Clinical trial NCT03289039
Conditions: Breast Cancer
Keywords: Breast Cancer
Sponsor: Dana-Farber Cancer Institute
Start date: 2017-10-25; Completion date: 2021-07-20
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is studying a drug called Neratinib with and without Fulvestrant as possible treatments for HER2-positive breast cancer .

The interventions involved in this study are:

* Neratinib and Fulvestrant
* Neratinib alone

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has approved Neratinib as a treatment for breast cancer. Fulvestrant has been FDA approved for treatment of metastatic hormone receptor positive breast cancer.

The purpose of this research study is to determine how well neratinib, by itself or together with Fulvestrant, works in treating breast cancer that has spread to other parts of the body. Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2).

Neratinib has been used in other research studies and information from those other research studies suggests that neratinib may help to shrink or stabilize HER2-positive breast cancer in this research study.

Arms: arm 1: * Neratinib will be administered orally once daily
* Neratinib is dosed at 240mg (six 40mg tablets) arm 2: * Neratinib will be administered orally once daily
* Neratinib is dosed at 240mg (six 40mg tablets)
* Fulvestrant will be administered intramuscular as an injection (shot) on day 1 and 15 of cycle 1, day 1 of cycle 2, and then on day 1 of each subsequent cycle.
* Fulvestrant is dosed as 250 mg/5mL (x2) for a total of 500 mg via intramuscular injection (two injections).
Interventions: intervention 1: Neratinib intervention 2: Fulvestrant
Intervention descriptions: intervention 1: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2) intervention 2: Fulvestrant, works in treating breast cancer that has spread to other parts of the body

Protocol documents:
Prot_SAP_000.pdf: 


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
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)


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
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


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
4
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


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
5
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


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
6
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 


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
7
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-


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
8
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. 


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
9
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


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
1 0

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. 


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
1 1
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).


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
1 2
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.


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
1 3
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.


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
1 4
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


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
1 5
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 


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
1 6
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 


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
1 7
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.


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
1 8
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 


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
1 9
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 


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 0
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 


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 1
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:




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 3
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.


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 4
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


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 5
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 


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 6
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 


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 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 


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 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]


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 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
Pr ot oc ol Versi o n Date: 0 6/ 0 3/ 2 0 2 1
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 


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 5
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). 


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 6
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.


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 7
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 


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 8
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.


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 9
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 


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
4 0
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


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
4 1
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.


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
4 2
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)


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
4 3
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:


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
4 4

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.




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
4 6
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


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
4 7
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


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
4 8
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, 


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
4 9
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 


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
5 0
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 


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
5 1
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 * *


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
5 2
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.


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
5 3
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; 


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
5 4
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.


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
5 5
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 


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
5 6
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. 


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
5 7
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. 


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
5 8
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.


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
5 9
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


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
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.




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
6 2
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).


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
6 3
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:


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
6 4
-
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


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
6 5
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.


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
6 6
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


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
6 7
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


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
6 8
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. 


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
6 9
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
Pr ot oc ol Versi o n Date: 0 6/ 0 3/ 2 0 2 1
7 0
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
Pr ot oc ol Versi o n Date: 0 6/ 0 3/ 2 0 2 1
7 1

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
Pr ot oc ol Versi o n Date: 0 6/ 0 3/ 2 0 2 1
7 2
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
Pr ot oc ol Versi o n Date: 0 6/ 0 3/ 2 0 2 1
7 3
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
Pr ot oc ol Versi o n Date: 0 6/ 0 3/ 2 0 2 1
7 4
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. 


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
7 5
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.  


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
7 6
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 


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
7 7
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). 


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
7 8
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.


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
7 9
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:  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _