A Phase 2 Study of Neratinib With or Without Fulvestrant in HER2-Positive, ER-Positive Metastatic Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Dana-Farber Cancer Institute



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2
S C H E M A
1 c ycle = 2 8 da ys
                    
     N = 1 5 2
Metastatic
H E R 2 +/ E R +
Breast Ca ncer; 
Pr o gresse d o n 
Trast uz u ma b, 
Pert uz u ma b, 
T- D M 1
 
  
   
  
 
  
  
 
A R M A: Nerati ni b ( dail y x 4 wee ks) + 
F ul vestra nt ( C 1 D 1, C 1 D 1 5, q 2 8 Da ys)
N = 7 6
A R M B: Nerati ni b ( dail y x 4 wee ks)
N = 7 6
F oll o w- u p
q 6 m o nt hs 
x 5 years 
Resta gi n g
q 2 c ycles;
C o nti n ue 
u ntil P D 
R A N D O MI Z E    
1: 1
Stratificati o n b y:

Pri or li nes of t hera p y ( ≤3, ≥4)

Pri or Use of F ul vestra nt ( Yes v N o)

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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......................................................................................................................................... 2
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 ve.................................................................................................... 5
1. 3 
Sec o n dar y O bjecti ves............................................................................................... 5
1. 4 
C orrelati ve O bjecti ves ............................................................................................. 5
2. 
B A C K G R O U N D................................................................................................................. 6
2. 1  
Metastatic H E R 2- P ositi ve, E R- P ositi ve Breast Ca ncer........................................... 6
2. 2  
Nerati ni b .................................................................................................................. 6
2. 3 
F ul vestra nt................................................................................................................ 7
2. 4 
Rati o nale.................................................................................................................. 7
2. 5 
C orrelati ve St u dies Bac k gr o u n d.............................................................................. 8
3. 
P A R TI CI P A N T S E L E C TI O N............................................................................................. 8
3. 1 
Eli gi bilit y Criteria.................................................................................................... 9
3. 2 
E xcl usi o n Criteria.................................................................................................. 1 0
3. 3 
I ncl usi o n of W o me n a n d Mi n orities...................................................................... 1 2
4. 
R E GI S T R A TI O N P R O C E D U R E S ................................................................................... 1 2
4. 1  
Ge neral G ui deli nes f or D F/ H C C I nstit uti o ns ........................................................ 1 2
4. 2 
Re gistrati o n Pr ocess f or D F/ H C C I nstit uti o ns....................................................... 1 2
4. 3  
Ge neral G ui deli nes f or Ot her I n vesti gati ve Sites.................................................. 1 2
4. 4 
Re gistrati o n Pr ocess f or Ot her I n vesti gati ve Sites................................................. 1 3
5. 
T R E A T M E N T P L A N........................................................................................................ 1 4
5. 1 
Treat me nt Re gi me n................................................................................................ 1 4
5. 2  
O varia n S u p pressi o n.............................................................................................. 1 4
5. 3 
Pre- Treat me nt Criteria........................................................................................... 1 4
5. 4  
A ge nt A d mi nistrati o n............................................................................................. 1 5
5. 5  
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...................... 2 0
5. 6 
Criteria f or Ta ki n g a Partici pa nt Off Pr ot oc ol T hera p y......................................... 2 1
5. 7  
D urati o n of F oll o w U p........................................................................................... 2 2
5. 8 
Criteria f or Ta ki n g a Partici pa nt Off St u d y........................................................... 2 2
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 ............................................................... 2 3
6. 1  
Nerati ni b d ose m o dificati o ns................................................................................. 2 3
6. 2 
F ul vestra nt d ose m o dificati o ns.............................................................................. 2 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............................ 2 8
7. 1 
E x pecte d T o xicities................................................................................................ 2 8
7. 2  
A d verse E ve nt C haracteristics............................................................................... 3 1
7. 3 
E x pe dite d A d verse E ve nt Re p orti n g...................................................................... 3 1
7. 4  
D F/ H C C E x pe dite d Re p orti n g G ui deli nes............................................................. 3 2
7. 5 
E x pe dite d 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)...................... 3 2

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7. 6 
Re p orti n g t o 
................................................................... 3 3
7. 7 
E x pe dite d Re p orti n g t o H os pital Ris k Ma na ge me nt ............................................. 3 4
7. 8 
R o uti ne A d verse E ve nt Re p orti n g......................................................................... 3 4
8. 
P H A R M A C E U TI C A L I N F O R M A TI O N.......................................................................... 3 4
8. 1  
Nerati ni b ................................................................................................................ 3 4
8. 2 
F ul vestra nt.............................................................................................................. 3 6
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 ........................................ 3 9
9. 1 
ct D N A C ollecti o n.................................................................................................. 3 9
9. 2  
Arc hi val Tiss ue...................................................................................................... 4 1
9. 3 
Fres h Tiss ue Bi o ps y C ollecti o n............................................................................. 4 2
9. 4 
Sites Perf or mi n g C orrelati ves................................................................................ 4 5
1 0. 
S T U D Y C A L E N D A R ....................................................................................................... 4 5
1 1.  
M E A S U R E M E N T O F E F F E C T ....................................................................................... 4 8
1 1. 1  
A ntit u m or Effect – S oli d T u m ors.......................................................................... 4 8
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........................................... 5 3
1 2. 1  
Data Re p orti n g....................................................................................................... 5 3
1 2. 2  
Data Safet y M o nit ori n g.......................................................................................... 5 3
1 2. 3  
M ultice nter G ui deli nes........................................................................................... 5 4
1 2. 4 
C olla b orati ve Researc h a n d F ut ure Use of Data a n d Sa m ples .............................. 5 4
1 3. 
S T A TI S TI C A L C O N SI D E R A TI O N S............................................................................... 5 5
1 3. 1 
St u d y Desi g n/ E n d p oi nts ........................................................................................ 5 5
1 3. 2 
Sa m ple Size, Accr ual Rate a n d St u d y D urati o n.................................................... 5 5
1 3. 3 
Stratificati o n Fact ors.............................................................................................. 5 5
1 3. 4  
A nal ysis of Pri mar y E n d p oi nts.............................................................................. 5 5
1 3. 5  
A nal ysis of Sec o n dar y E n d p oi nts.......................................................................... 5 6
1 3. 6  
A nal ysis of C orrelati ve E n d p oi nts......................................................................... 5 6
1 3. 7 
Re p orti n g a n d E xcl usi o ns...................................................................................... 5 7
1 4. 
P U B LI C A TI O N P L A N ..................................................................................................... 5 7
1 5. 
R E F E R E N C E S .................................................................................................................. 5 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 .................................................. 6 0
A P P E N DI X B  
Nerati ni b Pill Diar y.................................................................................... 6 1
A P P E N DI X C 
Patie nt I nstr ucti o ns f or Ma na ge me nt of Diarr hea...................................... 6 2
A P P E N DI X D  
Me dicati o ns t o use wit h ca uti o n w hile o n st u d y........................................ 6 5
A P P E N DI X E  
M U L TI C E N T E R G UI D E LI N E S............................................................... 6 6

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A P P E N DI X F 
S P E CI M E N R E Q UI SI TI O N ..................................................................... 7 9
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, t w o-ar m p hase II st u d y of nerati ni b wit h or wit h o ut f ul vestra nt i n patie nts 
wit h metastatic, E R- p ositi ve/ H E R 2- p ositi ve breast ca ncer. We h y p ot hesize t hat cr osstal k 
bet wee n H E R 2 a n d E R si g nali n g pat h wa ys pr o vi des esca pe mec ha nis ms f or t u m or gr o wt h, a n d 
t heref ore t u m ors t hat are b ot h H E R 2- p ositi ve a n d E R- p ositi ve ca n be effecti vel y treate d wit h 
nerati ni b i n c o m bi nati o n wit h f ul vestra nt, a n d t hat t he c o m bi nati o n will be m ore effecti ve t ha n 
nerati ni b al o ne.  
1. 2 
Pri m ar y O bjecti ve
T o esti mate t he efficac y, as meas ure d b y pr o gressi o n free s ur vi val ( P F S), of nerati ni b c o m bi ne d 
wit h f ul vestra nt c o m pare d wit h nerati ni b al o ne i n patie nts wit h i n o pera ble l ocall y a d va nce d or 
metastatic H E R 2- p ositi ve, E R- p ositi ve breast ca ncer.
1. 3 
Sec o n d ar y O bjecti ves
1. 3. 1
T o esti mate t he efficac y, as meas ure d b y o verall s ur vi val ( O S) of nerati ni b c o m bi ne d 
wit h f ul vestra nt c o m pare d wit h nerati ni b al o ne i n patie nts wit h i n o pera ble l ocall y 
a d va nce d or metastatic H E R 2- p ositi ve, E R- p ositi ve breast ca ncer. ( E N D P OI N T: O S)
1. 3. 2
T o esti mate t he cli nical acti vit y, as meas ure d b y o verall res p o nse rate ( O R R) of nerati ni b 
c o m bi ne d wit h f ul vestra nt c o m pare d wit h nerati ni b al o ne i n patie nts wit h i n o pera ble 
l ocall y a d va nce d or metastatic H E R 2- p ositi ve, E R- p ositi ve breast ca ncer. ( E N D P OI N T: 
O R R)
1. 3. 3
T o esti mate t he cli nical acti vit y, as meas ure d b y d urati o n of res p o nse, of nerati ni b 
c o m bi ne d wit h f ul vestra nt c o m pare d wit h nerati ni b al o ne i n patie nts wit h i n o pera ble 
l ocall y a d va nce d or metastatic H E R 2- p ositi ve, E R- p ositi ve breast ca ncer. ( E N D P OI N T: 
d urati o n of res p o nse)
1. 4  
C orrel ati ve O bjecti ves
1. 4. 1
T o deter mi ne t he pr o p orti o n of patie nts wit h E S R 1 ge ne m utati o ns i n baseli ne t u m or 
tiss ue
1. 4. 2
T o deter mi ne t he pr o p orti o n of patie nts wit h PI K 3 C A ge ne m utati o ns a n d l oss of P T E N 
e x pressi o n i n baseli ne t u m or tiss ue
1. 4. 3
T o deter mi ne t he pr o p orti o n of patie nts wit h PI K 3 C A ge ne m utati o ns i n circ ulati n g 
t u m or D N A (ct D N A) fr o m bl o o d o btai ne d at st u d y baseli ne

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1. 4. 4
T o deter mi ne c o nc or da nce of PI K 3 C A m utati o n stat us assesse d i n circ ulati n g free t u m or 
D N A a n d dista nt metastasis s peci me ns (i.e. li q ui d a n d s oli d bi o psies)
1. 4. 5
T o deter mi ne c o nc or da nce of E S R 1 m utati o n stat us assesse d i n circ ulati n g free t u m or 
D N A a n d dista nt metastasis s peci me ns (i.e. li q ui d a n d s oli d bi o psies)
1. 4. 6
T o perf or m m olec ular c haracterizati o n of p ote ntial resista nce mec ha nis ms, pre dicti ve 
bi o mar kers, a n d i m m u n ol o gical f u ncti o n b y c ollecti n g bl o o d a n d t u m or s peci me ns.  
2.
B A C K G R O U N D
2. 1  
Met ast atic H E R 2- P ositi ve, E R- P ositi ve Bre ast C a ncer  
Breast ca ncer is t he m ost c o m m o n mali g na nc y i n w o me n i n t he U nite d States. E ver y year, m ore 
t ha n 2 3 0, 0 0 0 w o me n are dia g n ose d, a n d m ore t ha n 4 0, 0 0 0 w o me n die of breast ca ncer.1 M ost of 
t hese deat hs are d ue t o metastatic breast ca ncer. T h o u g h e xisti n g treat me nts ma y effecti vel y 
c o ntr ol disease f or a peri o d of ti me, nearl y all t u m ors will ac q uire resista nce t o t hera p y, lea di n g 
t o t u m or gr o wt h a n d e ve nt uall y deat h. M ore effecti ve treat me nts are nee de d. A p pr o xi matel y 
t w o-t hir ds of breast ca ncers e x press t he estr o ge n rece pt or ( E R), a n d h or m o ne- directe d treat me nt 
has bee n a mai nsta y of t hera p y f or s uc h ca ncers f or deca des. H u ma n e pi der mal gr o wt h fact or 
rece pt or- 2 ( H E R 2) o vere x pressi n g t u m ors acc o u nt f or 2 0- 2 5 % of breast ca ncers, a n d are 
ass ociate d wit h hi g h gra de t u m ors, hi g her rates of rec urre nce, a n d hi g her rates of brai n 
metastases. A nti- H E R 2 t hera pies ha ve tra nsf or me d t he traject or y of H E R 2- p ositi ve disease, 
i m pr o vi n g patie nts’ o utc o mes dra maticall y. A p pr o xi matel y 1 0 % of all breast ca ncers c o-e x press 
H E R 2 a n d E R 2. T h o u g h t hese H E R 2 +/ E R + t u m ors ma ke u p a si g nifica nt p orti o n of metastatic 
breast ca ncers, t he y ha ve hist oricall y bee n st u die d t o get her wit h H E R 2 +/ E R- disease, mea ni n g 
t hat patie nts wit h H E R 2 +/ E R + disease us uall y recei ve H E R 2- directe d treat me nt i n c o m bi nati o n 
wit h c he m ot hera p y. T here is reas o n t o belie ve, h o we ver, t hat beca use of cr osstal k bet wee n 
H E R 2 a n d E R si g nali n g pat h wa ys, bl oc ka de of b ot h ma y be m ore effecti ve. 
2. 2  
Ner ati ni b
Nerati ni b is a p ote nt, oral, irre versi ble- bi n di n g i n hi bit or of t he er b B fa mil y of rece pt or t yr osi ne 
ki nases t hat i n hi bits si g nal tra ns d ucti o n t hr o u g h er b B 1 ( E G F R), er b B 2 ( H E R 2), a n d er b B 4. T he 
irre versi ble bi n di n g of t hese rece pt ors b y nerati ni b res ults i n s ustai ne d i n hi biti o n of gr o wt h 
pat h wa ys (a ut o p h os p h or ylati o n, si g nal tra ns d ucti o n, a n d cell pr oliferati o n) a n d ulti matel y cell 
c ycle arrest at t he ga p 1/ D N A s y nt hesis ( G 1/ S) p hase tra nsiti o n of t he di visi o n c ycle. T his a ge nt 
has de m o nstrate d pr o misi n g cli nical acti vit y i n patie nts wit h H E R 2- p ositi ve breast ca ncers. 2 
I n a p hase II trial of nerati ni b f or patie nts wit h H E R 2- p ositi ve, metastatic de- n o v o or pre-treate d 
breast ca ncer, t he O R R ( defi ne d as c o m plete or partial res p o nses) was 5 1 % ( 9 5 % C o nfi de nce 
I nter val [ CI] 1 6 % t o 3 9 %) a n d 2 6 % ( 9 5 % CI 3 8 % t o 6 4 %), res pecti vel y. At 1 6 wee ks, 7 5 % of 
first-li ne patie nts a n d 6 1 % of pre vi o usl y treate d patie nts were pr o gressi o n-free.3 I n a s u bse q ue nt, 
ra n d o mize d p hase t w o st u d y c o m pari n g nerati ni b m o n ot hera p y t o la pati ni b pl us ca pecita bi ne i n 
pre vi o usl y treate d metastatic breast ca ncer, t he O R R was 2 9 %  i n t he nerati ni b ar m. 4 T he maj or 

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t o xicit y of nerati ni b i n all st u dies has bee n diarr hea, w hic h is m ost c o m m o n d uri n g t he first c ycle 
of treat me nt.  
2. 3 
F ul vestr a nt
F ul vestra nt is a selecti ve estr o ge n rece pt or de gra der ( S E R D), w hic h bi n ds t o E R a n d lea ds t o its 
de gra dati o n. It is F D A a p pr o ve d f or patie nts w h o ha ve disease pr o gressi o n o n ot her a nti-estr o ge n 
a ge nts i n t he a d va nce d breast ca ncer setti n g. I n t w o p hase III trials, f ul vestra nt 2 5 0 m g m o nt hl y 
was f o u n d t o be as effecti ve as a nastr oz ole wit h res pect t o disease pr o gressi o n a n d o verall 
s ur vi val.7, 8 I n t he C O N FI R M trial, hi g h- d ose f ul vestra nt at 5 0 0 m g m o nt hl y was f o u n d t o be 
m ore effecti ve c o m pare d t o t he pre vi o us d osi n g of 2 5 0 m g m o nt hl y, w hic h pr o m pte d t he F D A’s 
s u bse q ue nt a p pr o val of f ul vestra nt 5 0 0 m g e ver y 2 8 da ys, f oll o wi n g a l oa di n g d ose of 5 0 0 m g o n 
da ys 1 a n d 1 5 d uri n g t he first m o nt h of t hera p y f or refract or y metastatic breast ca ncer. 9
O verall, f ul vestra nt de m o nstrate d a n o verall res p o nse rate of a p pr o xi matel y 1 0 % i n ar o matase 
i n hi bit or resista nt, f ul vestra nt nai ve E R + H E R 2- breast ca ncers.9 I n a retr os pecti ve st u d y of 
patie nts wit h H E R 2 +/ E R + breast ca ncer, f ul vestra nt de m o nstrate d a n o verall res p o nse rate of 9 % 
a n d cli nical be nefit rate of 4 2 % ( 4 3/ 1 0 1 patie nts), wit h a nti-t u m or acti vit y o bser ve d i n u p t o t he 
f o urt h li ne of e n d ocri ne t hera p y a n d se ve nt h li ne of o verall t hera p y.1 0 
2. 4  
R ati o n ale
H E R 2 is a me m ber of t he H E R/ E G F R fa mil y of plas ma me m bra ne- b o u n d rece pt or t yr osi ne 
ki nases. H E R 2 di merizes wit h itself or ot her me m bers of t he H E R fa mil y, lea di n g t o its 
acti vati o n a n d s u bse q ue nt d o w nstrea m gr o wt h- pr o m oti n g si g nali n g via a n u m ber of pat h wa ys. 
I n vesti gati o n of mec ha nis ms of resista nce t o h or m o ne- directe d t hera p y i n breast ca ncer has 
de m o nstrate d si g nifica nt cr osstal k bet wee n t he H E R 2 a n d E R pat h wa ys. I n H E R 2- p ositi ve cell 
li nes, a d diti o n of estr o ge n or ta m o xife n i n d uces acti vati o n of H E R 2 si g nali n g.1 1 I n E R + cell li nes 
t hat de vel o p resista nce t o ta m o xife n, H E R 2 e x pressi o n i ncreases si g nifica ntl y.1 2 A n d i n H E R 2 + 
xe n o grafts resista nt t o H E R 2- directe d t hera pies, E R e x pressi o n is u pre g ulate d. 1 3 T hese data 
s u g gest t hat E R- me diate d si g nali n g ma y pr o vi de a n i m p orta nt mec ha nis m of resista nce t o a nti-
H E R 2 t hera p y, a n d c o n versel y, t hat H E R 2-si g nali n g pr o m otes e n d ocri ne t hera p y resista nce. 
D ual bl oc ka de of H E R 2 a n d estr o ge n pat h wa ys c o ul d be a n effecti ve met h o d of treati n g 
H E R 2 +/ E R + disease.  
Data fr o m cli nical st u dies s u p p orts w hat has bee n see n i n t he la b orat or y. Ri ma wi a n d c ollea g ues 
e val uate d t he efficac y of ne oa dj u va nt la pati ni b, trast uz u ma b a n d h or m o nal t hera p y i n a si n gle-
ar m, p hase II st u d y of 6 6 w o me n wit h sta ge II t o III H E R 2 +/ E R + breast ca ncer. 1 4 T he y f o u n d 
t hat t his c o m bi nati o n, tar geti n g b ot h t he H E R 2 a n d E R pat h wa ys, was effecti ve, res ulti n g i n a 
pat h ol o gic c o m plete res p o nse ( p C R) rate of 2 1 %. 1 4 I n 2 0 1 5, C ha n et al. prese nte d 2 year f oll o w 
u p data fr o m t he E xte N E T trial, a p hase III, ra n d o mize d, place b o-c o ntr olle d trial of nerati ni b 
after c o m pleti o n of trast uz u ma b i n t he a dj u va nt setti n g i n H E R 2 + breast ca ncer. I n t his st u d y, 
earl y sta ge breast ca ncer patie nts wit h H E R 2 + disease w h o ha d c o m plete d a dj u va nt trast uz u ma b 
were ra n d o mize d t o recei ve eit her o ne year of nerati ni b or place b o. Of t he 2 8 4 1 patie nts e nr olle d 
i n t his st u d y, 5 7 % i n eac h ar m ha d H E R 2 +/ E R + disease. T h o u g h t he i m pr o ve me nt i n i n vasi ve 
disease-free s ur vi val (I D F S) was statisticall y si g nifica nt i n t he o verall st u d y p o p ulati o n, i n a pre-

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pla n ne d s u bset a nal ysis, t he str o n gest be nefit was see n i n t he ce ntrall y c o nfir me d H E R 2 +, E R + 
s u b gr o u p, I n t his gr o u p, patie nts recei vi n g nerati ni b ha d a n I D F S of 9 7. 0 % at 2 years, w hile 
I D F S i n patie nts recei vi n g place b o was 8 8. 4 %, c orres p o n di n g t o a hazar d rati o of 0. 2 5 ( 9 5 % CI 
0. 1 2- 0. 4 8). 1 5 I n c o ntrast, t he hazar d rati o f or patie nts wit h ce ntrall y c o nfir me d H E R 2 +, E R- 
ca ncers was 0. 9 6 ( 0. 5 3 – 1. 7 4). I m p orta ntl y, nearl y all patie nts wit h H E R 2 +/ E R + disease were 
als o ta ki n g a dj u va nt h or m o nal t hera p y. O ne p ote ntial mec ha nistic e x pla nati o n of t hese res ults is 
t hat tar geti n g b ot h t he H E R 2 a n d E R pat h wa ys si m ulta ne o usl y ma y o verc o me resista nce 
me diate d b y t he cr oss-tal k bet wee n t he t w o pat h wa ys. If tr ue, t his a p pr oac h ma y be a n effecti ve 
met h o d f or treati n g H E R 2 +/ E R + breast ca ncer. We pla n t o i n vesti gate t his f urt her i n t his trial.  
R ati o n ale f or Pri or F ul vestr a nt  ( A me n d me nt 2, Pr ot oc ol Versi o n 2 u p date)
T he pr ot oc ol was u p date d wit h Versi o n 2 t o all o w f or pri or f ul vestra nt, a re visi o n t o t he ori gi nal 
eli gi bilit y criteria ( 3. 2. 3) f or t he st u d y. I nter nal data fr o m 
 i n m o use 
m o dels a n d a d diti o nal pre-cli nical data fr o m S u d ha n et al. i n Cli nical Ca ncer Researc h s u g gests 
t hat e ve n i n f ul vestra nt resista nt H E R 2 + m o dels, t he a d diti o n of f ul vestra nt t o nerati ni b pr o vi des 
be nefit. 1 6 All o wi n g pri or f ul vestra nt will i ncrease t he eli gi ble patie nt p o p ulati o n a n d st u d y 
accr ual a n d will n ot si g nifica ntl y i m pact t he t hera pe utic si g nal i n t he e x peri me ntal ar m.
2. 5  
C orrel ati ve St u dies B ac k gr o u n d
2. 5. 1
Circ ulati n g T u m or D N A (ct D N A) 
F or a n u m ber of reas o ns t hat i ncl u de disc o mf ort t o t he patie nt, l o gistics, a n d lac k of 
cli nical i n dicati o n, serial t u m or bi o psies i n i n di vi d ual patie nts i n t he metastatic setti n g are 
i nfre q ue ntl y d o ne.  It has t heref ore bee n c halle n gi n g t o st u d y t he m olec ular e v ol uti o n of 
t u m ors o ver ti me a n d t hr o u g h pr o gressi o n o n serial treat me nt re gi me ns. B ot h n or mal a n d 
mali g na nt cells secrete cell-free D N A i nt o plas ma, ge nerati n g a n easil y accessi ble 
re p osit or y of eac h cell’s ge netic si g nat ure. E mer gi n g tec h n ol o g y n o w per mits w h ole 
e x o me se q ue nci n g fr o m circ ulati n g t u m or D N A (ct D N A) is olate d fr o m plas ma. We ai m 
t o e xa mi ne t he utilit y of t his a p pr oac h f or detecti n g m olec ular c ha n ges i n i n di vi d ual 
patie nts’ t u m ors o ver ti me b y c ollecti n g a n d a nal yzi n g ct D N A. 
2. 5. 2
Tiss ue Sa m ples
We will c ollect ne w metastatic bi o psies bef ore treat me nt be gi ns fr o m all e nr olle d patie nts 
u nless t here is n o safe, accessi ble site t o bi o ps y. ( Please see eli gi bilit y criteria). We will 
als o c ollect pri mar y, arc hi ve d t u m ors a n d arc hi ve d bi o psies of metastases f or a d diti o nal 
c orrelati ve testi n g. T hese sa m ples will be ba n ke d f or f ut ure researc h usi n g state- of-t he-art 
tec h n ol o gies t o c orrelate fi n di n gs wit h cli nical res p o nse.  
3.
P A R TI CI P A N T S E L E C TI O N
La b orat or y tests re q uire d f or eli gi bilit y m ust be c o m plete d wit hi n 4 wee ks pri or t o re gistrati o n. 
Sca ns a n d x-ra ys m ust be d o ne < 4 wee ks pri or t o re gistrati o n.  M U G A or ec h o m ust be d o ne 
wit hi n 6 0 da ys pri or t o re gistrati o n. 

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3. 1 
Eli gi bilit y Criteri a 
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if t he y meet all of t he f oll o wi n g criteria:
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 o pera ble l ocall y 
a d va nce d or metastatic E R + breast ca ncer. T o f ulfill t he re q uire me nt f or E R + disease, a 
breast ca ncer m ust e x press, b y i m m u n o hist oc he mistr y (I H C), E R i n ≥1 0 %  of cells, o n t he 
m ost rece nt bi o ps y. If E R q ua ntificati o n is n ot a vaila ble, a deter mi nati o n of E R + b y I H C 
will s uffice. Ce ntral c o nfir mati o n of E R stat us is n ot re q uire d.
3. 1. 2
Partici pa nts m ust ha ve d oc u me nte d H E R 2 + disease b y o vere x pressi o n a n d/ or ge ne 
a m plificati o n o n t he m ost rece nt bi o ps y, per c urre nt A S C O- C A P ( A merica n S ociet y of 
Cli nical O nc ol o g y – C olle ge of A merica n Pat h ol o gists) g ui deli nes. Ce ntral c o nfir mati o n 
of H E R 2 stat us is n ot re q uire d.
3. 1. 3
Partici pa nts m ust ha ve recei ve d pri or t hera p y wit h t he f oll o wi n g a ge nts i n a n y 
c o m bi nati o n, a n d i n setti n g (i.e., ne oa dj u va nt, a dj u va nt, metastatic, etc.).  T hese t hera pies 
d o n ot nee d t o be t he m ost rece nt li ne of t hera p y.

Trast uz u ma b

Pert uz u ma b

A d o-trast uz u ma b e mta nsi ne ( T- D M 1) 
3. 1. 4
Partici pa nts m ust a gree t o u n der g o a researc h bi o ps y of a reas o na bl y accessi ble 
metastatic lesi o n (c hest wall, s ki n, s u bc uta ne o us tiss ue, l y m p h n o des, s ki n, breast, b o nes, 
l u n g, a n d li ver metastases). If a reas o na bl y accessi ble metastatic lesi o n is n ot a vaila ble, 
t he patie nt ma y g o o n st u d y pr o vi de d t hat arc hi ve d tiss ue is a vaila ble. H o we ver, if a 
reas o na bl y accessi ble site is a vaila ble f or bi o ps y, t he patie nt m ust a gree t o bi o ps y. A n y 
patie nts n ot u n der g oi n g bi o ps y m ust be a p pr o ve d f or st u d y e nr oll me nt b y t he O verall 
Pri nci pal I n vesti gat or at D F CI. Bi o psies ma y be d o ne wit h l ocal a nest hesia or 
i ntra ve n o us c o nsci o us se dati o n, acc or di n g t o i nstit uti o nal g ui deli nes. If a bi o ps y re q uires 
ge neral a nest hesia, t he n it is o nl y all o we d if ac q uisiti o n of tiss ue is cli nicall y i n dicate d, 
a n d e xcess tiss ue ma y be c ollecte d f or researc h p ur p oses. Patie nts wit h o ut sites a vaila ble 
f or bi o ps y m ust ha ve a vaila ble tiss ue [arc hi ve d f or mali n-fi xe d paraffi n e m be d de d bl oc ks 
( F F P B), bl oc ks fr o m w hic h sli des ca n be create d, or fres h fr oze n tiss ue fr o m ori gi nal 
dia g n osis or metastatic setti n g] f or c orrelati ve st u dies. Tiss ue nee ds t o be l ocate d a n d 
a vaila ble at t he ti me of re gistrati o n See Secti o n 9. 3 f or m ore details.
3. 1. 5
W o me n ≥ 1 8 years of a ge.  Me n are n ot eli gi ble.
3. 1. 6
Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us 0- 2 (see A p pe n di x A). 
3. 1. 7
Partici pa nts m ust ha ve n or mal or ga n a n d marr o w f u ncti o n as descri be d bel o w:

A bs ol ute ne utr o p hil c o u nt ≥1, 0 0 0/ u L

Platelets ≥7 5, 0 0 0/ u L

He m o gl o bi n ≥8 g/ d L

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
T otal bilir u bi n ≤ 1. 5 X i nstit uti o nal u p per li mit of n or mal ( U L N) ;i n case of k n o w n 
Gil bert’s s y n dr o me, < 2 x U L N is all o we d

A S T( S G O T)/ A L T( S G P T) ≤3 X  i nstit uti o nal U L N wit h o ut li ver metastases, or ≤5 X  
i nstit uti o nal U L N wit h li ver metastases

Creati ni ne cleara nce ≥ 5 0 m L/ mi n

Left ve ntric ular ejecti o n fracti o n ≥5 0 %,  as deter mi ne d b y R V G ( M U G A) or 
ec h ocar di o gra m ( E C H O) wit hi n 6 0 da ys pri or t o i nitiati o n of pr ot oc ol t hera p y
3. 1. 8
Partici pa nts ma y ha ve recei ve d a n y n u m ber of pri or t hera pies as l o n g as t he y ha ve 
a de q uate perf or ma nce stat us a n d meet all ot her eli gi bilit y criteria.
3. 1. 9
W o me n of c hil d beari n g p ote ntial (i ncl u di n g pre me n o pa usal w o me n a n d w o me n less t ha n 
1 2 m o nt hs after me n o pa use) m ust ha ve a ne gati ve β- h u ma n  c h ori o nic g o na d otr o pi n 
( h C G) uri ne pre g na nc y test wit hi n 4 wee ks of re gistrati o n. 
3. 1. 1 0
T he effects of nerati ni b a n d f ul vestra nt o n t he de vel o pi n g h u ma n fet us are u n k n o w n.  F or 
t his reas o n a n d beca use S E R D a ge nts are k n o w n t o be terat o ge nic, w o me n of c hil d-
beari n g p ote ntial m ust a gree t o be a bsti ne nt, or t o use a hi g hl y effecti ve d o u ble barrier 
met h o d of  c o ntrace pti o n (e. g, a c o m bi nati o n of  male c o n d o m wit h a n 
i ntra va gi nal  de vice s uc h as t he cer vical ca p, dia p hra g m,  or va gi nal s p o n ge  wit h 
s per mici de) or a n o n- h or m o nal met h o d, w hile e nr olle d i n t he st u d y, u ntil at least 2 8 da ys 
after t he last d ose of nerati ni b or 1 year after t he last d ose of f ul vestra nt.  S h o ul d a 
w o ma n bec o me pre g na nt or s us pect s he is pre g na nt w hile s he is partici pati n g i n t his 
st u d y, s he s h o ul d i nf or m her treati n g p h ysicia n i m me diatel y. If a w o ma n is of 
c hil d beari n g p ote ntial, s he m ust a gree t o use a de q uate c o ntrace pti o n pri or t o t he st u d y, 
f or t he d urati o n of st u d y partici pati o n, a n d f or o ne year after c o m pleti o n of t he st u d y 
dr u g.
3. 1. 1 1
A bilit y t o u n dersta n d a n d willi n g ness t o si g n a writte n i nf or me d c o nse nt d oc u me nt.
3. 2 
E xcl usi o n Criteri a
A patie nt will be e xcl u de d fr o m t his st u d y if s he meets a n y of t he f oll o wi n g criteria:
3. 2. 1
Partici pa nts w h o ha ve a hist or y of aller gic reacti o ns attri b ute d t o c o m p o u n ds of si milar 
c he mical or bi ol o gic c o m p ositi o n t o nerati ni b or f ul vestra nt. 
3. 2. 2
Partici pa nts w h o ha ve k n o w n h y perse nsiti vit y t o a n y c o m p o ne nt of l o pera mi de or 
c olesti p ol.
3. 2. 3
Partici pa nts w h o ha ve recei ve d pre vi o us t hera p y wit h nerati ni b. 

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3. 2. 4
Partici pa nts w h o ha ve recei ve d a nti-ca ncer t hera p y (i ncl u di n g c he m ot hera p y, bi ol o gical 
t hera p y, i n vesti gati o nal a ge nts, h or m o nal t hera p y, or ot her a nti-ca ncer t hera p y) or 
ra di ot hera p y wit hi n ≤1 4  da ys pri or t o t he pla n ne d i nitiati o n of i n vesti gati o nal pr o d ucts, or 
t h ose w h o ha ve n ot rec o vere d t o gra de ≤1fr o m  a d verse e ve nts d ue t o t heir m ost rece nt 
t hera p y (e xce pti n g al o pecia).
3. 2. 5
Partici pa nts w h o ha ve ha d a n y maj or s ur ger y ≤2 8  da ys pri or t o t he pla n ne d i nitiati o n of 
st u d y t hera p y, or t h ose w h o ha ve n ot rec o vere d fr o m a d verse e ve nts d ue t o 
a ge nts/s ur ger y a d mi nistere d m ore t ha n 4 wee ks earlier. 
3. 2. 6
Partici pa nts w h o are recei vi n g a n y ot her i n vesti gati o nal a ge nts.
3. 2. 7
K n o w n brai n metastases 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. Partici pa nts wit h a hist or y of treate d ce ntral ner v o us s yste m ( C N S) metastases 
are eli gi ble. Treate d brai n metastases are defi ne d as t h ose wit h o ut o n g oi n g re q uire me nt 
f or c ortic oster oi ds, as ascertai ne d b y cli nical e xa mi nati o n a n d/ or brai n i ma gi n g ( ma g netic 
res o na nce i ma gi n g or C T sca n) c o m plete d d uri n g scree ni n g. A n y c ortic oster oi d use f or 
brai n metastases m ust ha ve bee n disc o nti n ue d wit h o ut t he s u bse q ue nt a p peara nce of 
s y m pt o ms f or ≥ 7 da ys pri or t o re gistrati o n. Treat me nt f or brai n metastases ma y i ncl u de 
w h ole brai n ra di ot hera p y, ra di os ur ger y, s ur ger y or a c o m bi nati o n as dee me d a p pr o priate 
b y t he treati n g p h ysicia n. Ra diati o n t hera p y m ust be c o m plete d at least 1 4 da ys pri or t o 
re gistrati o n, as s pecifie d i n Secti o n 3. 2. 4..  
3. 2. 8
Partici pa nt has acti ve, u nc o ntr olle d car diac disease, i ncl u di n g car di o m y o pat h y, 
c o n gesti ve heart fail ure ( Ne w Y or k Heart Ass ociati o n f u ncti o nal classificati o n of ≥2),  
u nsta ble a n gi na, m y ocar dial i nfarcti o n wit hi n 1 2 m o nt hs of e nr oll me nt, or ve ntric ular 
arr h yt h mia.
3. 2. 9
Partici pa nt has a Q Tc i nter val > 4 7 0 ms or k n o w n hist or y of Q Tc pr ol o n gati o n or T orsa de 
de P oi ntes. N ote: c orrecti o n ma y be ma de usi n g a n y met h o d of Q Tc calc ulati o n (i.e. 
Q Tc F)
3. 2. 1 0 Partici pa nt has a n acti ve i nfecti o n or u ne x plai ne d fe ver > 3 8. 5° C ( 1 0 1. 3° F).
3. 2. 1 1 Partici pa nt has ha d a n ot her mali g na nc y wit hi n t he past 5 years wit h t he e xce pti o n of a) 
a de q uatel y treate d basal cell carci n o ma, s q ua m o us cell s ki n ca ncer, or t h yr oi d ca ncer; b) 
carci n o ma i n sit u of t he breast, cer vi x or v ul va; or c) ca ncer c o nsi dere d c ure d b y s ur gical 
resecti o n or u nli kel y t o i m pact s ur vi val d uri n g t he d urati o n of t he st u d y, s uc h as l ocalize d 
tra nsiti o nal cell carci n o ma of t he bla d der, or be ni g n t u m ors of t he a dre nal or pa ncreas.
3. 2. 1 2 Partici pa nt has si g nifica nt c hr o nic gastr oi ntesti nal dis or der wit h diarr hea as a maj or 
s y m pt o m (e. g., Cr o h n’s disease, mala bs or pti o n, or Gra de ≥2  ( N CI C T C A E v. 4. 0) 
diarr hea of a n y eti ol o g y at scree ni n g).

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3. 2. 1 3 Partici pa nt has k n o w n acti ve i nfecti o n wit h he patitis B or he patitis C vir us. He patitis B 
a n d C ser ol o g y testi n g is n ot re q uire d, u nless acti ve i nfecti o n is s us pecte d.
3. 2. 1 4 Partici pa nt is u na ble or u n willi n g t o s wall o w ta blets.
3. 2. 1 5 Partici pa nt has e vi de nce of si g nifica nt me dical ill ness, a b n or mal la b orat or y fi n di n g, or 
ps yc hiatric ill ness/s ocial sit uati o ns t hat w o ul d, i n t he I n vesti gat or’s j u d g me nt, li mit 
c o m plia nce wit h st u d y re q uire me nts.
3. 2. 1 6 Pre g na nt w o me n are e xcl u de d fr o m t his st u d y beca use f ul vestra nt is a S E R D a ge nt wit h 
t he p ote ntial f or terat o ge nic or a b ortifacie nt effects.  Beca use t here is a n u n k n o w n b ut 
p ote ntial ris k f or a d verse e ve nts i n n ursi n g i nfa nts sec o n dar y t o treat me nt of t he m ot her 
wit h nerati ni b a n d/ or f ul vestra nt, breastfee di n g s h o ul d be disc o nti n ue d if t he m ot her is 
treate d wit h nerati ni b a n d/ or f ul vestra nt.  
3. 3 
I ncl usi o n of W o me n a n d Mi n orities
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. Me n are n ot eli gi ble, as n o data 
e xist t o o ur k n o wle d ge o n t he effect of f ul vestra nt i n male breast ca ncer. 
4.
R E GI S T R 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
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 via t he Office of Data Q ualit y. Re gistrati o ns m ust occ ur pri or t o t he i nitiati o n of 
pr ot oc ol t hera p y. A n y partici pa nt n ot re gistere d t o t he pr ot oc ol bef ore pr ot oc ol t hera p y be gi ns 
will be c o nsi dere d i neli gi ble a n d re gistrati o n will be de 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 ber of t he 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.
F oll o wi n g re gistrati o n, partici pa nts ma y be gi n pr ot oc ol t hera p y. 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 O verall Pri nci pal I n vesti gat or ( PI). If a partici pa nt 
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 partici pa nt’s re gistrati o n o n t he 
st u d y m ust be ca ncele d. Re gistrati o n ca ncellati o ns m ust be ma de i n O n C ore as s o o n as p ossi ble. 
4. 2  
Re gistr ati o n Pr ocess f or D F/ H C C I nstit uti o ns
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- 1 0 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 C o or di nati n g Ce nter  t hr o u g h t he 
St u d y C o or di nat or or Pr oject Ma na ger.  T he list of re q uire d f or ms ca n be f o u n d i n Secti o n 4. 4.

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It is rec o m me n de d t hat partici pa nts be gi n pr ot oc ol treat me nt wit hi n 7 b usi ness da ys, a n d n o m ore 
t ha n 3 0 da ys fr o m re gistrati o n. 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 O verall PI.  If a partici pa nt 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 
partici pa nt’s re gistrati o n o n t he st u d y m ust be ca ncele d.  T he St u d y C o or di nat or s h o ul d be 
n otifie d of ca ncellati o ns as s o o n as p ossi ble.
4. 4  
Re gistr ati o n Pr ocess f or Ot her I n vesti g ati ve Sites
T o re gister a partici 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 researc h n urse or 
data ma na ger a n d fa xe d 
or e- maile d
 t o t he Pr oject 
Ma na ger:

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

Eli gi bilit y C hec klist 

Baseli ne e xa m n ote i ncl u di n g me dical/s ur gical hist or y, E C O G, vital si g ns

E K G re p ort

M U G A or ec h ocar di o gra m re p ort

La b orat or y re p ort i ncl u di n g res ults f or C B C, C he mistries, Uri nal ysis, a n d Uri ne 
Pre g na nc y Test

T u m or E val uati o n ( M RI or C T a n d cli nical assess me nt of visi ble of pal pa ble lesi o ns) 
Re p ort

Pat h ol o g y Re p ort a n d d oc u me ntati o n of E R/ P R a n d H E R 2 stat us

B o ne Sca n Re p ort (if d o ne)

D oc u me ntati o n of tiss ue a vaila bilit y ( per eli gi bilit y criteria 3. 1. 8)
T h e C o or di n ati n g C e nt er will r e vi e w t h e s u b mitt e d d o c u m e nts i n or d er t o v erif y eli gi bilit y a n d 
c o ns e nt. T o c o m pl et e t h e r e gistr ati o n pr o c ess, t h e C o or di nati n g Ce nter will:

F oll o w 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- 1 0 1) a n d re gister t he partici pa nt o n t he 
pr ot oc ol.

U p o n recei vi n g c o nfir mati o n of re gistrati o n, t he C o or di nati n g Ce nter will i nf or m t he 
Partici pati n g I nstit uti o n a n d pr o vi de t he st u d y s pecific partici pa nt case n u m ber, a n d, if 
a p plica ble, assi g ne d treat me nt a n d/ or d ose le vel. 
T r e at m e nt m a y n ot b e gi n wit h o ut c o nfi r m ati o n f r o m t h e C o o r di n ati n g C e nt e r t h at t h e 
p a rti ci p a nt h as b e e n r e gist e r e d. 
Ra n d o mizati o n ca n o nl y occ ur d uri n g n or mal b usi ness h o urs, M o n da y t hr o u g h Fri da y fr o m 8: 0 0 
A M t o 5: 0 0 P M Easter n Sta n dar d Ti me.

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5.
T R E A T M E N T P L A N
5. 1 
Tre at me nt Re gi me n
Nerati ni b a n d f ul vestra nt will be a d mi nistere d i n 4 wee k c ycles, wit h 2 8 c o nsec uti ve da ys 
defi ne d as a treat me nt c ycle. Treat me nt will be a d mi nistere d o n a n o ut patie nt basis.  T here is n o 
s pecific or der of a d mi nistrati o n f or nerati ni b a n d f ul vestra nt. 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 ge nts or t hera pies ot her t ha n t h ose descri be d 
bel o w ma y be a d mi nistere d wit h t he i nte nt t o treat t he partici pa nt's mali g na nc y.
Re gi me n Descri pti o n
A ge nt
Pre me dic ati o ns; 
Prec a uti o ns
D ose
R o ute
Sc he d ule
C ycle 
Le n gt h
A R M A
Nerati ni b
L o pera mi de a n d 
C olesti p ol
(see Secti o n 
5. 3. 3)
2 4 0 m g   
(si x 4 0 m g 
ta blets)
Orall y
Nerati ni b: o nce 
dail y, c o nti n u o us 
L o pera mi de: Da ys 
1- 2 8, c o nti n u o us
C olesti p ol: Da ys 1-
2 8, c o nti n u o us
F ul vestra nt
5 0 0 m g 
(t w o 
i njecti o ns 
of 2 5 0 m g 
eac h)
I ntra m usc ularl y
C ycle 1: Da y 1, 1 5
C ycle 2 a n d all 
s u bse q ue nt c ycles: 
Da y 1
2 8 da ys 
( 4 wee ks)
A R M B
Nerati ni b
L o pera mi de a n d 
C olesti p ol
(see Secti o n 
5. 3. 3)
2 4 0 m g   
(si x 4 0 m g 
ta blets)
Orall y
Nerati ni b: o nce 
dail y, c o nti n u o us 
L o pera mi de: Da ys 
1- 2 8, c o nti n u o us
C olesti p ol: Da ys 1-
2 8, c o nti n u o us
2 8 da ys 
( 4 wee ks)
5. 2  
O v ari a n S u p pressi o n 
O varia n s u p pressi o n wit h L H R H a g o nists ( g oser oli n or le u pr oli de) per sta n dar d 
i nstit uti o nal or re gi o nal practices s h o ul d be f oll o we d i n pre- me n o pa usal a n d peri-
me n o pa usal patie nts (i.e start o n L H R H a g o nist at ti me of st u d y treat me nt start). 
P ost me n o pa usal patie nts are defi ne d as n o s p o nta ne o us me nses o ver 1 2 c o nsec uti ve 
m o nt hs or p ost bilateral s ur gical o o p h orect o m y. 
5. 3 
Pre- Tre at me nt Criteri a

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5. 3. 1
C ycle 1, Da y 1

A bs ol ute ne utr o p hil c o u nt ≥1, 0 0 0/ u L

Platelets ≥7 5, 0 0 0/ u L

He m o gl o bi n ≥8 g/ d L

T otal bilir u bi n ≤ 1. 5 X u p per li mit of n or mal ( U L N)

A S T( S G O T)/ A L T( S G P T) ≤3 X  i nstit uti o nal U L N wit h o ut li ver metastases, or ≤5 X  
i nstit uti o nal U L N wit h li ver metastases

Creati ni ne cleara nce ≥ 5 0 m L/ mi n

Left ve ntric ular ejecti o n fracti o n ≥5 0 %,  as deter mi ne d b y R V G ( M U G A) or 
ec h ocar di o gra m( E C H O) wit hi n 6 0 da ys pri or t o i nitiati o n of pr ot oc ol t hera p y
5. 3. 2
S u bse q ue nt C ycles 

A bs ol ute ne utr o p hil c o u nt ≥1, 0 0 0/ u L

Platelets ≥7 5, 0 0 0/ u L

He m o gl o bi n ≥8 g/ d L

T otal bilir u bi n ≤ 3 X u p per li mit of n or mal ( U L N)

A S T( S G O T)/ A L T( S G P T) ≤5 X  i nstit uti o nal U L N wit h o ut li ver metastases, or ≤8 X  
i nstit uti o nal U L N wit h li ver metastases

Creati ni ne cleara nce ≥ 5 0 m L/ mi n
5. 4  
A ge nt A d mi nistr ati o n
5. 4. 1
Nerati ni b
Nerati ni b is a d mi nistere d orall y o nce dail y, c o nti n u o usl y wit h n o brea ks, o n da ys 1- 2 8 of 
a 4- wee k ( 2 8- da y) c ycle, +/- 3 da ys. Nerati ni b is d ose d as 2 4 0 m g o nce dail y (si x 4 0 m g 
ta blets). D osi n g is n ot wei g ht- base d. Patie nts s h o ul d ta ke nerati ni b at a p pr o xi matel y t he 
sa me ti me of da y e ver y da y, prefera bl y i n t he m or ni n g, wit h f o o d. T he d ose is c o nsi dere d 
“ misse d” if n ot ta ke n wit hi n a p pr o xi matel y 1 2 h o urs of t he us ual a d mi nistrati o n ti me. 
D oses s h o ul d n ot be reta ke n if s ki p pe d, misse d, or v o mite d. Ta blets m ust be s wall o we d 
w h ole; t he y ma y n ot be cr us he d, c he we d, or diss ol ve d.  
Nerati ni b re q uires t he use of a nti- diarr heal pr o p h yla xis wit h l o pera mi de a n d c olesti p ol 
(see Secti o ns 5. 3. 3). I n vesti gat ors m ust e ns ure t hat partici pa nts ha ve l o pera mi de a n d 
c olesti p ol o n ha n d w he n starti n g t o ta ke t he i n vesti gati o nal pr o d uct. L o pera mi de a n d 
c olesti p ol are t he sta n dar d a nti- diarr heal t hera pies i n t his st u d y. If alter nati ve a nti-
diarr heal me dicati o n is use d, t he reas o n m ust be d oc u me nte d i n t he s o urce d oc u me nts. 
Acce pta ble reas o ns are n o n-t olera nce of sta n dar d t hera pies or lac k of efficac y. 
L o pera mi de a n d c olesti p ol will be dis pe nse d directl y b y t he site o n da y 1 of eac h c ycle.
D ose m o dificati o ns are deli neate d i n secti o n 6.  If si g nifica nt treat me nt –relate d t o xicities 
ha ve n ot rec o vere d t o Gra de ≤1 or baseli ne gra de, t he patie nt ma y s ki p u p t o 2 8 da ys 
fr o m t he last sc he d ule d d ose. Patie nts s h o ul d be re-e val uate d wee kl y d uri n g t he dela y 
w he ne ver p ossi ble. Patie nts ra n d o mize d t o t he f ul vestra nt ar m ( Ar m A) ma y c o nti n ue 

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f ul vestra nt d osi n g w hile nerati ni b is hel d, as l o n g as t he t o xicit y is felt t o be u nrelate d t o 
f ul vestra nt.
D osi n g ma y als o be s us pe n de d f or u p t o 2 8 da ys f or u na ntici pate d i nterc urre nt me dical 
e ve nts t hat are n ot ass ociate d wit h st u d y treat me nt t o xicit y or disease pr o gressi o n.
Patie nts are t o fill o ut a pill diar y f or e ver y c ycle ( A p pe n di x B) a n d ret ur n it t o cli nic staff 
at t he e n d of eac h c ycle.
5. 4. 2
F ul vestra nt
F ul vestra nt is a d mi nistere d i ntra m usc ularl y o n C ycle 1 Da y 1, C ycle 1 Da y 1 5, a n d t he n 
o n Da y 1 of eac h s u bse q ue nt 4- wee k ( 2 8- da y) c ycle +/- 3 da ys. F ul vestra nt is d ose d as 
2 5 0 m g/ 5 m L ( x 2) f or a t otal of 5 0 0 m g via i ntra m usc ular i njecti o n.  A d mi nister 
i ntra m usc ularl y sl o wl y i n t he b utt oc k. ( N O T E: 5 0 0 m g d ose will re q uire o ne 2 5 0 m g 
i njecti o n i n eac h b utt oc k). I m me diatel y acti vate nee dle pr otecti o n de vice u p o n 
wit h dra wal fr o m patie nt b y p us hi n g le ver ar m c o m pletel y f or war d u ntil nee dle ti p is f ull y 
c o vere d. Vis uall y c o nfir m t hat t he le ver ar m has f ull y a d va nce d a n d t he nee dle ti p is 
c o vere d. If u na ble t o acti vate, discar d i m me diatel y i nt o a n a p pr o ve d s har ps c o ntai ner.
N o d ose m o dificati o ns are all o we d. If a patie nt has a n i nt olera ble t o xicit y felt t o be 
relate d t o f ul vestra nt, f ul vestra nt d osi n g ca n be hel d f or u p t o 2 8 da ys ( 1 c ycle) t o all o w 
t he t o xicit y t o rec o ver t o baseli ne or gra de ≤1.  Nerati ni b d osi n g ca n c o nti n ue w hile 
f ul vestra nt is hel d.  C o m mercial s u p pl y of f ul vestra nt will be use d.
 
5. 4. 3
Ma n dat or y Diarr hea Pr o p h yla xis
Diarr hea is t he maj or d ose-li miti n g t o xicit y of nerati ni b, wit h o nset t y picall y occ urri n g 
earl y i n t he c o urse of treat me nt ( d uri n g t he first fe w da ys of t he first c ycle of treat me nt). 
Pri mar y pr o p h ylactic use of a nti diarr heal me dicati o n is ma n dat or y f or all patie nts ta ki n g 
nerati ni b. L o pera mi de a n d c olesti p ol are t he re q uire d sta n dar d t hera pies t o treat diarr hea. 
Sec o n d-li ne a nti diarr heal treat me nts a n d a dj u ncti ve t hera pies (i.e., octre oti de 
[ S A N D O S T A TI N ®]) ( or e q ui vale nt)) are als o rec o m me n de d f or use w he n a p pr o priate. 
T he I n vesti gat or m ust re vie w wit h t he patie nt t he Patie nt I nstr ucti o ns f or t he ma na ge me nt 
of diarr hea i n A p pe n di x C.
T he patie nt s h o ul d be gi ve n clear i nstr ucti o ns t o c o ntact t he I n vesti gat or i n t he e ve nt of 
persiste nt Gra de ≥2  diarr hea t o disc uss t he a p pr o priate c o urse of treat me nt. L o pera mi de 
a n d c olesti p ol s h o ul d be dis pe nse d directl y wit h nerati ni b. It is ver y i m p orta nt t o i nitiate 
treat me nt wit h l o pera mi de a n d c olesti p ol c o nc o mita ntl y wit h t he first d ose of nerati ni b t o 
mi ni mize occ urre nce a n d se verit y of diarr hea.
Refer t o pr ot oc ol Secti o n 6. 1. 2, Ta ble 2 f or D ose A dj ust me nt of Nerati ni b as a p plica ble.
T he I n vesti gat or or s uita bl y trai ne d a n d q ualifie d dele gate (e. g., M D, R N, N P, etc.) m ust 

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c o ntact t he patie nt b y p h o ne o n C ycle 1 Da y 2, C ycle 1 Da y 3, a n d C ycle 1 Da y 4 after 
t he first d ose of nerati ni b t o i n q uire a b o ut c o m plia nce wit h l o pera mi de a n d c olesti p ol, 
diarr hea or a n y ot her a d verse e ve nts. ( T hese p h o ne calls are ver y i m p orta nt a n d s h o ul d be 
rec or de d i n t he cli nical rec or ds t o get her wit h res p o nse fr o m t he patie nt a n d acti o n ta ke n.)
Patie nts s h o ul d be i nstr ucte d t o pr o m ptl y re p ort diarr hea s y m pt o ms a n d t o re p ort t he 
n u m ber of st o ols per da y a n d t he d ose of a n y a nti- diarr heal me dicati o n ta ke n eac h da y f or 
t he first 2 8 da ys of t hera p y.
5. 4. 3. 1 
L o pera mi de (I m o di u m ®)
F or t he first 1 4 da ys, l o pera mi de 4 m g ( 2 ta blets/ca ps ules) will be self-a d mi nistere d 
orall y 3 ti mes a da y (t otal 1 2 m g a da y). T he i nitial d ose of l o pera mi de will be 
a d mi nistere d orall y wit h t he first d ose of nerati ni b. After t he first 1 4 da ys, l o pera mi de 4 
m g ( 2 ta blets/ca ps ules) will be a d mi nistere d orall y t wice a da y (t otal 8 m g a da y) t hr o u g h 
t he first c ycle of t hera p y ( Da y 2 8) fr o m start of nerati ni b d osi n g, w het her t he patie nt is 
e x perie nci n g diarr hea or n ot. T hereafter, l o pera mi de will be a d mi nistere d as nee de d ( n ot 
t o e xcee d 1 6 m g per da y) per t he i n vesti gat or’s discreti o n. C o m mercial s u p pl y of 
l o pera mi de will be use d a n d pr o vi de d b y researc h p har macies (c ost c o vere d b y 
L o per a mi de D osi n g
Da y
L o pera mi de D ose
1- 1 4
Dail y d ose of 1 2 m g i n 3 di vi de d d oses of 4 m g
1 5- 2 8
Dail y d ose of 8 m g i n 2 di vi de d d oses of 4 m g
> 2 8
Dail y d ose as nee de d ( n ot t o e xcee d 1 6 m g per da y)
L o pera mi de D ose A dj ust me nt
Patie nts are e x pecte d t o ta ke l o pera mi de pr o p h yla xis as directe d. H o we ver, patie nts ma y 
re q uire i n di vi d ualizati o n of l o pera mi de pr o p h yla xis d ose ( u p t o a ma xi m u m d ose of 1 6 
m g per da y) wit h t he g oal of titrati n g t o 1- 2 b o wel m o ve me nts a da y.

F or patie nts w h o de vel o p diarr hea d uri n g C ycle 1, l o pera mi de s h o ul d be i ncrease d u p 
t o a ma xi m u m of 1 6 m g a da y.

If a patie nt is u na ble t o t olerate l o pera mi de d ue t o s y m pt o matic c o nsti pati o n, 
l o pera mi de s h o ul d be hel d u ntil after t he first b o wel m o ve me nt a n d t he n res u me d at a 
d ose re d uce d b y o ne le vel fr o m t heir c urre nt le vel.

F or rec urre nt s y m pt o matic c o nsti pati o n e ve nts, h ol d l o pera mi de u ntil after t he first 
b o wel m o ve me nt a n d t he n res u me at a d ose re d uce d t o t he ne xt l o wer d ose le vel.

If a patie nt is u na ble t o t olerate o nce- dail y l o pera mi de d ue t o c o nsti pati o n, h ol d 
l o pera mi de a n d disc uss s u bse q ue nt l o pera mi de d osi n g wit h t he I n vesti gat or or 
s uita bl y trai ne d a n d q ualifie d dele gate.

Nerati ni b d osi n g s h o ul d c o nti n ue if l o pera mi de is hel d.
Rec o m me n de d d ose re d ucti o ns f or l o pera mi de are liste d i n t he ta ble bel o w.
     L o per a mi de D ose Re d ucti o n Le vels f or C o nsti p ati o n.

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D ose Le vel
L o pera mi de D ose
Ta blets/ Ca ps ules per da y
0
4 m g TI D
6 ta blets/ca ps ules a da y
- 1
4 m g BI D
4 ta blets/ca ps ules a da y
- 2
2 m g TI D
3 ta blets/ca ps ules a da y
- 3
2 m g BI D
2 ta blets/ca ps ules a da y
- 4
2 m g o nce a da y
1 ta blet/ca ps ule a da y
A b bre viati o ns: BI D = t wice dail y; m g = milli gra ms; TI D = t hree ti mes dail y.
5. 4. 3. 2 
C olesti p ol (c olesti d)
L o pera mi de i n c o m bi nati o n wit h t wice dail y c olesti p ol is re q uire d f or 2 8 da ys at t he 
i nitiati o n of nerati ni b.  It is ver y i m p orta nt t o i nitiate a nti diarr heal me dicati o ns 
(l o pera mi de a n d c olesti p ol) wit h t he first d ose of nerati ni b a n d s h o ul d c o nti n ue 
t hr o u g h o ut t he first c ycle u nless patie nts ha ve tr o u ble t olerati n g t hese me dicati o ns. I n t hat 
case, pr o vi ders ha ve t he discreti o n t o ma ke c ha n ges i n t hese me dicati o ns. . Be y o n d C ycle 
1, o n g oi n g pr o p h yla xis is discreti o nar y per t he treati n g pr o vi der.
Patie nts will self-a d mi nister oral c olesti p ol at a d ose of 2 g t wice dail y, f or t he first 
treat me nt c ycle ( 2 8 da ys).
* * * N O T E: D uri n g Cycle 1: P atie nts s h o ul d t ake c olesti p ol 2 g m t wice d aily f or 2 8 d ays, 
wit h t he first d ose t ake n at le ast 4 h o urs bef ore ner ati ni b a n d l o per a mi de pr o p hyl axis, a n d 
t he sec o n d d ose t o be t ake n at le ast 2 h o urs after ner ati ni b  a n d l o per a mi de pr o p hyl axis * * *
C o m mercial s u p pl y of c olesti p ol will be use d a n d pr o vi de d b y researc h p har macies (c ost 
c o vere d b y 
Pri or t o pr ot oc ol versi o n 2, diarr hea pr o p h yla xis c o nsiste d of l o pera mi de i n c o m bi nati o n 
wit h dail y b u des o ni de f or t he first 2 8 da ys. Acti ve patie nts w h o are ta ki n g diarr hea 
pr o p h yla xis at t he ti me of pr ot oc ol versi o n 2 acti vati o n ca n eit her c o m plete b u des o ni de 
treat me nt or start c olesti p ol per t he treati n g i n vesti gat or's discreti o n.
5. 4. 3. 3  
A d diti o nal A nti- Diarr heal I nstr ucti o ns
Tre at me nt of di arr he a ( D a ys 1- 2 8)

F oll o w dietetic meas ures:
-
St o p all lact ose-c o ntai ni n g pr o d ucts.
-
Dri n k 8 t o 1 0 lar ge glasses of clear li q ui ds per da y.
-
Eat fre q ue nt s mall meals.
-
Rec o m me n d l o w fat re gi me n e nric he d wit h ba na nas, rice, a p plesa uce a n d 
t oast u ntil res ol uti o n of diarr hea.

F or patie nts wit h persiste nt Gra de 1 diarr hea ( < 4 st o ols per da y a b o ve baseli ne) 
des pite ma xi mal l o pera mi de use, L o m otil ® ( di p he n o x ylate h y dr oc hl ori de a n d 
atr o pi ne s ulfate) 1 ta blet ( 2. 5 m g) e ver y 6 t o 8 h o urs ma y be a d de d ( or e q ui vale nt).

F or Gra de 2 diarr hea d uri n g t he first 2 8 da ys ( 4 t o 6 st o ols per da y a b o ve baseli ne, 
des pite i nte nsi ve a nti- diarr heal t hera p y), c o nsi der a d di n g octre oti de (s h ort-acti n g) 1 5 0 

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μ g  s u bc uta ne o us [ S C] i njecti o n 3 ti mes a da y, or after i nitial d ose of s h ort-acti n g 
octre oti de, if well t olerate d, a si n gle d ose of octre oti de L A R 2 0 m g b y i ntra m usc ular 
(I M) i njecti o n ( or e q ui vale nt).

After res ol uti o n of diarr hea, l o pera mi de pr o p h yla xis ca n be decrease d i n 2- m g 
decre me nts wit h t he g oal of titrati n g t o 1- 2 b o wel m o ve me nts a da y.
F or ne w o nset u nc o m plic ate d Gr a de 1 or Gr a de 2 di arr he a ( > 2 8 D a ys a n d be y o n d)
Dietetic me as ures

St o p all lact ose-c o ntai ni n g pr o d ucts.

Dri n k 8 t o 1 0 lar ge glasses of clear li q ui ds per da y.

Eat fre q ue nt s mall meals.

Rec o m me n d l o w fat re gi me n e nric he d wit h ba na nas, rice, a p plesa uce a n d t oast u ntil 
res ol uti o n of diarr hea.
P h ar m ac ol o gic al Tre at me nt

A d mi nister l o pera mi de: i nitial d ose of 4 m g ( 2 ta blets/ca ps ules) wit h t he first b o ut of 
diarr hea f oll o we d b y 2 m g ( 1 ta blet/ca ps ule) e ver y 4 h o urs or after e ver y u nf or me d 
st o ol ( ma xi m u m 1 6 m g a da y) a n d c o nti n ue l o pera mi de at t his fre q ue nc y u ntil 
diarr hea free f or 1 2 h o urs.

F or patie nts wit h persiste nt Gra de 1 diarr hea o n a ma xi m u m d ose of l o pera mi de ( 1 6 
m g per da y) L o m otil ( di p he n o x ylate h y dr oc hl ori de a n d atr o pi ne s ulfate) 1 ta blet ( 2. 5 
m g) e ver y 6 h o urs t o 8 h o urs ma y be a d de d ( or e q ui vale nt).

F or Gra de 2 diarr hea d uri n g t he first 2 8 da ys of treat me nt ( 4 t o 6 st o ols per da y a b o ve 
baseli ne, des pite i nte nsi ve a nti diarr heal t hera p y), c o nsi der a d di n g octre oti de (s h ort 
acti n g) 1 5 0 μ g  S C TI D; or after i nitial d ose of s h ort-acti n g octre oti de, if well 
t olerate d, a si n gle d ose of octre oti de L A R 2 0 m g I M ( or e q ui vale nt me dicati o n).
F or Gr a de 3 or Gr a de 4 di arr he a wit h c o m plic ati n g fe at ures ( de h y dr ati o n, fe ver, 
a n d/ or Gr a de 3- 4 ne utr o pe ni a)
Dietetic me as ures (s a me as a b o ve)
P h ar m ac ol o gic tre at me nt

A d mi nister l o pera mi de: i nitial d ose of 4 m g ( 2 ta blets/ca ps ules) wit h t he first b o ut of 
diarr hea f oll o we d b y 2 m g ( 1 ta blet/ca ps ule) e ver y 4 h o urs or after e ver y u nf or me d 
st o ol ( ma xi m u m 1 6 m g a da y) a n d c o nti n ue l o pera mi de at t his fre q ue nc y u ntil 
diarr hea free f or 1 2 h o urs. T he n titrate t he a m o u nt of l o pera mi de use d t o kee p 
diarr hea c o ntr olle d ( < 4 st o ols/ da y).

A d mi nister octre oti de ( 1 0 0- 1 5 0 μ g  S C BI D or i ntra ve n o usl y (I V) ( 2 5- 5 0 μ g/ h)  if 
de h y drati o n is se vere, wit h d ose escalati o n u p t o 5 0 0 μ g  S C TI D).

Use I V fl ui ds as a p pr o priate.

C o nsi der pr o p h ylactic a nti bi otics as nee de d (e. g., fl u or o q ui n ol o nes) es peciall y if 
diarr hea is persiste nt be y o n d 2 4 h o urs or t here is fe ver or Gra de 3- 4 ne utr o pe nia.

St o ol c ult ures s h o ul d be d o ne t o e xcl u de i nfecti o us ca uses of Gra de 3 or 4 diarr hea or 
diarr hea of a n y gra de wit h c o m plicati n g feat ures ( de h y drati o n, fe ver, a n d/ or Gra de 3 
or 4 ne utr o pe nia) per t he I n vesti gat or’s discreti o n. Res ults fr o m occ ult bl o o d, fecal 

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le u k oc yte stai n, Cl ostri di u m difficile, Ca m p yl o bacter, Sal m o nella, a n d S hi gella 
testi n g, w he n perf or me d, s h o ul d be rec or de d i n t he cli nical rec or ds.

Patie nts wit h si g nifica nt diarr hea w h o are u nres p o nsi ve t o me dical treat me nt ma y 
re q uire treat me nt i nterr u pti o n or d ose re d ucti o n.
Patie nt i nstr ucti o ns f or t he ma na ge me nt of diarr hea are pr o vi de d i n A p pe n di x C.
5. 5  
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
All c o nc o mita nt me dicati o ns a n d c o nc o mita nt n o n p har mac ol o gical treat me nts/t hera pies will be 
rec or de d i n t he me dical rec or d fr o m 3 0 da ys pri or t o t he si g ni n g of t he i nf or me d c o nse nt f or m 
(I C F) u ntil t he Safet y F oll o w- u p Visit occ urri n g 2 8 da ys after t he last d ose of nerati ni b. T his will 
i ncl u de t he start date, st o p date, ge neric na me, a n d i n dicati o n f or treat me nt.
At scree ni n g, patie nts will be as ke d w hat me dicati o ns t he y ha ve ta ke n d uri n g t he pre vi o us 3 0 
da ys, w hic h me dicati o ns are o n g oi n g at t he ti me of scree ni n g, a n y me dical c o n diti o ns t hat 
re q uire me dicati o n, a n d all pri or ca ncer t hera pies. At eac h s u bse q ue nt st u d y visit, patie nts will be 
as ke d w hat c o nc o mita nt me dicati o ns t he y are c urre ntl y ta ki n g.
5. 5. 1
Per mitte d C o nc o mita nt Treat me nt 
A n y palliati ve a n d/ or s u p p orti ve care f or ca ncer-relate d s y m pt o ms, w hic h are n ot 
ot her wise s pecifie d i n t he list of pr o hi bite d me dicati o ns bel o w, is per mitte d at t he 
I n vesti gat or’s discreti o n. 
S pecificall y, t he f oll o wi n g treat me nts are per mitte d d uri n g t he st u d y:

Sta n dar d t hera pies f or pree xisti n g me dical c o n diti o ns a n d f or me dical a n d/ or s ur gical 
c o m plicati o ns. 

O varia n s u p pressi o n is all o we d.

Bis p h os p h o nates a n d R A N K (rece pt or acti vat or of n uclear fact or ka p pa- B) li ga n d 
i n hi bit ors (e. g., de n os u ma b), are all o we d re gar dless of i n dicati o n.
5. 5. 2
Pr o hi bite d C o nc o mita nt Treat me nt 
T he f oll o wi n g treat me nts are pr o hi bite d t hr o u g h o ut t he d urati o n of t he acti ve (treat me nt) 
sta ge/ p hase of t he st u d y: A n y c o nc urre nt c he m ot hera p y, h or m o nal t hera p y (e xce pt 
o varia n s u p pressi o n w hic h is per mitte d), s ur ger y relate d t o ca ncer, a ntica ncer 
i m m u n ot hera p y, or ot her a ntica ncer treat me nts i ncl u di n g ot her i n vesti gati o nal a ge nts b y 
oral or pare nteral r o ute. 
Patie nts w h o ha ve de m o nstrate d c o ntr ol of t heir e xtra-cra nial disease ( defi ne d f or t his 
p ur p ose as o bjecti ve res p o nse or S D mai ntai ne d f or at least 2 c ycles) fr o m st u d y t hera p y, 
b ut w h o ha ve de vel o pe d is olate d brai n metastases t hat are felt t o be treata ble wit h 
ra diati o n will be all o we d t o recei ve ra diati o n t hera p y a n d t he n c o nti n ue t heir assi g ne d 
st u d y t hera p y u ntil t he y eit her e x perie nce s yste mic pr o gressi o n of t heir disease a n d/ or 
f urt her pr o gressi o n i n t he brai n. Patie nts s h o ul d ha ve t heir st u d y t hera p y hel d u ntil 
ra diati o n is c o m plete d. Patie nts ca n restart st u d y t hera p y o nce cli nicall y sta ble as dee me d 

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b y t he i n vesti gat or.
A n y treat me nt re q uire d d uri n g t he first 2 m o nt hs of t he Pr o gra m Treat me nt P hase t hat 
mi g ht ha ve a n i nteracti o n wit h l o pera mi de (refer t o l o pera mi de pac ka ge i nsert) or 
c olesti p ol (refer t o c olesti p ol pac ka ge i nsert) is pr o hi bite d.
5. 5. 3
P ote ntial Dr u g- Dr u g I nteracti o ns
Beca use t here is a p ote ntial f or i nteracti o n of nerati ni b a n d f ul vestra nt  wit h ot her 
c o nc o mita ntl y a d mi nistere d dr u gs t hr o u g h t he c yt oc hr o me P 4 5 0 s yste m, t he case re p ort 
f or m m ust ca pt ure t he c o nc urre nt use of all ot her dr u gs, o ver-t he-c o u nter me dicati o ns, or 
alter nati ve t hera pies.  T he O verall PI s h o ul d be alerte d if t he partici pa nt is ta ki n g a n y 
a ge nt k n o w n t o affect or wit h t he p ote ntial t o affect selecte d C Y P 4 5 0 is oe nz y mes.  
A p pe n di x D prese nts g ui deli nes f or i de ntif yi n g me dicati o ns/s u bsta nces t hat c o ul d 
p ote ntiall y i nteract wit h t he st u d y a ge nt(s).
T he s ol u bilit y of nerati ni b is p H de pe n de nt a n d treat me nts t hat alter gastr oi ntesti nal p H 
s uc h as pr ot o n p u m p i n hi bit ors ( P PIs), H 2-rece pt or a nta g o nists, a n d a ntaci ds ma y l o wer 
t he s ol u bilit y of nerati ni b. It has bee n o bser ve d t hat a si n gle 2 4 0- m g d ose of nerati ni b 
c o m bi ne d wit h la ns o praz ole ma y decrease nerati ni b A U C b y u p t o 6 5 %. T he p ote ntial 
P K i nteracti o n of H 2-rece pt or a nta g o nists wit h nerati ni b has n ot bee n e val uate d. It is 
u n k n o w n w het her se parati n g P PI a n d nerati ni b d oses re d uces t he i nteracti o n. If a ntaci ds 
are necessar y, t he a ntaci d d ose a n d t he nerati ni b d ose s h o ul d be se parate d b y 3 h o urs. 
W he n ta ki n g c olesti p ol wit h nerati ni b a n d l o pera mi de d uri n g t he first 2 8 da ys ( C ycle 1) 
t here s h o ul d be cl ose m o nit ori n g d uri n g t he c o nc o mita nt a d mi nistrati o n wit h 
ket oc o naz ole (a n d itrac o naz ole, rit o na vir, sa q ui na vir, or er yt hr o m yci n), or a n y ot her 
C Y P 3 A 4 i n hi bit or f or i ncrease d si g ns a n d/ or s y m pt o ms of h y perc orticis m.  Refer t o t he 
c olesti d pac ka ge i nsert f or c o ntrai n dicati o ns, war ni n gs, a n d preca uti o ns f or c olesti p ol.
Patie nts ta ki n g di g o xi n, a P- gl yc o pr otei n ( P- g p) s u bstrate wit h a narr o w t hera pe utic 
wi n d o w, s h o ul d be m o nit ore d cl osel y. T he di g o xi n d ose s h o ul d be a dj uste d as nee de d, 
si nce nerati ni b is a n i n hi bit or of P- g p. C o-a d mi nistrati o n of nerati ni b wit h di g o xi n c o ul d 
res ult i n i ncrease d di g o xi n le vels a n d ass ociate d di g o xi n t o xicit y. 
Patie nts ta ki n g oral c o u mari n- deri vati ve a ntic oa g ula nts  (ie, warfari n a n d 
p he n pr oc o u m o n)  s h o ul d be m o nit ore d  cl osel y a n d t heir a ntic oa g ula nt  d ose a dj uste d as 
nee de d.
A v oi d gra pefr uit j uice, w hic h is a k n o w n C Y P 3 A 4 i n hi bit or.
5. 6  
Criteri a f or T a ki n g a P artici p a nt Off Pr ot oc 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 ve 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:

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F or Ce ntralize d S u bject Re gistrati o ns, t he researc h tea m s u b mits a c o m plete d Off Treat me nt/ Off 
St u d y f or m t o O D Q w he n a partici pa nt c o mes off st u d y. T his f or m ca n be f o u n d o n t he O D Q 
we bsite or o btai ne d fr o m t he C o or di nati n g Ce nter. 
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
Ge neral g ui deli nes f or d ose dela y a n d d ose re d ucti o n are o utli ne d bel o w. Ma na ge me nt 
g ui deli nes f or s pecific (e. g. diarr hea, p ul m o nar y t o xicit y, he patic t o xicit y,) a n d cli nicall y-
rele va nt t o xicities are pr o vi de d i n Secti o n 6. 1. T he d ose dela y a n d re d ucti o n i nstr ucti o ns 
pr o vi de d i n t hese secti o ns are i nte n de d t o ser ve as g ui deli nes t o all o w o n g oi n g treat me nt f or 
patie nts wit h o ut si g ns or s y m pt o ms of pr o gressi o n w hile e ns uri n g patie nt safet y.  I n a d diti o n t o 
t he g ui deli nes pr o vi de d bel o w, dr u g h ol ds a n d d ose re d ucti o ns f or t he ma na ge me nt of a d verse 
e ve nts are per mitte d at t he discreti o n of t he treati n g p h ysicia n.
T he descri pti o ns a n d gra di n g scales f o u n d i n t he re vise d N CI C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts ( C T C A E) versi o n 4. 0 will be utilize d f or 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 4. 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  
Ner ati ni b d ose m o dific ati o ns
Nerati ni b d ose dela ys a n d m o dificati o ns s h o ul d be ma de as i n dicate d i n t he f oll o wi n g ta ble(s). 
D ose re-escalati o n is n ot all o we d after a d ose re d ucti o n. 
If si g nifica nt treat me nt –relate d t o xicities ha ve n ot rec o vere d t o Gra de ≤1 or baseli ne gra de, t he 
patie nt ma y s ki p u p t o 2 8 da ys fr o m t he last sc he d ule d d ose. Patie nts s h o ul d be re-e val uate d 
wee kl y d uri n g t he dela y w he ne ver p ossi ble. I n patie nts ra n d o mize d t o t he f ul vestra nt ar m ( Ar m 
A), f ul vestra nt d osi n g ca n c o nti n ue w hile nerati ni b is hel d or if nerati ni b is disc o nti n ue d, as l o n g 
as t he t o xicit y is felt t o be u nrelate d t o f ul vestra nt. C ycles will n ot be dela ye d i n t he e ve nt 
nerati ni b is hel d, b ut will res u me as ori gi nall y sc he d ule d. T he misse d d ose(s) will n ot be ma de 
u p. 
D osi n g ma y als o be s us pe n de d f or u p t o 2 8 da ys f or u na ntici pate d i nterc urre nt me dical e ve nts
t hat are n ot ass ociate d wit h st u d y treat me nt t o xicit y or disease pr o gressi o n.
D ose Re d ucti o n T a ble
D ose Re d ucti o n Le vel
Ner ati ni b  D ose
Starti n g D ose 
2 4 0 m g, dail y
D ose le vel - 1
1 6 0 m g, dail y
D ose le vel - 2
1 2 0 m g, dail y
If a patie nt de vel o ps a t o xicit y re q uiri n g a d ose re d ucti o n bel o w D ose le vel - 2 ( 1 2 0 m g), nerati ni b 
s h o ul d be per ma ne ntl y disc o nti n ue d.

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6. 1. 1
Ge neral T o xicit y 
G ui deli nes f or d ose a dj ust me nts of nerati ni b f or ge neral t o xicities t hat are cli nicall y 
si g nifica nt a n d felt t o be dr u g relate d are s h o w n i n Ta ble 1. F or d ose m o dificati o ns f or 
k n o w n t o xicities ( diarr hea, p ul m o nar y t o xicit y, a n d he patic t o xicit y) please see ta bles 2, 
3, a n d 4.  
T a ble 1:  Ge ner al T o xicities Re q uiri n g D ose A dj ust me nt of Ner ati ni b
N CI C T C A E v. 4. 0
Acti o n
Gr a de 2 a d verse re acti o n *
1st a p peara nce
H ol d nerati ni b u ntil e ve nt res ol ves t o Gra de 
≤1;  t he n res u me nerati ni b at t he sa me d ose 
le vel.
2 n d a p peara nce
H ol d nerati ni b u ntil e ve nt res ol ves t o Gra de 
≤1;  t he n res u me nerati ni b at o ne d ose le vel 
l o wer.
3r d a p peara nce 
H ol d nerati ni b u ntil e ve nt res ol ves t o Gra de 
≤1;  t he n res u me nerati ni b at o ne a d diti o nal 
d ose le vel l o wer.
4t h a p peara nce
Disc o nti n ue nerati ni b per ma ne ntl y. 
* Gr a de 2 A N C ( ne utr o p hil c o u nt decre ase ≥1 0 0 0/ u L),  Gr a de 2 A ne mi a ( He m o gl o bi n < 1 0-
8. 0 g/ d L), a n d Cre ati ni ne Cle ar a nce t h at is ≥5 0  m L/ mi n ( Gr a de 2 C hr o nic Ki d ney Dise ase is 
cre ati ni ne cle ar a nce 5 9- 3 0 m L/ mi n) are acce pt a ble v al ues f or tre at me nt as i n dic ate d i n pre-
tre at me nt criteri a, secti o n 5. 2.  D o n ot h ol d ner ati ni b f or Gr a de 2 A N C, Gr a de 2 A ne mi a, or 
Cre ati ni ne Cle ar a nce t h at is ≥5 0 m L/ mi n.
Gr a de 3 a d verse re acti o n
1st a p peara nce
H ol d nerati ni b u ntil e ve nt res ol ves t o Gra de ≤1;  
t he n res u me nerati ni b at o ne d ose le vel l o wer.
2 n d a p peara nce
H ol d nerati ni b u ntil e ve nt res ol ves t o Gra de ≤1;  
t he n res u me nerati ni b at o ne a d diti o nal d ose 
le vel l o wer.
3r d a p peara nce 
Disc o nti n ue nerati ni b per ma ne ntl y.
Gr a de 4 a d verse re acti o n
1st a p peara nce
Disc o nti n ue nerati ni b per ma ne ntl y 
Base d o n Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts versi o n 
4. 0 ( N CI C T C A E v. 4. 0) 
6. 1. 2
Gastr oi ntesti nal T o xicit y: 
G ui deli nes f or a dj usti n g d oses of nerati ni b i n t he e ve nt of gastr oi ntesti nal t o xicit y of 
diarr hea are s h o w n i n Ta ble 2.  Refer t o Secti o n 5. 3. 3 f or a d diti o nal dietetic meas ures a n d 
p har mac ol o gical treat me nt.
T a ble 2:  G astr oi ntesti n al T o xicities Re q uiri n g D ose A dj ust me nt of Ner ati ni b

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N CI C T C A E V 4. 0
Acti o n
Gra de 1 Diarr hea [I ncrease of < 4 st o ols
per da y o ver baseli ne; mil d i ncrease i n
ost o m y o ut p ut c o m pare d t o baseli ne.]
O R
Gra de 2 Diarr hea [I ncrease of 4- 6 st o ols
per da y o ver baseli ne; m o derate i ncrease i n
ost o m y o ut p ut c o m pare d t o baseli ne;]
l asti n g < 5 d ays
O R
Gra de 3 Diarr hea [I ncrease of ≥7  st o ols
per da y o ver baseli ne; i nc o nti ne nce;
h os pitalizati o n i n dicate d; se vere i ncrease i n
ost o m y o ut p ut c o m pare d t o baseli ne
li miti n g self-care acti vities of dail y li vi n g
( A D L);] l asti n g < 2 d ays
 C o nti n ue nerati ni b at t he c urre nt d ose le vel. 
 A dj ust a nti- diarr heal treat me nt, as per t he 
g ui deli nes f or ma na ge me nt of diarr hea at t he 
first o nset of diarr hea. 
 I nstr uct patie nt t o f oll o w dietetic 
rec o m me n dati o ns i n t he g ui deli nes f or 
ma na ge me nt of diarr hea. 
 Fl ui d i nta ke of ~ 2 L/ da y s h o ul d be 
mai ntai ne d t o a v oi d de h y drati o n. 
 O nce t he e ve nt res ol ve d t o Gra de ≤ 1 or 
baseli ne, start l o pera mi de 4 m g wit h eac h 
s u bse q ue nt nerati ni b a d mi nistrati o n
Persisti n g a n d i nt olera ble Gr a de 2
Di arr he a  lasti n g > 5 da ys des pite bei n g
treate d wit h o pti mal me dical t hera p y, or
ass ociate d wit h fe ver, de h y drati o n, or
Gr a de 3- 4 ne utr o pe ni a
O R
Gr a de 3 Di arr he a  lasti n g > 2 da ys des pite
bei n g treate d wit h o pti mal me dical t hera p y,
or ass ociate d wit h fe ver, de h y drati o n, or
Gr a de 3- 4 ne utr o pe ni a
O R
A n y Gr a de 4 di arr he a  [ Life-t hreate ni n g
c o nse q ue nces; ur ge nt i nter ve nti o n
i n dicate d]
 H ol d nerati ni b u ntil rec o ver y t o Gra de ≤ 1 
or baseli ne.
 A dj ust a nti- diarr heal treat me nt, as per t he 
g ui deli nes f or ma na ge me nt of diarr hea at t he 
first o nset of diarr hea.
 I nstr uct patie nt t o f oll o w dietetic 
rec o m me n dati o ns i n t he g ui deli nes f or 
ma na ge me nt of diarr hea.
 Fl ui d i nta ke of ~ 2 L s h o ul d be mai ntai ne d, 
i ntra ve n o usl y if nee de d.
 If rec o ver y occ urs:

≤1  wee k after wit h h ol di n g treat me nt, 
res u me sa me d ose of nerati ni b.

Wit hi n 1- 3 wee ks after wit h h ol di n g 
treat me nt, res u me nerati ni b at o ne d ose 
le vel l o wer.

If e ve nt occ urs a 2 n d ti me a n d t he 
nerati ni b d ose has n ot alrea d y bee n 
decrease d, re d uce nerati ni b d ose t o t he 
ne xt l o wer d ose le vel.
 If s u bse q ue nt e ve nts occ ur, res u me at a n 

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N CI C T C A E V 4. 0
Acti o n
a d diti o nal d ose le vel l o wer o nce res ol ve d t o 
Gra de ≤ 1 or baseli ne
 O nce t he e ve nt res ol ve d t o Gra de ≤ 1 or 
baseli ne, start l o pera mi de 4 m g wit h eac h 
s u bse q ue nt nerati ni b a d mi nistrati o n
Base d o n Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts versi o n 
4. 0
6. 1. 3
P ul m o nar y T o xicit y
G ui deli nes f or a dj usti n g d oses of nerati ni b i n t he e ve nt of p ul m o nar y t o xicities are s h o w n 
i n Ta ble 3. I nterstitial l u n g disease, w hic h ca n s o meti mes be fatal, has bee n re p orte d wit h 
ot her oral t yr osi ne ki nase i n hi bit ors t hat tar get E R B B rece pt or ki nases, i ncl u di n g 
la pati ni b, gefiti ni b, a n d erl oti ni b. Rare cases of p ne u m o nitis ( 0. 6 %) a n d l u n g i nfiltrati o n 
( 0. 4 %) ha ve bee n re p orte d i n patie nts treate d wit h nerati ni b m o n ot hera p y, a n d c o nsi dere d 
dr u g-relate d. Patie nts recei vi n g nerati ni b s h o ul d be m o nit ore d f or ac ute o nset or 
w orse ni n g of p ul m o nar y s y m pt o ms s uc h as d ys p nea, c o u g h, a n d fe ver a n d treate d 
a p pr o priatel y.
T a ble 3:  P ul m o n ar y T o xicities Re q uiri n g D ose A dj ust me nt of Ner ati ni b
N CI C T C A E V 4. 0
Acti o n
Gr a de 2 P ne u m o nitis/I nterstiti al L u n g 
Dise ase [ S y m pt o matic; me dical i nter ve nti o n 
i n dicate d; li miti n g i nstr u me ntal A D L]
 H ol d nerati ni b u ntil rec o ver y t o Gra de ≤ 1 
or baseli ne.
 Re d uce nerati ni b o ne d ose le vel or 
disc o nti n ue nerati ni b as per I n vesti gat or’s 
best me dical j u d g me nt.
Gr a de 3 P ne u m o nitis/I nterstiti al L u n g 
Dise ase  [ Se vere s y m pt o ms; li miti n g self-care 
A D L; o x y ge n i n dicate d]
 Disc o nti n ue nerati ni b per ma ne ntl y.
6. 1. 4
Li ver T o xicit y 
G ui deli nes f or a dj ust me nt of nerati ni b i n t he e ve nt of li ver t o xicit y are s h o w n i n Ta ble 4. 
A b n or mal val ues i n A L T c o nc urre nt wit h a b n or mal ele vati o ns i n t otal bilir u bi n t hat meet 
t he criteria o utli ne d bel o w i n t he a bse nce of ot her ca uses of li ver i nj ur y are c o nsi dere d 
p ote ntial cases of dr u g-i n d uce d li ver i nj ur y ( p ote ntial H y’s La w cases) a n d s h o ul d al wa ys 
be c o nsi dere d i m p orta nt me dical e ve nts. 
Patie nts w h o e x perie nce Gra de ≥ 3 diarr hea re q uiri n g I V fl ui d treat me nt or a n y si g ns or 
s y m pt o ms of he pat ot o xicit y s uc h as w orse ni n g of fati g ue, na usea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or te n der ness, fe ver, ras h or e osi n o p hilia s h o ul d be e val uate d f or c ha n ges 

D F/ H C C Pr ot oc ol #: 1 7- 3 1 8
Pr ot oc ol Versi o n Date: 0 6/ 0 3/ 2 0 2 1
2 7
i n li ver f u ncti o n tests. Bilir u bi n a n d pr ot hr o m bi n ti me m ust als o be c ollecte d d uri n g 
he pat ot o xicit y e val uati o n.
T a ble 4: Li ver F u ncti o n Test A b n or m alities Re q uiri n g D ose A dj ust me nt of Ner ati ni b
N CI C T C A E V 4. 0
Acti o n
Gr a de 2 A S T/ A L T ( > 3. 0 - 5. 0 x U L N)
O R
Gr a de 2 bilir u bi n ( > 1. 5 - 3. 0 x U L N)
 C o nti n ue nerati ni b at sa me d ose.
Gr a de 3 A S T/ A L T  ( > 5 – 2 0 x U L N) 
O R 
Gr a de 3 bilir u bi n  ( > 3- 1 0 x U L N)
 F or partici pa nts wit h A S T/ A L T < gra de 1 at 
baseli ne, res u me nerati ni b at o ne d ose le vel 
l o wer if rec o ver y t o baseli ne occ urs wit hi n 2 1 
da ys.
 If gra de 3 A S T, A L T or bilir u bi n rec urs 
des pite o ne d ose re d ucti o n, res u me nerati ni b 
at a f urt her d ose re d ucti o n if rec o ver y t o 
baseli ne occ urs wit hi n 2 1 da ys. 
 If gra de 3 A S T/ A L T or bilir u bi n occ urs 
des pite t his sec o n d d ose re d ucti o n, 
per ma ne ntl y disc o nti n ue nerati ni b. Re p ort as 
S A E.
 
 E val uate alter nati ve ca uses. 
Gr a de 4 A S T/ A L T  ( > 2 0 x U L N) 
O R 
Gr a de 4 Bilir u bi n  ( > 1 0 x U L N)
 Per ma ne ntl y disc o nti n ue nerati ni b. 
 E val uate alter nati ve ca uses.
A L T > 3 x U L N 
A N D 
T ot al bilir u bi n  > 2 x U L N 
A N D 
Al k ali ne p h os p h at ase  < 2 x U L N 
( p ote ntial H y’s la w i n dicat ors of dr u g-i n d uce d 
li ver da ma ge)
 H ol d nerati ni b. T he patie nt s h o ul d ret ur n t o 
t he i n vesti gati o nal site a n d be e val uate d as 
s o o n as p ossi ble, prefera bl y wit hi n 4 8 h o urs 
fr o m a ware ness of t he a b n or mal res ults. T his 
e val uati o n s h o ul d i ncl u de la b orat or y tests, 
detaile d hist or y a n d p h ysical assess me nt. 
La b orat or y assess me nt m ust i ncl u de: re peat 
A S T a n d A L T, al b u mi n, t otal bilir u bi n, direct 
bilir u bi n, P T, P T T a n d al kali ne p h os p hatase. 
A detaile d hist or y, i ncl u di n g rele va nt 
i nf or mati o n, s uc h as re vie w of et ha n ol, 
c o nc o mita nt me dicati o ns, recreati o nal dr u g 
a n d s u p ple me nt c o ns u m pti o n, fa mil y hist or y, 
se x ual hist or y, tra vel hist or y, hist or y of 
c o ntact wit h a ja u n dice d patie nt, s ur ger y, 
bl o o d tra nsf usi o n, hist or y of li ver or aller gic 

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Pr ot oc ol Versi o n Date: 0 6/ 0 3/ 2 0 2 1
2 8
N CI C T C A E V 4. 0
Acti o n
disease, a n d w or k e x p os ure, s h o ul d be 
c ollecte d. F urt her testi n g f or ac ute he patitis 
A, B, or C i nfecti o n a n d li ver i ma gi n g (e. g., 
biliar y tract) ma y be warra nte d. All cases 
c o nfir me d o n re peat testi n g as meeti n g t he 
criteria me nti o ne d a b o ve (i.e., A L T > 3 x 
U L N ass ociate d wit h bilir u bi n > 2 x U L N a n d 
al kali ne p h os p hatase < 2 x U L N), wit h n o 
ot her ca use f or li ver f u ncti o n test 
a b n or malities i de ntifie d at t he ti me s h o ul d be 
c o nsi dere d p ote ntial H y’s La w cases, 
irres pecti ve of a vaila bilit y of all t he res ults of 
t he i n vesti gati o ns perf or me d t o deter mi ne 
eti ol o g y of t he a b n or mal li ver f u ncti o n tests.
C o ntact  
 i m me diatel y t o disc uss ne xt 
ste ps, i ncl u di n g e val uati o n of alter nati ve 
ca uses, a n d ma na ge me nt of i n vesti gati o nal 
pr o d uct(s).
T hese e ve nts m ust be re p orte d as S A Es.
N O T E: D uri n g e val uati o n of he pat ot o xicit y, bilir u bi n m ust be fracti o nate d, pr ot hr o m bi n ti me 
m ust be meas ure d, a n d li ver i ma gi n g s h o ul d be c o nsi dere d.
6. 2 
F ul vestr a nt d ose m o dific ati o ns
N o d ose m o dificati o ns are per mitte d f or f ul vestra nt. If a patie nt has a n i nt olera ble t o xicit y felt t o 
be relate d t o f ul vestra nt, f ul vestra nt d osi n g ca n be hel d f or u p t o 2 8 da ys t o all o w t he t o xicit y t o 
rec o ver t o baseli ne or gra de ≤1.  Nerati ni b d osi n g ca n c o nti n ue w hile f ul vestra nt is hel d. 
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 ve 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 haracteristics of a n 
o bser ve d A E ( Secti o n 7. 2) will deter mi ne w het her t he e ve 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.
7. 1 
E x pecte d T o xicities
7. 1. 1
A d verse E ve nts Lists
7. 1. 1. 1  
A d verse E ve nt List(s) f or Nerati ni b  
A list of t he a d verse e ve nts a n d p ote ntial ris ks ass ociate d wit h nerati ni b a p pears 
bel o w a n d will deter mi ne w het her d ose dela ys a n d m o dificati o ns will be ma de or 
w het her t he e ve 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.  F or 

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2 9
t o xicit y ma na ge me nt of diarr hea please refer t o Ta ble 2.
T a ble 5: Ner ati ni b T o xicit y [ A d a pte d fr o m 1 4- J U L- 2 0 1 7 I n vesti g at or’s Br oc h ure, versi o n 
5. 0]

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3 0
7. 1. 1. 2
Di arr he a
Diarr hea is t he m ost fre q ue nt T E A E re p orte d wit h nerati ni b, b ot h as m o n ot hera p y a n d i n 
c o m bi nati o n wit h ot her dr u gs, a n d ma y be se vere, a n d ass ociate d wit h de h y drati o n, 
partic ularl y i n s u bjects wit h c o nc o mita nt na usea a n d v o miti n g.
As diarr hea re prese nts t he m ost pre vale nt T E A E wit h nerati ni b, b ot h as m o n ot hera p y a n d 
i n c o m bi nati o n wit h ot her dr u gs, a n i nte nsi ve diarr hea ma na ge me nt pla n wit h 
pr o p h ylactic use of l o pera mi de a n d c olesti p ol is part of t his a n d all o n g oi n g a n d f ut ure 
nerati ni b cli nical st u dies ( Ustaris et al, 2 0 1 5). G ui deli nes f or d ose a dj ust me nt of nerati ni b 
i n t he e ve nt of diarr hea are als o pr o vi de d. A m o n g s u bjects recei vi n g l o pera mi de 
pr o p h ylactic a nti diarr heal me dicati o n, 1 1- 2 8 % of s u bjects e x perie nce d Gra de 3 diarr hea; 
n o Gra de 4 diarr hea were re p orte d t o date. I n c o ntrast, i n st u dies wit h o ut diarr hea 
pr o p h yla xis, 2 6- 4 0 % of s u bjects e x perie nce d Gra de 3 diarr hea.
St o m atitis
Der mat ol o gic t o xicities ass ociate d wit h E G F R i n hi bit ors i ncl u de dr y ness of t he s ki n a n d 
m uc us me m bra nes ( Na n ne y et al, 1 9 9 0; D u n ne a n d S u m ner, 2 0 0 8). Oral m uc ositis is t he 
m ore s pecific ter m t hat is use d t o descri be oral m uc osal i nfla m mati o n a n d ulcerati o n 
i n d uce d b y ca ncer t hera pies ( Lalla et al, 2 0 0 8). St o matitis was re p orte d b y 1 0. 8 % of 
nerati ni b-treate d s u bjects vers us 3. 2 % of place b o-treate d s u bjects wit h earl y sta ge H E R 2-
o vere x presse d/a m plifie d breast ca ncer w h o ha ve recei ve d pri or a dj u va nt trast uz u ma b 
base d t hera p y. T he maj orit y of t he e ve nts were Gra de 1 ( nerati ni b, 7. 5 %; place b o, 2. 6 %) 
a n d Gra de 2 ( nerati ni b, 2. 8 %; place b o, 0. 6 %) wit h a fe w Gra de 3 e ve nts ( nerati ni b, 0. 6 %; 
place b o, 0. 1 %). T here were n o Gra de 4 e ve nts. Ot her e ve nt ter ms i ncl u de d are m uc osal 
i nfla m mati o n, st o matitis, a p ht h o us st o matitis, m o ut h ulcerati o n, a n d oral m uc osal 
blisteri n g.
He p at ot o xicit y
He pat ot o xicit y wit h as y m pt o matic ele vati o ns of tra nsa mi nases a n d h y per bilir u bi ne mia 
are c o m m o nl y ass ociate d wit h oral T KIs ( Ca ba nillas et al, 2 0 1 1). T he ris k is us uall y 
ma na gea ble b y d ose a dj ust me nt or a s witc h t o a s uita ble alter nati ve T KI. All s u bjects 
e nr olle d i n t his a n d ot her nerati ni b cli nical trials ha ve t heir li ver f u ncti o n tests assesse d 
r o uti nel y. A b n or mal val ues i n A L T c o nc urre nt wit h a b n or mal ele vati o ns i n t otal bilir u bi n 
i n t he a bse nce of ot her ca uses of li ver i nj ur y are c o nsi dere d p ote ntial cases of dr u g-
i n d uce d li ver i nj ur y ( p ote ntial H y’s La w cases) a n d are al wa ys c o nsi dere d i m p orta nt 
me dical e ve nts. S y m pt o ms of m ulti ple l o ose b o wel m o ve me nts i n a da y or a n y w orse ni n g 
of fati g ue, na usea, v o miti n g, a b d o mi nal pai n or te n der ness, fe ver or ras h ma y i n dicate 
c ha n ges i n li ver f u ncti o n tests. 
Der m at ol o gic T o xicities  
Der mat ol o gic t o xicities ass ociate d wit h E G F R i n hi bit ors i ncl u de ras h, dr y ness of t he s ki n 
a n d m uc us me m bra nes, hair c ha n ges a n d al o pecia, nail c ha n ges, a n d ha n d a n d f o ot 
reacti o ns. Ras h was re p orte d m ore fre q ue ntl y b y nerati ni b-treate d s u bjects t ha n place b o-
treate d s u bjects ( 1 6. 3 % vers us 7. 9 %, res pecti vel y). T here were 0. 4 % of nerati ni b-treate d 
s u bjects w h o e x perie nce d Gra de 3 e ve nts. Ras h le d t o treat me nt disc o nti n uati o n i n 8 

D F/ H C C Pr ot oc ol #: 1 7- 3 1 8
Pr ot oc ol Versi o n Date: 0 6/ 0 3/ 2 0 2 1
3 1
( 0. 6 %) nerati ni b-treate d s u bjects. Nail c ha n ges are belie ve d t o res ult fr o m s ki n t hi n ni n g 
afflicti n g u p t o 1 5 % of s u bjects ( D u n ne a n d S u m ner, 2 0 0 8). 
7. 1. 1. 3  
A d verse E ve nt List f or F ul vestra nt
T he m ost c o m m o n, cli nicall y si g nifica nt a d verse reacti o ns occ urri n g i n ≥ 5 % of patie nts 
recei vi n g F ul vestra nt 5 0 0 m g were: i njecti o n site pai n, na usea, b o ne pai n, art hral gia, 
hea dac he, bac k pai n, fati g ue, pai n i n e xtre mit y, h ot flas h, v o miti n g, a n ore xia, ast he nia, 
m usc ul os keletal pai n, c o u g h, d ys p nea, a n d c o nsti pati o n. I ncrease d he patic e nz y mes 
( A L T, A S T, A L P) occ urre d i n > 1 5 % of F A S L O D E X patie nts a n d were n ot d ose-
de pe n de nt. Please see t he pac ka ge i nsert f or c o m plete i nf or mati o n re gar di n g a d verse 
e ve nts: 
htt p:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 2/ 0 2 1 3 4 4s 0 1 9s 0 2 0l bl. p df  
7. 2  
A d verse E ve nt C h ar acteristics

C T C A E ter m ( A E descri pti o n) a n d gr a de:  T he descri pti o ns a n d gra di n g scales f o u n d 
i n t he re vise d N CI C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) versi o n 
4. 0 will be utilize d f or A E re p orti n g.  All a p pr o priate treat me nt areas s h o ul d ha ve access 
t o a c o p y of t he C T C A E versi o n 4. 0.  A c o p y of t he C T C A E versi o n 4. 0 ca n be 
d o w nl oa de d fr o m t he C T E P we b site 
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 ge nt(s) t hat are liste d a b o ve s h o ul d be re p orte d o nl y if t he a d verse e ve nt 
varies i n nat ure, i nte nsit y or fre q ue 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.
-
Ot her A Es f or t he pr ot oc ol t hat d o n ot re q uire e x pe dite d re p orti n g are o utli ne d i n t he 
ne xt secti o n ( E x pe dite d A d verse E ve nt Re p orti n g) u n der t he s u b- hea di n g of Pr ot oc ol-
S pecific E x pe dite d A d verse E ve nt Re p orti n g E xcl usi o ns.

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 be 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 he A E is cle arly N O T rel ate d t o t he st u d y treat me nt.
7. 3 
E x pe dite d A d verse E ve nt Re p orti n g 
7. 3. 1
I n vesti gat ors m ust re p ort t o t he O verall PI a n y seri o us a d verse 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. 

D F/ H C C Pr ot oc ol #: 1 7- 3 1 8
Pr ot oc ol Versi o n Date: 0 6/ 0 3/ 2 0 2 1
3 2
7. 3. 2
F or m ulti-i nstit uti o n st u dies w here a D F/ H C C i n vesti gat or is ser vi n g as t he O verall 
Pri nci pal I n vesti gat 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 he D F/ H C C. T his a p plies t o a n y me dical e ve nt e q ui vale nt t o a n 
u ne x pecte d gra de 2 or 3 t o xicit y wit h a p ossi ble, pr o ba ble or defi nite attri b uti o n, a n y 
gra de 4 a n d gra de 5 ( deat h) t o xicit y re gar dless of st u d y p hase or attri b uti o n.
7. 4  
D F/ H C C E x pe dite d Re p orti n g G ui deli nes
I n vesti gati ve sites wit hi n D F/ H C C will re p ort S 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. 
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 he l ocal 
I R B’s p olicies a n d pr oce d ures i n re p orti n g a d verse e ve nts. A c o p y of t he s u b mitte d 
i nstit uti o nal S A E f or m s h o ul d be f or war de d t o t he O verall PI wit hi n t he ti mefra mes 
detaile d i n t he ta ble bel o w.  
D F/ H C C Re p ort a ble A Es
Attri b uti o n
Gr. 2 & 3 
A E
E x pecte d
Gr. 2 & 3 A E 
U ne x pecte d
Gr. 4 A E 
E x pecte d
Gr. 4 A E
U ne x pecte d
Gr. 5 A E 
E x pecte d or 
U ne x pecte d
U nrelate d
U nli kel y
N ot re q uire d
N ot re q uire d
5 cale n dar 
da ys #
5 cale n dar 
da ys
2 4 h o urs *
P ossi ble
Pr o ba ble
Defi nite
N ot re q uire d
5 cale n dar 
da ys
5 cale n dar 
da ys #
5 cale n dar 
da ys
2 4 h o urs *
# If liste d i n pr ot oc ol as e x pecte d a n d n ot re q uiri n g e x pe dite d re p orti n g, e ve nt d oes n ot nee d t o 
be re p orte d.
* F or partici pa nts e nr olle d a n d acti vel y partici pati n g i n t he st u d y or  f or A Es occ urri n g wit hi n 
3 0 da ys of t he last i nter ve nti o n, t he A E s h o ul d be re p orte d wit hi n 1 b usi ness da y of lear ni n g of 
t he e ve nt.
T he O verall PI will s u b mit S A E re p orts fr o m o utsi de i nstit uti o ns t o t he D F CI O H R S 
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 ve nts. 
7. 4. 1
Pr ot oc ol- S pecific E x pe dite d A d verse E ve nt Re p orti n g E xcl usi o ns
F or t his pr ot oc ol o nl y, t he o nl y e ve nt t hat d oes n ot re q uire d e x pe dite d re p orti n g t o t he 
O verall PI or t he D F CI I R B is disease pr o gressi o n.  H o we ver, t his still m ust be re p orte d 
t hr o u g h t he r o uti ne re p orti n g mec ha nis m (i.e. case re p ort f or m).
7. 5 
E x pe dite d 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 O verall PI, 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 he 
O verall PI will re p ort t o t he F D A, re gar dless of t he site of occ urre nce, a n y seri o us a d verse e ve nt 

D F/ H C C Pr ot oc ol #: 1 7- 3 1 8
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3 4
Pre g n a nc y
 
All i nitial re p orts of pre g na nc y m ust be re p orte d t o t he O verall PI a n d 
 b y 
t he i n vesti gati o nal staff wit hi n 2 4 h o urs of t heir k n o wle d ge of t he e ve nt. 
F or i n vesti gati o nal me dici nal pr o d ucts a n d f or mar kete d pr o d ucts use d as st u d y dr u g i n nerati ni b 
st u dies, a n e x p os ure d uri n g pre g na nc y occ urs if:

A fe male bec o mes, or is f o u n d t o be, pre g na nt eit her w hile recei vi n g or ha vi n g bee n 
directl y e x p ose d t o (e. g., e n vir o n me ntal e x p os ure) t he i n vesti gati o nal me dici nal pr o d uct, 
or t he fe male bec o mes, or is f o u n d t o be, pre g na nt after disc o nti n ui n g a n d/ or bei n g 
directl y e x p ose d t o t he i n vesti gati o nal me dici nal pr o d uct ( mater nal e x p os ure);

A male has bee n e x p ose d, eit her d ue t o treat me nt or e n vir o n me ntal, t o t he i n vesti gati o nal 
me dici nal pr o d uct pri or t o or ar o u n d t he ti me of c o nce pti o n a n d/ or is e x p ose d d uri n g his 
part ner’s pre g na nc y ( pater nal e x p os ure).
If a n y st u d y s u bject or st u d y s u bject’s part ner bec o mes or is f o u n d t o be pre g na nt d uri n g t he 
st u d y s u bject’s treat me nt wit h t he i n vesti gati o nal me dici nal pr o d uct, t he i n vesti gat or m ust s u b mit 
t his i nf or mati o n t o t he O verall PI a n d 
F oll o w- u p a n d a d diti o nal i nf or mati o n ma y be re q ueste d. 
7. 7 
E x pe dite d 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 or se nti nel e ve nts t hat re q uire re p orti n g acc or di n g t o i nstit uti o nal p olic y. 
7. 8  
R o uti ne A d verse E ve nt Re p orti n g
Gra de ≥1  diarr hea a n d all gra de 2 or hi g her A d verse E ve nts m ust  be re p orte d i n r o uti ne st u d y 
data s u b missi o ns t o t he O verall PI o n t he t o xicit y case re p ort f or ms.  A Es re p orte d t hr o u g h 
e x pe dite d pr ocesses (e. g., re p orte d t o t he I R B, F D A, etc.) m ust als o be re p orte d i n r o uti ne 
st u d y d at a s u b missi o ns.
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 nt 
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  
Ner ati ni b
8. 1. 1
Descri pti o n
T he c he mical na me is: 2- B ute na mi de, N-[ 4-[[ 3-c hl or o- 4-( 2-
p yri di n yl met h o x y) p he n yl]a mi n o]- 3-c ya n o- 7-et h o x y- 6- q ui n oli n yl]- 4-( di met h yla mi n o)-, 
( 2 E)-, ( 2 Z)- 2- b ute ne di oate ( 1: 1). Nerati ni b is als o k n o w n as P B- 2 7 2, H KI- 2 7 2, a n d H KI-
2 7 2 maleate a n d is a n irre versi ble i n hi bit or of t he H E R fa mil y of rece pt or t yr osi ne 

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ki nases. T he m olec ular f or m ula is C 3 0 H 2 9 Cl N 6 O 3- C 4 H 4 O 4. T he m olec ular wei g ht is 
6 7 3. 1 1. 
Cli nical p har mac o ki netic ( P K) res ults fr o m t he first-i n- h u ma n st u d y wit h asce n di n g 
si n gle a n d m ulti ple d oses i n s u bjects wit h ca ncer s h o we d t hat a bs or pti o n of nerati ni b was 
sl o w wit h T ma x ra n gi n g fr o m 3- 6. 5 h o urs p ost d ose. After si n gle or m ulti ple dail y oral 
d oses of nerati ni b wit h f o o d, t he pea k e x p os ure ( C ma x) a n d t he area u n der t he plas ma 
c o nce ntrati o n- vers us-ti me c ur ve ( A U C) i ncrease d wit h i ncreasi n g d ose. F urt her m ore, n o 
maj or acc u m ulati o n was o bser ve d w he n c o m pari n g Da y 1 4 e x p os ure wit h Da y 1 
e x p os ure f oll o wi n g o nce- dail y d osi n g of nerati ni b 2 4 0 m g a n d 3 6 0 m g wit h f o o d. T he 
mea n half-life f oll o wi n g a si n gle d ose o n Da y 1 ra n ge d fr o m 8 t o 1 7 h o urs, w hic h 
s u p p orts o nce- dail y d osi n g of nerati ni b.
8. 1. 2
F or m
Nerati ni b ( 4 0 m g ta blets) will be s u p plie d b y 
 a n d will be 
pac ka ge d i nt o b ottles f or patie nt a d mi nistrati o n ( 2 8 da y s u p pl y + 7 da ys t o all o w f or +/- 3 
da ys o n eac h e n d of t he c ycle a n d o ne a d diti o nal da y). T he c ol or of t he ta blets is re d dis h-
br o w n.
8. 1. 3
St ora ge a n d Sta bilit y
Nerati ni b ta blets s h o ul d be st ore d at 2 5 C ( 7 7 F) or bel o w wit h desicca nt. D o n ot freeze. 
E xc ursi o ns u p t o 3 0 C ( 8 6 F) are per mitte d.
8. 1. 4
Ha n dli n g
Nerati ni b ta blets re q uire n o s pecific ha n dli n g preca uti o ns. Q ualifie d pers o n nel, 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 ke t he pre parati o n, ha n dli n g, a n d safe dis p osal of t he c he m ot hera pe utic 
a ge nt i n a self-c o ntai ne d a n d pr otecti ve e n vir o n me nt. 
8. 1. 5
A vaila bilit y
Nerati ni 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 t o t he st u d y tea m 
a n d patie nts fr o m 
s i n vesti gati o nal s u p pl y of Nerati ni b.
8. 1. 6
Pre parati o n
Nerati ni b will be pre- pre pare d a n d pac ka ge d b y 
 a n d s hi p pe d 
directl y t o partici pati n g i nstit uti o n p har macies. Dr u g or ders will be place d b y eac h 
partici pati n g ce nter o nce 
 has recei ve d t he site i nf or mati o n 
re q uire d t o s hi p dr u g t o eac h site.  St u d y dr u g will be distri b ute d t o eac h ce nter.  O nce a 
patie nt meets criteria t o c o nti n ue t hera p y, he/s he will recei ve st u d y dr u g (after eac h st u d y 
visit). 

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8. 1. 7
A d mi nistrati o n
Nerati ni b will be pac ka ge d i n b ottles c o ntai ni n g a ma xi m u m of 2 1 0 ta blets ( 4 0 m g) ( T his 
is e q ual t o a 2 8 da y s u p pl y + 7 da ys t o all o w f or +/- 3 da ys o n eac h e n d of t he c ycle a n d 
o ne a d diti o nal da y). Ta blets will be self-a d mi nistere d orall y b y patie nts o nce dail y as si x 
4 0 m g ta blets (t otal 2 4 0 m g). F urt her d oses will be deter mi ne d at eac h c ycle, de pe n di n g 
o n t o xicities a n d nee d f or d ose a dj ust me nt. La beli n g of t he b ottles c o ntai ni n g ta blets will 
be d o ne i n acc or da nce wit h l ocal pr oce d ures (as re q uire d b y la w). Patie nts will ret ur n a n y 
u n use d pills at ne xt pr ot oc ol visit. 
8. 1. 8
Or deri n g
T he i n vesti gat or or t h ose na me d as s u b-i n vesti gat ors a gree t o s u p pl y st u d y dr u g 
( nerati ni b) o nl y t o t h ose s u bjects w h o are e nr olle d i n t he st u d y. T he i n vesti gat or or 
desi g nee will kee p a c urre nt a n d acc urate i n ve nt or y of all cli nical dr u g s u p plies pr o vi de d 
b y 
 T he st u d y site will mai ntai n a dis pe nsi n g l o g a n d 
c o m plia nce wit h t he treat me nt re gi me n will be calc ulate d at t he site fr o m t his i nf or mati o n 
at eac h visit. Eac h partici pati n g ce nter will or der its o w n i n ve nt or y of nerati ni b. Dr u g will 
be s hi p pe d directl y t o t hat partici pati n g site b y 
 A ne w 
prescri pti o n will be pr o vi de d t o eac h patie nt f or eac h c ycle of t hera p y. 
8. 1. 9
Acc o u nta 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 ve 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 vesti 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.)
8. 1. 1 0
Destr ucti o n a n d Ret ur n
At t he e n d of t he st u d y, u n use d s u p plies of nerati ni b s h o ul d be destr o ye d acc or di n g t o 
i nstit uti o nal p olicies. Destr ucti o n will be d oc u me nte d i n t he Dr u g Acc o u nta bilit y Rec or d 
F or m. 
8. 2 
F ul vestr a nt
8. 2. 1
Descri pti o n
F ul vestra nt i njecti o n f or i ntra m usc ular a d mi nistrati o n is a n estr o ge n rece pt or a nta g o nist. 
T he c he mical na me is 7-al p ha-[ 9-( 4, 4, 5, 5, 5- pe nta fl u or o pe nt yls ul p hi n yl) n o n yl]estra-
1, 3, 5-( 1 0)- trie ne- 3, 1 7 beta- di ol. T he m olec ular f or m ula is C 3 2 H 4 7 F 5 O 3 S a n d its 
str uct ural f or m ula is: O H O H ( C H 2) 9 S O( C H 2) 3 C F 2 C F 3 F ul vestra nt is a w hite p o w der 
wit h a m olec ular wei g ht of 6 0 6. 7 7. T he s ol uti o n f or i njecti o n is a clear, c ol orless t o 
yell o w, visc o us li q ui d.

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F ul vestra nt is c o m merciall y a vaila ble a n d c o nsi dere d sta n dar d- of-care f or patie nts wit h 
h or m o ne rece pt or p ositi ve, metastatic breast ca ncer. T he d ose, sc he d ule, a n d m o de of 
a d mi nistrati o n use d i n t his trial are i de ntical t o t he d ose, sc he d ule, a n d m o de of 
a d mi nistrati o n a p pr o ve d f or use f or t his i n dicati o n b y t he U. S. F D A.
F ul vestra nt will be c har ge d t o t he patie nt a n d/ or i ns ura nce c o m pa n y as it is c o nsi dere d 
sta n dar d- of-care.
8. 2. 2
F or m
F ul vestra nt i njecti o n is c o m merciall y a vaila ble as a sterile, si n gle patie nt, prefille d 
s yri n ge c o ntai ni n g 2 5 0 m g at a c o nce ntrati o n of 5 0 m g/ m L. T he s ol uti o n is a clear, 
c ol orless t o yell o w, visc o us li q ui d. I n a d diti o n t o t he f ul vestra nt, eac h i njecti o n c o ntai ns 
as i nacti ve i n gre die nts alc o h ol, U S P, be nz yl alc o h ol, N F, a n d be nz yl be nz oate, U S P, as 
c o-s ol ve nts a n d cast or oil, U S P, as a c o-s ol ve nt a n d release rate m o difier.
8. 2. 3
St ora ge a n d Sta bilit y
S yri n ges of f ul vestra nt s h o ul d be st ore d i n t he ori gi nal c o ntai ner a n d refri gerate d at 2-
8° C.
8. 2. 4
Ha n dli n g
F ul vestra nt re q uires n o s pecific ha n dli n g preca uti o ns. Q ualifie d pers o n nel, 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 ke t he pre parati o n, ha n dli n g, a n d safe dis p osal of t he c he m ot hera pe utic a ge nt i n a 
self-c o ntai ne d a n d pr otecti ve e n vir o n me nt. 
8. 2. 5
Pre parati o n
Re m o ve s yri n ge fr o m tra y a n d c hec k t hat it is n ot da ma ge d. Peel o pe n t he safet y nee dle 
o uter pac ka gi n g. Brea k t he seal of t he w hite plastic c o ver o n t he s yri n ge l uer c o n nect or t o 
re m o ve t he c o ver wit h t he attac he d r u b ber ti p ca p. T wist t o l oc k t he nee dle t o t he l uer 
l oc k c o n nect or. Re m o ve nee dle s heat h. Re m o ve e xcess air fr o m t he s yri n ge (a s mall 
b u b ble ma y re mai n).
8. 2. 6
A d mi nistrati o n
F ul vestra nt will be a d mi nistere d at a d ose of 5 0 0 m g ( 2 x 2 5 0 m g i njecti o ns) I M o n C ycle 
1 Da y 1, C ycle 1 Da y 1 5, C ycle 2 Da y 1, a n d o n Da y 1 of eac h s u bse q ue nt c ycle. C ycle 
le n gt h = 2 8 da ys. 
F ul vestra nt will be a d mi nistere d sl o wl y i nt o eac h b utt oc k. I m me diatel y u p o n wit h dra wal 
of s yri n ge fr o m patie nt acti vate nee dle pr otecti o n de vice b y p us hi n g le ver ar m f or war d 
u ntil nee dle ti p is f ull y c o vere d. Vis uall y c o nfir m t hat t he nee dle ar m has a d va nce d a n d 
t hat t he nee dle ti p is f ull y c o vere d. If u na ble t o acti vate, discar d i m me diatel y i nt o a n 

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a p pr o ve d s har ps c o ntai ner.
8. 2. 7
Or deri n g
F ul vestra nt is c o m merciall y a vaila ble a n d will be or dere d b y eac h prescri bi n g pr o vi der 
f or t he d urati o n f or t he st u d y.
8. 2. 8
Acc o u nta bilit y
F ul vestra nt is c o m merciall y a vaila ble a n d t heref ore acc o u nta bilit y s h o ul d be perf or me d 
as sta n dar d p olic y i n t he i n vesti gati o nal site.
8. 2. 9
Destr ucti o n
F ul vestra nt is c o m merciall y a vaila ble a n d t heref ore destr ucti o n s h o ul d be perf or me d as 
sta n dar d p olic y i n t he i n vesti gati o nal site.

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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
T a ble 6:  S peci me n C ollecti o n Sc he d ule
C ycle 1
S u bse q ue nt 
C ycles
S peci me n
Scree ni n g
D a y 1
( 1 D a y)
D a y 1 5
D a y 1
( 3 D a ys)
E n d of 
tre at me nt/ 
Pr o gressi o n
S hi p pi n g 
C o n diti o
n
S hi p t o
ct D N A C ollecti o n
( Secti o n 9. 1)
x  
x
x
x
A m bie nt
D F/ H C C 
C ore Bl o o d 
a n d Tiss ue 
Ba n k 
Arc hi val t u m or 
tiss ue ( bl oc ks or 
sli des) a
( Secti o n 9. 2)
x
A m bie nt
D F CI B O C 
st u d y tea m
Re q uire d Fres h 
t u m or tiss ue bi o ps y b 
( Secti o n 9. 3)
x
x 
Fr oze n i n 
O C T
D F/ H C C 
C ore Bl o o d 
a n d Tiss ue 
Ba n k 
O pti o nal Fres h t u m or 
tiss ue bi o ps y
( Secti o n 9. 3)
x
Fr oze n i n 
O C T
D F/ H C C 
C ore Bl o o d 
a n d Tiss ue 
Ba n k 
a. 
If ar c hi v al t u m or tiss u e is n ot a v ail a bl e, fr es h tiss u e bi o ps y m ust b e p erf or m e d pri or t o tr e at m e nt 
st art. Bi o ps y m a y b e d o n e as p art of s cr e e ni n g or o n C 1 D 1 b ef or e tr e at m e nt b e gi ns. F o r e xt e r n al 
sit e p ati e nts, bi o ps y s h o ul d b e d o n e aft er r e gistr ati o n or o n C 1 D 1 pri or t o tr e at m e nt st art. S e e 
s e cti o n 9. 3 b el o w.  
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. T h e bi o ps y 
m a y b e p erf or m e d at s cr e e ni n g or o n C y cl e 1 D a y 1 pri or t o d osi n g. F o r e xt e r n al sit e p ati e nts , 
bi o ps y s h o ul d b e d o n e aft er r e gistr ati o n or o n C 1 D 1 pri or t o tr e at m e nt st art.  S e e s e cti o n 9. 3 b el o w.  
9. 1 
ct D N A C ollecti o n 
9. 1. 1
C ollecti o n of Bl o o d S peci me n(s)
F or ct D N A a nal yses, t w o 1 0 m L bl o o d sa m ples will be dra w n i nt o t w o Strec k T u bes. 
Strec k T u bes will be s u p plie d t o sites.  Bl o o d will be c ollecte d at:

C ycle 1 Da y 1 ( pri or t o treat me nt start)

C ycle 1 Da y 1 5

S u bse q ue nt C ycles Da y 1

E n d of Treat me nt
 
E ver y eff ort will be ma de t o c o or di nate st u d y bl o o d dra ws wit h cli nicall y-i n dicate d bl o o d 
tests t o mi ni mize a d diti o nal ve ni p u nct ure.  Researc h c o or di nat ors will trac k partici pa nts 
cl osel y a n d ma ke e ver y eff ort t o c ollect bl o o d at re q uire d ti me p oi nts.  S o me bl o o d dra ws 

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will be misse d or fall o utsi de ti mefra me wi n d o w d ue t o t he f oll o wi n g circ u msta nces a n d 
will n ot be c o nsi dere d de viati o ns fr o m t he pr ot oc ol:

U na ntici pate d c ha n ges i n treat me nt re gi me ns a n d last mi n ute cli nic visits, 

T he serial ct D N A bl o o d dra ws ma y n ot occ ur as sc he d ule d, de pe n di n g o n t he 
partici pa nt’s cli nical sc he d ule a n d visits at t heir partici pati n g i nstit uti o n. We d o n ot 
pla n t o bri n g partici pa nts bac k t o cli nic s olel y f or t he p ur p ose of a researc h bl o o d 
dra w a n d will ma ke e ver y atte m pt t o c o or di nate it wit h a cli nicall y i n dicate d bl o o d 
dra w. Misse d ct D N A dra ws d ue t o t hese reas o ns will n ot be c o nsi dere d de viati o ns or 
vi olati o ns.
It is a ntici pate d t hat f ut ure st u dies will i ncl u de e val uati o n of ge netic, i m m u n ol o gic, 
h or m o nal, a n d/ or ot her iss ues relate d t o breast ca ncer.  We will i nf or m partici pa nts i n t he 
i nf or me d c o nse nt d oc u me nt t hat we will use t heir s peci me ns f or researc h relate d t o breast 
ca ncer a n d ot her ca ncers.  If i n vesti gat ors wis h t o o btai n i de ntifia ble i nf or mati o n as part 
of t heir bi o mar ker researc h, t he y will be re q uire d t o s u b mit s uc h pla ns f or I R B a p pr o val.
9. 1. 2
Ha n dli n g of Bl o o d S peci me ns(s)
Bl o o d will be pr ocesse d a n d ba n ke d i n t he D F/ H C C C ore Bl o o d a n d Tiss ue Ba n k f or 
f ut ure researc h p ur p oses or u ntil se nt t o t he Br oa d I nstit ute f or se q ue nci n g. 
Bl o o d c ollecte d i n Strec k t u bes at n o n- D F CI sites is t o be s hi p pe d t o D F CI wit hi n 2 4 
h o urs of c ollecti o n as per i nstr ucti o ns bel o w. U p o n recei pt at D F CI, Strec k T u bes will be 
ke pt at r o o m te m perat ure a n d pr ocesse d wit hi n 7 da ys. 
T u be preca uti o ns:

Fill t h e Str e c k t u b e c o m pl et el y a n d i m m e di at el y mi x b y g e ntl e i n v ersi o n 8 t o 1 0 
ti m es. I n a d e q u at e or d el a y e d mi xi n g m a y r es ult i n i n a c c ur at e r es ults. 

If sa m ples ca n n ot be s hi p pe d wit hi n 2 4 h o urs of c ollecti o n, c o ntact D F CI. D O N O T
F R E E Z E O R R E F RI G E R A T E T U B E S as t his c o ul d ca use iss ues wit h sa m ple 
i nte grit y.

D o n ot use t u bes after e x pirati o n date.

Fill t he t u be c o m pletel y.
9. 1. 3
S hi p pi n g of Bl o o d S peci me n(s)
C o m pl et e a S p e ci m e n R e q uisiti o n F or m ( A p p e n di x F) t o b e s e nt wit h t h e t u b es; m a k e 
a c o p y of t h e r e q uisiti o n f or t h e p arti ci p a nt’s r es e ar c h c h art pri or t o s e n di n g. 
S hi p M o n d a y t hr o u g h T h urs d a y wit hi n 2 4 h o urs of c oll e cti o n at a m bi e nt t e m p er at ur e 
o v er ni g ht t o:
Bri g ha m a n d W o me n’s H os pital
D F/ H C C C ore Bl o o d a n d Tiss ue Ba n k
2 0 S hatt uc k Street
T h or n B uil di n g – R o o m 4 2 8
B ost o n, M A 0 2 2 1 5

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D O N O T F R E E Z E O R R E F RI G E R A T E S T R E C K T U B E S.  Strec k t u bes m ust be st ore d 
at r o o m te m perat ure t o preser ve t he sa m ple. 
If bl o o d s peci me ns m ust be c ollecte d o n Fri da y, t he s peci me ns s h o ul d be st ore d o ver t he 
wee ke n d a n d s hi p pe d o n M o n da y. W he n st ori n g t u bes o ver a wee ke n d, Strec k t u bes 
s h o ul d be st ore d at r o o m te m perat ure u ntil s hi p me nt.
E mail t he assi g ne d st u d y c o or di nat or a n d 
wit h t he 
sa m ple i nf or mati o n a n d trac ki n g i nf or mati o n t he da y bef ore s hi p pi n g s peci me ns.  Please 
i ncl u de U P S or Fe d E x trac ki n g i nf or mati o n f or t he sa m ple. 
9. 2  
Arc hi v al Tiss ue
9. 2. 1
C ollecti o n of Arc hi val Tiss ue S peci me n(s)
Arc hi val tiss ue (eit her paraffi n bl oc ks or u nstai ne d sli des) will be c ollecte d f or m olec ular 
c haracterizati o n i ncl u di n g p ote ntial resista nce mec ha nis ms, pre dicti ve bi o mar kers, a n d 
i m m u n ol o gical f u ncti o n.  T u m or ( breast a n d/ or l y m p h n o de) tiss ue fr o m t he i nitial breast 
ca ncer s ur ger y is preferre d. F or partici pa nts dia g n ose d wit h de n o v o metastatic disease t he n 
tiss ue fr o m t he i nitial dia g n ostic bi o ps y s h o ul d be c ollecte d.  A d diti o nall y, a vaila ble 
arc hi val tiss ue fr o m s ur ger y or bi o ps y f or metastatic disease will be c ollecte d. 
T his material s h o ul d be pr o vi de d prefera bl y as paraffi n bl oc ks, if n ot, at least te n 5 micr o n 
secti o ns o n c har ge d or c oate d sli des a n d te n 5- 7 micr o n secti o ns o n re g ular n o n-c oate d 
sli des s h o ul d be s u b mitte d ( 2 0 sli des t otal wit h 1 0 fr o m pri mar y a n d 1 0 fr o m metastatic 
sites). F or t h ose patie nts t hat d o n ot u n der g o a baseli ne bi o ps y, 2 0 sli des fr o m t he metastatic 
site a n d 1 0 sli des fr o m t he pri mar y s h o ul d be s u b mitte d ( 3 0 sli des t otal). 
Tiss ue nee ds t o be l ocate d a n d a vaila bilit y m ust be c o nfir me d at t he ti me of re gistrati o n, 
as i n dicate d i n eli gi bilit y criteri o n 3. 1. 4. If arc hi val tiss ue is n ot a vaila ble, patie nts will be 
re q uire d t o u n der g o a t u m or bi o ps y pri or t o treat me nt start. T his bi o ps y ca n be d o ne 
d uri n g scree ni n g or o n C 1 D 1 bef ore treat me nt be gi ns. F or e xter n al site p artici p a nts,  
bi o ps y s h o ul d be perf or me d after re gistrati o n or o n C 1 D 1 pri or t o d osi n g.  Details f or t his 
bi o ps y i ncl u di n g c ollecti o n, pr ocessi n g, a n d s hi p pi n g are o utli ne d bel o w i n Secti o n 9. 3.
P atie nts will n ot be a ble t o st art st u d y dr u gs wit h o ut c o nfir m ati o n of tiss ue 
a v ail a bilit y or bi o ps y.  Tiss ue nee ds t o be s u b mitte d t o D F CI wit hi n 3 wee ks of st u d y 
i nitiati o n (treat me nt start).  
9. 2. 2
Ha n dli n g of Arc hi val Tiss ue S peci me ns(s)
La bel all bl oc ks or sli des wit h t he partici pa nts St u d y I D n u m ber, I nitials, Date of Birt h a n d 
s ur gical site (site of disease fr o m w hic h sa m ple was o btai ne d). I ncl u de a c o p y of t he 
ass ociate d de-i de ntifie d pat h ol o g y re p ort la bele d wit h t he partici pa nt’s St u d y I D n u m ber, 
I nitials, a n d Date of Birt h wit h bl oc ks/sli des.

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9. 2. 3
S hi p pi n g of Arc hi val Tiss ue S peci me n(s)
I ncl u de a c o p y of t he S peci me n Re q uisiti o n F or m ( A p pe n di x F) wit h y o ur s hi p me nt. 
Kee p a c o p y of t he re q uisiti o n i n t he partici pa nt’s researc h c hart.  Tiss ue nee ds t o be 
s u b mitte d t o D F CI wit hi n 3 wee ks of st u d y i nitiati o n (treat me nt start).  
S hi p at a m bie nt te m perat ure t o t he D F CI st u d y tea m: 
Da na Far ber Ca ncer I nstit ute
Breast O nc ol o g y
4 5 0 Br o o kli ne A ve n ue, Da na- 1 5 7
B ost o n, M A 0 2 2 1 5
E mail t he assi g ne d st u d y c o or di nat or wit h t he sa m ple a n d trac ki n g i nf or mati o n t he da y 
bef ore s hi p me nt. Bl oc ks will be ret ur ne d t o sites after t he c o m pleti o n of t he s peci me n 
a nal ysis.  Please i ncl u de U P S or Fe d E x trac ki n g i nf or mati o n f or t he sa m ple.  
9. 3 
Fres h Tiss ue Bi o ps y C ollecti o n
9. 3. 1
C ollecti o n of Pre-treat me nt Bi o ps y S peci me n(s)
Partici pa nts will u n der g o a re q uire d researc h bi o ps y of a reas o na bl y accessi ble metastatic 
lesi o n (c hest wall, s ki n, s u bc uta ne o us tiss ue, l y m p h n o des, s ki n, breast, b o nes, l u n g, a n d 
li ver metastases) bef ore treat me nt be gi ns. T he bi o ps y ma y occ ur d uri n g scree ni n g or o n 
C ycle 1 Da y 1 bef ore treat me nt be gi ns. F or e xter n al site p artici p a nts,  bi o ps y s h o ul d be 
perf or me d after re gistrati o n or o n C 1 D 1 pri or t o d osi n g. If t he bi o ps y is d o ne pri or t o 
re gistrati o n, please st ore t he sa m ple i n a - 8 0oC freezer u ntil t he ti me of s hi p me nt ( o nce 
t he partici pa nt is re gistere d). If a reas o na bl y accessi ble metastatic lesi o n is n ot a vaila ble, 
t he patie nt ma y g o o n st u d y pr o vi de d t hat arc hi ve d tiss ue is a vaila ble. H o we ver, if a 
reas o na bl y accessi ble site is a vaila ble f or bi o ps y, t he patie nt m ust a gree t o bi o ps y. A n y 
patie nts n ot u n der g oi n g bi o ps y m ust be a p pr o ve d f or st u d y e nr oll me nt b y t he O verall 
Pri nci pal I n vesti gat or at D F CI. 
Bi o psies ma y be d o ne wit h l ocal a nest hesia or i ntra ve n o us c o nsci o us se dati o n, acc or di n g 
t o i nstit uti o nal g ui deli nes. If a bi o ps y re q uires ge neral a nest hesia, t he n it is o nl y all o we d 
if ac q uisiti o n of tiss ue is cli nicall y i n dicate d, a n d e xcess tiss ue ma y be c ollecte d f or 
researc h p ur p oses. Patie nts wit h o ut sites a vaila ble f or bi o ps y m ust ha ve a vaila ble tiss ue 
[arc hi ve d f or mali n-fi xe d paraffi n e m be d de d bl oc ks ( F F P B), bl oc ks fr o m w hic h sli des ca n 
be create d, or fres h fr oze n tiss ue fr o m ori gi nal dia g n osis or metastatic setti n g] f or 
c orrelati ve st u dies. Tiss ue nee ds t o be l ocate d a n d a vaila ble at t he ti me of re gistrati o n. 
Tiss ue s peci me ns will be c ollecte d fr o m t u m or lesi o ns usi n g sta n dar d i nstit uti o nal 
pr oce d ures.
9. 3. 2
C ollecti o n of P ost- Pr o gressi o n Bi o ps y S peci me n(s)

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Patie nts will be as ke d at t he ti me of c o nse nt if t he y w o ul d li ke t o pr o vi de a n o pti o nal 
bi o ps y at t he ti me of pr o gressi o n.  If patie nts a gree t o partici pate i n t he o pti o nal 
pr o gressi o n bi o ps y at t he ti me of c o nse nt, t he y ma y ref use at t he ti me of pr o gressi o n if 
t he y wis h, wit h o ut res ulti n g i n a de viati o n or vi olati o n.  T his tiss ue will be use d f or 
m olec ular c haracterizati o n i ncl u di n g p ote ntial resista nce mec ha nis ms, pre dicti ve 
bi o mar kers, a n d i m m u n ol o gical f u ncti o n.  
Tiss ue s peci me ns will be c ollecte d fr o m t u m or lesi o ns usi n g sta n dar d i nstit uti o nal 
pr oce d ures.  
9. 3. 3
Tiss ue Bi o ps y G ui deli nes

T he c ost of t he bi o psies will be c o vere d b y t he st u d y  if t he y are bei n g d o ne f or 
rese arc h o nl y.   H o we ver, it is rec o g nize d t hat bi o psies mi g ht be c o nsi dere d t o ai d i n 
cli nical ma na ge me nt (f or e xa m ple, t o re-assess E R, P R, a n d H E R 2 stat us).  I n t he 
case of a cli nicall y i n dicate d bi o ps y ( wit h a n a d diti o nal “researc h pass”), t he c ost of 
t he bi o ps y will be c har ge d t o t he patie nt a n d/ or her i ns ura nce c o m pa n y.

Patie nts w h o u n der g o a n atte m pte d 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 n ot re q uire d t o u n der g o a 
re peat bi o ps y i n or der t o c o nti n ue o n pr ot oc ol.  
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 patie 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, a n d t he site is left t o t he 
discreti o n of t he patie nt a n d her treati n g p h ysicia n.  C ore bi o psies are preferre d; p u nc h 
bi o psies ma y be d o ne w he n necessar y, b ut fi ne nee dle as pirates are n ot all o we d.  
Breast:

A g oal of 3- 6 c ore bi o ps y will be o btai ne d usi n g sta n dar d i nstit uti o nal g ui deli nes f or a 
dia g n ostic c ore bi o ps y of a breast mass 
S ki n/ C hest wall: 

A g oal of t w o 5- m m p u nc h bi o psies will be o btai ne d
L y m p h n o de/ S oft tiss ue: 

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.
Li ver:

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 if 
t he y are cli nicall y i n dicate d.
B o ne:

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
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, if 
a patie nt has a n ot her accessi ble site of disease (e. g., s ki n, l y m p h n o de, li ver), t hat site 
s h o ul d be bi o psie d prefere ntiall y. If b o ne is t he o nl y bi o ps y-accessi ble site, t he n a 
g oal of 1- 3 c ore bi o ps y s peci me ns will be o btai ne d usi n g a n 1 1 t o 1 3- ga u ge nee dle.
Ple ase n ote t h at 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 bt ai ne d a n d 
are n ot me a nt t o re pl ace cli nic al j u d g me 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 pte 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 ple 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 ple ural fl ui d pri or t o st u d y e ntr y.
I n or der t o mi ni mize t he ris k of a bi o ps y, o nl y q ualifie d pers o n nel will perf or m t hese 
pr oce d ures.  Pri or t o t he pr oce d ure, t he p h ysicia n perf or mi n g t he pr oce d ure will disc uss 
t he ris ks wit h eac h st u d y partici pa nt, a ns wer a n y q uesti o ns, a n d o btai n a se parate pr oce d ure 
c o nse nt.  Patie nts will be e val uate d f or c o- m or bi dities or c o nc o mita nt me dicati o ns t hat ma y 
i ncrease t he ris k of p ote ntial c o m plicati o ns.  F or bi o psies of lesi o ns t hat are n ot s u perficial 
a n d clearl y pal pa ble, i ma gi n g st u dies s uc h as C T or ultras o u n d will be use d t o g ui de t he 
bi o ps y i n or der t o mi ni mize t he ris k of da ma ge t o a djace nt str uct ures.  After l y m p h n o de 
bi o psies, patie nts will be o bser ve d a mi ni m u m of 2 h o urs (ra n ge 2- 4 h o urs) after t he 
pr oce d ure, or acc or di n g t o sta n dar d i nstit uti o nal g ui deli nes.  After li ver bi o psies, patie nts 
will be o bser ve d a mi ni m u m of 4 h o urs (ra n ge 4- 6 h o urs) after t he pr oce d ure, or acc or di n g 
t o sta n dar d i nstit uti o nal g ui deli nes.  Less t ha n t he g oal q ua ntit y of tiss ue is acce pte 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.  
9. 3. 4
Ha n dli n g of Fres h Tiss ue Bi o ps y S peci me ns(s)
F oll o wi n g t he bi o ps y of a s peci me n, all tiss ue c ores will be s na p-fr oze n i n O C T c o m p o u n d 
i ntra- o perati vel y.  After t he bi o ps y is perf or me d, t he tiss ue mass is place d o n a dr y sterile 
ga uze a n d t he t u m or tiss ue is se parate d usi n g f orce ps.  T w o pieces (c ores) of t u m or tiss ue 
are place d o n a pre-fr oze n be d of O C T i n eac h cassette, t y picall y e n di n g u p wit h 3 cassettes 
per bi o ps y (t he last cassette will c o ntai n ma n y s mall pieces of t u m or tiss ue).  Cassettes are 
t he n fille d wit h O C T, c o m pletel y c o veri n g t he tiss ue a n d li miti n g t he a m o u nt of b u b bles 
(f orce ps ca n be use d t o p o p a n y b u b bles). Tiss ue m ust be fr oze n i m me diatel y b y placi n g 
cassettes o n dr y ice i n a bi o hazar d c o oler; freezi n g of sa m ples i n O C T wit h dr y ice ta kes 
a b o ut 1 0 mi n utes freezi n g ti me. O nce sa m ples are fr oze n, place i n plastic ba g; la bel ba g 
wit h date, pr ot oc ol n u m ber, patie nt n u m ber, patie nt i nitials, a n d n u m ber of bi o ps y sa m ples 
i ncl u de d.  St ore i n - 8 0oC freezer u ntil t he ti me of s hi p me nt. 
All sa m ples will be a n o n y mize d b y assi g ni n g a u ni q ue sa m ple I D n u m ber pri or t o use.  
Tiss ue bi o ps y c ollecti o n a n d pr ocessi n g materials are n ot pr o vi de d b y t he st u d y. C o de d 
la b orat or y s peci me ns will be st ore d i n t he T u m or Ba n k of t he D F/ H C C.  T hese s peci me ns 
will bec o me t he pr o pert y of D F/ H C C.  I n cases w here t he researc h sa m ple is f orfeite d f or 
cli nical p ur p oses, t his sa m ple will be fla g ge d i n s prea ds heet t o i n dicate it ca n be use d f or 
researc h p ur p oses if t here is a n y left o ver after cli nical use.

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T a ble 7: St u d y C ale n d ar
B aseli ne
C ycle 1
S u bse q ue nt C ycles
≤ 4 Wee ks 
pri or t o 
re gistr ati o n
D a y 1
D a y 2, 3, 4 
(I n pers o n 
or b y p h o ne)
D 1 5
D a y 1
E ver y 2 
c ycles
E ver y 3 
c ycles
E n d of 
t her a p y or 
Pr o gressi o n
F oll o w u p
(e ver y 6 
m o nt hs)
I nf or me d c o nse nt
X
Patie nt E d ucati o n f or Diarr hea
X
X
De m o gra p hics
X
Me dical/s ur gical hist or y
X
C o nc o mita nt me dicati o ns ( See Secti o n 5. 4)
X
X
X
X
Hei g ht
X
Vital Si g ns ( Wei g ht, Bl o o d Press ure)
X
X
X
X
P h ysical e xa mi nati o n, E C O G P S
X
X
X
X
1 2-lea d E K G
X
M U G A or ec h ocar di o gra m
 A
X
X
Uri ne Pre g na nc y test 
X
Uri nal ysis 
X
C B C, i ncl u di n g differe ntial a n d platelets B
X
X
X
X F
Ser u m c he mistries B
X
X
X
Researc h C ollecti o n: Bl o o d or Tiss ue C
X  C
X
X
X
X
T u m or E val uati o n 
( M RI or C T a n d cli nical assess me nt of 
visi ble of pal pa ble lesi o ns)  D
X
X
B o ne sca n  E
X
X
A d verse e ve nt e val uati o n
X
X
X
X
P h o ne call t o assess f or diarr hea ( See 
Secti o ns 5. 3. 3.) 
X
P h o ne call f or s ur vi val assess me nt a n d 
s u bse q ue nt t hera pies ( See Secti o n 5. 6)
X

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A.
Baseli ne M U G A or E C H O wit hi n 6 0 Da ys pri or t o re gistrati o n.  It is str o n gl y rec o m me n de d t o us t he sa me met h o d of car diac e val uati o n at eac h ti me p oi nt. 
E C H O/ M U G A assess me nt will be c o m plete d at t he e n d of e ver y 3 c ycles  a n d s h o ul d be c o m plete d wit hi n 7 da ys of t he s u bse q ue nt c ycle. If E C H O/ M U G A 
c o m plete d o n Da y 1 of t he a p plica ble c ycle, a preli mi nar y rea d of t he test will be nee de d bef ore t he patie nt ca n be d ose d o n Da y 2 of t he c ycle.  If a 
preli mi nar y rea d is n ot a vaila ble, t he patie nt s h o ul d be t ol d t o h ol d nerati ni b u ntil t he res ult bec o mes a vaila ble. 
B.
He mat ol o g y: P T T a n d P T/I N R dra w n at baseli ne f or all patie nts a n d at e n d of t hera p y/ pr o gressi o n f or patie nts w h o u n der g o t he o pti o nal bi o ps y. 
C he mistries: S o di u m, p otassi u m, c hl ori de, bicar b o nate, B U N, creati ni ne, t otal pr otei n, al b u mi n, t otal bilir u bi n, S G O T( A S T), S G P T( A L T), Al kali ne 
P h os p hatase
C.
See Secti o n 9.
D.
Patie nts s h o ul d ha ve i ma gi n g of t he C hest- A b d o me n- Pel vis at baseli ne. After c o m pleti o n of 1 2 c ycles, sca ns ca n decrease i n fre q ue nc y t o e ver y 3 c ycles.  If 
t here are n o pel vic lesi o ns or a b n or malities i de ntifie d, f ut ure i ma gi n g ma y i ncl u de c hest a n d a b d o me n o nl y, as a p pr o priate. F or alter nati ve i ma gi n g o pti o ns 
( n o n- C T), please see 1 1. 1. 3. Wi n d o w ar o u n d i ma gi n g is +/- 7 da ys. 
E.
B o ne sca n n ot re q uire d f or st u d y b ut ma y be d o ne at baseli ne a n d e ver y 2 c ycles ( +/- 7 da ys), if cli nicall y i n dicate d.
F.
P T T a n d P T/I N R o nl y, f or patie nts w h o u n der g o t he o pti o nal bi o ps y

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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
1 1. 1  
A ntit u m or Effect – S oli d T u m ors
F or t he p ur p oses of t his st u d y, partici pa nts s h o ul d be re-e val uate d f or res p o nse e ver y 2 c ycles ( or 
8 wee ks).    After c o m pleti o n of 1 2 c ycles, sca ns ca n decrease i n fre q ue nc y t o e ver y 3 c ycles. I n 
a d diti o n t o a baseli ne sca n, c o nfir mat or y sca ns s h o ul d als o be o btai ne d 4 wee ks  f oll o wi n g i nitial 
d oc u me ntati o n of o bjecti ve res p o nse. 
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y usi n g t he ne w i nter nati o nal criteria 
pr o p ose d b y t he Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) g ui deli ne ( versi o n 1. 1) 
[E ur J C a  4 5: 2 2 8- 2 4 7, 2 0 0 9].  C ha n ges i n t he lar gest dia meter ( 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.
1 1. 1. 1
Defi niti o ns
E val ua ble f or Tar 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 baseli 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 dere d e val ua ble f or tar get disease res p o nse.  T hese 
partici pa nts will ha ve t heir res p o nse 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 he e n d of c ycle 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 prese nt at 
baseli 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 disease, 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 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. 
1 1. 1. 2
Disease Para meters
Meas ura ble disease.  Meas ura ble lesi o ns are defi ne d as t h ose t hat ca n be acc uratel y 
meas ure d i n at least o ne di me nsi o n (l o n gest dia meter t o be rec or de d) as ≥ 2 0 m m b y 
c hest x-ra y or ≥1 0  m m wit h C T sca n, M RI, or cali pers b y cli nical e xa m.  All t u m or 
meas ure me nts m ust be rec or de d i n milli meters ( or deci mal fracti o ns of ce nti meters).
Mali g na nt l y m p h n o des.  T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas ura ble, a 
l y m p h n o de m ust be ≥1 5  m m i n s h ort a xis w he n assesse d b y C T sca n ( C T sca n slice 
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 disease.  All ot her lesi o ns ( or sites of disease), i ncl u di n g s mall lesi o ns 
(l o n gest dia meter < 1 0 m m or pat h ol o gical l y m p h n o des wit h ≥1 0  t o < 1 5 m m s h ort a xis), 
are c o nsi dere d n o n- meas ura ble disease.  B o ne lesi o ns, le pt o me ni n geal disease, 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, 

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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 dere d 
n o n- meas ura ble.
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- meas 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 ble 
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 selecti 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 ma xi m u m of 2 lesi o ns per or ga n a n d 5 
lesi 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 de 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 peate d 
meas ure me 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 selecte 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 lesi o ns will be calc 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 haracterize 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 ve 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 de d at baseli ne. Meas ure me nts of t hese lesi o ns are n ot re q uire d, b ut 
t he prese nce, a bse nce, or i n rare cases u ne 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 me nts s h o ul d be ta ke n a n d rec or de d i n metric n otati 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 ver 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 assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haracterize 
eac h i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w- u p. I ma gi n g- base 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 ge 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., s ki n n o d ules a n d pal pa ble l y m p h n o des) a n d ≥1 0  m m i n dia meter as 

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assesse d usi n g cali pers ( e. g., s ki n n o d ules).  I n t he case of s ki n lesi o ns, d oc 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 lesi o n, is rec o m me n de d. 
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 sca 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 sca 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 ge 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 val uati o n of t he 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 was 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 se q ue nce para meters f or all sca n ners, 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 sca 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.
1 1. 1. 4
Res p o nse Criteria
1 1. 1. 4. 1 
E val uati o n of Tar get Lesi o ns
C o m plete Res p o nse ( C R):  Disa p peara nce 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 get or n o n-tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 
m m.
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 nce t he baseli 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 nce 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 ncrease of 
2 0 %, t he s u m m ust als o de m o nstrate a n a bs ol ute i ncrease of at least 5 m m.  ( N ote:  
t he a p peara nce of o ne or m ore ne w lesi 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 ncrease t o q ualif y f or P D, ta ki n g as refere nce t he s mallest s u m dia meters w hile o n 
st u d y.
1 1. 1. 4. 2 
E val uati o n of N o n- Tar 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 

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s h ort a xis).
N ote:  If t u m or mar kers 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 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 le 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 get lesi o ns.  U ne 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 ncrease.    
Alt h o u g h a clear pr o gressi o n of “ n o n-tar get” 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. 4. 3 
E val uati o n of Ne w Lesi 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 nce 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 ‘ ne w’ b o ne lesi o ns ma y be si m pl y heali n g or 
flare 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 was n ot sca n ne d at baseli ne is c o nsi dere d ne 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 lesi o n 
was disc o vere d.
1 1. 1. 4. 4 
E val uati o n of Best O verall Res p o nse
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he treat me nt 
u ntil disease pr o gressi o n/rec urre nce (ta ki n g as refere nce f or pr o gressi ve disease t he 
s mallest meas ure me nts rec or de d si nce t he treat me nt starte d).  T he patie nt's best 
res p o nse assi g n me nt will de pe n d o n t he ac hie ve me nt of b ot h meas ure me nt a n d 
c o nfir mati o n criteria.
F or P artici p a nts wit h Me as ur a ble Dise ase ( i.e., T ar get Dise ase)
T ar get 
Lesi o ns
N o n- T ar get 
Lesi o ns
Ne w 
Lesi o ns
O ver all 
Res p o nse
Best O ver all Res p o nse w he n 
C o nfir m ati o n is Re q uire d *
C R
C R
N o
C R
> 4 w ks C o nfir mati o n * *
C R
N o n- C R/ N o n-
P D
N o
P R
C R
N ot e val uate d
N o
P R
> 4 w ks C o nfir mati o n * *

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P R
N o n- C R/ N o n-
P D/ n ot 
e val uate d
N o
P R
S D
N o n- C R/ N o n-
P D/ n ot 
e val uate d
N o
S D
D oc u me nte d at least o nce > 4 
w ks fr o m baseli ne * *
P D
A n y
Yes or N o
P D
A n y
P D * * *
Yes or N o
P D
A n y
A n y
Yes
P D
n o pri or S D, P R or C R

See R E CI S T 1. 1 ma n uscri pt f or f urt her details o n w hat is e vi de nce of a ne w lesi o n.
* *        O nl y f or n o n-ra n d o mize d trials wit h res p o nse as pri mar y e n d p oi nt.
* * *      I n e xce pti o nal circ u msta nces, u ne q ui v ocal pr o gressi o n i n n o n-tar get lesi o ns ma y be
            acce pte d as disease pr o gressi o n.
N ote:  Partici pa nts wit h a gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n of 
treat me nt wit h o ut o bjecti ve e vi de nce of disease pr o gressi o n at t hat ti me s h o ul d be 
re p orte d as “sy m pt o m atic deteri or ati o n. ”  E ver y eff ort s h o ul d be ma de t o d oc u me nt t he 
o bjecti ve pr o gressi o n e ve n after disc o nti n uati o n of treat me nt.
F or P artici p a nts wit h N o n- Me as ur a ble Dise ase ( i.e., N o n- T ar get Dise ase)
N o n- T ar get Lesi o ns
Ne w Lesi o ns
O ver all Res p o nse
C R
N o
C R
N o n- C R/ n o n- P D
N o
N o n- C R/ n o n- P D *
N ot all e val uate d
N o
n ot e val uate d
U ne q ui v ocal P D
Yes or N o
P D
A n y
Yes
P D

‘ N o n- C R/ n o n- P D’ is preferre d o ver ‘sta ble disease’ f or n o n-tar get disease si nce S D is 
i ncreasi n gl y use d as a n e n d p oi nt f or assess me nt of efficac y i n s o me trials s o t o assi g n 
t his cate g or y w he n n o lesi o ns ca n be meas ure d is n ot a d vise d
1 1. 1. 5
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 he 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 disease 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 he 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 val uati o n.

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D urati o n of sta ble disease:  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. 6 Pr o gressi o n- Free 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 ue 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 ue 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 date of last disease 
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 last disease 
e val uati o n f or t h ose wit h o ut pr o gressi o n re p orte d.
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 verse 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 O D Q will c ollect, ma na ge, a n d perf or m q ualit 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 vesti 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 O D Q acc or di n g t o t he sc he d ule set b y t he O D Q.
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 he b oar d is c haire d b y a me 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 nal re prese ntati o n. I nf or mati o n 
t hat raises a n y q uesti o ns a b o ut partici pa nt safet y or pr ot oc ol perf or ma nce will be a d dresse d b y 
t he O verall PI, statisticia n a n d st u d y tea m. S h o ul d a n y maj or c o ncer 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 pe n d t he st u d y.
T he D S M B will meet t wice a year t o re vie w accr ual, 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 ual; 
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 verse e ve nts re p orte d b y cate g or y; 

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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 t he p olicies a n d re q uire me nts of t he D F/ H C C M ulti- Ce nter Data a n d 
Safet y M o nit ori n g Pla n.  T he s pecific res p o nsi bilities of t he O verall PI, 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 oce d ures f or a u diti n g are prese nte d i n A p pe n di x E.

T he O verall PI/ C o or di nati n g Ce nter is res p o nsi ble f or distri b uti n g all I N D Acti o n Letters 
or Safet y Re p orts t o all partici pati n g i nstit uti o ns f or s u b missi o n t o t heir i n di vi d ual I R Bs 
f or acti o n as re q uire d.

Mec ha nis ms will be i n place t o e ns ure q ualit y ass ura nce, pr ot oc ol c o m plia nce, a n d 
a d verse e ve nt re p orti n g at eac h site.

E xce pt i n ver y u n us ual circ u msta nces, eac h partici pati n g i nstit uti o n will or der t he st u d y 
a ge nt(s) directl y fr o m s u p plier.  A partici pati n g site ma y or der t he a ge nt(s) o nl y after t he 
i nitial I R B a p pr o val f or t he site has bee n f or war de d t o t he C o or di nati n g Ce nter.
1 2. 4  
C oll a b or ati ve Rese arc 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 researc 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 mercial 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 der 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 nerate 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 nci n g 
wit h ot her scie ntists. De-i de ntifie d s peci me n or ge netic data ma y be place d i nt o o ne of m ore 
p u blicl y-accessi ble scie ntific data bases, s uc h as t he Nati o nal I nstit utes of Healt h’s Data base 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 hese p u blic data bases. T hr o u g h s uc h data bases, researc hers fr o m ar o u n d t he w orl d 
will ha ve access t o de-i de ntifie d sa m ples or data 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 data base, ma y o nl y be accesse d b y scie ntists at ot her researc h ce nters w h o ha ve 
recei ve d s pecial per missi o n t o re vie w de-i de ntifie d data.

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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 t w o-ar m p hase II st u d y of nerati ni b +/- f ul vestra nt i n patie nts wit h 
metastatic E R +/ H E R 2 + breast ca ncer. T he pri mar y o bjecti ve is t o c o m pare t he pr o gressi o n-free 
s ur vi val bet wee n nerati ni b m o n ot hera p y vers us nerati ni b pl us f ul vestra nt. T he e n d p oi nt is 
pr o gressi o n-free s ur vi val ( P F S) defi ne d as t he i nter val fr o m t he date of ra n d o mizati o n t o 
pr o gressi o n or deat h. Patie nts w h o are ali ve a n d pr o gressi o n-free will be ce ns ore d at t he date of 
last disease assess me nt. Ra n d o mizati o n will be 1: 1  wit hi n strat u m defi ne d b y t he n u m ber of 
pri or li nes of t hera p y ( ≤ 3 vers us ≥ 4) a n d pri or use of f ul vestra nt ( yes or n o). Pri or t o Versi o n 2 
of t he pr ot oc ol, partici pa nts were stratifie d b y t he n u m ber of pri or li nes of t hera p y ( ≤ 3 vers us ≥ 
4) a n d P R e x pressi o n ( 0- 1 0 % vs. 1 1 % or m ore).
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
T he t otal pla n ne d sa m ple size is 1 5 2 patie nts ( 7 6 patie nts o n eac h ar m), w hic h is calc ulate d 
base d o n t he n u m ber of ra n d o mize d patie nts a n d defi nes t he i nte nti o n-t o-treat p o p ulati o n f or 
efficac y a nal ysis. T he st u d y is size d t o ha ve 8 2. 3 % p o wer t o detect i m pr o ve me nt of me dia n P F S 
fr o m 4 m o nt hs wit h nerati ni b m o n ot hera p y t o 6 m o nt hs wit h nerati ni b + f ul vestra nt ( H R = 0. 6 7) 
usi n g a stratifie d l o gra n k test wit h a o ne-si de d al p ha le vel of 0. 1,  a n d fi nal a nal ysis t o occ ur 
w he n 1 2 5 P F S e ve nts are o bser ve d.   T his ass u mes t hat t he t otal pla n ne d sa m ple size is e nr olle d 
at a c o nsta nt accr ual o ver 1 8 m o nt hs wit h 6 m o nt hs of a d diti o nal f oll o w- u p, a n d a c o nsta nt 
hazar d of P F S a n d dr o p o ut s uc h t hat 5 % of patie nts are l ost-t o-f oll o w- u p at 1 year. O ne f utilit y 
a nal ysis is pla n ne d at 5 0 % i nf or mati o n ( 6 3 P F S e ve nts) a n d will st o p earl y if t he Z-statistic fr o m 
t he l o gra n k test is less t ha n 0 (i.e. o bser ve d H R fr o m a C o x m o del > 1. 0). N o earl y st o p pi n g f or 
efficac y will be c o nsi dere d. P o wer a n d sa m ple size were calc ulate d usi n g East v 6. 4 ( C ytel I nc., 
Ca m bri d ge M A). 
We a ntici pate e nr oll me nt of a p pr o xi matel y 8. 5 patie nts per m o nt h. Patie nts will be f oll o we d f or 
u p t o fi ve years after re m o val fr o m st u d y or u ntil deat h, w hic he ver occ urs first.
1 3. 3 
Str atific ati o n F act ors 
We will stratif y patie nts base d o n t w o fact ors: n u m ber of pri or li nes of t hera p y ( ≤ 3 vers us ≥ 4) 
a n d pri or use of f ul vestra nt ( yes or n o). 
1 3. 4  
A n al ysis of Pri m ar y E n d p oi nts
T he pri mar y a nal ysis of t he st u d y will be t he c o m paris o n of P F S per R E CI S T 1. 1 bet wee n 
nerati ni b m o n ot hera p y vers us nerati ni b pl us f ul vestra nt usi n g a stratifie d l o gra n k test wit h a 
o verall o ne-si de d T y pe I err or rate at 0. 1. 
All i nfere nces will be c o n d ucte d i n t he i nte nt-t o-treat ma n ner wit h all ra n d o mize d patie nts 

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e val uate d acc or di n g t o treat me nt assi g n me nt t hat was gi ve n, a n d t he s ur vi val f u ncti o n will be 
s u m marize d usi n g t he Ka pla n- Meier met h o ds acc or di n g t o ra n d o mize d treat me nt assi g n me nt. 
Fi nal a nal ysis will be perf or me d after 1 2 6 P F S e ve nts are o bser ve d or at least 1 2 m o nt hs after t he 
last patie nt is e nr olle d o n st u d y, w hic he ver occ urs first. 
1 3. 5  
A n al ysis of Sec o n d ar y E n d p oi nts
1 3. 5. 1
We will esti mate t he cli nical acti vit y, as meas ure d b y o verall s ur vi val ( O S) of nerati ni b 
c o m bi ne d wit h f ul vestra nt c o m pare d wit h nerati ni b al o ne i n patie nts wit h i n o pera ble 
l ocall y a d va nce d or metastatic H E R 2- p ositi ve, E R- p ositi ve breast ca ncer. O S is defi ne d 
as t he le n gt h of ti me fr o m ra n d o mizati o n u ntil deat h fr o m a n y ca use.
1 3. 5. 2
We will esti mate t he cli nical acti vit y, as meas ure d b y o bjecti ve res p o nse rate ( O R R) of 
nerati ni b c o m bi ne d wit h f ul vestra nt c o m pare d wit h nerati ni b al o ne i n patie nts wit h 
i n o pera ble l ocall y a d va nce d or metastatic H E R 2- p ositi ve, E R- p ositi ve breast ca ncer. 
O R R is defi ne d as t he pr o p orti o n of patie nts wit h C R or P R acc or di n g t o R E CI S T v 1. 1.
1 3. 5. 3
We will esti mate t he cli nical acti vit y, as meas ure d b y d urati o n of res p o nse ( D o R), of 
nerati ni b c o m bi ne d wit h f ul vestra nt c o m pare d wit h nerati ni b al o ne i n patie nts wit h 
i n o pera ble l ocall y a d va nce d or metastatic H E R 2- p ositi ve, E R- p ositi ve breast ca ncer. 
D o R is defi ne d as t he ti me fr o m t he date of first e vi de nce of C R or P R t o t he date of 
o bjecti ve pr o gressi o n (acc or di n g t o R E CI S T v 1. 1) or deat h fr o m a n y ca use, w hic he ver is 
earlier. 
T he hazar d rati o f or eac h sec o n dar y ti me-t o-e ve nt e n d p oi nt will be esti mate d wit h 9 5 % 
c o nfi de nce i nter vals deri ve d fr o m t he C o x pr o p orti o nal hazar d m o del, b ut n o h y p ot hesis testi n g 
will be c o n d ucte d.  O bjecti ve res p o nse per R E CI S T 1. 1 will be re p orte d wit h 9 5 % e xact 
c o nfi de nce i nter vals usi n g a Pears o n c hi-s q uare d test f or differe nce i n pr o p orti o ns wit h a o ne-
si de d al p ha of 0. 1.  
1 3. 6  
A n al ysis of C orrel ati ve E n d p oi nts
1 3. 6. 1
T he pr o p orti o n of patie nts wit h E S R 1 ge ne m utati o ns, PI K 3 C A ge ne m utati o ns, a n d l oss 
of P T E N e x pressi o n i n baseli ne t u m or tiss ue, a n d t he pr o p orti o n of patie nts wit h PI K 3 C A 
a n d E S R 1 ge ne m utati o ns i n circ ulati n g t u m or D N A (ct D N A) fr o m bl o o d o btai ne d at 
st u d y baseli ne will be s u m marize d usi n g 9 5 % bi n o mial e xact tests a n d e x pl orat or y 
a nal yses will c haracterize t he ass ociati o n of m olec ular p he n ot y pes wit h ot her patie nt a n d 
disease c haracteristics usi n g Fis her e xact tests. 

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1 3. 6. 2
T he c o nc or da nce of PI K 3 C A m utati o n stat us a n d E S R 1 m utati o n stat us assesse d i n 
circ ulati n g free t u m or D N A a n d dista nt metastasis s peci me ns (i.e. li q ui d a n d s oli d 
bi o psies) will be assesse d usi n g ka p pa statistics wit h 9 5 % c o nfi de nce i nter vals o btai ne d 
fr o m b o otstra p resa m pli n g.   O perati n g c haracteristics i ncl u di n g se nsiti vit y, s pecificit y, 
P P V a n d N P V will be use d t o s u m marize t he perf or ma nce of t he li q ui d bi o ps y a gai nst 
s oli d bi o ps y as t he ‘ g ol d sta n dar d’.  F or a n y q ua ntitati ve assess me nts of m utati o n stat us 
i n t he li q ui d bi o ps y, we will use R O C a nal ysis t o e x pl ore t hres h ol ds t o o pti mize t he li near 
c o m bi nati o n of se nsiti vit y a n d s pecificit y (i.e. Y o u de n i n de x) f or eit her a bs ol ute c o u nts 
or esti mates of t he allele fre q ue nc y. T he f oll o wi n g ta ble pr o vi des t he le vels of precisi o n 
i n esti mati n g se nsiti vit y f or var yi n g fail ure rates of t he paire d assa ys a n d a ntici pate d 
pre vale nce of 4 0 % ( PI K 3 C A) a n d 2 0 % ( E S R 1) ge ne m utati o ns.
Ma xi m u m Wi dt h of CI f or 
Se nsiti vit y
Fail ure rate
N u m ber of 
e val ua ble pairs
4 0 % pre vale nce
2 0 % pre vale nce
1 0 %
1 3 7
0. 3 9
0. 2 8
2 0 %
1 2 2
0. 4 1
0. 2 9
3 0 %
1 0 6
0. 4 4
0. 3 1
1 3. 6. 3
All ot her m olec ular c haracterizati o n of p ote ntial resista nce mec ha nis ms, pre dicti ve 
bi o mar kers, a n d i m m u n ol o gical f u ncti o n b y c ollecti n g bl o o d a n d t u m or s peci me ns will 
be e x pl orat or y a n d descri pti ve- o nl y.  
1 3. 7  
Re p orti n g a n d E xcl usi o ns
All eli gi ble partici pa nts i ncl u de d i n t he st u d y will be e val ua ble f or a nal ysis. 
1 3. 7. 1
E val uati o n of T o xicit y
All patie nts will be e val ua ble f or t o xicit y fr o m t he ti me of t heir first treat me nt. 
1 3. 7. 2
E val uati o n of t he Pri mar y Efficac y E n d p oi nt
All eli gi ble partici pa nts i ncl u de d i n t he st u d y will be assesse d f or res p o nse/ o utc o me t o 
t hera p y f or t he pri mar y e n d p oi nt, e ve n if t here are maj or pr ot oc ol t hera p y de viati o ns.  
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 2 4 m o nt hs of reac hi n g t he e n d of t he 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 nal ysis, as defi ne d i n t he secti o n o n Sa m ple Size, Accr ual Rate 
a n d St u d y D urati o n. If a re p ort is pla n ne d t o be p u blis he d i n a peer-re vie we d j o ur nal, t he n t hat 
i nitial release 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 be ma de p u blic n o later t ha n t hree 
( 3) years after t he e n d of t he st u d y. 

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1 5. R E F E R E N C E S
1. 
Esti mate d Ca ncer Deat hs b y Se x a n d A ge Gr o u p, 2 0 1 5. 2 0 1 5; 
htt p:// w w w.ca ncer. or g/acs/ gr o u ps/c o nte nt/ @e dit orial/ d oc u me nts/ d oc u me nt/acs pc-
0 4 4 5 0 9. p df . Accesse d J u ne 1 0, 2 0 1 5.
2. 
Ra bi n dra n S K, Discafa ni C M, R osfj or d E C, et al. A ntit u m or acti vit y of H KI- 2 7 2, a n 
orall y acti ve, irre versi ble i n hi bit or of t he H E R- 2 t yr osi ne ki nase. C a ncer rese arc h. 
2 0 0 4; 6 4( 1 1): 3 9 5 8- 3 9 6 5.
3. 
B urstei n HJ, S u n Y, Diri x L Y, et al. Nerati ni b, a n Irre versi ble Er b B Rece pt or T yr osi ne 
Ki nase I n hi bit or, i n Patie nts Wit h A d va nce d Er b B 2- P ositi ve Breast Ca ncer. J Cli n O nc ol.
4.  
A p hase t w o ra n d o mise d trial of nerati ni b m o n ot hera p y vers us la pati ni b pl us ca pecita bi ne 
c o m bi nati o n t hera p y i n patie nts wit h H E R 2 + a d va nce d breast ca ncer ☆. 
2 0 1 3; 4 9( 1 8): 3 7 6 3 – 3 7 7 2.
5.  
A wa da A, Diri x L, Bec k H L, et al. Safet y a n d Efficac y of Nerati ni b ( H KI- 2 7 2) i n 
C o m bi nati o n wit h Vi n orel bi ne i n Er b B 2 + Metastatic Breast Ca ncer. Prese nte d at t he Sa n 
A nt o ni o Breast Ca ncer S y m p osi u m, Dece m ber 2 0 0 9. .
6. 
C h o w L W- C, X u B, G u pta S, et al. C o m bi nati o n nerati ni b ( H KI- 2 7 2) a n d paclita xel 
t hera p y i n patie nts wit h H E R 2- p ositi ve metastatic breast ca ncer. Britis h J o ur n al of 
C a ncer. 2 0 1 3; 1 0 8( 1 0): 1 9 8 5- 1 9 9 3.
7.  
H o well A, R o berts o n J F, Q uares ma Al ba n o J, et al. F ul vestra nt, f or merl y I CI 1 8 2, 7 8 0, is 
as effecti ve as a nastr oz ole i n p ost me n o pa usal w o me n wit h a d va nce d breast ca ncer 
pr o gressi n g after pri or e n d ocri ne treat me nt. J o ur n al of cli nic al o nc ol o gy : offici al j o ur n al 
of t he A meric a n S ociety of Cli nic al O nc ol o gy. 2 0 0 2; 2 0( 1 6): 3 3 9 6- 3 4 0 3.
8.  
Os b or ne C K, Pi p pe n J, J o nes S E, et al. D o u ble- bli n d, ra n d o mize d trial c o m pari n g t he 
efficac y a n d t olera bilit y of f ul vestra nt vers us a nastr oz ole i n p ost me n o pa usal w o me n wit h 
a d va nce d breast ca ncer pr o gressi n g o n pri or e n d ocri ne t hera p y: res ults of a N ort h 
A merica n trial. J o ur n al of cli nic al o nc ol o gy : offici al j o ur n al of t he A meric a n S ociety of 
Cli nic al O nc ol o gy. 2 0 0 2; 2 0( 1 6): 3 3 8 6- 3 3 9 5.
9. 
Le o A D, Jer usale m G, Petr uzel ka L, et al. Fi nal O verall S ur vi val: F ul vestra nt 5 0 0 m g vs 
2 5 0 m g i n t he Ra n d o mize d C O N FI R M Trial. 2 0 1 3.
1 0. 
R o berts o n J F R, Ste ger G G, Ne ve n P, et al. Acti vit y of f ul vestra nt i n H E R 2-
o vere x pressi n g a d va nce d breast ca ncer. 2 0 1 0.
1 1.  
Ar pi n o G, Wiec h ma n n L, Os b or ne C K, Sc hiff R. Cr osstal k bet wee n t he estr o ge n rece pt or 
a n d t he H E R t yr osi ne ki nase rece pt or fa mil y: m olec ular mec ha nis m a n d cli nical 
i m plicati o ns f or e n d ocri ne t hera p y resista nce. E n d ocri ne revie ws. 2 0 0 8; 2 9( 2): 2 1 7- 2 3 3.
1 2.  
Massar we h S, Os b or ne C K, Crei g ht o n CJ, et al. Ta m o xife n Resista nce i n Breast T u m ors 
Is Dri ve n b y Gr o wt h Fact or Rece pt or Si g nali n g wit h Re pressi o n of Classic Estr o ge n 
Rece pt or Ge n o mic F u ncti o n. 2 0 0 8.
1 3.  
Gi ulia n o M, H u H, Wa n g Y- C, et al. U pre g ulati o n of E R Si g nali n g as a n A da pti ve 
Mec ha nis m of Cell S ur vi val i n H E R 2- P ositi ve Breast T u m ors Treate d wit h A nti- H E R 2 
T hera p y. 2 0 1 5.
1 4. 
Ri ma wi M F, Ma yer I A, F orer o A, et al. M ultice nter P hase II St u d y of Ne oa dj u va nt 
La pati ni b a n d Trast uz u ma b Wit h H or m o nal T hera p y a n d Wit h o ut C he m ot hera p y i n 
Patie nts Wit h H u ma n E pi der mal Gr o wt h Fact or Rece pt or 2 – O vere x pressi n g Breast 
Ca ncer: T B C R C 0 0 6. 2 0 1 3.

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1 5. 
C ha n A, Delal o ge S, H ol mes F A, et al. Nerati ni b after a dj u va nt c he m ot hera p y a n d 
trast uz u ma b i n H E R 2- p ositi ve earl y breast ca ncer: Pri mar y a nal ysis at 2 years of a p hase 
3, ra n d o mize d, place b o-c o ntr olle d trial ( E xte N E T). J o ur n al of Cli nic al O nc ol o gy. 
2 0 1 5; 3 3(s u p pl; a bstr 5 0 8).
1 6.  
S u d ha n D R, Sc h wartz LJ, et al. E xte n de d A dj u va nt T hera p y wit h Nerati ni b Pl us 
F ul vestra nt Bl oc ks E R/ H E R 2 Cr osstal k a n d Mai nati ns C o m plete Res p o nses of 
E R +/ H E R 2 + Breast Ca ncers: I m plicati o ns t o t he E xte N E T Trial. Cli nic al C a ncer 
Rese arc h : 2 0 1 8

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6 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
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
1 0 0
N or mal, n o c o m plai nts, n o e vi de nce of 
disease.
0
N or mal acti vit y.  F ull y acti ve, a ble t o 
carr y o n all pre- disease perf or ma nce 
wit h o ut restricti o n.
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.
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.
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 
nat ure ( e. g., li g ht h o use w or k, office 
w or k).
7 0
Cares f or self, 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.
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.
2
I n be d < 5 0 % of t he ti me.  A m b ulat or y 
a n d ca pa ble of all self-care, b ut 
u na ble 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.
5 0
Re q uires c o nsi dera ble assista nce a n d 
fre q ue nt me dical care.
4 0
Disa ble d, re q uires s pecial care a n d 
assista nce.
3
I n be 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.
3 0
Se verel y disa ble d, h os pitalizati o n 
i n dicate d.  Deat h n ot i m mi ne nt.
2 0
Ver y sic k, h os pitalizati 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 ne d t o be d or c hair.
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 C 
P atie nt I nstr ucti o ns f or M a n a ge me nt of Di arr he a 
 
Ple ase re vie w t hese i nstr ucti o ns wit h y o ur st u d y d oct or/te a m.  O nce all of y o ur q uesti o ns 
are a ns were d, si g n at t he b ott o m a n d m a ke s ure y o u are gi ve n a c o p y of t hese i nstr ucti o ns 
t o t a ke h o me. 
Diarr hea is t he m ost c o m m o n si de effect y o u ma y ha ve w hile partici pati n g i n t his st u d y.  
Diarr hea us uall y starts wit hi n a fe w h o urs t o a fe w da ys of t he first d ose of st u d y dr u g.  I n or der 
t o re d uce or e ve n pre ve nt diarr hea as far as p ossi ble, y o u will be s u p plie d wit h a nti- diarr heal 
me dici nes calle d l o pera mi de a n d c olesti p ol t o ta ke at t he start of t he st u d y. Use of a nti- di arr he al 
me dic ati o n is re q uire d f or all e nr olle d s u bjects t o hel p re d uce or pre ve nt di arr he a.  
L o pera mi de a n d c olesti p ol will be dis pe nse d directl y b y y o ur st u d y d oct or/tea m o n da y 1 wit h 
t he i nstr ucti o n t o i nitiate treat me nt wit h l o pera mi de a n d c olesti p ol o n t he sa me da y as y o u ta ke 
y o ur first d ose of nerati ni b. 
T he first d ose of c olesti p ol s h o ul d be t a ke n at le ast 4 h o urs bef ore ner ati ni b a n d 
l o per a mi de. T he sec o n d d ose of c olesti p ol s h o ul d be t a ke n at le ast 2 h o urs after ner ati ni b 
a n d l o per a mi de.   
Y o ur st u d y d oct or/tea m will call y o u o n C ycle 1 Da y 2, C ycle 1 Da y 3, a n d C ycle 1 Da y 4 after 
y o ur first d ose of st u d y dr u g t o fi n d o ut if y o u are e x perie nci n g diarr hea a n d t o pr o vi de f urt her 
treat me nt i nstr ucti o ns a n d a d vice if necessar y. 
If y o u are ha vi n g ne w- o nset diarr hea, persiste nt diarr hea or diarr hea wit h i ncrease of 7 or m ore 
st o ols per da y o ver us ual, call y o ur st u d y d oct or/tea m at p h o ne n u m ber 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ t o let t he m k n o w s o t he y ca n w or k wit h y o u t o c o ntr ol t he diarr hea.  
If y o u are dizz y or wea k beca use of diarr hea, g o t o t he st u d y d oct or’s office or g o t o t he h os pital 
i m me diatel y.
Please rec or d t he n u m ber of st o ols a n d a n y a nti- diarr heal me dicati o n ta ke n d uri n g all c ycles of 
t he st u d y al o n g wit h t he dail y d ose of st u d y me dicati o n. 
I nf or m ati o n t o pr o vi de w he n t al ki n g t o y o ur d oct or
W he n tal ki n g t o t he st u d y d oct or/tea m I will pr o vi de as m uc h of t he i nf or mati o n bel o w as 
p ossi ble, i n or der t o hel p m y st u d y d oct or/tea m t o assess m y diarr hea a n d deci de o n t he best 
treat me nt:

N u m ber of st o ols per da y as c o m pare d t o m y n or mal b o wel ha bits

Prese nce of diarr hea d uri n g t he ni g ht

Prese nce of fe ver, dizzi ness, a b d o mi nal pai n/cra m pi n g, or wea k ness

W hat t he st o ol l o o ks li ke, t hat is, water y st o ols, bl o o d, or m uc us  

W he n I t o o k m y last st u d y dr u g

A n y ot her i nf or mati o n t hat c o ul d e x plai n m y diarr hea (f o o d, rece nt tra vel, c o ntact wit h 
ot her pe o ple wit h diarr hea).

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1.
Me dic ati o ns t o tre at di arr he a
M y st u d y d oct or/tea m will pr o vi de me wit h l o pera mi de a n d c olesti p ol o n da y 1 wit h t he 
i nstr ucti o n t o start treat me nt wit h l o pera mi de a n d c olesti p ol al o n g wit h t he first d ose of nerati ni b.  
I nee d t o ta ke t he me dicati o ns as directe d b y m y st u d y d oct or/tea m. 

L o per a mi de:

I will start l o pera mi de wit h t he first d ose of nerati ni b 

I will ta ke 2 ta blet/ca ps ule ( 4 m g) t hree ti mes a da y f or t he first t w o wee ks; if I get 
c o nsti pate d, I s h o ul d c o ntact m y st u d y d oct or/tea m w h o will i nstr uct me o n h o w ofte n 
a n d h o w m uc h l o pera mi de t o ta ke b ut I s h o ul d n ot st o p ta ki n g l o pera mi de. 

After t he first t w o wee ks, I will ta ke 2 ta blets ( 4 m g) t wice a da y o n war ds t hr o u g h t he 
first c ycle of t hera p y ( 2 8 da ys) fr o m t he start of nerati ni b re gar dless of w het her I ha ve 
diarr hea or n ot.

If I c o nti n ue t o ha ve diarr hea w hile ta ki n g l o pera mi de, I s h o ul d c o ntact m y st u d y 
d oct or/tea m f or a d diti o nal a nti- diarr heal me dicati o n a n d c o ns ult. 

If I ha ve diarr hea wit h i ncrease of u p t o 6 st o ols per da y o ver us ual a n y ti me after 
c o m pleti n g t he first c ycle of t hera p y a n d I a m n ot ta ki n g a n y a nti- diarr heal me dicati o n, I 
will ta ke 2 ta blets/ca ps ules ( 4 m g) i m me diatel y after t he first l o ose st o ol a n d t he n 1 
ta blet ( 2 m g) e ver y 4 h o urs or after eac h l o ose st o ol t o a ma xi m u m d ose of 8 
ta blets/ca ps ules ( 1 6 m g) i n a n y 2 4 h o ur peri o d u ntil I ha ve n’t ha d a n y l o ose st o ol f or at 
least 1 2 h o urs.

C olesti p ol:

I will ta ke 2 g of c olesti p ol t wice a da y f or t he first 2 8 da ys of treat me nt al o n g wit h t he 
nerati ni b a n d l o pera mi de.

I will t a ke t he first d ose of c olesti p ol at le ast 4 h o urs bef ore ner ati ni b a n d 
l o per a mi de pr o p h yl a xis, a n d I will t a ke t he sec o n d d ose at le ast 2 h o urs after 
ner ati ni b a n d l o per a mi de pr o p h yl a xis. 

Ta ke c olesti p ol wit h ple nt y of water or ot her a p pr o priate li q ui d. D o n ot c ut, cr us h, or 
c he w ta blets.

Ot her me dicati o n ( St u d y d oct or/tea m t o write i n na me of me dicati o n a n d i nstr ucti o ns):  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
I n case of m ore se vere diarr hea a n d a n y diarr hea ass ociate d wit h fe ver, pai n, i nfecti o n, or 
de h y drati o n, I ma y recei ve I V fl ui ds, a nti bi otics a n d/ or ot her me dicati o ns.
2.
C h a n ges t o m y diet t o tre at di arr he a 
If I ha ve diarr hea, I will:

St o p all lact ose-c o ntai ni n g pr o d ucts ( mil k, y o g urt, c heese, etc)

Dri n k 8 t o 1 0 lar ge glasses of clear li q ui ds per da y

Eat fre q ue nt s mall meals

Eat l o w fat f o o ds s uc h as t he B R A T diet t hat i ncl u des b a na nas, rice, a p plesa uce, a n d/ or 
toast:

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-
T he B R A T diet is a bla n d diet t hat is l o w i n fat a n d fi ber a n d will n ot irritate t he 
st o mac h; 
-
Ba na nas are hi g h i n p otassi u m a n d ca n ca use c o nsti pati o n w hic h ca n hel p 
alle viate t he diarr hea
-
Ot her si milar f o o ds are crac kers, c o o ke d cereals a n d pasta
-
T his diet is n ot c o m plete i n n utrie nts a n d s h o ul d o nl y be ta ke n f or a s h ort peri o d 
of ti me a n d o nl y u p o n t he d oct or’s a d vice.
M y st u d y d oct or/tea m ma y ha ve ot her s u g gesti o ns f or me. ( St u d y d oct or/tea m t o write i n a n y 
s u g gesti o ns).
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
3.
St u d y Me dic ati o n a dj ust me nts 
If I a m e x perie nci n g l o ose st o ols or diarr hea a n d ca n n ot reac h m y st u d y d oct or/tea m 
i m me diatel y, I will start ta ki n g a nti- diarr heal me dicati o n per t he i nstr ucti o ns a b o ve u ntil f urt her 
a d vice is gi ve n b y m y st u d y d oct or/tea m. If I ha ve m ore t ha n 4- 6 st o ols per da y c o m pare d t o 
n or mal des pite ta ki n g a nti- diarr heal me dicati o n f or 2 4 h o urs, a n d I ca n n ot reac h m y st u d y 
d oct or/tea m, I will st o p ta ki n g t he st u d y me dicati o n a n d wait f or f urt her i nstr ucti o ns fr o m m y 
st u d y d oct or/tea m.
M y si g nat ure bel o w i n dicates I ha ve re vie we d t his i nf or mati o n a n d ha ve recei ve d t he f oll o wi n g 
me dicati o ns:

Nerati ni b Ta blets 

L o pera mi de

C olesti p ol
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
St u d y partici pa nt na me
        St u d y partici pa nt Si g nat ure a n d Date
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or dele gate na me  
        I n vesti gat or dele gate Si g nat ure a n d Date
O R
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or na me                                  I n vesti gat or Si g nat ure a n d Date

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A P P E N DI X D  
Me dic ati o ns t o use wit h c a uti o n w hile o n st u d y
List of C yt oc hr o me P 4 5 0 I n hi bit ors a n d I n d ucers ( u p d ate d list als o a v ail a ble at 
htt p:// me dici ne.i u p ui.e d u/cli n p h ar m/ d dis/t a ble. as p x )
I N HI BI T O R S 
N orfl o x aci n ( 3 A 4)
Rit o n a vir ( 3 A 4)
Cl arit hr o m yci n ( 3 A 4) 
S a q ui n a vir ( 3 A 4)
Er yt hr o m yci n ( 3 A 4) 
Tr ole a n d o m yci n ( 3 A 4)
Fl uc o n az ole ( 3 A 4) 
V oric o n az ole ( 3 A 4)
Fl u v o x a mi ne ( 3 A 4)
Gr a pefr uit j uice ( 3 A 4)
Gr a pefr uit-c o nt ai ni n g pr o d ucts ( 3 A 4) 
A mi o dar o ne
I n di n a vir ( 3 A 4) 
Ca n na bi n oi ds
Itr ac o n az ole ( 3 A 4) 
Fl u o xeti ne
Ket oc o n az ole ( 3 A 4)
L o pi na vir
Mi befr a dil ( 3 A 4) 
Metr o ni daz ole
Mic o n az ole ( 3 A 4) 
Q ui ni ne
Nef az o d o ne ( 3 A 4) 
Sertr ali ne
Nelfi n a vir ( 3 A 4) 
Z afirl u k ast
I N D U C E R S
Bar bit urates
C otri m o xaz ole
Efa vire nz
Et h os u xi mi de
Met ha d o ne 
Met yra p o ne
Me xileti ne
Ne vir a pi ne
Oral c o ntrace pti ves
Rifa b uti n ( 3 A 4) 
Rifa m pi n ( 3 A 4) 
St. J o h n’s w ort ( 3 A 4)
Tr o glitaz o ne
I n b ol df ace are i de ntifie d str o n g C Y P 3 A 4 i n d ucers/i n hi bit ors.
Fr o m: Tatr o B O. Dr u g I nter acti o n F acts 2 0 0 3: T he A ut h ority o n Dr u g I nter acti o n; . 2 0 0 3.

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A P P E N DI X E  
M U L TI C E N T E R G UI D E LI N E S
D a n a- F ar ber/ H ar v ar d C a ncer Ce nter
M ulti- Ce nter D at a a n d S afet y M o nit ori n g Pl a n

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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
1. 2
M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n Defi niti o ns
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 D F/ H C C S p o ns or
2. 2 C o or di nati n g Ce nter 
2. 3 Partici pati n g I nstit uti o n
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 Distri b uti o n
3. 2 Pr ot oc ol Re visi o ns a n d Cl os ures
3. 3 I nf or me d C o nse nt Re q uire me nts
3. 4 I R B D oc u me ntati o n
3. 5 I R B Re- A p pr o val
3. 6 Partici pa nt C o nfi de ntialit y a n d A ut h orizati o n State me nt
3. 7 D F/ H C C M ulti- Ce nter Pr ot oc ol Re gistrati o n P olic y
3. 8 D F/ H C C Pr ot oc ol Case N u m ber
3. 9 Safet y Assess me nts a n d T o xicit y M o nit ori n g
3. 1 1 Data Ma na ge me nt
4.
R E Q UI SI TI O NI N G I N V E S TI G A TI O N A L D R U G
5.
M O NI T O RI N G: Q U A LI T Y C O N T R O L
5. 1 O n g oi n g M o nit ori n g of Pr ot oc ol C o m plia nce
5. 2 M o nit ori n g Re p orts
5. 3 Accr ual M o nit ori n g
6.
A U DI TI N G: Q U A LI T Y A S S U R A N C E
6. 1 A u dit Pla n: D F/ H C C S p o ns ore d Trials
6. 2 A u dit N otificati o n
6. 3 A u dit Re p orts 
6. 4 Partici pati n g I nstit uti o n Perf or ma nce

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1.     I N T R O D U C TI O N
T he Da na- Far ber/ Har var d Ca ncer Ce nter M ulti- Ce nter Data 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 s h o ul d ser ve as a refere nce f or a n y sites e xter nal t o D F/ H C C t hat 
will be partici pati n g i n t he researc h pr ot oc ol.
1. 1   
P ur p ose
T o esta blis h sta n dar ds t hat 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 nce P orta bilit y a n d Acc o u nta 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.       
1. 2   
M ulti- Ce nter D at a a n d S afet y M o nit ori n g Pl a n Defi niti o ns
D F/ H C C M ulti- Ce nter Pr ot oc ol :  A researc h pr ot oc ol i n w hic h o ne  or m ore o utsi de 
i nstit uti o ns are c olla b orati n g wit h Da na- Far ber/ Har var d Ca ncer Ce nter w here  a D F/ H C C 
i n vesti gat or is t he s p o ns or. D F/ H C C i ncl u des Da na- Far ber/ Part ners Ca ncer Care ( D F/ P C C) 
Net w or k Cli nical Trial Affiliates. 
Le a d I nstit uti o n:  Da na- Far ber Ca ncer I nstit ute ( D F CI) is res p o nsi ble f or t he c o or di nati o n, 
de vel o p me nt, s u b missi o n, a n d a p pr o val of a pr ot oc ol as well as its s u bse q ue nt a me n d me nts per 
t he D F CI I R B a n d a p plica ble re g ulat or y g ui deli nes ( F o o d a n d Dr u g A d mi nistrati o n ( F D A) etc.).  
T he Lea d I nstit uti o n is t y picall y t he h o me of t he D F/ H C C S p o ns or. T he Lea d I nstit uti o n als o 
t y picall y ser ves as t he C o or di nati n g Ce nter f or t he D F/ H C C M ulti- Ce nter Pr ot oc ol.  
D F/ H C C S p o ns or:  T he  pers o n s p o ns ori n g t he s u b mitte d M ulti- Ce nter pr ot oc ol.  Wit hi n 
D F/ H C C, t his pers o n is t he O verall Pri nci pal I n vesti gat or w h o ta kes res p o nsi bilit y f or i nitiati o n, 
ma na ge me nt a n d c o n d uct of t he pr ot oc ol at all researc h l ocati o ns. I n a p plica ble pr ot oc ols, t he 
D F/ H C C S p o ns or will ser ve as t he si n gle liais o n wit h a n y re g ulat or y a ge ncies (i.e. F D A, etc.). 
T he D F/ H C C S p o ns or has ulti mate a ut h orit y o ver t he pr ot oc ol a n d is res p o nsi ble f or t he c o n d uct 
of t he st u d y at D F/ H C C a n d all Partici pati n g I nstit uti o ns. I n m ost cases t he D F/ H C C S p o ns or is 
t he sa me pers o n as t he D F/ H C C O verall Pri nci pal I n vesti gat or; h o we ver, b ot h r oles ca n be fille d 
b y t w o differe nt pe o ple. 
P artici p ati n g I nstit uti o n: 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 Partici pati n g I nstit uti o n ac k n o wle 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.   
C o or di n ati n g Ce nter:   T he e ntit y (i.e. Lea d I nstit uti o n or Pr oject Ma na ger) 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 n ge neral, t he Lea d I nstit uti o n is t he C o or di nati n g Ce nter f or t he D F/ H C C 
M ulti- Ce nter Pr ot oc ol. 

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D F/ H C C Office of D at a Q u alit y ( O D Q):  A gr o u p wit hi n D F/ H C C res p o nsi ble f or e ns uri n g 
hi g h- q ualit y sta n dar ds are use d f or data c ollecti o n a n d t he o n g oi n g ma na ge me nt of cli nical trials, 
a u diti n g, a n d data a n d safet y m o nit ori n g. O D Q als o c o or di nates q ualit y ass ura nce eff orts relate d 
t o m ulti-ce nter cli nical researc h.
D F/ H C C Cli nic al Tri als Rese arc h I nf or m atics Office ( C T RI O):  A gr o u p wit hi n D F/ H C C 
res p o nsi ble f or pr o vi di n g a c o m pre he nsi ve data ma na ge me nt platf or m f or ma na gi n g cli nical trial 
data.
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 D F/ H C C S p o ns or, t he C o or di nati n g Ce nter, a n d t he 
Partici pati n g I nstit uti o ns are e x pecte d t o a d here t o t he f oll o wi n g ge neral res p o nsi bilities: 
2. 1   
D F/ H C C S p o ns or
T he D F/ H C C S p o ns or, 
 will acce pt res p o nsi bilit y f or all as pects of 
c o n d ucti n g a D F/ H C C M ulti- Ce nter pr ot oc ol w hic h i ncl u des b ut is n ot li mite d t o: 

O versee t he c o or di nati o n, de vel o p me nt, s u b missi o n, a n d a p pr o val of t he pr ot oc ol as well 
as s u bse q ue nt a me n d me nts. 

E ns ure t hat t he i n vesti gat ors, st u d y tea m me m bers, a n d Partici pati n g I nstit uti o ns are 
q ualifie d a n d a p pr o priatel y res o urce d t o c o n d uct t he pr ot oc ol.  

I ncl u de t he M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n as a n a p pe n di x t o t he pr ot oc ol.

E ns ure all Partici pati n g I nstit uti o ns are usi n g t he c orrect versi o n of t he pr ot oc ol.

E ns ure t hat eac h partici pati n g i n vesti gat or a n d st u d y tea m me m ber recei ves a de q uate 
pr ot oc ol trai ni n g a n d/ or a Site I nitiati o n Visit pri or t o e nr olli n g partici pa nts a n d 
t hr o u g h o ut trial’s c o n d uct as nee de d.

E ns ure t he pr ot oc ol will be pr o vi de d t o eac h partici pati n g site i n a la n g ua ge 
u n dersta n da ble t o all a p plica ble site pers o n nel w he n E n glis h is n ot t he pri mar y la n g ua ge. 

M o nit or pr o gress a n d o verall c o n d uct of t he st u d y at all Partici pati n g I nstit uti o ns. 

E ns ure all D F CI I nstit uti o nal Re vie w B oar d (I R B), D F/ H C C a n d ot her a p plica ble (i.e. 
F D A) re p orti n g re q uire me nts are met. 

Re vie w data a n d mai ntai n ti mel y s u b missi o n of data f or st u d y a nal ysis. 

Act as t he si n gle liais o n wit h F D A (i n vesti gat or- hel d I N D trials).

E ns ure c o m plia nce wit h all re q uire me nts as set f ort h i n t he C o de of Fe deral Re g ulati o ns, 
a p plica ble D F/ H C C re q uire me nts, HI P A A re q uire me nts, a n d t he a p pr o ve d pr ot oc ol.

C o m mit t o t he pr o visi o n t hat t he pr ot oc ol will n ot be re writte n or m o difie d b y a n y o ne 
ot her t ha n t he D F/ H C C S p o ns or.

I de ntif y a n d q ualif y Partici pati n g I nstit uti o ns a n d o btai n accr ual c o m mit me nts pri or t o 
e xte n di n g t he pr ot oc ol t o t hat site.

M o nit or accr ual a n d a d dress Partici pati n g I nstit uti o ns t hat are n ot meeti n g t heir accr ual 
re q uire me nts. 
2. 2    
C o or di n ati n g Ce nter 

D F/ H C C Pr ot oc ol #: 1 7- 3 1 8
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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 Partici pati n g 
I nstit uti o ns i n t he D F/ H C C cli nical trial ma na ge me 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 nse nt d oc u me nt u p dates t o Partici pati n g I nstit uti o ns 
as nee de d.

O versee t he data c ollecti o n pr ocess fr o m Partici pati n g I nstit uti o ns.

Mai ntai n d oc u me ntati o n of Seri o us A d verse 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 Partici pati n g I nstit uti o ns 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 verse 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 verse E ve nt Re p orti n g P olic y t o all Partici pati n g I nstit uti o ns.

Pr o vi de Partici pati n g I nstit uti o ns wit h i nf or mati o n re gar di n g D F/ H C C re q uire me 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 Partici pati n g I nstit uti o ns 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 Partici pati n g I nstit uti o ns 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 Partici pati n g I nstit uti o ns (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 nicati o ns.
2. 3    
P artici p ati n g I nstit uti o n
Eac h Partici pati n g I nstit uti o n is e x pecte d t o c o m pl y wit h all a p plica ble fe deral re g ulati o ns a n d 
D F/ H C C re q uire me nts, t he pr ot oc ol a n d HI P A A re q uire me nts. 
T he ge neral res p o nsi bilities f or eac h Partici pati n g I nstit uti o n ma y i ncl u de b ut are n ot li mite d t o:

D oc u me nt t he dele gati o n of researc h s pecific acti vities t o st u d y pers o n nel.

C o m mit t o t he accr ual 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 me 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 l ocal 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 nce wit h D F/ H C C re q uire me 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 l ocal 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 da nce wit h D F/ H C C re q uire me nts.

D F/ H C C Pr ot oc ol #: 1 7- 3 1 8
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
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 date 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.
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
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 detail 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 Distri b uti o n
T he C o or di nati n g Ce nter will distri b ute t he fi nal D F CI I R B a p pr o ve d pr ot oc ol a n d a n y 
s u bse q ue nt a me n de d pr ot oc ols t o all Partici pati n g I nstit uti o ns.   
3. 2   
Pr ot oc ol Re visi o ns a n d Cl os ures
T he Partici pati n g I nstit uti o ns 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.  It is t he i n di vi d ual Partici pati n g I nstit uti o n’s res p o nsi bilit y t o n otif y its 
I R B of t hese re visi o ns.

N o n life-t hre ate ni n g re visi o ns:  Partici pati n g I nstit uti o ns will recei ve writte n n otificati o n 
of pr ot oc ol re visi o ns re gar di n g n o n life-t hreate ni n g e ve nts fr o m t he C o or di nati n g Ce nter. 
N o n-life-t hreate ni n g pr ot oc ol re visi o ns m ust be I R B a p pr o ve d a n d i m ple me nte d wit hi n 
9 0 da ys fr o m recei pt of t he n otificati o n.

Re visi o ns f or life-t hre ate ni n g c a uses:  Partici pati n g I nstit uti o ns will recei ve i m me diate 
n otificati o n fr o m t he C o or di nati n g Ce nter c o ncer ni n g pr ot oc ol re visi o ns re q uire d t o 
pr otect li ves wit h f oll o w- u p b y fa x, mail, e- mail, etc.  Life-t hreate ni n g pr ot oc ol re visi o ns 
will be i m ple me nte d i m me diatel y f oll o we d b y I R B re q uest f or a p pr o val.

Pr ot oc ol cl os ures a n d te m p or ar y h ol ds:  Partici pati n g I nstit uti o ns 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 Partici pati n g I nstit uti o ns o n a n o n g oi n g basis a b o ut pr ot oc ol accr ual data 
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. 3   
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 Partici pati n g I nstit uti o ns. T he Partici pati n g I nstit uti o n 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 pecificati o ns o utli ne d i n t he 
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 ge f or PI-I nitiate d M ulti- Ce nter 

D F/ H C C Pr ot oc ol #: 1 7- 3 1 8
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Pr ot oc ols.  T his d oc u me nt will be pr o vi de d se paratel y t o eac h Partici pati n g I nstit uti o n.
Partici pati n g I nstit uti o ns are t o se n d t heir versi o n of t he i nf or me d c o nse nt d oc u me nt a n d HI P A A 
a ut h orizati o n, if a se parate d oc u me nt, t o t he C o or di nati n g Ce nter f or re vie w a n d a p pr o val pri or 
t o s u b missi o n t o t heir l ocal I R B. 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 ocal I R B f or all c o nse nt versi o ns.
T he Pri nci pal I n vesti gat or ( PI) at eac h Partici pati n g I nstit uti o n will i de ntif y t he p h ysicia n 
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 
t hera pe utic pr ot oc ols. Partici pati n g i nstit uti o ns m ust f oll o w t he D F/ H C C re q uire me nt t hat o nl y 
atte n di n g p h ysicia ns o btai n i nf or me d c o nse nt a n d re-c o nse nt f or all i nter ve nti o nal dr u g, bi ol o gic, 
or de vice researc h.  
3. 4   
I R B D oc u me nt ati o n
T he f oll o wi n g m ust be o n file wit h t he C o or di nati n g Ce nter:

I nitial a p pr o val letter of t he Partici pati n g I nstit uti o n's I R B. 

C o p y of t he I nf or me d C o nse nt F or m(s) a p pr o ve d b y t he Partici pati n g I nstit uti o n’s I R B. 

Partici pati n g I nstit uti o n’s I R B a p pr o val f or all a me n d me nts.

A n n ual a p pr o val letters b y t he Partici pati n g I nstit uti o n's I R B.
3. 5   
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 Partici pati n g I nstit uti o ns 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 peri 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 pa nts if a re-a p pr o val letter is n ot recei ve d fr o m 
t he Partici pati n g I nstit uti o n o n or bef ore t he a n ni versar y of t he pre vi o us a p pr o val date.  
3. 6   
P artici p a nt C o nfi de nti alit y a n d A ut h oriz ati o n St ate me nt
I n 1 9 9 6, c o n gress passe d t he first fe deral la w c o veri n g t he pri vac y of healt h i nf or mati o n k n o w n 
as t he Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P P A). A n y i nf or mati o n, relate d t o 
t he p h ysical or me ntal healt h of a n i n di vi d ual is calle d Pr otecte d Healt h I nf or mati o n ( P HI). 
HI P A A o utli nes h o w a n d u n der w hat circ u msta nces P HI ca n be use d or discl ose d. 
I n or der f or c o vere d e ntities t o use or discl ose pr otecte d healt h i nf or mati o n d uri n g t he c o urse of a 
st u d y, t he st u d y partici pa nt m ust si g n a n a ut h orizati o n state me nt.  T his a ut h orizati o n state me nt 
ma y or ma y n ot be se parate fr o m t he i nf or me d c o nse nt d oc u me nt.  T he C o or di nati n g Ce nter, 
wit h t he a p pr o val fr o m t he D F CI I R B will pr o vi de a c o nse nt te m plate, wit h i nf or mati o n 
re gar di n g a ut h orizati o n f or t he discl os ure of pr otecte d healt h i nf or mati o n. 
T he D F/ H C C S p o ns or will use all eff orts t o li mit its use of pr otecte d healt h i nf or mati o n i n its 
trials. H o we ver, beca use of t he nat ure of t hese trials, certai n pr otecte d healt h i nf or mati o n m ust 
be c ollecte d. D F/ H C C has c h ose n t o use a ut h orizati o ns, si g ne d b y t he partici pa nt i n t he trial, 
rat her t ha n li mite d data sets wit h data use a gree me nts.

D F/ H C C Pr ot oc ol #: 1 7- 3 1 8
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3. 6. 1  
D F/ H C C M ulti- Ce nter Pr ot oc ol C o nfi de nti alit y
All d oc u me nts, i n vesti gati ve re p orts, or i nf or mati o n relati n g t o t he partici pa nt are strictl y 
c o nfi de ntial. W he ne ver reas o na bl y feasi ble, a n y partici pa nt s pecific 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 ber (as descri be d bel o w) be 
use d f or all partici pa nt s pecific d oc u me nts. Partici pa nt i nitials ma y be i ncl u de d or retai ne d f or 
cr oss verificati o n of i de ntificati o n. 
3. 7   
D F/ H C C M ulti- Ce nter Pr ot oc ol Re gistr ati o n P olic y
3. 7. 1  
P artici p a nt Re gistr ati o n a n d R a n d o miz ati o n 
R ef er t o pr ot o c ol S e cti o n 4. 3 a n d 4. 4 of t h e pr ot o c ol f or t h e p arti ci p a nt r e gistr ati o n 
pr o c ess.
3. 7. 2  I niti ati o n of T her a 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 recei vi n g treat me nt.  
Treat me nt ma y n ot be i nitiate d u ntil t he Partici pati n g I nstit uti o n 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. 7. 3 
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 Partici pati n g I nstit uti o ns 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 he pr ocess f or re q uesti n g a n eli gi bilit y e xce pti o n is defi ne d bel o w.
3. 8   
D F/ H C C Pr ot oc ol C ase N u m ber
At t he ti me of re gistrati o n, t he f oll o wi n g i de ntifiers are re q uire d f or all s u bjects: i nitials, 
date of birt h, ge n der, race a n d et h nicit y. O nce eli gi bilit y has bee n esta blis he d a n d t he 
partici pa nt s uccessf ull y re gistere d, t he partici pa nt is assi g ne d a u ni q ue pr ot oc ol case 
n u m ber.  T his n u m ber is u ni q ue t o t he partici pa nt o n t his trial a n d m ust be use d f or 
C R F/e C R F c o m pleti o n a n d c orres p o n de nce.  Partici pati n g I nstit uti o ns s h o ul d s u b mit all 
de-i de ntifie d s u bse q ue nt c o m m u nicati o n a n d d oc u me nts t o t he C o or di nati n g Ce nter, 
usi n g t his case n u m ber t o i de ntif y t he s u bject.  
3. 8. 1  
Pr ot oc ol De vi ati o ns, E xce pti o ns a n d Vi ol ati 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 researc h acti vit y t o 
e ns ure t hat researc 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 val, 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 part ures fr o m t he defi ne d pr oce d ures set f ort h i n t he 

D F/ H C C Pr ot oc ol #: 1 7- 3 1 8
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I R B a p pr o ve d pr ot oc ol t o be re p orte d t o t he D F/ H C C S p o ns or, w h o i n t ur n is res p o nsi ble 
f or re p orti n g t o t he D F CI I R B.
F or re p orti n g p ur p oses, D F/ H C C uses t he ter ms “ vi olati o n”, “ de viati o n” a n d “e xce pti o n” 
t o descri be de part ures fr o m a pr ot oc ol. All Partici pati n g I nstit uti o ns m ust a d here t o t hese 
re q uire me nts f or re p orti n g t o t he D F/ H C C S p o ns or a n d will f oll o w t heir i nstit uti o nal 
p olic y f or re p orti n g t o t heir l ocal I R B.
3. 8. 2  
Defi niti o ns
Pr ot oc ol De viati o n: A n y de part ure 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 w hic h is pr os pectively a p pr ove d  pri or t o its i m ple me ntati o n.
Pr ot oc ol E xce pti o n:  A n y pr ot oc ol de viati o n t hat relates t o t he eli gi bilit y criteria, e. g.
e nr oll me nt of a partici pa nt w h o d oes n ot meet all i ncl usi o n/e xcl usi o n criteria.
Pr ot oc ol Vi olati o n: A n y pr ot oc ol de part ure t hat was n ot pr os pectively a p pr ove d  b y t he 
I R B pri or t o its i nitiati o n or i m ple me ntati o n. 
3. 8. 3  
Re p orti n g Pr oce d ures
D F/ H C C S p o ns or: is res p o nsi ble f or e ns uri n g t hat clear d oc u me ntati o n is a vaila ble i n t he 
me dical rec or d a n d/ or re g ulat or y d oc u me nts t o descri be all pr ot oc ol e xce pti o ns, 
de viati o ns a n d vi olati o ns. T he D F/ H C C S p o ns or will als o be res p o nsi ble f or e ns uri n g t hat 
all pr ot oc ol vi olati o ns/ de viati o ns are pr o m ptl y re p orte d per D F CI I R B g ui deli nes. 
Partici pati n g I nstit uti o ns: Pr ot oc ol de viati o ns re q uire pr os pecti ve a p pr o val fr o m t he 
D F CI I R B. T he Partici pati n g I nstit uti o n m ust s u b mit t he de viati o n re q uest t o t he 
C o or di nati n g Ce nter w h o will t he n s u b mit t he de viati o n re q uest t o t he D F CI I R B. U p o n 
D F CI I R B a p pr o val t he de viati o n is s u b mitte d t o t he Partici pati n g I nstit uti o n I R B, per 
i nstit uti o nal p olic y. A c o p y of t he Partici pati n g I nstit uti o n’s I R B re p ort a n d deter mi nati o n 
will be f or war de d t o t he C o or di nati n g Ce nter wit hi n 1 0 b usi ness da ys after t he ori gi nal 
s u b missi o n. 
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. 
C o or di nati n g Ce nter:  U p o n recei pt of t he vi olati o n/ de viati o n re p ort fr o m t he 
Partici pati n g I nstit uti o n, t he C o or di nati n g Ce nter will s u b mit t he re p ort t o t he D F/ H C C 
S p o ns or f or re vie w. S u bse q ue ntl y, t he Partici pati n g I nstit uti o n’s I R B vi olati o n/ de viati o n 
re p ort will be s u b mitte d t o t he D F CI I R B f or re vie w per D F CI I R B re p orti n g g ui deli nes. 
3. 9   
S afet y Assess me nts a n d T o xicit y M o nit ori n g
T he st u d y tea ms at all partici pati n g i nstit uti o ns are res p o nsi ble f or pr otecti n g t he safet y, ri g hts 
a n d well- bei n g of st u d y partici pa nts. Rec or di n g a n d re p orti n g of a d verse e ve nts t hat occ ur d uri n g 
t he c o urse of a st u d y hel p e ns ure t he c o nti n ui n g safet y of st u d y partici pa nts. 

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All partici pa nts recei vi n g i n vesti gati o nal a ge nts a n d/ or ot her pr ot oc ol ma n date d treat me nt will be 
e val uate d f or safet y. T he safet y para meters i ncl u de all la b orat or y tests a n d he mat ol o gical 
a b n or malities, p h ysical e xa mi nati o n fi n di n gs, a n d s p o nta ne o us re p orts of a d verse e ve nts re p orte d 
b y partici pa nts.  All t o xicities e nc o u ntere d d uri n g t he st u d y will be e val uate d acc or di n g t o t he 
N CI criteria s pecifie d i n t he pr ot oc ol. Life-t hreate ni n g t o xicities m ust be re p orte d i m me diatel y t o 
t he D F/ H C C S p o ns or via t he C o or di nati n g Ce nter. 
A d diti o nal safet y assess me nts a n d t o xicit y m o nit ori n g will be o utli ne d i n t he pr ot oc ol.
3. 9. 1 
G ui deli nes f or Re p orti n g Seri o us A d verse E ve nts 
G ui deli nes f or re p orti n g A d verse E ve nts ( A Es) a n d Seri o us A d verse E ve nts ( S A Es) are 
detaile d i n pr ot oc ol Secti o n 7. 0.
Partici pati n g I nstit uti o ns m ust re p ort t he S A Es t o t he D F/ H C C S p o ns or a n d t he 
C o or di nati n g Ce nter f oll o wi n g t he D F CI I R B A d verse E ve nt Re p orti n g P olic y. 
T he C o or di nati n g Ce nter will mai ntai n d oc u me ntati o n of all Partici pati n g I nstit uti o n 
A d verse E ve nt re p orts a n d be res p o nsi ble f or c o m m u nicati n g t o all partici pati n g 
i n vesti gat ors, a n y o bser vati o ns re p orta ble u n der t he D F CI I R B Re p orti n g Re q uire me nts.  
Partici pati n g I nstit uti o ns will re vie w a n d s u b mit t o t heir 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
3. 9. 2 
G ui deli nes f or Pr ocessi n g I N D S afet 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 a n d e ns ure t hat all I N D Safet y 
Re p orts are distri b ute d t o t he Partici pati n g I nstit uti o ns. Partici pati n g I nstit uti o ns will 
re vie w a n d s u b mit t o t heir 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.
3. 1 0    D at a M a n a ge me nt
T he D F/ H C C C T RI O 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. T he D F/ H C C C T RI O 
pr o vi des a we b base d trai ni n g f or all e C R F users.
  
3. 1 0. 1 D at a 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 uer 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.  

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Res p o nses ma y be ret ur ne d o n t he writte n q uer y or o n a n a me n de d pa per case re p ort f or m, 
or i n t he case of electr o nic q ueries, wit hi n t he electr o nic data ca pt ure (e D C) s yste m. I n t he 
case of a writte n q uer y f or data s u b mitte d o n a pa per case re p ort f or m, t he q uer y m ust be 
attac he d t o t he s pecific data bei n g re-s u b mitte d i n res p o nse.  
If st u d y f or ms are n ot s u b mitte d o n sc he d ule, t he Partici pati n g I nstit uti o n will peri o dicall y 
recei ve a Missi n g F or m Re p ort fr o m t he C o or di nati n g Ce nter n oti n g t he missi n g f or ms. 
4.    R E Q UI SI TI O NI N G I N V E S TI G A TI O N A L D R U G
Nerati ni b will be or dere d fr o m 
 T he or deri n g of i n vesti gati o nal a ge nt is s pecifie d i n t he 
pr ot oc ol Secti o n 8. 1. 8.
F ul vestra nt is c o m merciall y a vaila ble.  C hec k wit h t he l ocal Direct or of P har mac y a n d/ or t he 
Researc h P har mac y t o e ns ure t hat t he a ge nt is i n st oc k. If t he a ge nt is n ot st oc ke d, e ns ure t hat t he 
a ge nt ca n be or dere d o nce t he pr ot oc ol is a p pr o ve d b y t he l ocal I R B.
5.    M O NI T O RI N G: Q U A LI T Y C O N T R O L
T he q ualit y c o ntr ol pr ocess f or a cli nical trial re q uires verificati o n of pr ot oc ol c o m plia nce a n d 
data acc urac y. As t he C o or di nati n g Ce nter, t he D F/ H C C Lea d I nstit uti o n wit h t he ai d of t he 
O D Q pr o vi des q ualit y c o ntr ol o versi g ht f or t he pr ot oc ol.
5. 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 Partici pati n g I nstit uti o ns will be re q uire d t o s u b mit partici pa nt s o urce d oc u me nts t o t he 
D F/ H C C Lea d I nstit uti o n or desi g nee f or m o nit ori n g. Partici pati n g I nstit uti o ns 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 D F/ H C C Lea d I nstit uti o n. 
T he D F/ H C C Lea d I nstit uti o n will i m ple me nt o n-site a n d virt ual m o nit ori n g acti vities t o e ns ure 
t hat Partici pati n g I nstit uti o ns 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 ualit y, a n d s u bject safet y. At mi ni m u m, t he D F/ H C C Lea d I nstit uti o n, or desi g nee, will m o nit or 
eac h partici pati n g site t wice a year w hile patie nts are recei vi n g st u d y treat me nt. S h o ul d a 
Partici pati n g I nstit uti o n be m o nit ore d o nce a n d t he n n ot accr ue a n y a d diti o nal partici pa nts or 
partici pa nt visits, t he n a sec o n d m o nit ori n g visit ma y n ot be necessar y. 
M o nit ori n g practices ma y i ncl u de b ut are n ot li mite d t o: s o urce verificati o n, re vie w a n d a nal ysis 
of t he f oll o wi n g: eli gi bilit y re q uire me nts of all partici pa nts, i nf or me d c o nse nt pr oce d ures, 
a d verse e ve nts a n d all ass ociate d d oc u me ntati o n, st u d y dr u g a d mi nistrati o n / treat me nt, 
re g ulat or y rec or ds a n d site trial master files, pr ot oc ol de viati o ns,  p har mac y rec or ds, res p o nse 
assess me nts, a n d data ma na ge me nt. A d diti o nall y, o n g oi n g c o m m u nicati o n will occ ur t hr o u g h 
re g ularl y sc he d ule d telec o nfere nces a n d b y e mail. S o urce d oc u me nts fr o m Partici pati n g 
I nstit uti o ns, will be c ollecte d at s pecific ti me p oi nts t o s u p p ort t he pri mar y a n d/ or sec o n dar y 
e n d p oi nts.
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 basis.  Partici pati n g 

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I nstit uti o ns will be re q uire d t o pr o vi de access t o partici pa nts’ c o m plete me dical rec or d a n d 
s o urce d oc u me nts f or verificati o n d uri n g o n-site visits. U p o n re q uest, Partici pati n g I nstit uti o ns 
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 researc h, a n d a n y ot her trial-relate d d oc u me ntati o n mai ntai ne d b y t he Partici pati n g 
site. If t here are pr ot oc ol c o m plia nce c o ncer ns, iss ues t hat i m pact s u bject safet y or t he i nte grit y 
of t he st u d y, or tre n ds i de ntifie d base d o n areas of nee d, a d diti o nal m o nit ori n g visits ma y occ ur. 
Virt u al M o nit ori n g:  O n-site m o nit ori n g visits will be s u p ple me nte d wit h virt ual m o nit ori n g 
visits.  T he D F/ H C C Lea d I nstit uti o n will re q uest s o urce d oc u me ntati o n fr o m Partici pati n g 
I nstit uti o ns as nee de d t o c o m plete virt ual m o nit ori n g acti vities. Partici pati n g I nstit uti o ns will be 
as ke d t o f or war d de-i de ntifie d c o pies of partici pa nts’ me dical rec or d a n d s o urce d oc u me nts t o 
t he D F/ H C C Lea d I nstit uti o n t o ai d i n t he s o urce d oc u me ntati o n verificati o n pr ocess.
I n a d diti o n t o m o nit ori n g perf or me d b y t he C o or di nati n g Ce nter, t he D F/ H C C O D Q ma y 
m o nit or data f or ti meli ness of s u b missi o n, c o m plete ness, a n d a d here nce t o pr ot oc ol 
re q uire me nts. T he D F/ H C C Lea d I nstit uti o n or desi g nee a n d, if a p plica ble, t he O D Q Data 
A nal ysts will perf or m o n g oi n g pr ot oc ol data c o m plia nce m o nit ori n g wit h t he s u p p ort of t he 
Partici pati n g I nstit uti o n’s C o or di nat ors, t he Pri nci pal I n vesti gat ors, a n d t he Pr ot oc ol C hair. 
5. 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 f or o n-site a n d re m ote m o nit ori n g of 
Partici pati n g I nstit uti o ns 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 ncrease t he 
m o nit ori n g acti vities at Partici pati n g I nstit uti o ns t hat are u na 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 ocal re g ulati o ns. Partici pati n g I nstit uti o ns ma y 
als o be s u bject t o a n a u dit as deter mi ne d b y t he D F/ H C C S p o ns or.
5. 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 nal site, t he D F/ H C C S p o ns or will esta blis h accr ual 
re q uire me nts f or eac h partici pati n g i nstit uti o n. Accr ual will be m o nit ore d f or eac h partici 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 accr ual e x pectati o ns 
ma y be s u bject t o ter mi nati o n.  Sites are e x pecte d t o accr ue at least 3 patie nts per year.
6.    A U DI TI N G: Q U A LI T Y A S S U R A N C E
A u diti n g is a met h o d of Q ualit y Ass ura nce. Its mai n f oc us is t o meas ure w het her sta n dar ds a n d 
pr oce d ures were f oll o we d. A u diti n g is t he s yste matic a n d i n de pe n de nt e xa mi nati o n of all trial 
relate d acti vities a n d d oc u me nts.  A u dits deter mi ne if e val uate d acti vities were a p pr o priatel y 
c o n d ucte d a n d w het her data was ge nerate d, rec or de d a n d a nal yze d, a n d acc uratel y re p orte d per 
t he pr ot oc ol, Sta n dar d O perati n g Pr oce d ures ( S O Ps), a n d t he C o de of Fe deral Re g ulati o ns 
( C F R).
6. 1  
A u dit Pl a n: D F/ H C C S p o ns ore d Tri als
All Partici pati n g I nstit uti o ns are s u bject t o a u dit b y t he D F/ H C C Office of Data Q ualit y ( O D Q). 

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T y picall 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 da 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.  
6. 2  
A u dit N otific ati o n
It is t he Partici pati n g I nstit uti o n’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 
sc he d ule d a u dit dates (i nter nal or e xter nal) a n d re-a u dit dates (if a p plica ble), w hic h i n v ol ve t his 
pr ot oc ol. All i nstit uti o ns will f or war d a 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 after t he a u dit date. 
6. 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 nati n g Ce nter, m ust f or war d t hese 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. Base d u p o n t he a u dit assess me nts t he D F/ H C C 
A u dit C o m mittee c o ul d acce pt or c o n diti o nall y acce pt t he a u dit rati n g a n d fi nal re p ort. 
C o n diti o nal a p pr o val c o ul d re q uire t he D F/ H C C S p o ns or t o i m ple me nt rec o m me n dati o ns or 
re q uire f urt her f oll o w- u p.  F or u nacce pta 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 he fi nal 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.
6. 4  
P artici p ati n g I nstit uti o n Perf or 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 har 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.
6. 4. 1 
C orrecti ve Acti o ns
Partici pati n g I nstit uti o ns t hat fail t o meet t he perf or ma nce g oals of accr ual, s u b missi o n of 
ti mel y a n d acc urate data, a d here nce 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 rec o m me n de d f or a si x- m o nt h pr o bati o n peri o d. S uc h 
i nstit uti o ns m ust res p o n d wit h a c orrecti ve acti o n pla n a n d m ust de m o nstrate d uri n g t he 
pr o bati o n peri o d t hat deficie ncies ha ve bee n c orrecte d, as e vi de nce d b y t he i m pr o ve d 
perf or ma nce meas ures. Partici pati n g I nstit uti o ns t hat fail t o de m o nstrate si g nifica nt 
i m pr o ve me nt will be c o nsi dere d b y t he D F/ H C C S p o ns or f or re v ocati o n of partici pati o n. 
A D F/ H C C S p o ns or a n d/ or t he D F CI I R B ma y ter mi nate a site’s partici pati o n if it is 
deter mi ne d t hat a site is n ot f ulfilli n g its res p o nsi bilities as descri be d a b o ve.

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A P P E N DI X F 
S P E CI M E N R E Q UI SI TI O N 
C o m plete t his f or m a n d i ncl u de wit h t he s peci me n s hi p me nt ( ma ke a c o p y f or t he partici pa nt’s researc h c hart).  La bel A L L materials 
wit h partici pa nt i nitials, D F CI partici pa nt st u d y I D, a n d t he date a n d ti me t he s peci me n was o btai ne d. I ncl u de a pat h ol o g y re p ort wit h 
a n y arc hi val tiss ue s peci me ns bei n g s u b mitte d.  Refer t o Secti o n 9 f or a d diti o nal details.
S hi p B L O O D a n d 
BI O P S Y s peci me ns t o:
D F/ H C C C ore Bl o o d & Tiss ue Ba n k
S hi p arc hi v al B L O C K S 
a n d S LI D E S t o:
Da na Far ber Ca ncer I nstit ute 
Bri g ha m a n d W o me n’s H os pital
2 0 S hatt uc k Street
                                                 
Breast O nc ol o g y
4 5 0 Br o o kli ne A ve n ue, Da na 1 5 7
T h or n B uil di n g- R o o m 4 2 8
B ost o n, M A 0 2 2 1 5
B ost o n, M A 0 2 2 1 5
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
S peci me n I nf or m ati o n
Partici pa nt I nitials ( F M L): _ _ _ _ _ _ _ _ D F CI Partici pa nt St u d y I D N u m ber: _ _ _ _ _ _ _ _    Date s peci me n(s) s hi p pe d: _ _ _ _ _ _ _ _ _ _ _
Ti me P oi nt :
 Scree ni n g 
 C ycle 1 Da y 1
 C ycle 1 Da y 1 5
 
 C ycle _ _ _ _ (fill i n) Da y 1 
 E n d of Treat me nt
                               
S peci me n T y pe 
(i n dic ate i ncl usi o n i n s hi p me nt by c hecki n g b ox)
P at h ol o g y N u m ber(s) or 
Seri al C o di n g (if a p plic a ble)
Q u a ntit y 
s u b mitte d
D ate s peci me n 
o bt ai ne d
Ti me s peci me n 
o bt ai ne d
( 2 4 H o ur Cl oc k)
 Strec k T u bes ( Circ ulati n g T u m or D N A)
 Arc hi val tiss ue bl oc k
 Sli des 
 Bi o ps y c ore(s) fr oze n in O C T
 Bi o ps y c ore(s) fr oze n in O C T
Site i nf or mati o n f or bl oc k/tiss ue ret ur n if c ollecte d:  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _