n or mal, or n ot d o ne. 
9. 6. 2. 3. Electr oc ar di o gr a m
T he a nal ys is of E C G res ults will be base d o n patie nts i n t he safet y a nal ysis set wit h baseli ne 
(sa m ple ta ke n pri or t o first d osi n g) a n d o n-treat me nt E C G data.  E C G meas ure me nts (a n 
a vera ge of t he tri plicate meas ure me nts) will be use d f or t he statistical a nal ysis a n d all data 
prese ntati o ns. A n y data o btai ne d fr o m E C Gs re peate d f or safet y reas o ns after t he n o mi nal 
ti me-p oi nts will n ot be a vera ge d al o n g wit h t he prece di n g tri plicates.  I nter val meas ure me nts 
fr o m re peate d E C Gs will be i ncl u de d i n t he o utlier a nalys is (cate g orical a nal ysis) as 
in di vi d ual val ues o btai ne d at u nsc he d ule d ti me p oi nts.
Q T ( ti me bet wee n t he start of t he Q wa ve a n d t he e n d of t he T wa ve) i nter vals will be 
c orrecte d f or heart rate ( H R , Q Tc) usi n g sta n dar d c orrec ti o n fact ors (ie, Fri dericia’s [defa ult 
c orrecti o n], Bazett’s, a n d p ossi bl y a st u d y -s pecific fact or, as a p pr o priate).  Data will be 
s u m marize d a n d liste d f or Q T, H R, res p o nse rate ( R R), partial res p o nse ( P R), Q R S, Q Tc F 
(a n d ot her c orrecti o n fact ors, e g, c orrecte d Q T i nter val b y  Bazett (Q Tc B ) as a p pr o priate), a n d 
b y  st u d y ar m a n d d ose.  I n di vi d ual Q T (all e val uate d c orrecti o ns) i nter vals will be liste d b y 
st u d y ar m, ti me a n d d ose.  T he m ost a p pr o priate c orrecti o n fact or will be selecte d a n d use d 
f or t he f oll o wi n g a nalys es of ce ntral te n de nc y an d o utliers a n d use d f or t he st u d y  
c o ncl usi o ns.  Descri pti ve statistics ( n, mea n, me dia n, sta n dar d de viati o n, mi ni m u m, a n d 
ma xi m u m) will be use d t o s u m marize t he a bs ol ute c orrecte d Q T i nter val a n d c ha n ges fr o m 
baseli ne i n c orrecte d Q T after treat me nt b y st u d y  ar m, d ose a n d ti me p oi nt.  F or eac h patie nt 
a n d b y treat me nt, t he ma xi m u m c ha n ge fr o m baseli ne will be calc ulate d as well as t he 
ma xi m u m p ost -baseli ne i nter val acr oss ti me -p oi nts.  Cate g orical a nal y sis will be c o n d ucte d 
f or t he ma xi m u m c ha n ge fr o m baseli ne i n c orrecte d Q T a n d t he ma xi m u m p ost-baseli ne Q T 
i nter val. 
S hift ta bles will be pr o vi de d f or baseli ne vs w orst o n treat me nt c orrecte d Q T ( o ne or m ore 
c orrecti o n met h o ds will be use d) usi n g ma xi m u m C T C A E Gra de.  S hift ta bles will als o be 
pr o vi de d f or E C G a b n or malit y  at baseli ne vs. o n treat me nt ( yes, n o, n ot d o ne: ( n, %)).  
Patie nts e x perie nci n g cli nicall y  rele va nt m or p h ol o gical E C G c ha n ges will be s u m marize d 
(i ncl u di n g fre q ue nc y a n d perce nta ge).
T he effect of dr u g c o nce ntrati o ns o n c orrecte d Q T c ha n ge fr o m baseli ne will be e x pl ore d 
gra p hicall y.  A d diti o nal c o nce ntrati o n -c orrecte d Q T a nal ys es ma y be perf or me d.  Data ma y 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 8
be p o ole d wit h ot her st u d y res ults a n d/ or e x pl ore d f urt her wit h P K/ p har mac o d y na mic
m o dels.
9. 7. I nteri m A n al ysis
N o f or mal i nteri m a nal ys is will be perf or me d.  Patie nts’ safety a n d disease pr o gressi o n will 
be m o nit ore d c o nti n u o usl y. 
T he criteria bel o w g ui di n g i nterr u pti o n of st u d y treat me nt are base d o n Ba yesia n p osteri or 
pr o ba bilities usi n g a n o n -i nf or mati ve Beta ( 0. 5, 0. 5) pri or distri b uti o n. T he pr o ba bilities will 
be calc ulate d f or t otal n u m ber of  partici pa nts assi g ne d or tra nsiti o ne d t o m o n ot hera p y wit h 
elra nata ma b acr oss its efficaci o us d ose ra n ge, i ncl u di n g Part 1 S C d oses ≥2 1 5 u g/ k g, Part 
1. 1, Part 2 A, a n d a n y patie nt fr o m Part 1 D tra nsiti o ne d t o m o n ot hera p y. 
If t he n u m ber of e val ua ble partici pa nts o bser ve d t o ha ve treat me nt-relate d Gra de 3-4 G B S
(i ncl u di n g v aria nts) res ults i n a p osteri or pr o ba bilit y t hat t he tr ue rate of s uc h e ve nts 
e xcee di n g 3 % is ≥0. 8 0, st u d y  treat me nt will be i nterr u pte d f or all acti ve partici pa nts pe n di n g 
re vie w of all safety i nf or mati o n . F or e xa m ple, if t he t otal n u m ber of  par tici pa nts e nr olle d i n 
t he c o h orts descri be d a b o ve is 6 2, o bser vi n g 3 or m ore partici pa nts wit h treat me nt -relate d 
Gra de 3 -4 G B S (incl u di n g v aria nts) will res ult i n t he i nterr u pti o n of st u d y  treat me nt f or all 
acti ve partici pa nts . 
If t he n u m ber of e val ua ble partici pa nts o bser ve d t o ha ve treat me nt-relate d Gra de 4 se ns or y 
ne ur o pat h y, Gra de 4 i m m u ne -relate d ne ur ol o gic A Es (excl u di n g I C A N S), or Gra de 3 - 4 
peri p heral m ot or n e ur o pat h y res ults i n a p osteri or pr o ba bilit y t hat t he tr ue rate of s uc h e ve nts 
e xcee di n g 1 0 % is ≥0. 8 0, st u d y  treat me nt will be i nterr u pte d f or all acti ve partici pa nts
pe n di n g re vie w of all safet y i nf or mati o n.  F or e xa m ple, if t he t otal n u m ber of  partici pa nts
e nr olle d i n t he c o h orts descri be d a b o ve is 6 2, o bser vi n g 9 or m ore partici pa nts wit h 
treat me nt-relate d Gra de 4 se ns or y ne ur o pat h y, Gra de 4 i m m u ne-relate d ne ur ol o gic A Es
(excl u di n g I C A N S), or Gra de 3 - 4 peri p heral m ot or n e ur o pat h y will res ult i n t he i nterr u pti o n 
of st u d y  treat me nt f or all acti ve partici pa nts . 
If a partici pa nt e nr olle d o n t he c o m bi nati o n wit h le n ali do mi de ar m de vel o ps ≥Gra de 3 
peri p heral m ot or ne ur o pat h y  (i ncl u di n g G B S), t hat partici pa nt will be ma na ge d acc or di n g t o 
Ta ble 5 a n d the re mai ni n g partici pa nts o n t he c o m bi nati o n ar m will be tra nsiti o ne d t o 
m o n ot hera p y wit h si n gle a ge nt P F - 0 6 8 6 3 1 3 5.
I n a d diti o n, if a ny of t he f oll o wi n g a d verse e ve nts occ ur, st u d y treat me nt will be i nterr u pte d 
f or all acti ve partici pa nts:

1 Gra de 5 e ve nt of C R S

1 Gra de 5 e ve nt of I CA N S

1 Gra de 5 treat me nt -relate d peri p heral ne ur o pat hy or I R ne ur ol o gic e ve nt
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 9

A n y  2 treat me nt-relate d Gra de 5 e ve nts (e xcl u di n g C R S a n d IC A N S a n d peri p heral 
ne ur o pat h y/ I R ne ur ol o gic e ve nt).
9. 8. D at a M o nit ori n g C o m mittee
T his st u d y  will n ot use a data m o nit ori n g c o m mittee ( D M C).
1 0. Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E
Pfizer or its a ge nt will c o n d uct peri o dic m o nit ori n g visits d uri n g st u d y c o n d uct t o e ns ure t hat 
t he pr ot oc ol a n d G o o d Cli nical Practices ( G C Ps ) are bei n g f oll o we d.  T he m o nit ors m a y 
re vie w s o urce d oc u me nts t o c o nfir m t hat t he data rec or de d o n C R Fs are acc urate.  T he 
i n vesti gat or a n d i nstit uti o n will all o w Pfizer m o nit ors/a u dit ors or its a ge nts a n d a p pr o priate 
re g ulat or y a ut h orities direct access t o s o urce d oc u me nts t o perf or m t his verificati o n.  T his 
verificati o n ma y  als o occ ur after st u d y c o m pleti o n.
D uri n g st u d y c o n d uct a n d/ or after st u d y c o m pleti o n, t he i n vesti gat or site ma y be s u bject t o 
re vie w by t he I RB/ E C, a n d/ or t o q ualit y  ass ura nce a u dits perf or me d b y Pfizer, or c o m pa nies 
w or ki n g wit h or o n be half of Pfizer, a n d/ or t o i ns pecti o n b y  a p pr o priate re g ulat or y 
a ut h orities.
T he i n vesti gat or(s) will n otif y  Pfizer or its a ge nts i m me diatel y of a n y re g ulat or y i ns pecti o n 
n otificati o n i n relati o n t o t he st u d y . F urt her m ore, t he i n vesti ga t or will c o o perate wit h Pfizer 
or its a ge nts t o pre pare t he i n vesti gat or site f or t he i ns pecti o n a n d will all o w Pfizer or its 
a ge nt, w he ne ver feasi ble, t o be prese nt d uri n g t he i ns pecti o n.  T he i n vesti gat or site a n d 
i n vesti gat or will pr o m ptl y res ol ve a ny d iscre pa ncies t hat are i de ntifie d bet wee n t he st u d y 
data a n d t he patie nt's me dical rec or ds.  T he i n vesti gat or will pr o m ptl y pr o vi de c o pies of t he 
i ns pecti o n fi n di n gs t o Pfizer or its a ge nt.  Bef ore res p o nse s u b missi o n t o t he re g ulat or y 
a ut h orities, t he i n vesti gat or will pr o vi de Pfizer or its a ge nts wit h a n o p p ort u nit y t o re vie w 
a n d c o m me nt o n res p o nses t o a n y  s uc h fi n di n gs.
It is i m p orta nt t hat t he i n vesti gat or(s) a n d t heir rele va nt pers o n nel are a vaila ble d uri n g t he 
m o nit ori n g visits a n d p ossi ble a u dits or i ns pecti o ns a n d t hat s ufficie nt ti me is de v ote d t o t he 
pr ocess.
1 1. D A T A H A N D LI N G A N D R E C O R D K E E PI N G
1 1. 1. C ase Re p ort F or ms/ Electr o nic D at a Rec or d
As use d i n t his pr ot oc ol, t he ter m C R F s h o ul d be u n derst o o d t o refer t o eit her a pa per f or m or 
a n electr o nic data rec o r d or b ot h, de pe n di n g o n t he data c ollecti o n met h o d use d i n t his st u d y.
A C R F is re q uire d a n d s h o ul d be c o m plete d f or eac h i ncl u de d patie nt .  T he c o m plete d 
ori gi nal C R Fs are t he s ole pr o pert y of Pfizer a n d s h o ul d n ot be ma de a vaila ble i n a n y f or m t o 
t hir d parties, e xce pt f or a ut h orize d re prese ntati ves of Pfizer or a p pr o priate re g ulat or y  
a ut h orities, wit h o ut writte n per missi o n fr o m Pfizer.
T he i n vesti gat or has ulti mate res p o nsi bilit y  f or t he c ollecti o n a n d re p orti n g of all cli nical, 
safety, a n d la b orat or y data e ntere d o n t he C R Fs a n d a n y ot her data c ollecti o n f or ms (s o urce 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 0
d oc u me nts) a n d e ns uri n g t hat t he y are acc urate, a ut he ntic/ ori gi nal, attri b uta ble, c o m plete, 
c o nsiste nt, le gi ble, ti mel y (c o nte m p ora ne o us), e n d uri n g, a n d a vaila ble w he n re q uire d.  T he 
C R Fs m ust be si g ne d b y t he i n vesti gat or or by a n a ut h orize d staff me m ber t o attest t hat t he 
data c o ntai ne d o n t he C R Fs are tr ue. A n y c orrecti o ns t o e ntries ma de i n t he C R Fs or s o urce 
d oc u me nts m ust be date d, i nitiale d , a n d e x plai ne d (if necess ar y) a n d s h o ul d n ot o bsc ure t he 
ori gi nal e ntr y .
I n m ost cases, t he s o urce d oc u me nts are t he h os pital or t he p hys icia n's c hart.  In t hese cases ,
data c ollecte d o n t he C R Fs m ust matc h t he data i n t h ose c harts. 
I n s o me cases, t he C R F ma y als o ser ve as t he s ource d oc u me nt.  I n t hese cases, a d oc u me nt 
s h o ul d be a vaila ble at t he i n vesti gator site a n d at Pfizer t hat clearl y i de ntifies t h ose data t hat 
will be rec or de d o n t he C R F, a n d f or w hic h t he C R F will sta n d as t he s o urce d oc u me nt.
W he n partici pa nt data are t o
be delete d, t he i n vesti gat or will e ns ure t hat all c o pies of s uc h 
data are pr o m ptl y  a n d irre v oca bly delete d fr o m all s yste ms .
1 1. 2. Rec or d Rete nti o n
T o e na ble e val uati o ns a n d/ or i ns pecti o ns/a u dits fr o m re g ulat or y a ut h orities or Pfizer, t he 
i n vesti gat or a grees t o kee p rec or ds, i ncl u di n g t he i de ntit y  of all partici pati n g patie nts
(s ufficie nt i nf or mati o n t o li n k rec or ds, e g, C R Fs a n d h os pital rec or ds), all ori gi nal si g ne d 
i nf or me d c o nse nt d oc u me nts , c o pies of all C R Fs, safet y re p orti n g f or ms, s o urce d oc u me nts, 
a n d detaile d rec or ds of treat me nt dis p ositi o n, a n d a de q uate d oc u me ntati o n of rele va nt 
c orres p o n de nce (e g, letters, meeti n g mi n utes, a n d tele p h o ne call re p orts).  T he rec or ds s h o ul d 
be retai ne d b y t he i n vesti gat or acc or di n g t o IC H g ui deli nes , acc or di n g t o l ocal re g ulati o ns, or 
as s pecifie d i n t he cli nical st u d y agree me nt ( C S A), w hic he ver is l o n ger.
If t he i n vesti gat or bec o mes u na ble f or a ny reas o n t o c o nti n ue t o retai n st u d y rec or ds f or t he 
re q uire d peri o d (e g, retire me nt, rel ocati o n), Pfizer s h o ul d be pr os pecti vely n otifie d.  T he 
st u d y rec or ds m ust be tra nsferre d t o a desi g nee acce pta ble t o Pfizer, s uc h as a n ot her 
i n vesti gat or, a n ot her i nstit uti o n, or t o a n i n de pe n de nt t hir d party arra n ge d b y Pfizer. 
I n vesti gat or rec or ds m ust be ke pt f or a mi ni m u m of 1 5 ye ars after c o m pleti o n or 
disc o nti n uati o n of t he st u d y or f or l o n ger if re q uire d b y  a p plica ble l ocal re g ulati o ns. 
T he i n vesti gat or m ust o btai n Pfizer's writte n per missi o n bef ore dis p osi n g of a n y rec or ds, 
e ve n if rete nti o n re q uire me nts ha ve bee n met.
1 1. 3. D at a Pr otecti o n
All parties will c o m pl y  wit h all a p plica ble la ws, i ncl u di n g la ws re gar di n g t he i m ple me ntati o n 
of or ga nizati o nal a n d tec h nical meas ures t o e ns ure pr otecti o n of partici pa nt data.
Partici pa nts’ pers o nal data will be st ore d at t he st u d y  site i n e ncr ypte d electr o nic a n d/ or pa per 
f or m a n d will be pass w or d-pr otecte d or sec ure d i n a l oc ke d r o o m t o e ns ure t hat o nl y  
a ut h orize d st u d y staff ha ve access. T he st u d y site will i m ple me nt a p pr o priate tec h nical a n d 
or ga nizati o nal meas ures t o e ns ure t hat t he pers o nal data ca n be rec o vere d i n t he e ve nt of 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 1
disaster. I n t he e ve nt of a p ote ntial pers o nal data breac h, t he st u d y site will be res p o nsi ble f or 
deter mi ni n g w het her a pers o nal data breac h has i n fact occ urre d a n d, if s o, pr o vi di n g breac h 
n otificati o ns as re q uire d b y  la w.
T o pr otect t he ri g hts a n d free d o ms of partici pa nts wit h re gar d t o t he pr ocessi n g of pers o nal 
data, partici pa nts will be assi g ne d a si n gle, partici pa nt -s pecific n u merical c o de. A n y 
partici pa nt rec or ds or data sets t hat are tra nsferre d t o t he s p o ns or will c o ntai n t he n u merical 
c o de; partici pa nt na mes will n ot be tra nsferre d. All ot her i de ntifia ble data tra nsferre d t o t he 
s p o ns or will be i de ntifie d b y t his si n gle, partici pa nt-s pecific c o de. T he st u d y site will 
mai ntai n a c o nfi de ntial list of partici pa nts w h o partici pate d i n t he st u d y , li n ki n g eac h 
partici pa nt’s n u merical c o de t o t heir act ual i de ntit y  a n d me dical rec or d I D. I n case of data 
tra nsfer, t he s p o ns or will pr otect t he c o nfi de ntialit y of partici pa nts’ pers o nal data c o nsiste nt 
wit h t he cli nical st u d y a gree me nt a n d a p plica ble pri vac y  la ws.
I nf or mati o n tec h n ol o g y s yste ms use d t o c ollect, pr ocess, a n d st ore st u d y-relate d data are 
sec ure d by t ec h nical a n d or ga nizati o nal sec urit y meas ures desi g ne d t o pr ot ect s uc h data 
a gai nst acci de ntal or u nla wf ul l oss, alterati o n, or u na ut h orize d discl os ure or access. 
T he s p o ns or mai ntai ns S O Ps o n h o w t o res p o n d i n t he e ve nt of u na ut h orize d access, use, or 
discl os ure of s p o ns or i nf or mati o n or s y ste ms.
1 2. E T HI C S
1 2. 1. Re g ul at or y a n d Et hic al C o nsi der ati o ns
T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes, i ncl u di n g t he 
Declarati o n of Helsi n ki a n d CI O M S I nter nati o nal Et hical G ui del i nes;

A p plica ble I C H G C P g ui deli nes;

A p plica ble la ws a n d re g ulati o ns, i ncl u di n g a p plica ble pri vac y  la ws.
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C D, S R S D(s), a n d ot her rele va nt d oc u me nts 
(e g, a d vertise me nts) m ust be re vie we d a n d a p pr o ve d b y  t he s p o ns or, s u b mitte d t o a n IR B/ E C 
b y  t he i n vesti gat or, a n d re vie we d a n d a p pr o ve d b y t he I R B/ E C bef ore t he st u d y is i nitiate d.
A n y  a me n d me nts t o t he pr ot oc ol will re q uire I R B/ E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n ges necessar y t o eli mi nate a n i m me diate 
hazar d t o st u d y  partici pa nts.
Pr ot oc ols a n d a n y s u bsta ntial a me n d me nts t o t he pr ot oc ol will re q uire healt h a ut h orit y  
a p pr o val pri or t o i nitiati o n e xce pt f or c ha n ges necessar y t o eli mi nate a n i m me diate hazar d t o 
st u d y partici pa nts.
T he i n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 2

Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y  t o t he I R B/ E C a n n uall y or 
m ore fre q ue ntl y  i n acc or da nce wit h t he re q uire me nts, p olicies, a n d pr oce d ures 
esta blis he d b y t he I R B/ E C.

N otif y i n g t he I R B/ E C of S A Es or ot her si g nifica nt safet y fi n di n gs as re q uire d b y 
I RB/ E C pr oce d ures.

Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at t he site a n d a d here nce t o 
re q uire me nts of 2 1 C F R, I C H G C P g ui deli nes, t he I R B/ E C, E ur o pea n re g ulati o n 
5 3 6/ 2 0 1 4 f or cl i nical st u dies, E ur o pea n Me dical De vice Re g ulati o n 2 0 1 7/ 7 4 5 f or 
cli nical de vice researc h, a n d all ot her a p plica ble l ocal re g ulati o ns.
1 2. 2. P atie nt I nf or m ati o n a n d C o nse nt
All parties will e ns ure pr otecti o n of patie nt pers o nal data a n d will n ot i ncl u de patie nt na mes 
or ot her i de ntifia ble data i n a n y re p orts, p u blicati o ns, or ot her discl os ures, e xce pt w here 
re q uire d by la w.
W he n st u d y  data are c o m pile d f or tra nsfer t o Pfizer a n d ot her a ut h orize d parties, patie nt
na mes, a d dress es, a n d ot her i de ntifia ble data will be re place d b y n u merical c o de s base d o n a 
n u m beri n g s ys te m pr o vi de d b y Pfizer i n or der t o de-i de ntif y st u d y patie nt s. T he i n vesti gat or
site will mai ntai n a c o nfi de ntial list of patie nts w h o partici pate d i n t he st u d y, li n ki n g eac h 
patie nt’s n u merical c o de t o his or her act ual i de ntit y. I n case of data tra nsfer, Pfizer will 
mai ntai n hi g h sta n dar ds of c o nfi de ntialit y a n d pr otecti o n of patie nt s’ pers o nal data c o nsiste nt 
wit h a p plica ble pri vac y  la ws.
T he i nf or me d c o nse nt d oc u me nt s a n d a n y patie nt recr uit me nt materials m ust be i n 
c o m plia nce wit h I C H G C P, l ocal re g ulat or y re q uire me nts, a n d le gal re q uire me nts, i ncl u di n g 
a p plica ble pri vac y la ws.  P ote ntial be nefit a n d ris ks of alter nati ve pr oce d ures will n ot be 
o utli ne d i n t he c o nse nt f or patie nts o n t his st u d y  per I C H G C P Secti o n 4. 8. 1 0 (i), if t he 
o utli ne of t his i nf or mati o n is n ot i n ali g n me nt wit h i nstit ute’s p olicies.
T he i nf or me d c o nse nt d oc u me nts use d d uri n g t he i nf or me d c o nse nt pr ocess a n d a n y patie nt
recr uit me nt materials m ust be re vie we d an d a p pr o ve d b y  Pfizer , a p pr o ve d b y t he I R B/ E C 
bef ore use, a n d a vaila ble f or i ns pecti o n.
T he i n vesti gat or m ust e ns ure t hat eac h st u d y  patie nt is f ull y i nf or me d a b o ut t he nat ure a n d 
o bjecti ves of t he st u d y a n d p ossi ble ris ks ass ociate d wit h partici pati o n. 
T he i n vesti gat or, or a pers o n desi g nate d b y t he i n vesti gat or, will o btai n writte n i nf or me d 
c o nse nt fr o m eac h patie nt bef ore a n y st u d y -s pecific acti vit y is perf or me d. T he i n vesti gat or 
will retai n t he ori gi nal of eac h patie nt's si g ne d c o nse nt d oc u me nt.
1 2. 3. Re p or ti n g of S afet y Iss ues a n d Seri o us Bre ac hes of t he Pr ot oc ol or I C H G C P
I n t he e ve nt of a ny pr o hi biti o n or restricti o n i m p ose d (ie, cli nical h ol d) b y a n a p plica ble 
re g ulat or y aut h orit y i n a n y area of t he w orl d, or if t he i n vesti gat or is a ware of a n y  ne w 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 3
i nf or mati o n t hat mi g ht i nfl ue nce t he e val uati o n of t he be nefits a n d ris ks of t he i n vesti gati o nal 
pr o d uct, Pfizer s h o ul d be i nf or me d i m me diatel y. 
I n a d diti o n, t he i n vesti gat or will i nf or m Pfizer i m me diatel y of a n y ur ge nt safety meas ures 
ta ke n by t he i n vesti gat or t o pr otect t he st u d y  patie nts a gai nst a n y i m me diate hazar d, a n d of 
a n y seri o us breac hes of t his pr ot oc ol or of I C H G C P t hat t he i n vesti gat or bec o mes a ware of.
1 3. D E FI NI TI O N O F E N D O F T RI A L
1 3. 1. E n d of Tri al i n All P artici p ati n g C o u ntries
E n d of trial i n all partici pati n g c o u ntries is defi ne d as last s u bject last visit ( L S L V).  F or m ore 
i nf or mati o n o n h o w e n d of st u d y is deter mi ne d, please see Secti o n 6. 5 .
1 4. S P O N S O R DI S C O N TI N U A T I O N C RI T E RI A
Pre mat ure ter mi nati o n of t his st u d y  ma y occ ur beca use of a re g ulat or y a ut h orit y decisi o n, 
c ha n ge i n o pi ni o n of t he I R B/ E C, or i n vesti gati o nal pr o d uct safet y pr o ble ms, or at t he 
discreti o n of Pfizer.  I n a d diti o n, Pfizer retai ns t he ri g ht t o disc o nti n ue de vel o p me nt of 
P F -0 6 8 6 3 1 3 5 at a n y ti me.
If a st u dy is pre mat urel y ter mi nate d, Pfizer will pr om ptl y  n otif y t he i n vesti gat or.  After 
n otificati o n, t he i n vesti gat o r m ust c o ntact all partici pati n g patie nts a n d t he h os pital p har mac y 
(if a p plica ble) wit hi n 2 b usi ness da y s.  As directe d b y Pfizer, all st u d y materials m ust be 
c ollecte d a n d all C R Fs c o m plete d t o t he greatest e xte nt p ossi ble.
1 5. P U B LI C A TI O N O F S T U D Y R E S U L T S
1 5. 1. D isse mi n ati o n of Cli nic al St u d y D at a
Pfizer f ulfills its c o m mit me nt t o p u blicl y  discl ose cli nical st u d y res ults t hr o u g h p osti n g t he 
res ults of st u dies o n w w w.cli nicaltrials. g o v ( Cli nical Trials. g o v), t he E u dra C T/ C TIS, a n d/ or 
w w w. pfizer.c o m, a n d ot her p u blic re gistries a n d we bsites i n acc or da nce wit h a p plica ble l ocal 
la ws/re g ulati o ns. I n a d diti o n, Pfizer re p orts st u d y res ults o utsi de of t he re q uire me nts of l ocal 
la ws/re g ulati o ns p urs ua nt t o its S O Ps.
I n all cases, st u dy res ults are re p orte d b y Pfizer i n a n o bj ecti ve, acc urate, bala nce d, a n d 
c o m plete ma n ner a n d are re p orte d re gar dless of t he o utc o me of t he st u d y or t he c o u ntr y i n 
w hic h t he st u d y  was c o n d ucte d.
w w w.cli nicaltrials. g o v
Pfizer p osts cli nical trial res ults o n w w w.cli nicaltrials. g o v f or Pfizer s p o ns or e d i nter ve nti o nal 
st u dies (c o n d ucte d i n patie nts) t hat e val uate t he safet y a n d/ or efficac y of a pr o d uct, 
re gar dless of t he ge o gra p hical l ocati o n i n w hic h t he st u d y is c o n d ucte d. T hese res ults are 
s u b mitte d f or p osti n g i n acc or da nce wit h t he f or mat a n d ti meli nes set f ort h b y U S la w.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 4
E u dra C T/ C TI S
Pfizer p osts cli nical trial res ults o n E u dra C T/ C TI S f or Pfizer s p o ns ore d i nter ve nti o nal st u dies 
i n acc or da nce wit h t he f or mat a n d ti meli nes set f ort h b y E U re q uire me nts.  
w w w. pfizer.c o m
Pfizer p osts C S R s y n o pses a n d plai n -la n g ua ge st u d y res ults s u m maries o n w w w. pfizer.c o m 
f or Pfizer s p o ns ore d i nter ve nti o nal st u dies at t he sa me ti me t he c orres p o n di n g st u dy res ults 
are p oste d t o w w w.cli nicaltrials. g o v. C S R s y n o pses will ha ve pers o nall y  i de ntifia ble 
i nf or mati o n a n o ny m ize d.
D oc u me nts wit hi n mar keti n g a p plicati o ns 
Pfizer c o m plies wit h a p plica ble l ocal la ws/re g ulati o ns t o p u blis h cli nical d oc u me nts i ncl u de d 
i n mar keti n g a p plicati o ns. Cli nical d oc u me nts i ncl u de s u m mar y d oc u me nts a n d C S Rs 
i ncl u di n g t he pr ot oc ol a n d pr ot oc ol a me n d me nts, sa m ple C R Fs, a n d S A Ps. Cli nical 
d oc u me nts will ha ve pers o nall y  i de ntifia ble i nf or mati o n a n o n ymize d.
Data s hari n g
Pfizer pr o vi des researc hers sec ure access t o partici pa nt le vel data or f ull C S Rs f or t he 
p ur p oses of “ b o na fi de scie ntific researc h ” t hat c o ntri b utes t o t he scie ntific u n dersta n di n g of 
t he disease, tar get, or c o m p o u n d class. Pfizer will ma ke data fr o m t hese trials a vala ble 1 8 
m o nt hs after st u d y  c o m pleti o n. Partici pa nt le vel data will be a n o n ymize d i n acc or da nce wit h 
a p plica ble pri vac y la ws a n d re g ulati o ns. C S Rs will ha ve pers o nall y i de ntifia ble i nf or mati o n 
a n o n ymize d.
Data re q uests are c o nsi dere d fr o m q ualifie d researc hers wit h t he a p pr o priate c o m pete ncies t o 
perf or m t he pr o p ose d a nal y ses. Researc h tea ms m ust i ncl u de a bi ostatisticia n. Data will n ot 
be pr o vi de d t o a p plica nts wit h si g nifica nt c o nflicts of i nterest, i ncl u di n g i n di vi d uals 
re q uesti n g access f or c o m mercial/c o m petiti ve or le gal p ur p oses..
1 5. 2. P u blic ati o n P olic y
F or m ultice nter trials, t he pri mar y  p u blicati o n will be a j oi nt p u blicati o n de vel o pe d by t he 
i n vesti gat or a n d Pfizer re p orti n g t he pri mar y e n d p oi nt(s) of the st u d y  c o veri n g all st u d y sites. 
T he i n vesti gat or a grees t o refer t o t he pri mar y  p u blicati o n i n a n y s u bse q ue nt p u blicati o ns. 
Pfizer will n ot pr o vi de a n y fi na ncial c o m pe nsati o n f or t he i n vesti gat or’s partici pati o n i n t he 
pre parati o n of t he pri mar y c o n gres s a bstract, p oster, prese ntati o n, or pri mar y ma n uscri pt f or 
t he st u d y. 
I n vesti gat ors are free t o p u blis h i n di vi d ual ce nter res ults t hat t he y dee m t o be cli nicall y 
mea ni n gf ul after p u blicati o n of t he o verall res ults of t he st u d y  or 1 2 m o nt hs after pri mar y 
c o m pleti o n date or st u d y c o m pleti o n at all sites, w hic he ver occ urs first, s u bject t o t he ot her 
re q uire me nts descri be d i n t his secti o n.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 5
T he i n vesti gat or will pr o vi de Pfizer a n o p p ort u nit y  t o re vie w a n y pr o p ose d p u blicati o n or 
a n y ot her ty pe of discl os ure of t he st u d y res ults (c ollecti vel y, “ p u blicati o n”) bef ore it is 
s u b mitte d or ot her wise discl ose d a n d will s u b mit all p u blicati o ns t o Pfizer 3 0 da ys bef ore 
s u b missi o n. If a ny pate nt acti o n is re q uire d t o pr otect i ntellect ual pr o pert y ri g hts, t he 
i n vesti gat or a grees t o dela y t he discl os ure f or a peri o d n ot t o e xcee d a n a d diti o nal 6 0 da ys 
u p o n re q uest fr o m Pfizer. T his all o ws Pfizer t o pr otect pr o prietar y  i nf or mati o n a n d t o pr o vi de 
c o m me nts, a n d t he i n vesti gat or will, o n re q uest, re m o ve a n y pre vi o usl y u n discl ose d 
c o nfi de ntial i nf or mati o n bef ore discl os ure, e xce pt f or a n y st u d y i nter ve nti o n or  Pfizer 
relate d i nf or mati o n necessar y f or t he a p pr o priate scie ntific prese ntati o n or u n dersta n di n g of 
t he st u d y res ults. F or j oi nt p u blicati o ns, s h o ul d t here be disa gree me nt re gar di n g 
i nter pretati o n a n d/ or prese ntati o n of s pecific a nalysis res ults, res ol uti o n of, a n d res p o nsi bilit y 
f or, s uc h disa gree me nts will be t he c ollecti ve res p o nsi bilit y of all a ut h ors of t he p u blicati o n.
F or all p u blicati o ns relati n g t o t he st u d y, t he i n vesti gat or a n d Pfizer will c o m pl y wit h 
rec o g nize d et hical sta n dar ds c o ncer ni n g p u blicati o ns a n d a ut h ors hi p, i ncl u di n g t h ose 
esta blis he d b y  t he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors. T he i n vesti gat or will 
discl ose a n y relati o ns hi p wit h Pfizer a n d a n y rele va nt p ote ntial c o nflicts of i nterest, i ncl u di n g 
a n y fi na ncial or pers o nal relati o ns hi p wit h Pfizer, i n a n y p u blicati o ns. All a ut h ors will ha ve 
access t o t he rele va nt statistical ta bles, fi g ures, a n d re p orts (i n t heir ori gi nal f or mat) re q uire d 
to de vel o p t he p u blicati o n. T he res ults of t his st u d y ma y be p u blis he d or prese nte d at 
scie ntific meeti n gs by t he i n vesti gat or after p u blicati o n of t he o verall st u d y res ults or 1 year 
after t he e n d of t he st u d y ( or st u d y ter mi nati o n), w hic he ver c o mes first.  
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 6
1 6. R E F E R E N C E S
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1 1.
D ha kal B, Ves ole D H, Hari P N. All o ge neic ste m cell tra ns pla ntati o n f or m ulti ple 
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0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 7
u ntreate d m ulti ple m y el o ma wit h o ut a n i nte nt f or i m me diate a ut ol o g o us ste m cell 
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1 7.
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2 0.
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2 1.
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2 2.
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E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 8
2 4.
Hi p p S, Tai Y T, Bla nset D, et al. A n o vel B C M A/ C D 3 bis pecific T -cell e n ga ger f or 
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2 5.
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2 7.
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3 2.
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P O M A L Y S T ( p o mali d o mi de ca ps ule). U S Prescri pti o n I nf or mati o n ( U S PI ); 2 9 Ma y 
2 0 2 0, S u m mit, NJ, U S A: Cel ge ne C or p. A vaila ble fr o m: 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 9
htt ps:// dail y me d. nl m. ni h. g o v/ dail y m e d/ dr u gI nf o.cf m?seti d = 2 b 2 5ef 0 1- 5c 9e -1 1e 1 -
b 8 6c -0 8 0 0 2 0 0c 9a 6 6 . Accesse d o n: 0 7 J ul 2 0 2 0.
3 5.
I m n o vi d ( pre vi o usl y P o mali d o mi de Cel ge ne). E P A R Pr o d uct I nf or mati on; 1 8 J u n 
2 0 1 9: E M A. A vaila ble fr o m: 
htt ps:// w w w.e ma.e ur o pa.e u/e n/ me dici nes/ h u ma n/ E P A R/re vli mi d #a ut h orisati o n -
details -secti o n. Accesse d o n: 0 7 J ul 2 0 2 0.
3 6.
P o mal y st ( p o mali d o mi de). Healt h Ca na da Pr o d uct M o n o gra p h; 2 Fe b 2 0 2 1 2 0 1 9, 
Sai nt -La u re nt, Q C: Cele ge ne. A vaila ble fr o m: 
htt ps:// w w w.e ma.e ur o pa.e u/e n/ me dici nes/ h u ma n/ E P A R/i m n o vi d . Accesse d o n: 0 7 J ul 
2 0 2 0.
3 7.
N CI .  Nati o nal Ca ncer I nstit ute: Da xa met has o ne. A vaila ble fr o m: 
htt ps:// w w w.ca ncer. g o v/a b o ut -
ca ncer/treat me nt/ dr u gs/ de xa met has o ne #: ~:te xt = De xa met h as o ne % 2 0is % 2 0a p pr o ve d
% 2 0t o % 2 0 be % 2 0 use d % 2 0t o % 2 0re d uce,t he % 2 0f oll o wi n g % 2 0t y pes % 2 0 of % 2 0ca ncer
% 2 0: % 2 0 Le u ke mia % 2 0 . Accesse d o n: 1 6 Ja n 2 0 2 1.
3 8.
Neela p u S S. Ma na gi n g t he t o xicities of C A R T -cell t hera p y. He mat ol O nc ol. 2 0 1 9; 3 7 
S u p pl 1: 4 8 - 5 2.
3 9.
Neela p u S S, T u m mala S, Ke briaei P, et al. C hi meric a nti ge n rece pt or T -cell t hera p y -
assess me nt a n d ma na ge me nt of t o xicities. Nat Re v Cli n O nc ol. 2 0 1 8; 1 5( 1): 4 7 - 6 2.
4 0.  
D urie B G M, H oeri n g A, A bi di M H, et al. B ortez o mi b wit h le nali d o mi de a n d 
de xa met has o ne vers us le nali d o mi de a n d de xa met has o ne al o ne i n patie nts wit h ne wl y  
dia g n ose d m y el o ma wit h o ut i nte nt f or i m me diate a ut ol o g o us ste m- cell tra ns pla nt 
( S W O G S 0 7 7 7): a ra n d o mise d, o pe n-la bel, p hase 3 trial. La ncet. 
2 0 1 7; 3 8 9( 1 0 0 6 8): 5 1 9 -2 7.
4 1.
Fac o n T, K u mar S, Ples ner T, et a l. Darat u m u ma b pl us Le nali d o mi de a n d 
De xa met has o ne f or U ntreate d M yel o ma. N E n gl J Me d. 2 0 1 9; 3 8 0( 2 2): 2 1 0 4 - 1 5.
4 2.  
Wa n g D D, Z ha n g S, Z ha o H, et al. Fi xe d d osi n g vers us b o d y size -base d d osi n g of 
m o n ocl o nal a nti b o dies i n a d ult cli nical trials. J Cli n P har mac o l. 2 0 0 9; 4 9( 9): 1 0 1 2- 2 4.
4 3.
Z ha n g S, S hi R, L i C, et al. Fi xe d d osi n g vers us b o d y size- base d d osi n g of t hera pe utic 
pe pti des a n d pr otei ns i n a d ults. J Cli n P har mac ol. 2 0 1 2; 5 2( 1): 1 8 - 2 8.
4 4. 
T o p p M S, G o k b u get N, Z u g maier G, et al. P hase II trial of t he a nti- C D 1 9 bis pecific T 
cell-e n ga ger bli nat u m o ma b s h o ws he mat ol o gic a n d m olec ular re missi o ns i n patie nts 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 0
wit h rela pse d or refract or y B -prec urs or ac ute l y m p h o blastic le u ke mia. J Cli n O nc ol. 
2 0 1 4; 3 2( 3 6): 4 1 3 4 - 4 0.
4 5.
Raj k u mar S V, Di m o p o ul os M A, Pal u m b o A, et al. I nte r nati o nal Myel o ma W or ki n g 
Gr o u p u p date d criteria f or t he dia g n osis of m ulti ple m y el o ma. La ncet O nc ol. 
2 0 1 4; 1 5( 1 2):e 5 3 8 - 4 8.
4 6.
S mit h TJ, K hatc heressia n J, L y ma n G H, et al. 2 0 0 6 u p date of rec o m me n dati o ns f or 
t he use of w hite bl o o d cell gr o wt h fact ors: a n e vi de nce-base d cli nical practice 
g ui deli ne. J Cli n O nc ol. 2 0 0 6; 2 4( 1 9): 3 1 8 7- 2 0 5.
4 7.
Cars o n J L , G u yatt G, He d dle N M, et al. Cli nical Practice G ui deli nes Fr o m t he 
A A B B: Re d Bl o o d Cell Tra nsf usi o n T hres h ol ds a n d St ora ge. J A M A. 
2 0 1 6; 3 1 6( 1 9): 2 0 2 5 -3 5.
4 8.
Sc hiffer C A, B o hl ke K, Dela ne y  M, et al. Platelet Tra nsf usi o n f or Patie nts Wit h 
Ca ncer: A merica n S ociet y of Cli nical O nc ol o g y  Cli nical Practice G ui deli ne U p date. J 
Cli n O nc ol. 2 0 1 8; 3 6( 3): 2 8 3- 9 9.
4 9. 
Ric har ds o n P G, Delf or ge M, Be ksac M, et al. Ma na ge me nt of treat me nt-e mer ge nt 
peri p heral ne ur o pat h y i n m ulti ple m y el o ma. Le u ke mia. 2 0 1 2; 2 6( 4): 5 9 5 -6 0 8.
5 0. 
T o p p M S, D uell J, Z u g maier G, et al. A nti- B- Cell Mat urati o n A nti ge n Bi T E 
M olec ule A M G 4 2 0 I n d uces Res p o nses i n M ulti ple M y el o ma. J Cli n O nc ol. 
2 0 2 0; 3 8( 8): 7 7 5 - 8 3.
5 1. 
F a nale M, Fa ya d L, Pr o B, et al. P hase I st u d y of b ortez o mi b pl us IC E ( BI C E) f or t he 
treat me nt of rela pse d/refract or y H o d g ki n ly m p h o ma. Br J Hae mat ol. 
2 0 1 1; 1 5 4( 2): 2 8 4 - 6.
5 2.
Ji Y, Li u P, Li Y, et al. A m o difie d t o xicit y pr o ba bilit y i nter val met h o d f or d ose-
fi n di n g trials. Cli n Trials. 2 0 1 0; 7( 6): 6 5 3- 6 3.
5 3.
O ke n M M, Creec h R H, T or me y  D C, et al. T o xicit y a n d res p o nse criteria of t he 
Easter n C o o perati ve O nc ol o g y  Gr o u p. A m J Cli n O nc ol. 1 9 8 2; 5( 6): 6 4 9-5 5.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 1
A p pe n di x 1. A B B R E VI A TI O N S
T he f oll o wi n g is a list of a b bre viati o ns t hat ma y be use d i n t he pr ot oc ol.  
A b bre vi ati o n
Ter m
A A B B
A merica n Ass ociati o n of Bl o o d Ba n ks
A C RI N
A merica n C olle ge of Ra di ol o g y  Ima gi n g Net w or k
A C T H
a dre n oc ortic otr o pic h or m o ne
A D A
a nti-dr u g a nti b o dies
A D L
acti vities of dail y li vi n g
A E
a d verse e ve nt
A H A
A merica n Heart Ass ociati o n
AI D S
ac q uire d i m m u n o deficie nc y  sy n dr o me
A L K
a na plastic l y m p h o ma ki nase
A L L
ac ute l y m p h o blastic le u ke mia
A L T
ala ni ne a mi n otra nsferase
A N C
a bs ol ute ne utr o p hil c o u nt
A N O V A
a nal ys is of varia nce
A P Cs
a nti ge n prese nti n g cells
A P RI L
a pr oliferati o n-i n d uci n g li ga n d
A S C O
A merica n S ociet y of Cli nical O nc ol o g y
A S C T
a ut ol o g o us ste m cell tra ns pla nt 
A S T
as partate a mi n otra nsferase
A S T C T
A merica n S ociet y f or Tra ns pla ntati o n a n d Cell ular T hera py
A U C
area u n der t he c ur ve
A U C 1 6 8
area u n der t he c ur ve meas ure d t o 1 6 8 h o urs
A U C i nf
area u n der t he c o nce ntrati o n vers us ti me c ur ve t o i nfi nit y
A U C last
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me 
zer o t o ti me of last meas ura ble c o nce ntrati o n 
A U C s d,
area u n der t he si n gle d ose c o nce ntrati o n -ti me c ur ve o ver 
d osi n g i nter val 
A U C 
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me 
zer o t o ti me t
a ut o-H S C T
a ut ol o g o us he mat o p oietic ste m cell tra ns pla ntati o n
A V
A tri o ve ntric ular
B B S
bi os peci me n ba n ki n g s yste m
B C M A
B -cell mat urati o n a nti ge n
BI D
t wice daily
B M
b o ne marr o w
B MI
b o d y  mass i n de x
B N P
B -t ype natri uretic pe pti de
B O R
best o verall res p o nse
B P
bl o o d press ure
B U N
bl o o d urea nitr o ge n
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 2
A b bre vi ati o n
Ter m
C
C y cle
C B C
c o m plete bl o o d c o u nt
C 0 D 1
C y cle 0 Da y 1
C 1 D 1
C y cle 1 Da y 1
C A R
c hi meric a nti ge n rece pt ors
C a v
a vera ge c o nce ntrati o n
C B
cli nical be nefit
C B R
cli nical be nefit rate
C D
cl uster of differe ntiati o n 
C E A
carci n oe m br yo nic a nti ge n
Ceff
efficaci o us c o nce ntrati o n
C H F
c o n gesti ve heart fail ure
CI
c o nfi de nce i nter val
C K
creati ne ki nase
C K -M B
creati ne ki nase M B
C L
cleara nce
C L / F
cleara nce after n o n -i ntra ve n o us a d mi nistrati o n
C ma x
ma xi m u m ( or pea k) c o nce ntrati o n
C mi n
mi ni m u m c o nce ntrati o n
C M V
c yt o me gal o vir us
C N S
ce ntral ner v o us s ys te m
C O VI D -1 9
c or o na vir us disease 2 0 1 9
C R
c o m plete res p o nse
C R A B
calci u m ele vati o n, re nal fail ure, a ne mia, l yt ic b o ne lesi o ns; 
Cra nial ner ve VI
a b d uce ns ner ve
Cr Cl
creati ni ne cleara nce
C R F
case re p ort f or m
C R h
c o m plete re missi o n wit h partial he mat ol o gical rec o ver y
C R P
C -reacti ve pr otei n
C R R
c o m plete res p o nse rate
C R S
c yt o ki ne release sy n dr o me
C S A
cli nical st u d y a gree me nt
C S F
cere br os pi nal fl ui d
C S R
cli nical st u d y re p ort
C T
c o m p ute d t o m o gra p h y
C T S A E
cli nical trial seri o us a d verse e ve nt
C T A
cli nical trial a p plicati o n
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C X D 1
C y cle X Da y 1
C Y P 3 A 4
C y t oc hr o me P 4 5 0 3 A 4
C V
c oefficie nt of variati o n
D C R
disease c o ntr ol rate 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 3
A b bre vi ati o n
Ter m
D DI 
dr u g -dr u g i nteracti o n
D F S
disease free s ur vi val
DI LI
dr u g -i n d uce d li ver i nj ur y
D LI
D o n or L y m p h oc y te I nf usi o n
D L T
d ose -li miti n g t o xicit y
D M C
data m o nit ori n g c o m mittee
D N A
de o x yri b o n ucleic aci d
D o C R
d urati o n of c o m plete res p o nse
D O R
d urati o n of res p o nse
D O S D
d urati o n of sta ble disease
D U
dis pe nsa ble u nit
E B V
e pstei n-barr vir us
E C
et hics c o m mittee
E C 2 0
effecti ve c o nce ntrati o n 2 0
E C 5 0
effecti ve c o nce ntrati o n 5 0
E C G
Electr ocar di o gra m
ec h o
Ec h ocar di o gra m
E C O G
Easter n C o o perati ve O nc ol o g y  Gr o u p
e C R F
electr o nic case re p ort f or m
E -D M C
e xter nal data m o nit ori n g c o m mittee
E D P
e x p os ure d uri n g pre g na nc y
E D V
e n d-diast olic v ol u me
E E G
E lectr oe nce p hal o gra m
e g
f or e xa m ple
E G F R
e pi der mal gr o wt h fact or rece pt or 
EI
e q ui vale nce i nter val
E M G
electr o m y o gra p h y
E O S
e n d of st u d y
E O T
e n d of treat me nt
E S C
E ur o pea n S ociet y of Car di ol o g y
E S V
e n d-s yst olic v ol u me
Etc
‘a n d ot her t hi n gs’ or ‘a n d s o f ort h’
E U
E ur o pea n U ni o n
E u dra C T
E ur o pea n Cli nical Trials Data base
F A P
fi nal a p pr o ve d pr ot oc ol
Fc
fra g me nt cr ystalliza ble
F D A
F o o d a n d Dr u g A d mi nistrati o n ( U nite d States)
F D G -P E T/ C T
fl u or o de o xy gl uc ose p ositr o n e missi o n t o m o gra p h y/c o m p ute d 
t o m o gra p hy
FI P
first i n patie nt
FI S H
fl u oresce nce i n sit u h y bri dizati o n
F L C
free li g ht c hai n a nalys is
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 4
A b bre vi ati o n
Ter m
F S H
f ollicle-sti m ulati n g h or m o ne
G B S
G uillai n -Barré S y n dr o me
G C P
G o o d Cli nical Practice
G G T
ga m ma -gl uta m y l tra nsferase
G H
gr o wt h h or m o ne
GI
gastr oi ntesti nal tract
G L P
G o o d La b orat or y  Practice
G M -C S F
gra n ul oc y te- macr o p ha ge c ol o n y  sti m ulati n g fact or
G n R H
g o na d otr o pi n -releasi n g h or m o ne a g o nist
G v H D
graft -vers us -h ost disease
H b A 1c
he m o gl o bi n A 1c
H Bc
he patitis B c ore
H Bc A b
he patitis B c ore a nti b o d y
H Bs
he patitis B s urface
H Bs A g
he patitis B s urface a nti ge n
H B V
he patitis B vir us
H C V
he patitis C vir us
H g b
He m o gl o bi n
HI V
h u ma n i m m u n o deficie nc y vir us
H L A
h u ma n le u k oc y te a nti ge n
H L H
L y m p h o histi oc y t osis
H R
heart rate
hrs
H o urs
H T L V
h u ma n T -cell l y m p h otr o pic vir us
I B
i n vesti gat or’s br oc h ure
I C A N S
I m m u ne Effect or Cell-Ass ociate d Ne ur ot o xicit y  S yn dr o me
I C D
I nf or me d c o nse nt d oc u me nt
I C E
I m m u ne Effect or Cell -Ass ociate d E nce p hal o pat h y
I C H
I nter nati o nal C o nfere nce o n Har m o nizati o n
I C P
I ntracra nial press ure
I C U
i nte nsi ve care u nit
I D
I de ntificati o n
ie
t hat is
I F N
i nterfer o n ga m ma
I g
I m m u n o gl o b uli n
I GF -1
I ns uli n-li ke gr o wt h fact or 1
I g G 2 Δa
i m m u n o gl o b uli n G 2 Δa
I g Gk
i m m u n o gl o b uli n G ka p pa
I H C
I m m u n o hist oc he mistr y
I L-
I nterle u ki n
I Mi D
i m m u n o m o d ulat or y dr u g
I M W G
i nter nati o nal m yel o ma w or ki n g gr o u p
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 5
A b bre vi ati o n
Ter m
I ND
i n vesti gati o nal ne w dr u g a p plicati o n
I N R
i nter nati o nal n or malize d rati o
I P ma n ual
I n vesti gati o nal Pr o d uct ma n ual
I R
I m m u ne-relate d
I RB
i nstit uti o nal re vie w b oar d
I R C
i nter nal re vie w c o m mittee
I R R
i nf usi o n relate d reacti o n
I S R
i njecti o n site reacti o n 
I T T
i nte nt t o treat
I UD
i ntra uteri ne de vice
I V
I ntra ve n o us
K 2E D T A
di p otassi u m e detic aci d et h yle ne dia mi netetraacetic aci d
K D
e q uili bri u m diss ociati o n c o nsta nt
L B B B
left b u n dle bra nc h bl oc k
L D H
lactate de hy d r o ge nase
L F T
li ver f u ncti o n test
L H
l utei nizi n g h or m o ne
L P F V
last patie nt first visit
L S L V
last s u bject last visit
L T F U
l o n g-ter m f oll o w-u p
L V E F
left ve ntric ular ejecti o n fracti o n
M
M o n ocl o nal
m A b
m o n ocl o nal a nti b o d y
M A B E L
mi ni m u m a ntici pate d bi ol o gical effect le vel
M A D
ma xi m u m a d mi nistere d d ose
M A D -1
1 d ose le vel bel o w t he M A D
M A S
macr o p ha ge acti vati o n s y n dr o me
M D
m ulti ple d ose
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
M F C
m ulti para metric fl o w c y t o metr y
M F D
ma xi m u m feasi ble d ose
M G U S
m o n ocl o nal ga m m o pat h y of u n deter mi ne d cli nical 
si g nifica nce
M H C
maj or hist oc o m pati bilit y  c o m ple x 
M M
m ulti ple m y el o ma
M M 1. S
a gl uc oc ortic oi d se nsiti ve m ulti ple m y el o ma cell li ne
M O L P- 8
a m ulti ple m yel o ma cell li ne wit h t( 1 1; 1 4)( q 1 3; q 3 2) 
c hr o m os o mal a b n or malit y a n d ne gati ve f or C D 2 8
M -Pr otei n
m y el o ma pr otei n
M R
mi ni mal res p o nse
M R D
mi ni mal resi d ual disease
M RI
ma g netic res o na nce i ma gi n g
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 6
A b bre vi ati o n
Ter m
M -s pi ke
m o n ocl o nal s pi ke
M T D
ma xi m u m t olerate d d ose
M T D- 1
1 d ose bel o w t he M T D
m T PI
m o difie d t o xicit y  pr o ba bilit y i nter val
M U G A
m ulti gate d ac q uisiti o n sca n
N 
n u m ber
N/ A
n ot a p plica ble
N A b
ne utralizi n g a nti b o d y
N CI  
Nati o nal Ca ncer I nstit ute 
N C T
Nati o nal Cli nical Trial
N C V
Ner ve c o n d ucti o n vel ocit y
N G F
ne xt ge nerati o n fl o w c y t o metr y
N G S
ne xt ge nerati o n se q ue nci n g
N K
nat ural killer
N O A E L
n o o bser ve d a d verse effect le vel
N S AI D S
n o nster oi dal a nti -i nfla m mat or y dr u gs
N S C L C
n o n -cell s mall cell l u n g ca ncer
N S G
N O D sci d ga m ma 
O B D
o pti mal bi ol o gical d ose
O P M -2
a t ype of m ulti ple m y el o ma cell li ne
O R
o bjecti ve res p o nse or o verall res p o nse
O R R
o bjecti ve res p o nse rate
O S
o verall s ur vi val
P A C L
Pr ot oc ol A d mi nistrati ve C ha n ge Letter
Pa O 2
partial press ure of o x y ge n
P C D
pri mar y  c o m pleti o n date
P D
p har mac o d y n a mic, pr o gressi ve disease
P E T
p ositr o n e missi o n t o m o gra p h y
P F S
pr o gressi o n -Free S ur vi val
P G x
p har mac o ge n o mics
PI
pri nci pal i n vesti gat or
P K
p har mac o ki netic
P M L
p r o gressi ve m ultif ocal le u k oe nce p hal o pat hy
P O
b y  m o ut h
P O E M S
p ol y ne ur o pat h y , or ga n o me gal y, e n d ocri n o pat h y, m yel o ma 
pr otei n, a n d s ki n c ha n ges
P P
p osteri or pr o ba bilit y
P P P
pre g na nc y  pre ve nti o n pr o gra m
P R
partial res p o nse
P R L
P r olacti n
P S
perf or ma nce stat us
P T
pr ot hr o m bi n ti me
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 7
A b bre vi ati o n
Ter m
P T T
partial t hr o m b o plasti n ti me
Q 1 W
e ver y wee k
Q 2 W
ever y  2 wee ks 
Q 3 W
e ver y t hree wee ks
Q 4 W
e ver y f o ur wee ks
Q D
e ver y da y
q P C R
q ua ntitati ve p ol y merase c hai n reacti o n 
Q T
ti me bet wee n t he start of t he Q wa ve a n d t he e n d of t he 
T wa ve
Q Tc
c orrecte d Q T i nter val
Q Tc B
c orrecte d Q T i nter val b y Bazett
Q Tc F
C orrecte d Q T i nter val b y Fri dericia
R ac
acc u m ulati o n rati o
R C L
re plicati o n c o m pete nt le nti vir us
R D
res p o nse/re missi o n d urati o n 
R E M S
ris k e val uati o n a n d miti gati o n strate g y 
R N A
ri b o n ucleic aci d
R O
rece pt or occ u pa nc y
R P 2 D
rec o m me n de d P hase 2 d ose
R R
res p o nse rate
R T -P C R
re verse tra nscri pti o n p ol y merase c hai n reacti o n
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S A R S -C o V -2
se vere ac ute res pirat or y s yn dr o me c or o na vir us -2
S B P
s yst olic bl o o d press ure
S C
S u bc uta ne o us
S C C H N
s q ua m o us cell ca ncer of hea d a n d nec k
sc F v
si n gle-c hai n varia ble fra g me nt
S C L C
s mall cell l u n g ca ncer
s C R
stri n ge nt c o m plete res p o nse
S C T
ste m cell tra ns pla nt
S D
sta ble disease
SI F E
ser u m i m m u n ofi xati o n electr o p h oresis 
sIL 2 R 
s ol u ble i nterle u ki n- 2 rece pt or al p ha 
S L A M F 7
Si g nali n g l y m p h oc y tic acti vati o n m olec ule F 7
S o A
Sc he d ule of Acti vities
S O C
sta n dar d of care
S O P
sta n dar d o perati n g pr oce d ure
S P C
S u m mar y  of Pr o d uct C haracteristics
S P D
s u m of t he pr o d ucts of t he ma xi mal per pe n dic ular dia meters 
of meas ure d lesi o ns
S P E P
ser u m pr otei n electr o p h oresis
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 8
A b bre vi ati o n
Ter m
S R S D
si n gle refere nce safety d oc u me nt
S T R
s h ort ta n de m re peat
S U V
sta n dar d u pta ke val ue
S W O G
s o ut h west o nc ol o g y gr o u p
T 1/ 2
ter mi nal eli mi nati o n half-life
T A L E N
tra nscri pti o n acti vat or-li ke effect or n ucleases
T B D
t o be deter mi ne d
T Bili
t otal bilir u bi n
T B N K
T -, B-, a n d nat ural killer l ym p h oc y tes
T B R
t u m or bac k gr o u n d rati o
T C R
T -cell rece pt or 
T E A E
treat me nt-e mer ge nt a d verse e ve nt
T L S
t u m or l ysis s yn dr o me
T ma x
ti me t o ma xi m u m c o nce ntrati o n
T N F
t u m or necr osis fact or
T N F 
t u m or necr osis fact or – al p ha
T N F R S F 1 7
t u m or necr osis fact or rece pt or s u perfa mil y Me m ber 1 7
T R A C
T -cell rece pt or al p ha c o nsta nt 
T R A Es
Treat me nt -e mer ge nt treat me nt -relate d a d verse e ve nts
Tre gs
T re g ulat or y  cells
T ss, ma x
ti me t o ma xi m u m c o nce ntrati o n
T T P
ti me t o pr o gressi o n
T T R
ti me t o res p o nse
U C
ur ot helial carci n o ma
U K
U nite d Ki n g d o m
UI F E
uri ne i m m u n ofi xati o n electr o p h oresis
U L N
u p per li mit of n or mal
U P E P
uri ne pr otei n electr o p h oresis
U P M
u nit pr o ba bilit y  mass
U S
U nite d States
U S PI
U nite d States pac ka ge i nsert
U V B
ultra vi olet B 
V C N
vect or c o p y n u m ber
V G P R
ver y  g o o d partial res p o nse
V ss
v ol u me of distri b uti o n at stea d y  state
V ss/ F
a p pare nt v ol u me of distri b uti o n after n o n -i ntra ve n o us 
a d mi nistrati o n
W B C
w hite bl o o d cell 
w ks
Wee ks
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 9
A p pe n di x 2. T H E I N T E R N A TI O N A L M Y E L O M A W O R KI N G G R O U P (I M W G) 
R E S P O N S E C RI T E RI A F O R M U L TI P L E M Y E L O M A 
All res p o nse cate g ories re q uire t w o c o nsec uti ve assess me nts ma de a n y ti me bef ore starti n g 
a n y ne w t hera p y.  Patie nts m ust ha ve meas ura ble disease at e nr oll me nt (st u d y e ntr y).  
Meas ura ble disease is defi ne d as: 

Ser u m M -pr otei n 0. 5 g/ d L ( 5 g/ L); ( See i ncl usi o n criteria f or m o dificati o ns);

Uri ne M -pr otei n 2 0 0 m g / 2 4 h;

Ser u m F L C assa y : i n v ol ve d F L C le vel 1 0 m g / d L pr o vi de d ser u m F LC rati o is 
a b n or mal.
W he ne ver m ore t ha n o ne para meter is use d t o assess res p o nse, t he o verall assi g ne d le vel of 
res p o nse is deter mi ne d b y t he l o wer or l o west le vel of res p o nse.  Patie nts will c o nti n ue i n t he 
last c o nfir me d res p o nse cate g or y u ntil t here is c o nfir mati o n of pr o gressi o n or i m pr o ve me nt 
t o a hi g her res p o nse stat us; patie nts ca n n ot m o ve t o a l o wer res p o nse cate g or y.
Res p o nse
I M W G Criteri a
Stri n ge nt 
C o m plete 
Res p o nse (s C R) 

C o m plete res p o nse as defi ne d bel o w pl us n or mal free li g ht c hai n 
( F L C) rati o a n d a bse nce of cl o nal cells i n b o ne marr o w bi o psy b y 
i m m u n o hist oc he mistr y ( κ/rati o ≤4: 1 or ≥1: 2 f or κ a n d patie nts, 
res pecti vely, after c o u nti n g ≥1 0 0 plas ma cells) .2

I n patie nts w here by t he o nl y  meas ura ble disease is b y ser u m F L C 
le vels, s C R is defi ne d as n or mal F L C rati o of 0. 2 6 t o 1. 6 5 pl us 
a bse nce of cl o nal cells i n b o ne marr o w as defi ne d a b o ve.
C o m plete 
R es p o nse ( C R)

Ne gati ve i m m u n ofi xati o n o n t he ser u m a n d uri ne a n d 
disa p peara nce of a n y s oft tiss ue plas mac yt o mas a n d < 5 % plas ma 
cells i n b o ne marr o w as pirates .1

In patie nts w here b y  t he o nl y meas ura ble disease is b y ser u m F L C 
le vels, C R is defi ne d as n or mal F L C rati o of 0. 2 6 t o 1. 6 5 pl us 
criteria liste d a b o ve.
V er y G o o d 
P artial R es 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 elect r o p h oresis.
or

9 0 % re d ucti o n i n ser u m M- pr otei n pl us uri ne M -pr otei n le vel 
< 1 0 0 m g/ 2 4 hr.

I n patie nts w here by t he o nl y  meas ura ble disease is b y ser u m F L C 
le vels, V G P R is defi ne d as a > 9 0 % decrease i n t he differe nce 
bet wee n i n v ol ve d (t u m or) a n d u ni n v ol ve d ( n o n-t u m or) ser u m F LC 
le vels.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1 0
Res p o nse
I M W G Criteri a
Partial Res p o nse 
( P R)

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 urs 
uri nar y  M-pr otei n b y  9 0 % or t o < 2 0 0 m g / 2 4 hr.

If t he ser u m a n d uri ne M-pr otei n are u n meas ura ble, 4 a 
≥5 0 % decrease i n t he differe nce bet wee n i n v ol ve d a n d u ni n v ol ve d 
F L C le vels is re q uire d i n place of t he M- pr otei n criteria.

I n patie nts w here by t he o nl y  meas ura ble disease is b y ser u m F L C 
le vels, P R is defi ne d as 5 0 % re d ucti o n i n differe nce bet wee n 
i n v ol ve d a n d u ni n v ol ve d F LC.

I n a d diti o n t o t hese criteria, if prese nt at baseli ne, a 5 0 % 
re d ucti o n i n t he size ( S P D)2 of s oft tiss ue plas mac y t o mas is als o 
re q uire d.  
Mi ni mal 
Res p o nse ( M R)
≥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 
uri ne M -pr otei n b y 5 0 – 8 9 %.  I n a d diti o n t o t he a b o ve liste d criteria, if 
prese nt at baseli ne, a 5 0 % re d ucti o n i n t he size (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]) 3
of s oft tiss ue plas ma c yt o mas is als o re q uire d.
N o 
C ha n ge/ Sta ble 
D isease ( S D)
N ot meeti n g criteria f or C R, V G P R, P R, M R or pr o gressi ve disease .
Pr o gressi ve 
D isease ( P D)5
A n y  o ne or m ore of t he f oll o wi n g criteria:

I ncrease of 2 5 % fr o m l o west res p o nse val ue i n a n y  o ne or m ore 
of t he f oll o wi n g:

Ser u m M -c o m p o ne nt a n d/ or (t he a bs ol ute i ncrease m ust be 
0. 5 g/ d L); 4

Ser u m M -pr otei n i ncrease 1 g/ d L, if t he l o west M c o m p o ne nt 
was 5 g/ d L;

Uri ne M -c o m p o ne nt a n d/ or (t he a bs ol ute i ncrease m ust be 
2 0 0 m g/ 2 4 hr.

I n patie nts wit h o ut meas ura ble ser u m a n d uri ne M-pr otei n 
le vels, 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 p peara nce of a ne w lesi o n(s), 5 0 % i ncrease fr o m na dir i n S P D 1
of > 1 lesi o n, 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 .
Cli nical Rela pse
Cli nical rela pse re q uires o ne or m ore of t he f oll o wi n g criteria:
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1 1
Res p o nse
I M W G Criteri a

Direct i n dicat ors of i ncreasi n g disease a n d/ or e n d or ga n 
d y sf u ncti o n ( C R A B feat ures) relate d t o t he u n derl yi n g cl o nal 
plas ma -cell pr oliferati ve dis or der; 

De vel o p me nt of ne w s oft tiss ue plas mac y t o mas or b o ne 
lesi o ns ( oste o p or otic fract ures d o n ot c o nstit ute pr o gressi o n);

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 
≥1 c m) i ncrease as meas ure d seriall y b y t he S P D 3 of t he 
meas ura ble lesi o n;

H y percalce mia ( > 1 1 m g / d L);

Decrease i n he m o gl o bi n of ≥2 g/ d L n ot relate d t o t hera p y or 
ot her n o n -m y el o ma-relate d c o n diti o ns;

Rise i n ser u m creati ni ne b y  2 m g / d L or m ore fr o m t he start of 
t he t hera py a n d attri b uta ble t o m y el o ma;

H y per visc osit y relate d t o ser u m para pr otei n.
C R A B feat ures =calci u m ele vati o n, re nal fail ure, a ne mia, l ytic b o ne lesi o ns; I M W G =I nter nati o nal M yel o ma 
W or ki n g Gr o u p; F L C =free li g ht c hai n; M -pr otei n = m yel o ma pr otei n; S P D =s u m of t he pr o d ucts of t he 
ma xi mal per pe n dic ular dia meters of meas ure d lesi o ns.
F o ot n otes:
1.
C o nfir mati o n wit h re peat b o ne marr o w  bi o ps y n ot re q uire d.  Caref ul atte nti o n s h o ul d be gi ve n t o ne w 
p ositi ve i m m u n ofi xati o n res ults a p peari n g i n patie nts w h o ha ve ac hie ve d a c o m plete res p o nse, w he n
t he is ot y pe is differe nt.  T his pr o ba bl y re prese nts oli g ocl o nal i m m u ne rec o nstit uti o n a n d s h o ul d n ot be 
c o nf use d wit h rela pse; t hese ba n ds t y picall y disa p pear o ver ti me.
2.
Prese nce/a bse nce of cl o nal cells o n i m m u n o hist oc he mistr y is base d u p o n t he κ/ / L rati o.  A n a b n or mal 
κ/ 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 κ/of > 4: 1 or < 1: 2.
3.
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 de dicate d C T 
sca ns w here a p plica ble.  Meas ure me nt of t u m or size will be deter mi ne d b y t he S P D.
4.
All rela pse cate g ories re q uire t w o c o nsec uti ve assess me nts ma de at a n y ti me bef ore classificati o n as 
rela pse or disease pr o gressi o n a n d/ or t he i nstit uti o n of a n y ne w t hera p y.  T o c o nfir m res p o nse or 
pr o gressi ve disease, t w o discrete sa m ples are re q uire d a n d testi n g ca n n ot be base d u p o n t he s plitti n g of 
a si n gle sa m ple.   I n t he I M W G criteria, C R patie nts m ust als o meet t he criteria f or pr o gressi ve disease 
s h o w n here t o be classifie d as pr o gressi ve disease f or t he p ur p oses of calc ulati n g ti me t o pr o gressi o n 
a n d pr o gressi o n -free s ur vi val.  T he defi niti o ns of rela pse, cli nical rela pse a n d rela pse fr o m C R are n ot 
t o be use d i n calc ulati o n of ti me t o pr o gressi o n or pr o gressi o n free s ur vi val.   Patie nts will be 
c o nsi dere d t o ha ve pr o gressi ve disease if t he y meet t he criteria f or pr o gressi o n b y a varia ble t hat was 
n ot c o nsi dere d meas ura ble at baseli ne; h o we ver, f or patie nts w h o ha d a meas ura ble ser u m or uri ne 
M -s pi ke at baseli ne, pr o gressi o n ca n n ot be defi ne d b y i ncreases i n ser u m F L C al o ne.
5.
F or pr o gressi ve disease, ser u m M -c o mp o ne nt i ncreases of ≥1 m g/ d L are s ufficie nt t o defi ne rela pse if 
starti n g M-c o mp o ne nt is ≥5 g/ d L.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1 2
A p pe n di x 3. I M W G MI NI M A L R E SI D U A L DI S E A S E
( M R D) Criteri a
Assess f or M R D (at least b y  ce ntrall y c ollecte d fl o w c yt o metr y a n d se q ue nci n g) f or all b o ne 
marr o w as pirates o btai ne d w hile a patie nt is i n s us pecte d or act ual C R . C o nfir mati o n wit h 
t w o c o nsec uti ve assess me nts is n ot re q uire d.
Res p o nse
I M W G Criteri a
S ustai ne d 
M R D - ne gati ve 1
M R D ne gati vit y  i n t he marr o w (N G S ) a n d by 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 -ne gati ve 2
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 -ne gati ve
A bse nce of cl o nal plas ma cells b y N G S o n b o ne marr o w as pirate 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 ym 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 05 n ucleate d cells or 
hi g her .
I ma gi n g-p ositi ve
M R D -ne gati ve
M R D ne gati vit y  as defi ne d b y N G S pl us disa p peara nce of e ver y area 
of i ncrease d tracer u p ta 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 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.
C T = c o m p ute d t o m o gra p h y; I M W G =I nter nati o nal M yel o ma W or ki n g Gr o u p; M R D = m i ni mal resi d ual 
disease; N G F = ne xt -ge nerati o n fl o w c yt o metr y; N G S = ne xt ge nerati o n se q ue nci n g; p ositr o n e missi o n 
t o mo gra p h y = P E T; S U V = sta n dar dize d u pta ke val ue.
F o ot n otes
1.
S ustai ne d M R D ne gati vit y, w he n re p orte d, s h o ul d als o a n n otate t he met h o d use d (e g, s ustai ne d 
se q ue nci n g M R D- ne gati ve).
2.
B o ne marr o w  m ulti para metric fl o w  c yt o metr y M F C s h o ul d f oll o w  N G F g ui deli nes.  T he refere nce 
N G F met h o d is a n ei g ht -c ol or t wo- t u be a p pr oac h, w hic h has bee n e xte nsi vel y vali date d.  T he t w o -t u be 
a p pr oac h i m pr o ves relia bilit y, c o nsiste nc y, a n d se nsiti vit y beca use of t he ac q uisiti o n of a greater 
n u m ber of cells.  T he c o m plete ei g ht -c ol or met h o d s h o ul d use a l y o p hilize d mi xt ure of a nti b o dies.  
5 mi lli o n cells s h o ul d be assesse d.  T he met h o d e m pl o ye d s h o ul d ha ve a se nsiti vit y of detecti o n of at 
least 1 i n 1 0 5 plas ma cells.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M




P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1 4
A p pe n di x 5. C R S A N D I C A N S MI TI G A TI O N A N D M A N A G E M E N T
C R S is a n o n -a nti ge n-s pecific c yt o ki ne-ass ociate d t o xicit y t hat occ urs as a res ult of 
hi g h -le vel i m m u ne acti vati o n.  C R S is a p ote ntiall y life-t hreate ni n g t o xicit y t hat has bee n 
o bser ve d f oll o wi n g a d mi nistrati o n of i m m u ne -base t hera pies f or ca ncer (a nti b o dies a n d 
a d o pti ve T-cell t hera pies).  C R S is li kel y t o be a c o m m o n t o xicit y t hat ca n be ma na ge d 
t hr o u g h s u p p orti ve care a n d a nti-c yt o ki ne i nter ve nti o ns. 
I n cases of s us pecte d c yt o ki ne release sy n dr o me, a ser u m sa m ple s h o ul d be pr o vi de d f or 
c yt o ki ne release assa y  a nal ysis b y t he l ocal la b (see Secti o n 7. 1. 3 ) s o as l o n g as t he sa m pli n g 
d oes n ot i nterfere w it h t he me dical treat me nt of t he patie nt.
Earl y i nter ve nti o n s h o ul d be u n derta ke n at t he first si g n of C R S; si g ns ma y  i ncl u de pyre xia, 
tac hycar dia, tac h y p nea a n d/ or h y p ote nsi o n a n d are te m p orall y relate d t o P F -0 6 8 6 3 1 3 5 i n t he 
a bse nce of alter nati ve eti ol o gies.  
T he ori gi nal C R S gra di n g s ys te m pr o p ose d by Lee et al i n 2 0 1 4 2 (Ta ble 1 3) s h o ul d be use d
o nl y  f or t he p ur p oses of gra di n g of C R S o n t he a d verse e ve nt case re p ort f or m ( C R F) , b ut n ot 
f or ma na ge me nt of C R S. Gra di n g b y  t he m ore rece nt A S T C T C R S criteria 3 (Ta ble 1 5 ) will 
be ca pt ure d al o n g wit h t he Lee et al 2 0 1 4 criteria o n t he C R S C R F , a n d ma na ge me nt 
g ui deli nes will f oll o w A S T C T C R S gra di n g. T hese treat me nt g ui deli nes3 9 ma y  be m o difie d 
as nee de d b y t he res p o nsi ble I n vesti gat or acc or di n g t o t he best practices at t heir i nstit ute .
T a ble 1 3.
Lee et al 2 0 1 4 C R S re vise d gr a di n g s yste m 2
T o xicit y 
Gr a de
C h ar acteristics
1
S y m pt o ms are n ot life t hreate ni n g a n d re q uire s y m pt o matic treat me nt 
o nl y , e g, Fe ver, na usea, fati g ue, hea dac he, m y al gia, malaise .
2
Gra de 2 h y p o xia * [ decrease d o x y ge n sat urati o n wit h acti vit y  (e g, p ulse 
o xi meter < 8 8 %); i nter mitte nt s u p ple me ntal o x yge n] ; or
H y p ote nsi o n res p o nsi ve t o fl ui ds or l o w - d ose of o ne vas o press or 
(Ta ble 1 4 ) or Gra de 2 or ga n t o xicit y .
3
Gra de 3 h y p o xia * [ decrease d o x y ge n sat urati o n at rest (e g, p ulse 
o xi meter < 8 8 % or partial press ure of o x y ge n ( Pa O 2) < = 5 5 m m H g)] ; or 
H y p ote nsi o n re q uiri n g hi g h -d ose vas o press ors or m ulti ple vas o press ors 
(Ta ble 1 4 ); or 
Gra de 3 or ga n t o xicit y  (e xce pt tra nsa mi nitis); or 
Gra de 4 tra nsa mi nitis .
4
Life -t hreate ni n g sy m pt o ms ;
Gra de 3 h y p o xia * [ decrease d o x y ge n sat urati o n at rest (e g, p ulse 
o xi meter < 8 8 % or partial press ure of o x y ge n ( Pa O 2) < = 5 5 m m H g)] or 
Gra de 4 or ga n t o xicit y  (e xcl u di n g tra nsa mi nitis).
5
D eat h.
* M o dificati o n t o t he Lee et al C R S Re vise d Gra di n g S yste m acc or di n g t o t he C T C A E v 4. 0 3.  Tra nsie nt 
decreases i n o x y ge n le vels bel o w  8 8 % will n ot be c o nsi dere d t o ha ve met t he criteria.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1 5
T he defi niti o ns f or hi g h -d ose vas o press ors are s h o w n i n Ta ble 1 4.
T a ble 1 4.
Defi niti o n of Hi g h D ose V as o press or
Press or
Hi g h D ose
( d oses less t ha n t hese w o ul d be c o nsi dere d l o w)
N ore pi ne p hri ne m o n ot hera p y
2 0 g/ mi n
D o pa mi ne m o n ot hera p y
1 0 g/ k g/ mi n
P he n y le p hri ne m o n ot hera p y
2 0 0 g/ mi n
E pi ne p hri ne m o n ot hera p y
1 0 g/ mi n
If o n vas o pressi n
Vas o pressi n + n ore pi ne p hri ne
e q ui vale nt of 1 0 g/ mi n *
If o n c o m bi nati o n vas o press ors
( n ot vas o pressi n)
N ore pi ne p hri ne e q ui vale nt of
2 0 g/ mi n *
* V A S S T Tri al v as o press or e q uiv ale nt e q u ati o n: n ore pi ne p hri ne e q uiv ale nt d ose = [ n ore pi ne p hri ne
(g/ mi n) ]
+ [ d o p a mi ne ( g/k g/ mi n) ÷ 2] + [e pi ne p hri ne ( g/ mi n) ] + [ p he nyle p hri ne ( g/ mi n) ÷ 1 0
T a ble 1 5 . A S T C T C R S re vise d gr a di n g s yste m 3
C R S p ar a meter:
Fe ver *
Wit h H y p ote nsi o n
A n d/ or † H y p o xi a
Gra de 1
T e m p. ≥3 8 °C
N o ne
N o ne
Gra de 2
T e m p. ≥3 8 ° C
N ot re q uiri n g vas o press ors
Re q uiri n g l o w -fl o w‡ nasal 
ca n n ula, l o w-fl o w‡ face mas k or 
bl o w -b y
Gra de 3
T e m p. ≥3 8 ° C
Re q uiri n g a vas o press or wit h or 
wit h o ut vas o pressi n
Re q uiri n g hi g h -fl o w‡ nasal 
ca n n ula, hi g h -fl o w‡ face mas k, 
n o nre breat her mas k, or Ve nt uri 
mas k
Gra de 4
T e m p. ≥3 8 ° C
Re q uiri n g m ulti ple vas o press ors 
(e xcl u di n g vas o pressi n)
Re q uiri n g p ositi ve press ure (e g, 
C P A P, Bi P A P, i nt u bati o n a n d 
mec ha nical ve ntilati o n)
Or ga n t o xicities ass ociate d wit h C R S s h o ul d still be gra de d acc or di n g t o C T C A E v 4. 0 3 a n d d o n ot 
i nfl ue nce C R S gra di n g.
* Fe ver is defi ne d as t e mperat ure ≥3 8 °C a n d n ot attri b uta ble t o a n y ot her ca use. I n patie nts w h o ha ve 
C R S t he n recei ve a nti p yretic or a ntic yt o ki ne t hera p y s uc h as t ociliz u ma b or ster oi ds, fe ver is n o l o n ger 
re q uire d t o gra de s u bse q ue nt C R S se verit y. I n t his case, C R S gra di n g is dri ve n b y h y p ote nsi o n a n d/ or 
h y p o xia.
† C R S gra de is deter mi ne d b y t he m ore se vere e ve nt: h y p ote nsi o n or h y p o xia n ot attri b uta ble t o a n y ot her 
ca use. F or e xa m ple, a patie nt wit h te m perat ure of 3 9. 5 °C h y p ote nsi o n re q uiri n g 1 vas o press or, a n d 
h y p o xia re q uiri n g l o w -fl o w nasal ca n n ula is classifie d as gra de 3 C R S.
‡ L o w -fl o w nasal ca n n ula or face mas k is defi ne d as o x y ge n deli vere d at ≤6 L/ mi n.  L o w fl o w  als o 
i ncl u des bl o w-b y  o x y ge n deli ver y, s o meti mes use d i n pe diatrics.  Hi g h-fl o w nasal ca n n ula or face mas k
is defi ne d as o x y ge n deli vere d at > 6 L/ mi n.  T his is m o difie d fr o m ori gi nal A S T C T criteria t o 
differe ntiate bet wee n l o w -fl o w a n d hi g h-fl o w face mas k.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1 6
C R S m a n a ge me nt g ui deli nes
3 8 ,3 9
A S T C T Gr a de 1 C R S:

M o nit or vital si g ns f or w orse ni n g of c o n diti o n .
Fe ver

Aceta mi n o p he n/ paraceta m ol a n d h y p ot her mia bla n ket f or t he treat me nt of fe ver .

N o n -ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds) s uc h as i b u pr ofe n ca n be use d 
as sec o n d treat me nt o pti o n f or fe ver if n ot c o ntrai n dicate d.

Assess f or i nfecti o n usi n g bl o o d a n d uri ne c ult ures, a n d c hest ra di o gra p h y.

E m piric br oa d -s pectr u m a nti bi otics a n d filgrasti m if ne utr o pe nic .

Mai nte na nce I V fl ui ds f or h ydrati o n .

S y m pt o matic ma na ge me nt of c o nstit uti o nal s y m pt o ms or or ga n t o xicit y .

C o nsi der t ociliz u ma b 8 m g/ k g * I V or silt u xi ma b 1 1 m g/ k g I V f or persiste nt 
(lasti n g > 3 da ys) a n d refract or y fe ver.
A S T C T Gr a de 2 C R S:

M o nit or vital si g ns e ver y 4
h o urs f or w orse ni n g of c o n diti o n.
Fe ver

Ma na ge as i n Gra de 1 C R S .
H y p ote nsi o n

I V fl ui d b ol us of 5 0 0-1 0 0 0 ml of n or mal sali ne . Ca n gi ve sec o n d I V fl ui d b ol us if 
s yst olic bl o o d press ure re mai ns < 9 0 m m H g.

C o nsi der t ociliz u ma b 8 m g/ k g ( ma xi m u m d ose 8 0 0 m g) I V or silt u xi ma b 
1 1 m g/ k g I V f or treat me nt of h y p ote nsi o n refract or y  t o fl ui d b ol uses; t ocilizu ma b 
ca n be re p eate d after 6 h if nee de d .

If hy p ote nsi o n persists after 2 fl ui d b ol uses a n d a nti -I L-6 t hera p y, start 
vas o press ors, c o nsi der tra nsfer t o i nte nsi ve care u nit (I C U), o btai n 
ec h ocar di o gra m ( E C H O), a n d i nitiate ot her met h o ds of he m o d yna mic m o nit ori n g .
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1 7

I n patie nts at hi g h-ris k ( b ul k y disease, ol der a ge or c o m or bi dities) or if 
h y p ote nsi o n persists after 1 -2 d oses o f a nti-I L-6 t hera p y , de xa met has o ne ca n be 
use d at 1 0 m g I V e ver y 6 hrs.
H y p o xi a

S u p ple me ntal o x y ge n .
T ociliz u ma b or silt u xi ma b ± c ortic oster oi ds a n d s u p p orti ve care, as i n dicate d f or 
h y p ote nsi o n .
A S T C T Gr a de 3 C R S:

M o nit or patie nt (i ncl u di n g c o nti n u o us E C G
m o nit ori n g) i n a n I C U a n d o btai n E C H O 
if n ot d o ne alrea dy.
Fe ver

Ma na ge as i n Gra de 1 C R S.
H y p ote nsi o n

I V b ol uses, as nee de d, as rec o m me n de d f or Gra de 2 C R S.

T ociliz u ma b a n d silt u xi ma b as rec o m me n de d f or Gra de 2 C R S if n ot 
a d mi nistere d pre vi o usl y.

Vas o pr ess ors as nee de d.

De xa met has o ne 1 0 m g I V e ver y 6 hrs; if refract or y, i ncrease t o 2 0 m g I V e ver y 
6 hrs .
H y p o xi a

S u p ple me ntal o x y ge n i ncl u di n g hi g h -fl o w o xy ge n deli ver y.

T ociliz u ma b or silt u xi ma b pl us c ortic oster oi ds a n d s u p p orti ve care, as descri be d 
a b o ve.
A S T C T Gr a de 4 C R S:

M o nit or patie nt (i ncl u di n g c o nti n u o us E C G m o nit ori n g) i n a n I C U a n d o btai n E C H O 
if n ot d o ne alrea dy.
Fe ver

Ma na ge as i n Gra de 1 C R S.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1 8
H y p ote nsi o n

I V b ol uses, a nti-I L-6 t hera p y , vas o press ors, a n d he m o d yna mic m o nit ori n g as 
rec o m me n de d f or gra de 3 C R S .

Met h y l pre d nis ol o ne 1 g/ da y IV .
H y p o xi a

S u p ple me ntal o x y ge n via p ositi ve press ure/ mec ha nical ve ntilati o n .

T ociliz u ma b or silt u xi ma b pl us c ortic oster oi ds a n d s u p p orti ve care, as descri be d 
a b o ve.
I m m u ne effect or cell- ass oci ate d ne ur ot o xicit y s y n dr o me (I C A N S)
Alt h o u g h less c o m m o nl y see n t ha n C R S, I CA N S has bee n o bser ve d wit h s o me T- cell 
directe d t hera pies a n d ma y  ma nifest as deliri u m, e nce p hal o pat h y, a p hasia, let har g y, diffic ulty 
c o nce ntrati n g, a gitati o n, tre m or, seiz ures, a n d cere bral e de ma. 3 If I CA N S is o bser ve d i n 
relati o n t o P F-0 6 8 6 3 1 3 5, t he A S T C T criteria 3 s h o ul d be f oll o we d f or its gra di n g a n d 
ma na ge me nt .3 8 ,3 9 T hese treat me nt g ui deli nes ma y be m o difie d as nee de d b y t he res p o nsi ble 
I n vesti gat or acc or di n g t o t he best practices at t heir i nstit ute.
T a ble 1 6.
I m m u ne Effect or Cell-Ass oci ate d E nce p h al o p at h y (I C E) Sc ore
C ate g or y
T as k
P oi nts
Orie ntati o n
Orie ntati o n t o y ear, m o nt h, cit y, h os pital
4
Na mi n g
A bilit y  t o na me 3 o bjects
3
F oll o wi n g c o m ma n ds
A bilit y  t o f oll o w si m ple c o m ma n ds
1
Writi n g
A bilit y  t o write a sta n dar d se nte nce
1
Atte nti o n
A bilit y  t o c o u nt bac k war ds fr o m 1 0 0 b y 1 0
1
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1 9
T a ble 1 7.
A S T C T I C A N S Gr a di n g
Ne ur ot o xicit y 
D o m ai n
Gr a de 1
Gr a de 2  
Gr a de 3
Gr a de 4
I C E sc ore*
7 - 9
3- 6 
0- 2
0 ( u nar o usa ble a n d 
u na ble t o perf or m 
I C E)
De presse d le vel 
of 
c o nsci o us ness †
A wa ke ns 
s p o nta ne o usl y
A wa ke ns 
t o v oice
A wa ke ns o nl y t o 
tactile sti m ul us
U nar o usa ble or 
re q uires vi g or o us or 
re petiti ve tactile 
sti m uli t o ar o use. 
St u p or or c o ma
Seiz ure
N/ A  
N/ A
A n y  cli nical 
seiz ure t hat 
res ol ves ra pi dly
or n o n -
c o n v ulsi ve 
seiz ures o n E E G 
t hat res ol ve wit h 
i nter ve nti o n
Life -t hreate ni n g 
pr ol o n ge d seiz ure 
( > 5 mi n); or re petiti ve
cli nical or electrical 
seiz ures wit h o ut ret ur n 
t o baseli ne i n bet wee n
M ot or fi n di n gs ‡
N/ A  
N/ A  
N/ A
Dee p f ocal m ot or 
wea k ness s uc h as 
he mi paresis or 
para paresis
Ele v ate d 
I C P/cere br al 
e de m a
N/ A  
N/ A
F ocal/l ocal 
e de ma o n 
ne ur oi ma gi n g ⁂
Diff use cere bral 
e de ma o n 
ne ur oi ma gi n g; 
decere brate or 
dec orticate p ost uri n g; 
or cra nial ner ve VI
(a b d uce ns ner ve )
pals y ; or pa pille de ma; 
or C us hi n g’s tria d
I C A N S gra de is deter mi ne d b y t he m ost se vere e ve nt (I C E sc ore, le vel of c o nsci o us ness, seiz ure, m ot or 
fi n di n gs, raise d i ntracra nial press ure[I C P]/cere bral e de ma) n ot attri b uta ble t o a n y ot her ca use; f or e xa m ple, a 
patie nt wit h a n I C E sc ore of 3 w h o has a g e neralize d seiz ure is classifie d as gra de 3 I C A N S.
* A patie nt wit h a n I C E sc ore of 0 ma y be classifie d as gra de 3 I C A N S if a wa ke wit h gl o bal a p hasia, b ut a 
patie nt wit h a n I C E sc ore of 0 ma y be classifie d as gra de 4 I C A N S if u nar o usa ble.
† De presse d le vel of  c o nsci o us ness s h o ul d be attri b uta ble t o n o ot her ca use (e g, n o se dati n g me dicati o n).
‡ Tre m ors a n d m y ocl o n us ass ociate d w it h i m m u ne effect or cell t hera pies ma y be gra de d acc or di n g t o 
C T C A E v 4. 0 3, b ut t he y d o n ot i nfl ue nce I C A N S gra di n g.
⁂
I ntracra nial he m orr ha ge wit h or wit h o ut ass ociate d e de ma is n ot c o nsi dere d a ne ur ot o xicit y feat ure a n d is 
e xcl u de d fr o m I C A N S gra di n g. It ma y be gra de d acc or di n g t o C T C A E v 4. 0 3.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2 0
I C A N S M a n a ge me nt g ui deli nes
3 8 ,3 9
A S T C T I C A N S Gr a de 1 :

Vi gila nt s u p p orti ve care; as pirati o n preca uti o ns; i ntra ve n o us (I V) h y drati o n .

Wit h h ol d oral i nta ke of f o o d, me dici nes, a n d fl ui ds, a n d assess s wall o wi n g .

C o n vert all oral me dicati o ns a n d/ or n utriti o n t o I V if s wall o wi n g is i m paire d .

A v oi d me dicati o ns t hat ca use ce ntral ner v o us s ys te m de pressi o n.

Ne ur ol o g y  c o ns ultati o n.

E val uate ele vate d i ntracra nial press ure (I C P), if s us pecte d, wit h f u n d osc o pic e xa m f or 
pa pille de ma a n d l u m bar p u nct ure f or cere br os pi nal fl ui d o pe ni n g press ure.

M a g netic res o na nce i ma gi n g (M RI )M RI of t he brai n wit h a n d wit h o ut c o ntrast; C T 
sca n of t he brai n ca n be perf or me d if M RI of t he brai n is n ot feasi ble.

Dail y  3 0 mi n electr oe nce p hal o gra m ( E E G) u ntil to xicit y  sy m pt o ms res ol ve; if n o 
seiz ures are detecte d o n E E G, c o nti n ue le vetiraceta m 7 5 0 m g e ver y 1 2 hrs.

C o nsi der a nti -I L-6 t hera p y  wit h t ociliz u ma b 8 m g/ k g ( ma xi m u m 8 0 0 m g) I V or 
silt u xi ma b 1 1 m g/ k g I V, if t here is c o nc urre nt C R S .
A S T C T I C A N S Gr a de 2 :

S u p p orti ve care a n d ne ur ol o gical w or k -u p as descri be d f or gra de 1 I C A N S .

A nti- I L-6 t hera p y  if ass ociate d wit h c o nc urre nt C R S, as descri be d f or gra de 1 IC A N S 
a n d if n ot a d mi nistere d pre vi o usl y .

De xa met has o ne 1 0 m g I V e ver y 6 h or met h yl pre d nis ol o ne 1 m g/ k g I V e ver y 1 2 h if 
refract or y t o a nti-I L-6 t hera p y , or f or I C A N S wit h o ut c o nc urre nt C R S.

C o nsi der tra nsferri n g patie nt t o i nte nsi ve -care u nit (IC U) if I C A N S ass ociate d wit h 
gra de ≥2 C R S .
A S T C T I C A N S Gr a de 3 :

S u p p orti ve care a n d ne ur ol o gical w or k -u p as i n dica te d f or gra de 1 I CA N S .

I C U tra nsfer is rec o m me n de d.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2 1

If E E G s h o ws n o n-c o n v ulsi ve stat us e pile ptic us :

Assess air wa y , breat hi n g, a n d circ ulati o n; c hec k bl o o d gl uc ose.

L oraze pa m 0. 5 m g i ntra ve n o usl y  (IV), wit h a d diti o nal 0. 5 m g I V e ver y  5 mi n, as 
nee de d, u p t o a t otal of 2 m g t o c o ntr ol electr o gra p hical seiz ures .

Le vetiraceta m 5 0 0 m g I V b ol us, as well as mai nte na nce d oses .

If seiz ures persist, tra nsfer t o i nte nsi ve-care u nit (I C U) a n d treat wit h 
p he n o bar bital l oa di n g d ose of 6 0 m g I V.

Mai nte na nce d oses after re s ol uti o n of n o n-c o n v ulsi ve stat us e pile ptic us are as 
f oll o ws: l oraze pa m 0. 5 m g I V e ver y 8 h f or t hree d oses; le vetiraceta m 1, 0 0 0 m g 
I V e ver y 1 2 hr; p he n o bar bital 3 0 m g I V e ver y 1 2 hr.

Lac osa mi de ma y  als o be c o nsi dere d f or treat me nt of seiz ures s h o ul d t he seiz ures 
persist b ut s h o ul d n ot be use d i n patie nts wit h c o nc urre nt C R S i n or der t o a v oi d 
arr h yt h mias a n d h y p ote nsi o n .

F or c o n v ulsi ve stat us e pile ptic us :

C o n v ulsi ve stat us e pile ptic us .

Assess air wa y , breat hi n g, a n d circ ulati o n; c hec k bl o o d gl uc ose.

Tra nsfer t o IC U .

L oraze pa m 2 m g I V, wit h a d diti o nal 2 m g I V t o a t otal of 4 m g t o c o ntr ol 
seiz ures.

Le vetiraceta m 5 0 0 m g I V b ol us, as well as mai nte na nce d oses .

If seiz ures persist, a d d p he n o bar bital treat me nt at a l oa di n g d ose of 1 5 m g/ k g I V.

Mai nte na nce d oses after res ol uti o n of c o n v ulsi ve stat us e pile ptic us are: l oraze pa m 
0. 5 m g I V e ver y  8 h f or t hree d oses; le vetiraceta m 1, 0 0 0 m g I V e ver y 1 2 h; 
p he n o bar bital 1 – 3 m g/ k g I V e ver y  1 2 h.

Lac osa mi de ma y  als o be c o nsi dere d f or treat me nt of seiz ures s h o ul d t he seiz ures 
persist b ut s h o ul d n ot be use d i n patie nts wit h c o nc urre nt C R S i n or der t o a v oi d 
arr h yt h mias a n d h y p ote nsi o n .

C o nti n u o us electr oe nce p hal o gra m m o nit ori n g s h o ul d be perf or me d, if seiz ures are 
refract or y t o treat me nt.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2 2

Hi g h -d ose met h y l pre d nis ol o ne I V 1 g/ da y  f or f ocal/l ocal e de ma.

A nti- I L-6 t hera p y  if ass ociate d wit h c o nc urrent C R S, as descri be d f or gra de 1 I CA N S 
a n d if n ot a d mi nistere d pre vi o usl y .

C ortic oster oi ds as o utli ne d f or gra de 2 I C A N S if s y m pt o ms w orse n des pite a nti-I L- 6 
t hera py, or f or I C A N S wit h o ut c o nc urre nt C R S; c o nti n ue c ortic oster oi ds u ntil 
i m pr o ve me nt t o gra de 1 I C A N S a n d t he n ta per.
A S T C T I C A N S Gr a de 4 :

S u p p orti ve care a n d ne ur ol o gical w or k -u p as o utli ne d f or gra de 1 I C A N S .

I C U m o nit ori n g; c o nsi der mec ha nical ve ntilati o n f or air wa y pr otecti o n.

A nti- I L-6 t hera p y  a n d re peat ne ur oi ma gi n g as descri be d f or gra de 3 I C A N S.

Hi g h -d ose met h y l pre d nis ol o ne I V 1 g/ da y c o nti n ue d u ntil i m pr o ve me nt t o 
gra de 1 I C A N S a n d t he n ta per; f or e xa m ple, met h yl pre d nis ol o ne I V 1 g/ day f or 
3 da y s, f oll o we d b y ra pi d ta per at 2 5 0 m g e ver y 1 2 h f or 2 da ys, 1 2 5 m g e ver y 1 2 h 
f or 2 da ys, a n d 6 0 m g e ver y 1 2 h f or 2 da ys.

F or seiz ures, treat as descri be d f or gra de 3 I C A N S.

M RI  of t he s pi ne s h o ul d be o btai ne d f or f ocal m ot or wea k ness.

T o ma na g e ele vate d I C P:

Ele vate hea d e n d of t he patie nt's be d t o a n a n gle of 3 0 de gre es.

H y per ve ntilati o n t o ac hie ve tar get partial press ure of arterial car b o n di o xi de 
( Pa C O 2) of 2 8– 3 0 m m H g, b ut mai ntai ne d f or n o l o n ger t ha n 2 4 h rs t o l o wer.

H y per os m olar t hera p y  wit h eit her ma n nit ol ( 2 0 g/ dl s ol uti o n) or h y pert o nic sali ne 
( 3 % or 2 3. 4 %, as detailed bel o w) :

Ma n nit ol: i nitial d ose 0. 5 – 1 g/ k g; mai nte na nce at 0. 2 5 – 1 g/ k g e ver y  6 hrs
w hile m o nit ori n g meta b olic pr ofile a n d ser u m os m olalit y  e ver y 6 hrs, a n d 
wit h h ol d ma n ni t ol if ser u m os m olalit y is ≥3 2 0 m Os m/ k g, or t he os m olalit y  
ga p is ≥4 0 .

H y pert o nic sali ne: i nitial 2 5 0 ml of 3 % h y pert o nic sali ne; mai nte na nce at 
5 0- 7 5 ml/ h w hile m o nit ori n g electr ol yt es e ver y 4 hrs, a n d wit h h ol d i nf usi o n if 
ser u m Na le vels reac h ≥1 5 5 m E q/l .

F or patie nts wit h i m mi ne nt her niati o n: i nitial 3 0 ml of 2 3. 4 % h y pert o nic 
sali ne; re peat after 1 5 mi n, if nee de d.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2 3

C o nsi der ne ur os ur ger y  c o ns ultati o n f or ve ntric ul o perit o neal s h u nt i n patie nts wit h 
cere bral e de ma a n d I V a nest hetics f or b urst-s u p pressi o n patter n o n E E G.

Meta b olic pr ofili n g e ver y  6 h a n d dail y C T sca n of hea d, wit h a dj ust me nts i n usa ge of 
t he af ore me nti o ne d me dicati o ns t o pre ve nt re b o u n d cere bral oe de ma, re nal fail ure, 
electr ol yt e a b n or malities, h yp o v ole mia, a n d h y p ote nsi o n .
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2 4
A p pe n di x 6. I N T E R N A TI O N A L M Y E L O M A W O R KI N G G R O U P (I M W G) 
M U L TI P L E M Y E L O M A DI A G N O SI S C RI T E RI A 4 5
Cl o nal b o ne marr o w plas ma cells 1 0 % or bi o ps y -pr o ve n b o n y or e xtra me d ullar y 
plas mac y t o ma a n d a n y o ne or m ore of t he f oll o wi n g myel o ma defi ni n g e ve nts:
1.
E vi de nce of e n d or ga n da ma ge t hat ca n be attri b ute d t o t he u n derl yi n g plas ma cell 
pr oliferati ve dis or der, s pecificall y:
a.
H y percalce mia: ser u m calci u m > 0· 2 5 m m ol/ L  ( > 1 m g/ d L) hi g her t ha n t he u p per 
li mit of n or mal or > 2· 7 5 m m ol/ L  ( > 1 1 m g / d L).
b.
Re nal i ns ufficie nc y : creati ni ne cleara nce < 4 0 m L  per mi n † or ser u m creati ni ne 
> 1 7 7 µ m ol/ L  ( > 2 m g / d L).
c.
A ne mia: he m o gl o bi n val ue of > 2 0 g/ L bel o w t he l o wer li mit of n or mal, or a 
he m o gl o bi n val ue < 1 0 0 g/ L.
d.
B o ne lesi o ns: o ne or m ore oste ol y tic lesi o ns o n s keletal ra di o gra p h y, C T, or 
P E T -C T .‡
2.
A n y  o ne or m ore of t he f oll o wi n g bi o mar kers of mali g na nc y:
e.
Cl o nal b o ne marr o w plas ma cell perce nta ge * 6 0 %.
f.
I n v ol ve d: u ni n v ol ve d ser u m free li g ht c hai n rati o § 1 0 0 > 1 f ocal lesi o ns o n M RI 
st u dies.
P E T -C T = 1 8F -fl u or o de o x y gl uc ose P E T wit h C T. 
* Cl o nalit y s h o ul d be esta blis he d b y s h o wi n g κ /-li g ht-c hai n restricti o n o n fl o w c yt o metr y, 
i m m u n o hist oc he mistr y, or i m m u n ofl u oresce nce.  B o ne marr o w plas ma cell perce nta ge s h o ul d prefera bl y be 
esti mate d fr o m a c ore bi o ps y s peci me n; i n case of a dis parit y bet w ee n t he as pirate a n d c ore bi o ps y, t he 
hi g hest val ue s h o ul d be use d.
† Meas ure d or esti mate d b y vali date d e q uati o ns. 
‡ If b o ne marr o w  has less t ha n 1 0 % cl o nal plas ma cells, m ore t ha n o ne b o ne lesi o n is re q uire d t o disti n g uis h 
fr o m s olitar y plas mac yt o ma wit h mi ni mal marr o w i n v ol ve me nt. 
§ T hese val ues are base d o n t he ser u m freelite assa y ( T he Bi n di n g Site Gr o u p, Bir mi n g ha m, U K).  T he i n v ol ve d 
free li g ht c hai n m ust be 1 0 0 m g/ L.  Eac h f ocal lesi o n m ust be 5 m m or m ore i n size.
Rela pse is defi ne d as pr o gressi o n of disease after a n i nitial res p o nse t o pre vi o us treat me nt, 
m ore t ha n si x m o nt hs after cessati o n of treat me nt.
Refract or y  is defi ne d as resista nce t o treat me nt d ue t o lac k of res p o nse or pr o gressi o n of 
disease d uri n g treat me nt or wit hi n si x m o nt hs after cessati o n of treat me nt. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2 5
A p pe n di x 7. M A N A G E M E N T O F I N F U SI O N R E L A T E D R E A C TI O N S, I N C L U DI N G 
A L L E R GI C R E A C TI O N S O R A N A P H Y L A XI S
I n t he e ve nt of i nf usi o n relate d reacti o ns, I n vesti gat ors s h o ul d i nstit ute treat me nt meas ures 
acc or di n g t o best me dical a n d n ursi n g practice.
T he f oll o wi n g treat me nt g ui deli nes s h o ul d be e m pl o y e d:
If c hills a n d fe ver ( > 1 0 0.4 F / 3 8.0 C ) occ ur, t he i nf usi o n s h o ul d be i nterr u pte d.  Patie nts ma y 
be trea te d sy m pt o maticall y  (as descri be d i n Secti o n 5. 5. 2 D ose Dela y ) a n d t he i nf usi o n 
s h o ul d be restarte d at 5 0 % of t he ori gi nal rate. 
H y perse nsiti vit y  reacti o ns:
1.
N CI -C T C A E Gra de 1 aller gic reacti o n :

M o nit or f or w orse ni n g c o n diti o n.  I f t he reacti o n w orse ns, st o p t he i nf usi o n.  
I nstit ute pre me dicati o n f or s u bse q ue nt i nf usi o ns as per Secti o n 5. 5. 2 D ose Dela y . 
2.
N CI -C T C A E Gra de 2 aller gic reacti o n :

St o p P F -0 6 8 6 3 1 3 5 i nf usi o n.

A d mi nister br o nc h o dilat ors, o x y ge n, aceta mi n o p he n, etc. as me dicall y i n dicate d.

Res u me i nf usi o n at 5 0 % of pre vi o us rate o nce reacti o n has decrease d t o Gra de 1 
i n se verit y.  M o nit or cl osel y f or a n y w orse ni n g.  If t he reacti o n rec urs, st o p 
i nf usi o n.  Instit ute pre me dicati o n f or s u bse q ue nt i nf usi o ns as per Secti o n 5. 5. 2
D ose Dela y .
3.
N CI -C T C A E Gra de 3 or Gra de 4 aller gic reacti o n or a na p hyl a xis:

A Gra de 3 a na p h yl a xis ( h yperse nsiti vit y  reacti o n) c o nsists of s ym pt o matic 
br o nc h os pas m re q uiri n g pare nteral me dicati o ns wit h or wit h o ut urticaria, 
aller g y-relate d e de ma/a n gi oe de ma, or hy p ote nsi o n.

A Gra de 4 a na p h yl a xis ( h yperse nsit i vit y reacti o n) is a life-t hreate ni n g e ve nt 
re q uiri n g ur ge nt i nter ve nti o n.
4.
Treat me nt of Gra de 3 or Gra de 4 aller gic reacti o n or a na p h y la xis:

St o p t he P F -0 6 8 6 3 1 3 5 i nf usi o n i m me diatel y  a n d disc o n nect i nf usi o n t u bi n g fr o m 
t he patie nt.

A d mi nister e pi ne p hri ne, br o nc h o dilat ors, a nti hista mi nes, gl uc oc ortic oi ds, 
i ntra ve n o us fl ui ds, vas o press or a ge nts, o x yge n, etc. as me dicall y i n dicate d.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2 6

Tele p h o ne S p o ns or or desi g nate d re prese ntati ve t o re p ort a n S A E as per Secti o n 8
A d verse E ve nt Re p orti n g.

F or a N CI -C T C A E Gra de 3 or 4 h y perse nsiti vit y  reacti o n, st u d y treat me nt will be 
disc o nti n ue d.
5.
Re -treat me nt f oll o wi n g Gra de 1 or Gra de 2 a ller gic reacti o ns:

O nce t he P F -0 6 8 6 3 1 3 5 i nf usi o n rate has bee n decrease d d ue t o a n aller gic 
reacti o n or c yt o ki ne release s yn dr o me, it will re mai n decrease d f or all s u bse q ue nt 
i nf usi o ns.

If t he patie nt has a sec o n d reacti o n at t he l o wer i nf usi o n rate, t he i nf usi o n s h o ul d 
be st o p pe d a n d t he patie nt s h o ul d recei ve n o f urt her P F- 0 6 8 6 3 1 3 5.

If t he patie nt e x perie nces a Gra de 3 or 4 aller gic reacti o n or a na p hyl a xis at a n y 
ti me, t he patie nt s h o uld recei ve n o f urt her P F -0 6 8 6 3 1 3 5.

If t here are q uesti o ns c o ncer ni n g w het her a n o bser ve d reacti o n is c o nsiste nt wit h 
a n aller gic reacti o n, c yt o ki ne release sy n dr o me, or a na p h yl a xis, t he me dical 
m o nit or s h o ul d be c o ntacte d i m me diatel y  t o assist wit h gra di n g t he reacti o n.
P K, p har mac o d y n a mic a n d A D A sa m pli n g s h o ul d c o nti n ue as l o n g as t he sa m pli n g d oes n ot 
i nterfere wit h t he me dical treat me nt of t he patie nt.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M




P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2 8

3 D L Ts - > de -escalate a n d c o nsi der c urre nt d ose as i nt olera ble.

Wit h 4 patie nts treate d at c urre nt d ose le vel :

0 D L T -> escalate;

1 D L Ts - > re mai n at t he sa me d ose;

2 D L Ts - > de -escalate;

3- 4 D L Ts -> de -escalate a n d c o nsi der c urre nt d ose as i nt olera ble.

Wit h 5 patie nts treate d at c urre nt d ose le vel :

0 or 1 D L T -> escalate;

2 D L Ts - > re mai n at t he sa me d ose;

3 -5 D L Ts -> de -escalate a n d c o nsi der c urre nt d ose as i nt olera ble.

Wit h 6 patie nts treate d at c urre nt d ose le vel :

0- 1 D L T -> escalate;

2 D L Ts - > re mai n at t he sa me d ose;

3 D L Ts - > de -escalate;

4- 6 D L Ts -> de -escalate a n d c o nsi der c urre nt d ose as i nt olera ble.

Wit h 7 patie nts treate d at
c urre nt d ose le vel :

0- 1 D L T -> escalate;

2- 3 D L Ts - > re mai n at t he sa me d ose;

4 -7 D L Ts -> de -escalate a n d c o nsi der c urre nt d ose as i nt olera ble.

Wit h 8 patie nts treate d at c urre nt d ose le vel :

0 -1 D L T -> escalate;

2 -3 D L Ts - > re mai n at t he sa me d ose;

4 D L Ts -> de -escalate;

5- 8 D L Ts -> de -escalate a n d c o nsi der c urre nt d ose as i nt olera ble.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2 9

Wit h 9 patie nts treate d at c urre nt d ose le vel :

0- 1 D L T -> escalate;

2 - 4 D L Ts - > re mai n at t he sa me d ose;

5- 9 D L Ts -> de -escalate a n d c o nsi der c urre nt d ose as i nt olera ble.

Wi t h 1 0 patie nts treate d at c urre nt d ose le vel:

0- 1 D L T -> escalate;

2 - 4 D L Ts - > re mai n at t he sa me d ose;

5- 1 0 D L Ts -> de -escalate a n d c o nsi der c urre nt d ose as i nt olera ble.

Wit h 1 1 patie nts treate d at c urre nt d ose le vel :

0 - 1 D L T -> escalate;

2- 4 D L Ts - > re mai n at t he sa me d ose;

5 D L Ts - > de -escalate ( m T PI s u g gests “re mai n at t he sa me d ose”);

6- 1 1 D L Ts -> de -escalate a n d c o nsi der c urre nt d ose as i nt olera ble.

Wit h 1 2 patie nts treate d at c urre nt d ose le vel :

0 -2 D L Ts -> escalate;

3- 5 D L Ts -> re mai n at t he s a me d ose;

6- 1 2 D L Ts -> de -escalate a n d c o nsi der c urre nt d ose as i nt olera ble.
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3 0
A p pe n di x 9. S U B C U T A N E O U S I N J E C TI O N SI T E L O C A TI O N S
I njecti o n site l ocati o ns i ncl u de a ma xi m u m of 8 u ni q ue a d mi nistrati o n sites distri b ute d acr oss 
4 a b d o mi nal q ua dra nts wit h a p ossi bilit y  of u p t o 2 i njecti o n l ocati o ns per q ua dra nt.  
L ocati o n 1 is pr o xi mal t o t he u m bilic us a n d L ocati o n 2 is distal t o t he u m bilic us.
A d mi nister t he re q uire d n u m ber of i njecti o ns i n t he f oll o wi n g or der:
1.
L o wer Left Q ua dra nt L ocati o n 1 ;
2.
L o wer Ri g ht Q ua dra nt L ocati o n 1;
3.
L o wer Left Q ua dra nt L ocati o n 2 ;
4.
L o wer Ri g ht Q ua dra nt L ocati o n 2 ;
5.
U p per Ri g ht Q ua dra nt L ocati o n 1 ;
6.
U p per Left Q ua dra nt L ocati o n 1 ;
7.
U p per Ri g ht Q ua dra nt L ocati o n 2 ;
8.
U p per Left Q ua dra nt L ocati o n 2 .
I njecti o ns t o t he a b d o me n are preferre d.  If S C i njecti o ns i n t he a b d o mi nal l ocati o n are n ot 
p ossi ble, S C i njecti o ns ca n be a d mi nistere d i n a distri b ute d ma n ner i n t he t hi g hs.  S C 
i njecti o ns i n t he u p per e xtre mities (e g, delt oi d, u p per a n d l o wer ar m) are n ot per mitte d.
Trac k t he patie nt’s i njecti o n site (s) se q ue ntiall y o n t his dia gra m wit h a re d pe n a n d mar k t he 
i njecti o n sites o n t he patie nt’s a b d o me n acc or di n g t o yo ur cli nic’s sta n dar d practice.
Rec or d t he l ocati o n, ti me of eac h i njecti o n a n d a n y i njecti o n site reacti o ns i n t he patie nt’s 
s o urce rec or ds a n d st u d y C R F. C o m plete o ne C R F per i njecti o n
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3 1
A p pe n di x 1 0. Alter n ati ve Me as ures D uri n g P u blic E mer ge ncies
T he alter nati ve st u d y meas ures descri be d i n t his secti o n are t o be f oll o we d d uri n g p u blic 
e mer ge ncies, i ncl u di n g t he C O VI D -1 9 pa n de mic. T his a p pe n di x a p plies f or t he d urati o n of 
t he C O VI D-1 9 pa n de mic i n partici pati n g c o u ntries a n d will bec o me effecti ve f or ot her p u blic 
e mer ge ncies o nl y u p o n writte n n otifica ti o n fr o m Pfizer. 
Use of t hese alter nati ve st u d y  meas ures are e x pecte d t o cease u p o n t he ret ur n of b usi ness as 
us ual circ u msta nces (i ncl u di n g t he lifti n g of a n y q uara nti nes a n d tra vel ba ns/a d vis ories). 
Eli gi bilit y
Re gar di n g eli gi bilit y , w hile S A R S-C o V 2 t esti n g is n ot ma n date d f or t his st u d y y o u s h o ul d 
f oll o w l ocal cli nical practice sta n dar ds f or testi n g.  If a partici pa nt has a p ositi ve test res ult 
f or acti ve S A R S -C o V 2 i nfecti o n, is k n o w n t o ha ve as y m pt o matic i nfecti o n or is s us pecte d of 
ha vi n g S A R S -C o V 2, he/s he s h o ul d be e xcl u de d at t his ti me.  Please n ote t he pr ot oc ol
e xcl u des patie nts wit h acti ve i nfecti o ns:
E xcl usi o n Criteria:
4.
Patie nts wit h acti ve u nc o ntr olle d bacterial, f u n gal or viral i nfecti o n, i ncl u di n g k n o w n 
h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n or ac q uire d i m m u n o deficie nc y  
s yn dr o me ( AI D S) relate d ill ness.
W he n t he i nfecti o n res ol ves, t he patie nt c o ul d be c o nsi dere d f or re -scree ni n g, if all o we d b y 
st u d y pr ot oc ol.
Tel e he alt h Visits
I n t he e ve nt t hat i n-cli nic f oll o w- u p st u d y visits ca n n ot be c o n d ucte d w here sa m ple c ollecti o n 
is n ot perf or me d or treat me nt n ot gi ve n, e ver y eff ort s h o ul d be ma de t o f oll o w u p o n t he 
safety of st u d y patie nts at sc he d ule d visits per t he Sc he d ule of Acti vities or u nsc he d ule d 
visits. Tele healt h visits ma y be use d t o c o nti n ue t o assess patie nt safety a n d c ollect data 
p oi nts. Tele healt h i ncl u des t he e xc ha n ge of healt hcare i nf or mati o n a n d ser vices via 
telec o m m u nicati o n tec h n ol o gies (e g, a u di o, vi de o, vi de o -c o nfere nci n g s oft ware) re m otel y, 
all o wi n g t he partici pa nt a n d t he i n vesti gat or t o c o m m u nicate o n as pects of cli nical care, 
i ncl u di n g me dical a d vice, re mi n ders, e d ucati o n, a n d safety m o nit ori n g. T he f oll o wi n g 
assess me nts m ust be perf or me d d uri n g a tele healt h visit 

Re vie w a n d rec or d st u d y i nter ve nti o n(s), i ncl u di n g c o m plia nce a n d misse d d oses.

Re vie w a n d rec or d a n y   A Es a n d S A Es si nce t he last c o ntact.  Refer t o Secti o n 8. 1. 4. 2 .

Re vie w a n d rec or d a n y ne w c o nc o mita nt me dicati o ns or c ha n ges i n c o nc o mita nt 
me dicati o ns si nce t he last c o ntact .
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3 2

Re vie w a n d rec or d c o ntrace p ti ve met h o d a n d res ults of pre g na nc y testi n g. C o nfir m 
t hat t he patie nt is a d heri n g t o t he c o ntrace pti o n met h o d(s) re q uire d i n t he pr ot oc ol. 
St u d y  p a rtici pa nts m ust be re mi n de d t o pr o m ptl y n otif y site staff a b o ut a ny c ha n ge i n t heir 
healt h stat us.
Alter n ati ve F acilities f or S afet y Assess me nts 
L a b or at or y Testi n g
If a st u dy partici pa nt is u na ble t o visit t he site f or pr ot oc ol -s pecifie d safet y la b orat or y 
e val uati o ns, testi n g m a y  be c o n d ucte d at a l ocal la b orat or y  if per mitte d b y l ocal re g ulati o ns.  
T h e l ocal la b orat or y ma y be a sta n dal o ne i nstit uti o n or wit hi n a h os pital. T he f oll o wi n g 
safety la b orat or y  e val uati o ns as liste d i n Ta ble 1 1 ma y  be perf or me d at a l ocal la b orat or y if 
necessar y : 

He mat ol o g y ;

Bl o o d c he mistr y ;

C oa g ulati o n ;

Uri nal y sis;

Pre g na nc y  test.
If a l ocal la b orat or y is use d, q ualifie d st u d y site pers o n nel m ust or der, recei ve, a n d re vie w 
res ults. Site staff m ust c ollect t he l ocal la b orat or y refere nce ra n ges a n d 
certificati o ns/accre ditati o ns f or fili n g at t he site.   La b orat or y  test res ults are t o be pr o vi de d t o 
t he site staff as s o o n as p ossi ble.   T he l ocal la b orat or y  re p orts s h o ul d be file d i n t he 
partici pa nt’s s o urce d oc u me nts/ me dical rec or ds. Rele v a nt data fr o m t he l ocal la b orat or y  
re p ort s h o ul d be rec or de d o n t he C R F.
If a partici pa nt re q uiri n g pre g na nc y testi n g ca n n ot visit a l ocal la b orat or y f or pre g na nc y 
testi n g, a h o me uri ne pre g na nc y testi n g kit wit h a se nsiti vit y of at least 2 5 I U/ m L ma y be 
use d b y  t he partici pa nt t o perf or m t he test at h o me, if c o m plia nt wit h l ocal re g ulat or y 
re q uire me nts. T he pre g na nc y  test o utc o me s h o ul d be d oc u me nte d i n t he partici pa nt’s s o urce 
d oc u me nts/ me dical rec or ds a n d rele va nt data rec or de d o n t he C R F. C o nfir m t hat t he 
partici pa nt is a d heri n g t o t he c o ntrace pti o n met h o d(s) re q uire d i n t he pr ot oc ol.
Electr oc ar di o gr a ms
If t he partici pa nt is u na ble t o visit t he st u d y site f or E C Gs, t he partici pa nt ma y visit an 
alter nati ve facilit y t o ha ve t he E C Gs perf orme d.
Q ualifie d st u d y  site pers o n nel m ust or der, 
recei ve, a n d re vie w res ults. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M


P F -0 6 8 6 3 1 3 5 
C 1 0 7 1 0 0 1 
Fi nal Pr ot oc ol A me n d me nt 9 , 2 8 Marc h
2 0 2 3
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3 3
St u d y I nter ve nti o n
If t he safety of a trial partici pa nt is at ris k beca use t he y ca n n ot c o m plete re q uire d e val uati o ns 
or a d here t o critical miti gati o n ste ps, t he n disc o nti n ui n g t hat partici pa nt fr o m st u d y 
i nter ve nti o n m ust be c o nsi dere d.
D ose Del a ys
T he f oll o wi n g is rec o m me n de d f or t he a d mi nistrati o n of P F -0 6 8 6 3 1 3 5 f or partici pa nts w h o 
ha ve acti ve [c o nfir me d ( p ositi ve b y  re g ulat or y a ut h orit y-a p pr o ve d test) or pres u me d (test 
pe n di n g/cli nical s us pici o n)] S A R S -C o V 2 i nfecti o n:

F or s y m pt o matic partici pa nts wit h acti ve S A R S- C o V 2 i nfecti o n, i n vesti gati o nal 
treat me nt s h o ul d be dela ye d f or at least 1 4 da ys fr o m t he start of s ym pt o ms. T his 
dela y  is i nte n de d t o all o w t he res ol uti o n of sy m pt o ms of S A R S -C o V 2 i nfecti o n .

Pri or t o restarti n g treat me nt, t he partici pa nt s h o ul d be afe brile f or 7 2 h o urs , a n d 
S A R S -C o V 2 -relate d sy m pt o ms s h o ul d ha ve rec o vere d t o ≤Gra de 1 f or a mi ni m u m of 
7 2 h o urs.  N otif y  t he st u d y tea m w he n treat me nt is restarte d.

C o nti n ue t o co nsi der p ote ntial dr u g -dr u g i nteracti o ns as descri be d Secti o n 5. 9 a n d 
A p pe n di x 1 1 f or a n y c o nc o mita nt me dicati o n a d mi nistere d f or treat me nt of 
S A R S -C o V 2 i nfecti o n.
A d verse E ve nts a n d Seri o us A d verse E ve nts
If a partici pa nt has C O VI D-1 9 d uri n g t he st u d y , t his s h o ul d be re p orte d as a n a d verse e ve nt 
( A E) or seri o us a d verse e ve nts ( S A E) a n d a p pr o priate me dical i nter ve nti o n pr o vi de d. 
Te m p orar y  disc o nti n uati o n of t he st u d y i nter ve nti o n ma y be me dically a p pr o priate u ntil t he 
partici pa nt has rec o vere d fr o m C O VI D - 1 9. 
It is rec o m me nde d t hat t he i n vesti gat or disc uss te m p orar y  or per ma ne nt disc o nti n uati o n of 
st u d y i nter ve nti o n wit h t he st u d y me dical m o nit or. 
0 9 0 1 7 7 e 1 9 d 0 b e 7 c a\ A p pr o v e d\ A p pr o v e d O n: 2 9- M ar- 2 0 2 3 1 9: 5 1 ( G M T)
E T M F C o py of:
 
  1 6 4. 0 1| C 1 0 7 1 0 0 1| 2 8- M ar- 2 0 2 3 | A cti v e | 1 0- A pr- 2 0 2 3 1 0: 1 0: 2 2 A M



SAP_001.pdf: 
Protocol C1071001 (PF-06863135) 
Statistical Analysis Plan 
13-Jul-2022
PFIZER CONFIDENTIAL
Page 1
PROTOCOL C1071001
A PHASE I, OPEN LABEL STUDY TO EVALUATE THE SAFETY, 
PHARMACOKINETIC, PHARMACODYNAMIC AND CLINICAL ACTIVITY 
OF PF-06863135, A B CELL MATURATION ANTIGEN (BCMA) CD3 
BISPECIFIC ANTIBODY, AS A SINGLE AGENT AND IN COMBINATION
WITH IMMUNOMODULATORY AGENTS IN PATIENTS WITH 
RELAPSED/REFRACTORY ADVANCED MULTIPLE MYELOMA (MM)
STATISTICAL ANALYSIS PLAN AMENDMENT 
(SAP)
Version: 
3
Author: 
  
Date:
13-Jul-2022
090177e19abf5ee5\Approved\Approved On: 14-Jul-2022 06:59 (GMT)
PPD


Protocol C1071001 (PF-06863135) 
Statistical Analysis Plan 
13-Jul-2022
PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
1.1. Amendment 3 ............................................................................................................5
1.2. Amendment 2 ............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives and Endpoint.................................................................................7
2.2.1. Part 1 IV and SC monotherapy Dose Escalation, Part 1.1 Priming 
and Maintenance Dose Escalation and Parts 1C, 1D and 1E Dose 
Escalation/Finding .............................................................................................7
2.2.2. Part 2 Dose Expansion................................................................................11
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING................................12
4. HYPOTHESES AND DECISION RULES.........................................................................13
4.1. Statistical Hypotheses .............................................................................................13
4.2. Statistical Decision Rules........................................................................................13
5. ANALYSIS SETS ...............................................................................................................14
5.1. Treatment Misallocations........................................................................................14
5.2. Protocol Deviations.................................................................................................15
5.2.1. Deviations Assessed Prior to Randomization.............................................15
5.2.2. Deviations Assessed Post-randomization...................................................15
6. ENDPOINTS AND COVARIATES ...................................................................................15
6.1. Efficacy Endpoints ..................................................................................................15
6.2. Safety Endpoints .....................................................................................................15
6.2.1. DLT Evaluability Criteria...........................................................................16
6.3. Pharmacokinetics Endpoints ...................................................................................18
6.4. PD/Biomarker Endpoints ........................................................................................19
6.4.1. Immunogenicity Endpoints.........................................................................20
6.4.2. Outcomes Research Endpoints ...................................................................21
6.5. Covariates................................................................................................................21
7. HANDLING OF MISSING VALUES ................................................................................21
090177e19abf5ee5\Approved\Approved On: 14-Jul-2022 06:59 (GMT)


Protocol C1071001 (PF-06863135) 
Statistical Analysis Plan 
13-Jul-2022
PFIZER CONFIDENTIAL
Page 3
7.1. Pharmacokinetics ....................................................................................................21
7.1.1. Concentrations Below the Limit of Quantification ....................................21
7.1.2. Deviations, Missing Concentrations and Anomalous Values.....................21
7.1.3. Pharmacokinetic Parameters.......................................................................21
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................21
8.1. Statistical Methods ..................................................................................................22
8.1.1. Analyses for Continuous Data....................................................................22
8.1.2. Analyses for Categorical Data....................................................................22
8.1.3. Analyses for Binary Endpoints...................................................................22
8.1.4. Analyses for Time-to-event Data................................................................22
8.2. Statistical Analyses .................................................................................................22
8.2.1. Primary Analysis ........................................................................................22
8.2.2. Efficacy Analyses .......................................................................................23
8.2.2.1. Progression-Free Survival (PFS) ...............................................23
8.2.2.2. Overall Survival (OS)................................................................26
8.2.2.3. Time to Response (TTR) ...........................................................27
8.2.2.4. Time to Complete Response (TTCR)........................................27
8.2.2.5. Time to VGPR or better (TTVGPR).........................................27
8.2.2.6. Duration of Response (DoR).....................................................28
8.2.2.7. Duration of sCR or CR (DoCR)................................................28
8.2.2.8. Overall Response Rate (ORR) ..................................................29
8.2.2.9. Clinical Benefit Rate (CBR) .....................................................30
8.2.2.10. Duration of Stable Disease (DoSD) ........................................30
8.2.2.11. Minimal Residual Disease (MRD)..........................................31
8.2.2.12. Duration of Treatment.............................................................31
8.2.3. Safety Analyses ..........................................................................................31
8.2.3.1. Adverse Events..........................................................................33
8.2.3.2. Laboratory Tests Abnormalities................................................33
8.2.3.3. Study Conduct and Patient Disposition.....................................33
8.2.3.4. Baseline Characteristics ............................................................33
8.2.3.5. Treatment Administration/Compliance.....................................34
8.2.3.6. Prior, Concomitant, and Further Therapies...............................35
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8.2.3.7. Electrocardiograms (ECG)........................................................36
8.2.4. Other Safety Data – Screening and Other Special Purpose Data ...............37
8.2.5. PK Analyses................................................................................................38
8.2.5.1. Pharmacokinetic Parameters .....................................................38
8.2.5.2. Pharmacokinetic Concentrations...............................................38
8.2.5.3. PD/Biomarker Endpoints ..........................................................39
8.2.5.4. Population PK and PK/PD Modeling........................................39
8.2.5.5. Immunogenicity Endpoints .......................................................39
9. REFERENCES ....................................................................................................................40
10. APPENDICES ...................................................................................................................41
LIST OF TABLES
Table 1.
Decision Rules..........................................................................................13
Table 2.
PK Parameters ..........................................................................................18
Table 3.
Biomarker Assays and Sample Sources ...................................................19
Table 4.
Progression Free Survival.........................................................................24
Table 5.
PFS Censoring Reasons and Hierarchy....................................................25
Table 7.
Criteria for Best Response........................................................................29
Table 8: 
Lee et al 2014 CRS revised grading system .............................................52
LIST OF FIGURES
Figure 1 C1071001 Study Design..............................................................................................7
APPENDICES
Appendix 1. Abbreviations......................................................................................................41
Appendix 2. THE INTERNATIONAL MYELOMA WORKING GROUP (IMWG) 
RESPONSE CRITERIA FOR MULTIPLE MYELOMA........................48
Appendix 3. IMWG MINIMAL RESIDUAL DISEASE (MRD) Criteria..............................51
Appendix 4. Cytokine Release Symptoms Revised Grading System......................................52
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1. AMENDMENTS FROM PREVIOUS VERSION(S)
1.1. Amendment 3
This amendment updates some response endpoint definitions and changes in Protocol 
Amendment 8. Texts taken directly from the Protocol Amendment 8 dated 06 Jun 2021 are
Italicized.
1.2. Amendment 2
This amendment incorporates the added subcutaneous administration cohorts in the amended 
protocol (amendment 2, V.25Apr2018) study design. Discussions of detailed study conduct 
features are referred to the amendment.  Discussions on combination treatment in the original
SAP were found not applicable and were removed in this amendment. In this amendment, the 
interim study monitoring using Bayesian predictive probability is clarified.
2. INTRODUCTION
This document describes the planned statistical analyses for Protocol C1071001 latest
amendment, dated 06 Jun 2021. This SAP is meant to supplement the study protocol. This 
SAP supersedes the statistical considerations identified in the protocol and, where 
considerations are substantially different, they will be identified as such. Any deviations 
from this analysis plan will be described in the clinical study report (CSR). Any post-hoc, or
unplanned analyses performed that are not specified in this SAP will be clearly identified in 
the CSR. This plan is developed and finalized prior to database lock of the clinical database. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline (Guidance for Industry: Statistical
Principles for Clinical Trials) and on the ICH E3 Guideline (Guidance for Industry: Structure 
and Content of Clinical Study Reports).
Interim data may be analyzed and reported in an interim CSR at any timepoint (including at 
the primary completion date [PCD]) before the final ORR collection are complete. The 
following CSRs will contain any updated data collected after the interim CSR cutoff date. 
2.1. Study Design
This is a Phase 1 open-label, multi-dose, multi-center, dose escalation, safety,
pharmacokinetic (PK) and pharmacodynamic study of PF-06863135 as monotherapy and in
combination with lenalidomide, pomalidomide or dexamethasone in adult patients with
advanced MM who have relapsed from or are refractory to standard therapy. This study will
be divided into dose escalation/finding part (Part 1) and dose expansion part (Part 2).
Part 1 dose escalation/finding (with either monotherapy or combination therapies) in order
to determine the recommended Phase 2 dose (RP2D) is further divided into:

Part 1 intravenous (IV) monotherapy and Part 1 subcutaneous (SC) monotherapy
cohorts as well as Part 1.1 priming and maintenance cohorts.

Part 1C lenalidomide combination, Part 1D pomalidomide combination and Part 1E
dexamethasone combination cohorts.
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Part 2 dose expansion phase will be divided into 4 cohorts as follows:

Part 2A (PF-06863135 as monotherapy).

Part 2C (PF-06863135 in combination with lenalidomide).

Part 2D (PF-06863135 in combination with pomalidomide).

Part 2E (PF-06863135 in combination with dexamethasone).
Approximately 120 patients are expected to be enrolled into Parts 1/1.1, 1C, 1D, 1E and
approximately 80 patients are expected to enroll into Part 2. Parts 1C, 1D and 1E will enroll
approximately 9-16 patients into each safety cohort. Actual number of patients enrolled will
depend on the combination tolerability with lenalidomide, pomalidomide and the number of
dose levels that are required to select the combination RP2Ds. Patients from the combination
cohorts of Parts 1C, 1D, 1E treated at the dose levels selected for Part 2 may be counted
towards the sample size of the corresponding cohorts of Part 2. Parts 2A, 2C, 2D and 2E will
enroll approximately 20 patients each.
A modified toxicity probability interval (mTPI) method, targeting a DLT rate of 25% and an 
acceptable equivalence interval of 20% 30% will be utilized for dose escalation in Part 1.  
All patients will also be monitored closely for DLTs until the end of Cycle 1. All patients will 
be monitored for late toxicities following the initial DLT period up to Day 60 from first dose.  
Once a dose level has been declared safe following the 60-day evaluation, patients at lower 
dose levels who have completed the 60-day late toxicity observation period may escalate to 
the next higher dose level, if criteria outlined in Section 3.1.4.1 of the protocol have been 
met.  Additional intra patient dose escalations will also be permitted after a minimal interval 
of 60 days.  No crossover is allowed, however, between patients assigned to monotherapy 
PF-06863135 and the different combination regimens.
For safety reasons, a staggered enrollment strategy will be applied for Parts 1 and 1.1 at 
each dose level; the first patient will be dosed on C1D1 and observed for 48 hours. If no 
safety concerns arise during this 48-hr. period, subsequent patients will be enrolled into the 
same dose level. All patients in Part 1 and Part 1.1 will be monitored closely for dose 
limiting toxicities (DLTs, see Section 3.2 of the protocol) during the first 21-day period for 
weekly dosing and 28-day period for Q2W dosing.
Following the initial dose, treatment with investigational product will continue until disease 
progression, subject withdrawal of consent or unacceptable toxicity occurs.  A follow up visit 
approximately 4 weeks after the last dose for adverse event (AE) and serious AE (SAE) 
collection will be conducted. If the subject completes the 1 month follow up visit prior to 
completion of the 60-day long term DLT observation period, a follow up phone call will be 
completed on Day 60, and no later than Day 65. Patients found to have anti-drug antibodies 
(ADA) at their final study visit and an ongoing AE possibly related to ADA will be asked to 
return to the clinic for ADA assessment at approximately 3 month intervals (if feasible given
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the underlying disease) until the adverse event or its sequelae return to baseline or stabilize 
at a level acceptable to the investigator and sponsor.
Following discontinuation of study treatment (unless subjects are lost to follow up, consent is 
withdrawn, or study is discontinued by the sponsor), survival status will be collected by 
telephone every 3 months until death, or up to 24 months after first treatment of the last 
subject, whichever comes first.  Subsequent anti-cancer therapies and relevant transplant 
information will also be collected.
Treatment with investigational product will continue until disease progression, subject
refusal or unacceptable toxicity occurs.  It is estimated that subjects will remain on treatment 
for approximately 4-12 weeks (exclusive of survival follow-up).  Actual duration can be
longer, if a subject derives benefit from study treatment. The last study treatment will be up 
to 24 months after first treatment of the last patient, and the study would then end after any 
additional follow-up visits required after the last study treatment.
Figure 1 C1071001 Study Design
2.2. Study Objectives and Endpoint
2.2.1. Part 1 IV and SC monotherapy Dose Escalation, Part 1.1 Priming and 
Maintenance Dose Escalation and Parts 1C, 1D and 1E Dose Escalation/Finding
Type
Primary Objectives:
Primary Endpoints:
Safety

To assess safety and 
tolerability at increasing dose 
levels of PF-06863135 as 

Number of DLTs following treatment with escalating 
doses of PF-06863135 as monotherapy and in 
combination with lenalidomide, pomalidomide, or 
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monotherapy and in 
combination with lenalidomide, 
pomalidomide, or 
dexamethasone in successive 
cohorts of patients with 
multiple myeloma in order to 
estimate the Maximum 
Tolerated Dose (MTD) or 
Maximum Administered 
Dose (MAD) and select the 
Recommended Phase 2 Dose 
(RP2D).
dexamethasone.  DLT is observed up to the end of 
Cycle 1 in each participant
Secondary Objectives: 
Secondary Endpoints: 
Safety

To evaluate the overall safety 
profile. 

Adverse Events as characterized by type, 
frequency, severity as graded by NCI CTCAE
version 4.03, timing, seriousness, and 
relationship to PF-06863135 treatment as 
monotherapy and in combination with lenalidomide, 
pomalidomide, or dexamethasone.  

Laboratory abnormalities as characterized by 
type, frequency, severity (as graded by NCI 
CTCAE version 4.03), and timing.
Efficacy

To evaluate anti-myeloma 
activity of PF-06863135 as 
monotherapy and in 
combination with lenalidomide, 
pomalidomide, or 
dexamethasone.

ORR defined using the International Working 
Group (IMWG) response criteria for multiple 
myeloma and is the percentage of participants 
with best overall confirmed BOR of sCR, CR, 
VGPR, or PR relative to the appropriate analysis 
set.

Time to event endpoints as follows:

TTR defined as the time from date of first
dose to the first documentation of objective 
treatment response (PR, VGPR, CR, or 
sCR, whichever is earlier in participants 
with BOR of PR, VGPR, CR or sCR).

CRR defined as the proportion of subjects 
with confirmed stringent Complete 
Response (sCR) and Complete Response 
(CR).

CBR defined as proportion of subjects with 
a BOR of sCR, CR (with or without MRD 
negativity) VGPR, PR, and MR.

DOR, defined as the time from the first 
documentation of OR to the first 
documentation of objective PD of 
progression, clinical relapse or to death due 
to any cause, whichever occurs first. 

DoCR or sCR, defined as the time from the
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first documentation of complete response to 
the first documentation of objective
progression, clinical relapse or death due to
any cause, whichever occurs first.

DOSD is defined for patients with stable 
disease as the time from the first 
documentation of objective stable disease to 
the first documentation of objective tumor 
progression or to death due to any cause, 
whichever occurs first.

PFS, defined as the time from date of first 
dose to date of first documentation of 
objective PD of progression, or death due to 
any cause (progression as defined by 
IMWG response criteria for PD).  

OS, defined as the time from date of first
dose to date of death due to any cause. 
Subjects are censored at the time of last 
follow-up.

Rate of patients with no MRD (by lab data) after 
treatment with PF-06863135 using IMWG MRD 
criteria
PK

To evaluate single dose and 
multiple dose PK of 
PF-06863135 given as 
monotherapy and in 
combination with lenalidomide 
or pomalidomide.
Additionally, PK of 
lenalidomide, pomalidomide, 
and dexamethasone will be 
evaluated when combined 
with PF-06863135 (Parts 1C,
1D, and 1E, respectively).

Pharmacokinetic parameters of PF-06863135:
Cycle 1 Day 1 dose and Cycle 2 Day 1 dose 
maximum concentration (Cmax), area under the 
concentration versus time curve from time zero
to the last quantifiable time point prior to the 
next dose (AUClast) and if data permit, clearance 
(CL or CL/F), volume of distribution at steady 
state (Vss or Vss/F), and terminal elimination 
t1/2..

Plasma lenalidomide, pomalidomide, and 
dexamethasone concentrations at selected time 
points (Parts 1C, 1D, and 1E, respectively). 
Immunogenicity

To evaluate immunogenicity
of PF-06863135 as 
monotherapy and in 
combination with , lenalidomide,
pomalidomide. or 
dexamethasone.  

Incidence and titers of anti-drug antibodies 
(ADA) and neutralizing antibodies (Nab) against 
PF-06863135.
Biomarker

To characterize the impact of 
PF-06863135 as monotherapy 
and in combination with 
lenalidomide, pomalidomide, or 
dexamethasone, on systemic 
soluble immune factors.

Pre- and post-dose quantification of soluble 
cytokines in serum.
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Tertiary/Exploratory 
Objectives: 
Tertiary/Exploratory Endpoints: 
Biomarker

Evaluate the effect of 
PF-06863135 as a 
monotherapy and in 
combination with 
lenalidomide, pomalidomide,
or  dexamethasone on plasma 
cell, T and B cell 
compartments.

BCMA expression on plasma cells in bone 
marrow, as assessed by multiparameter flow 
cytometry and immunohistochemistry;

Pre- and post-dose levels of soluble BCMA;

Enumeration of T, B, and NK subtypes in whole 
blood and bone marrow by flow cytometry 
analysis;

T-cell immunophenotyping, including but not 
limited to proliferation and activation markers in 
whole blood and bone marrow by flow 
cytometry analysis;

T-cell engagement, including but not limited to 
proliferation and activation markers in bone 
marrow by immunohistochemistry;

The relative expression of RNA transcripts,
including but not limited to, those associated 
with immune activation and immune regulation 
in bone marrow and peripheral blood;

The abundance and diversity of T-cell clones in 
bone marrow and peripheral blood.
Biomarker

To collect banked 
biospecimens for exploratory 
research, unless prohibited by 
local regulations or ethics 
committee decision.  

Collection of banked biospecimens unless 
prohibited by local regulations or ethics 
committee decision.  
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2.2.2. Part 2 Dose Expansion
Type
Primary Objectives: 
Primary Endpoints: 
Efficacy

To assess preliminary clinical 
efficacy at RP2D for 
PF-06863135 as 
monotherapy and in 
combination with
lenalidomide, pomalidomide,
or dexamethasone.

ORR (as Part 1)

DOR (as Part 1)
Secondary Objectives: 
Secondary Endpoints: 
Safety

To further characterize the 
safety and tolerability of 
PF-06863135 as 
monotherapy and in 
combination with 
lenalidomide, pomalidomide,
or dexamethasone.

Adverse Events as characterized by type, 
frequency, severity (as graded by NCI CTCAE 
version 4.03), timing, seriousness, and 
relationship to PF-06863135 treatment as 
monotherapy and in combination with 
pomalidomide, lenalidomide, or dexamethasone.  
The severity of CRS will be assessed according
to the grading described by Lee et al. (2014 and 
2019,2,3;

Laboratory abnormalities as characterized by 
type, frequency, severity (as graded by NCI 
CTCAE version 4.03), and timing.
Efficacy

To further evaluate 
anti-myeloma efficacy of 
PF-06863135 as 
monotherapy and in 
combination with 
lenalidomide, pomalidomide,
or dexamethasone.

Time to event endpoints (as Part 1)

Rate of patients with no MRD after treatment 
with PF-06863135 using IMWG MRD criteria4.
PK

Evaluate PK of PF-06863135
at RP2D as monotherapy and 
in combination with 
lenalidomide, pomalidomide,
or dexamethasone. 
Additionally, to collect
lenalidomide, pomalidomide, 
and dexamethasone
concentration data when 
combined with PF-06863135.

Concentrations of PF-06863135, lenalidomide, 
pomalidomide, and dexamethasone at selected 
time points.
Immunogenicity

To evaluate immunogenicity
of PF-06863135 as 
monotherapy and in 
combination with 
lenalidomide, pomalidomide,
or dexamethasone. 

Incidence and titers of anti-drug antibodies 
(ADA) and neutralizing antibodies (Nab) against 
PF-06863135.
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Biomarker

To characterize the impact of 
PF-06863135 as
monotherapy and in 
combination with 
lenalidomide, pomalidomide,
or dexamethasone on 
systemic soluble immune 
factors.

Pre- and post-dose quantification of soluble 
cytokines in serum.
Tertiary/Exploratory 
Objectives: 
Tertiary/Exploratory Endpoint): 
Biomarker

Evaluate the effect of 
PF-06863135 as 
monotherapy and in 
combination with 
lenalidomide, pomalidomide,
or dexamethasone on plasma 
cell, T and B cell 
compartments.

BCMA expression on plasma cells in bone 
marrow, as assessed by multiparameter flow 
cytometry and immunohistochemistry;

Pre- and post-dose levels of soluble BCMA;

Enumeration of T, B, and NK subtypes in whole 
blood and bone marrow by flow cytometry 
analysis;

T-cell immunophenotyping, including but not 
limited to proliferation and activation markers in 
whole blood and bone marrow by flow 
cytometry analysis;

T-cell engagement, including but not limited to 
proliferation and activation markers in bone 
marrow by immunohistochemistry;

The relative expression of RNA transcripts, 
including but not limited to, those associated 
with immune activation and immune regulation 
in bone marrow and peripheral blood;

The abundance and diversity of T-cell clones in 
bone marrow and peripheral blood.
Biomarker

To collect banked 
biospecimens for exploratory 
research, unless prohibited by 
local regulations or ethics 
committee decision.  

Collection of banked biospecimens unless 
prohibited by local regulations or ethics 
committee decision. 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
There are no formal interim statistical analyses in this open-label, unblinded clinical trial. 
Treatment safety and effectiveness are to be monitored continuously.
If the following criteria listed below are met in any of the cohorts in Part 2 dose expansion, 
further enrollment into the cohort meeting the criteria will be placed on hold, and a decision 
to stop the cohort may be made following a review of all safety information:
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
Number of patients with Grade 5 treatment-related AE ≥ 10%, or

Number of patients with Grade 4-5 treatment-related non-hematological AE >25%.
Adverse event information collected during dose escalation of subjects treated at the same 
dose levels will be included in the evaluation.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
Of the dose-escalation phase of the study, a Bayesian procedure is implemented to determine 
the MTD. 
4.2. Statistical Decision Rules
The initial Study Decision rules are described in the following table:
Table 1.
Decision Rules
Number of 
Subjects 
Having 
DLT
n=2
n=3
n=4
n=5
n=6
n=7
n=8
n=9
n=10
n=11
n=12
0
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
2
U
D
D
S
S
S
S
S
S
S
E
3
U
U
U
D
S
S
S
S
S
S
4
U
U
U
U
D
S
S
S
S
5
U
U
U
U
U
U
D
S
6
U
U
U
U
U
U
U
D: De-escalate the dose; E: Escalate the dose; S: Stay at the dose; U: Unacceptable toxicity
Note: If one subject has a DLT event observed in a dose cohort with 2 subjects enrolled, additional subjects 
may be enrolled for dose escalation assessment. Any DLT observed accounts for decision rules.
Dose escalation will stop under any of the following conditions:

The maximum sample size has been achieved;

6-12 subjects have been enrolled at a dose that is predicted to be the MTD;

All doses explored appear to be overly toxic and the MTD cannot be determined.
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5. ANALYSIS SETS
Analysis Set
Description
Applicable Analysis (for 
additional information refer to
section 6)
Full Analysis Set
(FAS)
all enrolled participants.
Primary endpoint, main analysis 
(section 6.1.1.1)
DLT Evaluable 
Set
patients that have experienced a DLT in the DLT 
observation period or received all of their planned doses 
of PF-06863135 in the initial DLT observation period if 
Q2W dosing is being evaluated or at least all but one of
their planned doses of PF-0686135 if Q1W dosing is 
being evaluated, provided a dose was not missed due to 
toxicity attributed to study drug. Safety information from 
any patients that do not meet DLT evaluable criteria 
could still be considered for overall dose escalation
decisions although they would not factor into mTPI 
decision rules.
DLT (see section 8.2.1)
Safety Analysis 
Set
all subjects who receive at least 1 full or partial dose of 
study medication.
DLT (see section 8.2.1)
Safety (see Section 8.2.3)
Demography and Baseline 
characteristics
PK 
Concentration 
Analysis Set
PF-06863135 PK Concentration Analysis Set is defined 
as all subjects randomized and treated who have at least 1 
measurable PF-06863135 concentration.
PK Analysis (see Section 8.2.5.)
PK Parameter 
Analysis Set
PF-06863135 PK parameter analysis population is 
defined as all enrolled subjects treated who have 
sufficient information to estimate at least 1 of the PF-
06863135 PK parameters of interest.
PK Analysis (see Section 8.2.5.)
PD/Biomarker 
Analysis Set
all enrolled subjects with at least 1 of the PD/Biomarkers
evaluated at pre- and/or post-dose.
PD/Biomarker Endpoints (see 
Section 8.2.5.4)
Immunogenicity 
Analysis Set
PF-06863135 Immunogenicity analysis set:
The immunogenicity analysis set is defined as patients 
who receive at least 1 dose of study treatment and have 
at least 1 ADA sample collected.
Immunogenicity Analysis(see 
Section 8.2.5.5.)
mITT Analysis 
Set (for 
evaluation of 
efficacy)
all subjects who have received at least one dose of study 
treatment. If the FAS is same as the mITT, the analysis 
should be run on FAS.
Efficacy Analysis (see Section 
8.2.3)
Response 
Evaluable Set
all patients who have received at least one dose of the 
study treatment, and has at least one post baseline 
efficacy assessment. 
Efficacy Analysis (see Section
8.2.3)
5.1. Treatment Misallocations
This is an unblinded MTD dose finding study. Subjects will be included in the cohort defined
by their initial dose.
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5.2. Protocol Deviations
Protocol deviations will be defined and this analysis plan to be updated before database lock.
5.2.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess subjects against the inclusion and exclusion criteria
as set out in Sections 4.1 and 4.2 of the protocol.
5.2.2. Deviations Assessed Post-randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population. 
6. ENDPOINTS AND COVARIATES
Baseline is defined as the last planned visit measurement on or prior to the first dose of study 
medication administration; otherwise, the last available measurement on or prior to the first
dose of study medication administration is to be adopted as Baseline. The start date is defined
as the first day of dosing. 
6.1. Efficacy Endpoints 
In this First in Patient study anti-tumor activity is a secondary objective for Part 1 and the 
primary objective for Part 2. All responses are as per investigator reported responses. 
Endpoints are as shown in Section 2.2.

Complete Response includes confirmed stringent Complete Response (sCR) and 
Complete Response (CR). CR Rate (CRR) is defined as the percentage of subjects 
meeting criterion for CB relative to the mITT analysis set.

Clinical Benefit (CB) includes confirmed response of sCR, CR (with and without MRD 
negativity), VGPR, PR, and MR. CB Rate (CBR) is defined as the percentage of subjects 
meeting criterion for CB relative to the mITT analysis set.

The OR Rate (ORR) is defined as the percentage of subjects meeting criterion for OR
relative to mITT analysis set.
6.2. Safety Endpoints

DLT is the primary endpoint of the dose escalation component of the study.  The
occurrence of DLTs observed in the dosing cohort is used to estimate the MTD.  Adverse 
Events constituting DLTs will be listed per dose level.

Adverse Events (AEs): Treatment Emergent Adverse Events, those with initial onset or 
increasing in severity after the first dose of study medication. 
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
AEs will be graded by the investigator according to CTCAE version 4.03 and coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). The number and 
percentage of subjects who experienced any AE, SAE, treatment related AE, and 
treatment related SAE will be summarized according to worst toxicity grades. The 
summaries will present AEs both on the entire study period and by cycle.

Laboratory abnormalities.

Vital signs.

ECGs.

Cytokine Release Syndrome: The severity of cytokine release syndrome (CRS) will be
assessed according to the modified grading described by Lee et al 2019 for SC cohorts 
and Lee et al 2014 for IV cohorts. (Appendix 5 of the protocol).
6.2.1. DLT Evaluability Criteria
For the purpose of dose escalation, the DLT observation period will be up to the end of Cycle
1 in each patient. For those patients receiving a priming dose, Cycle 0 and Cycle 1 would be
included in the DLT observation period. DLT evaluable patients will include patients that
have experienced a DLT in the DLT observation period or. DLT evaluable patients will also  
include those who received all of their planned doses of PF-06863135 in the initial DLT
observation period if Q2W dosing is being evaluated or at least all but one of their planned
doses of PF-0686135 if Q1W dosing is being evaluated, provided a dose was not missed due
to toxicity attributed to study drug. Safety information from any patients that do not meet
DLT evaluable criteria could still be considered for overall dose escalation decisions
although they would not factor into mTPI decision rules.
The following criteria will be used to assess adequate dosing for DLT evaluability:

Part 1 (no priming): At least 1 dose of the PF-06863135.

Part 1.1 Q1W: 75% of the planned PF-06863135 dose regimen in cycle 1, i.e. 28 days 
from C1D1. The total planned dose as per protocol = (maintenance dose * 4).
o
Dose administered dose will be the sum of Calculated Dose 
Administered=Volume of PF-06863135 administered * Concentration of PF-
06863135 formulation /body weight for the first 28 days.

Part 1.1 Q2W: 75% of the planned dose regimen in cycle 1, i.e. 28 days from C1D1. 
The total planned dose as per protocol = (maintenance dose * 2). 
o
Dose administered dose will be the sum of Calculated Dose 
Administered=Volume of PF-06863135 administered * Concentration of PF-
06863135 formulation/ body weight for the first 28 days.
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
Part 1C and 1D: [(75% of the planned PF-06863135 dose) AND (75% of the planned 
combination drug dose)] in cycle 1, i.e., 28 days from C1D1. 

The total planned PF-06863135 dose = (maintenance dose * 4).

The total planned Lenalidomide dose = (planned Lenalidomide dose in
mg * 21).

The total planned Pom dose = (planned Pomalidomide dose in mg * 
21).

Dose administered should be the sum of calculated actual dose
administered for the first 28 days.

Part 1E: [(75% of the planned PF-06863135 dose) AND (75% of the planned 
Dexamethasone dose)] in cycle 1, i.e., 28 days from C1D1. 

The total planned PF-06863135 dose = (maintenance dose * 4).

The total planned Dexamethasone dose = (planned Dexamethasone
dose in mg * 4). Dexamethasone will be administered at a dose of 40 
mg weekly. For subjects older than 75 years or underweight (body 
mass index [BMI] <18.5), the dexamethasone dose may be
administered at a dose of 20 mg weekly. Dexamethasone may be 
reduced, if necessary, according to Table 10 in the protocol.
Relative dose intensity at each cycle will be calculated as follows:

Part 1 (no priming): Cycle length is determined as entered by the site.
o
Dose administered will be the sum of “Calculated Dose Administered” for the 
cycle.
o
The total planned dose will be the (assigned dose of PF-06863135 *3)
o
If patient discontinues before end of the cycle, the planned dose for the will be 
based on dosing for number of days on the last cycle based on the dosing 
page. For example, if patient discontinues after CXD2, the planned dose will 
be (assigned dose of PF-06863135 *1).

Part 1.1 Q1W and Part 2A: Cycle length is determined as entered by the site.
o
The total planned dose = (maintenance dose of PF-06863135 * 4).
o
Dose administered will be the sum of “Calculated Dose Administered” for the 
cycle.
o
If patient discontinues before end of the cycle, the planned dose for the will be 
based on dosing for number of days on the last cycle based on the dosing 
page.

Part 1.1 Q2W: Cycle length is determined as entered by the site.
o
The total planned dose = (maintenance dose of PF-06863135 * 2). 
o
Dose administered will be the sum of “Calculated Dose Administered” for the 
cycle.
o
If patient discontinues before end of the cycle, the planned dose for the will be 
based on dosing for number of days on the last cycle based on the dosing 
page.
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
Part 1C and 1D: Cycle length is determined as entered by the site.

The total planned PF-06863135 dose = (maintenance dose * 4). 

The total planned Lenalidomide dose = (assigned dose of
Lenalidomide in mg * 21).

The total planned Pomalidomide dose = (assigned Pomalidomide dose 
of mg * 21.

Dose administered should be the sum of “calculated actual dose” for 
the cycle.

If patient discontinues before end of the cycle, the planned dose for the 
lenalidomide/pomalidomide will be based on daily dosing for 
min(number of days on the cycle, 21) as entered in the dosing page .

Part 1E: Cycle length is determined as entered by the site.

The total planned PF-06863135 dose = (maintenance dose * 4). 

The total planned Dexamethasone dose = (assigned dose of
Dexamethasone * 4).

Dose administered should be the sum of “calculated actual dose” for 
the cycle.

If patient discontinues before end of the cycle, the planned dose for the 
will be based on dosing for number of days on the last cycle based on 
the dosing page.
6.3. Pharmacokinetics Endpoints
Drug concentrations of PF-06863135 will be measured using validated methods.  For patients 
from Parts 1, 1.1, 1C, and 1D, PK parameters following the Cycle 1 Day 1 dose and Cycle 2 
Day 1 dose will be determined separately from the respective concentration-time data using 
standard noncompartmental methods. Actual sample collection times will be used for the 
parameter calculations.  For PF-06863135, PK parameters including maximum concentration 
(Cmax), time to maximum concentration (Tmax), area under the concentration-time curve over 
1 dosing interval (AUCτ), area under the concentration-time curve from time 0 to the last 
measurable concentration (AUClast), and, if data permit or if considered appropriate, area
under the concentration-time curve from time 0 extrapolated to infinity time (AUCinf), 
terminal elimination half-life (t½), clearance (CL or CL/F), volume of distribution at steady 
state (Vss), and accumulation ratio (Rac) will be calculated. PK parameters will be derived 
from the concentration-time data as follows:
Table 2.
PK Parameters
Parameter
Definition
Method of Determination
AUClast
Area under the concentration-time 
profile from time zero to the time of 
the last quantifiable concentration
Linear/Log trapezoidal method
AUC
Area under the concentration-time 
Linear/Log trapezoidal method
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Parameter
Definition
Method of Determination
profile from time zero to the time , 
the dosing interval
AUCinf
Area under the concentration-time
profile from time zero extrapolated to 
infinite time
AUC(0-t[last]) + (Clast*/kel),
where Clast* is the predicted serum concentration at 
the last quantifiable time point estimated from the
log-linear regression analysis.
Cmin
Lowest concentration observed during
interval
Observed directly from data
Cmax
Maximum observed concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence
T½
Terminal elimination half-life
Loge(2)/kel,
where kel is the terminal phase rate constant 
calculated by a linear regression of the log-linear 
concentration-time curve.  Only those data points 
judged to describe the terminal log-linear decline will 
be used in the regression.
CL (IV) or 
CL/F (SC)
Clearance (IV) or apparent clearance 
(SC)
Dose/ AUCinf for cycle 1; Dose/ AUCfor cycle 2
Vss
Volume of distribution at steady state
CLMRT
Rac
Observed accumulation ratio
AUCcycle 2, / AUCcycle 1, 
For patients enrolled in Part 2A, 2B 2C, and 2D of the study, trough PF-06863135
concentrations will be summarized descriptively by cycle.
Drug concentrations of lenalidomide (Parts 1C and 2C only), and pomalidomide (Parts 1D
and 2D only) will be measured using validated methods and summarized by descriptive 
statistics (n, mean, standard deviation, coefficient of variation, median, minimum, maximum, 
and geometric mean) according to dosing cohort and time for each part of the study.  No PK
parameters will be determined for lenalidomide, or pomalidomide.  
6.4. PD/Biomarker Endpoints
The biomarker endpoints will be used to help understand the in mechanism of action as well 
as potential mechanisms of resistance of PF-06863135 either as a monotherapy or in 
combination therapy.
Table 3.
Biomarker Assays and Sample Sources
Biomarker
Matrix
Assay
Soluble immune factors
Serum
Immunoassay
Soluble BCMA/related factors
Plasma
Mass spectrometry
BCMA expression
BM aspirate 
Flow cytometry 
BM biopsy
IHC
TBNK
Whole blood
Flow cytometry 
BM aspirate 
Flow cytometry
Immune cell phenotyping
Whole blood 
Flow Cytometry 
BM aspirate
Flow Cytometry 
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Table 3.
Biomarker Assays and Sample Sources
Biomarker
Matrix
Assay
BM biopsy (possible)
IHC
RNA profiling
Whole blood
RNA Sequencing 
BM aspirate and/or 
biopsy (possible)
RNA Sequencing
T cell repertoire analysis
Whole blood 
DNA Sequencing 
BM aspirate and/or 
Biopsy (possible)
DNA Sequencing
Abbreviations: BCMA = B-cell maturation antigen; BM = bone marrow; deoxyribonucleic acid = DNA; T, B, 
and NK cells = TBNK

BCMA expression and enumeration of CD138+ benign and malignant plasma cell 
populations in bone marrow pre- and post-dose, as assessed by multiparameter flow 
cytometry;

Pre- and post-dose levels of soluble BCMA;

Enumeration of T, B, and NK subtypes in whole blood;

T cell immunophenotyping, including but not limited to proliferation and activation 
markers in whole blood and bone marrow by flow cytometry analysis;

The relative expression of RNA transcripts, including but not limited to, those 
associated with immune activation and immune regulation in bone marrow and 
peripheral blood;

The abundance and diversity of T cell clones in bone marrow and peripheral blood;

BCMA expression on plasma cells and their spatial relationship to T cells by 
immunohistochemistry.

Collection of banked biospecimens unless prohibited by local regulations or ethics 
committee decision. Additional information on collection and potential use is 
provided in the Banked Biospecimens Section 7.7 Protocol C1071001.
6.4.1. Immunogenicity Endpoints
For the immunogenicity data, the percentage of subjects with positive ADA of PF-06863135 
and Nab each will be further characterized in terms of antibody specificity and summarized 
by dose level (Part 1) or by treatment arms.  For subjects with positive ADA or Nab,
categorization as treatment-emergent or treatment-boosted, the magnitude (titer), time of 
onset, and duration of ADA or Nab response will also be described, if data permit. Potential 
impact of immunogenicity on PK and clinical response including PD markers, 
safety/tolerability and efficacy of PF-06863135 will be explored, if warranted by the data).
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6.4.2. Outcomes Research Endpoints
Not applicable
6.5. Covariates 
The analyses of the MTD do not use covariates, and none will be defined. There are no 
planned comparisons between dose groups. 
7. HANDLING OF MISSING VALUES
Missing data will be excluded from the tabular summaries.
7.1. Pharmacokinetics
7.1.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ
will be replaced with the value for the lower limit of quantification).
7.1.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of the median values at each time point, statistics will be 
calculated having set concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (i.e., not done) or NS (i.e., no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been flagged 
anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
7.1.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will
be coded as NC (i.e., not calculated). (Note that NC values will not be generated beyond the
day that a subject discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular dose with ≥3 evaluable measurements.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
Overview of analysis:
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
Continuous data will be summarized using descriptive statistics (mean, median, SD,
minimum, maximum, and 2-sided 95% CI where applicable)

Categorical data (including point estimates) will be summarized by frequency counts, 
percentages and binomial 95% CIs using the Clopper-Pearson5 method.

Kaplan-Meier estimates (product-limit estimates) will be presented and displayed 
graphically where appropriate, together with a summary of associated statistics 
(including 2-sided 95% C is using log(-log) method according to Kalbfleisch and 
Prentice8).
8.1. Statistical Methods
The statistical summaries are non-inferential. The data are summarized by cohort defined by 
the initial dose, and route of administration of the study drug. 
8.1.1. Analyses for Continuous Data
Continuous data will be summarized with the mean, median, minimum, maximum and 
standard deviation.
8.1.2. Analyses for Categorical Data 
Categorical data will be summarized by number of unique subject incidence. 
8.1.3. Analyses for Binary Endpoints
Binary data will be summarized using number of unique subject incidence, and Wilson’s 
confidence interval for binomial proportions will be presented
8.1.4. Analyses for Time-to-event Data
The median, percentiles, and probabilities at particular points in time are estimated using the
method of Kaplan and Meier. Kaplan-Meier estimates (product-limit estimates) will be 
presented and displayed graphically where appropriate, together with a summary of 
associated statistics including the median PFS time with 2-sided 95% CIs. The CIs for the 
median will be calculated according to Brookmeyer and Crowley, 1982.6
8.2. Statistical Analyses 
8.2.1. Primary Analysis
The primary analysis will be based on the Safety Analysis Set.  The analysis objective is to 
summarize the adverse event incidence and will implement Pfizer standard summaries for 
adverse events. The occurrence of DLTs observed in the dosing cohorts is used to estimate 
the MTD as described in the Study Design section.  Adverse Events constituting DLTs will 
be listed per dose level. Because the intent is to find a desirable dose that meets the 
tolerability criteria based on DLT rate while demonstrating clinical activity based on 
response rate, descriptive statistics (n, frequency, and percentage) will be reported.
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Corresponding listings of data will be generated. Adverse events and cytokine release 
syndrome will be summarized by dose cohorts and in aggregate.  
8.2.2. Efficacy Analyses
No formal hypothesis testing will be performed on analysis of efficacy endpoints.   
Efficacy analysis will be summarized by dose cohorts.  Analysis of progression free survival 
and time to progression are defined as time from the date of first dose. Summaries of the n 
and % of subjects with PFS, and TTR and data listing by tumor type and dose will be 
generated.  If applicable, the PFS may also be summarized using the Kaplan-Meier method
at all or some of the following timepoints: 

OS at 6, 9, 12, 18, 24 months timepoints

PFS, DOR, DoSD and DoCR at 3, 6, 9, 12, 18 months timepoints

Reverse KM Follow-up probability is 3, 6, 9 months timepoints
The 95% confidence intervals will be generated. Confidence intervals for medians and 
quartiles will be based on the Brookmeyer-Crowley method. Confidence intervals for the 
estimated probability of an event at a particular time point will be generated using the 
Greenwood formula. Duration of response will be summarized with number of responders, 
number and percentage of event/censorship, mean, standard deviation, minimum, maximum 
and median of duration in unit of months.  ORR and CBR will be summarized by number of 
subjects meeting respective criteria, percentage.  The 95% confidence intervals will be 
generated for PFS, TTR, ORR, and CBR.  Definitions of PFS, TTR, DoR, ORR, and CBR are
outlined below.
8.2.2.1. Progression-Free Survival (PFS)
PFS is the time from date of first dose to date of first documentation of PD in a progression
or death due to any cause. PD or death after no more than 1 missing tumor assessment or date 
of first dose will be counted as an event according to the disease assessment date or date of 
death, as appropriate.  The definitions of relapse, clinical relapse and relapse from CR are not 
to be used in calculation of progression free survival.  Subjects will be considered to have 
progressive disease if they meet the criteria for progression even by a variable that was not
considered as a measurable marker at baseline; however, for subjects who had a measurable 
serum or urine M-spike at baseline, progression cannot be defined by increases in serum FLC 
alone.  In the IMWG criteria, clinical relapse subjects must also meet the criteria for 
progressive disease shown here to be classified as progressive disease for the purposes of 
calculating time to progression and progression-free survival.
Clinical relapse will be equivalent to PD. Note that a progression is defined as:

2 consecutive assessments of PD,

or 1 PD as last efficacy assessment followed by permanent treatment discontinuation,
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
or 1 PD following treatment discontinuation (EOT for both treatments in combined 
therapy - Part 1C and Part 1D). If the discontinuation is after PD but before the next 
response, then it is considered PD. If there are better responses before discontinuation,
it is not considered PD to allow for possible pseudo progression from the treatment 
which is clinically possible and accepted.
The mITT analysis set will be used. 
Censoring:  Subjects without an event or with an event after 2 or more missed tumor 
assessments will be censored as described in Table 4. In addition, if a new anti-cancer
therapy is started prior to an event, the subject will be censored on the date of the last 
adequate tumor assessment that documented no progression prior to the start of the new 
anti-cancer therapy.
An adequate post-baseline assessment is defined as an assessment where a response of sCR,
CR, VGPR, PR, MR, SD, Relapse or PD can be determined based on IMWG response 
criteria for multiple myeloma. Subjects with no baseline disease assessment (including
subjects with an inadequate baseline assessment) or with no adequate post-baseline disease
assessments within 46 days for cohorts with 21 day cycles and 60 days for cohorts with 28 
day cycles after the date of first dose will be censored on the date of first dose, unless the 
subject dies within 46 days for cohorts with 21 day cycles and 60 days for cohorts with 28 
day cycles of the date of the first dose, in which case, death will be an event on date of death.
Subjects will be considered to have progressive disease if they meet the criteria for 
progression by a variable that was not considered measurable at baseline.
Events and censoring rules are summarized in Table 4.
Table 4.
Progression Free Survival 
Situation
Date of Progression/Censoring1
Outcome
Inadequate baseline assessment 
First dosing date in Cycle 1 (or 
Cycle 0 for priming cohorts)
Censored
No on-study assessments
First dosing date in Cycle 1(or 
Cycle 0 for priming cohorts)
Censored
Alive, on treatment2 and no 
Progression 
Date of last objective tumor 
assessment3
Censored
New anti-cancer therapy
Date of last adequate disease 
assessment that documented no 
progression prior to new anti-
cancer therapy
Censored
Progression Documented on or 
between scheduled tumor 
assessments prior to treatment 
discontinuation2
Date of first objective tumor
assessment showing objective
progression
Progressed (Event)
Withdrawal of consent prior and 
refusal to follow-up
Date of last objective tumor 
assessment prior to 
Censored
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discontinuation2
Treatment discontinuation for 
undocumented progression, 
toxicity or other reason
Date of last objective tumor 
assessment prior to 
discontinuation2
Censored
Death prior to first planned 
tumor assessment 
Date of death
Death (Event)
Death without objective
progression prior to treatment 
discontinuation2
Date of death
Death (Event)
Death or progression after 2 or 
more missed tumor 
assessments4
Date of last objective tumor 
assessment prior to the event
Censored
Lost to follow-up
Date of last objective tumor 
assessment3
Censored
1.
For date of censorship, if a tumor assessment takes place over a number of days (e.g., superficial lesions one day, scans 
another), the last date is used as the assessment date.
2.
or within 28 days of discontinuation of treatment.
3.
Date of last adequate disease assessment that documented no progression
4.
This would be 46 days for cohorts with 21 day cycles and 60 days for cohorts with 28 day cycles
Reasons for censoring should be summarized according to the categories in Table 5.
Table 5.
PFS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline 
assessment
2
Start of new anti-cancer therapy before event.
Start of new anti-cancer
therapy
3 
Event after 2 or more missed tumor 
assessments/start date
Event after missing
assessments a
4
No event and [withdrawal of consent date ı date of 
first dose OR End of study (EOS) = Subject refused 
further FU] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition 
page 
Lost to follow-up
6
No event and [EOS present OR disposition page for 
any EPOCH after screening says subject will not 
continue into any subsequent phase of the study] and 
no adequate post-baseline disease assessment 
No adequate post-baseline 
disease assessment
7 
No event and none of the conditions in the prior 
hierarchy are met 
Ongoing without an event
a 2 or more missed tumor assessment.  
Disease Assessment Date: The Date of Disease Assessment at each nominal timepoint as 
provided by the investigator on the IMWG response CRF page will be utilized for the 
respective analyses.
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Adequate Baseline Disease Assessment: Adequate baseline is defined using the following 
criteria:

All baseline disease assessments (IMWG responses) must be within 28 days prior to and 
including the date of first dose;

Measurable disease based on IMWG criteria as defined by at least 1 of the following:

Serum M-protein ≥0.5 g/dL by SPEP;

Urinary M-protein excretion ≥200 mg/24 hours by UPEP;

Serum immunoglobulin FLC >10 mg/dL (>100 mg/L) AND abnormal serum
immunoglobulin kappa to lambda FLC ratio (<0.26 or >1.65).
Adequate Post-baseline Disease Assessment: An adequate disease assessment is defined as 
an assessment where a time-point response of sCR, CR, VGPR, PR, minimal response (MR), 
Stable Disease (SD) or PD has been provided.
Timepoints where the response is not evaluable or no assessment was performed will not be
used for determining the censoring date for time-to-event endpoints including PFS, DOR and
DOCR.
8.2.2.2. Overall Survival (OS)
OS is defined as the time from the date of first dose until death due to any cause and will be 
calculated in months as follows: 
OS (months) = [date of death or censoring – date of first dose +1] / 30.4375
Survival status is expected to be collected irrespective of study intervention discontinuation 
or participant’s request to discontinue study procedures. All participants who have not 
withdrawn consent for further participation in the study should be followed for survival until 
the end of the study. OS for participants not known to have died are censored on the date of 
last known alive.
OS time will be estimated using the same Kaplan-Meier method and displayed graphically as 
described for PFS in Section 8.2.2.1. Median OS and 2-sided 95% CI will be provided. The 
OS rate at 6, 9, 12, 18, and 24 months will be estimated with corresponding two-sided 95% 
CIs.  
Frequency (number and percentage) of participants with death events and censoring reasons 
will be presented by cohort along with the overall event and censor rates. The event and 
censoring reasons are as follows:
•
Death; 
•
Alive (Ongoing and no death);
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•
Withdrawal of consent;
•
Lost to follow-up.
The OS time or censoring time and the reasons for censoring will also be presented in a 
listing. The mITT Analysis will be used.
8.2.2.3. Time to Response (TTR)
In TTR analysis, TTR is defined, for participants with an objective response per IMWG 
criteria (i.e., subjects whose BOR are progressive disease, clinical relapse, stable disease, 
minimal response or deaths are excluded), as the time from the date of first dose to the first 
documentation of objective response that is subsequently confirmed. TTR will be calculated 
in days as follows: 
TTR (days) = [date of first objective response – date of first dose + 1] 
TTR will be summarized using simple descriptive statistics (mean, standard deviation, 
minimum, median, and maximum). Censoring:  Subjects will be censored same as censoring 
for primary definition of progression free survival (PFS) used in the study. This will be 
calculated on all responding subjects.
8.2.2.4. Time to Complete Response (TTCR)
TTCR is defined, for participants with an objective response per IMWG criteria is CR or 
sCR, as the time from the date of first dose to the first documentation of sCR or CR that is 
subsequently confirmed. TTCR will be calculated in days as follows: 
TTCR (days) = [date of first CR or sCR – date of first dose + 1] 
TTCR will be summarized using simple descriptive statistics (mean, standard deviation, 
minimum, median, and maximum). Censoring:  Subjects without response will be censored 
same as censoring for primary definition of progression free survival (PFS) used in the study.
This will be calculated on all subjects with objective response of CR or sCR.
8.2.2.5. Time to VGPR or better (TTVGPR)
TTVGPR or better is defined, for participants with an objective response per IMWG criteria
is VGPR, CR or sCR, as the time from the date of first dose to the first documentation of 
VFPR, CR or sCR that is subsequently confirmed. This will be calculated in days as follows: 
TTVGPR (days) = [date of first VGPR, CR or sCR – date of first dose + 1] 
TTVGPR or better will be summarized using simple descriptive statistics (mean, standard 
deviation, minimum, median, and maximum). Censoring:  Subjects without response will be 
censored same as censoring for primary definition of progression free survival (PFS) used in 
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the study. This will be calculated on all subjects with objective response of VGPR, CR or 
sCR.
8.2.2.6. Duration of Response (DoR)
DOR is defined, for participants with an objective response per IMWG criteria, as the time 
from the first documentation of objective response that is subsequently confirmed, until PD 
per IMWG criteria, or death due to any cause, whichever occurs first. It will be calculated as 
follows:
DOR (months) = [date of event or censoring – first date of objective response + 1] / 30.4375
The censoring rules for DOR are as described for PFS in Section 8.2.2.1, except that 
participants will not be censored for inadequate baseline assessment or for no adequate post-
baseline assessment, as only participants with an objective response are included in the 
analysis of DOR. 
If at least 3 participants achieve an objective response and subsequently have an event, DOR 
will be estimated using the same Kaplan-Meier method as described for PFS in 
Section 8.2.2.1 and displayed graphically where appropriate. Otherwise, only listings will be 
provided.  
The DOR rate at 3, 6, 9, 12 and 18 months (and in subsequent 6-month increments while 
there are participants still at risk) will be estimated with corresponding two-sided 95% CIs.  
8.2.2.7. Duration of sCR or CR (DoCR)
DoCR is the time from first observation of sCR or CR to the time of disease progression, or 
death due to any cause. The censoring rules for DoCR are the same as those for PFS outlined 
in Section 8.2.2.1 . This will be calculated on responding subjects with confirmed responses 
of CR or sCR. 
DoCR is defined, for participants with a sCR or CR per IMWG criteria, as the time from the 
first documentation of sCR or CR that is subsequently confirmed, until PD per IMWG 
criteria, or death due to any cause, whichever occurs first. It will be calculated as follows:
DoCR (months) = [date of event or censoring – first date of CR or sCR + 1] / 30.4375
The censoring rules for DoCR are as described for DOR in Section 8.2.2.4. 
If at least 3 participants achieve a CR or sCR and subsequently have an event, DoCR will be 
estimated using the same Kaplan-Meier method as described for DOR in Section 8.2.2.4 and 
displayed graphically where appropriate. Otherwise, only listings may be provided. 
The DoCR rate at 3, 6, 9, 12 and 18 months will be estimated with corresponding two-sided 
95% CIs.  
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8.2.2.8. Overall Response Rate (ORR)
The ORR is defined as the percentage of subjects with BOR of sCR, CR, VGPR, or PR 
relative to the appropriate analysis set. 
Criteria for IMWG Response as specified in Appendix 2 and 3. A response can be confirmed 
with a second response of same or better.
This is calculated from a sequence of objective status evaluations. The mITT analysis set and 
response evaluable analysis set will be used. 
Table 6.
Criteria for Best Response
sCR#
Stringent Complete Response: An objective status of Stringent Complete 
Response on at least two sequential disease assessments.
CR#
Complete Response: An objective status of Complete Response on at least 
two sequential disease assessments. 
VGPR
Very Good Partial Response: An objective status of Very Good Partial
Response on at least two sequential disease assessments.
PR
Partial Response: An objective status of Partial Response on at least two 
sequential disease assessments.
MR
Minimal response: An objective status of Minimal Response on at least two 
sequential disease assessments.
UsCR
Unconfirmed sCR: One objective status of Stringent Complete Response
(based on evidence from serum and urine studies and, if drawn, bone marrow 
biopsy) but the confirmation studies are either not done, or when done, do not 
meet the requirements necessary to confirm response. This must be 
documented before progression and before new anti-cancer therapy.
UCR
Unconfirmed CR: One objective status of Complete Response (based on 
evidence from serum and urine studies and, if drawn, bone marrow biopsy) 
but the confirmation studies are either not done, or when done, do not meet
the requirements necessary to confirm response. This must be documented 
before progression and before new anti-cancer therapy.
UVGPR
Unconfirmed VGPR: One objective status of Very Good Partial Response, but 
the confirmation studies are either not done, or when done, do not meet the 
requirements necessary to confirm response. This must be documented before 
progression and before new anti-cancer therapy.
UPR
Unconfirmed PR: One objective status of Partial Response, but the
confirmation studies are either not done, or when done, do not meet the
requirements necessary to confirm response. This must be documented before 
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Table 6.
Criteria for Best Response
progression and before new anti-cancer therapy.
SD
No Change/Stable Disease: At least one objective status of Stable Disease but 
not qualifying as any of the above. If radiographic studies were performed 
there should be no known progressive or new bone lesions. Subjects who had 
a single response of sCR, CR, VGPR, PR, or MR but no SD response can also 
confirm SD.
Progressive 
Disease (PD)
First objective status recoded of Progression. Progression is defined per the 
IMWG response criteria for Progressive Disease. Clinical relapse will be 
equivalent to PD. Note that a progression is defined as:

2 consecutive assessments of PD,

or 1 PD as last efficacy assessment followed by permanent treatment 
discontinuation, 

or 1 PD following treatment discontinuation (EOT for both treatments 
in combined therapy - Part 1C and Part 1D). If the discontinuation is 
after PD but before the next response, then it is considered PD. If 
there are better responses before discontinuation, it is not considered 
PD to allow for possible pseudo progression from the treatment which 
is clinically possible and accepted.
# CR and sCR: MRD tests should be initiated only at the time of suspected complete response.  Confirmation 
with two consecutive assessments is not required.
8.2.2.9. Clinical Benefit Rate (CBR)
A subject with a BOR of sCR, CR (with or without MRD negativity) VGPR, PR, and MR is 
defined as having Clinical Benefit (CB).  The CBR is defined as the percentage of subjects 
with CB according to the appropriate analysis set. Number and percentage of subjects having 
CB will be tabulated by treatment group. 
Proportion of subjects having minimal residual disease among sCR and CR subjects will be 
summarized by dose cohorts. The mITT analysis set will be used. 
8.2.2.10. Duration of Stable Disease (DoSD)
The DoSD is defined for patients with stable disease as the time from the first documentation 
of objective stable disease to the first documentation of objective tumor progression or to 
death due to any cause, whichever occurs first. It will be calculated as follows:
DoSD (months) = [date of event or censoring – first date of SD + 1] / 30.4375
The censoring rules for DoSD are as described for PFS in Section 8.2.2.1. This analysis will 
include only participants with confirmed stable disease or better. The DoSD rate at 3, 6, 9, 12 
and 18 months will be estimated with corresponding two-sided 95% CIs.
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For subjects with no adequate baseline assessment but with post-baseline assessments which 
can confirm SD, subjects will be censored to first dose date, then we will calculate DoSD= 
max ((date of event or censoring – first date of SD + 1) , 1). So DoSD will be 1 day instead 
of negative value.
8.2.2.11. Minimal Residual Disease (MRD)
MRD to be summarized as per Appendix 3 if data permits. 
Minimal Residual Disease (MRD) (assessed by central lab) negativity rate is the proportion 
of participants with negative MRD per IMWG sequencing criteria by bone marrow aspirate 
(BMA) at any time after first dose.
MRD negativity rate is defined as the proportion of participants with negative MRD 
(assessed by central lab) per IMWG sequencing criteria at any time after first dose of study 
intervention. MRD negativity will be defined by two thresholds, 10-5 and 10-6.
Point estimates of MRD negativity rate will be calculated along with the 2-sided 95% CIs 
using the Clopper-Pearson method5.
MRD negativity rate will also be summarized among participants who achieved CR or sCR 
with 2-sided 95% CIs.
If data permits, MRD-negativity status at 1-year, 2-year and 3-year from the time of first 
documentation of MRD-negativity may be summarized by number and percentage among 
participants who achieved CR or sCR and MRD negativity.
8.2.2.12. Duration of Treatment
The duration of treatment is calculated as follows:
Duration of treatment (months) = (last nonzero dose date - first dose date + 1)/30.4375
Duration of treatment will be summarized with descriptive statistics (n, mean, median, mode, 
standard deviation and range), frequency of occurrence <2months, >=2months and 
<4months, >=4 months and <6months, >=6months and <8months, and >=8months. Duration 
of treatment may also be presented graphically. 
8.2.3. Safety Analyses
Safety data will be summarized using Pfizer standard data summary procedures. Data will be 
summarized by cohort, defined by the initial dose. When the initial dose is determined to be 
the MTD, then the tables will also label the dose as the MTD. A breakdown of demographic 
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data will be provided for age, race, weight, body mass index, and height by cohort defined by 
initial dose. 
On-treatment period is defined as the time from the first dose of study intervention through
the minimum of (90 days (28 days for patients who completed the trial prior to approval of 
PA8 in June 2021) after last dose and start day of new anticancer therapy) – 1 day. Adverse 
events occurring on the same day as the first dose of study intervention and marked “After”
will be considered to have occurred during the on-treatment period. For all AE analysis 
relative to dosing time or date, AEs occurring on the same day of dosing but marked 
“Before” will be attributed to previous dose, and those marked as “After” will be attributed to 
the dose. 
The analysis sets to be used are the Safety Analysis set, DLT Evaluable Set will be used as 
applicable. 
For some summary tables, the following clustered terms for cytopenia based on PT may be 
used: 

Thrombocytopenia (PT=Thrombocytopenia; Platelet count decreased), 

Anaemia (PT=Anaemia; Haemoglobin decreased, Red blood cell count decreased, 
Haematocrit decreased, Normochromic anaemia, Normocytic anaemia, 
Normochromic normocytic anaemia), 

Neutropenia (PT=Neutropenia; Neutrophil count decreased, Neutrophil percentage 
decreased, Cyclic neutropenia, Agranulocytosis, Granulocytopenia, Granulocyte 
count decreased), Leukopenia (PT=Leukopenia; White blood cell count decreased),

Lymphopenia (PT=Lymphopenia; Lymphocyte count decreased, Lymphocyte 
percentage decreased, CD4 lymphocytes decreased, CD4 lymphocyte percentage 
decreased, CD8 lymphocytes decreased, CD8 lymphocyte percentage decreased), 

Hyperphosphataemia (PT=Blood phosphorus increased), 

Hypertension (PT=Blood pressure increased).
AE summarized as Peripheral Neuropathy includes MedDRA SMQ Peripheral neuropathy 
narrow and broad and SMQ Guillain-Barre syndrome narrow.
Hypogammaglobulinemia as an adverse even of clinical interest may be presented, using the 
following definition MedDRA PT terms: 'Blood immunoglobulin G decreased', 
'Hypogammaglobulinaemia', 'Hypoglobulinaemia', 'Immunoglobulins decreased', 'Globulins 
decreased'.
AE summarized as Infection includes any event from SOC Infections and infestations.
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8.2.3.1. Adverse Events
AEs will be graded by the investigator according to the CTCAE version 4.03 and coded 
using the MedDRA. The focus of AE summaries will be on Treatment Emergent Adverse 
Events, those with initial onset or increasing in severity after the first dose of study
medication.  The number and percentage of subjects who experienced any AE, serious AE 
(SAE), treatment related AE, and treatment related SAE will be summarized according to 
worst toxicity grades.  The summaries will present AEs both on the entire study period.  The 
Safety Analysis Set will be used.  
8.2.3.2. Laboratory Tests Abnormalities
The number and percentage of subjects who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory test.  The 
analyses will summarize laboratory tests in the entire study.  Shift tables may be provided to 
examine the distribution of laboratory abnormalities. The Safety Analysis Set will be used.  
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal high/low or not done. Baseline is defined as the latest non-missing value from the 
pre-treatment period.
8.2.3.3. Study Conduct and Patient Disposition
An accounting of the study subjects will be tabulated. The subject evaluation groups will be 
listed.  The Full Analysis Set will be used.  Subject discontinuation from treatment and study 
will be tabulated and listed separately with their reason for discontinuation.  The Safety 
Analysis Set will be used.
8.2.3.4. Baseline Characteristics
Baseline characteristics such as demographics, prior line of therapy, medical history, baseline 
Relapse or Refractory, baseline cytogenetic risk, IMWG Diagnosis Criteria, baseline bone 
marrow plasma cells, ECOG performance status will be tabulated and listed by dose. The 
Safety Analysis Set will be used.
8.2.3.4.1. Cytogenetic Risk
Cytogenetic risk will be calculated based on:

If Karyotype if Blank: then cytogenetic risk is “Missing”. 

If Karyotype is Normal: Then cytogenetic risk is “Standard”

If Karyotype is abnormal: 
o
Look for the following in abnormalities or other: 

Del 17p

T(4;14)

T(14;16)

Cytogenetic Del 13q

Cytogenetic Hypodiploidy

If collected, Plasma cell labeling index >3%
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If any of these exist, then risk is “high” else “standard”.
8.2.3.5. Treatment Administration/Compliance
Listings and tables by dose level will be provided.  Day 1 of a cycle is the date of first dose 
within that cycle. Each cycle is a 3-week period for Part 1, or 4-week period for Parts 1.1 1C,
1D, 1E, 2A, 2C, 2D, or 2E except cycle 0 for priming dose. The safety analysis set will be 
used.
The following will be summarized by subject for each dose level: 

Number of subjects per dose level;

Median and range of number of cycles started per subject;

Number (%) of subjects starting a cycle (1, 2, 3…);

Number (%) of subjects with cycle delays;

Number (%) of dose interruptions (include both known and unknown dates);

Number (%) of subjects with dose reductions;

Number (%) of each reason (AE vs. Other) for cycle delays, dose interruptions and dose 
reductions;

Time on treatment (median, range).
The following will be summarized by cycle received for each dose level:

Total number of cycles started;

Number of cycles started per subject (median, range);
The following will be summarized for cumulative dose by dose level and cycle: Summary 
statistics (mean, median, standard deviation and range) of cumulative dose and percent of 
starting dose (compared to Day 1 dose of each cycle).
Listings by subject (ordered by dose level): start date and stop date of each dosing period
within each cycle (including records with 0 mg), administered total daily dose for each 
period, any missed doses with unknown dates (Y/N), number of missed doses with unknown
dates, reason for any dosing changes. Listings by subject and each cycle (ordered by dose 
level): cycle length, total planned dose, administered total dose, percentage of planned dose,
dose delay (yes/no), dose reduction (yes/no), and dose interruption (yes/no). 
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8.2.3.6. Prior, Concomitant, and Further Therapies
Prior, concomitant, and further therapies (drug and non-drug treatments) will be coded by the 
World Health Organization (WHO) medical dictionary.  Summary tables, listings of prior, 
concomitant, and further therapies will be provided separately.
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation. 
8.2.3.6.1. Prior Anti-Cancer Therapy
Number and percentage of participants with any prior regimen will be presented along with
median and range of number of prior regimens. The number and percentage of participants in 
each of the following anticancer therapy categories will be tabulated:

Participants with at least 1 type of prior anticancer treatment;

Participants with at least 1 prior anticancer radiotherapy;

Participants with prior IMiDs and type (e.g., lenalidomide, pomalidomide, or 
thalidomide, Iberdomide, CC-92480);

Participants with prior PI and type (e.g., bortezomib, carfilzomib, ixazomib);

Participants with prior anti-CD38 mAb and type (eg, daratumumab, isatuximab);

Participants who are Triple-class refractory: refractory to at least 1 PI, and at least 1 
IMiD, and at least 1 anti CD38.

Participants who are Quad-class refractory: refractory to at least 2 PI, AND at least 2 
IMiD;

Participants who are Penta-class refractory: refractory to at least 2 PI, and at least 2 
IMiD, and at least 1 anti CD38;

Participants who received at least 2 PIs, 2 IMiDs and 1 anti-CD38;

Participants with prior Selinexor;

Participants with prior Elotuzumab;

Participants with prior transplant and type (autologous or allogeneic);

Refractory to last line of therapy;
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
Type of prior BCMA-targeted therapy (ADC, CAR-T).
The prior anticancer drugs will be coded in the WHO Drug coding dictionary and will be 
summarized based on the number and percentage of participants by preferred term. A 
participant will be counted only once within a given preferred term, even if he or she 
received the same medication at different times unless specified. 
Refractory is defined as having progression occurred after regimen during the regimen or 
discontinuation of the regimen due to progression.
8.2.3.7. Electrocardiograms (ECG)
Triplicate 12-lead ECGs will be performed per Schedule of Activities.  The Day 1 triplicate 
ECG prior to treatment administration will be used as baseline; if it is missing, values from 
the ECG taken at screening will be used for baseline.
ECG assessments reported by the site will include PR, HR, QT, QRS, and QTcF. A mean 
score is calculated and reported for any replicate measurements having the same nominal 
visit. All summary statistics, analyses and figures will be based on the triplicate averaged 
data. Any data obtained from ECGs repeated for safety reasons after the nominal time-points 
will not be averaged along with the preceding triplicates.
ECG summaries will include all ECG assessments from the on-treatment period. RR will be 
derived from HR. Fridericia’s correction (QTcF) will be based on the values collected on the 
CRF. QTcF will be derived from QT and HR in case QTcF is missing using the following 
formula:
3
(sec)
/
sec)
(
sec)
(
RR
m
QT
m
QTcF

All ECG assessments will be listed, and those collected outside the on-treatment period will 
be flagged in the listing.
QTcF will be summarized by maximum on-treatment values using the following categories:

<450 msec;

≥450 msec but ≤480 msec;

>480 msec but ≤500 msec;

>500 msec.
Unscheduled assessments will be utilized in addition to planned assessments. Shift tables will 
be provided for baseline QTcF value versus worst on-treatment value. Results of ECGS 
done as additional follow-up for prolonged PK t1/2 and unscheduled ECG results will be 
listed but not summarized. Additionally, maximum increases from baseline (including 
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scheduled and unscheduled assessments) will be summarized based on the following 
categories:

Change >60 msec;

Change >30 msec but ≤60 msec;

Change ≤30 msec.
Data listings will contain the means from a triplicate as well as the parameters from each of 
the 3 ECGs. Note that using the mean value may result in a participant having a measurement 
that is not represented by an actual ECG.
8.2.4. Other Safety Data – Screening and Other Special Purpose Data
Prior medication(s), non-drug treatment(s), medical history and physical examination will be 
listed in accordance with the sponsor reporting standards. Medical history will be mapped
using the MedDRA thesaurus.
Cytokine Release Syndrome (CRS) and Immune Cell-Associated Neurotoxicity syndrome 
(ICANS) are the AEs of special interested in the study and will be presented in the form of
summary tables and listings. 
CRS will be graded according to the modified grading described by Lee et al. (2014)
(Appendix 4) and the ASTCT consensus grading (Lee et al 2019). The ASTCT grading will 
be the primary CRS grading used for all analysis. The CRS grade as per the ASTCT (Lee et 
al. 2019) criteria captured in the CRS CRF page will be used for all summary tables 
containing CRS grades for SC cohorts. CRS grades as per Lee et al. 2014 captured in the AE 
CRF page will be used for all summary tables containing CRS grades for IV cohorts and
listed for all cohorts. 
Emphasis will be put on Cytokine Release Syndrome by analyzing all patient symptoms 
related to CRS, time to CRS onset, proportion of subjects treated with tocilizumab and time 
to CRS resolution.
Information on events of ICANS such as grade, symptoms and time to onset and duration
will be summarized and listed.
Duration of Adverse Events may be presented for AEs of interest such as CRS and ICANs
and is calculated as following:
Duration of AE = start data of the AE -stop date of the AE +1
Time to first onset of AE may be presented for AEs of interest such as CRS and ICANS and 
is computed as follows:
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Date of onset of AE = date of first onset of CRS - first dose date +1.
8.2.5. PK Analyses
8.2.5.1. Pharmacokinetic Parameters
To assess the pharmacokinetics of PF-06863135, the PK parameters detailed in Section 6.4
will be listed and summarized for subjects in the PK analysis set (as defined in Section 5 ).
Missing values will be handled as detailed in Section 7.1. Each PK parameter, if calculatable
by data, will be summarized by dose, cycle, and day and will include the set of summary 
statistics as specified in the table below:
Parameter
Summary statistics
AUC, Cmin, Cmax, CL, 
Vss, and Rac
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum, geometric mean
t1/2
N, arithmetic mean, median, cv%, standard deviation, 
minimum, maximum
Tmax
N, median, minimum, maximum
To assess the relationship between the PK parameters and dose, dose normalized AUCand 
Cmax will be plotted against regimen, dose (using a logarithmic scale), and will include 
individual subject values and the geometric means for each dose.  Geometric means will have 
a different symbol than the individual values.  The values will be dose normalized (by µg/kg 
or mg dose) by dividing the individual values and raw geometric means by dose.  A footnote 
will be added to the plots to indicate that geometric means are presented on the plot.
8.2.5.2. Pharmacokinetic Concentrations
To assess the PK profile of PF-06863135, PK concentrations will be listed; summarized (n, 
mean, standard deviation, coefficient of variation, median, minimum, maximum, and 
geometric mean) by dose, cycle, day and nominal time; and plotted for subjects in the PK 
analysis set (as defined in Section 5), where missing and BLQ values will be handled as 
detailed in Section 7 above.
Presentations for PF-06863135 time-concentration data will include:

A listing of all concentrations sorted by dose, subject ID, period and nominal time post-
dose.  The listing of concentrations will include the actual sample collection times, and 
the time of dosing.  Deviations from the nominal time will be given in a separate listing.

A summary of concentrations by dose and nominal time post-dose, where the set of 
statistics will include n, mean, median, standard deviation, coefficient of variation (cv), 
minimum, maximum and the number of concentrations above the lower limit of 
quantification.

Median concentrations against nominal time post-dose by dose (based on the summary of 
concentrations by dose and time post-dose), with all doses presented on the same plot.  
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Two plots will be generated, so that the concentrations can be presented on linear and 
logarithmic scales.
For summary statistics and median plots by sampling time, the nominal PK sampling time
will be used.  
8.2.5.3. PD/Biomarker Endpoints
For baseline continuous endpoint data, descriptive statistics, including the mean, standard 
deviation, median, minimum, and maximum values, will be provided by treatment arm.  
Appropriate statistical methods, e.g., multivariate analysis, logistic regression, longitudinal or 
repeated measure analysis or Cox-regression analysis, may be used to investigate any 
possible relationship of biomarker levels with PF-06863135 anti-myeloma efficacy, either as 
a monotherapy or in combination therapy. Summary statistics will be tabulated by visit and 
treatment group. 
8.2.5.4. Population PK and PK/PD Modeling
Pharmacokinetic and PD data from this study may be analyzed using modeling approaches 
and may also be pooled with data from other studies to investigate any 
association/correlation between PF-06863135 exposure and biomarkers (e.g., soluble 
BCMA) or significant safety endpoints. The results of these analyses, if performed, may be
reported separately.
8.2.5.5. Immunogenicity Endpoints
For the immunogenicity data, the percentage of subjects with positive ADA of PF-06863135
and neutralizing antibodies (Nab) each will be summarized by dose level (Part 1) or by 
treatment arms.  For subjects with positive ADA or Nab, the magnitude (titer), time of onset, 
and duration of ADA or Nab response will also be described, if data permit. Potential impact 
of immunogenicity on PK and clinical response including PD markers, safety/tolerability and 
efficacy of PF-06863135 will be explored, if data is warranted. 
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9. REFERENCES
1.
Ji Y., Li Y. & Yin, G. Bayesian dose finding in Phase I clinical trials based on a new 
statistical framework. Statistica Sinica 17(2007), 531-547.
2.
Lee D.W., Gardner R., Porter D.L., et al. Current concept in the diagnosis and 
management of cytokine release syndrome. Blood 124(2014): 188-95. 
3.
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biology of Blood and Marrow Transplantation. 2019;25(4):625-38.
4.
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working 
Group updated criteria for the diagnosis of multiple myeloma. The lancet oncology. 
2014;15(12):e538-e48.
5.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika. 1934;26:404-13.
6.
Ji Y, Liu P, Li Y, et al. A modified toxicity probability interval method for dose finding
trials. Clin Trials. 2010;7(6):653-63.
7.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 1982;38:29-41.
8.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition.
Hoboken, Wiley Interscience.
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10. APPENDICES
Appendix 1. Abbreviations
Abbreviation
Term
ADA
Anti-drug Antibody
AE
Adverse Event
AIDS
Acquired Immunodeficiency Syndrome
ALL
Acute Lymphoblastic Leukemia
ALK
Anaplastic Lymphoma Kinase
ALT
Alanine Aminotransferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
ANOVA
Analysis of Variance
APCs
Antigen Presenting Cells
APRIL
A Proliferation Inducing Ligand
ASCO
American Society of Clinical Oncology
ASCT
Autologous Stem Cell Transplant 
AST
Aspartate Aminotransferase
AUC
Area Under the Concentration-Time Curve
AUCinf
area under the concentration versus time curve to infinity
AUClast, AUC
concentration versus time curve
AUCsd,
area under the single dose concentration-time curve over dosing 
interval 
AUCss,
area under the single dose concentration-time curve over dosing
interval 
BBS
biospecimen banking system
BCMA
B-cell maturation antigen
BID
twice daily
BM
bone marrow
BOR
best overall response
BP
Blood Pressure
BUN
blood urea nitrogen
C
cycle
C1D1
Cycle 1 Day 1
CAR
chimeric antigen receptors
Cav
average concentration
CB
clinical benefit
CBC
Complete Blood Count
CBR
Clinical Benefit Response
CD
cluster of differentiation 
CDC
Complement Mediated Cytotoxicity
Ceff
efficacious concentration
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Abbreviation
Term
CHF
congestive heart failure
CI
confidence interval
CK
creatine kinase
CL
Systemic Clearance
Cmax
maximum (or peak) concentration
Cmin
minimum concentration
CMV
cytomegalovirus
CNS
Central Nervous System
CR
Complete Response
CRAB
calcium elevation, renal failure, anemia, lytic bone lesions; 
CrCl
creatinine clearance
CRF
Case Report Form
CRO
Contract Research Organization
CRP
C-Reactive Protein
CRR
complete response rate
CRS
cytokine release syndrome
CSA
Clinical Study Agreement
CSF
cerebrospinal fluid
CSR
Clinical Study Report
CT
Computed Tomography
CT SAE
clinical trial serious adverse event
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DILI
drug-induced liver injury
DLI
Donor Lymphocyte Infusion
DLT
Dose Limiting Toxicities
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DoCR
duration of complete response
DOR
duration of response
DOSD
duration of stable disease
DU
dispensable unit
EBV
Epstein-Barr virus
EC
ethics committee
EC20
effective concentration 20
EC50
effective concentration 50
ECG
Electrocardiograms
echo
echocardiogram
ECOG
Eastern Cooperative Oncology Group
E-DMC
external data monitoring committee
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Abbreviation
Term
EDP
Exposure During Pregnancy
EDV
end-diastolic volume
eg
for example
EI
Equivalence Interval
EOS
end of study
EOT
end of treatment
ESV
end-systolic volume
Etc
‘and other things’ or ‘and so forth’
EU
European Union
EudraCT
European Clinical Trials database
FAP
final approved protocol
Fc
fragment crystallizable
FDA
Food and Drug Administration (United States)
FDG-PET/CT
fluorodeoxyglucose positron emission tomography/computed
tomography
FIP
First In Patient
FISH
fluorescence in situ hybridization
FLC
free light chain analysis
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal tract
GLP
Good Laboratory Practice
GM-CSF
granulocyte- macrophage colony stimulating factor
GnRH
gonadotropin-releasing hormone agonist
HbA1c
hemoglobin A1c
HBc
hepatitis B core
HBs
hepatitis B surface
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
Hgb
hemoglobin
HIV
Human immunodeficiency Virus
HLA
human leukocyte antigen
HLH
lymphohistiocytosis
HR
heart rate
hrs
hours
HTLV
human T-cell lymphotropic virus
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ICU
intensive care unit
ID
Identification
ie
that is
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Abbreviation
Term
IFNg
interferon gamma
Ig
immunoglobulin
IgGk
immunoglobulin G kappa
IHC
Immunohistochemistry
IL-
interleukin
iMiD
immunomodulatory drug
IMWG
international myeloma working group
IND
Investigational New Drug
INR
International Normalized Ratio
IP
Investigational Product
IP
Intraperitoneal
IP manual
Investigational Product manual
IRB
Institutional Review Board
IRC
internal review committee
IRR
infusion related reaction
ITT
intent to treat
IUD
Intrauterine Device
IV
Intravenous
K2EDTA
dipotassium edetic acid ethylenediaminetetraacetic acid
KD
equilibrium dissociation constant
LDH
lactate dehydrogenase
LFT
Liver Function Tests
LPFV
last patient first visit
LSLV
Last Subject Last Visit
LTFU
long-term follow-up
LVEF
left ventricular ejection fraction
M
monoclonal
mAb
Monoclonal Antibody
MABEL
minimum anticipated biological effect level
MAD
maximum administered dose
MAS
macrophage activation syndrome
MD
multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
MFD
maximum feasible dose
MGUS
monoclonal gammopathy of undetermined clinical significance
MHC
major histocompatibility complex
MM
multiple myeloma
MM1.S
a glucocorticoid sensitive multiple myeloma cell line
MMAE
Monomethyl Auristatin E
MOLP-8
a multiple myeloma cell line with t(11;14)(q13;q32) chromosomal
abnormality and negative for CD28
M-Protein
myeloma protein
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Abbreviation
Term
MR
minimal response
MRD
minimal residual disease
MRI
Magnetic Resonance Imaging
M-spike
monoclonal spike
MTD
Maximum Tolerated Dose
mTPI
Modified Toxicity Probability Interval
MUGA
multigated acquisition scan
N/A
Not Applicable
NAb
neutralizing antibody
NCI
National Cancer Institute
NGF
next generation flow cytometry
NGS
next generation sequencing
NK
natural killer
NOAEL
no observed adverse effect level
NSAIDS
nonsteroidal anti-inflammatory drugs
NSG
NOD scid gamma
OBD
optimal biological dose
OPM-2
a type of multiple myeloma cell line
OR
objective response or overall response
ORR
Overall Response Rate
OS
overall survival
PCD
Primary Completion Date
PD
Progressive Disease
PD
Pharmacodynamic
PD-1
anti- programmed cell death protein-1
PD-L1
or anti- programmed death-ligand 1
PET
positron emission tomography
PFS
Progression Free Survival
PGx
pharmacogenomics
PI
principal investigator
PK
Pharmacokinetic
PO
by mouth
PP
posterior probability
PR
Partial Response
PR
Pulse Rate
PS
Performance Scale
pT
target probability
PT
Prothrombin Time
PTT
partial thromboplastin time
QD
every day
qPCR
quantitative polymerase chain reaction
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Abbreviation
Term
QT
time between the start of the Q wave and the end of the T wave
QTcF
Fridericia QT Correction Formula
Rac
accumulation ratio
RCL
replication competent lentivirus
RD
response/remission duration
RNA
Ribonucleic Acid
RO
receptor occupancy
RP2D
Recommended Phase 2 Dose
RR
Response Rate
RT-PCR
reverse transcription polymerase chain reaction
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
scFv
single-chain variable fragment
sCR
stringent complete response
SCT
stem cell transplant
SD
Stable Disease
SIFE
serum immunofixation electrophoresis
sIL2Ra
soluble interleukin-2 receptor alpha
SOP
standard operating procedure
SPD
sum of the products of the maximal perpendicular diameters of
measured lesions
SPEP
serum protein electrophoresis
SUV
standard uptake value
SWOG
Southwest oncology group
t1/2
terminal elimination half-life
TALEN
transcription activator-like effector nucleases
TBili
total bilirubin
TBNK
T-, B-, and natural killer lymphocytes
TBR
tumor background ratio
TCR
T cell receptor
TLS
tumor lysis syndrome
Tmax
time to maximum concentration
TNF
tumor necrosis factor
TNFa
tumor necrosis factor –alpha
TNFRSF17
tumor necrosis factor receptor superfamily Member 17
TRAC
T-cell receptor alpha constant
Tregs
T regulatory cells
Tss,max
time to maximum concentration
TTR
time to response
UIFE
urine immunofixation electrophoresis
ULN
Upper Limit of Normal
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Abbreviation
Term
UPEP
urine protein electrophoresis
UPM
Unit Probability Mass
US
United States
UVB
ultraviolet B
VGPR
very good partial response
Vss
Volume of Distribution at Steady State
WBC
White Blood Cell
wks
weeks
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Appendix 2. THE INTERNATIONAL MYELOMA WORKING GROUP (IMWG) 
RESPONSE CRITERIA FOR MULTIPLE MYELOMA 
All response categories require two consecutive assessments made any time before starting 
any new therapy.  Subjects must have measurable disease at enrollment (study entry).  
Measurable disease is defined as: 
Serum M-protein 0.5 g/dL;
Urine M-protein 200 mg/24 hrs;
Serum immunoglobulin FLC >10 mg/dL (>100 mg/L) AND abnormal serum 
immunoglobulin kappa to lambda FLC ratio (<0.26 or >1.65).
Whenever more than one parameter is used to assess response, the overall assigned level of
response is determined by the lower or lowest level of response.  Subjects will continue in 
the last confirmed response category until there is confirmation of progression or 
improvement to a higher response status; subjects cannot move to a lower response category.
Response
IMWG Criteria
Stringent Complete 
Response (sCR) 
Complete response as defined below plus normal free light chain (FLC) ratio and 
absence of clonal cells in bone marrow biopsy by immunohistochemistry (κ/ratio 
4:1 or 1:2 for κ and subjects, respectively, after counting 100 plasma cells)2
Complete Response 
(CR)
Negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomas and <5% plasma cells in bone marrow aspirates1
Very Good Partial 
Response (VGPR) 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis
or
90% reduction in serum M-protein plus urine M-protein level <100 mg/24 hr.
Partial Response 
(PR)

50% reduction of serum M-protein and reduction in 24 hours urinary M-protein 
by 90% or to <200 mg/24 hr.

If the serum and urine M-protein are unmeasurable,4 a 50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of 
the M-protein criteria.

If serum and urine M-protein are unmeasurable and serum-free light assay is also 
unmeasurable, 50% reduction in plasma cells is required in place of M-protein, 
provided baseline bone marrow plasma-cell percentage was 30%. 

In addition to these criteria, if present at baseline, a 50% reduction in the size 
(SPD)2 of soft tissue plasmacytomas is also required.  
Minimal Response 
(MR)
25% but 49% reduction of serum M-protein and reduction in 24-h urine M-protein 
by 50–89%.  In addition to the above listed criteria, if present at baseline, a 50% 
reduction in the size (sum of the products of the maximal perpendicular diameters of 
measured lesions [SPD])3 of soft tissue plasmacytomas is also required.
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No Change/Stable 
Disease (SD)
Not meeting criteria for CR, VGPR, PR, MR or progressive disease.
Progressive Disease 
(PD)5

Increase of 25% from lowest response value in any one or more of the 
following:

Serum M-component and/or (the absolute increase must be 0.5 g/dL),4

Serum M-protein increase 1 g/dL, if the lowest M component was 
5 g/dL;

Urine M-component and/or (the absolute increase must be 
200 mg/24 hrs;

In subjects without measurable serum and urine M-protein levels, the difference 
between involved and uninvolved FLC levels (absolute increase must be 
>10 mg/dL);

In subjects without measurable serum and urine M-protein levels and without 
measurable involved FLC levels, bone marrow plasma-cell percentage 
irrespective of baseline status (absolute increase must be 10%);

Appearance of a new lesion(s), 50% increase from nadir in SPD1 of >1 lesion, 
or 50% increase in the longest diameter of a previous lesion >1 cm in short 
axis;

50% increase in circulating plasma cells (minimum of 200 cells per L) if this 
is the only measure of disease.
Clinical Relapse
Clinical relapse requires one or more of the following criteria:

Direct indicators of increasing disease and/or end organ dysfunction 
(CRAB features) related to the underlying clonal plasma-cell 
proliferative disorder;

Development of new soft tissue plasmacytomas or bone lesions 
(osteoporotic fractures do not constitute progression);

Definite increase in the size of existing plasmacytomas or bone lesions.  
A definite increase is defined as a 50% (and 1 cm) increase as
measured serially by the SPD2 of the measurable lesion;

Hypercalcemia (>11 mg/dL);

Decrease in hemoglobin of 2 g/dL not related to therapy or other 
non-myeloma-related conditions;

Rise in serum creatinine by 2 mg/dL or more from the start of the 
therapy and attributable to myeloma;

Hyperviscosity related to serum paraprotein.
CRAB features=calcium elevation, renal failure, anemia, lytic bone lesions; IMWG=International Myeloma 
Working Group; FLC=free light chain; M-protein=myeloma protein; SPD=sum of the products of the maximal 
perpendicular diameters of measured lesions.
Footnotes:
1.
Confirmation with repeat bone marrow biopsy not required.  Careful attention should be given to new
positive immunofixation results appearing in subjects who have achieved a complete response, when the 
isotype is different.  This probably represents oligoclonal immune reconstitution and should not be 
confused with relapse; these bands typically disappear over time.
2.
Presence/absence of clonal cells on immunohistochemistry is based upon the κ//L ratio.  An abnormal κ/
ratio by immunohistochemistry requires a minimum of 100 plasma cells for analysis.  An abnormal ratio 
reflecting presence of an abnormal clone is κ/of >4:1 or <1:2. 
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3.
Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or dedicated CT scans 
where applicable.  Measurement of tumor size will be determined by the SPD.
4.
All relapse categories require two consecutive assessments made at any time before classification as relapse 
or disease progression and/or the institution of any new therapy.  To confirm response or progressive 
disease, two discrete samples are required and testing cannot be based upon the splitting of a single sample.  
In the IMWG criteria, CR subjects must also meet the criteria for progressive disease shown here to be 
classified as progressive disease for the purposes of calculating time to progression and progression-free 
survival.  The definitions of relapse, clinical relapse and relapse from CR are not to be used in calculation 
of time to progression or progression free survival.  Subjects will be considered to have progressive disease 
if they meet the criteria for progression by a variable that was not considered measurable at baseline; 
however, for subjects who had a measurable serum or urine M-spike at baseline, progression cannot be 
defined by increases in serum FLC alone. 
5.
For progressive disease, serum M-component increases of 1 gm/dL are sufficient to define relapse if 
starting M-component is 5 g/dL.
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Appendix 3. IMWG MINIMAL RESIDUAL DISEASE (MRD) Criteria
MRD tests should be initiated only at the time of suspected complete response.  Confirmation 
with two consecutive assessments is not required. 
Response
IMWG Criteria
Sustained 
MRD-Negative 1
MRD negativity in the marrow (NGS) and by imaging as defined below, 
confirmed minimum of 1 year apart.  Subsequent evaluations can be used to 
further specify the duration of negativity (eg, MRD-negative at 5 years).
Flow 
MRD-negative 2
Absence of phenotypically aberrant clonal plasma cells by NGF‡ on bone 
marrow aspirates using the EuroFlow standard operation procedure for MRD 
detection in multiple myeloma (or validated equivalent method) with a 
minimum sensitivity of 1 in 105 nucleated cells or higher.
Sequencing
MRD-negative 
Absence of clonal plasma cells by NGS on bone marrow aspirate in which 
presence of a clone is defined as less than two identical sequencing reads 
obtained after DNA sequencing of bone marrow aspirates using the 
LymphoSIGHT platform (or validated equivalent method) with a minimum 
sensitivity of 1 in 105 nucleated cells or higher.
Imaging-positive
MRD-negative
MRD negativity as defined by NGS plus disappearance of every area of 
increased tracer uptake found at baseline or a preceding PET/CT or decrease 
to less mediastinal blood pool SUV or decrease to less than that of 
surrounding normal tissue. 
CT = computed tomography; IMWG=International Myeloma Working Group; MRD = minimal residual 
disease; NGF = next-generation flow cytometry; NGS = next generation sequencing; positron emission 
tomography = PET; SUV = standardized uptake value.
Footnotes:
1.
Sustained MRD negativity, when reported, should also annotate the method used (eg, sustained sequencing 
MRD- negative).
2.
Bone marrow MFC should follow NGF guidelines.  The reference NGF method is an eight-colour 
two-tube approach, which has been extensively validated.  The two-tube approach improves reliability, 
consistency, and sensitivity because of the acquisition of a greater number of cells.  The complete 
eight-colour method should use a lyophilized mixture of antibodies.  5 million cells should be assessed.  
The method employed should have a sensitivity of detection of at least 1 in 105 plasma cells.
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Appendix 4. Cytokine Release Symptoms Revised Grading System
Table 7: 
Lee et al 2014 CRS revised grading system
Toxicity 
Grade
Characteristics
1
Symptoms are not life threatening and require symptomatic treatment 
only, eg, Fever, nausea, fatigue, headache, myalgia, malaise
2
Symptoms require and respond to moderate intervention
Oxygen requirement <40% or
Hypotension responsive to fluids or low-dose of one vasopressor or 
Grade 2 organ toxicity
3
Symptoms require and respond to aggressive intervention
Oxygen requirement ≥40% or 
Hypotension requiring high-dose vasopressors or multiple vasopressors or 
Grade 3 organ toxicity (except transaminitis) or 
Grade 4 transaminitis
4
Life-threatening symptoms
Requirement for ventilator support or Grade 4 organ toxicity (excluding
transaminitis)
5
Death
The original CRS grading system proposed by Lee et al in 20142 (Table 13) should be used
only for the purposes of grading of CRS on the adverse event case report form (CRF), but not
for management of CRS. Grading by the more recent ASTCT CRS criteria3 (Table 15) will be 
captured along with the Lee et al 2014 criteria on the CRS CRF, and management guidelines 
will follow ASTCT CRS grading. These treatment guidelines may be modified as needed by 
the responsible Investigator according to the best practices at their institute.
CRS parameter
Fever
With Hypotension
And/or Hypoxia
Grade 1
Temp. ı38eC
None
None
Grade 2
Temp. ı38eC
Not requiring 
vasopressors
Requiring low-flow
nasal cannula, low-
flow facemask or
blow-by
Grade 3
Temp. ı38eC
Requiring a 
vasopressor with or
without vasopressin
Requiring high-flow
nasal cannula, high-
flow facemask,
nonrebreather mask, 
or Venturi mask
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Grade 4
Temp. ı38eC
Requiring multiple 
vasopressors
(excluding 
vasopressin)
Requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation 
and mechanical 
ventilation)
Detailed grading criteria is provided in Appendix 5 of the protocol. 
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