Saci-IO HR+: Randomized Phase II Study of Sacituzumab Govitecan With or Without Pembrolizumab in Hormone Receptor-positive (HR+) / HER2- Metastatic Breast Cancer (MBC)
Phase: PHASE2
Conditions: Invasive Breast Cancer, Metastatic Breast Cancer, HR-Positive Breast Cancer, HER2-negative Breast Cancer
Sponsor: Ana C Garrido-Castro, MD

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P a g e 1 
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TI T L E:   Saci-I O H R +: Ra n d o mize d p hase II st u d y of sacit uz u ma b g o viteca n wit h or wit h o ut 
pe m br oliz u ma b i n h or m o ne rece pt or- p ositi ve ( H R +) / H E R 2- metastatic breast ca n cer ( M B C) 
C o or di n ati n g Ce nter:
Da na- Far ber Ca n cer I nstit ute
Pri nci p al I n vesti g at or ( PI):
A na C. Garri d o- Castr o, M D
 
 
 
  
Ot her I n vesti g at ors:
 
 
  
 
 
 
 
  
St atistici a n:
Pr oject M a n a ger: 
 
 
  
 
 
  
            
 
 
            
  
I n d ustr y- S u p plie d A ge nts: 
Sacit uz u ma b g o viteca n (I M M U- 1 3 2, Tr o del v y ™), 
 
Pe m br oliz u ma b ( M K- 3 4 7 5; Ke ytr u da T M), 
  
I N D #: 1 4 6 9 7 3
I N D S p o ns or: A na C. Garri d o- Castr o, M D  
Pr ot oc ol t y pe / V ersi o n / Versi o n D ate: S p o ns or A me n d me nt 8 / Versi o n 8 / Oct o ber 1 1, 2 0 2 4 

                                                 
 
 
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T A B L E O F C O N T E N T S 
S C H E M A ......................................................................................................................................... 1
1
O BJ E C TI V E S ...................................................................................................................... 5
1. 1
St u d y Desi g n ............................................................................................................ 5
1. 2
Pri mar y O bjecti ves................................................................................................... 5
1. 3
Sec o n dar y O bj ecti ves............................................................................................... 5
1. 4
C orrelati ve/ E x pl orat or y O bjecti ves f or E nr olle d Partici pa nts................................. 5
1. 5
C orrelati ve O bjecti ves f or Pre- Scree ne d Partici pa nts.............................................. 7
2
B A C K G R O U N D................................................................................................................. 8
2. 1
H R + / H E R 2- Metastatic Breast Ca ncer ( M B C) ..................................................... 8
2. 2
I m m u ne C hec k p oi nt I n hi bit ors i n Breast Ca ncer..................................................... 8
2. 3
Pe m br oliz u ma b ........................................................................................................ 9
2. 4
Sacit uz u ma b G o viteca n (I M M U- 1 3 2) ................................................................... 1 2
2. 5
Rati o nale f or C o m bi nati o n of Pe m br oliz u ma b a n d Sacit uz u ma b G o viteca n........ 1 7
2. 6
C orrelati ve St u dies Bac k gr o u n d............................................................................ 1 8
3
P A R TI CI P A N T S E L E C TI O N ........................................................................................... 2 1
3. 1
Eli gi bilit y Criteria.................................................................................................. 2 1
3. 2
E xcl usi o n Criteria.................................................................................................. 2 4
3. 3
Retreat me nt Eli gi bilit y Criteria.............................................................................. 2 6
3. 4
Retreat me nt E xcl usi o n Criteria.............................................................................. 2 8
3. 5
I n cl usi o n of W o me n a n d Mi n orities ...................................................................... 2 8
4
R E GI S T R A TI O N A N D R A N D O MI Z A TI O N P R O C E D U R E S ....................................... 2 9
4. 1
Ge neral G ui deli nes f or D F/ H C C I nstit uti o ns ........................................................ 2 9
4. 2
Re gistrati o n Pr ocess f or D F/ H C C I nstit uti o ns ....................................................... 2 9
4. 3
Ge neral G ui deli nes f or Ot her I n vesti gati ve Sites.................................................. 2 9
4. 4
Re gistrati o n Pr ocess f or Ot her I n vesti gati ve Sites................................................. 2 9
5
T R E A T M E N T P L A N........................................................................................................ 3 0
5. 1
Treat me nt Re gi me n ................................................................................................ 3 0
5. 2
Pre- Treat me nt Criteria........................................................................................... 3 1
5. 3
A ge nt A d mi nistrati o n............................................................................................. 3 2
5. 4
Defi niti o n of D ose- Li miti n g T o xicit y ( D L T)........................................................ 3 3
5. 5
Defi niti o n of P ote ntial Dr u g I n d uce d Li v er I nj ur y ( DI LI) .................................... 3 4
5. 6
Ge neral C o nc o mita nt Me dicati o n a n d S u p p orti ve Care G ui deli nes...................... 3 5
5. 7
Criteria f or T a ki n g a Partici pa nt Off Pr ot oc ol T hera p y ......................................... 3 8
5. 8
D urati o n of F oll o w U p........................................................................................... 4 0
5. 9
Criteria f or T a ki n g a Partici pa nt Off St u d y ........................................................... 4 0
6
D O SI N G D E L A Y S/ D O S E M O DI FI C A TI O N S ............................................................... 4 1
6. 1
D osi n g Dela ys/ O missi o n/ M o dificati o ns................................................................ 4 1
6. 2
Ma na ge me nt of T o xi cities Attri b uta ble t o Pe m br oliz u ma b................................... 4 3

                                                 
 
 
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6. 3
Ma na ge me nt of T o xi cities Attri b uta ble t o Sacit uz u ma b G o viteca n...................... 4 8
7
A D V E R S E E V E N T S:  LI S T A N D R E P O R TI N G R E Q UI R E M E N T S............................ 5 1
7. 1
A d verse E v e nts List............................................................................................... 5 2
7. 2
A d verse E v e nt C haracteristics............................................................................... 5 4
7. 3
E x pe dite d A d vers e E ve nt Re p orti n g ...................................................................... 5 5
7. 4
Re p orti n g t o t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) ....................................... 5 6
7. 5
Re p orti n g t o H os pital Ris k Ma na ge me nt............................................................... 5 6
7. 6
E x pe dite d Re p orti n g t o 
............................................................................... 5 6
7. 7
E x pe dite d Re p orti n g t o 
 ....................................................... 5 8
7. 8
R o uti ne A d verse E ve nt Re p orti n g......................................................................... 5 9
8
P H A R M A C E U TI C A L I N F O R M A TI O N.......................................................................... 6 0
8. 1
Pe m br oliz u ma b...................................................................................................... 6 0
8. 2
Sacit uz u ma b g o viteca n .......................................................................................... 6 2
9
BI O M A R K E R, C O R R E L A TI V E, A N D S P E CI A L S T U DI E S ........................................ 6 5
9. 1
Pre- Scree ni n g Arc hi v al Tiss ue .............................................................................. 6 7
9. 2
Fres h Tiss ue Bi o ps y............................................................................................... 6 7
9. 3
Arc hi val a n d Fres h Tiss ue – P ote ntial Testi n g ...................................................... 6 9
9. 4
Bl o o d C ollecti o n.................................................................................................... 7 3
9. 5
Bl o o d Sa m ples – P ote ntial Testi n g ........................................................................ 7 4
9. 6
St o ol C ollecti o n ..................................................................................................... 7 6
9. 7
A d diti o nal Tra nslati o nal A nal yses......................................................................... 7 8
9. 8
F ut ure Us e of S peci me ns a n d Data ........................................................................ 7 8
9. 9
Patie nt Re p orte d O utc o m es.................................................................................... 7 8
1 0
S T U D Y C A L E N D A R ....................................................................................................... 7 9
1 1
M E A S U R E M E N T O F E F F E C T........................................................................................ 8 3
1 1. 1
A ntit u m or Effect – S oli d t u m ors............................................................................ 8 3
1 1. 2
Ot her Res p o nse Para met ers................................................................................... 9 1
1 2
D A T A R E P O R TI N G / R E G U L A T O R Y R E Q UI R E M E N T S........................................... 9 1
1 2. 1
Data Re p orti n g ....................................................................................................... 9 1
1 2. 2
Data Safet y M o nit ori n g.......................................................................................... 9 1
1 2. 3
M ultice nter G ui deli nes........................................................................................... 9 1
1 2. 4
C olla b orati ve Researc h a n d F ut ure Us e of Data a n d Sa m ples .............................. 9 2
1 3
S T A TI S TI C A L C O N SI D E R A TI O N S............................................................................... 9 2
1 3. 1
St u d y Desi g n/ E n d p oi nts......................................................................................... 9 2
1 3. 2
Sa m ple Size, Accr u al Rate a n d St u d y D urati o n .................................................... 9 3
1 3. 3
Stratificati o n Fact ors.............................................................................................. 9 3
1 3. 4
I nteri m M o nit ori n g Pla n ........................................................................................ 9 4
1 3. 5
A nal ysis of Pri mar y E n d p oi nts.............................................................................. 9 4
1 3. 6
A nal ysis of Sec o n dar y E n d p oi nts.......................................................................... 9 5
1 3. 7
C orrelati ve E n d p oi nts ............................................................................................ 9 5

                                                 
 
 
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1 3. 8
Re p orti n g a n d E xcl usi o ns ...................................................................................... 9 9
1 4
P U B LI C A TI O N P L A N ................................................................................................... 1 0 0
1 5
R E F E R E N C E S ................................................................................................................ 1 0 0
A P P E N DI X A  
P E R F O R M A N C E S T A T U S C RI T E RI A ................................................ 1 0 8
A P P E N DI X B
C o ntrace pti ve G ui da n ce a n d Pre g na nc y Testi n g ..................................... 1 0 9
A P P E N DI X C
DI E T A N D P H Y SI C A L A C TI VI T Y A S S E S S M E N T S.......................... 1 1 1
A P P E N DI X D
DI E T A N D P H Y SI C A L A C TI VI T Y A S S E S S M E N T S.......................... 1 1 5
A P P E N DI X E
E O R T C Q L Q- C 3 0................................................................................... 1 1 6
A P P E N DI X F
E U R O Q O L  E Q- 5 D- 5 L........................................................................... 1 1 8
A P P E N DI X G  
N CI P R O- C T C A E ™  Q u esti o ns f or All Patie nts.................................... 1 2 0
A P P E N DI X H  
D F/ H C C M U L TI C E N T E R D A T A & S A F E T Y M O NI T O RI N G P L A N
 
1 2 3  
 

                                                 
 
 
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1
O B J E C TI V E S 
 
1. 1  
St u d y Desi g n 
 
T his is a ra n d o mize d p hase 2 o pe n la bel st u d y of s acit uz u ma b g o viteca n +/- 
pe m br oliz u ma b f or p atie nts wit h h or m o ne rece pt or- p ositi ve ( H R +) / H E R 2- metastatic 
breast ca ncer ( M B C). Patie nts will be ra n d o mize d i n a 1: 1 rati o t o sacit uz u ma b g o viteca n 
(I M M U- 1 3 2) wit h pe m br oliz u ma b ( Ar m A) or sacit uz u ma b g o viteca n al o n e ( Ar m B) a n d 
will be treate d u ntil u nacce pta ble t o xicit y or pr o gressi o n as defi ne d b y R E CI S T 1. 1 
criteria.  
 
1. 2  
Pri m ar y O bjecti ves 
 
T o c o m pare t h e pr o gressi o n-free s ur vi val ( P F S) of sacit uz u ma b g o viteca n wit h 
pe m br oliz u ma b t o t hat of sacit uz u ma b g o viteca n al o ne i n patie nts wit h H R + / H E R 2- 
M B C.
1. 3
Sec o n d ar y O bjecti ves
 
 
T o c o m pare t h e P F S of s acit uz u ma b g o viteca n wit h pe m br oliz u ma b t o t hat of 
sacit uz u ma b g o viteca n al o ne i n t he s u b gr o u p of patie nts wit h P D- L 1- p ositi ve 
H R + / H E R 2- M B C. 
 
T o c o m pare t h e efficac y of sacit uz u ma b g o viteca n wit h pe m br oliz u ma b t o t hat of 
sacit uz u ma b g o viteca n al o ne b y assessi n g ot her cli nical o utc o me meas ures, 
i ncl u di n g o verall s ur vi val ( O S), o bjecti ve res p o ns e rate ( O R R) b y R E CI S T 1. 1, 
d urati o n of res p o ns e ( D O R), ti me t o o bjecti ve res p o nse ( T T O R), ti me t o 
pr o gressi o n ( T T P), a n d cli nical be nefit rate ( C B R), i n all-c o mers (re gar dless of 
P D- L 1 stat us) a n d i n t he s u b gr o u p of patie nts wit h P D- L 1- p ositi ve H R + / H E R 2- 
M B C. 
 
T o e val uate t he s afet y a n d t olera bilit y of sacit uz u ma b g o viteca n a n d 
pe m br oliz u ma b c o m pare d t o sacit uz u ma b g o viteca n al o ne b y m o nit ori n g a d verse 
e ve nts, i ncl u di n g i m m u ne-rel ate d a d v erse e ve nts. 
 
1. 4  
C orrel ati v e/ E x pl or at or y O bjecti ves f o r E nr olle d P artici p a nts 
1. 4. 1
T o e x pl ore tiss ue bi o mar kers of a ntit u m oral i m m u ne acti vit y a n d t u m or ge n o mic 
i nsta bilit y as pre dict ors of res p o nse a n d resista n ce t o sacit uz u ma b g o viteca n pl us 
pe m br oliz u ma b c o m pare d t o sacit uz u ma b g o viteca n al o ne i n patie nts wit h H R + / H E R 2-
M B C.  
 
T o c haracteri ze bas eli ne Tr o p- 2 e x pressi o n b y hist ol o gical assess me nt a n d 
c orrel ate wit h disease res p o nse t o treat me nt ( P F S, O R R b y R E CI S T 1. 1, O S). 
 
T o assess c ha n g es i n Tr o p- 2 stai ni n g, fr o m baseli ne t o o n-treat me nt a n d at-
pr o gressi o n, a n d c orrel ate wit h disease res p o nse t o treat me nt ( P F S, O R R b y 
R E CI S T 1. 1, O S).  

                                                 
 
 
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T o c haracteri ze t u m or-i nfiltrati n g l y m p h oc ytes ( TI Ls), b y hist ol o gical 
assess me nt, at baseli ne a n d c orrel ate wit h disease res p o nse t o treat me nt ( P F S, 
O R R b y R E CI S T 1. 1, O S).  
 
T o c haracteri ze t he e x pressi o n of mar kers of i m m u ne cell s u bsets (i.e., C D 8 f or 
c yt ot o xic T cells, C D 6 8 f or macr o p h a ges), i n hi bit or y c hec k p oi nt pat h wa y 
m olec ules (i.e., P D- 1, P D- L 1, TI M 3, L A G 3), a n d c o-sti m ulat or y pat h wa y 
m olec ules (i.e., GI T R, O X 4 0) b y i m m u n o hist oc he mistr y (I H C) a n d/ or 
i m m u n ofl u oresce nce (I F).  
 
T o e x pl ore w h et her i m m u n os u p pressi ve a n d/ or i m m u ne-sti m ulati n g i m m u ne 
mar ker pr ofiles at bas eli ne c orrelate wit h diseas e res p o nse t o treat me nt ( P F S, 
O R R b y R E CI S T 1. 1, O S).  
T o c haracteri ze m utati o n al l oa d a n d ne o a nti ge n b ur de n at bas eli ne a n d c orrelate 
wit h disease res p o ns e t o treat me nt ( P F S, O R R b y R E CI S T 1. 1, a n d O S). 
 
T o c haracteri ze R N A e x pressi o n si g nat ures of i m m u ne pat h wa y acti vati o n a n d 
D N A da ma g e re p air deficie nc y at b aseli ne a n d c orrelate wit h disease res p o nse t o 
treat me nt ( P F S, O R R b y R E CI S T 1. 1, a n d O S).  
 
T o e x pl ore w h et her c h a n ges i n TI Ls, i m m u n os u p pressi ve a n d/ or i m m u ne-
sti m ulati n g i m m u ne mar ker pr ofiles, m utati o nal l oa d, ne oa nti ge n b ur d e n, a n d 
R N A e x pressi o n si g nat ures, bet wee n p aire d bi o psi es fr o m baseli ne a n d aft er 2 
c ycles of treat me nt, c orrelate wit h disease res p o nse t o treat me nt ( P F S, O R R b y 
R E CI S T 1. 1, O S).  
 
T o e x pl ore mec ha nis ms of resista nce t o sacit uz u ma b g o viteca n pl us 
pe m br oliz u ma b c o m pare d t o sacit uz u ma b g o viteca n al o ne i n paire d bi o psies fr o m 
baseli ne a n d at ti me of pr o gressi o n. 
 
T o e x pl ore w h et her t he n u m ber a n d/ or t y pe of m ut ati o ns i de ntifie d usi n g a ne xt 
ge nerati o n se q u e nci n g ( N G S) pa nel is c orrelate d wit h patie nt o utc o mes ( P F S, 
O R R b y R E CI S T 1. 1, a n d O S). T his will be perf or me d o n D F CI p artici pa nts o nl y.  
1. 4. 2
T o e x pl ore bl o o d bi o mar kers of a ntit u m oral i m m u ne acti vit y as pre di ct ors of res p o nse or 
resista nce t o sacit uz u ma b g o viteca n pl us pe m br oli z u ma b c o m pare d t o sacit uz u ma b 
g o viteca n al o ne i n p atie nts wit h H R + / H E R 2-
M B C. 
T o c haracteri ze serial c h a n ges i n i m m u ne mar ker pr ofile i n peri p heral bl o o d 
m o n o n uclear cells ( P B M Cs) a n d i n plas ma o ver t he c o urse of st u d y treat m e nt. 
 
T o e x pl ore w h et her i n d u cti o n of c ha n ges i n t he i m m u n os u p pressi ve a n d/ or 
i m m u ne-sti m ulati n g mar ker pr ofile i n P B M Cs c orrelates wit h diseas e res p o nse t o 
t hera p y ( P F S, O R R b y R E CI S T 1. 1, O S). 
 
T o i n vesti gate w het her t h ere is a n i m m u ne mar k er (i.e., P D- L 1) i n circ ulati n g 
P B M Cs t hat c orrelates t o t u m or i nfiltrati n g l y m p h oc yte ( TI L) perce nta g e i n 
baseli ne t u m or. 
 
T o c haracteri ze serial c h a n ges of ne o a nti ge n b ur d e n i n circ ulati n g t u m or D N A 
a n d c orrelate wit h diseas e res p o nse t o treat me nt ( P F S, O R R b y R E CI S T 1. 1, O S).  
 
T o e x pl ore serial c ha n g es i n bl o o d bi o mar kers as mec ha nis ms of resista n ce t o 
sacit uz u ma b g o viteca n pl us pe m br oliz u ma b c o m p are d t o sacit uz u ma b g o viteca n 
al o ne. 

                                                 
 
 
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1. 4. 3
T o e x pl ore t he str u ct ure a n d f u ncti o n of t he g ut micr o bi o me as pre di ct ors of res p o nse or 
resista nce t o sacit uz u ma b g o viteca n pl us pe m br oli z u ma b c o m pare d t o sacit uz u ma b 
g o viteca n al o ne i n p atie nts wit h H R + / H E R 2-
M B C.  
 
T o c haracteri ze str uct ure a n d f u ncti o n of t he g ut micr o bi o me at baseli ne a n d 
c orrel ate wit h disease res p o nse t o treat me nt ( P F S, O R R b y R E CI S T 1. 1, O S).  
T o e x pl ore w h et her c h a n ges i n t he o verall di versit y of g ut micr o bi o me, esti mate d 
b y S ha n n o n i n de x, c orrelate wit h disease res p o nse t o treat me nt ( P F S, O R R b y 
R E CI S T 1. 1, O S).  
 
T o e x pl ore c orrel ates of resista nce t o sacit uz u m a b g o viteca n pl us pe m br oliz u ma b 
c o m pare d t o sacit uz u ma b g o viteca n al o ne i n p aire d sa m ples fr o m baseli ne a n d at 
ti me of pr o gressi o n.  
1. 4. 4
T o e x pl ore patie nt re p ort e d o utc o mes as meas ure d b y t he f oll o wi n g:  
 T o assess a n d c o m p are t h e i m pact of treat me nt o n Healt h- Relate d Q ualit y of Life 
( H R Q o L) bet w ee n treat me nt ar ms, usi n g E ur o pea n Or ga nizati o n f or t he R esearc h 
a n d Treat me nt of Ca ncer ( E O R T C) q ualit y of life ( Q O L) q uesti o n naire versi o n 3 0 
( Q L Q- C 3 0) a n d t he E ur o pea n Q ualit y of Life ( E ur o Q O L) E Q- 5 D- 5 L i nstr u me nts. 
 T o assess a n d c o m p are t h e i m pact of treat me nt-rel ate d s y m pt o ms usi n g a set of 1 6 
rele va nt s y m pt o m c o nce pts fr o m t he Patie nt- Re p orte d O utc o mes ( P R O) v ersi o n 
of t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( P R O- C T C A E ™) ite m 
li brar y ( Decrease d a p petite, Na usea, V o miti n g, C o nsti pati o n, Diarr hea, 
A b d o mi nal pai n, S h ort ness of breat h, C o u g h, W h eezi n g, Ras h, Hair l oss, It c h y 
s ki n, Hi ves, M uscle Ac h es, J oi nt Ac hes, a n d Fati g ue). 
 
1. 5  
C orrel ati v e O bjecti v es f or Pre- Scree ne d P artici p a nts ( pri or t o S p o ns or A me n d me nt 
3, P D- L 1 eli gi bilit y a me n d me nt) 
 
1. 5. 1  T o e x pl ore tiss ue bi o mar kers t hat c haract erize t h e i m m u ne micr oe n vir o n me nt of 
H R +/ H E R 2- M B C 
 
T o c haracteri ze t u m or-i nfiltrati n g l y m p h oc ytes ( TI Ls) b y hist ol o gical assess me nt.  
T o c haracteri ze t he e x pressi o n of vari o us bi o mar k ers b y i m m u n o hist oc he mistr y 
(I H C) a n d/ or i m m u n ofl u oresce n ce (I F).
 
T o c haracteri ze t he e x pressi o n of mar kers of i m m u ne cell s u bsets (i.e., C D 8 f or 
c yt ot o xic T cells, C D 6 8 f or macr o p h a ges), i n hi bit or y c hec k p oi nt pat h wa y 
m olec ules (i.e., P D- 1, P D- L 1, TI M 3, L A G 3), a n d c o-sti m ulat or y pat h wa y 
m olec ules (i.e., GI T R, O X 4 0) b y i m m u n o hist oc he mistr y (I H C) a n d/ or 
i m m u n ofl u oresce nce (I F). 
 
T o c haracteri ze m utati o n al l oa d a n d ne o a nti ge n b ur de n.  
 
T o c haracteri ze R N A e x pressi o n si g nat ures of i m m u ne pat h wa y acti vati o n a n d 
D N A da ma g e re p air deficie nc y  
 
T o e x pl ore t he n u m ber a n d/ or t y pe of m utati o ns i de ntifie d usi n g a ne xt ge nerati o n 
se q ue nci n g ( N G S) pa nel or w h ole e x o me s e q ue nci n g.  
 

                                                 
 
 
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8 
2
B A C K G R O U N D 
2. 1
H R + / H E R 2- Met ast ati c Bre ast C a ncer ( M B C) 
W orl d wi de, breast ca ncer is t he m ost c o m m o n n o n-c uta ne o us ca ncer a n d t he lea di n g ca use of 
ca ncer d eat h i n w o m e n. 1 I n t he U nite d States, breast ca ncer acc o u nts f or nearl y o n e-t hir d of all 
ne w ca n cer dia g n os es a m o n g w o me n wit h o ver 2 5 0, 0 0 0 ne w cases p er y ear. 2 Metastatic breast 
ca ncer ( M B C) re mai ns i nc ura ble a n d is a m aj or ca use of m ort alit y i n t he U nite d States wit h o ver 
4 0, 0 0 0 A merica n w o me n d yi n g of breast ca ncer i n 2 0 1 9 al o ne. 2 H or m o ne rece pt or- p ositi ve ( H R +)
/ h u ma n e pi der mal gr o wt h fact or rece pt or 2- n e gati ve  ( H E R 2-) breast ca ncer, d efi ne d b y t he 
prese nce of estr o g e n a n d/ or pr o gester o ne rece pt ors a n d t h e a bs e nce of H E R 2, acc o u nts f or t h e 
maj orit y of breast ca ncers, a p pr o xi matel y 7 0 %. 3 Alt h o u g h i nitiall y se nsiti ve t o e n d o cri ne- b ase d 
t hera pies, i n cl u di n g C D K 4/ 6 i n hi bit ors, it e ve nt uall y de vel o ps resista nce t o h or m o ne t h era p y i n 
t he metastatic s etti n g.3 Pre-treate d H R + / H E R 2- M B C t hat has pr o gresse d o n h or m o ne t hera p y 
t y picall y dis pla ys l o w res p o nse rates t o c he m ot hera p y wit h s h ort me dia n pr o gressi o n free s ur vi v al
( P F S) of 4 t o 5 m o nt hs a n d me dia n o verall s ur vi val ( O S) ar o u n d 1 8 m o nt hs.4 T heref ore, i m pr o ve d 
t hera pies are ur ge ntl y nee de d f or patie nts wit h pre-treate d H R + / H E R 2- M B C t hat has pr o gresse d 
o n h or m o ne t hera p y. 
 
2. 2  
I m m u ne C hec k p oi nt I n hi bit ors i n Bre ast C a ncer 
 
I m m u ne c hec k p oi nt i n hi bit ors f u ncti o n b y bl oc ki n g rece pt ors, s uc h as c yt ot o xic T l y m p h oc yte 
a nti ge n- 4 ( C T L A- 4, C D 1 5 2) a n d pr o gra m me d cell deat h- 1 ( P D- 1, C D 2 7 9), t o re-acti vate 
c yt ot o xic T cell res p o ns es. P D- 1, w hic h is i n d uce d f oll o wi n g i nitial T cell acti vati o n t o re g ulate 
T cells, 5 bi n ds t he li ga n ds P D- L 1 a n d P D- L 2 t o att e n uate T cell rece pt or si g nali n g, 6 t here b y 
lea di n g t o decrease d T cell pr oliferati o n, c yt ot o xicit y, a n d c yt o ki ne pr o d ucti o n.7 I m m u ne 
c hec k p oi nt i n hi bit ors bl oc k t hese c h ec k p oi nts t o i m pr o ve t he c yt ot o xicit y a n d pr oliferati ve 
ca pacit y of t u m or i nfiltrati n g l y m p h oc ytes. I m m u ne c hec k p oi nt i n hi bit ors, i ncl u di n g m o n ocl o nal 
a nti b o dies a gai nst P D- 1 (i.e., pe m br oliz u ma b), P D- L 1 (i.e., atez oliz u ma b), a n d C T L A- 4 (i.e., 
i pili m u ma b), ha ve ge nerate d d ura ble res p o nses acr oss ma n y t u m or t y pes.8- 1 5
H o we ver, fe w p atie nts wit h breast ca n cer res p o n d t o i m m u ne c hec k p oi nt i n hi bit ors as si n gle 
a ge nts. 1 6 T hese t hera pies ha ve t heref ore bee n i n vesti gate d i n c o m bi nati o n wit h ot her a ge nts, 
i ncl u di n g c he m ot hera p y, tar gete d t hera p y, a n d i m m u n ot hera pe utic a ge nts. T his a p pr oac h has 
pr o ve d m ost s uccessf ul i n T N B C, w here t he c o m bi nati o n of t he c he m ot hera p y na b- p aclita xel a n d 
t he P D- L 1 m o n ocl o nal a nti b o d y atez oliz u ma b le d t o a statisticall y si g nifica nt i m pr o ve me nt i n P F S 
a n d a cli nicall y rele v a nt i m pr o ve me nt i n o verall s ur vi val f or patie nts wit h metastatic P D- L 1-
p ositi ve T N B C i n t he I M passi o n 1 3 0 trial ( Ta ble 1). 1 7 Base d o n t hese fi n di n gs, t he F D A gra nte d 
accelerat e d a p pr o val f or atez oliz u ma b i n c o m bi nati o n wit h na b- paclita xel f or t he first-li ne 
treat me nt of a d va n ce d or metastatic P D- L 1- p ositi ve T N B C i n Marc h 2 0 1 9. Ne vert hel ess, effecti ve 
i m m u ne c hec k p oi nt re gi me ns i n P D- L 1- ne gati ve T N B C, h or m o ne rece pt or- p ositi ve breast ca ncer, 
a n d H E R 2- p ositi ve breast ca ncer ha ve yet t o be est a blis he d, s o t he maj orit y of patie nts wit h breast 
ca ncer d o n ot be nefit fr o m i m m u ne c hec k p oi nt i n hi bit ors.
T a ble 1: 
Pr o gressi o n- Free S ur vi v al a n d O ver all S ur vi v al i n t he I M p assi o n 1 3 0 St u d y 1 7, 1 8 
Pr o gressi o n-free S ur vi v al
O v er all S ur vi v al

                                                 
 
 
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Atez oliz u m a b 
 + 
n a b- p aclit a xel 
( N = 4 5 1) 
Pl a ce b o 
 + 
n a b- p aclit a xel 
( N = 4 5 1) 
H a z a r d 
r ati o 
( 9 5 % CI) 
p- v al ue 
Atez oliz u m a b 
 + 
n a b- p aclit a xel 
( N = 4 5 1) 
Pl a ce b o 
 + 
n a b- p aclit a xel 
( N = 4 5 1) 
H a z a r d 
r ati o 
( 9 5 % CI) 
p- v al ue 
I T T 
7. 2 m o nt hs 
5. 5 m o nt hs 
0. 8 0
( 0. 6 9 - 0. 9 2)
p = 0. 0 0 2 5
2 1. 0 m o nt hs 
1 8. 7 m o nt hs 
0. 8 6
( 0. 7 2 - 1. 0 2)
p = 0. 0 8
P D- L 1 + a
7. 5 m o nt hs 
5. 0 m o nt hs 
0. 6 2 
( 0. 4 9 - 0. 7 8) 
p < 0. 0 0 1 
2 5. 0 m o nt hs 
1 8. 0 m o nt hs 
0. 7 1 
( 0. 5 4 - 0. 9 3) 
N A b
I T T = i nte nt t o treat; O S = o v erall s ur vi val; P D- L 1 = pr o gra m me d cell d eat h li g a n d 1 p ositi v e
a P D- L 1
- L 1 usi n g t h e S P 1 4 2 
a nti b o d y 
b Per t he statistical d esi g n, beca use t he O S differe n ce i n t h e I T T p o p ulati o n w as n ot si g nifica nt, t here was n o f or mal 
statistical testi n g of t he differe nce i n O S i n t he P D- L 1 + p o p ulati o n 
2. 3
Pe m br oliz u m a b
 
2. 3. 1  Mec ha nis m of A cti o n of Pe m br oliz u ma b  
 
Pe m br oliz u ma b is a p ote nt a n d hi g hl y selecti ve h u ma nize d m o n ocl o nal a nti b o d y ( m A b) of t he 
I g G 4/ ka p pa is ot y pe desi g ne d t o directl y bl oc k t he i nteracti o n bet wee n P D- 1 a n d its li ga n ds, P D-
L 1 a n d P D- L 2. 1 9 Ke ytr u daT M ( pe m br oliz u ma b) is a p pr o ve d i n t he U nite d States f or t he treat me nt 
of n u mer o us ca ncers i ncl u di n g mela n o ma, n o n-s mall cell l u n g ca ncer, hea d a n d nec k s q ua m o us 
cell ca n cer, classical H o d g ki n l y m p h o ma, pri mar y me diasti nal lar ge B-cell l y m p h o ma, ur ot helial 
carci n o ma, micr osatellite i nsta bilit y- hi g h ca ncer, g astric ca n cer, cer vical ca ncer, he p at ocell ular 
carci n o ma, a n d mer k el cell carci n o ma. 1 9 Please refer t o t he F ull Prescri bi n g I nf or mati o n f or 
pe m br oliz u ma b f or c o m plete prescri bi n g a n d safet y i nf or mati o n. 1 9 
2. 3. 2
N o ncli nical St u dies of Pe m br oliz u ma b  
A ni mal m o dels de m o nstrate d t hat P D- 1 i n hi biti o n i ncreas e d t he se verit y of s o me i nfecti o ns a n d 
e n ha nce d i nfla m mat or y res p o nses. 1 9 M. t u berc ul osis-i nfecte d P D- 1 k n o c k o ut mice e x hi bite d
mar ke dl y decrease d s ur vi val c o m pare d wit h wil d-t y pe c o ntr ols, w hic h c orrelate d wit h i ncreas e d 
bacterial pr oliferati o n a n d i nfla m mat or y res p o nses. 1 9 P D- 1 k n oc k o ut mice ha ve als o s h o w n 
decrease d s ur vi v al f oll o wi n g i nfecti o n wit h l y m p h oc ytic c h ori o me ni n gitis vir us. 1 9 
A d mi nistrati o n of pe m br oliz u ma b i n c hi m pa nzees wit h nat urall y occ urri n g c hr o nic he p atitis B 
i nfecti o n res ulte d i n t w o o ut of f o ur a ni mals wit h si g nifica ntl y i ncreas e d le vels of ser u m A L T, 
A S T, a n d G G T, w hic h p ersiste d f or at least 1 m o nt h after disc o nti n uati o n of pe m br oliz u ma b. 1 9
 
Pe m br oliz u ma b has n ot u n der g o ne precli nical fertilit y st u dies. 1 9 N o effects o n male a n d fe m ale 
re pr o d ucti ve or ga ns w ere o bser ve d i n 1- m o nt h a n d 6- m o nt h re peat- d os e t o xic ol o g y st u dies i n 
m o n ke ys, alt h o u g h m ost of t hese a ni mals were n ot se x uall y mat ure. 1 9
2. 3. 3
P har mac o ki netics of Pe m br oliz u ma b  
 

                                                 
 
 
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T he first-i n- h u ma n p h ase I st u d y ( P N 0 0 1, N C T 0 1 2 9 5 8 2 7) e val uate d t h e safet y a n d cli nical 
acti vit y of pe m br oliz u ma b as a m o n ot hera p y. Part A of t his st u d y was a 3 + 3 d ose escal ati o n 
st u d y i n s u bjects wit h s oli d t u m ors t o e val uate safet y, t olera bilit y, p har mac o ki netics ( P K), a n d 
p har mac o d y n a mics, a n d t o deter mi ne a ma xi m u m t olerate d d ose ( M T D) or preli mi nar y 
rec o m me n de d p h ase 2 d oses ( R P 2 Ds).1 9 D oses were 1, 3, a n d 1 0 m g/ k g e ver y 2 wee ks ( Q 2 W); 
d oses of eit her 2 m g/ k g or 1 0 m g/ k g were als o a d mi nistere d e ver y 3 wee ks ( Q 3 W). 1 9 All 3 d ose 
le vels were well t olerat e d a n d n o d ose-li miti n g t o xicities ( D L Ts) were o bs er ve d; t heref ore, t he 
M T D was n ot deter mi ne d.
1 9 T he R P 2 D was deter mi ne d base d o n safet y, P K, a n d 
p har mac o d y n a mic meas ure me nts, al o n g wit h t he stre n gt h of a ntit u m or acti vit y si g nals 
o bser ve d. 1 9
T he half-life (t 1/ 2) of pe m br oliz u ma b is a p pr o xi matel y 4 wee ks a n d t here is n o i n dicati o n of d ose 
de pe n de n c y or half-life i n t he t hree d ose gr o u ps ( 1, 3, a n d 1 0 m g/ k g). 1 9 T he l o n g t 1/ 2 s u p p orts a 
d osi n g i nter val of e ver y 2 or 3 wee ks. 1 9 T here was a d ose-relate d i ncreas e i n e x p os ure fr o m 1 t o 
1 0 m g/ k g. 1 9 Ser u m c o nce ntrati o ns of pe m br oliz u m a b were l o wer b y a fact or of a p pr o xi matel y 5 
i n patie nts recei vi n g 2 m g/ k g Q 3 W t ha n i n t h ose recei vi n g 1 0 m g/ k g Q 3 W.1 9 Stea d y-state tr o u g h 
c o nce ntrati o ns were 2 0 % greater i n t he patie nts recei vi n g 1 0 m g/ k g Q 2 W t ha n i n t h ose recei vi n g 
t he sa me d ose Q 3 W.1 9   
A p o p ulati o n p har mac o ki netic a nal ysis was perf or me d usi n g ser u m c o nce ntrati o n ti me data fr o m 
4 7 6 patie nts. 1 9 Wit hi n t he res ulti n g p o p ulati o n p har mac o ki netic m o d el, cleara nce a n d v ol u me 
para meters of pe m br oliz u ma b were f o u n d t o be d e pe n de nt o n b o d y wei g ht. 1 9 T he relati o ns hi p 
bet wee n cleara nce a n d b o d y wei g ht, wit h a n all o metric e x p o ne nt of 0. 5 9, is wit hi n t he ra n ge 
o bser ve d f or ot her a nti b o dies a n d w o ul d s u p p ort b ot h b o d y wei g ht n or malize d d osi n g or a fi xe d 
d ose acr oss all b o d y wei g hts. 1 9 Pe m br oliz u ma b has bee n f o u n d t o h a ve a wi de t hera p e utic ra n g e, 
a n d t he p o p ulati o n p har mac o ki netic e val u ati o n re veale d t h at t here was n o si g nifica nt i m pact of 
t u m or b ur de n or ca ncer t y pe o n e x p os ure.1 9
T he c h oice of t he 2 0 0 m g Q 3 W as a n a p pr o pri ate d ose f or t he s witc h t o fi x e d d osi n g was base d 
o n si m ulati o ns perf or me d usi n g t he p o p ulati o n p har mac o ki netic m o d el of pe m br oliz u ma b 
s h o wi n g t hat t he fi xe d d ose of 2 0 0 m g e ver y 3 wee ks pr o vi de d e x p os ures t hat 1) were o pti mall y 
c o nsiste nt wit h t h ose o btai ne d wit h t he 2 m g/ k g d ose e ver y 3 wee ks, 2) mai ntai ne d i n di vi d ual 
patie nt e x p os ures i n t he e x p os ure ra n g e ass oci ate d wit h ma xi mal efficac y res p o nse a n d 3) 
mai ntai ne d i n di vi d ual patie nt’s e x p os ure i n t he e x p os ure ra n g e esta blis he d as well t olerate d a n d 
safe.1 9 A fi xe d d ose re gi me n si m plifie d t he d osi n g re gi me n t o be m ore c o n ve nie nt f or p h ysicia ns, 
mi ni mizi n g t he p ote ntial f or d osi n g err ors, a n d re d uce d c o m ple xit y i n t he l o gistical c hai n at 
treat me nt facilities, decreasi n g wasta ge.1 9
T he p har mac o ki netic pr o perties of pe m br oliz u m a b were f urt her c haracteri ze d i n 2 9 9 3 patie nts 
wit h vari o us ca ncers w h o recei v e d pe m br oliz u ma b. 1 9 Pea k a n d tr o u g h c o nce ntrati o ns i ncrease d 
d ose pr o p orti o nall y i n t he d ose ra n g e of 2 t o 1 0 m g/ k g e ver y 3 wee ks, a n d stea d y-state 
c o nce ntrati o ns were reac he d b y 1 6 wee ks of re p eate d d osi n g wit h a n e ver y 3- wee k d osi n g 
re gi me n.1 9 Pe m br oliz u ma b d oes n ot rel y o n meta b olis m f or cleara nce a n d i nstea d u n der g oes 
cata b olis m t o s mall pe pti des a n d si n gle a mi n o aci ds via ge neral pr otei n de gra dati o n r o utes. 2 0
Cleara nce is 2 3 % l o wer at stea d y state t ha n aft er t he first d ose. 1 9 A ge, se x, race, t u m or b ur de n, 
re nal i m pair me nt (
), a n d mil d he patic i m pair me nt (

                                                 
 
 
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u p per li mit of n or mal ( U L N) a n d A S T > U L N or t otal bilir u bi n bet wee n 1 a n d 1. 5 ti mes U L N 
a n d a n y A S T) ha d n o cli nicall y mea ni n gf ul effect o n t he cleara nce of pe m br oliz u ma b. 1 9
2. 3. 4
Cli nical St u dies of Pe m br oliz u ma b 
Pe m br oliz u ma b has de m o nstrate d efficac y acr oss a ra n ge of ca ncer t y pes. Disc usse d here are t he 
efficac y res ults f or mela n o ma a n d n o n-s mall cell l u n g ca ncer as t w o re pres e ntati ve e xa m ples. 
W he n treate d wit h pe m br oliz u ma b m o n ot hera p y, t he O R R f or patie nts wit h i pili m u ma b- naï ve 
a n d i pili m u ma b-refract or y metastatic mela n o ma was 3 3 % or 3 4 % a n d 2 7 % or 2 9 % wit h e ver y 3 
or 2 wee k d osi n g, res pecti vel y. 1 9 T he maj orit y of res p o nses were see n i n patie nts wit h mela n o ma 
b y 1 6 wee ks of t hera p y; h o we ver, s o me res p o nses were re p orte d after 2 4 wee ks or m ore of 
t hera p y wit h pe m br oliz u ma b.1 9 I n s o me patie nts, a R E CI S T- d efi ne d pr o gressi o n f oll o we d b y 
res p o nse w as o bser ve d.1 9 T he O R R f or patie nts wit h treat me nt- naï ve met astatic n o n-s mall cell 
l u n g ca ncer treate d wit h pe m br oliz u ma b was 2 7 % as m o n ot hera p y i n P D- L 1 p ositi ve t u m ors a n d 
4 8- 5 8 % i n c o m bi nati o n wit h c he m ot hera p y. 1 9
 
I n t hes e st u dies, t he m ost fre q ue nt treat me nt-relate d a d verse e ve nts ( A Es) were fati g ue, na usea, 
c o u g h, pr uritis, diarr hea, a n d ras h. 1 9 M ost A Es were n ot c o nsi dere d seri o us.  T he m ost 
c o m m o nl y-re p orte d i m m u ne-rel ate d A Es were ras h, pr uritis, vitili g o, h y p ot h yr oi dis m, art hral gia, 
diarr hea, a n d p ne u m o nitis. 1 9 I m p orta nt i de ntifie d ris ks i ncl u de: p ne u m o nitis, t h yr oi d dis or ders 
( h y p ot h yr oi dis m a n d h y pert h yr oi dis m), c olitis, diarr hea, h e patitis, ne p hritis, u veitis, ras h/ pr uritis, 
a n d ne ur o pat h y. 1 9
 
2. 3. 5  Pe m br oliz u ma b i n Metastatic Breast Ca ncer
 
Rece nt trials ha ve re p ort e d t he safet y of pe m br oli z u ma b i n metastatic T N B C. I n t he p has e I b 
K E Y N O T E- 0 1 2 trial of pe m br oliz u ma b i n 3 2 patie nts wit h a d va nce d T N B C, c o m m o n t o xicities 
were mil d, occ urre d i n 5 6 % of patie nts, a n d were si milar t o t h ose o bser ve d i n ot her t u m or 
c o h orts, s uc h as art hral gi a ( 1 9 %), fati g ue ( 1 9 %), m yal gia ( 1 9 %),  a n d n a usea ( 1 6 %). 2 1 A t otal of 
fi ve patie nts ( 1 6 %) e x perie nce d gra de 3 or hi g h er t o xicit y, i ncl u di n g a ne mia, ase ptic me ni n gitis, 
l y m p h o pe nia, p yre xia, a n d hea dac he, a n d o n e pati e nt ( 3 %) e x p erie n ce d a treat me nt-relate d deat h 
d ue t o disse mi nate d i ntra vasc ular c oa g ulati o n. 2 1 
H o we ver, t he efficac y of pe m br oliz u ma b m o n ot hera p y i n T N B C has bee n l o w. I n t he p hase I b 
K E Y N O T E- 0 1 2 trial, 3 2 patie nts wit h pre-treate d metastatic T N B C ha d a n O R R of 1 8. 5 %. 2 1 I n 
t he p hase 2 K E Y N O T E- 0 8 6 trial, 1 7 0 patie nts wit h pre-treate d metastatic T N B C ha d a n O R R of 
5 %. 1 6 T he O R R i ncrease d t o 2 3 % i n C o h ort B of t his trial, w hic h e nr olle d 5 2 patie nts wit h 
treat me nt- naï ve, P D- L 1- p ositi ve metastatic T N B C.1 6  
T he effi cac y of pe m br oli z u ma b i n c o m bi nati o n wit h c he m ot hera p y h as bee n si milarl y l o w i n 
i nitial trials of u nselecte d patie nts wit h T N B C. I n a p hase 1 b/ 2 trial of p e m br oliz u ma b a n d 
eri b uli n, t he O R R was 2 9 % f or 6 5 patie nts wit h treat me nt- naï ve metastatic T N B C a n d 2 2 % f or 
4 1 patie nts wit h pretreat e d metastatic T N B C. 2 2 T he me dia n o verall s ur vi val f or t hese patie nts 
was 1 7. 7 m o nt hs a n d 1 6. 3 m o nt hs, res pecti vel y. 2 2 A lar ge p has e III trial of pe m br oliz u ma b i n 
c o m bi nati o n wit h m ulti ple differe nt c he m ot hera p y a ge nts f or treat me nt- naï ve metastatic T N B C 
s h o we d t hat pe m br oliz u ma b pl us c he m ot hera p y res ulte d i n a si g nifica nt a n d cli nicall y 

                                                 
 
 
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mea ni n gf ul i m pr o ve me nt i n P F S o nl y a m o n g patie nts wit h hi g hl y P D- L 1 p ositi ve disease, 
meas ure d as C o m bi ne d P ositi ve Sc ore ( C P S) 
 1 0 b y t he P D- L 1 I H C 2 2 C 3 assa y 
( N C T 0 2 8 1 9 5 1 8).1 1 9
 
C o m pare d t o metastatic T N B C, H R + / H E R 2- M B C has de m o nstrate d l o wer res p o nse rates t o 
i m m u ne c hec k p oi nt i n hi bit ors, i ncl u di n g pe m br oliz u ma b. I n t he p has e I b K E Y N O T E- 0 2 8 tri al, 
t he s mall c o h ort of 2 5 patie nts wit h P D- L 1- p ositi ve pretreate d H R + / H E R 2- M B C de m o nstrate d 
a n O R R of 1 2 % wit h pe m br oliz u ma b m o n ot hera p y. 2 3 T his O R R i n P D- L 1 + H R + M B C was 
hi g her t ha n t he O R R of 2. 8 % o bser ve d i n P D- L 1- u nselecte d H R + / H E R 2- M B C treate d wit h t he 
P D- L 1 i n hi bit or a vel u ma b i n t he p hase I J A V E LI N trial. 2 4 Si milarl y, t he p hase II st u d y of 
eri b uli n wit h or wit h o ut pe m br oliz u ma b s h o we d n o differe n ce i n P F S wit h t he a d diti o n of 
pe m br oliz u ma b t o eri b uli n c o m pare d t o eri b uli n al o ne i n 8 8 patie nts wit h pre-treate d H R + / 
H E R 2- M B C. 2 5 T he mec ha nis ms u n derl yi n g t he l o wer res p o nse rates of H R + / H E R 2- M B C t o 
i m m u ne c hec k p oi nt i n hi bit ors c o m pare d t o T N B C are lar gel y u n k n o w n, t h o u g h ma y be relat e d 
t o l o wer le vels of t u m or i nfiltrati n g l y m p h oc ytes, l o wer t u m or m utati o n b ur de n, a n d l o wer P D-
L 1 e x pressi o n. 2 6, 2 7
2. 4
S acit uz u m a b G o vitec a n (I M M U- 1 3 2) 
2. 4. 1
Mec ha nis m of A cti o n of Sacit uz u ma b G o viteca n  
Sacit uz u ma b g o viteca n is a n a nti b o d y- dr u g c o nj u gate ( A D C) c o m p ose d of h R S 7, a h u ma nize d 
- 3 8, a ca m pt ot heci n a nal o g, a n d C L 2 A, a li n ker w hi c h c o u pl es 
S N- 3 8 t o h R S 7. Tr o p h o blastic cell-s urface a nti ge n- 2 ( Tr o p- 2) is a cell s urface a nti ge n 
o vere x presse d i n m a n y e pit helial ca n cers a n d h as bee n li n ke d t o a g gressi ve disease a n d p o or 
pr o g n osis. T he a nti b o d y c o m p o ne nt bi n ds t o Tr o p- 2 s uc h t hat t he A D C c o n ce ntrates o n t u m or cell 
s urfaces. S N- 3 8 is t h e acti ve meta b olite of iri n oteca n a n d a t o p ois o meras e I i n hi bit or t hat i n d uces 
si n gle-stra n de d D N A brea ks d uri n g re plicati o n. If u nre paire d, t hes e brea ks pr o gress t o d o u ble-
stra n de d D N A brea ks a n d res ults i n cell deat h. T he C L 2 A li n ker is u ni q u e i n t hat it is s u bject t o 
p H- de pe n d e nt h y dr ol ysis. F oll o wi n g i nter nalizati o n of t he A D C-a nti ge n c o m ple x, S N- 3 8 is 
releas e d i n t he aci dic l ys os o me a n d kills t he tar g et cells. I n a d diti o n, S N- 3 8 ca n be h y dr ol yze d 
fr o m e xtracell ular, s urface- b o u n d A D C. T he rel ease d dr u g diff us es i nt o nei g h b ori n g cells i n a n 
a nti ge n-i n de pe n d e nt ma n ner a n d t his lea ds t o d eat h of cells i n t he i m me diate pr o xi mit y of t he 
tar get-e x pressi n g cells. T hese t w o mec h a nis ms of acti o n c o m bi ne t o e n a ble sacit uz u ma b g o viteca n 
t o tar get a n d kill ca ncer cells t hat o ver-e x press Tr o p- 2 as well as ot her cells i n t he t u m or wit h l o w 
or n o Tr o p- 2 e x pressi o n. 
 
2. 4. 2  N o ncli nical St u dies of Sacit uz u ma b G o viteca n  
 
P har mac ol o g y St u dies 
I n vitr o c yt ot o xicit y of sacit uz u ma b g o viteca n was assesse d i n 6 differe nt cell li nes 
re pres e ntati ve of se v eral differe nt e pit helial t u m ors; P C- 3 ( pr ostate), Cal u- 3 ( N S C L C), C O L O 
2 0 5 (c ol o n), Ca pa n 1 ( pa ncreatic), S K- M E S- 1 (s q ua m o us cell l u n g), a n d B x P C- 3 ( pa ncreatic). I n 
ge neral, t he I C 5 0 v al ues ra n ge d fr o m 1. 9 5 n M t o 2 3. 1 4 n M. 2 8

                                                 
 
 
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1 3 
T he a ntit u m or acti vit y of t he h R S 7- S N- 3 8 c o nj u gate was e x a mi ne d i n viv o i n mice beari n g a 
variet y of h u ma n e pit helial ca ncer xe n o grafts, w h ere it was s h o w n t o ha v e si g nifica nt a ntit u m or 
effects c o m pare d t o free S N- 3 8, iri n oteca n, or a n irrele v a nt I g G- S N- 3 8 c o nj u gate. 2 8- 3 0
P har mac o ki netics
T o xic o ki netic a nal ysis of t he 3- m o nt h re peat- d ose st u d y i n C y n o m ol g us m o n ke ys usi n g 
vali date d assa ys s h o w e d a d ose- pr o p orti o nal e x p os ure ( C ma x a n d A U C) t o sacit uz u ma b 
g o viteca n, t otal a nti b o d y, t otal S N- 3 8 a n d free S N- 3 8 wit h n o rele va nt g e n der differe n ces after 
t he first d ose. Ser u m half-life was esti mate d i n rec o ver y a ni mals a n d ra n ge d fr o m 6 7. 3 t o 1 5 2 
h o urs.  O n a vera ge t h e a m o u nt of free S N- 3 8 i n circ ulati o n was l o w, < 3 % free S N- 3 8 as 
c o m pare d t o t he t otal S N- 3 8 b o u n d t o sacit uz u ma b g o viteca n. T his c o nfir ms t hat t he maj orit y of 
S N- 3 8 a d mi nistere d as sacit uz u ma b g o viteca n re m ai ns b o u n d t o t he A D C i n t he ser u m a n d is n ot 
circ ulati n g as t he free c yt ot o xic pa yl oa d. T he i nacti ve meta b olite, S N- 3 8 G, rea dil y a p peare d i n 
ser u m wit h mea n T ma x ra n gi n g fr o m 4. 0 t o 1 2 h o urs. 
 
T o xic ol o g y 
I n ac ute t o xicit y st u dies i n S wiss- We bster Mice, s acit uz u ma b g o viteca n at d oses of u p t o 7 5 0 
m g/ k g/ d ose (i.e., c u m ulati ve d oses of u p t o 1 5 0 0 m g/ k g) ca use d mi ni mal l oss ( < 1 0 %) i n b o d y 
wei g ht. T here was n o e vi de nce of h e mat ol o gical t o xicit y a n d n o a b n or mal hist ol o g y fi n di n gs. 
Tra nsie nt i ncreases i n he patic tra nsa mi nases were o bser ve d t hat ret ur ne d t o n or mal b y t he e n d of 
t he st u d y.  
I n C y n o m ol g us m o n ke ys, sacit uz u ma b g o viteca n a d mi nistere d 5 0 m g/ k g/ d ose ( h u ma n e q ui val e nt 
d ose = 1 6 m g/ k g/ d ose) f or 4 treat me nt c y cles ( Da ys 1 a n d 8 of a 2 1- d a y c y cle) was c o nsi d ere d a 
n o- o bser ve d-a d verse-effect le vel, a n d 1 2 0 m g/ k g/ d ose a d mi nistere d 3 da ys a part was ass ociate d 
wit h let halit y. I n m o n ke ys, tar get or ga ns i ncl u d e d t he fe male re pr o d u cti ve tract; s ki n ( hair l oss, 
pi g me ntati o n); ki d ne y ( periarteritis); l y m p h oi d or ga ns (l y m p h oi d de pleti o n); b o ne marr o w 
(re d uce d cell ularit y) wit h c o nc o mita nt re d ucti o ns i n re d cells, w hite cells, a n d platelets; a n d t he 
gastr oi ntesti nal tract ( necr osis, er osi o ns, i nfla m mati o n, fi br osis, he m orr ha g e, e de ma). 
L ocal t olera n ce w as e val uate d i n t he G L P-c o m pli a nt m o n ke y st u dies. Alt h o u g h c ha n ges were 
o bser ve d at t he i njecti o n site, t he st u d y pat h ol o gist i nter prete d t hes e fi n di n gs as relate d t o 
pr oce d ural tra u ma a n d n ot t he st u d y dr u g. T hese c ha n ges c o nsiste d of mil d t o m o derate 
peri vasc ular he m orr h a ge, m o derate he m orr ha g e i n t he der mis a n d s u bc utis, a n d mi ni mal t o mil d 
peri vasc ular mi xe d cell i nfiltrati o n. 
S N- 3 8 was ne gati ve f or m uta ge nicit y i n a bacterial re verse m utati o n test a n d was f o u n d t o be 
clast o ge nic i n a n i n vitr o ma m malia n cell micr o n u cle us test. Neit her t he carci n o ge nicit y, n or 
effects of sacit uz u m a b g o viteca n o n fertilit y, earl y e m br y o nic de vel o p me nt, or pre- a n d p ost-
natal de vel o p me nt ha v e bee n assess e d. H o we v er, S N- 3 8 is a ca m pt ot heci n a n d he nce mi g ht be 
carci n o g e nic. F urt her m ore, S N- 3 8 is a k n o w n de v el o p me ntal t o xica nt ( Ca m pt osar ® Prescri bi n g 
I nf or mati o n). 
 
2. 4. 3  P har mac o ki netics of Sacit uz u ma b G o viteca n 
 

                                                 
 
 
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1 5 
Cli nical St u d y I M M U- 1 3 2- 0 1 ( U S F D A I N D # 1 1 5 6 2 1) is a n o n g oi n g, m ulti-ce nter, U S- o nl y, 
trial e val uati n g t he safet y, t o xicit y, a n d P K of sacit uz u ma b g o viteca n. O ver 5 0 0 s u bjects ha ve 
bee n e nr olle d i n t he trial, i ncl u di n g 2 1 5 hea vil y pretreate d p atie nts wit h metastatic breast ca ncer 
( M B C), 5 4 of w h o m are E R +/ H E R 2-. T he st u d y p o p ulati o n i ncl u des s u bjects wit h 
rela pse d/refract or y, metastatic e pit helial ca ncers. T he starti n g d ose f or t h e P hase 1 p orti o n was 
8 m g/ k g a d mi nistere d o n Da ys 1 a n d 8 of a 2 1- da y c ycle. Aft er e v al uati o n at t his a n d hi g her 
d oses i n a 3 + 3 P hase 1 d ose-fi n di n g desi g n, 8 a n d 1 0 m g/ k g sacit uz u ma b g o viteca n a d mi nistere d 
o n Da ys 1 a n d 8 of a 2 1- da y c ycle were c h ose n f or f urt her P has e 2 e v al uati o n i n certai n patie nt 
p o p ulati o ns; na mel y, breast ca ncer, n o n-s mall-cell l u n g ca ncer, s m all-cell l u n g ca ncer, c ol orectal 
ca ncer, pa n creatic ca n cer, ur ot helial ca ncer, e n d o metrial ca ncer, a n d es o p h a geal ca ncer.
 
I nitiall y i n P hase 2, s u bjects were recr uite d i n a se q ue ntial ma n ner t o t he 8 m g/ k g d ose a n d 
s u bse q ue ntl y t o t he 1 0 m g/ k g d ose. A n i nteri m a n al ysis was perf or me d w h e n 8 1 a n d 9 7 s u bjects 
wit h differe nt t u m or t y pes ha d bee n treate d at t he 2 d ose le vels, res p ecti vel y. T here di d n ot 
a p pear t o b e i m p orta nt differe nces i n safet y, a n d s u bjects recei vi n g t he 1 0 m g/ k g d ose ac hie ve d a 
si milar d urati o n of treat me nt as t h ose recei vi n g 8 m g/ k g. F urt her m ore, d at a s u g geste d t hat t he 
1 0 m g/ k g d ose was ass ociate d wit h sli g htl y better o bjecti ve ( o verall) res p o nse rate O R R a n d 
cli nical be nefit rate ( C B R). Res ults of t his st u d y ha ve bee n p u blis he d. 3 1 Base d o n t he e vi de n ce 
a vaila ble, it was deci de d t hat f urt her s u bject accr u al w o ul d pr ocee d at t he 1 0 m g/ k g d ose le vel. 
Sacit uz u ma b g o viteca n h as de m o nstrate d safet y a n d efficac y i n m ulti ple patie nt p o p ulati o ns. 
Pr o misi n g t u m or res p o nses ha ve bee n o bser ve d i n patie nts wit h a d va nce d, rela pse d/refract or y 
T N B C ( 3 3 % [ 3 6/ 1 0 8]), 3 2 ur ot helial carci n o ma ( 3 1 % [ 1 4/ 4 5]), 3 3 n o n-s mall l u n g ca ncer ( 1 9 % 
[ 9/ 4 7]),3 4 s mall-cell l u n g ca ncer ( 1 4 % [ 7/ 5 0]), 3 5 a n d ot hers. O ne of t h e m ore i m p orta nt safet y 
o bser vati o ns fr o m t hese st u dies is t hat it a p pears t hat t he t o xicit y pr ofile of s acit uz u ma b 
g o viteca n is m ore t olera ble t ha n w he n S N- 3 8 is a d mi nistere d as t he pare nt c o m p o u n d, iri n oteca n, 
or wit h ot her n o n-t u m or-tar geti n g S N- 3 8 pr o d ucts. 
 
I n t he p h ase-
i n t he a d va n ce d/ metastatic setti n g ( pri or ta xa n e re q uire d) were ra n d o mize d 1: 1 t o recei ve 
sacit uz u ma b g o viteca n ( 1 0 m g/ k g I V o n d 1, 8 e ver y 2 1 d) or treat me nt of p h ysicia n’s c h oice ( T P C; 
ca pecita bi ne, eri b uli n, vi n orel bi ne, or ge mcita bi ne) u ntil diseas e pr o gressi o n/ u nacce pta ble 
t o xicit y. Sacit uz u ma b g o viteca n ( n = 2 3 5) c o m pare d wit h T P C ( n = 2 3 3) si g nifica ntl y i m pr o ve d 
m P F S ( 5, 6 vs 1, 7 m o; H R, 0, 4 1; P < 0, 0 0 0 1) a n d me dia n O S ( 1 2, 1 vs 6, 7 m o; H R, 0, 4 8; P < 0, 0 0 0 1). 
O R R was 3 5 % f or sacit uz u ma b g o viteca n vs 5 % f or T P C ( P < 0, 0 0 0 1). 1 2 0 
T w o a d diti o nal cli nical trials usi n g sacit uz u ma b g o viteca n are o n g oi n g. O ne of t hese trials is i n 
breast ca n cer: t he P hase 3 ra n d o mize d T R O PI C S- 0 2 trial, I M M U- 1 3 2- 0 9 ( U S F D A I N D # 1 2 2 6 9 4, 
E u dra C T 2 0 1 8- 0 0 4 2 0 1- 3 3) i n rela pse d/refract or y H R +, H E R 2- ne gati ve m etastatic breast ca ncer 
c o m pari n g sacit uz u ma b g o viteca n t o treat me nt of p h ysicia n’s c h oice ( T P C). T he sec o n d o n g oi n g 
trial is i n metastatic ur ot helial ca ncer: t he I M M U- 1 3 2- 0 6 ( U S F D A I N D # 1 4 0 0 8 4) P hase 2 trial 
after fail ure of a plati n u m- base d re gi me n or a nti- P D 1- base d i m m u n ot hera p y.
2. 4. 5
Sacit uz u ma b G o viteca n i n Metastatic Breast Ca n cer

                                                 
 
 
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1 6 
I n t he p h ase 1/ 2 I M M U- 1 3 2- 0 1 trial, 1 0 8 patie nts wit h metastatic tri ple- ne gati ve breast ca ncer 
recei v e d sacit uz u ma b g o viteca n as a t hir d or hi g her li ne of t hera p y at 1 0 m g/ k g o n da ys 1 a n d 8 
e ver y 2 1 da ys u ntil pr o gressi o n or u nacce pta ble t o xicit y. 3 2 T he a ge ra n g e of all patie nts was fr o m 
3 1 t o 8 0 years ol d wit h a me dia n a ge of 5 5 y ears ol d. 3 2 T he patie nt p o p ulati o n were hea vil y pre-
treate d wit h a me di a n of 3 pri or a ntica n cer t hera pi es. S o me patie nts recei ve d u p t o 1 0 pri or 
t hera pies a n d 6 9 % of pati e nts ha d recei ve d pri or plati n u m a ge nts f or metast atic disease.3 2
T he m ost c o m m o n a d verse e ve nts were ne utr o pe nia, na usea, a n d diarr h ea ( Ta ble  3). 3 2 M ost 
a d verse e ve nts were ma n a ge d wit h s u p p orti ve me dicati o ns or d ose m o dificati o ns, a n d t he 
maj orit y of patie nts were a ble t o c o nti n ue at t he 1 0 m g/ k g d ose. 3 2 O nl y t hree patie nts ( 2. 8 %) 
disc o nti n ue d treat me nt d ue t o a d vers e e ve nts (treat me nt-relate d gra de 3 tra nsie nt i nf usi o n 
reacti o n a n d gra d e 2 fati g ue; n o n-treat me nt relate d h y perte nsi o n).3 2 N o treat me nt-relate d d eat hs 
occ urre d.
T a ble 3. Dr u g-rel ate d a d v erse e ve nts i n T N B C p atie nts
B o d y s yste m
A d v erse e v e nt ( A E)
All g r a des  Gr a de 3 or 4
He mat ol o gic 
Ne utr o pe nia
A n e mia
Le u k o pe nia
6 4 %
5 0 % 
2 1 % 
4 2 % 
1 1 % 
1 2 % 
Gastr oi ntesti n al
Na usea  
Diarr h ea 
V o miti n g
C o nsti p ati o n
6 7 %
6 2 % 
4 9 % 
3 4 %
6 %
8 %
6 % 
1 %
Ot h er 
Fati g u e 
Al o pecia  
Decrease d a p petite 
H y per gl y ce mia 
H y p o ma g n ese mia
H y p o p h os p hate mia 
5 5 %
3 6 %
3 0 %
2 4 % 
2 1 %
1 5 %
8 % 
0 %
0 %
4 %
1 %
9 %
O ut of t he 1 0 8 patie nts, t hree ac hie ve d c o m plete res p o nses a n d 3 3 partial res p o nses, f or a n 
o bjecti ve res p o nse rate of 3 3 % ( R E CI S T 1. 1). 3 2
was 4 5 % ( 4 9/ 1 0 8). 3 2 T he me dia n ti me t o o nset of res p o nse was 2 m o nt hs wit h a me dia n d urati o n 
of res p o nse of 7. 7 m o nt hs. 3 2 I m p orta ntl y, 6 patie nts were pr o gressi o n free f or m ore t ha n 1 year 
fr o m start of treat me nt.3 2 T he me dia n P F S was 5. 5 m o nt hs ( 9 5 % CI, 4. 1 t o 6. 3), a n d t he me dia n 
O S was 1 3. 0 m o nt hs ( 9 5 % CI, 1 1. 2 t o 1 3. 7). 3 2 Patie nts be nefite d fr o m sacit uz u ma b g o viteca n 
treat me nt irres p ecti ve of a ge, o nset of met astatic disease, n u m ber of pri or re gi me ns, or pres e nce 
or a bse nce of visceral metastases. 3 2 
Als o i n t he p hase 1/ 2 I M M U- 1 3 2- 0 1 trial, 5 4 pati e nts wit h H R + / H E R 2- M B C recei ve d 
sacit uz u ma b g o viteca n at 1 0 m g/ k g o n da ys 1 a n d 8 e ver y 2 1 da ys u ntil pr o gressi o n or 
u nacce pta ble t o xicit y. 3 6 All patie nts ha d recei ve d at least 2 pri or li nes of t h era p y i n a n y s etti n g, 
o ne of w hic h w as e n d ocri ne- base d t hera p y. 3 6 T he O R R f or t his p o p ulati o n was 3 1. 5 % wit h 
me dia n P F S of 5. 5 m o nt hs a n d me dia n O S of 1 2 m o nt hs. 3 6 Ke y gra de 3 a d verse e ve nts were 
ne utr o pe nia, a n e mia, a n d diarr hea. 3 6
I n A pril 2 0 2 0, t he F D A gra nte d accel erate d a p pr o val t o sacit uz u ma b g o viteca n f or patie nts wit h 
metastatic tri ple ne gati ve breast ca ncer w h o recei v e d at least t w o pri or t hera pies f or metastatic 

                                                 
 
 
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1 7 
disease base d o n t he res ult of t he si n gle-ar m p hase II trial. T he O R R was 3 3. 3 % ( 9 5 % CI: 2 4. 6, 
4 3. 1). T he me dia n res p o nse d urati o n was 7. 7 m o nt hs ( 9 5 % CI: 4. 9, 1 0. 8). 1 2 1
T he rati o nale t o s u p p ort e nr olli n g patie nts wit h pre-treate d H R + / H E R 2- M B C, w h o ha ve 
pr o gresse d o n a n y n u m ber of pri or h or m o ne t hera pies a n d u p t o o ne pri or c he m ot hera p y, o n t his 
ra n d o mize d p has e II st u d y e m pl o yi n g sacit uz u ma b g o viteca n as t he c o ntr ol ar m is t hat t hese 
patie nts ha ve s h ort-li ve d res p o nses t o c he m ot hera p y, 4, 3 7, 3 8 w hic h is t he us ual ne xt li ne of t hera p y 
after pr o gressi o n o n h or m o ne t hera pies. S pecificall y, t he O R R a n d me dia n P F S f or t hese patie nts 
o n sta n dar d- of-care c he m ot hera p y a g e nts as earl y li ne t hera pies are si milar t o t he O R R of 3 1 % 
a n d t he me dia n P F S of 6. 8 m o nt hs o bser ve d wit h sacit uz u ma b g o viteca n as a later li ne t hera p y 
f or hea vil y pre-treate d patie nts wit h H R + / H E R 2- M B C,3 9 i n dicati n g t hat t his A D C w o ul d li kel y 
perf or m at least as well as sta n dar d c he m ot hera pies i n a n earlier li ne s etti n g. F urt her m ore, s o me 
of t hese patie nts ha v e alrea d y bee n e x p ose d t o c h e m ot hera p y a ge nts wit h k n o w n cli nical be nefit, 
na mel y ta xa nes a n d a nt hrac ycli nes, i n t he ne o a dj u va nt or a dj u va nt setti n g, i ncreasi n g t he 
pr o ba bilit y t hat t heir rec urre nt metastatic t u m ors are resista nt t o t hese t hera pies. Fi nall y, a n d 
m ost i m p orta ntl y t o patie nts, sacit uz u ma b g o viteca n has l o wer rates of se v ere p ote ntiall y 
per ma ne nt t o xicit y, s uc h as ne ur o pat h y a n d heart fail ure, 3 2 t ha n ta xa nes a n d a nt hrac y cli nes. 
2. 5
R ati o n ale f or C o m bi n ati o n of Pe m br oliz u m a b a n d S acit uz u m a b G o vitec a n 
Patie nts wit h H R + M B C refract or y t o h or m o ne t h era pies a n d C D K 4/ 6 i n hi bit ors ha ve s h ort 
res p o nses t o c he m ot hera p y wit h a me dia n P F S of ar o u n d 4 t o 5 m o nt hs.4 I m m u ne c hec k p oi nt 
i n hi bit ors, alt h o u g h ass ociate d wit h d ura ble res p o nses i n ot her t u m ors, ha v e yiel de d 
disa p p oi nti n gl y l o w m o n ot hera p y res p o nses i n H R + M B C. 1 6 Eff orts t o b o ost res p o nses b y 
c o m bi ni n g i m m u n ot hera p y wit h c he m ot hera p y h a ve pr o ve d m ost s uccessf ul i n tri ple ne gati ve 
breast ca ncer. 1 7 H o we ver, t he o pti mal a ge nt t o c o m bi ne wit h i m m u n ot hera p y t o pr ol o n g s ur vi val 
i n H R + M B C re mai ns ur ge ntl y nee de d a n d u n k n o w n. 
 
Sacit uz u ma b g o viteca n, a n a nti- Tr o p- 2- S N- 3 8 A D C, ma y be a n effecti ve i m m u n ot hera p y 
c o m bi nati o n a ge nt f or p atie nts wit h H R + M B C. Tar geti n g Tr o p- 2, a tra ns m e m bra ne si g nali n g 
rece pt or o vere x press e d i n breast ca ncer, sacit uz u ma b g o viteca n res ulte d i n a me dia n P F S of 
a p pr o xi matel y 6 m o nt hs i n pre-treate d H R + M B C. 3 9 T his A D C ma y b o ost a ntica ncer i m m u nit y 
b y bi n di n g i m m u ne cell rece pt ors t o pr o m ote a nti b o d y- de pe n de nt cell ular c yt ot o xicit y 
( A D C C).2 9 I n a d diti o n, t he S N- 3 8 pa yl oa d of s acit uz u ma b g o viteca n is t he acti ve meta b olite of 
iri n oteca n, w hic h h as bee n s h o w n t o de plete re g ul at or y T cells, u pre g ulate M H C class I a n d P D-
L 1 e x pressi o n, a n d a u g me nt t he a ntit u m or acti vit y of a nti- P D- 1/ L 1 a nti b o dies i n m uri ne t u m or 
m o dels. 4 0 F urt her m ore, t he iri n oteca n a nal o g ue ca m pt ot heci n e n ha nces C D 8 + c yt ot o xic T cell 
effect or f u n cti o ns a n d a ntit u m or i m m u ne res p o nses b y i n hi biti n g N R 4 A tra nscri pti o n fact ors, 4 1 
w hic h ha ve rece ntl y bee n s h o w n t o a pla y ce ntral r ole i n i n d uci n g t he T cell d ysf u ncti o n 
ass ociate d wit h c hr o ni c a nti ge n sti m ulati o n i n s oli d t u m ors. 4 2, 4 3 Fi nall y, A D Cs ha ve e n ha n ce d 
t he effects of i m m u n ot hera p y i n ot her breast ca ncer s u bt y pes, as de m o nstrate d b y t he pr o misi n g 
preli mi nar y res ults of t he A D C trast uz u ma b e mta nsi ne ( T D M- 1) i n c o m bi n ati o n wit h 
atez oliz u ma b i n patie nts wit h a d va nce d P D- L 1 + H E R 2 + breast ca ncer i n t he K A T E 2 trial. 4 4
 
T h us, m ulti ple li nes of e vi de nce s u g gest t hat sacit uz u ma b g o viteca n will e n ha nce t he a ntit u m or 
i m m u ne effects of pe m br oliz u ma b i n H R + H E R 2- M B C. We h y p ot hesize t hat sacit uz u ma b 

                                                 
 
 
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g o viteca n will e n ha n ce T cell i nfiltrati o n i nt o t u m ors b y selecti vel y tar g eti n g breast ca ncer cells 
a n d e x p osi n g t u m or ne oa nti ge ns. T his trial t heref ore ai ms t o a ns wer t he q uesti o n of w het her 
pe m br oliz u ma b a d de d t o sacit uz u ma b g o viteca n will e xte n d s ur vi val f or H R + M B C patie nts. 
C o nsi deri n g t he p ote ntial i m m u n o m o d ulat or y effects of sacit uz u ma b g o viteca n descri be d a b o v e, 
we h y p ot hesize t hat p atie nts wit h H R + M B C t u m ors ma y deri ve b e nefit fr o m pe m br oliz u ma b 
w he n gi ve n i n c o m bi nati o n wit h sacit uz u ma b g o viteca n, a n d t hat t his be nefit will be o bser ve d 
a m o n g all patie nts wit h H R + t u m ors re gar dless of baseli ne P D- L 1 e x pressi o n. We will als o 
e x pl ore differe n ces i n t he efficac y of s acit uz u ma b g o viteca n pl us pe m br oliz u ma b vs. 
sacit uz u ma b g o viteca n al o ne i n t he s u b gr o u p of patie nts wit h P D- L 1- p ositi ve t u m ors, as 
 t he P har m D x 2 2 C 3 assa y, w hic h re prese nts a p pr o xi matel y 2 0- 2 5 % 
of H R + / H E R 2- metastatic t u m ors.
 
2. 6  
C orrel ati v e St u dies B ac k gr o u n d 
 
2. 6. 1  Bl o o d a n d Tiss ue A nal ysis 
 
T he i m p orta nce of a ntica ncer i m m u nit y has bec o me a p pare nt o ver t he last fe w years, as i m m u ne 
c hec k p oi nt i n hi bit ors ha v e i m pr o ve d s ur vi v al acr oss ma n y ca n cer t y pes. 4 5 H o we ver, less t ha n h alf 
of patie nts wit h s oli d t u m ors deri ve be nefit fr o m t hese dr u gs, 1 5, 4 6 a n d fe w patie nts wit h breast 
ca ncer be nefit. 1 6 T h us, el uci dati n g t he mec ha nis ms u n derl yi n g i m m u ne e vasi o n is cr ucial t o 
de vel o p ne w t hera pe utic strate gies t hat e n ha n ce t h e effi cac y of i m m u n ot hera p y i n breast ca ncer.
 
Gr o wi n g e vi d e nce s u g gests t hat patie nts wit h a d v a nce d s oli d t u m ors s h o w differe nces i n t u m or 
micr oe n vir o n me nt re g ar di n g t he prese nce or a bs e nce of a ge n e e x pressi o n pr ofile i n dicati ve of a 
pre-e xisti n g T-cell –i nfla me d t u m or micr oe n vir o n me nt. 4 7 T u m ors classifie d as T-cell i nfla me d 
har b or a si g nifica nt i nfiltrati o n of C D 8 + T cells a n d a t y pe-I i nterfer o n (I F N) si g nat ure. I n t his 
gr o u p, t he mai n mec ha nis ms of i m m u ne e vasi o n m a y be t h e o vere x pressi o n of i m m u n os u p pressi ve 
m olec ules i n t he t u m or micr oe n vir o n me nt, i ncl u di n g i m m u ne c hec k p oi nt m olec ules ( C T L A- 4, 
P D- 1/ P D- L 1, TI M- 3, L A G- 3), i n d olea mi ne- 2, 3- di o x y ge nase (I D O), a n d F o x P 3, c haracteristicall y 
e x presse d o n re g ulat or y T cells. I nteresti n gl y, t hese i m m u n os u p pressi ve m olec ules are sti m ulate d 
b y a t y pe-I I F N a ntit u m or res p o nse, res ulti n g i n T-cell e x ha usti o n a n d a da pti ve i m m u ne 
resista nce.4 7, 4 8 I n c o ntrast, ot her t u m ors are c h aracterize d b y l o w or a bse nt i ntrat u m oral C D 8 T 
cells a n d n o e vi d e nce of a t y pe-I I F N tra nscri pti o nal si g nat ure; t his t u m or p he n ot y pe is n o n- T-cell-
i nfla me d.4 7
T he T-cell i nfla me d p he n ot y pe has p ositi ve pr o g n ostic val ue f or s e veral t y pes of ca n cer, i n cl u di n g 
breast ca ncer, 4 9, 5 0 s u g gesti n g t hat a n atte m pt b y t he h ost t o ge nerate a n a nti-t u m or i m m u ne 
res p o nse reflects a bi ol o gic pr ocess ass oci ate d wit h i m pr o ve d cli nical o utc o mes. 4 7 I n breast 
o nc ol o g y, differe nt gr o u ps ha ve de m o nstrate d t hat t he a m o u nt of t u m or i nfiltrati n g l y m p h oc ytes 
( TI Ls) i n a t u m or s peci me n, c o m m o nl y assesse d b y hist ol o gical e val uati o n of a sta n dar d 
he mat o x yli n a n d e osi n-stai ne d sli de b y a trai ne d pat h ol o gist, is a si g nifica nt pre dict or of b ot h 
res p o nse t o t hera p y a n d o verall disease o utc o mes i n t he ne oa dj u va nt a n d a dj u va nt setti n gs.5 1- 5 7
Rece ntl y, m ore i n- de pt h met h o ds of i m m u n ol o gic pr ofili n g ha ve bee n e x pl ore d i n breast ca n cer, 
f or e x a m ple, m R N A e x pressi o n of i m m u ne-acti vati n g a n d i m m u n os u p pressi ve fact ors, a n d t hese 
a d diti o nal i m m u ne pr ofiles als o a p pear t o ha ve pr o g n ostic si g nifica nce. 4 9 F urt her m ore, i n t he 
metastatic setti n g, t he T-cell-i nfla me d p he n ot y pe a p pears t o be ass ociat e d wit h cli nical res p o nse 

                                                 
 
 
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t o se veral i m m u n ot hera pi es, i ncl u di n g c hec k p oi nt bl oc ka de.5 8 T h us, o ne of t he mai n o bjecti ves of 
t he c orrelati ve scie n ce i n t his trial is t he c haracterizati o n of a br oa d arra y of i m m u ne mar kers i n 
H R + / H E R 2- M B C t o i n vesti gate w het her t hese mar kers pre dict res p o ns e t o i m m u n ot hera p y. 
C o nsi deri n g t he mec ha nis m of acti o n of a nti- P D- 1/a nti- P D- L 1 dr u gs, t he a bse nce of si g nifica nt T-
cell i nfiltrate, i n a d diti o n t o l o w e x pressi o n of i m m u ne c hec k p oi nt m olec ules, ma y c orrelate wit h 
a n o n-i nfla me d t u m or p he n ot y pe t hat is ass ociate d wit h de n ov o  resista nce t o t hese a ge nts. F or t his 
gr o u p of patie nts, t hera pe utic strate gies t hat pr o m ote a n i ncrease i n c yt ot o xic T-cell i nfiltrati o n, 
s uc h as a nti b o d y- dr u g c o nj u gates, ma y be cr ucial t o s uccessf ull y o verc o mi n g T-cell e x cl usi o n a n d 
i m pr o ve t he li keli h o o d of be nefit of P D- 1 bl oc k a d e.  
 
A d diti o nall y, as part of t he c orrel ati ve w or k i n t his st u d y, we will c haracterize t he i m m u ne mar ker 
pr ofile of peri p h eral bl o o d m o n o n uclear cells ( P B M Cs) i n e nr olle d patie nts. F urt her m ore, gi ve n 
t he de m o nstrate d cli nical si g nifica nce of TI Ls i n breast ca ncer s peci me ns, we will e val uate
w het her t here is a peri p heral mar k er w h os e le vel c orres p o n ds t o TI L i nfiltrati o n. We will als o 
e val uate w h et her t here is a c orrelati o n bet wee n c h a n ges i n P B M C i m m u ne pr ofiles a n d res p o ns e 
t o treat me nt. E vi de nce of a n ass ociati o n w o ul d be of si g nifica nt i nterest, as it w o ul d i n dicate a 
p ote ntial bi o mar ker of res p o nse or resista nce i n t he peri p heral bl o o d. 
 
Fi nall y, sacit uz u ma b g o viteca n selecti vel y tar gets breast ca ncer cells b y bi n di n g t o Tr o p- 2 f or 
tar gete d deli ver y of S N- 3 8 directl y t o t u m or cells w hile mi ni mizi n g s yste mic e x p os ure of S N- 3 8 
t o decrease h ost t o xicit y. H o we ver, t he r ole of Tr o p- 2 e x pressi o n as a p ote ntial pre dicti ve 
bi o mar ker is u n k n o w n. T heref ore, w e will e val uat e t he ass ociati o n bet wee n baseli ne t u m or tiss ue 
Tr o p- 2 e x pressi o n a n d res p o nse. 
 
2. 6. 2  Ge n o mic A nal ysis 
 
I n a d diti o n t o t he i m m u ne micr oe n vir o n me nt, i ntri nsic t u m or fact ors ma y be ass ociate d 
wit h res p o nse t o i m m u ne c hec k p oi nt i n hi bit ors. Alt h o u g h s o me of t he mec ha nis ms relate d t o de 
n o v o or ac q uire d resista nce t o i m m u n ot hera p y ha ve rece ntl y bee n descri be d i n ot her t u m ors, 
i ncl u di n g l oss of f u ncti o n i n beta- 2- micr o gl o b uli n or defects i n t he i nterfer o n si g nali n g 
pat h wa y, 5 9, 6 0 resista nce pat h wa ys i n breast ca ncer re m ai n lar gel y u n k n o w n. Se veral ge ne
pat h wa ys ha v e bee n des cri be d as ca n di d ate resista nce mec ha nis ms i n ot her t u m ors, i ncl u di n g 
M Y C a m plificati o n,
6 1 W N T-
-cate ni n u pre g ul ati o n,6 2 
M A P K acti vati o n, a n d P T E N l oss.6 3- 6 5
E mer gi n g ge n o mic c orrelates of res p o nse t o i m m u n ot hera p y i n ot h er t u m ors i ncl u de m utati o nal 
l oa d,6 6, 6 7 t u m or a ne u pl oi d y,6 8 a n d mis matc h re pair defects. 6 9 N ota bl y, t here is little data o n 
ge n o mic c orrelates of res p o nse t o a nti- P D- 1 t hera p y i n patie nts wit h breast ca ncer. 
T heref ore, as a c orrelati v e st u d y i n t his trial, we will e x pl ore w h et her t he n u m ber a n d/ or 
t y pe of m utati o ns i de ntifi e d usi n g a t ar gete d ne xt g e nerati o n s e q ue nci n g ( N G S) pa nel, O nc o Pa nel, 
as well as m ore c o m pre he nsi ve se q ue nci n g i n a s u bset of patie nts, c orrelates wit h cli nical o utc o mes 
( P F S, O R R, C B R, a n d O S). O nc o Pa nel is a ca ncer ge n o mic assa y t o detect s o matic m utati o ns, 
c o p y n u m ber variati o ns, a n d str u ct ural v aria nts i n t u m or D N A e xtracte d fr o m fres h, fr oze n, or 
f or mali n-fi xe d paraffi n-e m be d de d sa m ples. T he O nc o Pa nel assa y s ur ve ys e x o nic D N A se q ue nces 
of 4 4 7 ca n cer ge nes a n d 1 9 1 re gi o ns acr oss 6 0 ge nes f or rearra n g e me nt det ecti o n. D N A is is olate d 
fr o m tiss ue c o ntai ni n g at least 2 0 % t u m or n uclei a n d a nal yze d b y massi vel y parallel se q ue nci n g 
usi n g a s ol uti o n- p hase A gile nt S ure Select h y bri d ca pt ure kit a n d a n Ill u mi na Hi Se q 2 5 0 0 

                                                 
 
 
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se q ue ncer. T his
C LI A-a p pr o ve d N G S assa y, w hic h has bee n e xte nsi vel y vali date d, 7 0 will be 
perf or me d at t he Ce nter f or A d va nce d M olec ular Dia g n ostics i n t he De part me nt of Pat h ol o g y at
Bri g ha m a n d W o me n's H os pital, w hile m ore c o m pre he nsi ve se q u e nci n g, s u c h as w h ole e x o m e or 
w h ole ge n o me se q ue nci n g, will be perf or me d at t he Br oa d I nstit ute of t he Massac h usetts I nstit ute 
of Tec h n ol o g y. 
 
2. 6. 3  Micr o bi o me A nal ysis 
T he g ut micr o bi o me m o d ulates i m m u ne s yste m de vel o p me nt, 7 1 b ut t he micr o bial p o p ulati o ns of 
healt h y i n di vi d uals var y mar ke dl y i n c o m p ositi o n. 7 2, 7 3 T he di versit y of i ntesti nal micr o bi ota 
re pres e nts a caref ul b ala nce bet w ee n i m m u ne t olera nce of be n eficial micr o bes a n d i nfla m mat or y 
res p o nses a gai nst pat h o ge ns. Alterati o ns i n t he g ut micr o bi ota a n d t heir res ulti n g i nteracti o ns wit h 
i ntesti nal e pit heli u m a n d t he h ost i m m u ne s yste m are ass ociate d wit h ma n y diseases, i ncl u di n g 
ca ncer. 7 4 Precli nical st u dies ha ve pr o vi de d str o n g e vi de nce f or t he r ol e of g ut micr o bi ota i n 
m o d ulati n g res p o nse a n d resista nce t o i m m u ne c h ec k p oi nt i n hi bit ors, raisi n g t he p ossi bilit y t hat 
st o ol micr o bi ota c o ul d be use d as a res p o nse bi o mar ker f or i m m u n ot hera p y. 7 5, 7 6 I nteresti n gl y, 
p ost me n o pa usal w o me n wit h breast ca ncer h a ve altere d c o m p ositi o n a n d l o w di versit y of t h eir g ut 
micr o bi ota c o m pare d t o healt h y c o ntr ols, as meas ure d b y t he S ha n n o n i n de x. 7 7 I de ntificati o n of 
bi o mar kers t h at pre di ct res p o nse t o i m m u n ot hera p y c o ul d s pare de n o v o  resista nt patie nts fr o m t h e 
u n necessar y ris k of i m m u ne-relat e d a d verse e v e nts. I n a d diti o n, t he i de ntificati o n of bacterial 
s pecies ass ociate d wit h res p o nse c o ul d o pe n ne w strate gies t o ma xi mize t he cli nical be nefit of 
ca ncer i m m u n ot hera p y t hr o u g h t he m o d ulati o n of g ut micr o bi ota. 
 
E mer gi n g e vi de nce s u g gests t hat t he g ut micr o bi o me ma y i nfl ue nce res p o nse t o c hec k p oi nt 
i n hi bit ors i n a n u m ber of 
mali g na ncies.7 8- 8 1 Precli nical st u dies i n 
m uri ne 
m o dels ha ve 
de m o nstrate d t hat micr o bi o me c o m p ositi o n is ass ociate d wit h res p o nse t o P D- L 1 i n hi bit ors, wit h 
mice e x hi biti n g a “fa v ora ble” micr o bi o me h a vi n g a great er li keli h o o d of res p o n di n g t o treat me nt 
as c o m pare d t o 
mice 
wit h a n “ u nfa v ora ble” 
micr o bi o me. St u dies als o de m o nstrate t hat 
tra ns pla nti n g feces fr o m mice wit h fa v ora ble micr o bi ota t o t h ose wit h u nfa v ora bl e micr o bi ota 
i ncreas es res p o nse rates, s u g gesti n g t hat m o dificati o n of t he micr o bi o me c o ul d ha ve a t hera pe utic 
effect i n patie nts recei vi n g c hec k p oi nt i n hi bit ors. 7 9
Tra nslati o nal w or k de m o nstrates t hat fecal 
tra ns pla nts fr o m p atie nts res p o n di n g t o c h ec k p oi nt i n hi bit ors t o n u de mice i ncreas es t he li keli h o o d 
of res p o nse t o i m m u n ot hera p y i n t hese a ni mals, w hereas tra ns pl a nts fr o m h u ma n n o n-res p o n ders 
lea ds t o a l o wer li keli h o o d of res p o nse.7 9, 8 0 T he e vi de nce li n ki n g t he g ut micr o bi o me t o c hec k p oi nt 
i n hi bit or efficac y i n h u m a ns has bee n relati vel y li mite d t o date, b ut a n u m ber of rece nt p u blicati o ns 
ha ve de m o nstrate d a relati o ns hi p bet wee n c o m p ositi o n of t he micr o bi o me a n d res p o nse t o 
i m m u n ot hera p y i n mela n o ma, n o n-s mall cell l u n g carci n o ma a n d re nal cell ca ncer.7 8- 8 1 N ota bl y, 
t he bacteri al s pecies ass o ciate d wit h a fa v ora ble res p o nse t o treat me nt ha ve differe d acr oss disease 
sites a n d st u dies.7 8, 8 1
Micr o bi o me c o m p ositi o n is i nfl ue nce d b y ma n y fact ors, i ncl u di n g a ge, ge netics, a n d use of 
a nti bi otics a n d pr o bi otics. 8 2- 8 4 St u dies de m o nstrate t hat dietar y c o m p ositi o n is o ne of t he pri mar y 
dri vers of micr o bi o me di versit y a n d ta x a. 8 2, 8 3 Ot her fact ors relate d t o e ner g y bala nce, t he b ala nce 
of cal ories i n g este d vers us e x pe n de d, s uc h as p h ysical acti vit y a n d b o d y wei g ht als o i m pact 
micr o bi o me c o m p ositi o n. 8 3, 8 4 Li mite d data i n h u ma ns s u g gest t hat fact ors i m pacti n g micr o bi o me 
c o m p ositi o n ma y als o be relate d t o c hec k p oi nt i n hi bit or res p o nse. A n a nal ysis of 1 1 3 patie nts wit h 

                                                 
 
 
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metastatic mela n o ma f o u n d si g nifica nt ass ociati o ns bet wee n dietar y fact ors (i n gesti o n of re d meat 
[ p = 0. 0 0 6], s u g ar-s w eet e ne d 
be v era ges [ p = 0. 0 4 8] a n d fr uits/ ve geta bles [ p = 0. 0 4 9]) a n d 
micr o bi o me c o m p ositi o n. 8 5 Use of a nti bi otics ( p = 0. 0 5) a n d pr o bi otics ( p = 0. 0 2) was als o ass ociate d 
wit h l o wer micr o bi o me 
- di versit y. E x pl orat or y a nal yses of 4 6 of t hese patie nts w h o were 
i nitiati n g treat me nt wit h a nti- P D- 1 t hera p y s u g geste d t hat i n di vi d uals i n t his c o h ort wit h a hi g her 
c o ns u m pti o n of dietar y fi ber ha d a 5-f ol d li keli h o o d of res p o nse t o a nti- P D- 1 t hera p y as c o m p are d 
t o i n di vi d uals wit h l o w fi ber c o ns u m pti o n ( pers o n al c o m m u nicati o n, War g o). T hese fi n di n gs are 
pr o v ocati ve b ut were bas e d o n a diet ar y s cree ni n g t o ol t hat pr o vi des a rel ati ve cr u d e assess me nt 
of dietar y i nta ke. T he st u d y als o di d n ot assess ot her m o difia ble fact ors t hat ca n i nfl ue nce 
micr o bi o me c o m p ositi o n, s uc h as p h ysi cal acti vit y, precl u di n g i de ntificati o n of a n o pti mal strat e g y 
of lifest yle m o dificati o n t o e n ha nce i m m u n ot hera p y res p o nse. 
 
I n a n eff ort t o i de ntif y pre dicti ve bi o mar kers of res p o nse or resista nce t o i m m u ne c hec k p oi nt 
i n hi bit ors, st o ol sa m ples will be c ollecte d t o d eter mi ne w h et her b aseli ne c haracteristics of t he 
str uct ure of t he g ut micr o bi o me or c h a n ges i n t he o verall di versit y of g ut micr o bi o me are 
ass ociate d wit h effi cac y of pe m br oliz u ma b i n c o m bi nati o n wit h sacit uz u ma b g o viteca n i n patie nts 
wit h H R + / H E R 2- M B C. A d diti o nall y, t o i de ntif y p ote ntiall y m o difia ble dri vers of micr o bi o me 
di versit y a n d c o m p ositi o n, partici pa nts will u n der g o assess me nt of dietar y c o m p ositi o n, p h ysical 
acti vit y a n d b o d y mass i n de x at t he sa me ti me p oi nts. 
 
2. 6. 4  Pre- Scree ni n g Partici pa nts ( pri or t o S p o ns or A me n d me nt 3, P D- L 1 eli gi bilit y 
a me n d me nt) 
 
T he mec ha nis ms u n derl yi n g t he l o wer res p o ns e rate of H R + M B C t o i m m u ne c hec k p oi nt 
i n hi bit ors are lar gel y u n k n o w n. L o wer m utati o n a n d ne oa nti ge n b ur de n, l o wer le vels of TI Ls, 
a n d l o wer P D- L 1 e x pressi o n ha ve all bee n p ost ulat e d as p ote ntial mec h a nis ms b ut ha ve n ot bee n 
s yste maticall y c haracteri ze d i n lar ge n u m b ers of p atie nts wit h H R + M B C. T he arc hi val t u m or 
tiss ue re q uire d t o deter mi ne t he P D- L 1 stat us of pre-scree ni n g partici pa nts prese nts a ri c h 
o p p ort u nit y t o defi ne t he i m m u ne la n dsca pe of H R + M B C. I n partic ular, rat es of differe nt 
i m m u ne cell s u bsets be y o n d TI Ls h a ve b ee n less well c haracterize d i n H R + M B C.  
T heref ore, w e will e x pl ore a vari et y of tiss ue bi o mar kers i n t he t u m or sa m pl es fr o m pre-
scree ni n g p artici pa nts, i n cl u di n g i m m u ne cell s u bsets, i n hi bit or y a n d c osti m ulat or y c hec k p oi nt 
pat h wa y m olec ules, t u m or m utati o n a n d ne oa nti g e n b ur de n, a n d i m m u ne-relate d tra ns cri pt o mic 
si g nat ures a n d ge n o mic p at h wa y alterati o ns. We will als o defi ne rates of P D- L 1 p ositi vit y b y 
differe nt P D- L 1 a nti b o dies a n d c o m pare rates of p ositi vit y.   
 
3  
P A R TI CI P A N T S E L E C TI O N 
Eli gi bilit y will be assesse d as part of t he s cree ni n g pr oce d ures f or all patie nts.  
3. 1  
Eli gi bilit y Criteri a  

                                                 
 
 
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2 2 
3. 1. 1
Partici pa nts m ust ha ve hist ol o gicall y or c yt ol o gicall y c o nfir me d i n vasi ve breast ca n cer 
wit h u nresecta bl e l ocall y a d va nce d or metastatic disease. Partici pa nts wit h o ut pat h ol o gic 
or c yt ol o gic c o nfir mati o n of metastatic diseas e s h o ul d ha ve u ne q ui v ocal e vi de nce of 
metastasis fr o m p h ysical e xa mi nati o n or ra di ol o gi c e val uati o n, i.e. visi ble c hest wall 
disease or metast ases o n i ma gi n g meeti n g sta n dar d ra di ol o g y criteria (i.e., l y m p h n o des 
lar ger t ha n 1 c m i n t he s h ort a xis dia meter).  
 
3. 1. 2  Partici pa nts m ust ha ve H R- p ositi ve, H E R 2- ne gati ve breast ca ncer ( E R
1 % a n d/ or, 
P R 1 %, H E R 2- ne gati ve per A S C O C A P g ui deli nes) o n l ocal pat h ol o g y re vie w. If a 
patie nt has m ore t ha n o n e hist ol o gical res ult, t he m ost rece nt sa m ple will be c o nsi dere d 
f or i ncl usi o n. 
 
3. 1. 3  Partici pa nts m ust ha ve eit her pr o gress e d o n or wit hi n 1 2 m o nt hs of a dj u va nt e n d ocri ne 
t hera p y wit hi n t he last 1 2 m o nt hs or ha ve pr o gresse d o n at least o ne li ne of e n d ocri ne 
t hera p y f or m etastatic dis ease a n d b e c o nsi dere d a p pr o priate ca n di dates f or 
c he m ot hera p y. 
 
3. 1. 4  Partici pa nts m ust ha ve e val ua ble or meas ura ble disease per R E CI S T 1. 1. S ee Secti o n 1 1 
f or t he assess me nt of meas ura ble disease. F or i nsta nce, p atie nts wit h b o ne o nl y disease 
will be all o we d t o partici pate. 
 
3. 1. 5  Partici pa nts m ust a gree t o u n der g o a researc h bi o ps y, if t u m or is safel y accessi ble, at 
baseli ne. Pre vi o usl y c ollecte d arc hi val tiss ue will als o be re q u este d, if a v aila ble, f or all 
partici pa nts. A s o urce of arc hi val t u m or tiss ue s h o ul d be i de ntifie d at ti me of re gistrati o n 
(see Secti o n 9 f or m ore d etails). Partici pa nts m ust a gree t o a ma n dat or y re p eat bi o ps y 3- 6 
wee ks after starti n g treat me nt, if t u m or is safel y accessi ble. 
 
3. 1. 6
Pri or c he m ot hera p y: Partici pa nts ma y ha ve recei v e d 0- 1 pri or c he m ot hera p e utic re gi me ns 
f or metastatic breast ca ncer a n d m ust ha ve b ee n off treat me nt wit h c h e m ot hera p y f or at 
least 1 4 da ys pri or t o st u d y treat me nt i nitiati o n. If a pri or c h e m ot hera p y was gi ve n f or 
less t ha n 1 c ycle, it will n ot be c o u nte d as a pri or li ne. N o pri or iri n oteca n or 
t o p ois o merase I-c o ntai ni n g a nti b o d y dr u g c o nj u gates i n t he metastatic or n e o/a dj u va nt 
setti n g are all o we d. All t o xicities relate d t o pri or c he m ot hera p y m ust ha v e res ol ve d t o 
C T C A E v 5. 0 gra de 1 or l o wer, u nless ot her wise s pecifie d i n 3. 1. 1 5, e x ce pt al o pecia ca n 
be a n y gra d e a n d n e ur o p at h y ca n be gra de 2 or l o wer.  
3. 1. 7
Pri or bi ol o gic t hera p y: Patie nts m ust ha ve disc o nti n ue d all bi ol o gic t hera p y at least 1 4
da ys pri or t o st u d y treat me nt i nitiati o n. All t o xicities relate d t o pri or bi ol o gic t hera p y 
m ust ha ve res ol ve d t o C T C A E v 5. 0 gra de 1 or l o wer, u nless ot her wise s pecifie d i n 
3. 1. 1 5. 

                                                 
 
 
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2 3 
3. 1. 8
Pri or tar gete d t hera p y: T ar gete d t hera p y (e. g., pri or C D K 4/ 6 i n hi bit ors) m ust ha ve bee n 
All t o xicities rel ate d t o pri or 
tar gete d t hera p y m ust ha ve res ol ve d t o C T C A E v 5. 0 gra de 1 or l o wer, u nl ess ot her wise 
s pecifie d i n 3. 1. 1 5. 
 
3. 1. 9
Pri or i n vesti gati o nal a ge nts f or treat me nt of ca ncer: I n v esti gati o nal a ge nts m ust ha ve 
bee n disc o nti n ue d  1 4 d a ys pri or t o i nitiati o n of st u d y t hera p y. All t o xicities relate d t o 
pri or i n vesti gati o nal a ge nts m ust ha ve res ol ve d t o C T C A E v 5. 0 gra de 1 or l o wer, u nless 
ot her wise s pecifie d i n 3. 1. 1 5.  
 
3. 1. 1 0  Pri or ra diati o n t hera p y: P atie nts ma y ha ve recei v e d pri or ra diati o n t hera p y. Ra diati o n 
t hera p y m ust be c o m plet e d at least 7 da ys pri or t o t he i nitiati o n of st u d y treat me nt (at 
least 7 da ys f or S R S), a n d all t o xicities relate d t o pri or ra diati o n t hera p y m ust ha ve 
res ol ve d t o C T C A E v 5. 0 gra de 1 or l o wer, u nless ot her wise s pecifie d i n 3. 1. 1 5. A 1- wee k 
- C N S 
disease. 
 
3. 1. 1 1  Pre vi o usl y treate d brai n metastases are per mitte d, wit h t he f oll o wi n g pr o visi o ns: 
 
 
7 da ys bef ore st u d y treat me nt i nitiati o n. 
 A n y c ortic oster oi d use f or brai n metastas es m ust ha ve bee n disc o nti n ue d 
pri or t o st u d y treat me nt i nitiati o n. 
 
3. 1. 1 2  Partici pa nts o n bis p h os p h o nates or R A N K li ga n d i n hi bit ors ma y c o nti n ue recei vi n g 
t hera p y d uri n g st u d y treat me nt a n d als o ma y i nitiate t hera p y wit h t hese a ge nts o n st u d y if 
cli nicall y i n dicate d.  
 
3. 1. 1 3  T he s u bject is 
1 8 years ol d.  
 
3. 1. 1 4  E C O G perf or ma nce stat us 0- 1 ( Kar n ofs k y > 6 0 %, see A p pe n di x A). 
 
3. 1. 1 5  Partici pa nts m ust ha ve n or mal or ga n a n d m arr o w f u ncti o n as defi ne d b el o w:  
A bs ol ute ne utr o p hil c o u nt  
0 0 0/ mc L 
 
Platelets   
 
 
 
He m o gl o bi n  
 
 
I N R/ P T/a P T T 
 
a ntic oa g ula nt t hera p y as l o n g as P T or a P T T is  
i n t hera pe utic ra n ge of a ntic oa g ula nt 
 
T otal bilir u bi n  
 
Gil bert’s S y n dr o me) 
 
A S T( S G O T)/ A L T( S G P T)  
 
d oc u me nte d li ver metast ases 
 
Ser u m creati ni ne  
 

                                                 
 
 
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2 4 
3 0 m L/ mi n/ 1. 7 3 m 2 f or partici pa nts 
wit h creati ni ne le v els a b o ve i nstit uti o nal U L N. 
3. 1. 1 6  Fe male s u bjects of c hil d beari n g p ote ntial m ust ha ve a ne g ati ve ser u m or uri ne pre g na n c y 
test wit hi n 2 wee ks pri or t o st u d y treat me nt i nitiati o n.
C hil d beari n g p ote ntial is defi ne d as p artici pa nts w h o ha ve n ot reac he d a p ost me n o pa usal 
me n o pa use) a n d ha ve n ot u n der g o ne s ur gi cal sterilizati o n (re m o val of o v ari es a n d/ or 
uter us).  
3. 1. 1 7  W o me n of c hil d beari n g p ote ntial ( W O C B P) m ust a gree t o us e a n a d e q uate met h o d of 
c o ntrace pti o n. C o ntrace pti o n is re q uire d starti n g wit h t he first d ose of st u d y me dicati o n 
t hr o u g h 1 8 0 da ys ( 6 m o nt hs) after t he l ast d ose of st u d y me dicati o n. E xa m ples of
c o ntrace pti ve met h o ds wit h a fail ure rate of < 1 % per year i ncl u de bilateral t u bal li gati o n, 
male sterilizati o n, a n d c o p per i ntra uteri n e de vices. Peri o dic a bsti ne nce (e. g., cale n dar, 
o v ulati o n, s y m pt ot her mal, or p ost- o v ulati o n met h o ds) a n d wit h dra wal are n ot acce pt a ble 
met h o ds of c o ntrace pti o n. H or m o nal c o ntrace pti ves are c o ntrai n dicate d f or H R + breast 
ca ncer ( A p p e n di x B). 
 
3. 1. 1 8  Males w h o are se x uall y acti ve wit h W O C B P m ust a gree t o f oll o w i nstr ucti o ns f or 
met h o d(s) of c o ntrace pti o n f or t he d urati o n of st u d y treat me nt wit h pe m br oliz u ma b a n d 3 
m o nt hs after t he last d ose of st u d y treat me nt ( A p p e n di x B).
 
3. 1. 1 9  T he partici pa nt m ust be ca pa ble of u n d ersta n di n g a n d c o m pl yi n g wit h t he pr ot oc ol a n d 
willi n g t o si g n a writte n i nf or me d c o ns e nt d oc u me nt.  
 
3. 2  
E xcl usi o n Criteri a 
 
3. 2. 1  Pri or t hera p y wit h a n y a nti- P D- 1, P D- L 1, or P D- L 2 a ge nt or sacit uz u ma b g o viteca n 
(I M M U- 1 3 2). Pri or t hera p y wit h iri n oteca n or t o p ois o merase I-c o ntai ni n g a nti b o d y dr u g 
c o nj u gates at a n y ti me f or earl y sta g e or metastati c disease.  
 
3. 2. 2  Pri or h y perse nsiti vit y t o t he e xci pie nts of p e m br oliz u ma b or sacit uz u ma b g o viteca n 
(I M M U- 1 3 2) t hera p y.  
 
3. 2. 3  K n o w n hist or y of U D P- gl uc ur o n os yltra nsferase 1 A 1 ( U G T 1 A 1) * 2 8 allele 
h o m oz y g osit y, w hic h is ass ociate d wit h i ncrease d ris k f or ne utr o p e nia a n d diarr hea 
relate d t o iri n oteca n.8 6  
N ote: C o nc urre nt a d mi nistrati o n of str o n g U G T 1 A 1 i n hi bit ors or i n d ucers is n ot all o we d 
d uri n g t he c o urse of t he st u d y ( See Secti o n 5. 6. 2). 
 
3. 2. 4  K n o w n brai n metastas es t hat are u ntreate d, s y m pt o matic, or re q uire t hera p y t o c o ntr ol 
s y m pt o ms.  
 

                                                 
 
 
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2 5 
3. 2. 5
Partici pa nt has k n o w n le pt o me ni n geal disease.
 
3. 2. 6
Maj or s ur ger y wit hi n 2 wee ks pri or t o st u d y treat m e nt i nitiati o n. Patie nts m ust ha ve 
rec o vere d fr o m a n y effects of a n y maj or s ur ger y. 
3. 2. 7
U nc o ntr olle d, si g nifica nt i nterc urre nt or rece nt ill ness i ncl u di n g, b ut n ot li mite d t o, 
o n g oi n g or acti ve i nfecti o n, u nc o ntr olle d n o n- mali g na nt s yste mic disease, u nc o ntr olle d 
seiz ures, or ps y c hiatric ill ness/s ocial sit uati o n t hat w o ul d li mit c o m plia nce wit h st u d y 
re q uire me nts i n t he o pi ni o n of t he treati n g i n vesti gat or.  
3. 2. 8
Partici pa nt has a me dical c o n diti o n t hat re q uires c hr o nic s yste mic ster oi d t hera p y ( > 1 0 
m g of pre d nis o ne dail y or e q ui vale nt) or a n y ot her f or m of i m m u n os u p pressi ve 
me dicati o n (i ncl u di n g disease m o dif yi n g a g e nts) a n d has re q uire d s uc h t hera p y i n t he last 
2 years. Re place me nt t hera p y (e. g. t h yr o xi ne, i ns uli n, or p h ysi ol o gic c ortic oster oi d 
re place me nt t hera p y f or a dre nal or pit uitar y i ns ufficie nc y, et c.) is n ot c o nsi dere d a f or m 
of s yste mic t hera p y.  
 
3. 2. 9  Partici pa nt has d oc u me nt e d hist or y of a ut oi m m u ne disease or s y n dr o me t h at c urre ntl y 
re q uires s yste mic ster oi ds or i m m u n os u p pressi ve a ge nts.  
 
3. 2. 1 0  Hist or y of ( n o n-i nfecti o us) p ne u m o nitis/i nterstitial l u n g disease t hat re q uire d ster oi ds or 
c urre nt p n e u m o nitis/i nterstitial l u n g disease. 
 
3. 2. 1 1  I n di vi d uals wit h a hist or y of a sec o n d m ali g na nc y are i neli gi ble e x ce pt f or t he f oll o wi n g 
circ u msta nces. I n di vi d uals wit h a hist or y of ot her mali g na ncies are eli gi ble if t he y ha ve 
bee n diseas e-free f or at l east 3 years or are dee me d b y t he i n vesti gat or t o be at l o w ris k 
f or rec urre nce of t hat mali g na nc y. I n di vi d uals wit h t he f oll o wi n g ca ncers t h at ha ve bee n 
dia g n ose d a n d treate d wit hi n t he past 3 years are eli gi ble: cer vical/ pr ostate carci n o ma i n 
sit u, s u perficial bla d der ca ncer, n o n- mela n o ma ca ncer of t h e s ki n. Patie nts wit h ot her 
ca ncers dia g n ose d wit hi n t he past 3 years a n d felt t o be at l o w ris k of rec urre nce s h o ul d 
be disc usse d wit h t he st u d y pri nci pal i n vesti gat or t o deter mi ne eli gi bilit y.  
3. 2. 1 2  Partici pa nt has a k n o w n hist or y of h u ma n i m m u n o deficie nc y vir us ( HI V), He patitis B 
( defi ne d as He patitis B s urface a nti ge n [ H Bs A g] reacti ve) or k n o w n acti ve He patitis C 
vir us ( defi ne d as detect e d H C V R N A [ q ualitati ve]) i nfecti o n. HI V- p ositi ve partici pa nts 
are i neli gi ble d ue t o t he p ote ntial f or p har mac o ki n etic i nteracti o ns of c o m bi nati o n 
a ntiretr o viral t hera p y wit h st u d y dr u gs a n d t he i ncrease d ris k of fat al i nfecti o ns. N ote: N o 
testi n g f or HI V, H e patitis B, or He patitis C is re q uire d u nless ma n date d b y l ocal healt h 
a ut h orit y. 
 

                                                 
 
 
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2 6 
3. 2. 1 3  T he partici pa nt has recei ve d a li ve vacci ne wit hi n 2 8 da ys pri or t o st u d y treat me nt 
i nitiati o n. E xa m ples of li ve vacci nes i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g: 
measles, m u m ps, r u bella, varicella/z oster, yell o w fe ver, ra bies, B C G, a n d t y p h oi d 
vacci ne. T h e use of t h e i nacti vate d seas o nal i nfl u e nza v acci n e is all o we d.  
 
3. 2. 1 4  Has a hist or y or c urre nt e vi de nce of a n y c o n diti o n, t hera p y, or la b orat or y a b n or malit y 
t hat mi g ht c o nf o u n d t he res ults of t he st u d y, i nterfere wit h t he s u bject’s partici pati o n f or 
t he f ull d urati o n of t he st u d y, or is n ot i n t he best i nterest of t he s u bject t o partici pate, i n 
t he o pi ni o n of t he treati n g i n vesti gat or.   
 
3. 2. 1 5  It is u n k n o w n w h et her p e m br oliz u ma b is e xcret e d i n h u ma n mil k.  Si nce ma n y dr u gs are 
e xcret e d i n h u ma n mil k, a n d beca use of t he p ot e ntial f or seri o us a d v erse reacti o ns i n t he 
n ursi n g i nfa nt, partici pa nts w h o are breast-fee di n g are n ot eli gi ble f or e nr oll me nt. 
3. 3
Retre at me nt Eli gi bilit y Criteri a
 
I n a d diti o n t o t he a b o ve criteria asi de fr o m pri or treat me nt wit h sacit uz u ma b g o viteca n a n d 
pe m br oliz u ma b, t he f oll o wi n g eli gi bilit y criteria are re q uire d: 
 
3. 3. 1  T he partici pa nt st o p pe d i nitial treat me nt wit h sacit uz u ma b g o viteca n a n d/ or 
pe m br oliz u ma b aft er attai ni n g a n i n vesti gat or-assesse d C R acc or di n g t o R E CI S T 1. 1, 
c o nfir me d i n at least t w o c o nsec uti ve resta gi n g sca ns, was treate d f or at least 2 4 wee ks 
wit h pe m br oliz u ma b a n d/ or sacit uz u ma b g o viteca n bef ore disc o nti n ui n g t hera p y, a n d 
recei v e d at least t hree c y cles ( wit h pe m br oliz u ma b a n d sacit uz u ma b g o viteca n ( Ar m A) 
or sacit uz u ma b g o viteca n al o ne ( Ar m B)) be y o n d t he date w h e n t he i nitial C R was 
declare d. 
 
3. 3. 2  T he partici pa nt e x perie n ce d a n i n vesti gat or-assess e d or ra di o gra p hic disease pr o gressi o n 
after st o p pi n g t heir i nitial treat me nt wit h sacit uz u ma b g o viteca n a n d/ or p e m br oliz u ma b 
( Ar m A) or s acit uz u ma b g o viteca n ( Ar m B). 
 
3. 3. 3  T he partici pa nt di d n ot recei ve a n y a nti-ca n cer treat me nt ot her t ha n sacit uz u ma b 
g o viteca n ( or p e m br oliz u ma b) si nce t he last d ose of pe m br oliz u ma b ( or sacit uz u ma b 
g o viteca n) f or Ar m A; t h e partici pa nt di d n ot recei ve a n y a nti-ca ncer treat me nt si nce t he 
last d ose of sacit uz u ma b g o viteca n f or Ar m B. 
 
3. 3. 4  Partici pa nts m ust a gree t o u n der g o a researc h bi o ps y, if t u m or is safel y accessi ble, pri or 
t o retreat me nt. Partici p a nts m ust a gree t o a ma n dat or y re peat bi o ps y at t he ti me of disease 
pr o gressi o n o n retreat me nt, 
m o nt hs was ac hie ve d d uri n g t he retreat me nt p hase.  
 
3. 3. 5
Pri or ra diati o n t hera p y: P atie nts ma y ha ve recei v e d pri or ra diati o n t hera p y. Ra diati o n 
t hera p y m ust be c o m plet e d at least 7 da ys pri or t o retreat me nt i nitiati o n (at least 7 da ys 
f or S R S), a n d all t o xicities relate d t o pri or ra diati o n t hera p y m ust ha ve res ol ve d t o 
C T C A E v 5. 0 gra de 1 or l o wer, u nless ot her wise s pecifie d i n 3. 3. 8. 
 

                                                 
 
 
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2 7 
3. 3. 6
Sta ble, pre vi o usl y treate d brai n metastases are p er mitte d, wit h t he f oll o wi n g pr o visi o ns: 
 
 
 
7 da ys bef ore st u d y treat me nt i nitiati o n 
A n y c ortic oster oi d use f or brai n metastas es m ust ha ve bee n disc o nti n ue d
pri or t o retreat me nt i nitiati o n.
 
3. 3. 7  E C O G perf or ma nce stat us 0- 1 ( Kar n ofs k y > 6 0 %, see A p pe n di x A). 
 
3. 3. 8  Partici pa nts m ust ha ve n or mal or ga n a n d m arr o w f u ncti o n as defi ne d b el o w:  
 
A bs ol ute ne utr o p hil c o u nt 
0 0 0/ mc L 
 
Platelets  
 
 
He m o gl o bi n 
 
I N R/ P T/a P T T 
 
a ntic oa g ula nt t hera p y as l o n g as P T or a P T T is  
i n t hera pe utic ra n ge of a ntic oa g ula nt 
 
T otal bilir u bi n  
 
Gil bert’s S y n dr o me) 
 
A S T( S G O T)/ A L T( S G P T)  
 
d oc u me nte d li ver metast ases 
 
Ser u m creati ni ne  
 
3 0 m L/ mi n/ 1. 7 3 m 2 f or partici pa nts 
wit h creati ni ne le v els a b o ve i nstit uti o nal U L N. 
3. 3. 9
Fe male s u bjects of c hil d beari n g p ote ntial m ust ha ve a ne g ati ve ser u m or uri ne pre g na n c y 
test wit hi n 2 wee ks pri or t o st u d y treat me nt i nitiati o n.
C hil d beari n g p ote ntial is defi ne d as: partici pa nts w h o ha ve n ot reac h e d a p ost me n o pa usal 
me n o pa use) a n d ha ve n ot u n der g o ne s ur gi cal sterilizati o n (re m o val of o v ari es a n d/ or 
uter us).  
3. 3. 1 0  W o me n of c hil d beari n g p ote ntial ( W O C B P) m ust a gree t o us e a n a d e q uate met h o d of 
c o ntrace pti o n. C o ntrace pti o n is re q uire d starti n g wit h t he first d ose of st u d y me dicati o n 
t hr o u g h 1 8 0 da ys ( 6 m o nt hs) after t he l ast d ose of st u d y me dicati o n. E xa m ples of
c o ntrace pti ve met h o ds wit h a fail ure rate of < 1 % per year i ncl u de bilateral t u bal li gati o n, 
male sterilizati o n, esta blis he d a n d pr o per use of h or m o nal c o ntrace pti ves t hat i n hi bit 
o v ulati o n, h or m o ne-releasi n g i ntra uteri ne de vices, a n d c o p per i ntra uteri ne de vices. 
Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt ot her mal, or p ost- o v ulati o n met h o ds) 
a n d wit h dra w al are n ot acce pta bl e met h o ds of c o ntrace pti o n ( A p p e n di x B).  
 

                                                 
 
 
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2 8 
3. 3. 1 1  Males w h o are se x uall y acti ve wit h W O C B P m ust a gree t o f oll o w i nstr ucti o ns f or 
met h o d(s) of c o ntrace pti o n f or t he d urati o n of st u d y treat me nt wit h pe m br oliz u ma b a n d 3 
m o nt hs after t he last d ose of st u d y treat me nt ( A p p e n di x B).  
3. 3. 1 2  Partici pa nts o n bis p h os p h o nates or R A N K li ga n d i n hi bit ors ma y c o nti n ue recei vi n g 
t hera p y d uri n g st u d y treat me nt a n d als o ma y i nitiate t hera p y wit h t hese a ge nts o n st u d y if 
cli nicall y i n dicate d.  
 
3. 4  
Retre at me nt E xcl usi o n Criteri a 
 
3. 4. 1  Maj or s ur ger y wit hi n 2 wee ks pri or t o st u d y treat m e nt i nitiati o n. Patie nts m ust ha ve 
rec o vere d fr o m a n y effects of a n y maj or s ur ger y.  
 
3. 4. 2  U nc o ntr olle d, si g nifica nt i nterc urre nt or rece nt ill ness i ncl u di n g, b ut n ot li mite d t o, 
o n g oi n g or acti ve i nfecti o n, u nc o ntr olle d n o n- mali g na nt s yste mic disease, u nc o ntr olle d 
seiz ures, or ps y c hiatric ill ness/s ocial sit uati o n t hat w o ul d li mit c o m plia nce wit h st u d y 
re q uire me nts i n t he o pi ni o n of t he treati n g i n vesti gat or.  
 
3. 4. 3  F or patie nts recei vi n g retreat me nt wit h pe m br oliz u ma b: Partici pa nt has a me dical 
c o n diti o n t hat re q uires c hr o nic s yste mic ster oi d t hera p y ( > 1 0 m g of pre d nis o ne dail y or 
e q ui vale nt) or a n y ot her f or m of i m m u n os u p pressi ve me dicati o n (i ncl u di n g disease 
m o dif yi n g a ge nts) a n d has re q uire d s uc h t h era p y i n t he last 2 years. Re place me nt t hera p y 
(e. g. t h yr o xi ne, i ns uli n, or p h ysi ol o gic c ortic oster oi d re place m e nt t hera p y f or a dre n al or 
pit uitar y i ns ufficie nc y, et c.) is n ot c o nsi dere d a f or m of s yste mic t hera p y.  
3. 4. 4
F or patie nts recei vi n g retreat me nt wit h pe m br oliz u ma b: Partici pa nt has d o c u me nte d 
hist or y of a ut oi m m u ne disease or s y n dr o me t hat c urre ntl y re q uires s yste mic ster oi ds or 
i m m u n os u p pressi ve a ge nts.  A hist or y of a ut oi m m u ne disease relate d t o pri or c hec k p oi nt 
i n hi bit or t hera p y is per mitte d o n a case- b y-case b asis u p o n re vie w b y t he pri nci pal 
i n vesti gat or.8 7
3. 4. 5
Hist or y or e vi de nce of acti ve, n o n-i nfecti o us p ne u m o nitis or i nterstitial l u n g disease. A 
hist or y of p ne u m o nitis relate d t o pri or c hec k p oi nt i n hi bit or t hera p y is per mitte d o n a 
case- b y-cas e basis u p o n re vie w b y t he pri nci p al i n vesti gat or. 8 7  
3. 4. 6
It is u n k n o w n w h et her p e m br oliz u ma b is e xcret e d i n h u ma n mil k.  Si nce ma n y dr u gs are 
e xcret e d i n h u ma n mil k, a n d beca use of t he p ot e ntial f or seri o us a d v erse reacti o ns i n t he 
n ursi n g i nfa nt, partici pa nts w h o are breast-fee di n g are n ot eli gi ble f or e nr oll me nt. 
 
3. 4. 7
T he partici pa nt has recei ve d a li ve vacci ne wit hi n 2 8 da ys pri or t o st u d y treat me nt 
i nitiati o n. E xa m ples of li ve vacci nes i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g: 
measles, m u m ps, r u bella, varicella/z oster, yell o w fe ver, ra bies, B C G, a n d t y p h oi d 
vacci ne. T h e use of t h e i nacti vate d seas o nal i nfl u e nza v acci n e is all o we d. 
3. 5
I ncl usi o n of W o me n a n d Mi n orities

                                                 
 
 
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B ot h me n a n d w o me n of all races a n d et h nic gr o u ps are eli gi ble f or t his trial.  
4
R E GI S T R A TI O N A N D R A N D O MI Z A TI O N P R O C E D U R E S
4. 1
Ge ner al G ui deli nes f or D F/ H C C I nstit uti o ns
 
D F/ H C C I nstit uti o ns will re gister eli gi ble partici pa nts i n t he Cli nical Trials Ma na ge me nt S yste m 
( C T M S) O n C ore. Re gistrati o ns m ust occ ur pri or t o t he i nitiati o n of a n y pr ot oc ol-s pecific t hera p y 
or i nter ve nti o n. A n y parti ci pa nt n ot re gistere d t o t h e pr ot oc ol bef ore pr ot o c ol-s pecific t hera p y or 
i nter ve nti o n be gi ns will be c o nsi dere d i neli gi ble a n d re gistrati o n will be d e nie d. A n i n vesti gat or 
will c o nfir m eli gi bilit y criteria a n d a me m b er of t h e st u d y tea m will c o m plete t he pr ot oc ol-
s pecific eli gi bilit y c hec klist.  
 
T he eli gi bilit y c hec klist(s) a n d all pa ges of t he c o nse nt f or m(s) will be e m aile d t o t he Office of 
Data Q ualit y ( O D Q) at q act @ part n ers. or g. T h e O D Q will (a) re vie w t he eli gi bilit y c hec klist, ( b) 
re gister t he partici pa nt o n t he pr ot oc ol, a n d (c) ra n d o mize t he partici pa nt.  Ra n d o mizati o n ca n 
o nl y occ ur d uri n g O D Q b usi ness h o urs ( 8: 3 0a m - 5 p m Easter n Ti me, M o n da y t hr o u g h Fri d a y 
e xcl u di n g h oli da ys). A n e mail c o nfir mati o n of t he re gistrati o n a n d/ or ra n d o mizati o n will be se nt 
t o t he S p o ns or-I n v esti gat or, st u d y c o or di nat or(s) fr o m t he Lea d Site, treati n g i n vesti gat or a n d 
re gisteri n g pers o n i m me diatel y f oll o wi n g ra n d o mizati o n. 
 
F oll o wi n g re gistrati o n, p artici pa nts ma y be gi n pr ot oc ol-s pecific t hera p y a n d/ or i nter ve nti o n. 
Iss u es t hat w o ul d ca us e treat me nt dela ys s h o ul d b e disc usse d wit h t he S p o ns or-I n vesti gat or. If 
t he s u bject d oes n ot recei ve pr ot oc ol t hera p y f oll o wi n g re gistrati o n, t he s u bject m ust be ta ke n 
off-st u d y i n t he C T M S ( O n C ore) wit h a n a p pr o priate date a n d reas o n e ntere d.   
 
4. 2  
Re gistr ati o n Pr o cess f o r D F/ H C C I nstit uti o ns
 
A p plica ble D F/ H C C p olic y ( R E GI S T- O P- 1) m ust be f oll o we d.   
 
4. 3
Ge ner al G ui deli nes f or Ot her I n vesti g ati ve Sites 
 
Eli gi ble partici pa nts will be e ntere d o n st u d y ce ntrall y at t he Da na- Far ber Ca ncer I nstit ute  
t hr o u g h t he Pr oject Ma na ger.  Sites ma y e mail t he Pr oject Ma na ger t o verif y sl ot le vel 
a vaila bilities.  T he re q uire d f or ms i n Secti o n 4. 4 s h o ul d be e maile d t o t he Pr oject Ma na g er. 
F oll o wi n g re gistrati o n, p artici pa nts s h o ul d be gi n pr ot oc ol t hera p y wit hi n 7 da ys. Iss ues t hat 
w o ul d ca use treat me nt dela ys s h o ul d be disc usse d wit h t he S p o ns or-I n v esti gat or.  If t he s u bject 
d oes n ot recei ve pr ot oc ol t hera p y f oll o wi n g re gistrati o n, t he s u bject m ust be ta ke n off st u d y i n 
t he C T M S ( O n C ore) wit h a n a p pr o pri ate date a n d reas o n e nt ere d.   
 
4. 4  
Re gistr ati o n Pr o cess f o r Ot her I n vesti g ati ve Sites 
 
T o re gister a p artici pa nt, t he f oll o wi n g d oc u me nts s h o ul d be c o m plete d b y t he partici pati n g site 
a n d e maile d t o t he Pr oject Ma na ger at C T O P M @ dfci. har v ar d.e d u : 
 C o m plete d D F/ H C C Eli gi bilit y C hec klist 

                                                 
 
 
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3 0 
 Si g ne d partici pa nt c o nse nt f or m 
HI P A A a ut h orizati o n f or m (if se parate fr o m t he m ai n c o nse nt f or m)
Re q uire d la b orat or y test res ults i ncl u di n g He mat ol o g y ( C B C wit h differe ntial), ser u m 
c he mistries (creati ni ne a n d/ or creati ni ne cleara nce, bilir u bi n, A L T a n d A S T, ma g nesi u m 
a n d p h os p h or o us), t h yr oi d f u ncti o n tests, c oa g ulati o n, a n d pre g na n c y test (if a p plica ble)  
T u m or Assess me nts ( C T/ C A P, M RI)
Pat h ol o g y re p ort c o nfir mi n g dia g n osis a n d E R, P R, a n d H E R 2 stat us 
Stat us of re q uire d researc h bi o ps y 
Cli nic visit n ote d oc u me nti n g me dical hist or y, p h ysical e xa m, vital si g ns, a n d E C O G 
T o c o m plete t he re gistrati o n pr ocess, t he Pr oject Ma na ger will: 
F oll o w t he D F/ H C C Sta n dar d O perati n g Pr oce d ure f or H u ma n S u bject Researc h Title d 
S u bject Pr ot oc ol Re gistr ati o n ( S O P #: R E GI S T- O P- 1) a n d re gister t he partici pa nt o n t he 
pr ot oc ol 
E mail t he st u d y tea m at t he partici pati n g site wit h t he partici pa nt st u d y n u m ber, treat me nt 
assi g n me nt a n d t o c o nfir m re gistrati o n/ra n d o mizati o n
 
N O T E: P a rti ci p a nts M U S T b e r e gist e r e d a n d r a n d o mi z e d p ri o r t o t h e st a rt of p r ot o c ol 
t r e at m e nt. R e gistr ati o n a n d r a n d o miz ati o n c a n o nl y be c o n d ucte d d uri n g t he b usi ness 
h o urs of 8: 0 0 A M a n d 5: 0 0 P M E aster n Ti me M o n d a y t hr o u g h Fri d a y . Sa me da y treat me nt 
re gistrati o ns will o nl y be acce pte d wit h pri or n otice a n d disc ussi o n wit h t he D F/ H C C Pr oject 
Ma na ger. 
5
T R E A T M E N T P L A N 
5. 1
Tre at me nt Re gi me n
 
T his is a n o pe n-la bel, ra n d o mize d, p hase II st u d y of sacit uz u ma b g o viteca n 1 0 m g/ k g I V o n d a ys 
1 a n d 8 of eac h 2 1- d a y c ycle a n d pe m br oliz u m a b 2 0 0 m g I V o n d a y 1 of eac h 2 1- da y c ycle.  O ne 
h u n dre d a n d te n p artici pa nts will be e nr olle d i n t he st u d y t o c o m pare t he efficac y of t he 
c o m bi nati o n t o sacit uz u ma b g o viteca n al o n e, as defi ne d b y P F S, i n patie nts wit h H R + / H E R 2- 
M B C.  
Treat me nt will be a d mi nistere d o n a n o ut patie nt b asis. F or patie nts ra n d o mize d t o c o m bi nati o n 
t hera p y o n Ar m A, s acit u z u ma b g o viteca n will be a d mi nistere d pri or t o pe m br oliz u ma b as 
s h o w n bel o w. T he ti me i nter val bet wee n t he e n d of t he sacit uz u ma b g o vit eca n i nf usi o n a n d t h e 
start of t he start of t he p e m br oliz u ma b i nf usi o n s h o ul d be d oc u me nte d eac h ti me. Re p orte d 
a d verse e ve nts a n d p ote ntial ris ks are descri be d i n Secti o n 7. A p pr o priate d ose m o dificati o ns are 
descri be d i n Secti o n 6. N o i n vesti gati o nal or c o m mercial a g e nts of t hera pies ot her t ha n t h ose 
descri be d b el o w ma y be a d mi nistere d wit h t he i nte nt t o treat t he partici p a nt’s mali g na nc y. 
Sacit uz u ma b g o viteca n (I M M U- 1 3 2, Tr o del v y ™), 
 
Pe m br oliz u ma b ( M K- 3 4 7 5; Ke ytr u da T M), 
  

                                                 
 
 
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3 1 
Re gi me n Descri pti o n
A ge nt
Pre me dic ati o n; 
Prec a uti o ns
D ose
R o ute
Sc he d ule
C ycle 
le n gt h
I nf usi o n
O bser v ati o n 
peri o d p ost-
i nf usi o n
Ar m A
Sacit uz u ma b 
g o viteca n
(I M M U- 1 3 2)
A nti p yretics, H 1 a n d 
H 2 bl oc kers, 5- H T 3 
or N K 1 rece pt or
a nta g o nist ( See 
Secti o n 5. 3)
1 0 m g/ k g
I V
Da ys 1 
a n d 8
2 1 da ys
( 3 wee ks)
Sl o w i nf usi o n 
( See Secti o n 
5. 3) 
3 0 mi n  
( +/- 1 0 mi n) 
after 1 st d ose; 
per i nstit uti o nal 
g ui deli nes f or 
s u bse q ue nt 
d oses
Pe m br oliz u ma b 
( M K- 3 4 7 5; 
Ke ytr u da T M) 
N ot r o uti nel y 
necessar y u nless 
pri or i nf usi o n 
reacti o n
2 0 0 m g 
I V  
Da y 1 
2 1 da ys 
( 3 wee ks) 
O ver 3 0 mi n 
( +/- 1 0 mi n)
3 0 mi n  
( +/- 1 0 mi n)
Ar m B  
 
 
Sacit uz u ma b 
g o viteca n
(I M M U- 1 3 2)
A nti p yretics, H 1 a n d 
H 2 bl oc kers,  5- H T 3 
or N K 1 rece pt or
a nta g o nist ( See 
Secti o n 5. 3)
1 0 m g/ k g
I V
Da ys 1 
a n d 8
2 1 da ys
( 3 wee ks)
Sl o w i nf usi o n 
( See Secti o n 
5. 3) 
3 0 mi n  
( +/- 1 0 mi n) 
after 1 st d ose;
per i nstit uti o nal 
g ui deli nes f or 
s u bse q ue nt 
d oses
5. 2
Pre- Tre at me nt Criteri a
 
5. 2. 1  C ycle 1, Da y 1 
 
Partici pa nts d o n ot nee d t o re- meet eli gi bilit y criteria o n C ycle 1, Da y 1.
 
 
A bs ol ute ne utr o p hil c o u nt  
1, 0 0 0/ mc L
 
Platelets  
1 0 0, 0 0 0/ mc L
 
T otal bilir u bi n
 
 
 
 
S y n dr o me) 
 
A S T( S G O T)/ A L T( S G P T)
 partici pa nts wit h d oc u m e nte d li ver metastas es 
 
Creati ni ne
 
3 0 
m L/ mi n/ 1. 7 3 m 2 f or partici pa nts wit h creati ni ne le vels 
a b o ve i nstit uti o nal U L N. 
 
 

                                                 
 
 
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3 2 
5. 2. 2
Da y 8 a n d D a y 1 of s u bs e q ue nt c ycl es
 
A bs ol ute ne utr o p hil c o u nt
1, 0 0 0/ mc L
 
Platelets  
7 5, 0 0 0/ mc L
 
T otal bilir u bi n 
 
 
wit h d oc u me nte d Gil bert’s S y n dr o me)
A S T( S G O T)/ A L T( S G P T)
partici pa nts wit h d oc u me nte d li ver metastases
 
Creati ni ne
 
 
 
m L/ mi n/ 1. 7 3 m 2 f or partici pa nts wit h creati ni ne le vels 
a b o ve i nstit uti o nal U L N. 
Please see Secti o n 6 re gar di n g d ose dela ys a n d dis c o nti n uati o n.  
5. 3
A ge nt A d mi nistr ati o n 
5. 3. 1
Pre ve ntati ve Me dicati o ns 
I nf usi o n- Relate d Reacti o ns: Pre me dicati o n f or pre ve nti o n of i nf usi o n-relate d reacti o ns wit h 
a nti p yretics a n d H 1 a n d H 2 bl oc kers s h o ul d be a d mi nistere d bef ore eac h sacit uz u ma b g o viteca n
i nf usi o n. C ortic oster oi ds ( h y dr oc ortis o ne 5 0 m g or e q ui vale nt P O or I V) ma y be a d mi nistere d 
pri or t o s u bse q ue nt i nf usi o ns if t he s u bject ha d e x perie nce d a n i nf usi o n-relate d reacti o n wit h a 
pre vi o us i nf usi o n. A d diti o nal details of rec o m me n de d treat me nt of i nf usi o n-relate d reacti o ns are 
descri be d i n Secti o n 6. 3. 1.
Na usea, V o miti n g: Sacit uz u ma b g o viteca n is c o nsi dere d t o b e hi g hl y e met o ge nic. Pre me di cati o n 
wit h a 2- dr u g a ntie metic re gi me n is rec o m me n de d. If na us ea a n d v o miti n g are p ersiste nt, a 3- dr u g 
re gi me n ma y be use d, i ncl u di n g a 5- H T 3 i n hi bit or ( o n da nsetr o n or pal o n osetr o n, or ot her a ge nts 
acc or di n g t o l ocal practices), a n N K 1-rece pt or a nta g o nist (f osa pre pita nt or a pre pita nt), a n d 
de xa met has o ne ( 1 0 m g P O or I V). A ntici pat or y na usea ca n b e treate d wit h ola nza pi ne. T h e 
rec o m me n de d treat me nt of dela ye d n a usea a n d v o miti n g is descri be d i n Secti o n 6. 3. 2. 
 
5. 3. 2  Pe m br oliz u ma b 
 
Pe m br oliz u ma b will be a d mi nistere d b y trai ne d m e dical pers o n n el at t he i n vesti gati o nal site.  
Treat me nt c o m plia nce will be m o nit ore d t hr o u g h d oc u me ntati o n of st u d y treat me nt 
a d mi nistrati o n i n t he s u bject’s me dical rec or d. 
 
Pe m br oliz u ma b will be a d mi nistere d i n cli nic o n da y 1 ( +/- 4 d a ys) of eac h c ycle. It will be 
a d mi nistere d as a 3 0- mi n ute I V i nf usi o n.  Sites s h o ul d ma ke e ver y eff ort t o tar get i nf usi o n 
ti mi n g t o be as cl ose t o 3 0 mi n utes as p ossi ble.  H o we ver, gi ve n t he vari a bilit y of i nf usi o n 
p u m ps fr o m site t o site, a wi n d o w of - 1 0 mi n utes a n d + 1 0 mi n utes is per mitte d (i.e., i nf usi o n 
ti me is 2 0- 4 0 mi n). 
 

                                                 
 
 
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3 3 
Sacit uz u ma b g o viteca n i nf usi o n a n d o bser vati o n peri o d after sacit uz u m a b g o viteca n s h o ul d be 
c o m plete d pri or t o t he a d mi nistrati o n of pe m br oliz u ma b w he n b ot h dr u gs are a d mi nistere d o n 
t he sa me da y of eac h c ycle.  T here s h o ul d be n o o verla p i n ti mi n g of t he t w o a d mi nistrati o ns. 
C o m pleti o n of 3 5 treat me nts (a p pr o xi matel y 2 years) wit h pe m br oliz u ma b re q uires st o p pi n g 
pe m br oliz u ma b.   T he n u m ber of treat me nts is cal c ulate d starti n g wit h t he first d ose.  
5. 3. 3
Sacit uz u ma b g o viteca n 
Sacit uz u ma b g o viteca n is a d mi nistere d i ntra ve n o usl y as a sl o w i nf usi o n as descri b e d bel o w. D o 
n ot a d mi nister it as a n I V p us h or b ol us. 
I ntra ve n o us access m ust be well est a blis he d pri or t o i nitiati n g i nf usi o n. Sacit uz u ma b g o viteca n 
ma y be a d mi nistere d via a peri p heral or ce ntral li ne. At t he ti me of d osi n g, t he I V li ne will be 
c o n necte d t o a n i nf usi o n c o ntai ner c o ntai ni n g t h e pre p are d v ol u me of sacit uz u ma b g o viteca n. 
Eit her gra vit y or a n i nf usi o n p u m p ma y be use d. O nl y n or mal sali ne s h o ul d be use d as t he i nf usi o n 
base s ol uti o n, si nce t he c o m pati bilit y of sacit uz u ma b g o viteca n wit h ot her i nf usi o n dil ue nts has 
n ot bee n deter mi ne d. 
T he i nitial i nf usi o n s h o ul d pr ocee d sl o wl y. A d mi nister t he first i nf usi o n o ver 3 h o urs ( +/- 1 0 
mi n utes). F or t he first i nf usi o n, m o nit or t he patie nt d uri n g t he i nf usi o n a n d f or at least 3 0 mi n utes 
after i nf usi o n. S u bse q ue nt i nf usi o ns ma y be a d mi nistere d o ver 1- 2 h o urs if pre vi o us i nf usi o ns 
were well t olerate d, a n d p atie nt ma y be m o nit ore d per i nstit uti o nal g ui deli nes. N o s pecific i nf usi o n 
rate is pres cri be d, t he c o n d uct of t he i nf usi o n m ust be patie nt s pecific d eter mi ne d as a p pr o priate 
b y t he ma na gi n g p h ysici a n. T he i ntra v e n o us li ne s h o ul d be fl us he d sl o wl y wit h 2 0 m L n or mal 
sali ne a n d t he e n d of i nf usi o n ti me rec or de d. I n t he e ve nt of i nf usi o n reacti o ns or vital si g n c ha n ges, 
t he i nf usi o n rate ma y be sl o we d, i nterr u pte d or ter mi nate d, as c o nsi dere d a p pr o priat e b y t he 
ma na gi n g p h ysicia n. 
5. 4
Defi niti o n of D ose- Li miti n g T o xicit y ( D L T)  
We will perf or m a safet y r u n-i n a nal ysis o n t he first 1 2 partici pa nts e nr olle d t o t he c o m bi nati o n 
ar m of t he trial. If t here are 4 or m ore d ose-li miti n g t o xicit y ( D L Ts) i n t he first 1 2 partici pa nts, 
e nr oll me nt will be halte d t o disc uss w het her t he st u d y will be a me n de d, wit h re-e v al uati o n of t he 
a p pr o priate d osi n g sc h e d ule a n d st u d y desi g n or cl ose d. 
Gra de 1 ma y dr o p t o a l o wer d ose of sacit uz u ma b g o viteca n ( Secti o n 6. 3, T a ble 6) a n d c o nti n ue 
treat me nt at t he discreti o n of t he treati n g p h ysicia n. 
 
A D L T is defi ne d as a n I P-relate d A E(s) (attri b ute d t o pe m br oliz u ma b a n d/ or t he c o m bi nati o n of 
pe m br oliz u ma b pl us sacit uz u ma b g o viteca n) occ urri n g d uri n g t he D L T assess me nt peri o d (t he 
first 2 1- da y c ycle of c o nc urre nt sacit uz u ma b g o viteca n a n d pe m br oliz u ma b), if j u d ge d b y t he 
i n vesti gat or t o be p ossi bl y, pr o ba bl y, or d efi nitel y relate d t o st u d y dr u g a d mi nistrati o n, t hat meets 
o ne of t he f oll o wi n g criteria: 
 
 A n y gra de 5 t o xicit y 
 Gra de 3 t hr o m b o c yt o pe nia if ass ociate d wit h cli ni call y si g nifica nt blee di n g re q uiri n g 

                                                 
 
 
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me dical i nter ve nti o n or  
 Gra de 4 t hr o m b o c yt o pe nia of a n y d urati o n 
 Gra de 4 n e utr o pe nia l asti n g 
 7 da ys after a p pr o priate a d mi nistrati o n of G- C S F 
3 fe brile n e utr o p e nia
 1 4 da ys, u nless dee me d b y t he 
i n vesti gat or t o be cli nicall y i nsi g nifica nt 
metastases
Gra de 2 bilir u bi n ele v ati o n (e xce pt bilir u bi n > 3 x U L N i n patie nts wit h d oc u me nte d 
Gil bert´s s y n dr o me) 
Cases of H y’s L a w
- he mat ol o gic t o xicit y: 
E xcl u di n g: 
cli nicall y c o m plicate d, a n d res ol ve s p o nta ne o usl y or res p o n d t o 
c o n ve nti o nal me dical i nt er ve nti o ns  
 t hat lasts < 7 2 h o urs, are n ot cli nicall y 
c o m plicate d, a n d res ol ve s p o nta ne o usl y or res p o n d t o c o n ve nti o nal 
me dical i nter ve nti o ns 
 
cli nical ma nifestati o ns of pa ncreatitis 
Gra de 3 or 4 l y m p h o pe nia t hat is n ot ass ociate d wit h s y m pt o ms or cli nical 
c o m plicati o ns
Gra de 3 n a usea/ v o miti n g or diarr hea < 7 2 h o urs wit h a de q uate a ntie metic 
a n d ot her s u p p orti ve care       
Gra de 3 fati g ue < 7 d a ys
Al o pecia of a n y gra d e 
 A n y Gra d e 2 treat me nt-relate d p ne u m o nitis or i nterstitial l u n g disease t hat di d n ot res ol ve 
wit h
 Gra de 1 wit hi n 1 4 da ys. 
> Gra d e 3 ot her n o n-la b orat or y t o xicit y lasti n g > 5 da ys des pite o pti mal s u p p orti ve care, 
e xcl u di n g al o peci a of a n y gra de 
Ma na ge me nt a n d d os e m o dificati o ns ass ociate d wit h t he a b o ve a d verse e v e nts are o utli ne d i n 
Secti o n 6. 
5. 5
Defi niti o n of P ote nti al Dr u g I n d uce d Li ver I nj ur y ( DI LI) 
Defi niti o n of dr u g i n d uce d li ver i nj ur y ( DI LI) criteria is ma n dat or y f or all pre- mar k ete d ass et 
pr ot oc ols e nr olli n g partici pa nts wit h o ut k n o w n a b n or malities i n li ver f u ncti o n at baseli ne A N D f or 
pr ot oc ols i n v ol vi n g partici pa nts wit h k n o w n li ver a b n or malities at b aseli n e or wit h ot her cli nical 
c o nf o u n ders w h ere ass et s pecific criteria f or p ote ntial dr u g i n d uce d li ver i nj ur y ha ve bee n defi ne d. 
All occ urre nces of p ote ntial DI LIs, meeti n g t he d efi ne d criteri a, m ust be re p orte d as S A Es. 
I n p artici pa nts wit h o ut k n o w n a b n or malities i n li ver f u ncti o n at b aseli ne, p ote ntial DI LI is 
defi ne d as:
1)      A L T or A S T el e vati o n > 3 ti mes u p per li mit of n or mal ( U L N) 

                                                 
 
 
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A N D
2)      T otal bilir u bi n > 2 ti mes U L N, wit h o ut i nitial fi n di n gs of c h olestasis (ele vate d ser u m 
al kali ne p h os p hatase) 
A N D
3)      N o ot her i m me diat el y a p pare nt p ossi ble ca uses of A S T or A L T ele vati o n a n d 
h y per bilir u bi ne mia, i ncl u di n g, b ut n ot li mite d t o, viral he patitis, pre-e xisti n g c hr o nic or ac ute 
li ver disease, or t h e a d mi nistrati o n of ot her dr u g(s) k n o w n t o be he p at ot o xic. 
I n p artici pa nts wit h k n o w n a b n or malities i n li ver f u ncti o n at baseli ne (e. g., li ver metastases), or 
wit h ot her cli nical c o nf o u n ders (e. g., Gil bert´s disease), p ot e ntial DI LI is d efi ne d as:
1)      A L T or A S T el e vati o n > 5 ti mes u p per li mit of n or mal ( U L N) 
A N D 
2)      T otal bilir u bi n > 3 ti mes U L N, wit h o ut i nitial fi n di n gs of c h olestasis (ele vate d ser u m 
al kali ne p h os p hatase) 
A N D 
3)      N o ot her i m me diat el y a p pare nt p ossi ble ca uses of i ncrease i n A S T or A L T ele vati o n a n d 
h y per bilir u bi ne mia, i ncl u di n g, b ut n ot li mite d t o, viral he patitis, pre-e xisti n g c hr o nic or ac ute 
li ver disease, or t h e a d mi nistrati o n of ot her dr u g(s) k n o w n t o be he p at ot o xic.
 
5. 6  
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p orti ve C are G ui deli nes
5. 6. 1
C o nc o mita nt Me dicati o n G ui deli nes  
Me dicati o ns or vacci nati o ns s pecificall y pr o hi bite d i n t he e xcl usi o n criteria ( 3. 2. 1 3) are n ot 
all o we d d uri n g t he o n g oi n g trial.  If t here is a cli nical i n dicati o n f or o ne of t hese or ot her 
me dicati o ns or vacci nati o ns s pecificall y pr o hi bit e d d uri n g t he trial, disc o nti n uati o n fr o m trial 
t hera p y ma y be re q uire d.  T he i n vesti gat or s h o ul d disc uss a n y q uesti o ns re gar di n g t his wit h t he 
S p o ns or-I n v esti gat or. 
 
Acce pt a ble C o nc o mita nt Me dicati o ns
All treat me nts t hat t he i n vesti gat or c o nsi ders necess ar y f or a s u bject’s welfare ma y be a d mi nistere d 
at t he discreti o n of t he i n vesti gat or i n kee pi n g wit h t he c o m m u nit y sta n dar ds of me dical care a n d 
d oc u me nte d i n t he me dical rec or d. All pri or treat me nt or me dicati o n a d mi nistere d d uri n g t he 2 8 
da ys prece di n g t he first d ose of trial treat me nt a n d a n y c o nc o mita nt t hera p y a d mi nistere d t o t he 
s u bject t hr o u g h o ut t he st u d y u ntil 3 0 da ys aft er t he last d ose of trial treat me nt, i ncl u di n g 
me dicati o n na me a n d i n dicati o n, will be rec or de d i n t he e C R Fs.  
Palliati ve a n d/ or s u p p orti ve me dicati o ns, s uc h as pai n me dicati o ns, b o ne- m o dif yi n g me dicati o ns 
( bis p h os p h o nates or d e n os u ma b), a nti-e m etics or a nti- diarr heal m e dicati o ns, tra nsf usi o ns a n d 
gr o wt h fact or s u p p ort are all o we d at t he i n vesti gat or’s discreti o n. Palliati ve ra di ot hera p y is 
per mitte d, b ut prese nce of ne w or w orse ni n g metastases will be c o nsi dere d pr o gressi o n. H o we ver, 
if t here is clear e vi de n ce of cli nical be n efit, treat me nt ma y be c o nti n ue d after c o m pleti o n of 
palliati ve ra di ot hera p y. I n t his case, sacit uz u ma b g o viteca n +/- pe m br oli z u ma b a d mi nistrati o n 
s h o ul d be i nterr u pte d o ne wee k bef ore t he pr oce d ure a n d rei nstate d n o earli er t ha n o ne wee k after 
t he pr oce d ure. Si milarl y, if patie nts re q uire s ur ger y f or reas o ns relate d t o t heir ca ncer or ot her 
reas o ns, sacit uz u m a b g o viteca n +/- pe m br oliz u m a b a d mi nistrati o n s h o ul d be i nterr u pte d o ne wee k 
bef ore t h e pr oce d ure a n d rei nstate d n o earlier t ha n t w o wee ks after t he pr oce d ure. 

                                                 
 
 
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Pr o hi bite d C o nc o mita nt Me dicati o ns
S u bjects are pr o hi bite d fr o m recei vi n g t he f oll o wi n g t hera pies d uri n g t he Scree ni n g ( 1 4 da ys pri or 
t o st u d y treat me nt i nitiati o n) a n d Treat me nt P hase of t his trial:
A nti ne o plastic s yste mic c he m ot hera p y or bi ol o gical t hera p y  
I m m u n ot hera p y n ot s pecifie d i n t his pr ot oc ol 
I n v esti gati o nal a ge nts ot her t ha n pe m br oliz u m a b or sacit uz u ma b g o viteca n 
 Li ve vacci nes wit hi n 2 8 da ys pri or t o t he first d ose of trial treat me nt a n d w hile partici pati n g 
i n t he trial.
E xa m ples of li ve vacci nes i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g: 
measles, m u m ps, r u bella, varicella/z oster, y ell o w fe ver, ra bies, B C G, a n d t y p h oi d vacci ne. 
T he use of t he i nacti vate d seas o nal vacci ne is all o we d.
S yste mic gl uc oc ortic oi ds s h o ul d be a v oi de d f or a n y p ur p ose ot her t ha n t o m o d ulate 
s y m pt o ms fr o m ra diati o n, pre ve nt h y pers e nsiti vit y reacti o ns, or t o treat a n e ve nt of cli nical 
i nterest of s us p ecte d i m m u n ol o gic eti ol o g y. If c orti c oster oi ds are re q uire d f or t his p ur p ose, 
t he 
mi ni m u m effecti ve d ose s h o ul d be use d.  T he use of p h ysi ol o gic d oses of 
c ortic oster oi ds ( 1 0 m g pre d nis o ne dail y or e q ui vale nt) ca n be use d wit h o ut pri nci pal 
i n vesti gat or ( PI) a ut h orizati o n. F or partici pa nts recei vi n g sacit uz u ma b g o viteca n, d oses of 
c ortic oster oi ds > 1 0 m g pre d nis o ne dail y or e q ui vale nt ma y be use d wit h PI a ut h orizati o n; 
pe m br oliz u ma b ma y n ot be gi ve n w hile o n hi g her d oses of c ortic oster oi ds ( > 1 0 m g 
pre d nis o ne d ail y or e q ui vale nt). T he use of de xa met has o ne f or n a usea a n d v o miti n g 
attri b ute d t o sacit uz u ma b g o viteca n refract or y t o ot her me dicati o ns (s uc h as a 5- H T 3 
i n hi bit or, i.e., o n da nsetr o n or pal o n osetr o n; a n N K 1-rece pt or a nta g o nist, i.e., f osa pre pita nt 
or a pre pita nt; ola n za pi ne 1 0 m g dail y f or da ys 1 t o 4; or ot her a ge nts acc or di n g t o l ocal 
practices) is per mitte d. 
 S u bjects ma y recei ve ot her me dicati o ns t hat t he i n vesti gat or dee ms t o be me dicall y 
necessar y. 
T here are n o pr o hi bite d t hera pies d uri n g t he P ost- Treat me nt F oll o w- u p P hase. 
5. 6. 2  S u p p orti ve Care G ui deli nes – Ge neral Me dicati o ns 
 
T he f oll o wi n g treat me nts are per mitte d t hr o u g h o ut t he d urati o n of t he st u d y Treat me nt P hase a n d 
d uri n g F oll o w- u p: 
 
 Sta n dar d t hera pi es f or pre-e xisti n g me dical c o n diti o ns u nless liste d as pr o hi bite d t hera p y. 
A n y me dicati o n i nte n de d s olel y f or s u p p orti ve care (e. g., a nal gesics, a nti- diarr heal, a nti-
de pressa nts) ma y b e us e d at t he i n vesti gat or’s discreti o n. At t h e dis creti o n of t he 
i n vesti gat or, pr o p h ylacti c a ntie metic a n d a nti- diarr heal m e dicati o n(s) ma y be use d as p er 
sta n dar d cli nical practice bef ore d oses of st u d y dr u gs or bef ore, d uri n g or after ra diati o n 
treat me nt. 
 Bis p h os p h o nate or de n os u ma b t hera p y t o be us e d i n acc or da n ce wit h t he a p pr o ve d la b ele d 
i n dicati o n a n d/ or nati o nall y rec o g nize d treat me nt g ui deli nes. Partici pa nts alrea d y recei vi n g 
bis p h os p h o nate/ de n os u ma b at t he ti me of st u d y e ntr y ca n c o nti n ue t he treat me nt. 

                                                 
 
 
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Partici pa nts ma y i nitiate treat me nt wit h bis p h os p h o nate/ de n os u ma b after st u d y e ntr y wit h 
p h ysicia n discreti o n. 
 Pai n me dicati o ns a d mi nistere d per sta n dar d cli nical practice are acce pta ble w hile t he 
patie nt is e nr olle d i n t he st u d y. 
 
Patie nts w h o e x perie nce t o xicities s h o ul d be treate d s y m pt o maticall y as cli nicall y i n dicate d. 
Me dicati o ns t hat are c o nsi dere d necessar y f or t he s u bject’s welfare a n d t h at are n ot e x pecte d t o 
i nterfere wit h t he e v al uati o n of st u d y treat me nt or be restrict e d ma y be gi v e n at t he discreti o n of 
t he i n vesti gat or.  A ncillar y treat me nts will be gi ve n as me dicall y i n dicate d. 
Partici pa nts s h o ul d recei ve a p pr o pri ate s u p p orti ve care m eas ures as dee me d necessar y b y t he 
treati n g i n vesti gat or.  S u g geste d s u p p orti ve care meas ures f or t he ma na g e me nt of A Es wit h 
p ote ntial i m m u n ol o gic eti ol o g y are o utli ne d al o n g wit h t he d ose m o dificati o n g ui deli nes i n 
Secti o n 6 [ Ta ble 4- 6].  W here a p pr o priate, t h ese g ui deli nes i ncl u de t he use of oral or I V 
treat me nt wit h c ortic oster oi ds, as well as a d diti o n al a nti-i nfla m mat or y a g e nts if s y m pt o ms d o n ot 
i m pr o ve wit h a d mi nistrati o n of c ortic oster oi ds.  N ote t hat se veral c o urses of ster oi d ta peri n g ma y 
be necessar y as s y m pt o ms ma y w orse n w h e n t he ster oi d d ose is decrease d.  F or eac h dis or d er, 
atte m pts s h o ul d be ma de t o r ule o ut ot her ca us es s uc h as metastatic disease or bacterial or viral 
i nfecti o n, w hic h mi g ht re q uire a d diti o nal s u p p orti ve care.  T he treat me nt g ui deli nes are i nte n d e d 
t o be a p plie d w he n t he I n vesti gat or deter mi nes t he e ve nts t o be rel ate d t o pe m br oliz u ma b.  
N ote: If aft er t he e val uati o n of t he e ve nt, it is deter mi ne d n ot t o be relate d t o pe m br oliz u ma b, t he 
I n v esti gat or d oes n ot nee d t o f oll o w t he treat me nt g ui da nce.  Refer t o Ta bl e 4- 6 i n Secti o n 6 f or 
g ui deli nes re gar di n g d os e m o dificati o n a n d s u p p orti ve care.  
It ma y b e necessar y t o p erf or m c o n diti o nal pr oce d ures s uc h as br o nc h osc o p y, e n d osc o p y, or s ki n 
p h ot o gra p h y as part of e v al uati o n of t he e ve nt.  
P ote ntial Dr u g I nt eracti o ns: 
N o f or mal 
p har m ac o ki netic 
dr u g- dr u g i nteracti o n st u dies 
ha ve 
bee n c o n d ucte d 
wit h 
pe m br oliz u ma b or sacit u z u ma b g o viteca n. S N- 3 8 (t he acti ve meta b olite of s acit uz u ma b g o viteca n) 
is 
meta b olize d 
via
h u ma n 
U D P- gl uc ur o n os yltra nsferas e 
1 A 1( U G T 1 A 1). 
C o nc o mita nt 
a d mi nistrati o n of str o n g i n hi bit ors or i n d ucers of U G T 1 A 1, wit h sacit uz u ma b g o viteca n, s h o ul d 
be a v oi de d d ue t o t he p ote ntial t o eit her i ncreas e (i n hi bit ors) or decrease (i n d ucers) t he e x p os ure 
t o S N- 3 8. If a patie nt re q uires a str o n g U G T 1 A 1 i n hi bit or or i n d ucer, t he y s h o ul d n ot e nr oll o nt o 
t his st u d y or s h o ul d st o p st u d y treat me nt if e nr olle d.  
Str o n g U G T 1 A 1 I n hi bit ors 
C o-a d mi nistrati o n of sacit uz u ma b g o viteca n wit h str o n g i n hi bit ors of U G T 1 A 1 (e. g., 
ataza n a vir, ge mfi br ozil, i n di na vir) ma y i ncrease s yste mic e x p os ure t o t he acti ve 
meta b olite, S N- 3 8. D o n ot a d mi nister str o n g U G T 1 A 1 i n hi bit ors wit h sacit uz u ma b
g o viteca n u nless t here are n o t hera p e utic alter n ati ves.  
Str o n g U G T 1 A 1 I n d ucers 

                                                 
 
 
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E x p os ure t o S N- 3 8 ma y be s u bsta ntiall y re d uce d i n patie nts c o nc o mita ntl y recei vi n g 
U G T 1 A 1 e n z y me i n d ucers (e. g., car ba m aze pi ne, p he n yt oi n, p he n o bar bital, ti pra na vir, 
rifa m pici n, nelfi na vir, rit o na vir, efa vire nz, la m otri gi ne, test oster o ne pr o pi o nate). D o 
n ot a d mi nister str o n g U G T 1 A 1 i n d ucers wit h sacit uz u ma b g o viteca n u nless t here are 
n o t hera pe utic alter nati ves. 
 
5. 7  
Criteri a f or T a ki n g a P artici p a nt Off Pr ot o c ol T her a p y 
 
D urati o n of t hera p y will de pe n d o n i n di vi d ual res p o nse, e vi de nce of disease pr o gressi o n a n d 
t olera nce. I n t he a bse nce of treat me nt dela ys d ue t o a d verse e v e nt(s), treat me nt ma y c o nti n ue u ntil 
o ne of t he f oll o wi n g criteria a p plies: 
 
1.  Disease pr o gressi o n b y R E CI S T 1. 1 criteria: 
 
A.  Partici pa nts w h o ha ve att ai ne d a c o nfir m e d c o m plete res p o nse ( C R) t hat ha ve bee n 
treate d f or at least 2 4 wee ks o n pr ot oc ol t hera p y a n d ha d at least t hree c ycles ( wit h 
pe m br oliz u ma b a n d s acit uz u ma b g o viteca n ( Ar m A) or s acit uz u ma b g o viteca n 
al o ne ( Ar m B)) be y o n d t he date w he n t he i nitial C R was declare d ma y be eli gi ble 
f or a d diti o nal sacit uz u ma b g o viteca n a n d/ or pe m br oliz u ma b t hera p y if t he y 
pr o gress after st o p pi n g st u d y treat me nt. T his retreat me nt is ter me d t he Sec o n d 
C o urse P hase T hera p y. See a d diti o nal details bel o w. 
 
2.  D ose re d u cti o n be y o n d 5 0 % of sacit uz u ma b g o vit eca n re q uires st o p pi n g sacit uz u ma b 
g o viteca n. T he patie nt 
ma y c o nti n ue o n treat me nt 
wit h pe m br oliz u ma b
u ntil 
pr o gressi o n or u p t o 3 5 d oses of p e m br oliz u ma b are c o m plet e d, w hic h e ver c o mes first.  
 
3.  I nterc urre nt ill ness t hat pre ve nts f urt h er a d mi nistrati o n of treat me nt. 
 
4.  U nacce pta ble a d vers e e v e nt(s).  
 
5.  Partici pa nt de m o nstrates a n i na bilit y or u n willi n g ness t o c o m pl y wit h t he me dicati o n 
re gi me n a n d/ or d o c u me ntati o n re q uire me nts. 
 
6.  Partici pa nt deci des t o wit h dra w fr o m t he pr ot oc ol t hera p y.  
 
N ote: Partici pa nts o n eit her treat me nt ar m ( Ar m A or Ar m B) ma y el ect t o st o p t hera p y 
(sacit uz u ma b g o viteca n a n d pe m br oliz u ma b O R sacit uz u ma b g o viteca n o nl y o n eit her 
ar m) wit h c o nfir me d C R after at least 2 4 wee ks of treat me nt. T hese parti ci pa nts are 
still re q uire d t o u n der g o re g ular diseas e resta gi n g e ver y 9- 1 2 wee ks. N ote: f or 
partici pa nts o n Ar m A, if o nl y sacit uz u ma b g o viteca n is disc o nti n ue d, Da y 8 
assess me nts ( A E ass ess me nt, la bs, vitals, etc.) are n ot nee de d. 
 
7.  Ge neral or s pecific c h a n ges i n t he partici pa nt's c o n diti o n re n der t he partici pa nt 
u nacce pta ble f or f urt her treat me nt i n t he j u d g me nt of t he treati n g i n vesti gat or.  
 

                                                 
 
 
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Partici pa nts will be re m o ve d fr o m t he pr ot oc ol t hera p y w he n a n y of t hes e criteria a p pl y.  T he 
reas o n f or re m o v al fr o m pr ot oc ol t hera p y, a n d t he date t he partici pa nt was re m o ve d, m ust be 
d oc u me nte d i n t he case re p ort f or m ( C R F) a n d i n t he C T M S s yste m ( O n C ore). Alter n ati ve care 
o pti o ns will be disc usse d wit h t he partici pa nt. 
I n t he e ve nt of u n us u al or life-t hreate ni n g c o m plicati o ns, treati n g i n vesti gat ors m ust i m me diatel y 
n otif y t he S p o ns or-I n vesti gat or,  A n a G arri d o- C astr o, M D, p h o n e: 6 1 7- 6 3 2- 3 8 0 0, or e m ail: 
a n a g arri d o- c astr o @ df ci. h ar v ar d. e d u  . 
Sec o n d C o urse P h ase T her a p y: 
 
Retreat me nt P hase (a vail a ble t o b ot h Ar ms) 
Partici pa nts
w h o st o p sacit uz u ma b g o viteca n a n d/ or pe m br oliz u ma b wit h C R after at least 2 4 
wee ks of treat me nt ma y be eli gi ble f or a d diti o nal pe m br oliz u ma b a n d/ or s acit uz u ma b g o viteca n
t hera p y if t he y pr o gress after st o p pi n g st u d y treat me nt. F or partici pa nts ra n d o mize d t o t he 
c o m bi nati o n ar m ( Ar m A): if b ot h sacit uz u ma b g o viteca n a n d pe m br oliz u ma b are disc o nti n ue d 
a n d partici p a nt e x perie nces pr o gressi o n, b ot h sacit uz u ma b g o viteca n a n d p e m br oliz u ma b ca n b e 
restarte d at p h ysicia n’s discreti o n; or if sacit uz u m a b g o viteca n is disc o nti n u e d a n d p e m br oliz u ma b 
is c o nti n ue d a n d partici pa nt e x perie nces pr o gressi o n, sacit uz u ma b g o viteca n ca n be a d de d t o t he 
pe m br oliz u ma b at p h ysicia n’s discreti o n.  F or p artici pa nts ra n d o mize d t o s acit uz u ma b g o viteca n 
m o n ot hera p y ( Ar m B): if sacit uz u ma b g o viteca n is disc o nti n ue d a n d partici pa nt e x peri e nces 
pr o gressi o n, sacit uz u ma b g o viteca n ca n b e restarte d at p h ysicia n’s discreti o n. T his retreat me nt is 
ter me d t he Sec o n d C o urs e P hase of t his st u d y a n d is o nl y a vaila ble if t he st u d y re mai ns o pe n a n d 
t he s u bject meets t he f oll o wi n g c o n diti o ns: 
o  St o p pe d i nitial treat me nt wit h sacit uz u ma b g o viteca n a n d/ or pe m br oliz u ma b after 
attai ni n g a n i n vesti gat or-assesse d C R acc or di n g t o R E CI S T 1. 1, c o nfir me d i n at least 
t w o c o nsec uti ve resta gi n g sca ns, was treate d f or at least 2 4 wee ks wit h pe m br oliz u ma b 
a n d/ or sacit uz u m a b g o vit eca n b ef ore disc o nti n ui n g t hera p y, a n d recei ve d at least t hree 
c ycles ( wit h pe m br oliz u ma b a n d sacit uz u m a b g o viteca n ( Ar m A) or s acit uz u ma b 
g o viteca n al o ne ( Ar m B)) be y o n d t he date w he n t he i nitial C R was declare d  
A N D 
 
o  E x perie nce d a n i n vesti gat or-assess e d or ra di o gra p hic disease pr o gressi o n after 
st o p pi n g t heir i nitial treat me nt wit h sacit uz u ma b g o viteca n a n d/ or pe m br oliz u ma b 
( Ar m A) or s acit uz u ma b g o viteca n ( Ar m B) 
o  Di d n ot recei ve a n y a nti-ca ncer treat me nt ot her t h a n:  
Ar m A: Sacit uz u ma b g o viteca n ( or pe m br oliz u m a b) si nce t h e last d ose of 
pe m br oliz u ma b ( or s acit uz u ma b g o viteca n) 
 Ar m B: N o ot her a nti-ca ncer treat me nt si nce t he last d ose of sacit uz u ma b 
g o viteca n 

                                                 
 
 
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o  Partici pa nts w h o st o p pe m br oliz u ma b after recei vi n g 3 5 d oses ma y be eli gi ble f or 
retreat me nt if t he y pr o gress after st o p pi n g st u d y treat me nt, pr o vi d e d t he y meet t he 
re q uire me nts detaile d i n Secti o ns 3. 3 a n d 3. 4. Partici pa nts ma y be retreate d i n t he 
Sec o n d C o urse P hase ( Retreat me nt) f or u p t o a n a d diti o nal 1 7 c ycles (a p pr o xi matel y 1 
year). 
T he retreat me nt secti o n of t he eli gi bilit y c hec klist s h o ul d be c o m plete d a n d si g ne d b y t he treati n g 
i n vesti gat or. D F/ H C C sit es will re-se n d t he c h ec klist t o O D Q f or pr ocessi n g. N o n- D F/ H C C sites 
will e mail d oc u me ntati o n t o t he C o or di nati n g Ce nter at ct o p m @ dfci. har var d. e d u f or re vie w. 
Pr o vi de d t he patie nt meets criteria per pr ot oc ol f or retreat me nt, t he C o or di nati n g Ce nter will 
pr ocess t he c hec klist a n d t he partici pati n g site will be n otifie d t hat t he patie nt ma y pr ocee d t o 
retreat me nt.
S u bjects w h o restart treat me nt will be retreate d at t he sa me d ose a n d d ose i nter val as w he n t he y 
last recei ve d pe m br oliz u ma b a n d/ or sacit uz u ma b g o viteca n. Visit re q uire me nts are as o utli ne d f or 
s u bjects o n t he i nitial treat me nt p hase of t he trial. T hese partici pa nts ma y res u me t he sca n sc he d ule 
t he y ha d pre vi o usl y d uri n g t he treat me nt brea k, i. e., e ver y 9 wee ks.   
 
5. 8  
D ur ati o n of F oll o w U p 
 
Partici pa nts will be f oll o we d o n-st u d y u ntil deat h. Partici pa nts re m o ve d fr o m pr ot oc ol t hera p y f or 
u nacce pta ble a d v erse e v e nt(s) will be f oll o we d u ntil res ol uti o n or sta bilizati o n of t he a d vers e 
e ve nt. A n a d diti o nal a d v erse e v e nt assess me nt will be perf or me d 9 0 da ys (- 1 5/ + 3 0 da ys) aft er t he 
last d ose of treat me nt f or partici pa nts w h o recei ve pe m br oliz u ma b, i ncl u di n g partici pa nts w h o 
st o p pe d earl y f or C R, are ca n di d ates f or retreat m e nt, a n d ha v e n ot y et restarte d pe m br oliz u m a b. 
T his ma y be c o n d ucte d b y p h o ne.   
 
Partici pa nts w h o disc o nti n ue d t hera p y f or reas o ns ot her t ha n pr o gressi o n will be f oll o we d f or first 
disease pr o gressi o n or u ntil t he start of a n ot her a nti-ca ncer t hera p y. T u m or assess me nts s h o ul d 
c o nti n ue t o be perf or m e d e ver y 9- 1 2 wee ks o n t hese partici pa nts u ntil first disease pr o gressi o n 
e ve nt, start of a n ot her a nti-ca ncer t hera p y, or deat h, w hic he ver occ urs first. Researc h bl o o ds are 
o pti o nal at t he ti me of t u m or assess me nts. At eit her t he ti me of diseas e pr o gressi o n or start of 
a n ot her a nti-ca ncer t hera p y, partici pa nts will t he n be f oll o we d f or s ur vi val.  
 
Partici pa nts will be f oll o we d or c o ntacte d e v er y 6 m o nt hs f or s ur vi val. 
 
5. 9  
Criteri a f or T a ki n g a P artici p a nt Off St u d y 
 
Partici pa nts will be re m o ve d fr o m st u d y w he n a n y of t he f oll o wi n g criteri a a p pl y: 
 
 L ost t o f oll o w- u p 
 Wit h dra wal of c o nse nt f or data s u b missi o n 
 Deat h 
 
T he reas o n f or ta ki n g a p artici pa nt off st u d y, a n d t he date t he p artici pa nt was re m o ve d, m ust be 
d oc u me nte d i n t he case re p ort f or m ( C R F). I n a d diti o n, t he st u d y tea m will e ns ure Off 

                                                 
 
 
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Treat me nt/ Off St u d y i nf or mati o n is u p date d i n O n C ore i n acc or da nce wit h D F/ H C C p olic y 
R E GI S T- O P- 1. 
 
6  
D O SI N G D E L A Y S/ D O S E M O DI FI C A TI O N S 
 
D ose dela ys a n d m o difi cati o ns will be ma de as i n dicate d i n t he f oll o wi n g ta ble(s). T he 
descri pti o ns a n d gra di n g scales f o u n d i n t h e re vise d N CI C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts ( C T C A E) versi o n 5. 0 will be utilize d f or d ose dela ys a n d d ose m o dificati o ns. A 
c o p y 
of t he 
C T C A E 
versi o n 
5. 0 
ca n 
be 
d o w nl oa de d fr o m t he 
C T E P 
we bsite:
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m .  
6. 1
D osi n g Del a ys/ O missi o n/ M o dific ati o ns
D osi n g i nterr u pti o ns wit hi n a 7- da y wi n d o w are p er mitte d i n t he case of m e dical / s ur gical e v e nts 
or l o gistical reas o ns n ot relate d t o st u d y t hera p y (e. g., electi ve s ur ger y, u nrelate d me dical e ve nts, 
patie nt vacati o n, a n d/ or h oli da ys). Partici pa nts wit h d oses hel d f or t hese reas o ns f or m ore t ha n 7 
da ys re q uire pri or a p pr o val fr o m t he S p o ns or-I n vesti gat or a n d s h o ul d res u me t hera p y wit hi n 6 
wee ks of t he sc h e d ule d i nterr u pti o n. T he reas o n f or i nterr u pti o n s h o ul d be d oc u me nte d i n t he 
partici pa nt's st u d y rec or d. If a d ose is hel d o n da y 1 of a c ycle, t he c ycle restarts w he n t he 
partici pa nt meets criteria t o start; t he assess me nt sc he d ule s h o ul d be a dj ust e d acc or di n gl y. 
 
I n t he a bse nce of a n u nacce pta ble t hera p y-relate d t o xicit y a n d/ or cli nical si g ns of disease 
pr o gressi o n, s u bjects ma y c o nti n ue treat me nt at t he discreti o n of t he i n vesti gat or. S u bjects m ust 
be i nstr ucte d t o n otif y t heir p h ysicia n i m me diatel y f or a n y a n d all t o xicities. 
 
G ui deli nes f or t he 
ma n a ge me nt of A Es (i.e., d ose i nterr u pti o ns a n d d ose re d u cti o ns) a n d 
rec o m me n dati o ns f or treati n g e x pecte d t o xicities are prese nte d i n t he ne xt secti o ns. C o ns ultati o n 
wit h a me di cal or s ur gi cal s pecialist, es peciall y pri or t o a n i n vasi ve di a g n ostic or t hera p e utic 
pr oce d ure, is rec o m me n de d. F or 
ma n a ge me nt of A Es w hic h ca n b e clearl y attri b ute d t o 
sacit uz u ma b g o viteca n or pe m br oliz u ma b, i n de pe n de nt d ose m o dificati o n f or eit her a ge nt is
all o we d. F or A Es wit h o ut clear attri b uti o n t o eit her st u d y treat me nt, m a na ge me nt of t o xicit y 
s h o ul d i ncl u de d ose m o dificati o ns of b ot h a ge nts. 
6. 1. 1
Ma na ge me nt of D osi n g Dela ys/I nterr u pti o ns/ M o dificati o ns attri b uta ble t o 
Pe m br oliz u ma b or Sacit u z u ma b G o viteca n:
Pe m br oliz u ma b s h o ul d be hel d ( del a ye d) or o mitte d f or t o xicities t hat are c o nsi dere d p ossi bl y, 
pr o ba bl y or defi nitel y relate d t o pe m br oliz u m a b ( per Secti o n 6. 2 g ui da nce). Sacit uz u ma b 
g o viteca n s h o ul d b e h el d ( dela y e d), d os e re d uce d, or o mitte d f or t o xiciti es t hat are c o nsi dere d 
p ossi bl y, pr o ba bl y or defi nitel y relate d t o sacit uz u ma b g o viteca n ( per Secti o n 6. 3 g ui da nce). If o n 
ar m A (first c o urse or retreat me nt), eit her dr u g ma y be disc o nti n ue d, w hile t he ot her dr u g 
c o nti n ues. 
If a s u bject o n Ar m A d oes n ot meet criteria f or treat me nt ( Secti o n 5. 2) d ue t o a t o xicit y 
t hat is c o nsi dere d attri b uta ble t o o nl y o n e of t he dr u gs of t h e c o m bi nati o n (e. g., platelets 
6 0, 0 0 0/ m m 3 attri b ute d t o sacit uz u ma b g o viteca n), t he dr u g ca usi n g t h e t o xicit y s h o ul d be 

                                                 
 
 
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hel d, a n d t he ot her st u d y dr u g ma y be a d mi nistere d ( u nless s pecifie d i n t he c orres p o n di n g 
A E ta ble of t hat st u d y dr u g). 
 
 F or s u bjects o n Ar m A, if o ne st u d y dr u g is dela y e d b ut t he ot her st u d y dr u g is gi ve n, t he n 
t he st u d y dr u g t hat was hel d s h o ul d be re-i nitiate d if a p pr o priate at t he ne xt re g ularl y 
sc he d ule d a d mi nistrati o n ti me, i.e. if hel d o n da y 1 of t he c y cle, t he n sacit uz u ma b g o viteca n 
c o ul d be rest arte d o n d a y 8 of t he c y cle or d a y 1 of t he ne xt c ycl e ( ± 2 da ys f or Da y 1) a n d 
pe m br oliz u ma b c o ul d be restarte d o n d a y 1 of t he ne xt c ycle ( ± 4 d a ys). 
 
 T here m ust be a mi ni m u m of 1 4 da ys ( ± 2 da ys) b et wee n Da y 8 a n d Da y 1 of t he ne xt c ycle 
of sacit uz u ma b g o viteca n. T here s h o ul d be a mi ni m u m of 2 1 da ys ± 4 da ys bet wee n 
a d mi nistrati o n of eac h d ose of pe m br oliz u ma b. 
 If treat me nt wit h sacit uz u ma b g o viteca n is hel d or o mitte d d ue t o a n A E a n d t he patie nt 
ca n n ot be retreate d wit h sacit uz u ma b g o viteca n wit hi n 6 wee ks fr o m t he last d ose, 
sacit uz u ma b g o viteca n s h o ul d be per ma ne ntl y disc o nti n ue d. Pe m br oliz u ma b ca n b e 
c o nti n ue d per pr ot o c ol (if t he A E is c o nsi dere d u nrelate d t o pe m br oliz u ma b). 
 
 If treat me nt wit h pe m br oliz u ma b is hel d or o mitte d d ue t o a n A E a n d t he p atie nt ca n n ot b e 
retreate d wit h pe m br oliz u ma b wit hi n 9 wee ks fr o m t he last d ose, pe m br oliz u ma b s h o ul d 
be per ma ne ntl y disc o nti n ue d. Sacit uz u ma b g o viteca n ca n be c o nti n ue d per pr ot oc ol (if t he 
A E is c o nsi dere d u nrelat e d t o sacit uz u ma b g o viteca n). 
 
 F or s u bjects o n Ar m A, if sacit uz u ma b g o viteca n is disc o nti n ue d a n d pe m br oliz u ma b is 
c o nti n ue d, Da y 8 ass ess me nts ( A E assess me nt, la bs, vitals, etc.) are n ot nee de d. 
6. 1. 2
Ma na ge me nt of Diarr h ea 
Diarr hea re q uires s pecial atte nti o n, as it ca n be ca use d b y eit her st u d y dr u g. See Secti o n 6. 2 a n d 
6. 3 f or a d diti o nal diarr hea ma na ge me nt g ui deli nes f or pe m br oliz u ma b a n d sacit uz u ma b g o viteca n, 
res pecti vel y. At e nr oll m e nt, patie nts s h o ul d recei ve i nstr ucti o ns o n t he m a na ge me nt of diarr hea. 
I n t he e ve nt of diarr hea, s u p p orti ve meas ures s h o ul d be i nitiate d as earl y as p ossi ble. T hese i ncl u de 
t he f oll o wi n g: 
 
 At t he first si g n of l o ose st o ols, t he patie nt s h o ul d i nitiate a nti- diarr heal t hera p y (f or 
e xa m ple, l o pera mi de) a n d n otif y t he i n vesti gat or/site f or f urt her i nstr ucti o ns a n d 
a p pr o priate f oll o w- u p. 
 Patie nts s h o ul d als o be e n c o ura ge d t o dri n k fl ui ds (f or e x a m ple, 8 t o 1 0 glass es of h y drati n g 
li q ui ds per da y).
 Site pers o n nel s h o ul d assess res p o nse wit hi n 2 4 h o urs.  
 If diarr hea d o es n ot res ol ve wit h a nti- diarr heal t hera p y wit hi n 2 4 h o urs t o eit her baseli n e 
or Gra de 1, b ot h st u d y dr u gs s h o ul d be s us pe n de d u ntil diarr hea is res ol ve d t o baseli ne or 
Gra de 1. 
 W he n sacit uz u ma b g o viteca n rec o m me n ces, d osi n g s h o ul d be a dj uste d as o utli ne d i n Ta ble 
6 i n Secti o n 6. 3.  
 

                                                 
 
 
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6. 3
M a n a ge me nt of T o xicities Attri b ut a ble t o S acit uz u m a b G o vitec a n 
 
N CI- C T C A E v 5. 0 is use d t o gra d e t he s e verit y of all A Es. T he g ui d eli nes f or ma n a ge me nt of 
t o xicities ass ociate d wit h sacit uz u ma b g o viteca n are bas e d o n t he assess me nt of s e verit y acc or di n g 
t o t hese criteri a. T o xicities s h o ul d be ma na g e d i n acc or da nce wit h sta n dar d me dical practice a n d 
treat me nt g ui deli nes. All cli nicall y a p pr o pri ate i m a gi n g or la b orat or y t esti n g s h o ul d be utilize d t o 
f ull y assess a t o xicit y t o deter mi ne t he a p pr o priate treat me nt. A p pr o pri ate f oll o w- u p st u dies s h o ul d 
be utilize d t o f oll o w all t o xicities t o res ol uti o n. Patie nts wit h k n o w n U G T 1 A 1 * 2 8 p ol y m or p his m 
ma y ha ve a hi g h er ris k of de vel o pi n g treat me nt relate d t o xicities. A d diti o nal m o nit ori n g ma y be 
re q uire d i n t h ose patie nts. 
 
D ose Dela ys – Sacit uz u ma b G o viteca n
Sacit uz u ma b g o viteca n is t o be a d mi nistere d i n 2 1- da y c ycl es o n Da y 1 a n d Da y 8; t he ne xt c ycle 
s h o ul d start 1 4 da ys ( ± 2 da ys) after t he Da y 8 d ose (i.e., t he Da y 8 i nf usi o n will be c o u nte d as t he 
first da y of t hat 1 4- d a y peri o d). Visit wi n d o ws of ± 2 d a ys fr o m t he s c he d ule d i nf usi o n are 
per mitte d. T he s c he d ule d Da y 1 a n d Da y 8 i nf usi o ns ma y be d ela ye d f or treat me nt-relate d 
t o xicities. 
Da y 8 
d osi n g of t hat c ycle s h o ul d be o mitte d a n d d osi n g s h o ul d res u me wit h t he Da y 1 of t h e f oll o wi n g 
c ycle.  T here s h o ul d be a mi ni m u m of 7 da ys ( ± 2 da ys) bet wee n t he Da y 1 a n d t he Da y 8 i nf usi o ns. 
T here s h o ul d b e a mi ni m u m of 1 4 da ys ( ± 2 d a ys) bet wee n t he Da y 8 i nf usi o n a n d t he Da y 1 
i nf usi o n of t he ne xt c ycle.  
 
F or p atie nts ra n d o mize d t o t he c o m bi nati o n ar m, if dr u gs are a d mi nistere d o n differe nt da ys i n t he 
sa me 2 1- da y c ycle, e ver y eff ort s h o ul d be ma de t o a d mi nister b ot h dr u gs o n t he sa me da y i n 
s u bse q ue nt c ycl es (all assess me nts bei n g a dj uste d acc or di n gl y), pr o vi de d t hat criteri a are met p er 
pr ot oc ol a n d t hat 1 4 da ys ( ± 2 da ys) ha ve ela pse d si nce t he a d mi nistrati o n of t he pre vi o us d ose of 
sacit uz u ma b g o viteca n a n d 2 1 ± 4 da ys si nce t he a d mi nistrati o n of t he pre vi o us d ose of 
pe m br oliz u ma b. If Da y 8 sacit uz u ma b g o viteca n d osi n g is dela ye d, ca usi n g a dj ust me nt t o Da y 1 
of t he f oll o wi n g c ycle, it is rec o m me n de d t o a d mi nister pe m br oliz u ma b o n t he sa me da y as Da y 1 
of t he ne xt c ycl e of sacit uz u ma b g o viteca n.   
 
D ose Re d ucti o ns a n d Dis c o nti n uati o n 
T he maj or t o xicities of sacit uz u ma b g o viteca n are e x pecte d t o be gastr oi ntesti nal s y m pt o ms a n d 
he mat ol o gic s u p pressi o n. All s u bjects will be cl osel y m o nit ore d o ver t he c o urse of t heir treat me nt 
a n d a g gressi vel y me dicall y ma na ge d, i ncl u di n g d ose re d ucti o n a n d i nterr u pti o n, i n or der t o pre v e nt 
t he nee d f or treat me nt disc o nti n uati o n a n d seri o us c o m plicati o ns of t hese t o xicities. Sacit uz u ma b
d ose re d u cti o ns a n d i nterr u pti o ns will be ma n a g e d base d o n t o xicit y se verit y, as assesse d b y 
N CI C T C A E v 5. 0. T he sacit uz u ma b g o viteca n d ose m ust n ot be re-escal ate d f oll o wi n g a d ose 
re d ucti o n. T h e ta ble bel o w s u m marizes rec o m me n dati o ns f or sacit uz u ma b g o viteca n d ose 
re d ucti o ns a n d disc o nti n uati o ns f or treat me nt-relate d t o xicities.
D ose h ol ds f or a ne mia are n ot ma n date d b ut ca n be a p plie d as cli nicall y i n dicate d. S u p p orti ve care 
(i.e., re d bl o o d cell tra nsf usi o ns) ma y be ma na ge d acc or di n g t o i nstit uti o nal g ui deli nes. 

                                                 
 
 
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6. 3. 1
Sacit uz u ma b G o viteca n I nf usi o n- Relate d Reacti o ns 
I nf usi o n-relat e d reacti o ns are defi ne d as s y m pt o ms t hat occ ur d uri n g a n d wit hi n t he first 6 h o urs 
after t h e i nf usi o n of sacit uz u ma b g o viteca n. S y m pt o ms ca n i ncl u de fe v er, c hills, ri g ors, art hral gias, 
m yal gias, urticaria, pr urit us, ras h, dia p h oresis, h y p ote nsi o n, dizzi ness, s y nc o pe, h y perte nsi o n, 
d ys p nea, c o u g h, a n d w heezi n g, as well as se vere h y perse nsiti vit y reacti o ns, i ncl u di n g a na p h ylacti c 
reacti o ns. I nf usi o n-relate d reacti o ns s h o ul d be treate d i n acc or d a nce wit h best cli nical practices 
a n d sta n dar d i nstit uti o nal g ui deli nes. Beca use of t he p ote ntial f or life-t hreate ni n g i nf usi o n-relate d 
reacti o ns, sacit uz u ma b g o viteca n s h o ul d o nl y be a d mi nistere d i n a s etti n g i n w hic h a p pr o priatel y 
trai ne d me dical staff, e mer ge nc y e q ui p me nt, a n d me dicati o ns are a vaila ble i n t he e ve nt t hat 
res uscitati o n is re q uire d. N CI C T C A E v 5. 0 is us e d t o gra de t he s e verit y of all i nf usi o n-relate d 
a d verse e ve nts.  
Gra de 3 a n d Gra de 4 E v e nts 
Gra de 3 a n d Gra d e 4 i nf usi o n-relate d reacti o ns ca n i ncl u de se vere or cli nicall y si g nifica nt 
car di o p ul m o nar y e ve nts a n d se vere aller gic reacti o ns, s uc h as s y m pt o matic br o nc h os pas m a n d 
a na p h ylactic reacti o ns. Gra de 3 i nf usi o n-relate d reacti o ns are defi ne d as t h ose w hic h are pr ol o n ge d 
a n d d o n ot i m pr o ve wit h s y m pt o matic treat me nt a n d/ or brief i nterr u pti o n of treat me nt; reacti o ns 
t hat rec ur f oll o wi n g treat me nt; a n d reacti o ns t hat re q uire h os pitalizati o n. Gra de 4 reacti o ns i ncl u de 
p ote ntiall y life-t hreate ni n g reacti o ns, re q uiri n g ur ge nt i nter ve nti o n. Se vere aller gic a n d 
a na p h ylactic reacti o ns s h o ul d be treate d i n acc or d a nce wit h best cli nical practices a n d sta n dar d 
i nstit uti o nal g ui deli nes. Sacit uz u ma b g o viteca n s h o ul d be per ma ne ntl y disc o nti n ue d wit h t he first 
occ urre nce of Gra d e 4 i nf usi o n-relate d reacti o n or rec urre nt Gra d e 2 or Gra de 3 i nf usi o n-relate d 
reacti o n des pite o pti mal ma na ge me nt.
Gra de 2 E v e nts
Gra de 2 i nf usi o n-rel ate d reacti o ns are defi ne d as t h ose t hat re q uire i nf usi o n i nterr u pti o n a n d 
res p o n d t o s y m pt o matic treat me nt. F or Gra de 2 i nf usi o n-relate d reacti o ns, t he i nf usi o n s h o ul d be 
i nterr u pte d f or at least 1 5 mi n utes u ntil s y m pt o ms res ol ve. Aft er s y m pt o ms res ol ve, t he i nf usi o n 
s h o ul d be res u me d at a sl o wer i nf usi o n rate det er mi ne d as a p pr o priate b y t he ma na gi n g p h ysicia n. 
F or rec urre nt Gra de 2 i nf usi o n reacti o ns t hat fail t o rec o ver wit hi n 6 h o urs, des pite o pti mal 
ma na ge me nt, sacit uz u ma b g o viteca n s h o ul d be per ma ne ntl y disc o nti n ue d. 
6. 3. 2
Sacit uz u ma b G o viteca n Gastr oi ntesti nal T o xicities
Na usea, v o miti n g, a n d diarr hea are fre q u e nt sacit uz u ma b g o viteca n-ass ociate d t o xicities. 
A p pr o priate treat me nt, i ncl u di n g, as nee d e d, fl ui d a n d electr ol yte re place me nt, is re q uire d t o 
mi ni mize t he ris k of seri o us c o nse q ue nces s uc h as de h y drati o n. I nstr ucti o ns f or Sacit uz u ma b
G o viteca n d ose re d u cti o n f or treat me nt-relate d g astr oi ntesti nal t o xicities are pr o vi de d a b o v e i n 
Ta ble 6. 
Na usea a n d V o miti n g 

                                                 
 
 
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I nstr u cti o ns f or t h e use of pre- me dicati o ns f or pr o p h ylactic treat me nt of n a usea a n d v o miti n g a n d 
a ntici pat or y na usea are pr o vi de d i n Secti o n 5. 3. 1. D o n ot h ol d t he d ose of s acit uz u ma b g o viteca n 
f or Gra d e 3 na usea u nless Gra de 3 na usea persists des pite ma xi mal o pti mal me dical ma na ge me nt. 
S u bjects s h o ul d be treate d f or dela y e d na us ea a n d v o miti n g o n Da ys 2 a n d 3 wit h 5- H T 3 rece pt or 
a nta g o nist ( o n da nsetr o n or pal o n osetr o n) m o n ot h era p y a n d ot her a ge nts if nee de d. Ster oi ds ma y 
be a d de d if s y m pt o ms d o n ot res ol ve wit h t hese ot her a ge nts. C o nsi der ola nza pi ne f or persiste nt 
or a ntici pat or y na us ea; a n ola nza pi n e d ose of 2. 5 m g or 5 m g at be dti me is rec o m me n de d.  N K 1 
rece pt or a nta g o nists (f os a pre pita nt a n d a pre pita nt) ma y be a d mi nistere d. 
 
Diarr hea 
Dietar y m o dificati o n s h o ul d be rec o m me n de d f or t he ma na ge me nt of diarr hea, i ncl u di n g a bla n d 
diet, s mall fre q ue nt meals, a de q uate fl ui d i nta ke of clear li q ui ds t o mai ntai n h y drati o n, a n d 
disc o nti n uati o n of lact os e-c o ntai ni n g f o o ds a n d dri n ks c o ntai ni n g alc o h ol. L o pera mi de s h o ul d be 
a d mi nistere d at t he o nset of treat me nt-relat e d diarr hea, at a n i nitial d ose of 4 m g, f oll o we d b y 2 
m g wit h e ver y e pis o de of diarr hea, t o a ma xi m u m d ose of 1 6 m g/ da y. If diarr hea is n ot res ol ve d 
after 2 4 h o urs, a d d di p he n o x ylate/atr o pi ne or o pi u m ti nct ure as cli nicall y i n dicate d. 
 
A d d octre oti de 1 0 0- 1 5 0 mc g s u bc uta n e o usl y 3 ti mes per da y (ti d) if diarr hea p ersists. F or Gra de 
4 diarr hea, c o nsi der s u bject h os pitalizati o n a n d treat me nt wit h I V fl ui ds a n d octre oti de. A nti bi otics 
ca n be a d mi nistere d as cli nicall y i n dicate d. 
 
S u bjects w h o e x hi bit a n e xcessi ve c h oli ner gic res p o nse t o treat me nt wit h s acit uz u ma b g o viteca n
(e. g., a b d o mi nal cra m pi n g, diarr h ea, s ali vati o n, et c.) ca n recei ve a p pr o pri ate pre m e dicati o n (e. g., 
atr o pi ne) f or s u bse q ue nt treat me nts. 
6. 3. 3
Sacit uz u ma b G o viteca n Ne utr o pe nia 
 
C o m plete bl o o d c o u nts m ust be o btai ne d pri or t o eac h sacit uz u ma b g o viteca n i nf usi o n, a n d 
sacit uz u ma b g o viteca n s h o ul d be a d mi nistere d if A N C meets t he f oll o wi n g criteria:
 
 Da y 1: A N C 
 1 0 0 0/ m m3
Da y 8: A N C 
1 0 0 0/ m m 3
 
T he r o uti ne pr o p h ylactic use of gr o wt h fact ors is n ot rec o m me n d e d h o we ver, t he y m a y be us e d 
per i n vesti gat or discreti o n; t his i ncl u des b ut is n ot li mite d t o a d mi nistrati o n i n t he i n t he setti n g of 
ne utr o pe nia i n s u bjects at hi g h ris k of p o or cli nical o utc o mes, i ncl u di n g t h ose wit h pr ol o n ge d 
ne utr o pe nia, A N C < 1 0 0 0/ m m 3, fe brile ne utr o pe nia, a n d seri o us i nfecti o ns. 
7
A D V E R S E E V E N T S:  LI S T A N D R E P O R TI N G R E Q UI R E M E N T S  
A d verse e v e nt ( A E) m o nit ori n g a n d re p orti n g is a r o uti ne part of e ver y cli nical trial.  T he f oll o wi n g 
list of re p orte d a n d/ or p ote ntial A Es ( Secti o n 7. 1) a n d t he c haract eristics of a n o bser ve d A E 
( Secti o n 7. 2) will deter mi ne w het her t he e v e nt re q uires e x pe dite d re p orti n g i n a d diti o n t o r o uti ne 
re p orti n g.

                                                 
 
 
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7. 1
A d verse E ve nts List
7. 1. 1
E x pecte d A d v erse E v e nts f or Pe m br oliz u ma b
I n t he p e m br oliz u ma b m o n ot hera p y trials ( P 0 0 1/ P 0 0 2, P 0 1 2, P 0 1 3, a n d P 0 2 8, pl us t he P 0 1 1 
m o n ot hera p y ar m), t h e o verall i nci de nce of A Es ra n ge d fr o m 8 3. 0 % ( 7 3 of 8 8 s u bjects i n P 0 1 2) 
t o 1 0 0 % ( 1 0 of 1 0 s u bjects i n P 0 1 1). T he m ost c o m m o nl y re p orte d A Es i n cl u de d fati g ue, 
diarr hea, decreas e d a p p etite, na usea, a n d a ne mia. T he i nci de nce of dr u g-rel ate d A Es ( D R A Es) 
ra n ge d fr o m 3 9. 8 % ( 3 5 of 8 8 s u bjects i n P 0 1 3) t o 8 0. 0 % ( 8 of 1 0 s u bjects i n P 0 1 1). T he m ost 
c o m m o nl y re p orte d D R A Es acr oss all st u dies were na usea, fati g ue, a n d diarr hea. T h e i nci de nce 
of Gra d e 3- 5 D R A Es acr oss st u dies ra n ge d fr o m 6. 8 % ( 6 of 8 8 i n P 0 1 3) t o 1 2. 0 % ( 1 8 7 of 1 5 6 2 
s u bjects) i n P 0 0 1/ P 0 0 2. T he m ost c o m m o nl y re p orte d Gra d e 3- 5 D R A Es were a ne mia, el e vate d 
ala ni ne a mi n otra nsferas e, a n d ele vat e d as partate a mi n otra nsferas e. M ost s u bjects w h o 
e x perie n ce d a n A E c o nti n ue d i n t he st u d y: t he i nci de nce of A Es lea di n g t o disc o nti n uati o n 
ra n ge d fr o m 1. 9 % ( 8 of 4 3 0 s u bjects i n P 0 2 8) t o 1 2. 3 % ( 1 9 2 of 1 5 6 2 s u bjects i n P 0 0 1/ P 0 0 2). 
T he maj orit y of A Es lea di n g t o disc o nti n uati o n were n ot c o nsi dere d t o be relate d t o 
pe m br oliz u ma b. Disc o nti n uati o ns d ue t o a D R A E were i nfre q ue nt a n d ra n g e d fr o m 0 % ( n o 
s u bjects i n P 0 1 1) t o 4. 5 % ( 4 of 8 8 s u bjects i n P 0 1 3). T he m ost c o m m o nl y re p orte d D R A Es 
lea di n g t o disc o nti n uati o n were p n e u m o nitis, ele vate d ala ni ne a mi n otra nsferase, a n d ele v ate d 
as partate a mi n otra nsferas e. 
List of A Es c o nsi dere d e x pecte d:  
 Car diac dis or ders: M y ocar ditis  
 E n d ocri ne dis or ders: A dre nal i ns ufficie n c y, H y pert h yr oi dis m, H y p o p h ysitis, 
H y p o pit uitaris m, H y p ot h yr oi dis m, Sec o n dar y a dre nal i ns ufficie n c y, T h yr oi d dis or der
 E ye dis or ders: U v eitis
 Gastr oi ntesti nal dis or ders: A b d o mi nal pai n, C olitis, Diarr hea, Pa ncreatitis 
 Ge neral dis or ders a n d a d mi nistrati o n site c o n diti o ns: Ast he nia, P yre xia 
 He pat o biliar y dis or ders: A ut oi m m u ne he patitis, He patitis, Scler osi n g c h ola n gitis 
 I nf usi o n relate d reacti o n 
 Meta b olis m a n d n utriti o n dis or ders: Dia betic k et oaci d osis, H y p o natre mia, T y pe 1 
dia betes mellit us 
 M usc ul os keletal a n d c o n necti ve tiss ue dis or ders: Art hral gia, Bac k p ai n, M y ositis, 
Vasc ulitis 
 Ner v o us s yste m dis or ders: G uillai n- Barré s y n dr o me, M yelitis 
 Re nal a n d uri nar y dis or d ers: Ne p hritis 
 Res pirat or y, t h oraci c a n d me diasti nal dis or ders: C o u g h, P ne u m o nitis 
 S ki n a n d s u bc uta ne o us tiss ue dis or ders: Pr uritis, Ras h, Se vere s ki n reacti o n, Vitili g o  
 
7. 1. 2  E x pecte d A d v erse E v e nts f or Sacit uz u ma b G o viteca n 
 
T he safet y pr ofile of sacit uz u ma b g o viteca n was i nitiall y c haracterize d base d o n 4 2 0 patie nts 
i ncl u de d i n t he o v erall s afet y p o p ulati o n i n t he I M M U- 1 3 2- 0 1 st u d y.  T h es e patie nts were treate d 
wit h breast ca ncer (i ncl u di n g 1 0 8 patie nts wit h metastatic tri ple ne gati ve breast ca ncer treate d wit h 

                                                 
 
 
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4 5 patie nts wit h ur ot helial ca ncer, 1 1 0 patie nts wit h l u n g ca ncer (s mall cell l u n g ca ncer 
a n d n o n-s mall cell l u n g ca ncer), a n d 1 0 1 patie nts wit h ot her e pit helial ca ncers (i ncl u di n g cer vical, 
c ol orectal, e n d o m etrial, e pit helial o varia n, es o p ha geal, gastric, gli o blast o ma m ultif or me, hea d a n d 
nec k, he pat o cell ular, pr ostate, pa ncreatic, a n d re nal).  T he mea n treat me nt d urati o n i n t hese 
patie nts was 1 6 0 da ys ( 7. 7 c ycles). T he f oll o wi n g is a s u m mar y of t he safet y pr ofile; a d diti o nal 
details ca n be f o u n d i n t he I n vesti gat or’s Br o c h ure.  
Nearl y all patie nts e x p erie nce d at least o n e a d verse e ve nt; a p pr o xi m atel y 7 5 % of p atie nts 
 4 1 % e x perie nce d o ne or m ore S A Es.  T he pr ot oc ol 
pr o vi de d i nstr ucti o ns f or d ose re d ucti o n a n d i nterr u pti o n, a n d treat me nt disc o nti n uati o n base d o n 
t o xicities. A Es le d t o treat me nt i nterr u pti o n i n 4 8 % of patie nts; h o we ver, o nl y 1 1 % of patie nts 
disc o nti n ue d d ue t o a d verse e v e nts. Fatal a d v erse e ve nts ( wit hi n 3 0 da ys of last d ose) occ urre d i n 
6. 7 % of patie nts; h o we ver nearl y all of t hese deat hs were i n t he s etti n g of disease pr o gressi o n.  
T he m ost fre q ue nt a d v erse e ve nts w ere g astr oi ntesti nal ( na usea, v o miti n g, a n d diarr h ea) a n d 
m yel os u p pressi ve ( n e utr o pe nia a n d a ne mia).  Na usea occ urre d i n 6 7 % ( 5 % 
Gra d e 3); v o miti n g 
occ urre d i n 4 4 % ( 4 % 
Gra de 3), a n d di arr h ea o cc urre d i n 6 2 % ( 9 % 
Gra de 3) of p atie nts. All 
patie nts were a d mi nistere d pr o p h ylactic a ntie metic treat me nts a n d na usea, v o miti n g, a n d diarr hea 
were m a na ge d acc or di n g t o sta n dar d treat me nt g ui deli nes. Wit h a g gressi ve ma na ge me nt of t hese 
t o xicities, fe w patie nts re q uire d treat me nt disc o nti n uati o n.  
T he m ost fre q ue nt m yel os u p pressi ve a d verse e ve nts were ne utr o pe ni a ( 4 1 %, 
Gra de 3 2 8 %) a n d 
a ne mia ( 4 1 %, 
Gra d e 3 1 1 %). Ne utr o p hil c o u nt decrease d o cc urre d i n 1 8 % of patie nts ( 1 3 % 
Gra de 3) a n d fe brile ne utr o pe nia occ urre d i n 6 %.  Alt h o u g h treat me nt was i nterr u pte d d ue t o 
ne utr o pe nia i n 2 1 % of p atie nts, o nl y o ne patie nt disc o nti n ue d d ue t o t his t o xicit y.  
I nfecti o ns occ urre d i n 4 3 % of patie nts ( 1 0 % 
Gra de 3); t he m ost fre q ue nt were c o m m o n, 
c o m m u nit y-ac q uire d, a n d less se vere, s uc h as uri nar y tract i nfecti o ns ( 1 2 %) a n d u p per res pirat or y 
tract i nfecti o ns ( 1 0 %); p ne u m o nia occ urre d i n 5 % ( 3 % Gra d e 3).  Se psis occ urre d i n 6 patie nts 
( 1. 4 %) a n d s e ptic s h oc k occ urre d i n 2 patie nts ( 0. 5 %).  
Ot her fre q ue nt a d vers e e ve nts i ncl u de d fati g ue ( 5 3 %) a n d al o pecia ( 4 2 %).  O nl y 2 patie nts ha d 
i nf usi o n-relate d h y perse nsiti vit y reacti o ns re q uiri n g per ma ne nt disc o nti n uati o n of treat me nt 
(a na p h yla xis i n o ne p atie nt a n d 
w heezi n g, c o u g h, a n d n asal c o n gesti o n i n a sec o n d 
patie nt).  Preli mi nar y dat a fr o m t his st u d y s u g gest t hat sacit uz u ma b g o viteca n is ass ociate d wit h a 
l o w rate of i m m u n o ge nicit y. Persiste nt p ositi ve a nti-
  
S N- 3 8 (t he acti ve m eta b olite of iri n oteca n) is met a b olize d b y U G T 1 A 1. Iri n oteca n-treate d 
patie nts w h o are h o m o z y g o us f or t he U G T 1 A 1 * 2 8 allele are at i ncrease d ris k f or ne utr o pe nia 
a n d diarr h ea. 8 6  Preli mi nar y res ults fr o m t he I M M U- 1 3 2- 0 1 st u d y s u g gest t hat t he fre q u e nc y of 
s o me e x p os ure-relate d a d verse e v e nts (i.e., ne utr o pe nia a n d fe brile ne utr o p e nia) ma y be hi g h er 
i n patie nts h o m oz y g o us f or t he * 2 8 allele as well; h o we ver, t he fre q ue ncies of ne utr o pe nia a n d 
ot her treat me nt-relate d a d verse e v e nts, n ota bl y diarr hea, di d n ot differ a m o n g t he s u b gr o u ps. 
 
P ote ntial A Es c o nsi dere d e x pecte d (f or a c o m pre h e nsi ve list of e x pecte d A Es, please refer t o t he 
I n v esti gat or’s Br oc h ure):
 Na usea, v o miti n g, diarr h ea, c o nsti pati o n, a n d a b d o mi nal pai n 
 Ne utr o pe nia, a ne mia re q uiri n g bl o o d tra nsf usi o n, t hr o m b oc yt o pe nia  
 Bacterial a n d viral i nfecti o ns, i ncl u di n g uri nar y tract i nfecti o ns a n d p ne u m o nia  

                                                 
 
 
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 Fe ver a n d fe brile ne utr o p e nia 
Fati g ue a n d h ea d ac he 
A n ore xia, de h y drati o n, a n d wei g ht l oss 
D ys ge usia, h y p o ge usia, a ge usia 
Al o pecia
 Ras h a n d pr urit us 
 A p pe n dicitis, ileitis, or c olitis (rare) 
 Se psis  
 A na p h yla xis (rare)
7. 2
A d verse E ve nt C h ar a cteristics  
 C T C A E ter m ( A E descri pti o n) a n d gr a de:  T he descri pti o ns a n d gra di n g scales f o u n d 
i n t he re vise d N CI C o m m o n Ter mi n ol o g y Criteria f or A d v erse E v e nts ( C T C A E) versi o n 
5. 0 will be utilize d f or A E re p orti n g.  All a p pr o pri ate treat me nt areas s h o ul d ha ve access 
t o a c o p y of t he C T C A E versi o n 5. 0.  A c o p y of t h e C T C A E versi o n 5. 0 ca n be 
d o w nl oa de d fr o m t he C T E P we b site 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m . 
 
 F or e x pe dite d re p orti n g p ur p oses o nl y:  
-
A Es f or t he a g e nt(s) t hat are liste d a b o v e s h o ul d be re p ort e d o nl y if t he a d v erse e v e nt 
varies i n nat ure, i nte nsit y or fre q u e nc y fr o m t he e x pecte d t o xicit y i nf or mati o n w hic h 
is pr o vi de d. 
 Attri b uti o n  of t he A E: 
- 
Defi nite – T he A E is cle arly rel ate d t o t he st u d y treat me nt. 
- 
Pr o ba ble – T he A E is likely rel ate d t o t he st u d y treat me nt.
- 
P ossi ble – T he A E m ay b e rel ate d  t o t he st u d y treat me nt. 
- 
U nli kel y – T he A E is d o u btf ully rel ate d t o t he st u d y treat me nt. 
- 
U nrelate d – T h e A E is cl e arly N O T rel ate d t o t he st u d y treat me nt. 
 
 E x pecte d ness  of t he A E: 
A d verse e ve nts ca n be ‘ E x pecte d’ or “ U n e x pect e d’
o  E x pecte d a d v erse e ve nt 
 
E x pecte d a d v erse e ve nts are t h ose t hat h a ve bee n pre vi o usl y i de ntifie d as 
res ulti n g fr o m a d mi nistrati o n of t he a ge nt. F or t he p ur p oses of t his st u d y, a n 
a d verse e ve nt is c o nsi dere d e x pecte d w he n it a p p ears i n t he c urre nt a d v erse
e ve nt list, t he I n v esti gat or’s Br oc h ure, t he pac ka g e i nsert or is i ncl u de d i n 
t he i nf or me d c o nse nt d o c u me nt as a p ote ntial ris k. 
o
U ne x pect e d a d verse e v e nt
F or t he p ur p os es of t his st u d y, a n a d vers e e ve nt is c o nsi dere d u n e x pect e d 

                                                 
 
 
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w he n it varies i n nat ure, i nte nsit y or fre q ue n c y fr o m i nf or mati o n pr o vi de d i n 
t he c urre nt a d vers e e v e nt list, t he I n vesti gat or’s Br oc h ure, t he p ac ka g e i nsert 
or w he n it is n ot i ncl u de d i n t he i nf or me d c o nse nt d oc u me nt as a p ote ntial ris k. 
 
I n v esti gat ors m ust re p ort t o t he S p o ns or-I n v esti gat or a n y seri o us a d v erse e ve nt ( S A E) t hat 
occ urs after t he i nitial d ose of st u d y treat me nt, d uri n g treat me nt, or wit hi n 3 0 da ys of t he last 
d ose of treat me nt o n t he l ocal i nstit uti o nal S A E f or m ( 9 0 da ys f or p e m br oliz u ma b).  
 
I n t he e ve nt of a n u na ntici pate d pr o ble m or life-t hreate ni n g c o m plicati o ns treati n g i n vesti gat ors 
m ust i m me diatel y n otif y t he S p o ns or-I n vesti gat or. 
 
All occ urre nces of p ote ntial DI LIs, meeti n g t he d efi ne d criteri a i n Secti o n 5. 5, m ust be re p orte d 
as S A Es. 
 
F or M ulti- Ce nter Tri als w here a D F/ H C C i n vesti gat or is ser vi n g as t he S p o ns or, eac h 
partici pati n g i nstit uti o n m ust  a bi de b y t he re p orti n g re q uire me nts set b y t h e D F/ H C C (liste d i n 
Secti o n 7. 3).  T he S p o ns or-I n vesti gat or a n d C o or di nati n g Ce nter s h o ul d be n otifie d of S A Es 
wit hi n 1 b usi ness da y of lear ni n g of t he e ve nt.  
 
7. 3  
E x pe dite d A d verse E ve nt Re p orti n g 
 
T he f oll o wi n g a d vers e e v e nts m ust be re p orte d t o t he D F CI I R B acc or di n g t o t he e x pe dite d 
re p orti n g g ui deli nes: 
 All l ocall y occ urri n g A d verse E ve nts t hat are S eri o us , U nex pecte d , a n d t here is a  
Re as o n a ble P ossi bility  t he A d vers e E ve nt is relat e d t o t he st u d y i nter ve nti o n s h o ul d be 
re p orte d t o t he I R B.  
 
I n v esti gati ve sites wit hi n D F/ H C C will re p ort A Es directl y t o t he D F CI Office f or H u ma n 
Researc h St u dies ( O H R S) per t he D F CI I R B re p orti n g p olic y.  
 All life t hreate ni n g a n d fatal Seri o us A d vers e E ve nts ( gra de 4 a n d 5) c o nsi dere d seri o us,  
u ne x pecte d, a n d rel ate d, m ust be s u b mitte d via a writte n a d vers e e ve nt re p ort t o O H R S 
wit hi n 5 w or ki n g d a ys  fr o m n otificati o n of t he e v e nt.  
 F or all ot her Seri o us A d v erse E ve nts c o nsi dere d s eri o us, u ne x pecte d, a n d relate d, a f ull  
writte n a d vers e e ve nt re p ort m ust be s u b mitte d t o O H R S wit hi n 1 0 w or ki n g d a ys  fr o m 
n otificati o n of t he e ve nt. 
 A n y u nrelate d a d vers e e v e nt d oes n ot re q uire re p orti n g t o O H R S e xce pt gra de 5 e ve nts 
w hic h m ust be re p orte d at t he ti me of c o nti n ui n g re vie w. 
 
 
Ot her i n vesti gati ve sites will re p ort S A Es t o t heir res pecti ve I R B acc or di n g t o t heir l ocal I R B’s 
p olicies a n d pr oce d ures f or re p orti n g a d v erse e ve nts. A c o p y of t he s u b mitte d i nstit uti o nal A E 
f or m will be f or w ar de d t o t he C o or di nati n g Ce nter. T he C o or di nati n g Ce nter will s u b mit A E 
re p orts fr o m o utsi de i nstit uti o ns t o t he D F CI I R B acc or di n g t o D F CI I R B p olicies a n d 
pr oce d ures i n re p orti n g a d verse e v e nts.

                                                 
 
 
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7. 4
Re p orti n g t o t he F o o d a n d Dr u g A d mi nistr ati o n ( F D A) 
T he S p o ns or-I n vesti gat or, as st u d y s p o ns or, will be res p o nsi ble f or all c o m m u nicati o ns wit h t he 
F D A. T h e S p o ns or-I n vesti gat or will re p ort t o t he F D A, re gar dl ess of t he site of occ urre n ce, a n y 
seri o us a d vers e e v e nt t hat meets t he F D A’s criteri a f or e x p e dite d re p orti n g f oll o wi n g t he 
re p orti n g re q uire me nts a n d ti meli nes set b y t he F D A. 
7. 5
Re p orti n g t o H os pit al Ris k M a n a ge me nt
Partici pati n g i n vesti gat ors will re p ort t o t heir l ocal Ris k Ma na ge me nt office a n y partici pa nt 
safet y re p orts, se nti nel e v e nts or u na ntici pate d pr o ble ms t hat re q uire re p orti n g per i nstit uti o nal 
p olic y.  
7. 6
E x pe dite d Re p orti n g t o 
 
A seri o us a d verse e v e nt is a n y a d vers e e ve nt occ urri n g at a n y d ose or d uri n g a n y use of 
pr o d uct (i.e., Ar m A o nl y) t hat: 
 
 Res ults i n deat h; 
 Is life t hreat e ni n g; 
 Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y; 
 Res ults i n or pr ol o n gs a n e xisti n g i n patie nt h os pitalizati o n; 
 Is a c o n ge nital a n o mal y/ birt h defect; 
 Is a ne w ca ncer (t h at is n ot a c o n diti o n of t he st u d y); 
 Is ass ociate d wit h a n o v er d ose;
 Is a n ot her i m p orta nt me dical e ve nt 
A n y seri o us a d verse e v e nt, or f oll o w u p t o a seri o us a d verse e ve nt, i ncl u di n g deat h d ue t o a n y 
ca use ot her t ha n pr o gressi o n of t he ca ncer u n d er st u d y t hat occ urs t o a n y s u bject fr o m t he ti me 
t he c o nse nt is si g ne d t hr o u g h 9 0 da ys f oll o wi n g cessati o n of pe m br oliz u ma b, or t he i nitiati o n of 
ne w a nti-ca ncer t hera p y, w hic he ver is earlier, w het her or n ot relat e d t o 
 pr o d uct, m ust be 
re p orte d wit hi n 2 4 h o urs t o t he S p o ns or-I n v esti gat or a n d wit hi n 2 w or ki n g da ys t o 
 
 o n a Me d Watc h 3 5 0 0 A F or m.  
 
N o n-seri o us E ve nts of Cli nical I nterest will be f or war de d t o 
a n d will be 
ha n dle d i n t he sa me ma n ner as S A Es. Me d watc h 3 5 0 0 A F or ms will be use d f or t hese re p orts. 
A d diti o nall y, a n y seri o us a d verse e ve nt, c o nsi dere d b y a n i n vesti gat or w h o is a q ualifie d 
p h ysicia n t o be relat e d t o 
 pr o d u ct t hat is br o u g ht t o t he atte nti o n of t he i n vesti gat or at a n y 
ti me o utsi de of t he ti me peri o d s pecifie d i n t he pre vi o us para gra p h als o m ust be re p orte d 
i m me diatel y t o 
S A E re p orts a n d a n y ot her rele v a nt s afet y i nf or m ati o n are t o be f or w ar de d t o t he 
 
 
 
A n y S A E t hat is re p orta ble t o t he F D A s h o ul d als o be tra ns mitte d t o 
 at t he 

                                                 
 
 
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n u m ber a b o ve.  
All s u bjects wit h seri o us a d verse e ve nts m ust be f oll o we d u p f or o utc o me. 
7. 6. 1
E ve nts of Cli nical I nt erest ( E CIs)
Selecte d n o n-seri o us a n d seri o us a d vers e e v e nts are als o k n o w n as E v e nts of Cli nical I nterest 
( E CI) a n d m ust be re p ort e d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g da ys t o 
 
 
F or t he ti me peri o d be gi n ni n g w he n t he c o nse nt f or m is si g ne d u ntil treat me nt 
all ocati o n/ra n d o mizati o n, a n y E CI, or f oll o w u p t o a n E CI, t hat occ urs t o a n y s u bject m ust be 
re p orte d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g da ys t o 
 if it 
ca uses t he s u bject t o be e xcl u de d fr o m t he trial, or is t he res ult of a pr ot oc ol-s pecifie d 
i nter ve nti o n, i ncl u di n g b ut n ot li mite d t o was h o ut or disc o nti n uati o n of us ual t hera p y, diet, 
place b o treat me nt or a pr oce d ure. 
F or t he ti me peri o d be gi n ni n g at treat me nt all ocati o n/ra n d o mizati o n t hr o u g h 9 0 da ys f oll o wi n g 
cessati o n of treat me nt, or 3 0 da ys f oll o wi n g cessati o n of treat me nt if t he s u bject i nitiates ne w 
a ntica ncer t hera p y, w hic he ver is earlier, a n y E CI, or f oll o w u p t o a n E CI, w het her or n ot relate d 
t o 
 pr o d u ct, m ust be re p ort e d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 4 h o urs t o 
 
E ve nts of cli nical i nterest f or t his trial i ncl u de: 
1.  O ver d ose of 
pr o d uct, as defi ne d i n - Defi niti o n of a n O ver d os e f or T his Pr ot oc ol 
a n d Re p orti n g of O ver d ose t o t he S p o ns or, t hat is n ot ass ociate d wit h cli nical s y m pt o ms 
or a b n or mal la b orat or y res ults.  
2.  A n ele vate d A S T or A L T la b val ue t hat is greater t ha n or e q ual t o 3 X t he u p per li mit of 
n or mal a n d a n el e vate d t otal bilir u bi n la b val ue t hat is greater t h a n or e q u al t o 2 X t he 
u p per li mit of n or mal a n d, at t he sa me ti me, a n al kali ne p h os p hatase la b v al ue t hat is less 
t ha n 2 X t he u p per li mit of n or mal, as deter mi ne d b y wa y of pr ot oc ol-s pecifie d la b orat or y 
testi n g or u nsc he d ule d la b orat or y testi n g. * 
 
* N ote:  T hese criteria are base d u p o n a v aila ble re g ulat or y g ui da nce d o c u me nts. T he p ur p ose 
of t he criteri a is t o s pecif y a t hres h ol d of a b n or mal he patic tests t hat ma y re q uire a n 
a d diti o nal e val uati o n f or a n u n derl yi n g eti ol o g y.  
7. 6. 2
Defi niti o n of a n O ver d os e of Pe m br oliz u ma b f or T his Pr ot oc ol a n d Re p orti n g of 
O ver d ose t o 
 
F or p ur p os es of t his trial, a n o ver d ose of pe m br oli z u ma b will be defi ne d as a n y d ose of 1, 0 0 0 m g 
or great er.  N o s pecific i nf or mati o n is a vaila ble o n t he treat me nt of o v er d ose of pe m br oliz u ma b. 
A p pr o priate s u p p orti ve treat me nt s h o ul d be pr o vi d e d if cli nicall y i n dicate d. I n t he e ve nt of 
o ver d ose, t he s u bject s h o ul d be o bser ve d cl osel y f or si g ns of t o xicit y.  A p pr o priate s u p p orti ve 
treat me nt s h o ul d be pr o vi de d if cli nicall y i n dicate d. 

                                                 
 
 
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If a n a d v erse e ve nt(s) is ass ociate d wit h (“res ults fr o m”) t he o v er d ose of a 
pr o d u ct, t he 
a d verse e ve nt(s) is re p ort e d as a seri o us a d verse e ve nt, e ve n if n o ot her seri o us ness criteria are 
met. 
 
If a d ose of 
s pr o d uct meeti n g t he pr ot oc ol defi niti o n of o ver d ose is ta ke n wit h o ut a n y 
ass ociate d cli nical s y m pt o ms or a b n or mal la b orat or y res ults, t he o ver d os e is re p orte d as a n o n-
seri o us E ve nt of Cli nical I nterest ( E CI), usi n g t he ter mi n ol o g y “acci de ntal or i nte nti o nal 
o ver d ose wit h o ut a d verse effect.” 
 
All re p orts of o ver d ose wit h a n d wit h o ut a n a d vers e e ve nt m ust be re p orte d wit hi n 2 4 h o urs t o 
t he S p o ns or a n d wit hi n 2 w or ki n g da ys h o urs t o 
 
 
 
7. 6. 3  Re p orti n g of Pre g na nc y a n d Lactati o n t o 
 
 
Alt h o u g h pre g na nc y a n d lactati o n are n ot c o nsi dere d a d vers e e v e nts, it is t he res p o nsi bilit y of 
i n vesti gat ors or t heir desi g nees t o re p ort a n y pre g n a nc y or lactati o n i n a s u bject (s p o nta ne o usl y 
re p orte d t o t he m) t hat o cc urs d uri n g t he trial. 
 
Pre g na ncies a n d lactati o ns t hat occ ur after t he c o nse nt f or m is si g ne d b ut bef ore treat me nt 
all ocati o n/ra n d o mizati o n m ust be re p orte d b y t he i n vesti gat or if t he y ca us e t he s u bject t o be 
e xcl u de d fr o m t he trial or are t he res ult of a pr ot o c ol-s pecifie d i nter v e nti o n, i ncl u di n g b ut n ot 
li mite d t o was h o ut or disc o nti n uati o n of us ual t hera p y, diet, place b o treat m e nt or a pr o ce d ure.   
 
Pre g na ncies a n d lactati o ns t hat occ ur fr o m t he ti me of treat me nt all ocati o n/ra n d o mizati o n 
t hr o u g h 1 2 0 da ys f oll o wi n g cessati o n of pe m br oli z u ma b t hera p y, or 3 0 da ys f oll o wi n g cessati o n 
of treat me nt if t he s u bject i nitiates ne w a ntica ncer t hera p y, w hic h e ver is earlier, m ust be 
re p orte d b y t he i n v esti gat or.  All re p orte d pre g na n cies m ust be f oll o we d t o t he 
c o m pleti o n/ter mi nati o n of t he pre g n a nc y. Pre g n a n c y o utc o mes of s p o nta ne o us a b orti o n, misse d 
a b orti o n, be ni g n h y dati dif or m m ole, bli g hte d o v u m, fetal deat h, i ntra uteri n e deat h, miscarria ge 
a n d still birt h m ust be re p orte d as seri o us e ve nts (I m p orta nt Me dical E ve nts). If t he pre g na n c y 
c o nti n ues t o ter m, t he o utc o me ( healt h of i nfa nt) m ust als o be re p orte d. 
 
S uc h e ve nts m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g da ys t o 
 
 
7. 7  
E x pe dite d Re p orti n g t o 
  
 
A seri o us a d verse e v e nt is a n y a d vers e e ve nt occ urri n g at a n y d ose or d uri n g a n y use of 
 
pr o d uct t hat: 
 
 Res ults i n deat h; 
 Is life-t hreate ni n g; 
 Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y; 
 Res ults i n or pr ol o n gs a n e xisti n g i n patie nt h os pitalizati o n; 
 Is a c o n ge nital a n o mal y/ birt h defect; 

                                                 
 
 
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8
P H A R M A C E U TI C A L I N F O R M A TI O N 
A list of t he a d verse e ve nts a n d p ote ntial ris ks ass ociate d wit h t he i n vesti gati o nal a n d ot her 
a ge nts a d mi nistere d i n t his st u d y ca n be f o u n d i n Secti o n 7. 1. 
8. 1
Pe m br oliz u m a b
 
Please refer t o t he I n v esti gat or’s Br oc h ure f or d etaile d a ge nt i nf or mati o n, a n d t o t he F D A la b el 
f or a d diti o nal i nf or mati o n. 
 
8. 1. 1  Descri pti o n 
 
Pe m br oliz u ma b is a h u ma nize d m o n ocl o nal a nti b o d y of t he I g G 4/ ka p p a is ot y pe, als o 
calle d M K- 3 4 7 5 a n d Ke ytr u da.  Pe m br oliz u ma b bl oc ks ne gati ve i m m u ne re g ulat or y 
si g nali n g b y bi n di n g t o t he P D- 1 rece pt or, i n hi biti n g t he i nteracti o n bet wee n P D- 1 a n d its 
li ga n ds. 
 
T he m olec ular wei g ht of pe m br oliz u ma b is 1 4 8. 9- 1 4 9. 5 K Da. 
 
8. 1. 2  F or m 
 
Cli nical s u p plies will be ma n ufact ure d a n d pr o vi d e d b y 
as s u m mari ze d i n t he 
f oll o wi n g ta ble. 
 
Ta ble: Pr o d uct Descri pti o n 
Pr o d uct N a me & P ote n c y
D os a ge F or m 
Pe m br oliz u ma b 1 0 0 m g/ 4 m L 
S ol uti o n f or I njecti o n 
 
8. 1. 3
St or a ge a n d St a bilit y 
St ore i ntact vials bet wee n 2° C- 8° C ( 3 6° F- 4 6° F).  D o n ot freeze.  Pr otect fr o m li g ht b y 
st ori n g i n t he ori gi nal b o x. 
 
A d mi nister pre pare d s ol uti o ns i m me diatel y after pre parati o n.  If n ot a d mi nistere d 
i m me diatel y, pre pare d s ol uti o ns ma y be st ore d refri gerate d f or u p t o 2 0 h o urs.  
Pe m br oliz u ma b s ol uti o ns ma y be st ore d at r o o m te m perat ure f or a c u m ulati ve ti me of u p 
t o 4 h o urs.  T his i ncl u des r o o m te m perat ure st ora g e of li q ui d dr u g pr o d uct s ol uti o n i n 
vials, r o o m te m perat ure st ora ge of i nf usi o n s ol uti o n i n t he I V ba g, a n d t he d urati o n of 
i nf usi o n. 
 
8. 1. 4  C o m p ati bilit y 
C o m pati ble I V b a g materials: P V C plasticize d wit h D E H P, n o n- P V C ( p ol y olefi n), E V A, 
or P E li ne d p ol y olefi n. 

                                                 
 
 
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8. 1. 5
H a n dli n g
Q ualifie d pers o n n el, 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 he e n vir o n me nt, s h o ul d u n derta k e t he pre p arati o n, ha n dli n g, a n d safe 
dis p osal of t he i m m u n ot hera pe utic a ge nt i n a self-c o ntai ne d a n d pr ot ecti ve e n vir o n me nt.  
 
8. 1. 6  A v ail a bilit y 
 
Pe m br oliz u ma b is a n i n vesti gati o nal a ge nt a n d will be s u p plie d free of c har ge fr o m 
 
 
8. 1. 7  Pre p ar ati o n 
 
Pe m br oliz u ma b s ol uti o n f or i nf usi o n m ust be dil ute d pri or t o a d mi nistrati o n.  All o w t he 
re q uire d n u m ber of vials t o e q uili brate t o r o o m te m perat ure.  D o n ot s ha ke t he vials.  D o 
n ot use if o pa q ue or e xtra ne o us partic ulate m atter ot her t ha n tra nsl uce nt t o w hite 
pr otei nace o us p articles is o bser ve d.  D o n ot use if disc ol ore d.  T o pre p are t he i nf usi o n 
s ol uti o n a d d t he d ose v ol u me of Pe m br oliz u ma b t o a n i nf usi o n ba g c o ntai ni n g 0. 9 & 
S o di u m C hl ori de I njecti o n, U S P of 5 % De xtr ose I njecti o n, U S P.  Ge ntl y i n vert t he ba g 
1 0- 1 5 ti mes t o mi x t he s ol uti o n.  T he fi nal c o nce ntrati o n m ust be bet wee n 1 m g/ m L t o 
1 0 m g/ m L.
8. 1. 8  A d mi nistr ati o n
R o ute of a d mi nistrati o n: I V i nf usi o n o nl y.  D o n ot a d mi nister as a n I V p us h or b ol us 
i njecti o n.
 
Met h o d of a d mi nistrati o n: I nf us e o ver a p pr o xi mat el y 3 0 mi n utes (ra n ge: 2 0- 4 0 mi n utes) 
usi n g a n i nf usi o n set c o ntai ni n g a l o w- pr otei n bi n di n g 0. 2 t o 5 m i n-li ne filter ma ke of 
p ol yet hers ulf o ne or p ol ys ulf o ne.  I nf usi o n rate s h o ul d n ot e xcee d 6. 7 m L/ mi n.  A ce ntral 
li ne is n ot re q uire d h o we ver if a s u bject has a ce ntral ve n o us cat heter i n place, it is 
rec o m me n de d t h at it be use d f or t he i nf usi o n.  D o n ot c o-a d mi nister dr u gs t hr o u g h t he 
sa me i nf usi o n li ne.  F oll o wi n g t he i nf usi o n, fl us h t he I V li ne wit h n or mal sali ne. 
 
8. 1. 9  Or deri n g 
 
Pe m br oliz u ma b will be o btai ne d directl y fr o m
 
 
8. 1. 1 0  Acc o u nt a bilit y 
 
T he i n vesti gat or, or a res p o nsi ble part y desi g nate d b y t he i n vesti gat or, s h o ul d mai ntai n a 
caref ul rec or d of t he i n v e nt or y a n d dis p ositi o n of t he a ge nt usi n g t he N CI Dr u g 
Acc o u nta bilit y Rec or d F or m ( D A R F) or a n ot her c o m para ble dr u g acc o u nta bilit y f or m.  
( See t he N CI I n v esti gat or’s Ha n d b o o k f or Pr oce d ures f or Dr u g Acc o u nta bilit y a n d 
St ora ge.) 

                                                 
 
 
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8. 1. 1 1  Destr ucti o n a n d Ret ur n 
 
At t h e e n d of t h e st u d y, u n us e d s u p pli es of pe m br oliz u ma b s h o ul d b e d estr o y e d 
a c c or di n g t o i nstit uti o n al p oli ci es. D estr u cti o n will b e d o c u m e nt e d i n t h e Dr u g 
A c c o u nt a bilit y R e c or d F or m. 
 
8. 2  
S acit uz u m a b g o vitec a n 
 
8. 2. 1  Descri pti o n 
 
Sacit uz u ma b g o viteca n is a n a nti b o d y- dr u g c o nj u g ate ( A D C) c o m p ose d of h R S 7, a 
 Tr o p- 2 (tr o p h o blast cell-s urface 
a nti ge n- 2), S N- 3 8, a ca m pt ot heci n a nal o g w hic h is a n i n hi bit or of t o p ois o merase I, a n d 
C L 2 A, a p H-se nsiti ve li n ker w hic h c o u ples S N-
   
 
T he m olec ular wei g ht of sacit uz u ma b g o viteca n is 1 6 0 1. 8 g/ m ol. 
8. 2. 2
F or m 
 
Sacit uz u ma b g o viteca n is f or m ulate d f or i n v esti gati o nal use o nl y. F or m ulati o n c o nsists of 
1 0 m g/ m L Sacit uz u ma b g o viteca n f or m ulat e d i n 2 2 m M M E S, p H 6. 5, t o get her wit h t he 
f oll o wi n g e xci pie nts ( 2 5 m M tre hal ose a n d 0. 0 1 % P ol ys or bate 8 0), w hic h are t he n 
l y o p hilize d. Glass vials of sacit uz u ma b g o viteca n 1 8 0 m g as a sterile, n o n- p yr o ge nic, 
l y o p hilize d p o w der are t o be st ore d u n der refri gerate d c o n diti o ns ( 2- 8º C) a n d pr otecte d 
fr o m li g ht u ntil use d. 
 
Eac h vial is la bele d “ Ca uti o n: Ne w Dr u g- Li mite d b y Fe deral ( or U nite d States) La w t o 
I n v esti gati o nal Use. S p o ns or: 
 a n d i de ntifie d b y st u d y dr u g na me, 
l ot n u m ber, a n d d ose. Si nce t he f or m ulate d dr u g pr o d uct c o ntai ns n o preser vati ve, vials 
s h o ul d be use d o nl y o nce. Sacit uz u ma b g o viteca n will be s u p plie d i n cart o ns, eac h 
c o ntai ni n g 1 vial. 
 
8. 2. 3
St or a ge a n d St a bilit y 
Sacit uz u ma b g o viteca n is p h ot ose nsiti ve a n d s h o ul d be pr otecte d fr o m li g ht d uri n g 
st ora ge a n d us e a n d m ust be st ore d u n der refri gerate d c o n diti o ns ( 2- 8º C) i n a l oc ke d 
r o o m t hat ca n be accesse d o nl y b y t he p har macist, t he st u d y I n v esti gat or, or a n ot her d ul y 
a ut h orize d st u d y/site pers o n nel. T he st u d y me dicati o ns m ust n ot be use d o utsi de of t he 
c o nte xt of t his pr ot oc ol. U n der n o circ u msta nces s h o ul d t he I n v esti gat or or ot her site 
pers o n nel s u p pl y st u d y dr u g t o ot her I n vesti gat ors, s u bjects, or cli nics, or all o w s u p plies 
t o be use d ot her t ha n as directe d b y t his pr ot oc ol wit h o ut pri or writte n a ut h orizati o n fr o m 
  
If a b n or malities of t he dr u g vial, rec o nstit ute d pr o d uct or s pecific a d verse e ve nts are 
n ote d t hat are t h o u g ht t o be attri b ute d t o t he st u d y dr u g, u n der n o circ u msta nces are 

                                                 
 
 
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a d diti o nal testi n g or pr oce d ures t o be p erf or me d o n t he affecte d st u d y dr u g vial or 
i nf usi o n ba g a n d st u d y dr u g s h o ul d n ot be discar de d. E ntire st u d y dr u g s h o ul d be retai ne d 
at t he site, a n d 
 s h o ul d be n otifie d i m me diatel y. 
 
8. 2. 4  C o m p ati bilit y 
 
O nl y n or mal sali ne s h o ul d be use d as t he i nf usi o n base s ol uti o n, si nce t he c o m pati bilit y 
of sacit uz u ma b g o viteca n wit h ot her i nf usi o n dil ue nts has n ot bee n e xa mi ne d. D o n ot mi x 
or a d mi nister as a n i nf usi o n, wit h ot her me dici nal pr o d ucts. 
 
8. 2. 5
H a n dli n g
Q ualifie d pers o n n el, 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 he e n vir o n me nt, s h o ul d u n derta k e t he pre p arati o n, ha n dli n g, a n d safe 
dis p osal of t he a nti b o d y dr u g c o nj u gate i n a s elf-c o ntai ne d a n d pr otecti ve e n vir o n me nt.  
 
8. 2. 6
A v ail a bilit y
Sacit uz u ma b g o viteca n is a n i n vesti gati o nal a ge nt a n d will be s u p plie d free of c har g e 
fr o m 
 
 
8. 2. 7  Pre p ar ati o n
 
O btai n t he a p pr o pri ate n u m ber of vials fr o m 2- 8° C st ora ge a n d all o w t he m t o war m t o 
r o o m te m perat ure pri or t o rec o nstit uti o n. T he pr o d uct vi als, as well as 
rec o nstit ute d/ dil ute d pr o d uct i n t he i nf usi o n b a g, m ust be pr otecte d fr o m li g ht 
f oll o wi n g i nstit uti o n al g ui deli nes.  
 
Rec o nstit ute wit h n or mal sali ne a n d dil ute i m me diatel y i nt o i nf usi o n ba gs. I nitiate t he 
i nf usi o n wit hi n 1 h o ur of rec o nstit uti o n/ dil uti o n. If i nf usi o n is dela ye d be y o n d 1 h o ur, 
refri gerate at 2- 8° C f or n o m ore t ha n 4 h o urs fr o m rec o nstit uti o n/ dil uti o n pri or t o 
i nf usi o n. T he vial s h o ul d re mai n i n t he b o x, pr otecte d fr o m li g ht, w hile war mi n g u p t o 
r o o m te m p, a n d o nce rec o nstit ute d a n d dil ute d i nt o t he I V ba g, a pa per slee ve s h o ul d be 
p ut o ver t he I V b a g d uri n g a d mi nistrati o n or if st ore d at 2- 8° C t o pr otect fr o m li g ht. If 
refri gerate d, all o w t he dil ute d s ol uti o n t o c o me t o r o o m te m perat ure pri or t o 
a d mi nistrati o n. If i nf usi o n is n ot i nitiate d wit hi n 4 h o urs after rec o nstit uti o n/ dil uti o n, 
dis p ose of t he ori gi nal pre parati o n a n d pre p are a n e w i nf usi o n ba g b y rec o nstit uti n g a n d 
dil uti n g fr o m ne w vials. Discar d a n y u n us e d p orti o n i n t he vial. T he pr o d u ct d oes n ot 
c o ntai n a pres er vati ve.
 
A p pr o priate us e of as e ptic tec h ni q ue s h o ul d be e m pl o ye d i n pre pari n g t he d ose. All o w 
t he sacit uz u ma b g o viteca n vials t o war m t o r o o m te m perat ure t o all o w fast er diss ol uti o n. 
T he l y o p hilize d p o w der i n eac h vial s h o ul d be rec o nstit ute d usi n g 2 0 m L of 0. 9 % sterile 
s o di u m c hl ori de ( n or mal sali ne). T he rec o nstit ute d s ol uti o n s h o ul d be ge ntl y s wirle d ( d o 
n ot s ha ke t he vials) a n d all o we d t o diss ol ve f or u p t o 1 5 mi n utes. Calc ulate t he re q uire d 
d ose ( m g) base d o n t he s u bject’s b o d y wei g ht at C ycl e 1, Da y 1 ( C 1 D 1). T he d ose is t o 
re mai n c o nst a nt t hr o u g h o ut t he st u d y u nless t here is a > 1 0 % c ha n ge i n b o d y wei g ht fr o m 

                                                 
 
 
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C 1 D 1.  M o dificati o ns t o t he st u d y dr u g d oses a d mi nistere d s h o ul d be ma de f or a > 1 0 % 
c ha n ge i n b o d y w ei g ht fr o m C 1 D 1 a n d acc or di n g t o l ocal a n d re gi o nal pres cri bi n g 
sta n dar ds. D ose m o dificati o ns f or c ha n ges i n b o d y wei g ht < 1 0 % ma y be m a de acc or di n g 
t o l ocal i nstit uti o nal g ui deli nes. Wei g ht ma y be r o u n de d per l ocal i nstit uti o nal practices.  
T he a p pr o pri ate calc ulate d a m o u nt s h o ul d t he n be wit h dra w n fr o m t he s u p plie d vials of 
st u d y dr u g. A 2 1- ga u ge n ee dle is rec o m me n de d. I nject t he s ol uti o n i nt o a glass or plastic 
i nf usi o n c o ntai ner sl o wl y t o mi ni mize f oa mi n g a n d d o n ot s ha ke t he c o nte nts. A dj ust t he 
v ol u me i n t he i nf usi o n c o ntai ner as nee de d wit h n or mal sali ne t o o btai n a c o nce ntrati o n 
of 1. 1- 3. 4 m g/ m L (t otal v ol u me s h o ul d n ot e xcee d 5 0 0 m L). O nl y n or mal sterile sali ne 
s h o ul d be use d si nce t he sta bilit y of t he rec o nstit ute d pr o d uct has n ot bee n deter mi ne d 
wit h ot her i nf usi o n- base d s ol uti o ns. T he pr o d uct d oes n ot c o ntai n a preser v ati ve; 
t heref ore, t he pre pare d st u d y dr u g s h o ul d be refri g erate d u ntil use d a n d all i nf usi o ns m ust 
be i nitiate d wit hi n 4 h o urs of t he i nitial rec o nstit uti o n. 
 
8. 2. 8
A d mi nistr ati o n
R o ute of a d mi nistrati o n: sl o w I V i nf usi o n o nl y.  D o n ot a d mi nister as a n I V p us h or b ol us 
i njecti o n.
 
Met h o d of a d mi nistrati o n: I ntra ve n o us access m ust be well esta blis he d pri or t o i nitiati n g 
i nf usi o n. At t he ti me of d osi n g, t he I V li ne will be c o n necte d t o a n i nf usi o n c o ntai ner 
c o ntai ni n g t he pre pare d v ol u me of sacit uz u ma b g o viteca n. Eit her gra vit y or a n i nf usi o n 
p u m p ma y be use d. I n-li ne filters a n d ot her a ncill ar y i nf usi o n e q ui p me nt is n ot 
rec o m me n de d f or use. T he i nitial i nf usi o n s h o ul d pr ocee d sl o wl y. A d mi nister 
t he first i nf usi o n o ver 3 h o urs. M o nit or t he patie nt d uri n g t he i nf usi o n, a n d f or at least 3 0 
mi n utes after i nf usi o n. S u bse q ue nt i nf usi o ns ma y be a d mi nistere d o ver 1- 2 h o urs 
if pre vi o us i nf usi o ns were well t olerate d. N o s pecific i nf usi o n rate is prescri be d, t he 
c o n d uct of t he i nf usi o n m ust be patie nt s pecific d eter mi ne d as a p pr o priat e b y t he 
ma na gi n g p h ysicia n. F oll o wi n g c o m pleti o n, t he i ntra ve n o us li ne s h o ul d be fl us he d sl o wl y 
wit h 2 0 m L n or mal sali ne a n d t he e n d of i nf usi o n ti me rec or d e d. I n t he e v e nt of i nf usi o n 
reacti o ns or vital si g n c h a n ges, t he i nf usi o n rat e ma y be sl o we d, i nterr u pt e d or 
ter mi nate d, as c o nsi dere d a p pr o priate b y t h e ma na gi n g p h ysicia n. 
 
8. 2. 9
Or deri n g
Sacit uz u ma b g o viteca n will be o btai ne d directl y fr o m 
 
 
8. 2. 1 0  Acc o u nt a bilit y 
T he i n vesti gat or, or a res p o nsi ble part y desi g nate d b y t he i n vesti gat or, s h o ul d mai ntai n a 
caref ul rec or d of t he i n v e nt or y a n d dis p ositi o n of t he a ge nt usi n g t he N CI Dr u g 
Acc o u nta bilit y Rec or d F or m ( D A R F) or a n ot her c o m para ble dr u g acc o u nta bilit y f or m.  
( See t he N CI I n v esti gat or’s Ha n d b o o k f or Pr oce d ures f or Dr u g Acc o u nta bilit y a n d 
St ora ge.)  

                                                 
 
 
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I n case of a Sacit uz u m a b g o viteca n te m perat ure e xc ursi o n, t he f oll o wi n g mail b o x ma y be 
use d f or n otificati o n wit h d oc u me ntati o n: 
8. 2. 1 1  Destr ucti o n a n d Ret ur n 
 
At t he e n d of t he st u d y, or if i nstr ucte d d uri n g t he st u d y, f oll o wi n g a ut h orizati o n b y st u d y 
ma na ge me nt, st u d y me di cati o n ma y be destr o y e d at t he site as dictate d b y t he a p pr o pri ate 
sta n dar d o perati n g pr oce d ures. Destr u cti o n m ust be d oc u me nte d wit h si g nat ure b y site’s 
p har macist or del e gate. 
9
BI O M A R K E R, C O R R E L A TI V E, A N D S P E CI A L S T U DI E S
 
All bi o mar ker a n al yses c o m plete d o n bl o o d a n d tiss ue sa m ples f or c orrel ati ve data will be 
e x pl orat or y. 
 
Pri or t o S p o ns or A me n d me nt 3, t he P D- L 1 eli gi bilit y a me n d me nt: All patie nts w h o u n der we nt 
pre-scree ni n g f or t he trial were re q uire d t o s u b mit a n arc hi v al tiss ue sa m ple f or ce ntral P D- L 1 
testi n g. If t he p artici pa nt e nr olle d o n t he trial, n o a d diti o nal arc hi val tiss ue was re q uire d. 
A d diti o nal tiss ue left o ver after ce ntral testi n g will be use d f or tiss ue a nal yses liste d i n Secti o n 
9. 3. A n y tiss ue left o ver after t hese a nal yses ha v e b ee n c o m plete d will be ba n ke d f or f ut ure 
researc h.  
 
After S p o ns or A me n d me nt 3, t he P D- L 1 eli gi bilit y a me n d me nt: Ce ntral P D- L 1 testi n g will n ot 
be re q uire d f or eli gi bilit y. Arc hi val tiss ue will be re q ueste d f or all patie nts f or t he p ur p oses of 
retr os pecti ve ce ntral P D- L 1 testi n g a n d ot her e x pl orat or y bi o mar ker a n al yses as descri be d i n t his 
secti o n. 
 
I n all patie nts i n w h o m t u m or is safel y accessi ble, baseli ne a n d o n treat me nt t u m or bi o psies are 
re q uire d. 
We pla n t o use t hese tiss ues t o perf or m i m m u ne pr ofili n g assa ys, i ncl u di n g 
c haracteri zati o n base d o n hist ol o g y ( TI Ls), pr otei n e x pressi o n, a n d m R N A e x pressi o n, as detaile d 
bel o w. We will perf or m tar gete d p a nel ( O nc o Pa n el) a n d w h ole e x o me se q ue nci n g t o det er mi ne 
m utati o nal l oa d a n d i de ntif y s pecific ge n o mic alterati o ns ass ociate d wit h res p o nse. A d diti o nall y, 
we will ba n k s peci me ns f or p ossi ble f ut ure a d diti o nal a nal yses. 
Serial bl o o d dra ws f or c orrelati ve scie n ce are re q uire d o n t his trial; bl o o d dra ws will be o btai n e d 
e ver y 9 w ee ks pri or t o t he i nf usi o n of st u d y dr u gs, at t he e n d- of-treat me nt visit i n patie nts w h o g o 
off st u d y f or pr o gressi ve disease, a n d all eff orts will be ma de t o o btai n a n a d diti o nal bl o o d dra w 
at t he ti me of pr o gressi ve disease i n patie nts w h o we nt off st u d y f or a n y reas o n ot h er t ha n 
pr o gressi ve disease. O n eac h bl o o d dra w, we will perf or m fl o w c yt o metr y t o c haracterize pr otei n 
e x pressi o n of i m m u ne me diat ors, as detaile d b el o w, a n d a d diti o nal bl o o d will be ba n ke d f or f ut ure 
a nal yses. 
 
I nstr u cti o ns f or t he c ollecti o n, la beli n g a n d s hi p me nt of bl o o d, tiss ue, a n d st o ol sa m ples are 
o utli ne d bel o w a n d f urt h er detaile d i n t he L a b Ma n ual.  
 

                                                 
 
 
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Please n ote t hat s o me of t he d o w nstrea m c orrel ati ve pla ns f or bl o o d a n d tiss ue i ncl u de w h ole 
e x o me se q ue n ci n g, R N A se q ue nci n g, si n gle cell se q ue nci n g, si n gle- n u cle us se q ue nci n g, t u m or 
tiss ue s patial pr ofili n g, ge ne e x pressi o n assa ys, a n d di gital s patial pr ofili n g, as well as a n al ysis of 
t he data ge n erate d, w hic h ma y be perf or me d at D F CI, B W H, Har v ar d Me di cal Sc h o ol, Yale 
Ca ncer Ce nter, t he Br oa d I nstit ute of MI T, A da pti ve Bi otec h n ol o gies, F o u n dati o n Me dici ne, 
Na n ostri n g Tec h n ol o gies, I n c., Re veal Ge n o mics, B ost o n Ge ne, 
 a n d/ or 
Ve nta na. All sa m ples will be se nt i n a de-i de ntifie d fas hi o n. O nl y desi g nate d st u d y pers o n nel at 
D F CI will ha ve access t o P HI. 
 
 
S peci me n C ollecti o n T a ble  
 
 
a.  Wit h R est a gi n g ( e v er y 9 w e e ks, c oi n ci di n g wit h d a y 1 of t h at c y cl e).  
b.  Fr es h t u m or bi o ps y of a c c essi bl e m et ast ati c l esi o n is m a n d at or y b ef or e tr e at m e nt b e gi ns a n d 
b et w e e n C 2 D 1 a n d C 3 D 1. T h e b as eli n e bi o ps y m a y b e p erf or m e d at s cre e ni n g or o n C y cle 1 D a y 1 
pri or t o d osi n g.  T h e o n-tr e at m e nt bi o ps y s h o ul d t a k e pl a c e aft er d osi n g o n C 2 D 1 a n d b ef or e d osi n g 
o n C 3 D 1. S e e s e cti o n 9. 2 b el o w.   
c.  Bl o o d s a m pl es ar e m a n d at or y f or p ati e nts wit h pr o gr essi v e dis eas e. F or p ati e nts w h o c o m e off 
tr e at m e nt f or ot h er r e as o ns, bl o o d s a m pl es ar e o pti o n al at e n d of tr e at m e nt a n d e v er y 9- 1 2 w e e ks 
d uri n g f oll o w u p. S ee S e cti o n 1 0, St u d y C al e n d ar. 
S peci me n
Scree ni n g
C 1 D 1
C 2 D 1
C 3 D 1
S u bse q ue nt 
C ycles 
D a y 1  
E O T/ P D
S hi p pi n g C o n diti o n
S hi p t o
La v e n der T o p 
T u b e ( Secti o n 9. 3) 
 
x  
 
 
 
 
A m bie nt  
D F CI T- H u b  
Strec k T u b e 
( Secti o n 9. 3) 
 
x 
 
 
x a 
xc 
A m bie nt
D F CI T- H u b 
C P T T u b es
( Secti o n 9. 3) 
 
x 
 
 
 
x a 
xc 
A m bie nt 
D F CI T- H u b 
Arc hi v al t u m or 
tiss u e ( bl o c ks or 
sli des) 
( Secti o n 9. 1) 
x 
 
 
 
 
A m bie nt 
B O C Tra nslati o n al 
Tea m 
Re q uire d fres h 
t u m or tiss u e 
bi o ps y b  
( Secti o n 9. 2)
 x
x 
 
 
F F P E, R N Alater: 
A m bie nt 
O C T: Fr oze n ( dr y ice)  
Flas h Fr oze n w/ o 
me dia e
D F CI T- H u b:  
O C T, R N Alater,
F F P E/f or mali n 
C C G T ea m: Flas h 
Fr o ze n w/ o me dia e
O pti o n al fres h 
t u m or tiss u e bi o ps y
( Secti o n 9. 2) 
 
 
 
 
 
x 
F F P E, R N Alater: 
A m bie nt 
O C T: Fr oze n ( dr y ice) 
D F CI T- H u b: 
O C T, R N Alater,
F F P E/f or mali n 
St o ol sa m ple 
c ollecti o n 
( Secti o n 9. 4)
x 
 
x 
 
xd 
A m bie nt 
D F CI T- H u b 

                                                 
 
 
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d.  St o ol s a m pl e will b e c oll e ct e d at ti m e of pr o gr essi o n if r es p o ns e w as o bs er v e d wit h tre at m e nt. 
e.  O nl y f or s u bs et of D F CI p ati e nts, w h o u n d er g o si n gl e- n u cl e us R N A s e q u e n ci n g. S e e L a b M a n u al 
a n d S e cti o n 9. 3. 3. 
9. 1
Ce ntr al P D- L 1 Testi n g o n Arc hi v al Tiss ue
Testi n g f or P D- L 1 p ositi vit y will be perf or me d b y Disc o ver y Life Scie nces ( D L S)/ Q ual Te k 
M olec ular La b orat ories. P D- L 1 pr otei n e x pressi o n will be deter mi ne d b y usi n g t he a nti- P D- L 1 
a nti b o d y cl o ne I H C 2 2 C 3 P har m D x c o m merci al kits ( A gile nt).  P D- L 1 I H C 2 2 C 3 P har m D x is a 
q ualitati ve i m m u n o hist oc he mical assa y usi n g M o n ocl o nal M o use A nti- P D- L 1. Cl o ne 2 2 C 3 is 
i nte n de d f or use i n t he d etecti o n of P D- L 1 pr otei n i n f or mali n-fi xe d, paraffi n-e m be d de d ( F F P E) 
tiss ue. P D- L 1 pr otei n e x pressi o n will be deter mi n e d b y usi n g C o m bi ne d P ositi ve Sc ore ( C P S), 
w hic h is t he n u m ber of P D- L 1 stai ni n g cells (t u m or cells, l y m p h oc ytes, macr o p ha g es) di vi de d b y 
t he t otal n u m ber of via bl e t u m or cells, m ulti plie d b y 1 0 0. T he s peci me n will be c o nsi dere d P D-
L 1- p ositi ve 
 
 
9. 1. 1  C ollecti o n 
 
1 bl oc k or 2 5 u nstai ne d sli des ( 4- 5 u m sli de t hic k ness) a n d 1 re prese ntati v e H & E of t u m or tiss ue 
s h o ul d be re q ueste d fr o m a past pr oce d ure. T u m or tiss ue will be re q ueste d fr o m t he m ost rece nt 
s peci me n a vaila ble, a n d metastatic arc hi val tiss ue will be re q ueste d w he n a vaila ble o ver pri mar y 
arc hi val tiss ue. Alt h o u g h b o ne tiss ue is n ot preferre d, it is all o we d ( u nless d ecalcifi e d) if n o ot her 
t u m or tiss ue is a vaila ble. See secti o n 9. 3 f or a d diti o nal i nf or mati o n re gar di n g pla n ne d/ p ote ntial 
researc h usi n g arc hi val tiss ue sa m ples.  
 
 
9. 1. 2  S hi p pi n g  
 
Arc hi val tiss ue sli des will be s hi p pe d t o t he D F CI tra nslati o nal tea m as des cri be d i n t he 
la b orat or y ma n u al. 
 
9. 2  
Fres h Tiss ue Bi o ps y  
 
9. 2. 1  O bjecti ves 
 
T he st u d y will o btai n paire d t u m or bi o psies f or patie nts e nr olle d (after s acit uz u ma b g o viteca n 
m o n ot hera p y a n d after sacit uz u ma b g o viteca n i n c o m bi nati o n wit h pe m br oliz u ma b). Paire d 
bi o psies will be use d t o e val uate c h a n ges i n TI Ls, e x pressi o n of i m m u ne mar kers (e. g., i m m u ne 
cell s u bsets, i n hi bit or y a n d c o-sti m ulat or y pat h wa y m olec ules b y i m m u n o hist oc he mistr y a n d/ or 
i m m u n ofl u oresce nce) a n d ot her rele v a nt mar k ers. A d diti o nall y, t he bi o psies will be s u bj ecte d t o 
w h ole e x o me se q ue n ci n g ( W E S) t o deter mi ne c h a n ges i n m utati o nal l oa d, m utati o nal si g nat ures, 
a n d ge n o mic alterati o ns i n a nti ge n prese ntati o n a n d ot her i m m u n ot hera p y-res p o nse pat h wa ys. A 
p orti o n of t he bi o psies will be use d t o perf or m si n gle-cell R N A se q ue nci n g t o deter mi ne m R N A 
e x pressi o n si g nat ures i n t u m or a n d i m m u ne cells t hat c orrelate wit h res p o nse a n d resista nce t o 
i m m u n ot hera p y. 
 

                                                 
 
 
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9. 2. 2
C ollecti o n of S peci me ns 
Bi o psies will be perf or m e d at t he bel o w ti me p oi nts, if t u m or is safel y accessi ble f or bi o ps y.  
Ma n dat or y: 
 Baseli ne d uri n g t he Scree ni n g P hase or o n C 1 D 1 pri or t o d osi n g 
 After 3- 6 wee ks of treat me nt (a n y ti me fr o m C 2 D 1- C 3 D 1) 
O pti o nal: 
 At ti me of pr o gressi o n  
Retreat me nt  
F or patie nts pr ocee di n g t o t he retreat me nt p hase, bi o psies will be perf or me d at t he bel o w 
ti me p oi nts: 
Ma n dat or y: 
 At ti me of pr o gressi o n, pri or t o restarti n g sacit uz u ma b g o viteca n + p e m br oliz u ma b ( Ar m 
A) or sacit uz u ma b g o viteca n ( Ar m B) 
At ti me of pr o gressi o n o n retreat me nt, if a c o m pl ete or partial res p o nse, or sta ble disease 
 
If d osi n g is dela ye d placi n g t he bi o ps y o utsi de of t he all o wa ble wi n d o w, t he bi o ps y s h o ul d be 
resc he d ul e d t o b e wit hi n t he wi n d o w. If n ot feasi ble, t he bi o ps y s h o ul d b e o btai ne d as cl ose t o 
wit hi n t he wi n d o w as p ossi ble. Tiss ue s peci me ns will be c ollecte d fr o m rec urre nt or met astatic 
lesi o ns usi n g sta n dar d i nstit uti o nal pr oce d ures. T he a m o u nt of tiss ue c ollecte d will f oll o w t he 
g ui deli nes liste d bel o w. If a partici pa nt has m ore t ha n o ne site of disease, o nl y o ne site nee ds t o be 
bi o psie d i n or der t o g o o n t o t he st u d y a n d t he site is left t o t he discreti o n of t he patie nt a n d t heir 
treati n g p h ysicia n. Fi ne n ee d as pirates ( F N A) are n ot all o we d. Partici pa nts w h o u n der g o a researc h 
bi o ps y pr oce d ure f or t he p ur p ose of t his pr ot oc ol, a n d i n w h o m i na de q uate tiss ue is o btai ne d, are 
still eli gi ble a n d are n ot re q uire d t o u n der g o a re p eat bi o ps y i n or der t o e nter t he st u d y. 
 Bre ast : A g oal of 3- 6 c ore bi o ps y s peci me ns will be o btai ne d usi n g sta n d ar d i nstit uti o nal 
g ui deli nes f or a dia g n osti c c ore bi o ps y of a breast mass. 
 Ski n/c hest w all : A g oal of 1- 2 4- m m p u nc h bi o psies will be o btai ne d. 
 Ly m p h n o de : A g oal of 3- 6 c ore bi o ps y s peci me ns will be o btai ne d usi n g a n 1 8- ga u ge 
nee dle.
 Liver : A g oal of 3- 6 c ore bi o ps y s peci me ns will be o btai ne d usi n g a n 1 8- ga u ge nee dle. 
 L u n g : Beca use of t he ris k of p ne u m ot h ora x ass ociate d wit h c ore nee dle bi o psies of l u n g 
n o d ules, n o c ore bi o psies of l u n g n o d ules will be perf or me d o n t his pr ot oc ol, u nless t he y 
are cli nicall y i n dicate d.
 B o ne : Beca use t he yiel d of mali g na nt tiss ue fr o m b o ne bi o psies te n ds t o be relati vel y l o w, 
n o b o ne bi o psies will be perf or me d o n t his pr ot oc ol, u nless t he y are cli nicall y i n dicate d.  

                                                 
 
 
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 Ple ur al fl ui d : A g oal of 5 0 0 cc of pl e ural fl ui d will be o btai n e d wit h a sta n dar d 
t h orace ntesis pr o ce d ure, wit h or wit h o ut i ma ge g ui da nce, acc or di n g t o t he cli nical 
j u d g me nt of t he treati n g p h ysicia n a n d cli nicia n p erf or mi n g t he pr o ce d ure. Less t ha n t he 
g oal a m o u nt is acce pt a ble a n d s h o ul d b e bas e d u p o n t he cli nical j u d g me nt of t he 
I n v esti gat or a n d t he cli ni cia n perf or mi n g t he pr oce d ure. If m ore t ha n t he g oal a m o u nt of 
fl ui d is o btai ne d, t he n t he e ntire s peci me n ( wit h t he e xce pti o n of w h at is nee de d f or cli nical 
p ur p oses, if a p plica bl e) will be st ore d i n t he tiss ue ba n k. 
 Ascites fl ui d : A g oal of 5 0 0 cc of as cites fl ui d will be o btai ne d wit h a sta n d ar d parace nt esis 
pr oce d ure, wit h or wit h o ut i ma ge g ui da nce, acc or di n g t o t he cli nical j u d g me nt of t he 
treati n g p h ysicia n a n d cli nicia n perf or mi n g t he pr oce d ure. Less t h a n t he g oal a m o u nt is 
acce pta ble a n d s h o ul d be base d u p o n t he cli nical j u d g me nt of t he I n vesti gat or a n d t he 
cli nicia n perf or mi n g t he pr oce d ure. If m ore t ha n t he g oal a m o u nt of fl ui d is o btai ne d, t he n 
t he e ntire s peci me n ( wit h t he e xce pti o n of w hat is nee de d f or cli nical p ur p oses, if 
a p plica ble) will be st ore d i n t he tiss ue ba n k. 
 
Please n ote t hat t he a b o ve are g ui deli nes f or t he a m o u nt of tiss ue t o be o btai ne d at t he baseli ne 
bi o ps y a n d are n ot mea nt t o re place cli nical j u d g m e nt at t he ti me t he pr oce d ure is perf or me d. Less 
t ha n t he g oal q ua ntit y of tiss ue is acce pt e d f or eac h t y pe of bi o ps y a n d will be left t o t he cli nical 
j u d g me nt of t he p h ysicia n perf or mi n g t he pr oce d ure. If ascites or pl e ural fl ui d is t o be use d as t he 
i n vesti gati o nal bi o ps y s peci me n, c o nsi derati o n s h o ul d be gi ve n t o c o nfir mi n g t he mali g na nt nat ure 
of t he ascites or pl e ural fl ui d pri or t o st u d y e ntr y. 
 
If a patie nt is u n der g oi n g resecti o n of a lesi o n f or cli nical reas o ns (i.e. we d ge resecti o n of a ne w 
l u n g lesi o n f or c o nfir mati o n of dia g n osis or re-testi n g of h or m o ne rece pt or or H E R 2 stat us; or, 
resecti o n of a c hest wall lesi o n; or, resecti o n of a l y m p h n o de), t he n t he patie nt ma y o pt t o ha ve a 
p orti o n of t hat tiss ue st ore d f or res earc h at t he ti me of t he pr oce d ure ( pr o vi de d t hat t he tiss ue is 
c ollecte d a n d pr ocesse d as s pecifie d i n t his secti o n a n d t he La b Ma n ual), i n w hic h case, t he 
partici pa nt w o ul d n ot be re q uire d t o u n der g o a se parate res earc h bi o ps y f or e ntr y i nt o t his pr ot oc ol.
9. 2. 3
S hi p pi n g
 
Tiss ue will be s hi p pe d t o t he D F CI Breast Tra nslati o nal H u b- S mit h ( T- H u b) per t he i nstr ucti o ns 
i n t he la b orat or y ma n u al. 
 
9. 3  
Arc hi v al a n d Fres h Tiss ue – P ote nti al Testi n g 
9. 3. 1
Arc hi val Tiss ue fr o m Pre- Scree ni n g a n d E nr olle d Partici pa nts 
Pri or t o S p o ns or A me n d me nt 3, t he P D- L 1 eli gi bilit y a me n d me nt: After 5 u nstai ne d sli des were 
se nt t o D L S/ Q ual Te k f or P D- L 1 testi n g, t he re mai ni n g tiss ue ( u p t o 1 0 u nstai ne d sli des a n d 1 
H & E) was se nt t o t he D F CI St u d y Tea m t o creat e a s mall tiss ue ba n k. Vari o us assa ys descri b e d 
i n Secti o n 9. 3. 3 will be perf or me d, i n or der t o c h aracterize t he i m m u ne micr oe n vir o n me nt of 
H R +/ H E R 2- breast ca ncer. T his w or k ma y be p u blis he d se parat el y fr o m t his trial. A n y 
re mai ni n g tiss ue left o ver after t his w or k h as bee n perf or me d will be ba n ke d f or f ut ure researc h. 

                                                 
 
 
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After S p o ns or A me n d me nt 3, t he P D- L 1-eli gi bilit y a me n d me nt: A t otal of 1 5 u nstai ne d sli des 
( 4- 5 micr o n t hic k ness) fr o m a n arc hi val F F P E t u m or sa m ple ( metastatic or pri mar y t u m or) will 
be re q uest e d f or t he p ur p oses of ce ntral P D- L 1 testi n g a n d ot her pla n ne d assa ys as descri be d i n 
Secti o n 9. 3. 3. U p t o fi ve sli des ma y be se nt t o D L S/ Q ualte k f or ce ntral P D- L 1 testi n g, w hic h will 
occ ur retr os pecti vel y. A n y re mai ni n g tiss ue left o v er aft er t his w or k has b ee n perf or me d will be 
ba n ke d f or f ut ure researc h.  
9. 3. 2
Fres h Tiss ue Bi o psies 
 
E nr olle d partici pa nts wit h accessi ble disease will u n der g o re q uire d paire d researc h bi o psies at 
baseli ne a n d o n treat me nt a n d a n o pti o nal bi o ps y at pr o gressi o n. I n t he cas e of retreat me nt, t here 
ma y be a d diti o nal bi o psies perf or me d at pr o gressi o n ti me p oi nts. Tiss ue c ollecte d fr o m t hes e 
bi o psies will be use d i n acc or da n ce wit h secti o n 9. 3. 3. 
9. 3. 3
P ote ntial Tiss ue Assa ys 
Assa y 1: T u m or i nfiltrati n g l y m p h oc yte ( TI L) p erce nta ge a n d deter mi nati o n of l y m p h oc yte 
pre d o mi na nt breast ca ncer ( L P B C) 
 Paraffi nize d, he mat o x yli n a n d e osi n-stai ne d sli des ta ke n fr o m 1- 2 tiss ue pla nes will be 
deri ve d fr o m eac h bi o ps y a n d will be re vie we d b y certifie d pat h ol o gists.  I n t he res earc h 
setti n g, all cas es are re vi e we d b y t w o pat h ol o gists a n d a n y disc or da nt res ults res ol ve d b y 
c o nse ns us re vie w. T he e xte nt of l y m p h oc ytic i nfiltrate i n t u m or tiss ue will be assesse d, a n d 
str o mal TI L perce nta g e will be deter mi ne d. M ore detaile d g ui deli nes f or t he q ua ntificati o n 
of str o mal TI Ls i n breast ca ncer ca n be f o u n d i n t he rec o m me n dati o ns fr o m t he 
I nter nati o nal TI Ls W or ki n g Gr o u p.8 8 
 
 After ass ess me nt of t he TI L p erce nta ge, t he p at h ol o gists will cate g orize t he s peci me n as 
l y m p h oc yte pre d o mi na nt breast ca ncer ( L P B C), defi ne d as a t u m or t hat c o ntai ns > 6 0 % 
str o mal l y m p h oc ytes, or n o n- L P B C. 
 
Assa y 2: I m m u n o hist oc he mistr y a n d i m m u n ofl u oresce nce assa ys 
 Tiss ue will be c ollecte d a n d fi xe d b y 1 0 % n e utral b uffere d f or mali n o ver ni g ht, de h y drate d, 
a n d paraffi n e m be d d e d. F o ur micr o meter-t hic k s ecti o ns will be c ut. T h e paraffi n bl oc ks 
a n d u nstai ne d sli des will be st ore d at r o o m te m p erat ure. I m m u n o hist oc he mical stai ni n g 
will be perf or me d i n t he Ce nter f or I m m u n o- O nc ol o g y Pat h ol o g y C ore at Da na-
Far b er/ Har var d C a ncer Ce nter ( D F/ H C C) S peciali ze d Hist o pat h ol o g y C ore. 
U nstai ne d sli des fr o m a metastatic site or n e wl y ac q uire d bi o ps y m a y be se nt t o B W H 
Pat h ol o g y, Yale Ca ncer Ce nter, 
 or Ve nta na f or e x pl orat or y 
assess me nt of Tr o p- 2 e x pressi o n a n d ot her bi o mar kers.  
F or mali n-fi xe d, p araffi n-e m be d de d ( F F P E) t u m or sli des will be pre pare d a n d H & E stai ne d 
f or ass ess me nt of TI L i n pre- a n d p ost-treat me nt t u m or sa m ples. S u bs ets of differe nt 
i m m u ne p o p ulati o ns (effect or/ me m or y C D 8 cells, T re g ulat or y cells, de n dritic cells, t u m or 

                                                 
 
 
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ass ociate d m acr o p h a ges, a n d Tie- 2 e x pressi n g m o n oc ytes ( T E M)) will b e i de ntifie d usi n g
i m m u n o hist oc he mical (I H C) a n d/ or i m m u n ofl u oresce n ce (I F) stai ni n g o n F F P E t u m or 
sli des. C yclic i m m u n ofl u oresce n ce ( C y CI F) at Har var d 
Me dical Sc h o ol ma y als o be 
utilize d t o defi ne i m m u ne cell s u b p o p ulati o ns a n d si n gle cells wit h t his hi g hl y m ulti ple xe d 
i m m u n ostai ni n g met h o d. 
 
 Ce ntral P D- L 1 I H C testi n g ma y als o be perf or m e d o n t he t u m or tiss ue researc h bi o psies 
c ollecte d o n st u d y. U p t o fi ve F F P E u nstai ne d sli des ( 4- 5 micr o n t hic k ness) ma y be se nt t o 
D L S/ Q ualte k f or ce ntral P D- L 1 testi n g, w hic h will occ ur retr os p ecti vel y. T his will all o w 
c haracteri zati o n of c ha n ges i n P D- L 1 e x pressi o n wit h e x p os ure t o t hera p y a n d will als o 
e na ble c o m paris o n of P D- L 1 res ults bet wee n metastatic res earc h t u m or bi o psies a n d 
arc hi val t u m or sa m ples ( Secti o n 9. 1 a n d 9. 3. 1).  
 
Testi n g f or P D- L 1 p ositi vit y will be perf or me d b y Disc o ver y Life Scie n ces ( D L S)/ Q ual Te k 
M olec ular L a b orat ori es. P D- L 1 pr otei n e x pressi o n will be deter mi ne d b y usi n g t he a nti-
P D- L 1 a nti b o d y cl o ne I H C 2 2 C 3 P har m D x c o m mercial kits ( A gile nt). T he s peci me n will
be c o nsi dere d P D- L 1-
 
 
 I n v esti gat ors at o ur i nstit uti o n ha ve de v el o pe d I H C stai ni n g o n paraffi n e m be d de d tiss ues 
f or P D- L 1, P D- L 2, TI M- 3, a n d L A G- 3 t hr o u g h o ur ce nter f or I m m u n o- O nc ol o g y 
Pat h ol o g y C ore ( Sc ott R o di g M D, P h D, C ore Direct or).  P D- L 1 I H C has rece ntl y bee n 
esta blis he d i n a C LI A a p pr o ve d la b orat or y a n d t h e re m ai ni n g assa ys f or C LI A la b orat or y 
c o n d uct are bei n g fi nalize d.  
 
T hese i n vesti gat ors ha v e p u blis he d t he met h o ds, pr ot oc ols, a n d data esta blis hi n g t he 
se nsiti vit y a n d s pecificit y of I H C stai ni n g ass a ys usi n g t he 
m o n ocl o nal a nti b o dies 
rec o g nizi n g P D- L 1 ( C D 2 7 4, B 7- H 1, a nti b o d y cl o ne 7 G 1 1, ge nerate d i n t he la b of G or d o n 
Free ma n, D F CI) a n d P D- L 2 ( C D 2 7 3, B 7- D C, cl o ne 9 E 5, g e nerate d i n t he la b orat or y of 
G or d o n Free ma n, D F CI). 8 9, 9 0 
T u m or a n d i m m u ne cell e x pressi o n of P D- L 1 will be e val uate d at differe nt c ut- off p oi nts 
(i.e. 1 %, 5 %, 1 0 %, 5 0 %). All I H C stai ne d sli des will be e val uate d b y a pat h ol o gist a n d H-
sc ores will be re p orte d. A s u bset of sli des will be re vie we d b y a sec o n d pat h ol o gist t o 
e ns ure c o n c or da n ce of i nter pretati o n. 
 
T he se mi- q ua ntitati ve s c ori n g f or t his st u d y is i n acc or da nce wit h t h ose p u blis he d 
pre vi o usl y a n d as descri be d a b o ve, will i ncl u de sc ores f or b ot h t he n e o plastic a n d n o n-
ne o plastic cells wit hi n t h e t u m or micr o e n vir o n me nt. Data deri ve d fr o m pat h ol o gist vis ual 
sc ori n g (se mi- q ua ntitati v e, b ut wit h i ncrease d s p ecificit y f or d eli neati n g ne o plastic a n d 
n o n- ne o plastic cells) a n d pat h ol o gist-assiste d, a ut o mate d sc ori n g ( q ua ntitati ve, b ut wit h o ut 
acc uratel y deli neati n g ne o plastic a n d n o n- ne o plastic cells) f or eac h mar ker of i nterest will 
be assesse d f or its cli nical val ue.  
 
 F F P E t u m or sli des will als o be assesse d b y I H C a n d/ or I F assa ys f or ot her mar kers, 
i ncl u di n g M H C class I a n d II mar kers ( H L A- A B C, H L A- D R) a n d de n dritic cell m ar kers 
( C D 1 1c, C D 1c, C D 1 2 3), as dee me d a p pr o priate a n d i nf or mati ve base d o n t he literat ure at 

                                                 
 
 
           D F/ H C C Pr ot o c ol #: 2 0- 1 5 3 
 
           
               Pr ot o c ol Versi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
7 2 
t he ti me of c orrelati ve sci e nce p erf or m a nce. 
Assa y 3: B ul k a n d Si n gle- N ucle us R N A Se q u e nci n g
R N A a nal ysis ma y b e p erf or me d, a n d tiss ue f or R N A a n al ysis will be st ore d, i n t he D F CI- T- H u b. 
Messe n ger R N A ( m R N A) e x pressi o n wit hi n t u m or bi o ps y s peci me ns m a y be assesse d usi n g t he 
m ost c urre nt a n d i nf or m ati ve met h o d ol o gies at t he ti me t hat c orrelati ve s cie nce is perf or me d o n 
all s peci me ns. Na n o Stri n g si g nat ures a n d/ or w h ole tra nscri pt o me se q u e nci n g ma y be use d. 
P ote ntial ge nes of i nterest, base d o n pri or i m m u ne pr ofili n g of breast t u m ors i ncl u de C X C L 9, 
C C L 5, C D 8 A C D 8 0, C X C L 1 3, I G K C, C D 2 1, I D O 1, P D- 1, P D- L 1, P D- L 2, C T L A 4, a n d F O X P 3. 9 1
Per o u a n d ot hers h a ve pre vi o usl y s h o w n t hat wit hi n T N B C, e xists all of t he i ntri nsic s u bt y pes of 
breast ca ncer. T h us, we pr o p ose t o use t he P A M 5 0 al g orit h m 9 2 a n d t he Cla u di n-l o w pre dict or 9 3  i n 
or der t o deter mi ne t he i ntri nsic s u bt y pe of eac h sa m ple. S pecificall y, usi n g t he R N A-se q dat a, a 
gl o bal n or malizati o n ste p will be perf or me d t o a dj ust t he T N B C R N A-se q data o btai ne d i n t his 
st u d y relati ve t o t he T N B C s u bset of patie nts i n t he T C G A R N A-se q st u d y. O nce t his 
n or malizati o n is c o m plete, t he P A M 5 0 al g orit h m will be r u n as descri be d i n Par ker et al. 2 0 0 9, 
a n d t he n t he Cla u di n-l o w pre dict or will be r u n as descri be d i n Prat et al., t h us classif yi n g 
sa m ples i nt o 1 of 6 i ntri nsic s u bt y pes. T he i ntri nsic s u bt y pe classificati o ns will be teste d f or 
ass ociati o ns wit h disease res p o nse t o treat me nt usi n g u ni variate a n d m ulti variate testi n g i n 
m o dels t hat i ncl u de t he sta n dar d cli nical para m eters a n d wit h m o dels i ncl u di n g ot her ge n o mic 
pre dict ors. 
F or a s u bs et of patie nts w h o are e nr olle d at D F CI, si n gle- n ucle us R N A se q ue nci n g will be 
perf or me d o n bi o psies at baseli ne, o n treat me nt, a n d, w he n a vaila bl e, o n pr o gressi o n. T hese 
st u dies will deter mi ne w het her c h a n ges i n R N A e x pressi o n si g nat ures s pecific t o t u m or a n d 
i m m u ne cells c orrel ate wit h treat me nt res p o nse a n d resista nce. T h ese a n al yses will als o 
i n vesti gate w het her p arti c ular i m m u ne cell s u bsets are e nric he d i n res p o n d ers c o m pare d t o n o n-
res p o n ders, as s u g geste d b y st u dies i n ot her t u m ors treate d wit h c h ec k p oi nt i n hi bit ors. A d diti o nal 
si n gle-cell tec h ni q ues ma y be a d de d t o t he si n gle-cell R N A se q ue n ci n g, s uc h as cell ular i n de xi n g 
of tra nscri pt o mes a n d e pit o pes b y se q ue nci n g ( CI T E-se q), a m et h o d t hat q ua ntifies cell-s urface 
pr otei ns at a si n gle-cell le vel. 9 4  
 
Assa y 4: W h ole E x o me, W h ole Ge n o me Se q u e nci n g, D N A Met h ylati o n 
 
All D N A se q ue nci n g will be perf or me d at t he Br oa d I nstit ute; t his ma y i ncl u de S N P-arra ys f or 
ger mli ne ge n o mic a nal ys es, as well as e x o me a n d/ or w h ole g e n o me s e q u e nci n g. T u m or bi o ps y 
s peci me ns ma y b e ass esse d usi n g t he m ost c urre nt a n d i nf or m ati ve met h o d ol o gies at t he ti me t hat 
c orrel ati ve scie nce is perf or me d. P ote ntial assa ys t hat ma y be perf or me d o n fr oze n or F F P E
metastatic sa m ples a n d/ or F F P E pri mar y sa m ples i ncl u de: 
 
 A F F Y S N P 6. 0, or Ill u mi na S N P arra ys f or ge n ot y pes a n d D N A c o p y n u m b er c h a n ges m a y 
be perf or me d.
 D N A met h ylati o n: Ill u mi na I nfi ni u m 4 5 0 K met h ylati o n arra ys. 
 

                                                 
 
 
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7 3 
Pre vi o usl y perf or me d, C LI A-a p pr o v e d N G S p a nels (i.e., D F CI’s O n c o pa nel) o n partici pa nts 
(eit her fr o m t he pre-scree ni n g p o p ulati o n or t he e nr olle d p o p ulati o n) ma y be re q ueste d a n d utilize d 
i n t hese a nal yses.  
 
9. 3. 4  Sites Perf or mi n g C orrelati ve St u dies a n d/ or Data A nal ysis 
 
De-i de ntifie d bi os peci me ns a n d data ma y be s h are d wit h t he f oll o wi n g e ntities f or t he p ur p os es 
descri be d a b o ve: 
 
D F CI Breast Tra nslati o n al H u b- S mit h ( T- H u b) D F CI Ce nter f or I m m u n o- O nc ol o g y 
D F CI C ore Bl o o d a n d Tiss ue Ba n k 
T he Br oa d I nstit ute of MI T 
Na n ostri n g Tec h n ol o gies, I n c 
Bri g ha m a n d W o me n’s H os pital (i ncl u di n g Ce nter f or A d va nce d M olec ul ar Dia g n ostics) 
Har var d Me dical Sc h o ol 
Yale Ca ncer Ce nter 
A da pti ve Bi otec h n ol o gies 
F o u n dati o n Me dici ne, I n c. 
Disc o ver y Life Scie nces/ Q ualte k 
Re veal Ge n o mics 
B ost o n Ge ne 
 
Ve nta na 
 
9. 4  
Bl o o d C ollecti o n 
 
Researc h bl o o d c ollecti o n is ma n dat or y f or all patie nts f or fl o w c yt o metr y of P B M Cs a n d p ote ntial 
D N A is olati o n. T he sa m ples will be ba n ke d i n t he D F CI Breast Tra nslati o nal H u b- S mit h ( T-
H u b)f or t hese a n d f ut ure researc h p ur p os es. T h es e s peci me ns will bec o m e t he pr o pert y of t he 
D F/ H C C. 
T he f oll o wi n g researc h bl o o d sa m ples are re q uire d: 
C ycle 1 Da y 1: 
 2 la ve n der t o p t u bes ( 1 0 m L) f or w h ole bl o o d 
 2 Strec k t u bes ( 1 0 m L) f or w h ole bl o o d 
 2 C P T t u bes ( 8 m L eac h) f or w h ole bl o o d 
 
 Wit h Resta gi n g ( E ver y 9 wee ks, c oi nci di n g wit h Da y 1 of t hat c y cle):  
 2 Strec k t u bes ( 1 0 m L) f or w h ole bl o o d 
 2 C P T t u bes ( 8 m L eac h) f or w h ole bl o o d 
Off Treat me nt ( wit h or wit h o ut pr o gressi ve diseas e):
 2 Strec k t u bes ( 1 0 m L) f or w h ole bl o o d 
 2 C P T t u bes ( 8 m L eac h) f or w h ole bl o o d 

                                                 
 
 
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7 4 
T he f oll o wi n g researc h bl o o d sa m ples are o pti o nal f or patie nts w h o c o m e off treat me nt f or a reas o n 
ot her t ha n pr o gressi ve disease u ntil pr o gressi ve disease, start of a n ot h er a nti-ca ncer t hera p y, or 
deat h: 
F oll o w U p (e v er y 9- 1 2 wee ks): 
 2 Strec k t u bes ( 1 0 m L) f or w h ole bl o o d 
 2 C P T t u bes ( 8 m L eac h) f or w h ole bl o o d 
If sa m ple c ollecti o n is misse d at baseli ne or at t he ti me of pr o gressi o n, t he n t he sa m ple s h o ul d be 
dra w n at a f ut ure a p p oi nt me nt bef ore starti n g a n ot her a nti-ca ncer t hera p y if p ossi ble. 
 
F or retreat me nt p atie nts t he f oll o wi n g researc h bl o o d sa m ples are re q uire d:
Wit h Resta gi n g ( E ver y 9 wee ks, c oi nci di n g wit h Da y 1 of t hat c ycl e): 
 2 Strec k t u bes ( 1 0 m L) f or w h ole bl o o d 
 2 C P T t u bes ( 8 m L eac h) f or w h ole bl o o d 
 
            E n d of Treat me nt ( wit h or wit h o ut pr o gressi ve disease): 
 2 Strec k t u bes ( 1 0 m L) f or w h ole bl o o d 
 2 C P T t u bes ( 8 m L eac h) f or w h ole bl o o d 
 
9. 4. 1  S hi p pi n g 
 
Bl o o d sa m ples will be pre pare d a n d s hi p pe d t o t he D F CI T- H u b p er t he i nstr ucti o ns i n t he 
la b orat or y ma n u al. 
9. 5
Bl o o d S a m ples – P ote nti al Testi n g 
 
9. 5. 1  I m m u ne M ar kers 
 
Bl o o d will be c ollecte d at baseli ne, wit h resta gi n g (e ver y 9 wee ks pri or t o t he i nf usi o n of st u d y 
dr u gs), a n d at ti me of pr o gressi o n f or e val uati o n of i m m u ne mar kers. T he ba n ke d sa m ples will be 
use d t o a nal yze D N A, R N A, a n d pr otei n i n f ut ure st u dies. 
 
9. 5. 1. 1  C ollecti o n  
 
T w o ali q u ots of 8 ml of w h ole bl o o d will be c ollecte d i n C P T t u bes. C oll ecti o n wit h ot her C P T 
t u be sizes (f or t he sa m e t otal v ol u me) ma y be acce pta ble after disc ussi o n wit h t he PI a n d 
C o or di nati n g Ce nter (i.e., f o ur 4 ml C P Ts). T he bl o o d sa m ple will be c ollecte d a n d pr o cesse d at 
baseli ne, wit h resta gi n g (e ver y 9 wee ks) pri or t o t he i nf usi o n of st u d y dr u gs, a n d at ti me of 
pr o gressi o n f or e val uati o n of i m m u ne mar kers.  
9. 5. 1. 2  P ote ntial Testi n g 
9. 5. 1. 2. 1  Fl o w C yt o metr y 
 

                                                 
 
 
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7 5 
P B M Cs will be ge nerate d as descri be d i n t he La b Ma n ual a n d use d t o ass ess i m m u ne cell 
p o p ulati o ns. S urface stai ni n g wit h a pa nel of a nti b o dies a n d fl o w c yt o metr y o n P B M Cs will t he n 
be perf or me d. A sel ecti o n of t he f oll o wi n g a nti b o dies ma y be use d, a n d/ or a d diti o nal a nti b o dies, 
as dee me d a p pr o priat e a n d i nf or mati ve base d o n t h e state of t he i m m u ne pr ofili n g literat ure at 
t he ti me of c orrelati ve sci e nce is perf or me d: C D 8, P D- 1, P D- L 1, P D- L 2, C D 4, F O X P 3, C D 1 2 7. 
 
9. 5. 2  Cell-free D N A (cf D N A) a nal ysis 
 
Bl o o d will be c ollecte d at baseli ne, e v er y 9 wee ks pri or t o i nf usi o n of st u d y dr u gs, a n d at ti me of 
pr o gressi o n f or e v al uati o n of cell-free D N A (cf D N A). T h e ba n k e d sa m ples will be use d t o a nal y ze 
D N A, R N A a n d pr otei n i n f ut ure st u dies. 
 
9. 5. 2. 1  C ollecti o n of cf D N A s p eci me n(s) 
 
T w o 1 0 ml ali q u ots of w h ole bl o o d will be c ollecte d i n Strec k T u bes. T he bl o o d sa m ple will be 
c ollecte d a n d pr ocesse d at baseli ne, wit h resta gi n g (e ver y 9 wee ks pri or t o i nf usi o n of st u d y dr u gs), 
a n d at ti me of pr o gressi o n.  
9. 5. 3  Ger mli ne M utati o nal Stat us 
 
M utati o ns i de ntifie d i n tar get ge n es will b e ass esse d usi n g ger mli ne D N A fr o m t he bas eli ne bl o o d 
sa m ple. We will ass ess g er mli ne m utati o nal stat us of cli nicall y acti o na ble g e nes rel ate d t o fa milial 
ris ks of breast, c ol o n, o v aria n, e n d o m etrial, a n d p a ncreatic ca ncers, as well as mela n o ma. Ge nes 
will be a nal yze d b ot h f or si n gle- base c ha n g es a n d lar ge rearra n ge me nts b y ne xt- ge nerati o n 
se q ue nci n g. G er mli ne m utati o nal pr ofili n g will be i ncl u de d as a s ec o n d ar y c orrelati ve a n al ysis i n 
t his trial t o e x pl ore t he acti vit y of sacit uz u m a b g o viteca n a n d pe m br oliz u ma b, c o m pare d t o 
sacit uz u ma b g o viteca n al o ne, i n patie nts wit h H R + / H E R 2- M B C a n d ger mli ne mis matc h re pair 
a n d ot her D N A re p air pat h wa y alterati o ns. 
 
9. 5. 3. 1  C ollecti o n of ger mli ne s peci me n(s) 
 
A n a d diti o nal t w o 1 0 ml of w h ole bl o o d will be c ollecte d i n la v e n der t o p t u bes at b aseli ne. T h e 
bl o o d sa m ple will be c oll ecte d a n d pr o cesse d at b aseli ne. Fill t he la ve n d er t o p t u be c o m pletel y a n d 
i m me diatel y mi x b y ge ntle i n versi o n 8 t o 1 0 ti mes. I na de q u ate or del a ye d mi xi n g ma y res ult i n 
i nacc urate res ults. T he ba n ke d sa m ples will be use d t o a nal yze D N A, R N A, a n d pr otei n i n f ut ure 
st u dies. I n a d diti o n, o ne of t hese t u bes will be use d t o deter mi ne t he uri di ne di p h os p hate-
gl uc ur o n os yl tra nsferase 1 A 1 ( U G T 1 A 1 ) ge n ot y pe t o ass ociate t his wit h t he i nci de nce of a d vers e 
e ve nts, partic ularl y ne utr o pe nia, as t his ge n ot y pe h as bee n li n ke d t o i ncreas e d t o xicit y of iri n oteca n 
i n ot her st u dies.3 2 E x pl orat or y a nal ysis will als o be d o ne f or effi cac y. 
9. 5. 4  Sites Perf or mi n g C orrelati ves 
 
De-i de ntifie d bi os peci me ns a n d data ma y be s h are d wit h t he f oll o wi n g e ntities f or t he p ur p os es 
descri be d a b o ve: 
 
D F CI C ore Bl o o d a n d Tiss ue Ba n k 
 
D F CI Ce nter f or I m m u n o- O nc ol o g y  

                                                 
 
 
           D F/ H C C Pr ot o c ol #: 2 0- 1 5 3 
 
           
               Pr ot o c ol Versi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
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D F CI Breast Tra nslati o n al H u b- S mit h ( T- H u b) 
T he Br oa d I nstit ute of MI T 
Bri g ha m a n d W o me n’s H os pital 
Na n ostri n g Tec h n ol o gies, I n c. 
A da pti ve Bi otec h n ol o gies 
F o u n dati o n Me dici ne, I n c.  
Re veal Ge n o mics 
B ost o n Ge ne 
 
9. 6  
St o ol C ollecti o n  
 
9. 6. 1  C ollecti o n  
 
All st o ol sa m ples will b e c ollecte d b y eac h p atie nt at h o me usi n g a h o m e- base d, s elf-c ollecti o n 
a n d mail met h o d f or st o ol t hat has bee n pr o ve n t o pr o vi de nearl y e q ui vale nt meta ge n o mic a n d 
metatra nscri pt o mic dat a as t he state- of-t he-art, fres h-fr oze n sa m ple c ollecti o n pr ot oc ol.
9 5
 
Sa m ples will be c ollecte d at t he bel o w ti me p oi nts: 
 Baseli ne 
 After 3- 6 wee ks of treat me nt (a n y ti me fr o m C 2 D 1- C 3 D 1 is all o we d) 
 At ti me of pr o gressi o n f or t h ose patie nts w h o ac hie ve d res p o nse ( p artial or c o m plete) t o 
treat me nt 
 
 Retreat me nt patie nts will o nl y c ollect a sa m ple at t he bel o w ti me p oi nt:  
 At t he ti me of pr o gressi o n after retreat me nt, if res p o nse was a g ai n o bser ve d  
 
A patie nt q uesti o n naire is i ncl u de d i n t he kits. T h e q uesti o n naire s h o ul d be c o m plete d at t he ti me 
of st o ol c ollecti o n a n d maile d bac k al o n g wit h t he sa m ple. St o ol sa m ples a n d q uesti o n naires t hat 
are n ot c ollecte d at t h e pr ot oc ol-s pecifi e d c ollecti o n ti me p oi nts will n ot be pr ot oc ol vi olati o ns.  
Retreat me nt st o ol sa m ples are o pti o nal.  
 
9. 6. 2  Ha n dli n g a n d s hi p pi n g of st o ol s peci me ns 
 
All kits will be pr o vi de d t o t he patie nts at a cli nic visit. Patie nts will als o be pr o vi de d wit h a mailer 
i n w hic h t o ret ur n t he sa m ple. All sa m ples will be s hi p pe d wit hi n 2 4 h o urs of c ollecti o n at a m bie nt 
te m perat ure t o t he D F CI Breast Tra nslati o nal H u b- S mit h ( T- H u b), w here t he y will be pr ocesse d 
a n d st ore d (see La b Ma n ual). Sa m ples will be st ore d u ntil s hi p pe d o ut t o a n e xter nal la b ve n d or, 
s uc h as Micr o bi o me D x, w h o will perf or m t he a n al ysis of t he sa m ples.  
 
9. 6. 3  A nal ysis  
 
We will  q ua ntif y micr o bi o me feat ures fr o m a m pli c o n, meta ge n o me, a n d m etatra nscri pt o me usi n g 
esta blis he d pi peli nes t o i de ntif y strai n-le vel ta x o n o mic, f u ncti o nal, tra nscri pti o nal, a n d 
micr o biall y- me diate d meta b olite pr ofiles ass ociate d wit h res p o nse t o pe m br oliz u ma b (see Secti o n 
1 3. 7. 2). T his w or k will d eter mi ne t he ass ociati o n of t hese micr o bi o me feat ures wit h res p o nse t o 

                                                 
 
 
           D F/ H C C Pr ot o c ol #: 2 0- 1 5 3 
 
           
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7 7 
t he c o m bi nati o n i m m u n ot hera p y-c o ntai ni n g re gi me n vers us t he m o n ot hera p y re gi me n wit h o ut 
i m m u n ot hera p y.   
9. 6. 4
Sites perf or mi n g c orrelati ve a nal ysis
De-i de ntifie d bi os peci me ns a n d data ma y be s h are d wit h t he f oll o wi n g e ntities f or t he p ur p os es 
descri be d a b o ve:
B W H/ Har var d C o h orts Bi ore p osit or y
Micr o bi o me D x – E xter n al La b Ve n d or
D F CI Breast Tra nslati o n al H u b- S mit h ( T- H u b) 
 
Bri g ha m a n d W o me n’s H os pital 
 
9. 6. 5  Diet a n d P h ysical Acti vit y Assess me nts 
 
Dietar y c o m p ositi o n will be assess e d t hr o u g h t he Bl oc k Fat/ S u gar/ Fr uit/ Ve geta ble Scree n er, 
s u p ple me nte d wit h 3 a d diti o nal q uesti o ns a b o ut fi ber i nta ke fr o m t he Bl oc k Ve geta ble/ Fr uit/ Fi ber 
Scree ner. T h e dietar y assess me nt c o ntai ns 5 8 t ot al q uesti o ns a n d t a kes a b o ut 1 0- 1 2 mi n utes t o 
c o m plete. A nal ysis pr o d uces esti mates of sat urat e d fat, tra ns fat, t otal s u g ars, "a d de d s u gars" (i n 
s weete ne d cereals, s oft dri n ks, a n d s weets), fr uit a n d fr uit j uice, ve geta ble i nta ke, gl yce mic l oa d, 
gl yce mic i n de x a n d fi b er i nta ke. 
 
P h ysical acti vit y patter ns will be assesse d wit h t he Leis ure Sc ore I n de x of G o di n Leis ure- Ti me 
E xercise Q u esti o n naire ( L SI). T he L SI is a s h ort i nstr u me nt w hic h as ks partici pa nts t o q ua ntif y 
t he n u m ber of mi n utes s pe nt i n t he last wee k e n ga gi n g i n vi g or o us, m o derate, a n d li g ht/ mil d 
p h ysical acti vit y.  T he L SI has u n der g o ne e xte nsi ve relia bilit y a n d vali dit y testi n g i n a n u m ber of 
ca ncer a n d g e neral p o p ulati o ns 9 6. We will be usi n g a m o difie d f or m of t he i nstr u me nt w hic h 
i ncl u des n ot o nl y fre q ue nc y of acti vit y b ut als o e xercise d urati o n.  Wee kl y mi n utes of m o derate 
a n d vi g or o us p h ysical acti vit y will be cal c ulate d at eac h ti me p oi nt usi n g sta n dar d s c ori n g 
al g orit h ms. 
Please refer t o A p p e n dices B a n d C f or t he Diet a n d P h ysical Acti vit y Assess me nts.  
 
Assess me nts will be c o n d ucte d at t he bel o w ti me p oi nts (i n c o nj u ncti o n wit h c ollecti o n of st o ol 
sa m ples): 
 Baseli ne 
 After 3- 6 wee ks of treat me nt (a n y ti me fr o m C 2 D 1- C 3 D 1 is all o we d)  
 At ti me of pr o gressi o n f or t h ose patie nts w h o ac hie ve d res p o nse ( p artial or c o m plete) t o 
treat me nt 
 
Retreat me nt patie nts will o nl y c ollect c o m plete a n assess me nt at t he bel o w ti me p oi nt:  
 At t he ti me of pr o gressi o n after retreat me nt, if res p o nse was a g ai n o bser ve d  
 
T he assess me nts s h o ul d be c o m plete d at t he ti me of st o ol c ollecti o n a n d maile d bac k al o n g wit h 
t he sa m ple a n d st o ol q uesti o n naire. Diet a n d p h ysi cal acti vit y assess me nts t hat are n ot c ollecte d at 
t he pr ot oc ol-s p ecifie d c ollecti o n ti me p oi nts will n ot be pr ot oc ol vi olati o ns. Retreat me nt 

                                                 
 
 
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assess me nts are o pti o nal. 
 
9. 7  
A d diti o n al Tr a nsl ati o n al A n al yses 
 
T he a b o v e- me nti o ne d a n al yses ma y b e altere d b as e d o n n o vel de vel o p me nts i n t he fiel d of ca ncer 
i m m u ne pr ofili n g at t he ti me of c orrelati ve scie n ce. A d diti o nal mar kers or alter nati ve tec h n ol o gies 
( base d o n scie ntific d e v el o p me nts a n d/ or n o vel tec h n ol o gies) ma y als o be use d, t o e x pl ore 
p ote ntial pr o g n ostic or pre dicti ve ca n di date m ar kers/ pa nels or mar kers relat e d t o treat me nt be n efit 
a n d/ or safet y, t o i m pr o ve dia g n ostic tests, or t o u n dersta n d breast ca n cer bi ol o g y. 
 
9. 8  
F ut ure Use of S peci me ns a n d D at a 
 
All bi os peci me ns a n d dat a will be ba n ke d f or f ut ure researc h a n d ma y be m a de a v aila ble t o ot her 
researc hers f or pr o p ose d researc h pr oj ects. T hese pr ojects will be a p pr o v e d b y t he PI, Breast 
Users C o m mittee, a n d/ or t he I R B, as a p pr o priat e.   
 
9. 9  
P atie nt Re p orte d O utc o mes 
 
We pla n t o assess patie nt re p orte d o utc o mes utilizi n g t he E O R T C Q L Q- C 3 0 ( A p pe n di x E) a n d 
E ur o Q O L E Q 5 D- 5 L ( A p pe n di x F) i nstr u me nts , as well as s pecific q uesti o ns fr o m t he N CI P R O-
C T C A E ( A p pe n di x G) li brar y. T he q uesti o ns ha ve bee n select e d caref ull y t o ca pt ure t he m ost 
c o m m o n a d verse e ve nts ass ociate d wit h sacit uz u ma b g o viteca n a n d p e m br oliz u ma b.  
 
T he Q L Q- C 3 0 meas ure c o m prises 9 m ulti ple-ite m scales a n d 6 si n gle ite ms. M ulti ple-ite m scales 
of Q L Q- C 3 0 c o nsiste d of 6 f u ncti o nal scales ( p h ysical, r ole, e m oti o nal, c o g niti ve, s ocial a n d 
gl o bal Q O L) a n d 3 s y m pt o m scales (fati g ue, na usea a n d v o miti n g, pai n). Si x si n gle-ite m scales of 
Q L Q- C 3 0 i n v ol ve d ys p nea, slee p dist ur ba nce, a p petite l oss, c o nsti pati o n, diarr hea a n d fi na nci al 
i m pact. All of t he d eri v e d scales ra n g e i n sc ore fr o m 0 t o 1 0 0. F or t h e o verall H R Q o L a n d 
f u ncti o ni n g scales, a hi g her sc ore is c orrelate d wit h better H R Q o L, w hereas a hi g her sc ore 
re pres e nts w orse H R Q o L f or s y m pt o m scales. 
 
T he E Q- 5 D- 5 L ge n eric Q O L q uesti o n naire is c o m prise d of 5 di me nsi o ns:  m o bilit y, self-care, 
us ual acti vities, pai n or disc o mf ort, a n d a n xiet y or de pressi o n. Eac h di me nsi o n has 3 le v els: ( 1) n o 
pr o ble m, ( 2) s o me pr o ble m, or ( 3) e xtre me pr o ble m. T h us, t he fi nal sc ori n g c o nsists of 
2 4 3 p ossi ble c o m bi nati o ns or healt h states. T he utilit y val ue f or eac h state is assi g ne d o n t he basis 
of a set of prefere n ce wei g hts (tariffs) elicite d fr o m t he ge neral p o p ulati o n a n d is s pecific f or eac h 
c o u ntr y.  
 
P R O- C T C A E is a P R O meas ure d e vel o pe d t o e v al uate s y m pt o matic t o xicit y i n patie nts o n ca ncer 
cli nical trials. Treat me nt-relate d s y m pt o ms were s electe d fr o m P R O- C T C A E f or c ollecti o n i n t his 
pr ot oc ol base d o n t he pre vi o usl y re p orte d a d vers e e ve nt pr ofile f or s acit u z u ma b g o viteca n a n d 
pe m br oliz u ma b. T hes e s y m pt o ms are decreas e d a p petite, na usea, v o miti n g, c o nsti pati o n, diarr hea, 
a b d o mi nal pai n, s h ort ness of breat h, hair l oss, a n d fati g ue. P R O- C T C A E res p o nses are sc ore d 
fr o m 0 t o 4 wit h n o sta n dar dize d s c ori n g r ules. 
 
Assess me nts will be c o n d ucte d at t he bel o w ti me p oi nts: 

                                                 
 
 
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 Baseli ne 
E ver y 9 wee ks at t he da y 1 visit f oll o wi n g resta gi n g visits  
At t he e n d of treat me nt visit 
Retreat me nt patie nts will c o m plete assess me nts at t he bel o w ti me p oi nt: 
E ver y 9 wee ks at t he da y 1 visit f oll o wi n g resta gi n g visits  
At t he e n d of treat me nt visit 
T he assess me nts s h o ul d be c o m plete d i n cli nic at st u d y visits at t he a b o ve ti me p oi nts. Q ualit y of 
life assess me nts t hat are n ot c ollecte d at t he pr ot o c ol-s pecifie d c ollecti o n ti me p oi nts will n ot be 
pr ot oc ol vi olati o ns. Retreat me nt assess me nts are o pti o nal. 
 
 
1 0  S T U D Y C A L E N D A R 
 
Scree ni n g e v al uati o ns are t o be c o n d u cte d wit hi n 2 8 da ys pri or t o st u d y treat me nt i nitiati o n u nless 
ot her wise s pecifie d. Scree ni n g assess me nts o cc urri n g wit hi n 3 da ys pri or t o i nitiati n g st u d y 
treat me nt d o n ot nee d t o be re peate d o n C ycle 1 Da y 1. 
As detaile d i n t he St u d y Cale n dar, a ne g ati ve pre g na nc y test i n w o me n of c hil d- beari n g p ote ntial 
m ust be d oc u me nte d wit hi n 2 wee ks bef ore t he first d ose of st u d y me dicati o n. 
I n t he e ve nt t hat t he partici pa nt’s c o n diti o n is deteri orati n g, la b orat or y e val uati o ns s h o ul d be 
re peat e d wit hi n 4 8 h o urs pri or t o i nitiati o n of t he ne xt c ycle of t h era p y. 
Assess me nts m ust be perf or me d pri or t o a d mi nistrati o n of a n y st u d y a ge nt. St u d y assess me nts a n d 
a ge nts s h o ul d be a d mi nistere d wit hi n + 2 da ys of t he pr ot oc ol-s pecifi e d dat e f or Da y 1 a n d Da y 8, 
u nless ot her wise n ote d; T here s h o ul d be a mi ni m u m of 1 4 da ys ( ± 2 da ys) bet wee n Da y 8 
sacit uz u ma b g o viteca n d osi n g a n d Da y 1 sacit uz u ma b g o viteca n d osi n g of t he ne xt c ycle. 
D ose dela ys of b ot h dr u gs are all o we d per pr ot o c ol. If Da y 1 d osi n g is d ela ye d, all s u bse q ue nt 
assess me nts will be a dj uste d acc or di n gl y. F or patie nts ra n d o mize d t o t h e c o m bi nati o n ar m, if dr u gs 
are a d mi nistere d o n differe nt da ys i n t he s a me 2 1- da y c y cle, e ver y eff ort s h o ul d be ma de t o 
a d mi nister b ot h dr u gs o n t he sa me d a y i n s u bs e q ue nt c y cles (all assess me nts bei n g a dj uste d 
acc or di n gl y), pr o vi d e d t hat criteria are met per pr ot oc ol a n d t hat 1 4 da ys ( ± 2 da ys) ha ve ela pse d 
si nce t he a d mi nistrati o n of t he pre vi o us d ose of s acit uz u ma b g o viteca n a n d 2 1 ± 4 da ys si nce t he 
a d mi nistrati o n of t he pre vi o us d ose of pe m br oliz u ma b. If Da y 8 sacit uz u m a b g o viteca n d osi n g is 
dela ye d, ca usi n g a dj ust me nt t o Da y 1 of t he f oll o wi n g c ycle, it is rec o m me n de d t o a d mi nister 
pe m br oliz u ma b o n t he sa me da y as Da y 1 of t he n e xt c ycle of s acit uz u ma b g o viteca n. 
 
F or retreat me nt p atie nts, a n y baseli ne ass ess me nts (i ncl u di n g t u m or i ma gi n g a n d researc h 
sa m ples) s h o ul d be c o m plete d wit hi n 1 4 da ys of Da y 1 of sec o n d c o urs e treat me nt, u nless state d 
ot her wise.   

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p.  A n a d v erse e v e nt assess m e nt is perf or me d 9 0 d a ys (- 1 5/ + 3 0 d a ys) after t he last d ose of p e m br oliz u ma b ( Ar m A p atie nts o nl y). T his ma y b e c o n d u cte d i n 
p ers o n or b y p h o n e b y t he i n vesti g at or or s uita bl y trai ne d a n d q u alifie d d ele gate (e. g., M D, R N, N P, etc.). 
q.
Patie nt re p orte d o utc o mes p er Secti o n 9. 9 s h o ul d b e perf or me d d uri n g scree ni n g or o n C 1 D 1 pri or t o treat me nt ( baseli ne), at t h e cli nic visit f oll o wi n g a 
resta gi n g sca n, a n d at e n d of treat me nt/ pr o gressi v e disease. 
r. 
F or s u bjects o n Ar m A, if sacit u z u ma b g o viteca n is disc o nti n u e d a n d p e m br oliz u ma b is c o nti n ue d, Da y 8 assess me nts ( A E assess m e nt, la bs, vitals, etc.) are 
n ot n ee d e d. 
 

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1 1
M E A S U R E M E N T O F E F F E C T 
F or t h e p ur p os es of t his st u d y, partici pa nts s h o ul d be re-e v al uate d f or res p o nse e v er y 9 wee ks. If 
treat me nt is dela ye d, sca ns will als o be dela ye d t o ali g n wit h c ycles of treat me nt recei v e d, rat her 
t ha n wee ks o n st u d y.  
 
 
1 1. 1
A ntit u m or Effect – S oli d t u m ors 
 
Res p o nse a n d pr o gressi o n i n sites of metastases will be e val uate d i n t his st u d y usi n g t he 
i nter nati o nal criteria pr o p ose d b y t he R E CI S T 1. 1 criteria9 7. C ha n ges i n t he lar gest dia m eter 
( u ni di me nsi o nal meas ure me nt) of t he t u m or lesi o ns a n d t he s h ortest dia meter i n t he case of 
mali g na nt l y m p h n o des are use d i n t he R E CI S T criteria.  
F or a n y s u bject w h o s h o ws first ra di ol o gic e vi de n ce of pr o gressi ve disease ( P D) b y R E CI S T 1. 1 
a n d is dee me d cli nicall y sta ble, it is at t he discreti o n of t he i n vesti gat or t o c o nti n ue treati n g t he
s u bject u ntil pr o gressi o n is c o nfir me d at t he ne xt s c he d ule d resta gi n g. T hes e cases s h o ul d b e 
disc usse d wit h t he Pri nci pal I n v esti gat or. 
 If pr o gressi o n is n ot c o nfir me d o n t he s u bse q ue nt sca n, t he s u bject s h o ul d c o nti n ue t o 
recei v e treat me nt if t he treati n g i n vesti gat or feels t hat t he partici pa nt is cli nicall y sta ble,
de m o nstrates i m pr o ve d c o n diti o n, or is clearl y c o nti n ui n g t o be nefit fr o m t he treat me nt. 
I n t his case, ra di o gra p hic sca ns s h o ul d c o nti n ue t o be perf or me d acc or di n g t o t he st u d y 
cale n dar (i.e., e ver y 9 w ee ks). 
 If ra di ol o gic pr o gressi o n is c o nfir me d o n t he s u bse q ue nt sca n, t he n t he s u bj ect s h o ul d be 
disc o nti n ue d fr o m all st u d y treat me nt. 
I n all partici pa nts, t he dat e of pr o gressi o n f or t he pri mar y e n d p oi nt will be d oc u me nte d as t he 
first date pr o gressi o n was o bser ve d. 
1 1. 1. 1  R E CI S T 1. 1 Defi niti o ns 
 
E val ua ble f or T ar get Disease res p o nse.
O nl y t h ose partici pa nts w h o ha ve meas ura ble 
disease prese nt at bas eli ne, ha ve recei ve d at least o ne c ycle of t hera p y, a n d ha ve ha d t heir 
disease re-e val uate d will be c o nsi d ere d e val u a ble f or tar g et diseas e res p o nse. T hese 
partici pa nts will ha ve t h eir res p o ns e classifie d acc or di n g t o t he defi niti o ns state d bel o w. 
( N ote: Partici pa nts w h o e x hi bit o bjecti ve disease pr o gressi o n pri or t o t h e e n d of c y cle 1 
will als o be c o nsi dere d e val ua ble.) 
 
E val ua ble N o n- Tar get Disease Res p o nse. Partici pa nts w h o ha ve lesi o ns pres e nt at b aseli ne 
t hat are e val ua ble b ut d o n ot meet t he defi niti o ns of meas ura ble diseas e, h a ve recei v e d at 
least o ne c ycle of t hera p y, a n d ha ve ha d t heir disease re-e val uate d will be c o nsi dere d 
e val ua ble f or n o n-tar get disease.  T he res p o nse assess me nt is base d o n t he prese nce, 
a bse nce, or u ne q ui v ocal pr o gressi o n of t he lesi o ns.  

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1 1. 1. 2  Disease Para meters
Meas ura ble diseas e. 
Meas ura ble lesi o ns are d efi ne d as t h ose t hat ca n be acc uratel y 
x-
m ust be rec or d e d i n milli meters ( or d eci mal fracti o ns of ce nti meters).
N ote: T u m or lesi o ns t hat are sit uate d i n a pre vi o usl y irra diate d area mi g ht b e c o nsi dere d 
meas ura ble if t h e i n vesti gat or t hi n ks it a p pr o priat e t o i ncl u de t he m. 
 
Mali g na nt l y m p h n o des. T o be c o nsi dere d p at h ol o gicall y e nlar ge d a n d meas ura ble, a 
t hic k ness rec o m me n de d t o be n o greater t ha n 5 m m). At baseli ne a n d i n f oll o w- u p, o nl y 
t he s h ort a xis will be meas ure d a n d f oll o we d. 
 
N o n- meas ura ble diseas e. All ot her lesi o ns ( or sites of disease), i ncl u di n g s mall lesi o ns 
are c o nsi dere d n o n- meas ura ble diseas e.  B o ne lesi o ns,  ascites, ple ural/ pericar dial 
eff usi o ns, l y m p ha n gitis c utis/ p ul m o nitis, i nfla m mat or y breast disease, a b d o mi nal masses 
( n ot f oll o we d b y C T or M RI), a n d c ystic lesi o ns are all c o nsi d ere d n o n- meas ura bl e.
 
N ote: C ystic lesi o ns t hat meet t he criteria f or ra di o gra p hicall y defi ne d si m ple c ysts s h o ul d 
n ot be c o nsi dere d as mali g na nt lesi o ns ( neit her meas ura ble n or n o n- m eas ura ble) si nce t he y 
are, b y defi niti o n, si m ple c ysts. 
 
‘ C ystic lesi o ns’ t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d as meas ura bl e 
lesi o ns, if t he y meet t he defi niti o n of meas ura bilit y descri be d a b o ve. H o we ver, if n o n-
c ystic lesi o ns are prese nt i n t he sa me partici pa nt, t hese are preferre d f or sel ecti o n as tar get 
lesi o ns. 
 
Tar get lesi o ns. All meas ura ble lesi o ns u p t o a m a xi m u m of 2 lesi o ns per or g a n a n d 5 l esi o ns 
i n t otal, re prese ntati ve of all i n v ol ve d or ga ns, s h o ul d be i de ntifie d as t ar get lesi o ns a n d 
rec or d e d a n d meas ure d at baseli ne.  Tar get lesi o ns s h o ul d be selecte d o n t he basis of t heir 
size (lesi o ns wit h t he l o n gest dia meter), be re prese ntati ve of all i n v ol ve d or ga ns, b ut i n 
a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o re pr o d uci ble re p eate d m eas ure m e nts. It 
ma y be t he case t hat, o n occasi o n, t he lar gest lesi o n d oes n ot le n d itself t o re pr o d uci ble 
meas ure me nt i n w hic h circ u msta nce t he ne xt lar gest lesi o n w hic h ca n be meas ure d 
re pr o d uci bl y s h o ul d be s electe d. A s u m of t he dia meters (l o n gest f or n o n- n o dal lesi o ns, 
s h ort a xis f or n o dal lesi o ns) f or all tar get l esi o ns will be cal c ulate d a n d re p orte d as t he 
baseli ne s u m dia meters. If l y m p h n o des are t o be i ncl u de d i n t he s u m, t he n o nl y t he s h ort 
a xis is a d de d i nt o t he s u m. T he baseli ne s u m dia meters will be use d as refere nce t o f urt her 
c haracteri ze a n y o bjecti ve t u m or re gressi o n i n t he meas ura ble di me nsi o n of t he disease.  
 
N o n-tar get lesi o ns. All ot her lesi o ns ( or sites of disease) i ncl u di n g a n y meas ura ble lesi o ns 
o ver a n d a b o v e t he 5 tar get lesi o ns s h o ul d be i de ntifie d as n o n-t ar get lesi o ns a n d s h o ul d 
als o be rec or d e d at b as eli ne. Meas ure me nts of t hese lesi o ns are n ot re q uire d, b ut t he 

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prese nce, a bse n ce, or i n rare cases u n e q ui v ocal pr o gressi o n of eac h s h o ul d be n ote d 
t hr o u g h o ut f oll o w u p. 
1 1. 1. 3  Met h o ds f or E val uati o n of Disease
 
All meas ure m e nts s h o ul d be ta k e n a n d rec or de d i n metric n ot ati o n usi n g a r uler, cali pers, 
or a di gital meas ure me nt t o ol. All baseli ne e val uati o ns s h o ul d be perf or me d as cl osel y as 
p ossi ble t o t he be gi n ni n g of treat me nt a n d ne v er m ore t ha n 4 wee ks bef ore t he be gi n ni n g 
of t he treat me nt. 
 
T he sa me met h o d of ass ess me nt a n d t he sa me t ec h ni q ue s h o ul d be use d t o c haracteri ze 
eac h i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w- u p. I ma gi n g- b ase d 
e val uati o n is preferre d t o e val uati o n b y cli nical e xa mi nati o n u nless t he lesi o n(s) bei n g
f oll o we d ca n n ot be i ma g e d b ut are assessa ble b y cli nical e xa m.  
 
Cli nical lesi o ns.
Cli nical lesi o ns will o nl y be c o nsi dere d meas ura ble w he n t he y are 
s u perficial (e. g.
assesse d usi n g cali pers ( e. g., s ki n n o d ules). I n t h e case of s ki n l esi o ns, d o c u me ntati o n b y 
c ol or p h ot o gra p h y, i ncl u di n g a r uler t o esti mate t he size of t he l esi o n, is rec o m me n de d.  
 
C hest x-ra y.  Lesi o ns o n c hest x-ra y are acce pta bl e as meas ura ble lesi o ns w he n t he y are 
clearl y defi ne d a n d s urr o u n de d b y aerate d l u n g; h o we ver, C T is prefera ble.  
 
C o n ve nti o nal C T a n d M RI. T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T sca n 
base d o n t he ass u m pti o n t hat C T t hic k ness is 5 m m or less. If C T s ca ns ha ve slice t hic k ness 
greater t ha n 5 m m, t he mi ni m u m size of a meas ura ble lesi o n s h o ul d be t wice t he slice 
t hic k ness. M RI is als o acce pta ble i n certai n sit uati o ns (e. g., f or b o d y s ca ns).   
 
Use of M RI re mai ns a c o m ple x iss ue. M RI has e xcelle nt c o ntrast, s patial, a n d te m p oral 
res ol uti o n; h o we ver, t here are ma n y i ma g e ac q uisiti o n varia bles i n v ol ve d i n M RI, w hic h 
greatl y i m pact i ma ge q ualit y, lesi o n c o ns pic uit y, a n d meas ure me nt. F urt her m ore, t he 
a vaila bilit y of M RI is varia ble gl o ball y. As wit h C T, if a n M RI is perf or me d, t he tec h nical 
s pecificati o ns of t he sca n ni n g se q ue nces use d s h o ul d be o pti mize d f or t he e v al uati o n of t h e 
t y pe a n d site of disease. F urt her m ore, as wit h C T, t he m o dalit y use d at f oll o w- u p s h o ul d 
be t he sa me as w as use d at baseli ne a n d t he lesi o ns s h o ul d be meas ure d/assesse d o n t he 
sa me p ulse se q ue nce. It is be y o n d t he sc o pe of t he R E CI S T g ui deli nes t o prescri be s pecific 
M RI p ulse s e q ue nce para meters f or all sca n n ers, b o d y parts, a n d diseases. I deall y, t he sa me 
t y pe of sca n ner s h o ul d be use d, a n d t he i ma ge ac q uisiti o n pr ot oc ol s h o ul d be f oll o we d as 
cl osel y as p ossi ble t o pri or sca ns. B o d y s ca ns s h o ul d be perf or me d wit h breat h- h ol d 
sca n ni n g tec h ni q ues, if p ossi ble. 
 
F D G- P E T.
W hile F D G- P E T res p o nse assess me nts nee d a d diti o nal st u d y, it is s o meti mes 
reas o na bl e t o i nc or p orat e t he us e of F D G- P E T s ca n ni n g t o c o m ple me nt C T sca n ni n g i n 
assess me nt of pr o gressi o n ( partic ularl y p ossi ble ' n e w' disease). Ne w lesi o ns o n t he basis of 
F D G- P E T i ma gi n g ca n b e i de ntifie d acc or di n g t o t he f oll o wi n g al g orit h m: 
 

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(a) Ne g ati ve F D G- P E T at baseli ne, wit h a p ositi ve F D G- P E T at f oll o w- u p is a si g n of 
P D base d o n a ne w lesi o n. 
( b) N o F D G- P E T at bas eli ne a n d a p ositi ve F D G- P E T at f oll o w- u p: If t he p ositi ve 
F D G- P E T at f oll o w- u p c orres p o n ds t o a ne w site of disease c o nfir m e d b y C T, t his is 
P D. If t he p ositi ve F D G- P E T at f oll o w- u p is n ot c o nfir me d as a ne w site of disease o n 
C T, a d diti o nal f oll o w- u p C T sca ns are nee de d t o d eter mi ne if t here is tr ul y pr o gressi o n 
occ urri n g at t hat site (if s o, t he dat e of P D will b e t he date of t he i nitial a b n or mal F D G-
P E T sca n). If t he p ositi ve F D G- P E T at f oll o w- u p c orres p o n ds t o a pre-e xisti n g site of 
disease o n C T t hat is n ot pr o gressi n g o n t he basis of t he a nat o mic i ma ges, t his is n ot 
P D. 
(c)  F D G- P E T m a y be use d t o u p gra de a res p o ns e t o a C R i n a ma n ner si milar t o a 
bi o ps y i n cases w here a resi d ual ra di o gra p hic a b n or malit y is t h o u g ht t o re prese nt 
fi br osis or s carri n g. T he use of F D G- P E T i n t his circ u msta nce s h o ul d be pr os pecti vel y 
descri be d i n t he pr ot o c ol a n d s u p p orte d b y diseas e-s pecifi c me dical literat ure f or t h e 
i n dicati o n. H o we ver, it m ust be ac k n o wle d ge d t hat b ot h a p pr oac h es ma y lea d t o false 
p ositi ve C R d ue t o li mitati o ns of F D G- P E T a n d bi o ps y res ol uti o n/se nsiti vit y. 
 
N ote:  A ‘ p ositi ve’ F D G- P E T sca n lesi o n mea ns o ne w hic h is F D G a vi d wit h a n u pta ke 
greater t ha n t wice t hat of t he s urr o u n di n g tiss ue o n t he atte n uati o n c orrecte d i ma ge. 
 
P E T- C T. At pres e nt, t he l o w d ose or atte n u ati o n c orrecti o n C T p orti o n of a c o m bi ne d P E T-
C T is n ot al wa ys of o pti mal dia g n ostic C T q ualit y f or use wit h R E CI S T meas ure me nts. 
H o we ver, if t he site ca n d oc u me nt t hat t he C T perf or me d as part of a P E T- C T is of i de ntical
dia g n ostic q ualit y t o a dia g n ostic C T ( wit h I V a n d oral c o ntrast), t he n t h e C T p orti o n of 
t he P E T- C T ca n be us e d f or R E CI S T meas ure m e nts a n d ca n be us e d i nterc ha n gea bl y wit h 
c o n ve nti o nal C T i n acc uratel y meas uri n g ca ncer lesi o ns o ver ti me. N ote, h o we ver, t hat t he 
P E T p orti o n of t he C T i ntr o d uces a d diti o nal data w hic h ma y bias a n i n vesti gat or if it is n ot 
r o uti nel y or seriall y perf or me d. 
 
MI B G ( m et a-i o d o b e n z yl g u a ni di n e). T h e f oll o wi n g is r e c o m m e n d e d, t o ass ur e hi g h 
q u alit y i m a g es ar e o bt ai n e d. 
 
P ati e nt pr e p ar ati o n: I o di d es, us u all y S S KI (s at urat e d s ol uti o n of p ot assi u m i o di d e), ar e 
a d mi nist er e d t o r e d u ce t h yr oi d al a c c u m ul ati o n of fr e e r a di oi o di n e, pr ef er a bl y 
b e gi n ni n g t h e d a y pri or t o i nj e cti o n a n d c o nti n ui n g f or 3 a d diti o n al d a ys ( 4 d a ys t ot al).
F or i nf a nts a n d c hil dr e n, o n e dr o p t.i. d. is s uffi ci e nt, f or a d ol es c e nts 2 dr o ps t.i. d., a n d 
f or a d ults 3 dr o ps t.i. d. P arti ci p a nts a n d/ or p ar e nts ar e as k e d a b o ut e x p os ur e t o p ot e nti al 
i nt erf eri n g a g e nts. If n o n e is n ot e d, a n i n d w elli n g i ntr a v e n o us li n e is est a blis h e d. T h e 
d os e of MI B G is a d mi nist er e d b y sl o w i ntr a v e n o us i nj e cti o n o v er 9 0 s e c o n ds. 
 
I m a g es fr o m t h e h e a d t o t h e dist al l o w er e xtr e miti es s h o ul d b e o bt ai n e d. 
 
I- 1 2 3 MI B G s ci nti gr a p h y is p erf or m e d t o o bt ai n b ot h pl a n ar a n d t o m o gra p hi c i m a g es.  
 
Pl a n ar: A nt eri or a n d p ost eri or vi e ws fr o m t h e t o p of t h e h e a d t o t h e pr o xi m al l o w er 
e xtr e miti es ar e o bt ai n e d f or 1 0 mi n ut es at 2 4 h o urs a n d o c c asi o n all y at 4 8 h o urs 

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m a xi m u m 1 0 m Ci). A nt eri or vi e ws of t h e dist al l o w er e xtr e miti es ar e a d e q u at e. A l ar g e 
fi el d of vi e w d u al h e a d g a m m a c a m er a wit h l o w e n er g y c olli m at ors is pref err e d. 
 
S P E C T: M ost p arti ci p a nts r e c ei vi n g I- 1 2 3 MI B G als o u n d er g o S P E C T at 2 4 h o urs, 
usi n g a si n gl e or m ulti- h e a d e d c a m er a wit h a l o w e n er g y c olli m at or. T h e c a m er a is 
r ot at e d t hr o u g h 3 6 0 d e gr e es, 1 2 0 pr oj e cti o ns at 2 5 s e c o n ds p er st o p. D at a ar e 
r e c o nstr u ct e d usi n g filt er e d b a c k pr oj e cti o ns wit h a B utt er w ort h filt er a n d a c ut off 
fr e q u e n c y of 0. 2- 0. 5. S P E C T/ C T m a y b e p erf or m e d at i nstit uti o ns wit h t his c a p a cit y. 
 
Ultras o u n d. Ultras o u n d is n ot usef ul i n assess me nt of lesi o n size a n d s h o ul d n ot be use d as 
a met h o d of meas ure me nt. Ultras o u n d e xa mi nati o ns ca n n ot be re pr o d uce d i n t heir e ntiret y 
f or i n de pe n de nt re vie w at a later data a n d, b eca us e t he y are o p erat or de pe n de nt, it ca n n ot 
be g uara ntee d t hat t he sa me tec h ni q ue a n d meas ure me nts will be ta ke n fr o m o ne 
assess me nt t o t he ne xt. If ne w lesi o ns are i de ntifie d b y ultras o u n d i n t he c o urse of t he st u d y, 
c o nfir mati o n b y C T or M RI is a d vise d. If t here is c o ncer n a b o ut ra diati o n e x p os ure fr o m 
C T, M RI ma y be us e d i nstea d of C T i n selecte d i nsta nces.  
 
E n d osc o p y, La par osc o p y. T he utilizati o n of t hese tec h ni q ues f or o bjecti ve t u m or 
e val uati o n is n ot a d vise d. H o we ver, s uc h tec h ni q ues ma y be usef ul t o c o nfir m c o m plete 
pat h ol o gical res p o nse w he n bi o psies are o btai ne d or t o deter mi ne rela pse i n trials w here 
rec urre nce f oll o wi n g c o m plete res p o nse ( C R) or s ur gical res ecti o n is a n e n d p oi nt. 
 
T u m or mar kers. T u m or mar kers al o ne ca n n ot be use d t o assess res p o nse. If mar k ers are 
i nitiall y a b o ve t he u p per n or mal li mit, t he y m ust n or malize f or a partici pa nt t o be 
c o nsi dere d i n c o m plete cli nical res p o nse. S pecific g ui deli nes f or b ot h C A- 1 2 5 res p o nse (i n 
rec urre nt o varia n ca ncer) a n d P S A res p o nse (i n rec urre nt pr ost ate ca ncer) h a ve bee n 
p u blis he d [ J N CI 9 6: 4 8 7- 4 8 8, 2 0 0 4; J Cli n O n c ol  1 7, 3 4 6 1- 3 4 6 7, 1 9 9 9; J Cli n O nc ol
2 6: 1 1 4 8- 1 1 5 9, 2 0 0 8].  I n a d diti o n, t he G y nec ol o gi c Ca ncer I nter gr o u p has de vel o pe d C A-
1 2 5 pr o gressi o n criteri a w hic h are t o be i nte grate d wit h o bjecti ve t u m or assess me nt f or use 
i n first-li ne trials i n o varia n ca n cer [J N CI 9 2: 1 5 3 4- 1 5 3 5, 2 0 0 0]. 
 
C yt ol o g y, Hist ol o g y.
T hese tec h ni q ues ca n be use d t o differe ntiate bet wee n partial 
res p o nses ( P R) a n d c o m plete res p o nses ( C R) i n rare cases (e. g., resi d ual lesi o ns i n t u m or 
t y pes, s uc h as ger m cell t u m ors, w here k n o w n resi d ual be ni g n t u m ors ca n re mai n). 
 
T he c yt ol o gical c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n t hat a p pears or 
w orse ns d uri n g treat me nt w he n t he meas ura ble t u m or has met criteria f or res p o nse or sta bl e 
disease is ma n dat or y t o differe ntiat e bet wee n res p o nse or sta ble disease (a n eff usi o n ma y 
be a si de effect of t he treat me nt) a n d pr o gressi ve disease.
1 1. 1. 3. 1 E val uati o n of Tar g et Lesi o ns 
C o m plete Res p o nse ( C R): Disa p peara n ce of all tar get lesi o ns. A n y pat h ol o gical l y m p h 
n o des ( w het her tar g et or n o n-tar get) m ust ha v e re d ucti o n i n s h ort a xis t o < 1 0 m m. 

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Partial Res p o nse ( P R): At least a 3 0 % decrease i n t he s u m of t he dia meters of tar get 
lesi o ns, ta ki n g as refere n ce t he bas eli ne s u m dia meters.
Pr o gressi ve Disease ( P D): At least a 2 0 % i ncrease i n t he s u m of t he dia meters of tar get 
lesi o ns, ta ki n g as refere n ce t he s mallest s u m o n st u d y (t his i ncl u des t he baseli ne s u m if 
t hat is t he s mallest o n st u d y). I n a d diti o n t o t he relati ve i ncreas e of 2 0 %, t he s u m m ust 
als o de m o nstrate a n a bs ol ute i ncreas e of at least 5 m m. ( N ote:  t he a p peara nce of o n e 
or m ore ne w l esi o ns is als o c o nsi dere d pr o gressi o ns). 
Sta ble Disease ( S D): Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt 
i ncreas e t o q ualif y f or P D, ta ki n g as refere nce t h e s mallest s u m dia meters w hile o n 
st u d y. 
1 1. 1. 3. 2  E val uati o n of N o n- T ar get Lesi o ns 
C o m plete Res p o nse ( C R): Disa p peara nce of all n o n-tar get lesi o ns a n d n or malizati o n 
of t u m or mar ker le vel. All l y m p h n o des m ust be n o n- pat h ol o gical i n size ( < 1 0 m m 
s h ort a xis). 
N ote: If t u m or m ar kers are i nitiall y a b o ve t he u p p er n or mal li mit, t he y m ust n or malize 
f or a patie nt t o be c o nsi dere d i n c o m plete cli nical res p o nse. 
N o n- C R/ N o n- P D: Persiste nce of o ne or m ore n o n-tar get lesi o n(s) a n d/ or mai nte na nce 
of t u m or mar ker l e vel a b o ve t he n or mal li mits. 
Pr o gressi ve Disease ( P D): A p peara nce of o ne or m ore ne w lesi o ns a n d/ or u ne q uiv oc al 
pr o gressi o n  of e xisti n g n o n-tar g et lesi o ns. U n e q uiv oc al pr o gressi o n  s h o ul d n ot 
n or mall y tr u m p tar get lesi o n stat us. It m ust be re prese ntati ve of o verall disease stat us 
c ha n ge, n ot a si n gle lesi o n i ncreas e.
Alt h o u g h a clear pr o gressi o n of “ n o n-tar g et” lesi o ns o nl y is e xce pti o nal, t he o pi ni o n of 
t he treati n g p h ysicia n s h o ul d pre vail i n s uc h circ u msta nces, a n d t he pr o gressi o n stat us 
s h o ul d be c o nfir me d at a later ti me b y t he re vie w pa nel ( or Pri nci pal I n vesti gat or).
1 1. 1. 3. 3  E val uati o n of Ne w L esi o ns 
T he fi n di n g of a ne w lesi o n s h o ul d be u ne q ui v ocal (i.e., n ot d ue t o differe n ce i n 
sca n ni n g tec h ni q ue, i ma gi n g m o dalit y, or fi n di n gs t h o u g ht t o re prese nt s o met hi n g ot her 
t ha n t u m or (f or e xa m ple, s o me ‘ n e w’ b o ne l esi o ns ma y be si m pl y heali n g or fl are of 
pre-e xisti n g lesi o ns). H o we ver, a lesi o n i de ntifie d o n a f oll o w- u p sca n i n a n a nat o mical 
l ocati o n t hat w as n ot sca n ne d at b aseli ne is c o nsi dere d n e w a n d will i n dicate P D. If a 
ne w lesi o n is e q ui v ocal ( beca use of s mall size etc.), f oll o w- u p e val uati o n will clarif y if 
it tr ul y re prese nts ne w disease a n d if P D is c o nfir me d, pr o gressi o n s h o ul d be declare d 
usi n g t he date of t he i nitial sca n o n w hic h t he l esi o n was disc o vere d. 
 

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1 1. 1. 4  D urati o n of Res p o nse  
 
D urati o n of o verall res p o nse:  T he d urati o n of o verall res p o nse is meas ure d fr o m t he ti me 
meas ure me nt criteria are met f or C R or P R ( w hic h e ver is first rec or de d) u ntil t he first date 
t hat rec urre nt or pr o gressi ve disease is o bjecti vel y d oc u me nte d (ta ki n g as refere nce f or 
pr o gressi ve diseas e t he s mallest meas ure me nts rec or de d si nce t he treat me nt starte d, or 
deat h d ue t o a n y ca use. Partici pa nts wit h o ut e ve nts re p orte d are ce ns ore d at t he last disease 
e val uati o n). 
 
D urati o n of o verall c o m plete res p o nse: T h e d urati o n of o verall C R is meas ure d fr o m t he 
ti me meas ure me nt criteria are first met f or C R u ntil t he first date t hat pr o gressi ve disease 
is o bjecti vel y d oc u me nte d, or deat h d ue t o a n y ca use. Partici pa nts wit h o ut e ve nts re p orte d 
are ce ns ore d at t he last disease e v al uati o n.
 
D urati o n of sta bl e diseas e: Sta ble disease is meas ure d fr o m t he start of t he treat me nt u ntil 
t he criteria f or pr o gressi o n are met, ta ki n g as refere nce t he s mallest meas ure me nts rec or de d 
si nce t he treat me nt starte d, i ncl u di n g t he baseli ne meas ure me nts.  
1 1. 1. 5  Ti me t o Res p o nse 
Ti me t o o bjecti ve res p o nse: T he ti me t o o bjecti ve res p o nse is defi n e d as t he ti me fr o m 
ra n d o mizati o n t o t he date of t he first d oc u me nte d C R or P R ( w hic he ver is first rec or d e d). 
 
1 1. 1. 6  Cli nical Be nefit Rate  
Cli nical Be nefit Rate: Cli nical Be nefit Rate ( C B R) is defi ne d as C R, P R a n d sta ble disease 
 
 
1 1. 1. 7  S ur vi val 
O verall S ur vi val: O verall S ur vi val ( O S) is defi ne d as t he ti me fr o m ra n d o mizati o n ( or 
re gistrati o n) t o deat h d u e t o a n y ca use, or ce ns ore d at date last k n o w n ali ve. 
Pr o gressi o n- Free S ur vi val: Pr o gressi o n- Free S ur vi val ( P F S) is defi ne d as t he ti me fr o m 
ra n d o mizati o n ( or re gistrati o n) t o t he earlier of pr o gressi o n or deat h d u e t o a n y ca use. 
Partici pa nts ali ve wit h o ut disease pr o gressi o n are ce ns ore d at d ate of last dis ease 
e val uati o n. 
Ti me t o Pr o gressi o n: Ti me t o Pr o gressi o n ( T T P) is defi ne d as t he ti me fr o m 
ra n d o mizati o n ( or re gistrati o n) t o pr o gressi o n, or ce ns ore d at date of l ast disease 
e val uati o n f or t h ose wit h o ut pr o gressi o n re p ort e d. 
1 1. 1. 8  Res p o nse Re vie w 
 

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Ce ntral Re vie w will be c o n d ucte d b y t he D F/ H C C T u m or I ma gi n g Metric C ore f or 
D F/ H C C I nstit uti o ns. 
1 1. 2
Ot her Res p o nse P ar a meters
N/ A
1 2
D A T A R E P O R TI N G / R E G U L A T O R Y R E Q UI R E M E N T S
A d verse e ve nt lists, g ui deli nes, a n d i nstr ucti o ns f or A E re p orti n g ca n be f o u n d i n Secti o n 7. 0 
( A d vers e E ve nts: List a n d Re p orti n g Re q uire me nts). 
1 2. 1
D at a Re p orti n g 
1 2. 1. 1  Met h o d 
T he Office of D ata Q u alit y ( O D Q) will c ollect, ma na ge, a n d perf or m q u alit y c hec ks o n t he 
data f or t his st u d y. 
 
1 2. 1. 2  Res p o nsi bilit y f or Data S u b missi o n 
 
I n v esti gati ve sites wit hi n D F/ H C C or D F/ P C C are res p o nsi ble f or s u b mitti n g data a n d/ or 
data f or ms t o t he Office of Data Q u alit y i n acc or d a nce wit h D F/ H C C S O Ps. 
 
1 2. 2
D at a S afet y M o nit ori n g 
T he D F/ H C C Data a n d Safet y M o nit ori n g B oar d ( D S M B) will re vie w a n d m o nit or st u d y pr o gress, 
t o xicit y, safet y a n d ot her data fr o m t his st u d y. T h e b oar d is c haire d b y a m e dical o nc ol o gist fr o m 
o utsi de of D F/ H C C a n d has e xter nal a n d i nter n al re pres e ntati o n. I nf or mati o n t hat raises a n y 
q uesti o ns a b o ut partici p a nt safet y or pr ot oc ol p erf or ma n ce will be a d dresse d b y t h e S p o ns or-
I n v esti gat or, statisticia n a n d st u d y tea m. S h o ul d a n y maj or c o n cer ns arise, t he D S M B will offer 
rec o m me n dati o ns re gar di n g w het her or n ot t o s us p e n d t he st u d y. 
 
T he D S M B will meet t wi ce a year t o re vie w accr u al, t o xicit y, res p o nse a n d re p orti n g i nf or mati o n. 
I nf or mati o n t o be pr o vi de d t o t he D S M B ma y i ncl u de partici pa nt accr u al; treat me nt re gi me n 
i nf or mati o n; a d verse e ve nts a n d seri o us a d v erse e ve nts re p orte d b y cate g or y; s u m mar y of a n y 
deat hs o n st u d y; a u dit res ults; a n d a s u m mar y pr o vi de d b y t he st u d y tea m. Ot her i nf or mati o n (e. g., 
sca ns, la b orat or y val ues) will be pr o vi de d u p o n re q uest.  
 
1 2. 3  M ultice nter G ui deli nes 
T his pr ot oc ol will a d here t o D F/ H C C P olic y M U L TI- 1 0 0 a n d t he re q uire m e nts of t he D F/ H C C 
M ulti- Ce nter Data a n d S afet y M o nit ori n g Pla n. T he s pecific res p o nsi bilities of t he S p o ns or-
I n v esti gat or, C o or di nati n g Ce nter, a n d Partici pati n g I nstit uti o ns a n d t he pr o ce d ures f or a u diti n g 
are prese nte d i n A p p e n di x H. 

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1 2. 4
C oll a b or ati ve Rese a rc h a n d F ut ure Use of D at a a n d S a m ples
Tiss ue, bl o o d, st o ol, b o dil y fl ui ds, a n d ot her materials deri ve d fr o m t hese will be c ollecte d i n t his 
st u d y t o a nal yze ge nes, D N A, R N A, pr otei ns a n d cells f or t he st u d y’s c orrelati ve e n d p oi nts a n d 
p ote ntial f ut ure res earc h, utilizi n g ne w t y pes of bi o mar ker testi n g as it bec o mes a vaila ble.  
T hese sa m ples a n d a n y data ge nerate d as a part of t hese cli nical trials ma y be use d f or f ut ure 
researc h st u dies a n d ma y be pr o vi de d t o c olla b orati n g i n vesti gat ors b ot h wit hi n a n d o utsi de of t he 
D F/ H C C f or eit her c orrelati ve e n d p oi nts or sec o n dar y use. Sa m ples a n d data ma y be s hare d wit h 
o utsi de n o n- pr ofit aca de mic i n vesti gat ors, as well as wit h f or- pr ofit p har mace utical i n vesti gat ors 
or c o m merci al e ntities, wit h w h o m we c olla b orate. W he n sa m ples or data are se nt t o c olla b orat ors 
a n d w he n a n y researc h is perf or me d o n t he m, all i nf or mati o n will be i de ntifie d wit h a c o de, a n d 
will n ot c o ntai n a n y P HI, s uc h as na me, birt h da y, or M R Ns.  
 
I n or d er t o all o w t he greatest a m o u nt of researc h t o be perf or me d o n t he s peci me ns a n d i nf or mati o n 
ge nerat e d as a part of t his trial, researc hers i n t his st u d y ma y s hare res ults of ge netic se q ue n ci n g 
wit h ot her scie ntists. De-i de ntifie d s peci me n or ge netic data ma y b e place d i nt o o ne of m ore 
p u blicl y accessi ble scie ntific data bas es, s uc h as t he Nati o nal I nstit utes of Healt h’s Data bas e f or 
Ge n ot y pes a n d P he n ot y pes ( d b Ga P). T he res ults fr o m t he c orrelati ve researc h o n t his st u d y will 
be s hare d wit h t hes e p u blic data bas es. T hr o u g h s u c h data b ases, researc h ers fr o m ar o u n d t he w orl d 
will ha ve access t o d e-i d e ntifie d sa m ples or d ata f or f ut ure researc h. M ore detaile d i nf or mati o n, 
be y o n d t he p u blic d ata base, ma y o nl y be accesse d b y scie ntists at ot her researc h ce nters w h o h a ve 
recei v e d s peci al per missi o n t o re vie w de-i de ntifie d data. 
 
1 3  S T A TI S TI C A L C O N SI D E R A TI O N S 
 
1 3. 1  St u d y Desi g n/ E n d p oi nts 
 
T his is a ra n d o mize d p hase II o pe n la b el st u d y of sacit uz u ma b g o viteca n +/- pe m br oliz u ma b f or 
patie nts wit h H R + / H E R 2- M B C. Sacit uz u ma b g o viteca n will be a d mi nistere d at a d os e of 1 0 
m g/ k g I V o n d a ys 1 a n d 8 of eac h 2 1- da y c ycle, a n d pe m br oliz u ma b will be a d mi nistere d at a 
d ose of 2 0 0 m g I V o n da y 1 of eac h 2 1- da y c ycle. T he tar get e nr oll me nt is 1 1 0 patie nts; 5 5 per 
ar m of treat me nt. 
 
T he pri mar y e n d p oi nt is P F S defi ne d as t he ti me fr o m st u d y ra n d o mizati o n t o disease 
pr o gressi o n, per R E CI S T 1. 1 or me dical j u d g me nt, t he latter base d o n esta blis he d cli nical 
para meters, s uc h as risi n g t u m or mar kers a n d p h ysical e xa m e vi de n ce of pr o gressi o n, i.e., 
w orse ni n g c hest w all disease, or d eat h d ue t o a n y ca use, w hic h e ver occ urre d first.  Patie nts ali ve 
wit h o ut disease pr o gressi o n are ce ns ore d at t he dat e of last disease e val uati o n.  T he pri mar y 
o bjecti ve is t o c o m pare i n t he i nte nt-t o-treat (I T T) p o p ulati o n (as defi ne d i n Secti o n 1 3. 5) t he 
P F S i n patie nts ra n d o mize d t o recei ve sacit uz u ma b g o viteca n i n c o m bi nati o n wit h 
pe m br oliz u ma b ( Ar m A) vers us t h ose ra n d o mize d t o recei ve s acit uz u ma b g o viteca n 
m o n ot hera p y ( Ar m B). 
 
Sec o n dar y e n d p oi nts i ncl u de: 

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 P F S acc or di n g t o R E CI S T 1. 1 i n t he P D- L 1- p ositi ve 
O verall res p o nse rate ( O R R) acc or di n g t o R E CI S T 1. 1 i n t he I T T a n d P D- L 1 + p o p ulati o n 
O verall s ur vi val ( O S) i n t he I T T a n d P D- L 1 + p o p ulati o n 
Cli nical be nefit rat e ( C B R) acc or di n g t o R E CI S T 1. 1, defi ne d as C R, P R or sta ble disease 
f or 
 i n t he I T T a n d P D- L 1 + p o p ulati o n 
Ti me t o pr o gressi o n ( T T P) i n t he I T T a n d P D- L 1 + p o p ulati o n 
D urati o n of res p o nse ( D O R) a n d ti me t o o bjecti ve res p o nse ( T T O R) i n t he I T T a n d P D-
L 1 + p o p ulati o n 
T o xicit y gra de d acc or di n g t o N CI C T C A E, Versi o n 5. 0 
1 3. 2
S a m ple Size, Accr u al R ate a n d St u d y D ur ati o n
Base d o n data of rece nt trials i n a si milar p o p ulati o n of patie nts wit h metastatic breast ca n cer
treate d wit h sacit uz u ma b g o viteca n, a m e dia n P F S of 5. 5 m o nt hs w o ul d be e x pect e d wit h 
sacit uz u ma b g o viteca n m o n ot hera p y. 3 2 C urre ntl y, t here are n o p u blis he d data a b o ut t he P F S of 
patie nts wit h H R + / H E R 2- M B C treate d wit h s acit uz u ma b g o viteca n i n c o m bi nati o n wit h a nti-
P D- 1 t hera p y. We a ntici pate t hat ac hie vi n g a P F S of at least 8. 5 m o nt hs f or c o m bi nati o n t hera p y 
( Ar m A) i n t h e prese nt st u d y w o ul d ma k e t he re gi me n w ort h y of f urt her i n v esti gati o n. C o nsi deri n g 
a o ne-si de d 0. 1 t y pe-I err or a n d 8 0 % p o wer t o d etect a 3- m o nt h a bs ol ute differe nce i n me dia n P F S 
at t he ti me of fi nal a n al ysis ( hazar d rati o = 0. 6 5), 1 1 0 patie nts w o ul d n ee d t o be e nr olle d o n t he 
trial. 
 
T he fi nal a nal ysis will occ ur w he n 1 0 0 P F S e ve nts are o bser v e d, or 2 m o nt hs after t he last patie nt 
is ra n d o mize d, w hic h e ver occ urs first. A n i nteri m a nal ysis f or f utilit y will occ ur w h e n ~ 5 0 % of 
t he i nf or mati o n is o btai n e d ( 5 0 P F S e ve nts). T he st u d y w o ul d st o p earl y if t he Z-statistic fr o m a 
l o g-ra n k test is less t ha n 0. It is esti mate d t hat t he i nteri m a nal ysis will occ ur a p pr o xi matel y 1 8 
m o nt hs after t he first pati e nt is ra n d o mize d. 
 
T he e x pecte d accr ual rat e is 4- 5 patie nts per m o nt h, wit h accr ual of 1 1 0 patie nts a ntici pate d t o be 
c o m plete d at 2 4 m o nt hs. T he e x pecte d st u d y d urati o n t o pri mar y a nal ysis of P F S is 2. 5 t o 3 years. 
1 3. 2. 1 C ha n ge i n ti mi n g of t he fi nal a n al ysis 
At t he ti me of t he Oct o b er 2 0 2 3 D S M B re p orti n g, it beca me cl ear t hat 1 0 0 P F S e ve nts w o ul d n ot 
be reac h e d i n t his st u d y ( d ue t o hi g her rates of treat me nt disc o nti n uati o n f or reas o ns ot her t ha n 
pr o gressi o n t ha n e x pecte d) a n d s o t he fi nal P F S a nal ysis w o ul d o nl y occ ur 9 m o nt hs aft er t he last 
patie nt was ra n d o mize d. T his w o ul d res ult i n a l o n ger st u d y ti meli ne t ha n e x pecte d ( 4 5 m o nt hs
si nce accr ual w as c o m plete d at 3 6 m o nt hs). C ha n gi n g t he fi nal a nal ysis fr o m 9 m o nt hs after t he 
last patie nt is ra n d o mize d t o 2 m o nt hs after t he l ast patie nt is ra n d o mize d (i.e., 3 8- m o nt h st u d y 
d urati o n t o pri mar y P F S a nal ysis) w o ul d res ult i n a p pr o xi matel y 5 % decrease i n st u d y p o wer. 
Gi ve n t he treat me nt la n dsca pe a n d e m er gi n g d ata f or T R O P 2 a nti b o d y dr u g c o nj u gates f or 
metastatic H R- p ositi ve/ H E R 2- ne gati ve breast ca ncer, t his relati vel y s m all l oss of p o wer was
c o nsi dere d acce pt a ble a g ai nst t he alter nati ve of waiti n g t o re p ort t he res ults a n d, he nce, t he fi nal 
a nal ysis will n o w be c o n d ucte d 2 m o nt hs after t he last patie nt is ra n d o mize d.  
1 3. 3
Str atific ati o n F act o rs

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T here are n o pla n n e d stratificati o n fact ors f or t his trial.  
1 3. 4 I nteri m M o nit ori n g Pl a n 
We will perf or m a safet y r u n-i n a nal ysis i n t he first 1 2 patie nts ra n d o mize d t o t he c o m bi nati o n 
t hera p y ar m. If t here are 4 or m ore d ose-li miti n g t o xicit y ( D L Ts) i n t he first 1 2 patie nts i ncl u de d,  
e nr oll me nt will be halte d t o disc uss w het her t he st u d y will be a me n de d, wit h re-e v al uati o n of t he 
a p pr o priate d osi n g sc h e d ule a n d st u d y desi g n or cl ose d. T he pr o ba bilit y of o bser vi n g 4 or m ore 
D L Ts i n t he first 1 2 if t he tr ue D L T rate is 1 5 % or l o wer is less t ha n 1 0 %. T he pr o ba bilit y of 
o bser vi n g 4 or m ore D L Ts i n t he first 1 2 if t he tr ue D L T rat e is 3 0 % or hi g her is great er t ha n 
5 0 %. Secti o n 5. 4 descri b es t he D L T defi niti o ns use d i n t his c urre nt st u d y, w hic h will be assesse d 
i n t he first c ycle ( 2 1 d a ys). I n t he case t hat e nr oll me nt c o nti n ues, t hese first 1 2 patie nts will be 
i ncl u de d i n t he effi cac y a nal ysis.  
A n a d diti o nal i nteri m a nal ysis f or f utilit y will occ ur w he n ~ 5 0 % of t he i nf or mati o n is o btai ne d 
(after 5 0 P F S e ve nts ha v e occ urre d). T h e st u d y w o ul d st o p earl y if t he Z-statistic fr o m a l o g-ra n k 
test is less t ha n 0.  
 
1 3. 5  A n al ysis of Pri m ar y E n d p oi nts 
 
T he pri mar y o bjecti ve is t o c o m pare t he me di a n P F S ac hie v e d wit h t he e x p eri me ntal c o m bi nati o n 
of sacit uz u ma b g o viteca n pl us pe m br oliz u ma b vers us sacit uz u ma b g o viteca n al o ne, a n d t his will 
be assesse d a m o n g all patie nts w h o i nitiate d pr ot oc ol t hera p y acc or di n g t o t he ra n d o mize d 
treat me nt assi g n me nt. 
 
P F S is defi ne d as t he ti me fr o m st u d y ra n d o mizati o n t o disease pr o gressi o n, acc or di n g t o R E CI S T 
1. 1 or me dical j u d g me nt, t he latter b ase d o n esta blis he d cli nical para meters, s uc h as risi n g t u m or 
mar kers a n d p h ysical e x a m e vi de nce of pr o gressi o n, i.e., w orse ni n g c hest wall disease, or deat h 
d ue t o a n y ca use, w hic he ver occ urre d first. Patie nts ali ve wit h o ut disease pr o gressi o n are ce ns ore d 
at t he dat e of last diseas e e val uati o n. Defi niti ve a nal ysis of t he effi cac y data will be b ase d o n t he 
m o difie d i nte nt-t o-treat pri nci ple w here all patie nts w h o i nitiate pr ot oc ol t h era p y will be a nal y ze d 
as ra n d o mize d. 
T he Ka pla n- Meier esti mates will als o be cal c ulate d se paratel y f or patie nts all ocate d t o eac h 
treat me nt re gi me n. 
M ulti varia ble C o x pr o p orti o nal hazar ds m o dels will be use d t o esti mate
treat me nt efficac y i n P F S wit h a dj usti n g f or p ote ntial c o nf o u n ders s uc h as a ge at st u d y e ntr y, sta g e 
(l ocall y a d v a nce d or met astatic), visceral m etastas es ( yes or n o), le vel of E R e x pressi o n ( 1- 9 % vs. 
1 0 % or greater), a n d ra pi d rec urre n ce after c o m pleti o n of a dj u va nt t hera p y < 6 m o nt hs ( yes or n o). 
P ote ntial i nteracti o ns bet wee n treat me nt a n d cli ni cal fact ors will be e x pl ore d i n t he C o x m o dels. 
M o del dia g n ostics will be perf or me d t o c hec k w h et her t he pr o p orti o nalit y ass u m pti o n is vali d i n 
t h ose m o dels. S h o ul d it fail, a p pr o priate a nal ysis, s uc h as m o dels wit h ti me- de pe n de nt effects, will 
be e x pl ore d. A n e x pl orat or y s u bset a nal ysis i n t he eli gi ble- o nl y p o p ulati o n will als o be perf or me d,
a n d res ults of t his a nal ysis will be c o m pare d wit h t h ose fr o m t he i nte nt-t o-treat p o p ulati o n i n t he 
pri mar y a nal ysis. A n y s u bsta ntial differe n ce will be caref ull y e x a mi ne d. 
 

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1 3. 6
A n al ysis of Sec o n d ar y E n d p oi nts
Efficac y E n d p oi nts  
A m o n g patie nts w h o i nitiate d pr ot oc ol t h era p y a n d w h ose t u m or was ce ntrall y c o nfir me d 
t o be P D- L 1-
usi n g t he P har m D x 2 2 C 3 assa y), t he efficac y, 
as assesse d b y P F S, of s acit uz u ma b g o viteca n pl us pe m br oliz u ma b will b e c o m pare d t o 
sacit uz u ma b g o viteca n al o ne. P D- L 1 stat us will be defi ne d b y ce ntral c o nfir mati o n of P D-
L 1 testi n g o n t he baseli ne researc h bi o ps y, if a vaila ble; if n ot a vaila ble, t he n t he ce ntral 
P D- L 1 testi n g res ults fr o m t he arc hi v al sa m ple will be use d. T he c o m paris o n of P F S 
bet wee n treat me nt ar ms i n t he P D- L 1- p ositi ve s u b gr o u p will be e x pl orat or y. 
 
I n t he m o difie d I T T a n d P D- L 1- p ositi ve p o p ulati o n, all patie nts w h o i nitiate d pr ot oc ol 
t hera p y will als o be e v al uate d f or O R R (acc or di n g t o R E CI S T 1. 1), C B R, D O R, T T O R 
a n d O S.  
Ra di o gra p hic res p o ns e will be assesse d usi n g R E CI S T 1. 1 criteria, as d efi ne d i n secti o n 
1 1. O bjecti ve res p o nse will re q uire c o nfir mat or y sca ns or e x a m as i n di cate d. T h e O R R 
( C R + P R), acc or di n g t o R E CI S T 1. 1, will be re p orte d wit h 9 5 % c o nfi de nce i nter v als. 
t o R E CI S T 1. 1 a n d will 
be re p orte d wit h 9 5 % c o nfi de nce i nter v als. Me dia n D O R a n d T T O R will be re p orte d wit h 
ra n ges. O v erall s ur vi val, defi ne d as t he ti me fr o m ra n d o mizati o n ( or re gistrati o n) t o deat h 
d ue t o a n y ca use wit h ce ns ori n g at date l ast k n o w n ali ve, will be re p orte d wit h Ka pla n 
Meier esti mates. 
 
F or O S, t he l o g-ra n k test will be o ne-si de d. Treat me nt efficac y i n t hese sec o n d ar y 
e n d p oi nts will be assesse d b y C o x m o dels a dj usti n g f or cli nical fact ors s uc h as a ge at st u d y 
e ntr y, sta ge (l ocall y a d va nce d or metastatic), visceral met astases ( yes or n o), le vel of E R 
e x pressi o n ( 1- 9 % vs. 1 0 % or greater), a n d ra pi d rec urre nce after c o m pleti o n of a dj u va nt 
t hera p y < 6 m o nt hs ( yes or n o). Dic h ot o m o us e n d p oi nts of res p o nse will be c o m pare d usi n g 
C oc hra n- Mae ntel- H ae ns zel c hi-s q uare d tests.  
 
Safet y a n d t olera bilit y 
All patie nts will be e v al ua ble f or t o xicit y fr o m t he ti me of t heir first treat me nt wit h a n y st u d y 
a ge nt. T o xicit y will be gra de d acc or di n g t o N CI C T C A E, Versi o n 5. 0. T o xicities will be 
s u m marize d b y ma xi m u m gra de a n d b y treat me nt ar m.  I nci de n ce rate of eac h t o xicit y will be 
re p orte d wit h 9 5 % c o nfi de nce i nter v als. T he i nci de nce rates of a n y gra d e 3 or hi g her t o xicit y will 
be c o m pare d acr oss ar ms usi n g a t w o-si de d Fis her’s e xact test.
1 3. 7
C orrel ati v e E n d p oi nts
1 3. 7. 1  T u m or bi o psies a n d TI L assess me nt  
Pre vi o us st u dies ha ve de m o nstrate d t hat, i n a d diti o n t o direct c yt ot o xic effects, c h e m ot hera p y-
i n d uce d cell deat h ca n be i m m u n o ge nic, ca usi n g T cell t u m or i nfiltrati o n a n d se nsitizi n g t u m ors 
t o i m m u ne c hec k p oi nt bl oc ka de.9 8 C yt ot o xic C D 8 + T cell i nfiltrati o n has bee n re p orte d t o i ncrease 
after treat me nt wit h c he m ot hera p y acr oss differe nt t u m or t y pes. 9 9- 1 0 1 Rece ntl y, Her bst et al. 

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de m o nstrate d t hat patie nts w h o ha d a n i ncrease of at least 5 % i n e x pressi o n of P D- L 1 i n t he t u m or 
micr oe n vir o n me nt 
were 
m ore li kel y t o res p o n d t o t he P D- L 1 i n hi bit or atez oliz u ma b.
5 8
M o dificati o ns i n m olec ular si g nat ures of t he t u m or micr oe n vir o n me nt als o c orrel ate d wit h 
res p o nse t o t hera p y. 
 
T u m or-i nfiltrati n g l y m p h oc ytes ( TI Ls) b y hist ol o gical assess me nt will be q u a ntitati ve a n d 
e val uate d as a perce nta ge of cells stai ne d ( 0- 1 0 0 %). Data fr o m L oi a n d c ollea g ues s u g gest t hat t he 
mea n n u m ber of TI Ls i n first-li ne H R + / H E R 2- M B C is li kel y si milar t o t hat o bser v e d i n first-
li ne metastatic H E R 2- p ositi ve sa m ples fr o m t he C L E O P A T R A st u d y.1 0 2 T he me dia n TI L val ue 
was 1 0 % wit h a mea n n u m ber of TI Ls of 1 7 % (sta n dar d de viati o n as a c o nti n u o us varia ble of
2 1 %). TI Ls will be a nal yze d as a c o nti n u o us varia ble usi n g descri pti ve statistics t o s u m marize t he 
distri b uti o n o bser ve d a m o n g st u d y partici pa nts. 
A) T o assess t he relati o ns hi p bet wee n baseli ne TI Ls a n d pr o gressi o n-free s ur vi val, we pla n t o 
perf or m a ma n d at or y researc h bi o ps y of a safel y accessi ble t u m or lesi o n at bas eli ne.  T h e 
ass ociati o n of TI Ls a n d P F S will be e val uate d i n a pr o p orti o nal hazar ds re gressi o n m o del wit h 
treat me nt effect a n d st u d y stratificati o n fact ors as  c o variates.1 0 3 Li near a n d n o n-li near c o m p o ne nts 
of t he m o del will be ass esse d usi n g Wal d-t y pe tests. If a n o n-li near ass o ciati o n is detecte d, t he 
p oi nt esti mate a n d 9 5 % pre dicti o n ba n ds will be re p orte d f or t he l o g relati ve hazar d o v er t he e ntire 
distri b uti o n of TI Ls. If n o si g nifica nt n o n-li near effects are o bser v e d, t he ste p- d o w n m o del will 
e val uate t he li near m ulti variate pr o p orti o nal hazar ds re gressi o n m o del a n d re p ort t he a dj uste d 
hazar d rati o a n d 9 5 % c o nfi de nce i nter v al f or a li near i ncreas e i n TI Ls. I n a d diti o n, m o dificati o n 
of t he treat me nt effect will be e x pl ore d as a n i nt eracti o n t est, a n d if n o n-si g nifica nt (t w o-si de d 
al p ha = 0. 0 5), t he st e p- d o w n m o del wit h mai n effects will be re p orte d.  
 
B) T o assess t he a bs ol ut e c ha n g e i n t he perce nt a ge of TI Ls b ef ore a n d aft er starti n g treat me nt, a 
ma n dat or y bi o ps y at 3- 6 wee ks p ost-treat me nt (a n y ti me bet wee n C 2 D 1 a n d C 3 D 1) is re q uire d, if 
t u m or is safel y accessi bl e. T his o n-treat me nt bi o ps y will be perf or me d i n, at least, t he first 2 7 
patie nts wit h accessi ble disease i n eac h ar m. Ass u mi n g t he dr o p- o ut/ n o n-e val ua ble rate will be 
1 0 %, 2 4 paire d s a m ples will be a vaila ble.  
 
Descri pti ve statistics will be use d t o s u m marize t he distri b uti o n of TI Ls o bser ve d at b aseli ne a n d 
after 3- 6 w ee ks of t hera p y (e. g., mea n, sta n dar d de viati o n, me dia n, a n d i nter- q uartile ra n ge). T he 
e val uati o n of c ha n g e i n TI Ls wit hi n eac h ar m will be base d o n a paire d t-test (a bs ol ute differe nce) 
usi n g a o ne-si de d al p h a = 0. 0 5 f or eac h ar m. Base d o n t he varia bilit y of TI Ls re p orte d b y L oi a n d 
c ollea g ues i n paire d s peci me ns bef ore a n d after treat me nt wit h c h e m ot hera p y f or T N B C, wit h 2 4 
e val ua ble paire d s peci m e ns a ntici pate d per ar m a n d a sta n dar d de viati o n of ei g ht, t here will be 
8 2 % p o wer t o detect a n i ncreas e i n mea n TI Ls fr o m 2 2. 3 % t o 2 6. 5 %, u n der a n ass u m pti o n of a n 
a d diti ve s hift m o del wit h a Ga ussia n c o m m o n de nsit y f u ncti o n. 
 
If paire d bi o psies at baseli ne a n d at 3- 6 wee ks after treat me nt are o btai ne d i n 2 4 paire d sa m ples i n 
eac h ar m (ass u mi n g a dr o p- o ut/ n o n-e val ua ble rat e of 1 0 % i n t he e ntire st u d y p o p ulati o n), t here 
will be statistical p o wer t o detect t he f oll o wi n g c ha n ge i n TI Ls bet wee n b ot h st u d y ar ms. Ass u mi n g 
t hat t he mea n differe nce i n TI Ls fr o m pre-treat me nt t o 3- 6 wee ks after starti n g pr ot oc ol t hera p y is 
1 0. 4 % i n Ar m A (sacit uz u ma b g o viteca n  + pe m br oliz u ma b) a n d 4. 2 % i n Ar m B (sacit uz u ma b 
g o viteca n al o ne), wit h a sta n dar d de viati o n of 8, usi n g a Wilc o x o n- Ma n n- W hit ne y test wit h o ne-

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si de d al p ha of 0. 0 5, t he st u d y has 8 0 % p o wer t o detect t he differe n ce of c h a n ge i n TI Ls bet wee n 
Ar m A (sacit uz u ma b g o viteca n  + p e m br oliz u ma b) a n d Ar m B (sacit uz u ma b g o viteca n al o ne). 
O pti o nal re peat bi o psies will be perf or me d at ti me of pr o gressi o n t o e x pl ore c h a n ges i n TI Ls a n d 
ot her tiss ue mar kers. Descri pti ve statistics will be use d t o s u m marize t he c ha n ge i n TI Ls, a n d 
i nfere n ces o n treat me nt-effects will use n o n- para m etric tests (e. g., Wilc o x o n ra n k s u m) wit h t w o-
si de d al p ha 0. 0 5.  T h e ass ociati o n of c ha n g es i n TI Ls wit h cli nical o utc o m es of P F S a n d O S will 
be e x pl orat or y a n d h y p ot hesis ge nerati n g i n t he s u bset of patie nts wit h e val ua ble re peat bi o psies. 
A nal ysis pla ns will c o nsi der usi n g C o x m o dels wit h ti me- var yi n g c o v ari ates t o acc o u nt f or t he 
p ost- baseli ne assess me nts. 
 
C) F or sec o n dar y c orrelati ve e n d p oi nts t o c haracterize t he e x pressi o n of t u m or mar kers b y 
i m m u n o hist oc he mistr y (I H C) a n d/ or i m m u n ofl u oresce n ce (I F), des cri pti ve statistics a n d 
a g gl o merati ve hi erarc hical cl usteri n g t ec h ni q ues will be use d t o s u m mari ze t he distri b uti o n a n d 
patter ns of pr ofiles o bser ve d i n baseli ne s a m ples. Tests of ass ociati o n wit h cli nical o utc o mes ( P F S, 
O S, O R R) will be e x pl orat or y usi n g C o x pr o p orti o nal hazar d a n d l o gistic re gressi o n m o dels, a n d 
i nfere n ces will use t he Be nja mi ni- H oc h ber g met h o d t o c o ntr ol t he false disc o ver y rate. A n y 
p ositi ve fi n di n gs will re q uire vali dati o n i n f ut ure st u dies wit h i n de pe n de nt sa m ples f or u n bias e d 
esti mates of t he ass ociati o n wit h treat me nt effects a n d cli nical o utc o mes.  
 
Efficac y e n d p oi nts will be a nal yze d acc or di n g t o Tr o p- 2 e x pressi o n, w hic h will be e val uate d as 
perce nt of p ositi ve cells, i nte nsit y, a c o m p osite sc ore, or a n ot her met h o d. A nal yses of Tr o p- 2 
e x pressi o n are d escri pti v e a n d e x pl orat or y i n nat ure a n d i nte n de d t o e xa mi ne t he distri b uti o n of 
Tr o p- 2 e x pressi o n le vels at differe nt bi o ps y sites a n d assess ass ociati o ns bet wee n Tr o p- 2 
e x pressi o n a n d efficac y o utc o mes, s uc h as P F S, O S a n d O R R, f or w hic h se parate a nal yses will be 
perf or me d acc or di n g t o Tr o p- 2 e x pressi o n (a b o v e a n d bel o w me di a n) a n d treat me nt gr o u p.   
 
D) Si n gle-cell R N A se q u e nci n g will be perf or me d o n bi o psies at baseli ne, o n treat me nt, a n d, 
w he n a vaila bl e, at pr o gressi o n f or a s u bset of patie nts e nr olle d at D F CI t o assess t he relati o ns hi p 
of ti me p oi nt-s pecific t u m or a n d i m m u ne cell s u b p o p ulati o ns wit h cli nical o utc o mes i n 
e x pl orat or y a n al yses. I n a d diti o n, c ha n ges i n si n gle-cell R N A e x pressi o n si g nat ures acr oss t hese 
ti me p oi nts will be c orrelate d wit h res p o nse. Sta n d ar d pre pr ocessi n g a n d q u alit y c o ntr ol 
al g orit h ms will be perf or me d t o filter o ut l o w q ualit y cells a n d t o n or malize t he e x pressi o n data. 
Differe ntiall y e x press e d ge nes will be i de ntifie d usi n g t he Be nja mi ni- H oc h ber g pr oce d ure t o 
c o ntr ol t he false disc o v er y rate f or m ulti ple c o m paris o ns. Descri pti ve statistics a n d cl usteri n g 
tec h ni q ues, i ncl u di n g pri nci pal c o m p o ne nt a n al ysis a n d t- distri b ute d st oc hastic nei g h b or 
e m be d di n g, will be e m pl o ye d t o s u m marize t he distri b uti o ns of t he e x pressi o n data a n d i de ntif y 
t u m or a n d i m m u ne cell s u b p o p ulati o ns. C ha n ges i n cell s u b p o p ulati o ns bet wee n bas eli ne, o n-
treat me nt, a n d at pr o gressi o n bi o psies will be assesse d wit h Wilc o x o n si g ne d-ra n k t ests, w hile 
differe n ces i n cell s u b p o p ulati o ns bet wee n res p o n ders a n d n o n-res p o n ders will be c o m pare d wit h 
Ma n n- W hit ne y tests. Preli mi nar y ass ociati o ns of t u m or a n d i m m u ne cell s u b p o p ulati o ns wit h 
pr o gressi o n-free a n d o verall s ur vi val will be e x pl ore d usi n g C o x pr o p orti o nal hazar d m o dels.  
 
1 3. 7. 2  I m m u n o ge n o mic a nal ysis 

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T u m or a n d matc he d g er mli ne bl o o d se q ue nci n g data will be pr ocesse d wit h sta n dar d q ualit y 
c o ntr ol met h o ds, f or i nsta nce, e xcl u di n g sa m ples wit h p o or se q ue nci n g c o vera ge a n d l o w 
esti mate d p urit y as pre vi o usl y descri be d. 1 0 4 We will use esta blis he d w h ole e x o me se q ue n ci n g 
( W E S) pi peli nes t o deter mi ne si n gle n ucle oti de varia nts, s mall i nserti o ns/ deleti o ns, a n d lar ger 
str uct ural vari a nts wit h c o m p utati o nal filteri n g of artifacts i ntr o d uce d b y F F P E- base d D N A 
e xtracti o n a n d D N A o xi d ati o n d uri n g se q ue nci n g. 1 0 4, 1 0 5 We will li mit o ur searc h t o hi g hl y 
deleteri o us vari a nts, s pecificall y k n o w n h ots p ot or p utati ve tr u ncati n g m utati o ns, s uc h as 
fra mes hift i nserti o ns/ deleti o ns, n o nse nse m utati o ns, a n d s plice-site alterati o ns. A d diti o nal 
sta n dar d a n al ysis met h o ds will be use d t o assess t u m or p urit y a n d pl oi d y, c o p y n u m ber 
alterati o ns, a n d m utati o nal cl o nalit y, t he latter t o disti n g uis h ge n o mic alterati o ns m ore li kel y t o 
be f o u n der m utati o ns fr o m t h ose m ore li kel y t o ha ve bee n ac q uire d wit h e v ol uti o n or 
rec urre nce.1 0 4, 1 0 6 Esta blis he d a nal ysis pr oce d ures will li ke wise be a p plie d t o R N A se q ue nci n g
( R N Ase q) dat a t o esti mate tra nscri pt a b u n d a nces, differe ntial g e ne e x pressi o n, a n d si g nifica ntl y 
e nric he d p at h wa ys. 1 0 7 T he ass ociati o n of res p o nse wit h ge n o mic alterati o ns, b ot h i n di vi d ual 
ge nes a n d ge n es c o m bi ne d i n pat h wa ys, will be re p orte d b y c o nti n ge nc y ta bles a n d teste d f or 
si g nifica nce usi n g Fis h er’s e xact test. T h e false disc o ver y rate will be c o ntr olle d wit h t he 
Be nja mi ni- H oc h ber g met h o d. 
 
We will c o m pare ge n o mi c a n d tra ns cri pt o mic mar kers bet wee n res p o n d ers a n d n o n-res p o n d ers 
i n b ot h a n u n biase d a nal ysis a n d a directe d assess me nt of i m m u ne mec ha nis ms, i ncl u di n g 
a nti ge n prese nt ati o n, i nterfer o n-  si g nali n g, T-cell effect or pat h wa ys, a n d m utati o nal 
si g nat ures.1 0 7- 1 0 9 I n a d diti o n, we will i n vesti gate a nti ge n prese ntati o n ge n es, s uc h as M H C class I 
ge nes ( H L A- A , H L A- B, H L A- C, B 2 M ), M H C class II g e nes (H L A- D M A/ B H L A- D O A/ B , H L A-
D P A 1/ B 1 , H L A- D Q A 1/ 2, H L A- D Q B 1/ 2, H L A- D R A, H L A- D R B/ 1/ 3/ 4/ 5 ), master re g ul at ors of 
t hese t w o fa milies of ge n es (N L R C 5  a n d CII T A , res pecti vel y), ge n es i m plicate d i n pe pti de 
pr ocessi n g a n d l oa di n g ( T A P 1 , T A P 2 , T A P B P ), a n d ge nes rel ate d t o i nterfer o n-
t o u pre g ulate M H C class I, i ncl u di n g J A K 1/ 2, i nterfer o n-
I F N G R 1/ 2), i nterfer o n 
re g ulat or y fact or 1 (I R F 1), s u p press or of c yt o ki ne si g nali n g 1 (S O C S 1 ), a n d pr otei n i n hi bit or of 
acti vate d S T A T 4 ( PI A S 4 ).5 9, 1 1 0
W E S a n d R N Ase q a n al yses will als o i n vesti gate t he ass ociati o n bet wee n i m m u ne pat h wa ys a n d 
res p o nse. W E S dat a will be a nal yze d t o calc ul ate t u m or m utati o n b ur de n, w hic h is ass ociate d 
wit h res p o nse t o i m m u n ot hera p y i n ot her t u m ors. 1 0 8 H L A ge n ot y pes will be assesse d wit h 
O pti T y pe, a n i nte ger li near pr o gra m mi n g al g orit h m t hat pre dicts H L A ge n ot y pe wit h a n o verall 
acc urac y of 9 7 %. 1 1 1 Ne oa nti ge n pre dicti o n will be acc o m plis he d wit h Net M H C pa n, a met h o d 
t hat utilizes b ot h bi n di n g affi nit y a n d a nti ge n pr o cessi n g data o btai ne d fr o m mass 
s pectr o metr y.1 1 1 
Si milarl y, R N Ase q data will be a nal yze d t o esti mate i m m u ne cell s u b p o p ulati o ns a n d o verall 
i m m u ne cell i nfiltrate wit h t he di gital c yt o metr y met h o d CI B E R S O R T x.1 1 2 T he c yt ol ytic acti vit y 
of t he l ocal i m m u ne cell i nfiltrate will be calc ulat e d as t he ge o metric mea n of P R F 1 a n d G Z M A
e x pressi o n, 1 1 3 a n d ge ne set e nric h me nt a n al ysis will be perf or me d usi n g ca n o nical m olec ular 
si g nat ures,1 1 4 s uc h as t he Hall mar k ge ne s ets,1 1 5 as well as a caref ull y c urat e d c o m pe n di u m of 
i m m u ne si g nat ures.1 1 6 E xisti n g tra nscri pti o nal si g nat ures re p orte d t o be ass ociate d wit h res p o nse 
t o i m m u n ot hera p y, s uc h as i nterfer o n-  a n d T cell effect or si g nat ures,1 1 0, 1 1 7 will be assesse d i n 
t he s u bset of patie nts treate d wit h pe m br oliz u ma b. As b ul k R N Ase q o nl y detects T cell rece pt ors 

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( T C R) o n t he m ost a b u n da nt T cells at a rate cl ose t o 1 T C R per 1 0 milli o n rea ds, 1 1 8 we will 
c o nsi der tar g et s pecific T C R se q ue nci n g met h o ds, w hic h ca pt ure greater T C R di versit y. 1 1 9
1 3. 7. 3  A nal ysis of i ntesti nal micr o bi o me
Micr o bial D N A is e xtracte d usi n g t he Ma g- Bi n d U ni versal Pat h o ge n D N A Kit ( O me ga Bi o-
Te k). Briefl y, 2 5 0 m g of t he s peci me n is tra nsferre d t o a dee p- well plate f or bea d beati n g 
f oll o we d b y D N A preci pitati o n a n d p urificati o n f oll o wi n g t he ma n ufact urer’s i nstr ucti o ns. 
Fi nall y, D N A is el ute d i n 1 0 0 uls of El uti o n B uffer a n d st ore d at - 8 0° C u ntil f urt her use. 1 6 S 
se q ue nci n g li brari es are ge nerat e d b y a m plif yi n g t he v 3- v 4 h y per v aria ble re gi o ns of t he 1 6 S 
ge ne i n a p ol y merase c h ai n reacti o n usi n g pri mers F 3 4 1a n d R 7 8 5. Res ulti n g a m plic o ns are 
ta g ge d wit h u ni q ue m olec ular barc o des t hat are later use d t o de m ulti ple x se q ue nci n g rea ds i nt o 
i n di vi d ual sa m ple b uc kets. Li braries are l oa d e d o n a Mi Se q fl o w cell a n d se q ue nce d f oll o wi n g 
Ill u mi na’s l oa di n g i nstr u cti o ns. Se q ue nce dat a are retrie ve d fr o m t he i nstr u me nt b y c o n verti n g 
base call f or mat files i nt o fast q files f or d ata pr ocessi n g p ur p oses.  
Micr o bi o me D X uses Bac Pr o ™, a pr o prietar y al g orit h m, t o i ns pect a n d vali date se q ue n ci n g files 
b y e m pl o yi n g de m ulti ple xi n g, tri m mi n g, mer gi n g, a n d q ualit y filteri n g ste ps. Paire d se q ue n ci n g 
rea ds are mer ge d usi n g a n o verla p of 2 5 b p all o wi n g f or 1 0 base mis matc h es. Mer ge d s e q ue nces 
are dere plicate d a n d cl ust ere d i n a d e- n o v o fas hi o n usi n g V S E A R C H, w hile filteri n g o ut 
se q ue nce c hi meras a n d si n glet o ns. Re prese ntati ve se q ue nces fr o m eac h cl uster are ma p pe d 
a gai nst t he SI L V A data b ase at 9 9 % se q ue nce i de ntit y t o o btai n acc urate ta x o n o mic 
classificati o ns a n d relati ve a b u n da n ces. I n p arallel, feat ure ta bles are c o nstr ucte d t o deri ve al p ha 
di versit y i n dices, a n d dista nce matri ces are b uilt t o deri ve beta di v ersit y i n dices. T he Bac Pr o T M 
pi peli ne ge nerates a c o m pre he nsi ve re p ort t hat i ncl u des al p ha di versit y sc ores descri bi n g 
c o m m u nit y ric h ness a n d e ve n ness, ta x o n o mic c o m p ositi o n wit h relati ve a b u n da nces, a n d beta 
di versit y metrics t o deter mi ne t he i n- bet wee n s a m ple differe nces b ase d o n t he bacterial 
c o m m u nities i de ntifie d.  
1 3. 7. 4  Patie nt Re p orte d O utc o m es 
S u m mar y statistics of t he sc ores f or t he deri v e d f u ncti o nal a n d s y m pt o m q ualit y of life scales 
acc or di n g t o t he s c ori n g ma n uals a n d gl o bal healt h stat us sc ores will be s u m marize d a n d 
c o m pare d b y treat me nt ar m at eac h ti me p oi nt. 
 
1 3. 8  Re p orti n g a n d E xcl usi o ns 
 
1 3. 8. 1  E val uati o n of Efficac y
F or t his P hase II trial, t he efficac y e v al ua ble p o p ulati o n is a m o difie d i nte nt-t o-treat (I T T) 
p o p ulati o n. T he m o difie d I T T p o p ulati o n c o nsists of all patie nts w h o i nitiate pr ot oc ol 
t hera p y, e v e n if t here are maj or pr ot oc ol t hera p y d e viati o ns.  
 
1 3. 8. 2  E val uati o n of Safet y 

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T he safet y p o p ulati o n will be use d i n t he safet y data s u m maries. T he s afet y p o p ulati o n 
c o nsists of all patie nts w h o t o o k at least o ne d ose of sacit uz u ma b g o viteca n or 
pe m br oliz u ma b o n st u d y a n d w h o ha ve at least o ne p ost- baseli ne safet y ass ess me nt. N ote 
t hat a patie nt w h o ha d n o a d verse e ve nts c o nstit utes a safet y ass ess me nt. Patie nts w h o ha ve 
recei v e d at least o n e d ose of st u d y dr u g b ut ha v e n o p ost-treat me nt s afet y d ata of a n y ki n d 
will be e xcl u de d. E val uati o n of safet y a nal ys es will use treat me nts as treat e d rat her t ha n as 
pla n ne d.
 
1 4  P U B LI C A TI O N P L A N 
 
T he res ults s h o ul d be ma de p u blic wit hi n 1 year of reac hi n g t he e n d of t h e st u d y. T he e n d of t he 
st u d y is t he ti me p oi nt at w hic h t he last data ite ms are t o be re p orte d, or after t he o utc o me data are 
s ufficie ntl y mat ure f or a n al ysis, as defi ne d i n t h e s ecti o n o n Sa m ple Size, Accr ual Rat e a n d St u d y 
D urati o n. If a re p ort is pl a n ne d t o b e p u blis he d i n a peer-re vie we d j o ur n al, t he n t hat i nitial rel ease 
ma y be a n a bstract t hat meets t he re q uire me nts of t he I nter nati o nal C o m mittee of Me dical J o ur nal 
E dit ors. A f ull re p ort of t he o utc o mes s h o ul d b e m a de p u blic n o later t ha n t hree ( 3) y ears after t he 
e n d of t he st u d y. 
 
 
1 5  R E F E R E N C E S 
 
1. 
Bra y, F. , et al. Gl o bal ca ncer statistics 2 0 1 8: G L O B O C A N esti mates of i nci de nce a n d 
m ortalit y w orl d wi de f or 3 6 ca ncers i n 1 8 5 c o u ntri es. C A C a ncer J Cli n  6 8 , 3 9 4 – 4 2 4 
( 2 0 1 8). 
2. 
A merica n Ca n cer S oci et y: Ca ncer Facts a n d Fi g ures 2 0 1 9.  ( A merica n Ca ncer S ociet y, 
Atla nta, G A, 2 0 1 9). 
3. 
Wa ks, A. G. & Wi n er, E. P. Breast Ca ncer Treat m e nt: A Re vie w. J A M A 3 2 1 , 2 8 8- 3 0 0 
( 2 0 1 9).
4. 
T wel ves, C. , et al. S u b gr o u p A nal yses fr o m a P hase 3, O pe n- L a bel, Ra n d o mize d St u d y 
of Eri b uli n Mes ylate Vers us Ca pecita bi ne i n Pretreate d Patie nts wit h A d va nce d or 
Metastatic Breast Ca n cer. Bre ast C a ncer ( A uckl) 1 0 , 7 7- 8 4 ( 2 0 1 6).
5. 
S har pe, A. H. & Pa u ke n, K. E. T he di vers e f u ncti o ns of t he P D 1 i n hi bit or y pat h wa y. N at 
Rev I m m u n ol  1 8 , 1 5 3 – 1 6 7 ( 2 0 1 8). 
6. 
C he m nitz, J. M., Parr y, R. V., Nic h ols, K. E., J u ne, C. H. & Rile y, J. L. S H P- 1 a n d S H P- 2 
ass ociate wit h i m m u n orece pt or t yr osi ne- b ase d s witc h m otif of pr o gra m me d deat h 1 u p o n 
pri mar y h u ma n T cell sti m ulati o n, b ut o nl y rece pt or li gati o n pre ve nts T cell acti vati o n. J 
I m m u n ol 1 7 3 , 9 4 5 – 9 5 4 ( 2 0 0 4). 
7. 
Wei, F. , et al. Stre n gt h of P D- 1 si g nali n g differe ntiall y affects T-cell effect or f u ncti o ns. 
Pr oc N atl Ac a d Sci U S A  1 1 0 , E 2 4 8 0 – 2 4 8 9 ( 2 0 1 3). 
8. 
T o palia n, S. L. , et al. Safet y, acti vit y, a n d i m m u ne c orrel ates of a nti- P D- 1 a nti b o d y i n 
ca ncer. N E n gl J Me d  3 6 6 , 2 4 4 3 – 2 4 5 4 ( 2 0 1 2). 
9. 
Gar o n, E. B. , et al. Pe m br oliz u ma b f or t he treat me nt of n o n-s mall-cell l u n g ca ncer. N 
E n gl J Me d  3 7 2 , 2 0 1 8 – 2 0 2 8 ( 2 0 1 5). 
1 0. 
M otzer, R.J. , et al. Ni v ol u ma b f or Metastatic Re n al Cell Carci n o ma: Res ults of a 
Ra n d o mize d P hase II Tri al. J Cli n O nc ol  3 3 , 1 4 3 0 – 1 4 3 7 ( 2 0 1 5). 
1 1. 
R ose n ber g, J. E. , et al. At ez oliz u ma b i n patie nts wit h l ocall y a d va nce d a n d metastatic 

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 0 2 
ca ncers: precli nical st u dies i n h u ma n ca ncer x e n o graft m o dels a n d m o n ke ys. Cli n C a ncer 
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D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
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D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
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8 1.
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D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
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8 6.
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9 1. 
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1 0 1. 
Pe n g, J. , et al. C he m ot hera p y I n d uces Pr o gra m me d Cell Deat h- Li ga n d 1 O vere x pressi o n 
via t he N uclear Fact or- ka p pa B t o F oster a n I m m u n os u p pressi ve T u m or 

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 0 6 
Micr oe n vir o n me nt i n O v aria n Ca ncer. C a ncer Res  7 5 , 5 0 3 4- 5 0 4 5 ( 2 0 1 5). 
1 0 2. 
L ue n, S.J. , et al. T u m o ur-i nfiltrati n g l y m p h oc ytes i n a d va nce d H E R 2- p ositi ve breast 
ca ncer treate d wit h pert u z u ma b or place b o i n a d diti o n t o trast uz u ma b a n d d oceta xel: a 
retr os pecti ve a nal ysis of t he C L E O P A T R A st u d y. L a ncet O nc ol  1 8 , 5 2- 6 2 ( 2 0 1 7). 
1 0 3. 
Harrell, F. E. Re gressi o n m o deli n g strate gies: R pac ka ge v ersi o n 3. 6- 3.  ( htt p:// C R A N. R-
pr oject. or g/ pac ka ge =r ms , 2 0 1 3). 
1 0 4. 
Mia o, D. , et al. Ge n o mic c orrel ates of res p o nse t o i m m u ne c hec k p oi nt bl oc ka de i n 
micr osatellite-sta ble s oli d t u m ors. N at Ge net 5 0 , 1 2 7 1 – 1 2 8 1 ( 2 0 1 8). 
1 0 5. 
Wala, J. A. , et al. S v A B A: ge n o me- wi de det ecti o n of str uct ural varia nts a n d i n dels b y 
l ocal asse m bl y. Ge n o m e Res  2 8 , 5 8 1 – 5 9 1 ( 2 0 1 8). 
1 0 6. 
Carter, S. L. , et al. A bs ol ute q ua ntificati o n of s o m atic D N A alterati o ns i n h u ma n ca ncer. 
N at Bi otec h n ol  3 0 , 4 1 3 – 4 2 1 ( 2 0 1 2). 
1 0 7. 
Mia o, D. , et al. Ge n o mic c orrel ates of res p o nse t o i m m u ne c hec k p oi nt t hera pies i n clear 
cell re nal cell carci n o ma. Scie nce  3 5 9 , 8 0 1 – 8 0 6 ( 2 0 1 8). 
1 0 8. 
Cristesc u, R. , et al. Pa n-t u m or ge n o mic bi o mar kers f or P D- 1 c hec k p oi nt bl oc ka de- b ase d 
i m m u n ot hera p y. Scie nce  3 6 2 ( 2 0 1 8). 
1 0 9. 
Sa de- Fel d ma n, M. , et al. Resista nce t o c hec k p oi nt bl oc ka de t hera p y t hr o u g h i nacti vati o n 
of a nti ge n pres e ntati o n. N at C o m m u n  8 , 1 1 3 6 ( 2 0 1 7). 
1 1 0. 
A yers, M. , et al. I F N- g a m ma-relate d m R N A pr ofile pre dicts cli nical res p o nse t o P D- 1 
bl oc ka de. J Cli n I nvest  1 2 7 , 2 9 3 0 – 2 9 4 0 ( 2 0 1 7). 
1 1 1. 
Sz ole k, A. , et al. O pti T y pe: precisi o n H L A t y pi n g fr o m ne xt- ge n erati o n s e q ue nci n g dat a. 
Bi oi nf or m atics  3 0 , 3 3 1 0- 3 3 1 6 ( 2 0 1 4). 
1 1 2. 
Ne w ma n, A. M. , et al. Deter mi ni n g cell t y pe a b u n da nce a n d e x pressi o n fr o m b ul k tiss ues 
wit h di gital c yt o metr y. N at Bi otec h n ol  ( 2 0 1 9). 
1 1 3. 
R o o ne y, M. S., S h u kla, S. A., W u, C.J., Getz, G. & Hac o he n, N. M olec ular a n d ge netic 
pr o perties of t u m ors ass o ciate d wit h l ocal i m m u ne c yt ol ytic acti vit y. Cell  1 6 0 , 4 8 – 6 1 
( 2 0 1 5). 
1 1 4. 
Li berz o n, A. , et al. T he M olec ular Si g nat ures Data base ( M Si g D B) hall mar k ge ne set 
c ollecti o n. Cell Syst  1 , 4 1 7- 4 2 5 ( 2 0 1 5). 
1 1 5. 
S u bra ma nia n, A. , et al. G e ne set e nric h me nt a nal ysis: a k n o wle d ge- bas e d a p pr oac h f or 
i nter preti n g ge n o me- wi de e x pressi o n pr ofiles. Pr oc N atl Ac a d Sci U S A  1 0 2 , 1 5 5 4 5-
1 5 5 5 0 ( 2 0 0 5). 
1 1 6. 
G o dec, J. , et al. C o m pe n di u m of I m m u ne Si g nat ures I de ntifies C o nser ve d a n d S pecies-
S pecific Bi ol o g y i n Res p o nse t o I nfla m mati o n. I m m u nity 4 4 , 1 9 4- 2 0 6 ( 2 0 1 6). 
1 1 7. 
Fe hre n bac h er, L. , et al. Atez oliz u ma b vers us d oceta xel f or p atie nts wit h pre vi o usl y 
treate d n o n-s mall-cell l u n g ca ncer ( P O P L A R): a m ultice ntre, o pe n-la b el, p hase 2 
ra n d o mise d c o ntr olle d tri al. L a ncet  3 8 7 , 1 8 3 7 – 1 8 4 6 ( 2 0 1 6). 
1 1 8. 
Br o w n, S. D., Rae b ur n, L. A. & H olt, R. A. Pr ofili n g tiss ue-resi de nt T cell re pert oires b y 
R N A se q ue nci n g. G e n o me Me d  7 , 1 2 5 ( 2 0 1 5). 
1 1 9. 
R osati, E. , et al. O ver vie w of met h o d ol o gies f or T-cell rece pt or re pert oire a nal ysis. B M C 
Bi otec h n ol  1 7 , 6 1 ( 2 0 1 7). 
1 2 0.    Bar dia A, T ola ne y S M, L oirat D, et al. A S C E N T: A ra n d o mize d p h ase III st u d y of 
sacit uz u ma b g o viteca n ( S G) vs treat me nt of p h ysicia n’s c h oice ( T P C) i n patie nts ( pts) 
wit h pre vi o usl y treate d metastatic tri ple- ne g ati ve breast ca ncer ( m T N B C). A n nals of 
O nc ol o g y ( 2 0 2 0) 3 1 (s u p pl _ 4): S 1 1 4 2- S 1 2 1 5. 1 0. 1 0 1 6/a n n o nc/a n n o nc 3 2 5 
1 2 1.  
Sacit uz u ma b G o viteca n Pac ka ge I ns ert 

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Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 0 7 
 

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Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 0 8 
A P P E N DI X A 
P E R F O R M A N C E S T A T U S C RI T E RI A 
 
E C O G Perf or m a nce St at us Sc ale 
K ar n ofs k y Perf or m a nce Sc ale
Gra de
Descri pti o ns
Perce nt 
Descri pti o n
0
N or mal acti vit y.  F ull y acti ve, a ble 
t o carr y o n all pre- diseas e 
perf or ma n ce wit h o ut restricti o n.
1 0 0 
N or mal, n o c o m plai nts, n o e vi de nce 
of disease.
9 0 
A ble t o carr y o n n or mal acti vit y; 
mi n or si g ns or s y m pt o ms of disease.
1
S y m pt o ms, b ut a m b ulat or y.  
Restricte d i n p h ysicall y stre n u o us 
acti vit y, b ut a m b ulat or y a n d a ble 
t o carr y o ut w or k of a li g ht or 
se de ntar y n at ure (e. g., li g ht 
h o use w or k, offi ce w or k).
8 0 
N or mal acti vit y wit h eff ort; s o me 
si g ns or s y m pt o ms of disease. 
7 0
Cares f or s elf, u na ble t o carr y o n 
n or mal acti vit y or t o d o acti ve w or k.
2
I n b e d < 5 0 % of t he ti me.  
A m b ulat or y a n d ca p a ble of all 
self-care, b ut u na bl e t o carr y o ut 
a n y w or k acti vities.  U p a n d a b o ut 
m ore t ha n 5 0 % of wa ki n g h o urs. 
6 0 
Re q uires occasi o nal assista nce b ut is 
a ble t o care f or m ost of his/ her 
nee ds. 
5 0 
Re q uires c o nsi dera ble assista nce a n d 
fre q ue nt me di cal care. 
3
I n b e d > 5 0 % of t he ti me.  Ca pa ble 
of o nl y li mite d self-care, c o nfi ne d 
t o be d or c hair m ore t ha n 5 0 % of 
wa ki n g h o urs. 
4 0 
Disa ble d, re q uires s pecial care a n d 
assista nce.
3 0 
Se verel y disa ble d, h os pit alizati o n 
i n dicate d.  Deat h n ot i m mi ne nt. 
4
1 0 0 % be dri d de n.  C o m pletel y 
disa ble d.  Ca n n ot carr y o n a n y 
self-care.  T otall y c o nfi n e d t o be d 
or c hair. 
2 0 
Ver y sic k, h os pitalizati o n i n dicate d. 
Deat h n ot i m mi ne nt.
1 0 
M ori b u n d, fatal pr ocesses 
pr o gressi n g ra pi dl y.
5
Dea d. 
0 
Dea d. 

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A P P E N DI X B 
C O N T R A C E P TI V E G UI D A N C E A N D P R E G N A N C Y T E S TI N G
W o m a n of C hil d be ari n g P ote nti al ( W O C B P) 
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc h e a n d u ntil bec o mi n g p ost- me n o pa usal u nless 
per ma ne ntl y sterile (see bel o w)  
W o me n i n t he f oll o wi n g cate g ories are n ot c o nsi dere d W O C B P: 
 
Pre me narc hal
 
Pre me n o pa usal fe male wit h 1 of t he f oll o wi n g: 
 
D oc u me nte d h ysterect o m y 
 
D oc u me nte d bilateral sal pi n gect o m y
 
D oc u me nte d bilateral o o p h orect o m y 
N ote:  D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t he partici pa nt’s me dical 
rec or ds, me di cal e x a mi nati o n, or me dical hist or y i nter vie w. 
 
P ost me n o pa usal fe male 
 
A p ost me n o pa usal state is defi ne d as n o me ns es f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca us e.  
 
A hi g h f ollicle sti m ulati n g h or m o ne ( F S H) le vel i n t he p ost me n o pa usal ra n ge ma y be 
use d t o c o nfir m a p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal c o ntrace pti o n 
or h or m o nal re place me nt t hera p y ( H R T). H o we v er, i n t he a bse nce of 1 2 m o nt hs of 
a me n orr h ea, c o nfir mati o n wit h t w o F S H meas ure me nts i n t he p ost me n o pa usal ra n ge 
is re q uire d.  
 
Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne of 
t he n o n- h or m o nal, hi g hl y effecti ve, c o ntrace pti o n met h o ds if t he y wis h t o c o nti n ue t heir 
H R T d uri n g t he st u d y. Ot her wise, t he y m ust disc o nti n ue H R T t o all o w c o nfir mati o n of 
p ost me n o pa usal stat us bef ore st u d y e nr oll me nt. 
C o ntr ace pti o n Re q uire me nts
M ale P arti ci p a nts:
Male partici pa nts wit h fe male part ners of c hil d beari n g p ote ntial are eli gi ble t o partici pate if t he y 
a gree t o o n e of t he f oll o wi n g f or t he d urati o n of st u d y treat me nt a n d 3 m o nt hs after t he last d ose 
of st u d y treat me nt:  
 
Be a bsti ne nt fr o m pe nile- va gi nal i nterc o urs e as t heir us ual a n d preferre d lifest yle (a bsti ne nt 
o n a l o n g ter m a n d persiste nt basis) a n d a gree t o re mai n a bsti ne nt 
 
Use a male c o n d o m pl us part ner use of a c o ntrace pti ve met h o d wit h a fail ure rat e of < 1 % per 
year as d escri b e d i n Ta bl e 9 w he n ha vi n g p e nile- v a gi nal i nterc o urs e wit h a w o ma n of 
c hil d beari n g p ote ntial w h o is n ot c urre ntl y pre g n a nt. 
 N ote: Me n wit h a pre g n a nt or breastfee di n g part n er m ust a gree t o re mai n a bsti ne nt fr o m 
pe nile va gi nal i nterc o urs e or use a m ale c o n d o m d uri n g eac h e pis o de of pe nile 
pe netrati o n. 

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1 1 1
A P P E N DI X C
DI E T A N D P H Y SI C A L A C TI VI T Y A S S E S S M E N T S
Please n ote: t he bel o w is a c o p y of t he Bl oc k F at/ S u g ar/ Fr uit/ Ve get a ble Scree ner f or 
refere nce. Ple ase us e t he offici al Sc a ntr o n versi o n of t he Scree ner r at her t h a n t he a p pe n dix. 

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4
1 1 2

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4
1 1 3

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4
1 1 4

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4
1 1 5
A P P E N DI X D
DI E T A N D P H Y SI C A L A C TI VI T Y A S S E S S M E N T S
Bel o w is a c o p y of t he G or di n Leis ure- Ti me E xercise Q uesti o n n aire ( L SI) wit h t hree 
a d diti o nal q uesti o ns a b o ut fi ber i nta ke fr o m t he Bl oc k Ve get a ble/ Fr uit/ Fi ber Scree ner .

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
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1 1 6 
A P P E N DI X E 
E O R T C Q L Q- C 3 0 
We are i ntereste d i n s o me t hi n gs a b o ut y o u a n d y o ur healt h. Please a ns wer all of t he q uesti o ns 
y o urself b y circli n g t he n u m ber t hat best a p plies t o y o u. T here are n o "ri g ht" or " wr o n g" a ns wers. 
T he i nf or mati o n t hat y o u pr o vi de will re mai n strictl y c o nfi de ntial. 
Please fill i n y o ur i nitials:
Y o ur birt h date ( Da y, M o nt h, Year):
T o da y's date ( Da y, M o nt h, Year):  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
N ot at 
All
A 
Little
Q uite a 
Bit
Ver y 
M uc h  
1.
D o y o u ha ve a n y tr o u ble d oi n g stre n u o us acti vities, 
li ke carr yi n g a hea v y s h o p pi n g ba g or a s uitcase? 
1 
2 
3 
4 
2.
D o y o u ha ve a n y tr o u ble ta ki n g a l o n g wal k? 
1 
2 
3 
4 
3.
D o y o u ha ve a n y tr o u ble ta ki n g a s h ort wal k o utsi de of t he h o use? 
1 
2 
3 
4 
4.
D o y o u nee d t o sta y i n be d or a c hair d uri n g t he da y? 
1 
2 
3 
4 
5.
D o y o u nee d hel p wit h eati n g, dressi n g, was hi n g 
y o urself or usi n g t he t oilet? 
1 
2 
3 
4 
D uri n g t he p ast wee k:                                 
6.
Were y o u li mite d i n d oi n g eit her y o ur w or k or ot her dail y acti vities? 
1 
2 
3 
4 
7.
Were y o u li mite d i n p urs ui n g y o ur h o b bies or ot her
 
leis ure ti me acti vities? 
1 
2 
3 
4 
 
8. 
Were y o u s h ort of breat h? 
1 
2 
3 
4 
 
9. 
Ha ve y o u ha d pai n? 
1 
2 
3 
4 
 
1 0. Di d y o u nee d t o rest? 
1 
2 
3 
4 
 
1 1. Ha ve y o u ha d tr o u ble slee pi n g? 
1 
2 
3 
4 
 
1 2. Ha ve y o u felt wea k? 
1 
2 
3 
4 
 
1 3. Ha ve y o u lac ke d a p petite? 
1 
2 
3 
4 
 
1 4. Ha ve y o u felt na useate d? 
1 
2 
3 
4 

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Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 1 7 
1 5.
Ha ve y o u v o mite d? 
1 
2 
3 
4 
1 6.
Ha ve y o u bee n c o nsti pate d? 
1 
2 
3 
4 
1 7.
Ha ve y o u ha d diarr hea?
1 
2 
3 
4 
1 8.
Were y o u tire d?
1 
2 
3 
4 
 
1 9. Di d pai n i nterfere wit h y o ur dail y acti vities? 
1 
2 
3 
4 
 
2 0. Ha ve y o u ha d diffic ult y i n c o nce ntrati n g o n t hi n gs, 
 
li ke rea di n g a ne ws pa per or watc hi n g tele visi o n? 
1 
2 
3 
4 
 
2 1. Di d y o u feel te nse? 
1 
2 
3 
4 
 
2 2. Di d y o u w orr y? 
1 
2 
3 
4 
 
2 3. Di d y o u feel irrita ble? 
1 
2 
3 
4 
 
2 4. Di d y o u feel de presse d? 
1 
2 
3 
4 
 
2 5. Ha ve y o u ha d diffic ult y re me m beri n g t hi n gs? 
1 
2 
3 
4 
 
2 6. Has y o ur p h ysical c o n diti o n or me dical treat me nt 
i nterfere d wit h y o ur fa mil y life?
1 
2 
3 
4 
2 7.
Has y o ur p h ysical c o n diti o n or me dical treat me nt 
i nterfere d wit h y o ur s ocial acti vities? 
1 
2 
3 
4 
2 8.
Has y o ur p h ysical c o n diti o n or me dical treat me nt 
ca use d y o u fi na ncial diffic ulties?
1 
2 
3 
4 
F or t he f oll o wi n g 
q uesti o ns 
ple ase 
circle t he 
n u m ber 
bet wee n 
1 
a n d 
7 t h at 
best a p plies t o y o u 
2 9.
H o w w o ul d y o u rate y o ur o verall healt h d uri n g t he past wee k?
 
 1 
2 
3 
4 
5 
6 
7 
Ver y p o or
E xcelle nt
3 0.
H o w w o ul d y o u rate y o ur o verall q ualit y of life d uri n g t he past wee k?
 
 1 
2 
3 
4 
5 
6 
7 

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Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 1 8 
A P P E N DI X F
E U R O Q O L  E Q- 5 D- 5 L
U n der eac h hea di n g, please tic k t he O N E b o x t hat best descri bes y o ur healt h T O D A Y.
M O BI LI T Y 
I h a ve n o pr o bl e ms i n wal ki n g a b o ut
I h a ve sli g ht pr o ble ms i n wal ki n g a b o ut 
 
I h a ve m o derate pr o bl e ms i n wal ki n g a b o ut
 
I h a ve se v ere pr o ble ms i n wal ki n g a b o ut 
 
I a m u na ble t o w al k a b o ut 
 
S E L F- C A R E 
I h a ve n o pr o bl e ms was hi n g or dressi n g m yself 
 
I h a ve sli g ht pr o ble ms w as hi n g or dressi n g m yself 
 
I a m u na ble t o was h or dress m yself 
 
U S U A L A C TI VI TI E S (e. g., w ork, st u dy, h o use w ork, f a mily or leis ure activities) 
I h a ve n o pr o bl e ms d oi n g m y us ual acti vities 
 
I h a ve sli g ht pr o ble ms d oi n g m y us ual acti vities 
 
I h a ve m o derate pr o bl e ms d oi n g m y us ual acti vities 
 
I h a ve se v ere pr o ble ms d oi n g m y us ual acti vities 
 
I a m u na ble t o d o m y us u al acti vities 
 
P AI N / DI S C O M F O R T 
I h a ve n o pai n or dis c o mf ort 
 
I h a ve sli g ht pai n or disc o mf ort 
 
I h a ve m o derate p ai n or disc o mf ort 
 
I h a ve se v ere p ai n or disc o mf ort 
 
I h a ve e xtre me p ai n or disc o mf ort 
 
A N XI E T Y / D E P R E S SI O N 
I a m n ot a n xi o us or de presse d 
 
I a m sli g htl y a n xi o us or de presse d 
 
I a m m o derat el y a n xi o us or de presse d 
 

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3
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1 1 9
I a m se verel y a n xi o us or de presse d
I a m e xtre m el y a n xi o us or de presse d
We w o ul d li ke t o k n o w h o w g o o d or ba d y o ur h ealt h is T O D A Y.
T his scale is n u m bere d fr o m 0 t o 1 0 0. 
1 0 0 mea ns t he best healt h y o u ca n i ma gi ne. 0 mea ns t he w orst 
healt h y o u ca n i ma gi ne.
Mar k a n X o n t he s cale t o i n dicate h o w y o ur healt h is T O D A Y.
N o w, please write t he n u m ber y o u mar ke d o n t h e scale i n t he b o x 
bel o w. 
Y O U R H E A L T H T O D A Y = 

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
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1 2 3 
A P P E N DI X H
D F/ H C C M U L TI C E N T E R D A T A & S A F E T Y M O NI T O RI N G P L A N
D F CI I R B Pr ot oc ol #: 2 0- 1 5 3 
 
 
T A B L E O F C O N T E N T S 
1.
I N T R O D U C TI O N
1. 1
P ur p ose
2.
G E N E R A L R O L E S A N D R E S P O N SI BI LI TI E S 
2. 1
C o or di n ati n g Ce nter
2. 2
E xter n al Site  
3.
D F/ H C C R E Q UI R E M E N T S F O R M U L TI- C E N T E R P R O T O C O L S 
 
3. 1 
Pr ot oc ol R e visi o ns a n d Cl os ures  
3. 2 
I nf or me d C o nse nt Re q uire me nts  
3. 3 
I R B Re- A p pr o v al 
3. 4 
D F/ H C C M ulti- Ce nter Pr ot oc ol C o nfi de nti alit y 
3. 5
P artici p a nt Re gistr ati o n a n d R a n d o miz ati o n
3. 6
D at a M a n a ge me nt 
3. 7
Pr ot oc ol R e p orti n g Re q uire me nts 
 
 
4. 
M O NI T O RI N G: Q U A LI T Y C O N T R O L 
 
4. 1 
O n g oi n g M o nit ori n g of Pr ot oc ol C o m pli a nce
4. 2
M o nit ori n g Re p orts 
4. 3
Accr u al M o nit ori n g 
5.
A U DI TI N G: Q U A LI T Y A S S U R A N C E
 
5. 1 
D F/ H C C I nter n al A u dits 
5. 2 
A u dit N otific ati o ns 
5. 3 
A u dit Re p orts  
5. 4 
E xter n al Site Perf o r m a nce 
 
 

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 2 4 
1. I N T R O D U C TI O N  
T he Da na- Far ber/ Har v ar d Ca ncer Ce nter M ulti- Ce nter Dat a a n d Safet y M o nit ori n g Pla n 
( D F/ H C C D S M P) o utli nes t he pr oce d ures f or c o n d ucti n g a D F/ H C C M ulti- Ce nter researc h 
pr ot oc ol. T he D F/ H C C D S M P ser ves as a refere nce f or a n y sites e xter nal t o D F/ H C C t hat are 
partici pati n g i n a D F/ H C C cli nical trial.  
1. 1
P ur p ose
T o esta blis h sta n dar ds t h at will e ns ure t hat a Da na- Far ber/ Har var d Ca ncer Ce nter M ulti- Ce nter 
pr ot oc ol will c o m pl y wit h Fe deral Re g ulati o ns, Healt h I ns ura n ce P orta bilit y a n d Acc o u nt a bilit y 
Act ( HI P A A) re q uire me nts a n d a p plica ble D F/ H C C Sta n dar d O perati n g Pr oce d ures.       
 
2 
G E N E R A L R O L E S A N D R E S P O N SI BI LI TI E S  
 
F or D F/ H C C M ulti- Ce nter Pr ot oc ols, t he f oll o wi n g ge neral res p o nsi bilities a p pl y, i n a d diti o n t o 
t h ose o utli ne d i n D F/ H C C P olicies f or S p o ns or-I n vesti gat ors: 
 
2. 1 
C o or di n ati n g Ce nter  
 
T he C o or di nati n g Ce nter is t he e ntit y t hat pr o vi des a d mi nistrati ve s u p p ort t o t he D F/ H C C 
S p o ns or i n or der t hat he/s he ma y f ulfill t he res p o nsi bilities o utli ne d i n t he pr ot oc ol d oc u me nt a n d 
D S M P, a n d as s pecifie d i n a p plica ble re g ulat or y g ui deli nes (i.e., C T E P M ulti- Ce nter 
G ui deli nes). 
 
T he ge neral res p o nsi bilities of t he C o or di nati n g Ce nter ma y i ncl u de b ut are n ot li mite d t o:
 Assist i n pr ot oc ol de vel o p me nt.  
 Mai ntai n F D A c orres p o n de nce as a p plica ble.
 Re vie w re gistrati o n materials f or eli gi bilit y a n d re gister partici pa nts fr o m P artici pati n g 
I nstit uti o ns i n t he D F/ H C C cli nical trial ma na ge m e nt s yste m ( C T M S). 
 Distri b ute pr ot oc ol a n d i nf or me d c o ns e nt d oc u me nt u p dates t o E xter nal Sites as nee d e d.  
 O versee t he data c ollecti o n pr ocess fr o m E xter nal Sites.  
 Mai ntai n d oc u me ntati o n of Seri o us A d vers e E ve nt ( S A E) re p orts a n d 
de viati o ns/ vi olati o n s u b mitte d b y E xter nal Sites a n d pr o vi de t o t he D F/ H C C S p o ns or f or 
ti mel y re vie w a n d s u b missi o n t o t he D F CI I R B, as necessar y.  
 Distri b ute seri o us a d vers e e ve nts re p orte d t o t he D F/ H C C S p o ns or t hat fall u n der t he 
D F CI I R B A d vers e E ve nt Re p orti n g P olic y t o all E xter nal Sites.  
 Pr o vi de E xter nal Sites wit h i nf or mati o n re gar di n g D F/ H C C re q uire m e nts t hat t he y will 
be e x pecte d t o c o m pl y wit h. 
 
 Carr y o ut pla n t o m o nit or E xter nal Sites eit her b y o n-site or re m ote m o nit ori n g.  
 Mai ntai n Re g ulat or y d oc u me nts of all E xter nal Sites w hic h i ncl u des b ut is n ot li mite d t o 
t he f oll o wi n g: l ocal I R B a p pr o vals/ n otificati o ns fr o m all Partici pati n g I nstit uti o ns, 
c o nfir mati o n of Fe deral wi de Ass ura nces ( F W As) f or all sites, all S A E s u b missi o ns, 
Scree ni n g L o gs f or all sites, I R B a p pr o ve d c o nse nts f or all sites
 C o n d uct re g ular c o m m u nicati o ns wit h all E xter nal Sites (c o nfere nce calls, e mails, etc.) 
a n d mai ntai n d oc u me ntati o n all rele va nt c o m m u ni cati o ns.  

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 2 5 
2. 2
E xter n al Site  
A n E xter nal Site is a n i nstit uti o n t hat is o utsi de t he D F/ H C C a n d D F/ P C C c o ns orti u m t hat is 
c olla b orati n g wit h D F/ H C C o n a pr ot oc ol w here t he s p o ns or is a D F/ H C C i n vesti gat or.  T he 
E xter nal Site ac k n o wl e d ges t he D F/ H C C S p o ns or as ha vi n g t he ulti mate a ut h orit y a n d 
res p o nsi bilit y f or t he o verall c o n d uct of t he st u d y. 
Eac h E xter n al Site is e x pecte d t o c o m pl y wit h all a p plica ble D F/ H C C re q uire me nts state d wit hi n 
t his Data a n d Safet y M o nit ori n g Pla n a n d/ or t he pr ot oc ol d oc u me nt. 
T he ge neral res p o nsi bilities f or eac h E xter nal Site ma y i ncl u de b ut are n ot li mite d t o: 
 D oc u me nt t he dele g ati o n of researc h s p ecific acti vities t o st u d y pers o n nel.  
 C o m mit t o t he accr u al of partici pa nts t o t he pr ot oc ol.
 S u b mit pr ot oc ol a n d/ or a me n d me nts t o t heir l ocal I R B.  
 Mai ntai n re g ulat or y files as per s p o ns or re q uire m e nts.  
 Pr o vi de t he C o or di nati n g Ce nter wit h re g ulat or y d oc u me nts or s o urce d oc u me nts as 
re q ueste d. 
 Partici pate i n pr ot oc ol trai ni n g pri or t o e nr olli n g partici pa nts a n d t hr o u g h o ut t he trial as 
re q uire d (i. e. telec o nfere nces).
 U p date C o or di nati n g Ce nter wit h researc h staff c ha n ges o n a ti mel y basis.  
 Re gister partici pa nts t hr o u g h t he C o or di nati n g Ce nter pri or t o be gi n ni n g researc h relate d 
acti vities.  
 S u b mit Seri o us A d verse E ve nt ( S A E) re p orts t o l ocal I R B per i nstit uti o nal re q uire me nts 
a n d t o t he C o or di nati n g Ce nter, i n acc or da n ce wit h D F/ H C C re q uire m e nts. 
 S u b mit pr ot oc ol de viati o ns a n d vi olati o ns t o l ocal I R B per i nstit uti o nal re q uire me nts a n d 
t o t he D F/ H C C S p o ns or i n acc or d a nce wit h D F/ H C C re q uire me nts. 
 Or der, st ore a n d dis pe nse i n vesti gati o nal a ge nts a n d/ or ot her pr ot oc ol ma n d ate d dr u gs per 
fe deral g ui deli nes a n d pr ot oc ol re q uire me nts. 
 Ha ve office s pace, office e q ui p me nt, a n d i nter net access t hat meet HI P A A sta n dar ds.  
 Partici pate i n a n y q ualit y ass ura nce acti vities a n d meet wit h m o nit ors or a u dit ors at t he 
c o ncl usi o n of a visit t o re vie w fi n di n gs.  
 Pr o m ptl y pr o vi de f oll o w- u p a n d/ or c orrecti ve acti o n pla ns f or a n y m o nit ori n g q ueries or 
a u dit fi n di n gs.  
 N otif y t he s p o ns or i m me diatel y of a n y re g ulat or y a ut h orit y i ns pecti o n of t his pr ot oc ol at 
t he E xter nal Site. 
 
3 
D F/ H C C R E Q UI R E M E N T S F O R M U L TI- C E N T E R P R O T O C O L S  
 
Certai n D F/ H C C P olic y re q uire me nts a p pl y t o E xter nal Sites partici pati n g i n D F/ H C C researc h. 
T he f oll o wi n g secti o n will clarif y D F/ H C C re q uire me nts a n d f urt her det ail t he e x pectati o ns f or 
partici pati n g i n a D F/ H C C M ulti- Ce nter pr ot oc ol.  
 
3. 1 
Pr ot oc ol R e visi o ns a n d Cl os ures  

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 2 6 
T he E xter nal Sites will recei ve n otificati o n of pr ot oc ol re visi o ns a n d cl os ures fr o m t he 
C o or di nati n g Ce nter.  W he n u n der a se parate I R B, it is t he i n di vi d ual E xter nal Site’s res p o nsi bilit y 
t o n otif y its I R B of t hese re visi o ns. 
 
 Pr ot oc ol re visi o ns:  E xt er nal Sites will recei ve writte n n otificati o n of pr ot oc ol 
re visi o ns fr o m t he C o or di nati n g Ce nter. All pr ot oc ol re visi o ns s h o ul d be I R B 
a p pr o ve d a n d i m ple me nt e d wit hi n a ti mel y ma n ner fr o m recei pt of t he n otificati o n. 
 Pr ot oc ol cl os ures a n d te m p or ar y h ol ds:  E xter nal Sites will recei ve n otificati o n of 
pr ot oc ol cl os ures a n d te m p orar y h ol ds fr o m t he C o or di nati n g Ce nter. Cl os ures a n d 
h ol ds will be effecti ve i m me diatel y.  I n a d diti o n, t he C o or di nati n g Ce nter, will 
u p date t he E xter nal Sites o n a n o n g oi n g basis a b o ut pr ot oc ol accr ual d ata s o t hat 
t he y will be a ware of i m mi ne nt pr ot oc ol cl os ures. 
3. 2
I nf or me d C o nse nt Re q uire me nts
T he D F/ H C C a p pr o ve d i nf or me d c o nse nt d oc u me nt will ser ve as a te m plate f or t he i nf or me d 
c o nse nt f or E xter n al Sites. T he E xter nal Site c o nse nt f or m m ust f oll o w t he c o nse nt te m plate as 
cl osel y as p ossi ble a n d s h o ul d a d here t o s p ecificati o ns o utli ne d i n t h e D F/ H C C G ui da nce 
D oc u me nt o n M o del C o nse nt La n g ua g e f or I n vesti gat or- S p o ns ore d M ulti- Ce nter Trials.  T his 
d oc u me nt will be pr o vi de d se paratel y t o eac h E xt er nal Site u p o n re q u est. 
 
E xter nal Sites m ust se n d t heir versi o n of t h e i nf or me d c o nse nt d oc u m e nt t o t he C o or di nati n g 
Ce nter f or s p o ns or re vie w a n d a p pr o val. If t h e HI P A A a ut h orizati o n is a se parate d oc u me nt, pleas e 
s u b mit t o t he s p o ns or f or t he st u d y rec or d. O nce s p o ns or a p pr o val is o btai ne d, t he E xter nal site 
ma y s u b mit t o t heir I R B of rec or d, as a p plica ble. I n t hes e cases, t he a p pr o ve d c o nse nt f or m m ust 
als o be s u b mitte d t o t he C o or di nati n g Ce nter after a p pr o val b y t he l o cal I R B f or all c o ns e nt 
versi o ns. 
T he Pri nci pal I n vesti gat or ( PI) at eac h E xter nal Site will i de ntif y t he a p pr o priate me m bers of t he 
st u d y tea m w h o will be o btai ni n g c o nse nt a n d si g ni n g t he c o nse nt f or m f or pr ot oc ols. E xter nal 
Sites m ust f oll o w t he D F/ H C C re q uire me nt t hat f or all i nter ve nti o nal dr u g, bi ol o gic, or de vice 
researc h, o nl y atte n di n g p h ysicia ns ma y o btai n i nitial i nf or me d c o nse nt a n d a n y re-c o nse nt t hat 
re q uires a f ull re vise d c o nse nt f or m.   
3. 3
I R B Re- A p pr o v al
 
Verificati o n of I R B re-a p pr o val fr o m t he E xter nal Sites is re q uire d i n or der t o c o nti n ue researc h 
acti vities.  T here is n o grace p eri o d f or c o nti n ui n g a p pr o vals. 
T he C o or di nati n g Ce nter will n ot re gister partici p a nts if a re-a p pr o v al letter is n ot recei ve d fr o m 
t he E xter nal Site o n or bef ore t he a n ni versar y of t h e pre vi o us a p pr o val date.   
3. 4
D F/ H C C M ulti- Ce nter Pr ot oc ol C o nfi de nti alit y
  

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 2 7 
All d oc u me nts, i n vesti gati ve re p orts, or i nf or m ati o n relati n g t o t he partici p a nt are strictl y 
c o nfi de ntial. W he n e ver reas o na bl y feasi ble, a n y p artici pa nt s pecifi c re p orts (i.e., Pat h ol o g y 
Re p orts, M RI Re p orts, O perati ve Re p orts, etc.) s u b mitte d t o t he C o or di nati n g Ce nter s h o ul d be 
de-i de ntifie d. It is rec o m me n de d t hat t he assi g ne d pr ot oc ol case n u m b er (as descri be d bel o w) be 
use d f or all partici pa nt s pecific d oc u m e nts. Partici pa nt i nitials ma y be i ncl u de d or ret ai ne d f or 
cr oss verificati o n of i de ntificati o n.  
3. 5 
P artici p a nt Re gistr ati o n a n d R a n d o miz ati o n
Please refer t o Pr ot oc ol Secti o n 4. 3 a n d 4. 4 f or p artici pa nt re gistrati o n i nf or mati o n. Treat me nt 
ca n n ot be gi n u ntil site has recei v e d c o nfir m ati o n t hat partici pa nt has b ee n re gistere d wit h 
D F/ H C C C T M S.  
   3. 5. 1 
I nitiati o n of T hera p y 
Partici pa nts m ust be re gistere d wit h t he D F/ H C C C T M S bef ore t he i nitiati o n of 
treat me nt or ot her pr ot oc ol-s pecific i nter v e nti o ns. Treat me nt a n d ot h er pr ot oc ol-
s pecific i nter v e nti o ns ma y n ot be i nitiate d u ntil t he E xter nal Site recei ves 
c o nfir mati o n of t he partici pa nt’s re gistrati o n fr o m t he C o or di nati n g Ce nter. T he 
D F/ H C C S p o ns or a n d D F CI I R B m ust be n otifie d of a n y vi olati o ns t o t his p olic y. 
   3. 5. 2 
Eli gi bilit y E xce pti o ns 
N o e xce pti o ns t o t he eli gi bilit y re q uire me nts f or a pr ot oc ol wit h o ut D F CI I R B 
a p pr o val will be per mitte d. All E xter nal Sites are re q uire d t o f ull y c o m pl y wit h t his 
re q uire me nt. T h e pr ocess f or re q u esti n g a n eli gi bilit y e xce pti o n is defi ne d b el o w. 
3. 6 
D at a M a n a ge me nt
D F/ H C C de vel o ps case re p ort f or ms ( C R F/e C R Fs), f or use wit h t he pr ot oc ol.  T hese f or ms are 
desi g ne d t o c ollect data f or eac h st u d y. D F/ H C C pr o vi des a we b- base d trai ni n g f or all e C R F 
users.
   3. 6. 1 
Data F or ms Re vie w 
Data s u b missi o ns are m o nit ore d f or ti meli ness a n d c o m plete ness of s u b missi o n. If 
st u d y f or ms are recei ve d wit h missi n g or q uesti o na ble data, t he s u b mitti n g i nstit uti o n 
will recei ve a writte n or electr o nic q u er y fr o m t he D F/ H C C Office of Data Q ualit y, 
C o or di nati n g Ce nter, or desi g nee.  
Res p o nses t o all q ueries s h o ul d be c o m plete d a n d s u b mitte d wit hi n 1 4 cale n dar da ys.   
If st u d y f or ms are n ot s u b mitte d o n sc he d ule, t he E xter nal Sites will peri o dicall y 
recei v e a Missi n g F or m Re p ort fr o m t he C o or di n ati n g Ce nter n oti n g t he missi n g 
f or ms.  

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 2 8 
3. 7
Pr ot oc ol R e p orti n g Re q uire me nts  
 
   3. 7. 1 
Pr ot oc ol De viati o ns, E xce pti o ns a n d Vi olati o ns 
 
Fe deral Re g ulati o ns re q uire a n I R B t o re vie w pr o p ose d c ha n ges i n a res earc h acti vit y 
t o e ns ure t hat res earc hers d o n ot i nitiate c ha n ges i n a p pr o ve d researc h wit h o ut I R B 
re vie w a n d a p pr o v al, e xce pt w he n necessar y t o eli mi nate a p pare nt i m me diate hazar ds 
t o t he partici pa nt. D F/ H C C re q uires all de p art ures fr o m t he defi ne d pr oce d ures set 
f ort h i n t he I R B a p pr o ve d pr ot oc ol t o be re p ort e d t o t he D F/ H C C S p o ns or a n d t o t he 
I R B of rec or d.  
 
   3. 7. 2 
Re p orti n g Pr oce d ures 
 
Re q uests t o de viate fr o m t he pr ot oc ol re q uire a p pr o val fr o m t he I R B of rec or d a n d t he 
s p o ns or.  
 
All pr ot oc ol vi olati o ns m ust be se nt t o t he C o or di nati n g Ce nter i n a ti mel y ma n ner. T he 
C o or di nati n g Ce nter will pr o vi de trai ni n g f or t h e re q uire me nts f or t h e re p orti n g of 
vi olati o ns.  
 
  3. 7. 3 G ui deli nes f or Pr o cessi n g I N D Safet y Re p orts  
 
T he D F/ H C C S p o ns or will re vie w all I N D Safet y Re p orts per D F/ H C C re q uire me nts 
a n d e ns ure t h at all I N D S afet y Re p orts are distri b ute d t o t he E xter nal Sites as re q uire d 
b y D F/ H C C P olic y. E xter nal Sites will re vie w/s u b mit t o t he I R B acc or di n g t o t heir 
i nstit uti o nal p olicies a n d pr oce d ures. 
 
4 
M O NI T O RI N G: Q U A LI T Y C O N T R O L  
 
T he C o or di nati n g Ce nter, wit h t he ai d of t he D F/ H C C Office of Data Q u alit y, pr o vi des q ualit y 
c o ntr ol o versi g ht f or t he pr ot oc ol. 
 
4. 1 
O n g oi n g M o nit ori n g of Pr ot oc ol C o m pli a nce  
 
T he E xter nal Sites ma y b e re q uire d t o s u b mit partici pa nt s o urce d o c u me nts t o t he C o or di nati n g 
Ce nter f or m o nit ori n g. E xter nal Sites ma y als o be s u bject t o o n-site m o nit ori n g c o n d ucte d b y t he 
C o or di nati n g Ce nter.  
 
T he C o or di nati n g Ce nter will i m ple me nt o n g oi n g m o nit ori n g acti vities t o e ns ure t hat E xter n al 
Sites are c o m pl yi n g wit h re g ulat or y a n d pr ot oc ol re q uire me nts, data q u alit y, a n d partici pa nt 
safet y. M o nit ori n g practi ces ma y i ncl u de b ut are n ot li mite d t o s o urce data verificati o n, a n d 
re vie w a n d a nal ysis of eli gi bilit y re q uire me nts, i nf or me d c o nse nt pr o ce d ures, a d verse e ve nts a n d 
all ass ociate d d oc u m e ntati o n, re vie w of st u d y dr u g a d mi nistrati o n/treat me nt, re g ulat or y files, 
pr ot oc ol de part ures re p orti n g, p har mac y rec or ds, res p o nse assess me nts, a n d data ma na g e me nt.  
 
A d diti o nall y, a pla n will be f or m ulate d t o pr o vi de re g ular a n d o n g oi n g c o m m u nicati o n t o 

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 2 9 
E xter nal Sites a b o ut st u d y relate d i nf or m ati o n w hic h will i ncl u de partici pati o n i n re g ular 
telec o nfere n ces i nitiate d b y t he C o or di nati n g Ce nter. Telec o nfere n ces will occ ur m o nt hl y a n d 
will c o nti n ue re g ularl y u ntil c o m pleti o n of pr ot oc ol t hera p y. 
U p o n c o m pleti o n of pr ot oc ol t hera p y, telec o nfere nces will occ ur e ver y 3 m o nt hs u ntil st u d y 
c o m pleti o n. A d diti o nal c o m m u nicati o n ma y be distri b ute d via “ Ne wsletter” or e mail as d ee me d 
a p pr o priate b y D F/ H C C S p o ns or. 
O n- Site M o nit ori n g: O n-site m o nit ori n g will occ ur o n a n as- nee de d b asis. E xter nal Sites will b e 
re q uire d t o pr o vi d e access t o partici pa nts’ c o m pl ete me dical rec or d a n d s o urce d oc u m e nts f or 
s o urce d oc u m e ntati o n verificati o n d uri n g t he visit. I n a d diti o n, E xter n al Sites s h o ul d pr o vi de 
access t o re g ulat or y d oc u me nts, p har mac y rec or ds, l ocal p olicies relate d t o t he c o n d uct of res earc h, 
a n d a n y ot her trial-relat e d d oc u me ntati o n mai nt ai ne d b y t he E xter nal Site. O n-site m o nit ori n g 
visits ca n be s u bstit ute d wit h re m ote ( virt ual) m o nit ori n g visits at t he discreti o n of t he Pri nci pal
I n v esti gat or. 
Re m ote M o nit ori n g:  Re m ote m o nit ori n g will be perf or me d o n a n as- nee d e d basis b y t he Cli nical 
Trial M o nit or. Sites will be as ke d t o pr o vi de s o urce d oc u m e ntati o n via e m ail or mail as s pecifie d 
b y t he Cli nical Trial M o nit or f or virt ual m o nit ori n g. 
 
4. 2 
M o nit ori n g Re p orts  
 
T he D F/ H C C S p o ns or will re vie w all m o nit ori n g re p orts t o e ns ure pr ot oc ol c o m plia nce. T he 
D F/ H C C S p o ns or ma y i ncreas e t he m o nit ori n g acti vities at E xter nal Sites t hat are u n a ble t o 
c o m pl y wit h t he pr ot oc ol, D F/ H C C S p o ns or re q uire me nts or fe deral a n d l o cal re g ulati o ns.  
 
4. 3 
Accr u al M o nit ori n g  
 
Pri or t o e xte n di n g a pr ot oc ol t o a n e xter n al site, t he D F/ H C C S p o ns or will esta blis h accr u al 
re q uire me nts f or eac h E xter nal Site. Accr ual will be m o nit ore d f or eac h p artici pati n g i nstit uti o n 
b y t he D F/ H C C S p o ns or or desi g nee. Sites t hat are n ot meeti n g t heir accr u al e x pect ati o ns ma y be 
s u bject t o ter mi nati o n. Sites are e x pect e d t o accr u e at least 3 patie nts per y ear. 
 
5 
A U DI TI N G: Q U A LI T Y A S S U R A N C E  
 
5. 1 
D F/ H C C I nter n al A u dits  
  
All E xter nal Sites are s u bject t o a u dit b y t he D F/ H C C Office of Data Q u alit y ( O D Q). T y pi call y, 
a p pr o xi matel y 3- 4 partici pa nts w o ul d be a u dite d at t he site o ver a 2- d a y peri o d. If vi olati o ns 
w hic h i m pact partici pa nt safet y or t he i nte grit y of t he st u d y are f o u n d, m ore partici pa nt rec or ds 
ma y be a u dite d.  
 
5. 2 
A u dit N otific ati o ns  
 
It is t he E xter nal Site’s res p o nsi bilit y t o n otif y t he C o or di nati n g Ce nter of all e xter nal a u dits or 
i ns pecti o ns (e. g., F D A, E M A, N CI) t hat i n v ol ve t his pr ot oc ol. All i nstit uti o ns will f or war d a 

D F/ H C C Pr ot o c ol #: 2 0- 1 5 3  
Pr ot o c ol V ersi o n Date: 1 0/ 1 1/ 2 0 2 4 
 
1 3 0 
c o p y of fi nal a u dit a n d/ or re-a u dit re p orts a n d c orrecti ve acti o n pla ns (if a p plica ble) t o t he 
C o or di nati n g Ce nter, wit hi n 1 2 wee ks aft er t he a u dit date.  
 
5. 3 
A u dit Re p orts  
 
T he D F/ H C C S p o ns or will re vie w all fi nal a u dit re p orts a n d c orrecti ve acti o n pla ns, if 
a p plica ble. T he C o or di n ati n g Ce nter m ust f or war d a n y re p orts t o t he D F/ H C C O D Q per 
D F/ H C C p olic y f or re vie w b y t he D F/ H C C A u dit C o m mittee. F or u nacce pt a ble a u dits, t he 
D F/ H C C A u dit C o m mittee w o ul d f or war d t h e fi n al a u dit re p ort a n d c orrecti ve acti o n pla n t o t he 
D F CI I R B as a p plica ble. 
 
5. 4 
E xter n al Site Perf o r m a nce  
 
T he D F/ H C C S p o ns or a n d t he D F CI I R B are c h ar ge d wit h c o nsi deri n g t he t otalit y of a n 
i nstit uti o n’s perf or ma nce i n c o nsi deri n g i nstit uti o nal partici pati o n i n t he pr ot oc ol. 
 
E xter nal Sites t hat fail t o meet t he perf or ma n ce g o als of accr u al, s u b missi o n of ti mel y a n d acc urate 
data, a d h ere n ce t o pr ot oc ol re q uire me nts, a n d c o m plia nce wit h state a n d fe deral re g ulati o ns, ma y 
be p ut o n h ol d or cl ose d.