Clinical trial NCT02658084
Conditions: Breast Cancer Metastatic Breast Cancer
Keywords: HER2-Positive Metastatic Breast Cancer
Sponsor: University of Miami
Start date: 2017-04-12; Completion date: 2018-10-11
Enrollment: 2 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study proposes to evaluate the safety and efficacy of the combination of trastuzumab emtansine (T-DM1) and vinorelbine in HER2+ metastatic breast cancer patients.

Detailed description:
This is a Phase I/II, single arm, open-label clinical trial designed to establish the recommended phase II dose (RP2D) of vinorelbine with a fixed dose of trastuzumab emtansine. The study will also evaluate the safety and efficacy of the RP2D in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic, locally advanced, or unresectable breast cancer. The study will be opened to accrual at the University of Miami Sylvester Comprehensive Cancer Center (SCCC) main campus and constituent satellite sites, Deerfield Beach and Plantation.

This phase I/II study will have a total of 50 enrolled patients, taking into account 10% drop-out in the phase II follow-up. The duration anticipated to enroll all study subjects in Phase I/II is 2 years. The estimated duration for the Investigators to complete this study (Phase I/II) is 4.5 to 5 years.

For the phase I portion, standard 3+3 dose escalation/de-escalation design will be applied. Approximately 15 to 21 patients will be needed to establish the recommended phase II dose (RP2D). For the phase II portion of the study, up to 35 patients will be treated at the RP2D (MTD) including 6 patients treated at RP2D in phase I. Patients may remain on treatment with the combination until disease progression or unmanageable toxicity.

Tumor assessments will be conducted every 6 weeks (±7 days) to week 18. Thereafter, these assessments will be done every 12 weeks (±7 days). These will shall occur regardless of dose delays or dose interruptions, until Investigator-assessed progressive disease (PD), or death, whichever occurs first. More frequent tumor assessments may be performed as clinically indicated, at the discretion of the treating Investigator.

For the phase II portion of the study - patients who discontinue treatment for reasons other than PD will continue to have required tumor assessments completed until PD or the initiation of a new therapy. Once patients have progressed, they will be followed for survival approximately every 3 months for at least 3 years. Subsequent anti-cancer therapies will be documented until study completion.

Patients who are discontinued from study treatment will return for the Study Treatment Discontinuation Visit approximately 30 days (±7 days) after the last dose of study treatment.

Arms: arm 1: One cycle of Trastuzumab Emtansine (T-DM1)/Vinorelbine combination treatment is defined as 21-days (i.e. 3 weeks). The recommended (starting) dose of trastuzumab emtansine is 3.6 mg/kg given as an intravenous infusion on Day 1 of every 21-day cycle. The starting dose of Vinorelbine is 22.5 mg/m2 given as a direct intravenous push over 6-10 minutes on day 1 and day 8 of every 3-week (i.e. 21-day) cycle. Participants will be treated until documented disease progression or other criteria for discontinuation. Approximately 15 to 21 patients will be needed to establish the recommended phase II dose (RP2D). arm 2: One cycle of trastuzumab emtansine (T-DM1)/vinorelbine combination treatment is defined as 21-days (i.e. 3 weeks). Participants will receive the recommended Phase 2 Dose (RPSD) of Vinorelbine with the fixed dose (3.6 mg/kg) of Trastuzumab Emtansine. Participants will be treated until documented disease progression or other criteria for discontinuation. Up to 35 patients will be treated at the RP2D (MTD) including 6 patients treated at RP2D in phase I.
Interventions: intervention 1: Vinorelbine intervention 2: Trastuzumab Emtansine
Intervention descriptions: intervention 1: Administered as an intravenous infusion on Day 1 and Day 8 of every 21-day cycle. intervention 2: Administered as an intravenous infusion on Day 1 of every 21-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
P a g e  1  of  9 7  
 
 
 
E P r ost  #  2 0 1 5 1 0 5 5  
I N D # (I N D E X E M P T ) 
A  P h as e I/II  St u d y t o  E v al u at e t h e  S af et y  a n d  Effi c a c y  of  Vi n o r el bi n e  wit h 
T r ast u z u m a b  E mt a nsi n e i n  P r e -T r e at e d  H E R 2 -P ositi v e  M et ast ati c  B r e ast 
C a n c e r  
 
S P O N S O R -I N V E S TI G A T O R: 
R es h m a  M a ht a ni,  D O  
 
Assist a nt  Pr of ess or  of  M e di ci n e  
Di visi o n  of  H e m at ol o g y/  O n c ol o g y 
U ni v ersit y  of  Mi a mi -S yl v est er 
C o m pr e h e nsi v e  C a n c er  C e nt er ( S C C C)  
 
I N V E S TI G A TI O N A L  A G E N T( S) : 
Vi n or el bi n e  –  C o m m er ci al  s u p pl y 
Tr ast u z u m a b  e mt a nsi n e ( K a d c yl a ®)  – 
G e n e nt e c h, I n c.  
 
O T H E R  A G E N T( S) : 
( N/ A)  
 
I N D  S T A T U S : 
I N D  or I D E  #: (I N D  e x e m pt) 
I N D  S p o ns o r: ( I N D  e x e m pt) 
 
P R O T O C O L  V E R SI O N  A N D  D A T E : 
 
3. 0  d at e d  2 8 N o v 2 0 1 7 
 
 
 
 
C o nfi d e nti alit y  St at e m e nt :  T h e i nf or m ati o n  c o nt ai n e d i n t his  d o c u m e nt,  es p e ci all y  u n p u blis h e d  d at a, is 
c o nfi d e nti al  pr o p ert y.   T h e i nf or m ati o n i n t his  d o c u m e nt  m a y  n ot  b e  dis cl os e d t o  ot h ers  u nl ess f e d er al  or 
st at e l a w  or r e g ul ati o ns r e q uir e s u c h  dis cl os ur e.   S u bj e ct t o t h e f or e g o i n g, t his i nf or m ati o n  m a y  b e 
dis cl os e d  o nl y t o t h os e  p ers o ns i n v ol v e d i n t h e st u d y  w h o  h a v e  a  n e e d t o  k n o w,  wit h t h e  o bli g ati o n  n ot t o 
f urt h er  diss e mi n at e t his i nf or m ati o n.         




C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
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V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  3  of  9 7  
 
 
 
 
  
 
  
 
 
 
   
 
   
 
   
 
 
 
 
 
 
 
 
 
   
   
   
   
   
 
 
 
 
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  4  of  9 7  
 
 
P R O T O C O L  R E VI SI O N  HI S T O R Y  
 
V e rsi o n  #  
S u m m a r y  of  C h a n g es  
V e rsi o n  D at e  
3 . 0 
S af et y  a n d  D osi n g  c h a n g es  p e r  D S M C  n otifi c ati o n:  
T h e  d o c u m e nt  w as  u p d at e d t hr o u g h o ut t o  m a k e 
a d mi nistr ati v e  c h a n g es t o i m pr o v e t h e  cl arit y  a n d 
c o nsist e n c y  of  pr ot o c ol.  
S e cti o n  3. 0 ( E n d p oi nts)  u p d at e d t o  pr o vi d e  cl arifi c ati o n  o n 
w h o is  e v al u a bl e f or  D L T.  
S e cti o n  7. 1 ( D os e  Es c al ati o n/ D os e  D e -Es c al ati o n)  u p d at e d 
t o i m pr o v e  cl arit y  a n d  c o nsist e n c y 
S e cti o n  7. 3. 1  u p d at e d t o  a d d  gr a d e  5 t o  S A Es  a n d i n cl u d e 
o nl y  p ossi bl e,  pr o b a bl e,  or  d efi nit e fi n di n gs t o  b e 
c o nsi d er e d  D L T.   U p d at e d  D L T l a n g u a g e t o i n cl u d e  n o n-
h e m at ol o gi c  gr a d e  3 +  A Es t h at li mit t h e  p ati e nt’s  a bilit y t o 
c o m p l et e tr e at m e nt  or  ar e  pr o bl e m ati c i n t h e  e y es  of t h e 
i n v esti g at or will  b e  c o nsi d er e d  D L T.  U p d at e d t h e ti m e t o 
e v al u at e  D L Ts t o  2 1- 4 2  d a ys r at h er t h a n  4 2.  
S e cti o n  8. 0 ( Tr e at m e nt  Pl a n)  u p d at e d t o  a d d  ± 5  mi n ut es t o 
t h e  a d mi nistr ati o n  of s u bs e q u e nt i nf usi o ns. A d d e d t h at 
st u d y  pr o c e d ur es  c a n  b e  h el d  d u e t o  A E,  S A E,  or  at t h e 
dis cr eti o n  of t h e i n v esti g at or if it is  n e c ess ar y.  
S e cti o n  1 2. 0 ( S c h e d ul e  of  Cli ni c al  a n d  L a b or at or y 
E v al u ati o ns)  u p d at e d t o  a d d t h at  o n c e  p ati e nt  m e ets  all 
eli gi bilit y  crit eri a, t h e  d at e  o f first  d os e is  c o nsi d er e d t h e 
e nr oll m e nt  d at e.  Cl arifi e d t h at s cr e e ni n g  e v al u ati o ns 
s h o ul d  b e  d o n e  wit hi n  2 8- d a ys  pri or t o  e nr oll m e nt  u nl ess 
ot h er wis e s p e cifi e d. 
S e cti o n  1 8. 0 (I n v esti g at or  R es p o nsi biliti es)  u p d at e d t o 
r e m o v e l a n g u a g e r e g ar di n g I N D  a n n u al r e p orts si n c e t his 
is  a n I N D  e x e m pt st u d y.  R e m o v e d l a n g u a g e r e g ar di n g 
1 5 7 2.  
A p p e n di x  A ( E x p e dit e d  A d v ers e  E v e nt ( A E)  R e p orti n g ) 
R e q uir e m e nts  u p d at e d t o r e m o v e  F D A  E x p e diti n g 
R e p orti n g s e cti o n  as t his is  a n I N D  e x e m pt st u d y. 
R e m o v e d l a n g u a g e r e g ar di n g  M e d W at c h  3 5 0 0 A f or m.  
2 8 N O V 2 0 1 7  


C O N FI D E N TI A L  
 
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e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  5  of  9 7  
 
2. 0   
V e rsi o n  n u m b e ri n g  a n d  P h a r m a c y  c h a n g es :  
T h e st arti n g  d os e  of  vi n or el bi n e is  2 2. 5  m g/ m 2  gi v e n  a s  a 
dir e ct i ntr a v e n o us  p b  o v er  8  mi n ut es  ± ( pl us  or  mi n us) _ 2 
mi n ut es  o n  d a y  1  a n d  d a y  8  of  e v er y  3- w e e k (i. e.  2 1- d a y) 
c y cl e.  
1 4 N O V 2 0 1 6  
1. 3  
A d mi nist r ati v e/ e dit o ri al  c h a n g es f o r  c o nsist e n c y: 
R e m o v e d  all r ef er e n c es t o  F D G -P E T s c a ns fr o m s e cti o n 
1 3. 1. 3  as  t h es e  ar e  n ot r e q uir e d  pr o c e d ur es i n t his  st u d y. 
C orr e ct e d  dr u g  n a m e i n titl e  of  Fi g ur es  1  a n d  3 f or 
c o nsist e n c y  wit h  pr ot o c ol t e xt.  
0 9 M A R 2 0 1 6  
1. 2  
A d mi nist r ati v e/ e dit o ri al  c h a n g es t o  eli mi n at e 
d u pli c ati o n:  (I n cl usi o n  crit eri a s e cti o n  5. 1. 1 5 r e m o v e d 
e xtr a  e ntr y f or  al k ali n e  p h os p h as e  ≤  5  X  U L N)  
0 9 M A R 2 0 1 6  
1. 1  
A d mi nist r ati v e/ e dit o ri al  c h a n g es f o r  c o nsist e n c y  a n d t o 
mi ni mi z e  c o nf usi o n  ( e. g.  v er bi a g e r e g ar di n g i m a gi n g)  
0 9 M A R 2 0 1 6  
1. 0  
V e rsi o n  n u m b e ri n g  a n d  S p o ns o r’s  S af et y  e dits:  
V ersi o n  n u m b eri n g r e v ert e d t o  1. 0 t o r efl e ct  pr ot o c ol 
d e v el o p m e nt  offi c e’s f or m at t o  pr o vi d e  o nl y  w h ol e 
n u m b er e d  v ersi o ns t o t h e I R B f or  a p pr o v al.   G e n e nt e c h 
s af et y  e dits  a n d r e q u est f or r e p orts  w er e  a d d e d t o  p.  9 3 
a n d t o  S e cti o n  1 8 . 6 ( p. 8 7) 
0 9 M A R 2 0 1 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
 
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P a g e  6  of  9 7  
 
 
 
T A B L E  O F  C O N T E N T S  
C O N T A C T I N F O R M A TI O N  .............................................................................................................................. 2 
 
P R O T O C O L  R E VI SI O N  HI S T O R Y  ..................................................................................................................... 4 
T A B L E  O F  C O N T E N T S  ..................................................................................................................................... 6 
A B B R E VI A TI O N S  &  D E FI NI TI O N S  ................................................................................................................... 9 
P R O T O C O L  S Y N O P SI S  .................................................................................................................................. 1 0  
P R O T O C O L  S C H E M A  .................................................................................................................................... 1 5  
  B A C K G R O U N D ....................................................................................................................................... 1 7  
 Br e ast  C a n c er  .................................................................................................................................... 1 7  
 Tr ast u z u m a b  e mt a nsi n e ( T -D M 1)  ..................................................................................................... 1 8  
 Tr ast uz u m a b  e mt a nsi n e ( T -D M 1):  Cli ni c al  e x p eri e n c e  ..................................................................... 1 8  
 Tr ast uz u m a b  e mt a nsi n e ( T -D M 1):  Cli ni c al  S af et y  ............................................................................. 2 1  
 B a c k gr o u n d  o n  Vi n or el bi n e ............................................................................................................... 2 2  
 R ati o n al e f or  St u d y  D esi g n  ................................................................................................................ 2 2  
 O BJ E C TI V E S  ........................................................................................................................................... 2 4  
 Pri m ar y  O bj e cti v es  ............................................................................................................................ 2 4  
 S e c o n d ar y  O bj e cti v es  ........................................................................................................................ 2 4  
 E N D P OI N T S  ........................................................................................................................................... 2 4  
 Pri m ar y  e n d p oi nts:  P h as e I  ............................................................................................................... 2 4  
 Pri m ar y  e n d p oi nts:  P h as e II  .............................................................................................................. 2 4  
 S e c o n d ar y  e n d p oi nts  ........................................................................................................................ 2 5  
 S U BJ E C T  R E C R UI T M E N T  &  S C R E E NI N G  ................................................................................................. 2 5  
 P A TI E N T  S E L E C TI O N  .............................................................................................................................. 2 6  
 I n cl usi o n  Crit eri a ............................................................................................................................... 2 6  
 E x cl usi o n  Crit eri a  ............................................................................................................................... 2 7  
 E nr oll m e nt  Pr o c e d ur es  ......................................................................................................................... 2 8  
 C a n c ell ati o n  G ui d eli n es ..................................................................................................................... 2 9  
 E m er g e n c y  R e gistr ati o n  .................................................................................................................... 2 9  
 S T U D Y  D E SI G N ....................................................................................................................................... 2 9  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
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V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  7  of  9 7  
 
 D os e  Es c al ati o n/  D os e  D e -Es c al ati o n  ................................................................................................ 3 0  
 D os e  Es c al ati o n  R ul es ........................................................................................................................ 3 0  
 D os e -Li miti n g  T o xi cit y ( D L T)  .............................................................................................................. 3 2  
 T R E A T M E N T  P L A N  ................................................................................................................................. 3 3  
 Tr ast uz u m a b  e mt a nsi n e  ................................................................................................................... 3 3  
 Vi n or el bi n e  ........................................................................................................................................ 3 4  
 Tr e at m e nt  S c h e m a  ............................................................................................................................ 3 4  
 Tr e at m e nt  Dis p e ns ati o n,  C o m pli a n c e  a n d  A c c o u nt a bilit y  ............................................................... 3 5  
 S u p p orti v e  C ar e  G ui d eli n es  ............................................................................................................... 3 5  
 D ur ati o n  of  Tr e at m e nt  ...................................................................................................................... 3 7  
 D ur ati o n  of  F oll o w - U p ...................................................................................................................... 3 7  
 A G E N T S ( D R U G  F O R M U L A TI O N  A N D  P R O C U R E M E N T)  ........................................................................ 3 7  
 Tr ast uz u m a b  e mt a nsi n e  ................................................................................................................... 3 7  
 Vi n or el bi n e  ........................................................................................................................................ 4 7  
 T R E A T M E N T/  D O S E  M O DI FI C A TI O N S/  D O S E  D E L A Y S  ......................................................................... 5 2  
 U n a c c e pt a bl e  T o xi cit y  ..................................................................................................................... 5 2  
 D os e  M o difi c ati o n/  D os e  D el a y  G ui d eli n es f or  Tr ast uz u m a b  e mt a nsi n e  ....................................... 5 2  
 D os e  M o difi c ati o n/  D os e  D el a y  G ui d eli n es f or  Vi n or el bi n e  ........................................................... 5 7  
 T R E A T M E N T  DI S C O N TI N U A TI O N  ........................................................................................................ 5 8  
 S C H E D U L E  O F  C LI NI C A L  &  L A B O R A T O R Y  E V A L U A TI O N S  .................................................................... 5 9  
 Pr e -Tr e at m e nt  E v al u ati o ns ( S cr e e ni n g)  .......................................................................................... 5 9  
 E v al u ati o ns  o n  Tr e at m e nt  ............................................................................................................... 6 1  
 Off -Tr e at m e nt  E v al u ati o ns ( E n d  of  Tr e at m e nt  or  E O T  visit)  ........................................................... 6 4  
 F oll o w -u p  E v al u ati o ns  ..................................................................................................................... 6 5  
 C al e n d ar  of  Cli ni c al  a n d  L a b or at or y  E v al u ati o ns  ............................................................................ 6 6  
 M E A S U R E M E N T  O F  E F F E C T  ................................................................................................................. 6 8  
 A ntit u m or  Eff e ct  –  S oli d  T u m ors  ..................................................................................................... 6 8  
 A D V E R S E  E V E N T S  ................................................................................................................................ 7 4  
 P ur p os e  ........................................................................................................................................... 7 4  
 A d v ers e  E v e nt  ................................................................................................................................. 7 5  
 S eri o us  A d v ers e  E v e nts (s e e  als o  A p p e n di x  A)  ............................................................................... 7 6  
 A d v ers e  E v e nt  C oll e cti o n  P eri o d  ..................................................................................................... 7 7  
 A d v ers e  E v e nt  R e p orti n g  R e q uir e m e nts  ......................................................................................... 7 7  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
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 A d diti o n al  G e n er al  G ui d eli n es f or  C o nsist e nt  C a us alit y  Ass ess m e nts ............................................ 7 8  
 E x p e dit e d  A d v ers e  E v e nt  R e p orti n g  R e q uir e m e nts  ........................................................................ 7 8  
 Alt er n at e  D efi niti o ns  ....................................................................................................................... 7 9  
 S T A TI S TI C A L  C O N SI D E R A TI O N S  ........................................................................................................... 7 9  
 P ati e nt  e nr oll m e nt  a n d f oll o w -u p ................................................................................................... 7 9  
 D A T A  R E P O R TI N G  ................................................................................................................................ 8 1  
 D at a  a n d  S af et y  M o nit ori n g  ............................................................................................................ 8 1  
 S T U D Y  M O NI T O RI N G  .......................................................................................................................... 8 5  
 IN V E S TI G A T O R  R E S P O N SI BI LI TI E S  ....................................................................................................... 8 5  
 I n v esti g at or  R es p o nsi bilit y/ P erf or m a n c e ....................................................................................... 8 5  
 C o nfi d e nti alit y  ................................................................................................................................. 8 5  
 I nf or m e d  C o ns e nt  a n d  P er missi o n t o  Us e  Pr ot e ct e d  H e alt h I nf or m ati o n ..................................... 8 5  
 S o ur c e  D o c u m e nt ati o n  a n d I n v esti g at or  Fil es  ................................................................................ 8 6  
 R e c or di n g  a n d  Pr o c essi n g  of  D at a  .................................................................................................. 8 6  
 R e p orts t o  S p o ns or  ......................................................................................................................... 8 7  
 N o n -Pr ot o c ol  R es e ar c h  ................................................................................................................... 8 7  
 Et hi cs  ............................................................................................................................................... 8 7  
 Ess e nti al  d o c u m e nts f or t h e  c o n d u ct  of  a  cli ni c al tri al  ................................................................... 8 7  
R E F E R E N C E S  ................................................................................................................................................ 8 8  
A P P E N DI X  A:  E X P E DI T E D  A D V E R S E  E V E N T ( A E)  R E P O R TI N G  R E Q UI R E M E N T S  ........................................... 9 1  
A P P E N DI X  B:  D A T A  S U B MI S SI O N  S C H E D U L E  .............................................................................................. 9 3  
A P P E N DI X  C:  P E R F O R M A N C E  S T A T U S  S C A L E S  ............................................................................................ 9 4  
A P P E N DI X  D:  N Y H A  C L A S SI FI C A TI O N  O F  H E A R T  DI S E A S E  ........................................................................... 9 5  
A P P E N DI X  E:  A L G O RI T H M  F O R  C O N TI N U A TI O N  &  DI S C O N TI N U A TI O N  O F  T R A S T U Z U M A B  E M T A N SI N E 
B A S E D  O N  L E F T  V E N T RI C U L A R  EJ E C TI O N  F R A C TI O N  A S S E S S M E N T S I N  P A TI E N T S  ..................................... 9 6  
S A F E T Y  R E P O R TI N G  F A X  C O V E R  S H E E T ....................................................................................................... 9 7  
 
Fi g ur e  1:  P h as e I  ...........................................................................................................................  1 5 
Fi g ur e  2:  P h as e II  ..........................................................................................................................  1 6 
Fi g ur e  3:  S c h e m a f or  P h as e I  D os e  Es c al ati o n/  D e -es c al ati o n  .....................................................  3 1 
  


C O N FI D E N TI A L  
 
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A B B R E VI A TI O N S  &  D E FI NI TI O N S  
 
T e r m  
A b b r e vi ati o n   D efi niti o n  
D os e -Li miti n g  T o xi cit y   
D L T   
D es cri b es si d e  eff e cts  of  a  dr u g  or  ot h er 
tr e at m e nt t h at  ar e s eri o us  e n o u g h t o  pr e v e nt  a n 
i n cr e as e i n  d os e  or l e v el  of t h at tr e at m e nt.   
( D L Ts  ar e  d efi n e d  b ef or e  b e gi n ni n g t h e tri al 
a n d  ar e  pr ot o c ol- s p e cifi c.)  
M a xi m u m  T ol er at e d  D os e   
M T D   
T h e  hi g h est  d os e  of  a  dr u g  or tr e at m e nt t h at 
d o es  n ot  c a us e  u n a c c e pt a bl e si d e  eff e cts.   T h e 
M T D is  d et er mi n e d i n  cli ni c al tri als  b y t esti n g 
i n cr e asi n g  d os es  o n  diff er e nt  gr o u ps  of  p e o pl e 
u ntil t h e  hi g h est  d os e  wit h  a c c e pt a bl e si d e 
eff e cts is f o u n d.  
O v er a ll  S ur vi v al 
O S  
T h e l e n gt h  of ti m e fr o m t h e  d at e  of t h e st art  of 
tr e at m e nt f or  a  dis e as e, t h at  p ati e nts  di a g n os e d 
wit h t h e  dis e as e  ar e still  ali v e.    
Pr o gr essi o n -Fr e e  S ur vi v al   
P F S   
T h e l e n gt h  of ti m e  d uri n g  a n d  aft er t h e 
tr e at m e nt  of  a  dis e as e t h at  a  p ati e nt li v es  wit h 
t h e  dis e as e  b ut it  d o es  n ot  g et  w ors e.   
R e c o m m e n d e d  P h as e  2 
D os e  
R P 2 D   
T h e  hi g h est  d os e l e v el  b el o w t h e  m a xi m all y 
a d mi nist er e d  d os e ( hi g h est  d os e  a d mi nist er e d) 
at  w hi c h  ≤ 1  o ut  of  6  p ati e nts tr e at e d,  m a y  h a v e 
e x p eri e n c e d  a  D L T.  
Ti m e t o  Pr o gr essi o n   
T T P   
T h e l e n gt h  of ti m e fr o m t h e  d at e  of  di a g n osis  or 
t h e st art  of tr e at m e nt f or  a  dis e as e  u ntil t h e 
dis e as e st arts t o  g et  w ors e  or s pr e a d t o  ot h er 
p arts  of t h e  b o d y.   
 
R ef e r e n c e :  N ati o n al  C a n c er I nstit ut e ( N CI)  Di cti o n ar y  of  C a n c er  T er ms 
htt p:// w w w. c a n c er. g o v/ di cti o n ar y      
 




C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  1 1  of  9 7  
 
•   T o  e v al u at e t h e  effi c a c y ,  as  d et er mi n e d  b y  P F S, of t h e  R P 2 D  of  vi n or el bi n e  c o m bi n e d 
wit h  a fi x e d  d os e  of tr ast u z u m a b  e mt a nsi n e i n  pr e- tr e at e d  H E R 2- p ositi v e  M B C. 
P h as e II  S e c o n d ar y  O bj e cti v es:  
•   T o  d et er mi n e t h e  o v er all r es p o ns e r at e ( O R R),  cli ni c al  b e n efit r at e ( C B R) ,  a n d  o v er all 
s ur vi v al ( O S)  of t h e  R P 2 D  of  vi n or el bi n e  c o m bi n e d  wit h  a fi x e d  d os e  of tr ast u z u m a b 
e mt a nsi n e  
E x p e ct e d 
N u m b e r  of 
P ati e nts  
5 0  
E x p e ct e d 
N u m b e r  of 
C e nt e rs  
1  –  S yl v est er  C o m pr e h e nsi v e  C a n c er  C e nt er ( S C C C)  M ai n  C a m p us  (i n cl usi v e  of  c o nstit u e nt 
S at ellit e  Sit es:  D e erfi el d  B e a c h  a n d  Pl a nt ati o n )  
E x p e ct e d 
D u r ati o n 
of t h e 
P r ot o c ol  
E x p e ct e d t ot al st u d y  d ur ati o n is  4. 5 t o  5  y e ars.  
I n cl usi o n 
C rit e ri a  
  Hist ol o gi c all y  or  c yt ol o gi c all y  d o c u m e nt e d  br e ast  c a n c er.  
  M et ast ati c  or  u nr es e ct a bl e l o c all y  a d v a n c e d/r e c urr e nt  br e ast  c a n c er.  
  H E R 2 -p ositi v e  dis e as e  d o c u m e nt e d  as: I H C  3 +  p ositi v e,  a n d/ or  FI S H  ≥  2. 0,  a n d/ or  g e n e 
c o p y  n u m b er  gr e at er t h a n  6,  o n  pr e vi o usl y  c oll e ct e d t u m or  o r  m et ast ati c sit e.  I H C 
t esti n g,  FI S H  ass a y(s),  a n d  g e n e  c o p y  n u m b er  m a y  all  h a v e  b e e n  p erf or m e d;  h o w e v er,  a 
p ositi v e r es ult fr o m  o nl y  o n e   of t h e  a b o v e is r e q uir e d f or  eli gi bilit y. 
  D o c u m e nt e d  dis e as e  pr o gr essi o n  o n t h e l ast r e gi m e n  b y r a di o gr a p hi c  m e as ur e m e nt 
( pr o gr essi o n  d e m o nstr at e d  b y t u m or  m ar k ers  o nl y is  u n a c c e pt a bl e). 
  D o c u m e nt e d  dis e as e  pr o gr essi o n ( b y i n v esti g at or  ass ess m e nt)  aft er  at l e ast  o n e r e gi m e n 
of  H E R 2 -dir e ct e d t h er a p y i n t h e  m et ast ati c  or  u nr es e ct a bl e l o c all y  a d v a n c e d/r e c urr e nt 
s etti n g.  
  F or  p ati e nts  wit h  h or m o n e r e c e pt or- p ositi v e  dis e as e:  dis e as e  pr o gr essi o n  or r e c urr e n c e i n 
a n y s etti n g  o n  pri or  h or m o n al t h er a p y,  gi v e n  wit h  or  wit h o ut  H E R 2  dir e ct e d t h er a p y. 
  M e as ur a bl e  or  b o n e  o nl y  dis e as e.  
  Pri or tr e at m e nt  wit h  a t a x a n e, i n t h e  n e o a dj u v a nt,  a dj u v a nt, l o c all y  a d v a n c e d  or 
m et ast ati c s etti n g.  
  A  mi ni m u m  of  6  w e e ks  of  pri or tr ast u z u m a b f or t h e tr e at m e nt  of  m et ast ati c  or 
u nr es e ct a bl e l o c all y  a d v a n c e d/r e c urr e nt  dis e as e is r e q uir e d.   
 Pri or  us e  of  P ert u z u m a b i n  a n y  s etti n g is  p er mitt e d  ( b ut  n ot r e q uire d) . 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  1 2  of  9 7  
 
 Pri or  us e  of  L a p ati ni b i n  a n y s etti n g is  p er mitt e d ( b ut  n ot r e q uir e d).  
 A g e  ≥  1 8  y e ars  
 Lif e  e x p e ct a n c y  ≥ 3  m o nt hs  
 E ast er n  C o o p er ati v e  O n c ol o g y  Gr o u p ( E C O G)  p erf or m a n c e st at us  of  0  or  1.   S e e 
A p p e n di x  C f or  d et ails. 
 P ati e nts  m ust  h a v e  n or m al  or g a n  a n d  m arr o w f u n cti o n  as  d efi n e d  b el o w: 
•   a bs ol ut e  n e utr o p hil  c o u nt ( A N C)  > 1, 5 0 0  c ells/ m m 3 
•   pl at el ets  > 1 0 0, 0 0 0  c ells/ m m 3  
•   h e m o gl o bi n  >  9. 0  g/ d L ( P ati e nts  ar e  p er mitt e d t o r e c ei v e tr a nsf us e d r e d  bl o o d 
c ells t o  a c hi e v e t his l e v el.)  
•   t ot al  bilir u bi n  ≤ 1. 5  X i nstit uti o n al  up p er li mit  of  n or m al ( U L N) [ N ot e :  F or 
p ati e nts  wit h  pr e vi o usl y  d o c u m e nt e d  Gil b ert’s s y n dr o m e, t ot al  bilir u bi n  ≤  3 
m g/ d L.]  
•   A S T( S G O T)  ≤ 2. 5  X  U L N  
•   A L T( S G P T)  ≤ 2. 5  X  U L N  
•   al k ali n e  p h os p h at as e ( al k  p h os)  ≤ 2. 5  X  U L N  
•   s er u m  cr e ati ni n e  <  1. 5  X  U L N  
 I nt er n ati o n al n or m ali z e d r ati o (I N R)  <  1. 5  X  U L N  
 L eft  v e ntri c ul ar  ej e cti o n fr a cti o n ( L V E F)  ≥  5 0 %  b y  eit h er  e c h o c ar di o gr a m ( E C H O)  or 
m ulti pl e -g at e d  a c q uisiti o n s c a n ( M U G A )  wit hi n s cr e e ni n g  wi n d o w.  
 ( T his tri al is  o p e n t o  m al es a n d f e m al es.)  N e g ati v e r es ults  of s er u m  pr e g n a n c y t est f or 
pr e m e n o p a us al  w o m e n  of r e pr o d u cti v e  c a p a cit y  a n d f or  w o m e n  <  1 2  m o nt hs  aft er 
m e n o p a us e.  F or  m e n  a n d  w o m e n  of  c hil d b e ari n g  p ot e nti al,  a gr e e m e nt  b y t h e  p ati e nt 
a n d/ or  p art n er t o  us e  t w o eff e cti v e,  n o n- h or m o n al  f orms  of  b arri er  c o ntr a c e pti o n  at t h e 
s a m e ti m e, t hr o u g h o ut tr e at m e nt  o n st u d y.  W o m e n s h o ul d  a gr e e t o  c o nti n u e d  us e f or  at 
l e ast 9 0  d a ys  aft er t h e  e n d  of tr e at m e nt.  M e n s h o ul d  a gr e e t o  c o nti n u e d  us e f or  at l e ast  7 
m o nt hs  aft er t h e  e n d  of tr e at m e nt.  E x a m pl es  o f  b arri er  c o ntr a c e pti o n i n cl u d e:  c o n d o m  or 
o c cl usi v e  c a p ( di a p hr a g m  or  c er vi c al/ v a ult  c a ps)  wit h s p er mi ci d e.   
 A bilit y t o  u n d erst a n d  a n d  willi n g n ess t o si g n  a  writt e n i nf or m e d  c o ns e nt  a n d  HI P A A 
d o c u m e nt. 
 
E x cl usi o n 
C rit e ri a  
  C h e m ot h er a p y  ≤ 2 1  d a ys  pri or t o  first  d os e  of st u d y tr e at m e nt   
  If l ast  d os e  of tr ast u z u m a b  w as: 
•   6 m g/ k g t h e n  ≤ 2 1  d a ys  pri or t o  first  d os e  of st u d y tr e at m e nt 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  1 3  of  9 7  
 
•   4 m g/ k g t h e n  ≤ 1 4  d a ys  pri or t o  first  d os e  of st u d y tr e at m e nt 
•   2 m g/ k g t h e n  ≤ 7  d a ys  pri or t o  first  d os e  of st u d y tr e at m e nt 
  L a p ati ni b  ≤ 1 4  d a ys  pri or t o  first  d os e  of st u d y tr e at m e nt 
  P ert u z u m a b  ≤ 2 1  d a ys  pri or t o first  d os e  of st u d y tr e at m e nt  
  H or m o n e t h er a p y  ≤ 7  d a ys  pri or t o  first  d os e  of st u d y tr e at m e nt 
  I n v esti g ati o n al t h er a p y  or  a n y  ot h er s u c h  e x p eri m e nt al t h er a p y  ≤ 2 8  d a ys  pri or t o first 
d os e  of st u d y tr e at m e nt 
  Pri or tr e at m e nt  wit h tr ast u z u m a b  e mt a nsi n e, ( o n  or  off  a st u d y  pr ot o c ol) 
  Pri or  us e  of  vi n or el bi n e (i n  a n y s etti n g). 
  Pr e vi o us r a di ot h er a p y f or t h e tr e at m e nt  of  u nr es e ct a bl e, l o c all y  a d v a n c e d, r e c urr e nt  or 
m et ast ati c  br e ast  c a n c er is   n ot all o w e d if:  
•   T h e l ast fr a cti o n  of r a di ot h er a p y  h as  b e e n  a d mi nist er e d  wit hi n  1 4  d a ys  pri or t o 
st u d y  e nr oll m e nt   
•   M or e t h a n  2 5 %  of  m arr o w -b e ari n g  b o n e  h as  b e e n irr a di at e d  
 Br ai n  m et ast as es t h at  ar e  u ntr e at e d  or s y m pt o m ati c,  or r e q uir e  a n y r a di ati o n, s ur g er y,  or 
c o nti n u e d st er oi d t h er a p y t o  c o ntr ol s y m pt o ms fr o m  br ai n  m et ast as es  wit hi n  1 4  d a ys  of 
st u d y  e nr oll m e nt.  
 Hist or y  of i nt ol er a n c e (i n cl u di n g  Gr a d e  3  or  4 i nf usi o n r e a cti o n)  or  h y p ers e nsiti vit y t o 
tr ast u z u m a b  or  m uri n e  pr ot ei ns. 
 Hist or y  of  e x p os ur e t o t h e f oll o wi n g  c u m ul ati v e  d os es  of  a nt hr a c y cli n es: 
•   D o x or u bi ci n  ≥ 5 5 0 m g/ m 2  
•   Li p os o m al  d o x or u bi ci n  > 5 0 0  m g/ m 2 
•   E pir u bi ci n  > 9 0 0  m g/ m 2 
•   Mit o x a ntr o n e  >  1 2 0  m g/ m
2 
•   If  a n ot h er  a nt hr a c y cli n e,  or  m or e t h a n  o n e  a nt hr a c y cli n e,  h as  b e e n  us e d, t h e 
c u m ul ati v e  d os e  m ust  n ot  e x c e e d t h e  e q ui v al e nt  of  ≥ 5 5 0  m g/ m 2  d o x or u bi ci n. 
 C urr e nt  p eri p h er al  n e ur o p at h y  of  Gr a d e  ≥ 3  p er t h e  N CI  C T C A E,  v 4. 0  
 T h e  p ati e nt  h as  n ot r e c o v er e d fr o m  a n y  ot h er  a c ut e t o xi cit y (t o  Gr a d e  ≤ 1  as  p er  N CI 
C T C A E  v 4. 0 3)  pri or t o st u d y  e nr oll m e nt.  
 Hist or y  of  ot h er  m ali g n a n c y  wit hi n t h e l ast  3  y e ars,  e x c e pt f or  a p pr o pri at el y tr e at e d 
c ar ci n o m a  i n sit u of t h e  c er vi x,  n o n- m el a n o m a s ki n  c ar ci n o m a,  St a g e I  ut eri n e  c a n c er,  or 
ot h er  c a n c ers  wit h  a si mil ar  o ut c o m e.  
 C ar di o p ul m o n ar y  F u n cti o n  Crit eri a: 
•   C urr e nt  u nst a bl e  v e ntri c ul ar  arr h yt h mi a r e q uiri n g tr e at m e nt  
•   Hist or y  of s y m pt o m ati c  c o n g esti v e  h e art f ail ur e ( C H F)  as  p er  N e w  Y or k  H e art 
Ass o ci ati o n [ N Y H A]  Cl ass es II −I V; s e e  A p p e n di x  D f or  d et ails.  
•   Hist or y  of  m y o c ar di al i nf ar cti o n  or  u nst a bl e  a n gi n a  wit hi n  6  m o nt hs  of st u d y 
e nr oll m e nt  
•   Hist or y  of  a  d e cr e as e i n  L V E F t o  <  4 0 %  or s y m pt o m ati c  C H F  wit h  pr e vi o us 
tr ast u z u m a b tr e at m e nt 
•   S e v er e  d ys p n e a  at r est  d u e t o  c o m pli c ati o ns  of  a d v a n c e d  m ali g n a n c y  or 
r e q uiri n g  c urr e nt  c o nti n u o us  o x y g e n t h er a p y 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  1 4  of  9 7  
 
 C urr e nt s e v er e,  u n c o ntr oll e d s yst e mi c  dis e as e ( e. g.,  cli ni c all y si g nifi c a nt  c ar di o v as c ul ar, 
p ul m o n ar y,  or  m et a b oli c  dis e as e) 
•   M aj or s ur gi c al  pr o c e d ur e  or si g nifi c a nt tr a u m ati c i nj ur y  wit hi n  2 8  d a ys - b ef or e 
e nr oll m e nt  or  a nti ci p ati o n  of t h e  n e e d f or  m aj or s ur g er y  d uri n g t h e  c o urs e  of 
st u d y tr e atm e nt  
•   C urr e nt  pr e g n a n c y  or l a ct ati o n 
•   C urr e nt  k n o w n  u n c o ntr oll e d  a cti v e i nf e cti o n  wit h  HI V,  h e p atitis  B,  a n d/ or 
h e p atitis  C  vir us  
 A n y  u n c o ntr oll e d, i nt er c urr e nt ill n ess i n cl u di n g  b ut  n ot li mit e d t o  o n g oi n g  or  a cti v e 
i nf e cti o n, s y m pt o m ati c  c o n g esti v e  h e art f ail ur e,  u nst a bl e  a n gi n a  p e ct oris,  c ar di a c 
arr h yt h mi a.   
1 9.  A n y  ot h er s eri o us  m e di c al  or  ps y c hi atri c ill n ess/ c o n diti o n li k el y i n t h e j u d g m e nt  of t h e 
I n v esti g at or(s) t o i nt erf er e  or li mit  c o m pli a n c e  wit h st u d y r e q uir e m e nts/tr e at m e nt.  
 
 
 
 




C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  1 6  of  9 7  
 
 
Fi g ur e  2 :  P h as e II 
 
 
 




C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  1 8  of  9 7  
 
 T r ast u z u m a b  e mt a nsi n e  ( T-D M 1)  
D es pit e t h e  a v ail a bilit y  of  ot h er  H E R 2 t ar g et e d t h er a pi es s u c h  as l a p ati ni b,  as  w ell  as 
s e v er al  ot h er  c yt ot o xi c  dr u gs,  m ost  p ati e nts  wit h  H E R 2 +  br e ast  c a n c er  will  ulti m at el y 
d e v el o p  pr o gr essi o n  of  dis e as e  a n d t h e  a p pr o v al  of  ot h er  o pti o ns f or t h es e  p ati e nt s is 
e a g erl y  a w ait e d.  T -D M 1 is  a  n o v el  a nti b o d y -dr u g  c o nj u g at e ( A D C)  a n d  w as  a p pr o v e d i n 
2 0 1 2 f or t h e tr e at m e nt  of  H E R 2 +  m et ast ati c  br e ast  c a n c er  p ati e nts  w h os e  dis e as e  h a d 
pr o gr ess e d  o n tr ast u z u m a b  a n d  a t a x a n e.  
A D Cs r e pr es e nt  a  n e w t h er a p e uti c  a p pr o a c h  i n t h at t h es e  a g e nts  utili z e t h e li n k a g e  of  a 
c yt ot o xi c   a g e nt  t o   hi g hl y  s p e cifi c   m o n o cl o n al   a nti b o di es.   T his   m e c h a nis m  t h er e b y  
t ar g ets  u ni q u e  a n d/ or  o v er e x pr ess e d  c ell s urf a c e t u m or  a nti g e ns  a n d f o c us es t h e  d eli v er y 
of s u c h  a g e nts t o t u m or  c ells,  p ot e nti al l y  cr e ati n g  a  m or e f a v or a bl e t h er a p e uti c  wi n d o w 
t h a n  c o ul d  b e  a c hi e v e d  b y t h eir  a d mi nistr ati o n  as fr e e  dr u gs. 
T- D M 1  is  s p e cifi c all y   d esi g n e d  f or  t h e  tr e at m e nt   of   H E R 2-p ositi v e   c a n c er.  It  is  
c o m p os e d  of t h e f oll o wi n g  c o m p o n e nts: tr ast u z u m a b,  a  h u m a ni z e d  a nt i b o d y  dir e ct e d 
a g ai nst t h e  e xtr a c ell ul ar r e gi o n  of  H E R 2;  D M 1,  a n  a nti -mi cr ot u b ul e  a g e nt  d eri v e d fr o m 
m a yt a nsi n e;   a n d  s u c ci ni mi d yl   4 -[ N-m al ei mi d o m et h yl]   c y cl o h e x a n e - 1-c ar b o x yl at e 
( S M C C),  a t hi o et h er li n k er  m ol e c ul e  us e d t o  c o nj u g at e  D M 1 t o tr ast u z u m a b.9 ,1 0 
T- D M 1  bi n ds t o  H E R 2  wit h  a n  affi nit y si mil ar t o t h at  of  u n c o nj u g at e d tr ast u z u m a b .1 1 It 
is   h y p ot h esi z e d  t h at   aft er   bi n di n g  t o   H E R 2,  T- D M 1  u n d er g o es  r e c e pt or -m e di at e d 
i nt er n ali z ati o n, r esulti n g i n i ntr a c ell ul ar r el e as e  of  D M 1  a n d s u bs e q u e nt  c ell  d e at h.  D M 1 
is  a n i n hi bit or  of t u b uli n  p ol y m eri z ati o n; it  bi n ds t o t u b uli n  c o m p etiti v el y  wit h  vi n c a 
al k al oi ds. 9  T-D M 1  als o  h as  b e e n s h o w n i n  pr e cli ni c al st u di es t o r et ai n t h e  a cti viti es  of 
u n c o nj u g at e d  tr ast u z u m a b  i n cl u di n g  i n hi biti o n   of   H E R 2  s h e d di n g,  i n hi biti o n   of  
PI 3 K/ A K T si g n ali n g  p at h w a ys,  a n d  a nti b o d y  d e p e n d e nt  c ell ul ar  c yt ot o xi cit y. 1 1   
C o m pl et e d  a n d  o n g oi n g  P h as e I, II  a n d III st u di es  of  T- D M 1  h a v e  d e m o nstr at e d   its 
cli ni c al  a cti vit y  w h e n  gi v e n  as  a si n gl e  a g e nt t o  p ati e nts  wit h  H E R 2 -p ositi v e  M B C  w h o 
h a v e  pr o gr ess e d  o n  a tr ast u z u m a b -c o nt ai ni n g  c h e m ot h er a p y r e gi m e n.  D at a fr o m  cli ni c al 
tri als  of T- D M 1  t h at  ar e r el e v a nt t o t h e  d esi g n  of t h e  c urr e nt tri al  ar e s u m m ari z e d  b el o w. 
Pl e as e r ef er  t o t h e T- D M 1  I n v esti g at or’s  Br o c h ur e (I B) f or f urt h er i nf or m ati o n  o n  all 
c o m pl et e d  a n d  o n g oi n g st u di es. 
 T r ast u z u m a b  e mt a n si n e ( T-D M 1):  Cli ni c al  e x p e ri e n c e   
T h e f oll o wi n g  p h as e II  a n d  p h as e III st u di es  h a v e  d e m o nstr at e d  cli ni c al  b e n efit  of  T-
D M 1  i n   w o m e n   wit h   m et ast ati c   br e ast   c a n c er:   T D M 4 4 5 0 g,   T D M 5 2 4 8 g,   a n d   T D M  
4 3 7 0 g/ B O 2 1 9 7 7. 
 St u d y  T D M 4 4 5 0 g ( Si n gl e- A g e nt  T -D M 1 i n  Pr e vi o usl y  U ntr e at e d  M et ast ati c  Br e ast 
C a n c er  P ati e nts)  
T D M 4 4 5 0  w as  a r a n d o mi z e d,  m ulti c e nt er,  P h as e II st u d y  of t h e  effi c a c y  a n d 
s af et y  of T- D M 1  v ers us tr ast u z u m a b  pl us  d o c et a x el i n  p ati e nts  wit h  m et ast ati c 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  1 9  of  9 7  
 
H E R 2 -p ositi v e  br e ast  c a n c er  w h o  h a v e  n ot r e c ei v e d  pri or  c h e m ot h er a p y f or 
m et ast ati c  dis e as e .1 2   T his st u d y  c o m pl et e d  e nr oll m e nt i n  D e c e m b er  2 0 0 9 ( n  = 
1 3 7).  T h e  pri m ar y  o bj e cti v es  w er e t o  ass ess t h e  effi c a c y  of  T- D M 1  c o m p ar e d 
wit h t h e  c o m bi n ati o n  of tr ast u z u m a b  a n d  d o c et a x el,  as  m e as ur e d  b y  P F S  b as e d 
o n i n v esti g at or t u m or  ass ess m e nts,  a n d t o  c h ar a ct eri z e t h e s af et y  of  T- D M 1  
c o m p ar e d  wit h t h e  c o m bi n ati o n  of tr ast u z u m a b  a n d  d o c et a x el i n t his  p o p ul ati o n.  
S e c o n d ar y  e n d p oi nts i n cl u d e d  O R R, s ur vi v al,  a n d  d ur ati o n  of r es p o ns e,  cli ni c al 
b e n efit r at e,  a n d  q u alit y  of lif e. 
S e v e nt y  p ati e nts  w er e  r a n d o mi z e d t o t h e  c o ntr ol  ar m  a n d  6 7  p ati e nts t o t h e  T-
D M 1   ar m.  T h e  m e di a n  d ur ati o n  of f oll o w- u p  w as  a p pr o xi m at el y  1 4  m o nt hs f or 
t h e  effi c a c y  a n al ysis  a n d  a p pr o xi m at el y  2 3  m o nt hs f or t h e  u p d at e d s af et y 
a n al ysis.   
T h e  m e di a n  d ur ati o n  of tr e at m e nt  w as  8. 1 m o nt hs f or tr ast u z u m a b,  5. 5  m o nt hs 
f or  d o c et a x el,  a n d  1 0. 4  m o nt hs f or  T-D M 1 . I n t h e  pri m ar y  effi c a c y  a n al ysis, T-
D M 1   pr o vi d e d  a n i m pr o v e m e nt i n  P F S.  T h e  m e di a n  P F S  w as  1 4. 2  m o nt hs i n t h e 
T- D M 1   ar m  v ers us  9. 2  m o nt hs i n t h e tr ast u z u m a b  pl us  d o c et a x el  ar m.  T h e 
h a z ar d r ati o ( H R) f or  P F S  w as  0. 5 9 4 ( 9 5 %  CI:  0. 3 6 4,  0. 9 6 8;  p  =  0. 0 3 5 3).  T h e 
O R R i n t h e  T- D M 1  ar m  w as  6 4. 2 % ( 9 5 %  CI:  5 1. 8 %,  7 4. 8 %)  c o m p ar e d  wit h 
5 8. 0 % ( 9 5 %  CI:  4 5. 5 %,  6 9. 2 %) i n t h e  c o ntr ol  ar m ( b as e d  o n  6 9  e v al u a bl e 
p ati e nts).  T h e  cli ni c al  b e n efit r at e  w as  7 4. 6 % ( 9 5 %  CI:  6 3. 2 %,  8 4. 2 %) i n t h e  T-
D M 1  ar m  v ers us  8 1. 2 % ( 9 5 %  CI:  7 0. 7 %,  8 9. 1 %) i n t h e tr ast u z u m a b  pl us 
d o c et a x el  ar m ( b as e d  o n  6 9  e v al u a bl e  p ati e nts).   
B as e d  o n s af et y  d at a  a n al y z e d  at t h e  d at a  c ut off  d at e, si n gl e -a g e nt  T- D M 1  
a p p e ars t o  h a v e  a f a v or a bl e  o v er all s af et y  pr ofil e  c o m p ar e d  wit h tr ast u z u m a b  a n d 
d o c et a x el i n first -li n e  M B C.  T h e i n ci d e n c e  of  Gr a d e  ≥  3  A Es i n t h e  c o ntr ol  ar m 
( 9 0. 3 %;  n  =  6 6)  w as  n e arl y t wi c e t h at  of T- D M 1  ( 4 6. 4 %;  n  = 6 9).  T h e r at es  of 
S A Es f or  b ot h  ar ms  w er e si mil ar ( c o ntr ol  ar m  2 5. 8 %  vs.  T- D M 1  2 0. 3 %).  O n e 
p ati e nt i n t h e  T- D M 1   gr o u p  di e d  as  a r es ult  of  a n  A E (s u d d e n  d e at h).  T his 
p ati e nt  w as r a n d o mi z e d t o r e c ei v e tr ast u z u m a b  pl us  d o c et a x el  b ut  mist a k e nl y 
r e c ei v e d  a si n gl e  d os e  of  6  m g/ k g T- D M 1  i nst e a d  of  6  m g/ k g tr ast u z u m a b.  ( D at a 
o n  Fil e,  G e n e nt e c h)  O n e  p ati e nt i n t h e tr ast u z u m a b  pl us  d o c et a x el  gr o u p  di e d 
d u e t o  c ar di o p ul m o n ar y f ail ur e.  Wit h r es p e ct t o  c ar di ot o xi cit y,  b as e d  o n l o c al 
ass ess m e nts  of  L V E F,  T- D M 1  w as  n ot  ass o ci at e d  wit h  a n i n cr e as e i n 
c ar di ot o xi cit y  c o m p ar e d  wit h tr ast u z u m a b  pl us  d o c et a x el.  
 St u d y  T D M 4 2 5 8 g ( Si n gl e- A g e nt  T -D M 1 i n  Pr e vi o usl y  Tr e at e d  M et ast ati c  Br e ast 
C a n c er  P ati e nts)  
St u d y  T D M 4 2 5 8 g  w as  a si n gl e  ar m  p h as e II st u d y t h at  e v al u at e d t h e s af et y  a n d 
effi c a c y  of  T- D M 1   a d mi nist er e d  at  a  d os e  of  3. 6  m g/ k g (i ntr a v e n o us [I V])  q 3 w 
i n  H E R 2- p ositi v e  M B C  p ati e nts  w h o  h a d  pr o gr ess e d  o n  pr e vi o us  H E R 2-dir e ct e d 
t h er a p y  a n d  c o n v e nti o n al  c h e m ot h er a p y.1 0 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  2 0  of  9 7  
 
T h e  pri m ar y  o bj e cti v es f or t his st u d y  w er e t o  ass ess  O R R  b y i n d e p e n d e nt 
r a di ol o gi c r e vi e w  ass o ci at e d  wit h T- D M 1   3. 6  m g/ k g I V  q 3 w,  a n d t o  c h ar a ct eri z e 
t h e s af et y  a n d t ol er a bilit y  of  T-D M 1   at t his  d os e.   T h e st u d y  w as  a cti v at e d  o n 
J ul y  2 0,  2 0 0 7,  a n d  e nr oll m e nt  w as  c o m pl et e d ( n  =  1 1 2)  o n J ul y  3 1,  2 0 0 8.  T h e 
fi n al  a n al ysis  of  O R R  w as  p erf or m e d  wit h  a  d at a  c ut off  d at e  of J u n e  2 5,  2 0 0 9,  1 1 
m o nt hs  aft er t h e l ast  p ati e nt  w as  e nr oll e d.  T h e r e p ort e d  O R R i n  all  p ati e nts  w as 
2 5. 9 % ( 9 5 %  CI,  1 8. 4 %,  3 4. 4 %)  b y I n d e p e n d e nt  R e vi e w  C o m mitt e e (I R C)  a n d 
w as  3 7. 5 % ( 9 5 %  c o nfi d e n c e i nt er v al [ CI],  2 8. 6 %,  4 6. 6 %)  b y i n v esti g at or 
ass ess m e nt.  T h e  cli ni c al  b e n efit r at e ( d efi n e d  as  c o m pl et e r es p o ns e [ C R],  p arti al 
r es p o ns e [ P R],  or st a bl e  dis e as e [ S D] f or >  6  m o nt hs)  w as  3 9. 3 %  b y i n d e p e n d e nt 
r e vi e w  a n d  4 6. 3 %  b y i n v esti g at or  ass ess m e nt.  T h e  m e di a n  P F S  w as  4. 6  m o nt hs 
b y  b ot h t h e I R C  a n d t h e i n v esti g at ors. I n t h e s u bs et  of  p ati e nts  w h os e  ar c hi v al 
pri m ar y t u m ors  w er e r etr os p e cti v el y  c o nfir m e d t o  b e  H E R 2- p ositi v e ( 7 4  of  9 5 
p ati e nts  wit h s u b mitt e d t u m or s a m pl es), t h e  O R R  w as  3 3. 8 %  b y i n d e p e n d e nt 
r e vi e w  a n d  4 7. 3 %  b as e d  o n i n v esti g at or  ass ess m e nt. 
T h e  m ost  c o m m o n  a d v ers e  e v e nts ( A Es;  o c c urri n g i n  ≥  2 0 %  of  p ati e nts)  w er e 
f ati g u e ( 6 5. 2 %),  n a us e a ( 5 0. 9 %),  h e a d a c h e ( 4 0. 2 %),  e pist a xis ( 3 5. 7 %),  p yr e xi a 
( 3 4. 8 %),  c o nsti p ati o n ( 3 0. 4 %),  c o u g h ( 2 7. 7 %),  h y p o k al e mi a ( 2 6. 8 %),  di arr h e a 
( 2 5. 9 %),  v o miti n g ( 2 4. 1 %),  art hr al gi a ( 2 2. 3 %),  p ai n i n  e xtr e mit y ( 2 2. 3 %), 
a n e mi a ( 2 0. 5 %),  a n d  d ys p n e a ( 2 0. 5 %) ( 1 0 ).  M ost  of t h es e  A Es  w er e  Gr a d e  1− 2. 
T h e t hr e e  m ost  c o m m o n  Gr a d e  3 − 4  A Es  o bs er v e d i n t his tri al  w er e  h y p o k al e mi a 
( 8. 9 %), t hr o m b o c yt o p e ni a ( 8. 0 %),  a n d f ati g u e ( 4. 5 %).  T h er e  w as  o n e r e p ort e d 
Gr a d e  5  e v e nt i n  a  p ati e nt  w h o  di e d  of r es pir at or y f ail ur e  attri b ut e d  b y t h e 
i n v esti g at or t o  u n d erl yi n g  dis e as e. ( D at a  o n  Fil e,  G e n e nt e c h)  N o  gr a d e ≥  3 l eft 
v e ntri c ul ar s yst oli c  d ysf u n cti o n  e v e nts (s y m pt o m ati c  c o n g esti v e  h e art f ail ur e 
[ C H F]  a n d/ or l eft  v entri c ul ar  ej e cti o n fr a cti o n [ L V E F]  of  <  4 0 %)  w er e  o bs er v e d.  
 T D M  4 3 7 0 g/ B O 2 1 9 7 7 ( E MI LI A) 
T D M 4 3 7 0 g/ B O 2 1 9 7 7  w as  a r a n d o mi z e d,  P h as e III st u d y  of  T- D M 1  v ers us 
l a p ati ni b  +  c a p e cit a bi n e f or t h e tr e at m e nt  of  p ati e nts  wit h  H E R 2- p ositi v e 
u nr es e ct a bl e l o c all y  a d v a n c e d  or  m et ast ati c  br e ast  c a n c er  pr e vi o usl y tr e at e d  wit h 
tr ast u z u m a b  a n d  a t a x a n e.1 3 P ati e nts r e c ei v e d  T- D M 1  ( 3. 6  m g/ k g I V  o n  D a y  1  of 
a  2 1 - d a y  c y cl e)  or l a p ati ni b ( 1 2 5 0  m g  or all y  o n c e  p er  d a y)  pl us  c a p e cit a bi n e 
( 1 0 0 0  m g/ m2 or all y t wi c e  d ail y  o n  D a ys  1 − 1 4  of  a  2 1 -d a y  c y cl e)  u ntil  P D  or 
u n m a n a g e a bl e t o xi cit y.  Eli gi bl e  p ati e nts  m ust  h a v e  h a d   c o nfir m e d  H E R 2-
p ositi v e  M B C (i m m u n o hist o c h e mistr y [I H C]  3 +  a n d/ or fl u or es c e n c e i n sit u 
h y bri di z ati o n [ FI S H]  p ositi v e)  a n d  m ust  h a v e r e c ei v e d  pri or t h er a p y  wit h 
tr ast u z u m a b  a n d  a t a x a n e.  Pri m ar y  e n d p oi nts  w er e  P F S  b y i n d e p e n d e nt r e vi e w, 
o v er all s ur vi v al ( O S),  a n d s af et y.  
Fr o m  F e br u ar y  2 0 0 9 t hr o u g h  O ct o b er  2 0 1 1,  a t ot al  of  9 9 1  p ati e nts  w er e  e nr oll e d; 
4 9 6  w er e  assi g n e d t o l a p ati ni b  +  c a p e cit a bi n e,  a n d  4 9 5  w er e  assi g n e d t o  T-


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  2 1  of  9 7  
 
D M 1 .1 3   M e di a n  d ur ati o n  of f oll o w- u p f or t h e first  a n d s e c o n d i nt eri m  a n al ysis 
w as  a p pr o xi m at el y  1 3  m o nt hs  a n d  1 9  m o nt hs, r es p e cti v el y.   B as eli n e  p ati e nt 
d e m o gr a p hi cs,  pri or t h er a p y,  a n d  dis e as e  c h ar a ct eristi cs  w er e  b al a n c e d.  T h e 
st u d y  m et t h e  pri m ar y  e n d p oi nt  wit h  a n i m pr o v e m e nt i n  P F S  b y i n d e p e n d e nt 
r e vi e w  wit h  a  H R  =  0. 6 5, ( 9 5 %  CI,  1 8. 4 %,  3 4. 4 %),  p < 0. 0 0 1.  T h e  m e di a n  P F S 
w as  9. 6  m o nt hs i n t h e  T- D M 1   ar m  a n d  6. 4  m o nt hs i n t h e l a p ati ni b  +  c a p e cit a bi n e 
ar m.  A str o n g tr e n d i n  O S  w as  o bs er v e d i n f a v or  of t h e  T- D M 1   ar m ( H R  =  0. 6 2, 
[ 9 5 %  CI  0. 4 8- 0. 8 1],  p  =  0. 0 0 0 5).   At t h e first i nt eri m  a n al ysis,  m e di a n  O S  w as 
n ot r e a c h e d i n t h e  T- D M 1   ar m  a n d  w as  2 3. 3  m o nt hs i n t h e l a p ati ni b  + 
c a p e cit a bi n e; t h e i nt eri m  effi c a c y st o p pi n g  b o u n d ar y f or  O S  w as  n ot  cr oss e d. 
H o w e v er,  at t h e s e c o n d i nt eri m  a n al ysis,  O S  d at a  cr oss e d t h e  pr es p e cifi e d 
b o u n d ar y t h at s h o w e d  p ati e nts r e c ei vi n g  T- D M 1 ( m e di a n  O S  =  3 0. 9  m o nt hs) 
s ur vi v e d si g nifi c a ntl y l o n g er t h a n t h e  c o ntr ol  gr o u p ( m e di a n  O S = 2 5. 1  m o nt hs), 
wit h  a  H R = 0. 6 8,  9 5 %  CI,  0. 5 5 -0. 8 5,  p < 0. 0 0 1).  T h e  O R R  w as  4 3. 6 % f o r t h e T-
D M 1  ar m  v ers us  3 0. 8 % f or t h e l a p ati ni b  +  c a p e cit a bi n e  ar m,  wit h  a  m e di a n 
d ur ati o n  of  o bj e cti v e r es p o ns e ( D O R)  of  1 2. 6  m o nt hs  v ers us  6. 5  m o nt hs, 
r es p e cti v el y.  
T- D M 1   w as  w ell t ol er at e d,  wit h  n o  u n e x p e ct e d s af et y si g n als.  T h e  m ost  c o m m o n 
Gr a d e  ≥  3  A Es i n t h e  T- D M 1  ar m  w er e t hr o m b o c yt o p e ni a ( 1 2. 9 %  vs.  0. 2 %), 
i n cr e as e d  A S T ( 4. 3 %  vs.  0. 8 %),  a n d i n cr e as e d  A L T ( 2. 9 %  vs.  1. 4 %); t h e  m ost 
c o m m o n  Gr a d e  ≥  3  A Es i n t h e l a p ati ni b  +  c a p e cit a bi n e  ar m  w er e  di arr h e a 
( 2 0. 7 %  vs.  1. 6 %)  p al m ar  pl a nt ar  er yt hr o d ys est h esi a ( 1 6. 4 %  vs.  0),  a n d  v o miti n g 
( 4. 5 %  vs.  0. 8 %) ( V er m a  et  al  2 0 1 2).  T h e i n ci d e n c e  of  Gr a d e  3/ 4  A Es i n t h e T-
D M 1  ar m  w as  4 0. 8 %  v ers us  5 7. 0 % i n t h e l a p ati ni b  +  c a p e cit a bi n e  ar m.  
 T r ast u z u m a b  e mt a nsi n e  ( T-D M 1) :  Cli ni c al  S af et y 
I n  cli ni c al tri als, T- D M 1  h as  b e e n  e v al u at e d  as si n gl e - a g e nt i n  8 8 4  p ati e nts  wit h  H E R 2- 
p ositi v e  m et ast ati c  br e ast  c a n c er.  T h e  m ost  c o m m o n (fr e q u e n c y  ≥  2 5 %)  a d v ers e  dr u g 
r e a cti o ns ( A D Rs) s e e n i n  8 8 4  p ati e nts tr e at e d  wit h T- D M 1  w er e f ati g u e,  n a us e a, 
m us c ul os k el et al  p ai n, t hr o m b o c yt o p e ni a,  h e a d a c h e, i n cr e as e d tr a ns a mi n as es,  a n d 
c o nsti p ati o n. 
A d v ers e  e v e nts  w er e i d e ntifi e d i n  p ati e nts  wit h  H E R 2- p ositi v e  m et ast ati c  br e ast  c a n c er 
tr e at e d i n  a r a n d o mi z e d tri al,  T D M 4 3 7 0 g/ B O 2 1 9 7 7 ( E MI LI A).   P ati e nts  w er e 
r a n d o mi z e d t o r e c ei v e T- D M 1   or l a p ati ni b  pl us  c a p e cit a bi n e.   T h e  m e di a n  d ur ati o n  of 
st u d y tr e at m e nt  w as  7. 6  m o nt hs f or  p ati e nts i n t h e  T- D M 1  -tr e at e d  gr o u p  a n d  5. 5 
m o nt hs  a n d  5. 3  m o nt hs f or  p ati e nts tr e at e d  wit h l a p ati ni b  a n d  c a p e cit a bi n e, 
r es p e cti v el y.  T w o  h u n dr e d  a n d  el e v e n ( 4 3. 1 %)  p ati e nts  e x p eri e n c e d  ≥  Gr a d e  3  a d v ers e 
e v e nts i n t h e  T- D M 1  -tr e at e d  gr o u p  c o m p ar e d  wit h  2 8 9 ( 5 9. 2 %)  p ati e nts i n t h e 
l a p ati ni b  pl us  c a p e cit a bi n e-tr e at e d  gr o u p.  D os e  a dj ust m e nts f or  T-D M 1  w e r e  p er mitt e d. 
T hirt y -t w o  p ati e nts ( 6. 5 %)  dis c o nti n u e d T- D M 1   d u e t o  a n  a d v ers e  e v e nt,  c o m p ar e d 
wit h  4 1  p ati e nts ( 8. 4 %)  w h o  dis c o nti n u e d l a p ati ni b,  a n d  5 1  p ati e nts ( 1 0. 5 %)  w h o 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  2 2  of  9 7  
 
dis c o nti n u e d  c a p e cit a bi n e  d u e t o  a n  a d v ers e  e v e nt.  T h e  m ost  c o m m o n  a d v ers e  e v e nts 
l e a di n g t o  T-D M 1   wit h dr a w al  w er e t hr o m b o c yt o p e ni a  a n d i n cr e as e d tr a ns a mi n as es. 
Ei g ht y  p ati e nts ( 1 6. 3 %) tr e at e d  wit h  T- D M 1   h a d  a d v ers e  e v e nts l e a di n g t o  d os e 
r e d u cti o ns.  T h e  m ost fr e q u e nt  a d v ers e  e v e nts l e a di n g t o  d os e r e d u cti o n  of  T-D M 1  (i n  ≥ 
( 1 %  of  p ati e nts) i n cl u d e d t hr o m b o c yt o p e ni a, i n cr e as e d tr a ns a mi n as es,  a n d  p eri p h er al 
n e ur o p at h y.  A d v ers e  e v e nts t h at l e d t o  d os e  d el a ys  o c c urr e d i n  1 1 6 ( 2 3. 7 %)  of  T- D M 1  
tr e at e d  p ati e nts.  T h e  m ost fr e q u e nt  a d v ers e  e v e nts l e a di n g t o  a  d os e  d el a y  of T- D M 1  (i n 
≥  1 %  of  p ati e nts)  w er e  n e utr o p e ni a, t hr o m b o c yt o p e ni a, l e u k o p e ni a, f ati g u e, i n cr e as e d 
tr a ns a mi n as es  a n d  p yr e xi a. 
T h e  m ost  c o m m o n  A D Rs s e e n  wit h  T- D M 1  w er e  n a us e a, f ati g u e,  m us c ul os k el et al  p ai n, 
t hr o m b o c yt o p e ni a, i n cr e as e d tr a ns a mi n as es,  h e a d a c h e,  a n d  c o nsti p ati o n (fr e q ue n c y  > 
2 5 %) .  T h e  m ost  c o m m o n  N CI –C T C A E ( v ersi o n  3)  ≥  Gr a d e  3  A D Rs  w er e 
t hr o m b o c yt o p e ni a, i n cr e as e d tr a ns a mi n as es,  a n e mi a,  h y p o k al e mi a,  p eri p h er al 
n e ur o p at h y  a n d f ati g u e  (fr e q u e n c y  > 2 %). 
 B a c k g r o u n d  o n  Vi n o r el bi n e  
Vi n or el bi n e  b el o n gs t o t h e  gr o u p  of  vi n c a  al k al oi ds,  w hi c h  bl o c k  c ell  di visi o n  wit h 
G 2/ M i n t h e  c ell  c y cl e  b y i n hi biti n g t h e  ass e m bl y  of  mi cr ot u b uli,  w hi c h  ar e  n e c ess ar y 
f or  c ell  di visi o n.  Vi n or el bi n e  m o n ot h er a p y is  m ost fr e q u e ntl y  a d mi nistr at e d  as  3 0 
m g/ m 2  w e e kl y  a n d r es ults i n r es p o ns e r at es  of  4 0-6 0 %  as first li n e tr e at m e nt  wit h 
M B C .1 4 -1 8 I n  c o m bi n ati o n  wit h  ot h er  c yt ost ati c  a g e nts,  vi n or el bi n e  h as s h o w n  hi g h 
r es p o ns e r at es  of  6 2-6 5 %,  wit h ti m e t o  pr o gr essi o n si mil ar t o  ot h er  c o m bi n ati o n 
c h e m ot h er a p y r e gi m e ns .1 9 , 2 0 A  pr os p e cti v e r a n d o mi z e d  P h as e III st u d y  c o m p ar e d  a 
c y cl o p h os p h a mi d e,  a nt hr a c y cli n e, fl u or o p yri mi di n e r e gi m e n t o  vi n or el bi n e  2 5  m g/ m 2 
i n  c o m bi n ati o n  wit h  d o x or u bi ci n  5 0  m g/ m2 f or first li n e tr e at m e nt  of  m et ast asi zi n g 
br e ast  c a n c er  a n d f o u n d  c o m p ar a bl e  effi c a c y. 2 1  Vi n or el bi n e is r e g ar d e d  as l ess t o xi c 
t h a n t a x a n es  a n d  a nt hr a c y cli n es,  a n d  dis pl a ys l ess  n e ur ot o xi cit y  c o m p ar e d  wit h  ot h er 
vi n c a  al k al oi ds,  w hi c h  c a n  b e  a  pr o bl e m  wit h  pr ol o n g e d tr e at m e nt.  T h e r es ults  of  a 
P h as e III st u d y  c o m p ari n g  vi n or el bi n e  pl us tr ast u z u m a b  wit h  d o c et a x el  pl us 
tr ast u z u m a b,  as first li n e t h er a p y f or  H E R 2- p ositiv e  br e ast  c a n c er s h o w e d t h at t h e 
vi n or el bi n e  a n d tr ast u z u m a b  c o m bi n ati o n r es ult e d i n f e w er  a d v ers e  eff e cts t h a n t h e 
d o c et a x el  a n d tr ast u z u m a b  c o m bi n ati o n.  Effi c a c y  of t h e t w o  c o m bi n ati o ns  w as 
si mil ar.2 2  T h e r es ults  of  a  P h as e I st u d y s h o w e d t h at t h e  m a xi m u m t ol er at e d  d os e  of 
vi n or el bi n e is  3 5  m g/ m 2  w e e kl y, if  vi n or el bi n e is  a d mi nistr at e d  as  m o n ot h er a p y.2 3 
Gr a n ul o c yt o p e ni a  w as  a li miti n g t o xi cit y i n t his st u d y.  R es ults fr o m  a n ot h er  P h as e I 
st u d y s h o w e d t h at t h e  m a xi m u m t ol er at e d  d os e is  4 0  m g/ m 2  w h e n  vi n or el bi n e is 
a d mi nistr at e d  o n  D a y  1  a n d  D a y  8  e v er y  3  w e e ks.  T h e  d os e f or t h e s u bs e q u e nt  P h as e II 
st u d y  w as  d et er mi n e d t o  b e  3 5  m g/ m 2 . 2 4    
 R ati o n al e f o r  St u d y  D esi g n 
Alt h o u g h   as   pr e vi o usl y  st at e d,   a  t a x a n e,  tr ast u z u m a b   a n d   p ert u z u m a b  s h o ul d   b e  
c o nsi d er e d   a  st a n d ar d  first  li n e  t h er a p y   b as e d   o n  t h e   C L E O P A T R A   d at a,   u p o n  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  2 3  of  9 7  
 
pr o gr essi o n  m a n y  ot h er  c yt ot o xi c  a g e nts  ar e  als o r o uti n el y  us e d i n  c o m bi n ati o n  wit h 
tr ast u z u m a b.  Vi n or el bi n e,  as  a si n gl e  a g e nt,  h as  hist ori c all y  d e m o nstr at e d  effi c a c y  a n d 
g o o d t ol er a bilit y i n s e v er al  e arl y st u di es i n t h e  m et ast ati c s etti n g .1 5 ,2 5 ,2 6  It s e e m e d  n at ur al 
t o  e x pl or e t h e  c o m bi n ati o n  of t his  a g e nt  wit h tr ast u z u m a b,  a n d t w o  e arl y st u di es,2 7 ,2 8 w er e 
m o u nt e d t o  d e m o nstr at e its  effi c a c y  a n d  a p p e ali n g s af et y  pr ofil e,  w hil e t h e  pr e cli ni c al 
d at a  of t h eir s y n er g y  e m er g e d .2 9  I n f a ct,  as  d e m o nstr at e d i n t h e s u bs e q u e nt r a n d o mi z e d 
p h as e II tri al ,2 7 ,3 0 b ot h  vi n or el bi n e/tr ast u z u m a b  a n d t a x a n e/tr ast u z u m a b tr e at m e nts  w er e 
a cti v e   as  first -li n e  t h er a p y  f or   H E R 2-p ositi v e,   m et ast ati c   br e ast   c a n c er   a n d   h a d  
c o m p ar a bl e r at es  of  effi c a c y  a n d t ol er a bilit y.   T h e  o b vi o us  a d v a nt a g es  of  vi n or el bi n e 
o v er t h e tr a diti o n al t a x a n e- b as e d r e gi m e ns i n cl u d e l a c k  of  al o p e ci a, l o w er r at es  of  gr a d e 
3/ 4  n e ur o p at h y  a n d st er oi d -fr e e  a d mi nistr ati o n.   W hil e t h e  a p pr o v al  of  p ert u z u m a b is  a 
w el c o m e  a d diti o n t o t h e  d o c et a x el -b as e d  d o u bl et  wit h tr ast u z u m a b, t his r e gi m e n still 
c a us es   al o p e ci a   a n d  r e q uir es  st er oi ds   as   pr e m e di c ati o n.   T h er ef or e   vi n or e l bi n e-b as e d 
c o m bi n ati o ns  ar e  a n  attr a cti v e  o pti o n t o  e x pl or e.   
Wit h t h e  a p pr o v al  of  T -D M 1, f urt h er st u di es  ar e  w arr a nt e d t o  e v al u at e t h e  effi c a c y  a n d 
t ol er a bilit y  of t his  a g e nt i n  e arli er li n es  of t h er a p y  a n d i n  c o m bi n ati o n  wit h  ot h er  a g e nts. 
First li n e  d at a i n  c o m bi n ati o n  wit h  P ert u z u m a b,  a n ot h er  H E R 2 t ar g et e d t h er a p y,  will  b e 
r e p ort e d  w h e n r es ults  ar e  a v ail a bl e fr o m t h e  M A RI A N N E st u d y.  H o w e v er, i n  or d er t o 
i m pr o v e  u p o n t h e  alr e a d y i m pr essi v e  effi c a c y  d at a, t h er e is  a r ati o n al e t o  c o m bi n e t his 
a g e nt  wit h  ot h er  c yt ot o xi cs  as  w ell  as  H E R 2  dir e ct e d t h er a pi es. It is  g e n er all y  a c c e pt e d 
t h at  c o m bi n ati o n t h er a pi es t e n d t o i m pr o v e r es p o ns e r at es  at t h e  c ost  of t o xi cit y.  F or 
e x a m pl e,  R o rb ert  et  al . r e p ort e d  a r a n d o mi z e d  p h as e III st u d y  of tr ast u z u m a b,  p a clit a x el, 
a n d   c ar b o pl ati n   c o m p ar e d   wit h  tr ast u z u m a b   a n d   p a clit a x el  i n   w o m e n   wit h   H E R - 2-
o v er e x pr essi n g  m et ast ati c  br e ast  c a n c er .3 1 T h e  a d diti o n  of  c ar b o pl ati n  t o  p a clit a x el  a n d 
tr ast u z u m a b i m pr o v e d  O R R  as  w ell  as  P F S.  Gi v e n t h e f a ct t h at  T-D M 1 is  a n i n h er e nt 
d o u bl et, t h e  a d diti o n  of  a n ot h er  c yt ot o xi c s u c h  as  vi n or el bi n e  c o ul d  p ot e nti all y i m pr o v e 
u p o n t h e i m pr essi v e  effi c a c y  d at a t h at  h a v e  alr e a d y  b e e n r e p ort e d  wit h t his  a g e nt,  wit h 
pr o b a bl y  a  m o d est i n cr e as e i n t o xi cit y.  I n  a d diti o n, t h e r ati o n al e  of  c o m bi ni n g t w o  a g e nts 
t h at  t ar g et   mi cr ot u b ul es   h as   b e e n   est a blis h e d  i n  t h e   n e o a dj u v a nt  s etti n g   utili zi n g  
d o c et a x el,  vi n or el bi n e  a n d tr ast u z u m a b  2 8 as  w ell i n  a  p h as e II st u d y i n t h e  m et ast ati c 
s etti n g  wit h t h e s a m e  a g e nts, r e p ort e d  b y  Li vi n gst o n e  et  al . i n  2 0 1 1.3 2 F urt h er m or e,  gi v e n 
t h at  o n e  of t h e t o xi citi es r e p ort e d  wit h  T-D M 1 is t hr o m b o c yt o p e ni a,  w hil e  vi n or el bi n e is 
g e n er all y   a   pl at el et -s p ari n g   a g e nt,  t h e   c o m bi n ati o n   c o ul d   p ot e nti all y   b e   hi g hl y  
effi c a ci o us  wit h o ut  o v erl a p pi n g t o xi cit y  pr ofil es.  Fi n all y, t h er e  a r e  pr e-cli ni c al  d at a t h at 
s u g g est  t h e   c o m bi n ati o n   of  t h es e  t w o   a g e nts   m a y   b e  s y n er gisti c  i n   a ni m al   m o d els.  
T h er ef or e,  t h e   c urr e nt  st u d y   pr o p os e s  t o   e v al u at e  t h e  s af et y   a n d   effi c a c y   of   t h e 
c o m bi n ati o n  of tr ast u z u m a b  e mt a nsi n e  ( T-D M 1)  a n d  vi n or el bi n e  i n H E R 2 +  m et ast ati c 
br e ast  c a n c er  p ati e nts.  
  
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  2 4  of  9 7  
 
 O B J E C TI V E S  
 P ri m a r y  O bj e cti v es  
P h as e I  
•   T o i d e ntif y t h e  m a xi m u m t ol er at e d  d os e ( M T D)  of  vi n or el bi n e  c o m bi n e d  wit h  a 
fi x e d  d os e  of tr ast u z um a b  e mt a nsi n e  t o  b e r e c o m m e n d e d f or t h e  p h as e II  p orti o n  of 
t h e st u d y ( R P 2 D). 
•   T o i d e ntif y  d os e li miti n g t o xi citi es ( D L T).  
P h as e II  
•   T o  e v al u at e t h e  effi c a c y,  as  d et er mi n e d  b y  P F S,   of t h e  R P 2 D  of  vi n or el bi n e 
c o m bi n e d  wit h  a fi x e d  d os e  of  tr ast u z u m a b  e mt a nsi n e i n pr e -tr e at e d H E R 2 - p ositi v e 
M B C .  
 S e c o n d a r y  O bj e cti v es  
P h as e II  
•   T o  d et er mi n e t h e  o v er all r es p o ns e r at e ( O R R),  cli ni c al  b e n efit r at e ( C B R) ,  a n d 
o v er all s ur vi v al ( O S)  of t h e  R P 2 D  of  vi n or el bi n e  c o m bi n e d  wit h  a fi x e d  d os e  of 
tr ast u z u m a b  e mt a nsi n e. 
 
 E N D P OI N T S  
 P ri m a r y  e n d p oi nts :  P h as e I 
•   A d v ers e  e v e nts i n cl u di n g  d os e -li miti ng t o xi citi es ( D L Ts)  a n d s eri o us  a d v ers e  e v e nts 
( S A Es).   A Es   will   b e   ass ess e d   a n d   assi g n e d  s e v erit y   usi n g  t h e   N ati o n al   C a n c er  
I nstit ut e  C o m m o n  T er mi n ol o g y  Crit eri a f or  A d v ers e  E v e nts ( N CI  C T C A E),  V ersi o n 
4. 0 3. 
•   T h e  M a xi m u m  T ol er at e d  D os e ( M T D)  of  vi n or el bi n e  a n d tr ast u z u m a b  e mt a nsi n e 
c o m bi n ati o n t h er a p y. 
 E v al u a bl e  P o p ul ati o n :  
•  E v al u a bl e f or  S af et y :  Eli gi bl e  p ati e nts  w h o r e c ei v e  at l e ast  o n e  d os e  of 
vi n or el bi n e  or tr ast u z u m a b  e mt a nsi n e, i n cl u di n g t h os e  w h o  e x p eri e n c e  a  D L T 
as  d efi n e d i n  S e cti o n   7. 3.  
 P ri m a r y  e n d p oi nts:  P h as e II  
•   Pr o gr essi o n- Fr e e  S ur vi v al ( P F S) :  P ati e nts  will  b e  e v al u at e d  d uri n g tr e at m e nt  a n d  b y 
f oll o w-u p  ass ess m e nts  p ost -tr e at m e nt  at:  3 0- d a ys ( + 5  d a ys).  P F S is  d efi n e d  as t h e 
ti m e fr o m d at e  fr o m first tr e at m e nt r e c ei v e d  o n st u d y  u ntil  d o c u m e nt e d  dis e as e 
pr o gr essi o n  or  d e at h ( b y  a n y  c a us e, i n t h e  a bs e n c e  of  pr o gr essi o n). I n  pr o gr essi o n-


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  2 5  of  9 7  
 
fr e e  p ati e nts,  P F S  will  b e  c e ns or e d  at t h e l ast  e v al u a bl e t u m or  ass ess m e nt ( R E CI S T 
v 1. 1). 
 
 E v al u a bl e  P o p ul ati o n: 
•   E v al u a bl e f or  Pr o gr essi o n- Fr e e  S ur vi v al ( P F S) :  Eli gi bl e  p ati e nts  w h o r e c ei v e 
at l e ast  o n e  d os e  of  vi n or el bi n e/tr ast u z u m a b  e mt a nsi n e  c o m bi n ati o n t h er a p y. 
 S e c o n d a r y  e n d p oi nts  
•   Cli ni c al  R es p o ns e i n cl u di n g  o bj e cti v e r es p o ns e r at e ( O R R)  a n d  cli ni c al  b e n efit r at e 
( C B R):  p er  R E CI S T  v 1. 1 t o  R P 2 D  of  vi n or el bi n e  a n d tr ast u z u m a b  e mt a nsi n e 
c o m bi n ati o n t h er a p y.  O R R  will  b e  c al c ul at e d  as t h e  p er c e nt a g e  of  p ati e nts  wit h  b est 
o v er all r es p o ns e  of  p arti al  or  c o m pl et e r es p o ns e  o n t h er a p y ( P R  or  C R).   C B R  will 
b e  c al c ul at e d  as t h e  p er c e nt a g e  of  p ati e nts  wit h  P R ,  C R  a n d  S D f or  >/ =  6  m o nt hs. 
•   O v er all  S ur vi v al ( O S) :  P ati e nts  will  b e  e v al u at e d  d uri n g tr e at m e nt  a n d  b y f oll o w- u p 
ass ess m e nts  p ost -tr e at m e nt  at:  3 0-d a ys ( + 5  d a ys).  F oll o w - u p f or  O S  will  o c c ur 
e v er y  1 2  w e e ks ( ± 2  w e e ks)  u ntil  d e at h  or  wit h dr a w al  of  c o ns e nt fr o m t h e st u d y.  O S 
is  d efi n e d  as t h e  el a ps e d ti m e fr o m  d at e fr o m first tr e at m e nt r e c ei v e d  o n st u d y t o 
d e at h  or  d at e  of  c e ns ori n g.  P ati e nts  ali v e  or t h os e l ost t o f oll o w- u p  will  b e  c e ns or e d 
at t h e l ast  d at e  of  c o nt a ct ( or l ast  d at e  k n o w n t o  b e  ali v e).  
 E v al u a bl e  P o p ul ati o n: 
•   E v al u a bl e f or  Cli ni c al  R es p o ns e  ( O R R  a n d  C B R):  Eli gi bl e  p ati e nts  w h o 
r e c ei v e  at l e ast t w o  c y cl es  of  vi n or el bi n e/tr ast u z u m a b  e mt a nsi n e  c o m bi n ati o n 
t h er a p y  at t h e  R P 2 D,  h a v e  m e as ur a bl e  dis e as e  at  b as eli n e,  a n d  h a v e  at l e ast 
o n e  p ost- b as eli n e  dis e as e r es p o ns e  ass ess m e nt.  
•   E v al u a bl e f or  O v er all  S ur vi v al ( O S) :  P ati e nts  w h o r e c ei v e  at l e ast  o n e  d os e 
of  vi n or el bi n e/tr ast u z u m a b  e mt a nsi n e  c o m bi n ati o n t h er a p y. 
 
 S U B J E C T  R E C R UI T M E N T  &  S C R E E NI N G  
M e n  a n d  w o m e n  of  all r a c es  a n d  et h ni c  gr o u ps  ar e  eli gi bl e f or t his tri al.   S u bj e cts  will  b e 
r e cr uit e d  at  S yl v est er  C o m pr e h e nsi v e  C a n c er  C e nt er ( S C C C)  m ai n  c a m p us  a n d S at ellit e 
Sit es  (i. e.  D e erfi el d  B e a c h  a n d  Pl a nt ati o n).  I nf or m e d  c o ns e nt f or ms (I C F)  will  b e tr a nslat e d 
a n d  a v ail a bl e i n  b ot h  E n glis h  a n d  S p a nis h. 
 
 
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  2 6  of  9 7  
 
 P A TI E N T  S E L E C TI O N  
 I n cl usi o n  C rit e ri a  
1.  Hist ol o gi c all y  or  c yt ol o gi c all y  d o c u m e nt e d  br e ast  c a n c er.   
2.  M et ast ati c  or  u nr es e ct a bl e l o c all y  a d v a n c e d/r e c urr e nt  br e ast  c a n c er.  
3.  H E R 2 -p ositi v e  dis e as e  d o c u m e nt e d  as:  I H C  3 +  p ositi v e,  a n d/ or  FI S H  ≥  2. 0,  a n d/ or 
g e n e  c o p y  n u m b er  gr e at er t h a n  6,  o n  pr e vi o usl y  c oll e ct e d t u m or  or  m et ast ati c sit e .  
I H C t esti n g,  FI S H  ass a y( s),  a n d  g e n e  c o p y  n u m b er  m a y  all  h a v e  b e e n  p erf or m e d; 
h o w e v er,  a  p ositi v e r es ult fr o m  o nl y  o n e  of t h e  a b o v e is r e q uir e d f or  eli gi bilit y.  
4.  D o c u m e nt e d  d is e as e  pr o gr essi o n  o n t h e l ast r e gi m e n  b y r a di o gr a p hi c  m e as ur e m e nt 
( pr o gr essi o n  d e m o nstr at e d  b y t u m or  m ar k ers  o nl y is  u n a c c e pt a bl e). 
5.  D o c u m e nt e d  dis e as e  pr o gr essi o n ( b y i n v esti g at or  ass ess m e nt)  aft er  at l e ast  o n e 
r e gi m e n  of  H E R 2-dir e ct e d t h er a p y i n t h e  m et ast ati c  or  u nr es e ct a bl e l o c all y 
a d v a n c e d/r e c urr e nt s etti n g . 
6.  F or  p ati e nts  wit h  h or m o n e r e c e pt or- p ositi v e  dis e as e:  dis e as e  pr o gr essi o n  or 
r e c urr e n c e i n  a n y s etti n g  o n  pri or  h or m o n al t h er a p y,  gi v e n  wit h  or  wit h o ut  H E R 2 
dir e ct e d t h er a p y.  
7.  M e as ur a bl e  or  b o n e  o nl y  dis e as e.  
8.  Pri or tr e at m e nt  wit h  a t a x a n e, i n t h e  n e o a dj u v a nt,  a dj u v a nt, l o c all y  a d v a n c e d  or 
m et ast ati c s etti n g.  
9.  A  mi ni m u m  of  6  w e e ks  of  pri or tr ast u z u m a b f or t h e tr e at m e nt  of  m et ast ati c  or 
u nr es e ct a bl e l o c all y  a d v a n c e d/r e c urr e nt  dis e as e is r e q uir e d.   
1 0.  Pri or  us e  of  P ert u z u m a b i n  a n y  s etti n g is  p er mitt e d  ( b ut  n ot r e q uir e d). 
1 1.  Pri or  us e  of  L a p ati ni b i n  a n y s etti n g is  p er mitt e d ( b ut  n ot r e q uir e d). 
1 2.  A g e  ≥  1 8  y e ars  
1 3.  Lif e  e x p e ct a n c y  ≥ 3  m o nt hs  
1 4.  E ast er n  C o o p er ati v e  O n c ol o g y  Gr o u p ( E C O G)  p erf or m a n c e st at us  of  0  or  1.   S e e 
A p p e n di x  C f or  d et ails. 
1 5.  P ati e nts  m ust  h a v e  n or m al  or g a n  a n d  m arr o w f u n cti o n  as  d efi n e d  b el o w: 
•   a bs ol ut e  n e utr o p hil  c o u nt  ( A N C)  > 1, 5 0 0 c ells /m m 3  
•   pl at el ets   > 1 0 0, 0 0 0 c ells/ m m 3  
•   h e m o gl o bi n  >  9. 0  g/ d L ( P ati e nts  ar e  p er mitt e d t o r e c ei v e tr a nsf us e d r e d  bl o o d 
c ells t o  a c hi e v e t his l e v el.)  
•   t ot al bilir u bi n  ≤ 1. 5  X i nstit uti o n al  u p p er li mit  of  n or m al ( U L N)  [N ot e :  F or 
p ati e nts  wit h  pr e vi o usl y  d o c u m e nt e d  Gil b ert’s s y n dr o m e, t ot al  bilir u bi n  ≤  3 
m g/ d L .] 
•   A S T( S G O T)  ≤ 2. 5  X  U L N  
•   A L T ( S G P T)  ≤ 2. 5  X  U L N 
•   al k ali n e  p h os p h at as e ( al k  p h os)  ≤ 2. 5  X  U L N  
•   s er u m  cr e ati ni n e  <  1. 5  X  U L N  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  2 7  of  9 7  
 
1 6.  Int er n ati o n al  n or m ali z e d r ati o (I N R)  <  1. 5  X  U L N  
1 7.  L eft  v e ntri c ul ar  ej e cti o n fr a cti o n ( L V E F)  ≥  5 0 %  b y  eit h er  e c h o c ar di o gr a m ( E C H O) 
or  m ulti pl e- g at e d  a c q uisiti o n s c a n ( M U G A) . 
1 8.  ( T his tri al is  o p e n t o  m al es a n d f e m al es.)  N e g ati v e r es ults  of s er u m  pr e g n a n c y t est f or 
pr e m e n o p a us al  w o m e n  of r e pr o d u cti v e  c a p a cit y  a n d f or  w o m e n  <  1 2  m o nt hs  aft er 
m e n o p a us e.  F or  m e n  a n d  w o m e n  of  c hil d b e ari n g  p ot e nti al,  a gr e e m e nt  b y t h e  p ati e nt 
a n d/ or  p art n er t o  us e   t w o  eff e cti v e n o n- h or m o n al  f o r ms  of b a r ri e r  c o nt r a c e pti o n  
at t h e s a m e ti m e , t hr o u g h o ut tr e at m e nt  o n st u d y.  W o m e n s h o ul d  a gr e e t o  c o nti n u e d 
us e f or  at l e ast  9 0  d a ys   aft er t h e  e n d  of tr e at m e nt.  M e n s h o ul d  a gr e e t o  c o nti n u e d us e 
f or at l e ast  7  m o nt hs  aft er t h e  e n d  of tr e at m e nt .  E x a m pl es  of  n o n- h or m o n al  b arri er 
c o ntr a c e pti o n i n cl u d e:  c o n d o m  or  o c cl usi v e  c a p ( di a p hr a g m  or  c er vi c al/ v a ult  c a ps) 
wit h s p er mi ci d e.    
1 9.  A bilit y t o  u n d erst a n d  a n d  willi n g n ess t o si g n  a  writt e n i nf or m e d  c o ns e nt  a n d  HI P A A 
d o c u m e nt. 
 E x cl usi o n  C rit e ri a  
1.  C h e m ot h er a p y  ≤ 2 1  d a ys  pri or t o  first  d os e  of st u d y tr e at m e nt   
2.  If l ast  d os e  of tr ast u z u m a b w as : 
•   6 m g/ k g t h e n  ≤ 2 1  d a ys  pri or t o  first  d os e  of st u d y tr e at m e nt 
•   4 m g/ k g t h e n  ≤ 1 4  d a ys  pri or t o  first  d os e  of st u d y tr e at m e nt 
•   2 m g/ k g t h e n  ≤ 7  d a ys  pri or t o  first  d os e  of st u d y tr e at m e nt 
3.  L a p ati ni b  ≤ 1 4  d a ys  pri or t o  first  d os e  of st u d y tr e at m e nt 
4.  P ert u z u m a b  ≤ 2 1  d a ys  pri or t o first  d os e  of st u d y tr e at m e nt  
5.  H or m o n e t h er a p y  ≤ 7  d a ys  pri or t o  first  d os e  of st u d y tr e at m e nt  
6.  I n v esti g ati o n al t her a p y  or  a n y  ot h er s u c h  e x p eri m e nt al  t h er a p y  ≤ 2 8  d a ys pri or t o  first 
d os e  of  st u d y tr e at m e nt  
7.  Pri or tr e at m e nt  wit h tr ast u z u m a b  e mt a nsi n e,  ( o n  or  off a st u d y  pr ot o c ol) 
8.  Pri or  us e  of  vi n or el bi n e ( i n  a n y s etti n g). 
9.  Pr e vi o us r a di ot h er a p y f or t h e tr e at m e nt  of  u nr es e ct a bl e, l o c all y  a d v a n c e d, r e c urr e nt  or 
m et ast ati c  br e ast  c a n c er is  n ot  all o w e d if:  
•   T h e l ast fr a cti o n  of r a di ot h er a p y  h as  b e e n  a d mi nist er e d  wit hi n  1 4  d a ys  pri or t o 
st u d y  e nr oll m e nt   
•   M or e t h a n  2 5 %  of  m arr o w - b eari n g  b o n e  h as  b e e n irr a di at e d  
1 0.  Br ai n  m et ast as es t h at  ar e  u ntr e at e d  or s y m pt o m ati c,  or r e q uir e  a n y r a di ati o n, s ur g er y, 
or  c o nti n u e d st er oi d t h er a p y t o  c o ntr ol s y m pt o ms fr o m  br ai n  m et ast as es  wit hi n  1 4 
d a ys  of st u d y  e nr oll m e nt. 
1 1.  Hist or y  of i nt ol er a n c e (i n cl u di n g  Gr a d e  3  or  4 i nf usi o n r e a cti o n)  or  h y p ers e nsiti vit y t o 
tr ast u z u m a b  or  m uri n e  pr ot ei ns. 
1 2.  Hist or y  of  e x p os ur e t o t h e f oll o wi n g  c u m ul ati v e  d os es  of  a nt hr a c y cli n es: 
•   D o x or u bi ci n  ≥ 5 5 0 m g/ m 2  
•   Li p os o m al  d o x or u bi ci n  > 5 0 0  m g/ m 2 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  2 8  of  9 7  
 
•   E pir u bi ci n  > 9 0 0  m g/ m 2 
•   Mit o x a ntr o n e  >  1 2 0  m g/ m
2 
•   If  a n ot h er  a nt hr a c y cli n e,  or  m or e t h a n  o n e  a nt hr a c y cli n e,  h as  b e e n  us e d, t h e 
c u m ul ati v e  d os e  m ust  n ot  e x c e e d t h e  e q ui v al e nt  of  ≥ 5 5 0  m g/ m 2  d o x or u bi ci n. 
1 3.  C urr e nt  p eri p h er al  n e ur o p at h y  of  Gr a d e  ≥ 3  p er t h e  N CI  C T C A E,  v 4. 0  
1 4.  T h e  p ati e nt  h as  n ot r e c o v er e d fr o m  a n y  ot h er  a c ut e t o xi cit y (t o  Gr a d e  ≤ 1  as  p er  N CI 
C T C A E  v 4. 0 3)  pri or t o st u d y  e nr oll m e nt. 
1 5.  Hist or y  of  ot h er  m ali g n a n c y  wit hi n t h e l ast  3  y e ars,  e x c e pt f or  a p pr o pri at el y tr e at e d 
c ar ci n o m a  i n sit u of t h e  c er vi x,  n o n- m el a n o m a s ki n  c ar ci n o m a,  St a g e I  ut eri n e  c a n c er, 
or  ot h er  c a n c ers  wit h  a si mil ar  o ut c o m e . 
1 6.  C ar di o p ul m o n ar y  F u n cti o n  Crit eri a: 
•   C urr e nt  u nst a bl e  v e ntri c ul ar  arr h yt h mi a r e q uiri n g tr e at m e nt  
•   Hist or y  of s y m pt o m ati c  c o n g esti v e  h e art f ail ur e ( C H F )  as  p er N e w  Y or k 
H e art  Ass o ci ati o n [ N Y H A]  Cl ass es II −I V ; s e e  A p p e n di x  D f or  d et ails. 
•   Hist or y  of  m y o c ar di al i nf ar cti o n  or  u nst a bl e  a n gi n a  wit hi n  6  m o nt hs  of st u d y 
e nr oll m e nt 
•   Hist or y  of  a  d e cr e as e i n  L V E F t o  <  4 0 %  or s y m pt o m ati c  C H F  wit h  pr e vi o us 
tr ast u z u m a b tr e at m e nt 
•   S e v er e  d ys p n e a  a t r est  d u e t o  c o m pli c ati o ns  of  a d v a n c e d  m ali g n a n c y  or 
r e q uiri n g  c urr e nt  c o nti n u o us  o x y g e n t h er a p y 
1 7.  C urr e nt s e v er e,  u n c o ntr oll e d s yst e mi c  dis e as e ( e. g.,  cli ni c all y si g nifi c a nt 
c ar di o v as c ul ar,  p ul m o n ar y,  or  m et a b oli c  dis e as e) 
•   M aj or s ur gi c al  pr o c e d ur e  or si g ni fi c a nt tr a u m ati c i nj ur y  wit hi n  2 8  d a ys -
b ef or e  e nr oll m e nt  or  a nti ci p ati o n  of t h e  n e e d f or  m aj or s ur g er y  d uri n g t h e 
c o urs e  of st u d y tr e at m e nt  
•   C urr e nt  pr e g n a n c y  or l a ct ati o n 
•   C urr e nt  k n o w n  u n c o ntr oll e d  a cti v e i nf e cti o n  wit h  HI V,  h e p atitis  B,  a n d/ or 
h e p atitis  C  vir us 
1 8.  A n y  u n c o ntr oll e d, i nt er c urr e nt ill n ess i n cl u di n g  b ut  n ot li mit e d t o  o n g oi n g  or  a cti v e 
i nf e cti o n, s y m pt o m ati c  c o n g esti v e  h e art f ail ur e,  u nst a bl e  a n gi n a  p e ct oris,  c ar di a c 
arr h yt h mi a .  
1 9.  A n y  ot h er  s eri o us  m e di c al  or  ps y c hi atri c ill n ess/ c o n diti o n li k el y  i n t h e j u d g m e nt  of 
t h e I n v esti g at or(s) t o i nt erf er e  or li mit  c o m pli a n c e  wit h st u d y r e q uir e m e nts/tr e at m e nt.  
 
 E n r oll m e nt  P r o c e d u r es  
T o  e nt er  a  p ati e nt, t h e I n v esti g at or  or  St u d y  T e a m  will  c o nt a ct t h e  Cli ni c al  R es e ar c h 
S er vi c es’ ( C R S)  R e pr es e nt ati v e.   All  el i gi bilit y r e q uir e m e nts  m ust  b e r e vi e w e d  pri or t o t h e 
p ati e nt  e nt eri n g t h e st u d y.   T h e f oll o wi n g i nf or m ati o n  m ust  b e  pr o vi d e d t o t h e  C R S 
R e pr es e nt ati v e:  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  2 9  of  9 7  
 
1)   C o m pl et e d  a n d si g n e d  pr ot o c ol- s p e cifi c  eli gi bilit y  c h e c klist;  
2)   All  p a g es  of t h e  ori gi n al si g n e d i nf or m e d  c o ns e nt f or m (I C F) i n cl u di n g  HI P A A  F or m 
B;  
3)   R el e v a nt s o ur c e  d o c u m e nts i n cl u di n g  b ut  n ot  li mit e d t o: s u bj e ct  m e di c al  hist or y, 
c o n c o mit a nt  m e di c ati o ns   a n d  p h ysi c al  e x a m,  a d missi o n  or  dis c h ar g e  n ot es,  di a g n osti c 
r e p orts,  p at h ol o gi c  c o nfir m ati o n  of  di a g n osis,  a n d r el e v a nt s u bj e ct-s p e cifi c  writt e n 
c o m m u ni c ati o n. 
 
 C a n c ell ati o n  G ui d eli n es  
If  a  p ati e nt  d o es  n ot r e c ei v e  pr ot o c ol t h er a p y, t h e  p ati e nt  m a y  wit h dr a w.   C o nt a ct t h e 
C R S  R e pr es e nt ati v e,  or  e - m ail t h e i nf or m ati o n i n cl u di n g t h e r e as o ns f or  wit h dr a w al 
wit hi n  1 0- b usi n ess  d a ys.  
 E m e r g e n c y  R e gist r ati o n  
If  a n  e m er g e n c y r e gistr ati o n t a k es  pla c e  aft er  b usi n ess  h o urs, t h e it e ms list e d  a b o v e 
m ust  b e s u b mitt e d  b y t h e  n e xt  b usi n ess  d a y.  
 
 S T U D Y  D E SI G N  
T his is  a  P h as e I/II, si n gl e  ar m,  o p e n -l a b el  cli ni c al tri al  d esi g n e d t o  est a blis h t h e 
r e c o m m e n d e d  p h as e II  d os e ( R P 2 D)  of  vi n or el bi n e  wit h  a fi x e d  d os e  of tr ast u z u m a b 
e mt a nsi n e.  T h e st u d y  will  als o  e v al u at e t h e s af et y  a n d  effi c a c y  of t h e  R P 2 D i n  p ati e nts  wit h 
H E R 2 -p ositi v e  m et ast ati c , l o c all y  a d v a n c e d, or  u nr es e ct a bl e  br e ast  c a n c er.  T h e st u d y  will  b e 
o p e n e d  t o  a c cr u al at t h e  U ni v ersit y  of  Mi a mi  S yl v est er  C o m pr e h e nsi v e  C a n c er  C e nt er 
( S C C C)  m ai n  c a m p us  a n d  c o nstit u e nt s at ellit e sit es, D e erfi el d  B e a c h  a n d  Pl a nt ati o n.  
T his  p h as e I/II st u d y  will  h a v e  a t ot al  of  5 0  e nr oll e d  p ati e nts, t a ki n g i nt o  a c c o u nt  1 0 %  dr o p -
o ut i n  t h e p h as e II f oll o w- u p.  T h e  d ur ati o n  a nti ci p at e d t o  e nr oll  all st u d y s u bj e cts i n  P h as e 
I/II is  2  y e ars.  T h e  esti m at e d  d ur ati o n f or t h e I n v esti g at ors t o  c o m pl et e t his st u d y ( P h as e 
I/II) is  4. 5 t o  5  y e ars. 
F or t h e  p h as e I  p orti o n, st a n d ar d  3 + 3  d os e  es c al ati o n/ d e- es c al ati o n  d esi g n  wil l  b e  a p pli e d. 
A p pr o xi m at el y  1 5 t o  2 1  p ati e nts  will  b e  n e e d e d t o  est a blis h  t h e r e c o m m e n d e d  p h as e II d os e 
( R P 2 D).  F or t h e  p h as e II  p orti o n  of t h e st u d y,  u p t o  3 5  p ati e nts  will  b e tr e at e d  at t h e  R P 2 D 
(M T D ) i n cl u di n g  6 p ati e nts tr e at e d  at  R P 2 D i n  p h as e I.  P ati e nts  m a y r e m ai n  o n tr e at m e nt 
wit h t h e  c o m bi n ati o n  u ntil  dis e as e  pr o gr essi o n  or  u n m a n a g e a bl e t o xi cit y. 
T u m or  ass ess m e nts  will  b e  c o n d u ct e d  e v er y  6  w e e ks ( ± 7  d a ys) t o  w e e k  1 8 .  T h er e aft er, t h es e 
ass ess m e nt s will  b e  d o n e  e v er y  1 2  w e e ks ( ± 7  d a ys).  T h es e  wil l   o c c ur r e g ar dl ess  of  d os e 
d el a ys  or  d os e i nt err u pti o ns,  u ntil I n v esti g at or- ass ess e d  pr o gr essi v e  dis e as e ( P D),  or  d e at h, 
w hi c h e v er  o c c urs first.  M or e fr e q u e nt t u m or  ass ess m e nts  m a y  b e  p erf or m e d  as  cli ni c all y 
i n di c at e d,  at t h e  dis cr eti o n  of t h e tr e ati n g In v esti g at or.  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  3 0  of  9 7  
 
F or t h e  p h as e II  p orti o n  of t h e st u d y -  p ati e nts   w h o  dis c o nti n u e tr e at m e nt f or r e as o ns  ot h er 
t h a n  P D  will  c o nti n u e t o  h a v e r e q uir e d t u m or  ass ess m e nts  c o m pl et e d  u ntil  P D  or t h e 
i niti ati o n of  a  n e w t h er a p y.  O n c e  p ati e nts  h a v e  pr o gr ess e d, t h e y  wi ll  b e f oll o w e d f or 
s ur vi v al  a p pr o xi m at el y  e v er y  3  m o nt hs  f or  at l e ast  3  y e ars.  S u bs e q u e nt  a nti-c a n c er t h er a pi es 
will  b e  d o c u m e nt e d  u ntil st u d y  c o m pl eti o n. 
P ati e nts  w h o  ar e  dis c o nti n u e d fr o m st u d y tr e at m e nt  will r et ur n f or t h e  St u d y  Tr e at m e nt 
Dis c o nti n u ati o n  Visit  a p pr o xi m at el y  3 0  d a ys ( ± 7  d a ys)  aft er t h e l ast  d os e  of st u d y tr e at m e nt.   
S e e  als o  Pr ot o c ol  S c h e m a.  
 D os e  Es c al ati o n/  D os e  D e- Es c al ati o n 
F or t h e  P h as e I  p orti o n  of t h e st u d y,  p ati e nts  will  b e s e q u e nti all y  assi g n e d t o  u p t o  5 
d os e l e v els  a c c or di n g t o st a n d ar d  3 + 3  d os e  es c al ati o n/ d e- es c al ati o n  d esi g n,  as  d et ail e d 
b el o w. I n  or d er t o  o p e n t h e  n e xt  hi g h er  c o h ort  all  p ati e nts  wit hi n t h e  pr e vi o us  c o h ort 
wit h o ut  D L T,  m ust  h a v e r e c ei v e d  a  mi ni m u m  of  2  c y cl es.    
T a bl e  1 :  D os e  Es c al ati o n S c h e d ul e  
D os e  Es c al ati o n  S c h e d ul e  
D os e  L e v el  
D os e *  
Vi n or el bi n e  
(m g/ m 2) 
Tr ast uz u m a b  e mt a nsi n e  
( m g/ k g) 
L e v el  -1  
2 0  
3. 6  (fi x e d  d os e) 
L e v el  1  
( St a rti n g) 
2 2. 5 
L e v el  2  
2 5  
L e v el  3  
2 7. 5  
L e v el  4  
3 0  
 
 D os e  Es c al ati o n  R ul es   
T h er e  will  b e  n o  d os e  m o difi c ati o n(s)  of   vi n or el bi n e  n or tr ast u z u m a b  e mt a nsi n e 
p er mitt e d  d uri n g  t h e p h as e I   p orti o n  of t h e st u d y.   D os e  m o difi c ati o ns  of tr ast u z u m a b 
e mt a nsi n e  a n d  vi n or el bi n e  will  b e  p er mitt e d  o nl y  o n t h e  p h as e II  p orti o n  of t h e st u d y i n 
c as es  of  h e p at ot o xi cit y,   n e utr o p e ni a, t hr o m b o c yt o p e ni a  a n d  n e ur o p at h y. M a n a g e m e nt 
g ui d eli n es  a n d  d os e  m o difi c ati o ns  ar e  d et ail e d l at er i n t h e  pr ot o c ol i n  S e cti o n  1 0. 0.  
F or t h e  p h as e I  p orti o n  of t h e st u d y, if  n o  d os e- li miti n g t o xi cit y ( D L T)  ar e r e a c h e d  at  a 
d os e l e v el, t h e  d os e is  es c al at e d f or t h e  n e xt  c o h ort  of  p ati e nts. If  o nl y  o n e  of t hr e e 
p ati e nts  at  a  p arti c ul ar  d os e l e v el is  n ot e d t o  h a v e  a  D L T, t h e n  u p t o t hr e e  m or e  p ati e nts 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  3 1  of  9 7  
 
c a n  b e  e nt er e d  o nt o t h at  d os e l e v el. If  o n e  of t h e  a d diti o n al  gr o u p s uff er  D L T, t h e n  d os e 
es c al ati o n is st o p p e d ( as  2  o ut  of  6  p ati e nts  w o ul d  h a v e t h e n s uff er e d  a  D L T),  a n d t h e 
m a xi m u m t ol er at e d  d os e ( M T D)  w o ul d  b e r e a c h e d.  I n t his  c as e, t hr e e  a d diti o n al 
p ati e nts  will  b e  e nt er e d  o n t h e  pr e c e di n g  d os e l e v el t o  e ns ur e t h at t h e  c orr e ct  M T D  w as 
d et er mi n e d,  a n d t his  pr e c e di n g  d os e  will  b e t h e  d os e t o  b e t a k e n i nt o t h e  p h as e II 
p orti o n  of t h e tri al (s e e  T a bl e  2 ). 
D os e  es c al ati o n  will  pr o c e e d  wit hi n  e a c h  c o h ort  a c c or di n g t o t h e f oll o wi n g s c h e m e:   
( D L T is  d efi n e d  a b o v e.)   
T a bl e  2 :  Es c al ati o n  S c h e m e 
N u m b e r  of  P ati e nts 
wit h  D L T  at  a  Gi v e n 
D os e  L e v el  
Es c al ati o n  D e cisi o n  R ul e 
0  o ut  of  3  
E nt er  3  p ati e nts  at t h e  n e xt  ( hi g h er) d os e  l e v el. 
1  o ut  of  3 
E nt er  at l e ast  3  m or e  p ati e nts  at t his  (s a m e) d os e l e v el.  
•  If  0  of t h es e  3  p ati e nts  e x p eri e n c e  D L T,  pr o c e e d t o t h e  n e xt 
d os e l e v el.  
•  If  1  or  m or e  of t his  gr o u p s uff er  D L T, t h e n  d os e  es c al ati o n 
is st o p p e d,  a n d t his  d os e is  d e cl ar e d t h e m a xi m u m t ol er at e d  
d os e  ( M T D).   
> 2  (fr o m t h e  ori gi n al 
c o h ort  of  3) 
D os e  es c al ati o n  will  b e st o p p e d.   T his  d os e l e v el  will  b e 
d e cl ar e d t h e  m a xi m all y  a d mi nist er e d  d os e  or  M A D ( hi g h est 
d os e  a d mi nist er e d).   T hr e e ( 3)  a d diti o n al  p ati e nts  will  b e 
e nt er e d  at t h e   n e xt l o w er  d os e l e v el if  o nl y  3  p ati e nts  w er e 
tr e at e d  pr e vi o usl y  at t h at  d os e. 
N O T E :  E nr oll m e nt  of  p ati e nts  will  b e s p a c e d  at l e ast 3  w e e ks  ( 2 1 d a ys)  a p art  all o wi n g 
f or  e v al u ati o n  of  D L T.   Si m ult a n e o us  e nr oll m e nt is  o nl y  p er mitt e d  u n d er t h e f oll o wi n g 
cir c u mst a n c es:   
•   If t h e first  p ati e nt t o r e c ei v e  a  d os e l e v el  d o es  n ot  e x p eri e n c e  D L T,  p ati e nts  2  a n d  3 
m a y  b e  e nr oll e d si m ult a n e o usl y  at t h e s a m e  d os e l e v el.  
 
 
 
 
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  3 2  of  9 7  
 
Fi g ur e  3 :  S c h e m a f or  P h as e I  D os e  Es c al ati o n/  D e-es c al ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 D os e - Li miti n g  T o xi cit y ( D L T)  
 P h as e I  Pr ot o c ol- S p e cifi e d  D L T(s)  
T h e  o c c u r r e n c e  of  a n y  of t h e f oll o wi n g  d u ri n g t h e fi rst  2  c y cl es (i. e. fi rst  2 1- 4 2 
d a ys)  of st u d y t r e at m e nt  will  c o nstit ut e  a  D L T  ( o nl y t r e at m e nt  r el at e d  p ossi bl e, 
p r o b a bl e,  o r  d efi n e  att ri b uti o ns  will  b e  c o nsi d e r e d  D L Ts) : 
• Gr a d e  3  or  gr e at er  n o n -h e m at ol o gi c t o xi citi es t h at li mit t h e  a bilit y  of t h e  p ati e nt t o 
t ol er at e tr e at m e nt  o n s c h e d ul e  or  ar e  c o nsi d er e d  p arti c ul arl y  pr o bl e m ati c i n t h e  vi e w  of 
t h e i n v esti g at or. If  a  p ati e nt’s t o xi cit y  d o es  n ot r es ol v e t o l ess t h a n  gr a d e  1  wit hi n s e v e n 
d a ys, t his  q u alifi es  as  a  D L T  at t h e  dis cr eti o n  of t h e i n v esti g at or.  
•  Gr a d e  3  n e ur o p at h y  w hi c h  d o es  n ot r es ol v e t o  gr a d e  2  or l ess  wit hi n  2 1 d a ys  of 
tr e at m e nt. 
S c h e m a f o r  Es c al ati n g/ D e -Es c al ati n g  Vi n o r el bi n e f r o m  a  St a rti n g  D os e  of  2 2. 5  m g/ m
2
 wit h   
a fi x e d  d os e ( 3. 6  m g/ k g fl at  d os e)  of  T r ast u z u m a b  e mt a nsi n e  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  3 3  of  9 7  
 
•  Gr a d e  4  n e utr o p e ni a  w hi c h  d o es  n ot r es ol v e t o  gr a d e  2  or l ess  wit hi n  1 4  d a ys  d es pit e 
t h e  us e  of  gr o wt h f a ct or s u p p ort,  w h e n  p er mitt e d  p er  pr ot o c ol. 
•  Gr a d e  3  el e v ati o n  of li v er f u n cti o n t ests ( L F Ts) t h at  d o es  n ot r es ol v e t o  gr a d e  2  or l ess 
wit hi n  1 4  d a ys. 
•  R e- o c c urr e n c e  of  gr a d e  4  n e utr o p e ni a  or  gr a d e  3  el e v ati o n  of  L F Ts  d es pit e t w o  d os e 
m o difi c ati o ns  or  o n e  d os e  m o difi c ati o n  a n d  o n e  pr ot o c ol s p e cifi e d  d os e  d el a y. 
•  Gr a d e  3 l eft  v e ntri c ul ar s yst oli c  d ysf u n cti o n t h at  d o es  n ot r es ol v e t o  gr a d e  2  or l ess 
wit hi n  2 1  d a ys  of tr e at m e nt. 
•  Gr a d e  5  p ossi bl e,  pr o b a bl e,  or  d efi nit el y r el at e d t o tr e at m e nt.  
 
 T R E A T M E N T  P L A N  
O n e  c y cl e  of tr ast u z u m a b  e mt a nsi n e/ vi n or el bi n e  c o m bi n ati o n tr e at m e nt is  d efi n e d  as  2 1-
d a ys ( i. e.  3  w e e ks).  F or  e a c h  d a y  of tr e at m e nt, tr ast u z u m a b  e mt a nsi n e s h o ul d  al w a ys  b e 
a d mi nist er e d  pri or t o  vi n or el bi n e.  
 T r ast u z u m a b  e mt a nsi n e  
F or  a d diti o n al i nf or m ati o n  o n  Tr ast u z u m a b  e mt a nsi n e i n cl u di n g  m e c h a nis m  of  a cti o n, 
dr u g  m et a b olis m,  p h ar m a c o ki n eti cs  & t o xi c ol o g y,  k n o w n si d e  eff e cts,  c o m p ositi o n,  a n d 
st or a g e r e c o m m e n d ati o ns, s e e  [ S e cti o n  9. 1]. 
T h e r e c o m m e n d e d (st arti n g)  d os e  of tr ast u z u m a b  e mt a nsi n e is  3. 6  m g/ k g  gi v e n  as  a n 
i ntr a v e n o us i nf usi o n  e v er y  3  w e e ks ( 2 1-d a y  c y cl e).  D o  n ot  a d mi nist er  tr ast u z u m a b 
e mt a nsi n e   at  d os es  gr e at er t h a n  3. 6  m g/ k g.  D o  n ot s u bstit ut e tr ast u z u m a b  e mt a nsi n e f or 
or  wit h  tr ast uz u m a b.  
 
Cl os el y  m o nit or t h e i nf usi o n sit e f or  p ossi bl e s u b c ut a n e o us i nfiltr ati o n  d uri n g  dr u g 
a d mi nistr ati o n.  D osi n g  will  b e  a c c o r di n g t o t h e  a ct u al  w ei g ht  o n  d a y  1  of  e a c h  c y cl e .  
 
T h er e  will  b e  n o  d os e  m o difi c ati o ns  of tr ast u z u m a b  e mt a nsi n e  p er mitt e d f or t h e  p h as e I 
p orti o n  of t h e st u d y (fi x e d  d os e  of  3. 6 m g/ k g f or  all  c o h orts).  S e e  S e cti o n  7. 0  a n d  1 0. 0. 
   
 
First i nf usi o n :  A d mi nist er i nf usi o n  o v er  9 0  mi n ut es.  P ati e nts s h o ul d  b e  o bs er v e d  d uri n g 
t h e i nf usi o n  a n d f or  at l e ast  9 0  mi n ut es f oll o wi n g t h e i niti al  d os e f or f e v er,  c hills,  or 
ot h er i nf usi o n- r el at e d r e a cti o ns. 
 
S u bs e q u e nt i nf usi o ns:  A d mi nist er  o v er  3 0  mi n ut es ( ±  5  mi n ut es) if  pri or i nf usi o ns  w er e 
w ell t ol er at e d.  
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  3 4  of  9 7  
 
 Vi n o r el bi n e 
F or  a d diti o n al i nf or m ati o n  o n  Vi n or el bi n e i n cl u di n g  m e c h a nis m  of  a cti o n,  dr u g 
m et a b olis m,  p h ar m a c o ki n eti cs  & t o xi c ol o g y,  k n o w n si d e  eff e cts,  c o m p ositi o n,  a n d 
st or a g e r e c o m m e n d ati o ns, s e e [ S e cti o n  9. 2 ]. 
T h e st arti n g  d os e  of  vi n or el bi n e is  2 2. 5  m g/ m 2 gi v e n  as  a  dir e ct  i ntr a v e n o us  p b  o v er  8 
mi n ut es   ± ( pl us  or  mi n us)  2  mi n ut es  o n  d a y  1  a n d  d a y  8  of  e v er y  3- we e k (i. e.  2 1 -d a y) 
c y cl e.   Pr e m e di c at e  wit h  Z ofr a n  8 m g. I ntr a v e n o us  d os es s h o ul d  b e f oll o w e d  b y  at l e ast 
7 5- 1 2 5  m L  of s ali n e  or  D 5 W t o r e d u c e t h e i n ci d e n c e  of  p hl e bitis  a n d i nfl a m m ati o n.   
T h er e  will  b e  n o  d os e  m o difi c ati o ns  of  vi n or el bi n e  p er mitt e d  d uri n g t h e  p h as e I  p orti o n 
of t h e  pr ot o c ol.  S e e  S e cti o n  7. 0  a n d  1 0. 0. 
 T r e at m e nt  S c h e m a  
T a bl e  3 :  Tr e at m e nt  S c h e m a 
R e gi m e n  D es c ri pti o n  
A g e nt  
Pr e m e di c ati o ns; 
Pr e c a uti o ns  
D os e   
R o ut e   
S c h e d ul e  
C y cl e 
L e n gt h  
Tr ast uz u m a b 
e mt a nsi n e  
P ati e nts s h o ul d  b e 
o bs er v e d  d uri n g 
t h e i nf usi o n  a n d 
f or  at l e ast  9 0 
mi n ut es  aft er t h e 
1 st d os e f or f e v er, 
c hills,  or  ot h er 
i nf usi o n-r el at e d 
r e a cti o ns 
* *   3. 6 
m g/ k g  
I V  o v er  9 0  mi n ut es 
f or t h e  1st d os e; I V 
o v er  3 0  mi n ut es f or 
s u bs e q u e nt 
i nf usi o ns if  pri or 
i nf usi o ns  w er e  w ell 
t ol er at e d 
D a y  1  
2 1  d a ys   
( 3  w e e ks) 
 
 
 
Vi n or el bi n e  
Pr e m e di c at e  wit h 
Z ofr a n  8 m g ; 
I ntr a v e n o us  d os es 
s h o ul d  b e 
f oll o w e d  b y  at 
l e ast  7 5- 1 2 5  m L 
of s ali n e  or  D 5W 
t o r e d u c e t h e 
i n ci d e n c e  of 
p hl e bitis  a n d 
i nfl a m m ati o n. 
* *   2 2. 5 
m g/ m 2 
Dir e ct  I V p us h  o v er 
6- 1 0  mi n ut es  
D a ys  1  a n d  8  
* * D os es  as  a p pr o pri at e f or  st arti n g d os e l e v el.  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  3 5  of  9 7  
 
 
 T r e at m e nt  Dis p e ns ati o n,  C o m pli a n c e  a n d  A c c o u nt a bilit y  
T r ast u z u m a b  e mt a nsi n e a n d  vi n or el bi n e  will  b e  a d mi nist er e d i n t h e  o ut p ati e nt s etti n g.  
If  a  d os e  of tr ast u z u m a b  e mt a nsi n e  or  vi n or el bi n e is  h el d  d u e t o  A E,  S A E,  or  at t h e 
i n v esti g at or’s  dis cr eti o n, t h e n  h e/s h e s h o ul d r es u m e tr e at m e nt  at t h e i n v esti g at ors 
dis cr eti o n t a ki n g i nt o  a c c o u nt  all  of t h e  d os e  es c al ati o n/ m o difi c ati o n/ dis c o nti n u ati o n 
g ui d eli n es  pr o vi d e d i n  S e cti o n  7. 0  a n d  1 0. 0, r es p e cti v el y.   T h e  pr o c e d ur es  c a n  h el d  d u e 
t o  A E,  S A E,  or  at t h e  dis cr eti o n  of t h e i n v esti g at or if it is  n e c ess ar y.  
 S u p p o rti v e  C a r e  G ui d eli n es      
 C o n c urr e nt  M e di c ati o ns /  T h er a p y  
C o n c o mit a nt t h er a p y  a n d  pr e m e di c ati o n  ar e  d efi n e d  as  n o n- i n v esti g ati o n al 
m e di ci n a l  pr o d u cts. C o n c o mit a nt t h e r a p y i n cl u d es  a n y  p r es c ri pti o n 
m e di c ati o n,  o v e r- t h e-c o u nt e r  p r e p a r ati o n,  o r  h e r b al t h e r a p y  b et w e e n t h e  1 4 
d a ys  p r e c e di n g st u d y  e n r oll m e nt  a n d t h e  St u d y  T r e at m e nt  Dis c o nti n u ati o n 
Visit.   Aft er t h e st u d y tr e at m e nt  dis c o nti n u ati o n  v isit,  o nl y  a nti-c a n c er t h er a pi es 
will  b e  c oll e ct e d  as  p art  of t h e s ur vi v al f oll o w - u p  p eri o d.  N o n- pr ot o c ol  a nti-
c a n c er t h er a pi es  a d mi nist er e d  d uri n g t h e tr e at m e nt  p eri o d  ar e  n ot  all o w e d  as 
c o n c o mit a nt t h er a p y.  
P r e m e di c ati o n  is  all o w e d  a c c or di n g t o st a n d ar d pr a cti c e  g ui d eli n es. 
C o n c o mit a nt  us e  of  e r yt h r o p oi esis -sti m ul ati n g  a g e nts  a n d/ o r  c ol o n y-
sti m ul ati n g f a ct o rs  is  all o w e d  p er  g ui d eli n es  gi v e n i n s e cti o n 8. 5.  
P alli ati v e  r a di ot h e r a p y  m a y  b e  p er mitt e d t o tr e at  pr e - e xisti n g  p ai nf ul  b o n e 
m et ast as es.  H o w e v er,  b o n e l esi o ns t h at  ar e r a di at e d  pri or t o st art  of  pr ot o c ol 
tr e at m e nt  c a n n ot  b e  us e d  as t h e  b o n e- o nl y  dis e as e f or  e ntr y  o nt o st u d y (i. e. 
p ati e nts  m ust  h a v e  ot h er  ar e a  of  b o n e  dis e as e).   
P alli ati v e  r a di ot h e r a p y  m a y  b e  p er mitt e d t o tr e at  br ai n  m et ast as es (f or  p ati e nts 
w h o  h a v e  dis e as e  c o ntr ol  o utsi d e  of t h e  br ai n)  b ut  m ust  b e  c o m pl et e d  wit hi n  1 4 
d a ys  of  e nr oll m e nt  o n  pr ot o c ol.  
Ot h er  m e di c ati o ns  c o nsi d er e d  n e c ess ar y f or t h e  p ati e nt’s s af et y  a n d  w ell - b ei n g 
m a y  b e  gi v e n  at t h e  dis cr eti o n  of t h e i n v esti g at or.  Us e  of  bis p h os p h o n at es  o r 
d e n os u m a b  is  p er mitt e d f or t h e  c o ntr ol  of  b o n e  p ai n,  pr e v e nti o n  a n d/ or 
tr e at m e nt  of  b o n e m et ast as es ,  a n d tr e at m e nt  of  ost e o p or osis. If  bis p h os p h o n at es 
ar e r e q uir e d f or t h e tr e at m e nt  of  n e w -o ns et s y m pt o m ati c  m ali g n a n c y -ass o ci at e d 
h y p er c al c e mi a, t u m or  ass ess m e nts s h o ul d  b e  p erf or m e d t o  ass ess f or  p ot e nti al 
dis e as e  pr o gr essi o n . 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  3 6  of  9 7  
 
P ati e nts  o n  L H R H  a g o nists  m a y  c o nti n u e if  d e e m e d  n e c ess ar y  b y t h e 
i n v esti g at or  as  a  c o n c o mit a nt  m e di c ati o n if  us e d f or  n o n − br e ast  c a n c er 
i n di c ati o ns.  T his s h o ul d  b e  a p pr o v e d  b y t h e  PI.  
P ati e nts  w h o  ar e  o n  a nti - c o a g ul a nt t r e at m e nt s h o ul d  b e  m o nit or e d  cl os el y 
d uri n g tr e at m e nt  wit h tr a st u z u m a b  e mt a nsi n e.  P ati e nts t a ki n g  a nti c o a g ul a nts  or 
st arti n g  a nti c o a g ul a nts  w hil e  o n st u d y s h o ul d  h a v e  w e e kl y  pl at el et  c o u nts 
m o nit or e d f or  2  c y cl es i n  or d er t o  ass ess  w h et h er  a tr ast u z u m a b  e mt a nsi n e  d os e 
r e d u cti o n  m a y  b e  n e c ess ar y. 
C Y P 3 A I n hi bit o rs :  E x er cis e  c a uti o n i n  p ati e nts  c o n c urr e ntl y t a ki n g  dr u gs 
k n o w n t o i n hi bit  dr u g  m et a b olis m  b y  h e p ati c  c yt o c hr o m e  P 4 5 0 is o e n z y m es i n 
t h e  C Y P 3 A s u bf a mil y.  C o n c urr e nt  a d mi nistr ati o n  of  N A V E L BI N E  wit h  a n 
i n hi bit or  of t his  m et a b oli c  p at h w a y  m a y  c a us e  a n  e arli er  o ns et  a n d/ or  a n 
i n cr e as e d s e v erit y  of  a d v ers e r e a cti o ns.   S e e  als o  A p p e n di x E. 
 Pr o hi bit e d  T h er a p y 
Us e  of  c ert ai n t h er a pi es is  pr o hi bit e d  d uri n g t h e st u d y  pri or t o  dis c o nti n u ati o n  of 
st u d y tr e at m e nt ( c oll e cti v el y, t h es e  will  b e r ef err e d t o  as  n o n - pr ot o c ol t h er a py). 
T h es e t h er a pi es i n cl u d e  a n yt hi n g i nt e n d e d f or t h e tr e at m e nt  of  br e ast  c a n c er, 
ot h er t h a n tr ast u z u m a b  e mt a nsi n e  a n d  vi n or el bi n e,  w h et h er  a p pr o v e d  b y  n ati o n al 
h e alt h  a ut h oriti es  or  e x p eri m e nt al.  T his i n cl u d es  c yt ot o xi c  c h e m ot h er a p y, 
i m m u n ot h er a p y,    h or mo n al t h er a p y ( ot h er t h a n  m e g estr ol  a c et at e  or  L H R H 
a g o nists  us e d f or  n o n − br e ast  c a n c er i n di c ati o ns),  a n d  bi ol o gi c  or t ar g et e d  a g e nts 
( ot h er t h a n  gr a n ul o c yt e  c ol o n y-sti m ul ati n g f a ct or  a n d  er yt hr o p oi esis -sti m ul ati n g 
a g e nts).  
R a di ot h er a p y f or  u n e q ui v o c al  dis e as e  pr o gr essi o n is  n ot  p er mitt e d  w hil e  o n 
st u d y tr e at m e nt,  wit h t h e  e x c e pti o n  of  n e w  br ai n  m et ast as es  or is ol at e d 
pr o gr essi o n  of  pr e vi o usl y tr e at e d  br ai n l esi o ns.  P ati e nts  w h o  h a v e  dis e as e  c o ntr ol 
o utsi d e  of t h e  br ai n,  d efi n e d  as  c o nti n u e d  P R  or  C R  of  a n y  d ur ati o n,  or st a bl e 
dis e as e,  b ut  w h o  h a v e  d e v el o p e d  br ai n  m et ast as es t h at  ar e tr e at a bl e  wit h 
r a di ati o n  will  b e  all o w e d t o  c o nti n u e t o r e c ei v e st u d y t h er a p y  u ntil t h e y  eit h er 
e x p eri e n c e s yst e mi c  pr o gr essi o n  of t h eir  dis e as e  a n d/ or f urt h er  pr o gr essi o n i n t h e 
br ai n t h at  c a n n ot  b e tr e at e d  wit h  a d diti o n al r a di ati o n.  P ati e nts  m ust  n ot  miss 
m or e t h a n  o n e  c y cl e  of st u d y tr e at m e nt f or t h e tr e at m e nt  of t h eir  br ai n  m et ast as es 
a n d  m ust  h a v e  a n  E C O G  p erf or m a n c e st at us  of  0  or  1 t o  c o nti n u e  o n t h er a p y. 
T h e  M e di c al  M o nit or s h o ul d  b e i nf or m e d  b ef or e  a  d e cisi o n is  m a d e t o r es u m e 
st u d y tr e at m e nt  aft er r a di ot h er a p y f or  br ai n  m et ast as es.  
I n  cli ni c al  pr a cti c e,  p h ysi ci a ns  will t y pi c all y  c o nti n u e  H E R 2-dir e ct e d t h er a p y 
wit h  or  wit h o ut  c h e m ot h er a p y i n  p ati e nts  wit h  H E R 2 - p ositi v e  bre ast  c a n c er  w h o 
r e c ei v e l o c al tr e at m e nt f or  n e w  br ai n  m et ast as es  b ut  ot h er wis e  m ai nt ai n  c o ntr ol 
of t h eir s yst e mi c  dis e as e.  A r etr os p e cti v e st u d y i n  8 6  p ati e nts  d e m o nstr at e d t h at 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  3 7  of  9 7  
 
t h e  m e di a n s ur vi v al  of  p ati e nts  wit h  H E R 2- p ositi v e  dis e as e ( n  =  2 6)  w h o 
c o nti n u e d tr e at m e nt  wit h tr ast u z u m a b  aft er  b ei n g  di a g n os e d  wit h  br ai n 
m et ast as es  w as si g nifi c a ntl y l o n g er t h a n f or t h os e  p ati e nts ( n  =  6 0)  w h o  di d  n ot 
h a v e  H E R 2 - p ositi v e  dis e as e ( 1 1. 9  m o nt hs  vs.  3  m o nt hs,  p  =  0. 0 5) ( C h ur c h  et  al. 
2 0 0 8).  B y  all o wi n g  c o nti n u e d st u d y tr e at m e nt  aft er is ol at e d  pr o gr essi o n i n t h e 
br ai n  h as  b e e n i d e ntifi e d  a n d tr e at e d, t his st u d y  will  e x pl or e t h e s af et y  a n d 
effi c a c y  of st u d y tr e at m e nt r e gi m e ns i n t his s etti n g.  
 D u r ati o n  of  T r e at m e nt  
P ati e nts  m a y r e m ai n  o n tr e at m e nt  wit h t h e  vi n or el bi n e/ tr ast u z u m a b  e mt a msi n e 
c o m bi n ati o n  u ntil  d o c u m e nt e d  dis e as e  pr o gr essi o n  or  ot h er  crit eri a f or  dis c o nti n u ati o n 
is  m et ( S e cti o n  1 1. 0). 
 D u r ati o n  of  F oll o w- U p   
All  p ati e nts  will  b e f oll o w e d  at  3 0 - d a ys ( + 5  d a ys)  aft er t h e l ast  d os e  of  vi n or el bi n e/ 
tr ast u z u m a b  e mt a nsi n e  c o m bi n ati o n t h er a p y.  
P ati e nts ( r e g ar dl ess  of r e as o n f or tr e at m e nt  dis c o nti n u ati o n)  will t h e n  b e f oll o w e d f or 
s ur vi v al  u ntil  d e at h, l ost t o f oll o w- u p,  wit h dr a w al  of  c o ns e nt *,  or st u d y t er mi n ati o n  b y 
t h e  Pri n ci p al I n v esti g at or.   S e e  S e cti o n  1 2. 4 for  d et ails.  
* N ot e:  S o m e  p ati e nts  m a y  wit h dr a w t h eir  c o ns e nt fr o m st u d y  tr e at m e nt b ut still  a gr e e 
t o  p arti ci p at e i n s ur vi v al f oll o w- u p.   F or t h es e  p ati e nts s ur vi v al f oll o w- u p s h all  o c c ur 
u ntil  d e at h, l ost t o f oll o w- u p  or  wit h dr a w al fr o m st u d y.   S e e  als o s e c ti o n  1 2. 4 f or 
d et ails.  
 
 A G E N T S ( D R U G  F O R M U L A TI O N  A N D  P R O C U R E M E N T)  
 T r ast u z u m a b  e mt a nsi n e  
[ R ef er t o t h e c urr e nt  v ersi o n  of t h e  I n v esti g at or’s  Br o c h ur e f or  m or e i nf or m ati o n.]   
 Ot h er  n a m e(s)  
K A D C Y L A ®,  T -D M 1,  T R A S T U Z U M A B -M C C - D M 1,  P R O 1 3 2 3 6 5, 
R O 5 3 0 4 0 2 0,  tr ast u z u m a b  e mt a nsi n e 
 M e c h a nis m  of  A cti o n  
Tr ast u z u m a b  e mt a nsi n e ( K a d c yl a ® als o  k n o w n  as  T- D M 1, tr ast u z u m a b 
e mt a nsi n e) is  a  n o v el  a nti b o d y- dr u g  c o nj u g at e ( A D C) t h at is s p e cifi c all y 
d esi g n e d f or t h e tr e at m e nt   of  h u m a n  e pi d er m al  gr o wt h f a ct or r e c e pt or  2 ( H E R 2)-
p ositi v e  m ali g n a n ci es.   Tr ast u z u m a b  e mt a nsi n e is  c o m p os e d  of tr ast u z u m a b,  a 
h u m a ni z e d  a nti b o d y  dir e ct e d  a g ai nst t h e  e xtr a c ell ul ar r e gi o n  of  H E R 2;  D M 1,  a n 
a nti - mi cr ot u b ul e  a g e nt  d eri v e d fr o m  m a yt a nsi n e;  a n d  4-[ N-


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  3 8  of  9 7  
 
m al ei mi d o m et h yl] c y cl o h e x a n e - 1-c ar b o x yl at e ( M C C),  d eri v e d fr o m  s u c ci ni mi d yl 
4- [ N-m al ei mi d o m et h yl] c y cl o h e x a n e - 1-c ar b o x yl at e ( S M C C),  a t hi o et h er  li n k er 
t h at  c o nj u g at es  D M 1 t o tr ast u z u m a b.  Tr ast u z u m a b  e mt a nsi n e  bi n ds t o  H E R 2 
wit h  affi nit y si mil ar t o t h at  of tr ast u z u m a b.  Aft er  bi n di n g t o  H E R 2, tr ast u z u m a b  
e mt a nsi n e   u n d er g o es r e c e pt or-m e di at e d i nt er n ali z ati o n, r es ulti n g i n i ntr a c ell ul ar 
r el e as e  of  D M 1  a n d s u bs e q u e nt  c ell  d e at h.  D M 1 is  a n i n hi bit or  of t u b uli n 
p ol y m eri z ati o n. Its  p ar e nt  m ol e c ul e,  m a yt a nsi n e,  w as st u di e d i n  a p pr o xi m at el y 
8 0 0  p ati e nts  w h o  w er e  a d mi nist er e d  m a yt a nsi n e  e v er y  3  w e e ks ( q 3 w)  eit h er  as  a 
si n gl e  d os e  or f or  3  c o ns e c uti v e  d a ys.  R es p o ns es  w er e s e e n i n  p ati e nts  wit h 
br e ast  a n d l u n g  c a n c er;   h o w e v er,  b e c a us e  of its  n arr o w t h er a p e uti c i n d e x,  cli ni c al 
d e v el o p m e nt  w as  n ot  c o nti n u e d.  
Tr ast u z u m a b  e mt a nsi n e r e c o g ni z es  a n  e pit o p e  o n t h e  e xtr a c ell ul ar  d o m ai n ( E C D) 
of  H E R 2.  F oll o wi n g  a nti g e n-s p e cifi c  bi n di n g  of tr ast u z u m a b  e mt a nsi n e t o 
H E R 2, it is  h y p ot h esi z e d t h at t h e  c o m pl e x  of r e c e pt or  a n d  A D C  u n d er g o es 
r e c e pt or-m e di at e d i nt er n ali z ati o n  i nt o  e n d os o m es.  F oll o wi n g i nt er n ali z ati o n, t h e 
e n d os o m e is f us e d  wit h t h e l ys os o m al  c o m p art m e nt, t h e  A D C  u n d er g o es 
l ys os o m al  d e gr a d ati o n  a n d t h e  a cti v e  m et a b olit es l ys-M C C -D M 1  a n d  D M 1  ar e 
r el e as e d [ 1 3, 1 4].  D M 1 is  a  hi g hl y  p ot e nt t hi ol c o nt ai ni n g  d eri v ati v e of 
m a yt a nsi n e  a n d is s y nt h esi z e d fr o m  a ns a mit o ci n  P 3.  D M 1  bi n ds  β -t u b uli n t o 
i n hi bit t u b uli n  p ol y m eri z ati o n, r es ulti n g i n  c ell  d e at h [ 7]. I n  vitr o st u di es  of 
tr ast u z u m a b  e mt a nsi n e  d e m o nstr at e  e n h a n c e d  c yt ot o xi cit y i n  H E R 2-
o v er e x pr essi n g  br e ast  c a n c er  c ell li n es  c o m p ar e d t o  br e ast  c a n c er  c ell li n es  wit h 
l o w  H E R 2  e x pr essi o n. 
T h e r e q uir e m e nt f or r e c e pt or  bi n di n g f or tr ast u z u m a b  e mt a nsi n e  a cti vit y  h as 
b e e n  d e m o nstr at e d i n  vi v o  w h er e  a  n o n- H E R 2 - bi n di n g is ot y p e-m at c h e d  A D C 
s er v e d  as  a  c o ntr ol. I n t h es e  e x p eri m e nt s, t h e  c o ntr ol  a nti b o d y-M C C -D M 1  h a d 
n o  a nti-t u m or  a cti vit y i n t h e  H E R 2 - p ositi v e f or br e ast  c a n c er  m o d el  w h er e as 
tr ast u z u m a b  e mt a nsi n e  e x hi bit e d si g nifi c a nt  a nti-t u m or  a cti vit y. 
 Dr u g  M et a b olis m,  P h ar m a c o ki n eti cs  a n d  T o xi c ol o g y 
T h e r e c o m m e n d e d  d os e  of tr ast u z u m a b  e mt a nsi n e f or  br e ast  c a n c er is  3. 6  m g/ k g 
gi v e n  as  a n I V i nf usi o n  q 3 w.  T h e  P K  a n al ysis fr o m t h e  P h as e I st u d y 
( T D M 3 5 6 9 g) f oll o wi n g  a d mi nistr ati o n  of  0. 3  m g/ k g t o  4. 8  m g/ k g tr ast u z u m a b 
e mt a nsi n e  q 3 w s h o w e d t h at  at t h e  d os e  of  3. 6  m g/ k g  q 3 w, t h e s yst e mi c  cl e ar a n c e 
w as  a p pr o xi m at el y  1 2. 7  m L/ d a y/ k g  a n d t h e  eli mi n ati o n  h alf- lif e  w as 
a p pr o xi m at el y  3. 1  d a ys.  T h e  cl e ar a n c e  of tr ast u z u m a b  e mt a nsi n e  w as  n o nli n e ar 
at  d os es l ess t h a n  or  e q u al t o  1. 2  m g/ k g.  At  all  d os e l e v els,  cl e ar a n c e  of 
tr ast u z u m a b  e mt a nsi n e  w as f ast er t h a n t h at  of tr ast u z u m a b.  A  q w  d osi n g r e gi m e n 
w as  als o  e v al u at e d i n  St u d y  T D M 3 5 6 9 g,  a n d  2. 4  m g/ k g  q w  w as i d e ntifi e d  as t h e 
M T D f or  q w  d osi n g.  K e y tr ast u z u m a b  e mt a nsi n e  P K  p ar a m et ers (i e,  C L,  Vss  a n d 
t 1/ 2)  at  2. 4  m g/ k g  q w  w er e si mil ar t o t h os e  o bs er v e d  at  3. 6  m g/ k g  q 3 w  d osi n g. 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  3 9  of  9 7  
 
T h er e  w as  n o  a c c u m ul ati o n  of tr ast u z u m a b  e mt a nsi n e  w h e n  gi v e n  q 3 w.  T h e 
esti m at e d  v ol u m e  of  distri b uti o n  w as  3 0. 7 t o  5 8. 4  m L/ k g  a cr oss  all  d os e l e v els 
t est e d.  M e as ur a bl e l e v els  of fr e e  D M 1  w er e f o u n d,  b ut  ar e  a p pr o xi m at el y  1 0, 0 0 0 
f ol d ( b y  m ass r ati o)  a n d  a p pr o xi m at el y  5 0-f ol d ( b y  m ol ar r ati o) l o w er t h a n 
tr ast u z u m a b  e mt a nsi n e l e v els.  
I n t h e  P h as e II  a n d III st u di es i n  M B C  p ati e nts ( T D M 4 2 5 8 g,  T D M 4 3 7 4 g, 
T D M 4 6 8 8 g,  T D M 4 4 5 0 g/ B O 2 1 9 7 6  a n d  T D M 4 3 7 0 g/ B O 2 1 9 7 7),  P K  p ar a m et er 
v al u es f or tr ast u z u m a b  e mt a nsi n e  aft er  a  3. 6  m g/ k g  d os e  gi v e n  q 3 w  w er e si mil ar 
t o t h os e  o bs er v e d f or t h e  q 3 w  d osi n g r e gi m e n i n t h e  P h as e I st u d y. 
A r o b ust  p o p ul ati o n  P K ( p o p P K)  m o d el  h as  b e e n  d e v el o p e d  usi n g t h e 
a c c u m ul at e d  cli ni c al  d at a.  T h e  p o p P K  m o d el  c a n  pr e di ct tr ast u z u m a b  e mt a nsi n e 
e x p os ur e  a n d i nt eri n di vi d u al  v ari a bilit y i n  a l ar g e  a n d r e pr es e nt ati v e  p ati e nt 
p o p ul ati o n t h at  h as r e c ei v e d  pri or tr ast u z u m a b- b as e d t h er a p y.  T h e  p o p ul ati o n 
p ar a m et er  v al u es f or  cl e ar a n c e  a n d  v ol u m e  of  distri b uti o n  of t h e  c e ntr al 
c o m p art m e n t ( V c) f or  a t y pi c al  p ers o n  w er e  esti m at e d t o  b e  0. 6 8  L/ d a y  a n d  3. 1 3 
L, r es p e cti v el y.  T h e  p o p P K  a n al ysis s h o w e d  a  m e a n t ½  of  3. 9 4  d a ys f or 
tr ast u z u m a b  e mt a nsi n e.  N o  a dj ust m e nts i n t h e st arti n g  d os e  of tr ast u z u m a b 
e mt a nsi n e  a p p e ar t o  b e  n e c ess ar y i n  p ati e nt  s u b p o p ul ati o ns  b as e d  o n  d at a 
a v ail a bl e t o  d at e,  as it  a p p e ars t h at  d os e  a dj ust m e nts  w o ul d  b e  u nli k el y t o r es ult 
i n  a  m e a ni n gf ul r e d u cti o n i n i nt er-i n di vi d u al  P K  v ari a bilit y. 
 M a n a g e m e nt  of  A g e nt -S p e cifi c  A d v ers e  E v e nts  
T h e s af et y  pl a n f or  p ati e nts i n t h e t r ast u z u m a b  e mt a nsi n e tr e at m e nt  ar m is  b as e d 
o n  n o n cli ni c al t o xi citi es  of tr ast u z u m a b  e mt a nsi n e, t h e  cli ni c al  e x p eri e n c e  wit h 
t his  m ol e c ul e i n  c o m pl et e d  a n d  o n g oi n g st u di es,  a n d  cli ni c al t o xi citi es r el at e d t o 
its  c o m p o n e nts (tr ast u z u m a b  a n d  m a yt a nsi n e, t h e  p ar e nt  dr u g  of  D M 1). 
T h e f oll o wi n g s u m m ari z es t h e i m p ort a nt ris ks  ass o ci at e d  wit h tr ast u z u m a b 
e mt a nsi n e i d e ntifi e d i n  m ulti pl e  br e ast  c a n c er st u di es t o  d at e.  
P ul m o n ar y  T o xi cit y 
C as es  of i nt erstiti al l u n g  dis e as e (I L D), i n cl u di n g  p n e u m o nitis, s o m e l e a di n g t o 
a c ut e r es pir at or y  distr ess s y n dr o m e  or f at al  o ut c o m e  h a v e  b e e n r e p ort e d i n 
cli ni c al tri als  wit h tr ast u z u m a b  e mt a nsi n e ( K a d c yl a ® [tr ast u z u m a b  e mt a nsi n e]. 
G e n e nt e c h, I n c.  F e br u ar y  2 0 1 3).  P n e u m o nitis  at  a n i n ci d e n c e  of  0. 8 % ( 7  o ut  of 
8 8 4 tr e at e d  p ati e nts)  h as  b e e n r e p ort e d,  wit h  o n e  c as e  of  gr a d e  3  p n e u m o nitis. 
Si g ns  a n d s y m pt o ms i n cl u d e  d ys p n e a,  c o u g h, f ati g u e,  a n d  p ul m o n ar y i nfiltr at es. 
T h es e  e v e nts  m a y  or  m a y  n ot  o c c ur  as s e q u el a e  of i nf usi o n r e a cti o ns. I n t h e 
r a n d o mi z e d tri al  T D M  4 3 7 0 g/ B O 2 1 9 7 7 ( E MI LI A) t h e  o v er all fr e q u e n c y  of 
p n e u m o nitis  w as  1. 2 %.  Tr e at m e nt i n cl u d e d  a d mi nistr ati o n  of st er oi ds,  o x y g e n, 
a n d st u d y  dr u g  dis c o nti n u ati o n ( D at a  o n  Fil e.  G e n e nt e c h, I n c.)   


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  4 0  of  9 7  
 
P er m a n e ntl y  dis c o nti n u e tr e at m e nt  wit h tr ast u z u m a b  e mt a nsi n e i n  p ati e nts 
di a g n os e d  wit h I L D  or  p n e u m o nitis ( K a d c yl a ® [tr ast u z u m a b  e mt a nsi n e]. 
G e n e nt e c h, I n c.  F e br u ar y  2 0 1 3).   P ati e nts  wit h  d ys p n e a  at r est  d u e t o 
c o m pli c ati o ns  of  a d v a n c e d  m ali g n a n c y  a n d  c o- m or bi diti es  m a y  b e  at i n cr e as e d 
ris k  of  p ul m o n ar y t o xi cit y.   
H e p at ot o xi cit y  
H e p at ot o xi cit y,  pr e d o mi n a ntl y i n t h e f or m  of  as y m pt o m ati c tr a nsi e nt i n cr e as es i n 
t h e  c o n c e ntr ati o ns  of s er u m tr a ns a mi n as es ( Gr a d e  1  −  4 tr a ns a mi nitis),  h as  b e e n 
o bs er v e d  w hil e  o n tr e at m e nt  wit h tr ast u z u m a b  e mt a nsi n e i n  cli ni c al tri als 
( K a d c yl a ®  Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, I n c.  F e br u ar y  2 0 1 3).  A 
c u m ul ati v e  eff e ct  of tr ast u z u m a b  e mt a nsi n e  o n tr a ns a mi n as es  h as  b e e n  o bs er v e d 
( D at a  o n  Fil e.  G e n e nt e c h, I n c.) 
C as es  of s e v er e  h e p at ot o xi cit y, i n cl u di n g  d e at h  d u e t o  dr u g-i n d u c e d li v er i nj ur y 
( DI LI)  a n d  h e p ati c  e n c e p h al o p at h y,  h a v e  b e e n  o bs er v e d i n  p ati e nts tr e at e d  wit h 
tr ast u z u m a b  e mt a nsi n e ( Tr ast u z u m a b  E mt a nsi n e. I n v esti g at or’s  Br o c h ur e 
V ersi o n  7).  W hil e t h er e is  e vi d e n c e  of  dr u g-i n d u c e d li v er t o xi cit y 
( pr e d o mi n a ntl y i n t h e f or m  of  as y m pt o m ati c i n cr e as es i n t h e  c o n c e ntr ati o ns  of 
s er u m tr a ns a mi n as es) i n  p ati e nts tr e at e d  wit h tr ast u z u m a b  e mt a nsi n e, its 
p ot e nti al t o  c a us e li v er i nj ur y  wit h  cli ni c all y  m e a ni n gf ul  c h a n g es i n li v er 
f u n cti o n is  u n cl e ar  as t h e  o bs er v e d  c as es  w er e  c o nf o u n d e d  b y  c o n c o mit a nt 
m e di c ati o ns  wit h  k n o w n  h e p at ot o xi c  p ot e nti al  a n d/ or  u n d erl yi n g  c o n diti o ns. 
N e v ert h el ess,  a  c o ntri b ut or y r ol e  of tr ast u z u m a b  e mt a nsi n e i n  t h es e  c as es  c a n n ot 
b e  e x cl u d e d.   
M o nit or s er u m tr a ns a mi n as es  a n d  bilir u bi n  pri or t o i niti ati o n  of tr ast u z u m a b 
e mt a nsi n e tr e at m e nt  a n d  pri or t o  e a c h tr ast u z u m a b  e mt a nsi n e  d os e ( K a d c yl a ® 
Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, I n c.  F e br u ar y  2 0 1 3).  R e d u c e t h e  d os e  or 
dis c o nti n u e tr ast u z u m a b  e mt a nsi n e  as  a p pr o pri at e i n  c as es  of i n cr e as e d s er u m 
tr a ns a mi n as es  a n d/ or t ot al  bilir u bi n.  P er m a n e ntl y  dis c o nti n u e tr ast u z u m a b 
e mt a nsi n e tr e at m e nt i n  p ati e nts  wit h s er u m tr a ns a mi n as es  >  3  x  U L N  a n d 
c o n c o mit a nt t ot al  bilir u bi n  >  2  x  U L N.  Tr ast u z u m a b  e mt a nsi n e  h as  n ot  b e e n 
st u di e d i n  p ati e nts  wit h s er u m tr a ns a mi n as es  >  2. 5  x  U L N  or  bilir u bi n  >  1. 5  x 
U L N  pri or t o t h e i ni ti ati o n  of tr e at m e nt. 
C as es  of  n o d ul ar r e g e n er ati v e  h y p er pl asi a ( N R H)  of t h e li v er  h a v e  b e e n 
i d e ntifi e d fr o m li v er  bi o psi es i n  p ati e nts tr e at e d  wit h tr ast u z u m a b  e mt a nsi n e 
( K a d c yl a ®  Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, I n c.  F e br u ar y  2 0 1 3).  N R H  w as 
als o  o bs er v e d i n  o n e f at al  c as e  of  h e p ati c f ail ur e.   N R H is  a r ar e li v er  c o n diti o n 
c h ar a ct eri z e d  b y  wi d es pr e a d  b e ni g n tr a nsf or m ati o n  of  h e p ati c  p ar e n c h y m a i nt o 
s m all r e g e n er ati v e  n o d ul es;  N R H  m a y l e a d t o  n o n- cirr h oti c  p ort al  h y p ert e nsi o n. 
N R H s h o ul d  b e  c o nsi d er e d i n  all  p ati e nts  wit h  cli ni c al s y m pt o ms  of  p ort al 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  4 1  of  9 7  
 
h y p ert e nsi o n  a n d/ or  a  cirr h osis-li k e  p att er n s e e n  o n  c o m p ut e d t o m o gr a p h y ( C T) 
s c a n  of t h e li v er  b ut  wit h  n or m al tr a ns a mi n as es  a n d  n o  ot h er  m a nif est ati o ns  of 
cirr h osis  or li v er f ail ur e f oll o wi n g l o n g- t er m tr e at m e nt  wit h tr ast u z u m a b 
e mt a nsi n e.   Di a g n osis  of  N R H  c a n  b e  c o nfir m e d  o nl y  b y  hist o p at h ol o g y.  U p o n 
di a g n osis  of  N R H, tr ast u z u m a b  e mt a nsi n e tr e at m e nt  m ust  b e  p er m a n e ntl y 
dis c o nti n u e d. 
L eft  V e ntri c ul ar  D ysf u n cti o n  
P ati e nts tr e at e d  wit h tr ast u z u m a b  e mt a nsi n e  ar e  at i n cr e as e d ris k  of  d e v el o pi n g 
l eft  v e ntri c ul ar  d ysf u n cti o n ( K a d c yl a ®  Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, I n c. 
F e br u ar y  2 0 1 3).   A  d e cr e as e  of  L V E F t o  <  4 0 %  h as  b e e n  o bs er v e d i n  p ati e nts 
tr e at e d  wit h tr ast u z um a b  e mt a nsi n e. I n t h e r a n d o mi z e d tri al,  T D M 
4 3 7 0 g/ B O 2 1 9 7 7 ( E MI LI A), l eft  v e ntri c ul ar  d ysf u n cti o n  o c c urr e d i n  1. 8 %  of 
p ati e nts i n t h e tr ast u z u m a b  e mt a nsi n e  -tr e at e d  gr o u p  a n d  3. 3 %  of  p ati e nts i n t h e 
l a p ati ni b  pl us  c a p e cit a bi n e-tr e at e d  gr o u p.   
Ass ess  L V E F  p ri or t o i niti ati o n  of tr ast u z u m a b  e mt a nsi n e  a n d  at r e g ul ar i nt er v als 
( e. g.  e v er y t hr e e  m o nt hs)  d uri n g tr e at m e nt t o  e ns ur e t h e  L V E F is  wit hi n t h e 
i nstit uti o n’s  n or m al li mits ( K a d c yl a ®  Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, I n c. 
F e br u ar y  2 0 1 3).  Tr e at m e nt  wit h tr ast u z u m a b  e mt a nsi n e  h as  n ot  b e e n st u di e d i n 
p ati e nts  wit h  L V E F  <  5 0 %  pri or t o i niti ati o n  of tr e at m e nt.  If,  at r o uti n e 
m o nit ori n g,  L V E F is  <  4 0 %,  or is  4 0 % t o  4 5 %  wit h  a  1 0 %  or  gr e at er  a bs ol ut e 
d e cr e as e  b el o w t h e  pr etr e at m e nt  v al u e,  wit h h ol d tr ast u z u m a b  e mt a nsi n e  a n d 
r e p e at  L V E F  ass ess m e nt  wit hi n  a p pr o xi m at el y  3  w e e ks.  P er m a n e ntl y 
dis c o nti n u e tr ast u z u m a b  e mt a nsi n e if t h e  L V E F  h as  n ot i m pr o v e d  or  h as 
d e cli n e d f urt h er.  
I nf usi o n-r el at e d  R e a cti o ns  
Tr e at m e nt  wit h tr ast u z u m a b  e mt a nsi n e  h as  n ot  b e e n st u di e d i n  p ati e nts  w h o  h a d 
tr ast u z u m a b  p er m a n e ntl y  dis c o nti n u e d  d u e t o i nf usi o n-r el at e d r e a cti o ns (I R R) 
a n d/ or  h y p ers e nsiti vit y; tr e at m e nt  wit h tr ast u z u m a b  e mt a nsi n e is  n ot 
r e c o m m e n d e d f or t h es e  p ati e nts ( K a d c yl a ®  Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, 
I n c.  F e br u ar y  2 0 1 3). 
I nf usi o n-r el at e d r e a cti o ns,  c h ar a ct eri z e d  b y  o n e  or  m or e  of t h e f oll o wi n g 
s y m pt o ms  − fl us hi n g,  c hills,  p yr e xi a,  d ys p n e a,  h y p ot e nsi o n,  w h e e zi n g, 
br o n c h os p as m,  a n d t a c h y c ar di a  h a v e  b e e n r e p ort e d i n  cli ni c al tri als  of 
tr ast u z u m a b  e mt a nsi n e ( K a d c yl a ®  Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, I n c. 
F e br u ar y  2 0 1 3). I n t h e r a n d o mi z e d tri al,  T D M  4 3 7 0 g/ B O 2 1 9 7 7 ( E MI LI A), t h e 
o v er all fr e q u e n c y  of I R Rs i n  p ati e nts tr e at e d  wit h tr ast u z u m a b  e mt a nsi n e  w as 
1. 4 %. I n  m ost  p ati e nts, t h es e r e a cti o ns r es ol v e d  o v er t h e  c o urs e  of s e v er al  h o urs 
t o  a  d a y  aft er t h e i nf usi o n  w as t er mi n at e d.  Tr ast u z u m a b  e mt a nsi n e tr e at m e nt 
s h o ul d  b e i nt err u pt e d i n  p ati e nts  wit h s e v er e I R R.  Tr ast u z u m a b  e mt a nsi n e 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  4 2  of  9 7  
 
tr e at m e nt s h o ul d  b e  p er m a n e ntl y  dis c o nti n u e d i n t h e  e v e nt  of  a lif e-t hr e at e ni n g 
I R R.  P ati e nts s ho ul d  b e  o bs er v e d  cl os el y f or I R R r e a cti o ns,  es p e ci all y  d uri n g t h e 
first i nf usi o n. 
O n e  c as e  of  a s eri o us,  all er gi c/ a n a p h yl a cti c -li k e r e a cti o n  h as  b e e n  o bs er v e d i n 
cli ni c al tri als  of si n gl e - a g e nt tr ast u z u m a b  e mt a nsi n e ( K a d c yl a ®  Pr es cri bi n g 
I nf or m ati o n.  G e n e nt e c h, I n c.  F e br u ar y  2 0 1 3).  M e di c ati o ns t o tr e at s u c h 
r e a cti o ns,  as  w ell  as  e m er g e n c y  e q ui p m e nt, s h o ul d  b e  a v ail a bl e f or i m m e di at e 
us e.  
T hr o m b o c yt o p e ni a 
T hr o m b o c yt o p e ni a,  or  d e cr e as e d  pl at el et  c o u nt,  w as r e p ort e d i n  cli ni c al tri als  of 
tr ast u z u m a b  e mt a nsi n e ( 1 0 3  of  8 8 4 tr e at e d  p ati e nts  wit h  ≥  Gr a d e  3;  2 8 3  of  8 8 4 
tr e at e d  p ati e nts  wit h  a n y  Gr a d e) ( K a d c yl a ®  Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, 
I n c.  F e br u ar y  2 0 1 3).  T h e  m aj orit y  of t h es e  p ati e nts  h a d  Gr a d e  1  or  2  e v e nts ( < 
L L N t o  ≥  5 0, 0 0 0/ m m 3)  wit h t h e  n a dir  o c c urr i n g  b y  d a y  8  a n d  g e n er all y 
i m pr o vi n g t o  Gr a d e  0  or  1 ( ≥  7 5, 0 0 0 / m m 3)  b y t h e  n e xt s c h e d ul e d  d os e. I n 
cli ni c al tri als  of tr ast u z u m a b  e mt a nsi n e, t h e i n ci d e n c e  a n d s e v erit y  of 
t hr o m b o c yt o p e ni a  w er e  hi g h er i n  Asi a n  p ati e nts.  C as es  of  bl e e di n g  e v e nts  wit h  a 
f at al  o ut c o m e  h a v e  b e e n  o bs er v e d.  S e v er e  c as es  of  h e m orr h a gi c  e v e nts, 
i n cl u di n g  c e ntr al  n er v o us s yst e m  h e m orr h a g e,  h a v e  b e e n r e p ort e d i n  cli ni c al 
tri als  wit h tr ast u z u m a b  e mt a nsi n e; t h es e  e v e nts  w er e i n d e p e n d e nt  of  et h ni cit y. I n 
s o m e  of t h e  o bs er v e d  c as es t h e  p ati e nts  w er e  als o r e c ei vi n g  a nti - c o a g ul ati o n 
t h er a p y.  
P ati e nts  wit h t hr o m b o c yt o p e ni a ( ≤ 1 0 0, 0 0 0/ m m 3)   a n d  p ati e nts  o n  a nti- c o a g ul a nt 
tr e at m e nt s h o ul d  b e  m o nit or e d  cl os el y  w hil e  o n tr e at m e nt  wit h tr ast u z u m a b 
e mt a nsi n e. It is r e c o m m e n d e d t h at  pl at el et  c o u nts  ar e  m o nit or e d  pri or t o  e a c h 
tr ast u z u m a b  e mt a nsi n e  d os e.  Tr ast u z u m a b  e mt a nsi n e  h as  n ot  b e e n st u di e d i n 
p ati e nts  wit h  pl at el et  c o u nts  < 1 0 0, 0 0 0/ m m 3  pri or t o i niti ati o n  of tr e at m e nt. I n 
t h e  e v e nt  of  d e cr e as e d  pl at el et  c o u nt t o  Gr a d e  3  or  gr e at er ( <  5 0, 0 0 0/ m m 3)  d o 
n ot  a d mi nist er tr ast u z u m a b  e mt a nsi n e  u ntil  pl at el et  c o u nts r e c o v er t o  Gr a d e  1 ( ≥ 
7 5, 0 0 0/ m m 3). 
S e v er e  H e m orr h a g e  
S e v er e  h e m orr h a g e  wit h f at al  o ut c o m es i n cl u di n g  c e ntr al  n er v o us s yst e m 
bl e e di n g  h as  b e e n r e p ort e d i n  p ati e nts r e c ei vi n g tr ast u z u m a b  e mt a nsi n e.  T his 
dr u g s h o ul d  b e  us e d  wit h  c a uti o n i n  p ati e nts  wit h t hr o m b o c yt o p e ni a (s e e  a b o v e). 
A nti - c o a g ul ati o n t h er a p y  a n d  a nti-pl at el et  a g e nts  m a y i n cr e as e t h e ris k  of 
bl e e di n g.  A v oi d a n c e  of t h es e  a g e nts,  or  a d diti o n al  m o nit ori n g  wit h  c o n c o mit a nt 
us e,  m a y  b e i n di c at e d.  
E m br y o -F et al  T o xi cit y  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  4 3  of  9 7  
 
Tr ast u z u m a b  e mt a nsi n e  c a n  c a us e f et al  h ar m  w h e n  a d mi nist er e d t o  a  pr e g n a nt 
w o m a n ( K a d c yl a ®  Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, I n c.  F e br u ar y  2 0 1 3). 
T h er e  ar e  n o  a d e q u at e  a n d  w ell - c o ntr oll e d st u di es  of tr ast u z u m a b  e mt a nsi n e i n 
pr e g n a nt  w o m e n  a n d  n o r e pr o d u cti v e  a n d  d e v el o p m e nt al t o xi c ol o g y st u di es  h a v e 
b e e n  c o n d u ct e d  wit h tr ast u z u m a b  e mt a nsi n e.  N e v ert h el ess, tr e at m e nt  wit h 
tr ast u z u m a b, t h e  a nti b o d y  c o m p o n e nt  of tr ast u z u m a b  e mt a nsi n e,  d uri n g 
pr e g n a n c y i n t h e  p ost m ar k eti n g s etti n g  h as r es ult e d i n  oli g o h y dr a m ni os, s o m e 
ass o ci at e d  wit h f at al  p ul m o n ar y  h y p o pl asi a, s k el et al  a b n or m aliti es  a n d  n e o n at al 
d e at h.  D M 1, t h e  c yt ot o xi c  c o m p o n e nt  of tr ast u z u m a b  e mt a nsi n e,  c a n  b e  e x p e ct e d 
t o  c a us e  e m br y o-f et al t o xi cit y  b as e d  o n its  m e c h a nis m  of  acti o n. 
If tr ast u z u m a b  e mt a nsi n e is  us e d  d uri n g  pr e g n a n c y,  or if t h e  p ati e nt  b e c o m es 
pr e g n a nt  w hil e r e c ei vi n g tr ast u z u m a b  e mt a nsi n e,  a p pris e t h e  p ati e nt  of t h e 
p ot e nti al  h a z ar d t o t h e f et us ( K a d c yl a ®  Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, I n c. 
F e br u ar y  2 0 1 3).  V erif y  pr e g n a n c y st at us  pri or t o t h e i niti ati o n  of tr ast u z u m a b 
e mt a nsi n e.  A d vis e  p ati e nts  of t h e ris ks  of  e m br y o- f et al  d e at h  a n d  birt h  d ef e cts 
a n d t h e  n e e d f or  c o ntr a c e pti o n  d uri n g  a n d  aft er tr e at m e nt.  A d vis e  p ati e nts t o 
c o nt a ct t h eir  h e alt h c ar e  pr o vi d er i m m e di at el y if t h e y s us p e ct t h e y  m a y  b e 
pr e g n a nt. If tr ast u z u m a b  e mt a nsi n e is  a d mi nist er e d  d uri n g  pr e g n a n c y  or if  a 
p ati e nt  b e c o m es  pr e g n a nt  w hil e r e c ei vi n g tr ast u z u m a b  e mt a nsi n e, i m m e di at el y 
r e p ort  e x p os ur e t o t h e  G e n e nt e c h  A d v ers e  E v e nt  Li n e  at  1- 8 8 8- 8 3 5- 2 5 5 5. 
E n c o ur a g e  w o m e n  w h o  m a y  b e  e x p os e d  d uri n g  pr e g n a n c y t o  e nr oll i n t h e 
M ot H E R  Pr e g n a n c y  R e gistr y  b y  c o nt a cti n g  1- 8 0 0- 6 9 0- 6 7 2 0. 
It is  n ot  k n o w n  w h et h er tr ast u z u m a b  e mt a nsi n e, s p e cifi c all y, is  e x cr et e d i n 
h u m a n  mil k,  b ut I g G is  k n o w n t o  b e  e x cr et e d i n  h u m a n  mil k ( K a d c yl a ® 
Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, I n c.  F e br u ar y  2 0 1 3).  I n l a ct ati n g  m o n k e ys, 
tr ast u z u m a b  w as  e x cr et e d i n s m all  a m o u nts ( a b o ut  0. 3 %  of  m at er n al s er u m 
c o n c e ntr ati o ns) i n  br e ast  mil k  aft er  p ost- p art u m  d os es  of  2 5  m g/ k g ( a b o ut  7 
ti m es t h e cli ni c al  d os e  of tr ast u z u m a b  e mt a nsi n e).   B e c a us e  m a n y  dr u gs  ar e 
e x cr et e d i n  h u m a n  mil k  a n d  b e c a us e  of t h e  p ot e nti al f or s eri o us  a d v ers e r e a cti o ns 
i n  n ursi n g i nf a nts fr o m tr ast u z u m a b  e mt a nsi n e,  a  d e cisi o n s h o ul d  b e  m a d e 
w h et h er t o  dis c o nti n u e  n ursi n g  or  dis c o nti n u e tr ast u z u m a b  e mt a nsi n e, t a ki n g i nt o 
a c c o u nt t h e i m p ort a n c e  of t h e  dr u g t o t h e  m ot h er. 
N e ur ot o xi cit y  
P eri p h er al  n e ur o p at h y,  m ai nl y  as  Gr a d e  1  a n d  pr e d o mi n a ntl y s e ns or y,  w as 
r e p ort e d i n  cli ni c al tri als  of tr ast u z u m a b  e mt a nsi n e ( 1 4  of  8 8 4 tr e at e d  p ati e nts 
wit h  ≥  Gr a d e  3;  1 9 6  of  8 8 4 tr e at e d  p ati e nts  wit h  a n y  Gr a d e) ( K a d c yl a ® 
Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, I n c.  F e br u ar y  2 0 1 3). I n t h e  E MI LI A st u d y, 
t h e  o v er all fr e q u e n c y  of  p eri p h er al  n e ur o p at h y  w as  2 1. 2 % i n t h e tr ast u z u m a b 
e mt a nsi n e -tr e at e d  gr o u p  an d  1 3. 5 % i n t h e l a p ati ni b  pl us  c a p e cit a bi n e -tr e at e d 
gr o u p.  T h e i n ci d e n c e  of  ≥  Gr a d e  3  p eri p h er al  n e ur o p at h y  w as  2. 2 % i n t h e 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  4 4  of  9 7  
 
tr ast u z u m a b  e mt a nsi n e -tr e at e d  gr o u p  a n d  0. 2 % i n t h e l a p ati ni b  pl us 
c a p e cit a bi n e -tr e at e d  gr o u p.  Tr ast u z u m a b  e mt a nsi n e s h o ul d  b e t e m por aril y 
dis c o nti n u e d i n  p ati e nts  e x p eri e n ci n g  Gr a d e  3  or  4  p eri p h er al  n e ur o p at h y  u ntil 
r es ol uti o n t o  ≤  Gr a d e  2.   P ati e nts s h o ul d  b e  cli ni c all y  m o nit or e d  o n  a n  o n g oi n g 
b asis f or si g ns  or s y m pt o ms  of  n e ur ot o xi cit y. 
E xtr a v as ati o n 
I n tr ast u z u m a b  e mt a nsi n e cli ni c al st u di es, r e a cti o ns s e c o n d ar y t o  e xtr a v as ati o n 
h a v e  b e e n  o bs er v e d ( K a d c yl a ®  Pr es cri bi n g I nf or m ati o n.  G e n e nt e c h, I n c. 
F e br u ar y  2 0 1 3).  T h es e r e a cti o ns,  o bs er v e d  m or e fr e q u e ntl y  wit hi n  2 4  h o urs  of 
i nf usi o n,  w er e  us u all y  mil d  a n d  c o m pris e d  er yt h e m a, t e n d er n ess, s ki n irrit ati o n, 
p ai n,  or s w elli n g  at t h e i nf usi o n sit e.  S p e cifi c tr e at m e nt f or tr ast u z u m a b 
e mt a nsi n e  e xtr a v as ati o n is  u n k n o w n.  T h e i nf usi o n sit e s h o ul d  b e  cl os el y 
m o nit or e d f or  p ossi bl e s u b c ut a n e o us i nfiltr ati o n  d uri n g  dr u g  a d mi nistr ati o n. 
 C o m p o siti o n 
Tr ast u z u m a b  e mt a nsi n e is  pr o vi d e d  as  a l y o p hili z e d  pr o d u ct.  T h e tr ast u z u m a b 
e mt a nsi n e  Dr u g  S u bst a n c e is  pr o d u c e d i n t w o st e ps fr o m  a nti b o d y (tr ast u z u m a b), 
dr u g ( D M 1),  a n d li n k er ( S M C C).   A  pr e d efi n e d  m ol ar r ati o  of  S M C C is  mi x e d 
wit h t h e  a nti b o d y: t h e  N -h y dr o x ys u c ci ni mi d e  est er  of  S M C C r e a cts  wit h 
a nti b o d y l ysi n e r esi d u es t o  pr o d u c e t h e  m al ei mi d e- m o difi e d  a nti b o d y 
(tr ast u z u m a b-M C C).   F oll o wi n g  p urifi c ati o n  b y  ultr afiltr ati o n/ di afiltr ati o n 
( U F/ D F), t h e s ulf h y dr yl- c o nt ai ni n g  c yt ot o xi c  dr u g ( D M 1) is  a d d e d,  a n d t h e 
s u bs e q u e nt r e a cti o n  pr o d u c es t h e t hi o et h er-li n k e d  c o nj u g at e.  Tr ast u z u m a b 
e mt a nsi n e  c o nj u g at e is  p urifi e d  b y  U F/ D F.  
 St or a g e  R e c o m m e n d ati o ns  a n d  D os a g e  F or ms 
Tr ast u z u m a b  e mt a nsi n e is s u p pli e d  as  a si n gl e- us e l y o p hili z e d f or m ul ati o n i n  a 
c ol orl ess   2 0-m L  T y p e I  gl ass  vi al  cl os e d  b y  m e a ns  of  a  Fl ur o T e c - c o at e d st o p p er 
a n d  a n  o v ers e al  wit h fli p- off  c a p.  U p o n r e c ei pt  of tr ast u z u m a b  e mt a nsi n e,  vi als 
s h o ul d  b e r efri g er at e d  at  2° C − 8° C ( 3 6° F − 4 6° F)  u ntil  us e.  T H E  VI A L  M U S T 
N O T  B E  F R O Z E N  O R  S H A K E N.  
Tr ast u z u m a b  e mt a nsi n e  m ust  b e st or e d i n t h e  ori gi n al  c art o n t o  pr ot e ct it fr o m 
li g ht.  D o  n ot  us e t h e  pr o d u ct  b e y o n d t h e  e x pir ati o n  d at e  pr o vi d e d  b y t h e 
m a n uf a ct ur er.  T h e r e c o nstit ut e d  pr o d u ct  c o nt ai ns  n o  pr es er v ati v e  a n d is i nt e n d e d 
f or si n gl e  us e  o nl y.  A n y r e m ai ni n g  m e di c ati o n s h o ul d  b e  dis c ar d e d.  All  vi als  of 
tr ast u z u m a b  e mt a nsi n e s h o ul d  b e  h a n dl e d  b y  a p pr o pri at el y tr ai n e d sit e st aff 
w e ari n g  gl o v es  a n d  usi n g  a p pr o pri at e  pr o c e d ur es i n  pl a c e  at t h e  cli ni c al sit e f or 
pr e p ar ati o n  of  c h e m ot h er a p e uti c  dr u gs.  Vi als s h o ul d  b e  vis u all y i ns p e ct e d  u p o n 
r e c ei pt t o  e ns ur e t h at t h e y  ar e i nt a ct  wit h o ut  e xt eri or  c o nt a mi n ati o n.  Dis c ar d  a n y 
cr a c k e d  vi als  a n d r e p ort  vi als  wit h s urf a c e  c o nt a mi n ati o n t o t h e  cli ni c al sit e 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  4 5  of  9 7  
 
m a n a g er f or  ass ess m e nt.  T h e l y o p hili z e d  pr o d u ct s h o ul d  b e r e c o nstit ut e d  usi n g 
St eril e  W at er f or I nj e cti o n ( S W FI).  
Usi n g  a  n e w s yri n g e,  8  m L  of  S W FI s h o ul d  b e  a d d e d t o t h e  vi al  a n d t h e  vi al 
s wirl e d  g e ntl y  u ntil t h e  pr o d u ct is  c o m pl et el y  diss ol v e d.  T h e  vi al s h o ul d  n ot  b e 
s h a k e n.  T h e r es ulti n g  pr o d u ct  c o nt ai ns  2 0  m g/ m L tr ast u z u m a b  e mt a nsi n e,  1 0 
m M s o di u m s u c ci n at e,  p H  5. 0,  6 0  m g/ m L s u cr os e,  a n d  0. 0 2 % ( w/ v)  p ol ys or b at e 
2 0.  E a c h  2 0- m L  vi al  c o nt ai ns  e n o u g h tr ast u z u m a b  e mt a nsi n e t o  all o w  d eli v er y  of 
1 6 0  m g tr ast u z u m a b  e mt a nsi n e. 
T h e r e c o nstit ut e d  pr o d u ct  c o nt ai ns  n o  pr es er v ati v e  a n d is i nt e n d e d f or si n gl e  us e 
o nl y.  T h e  vi al s h o ul d  b e i ns p e ct e d t o  e ns ur e t h e r e c o nstit ut e d  pr o d u ct is  a  cl e ar 
c ol orl ess s ol uti o n,  a n d is fr e e  of  p arti c ul at es  b ef or e  pr o c e e di n g.  Dr u g fr o m  a n y 
vi al t h at  a p p e ars  a b n or m al  u p o n i ns p e cti o n s h o ul d  n ot  b e  a d mi nist er e d t o 
p ati e nts.  Usi n g  a  n e w s yri n g e, t h e i n di c at e d  v ol u m e  of tr ast u z u m a b  e mt a nsi n e 
s ol uti o n s h o ul d  b e r e m o v e d fr o m t h e  vi al(s)  a n d  a d d e d t o t h e I V  b a g  c o nt ai ni n g 
at l e ast  2 5 0  m L  of  0. 4 5 % s o di u m  c hl ori d e ( pr ef err e d)  or  0. 9 % s o di u m  c hl ori d e 
i nj e cti o n  an d  g e ntl y i n v ert e d t o  mi x t h e s ol uti o n.  A  0. 2 2- μ m  n o n - pr ot ei n 
a ds or pti v e  p ol y et h ers ulf o n e i n- li n e filt er is r e c o m m e n d e d  w h e n  usi n g  0. 4 5 % 
s o di u m  c hl ori d e  a n d r e q uir e d  w h e n  usi n g  0. 9 % s o di u m  c hl ori d e i nj e cti o n.  T h e 
s ol uti o n  of tr ast u z u m a b  e mt a nsi n e s h o ul d  n ot  b e s h a k e n.  T h e s ol uti o n  of 
tr ast u z u m a b  e mt a nsi n e f or i nf usi o n s h o ul d  b e  us e d i m m e di at el y. If  n ot  us e d 
i m m e di at el y, st or a g e ti m es s h o ul d  n ot  b e l o n g er t h a n  2 4  h o urs  at  2° C − 8° C 
( 3 6 − 4 6° F) f or s ol uti o ns  of tr ast u z u m a b  e mt a nsi n e  dil ut e d i n  p ol y vi n yl  c hl ori d e 
( P V C)  or l at e x-fr e e  P V C-fr e e  p ol y ol efi n,  p ol y pr o p yl e n e,  or  p ol y et h yl e n e  b a gs 
c o nt ai ni n g  0. 4 5 %  or  0. 9 %  S o di u m  C hl ori d e f or I nj e cti o n,  U S P.  
F or m ul ati o n : 
Tr ast u z u m a b  e mt a nsi n e si n gl e - us e  vi als  c o nt ai n  1 0 0  m g  p er  vi al  or  1 6 0  m g  p er 
vi al  of tr ast u z u m a b  e mt a nsi n e  as l y o p hili z e d  p o w d er. 
Pr e p ar ati o n : 
I n  or d er t o  pr e v e nt  m e di c ati o n  err ors it is i m p ort a nt t o  c h e c k t h e  vi al l a b els t o 
e ns ur e t h at t h e  dr u g  b ei n g  pr e p ar e d  a n d  a d mi nist er e d is tr ast u z u m a b  e mt a nsi n e 
a n d  n ot tr ast u z u m a b. 
A d mi nistr ati o n : 
•  A d mi nist er tr ast u zu m a b  e mt a nsi n e  as  a n i ntr a v e n o us i nf usi o n  o nl y  wit h  a  0. 2 2 
mi cr o n i n -li n e  n o n- pr ot ei n  a ds or pti v e  p ol y et h ers ulf o n e ( P E S) filt er.  D o  n ot 
a d mi nist er  as  a n i ntr a v e n o us  p us h  or  b ol us. 
•  D o  n ot  mi x tr ast u z u m a b  e mt a nsi n e,  or  a d mi nist er  as  a n i nf usi o n,  wit h  ot h er 
m e di ci n al  pr o d u cts. 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  4 6  of  9 7  
 
R e c o nstit uti o n : 
•  Us e  as e pti c t e c h ni q u e f or r e c o nstit uti o n  a n d  pr e p ar ati o n  of  d osi n g s ol uti o n. 
A p pr o pri at e  pr o c e d ur es f or t h e  pr e p ar ati o n  of  c h e m ot h er a p e uti c  dr u gs s h o ul d  b e 
us e d. 
•  Usi n g  a st eril e s yri n g e, sl o wl y i nj e ct  5  m L  of  St eril e  W at er f or I nj e cti o n i nt o 
t h e  1 0 0  m g tr ast u z u m a b  e mt a nsi n e  vi al,  or  8  m L  of  St eril e  W at er f or I nj e cti o n 
i nt o t h e  1 6 0  m g tr ast u z u m a b  e mt a nsi n e  vi al t o  yi el d  a s ol uti o n  c o nt ai ni n g  2 0 
m g/ m L.  S wirl t h e  vi al  g e ntl y  u ntil  c o m pl et el y  diss ol v e d.  D o  n ot s h a k e. I ns p e ct 
t h e r e c o nstit ut e d s ol uti o n f or  p arti c ul at es  a n d  dis c ol or ati o n. 
•  T h e r e c o nstit ut e d s ol uti o n s h o ul d  b e  cl e ar t o sli g htl y  o p al es c e nt  a n d fr e e  of 
visi bl e  p arti c ul at es.  T h e  c ol or  of t h e r e c o nstit ut e d s ol uti o n s h o ul d  b e  c ol orl ess t o 
p al e  br o w n.  D o  n ot  us e i f t h e r e c o nstit ut e d s ol uti o n  c o nt ai ns  visi bl e  p arti c ul at es 
or is  cl o u d y  or  dis c ol or e d. 
•  T h e r e c o nstit ut e d l y o p hili z e d  vi als s h o ul d  b e  us e d i m m e di at el y f oll o wi n g 
r e c o nstit uti o n  wit h  St eril e  W at er f or I nj e cti o n. If  n ot  us e d i m m e di at el y, t h e 
r e c o nstit ut e d trast u z u m a b  e mt a nsi n e  vi als  c a n  b e st or e d f or  u p t o  4  h o urs i n  a 
r efri g er at or  at  2º C t o  8º C ( 3 6° F t o  4 6° F);  dis c ar d  u n us e d tr ast u z u m a b  e mt a nsi n e 
aft er  4  h o urs.  D o  n ot fr e e z e. 
•  T h e r e c o nstit ut e d  pr o d u ct  c o nt ai ns  n o  pr es er v ati v e  a n d is i nt e n d e d f or si n gl e-
us e  o nl y.  
Dil uti o n : 
D et er mi n e t h e  c orr e ct  d os e ( m g)  of tr ast u z u m a b  e mt a nsi n e.  
•  C al c ul at e t h e  v ol u m e  of t h e  2 0  m g/ m L r e c o nstit ut e d tr ast u z u m a b  e mt a nsi n e 
s ol uti o n  n e e d e d. 
•  Wit h dr a w t his  a m o u nt fr o m t h e  vi al  a n d  a d d it t o  a n i nf usi o n  b a g  c o nt ai ni n g 
2 5 0  m L  of  0. 9 %  S o di u m  C hl ori d e I nj e cti o n.  D o  n ot  us e  D e xtr os e ( 5 %) s ol uti o n.  
•  G e ntl y i n v ert t h e  b a g t o  mi x t h e s ol uti o n i n  or d er t o  a v oi d f o a mi n g. 
•  T h e  dil ut e d tr ast u z u m a b  e mt a nsi n e i nf usi o n s ol uti o n s h o ul d  b e  us e d 
i m m e di at el y. If  n ot  us e d i m m e di at el y, t h e s ol uti on  m a y  b e st or e d i n  a 
r efri g er at or  at  2° C t o  8° C ( 3 6° F t o  4 6° F) f or  u p t o  4  h o urs  pri or t o  us e.  D o  n ot 
fr e e z e  or s h a k e. 
 Dis p e ns ati o n  a n d  A c c o u nt a bilit y 
Tr ast u z u m a b  e mt a nsi n e  will  b e s u p pli e d  b y  G e n e nt e c h, I n c.  f or t h e  p h as e  1 
p orti o n  of t h e st u d y.  F or t h e  p h as e  2  p orti o n  of t h e st u d y,  dr u g s u p pl y  will  b e 
d et er mi n e d  aft er t h e  o ut c o m e  of t h e  p h as e  1 st u d y. 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  4 7  of  9 7  
 
R e c o n cili ati o n:  G e n e nt e c h, I n c.  a gr e es t o  c o n d u ct r e c o n cili ati o n f or t h e  pr o d u ct, 
r e c o n cili ati o n  p eri o di cit y  a n d f or m at,  b ut  a gr e e  at  mi ni m u m t o  e x c h a n g e 
q u art erl y ( n o l ess fr e q u e ntl y t h a n  m o nt hl y) li n e listi n gs  of  c as es r e c ei v e d  b y t h e 
ot h er  p art y. If  dis cr e p a n ci es  ar e i d e ntifi e d,  G e n e nt e c h, I n c .  will  c o o p er at e i n 
r es ol vi n g t h e  dis cr e p a n ci es.  T h e r es p o nsi bl e i n di vi d u als f or  e a c h  p art y s h all 
h a n dl e t h e  m att er  o n  a  c as e -b y - c as e  b asis  u ntil s atisf a ct or y r es ol uti o n.  T h e 
s p o ns or s h all r e c ei v e r e c o n cili ati o n  g ui d a n c e  d o c u m e nts  wit hi n t h e ‘ A cti v ati o n 
P a c k a g e’.  
 
 Vi n o r el bi n e  
[ R ef er t o t h e  F D A-a p pr o v e d  p a c k a g e i ns ert f or  m or e i nf or m ati o n.]   
 Ot h er  n a m e(s)  
Vi n or el bi n e t artr at e,  N A V E L BI N E ®  
 M e c h a nis m  of  A cti o n  
Vi n or el bi n e  ( N A V E L BI N E ®) is  a  vi n c a  al k al oi d t h at i nt erf er es  wit h  mi cr ot u b ul e 
ass e m bl y.  T h e  a ntit u m or  a cti vit y  of  vi n or el bi n e is t h o u g ht t o  b e  d u e  pri m aril y t o 
i n hi biti o n  of  mit osis  at  m et a p h as e t hr o u g h its i nt er a cti o n  wit h t u b uli n. 
Vi n or el bi n e  m a y  als o i nt erf er e  wit h:  1)  a mi n o  a ci d,  c y cli c  A M P,  a n d  gl ut at hi o n e 
m et a b olis m,  2)  c al m o d uli n - d e p e n d e nt  C a + +-tr a ns p ort  A T P as e  a cti vit y,  3) 
c ell ul ar r es pir ati o n,  a n d  4)  n u cl ei c  a ci d  a n d li pi d  bi os y nt h esis.  Vi n or el bi n e 
i n hi bit e d  mit oti c  mi cr ot u b ul e f or m ati o n i n i nt a ct  m o us e  e m br y o t e ct al  pl ates  at  a 
c o n c e ntr ati o n  of  2  μ M i n d u ci n g  a  bl o c k a d e  of  c ells  at  m et a p h as e,  b ut  pr o d u c e d 
d e p ol y m eri z ati o n  of  a x o n al  mi cr ot u b ul es  at  a  c o n c e ntr ati o n  4 0  μ M, s u g g esti n g  a 
m o d est s el e cti vit y  of  vi n or el bi n e f or  mit oti c  mi cr ot u b ul es.  
 Dr u g  M et a b olis m,  P h ar m a c o ki n eti cs  a n d  T o xi c ol o g y 
T h e  p h ar m a c o ki n eti cs  of  vi n or el bi n e  ( N A V E L BI N E ®) w er e st u di e d i n  4 9 
p ati e nts  w h o r e c ei v e d  d os es  of  3 0  m g/ m  a d mi nist er e d  as  1 5- t o  2 0- mi n ut e 
c o nst a nt-r at e i nf usi o ns.  Vi n or el bi n e  c o n c e ntr ati o ns i n  pl as m a  d e c a y i n  a tri p h asi c 
m a n n er.  T h e t er mi n al  p h as e  h alf -lif e  a v er a g es  2 7. 7 t o  4 3. 6  h o urs  a n d t h e  m e a n 
pl as m a  cl e ar a n c e r a n g es fr o m  0. 9 7 t o  1. 2 6  L/ hr/ k g. 
Distri b uti o n  
St e a d y -st at e  v ol u m e  of  distri b uti o n ( V )  v al u es r a n g e fr o m  2 5. 4 t o  4 0. 1  L/ k g. 
Vi n or el bi n e  d e m o nstr at e d  hi g h  bi n di n g t o  h u m a n  pl at el ets  a n d l y m p h o c yt es.  T h e 
fr e e fr a cti o n  w as  a p pr o xi m at el y  0. 1 1 i n  h u m a n  pl as m a  o v er  a  c o n c e ntr ati o n 
r a n g e  of  2 3 4 t o  1 1 6 9  n g/ m L.  T h e  bi n di n g t o  pl as m a  c o nstit u e nts i n  c a n c er 
p ati e nts r a n g e d fr o m  7 9. 6 % t o  9 1. 2 %.  Vi n or el bi n e  bi n di n g  w as  n ot  alt er e d i n t h e 
pr es e n c e  of  cis pl ati n,  5 -fl u or o ur a cil,  or  d o x or u bi ci n. 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  4 8  of  9 7  
 
M et a b olis m  
Vi n or el bi n e  u n d er g o es s u bst a nti al  h e p ati c  eli mi n ati o n i n  h u m a ns,  wit h l ar g e 
a m o u nts r e c o v er e d i n f e c es. 
T w o  m et a b olit es  of  vi n or el bi n e  h a v e  b e e n i d e ntifi e d i n  h u m a n  bl o o d,  pl as m a, 
a n d  uri n e;  vi n or el bi n e  N o xi d e  a n d  d e a c et yl vi n or el bi n e.  D e a c et yl vi n or el bi n e  h as 
b e e n  d e m o nstr at e d t o  b e t h e  pri m ar y  m et a b olit e  of  vi n or el bi n e i n  h u m a ns,  a n d 
h as  b e e n s h o w n t o  p oss ess  a ntit u m or  a cti vit y si mil ar t o  vi n or el bi n e.  T h er a p e uti c 
d os es  of  vi n or el bi n e ( 3 0  m g/ m )  yi el d  v er y s m all, if  a n y,  q u a ntifi a bl e l e v els  of 
eit h er  m et a b olit e i n  bl o o d  or  uri n e.  T h e  m et a b olis m  of  vi n or el bi n e is  m e di at e d 
b y  h e p ati c  c yt o c hr o m e  P 4 5 0 is o e n z y m es i n t h e  C Y P 3 A s u bf a mil y. 
E x cr eti o n  
Aft er i ntr a v e n o us  a d mi nistr ati o n  of r a di o a cti v e  vi n or el bi n e,  a p pr o xi m at el y  1 8 % 
a n d  4 6 %  of  a d mi nist er e d r a di o a cti vit y  w as r e c o v er e d i n  uri n e  a n d f e c es, 
r es p e cti v el y. I n  a  diff er e nt st u d y,  1 0. 9 %  +  0. 7 %  of  a  3 0- m g/ m i ntr a v e n o us  d os e 
w as  e x cr et e d  as  p ar e nt  dr u g i n  uri n e.  
S p e cifi c  P o p ul ati o ns 
El d erl y:  A g e  h as  n o  eff e ct  o n t h e  p h ar m a c o ki n eti cs ( C L,  V  a n d t )  of  vi n or el bi n e. 
Dr u g I nt er a cti o ns  
T h e  p h ar m a c o ki n eti cs  of  vi n or el bi n e  ar e  n ot i nfl u e n c e d  b y t h e  c o n c urr e nt 
a d mi nistr ati o n  of  cis pl ati n.  
C ar ci n o g e n esis,  M ut a g e n esis, I m p air m e nt  of  F ertilit y  
T h e  c ar ci n o g e ni c  p ot e nti al  of  N A V E L BI N E  h as  n ot  b e e n st u di e d.  Vi n or el bi n e 
h as  b e e n s h o w n t o  aff e ct  c hr o m os o m e  n u m b er  a n d  p ossi bl y str u ct ur e i n  vi v o 
( p ol y pl oi d y i n  b o n e  m arr o w  c ells fr o m  C hi n es e  h a mst ers  a n d  a  p ositi v e 
mi cr o n u cl e us t est i n  mi c e). It  w as  n ot  m ut a g e ni c i n t h e  A m es t est  a n d  g a v e 
i n c o n cl usi v e r es ults i n t h e  m o us e l y m p h o m a  T K  L o c us  ass a y. 
Vi n or el bi n e  di d  n ot  aff e ct f ertilit y t o  a st atisti c all y si g nifi c a nt  e xt e nt  w h e n 
a d mi nist er e d t o r ats  o n  eit h er  a  o n c e- w e e kl y ( 9  m g/ m ,  a p pr o xi m at el y  o n e t hir d 
t h e  h u m a n  d os e)  or alt er n at e - d a y s c h e d ul e ( 4. 2  m g/ m,  a p pr o xi m at el y  0. 1 4 ti m es 
t h e  h u m a n r e c o m m e n d e d  d os e)  pri or t o  a n d  d uri n g  m ati n g. I n  m al e r ats, 
a d mi nistr ati o n  of  vi n or el bi n e t wi c e  w e e kl y f or  1 3  or  2 6  w e e ks  at  d os e l e v els  of 
2. 1  a n d  7. 2  m g/ m ( a p pr o xi m at el y  0. 0 7  a n d  0. 2 4  ti m es t h e r e c o m m e n d e d  h u m a n 
d os e), r es p e cti v el y, r es ult e d i n  d e cr e as e d s p er m at o g e n esis  a n d  pr ost at e/s e mi n al 
v esi cl e s e cr eti o n.  
 M a n a g e m e nt  of  A g e nt -S p e cifi c  A d v ers e  E v e nts  
T h e r es ults  of  cli ni c al st u di es s h o w t h at tr e at m e nt  wit h  vi n or el bi n e 
( N A V E L BI N E ®) is ass o ci at e d  wit h r el ati v el y  mil d  or  m o d er at e si d e -eff e cts, t h e 
m ost fr e q u e nt si d e  eff e ct  b ei n g  n e utr o p e ni a.  A p art fr o m  h air l oss,  n a us e a  a n d 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  4 9  of  9 7  
 
v o miti n g,  w hi c h  ar e t y pi c al si d e- eff e cts  of tr e at m e nt  wit h  c yt ost ati c  a g e nts, 
g astr oi nt esti n al si d e -eff e cts  ar e  als o  fr e q u e ntl y s e e n;  h o w e v er, t h es e  ar e r ar el y  of 
a s eri o us  n at ur e. I n  o n e st u d y,  Gr a d e  3  or  4  n a us e a  a n d  v o miti n g  w er e r e p ort e d i n 
4 %  of t h e  p ati e nts.  3 0 %  of  p ati e nts  e x p eri e n c e d  mil d  or  m o d er at e  c o nsti p ati o n 
a n d  n e ur ot o xi cit y  w as  o bs er v e d i n  2 0 %  of  p ati e nts .  T h os e  A Es  w er e r e v ersi bl e 
a n d s el d o m s eri o us.  Ot h er si d e- eff e cts s u c h  as  c h est  p ai n  a n d r es pir at or y 
pr o bl e ms  ar e r el ati v el y r ar e  a m o n g  p ati e nts tr e at e d  wit h  vi n or el bi n e.   T h e  m ost 
fr e q u e ntl y  o bs er v e d  a b n or m al l a b or at or y  v al u e is i n cr e as e d  A L P l e v els,  w hic h 
m a y  b e r el at e d t o  b ot h  vi n or el bi n e tr e at m e nt  or  a  hi g h i n ci d e n c e  of li v er  or  b o n e 
m et ast as es i n t h e  p ati e nts tr e at e d ( Pi err e  F a br e).  
 
M y el os u p pr essi o n 
M y el os u p pr essi o n  m a nif est e d  b y  n e utr o p e ni a,  a n e mi a  a n d t hr o m b o c yt o p e ni a 
o c c ur  wit h  N A V E L BI N E ®  as  a si n gl e  a g e nt  a n d i n  c o m bi n ati o n  wit h  cis pl ati n. 
N e utr o p e ni a is t h e  m aj or  d os e- li miti n g t o xi cit y  wit h  N A V E L BI N E.  Gr a d e  3- 4 
n e utr o p e ni a  o c c urr e d i n  5 3 %  of  p ati e nts tr e at e d  wit h  N A V E L BI N E  at  3 0  m g/ m 
p er  w e e k.  D os e  a dj ust m e nt  d u e t o  m y el os u p pr essi o n  o c c urr e d i n  5 1 %  of  p ati e nts. 
I n  cli ni c al tri als  wit h  N A V E L BI N E  a d mi nist er e d  at  3 0  m g/ m  p er  w e e k, 
n e utr o p e ni a r es ult e d i n  h os pit ali z ati o ns f or  p yr e xi a  a n d/ or s e psis i n  8 %  of 
p ati e nts.  D e at h  d u e t o s e psis  o c c urr e d i n  1 %  of  p ati e nts.  N e utr o p e ni a  n a dirs 
o c c ur  b et w e e n  7  a n d   1 0  d a ys  aft er  d osi n g  wit h  n e utr o p e ni a  c o u nt r e c o v er y 
us u all y  o c c urri n g  wit hi n t h e f oll o wi n g  7 t o  1 4  d a ys.  M o nit or  c o m pl et e  bl o o d 
c o u nts  pri or t o  e a c h  d os e  of  N A V E L BI N E.  D o  n ot  a d mi nist er  N A V E L BI N E t o 
p ati e nts  wit h  n e utr o p hil  c o u nts  < 1, 0 0 0  c ells/ m m.  A dj ust m e nts i n t h e  d os a g e  of 
N A V E L BI N E s h o ul d  b e  b as e d  o n  n e utr o p hil  c o u nts  o bt ai n e d  o n t h e  d a y  of 
tr e at m e nt. 
H e p ati c  T o xi cit y  
Dr u g -i n d u c e d li v er i nj ur y  m a nif est  b y  el e v ati o ns  of  as p art at e  a mi n otr a nsf er as e 
a n d  bilir u bi n  c a n  o c c ur i n  p ati e nts r e c ei vi n g  N A V E L BI N E  al o n e  or i n 
c o m bi n ati o n  wit h  c yt ot o xi c  a g e nts.  Ass ess  h e p ati c f u n cti o n  pri or t o i niti ati o n  of 
N A V E L BI N E  a n d  p eri o di c all y  d uri n g tr e at m e nt.  R e d u c e t h e  d os e  of 
N A V E L BI N E f or  p ati e nts  w h o  d e v el o p  el e v ati o ns i n t ot al  bilir u bi n  >  2 ti m es 
u p p er li mit  of  n or m al.  
S e v er e  C o nsti p ati o n  a n d  B o w el  O bstr u cti o n 
S e v er e  a n d f at al  p ar al yti c il e us,  c o nsti p ati o n, i nt esti n al  o bstr u cti o n,  n e cr osis,  a n d 
p erf or ati o n  o c c ur  wit h  N A V E L BI N E  a d mi nistr ati o n. I nstit ut e  a  pr o p h yl a cti c 
b o w el r e gi m e n t o  miti g at e  p ot e nti al  c o nsti p ati o n,  b o w e l  o bstr u cti o n  a n d/ or 
p ar al yti c il e us,  c o nsi d eri n g  a d e q u at e  di et ar y fi b er i nt a k e,  h y dr ati o n,  a n d r o uti n e 
us e  of st o ol s oft e n ers. 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  5 0  of  9 7  
 
E xtr a v as ati o n  a n d  Tiss u e I nj ur y 
E xtr a v as ati o n  of  N A V E L BI N E  c a n r es ult i n s e v er e irrit ati o n, l o c al tiss u e 
n e cr osis  a n d/ or t hr o m b o p hl e bitis. If si g ns  or s y m pt o ms  of  e xtr a v as ati o n  o c c ur, 
i m m e di at el y st o p  a d mi nistr ati o n  of  N A V E L BI N E  a n d i nstit ut e r e c o m m e n d e d 
m a n a g e m e nt  pr o c e d ur es.  
N e ur ol o gi c  T o xi cit y  
S e ns or y  a n d  m ot or  n e ur o p at hi es, i n cl u di n g s e v er e  n e ur o p at hi es,  o c c ur i n  p ati e nts 
r e c ei vi n g  N A V E L BI N E.  M o nit or  p ati e nts f or  n e w  or  w ors e ni n g si g ns  a n d 
s y m pt o ms  of  n e ur o p at h y s u c h  as  p ar est h esi a,  h y p er est h esi a,  h y p or efl e xi a  a n d 
m us cl e  w e a k n ess  w hil e r e c ei vi n g  N A V E L BI N E.  Dis c o nti n u e  N A V E L BI N E f or 
N CI  C T C A E  Gr a d e  2  or  gr e at er  n e ur o p at h y.  
P ul m o n ar y  T o xi cit y  a n d  R es pir at or y  F ail ur e 
P ul m o n ar y t o xi cit y, i n cl u di n g s e v er e  a c ut e  br o n c h os p as m, i nt erstiti al 
p n e u m o nitis,  a c ut e r es pir at or y  distr ess s y n dr o m e ( A R D S)  o c c urs  wit h  us e  of 
N A V E L BI N E. I nt erstiti al  p n e u m o nitis  a n d  A R D S i n cl u d e d f at aliti es.  T h e  m e a n 
ti m e t o  o ns et  of i nt erstiti al  p n e u m o nitis  a n d  A R D S  aft er  vi n or el bi n e 
a d mi nistr ati o n  w as  o n e  w e e k (r a n g e  3 t o  8  d a ys). I nt err u pt  N A V E L BI N E i n 
p ati e nts  w h o  d e v el o p  u n e x pl ai n e d  d ys p n e a,  or  h a v e  a n y  e vi d e n c e  of  p ul m o n ar y 
t o xi cit y.  P er m a n e ntl y  dis c o nti n u e  N A VE L BI N E f or  c o nfir m e d i nt erstiti al 
p n e u m o nitis  or  A R D S. 
E m br y o -F et al  T o xi cit y  
N A V E L BI N E  c a n  c a us e f et al  h ar m  w h e n  a d mi nist er e d t o  a  pr e g n a nt  w o m a n. I n 
a ni m al r e pr o d u cti o n st u di es i n  mi c e  a n d r a b bits,  e m br y o  a n d f et al t o xi cit y  w er e 
o bs er v e d  wit h  a d mi nistr ati o n  of  vi n or el bi n e  at  d os es  a p pr o xi m at el y  0. 3 3  a n d 
0. 1 8 ti m es t h e  h u m a n t h er a p e uti c  d os e, r es p e cti v el y. If t his  dr u g is  us e d  d uri n g 
pr e g n a n c y,  or if t h e  p ati e nt  b e c o m es  pr e g n a nt  w hil e t a ki n g t his  dr u g,  a p pris e t h e 
p ati e nt  of t h e  p ot e nti al  h a z ar d t o  a f et us.  A d vis e f e m al es  of r e pr o d u cti v e 
p ot e nti al t o  us e  hi g hl y  eff e cti v e  c o ntr a c e pti o n  d uri n g t h er a p y  wit h 
N A V E L BI N E.  
 
 C o m p ositi o n 
Vi n or el bi n e ( N A V E L BI N E ®,  vi n or el bi n e t artr at e) is  a s e mi -s y nt h eti c  vi n c a 
al k al oi d f or i ntr a v e n o us i nj e cti o n.  C h e mi c all y,  vi n or el bi n e  t artr at e is  3', 4'-
di d e h y dr o- 4' -d e o x y -C' - n or vi n c al e u k o bl asti n e [ R-( R *, R *)- 2,  3-
di h y dr o x y b ut a n e di o at e ( 1: 2)(t artr at e)]  a n d  h as t h e f oll o wi n g str u ct ur e: 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  5 1  of  9 7  
 
 
C 4 5H 5 4N 4O 8• 2 C4H 6O 6 
M. W.  1 0 7 9. 1 2 
N A V E L BI N E ® I nj e cti o n is  a st eril e  n o n p yr o g ei n c  a q u e o us s ol uti o n.  E a c h 
millilit er  of s ol uti o n  c o nt ai ns  vi n or el bi n e t artr at e  e q ui v al e nt t o  1 0  m g  vi n or el bi n e 
i n  W at er f or I nj e cti o n.  T h e  p H  of  N A V E L BI N E I nj e cti o n is  a p pr o xi m at el y  3. 5. 
 
 St or a g e  R e c o m m e n d ati o ns  a n d  D os a g e  F or ms  
Vi n or el bi n e  ( N A V E L BI N E ®) is  d eli v er e d i n  vi als  c o nt ai ni n g  1 0  m g/ ml  a n d 
m ust  b e st or e d  at  2- 8  d e gr e es  c elsi us.  Vi n or el bi n e is  pr e p ar e d  wit h  a  mi ni m u m  of 
5 0  ml st eril e s ali n e s ol uti o n (s o di u m  c hl ori d e)  0. 9 %  or  gl u c os e  5 %.  Aft er 
pr e p ar ati o n  vi n or el bi n e  m ust  b e  us e d  wit hi n  1 2  h o urs;  h o w e v er,  2 4  h o urs if t h e 
s ol uti o n is st or e d i n r efri g er at or.  
N A V E L BI N E I nj e cti o n is  a  cl e ar,  c ol orl ess t o  p al e  y ell o w  a q u e o us s ol uti o n 
a v ail a bl e i n si n gl e - d os e  vi als  wit h r o y al  bl u e  c a ps, i n di vi d u all y  p a c k a g e d i n  a 
c art o n  as : 
•   1 0  m g/ 1  m L ( N D C  6 4 3 7 0- 5 3 2- 0 1). 
•   5 0  m g/ 5  m L ( N D C  6 4 3 7 0- 5 3 2- 0 2). 
St or e t h e  vi als  at  2° t o  8° C ( 3 6° t o  4 6° F) i n t h e  c art o n.  Pr ot e ct fr o m li g ht.  D O 
N O T  F R E E Z E.  U n o p e n e d  vi als  of  N A V E L BI N E  ar e st a bl e  at  2 5° C ( 7 7° F) f or 
u p t o  7 2  h o urs.  
N A V E L BI N E is  a  c yt ot o xi c   dr u g.  F oll o w  a p pli c a bl e s p e ci al  h a n dli n g  a n d 
dis p os al  pr o c e d ur es. 
 Dis p e ns ati o n  a n d  A c c o u nt a bilit y 
Vi n or el bi n e  ( N A V E L BI N E ®) will  b e  c o m m er ci all y s u p pli e d.   T his  p r o d u ct is 
f o r i nt r a v e n o us (I V)  us e  o nl y.  N A V E L BI N E ® m ust  o nl y  b e  a d mi nist e r e d 
i nt r a v e n o usl y. It is  e xt r e m el y i m p o rt a nt t h at t h e i nt r a v e n o us  n e e dl e  o r 
c at h et e r  b e  p r o p e rl y  p ositi o n e d  b ef o r e  a n y  N A V E L BI N E ®  is i nj e ct e d. 
I nt r at h e c al  a d mi nist r ati o n  of  ot h e r  vi n c a  al k al oi ds  h as  r es ult e d i n  d e at h.  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  5 2  of  9 7  
 
S yri n g es  c o nt ai ni n g t his  pr o d u ct s h o ul d  b e l a b el e d  " W A R NI N G  –  F O R I V  U S E 
O N L Y.  F A T A L if  gi v e n i ntr at h e c all y. "  
 
  T R E A T M E N T/  D O S E  M O DI FI C A TI O N S /  D O S E  D E L A Y S 
 U n a c c e pt a bl e  T o xi cit y  
If  a tr e at m e nt-r el at e d ( p ossi bl e,  pr o b a bl e,  or  d efi nit e)  d e at h  o c c urs,  e nr oll me nt  will  b e 
s us p e n d e d  a n d  c o nti n u ati o n  of t h e st u d y  will  b e r e ass ess e d  b y t h e  D S M C (s e e  S e cti o n 
1 6. 0). 
F or t h e  p ur p os es  of s af et y  m o nit ori n g,  w e  d efi n e  u n a c c e pt a bl e t o xi cit y t o  b e  a n y  of t h e 
f oll o wi n g tr e at m e nt-r el at e d ( p ossi bl e,  pr o b a bl e,  or  d efi nit e)  a d vers e  e v e nts:  
•  Gr a d e  3  n e ur o p at h y  w hi c h  d o es  n ot r es ol v e t o  gr a d e  2  or l ess  wit hi n t w o  c y cl es 
of tr e at m e nt  
•  Gr a d e  4  n e utr o p e ni a  w hi c h  d o es  n ot r es ol v e t o  gr a d e  2  or l ess  wit hi n  1 4  d a ys 
•  Gr a d e  3  el e v ati o n  of li v er f u n cti o n t ests ( L F Ts) t h at  d o es  n ot r es ol v e t o  gr a d e  2 
or l ess  wit hi n  1 4  d a ys 
•  R e - o c c urr e n c e  of  gr a d e  4  n e utr o p e ni a  or  gr a d e  3  el e v ati o n  of  L F Ts  d es pit e  2 
d os e  m o difi c ati o ns  or  o n e  d os e  m e di c ati o n  a n d  o n e  pr ot o c ol s p e cifi e d  d os e 
d el a y.  
•  Gr a d e  3 l eft  v e ntri c ul ar s yst oli c  d ysf u n cti o n t h at  d o es  n ot r es ol v e  t o  gr a d e  2  or 
l ess  wit hi n  o n e  c y cl e  of tr e at m e nt 
N O T E :  Gr a d e  5 ( d e at h)  n ot r el at e d t o tr e at m e nt  will  n ot  b e  c o nsi d er e d a n  u n a c c e pt a bl e 
a d v ers e  e v e nt.  
 D os e  M o difi c ati o n/  D os e  D el a y  G ui d eli n es f o r  T r ast u z u m a b  e mt a nsi n e  
 P h as e I  
T h er e  will  b e  n o  d os e  m o difi c ati o ns  of tr ast u z u m a b  e mt a nsi n e  p er mitt e d f or t h e  p h as e I 
p orti o n  of t h e st u d y (fi x e d  d os e  of  3. 6 m g/ k g f or  all  c o h orts). 
 P h as e II  
O n c e t h e  R P 2 D  d os e  of t h e  c o m bi n ati o n  of  vi n or el bi n e  a n d tr ast u z u m a b  e mt a nsi n e is 
d et er mi n e d i n t h e  p h as e I  p orti o n  of t h e  pr ot o c ol, it  will  b e t h e st arti n g  d os e  us e d t o 
tr e at  all  p ati e nts  d uri n g  p h as e II.  H o w e v er,  m o difi c ati o ns i n  b ot h  dr u gs  will  b e 
p er mitt e d,  as  d et ail e d  b el o w.  
Tr ast uz u m a b  e mt a nsi n e  d os e  will  n ot  b e r e- es c al at e d  aft er  a  d os e r e d u cti o n is  m a d e. 
If  a  pl a n n e d  dos e is  d el a y e d  or  miss e d, it s h o ul d  b e  a d mi nist er e d  as s o o n  as  p ossi bl e;  d o 
n ot  w ait  u ntil t h e  n e xt  pl a n n e d  c y cl e.  T h e s c h e d ul e  of  a d mi nistr ati o n s h o ul d  b e  a dj ust e d 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  5 3  of  9 7  
 
t o  m ai nt ai n  a  3-  w e e k i nt er v al  b et w e e n  d os es.  T h e i nf usi o n  m a y  b e  a d mi nist er e d  at t h e 
d os e  a n d r at e t h e  p ati e nt t ol er at e d i n t h e  m ost r e c e nt i nf usi o n. 
T h e i nf usi o n r at e  of tr ast u z u m a b  e mt a nsi n e s h o ul d  b e sl o w e d  or i nt err u pt e d if t h e 
p ati e nt  d e v el o ps  a n i nf usi o n-r el at e d r e a cti o n.  P er m a n e ntl y  dis c o nti n u e tr ast u z u m a b 
e mt a nsi n e f or lif e -t hr e at e ni n g i nf usi o n r el at e d r e a cti o ns,  a n d  dis c o nti n u e  p arti ci p ati o n 
o n  pr ot o c ol. 
M a n a g e m e nt  of i n cr e as e d s er u m tr a ns a mi n as es,  h y p er bilir u bi n e mi a, l eft  v e ntri c ul ar 
d ysf u n cti o n, t hr o m b o c yt o p e ni a,  p ul m o n ar y t o xi cit y  or  p eri p h er al  n e ur o p at h y  m a y 
r e q uir e t e m p or ar y i nt erru pti o n,  d os e r e d u cti o n  or tr e at m e nt  dis c o nti n u ati o n  of 
tr ast u z u m a b  e mt a nsi n e  as  p er  g ui d eli n es  pr o vi d e d i n  T a bl es  4 t o  7. 
T a bl e  4:  R e c o m m e n d e d  D os e  R e d u cti o n  S c h e d ul e f or  A d v ers e  E v e nts 
D os e  R e d u cti o n  S c h e d ul e  
D os e  L e v el  
St arti n g  d os e  
3. 6  m g/ k g  
First  d os e r e d u cti o n  
3  m g/ k g  
S e c o n d  d os e r e d u cti o n  
2. 4  m g/ k g  
R e q uir e m e nt f or f urt h er  d os e r e d u cti o n  
Dis c o nti n u e tr e at m e nt  
 
H e p at ot o xi cit y   
S eri o us  h e p at ot o xi cit y  h as  b e e n r e p ort e d, i n cl u di n g li v er f ail ur e  a n d  d e at h i n  p ati e nts 
tr e at e d wit h tr ast u z u m a b  e mt a nsi n e.  M o nit or s er u m tr a ns a mi n as es  a n d  bilir u bi n  pri or t o 
i niti ati o n  of tr ast u z u m a b  e mt a nsi n e tr e at m e nt  a n d  pri or t o  e a c h tr ast u z u m a b  e mt a nsi n e 
d os e. 
P ati e nts  wit h i n cr e as e d t ot al  bilir u bi n  b e c a us e  of  Gil b ert s y n dr o m e  ar e  all o w e d t o 
c o nti n u e tr ast u z u m a b  e mt a nsi n e  d osi n g  wit h o ut  a  d os e  h ol d  or  d os e  m o difi c ati o n if t h e 
dir e ct ( c o nj u g at e d)  bilir u bi n l e v el is  wit hi n t h e  n or m al r ef er e n c e r a n g e.  
A r e d u cti o n i n t h e  d os e  of tr ast u z u m a b  e mt a nsi n e is r e c o m m e n d e d i n t h e  c as e  of 
h e p at ot o xi cit y  e x hi bit e d  as i n cr e as es i n s er u m tr a ns a mi n as es  a n d/ or  h y p er bilir u bi n e mi a 
(s e e  T a bl es  5  a n d  6). 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  5 4  of  9 7  
 
T a bl e  5:  D os e  M o difi c ati o n  G ui d eli n es f or I n cr e as e d  S er u m  Tr a ns a mi n as es 
( A S T/ A L T) 
G r a d e  2                                                                    
(>   2. 5 t o ≤    5 ×  U L N)  
G r a d e  3  
(>  5 t o  ≤    2 0 ×  U L N)  
G r a d e  4  
(>   2 0 ×  U L N)  
Tr e at  at s a m e  d os e l e v el.  
 
D o  n ot  a d mi nist er tr ast u z u m a b 
e mt a nsi n e  u ntil  A S T/ A L T r e c o v ers 
t o  Gr a d e  ≤  2,  a n d t h e n r e d u c e  o n e 
d os e l e v el.  
P er m a n e ntl y  dis c o nti n u e 
tr ast u z u m a b  e mt a nsi n e. 
A L T  =  al a ni n e tr a ns a mi n as e;  A S T  =  as p art at e tr a ns a mi n as e;  U L N  =  u p p er li mit  of  n or m al.  
T a bl e  6 :  D os e  M o difi c ati o n  G ui d eli n es f or  H y p er bilir u bi n e mi a 
G r a d e  2  
(>  1. 5 t o  ≤  3  ×  U L N)  
G r a d e  3  
(>  3 t o  ≤  1 0  ×  U L N)  
G r a d e  4  
(>  1 0  ×  U L N)  
D o  n ot  a d mi nist er  tr ast u z u m a b 
e mt a nsi n e  u ntil t ot al  bilir u bi n 
r e c o v ers t o  Gr a d e ≤   1,  a n d 
t h e n tr e at  at s a m e  d os e l e v el. 
D o  n ot  a d mi nist er tr ast u z u m a b 
e mt a nsi n e  u ntil t ot al  bilir u bi n 
r e c o v ers t o  Gr a d e ≤   1,  a n d t h e n 
r e d u c e  o n e  d os e l e v el.  
P er m a n e ntl y  dis c o nti n u e 
tr ast u z u m a b  e mt a nsi n e. 
P er m a n e ntl y  dis c o nti n u e tr ast u z u m a b  e mt a nsi n e tr e at m e nt i n  p ati e nts  wit h s er u m 
tr a ns a mi n as es  >  3  x  U L N  a n d  c o n c o mit a nt t ot al  bilir u bi n  >  2  x  U L N. 
P er m a n e ntl y  dis c o nti n u e tr ast u z u m a b  e mt a nsi n e i n  p ati e nts  di a g n os e d  wit h  n o d ul ar 
r e g e n er ati v e  h y p er pl asi a ( N R H). 
T hr o m b o c yt o p e ni a  
P ati e nts r e c ei vi n g tr ast u z u m a b  e mt a nsi n e  w h o  e x p eri e n c e  a n y  of t h e f oll o wi n g  e v e nts 
list e d  b el o w,  aft er  a d e q u at e r e c o v er y t o  a  pl at el et  c o u nt  of  Gr a d e  ≤  1 ( ≥  7 5, 0 0 0/ μ L),  m a y 
c o nti n u e tr e at m e nt  wit h tr ast u z u m a b  e mt a nsi n e  at  o n e  d os e l e v el r e d u cti o n i n 
s u bs e q u e nt tr e at m e nt  c y cl es (s e e  T a bl e  4).  P ati e nts  w h o  e x p eri e n c e  a n y  e v e nt list e d 
b el o w  w hil e r e c ei vi n g t h e  2. 4  m g/ k g  d os e  will  b e  dis c o nti n u e d fr o m st u d y tr e at m e nt.  A 
d os e  d el a y  of  u p t o  4 2  d a ys fr o m t h e l ast  d os e r e c ei v e d is  p er mitt e d.  Pl at el et  c o u nts 
s h o ul d  b e  o bt ai n e d  n o l ess fr e q u e ntl y t h a n  e v er y  w e e k t o  e v al u a t e r e c o v er y  w h e n e v er 
a n y  of t h e  e v e nts list e d  b el o w  o c c ur. If  pl at el et  c o u nts  d o  n ot r e c o v er t o  Gr a d e  ≤  1 
wit hi n  4 2  d a ys fr o m t h e l ast  d os e r e c ei v e d, t h e  p ati e nt  will  b e  dis c o nti n u e d fr o m st u d y 
tr e at m e nt.  N o r e-es c al ati o n  of t h e tr ast u z u m a b  e mt a nsi n e  d os e  is  all o w e d. 
N ot e :  alt h o u g h  C B Cs  wit h  pl at el ets  ar e r e q uir e d  wit hi n  7 2  h o urs  pri or t o st u d y tr e at m e nt 
a d mi nistr ati o n  at  e a c h  c y cl e, t h e i n v esti g at or  m a y  m o nit or  pl at el et  c o u nts ( or  a n y  ot h er 
l a b or at or y t est)  m or e fr e q u e ntl y  as  cli ni c all y i n di c at e d.  D os e r e du c e i n s u bs e q u e nt 
tr e at m e nt  c y cl es i n t h e  e v e nt  of: 
•  Pl at el et  c o u nt  <  1 0, 0 0 0/ μ L  of  a n y  d ur ati o n 
•  Pl at el et  c o u nt  of  Gr a d e  4 ( <  2 5, 0 0 0/ μ L) t h at  d o es  n ot r e c o v er t o  Gr a d e  ≤  1  aft er  7  d a ys 
fr o m t h e  o ns et  d at e  of t h e  Gr a d e  4  e v e nt 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  5 5  of  9 7  
 
•  F or  p ati e nts  o n  a nti c o a g ulati o n t h er a p y,  pl at el et  c o u nt  of  Gr a d e  ≥  3 ( <  5 0, 0 0 0/ μ L)  of 
a n y  d ur ati o n. 
L eft  V e ntri c ul ar  D ysf u n cti o n ( L V E F)  ( S e e  A p p e n di x E f or  M a n a g e m e nt  Al g orit h m) 
P ati e nts  wit h o ut si g nifi c a nt  c ar di a c  hist or y  a n d  wit h  a  b as eli n e  L V E F  ≥  5 0 %  as 
d et er mi n e d  b y  E C H O  or  M U G A s c a n  ar e  eli gi bl e f or st u d y  p arti ci p ati o n.  Ej e cti o n 
fr a cti o ns  will  b e  m o nit or e d  pri or t o  c y cl e  3  a n d  e v er y f o ur  c y cl es t h er e aft er ( at  a n y 
ti m e p oi nt  wit hi n r es p e cti v e  c y cl es)  u ntil t h e  ass ess m e nt  at t h e  St u d y  Tr e at m e nt 
Dis c o nti n u ati o n  Visit.  T a bl e  7  a n d  A p p e n di x  E  s u m m ari z es t h e  m a n a g e m e nt  of 
tr ast u z u m a b  e mt a nsi n e  o n t h e  b asis  of  m e as ur e d  L V E F  a n d  c h a n g es i n  L V E F fr o m 
b as eli n e i n  p ati e nts. If t h e  L V E F is  r e p ort e d  as  a r a n g e, t h e  m e di a n  of t h e r a n g e s h o ul d 
b e t a k e n. If  a n i n v esti g at or is  c o n c er n e d t h at  a n  A E  m a y  b e r el at e d t o  c ar di a c 
d ysf u n cti o n,  a n  a d diti o n al  L V E F  m e as ur e m e nt  m a y  b e  p erf or m e d.  Tr ast u z u m a b 
e mt a nsi n e  will  b e  dis c o nti n u e d i n  a n y  p ati e nt  w h o  d e v el o ps s y m pt o m ati c  C H F.  C H F 
s h o ul d  b e tr e at e d  a n d  m o nit or e d  a c c or di n g t o st a n d ar d  m e di c al  pr a cti c e. 
T h e  d e cisi o n t o st o p  or  c o nti n u e tr ast u z u m a b  e mt a nsi n e s h o ul d  b e  b as e d  o n t h e 
al g orit h m s h o w n i n  T a bl e  7.  Tr ast u z u m a b  e mt a nsi n e  m ust  b e  dis c o nti n u e d i n  al l  p ati e nts 
f or  w h o m  a  c o nfir m e d  dr o p  of  L V E F t o  b el o w  4 0 % is  d o c u m e nt e d ( wit h  a r e p e at 
ass ess m e nt  wit hi n  2 1  d a ys).  F or  p ati e nts  w h os e  L V E F  dr o ps t o  v al u es  b et w e e n  4 0 %  a n d 
4 5 %  wit h  a n  a bs ol ut e  d e cr e as e i n  L V E F  of  ≥  1 0 %  p oi nts fr o m  b as eli n e, tr ast u z u m a b 
e mt a nsi n e s h o ul d  b e  h el d.  F or t h es e  p ati e nts, t h e  L V E F s h o ul d  b e r e p e at e d i n  2 1  d a ys, 
a n d tr ast u z u m a b  e mt a nsi n e s h o ul d  b e  dis c o nti n u e d if t h e  L V E F  h as  n ot r e c o v er e d t o 
wit hi n  1 0 %  a bs ol ut e  diff er e n c e  b el o w  b as eli n e. If  cli ni c all y si g nifi c a nt  c ar di a c 
d ysf u n cti o n  or  c ar di a c f ail ur e  d e v el o ps  or  p ersists  or if si g nifi c a nt  m e di c al  m a n a g e m e nt 
is r e q uir e d t o  m ai nt ai n  ej e cti o n fr a cti o n, t h e  p ati e nt s h o ul d  b e  dis c o nti n u e d fr o m st u d y 
tr e at m e nt. 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  5 6  of  9 7  
 
T a bl e  7 :  D os e  M o difi c ati o ns f or  L eft  V e ntri c ul ar D ysf u n cti o n 
S y m pt o m ati c 
C H F  
L V E F  <  4 0 % 
L V E F  4 0 % t o 
≤   4 5 %  a n d 
d e c r e as e is 
≥   1 0 %  p oi nts 
f r o m  b as eli n e 
L V E F  4 0 % t o 
≤   4 5 %  a n d 
d e c r e as e is 
<  1 0 %  p oi nts 
f r o m  b as eli n e 
L V E F  >  4 5 % 
Dis c o nti n u e   
tr ast u z u m a b 
e mt a nsi n e   
 
D o  n ot 
a d mi nist er 
tr ast u z u m a b 
e mt a nsi n e.   
 
R e p e at  L V E F 
ass ess m e nt 
wit hi n  3  w e e ks. 
If  L V E F  <  4 0 % 
is  c o nfir m e d, 
dis c o nti n u e  
tr ast u z u m a b 
e mt a nsi n e.  
 
D o  n ot 
a d mi nist er   
tr ast u z u m a b 
e mt a nsi n e.  
 
R e p e at  L V E F 
ass ess m e nt 
wit hi n  3 
w e e ks. If t h e 
L V E F  h as  n ot 
r e c o v er e d t o 
wit hi n  1 0 % 
p oi nts fr o m 
b as eli n e, 
dis c o nti n u e  
tr ast u z u m a b 
e mt a nsi n e . 
C o nti n u e 
tr e at m e nt  wit h 
tr ast u z u m a b 
e mt a nsi n e . 
 
R e p e at  L V E F 
ass ess m e nt 
wit hi n  3 
w e e ks.  
C o nti n u e 
tr e at m e nt  wit h 
tr ast u z u m a b 
e mt a nsi n e . 
C H F  =  C o n g esti v e  H e art  F ail ur e;  L V E F  =  L eft  V e ntri c ul ar  Ej e cti o n  Fr a cti o n  
S e e  als o  A p p e n di x  E  f or  M a n a g e m e nt  Al g orit h m 
 
P ul m o n ar y  T o xi cit y  
Tr ast u z u m a b  e mt a nsi n e s h o ul d  b e  p er m a n e ntl y  dis c o nti n u e d i n  p ati e nts  di a g n os e d  wit h 
i nt erstiti al l u n g  dis e as e (I L D)  or  p n e u m o nitis. 
P eri p h er al  N e ur o p at h y   
Tr ast u z u m a b  e mt a nsi n e s h o ul d  b e t e m p or aril y  dis c o nti n u e d i n  p ati e nts  e x p eri e n ci n g 
Gr a d e  3  or  4  p eri p h er al  n e ur o p at h y  u ntil r es ol uti o n t o  ≤  Gr a d e  2.  
Tr ast u z u m a b  e mt a msi n e  o v er d os a g e 
T h er e is  n o  k n o w n  a nti d ot e f or  o v er d os e  of tr ast u z u m a b  e mt a nsi n e. I n  cli ni c al tri als, 
o v er d os e  of tr ast u z u m a b  e mt a nsi n e  h as  b e e n r e p ort e d  at  a p pr o xi m at el y t w o ti m es t h e 
r e c o m m e n d e d  d os e  w hi c h r es ult e d i n  Gr a d e  2 t hr o m b o c yt o p e ni a (r es ol v e d  4  d a ys l at er) 
a n d  o n e  d e at h.  I n t h e f at al  c as e, t h e  p ati e nt i n c orr e ctl y r e c ei v e d tr ast u z u m a b  e mt a nsi n e 
at  6  m g/ k g  a n d  di e d  a p pr o xi m at el y  3  w e e ks f oll o wi n g t h e  o v er d os e;  a  c a us e  of  d e at h  a n d 
a  c a us al r el ati o ns hi p t o tr ast u z u m a b  e mt a nsi n e  w er e  n ot  est a blis h e d. 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  5 7  of  9 7  
 
 D os e  M o difi c ati o n/  D os e  D el a y  G ui d eli n es f o r  Vi n o r el bi n e  
T h er e  will  b e  n o  d os e  m o difi c ati o n  of  vi n or el bi n e  d uri n g t h e  p h as e I  p orti o n  of t h e 
pr ot o c ol. 
 P h as e I  D os e  D el a ys  
If  n e utr o p hils  <  1. 5  x  1 09/ L  or  pl at el ets  <  7 5  x  1 09/ L  w h e n  m e as ur e d  o n t h e D a y  1  of 
a n y  gi v e n  c y cl e  of tr e at m e nt, t h e tr e at m e nt  will  b e  p ost p o n e d f or  1  w e e k  u ntil t h e  bl o o d 
c o u nts  h a v e r et ur n e d t o  n or m al l e v els ( n e utr o p hils  >  1. 5  x  1 0 9/ L  a n d t hr o m b o c yt es 
> 7 5 x 1 0 9/ L).  I n t his i nst a n c e t h e  a d mi nistr ati o n  of  b ot h  dr u gs s h o ul d  b e  p ost p o n e d. 
H o w e v er if  n e utr o p hils  <  1. 5  x  1 0 9/ L  or  pl at el ets  <  7 5  x  1 09/ L  w h e n  m e as ur e d  o n t h e 
D a y  8  of  a n y  gi v e n  c y cl e  of tr e at m e nt , t h e  d a y  8  d os e  of  vi n or el bi n e s h o ul d  b e s ki p p e d 
a n d  a n ot h er  c y cl e  will  b e st art e d  3  w e e ks fr o m t h e l ast  d os e  of tr ast u z u m a b  e mt a nsi n e. 
If  o n t h e  d at e t h e  n e xt  c y cl e is  d u e,  n e utr o p hils  h a v e  n ot r e c o v er e d t o  ≥ 1. 5  x  1 09/ L, 
p r o p h yl a cti c  us e  of  g r o wt h f a ct o r  s u p p o rt will  b e  p er mitt e d t o  all o w  d osi n g  of t h e 
n e xt  c y cl e. I n t his  c as e, f or f ut ur e  c y cl es  gr o wt h f a ct or s u p p ort  will  b e  p er mitt e d. If 
wit h t h e  us e  of  gr o wt h f a ct or s u p p ort,  n e utr o p e ni a  h as  n ot r es ol v e d t o  gr a d e  2  or l ess 
wit hi n  1 4  d a ys, t his  will  b e  c o nsi d er e d  a  D L T.  S e e  als o  S e cti o n  7. 3.   
  P h as e II  
O n c e t h e  R P 2 D  d os e  of t h e  c o m bi n ati o n  of  vi n or el bi n e  a n d tr ast u z u m a b  e mt a nsi n e is 
d et er mi n e d i n t h e  p h as e I  p orti o n  of t h e  pr ot o c ol, it  will  b e t h e st arti n g  d os e  us e d t o 
tr e at  all  p ati e nts  d uri n g  p h as e II. H o w e v er,  m o difi c ati o ns i n  b ot h  dr u gs  will  b e 
p er mitt e d,  as  d et ail e d  b el o w.  
H e m at ol o gi c al t o xi cit y  a n d  Us e  of  Gr o wt h  F a ct or  S u p p ort  
Vi n or el bi n e  d os e  m ust  b e  a dj ust e d if  n e utr o p e ni a  a n d t hr o m b o c yt o p e ni a  o c c ur. If 
n e utr o p hils  <  1. 5  x  1 0 9/ L  or  pl at el ets  <  7 5 x  1 0 9/ L  w h e n  m e as ur e d  o n t h e D a y  1  of  a n y 
gi v e n  c y cl e  of tr e at m e nt, t h e tr e at m e nt  will  b e  p ost p o n e d f or  1  w e e k  u ntil t h e  bl o o d 
c o u nts  h a v e r et ur n e d t o  n or m al l e v els ( n e utr o p hils  >  1. 5  x  1 0 9/ L  a n d t hr o m b o c yt es 
> 7 5 x 1 0 9/ L).  (I n t his i nst a n c e tr ast u z u m a b  e mt ansi n e s h o ul d  als o  b e  p ost p o n e d.) 
H o w e v er if  n e utr o p hils  <  1. 5  x  1 0 9/ L  or  pl at el ets  <  7 5  x  1 09/ L  w h e n  m e as ur e d  o n t h e 
D a y  8   of  a n y  gi v e n  c y cl e  of tr e at m e nt, t h e  d a y  8  d os e  of  vi n or el bi n e s h o ul d  b e s ki p p e d 
a n d  a n ot h er  c y cl e  will  b e st art e d  3  w e e ks fr o m t h e l ast  d os e  of tr ast u z u m a b  e mt a nsi n e. 
If  o n t h e  d at e t h e  n e xt  c y cl e is  d u e,  n e utr o p hils  h a v e  n ot r e c o v er e d t o  ≥ 1. 5  x  1 09/ L, 
pr o p h yl a cti c  us e  of  gr o wt h f a ct or s u p p ort  will  b e  p er mitt e d t o  all o w  d osi n g  of t h e  n e xt 
c y cl e. I n t his  c as e, f or f ut ur e  c y cl es  gr o wt h f a ct or s u p p ort  will  b e  p er mitt e d.    
I n t h e  e v e nt  of  Gr a d e  4 t o xi cit y,  or i n t h e  e v e nt  of  Gr a d e  3  or  4 t o xi cit y  ass o ci at e d wit h 
f e bril e  n e utr o p e ni a, t h er e  will  b e  a  d os e r e d u cti o n i n  Vi n or el bi n e  p er mitt e d.  T h es e  d os e 
l e v el r e d u cti o ns  will  b e s u p pli e d i n  a n  a m e n d m e nt  o n c e t h e  M T D  h as  b e e n  d et er mi n e d 
i n t h e  p h as e I  p orti o n  of t h e st u d y. 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  5 8  of  9 7  
 
N e ur ol o gi c al t o xi cit y  
I n t h e  e v e nt  of  n e ur ol o gi c al t o xi cit y, i n cl u di n g  a b d o mi n al i nfl ati o n  d u e t o  o bsti p ati o n, 
at  N CI - C T C A E  Gr a d e  3  or  4, tr e at m e nt  wit h  vi n or el bi n e  will  b e s us p e n d e d  u ntil 
i m pr o v e m e nt t o  Gr a d e  2  or l ess.  T h e  d os e  will t h e n  b e r e d u c e d  b y  2 0 %.  
Li v er t o xi cit y  
If  d uri n g tr e at m e nt  wit h  vi n or el bi n e  bilir u bi n i n cr e as es t o  m or e t h a n t wi c e t h e  U L N  or 
A L T/ A S T i n cr e as es t o  m or e t h a n  3  x  U L N ( n ot r el at e d t o li v er  m et ast as es), t h e  d os e 
will  b e r e d u c e d  b y  5 0 %.   
Ot h er t o xi cit y  
S y m pt o ms  esti m at e d  as  N CI - C T C A E  Gr a d e  3  or  4  a g ai nst t h e  b a c k gr o u n d  of t h e 
vi n or el bi n e tr e at m e nt  e nt ail  a  d os e r e d u cti o n  of  2 0 %.  
Tr e at m e nt  wit h  vi n or el bi n e  m ust  b e  dis c o nti n u e d f or t h e f oll o wi n g r e as o ns:  
•  R es pir at or y i ns uffi ci e n c y r e q uiri n g  br o n c h o dil ati o n i n s pit e  of  e xt e nsi v e 
pr e m e di c ati o n   
•  G e n er ali z e d  urti c ari a 
•  T er mi n ati o n  of  vi n or el bi n e  at  h y p ers e nsiti vit y r e a cti o ns  ot h ers t h a n  h y p ot e nsi o n, 
a n gi o e d e m a, r es pir at or y i ns uffi ci e n c y  or  g e n er ali z e d  urti c ari a is  d o n e  at t h e 
i n v esti g at or’s  dis cr eti o n. 
 
  T R E A T M E N T  DI S C O N TI N U A TI O N  
Tr e at m e nt  m a y  b e  dis c o nti n u e d f or  a n y  of t h e f oll o wi n g r e as o ns: 
•   T h e  p ati e nt  e x p eri e n c es  a  D L T  (s e e  S e cti o n  7. 3) 
•   T h e  p ati e nt  d e m o nstr at es  pr o gr essi o n  of  dis e as e ( E x c e pti o n:  P ati e nts  m a y r e m ai n  o n t h e 
st u d y if i n t h e  o pi ni o n  of t h e I n v esti g at or,  h e/s h e is  d eri vi n g  cli ni c al  b e n efit fr o m st u d y 
tr e at m e nt) 
•   T h e  p ati e nt  wit h dr a ws  c o ns e nt fr o m t h e st u d y 
•   T h e  p ati e nt  h as  n ot r e c ei v e d st u d y tr e at m e nt f or  2  c y cl es ( 4 2  d a ys )  d u e t o  a n  a d v ers e 
e v e nt (t o xi cit y)  
•   T h e  p ati e nt  e x p eri e n c es  a n  a d v ers e  e v e nt t h at i n t h e  o pi ni o n  of t h e I n v esti g at or  m a k es 
c o nti n u e d st u d y  tr e at m e nt  a n  u n a c c e pt a bl e ris k ( als o s e e  S e cti o n 1 0. 0) 
•   T h e  p ati e nt  b e c o m es  pr e g n a nt ( als o s e e  S e cti o n  1 4. 7  E x p e dit e d  A d v ers e  E v e nt 
R e p orti n g  R e q uir e m e nts) 
•   T h e  p ati e nt r e q uir es  c o nti n u o us tr e at m e nt  wit h  a  pr o hi bit e d  c o n c o mit a nt  dr u g(s) f or 
w hi c h  n o s af e  alt er n ati v es  c a n  b e s u bstit ut e d 
•   T h e  p ati e nt is si g nifi c a ntl y  n o n c o m pli a nt  wit h t h e r e q uir e m e nts  of t h e  pr ot o c ol  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  5 9  of  9 7  
 
S h o ul d  dis c o nti n u ati o n  of st u d y t h er a p y  o c c ur,  all  eff orts s h o ul d  b e  m a d e t o  e x e c ut e/ r e p ort 
E n d - of-Tr e at m e nt  a n d  F oll o w - u p  E v al u ati o ns  as  c o m pl et el y  as  p ossi bl e  a n d t o  d et er mi n e/ 
d o c u m e nt t h e r e as o n f or  dis c o nti n u ati o n ( u nl ess t h e  p ati e nt  wit h dr a ws  c o ns e nt f or f oll o w-
u p).  
Alt h o u g h  u n e x p e ct e d t er mi n ati o n  of st u d y tr e at m e nt  m a y  o c c ur, it is  p ossi bl e t h e s u bj e ct 
m a y still  a gr e e t o f oll o w - u p.  I n s u c h  a s c e n ari o, t h e  E O T  visit  a n d  pr o c e d ur es s h all  o c c ur 
b ut it is i m p ort a nt t o  u n d erst a n d t h at t h e s u bj e ct is still i n  F oll o w - u p.   
If  h o w e v er  a s u bj e ct  wit h dr a ws  c o ns e nt t o  p arti ci p at e i n t h e st u d y, t his  c o nstit ut es t h e  E n d 
of  St u d y f or t h e  p ati e nt.   E v e n s o  att e m pts s h o ul d  b e  m a d e t o  o bt ai n  p er missi o n t o r e c or d  at 
l e ast  S ur vi v al  D at a  u p  u ntil t h e  pr ot o c ol-s p e cifi e d  e n d  of  F oll o w- u p  p eri o d.   M et h o ds  us e d 
f or  att e m pt e d  c o nt a ct  m ust  als o  b e  d o c u m e nt e d  pr o p erl y ( e. g.  n u m b er  of t el e p h o n e  c alls t o 
s u bj e ct,  c ertifi e d l ett ers,  et c.).  
If  a  p ati e nt  wis h es t o  wit h dr a w  c o ns e nt fr o m t h e st u d y, t h e  PI  m ust  b e  n otifi e d.   T h e 
i nf or m ati o n r e g ar di n g  wit h dr a w al (i. e. s u bj e ct i d e ntifi ers  a n d  d at e  of  wit h dr a w al) s h o ul d  b e 
d o c u m e nt e d i n t h e s u bj e ct’s r e c or d  a n d  u p d at e d  wit hi n  a n y  ot h er r es e ar c h  d at a b as e(s).   
 
  S C H E D U L E  O F  C LI NI C A L  &  L A B O R A T O R Y  E V A L U A TI O N S  
Pri or t o  p erf or mi n g  a n y st u d y -s p e cifi c  pr o c e d ur es  or  e v al u ati o ns,  writt e n i nf or m e d  c o ns e nt 
a n d  a ut h ori z ati o n f or t h e  us e  of  pr ot e ct e d  h e alt h i nf or m ati o n ( HI P A A)  m ust  b e  o bt ai n e d i n 
a c c or d a n c e  wit h  all  a p pli c a bl e  p oli ci es, r e g ul ati o ns  a n d l a ws.    
If t h e ti mi n g  of  a  pr ot o c ol- m a n d at e d  pr o c e d ur e  c oi n ci d es  wit h  a  h oli d a y  a n d/ or  w e e k e n d 
t h at  pr e cl u d es t h e  pr o c e d ur e  wit hi n t h e  all ott e d  wi n d o w, t h e  pr o c e d ur e s h o ul d  b e  p erf or m e d 
wit hi n  3  d a ys ,  u nl ess  ot h er wis e s p e cifi e d. 
 P r e -T r e at m e nt  E v al u ati o ns ( S c r e e ni n g)  
T h e f oll o wi n g  m ust  b e  c oll e ct e d/  p erf or m e d  wit hi n  2 8  d a ys  pri or t o  C y cl e  1,  d a y  1  of 
tr e at m e nt.   Cli ni c al  a n d l a b or at or y  e v al u ati o ns  p erf or m e d  as  p art  of r o uti n e st a n d ar d  of 
c ar e  d o  n ot  n e e d t o  b e r e p e at e d if  p erf or m e d  wit hi n t h e  a p pr o pri at e  wi n d o w.  
•   M e di c al  hist or y  
o   D o c u m e nt e d  H E R - 2 st at us 
•   C o m pl et e  p h ysi c al  e x a mi n ati o n  t o i n cl u d e: 
o   E v al u ati o n  of t h e  pr es e n c e/ a bs e n c e  of  e nl ar g e d l y m p h  n o d es, 
h e p at o m e g al y  a n d s pl e n o m e g al y, 
o   H e a d,  e y e,  e ar,  n os e  a n d t hr o at, 
o   C ar di o v as c ul ar,  
o   M us c ul os k el et al,  
o   R es pir at or y,  
o   G astr oi nt esti n al,  a n d  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  6 0  of  9 7  
 
o   N e ur ol o gi c al s yst e ms  
•   E C O G  P erf or m a n c e  St at us ( E C O G  P S) ; s e e  als o  A p p e n di x  C 
•   W ei g ht  ( wt) 
•   H ei g ht  ( ht) 
•   Vit al si g ns   
o   Bl o o d  pr ess ur e ( B P) 
o   H e art r at e ( H R)  
o   R es pir at or y r at e ( R R)  
o   Or al t e m p er at ur e (t e m p)  
•   C o m pl et e  bl o o d  c o u nt ( C B C)  
o   diff  a n d  P L T 
•   C o m pr e h e nsi v e  m et a b oli c  p a n el ( C M P), i n cl u di n g: 
o   S o di u m, 
o   P ot assi u m,  
o   C hl ori d e, 
o   Bi c ar b o n at e, 
o   Gl u c os e, 
o   Bl o o d  ur e a  nitr o g e n ( B U N), 
o   Cr e ati ni n e , 
o   C al ci u m , 
o   P h os p h or us, 
o   M a g n esi u m , 
o   T ot al  bilir u bi n , 
o   Dir e ct  bilir u bi n , 
o   T ot al  pr ot ei n , 
o   Al b u mi n , 
o   Al a ni n e  a mi n otr a nsf er as e  ( A L T), 
o   As p art at e  a mi n otr a nsf er as e ( A S T) ,  a n d 
o   Al k ali n e  p h os p h at as e ( al k  p h os) 
•   Uri n al ysis  ( U/ A) 
•   Uri n e  or s er u m  Pr e g n a n c y t est (f or  w o m e n  of  c hil d - b e ari n g  p ot e nti al  or 
W o C B P) ,  wit hi n  3  d a ys  pri or t o  D a y  1  of st u d y tr e at m e nt 
•   I N R (f or  p ati e nts  o n  c o u m ari n  a nti c o a g ul a nts) 
•   1 2- L e a d  El e ctr o c ar di o gr a m ( E C G)  
•   E c h o c ar di o gr a m  or  M ulti pl e  G at e d  A c q uisiti o n  S c a n ( E C H O  or  M U G A ) t h e 
s a m e pr o c e d ur e  us e d  at  S cr e e ni n g  m ust  b e  us e d t hr o u g h o ut t h e st u d y 
•   I m a gi n g st u di es; t h e s a m e r a di o gr a p hi c  pr o c e d ur e(s) us e d  at  S cr e e ni n g  m ust  b e 
us e d t hr o u g h o ut t h e st u d y (f or t u m or  e v al u ati o n ;  m e as ur a bl e  a n d  u n m e as ur a bl e 
dis e as e   of  all  k n o w n  a n d/ or s us p e ct e d sit es  of  dis e as e) 
o   Br ai n  M RI/  C T, if  p ati e nt  h as  d o c u m e nt e d  br ai n  m et ast as es   
o   C T  or  M RI  of t h e  c h est,  a b d o m e n  a n d  p el vis ( C/ A/ P) 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  6 1  of  9 7  
 
o   B o n e s c a n (if  a n is ot o p e- b as e d  b o n e s c a n  w as  p erf or m e d  > 2 8  d a ys  b ut 
≤ 6 0  d a ys  pri or t o  e nr oll m e nt, t h e  b o n e s c a n  d o es  n ot  n e e d t o  b e r e p e at e d 
a n d  n o n-is ot o pi c r a di o gr a p hi c  m o d aliti es s h o ul d  b e  utili z e d t o  d o c u m e nt 
t h e  e xt e nt  of  b o n e  m et ast as es) 
•   T u m or s a m pl e(s) f or  l o c al H E R -2 t esti n g , r e q u est e d b ut  n ot  r e q ui r e d  as  p er 
l o c al/ i nstit uti o n al  g ui d eli n es  
 E v al u ati o ns  o n  T r e at m e nt 
C oll e cti o n  of  C o n c o mit a nt  M e di c ati o ns  a n d  A d v ers e  E v e nts ( A Es) s h o ul d  o c c ur 
t hr o u g h o ut t h e st u d y,  as  d es cri b e d.  P ati e nts s h o ul d  b e  ass ess e d  f or t o xi cit y  pri or t o 
e a c h  d os e;  d osi n g  will  o c c ur  o nl y if t h e  cli ni c al  ass ess m e nt  a n d l o c al l a b or at or y t est 
v al u es  ar e  a c c e pt a bl e.  
T u m o r  ass ess m e nts  (i n cl u di n g  B o n e  S c a n  as  n e e d e d) wil l  b e  c o n d u ct e d  e v e r y  6 
w e e ks ( ± 7  d a ys) f r o m t h e  d at e  of  R a n d o mi z ati o n  t o  C y cl e  6.  T h e r e aft e r, t h es e 
ass ess m e nts  will  b e  d o n e  e v e r y  1 2  w e e ks ( ±  7  d a ys).  T h es e s h all  o c c ur r e g ar dl ess  of 
d os e  d el a ys  or  d os e i nt err u pti o ns,  u ntil I n v esti g at or- ass ess e d  pr o gr essi v e  dis e as e ( P D), 
e arl y tr e at m e nt  dis c o nti n u ati o n  or  d e at h,  w hi c h e v er  o c c urs first.  M or e fr e q u e nt t u m or 
ass ess m e nts  m a y  b e  p erf or m e d  as  cli ni c all y i n di c at e d,  at t h e  dis cr eti o n  of t h e tr e ati n g 
I n v esti g at or.  S e e  als o s e cti o n  1 3. 0 f or  d et ails. 
Aft er s cr e e ni n g/ b as eli n e,  e j e cti o n fr a cti o ns  will  b e  m o nit or e d  b y  E C H O  or  M U G A 
pri or t o  c y cl e  3  a n d  e v er y f o ur  c y cl es  (i. e.  e v er y  1 2  w e e ks,  ± 7  d a ys) t h er e aft er ( at  a n y 
ti m e p oi nt  wit hi n r es p e cti v e  c y cl es)  u ntil t h e  ass ess m e nt  at t h e  St u d y  Tr e at m e nt 
Dis c o nti n u ati o n  Visit.  S e e  als o s e cti o n  1 0. 2. 2,  T a bl e  7   a n d  A p p e n di x  E. 
P ati e nts t a ki n g  a nti c o a g ul a nts  or st arti n g  a nti c o a g ul a nts  w hil e  o n st u d y s h o ul d  h a v e 
w e e kl y  pl at el et  c o u nts  m o nit or e d f or  at l e ast  2  c y cl es i n  or d er t o  ass ess  w h et h er  a 
tr ast u z u m a b  e mt a nsi n e  d os e r e d u cti o n  m a y  b e  n e c ess ar y. 
 All  C y cl es ,  d a y  1 ( ±3  d a ys)  
•   C o m pl et e  p h ysi c al  e x a mi n ati o n t o i n cl u d e: 
o   E v al u ati o n  of t h e  pr es e n c e/ a bs e n c e  of  e nl ar g e d l y m p h  n o d es, 
h e p at o m e g al y  a n d s pl e n o m e g al y, 
o   H e a d,  e y e,  e ar,  n os e  a n d t hr o at, 
o   C ar di o v as c ul ar,  
o   M us c ul os k el et al,  
o   R es pir at or y,  
o   G astr oi nt esti n al,  a n d  
o   N e ur ol o gi c al s yst e ms  
•   E C O G  P erf or m a n c e  St at us ( E C O G  P S); s e e  als o  A p p e n di x  C 
•   W ei g ht ( wt)  
•   Vit al si g ns   
o   Bl o o d  pr ess ur e ( B P) 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  6 2  of  9 7  
 
o   H e art r at e ( H R)  
o   R es pir at or y r at e ( R R)  
o   Or al t e m p er at ur e (t e m p)  
•   C o m pl et e  bl o o d  c o u nt ( C B C) 
o   diff  a n d  P L T 
•  
C o m pr e h e nsi v e  m et a b oli c  p a n el ( C M P)  
o   S o di u m, 
o   P ot assi u m,  
o   C hl ori d e, 
o   Bi c ar b o n at e,  
o   Gl u c os e,  
o   Bl o o d  ur e a  nitr o g e n ( B U N), 
o   Cr e ati ni n e,  
o   C al ci u m,  
o   P h os p h or us, 
o   M a g n esi u m,  
o   T ot al  bilir u bi n,  
o   Dir e ct  bilir u bi n,  
o   T ot al  pr ot ei n, 
o   Al b u mi n, 
o   Al a ni n e  a mi n otr a nsf er as e ( A L T),  
o   As p art at e  a mi n otr a nsf er as e ( A S T),  a n d  
o   Al k ali n e  p h os p h at as e ( al k  p h os) 
•   I NR (f or  p ati e nts  o n  c o u m ari n  a nti c o a g ul a nts) 
 C y cl e  1,  d a y  8 ( ± 3  d a ys)  
•   Vit al si g ns   
o   Bl o o d  pr ess ur e ( B P) 
o   H e art r at e ( H R)  
o   R es pir at or y r at e ( R R)  
o   Or al t e m p er at ur e (t e m p)  
•   C o m pl et e  bl o o d  c o u nt ( C B C)  
o   diff  a n d  P L T 
 C y cl e  2,  d a y  8 ( ± 3  d a ys)  
•   Vit al si g ns   
o   Bl o o d  pr ess ur e ( B P)  
o   H e art r at e ( H R)  
o   R es pir at or y r at e ( R R)  
o   Or al t e m p er at ur e (t e m p)  
•   C o m pl et e  bl o o d  c o u nt ( C B C)  
o   diff  a n d  P L T 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  6 3  of  9 7  
 
 C y cl e  3,  d a y  8 ( ± 3  d a ys)  
•   Vit al si g ns   
o   Bl o o d  pr ess ur e ( B P) 
o   H e art r at e ( H R)  
o   R es pir at or y r at e ( R R)  
o   Or al t e m p er at ur e (t e m p)  
•   C o m pl et e  bl o o d  c o u nt ( C B C) 
o   diff  a n d  P L T 
•   Uri n e  or s er u m  Pr e g n a n c y t est (f or  w o m e n  of  c hil d - b e ari n g  p ot e nti al  or 
W o C B P)  
 C y cl e  4,  d a y  8 ( ± 3  d a ys)  
•   Vit al si g ns   
o   Bl o o d  pr ess ur e ( B P) 
o   H e art r at e ( H R)  
o   R es pir at or y r at e ( R R)  
o   Or al t e m p er at ur e (t e m p)  
•   C o m pl et e  bl o o d  c o u nt ( C B C) 
o  diff  a n d  P L T  
 C y cl e  5,  d a y  8 ( ± 3  d a ys)  
•   Vit al si g ns   
o   Bl o o d  pr ess ur e ( B P) 
o   H e art r at e ( H R)  
o   R es pir at or y r at e ( R R)  
o   Or al t e m p er at ur e (t e m p)  
•   C o m pl et e  bl o o d  c o u nt ( C B C) 
o   diff  a n d  P L T 
 C y cl e  6,  d a y  8 ( ± 3  d a ys)  
•   Vit al si g ns   
o   Bl o o d  pr ess ur e ( B P) 
o   H e art r at e ( H R)  
o   R es pir at or y r a t e ( R R) 
o   Or al t e m p er at ur e (t e m p)  
•   C o m pl et e  bl o o d  c o u nt ( C B C) 
o   diff  a n d  P L T 
•   Uri n e  or s er u m  Pr e g n a n c y t est (f or  w o m e n  of  c hil d - b e ari n g  p ot e nti al  or 
W o C B P)  
•   C o m pr e h e nsi v e  m et a b oli c  p a n el ( C M P) 
 S u bs e q u e nt  C y cl es,  D a ys  1  a n d  8  ( as s p e cifi e d) 
•   C o m pl et e  p h ysi c al  e x a mi n ati o n t o i n cl u d e: 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  6 4  of  9 7  
 
o   E v al u ati o n  of t h e  pr es e n c e/ a bs e n c e  of  e nl ar g e d l y m p h  n o d es, 
h e p at o m e g al y  a n d s pl e n o m e g al y, 
o   H e a d,  e y e,  e ar,  n os e  a n d t hr o at, 
o   C ar di o v as c ul ar,  
o   M us c ul os k el et al,  
o   R es pir at or y,  
o   G astr oi nt esti n al,  a n d  
o   N e ur ol o gi c al s yst e ms  
•   E C O G  P erf or m a n c e  St at us ( E C O G  P S); s e e  als o  A p p e n di x  C 
•   W ei g ht ( wt)  
•   Vit al si g ns   
o   Bl o o d  pr ess ur e ( B P) 
o   H e art r at e ( H R)  
o   R es pir at or y r at e ( R R)  
o   Or al t e m p er at ur e (t e m p)  
•   C o m pl et e  bl o o d  c o u nt ( C B C)  
o   diff  a n d  P L T 
•   C o m pr e h e nsi v e  m et a b oli c  p a n el ( C M P) 
•   Uri n e  or s er u m  Pr e g n a n c y t est (f or   w o m e n  of  c hil d- b e ari n g  p ot e nti al  or 
W o C B P)  
•   I N R (f or  p ati e nts  o n  c o u m ari n  a nti c o a g ul a nts) 
 
 Off - T r e at m e nt  E v al u ati o ns ( E n d  of T r e at m e nt   o r E O T  visit)  
T h e f oll o wi n g  ass ess m e nts  m ust  b e  p erf or m e d  at t h e  E O T  visit  a n d s h o ul d  o c c ur  3 0-
d a ys ( ± 5  d a ys)  aft er t h e l ast  d os e  of st u d y tr e at m e nt.  
•   C o m pl et e  p h ysi c al  e x a mi n ati o n t o i n cl u d e:  
o   E v al u ati o n  of t h e  pr es e n c e/ a bs e n c e  of  e nl ar g e d l y m p h  n o d es, 
h e p at o m e g al y  a n d s pl e n o m e g al y, 
o   H e a d,  e y e,  e ar,  n os e  a n d t hr o at, 
o   C ar di o v as c ul ar,  
o   M us c ul os k el et al,  
o   R es pir at o r y, 
o   G astr oi nt esti n al,  a n d  
o   N e ur ol o gi c al s yst e ms  
•   E C O G  P erf or m a n c e  St at us ( E C O G  P S); s e e  als o  A p p e n di x  C  
•   W ei g ht ( wt)  
•   Vit al si g ns   
o   Bl o o d  pr ess ur e ( B P) 
o   H e art r at e ( H R)  
o   R es pir at or y r at e ( R R)  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  6 5  of  9 7  
 
o   Or al t e m p er at ur e (t e m p)  
•   C o m pl et e  bl o o d  c o u nt ( C B C)  
o   diff  a n d  P L T 
•   C o m pr e h e nsi v e  m et a b oli c  p a n el ( C M P) 
•   I N R (f or  p ati e nts  o n  c o u m ari n  a nti c o a g ul a nts) 
 F oll o w- u p  E v al u ati o ns   
Aft er tr e at m e nt  c o m pl eti o n t h e f oll o wi n g  ass ess m e nts s h o ul d  b e  p erf or m e d  as 
i n di c at e d.   
P ati e nts (r e g ar dl ess  of r e as o n f or tr e at m e nt  dis c o nti n u ati o n)  will t h e n  b e f oll o w e d f or 
s ur vi v al  e v er y  1 2  w e e ks ( ± 2  w e e ks)  f or  at l e ast  3  y e ars,  u ntil  d e at h, l ost t o f oll o w- u p, 
wit h dr a w al  of  c o ns e nt *,  or st u d y t er mi n ati o n  b y t h e  Pri n ci p al I n v esti g at or.   A t el e p h o n e 
c all t o t h e  p ati e nt  a n d/ or t h e  p ati e nt’s f a mil y  m a y  b e  m a d e t o  e v al u at e t h e  p ati e nt’s 
st at us  o n t h e f oll o wi n g: 
•  
P ost- st u d y  a nti c a n c er t h er a p y st at us  
•  
S ur vi v al st at us 
    
P ati e nts  w h o  dis c o nti n u e st u d y tr e at m e nt f or r e as o ns  ot h er t h a n  dis e as e  pr o gr essi o n  will 
c o nti n u e t o  u n d er g o t u m or  ass ess m e nts  a p pr o xi m at el y  e v er y  6  w e e ks ( ± 7  d a ys) fr o m 
t h e  d at e  of  e nr oll m e nt f or t h e first  y e ar (first  1 2  m o nt hs  aft er  E n d  of  Tr e at m e nt), t h e n 
e v er y  1 2  w e e ks ( ± 7  d a ys) t h er e aft er  f or  at l e ast  3  y e ars,  u ntil I n v esti g at or-ass ess e d 
dis e as e  pr o gr essi o n,  d e at h, l ost t o f oll o w- u p,  or  wit h dr a w al  of  c o ns e nt *.  O n c e  p ati e nt 
m e ets  all  eli gi bilit y  crit eri a, t h e  d at e  of first  d os e is  c o nsi d er e d t h e  e nr oll m e nt  d at e.    
* N ot e:  S o m e  p ati e nts  m a y  wit h dr a w t h eir  c o ns e nt fr o m st u d y  tr e at m e nt b ut still  a gr e e 
t o  p arti ci p at e i n s ur vi v al f oll o w- u p.   F or t h es e  p ati e nts s ur vi v al f oll o w- u p s h all  o c c ur 
e v er y  1 2  w e e ks ( ± 7  d a ys)  u ntil  d e at h, l ost t o f oll o w- u p  or  wit h dr a w al fr o m st u d y.   
A t el e p h o n e  c all t o t h e  p ati e nt  a n d/ or t h e  p ati e nt’s f a mil y  m a y  al s o  b e  m a d e t o  e v al u at e 
t h e  p ati e nt’s st at us  o n t h e f oll o wi n g: 
•  
P ost- st u d y  a nti c a n c er t h er a p y st at us  
•  
S ur vi v al st at us 








C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  6 9  of  9 7  
 
M ali g n a nt l y m p h  n o d es.   T o  b e  c o nsi d er e d  p at h ol o gi c all y  e nl ar g e d  a n d 
m e as ur a bl e,  a l y m p h  n o d e  m ust  b e  > 1 5  m m i n s h ort  a xis  w h e n  ass ess e d  b y  C T 
s c a n ( C T s c a n sli c e t hi c k n ess r e c o m m e n d e d t o  b e  n o  gr e at er t h a n  5  m m).   At 
b as eli n e  a n d i n f oll o w- u p,  o nl y t h e s h ort  a xis  will  b e  m e as ur e d  a n d f oll o w e d. 
N o n -m e as ur a bl e  dis e as e .   All ot h er l esi o ns ( or sit es  of  dis e as e), i n cl u di n g s m all 
l esi o ns (l o n g est  di a m et er  < 1 0  m m  or  p at h ol o gi c al l y m p h  n o d es  wit h  ≥  1 0 t o  < 1 5 
m m s h ort  a xis),  ar e  c o nsi d er e d  n o n- m e as ur a bl e  dis e as e.   B o n e l esi o ns, 
l e pt o m e ni n g e al  dis e as e,  as cit es,  pl e ur al/ p eri c ar di al  eff usi o ns, l y m p h a n gitis 
c utis/ p ul m o nitis, i nfl a m m at or y  br e ast  dis e as e,  a n d  a b d o mi n al  m ass es ( n ot 
f oll o w e d  b y  C T  or  M RI),  ar e  c o nsi d er e d  as  n o n-m e as ur a bl e.  
N ot e:   C ysti c l esi o ns t h at  m e et t h e  crit eri a f or r a di o gr a p hi c all y  d efi n e d si m pl e 
c ysts s h o ul d  n ot  b e  c o nsi d er e d  as  m ali g n a nt l esi o ns ( n eit h er  m e as ur a bl e  n or  n o n-
m e as ur a bl e) si n c e t h e y  ar e,  b y  d efi niti o n, si m pl e  c ysts.  
‘ C ysti c l esi o ns’ t h o u g ht t o r e pr es e nt  c ysti c  m et ast as es  c a n  b e  c o nsi d er e d  as 
m e as ur a bl e l esi o ns, if t h e y  m e et t h e  d efi niti o n  of  m e as ur a bilit y  d es cri b e d  a b o v e. 
H o w e v er, if  n o n- c ysti c l esi o ns  ar e  pr es e nt i n t h e s a m e  p ati e nt, t h es e  ar e  pr ef err e d 
f or s el e cti o n  as t ar g et l esi o ns. 
T ar g et l esi o ns.    All  m e as ur a bl e l esi o ns  u p t o  a  m a xi m u m  of  2 l esi o ns  p er  or g a n 
a n d  5 l esi o ns i n t ot al, r e pr es e nt ati v e  of  all i n v ol v e d  or g a ns, s h o ul d  b e i d e ntifi e d 
as  t a r g et l esi o ns  a n d r e c or d e d  a n d  m e as ur e d  at  b as eli n e.   T ar g et l esi o ns s h o ul d 
b e s el e ct e d  o n t h e  b asis  of t h eir si z e (l esi o ns  wit h t h e l o n g est  di a m et er),  b e 
r e pr es e nt ati v e  of  all i n v ol v e d  or g a ns,  b ut i n  a d diti o n s h o ul d  b e t h os e t h at l e n d 
t h e ms el v es t o r e pr o d u ci bl e r e p e at e d  m e as ur e m e nts.  It  m a y  b e t h e  c as e t h at,  o n 
o c c asi o n, t h e l ar g est l esi o n  d o es  n ot l e n d its elf t o r e pr o d u ci bl e  m e as ur e m e nt i n 
w hi c h  cir c u mst a n c e t h e  n e xt l ar g est l esi o n  w hi c h  c a n  b e  m e as ur e d r e pr o d u ci bl y 
s h o ul d  b e s el e ct e d.   A s u m  of t h e  di a m et ers (l o n g est f or  n o n- n o d al l esi o ns, s h ort 
a xis f or  n o d al l esi o ns) f or  all t ar g et l esi o ns  will  b e  c al c ul at e d  a n d r e p ort e d  as t h e 
b as eli n e s u m  di a m et ers.  If l y m p h  n o d es  ar e t o  b e i n cl u d e d i n t h e s u m, t h e n  o nl y 
t h e s h ort  a xis is  a d d e d i nt o t h e s u m.   T h e  b as eli n e s u m  di a m et ers  will  b e  us e d  as 
r ef er e n c e t o f urt h er  c h ar a ct eri z e  a n y  o bj e cti v e t u m or r e gr essi o n i n t h e 
m e as ur a bl e  di m e nsi o n  of t h e  dis e as e.  
N o n -t ar g et l esi o ns.   All  ot h er l esi o ns ( or sit es  of  dis e as e) i ncl u di n g  a n y 
m e as ur a bl e l esi o ns  o v er  a n d  a b o v e t h e  5 t ar g et l esi o ns s h o ul d  b e i d e ntifi e d  as 
n o n- t a r g et l esi o ns a n d s h o ul d  als o  b e r e c or d e d  at  b as eli n e.   M e as ur e m e nts  of 
t h es e l esi o ns  ar e  n ot r e q uir e d,  b ut t h e  pr es e n c e,  a bs e n c e,  or i n r ar e  c as es 
u n e q ui v o c al  pr o gr essi o n  of  e a c h s h o ul d  b e  n ot e d t hr o u g h o ut f oll o w- u p. 
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  7 0  of  9 7  
 
 M et h o ds f or  E v al u ati o n  of  M e as ur a bl e  Dis e as e 
All  m e as ur e m e nts s h o ul d  b e t a k e n  a n d r e c or d e d i n  m etri c  n ot ati o n  usi n g  a r ul er 
or  c ali p ers.   All  b as eli n e  e v al u ati o ns s h o ul d  b e  p erf or m e d  as  cl os el y  as  p ossi bl e 
t o t h e  b e gi n ni n g  of tr e at m e nt  a n d  n e v er  m or e t h a n  4  w e e ks  b ef or e t h e  b e gi n ni n g 
of t h e tr e at m e nt.  
T h e s a m e  m et h o d  of  ass ess m e nt  a n d t h e s a m e t e c h ni q u e s h o ul d  b e  us e d t o 
c h ar a ct eri z e  e a c h i d e ntifi e d  a n d r e p ort e d l esi o n  at  b as eli n e  a n d  d uri n g  f oll o w- u p. 
I m a gi n g-b as e d  e v al u ati o n is  pr ef err e d t o  e v al u ati o n  b y  cli ni c al  e x a mi n ati o n 
u nl ess t h e l esi o n(s)  b ei n g f oll o w e d  c a n n ot  b e i m a g e d  b ut  ar e  ass ess a bl e  b y 
cli ni c al  e x a m.  
 
Cli ni c al l esi o ns   Cli ni c al l esi o ns  will  o nl y  b e  c o nsi d er e d  m e as ur a bl e  w h e n t h e y 
ar e s u p erfi ci al ( e. g., s ki n  n o d ul es  a n d  p al p a bl e l y m p h  n o d es)  a n d  ≥ 1 0  m m 
di a m et er  as  ass ess e d  usi n g  c ali p ers ( e. g., s ki n  n o d ul es).  I n t h e  c as e  of s ki n 
l esi o ns,  d o c u m e nt ati o n  b y  c ol or  p h ot o gr a p h y, i n cl u di n g  a r ul er t o  esti m at e t h e 
si z e  of t h e l esi o n, is r e c o m m e n d e d.  
 
C h est  x -r a y  L esi o ns  o n  c h est  x- r a y  ar e  a c c e pt a bl e  as  m e as ur a bl e l esi o ns  w h e n 
t h e y  ar e  cl e arl y  d efi n e d  a n d s urr o u n d e d  b y  a er at e d l u n g.   H o w e v er,  C T is 
pr ef er a bl e.   
 
C o n v e nti o n al  C T  a n d  M RI   T his  g ui d eli n e  h as  d efi n e d  m e as ur a bilit y  of l esi o ns 
o n  C T s c a n  b as e d  o n t h e  ass u m pti o n t h at  C T sli c e t hi c k n ess is  5  m m  or l ess.  If 
C T s c a ns  h a v e sli c e t hi c k n ess  gr e at er t h a n  5  m m, t h e  mi ni m u m si z e f or  a 
m e as ur a bl e l esi o n s h o ul d  b e t wi c e t h e sli c e t hi c k n ess.   M RI is  als o  a c c e pt a bl e i n 
c ert ai n sit u ati o ns ( e . g. f or  b o d y s c a ns).  
 
Us e  of  M RI r e m ai ns  a  c o m pl e x iss u e.   M RI  h as  e x c ell e nt  c o ntr ast, s p ati al,  a n d 
t e m p or al r es ol uti o n;  h o w e v er, t h er e  ar e  m a n y i m a g e  a c q uisiti o n  v ari a bl es 
i n v ol v e d i n  M RI,  w hi c h  gr e atl y i m p a ct i m a g e  q u alit y, l esi o n  c o ns pi c uit y,  a n d 
m e as ur e m e nt.   F urt h er m or e, t h e  a v ail a bilit y  of  M RI is  v ari a bl e  gl o b all y.   As  wit h 
C T, if  a n  M RI is  p erf or m e d, t h e t e c h ni c al s p e cifi c ati o ns  of t h e s c a n ni n g 
s e q u e n c es  us e d s h o ul d  b e  o pti mi z e d f or t h e  e v al u ati o n  of t h e t y p e  a n d sit e  of 
dis e as e.   F urt h er m or e,  as  wit h  C T, t h e  m o d alit y  us e d  at f oll o w- u p s h o ul d  b e t h e 
s a m e  as  w as  us e d  at  b as eli n e  a n d t h e l esi o ns s h o ul d  b e  m e as ur e d/ ass ess e d  o n t h e 
s a m e  p uls e s e q u e n c e.  It is  b e y o n d t h e s c o p e  of t h e  R E CI S T  g ui d eli n es t o 
pr es cri b e s p e cifi c  M RI  p uls e s e q u e n c e  p ar a m et e rs f or  all s c a n n ers,  b o d y  p arts, 
a n d  dis e as es.  I d e all y, t h e s a m e t y p e  of s c a n n er s h o ul d  b e  us e d  a n d t h e i m a g e 
a c q uisiti o n  pr ot o c ol s h o ul d  b e f oll o w e d  as  cl os el y  as  p ossi bl e t o  pri or s c a ns.  
B o d y s c a ns s h o ul d  b e  p erf or m e d  wit h  br e at h- h ol d s c a n ni n g t e c h ni q u es, if 
p ossi bl e. 
 
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  7 1  of  9 7  
 
Ultr as o u n d  is  n ot  us ef ul i n  ass ess m e nt  of l esi o n si z e  a n d s h o ul d  n ot  b e  us e d  as  a 
m et h o d  of  m e as ur e m e nt.   Ultr as o u n d  e x a mi n ati o ns  c a n n ot  b e r e pr o d u c e d i n t h eir 
e ntir et y f or i n d e p e n d e nt r e vi e w  at  a l at er  d at e  a n d,  b e c a us e t h e y  ar e  o p er a t or 
d e p e n d e nt, it  c a n n ot  b e  g u ar a nt e e d t h at t h e s a m e t e c h ni q u e  a n d  m e as ur e m e nts 
will  b e t a k e n fr o m  o n e  ass ess m e nt t o t h e  n e xt.  If  n e w l esi o ns  ar e i d e ntifi e d  b y 
ultr as o u n d i n t h e  c o urs e  of t h e st u d y,  c o nfir m ati o n  b y  C T  or  M RI is  a d vis e d.  If 
t h er e is  c o n c er n  a b o ut r a di ati o n  e x p os ur e  at  C T,  M RI  m a y  b e  us e d i nst e a d  of  C T 
i n s el e ct e d i nst a n c es. 
 
E n d os c o p y,  L a p ar os c o p y    T h e  utili z ati o n  of t h es e t e c h ni q u es f or  o bj e cti v e t u m or 
e v al u ati o n is  n ot  a d vis e d.   H o w e v er, s u c h t e c h ni q u es  m a y  b e  us ef ul t o  c o nfir m 
c o m pl et e  p at h ol o gi c al r es p o ns e  w h e n  bi o psi es  ar e  o bt ai n e d  or t o  d et er mi n e 
r el a ps e i n tri als  w h er e r e c urr e n c e f oll o wi n g  c o m pl et e r es p o ns e ( C R)  or s ur gi c al 
r es e cti o n is  a n  e n d p oi nt. 
T u m or  m ar k ers    T u m or  m ar k ers  al o n e  c a n n ot  b e  us e d t o  ass ess r es p o ns e.  If 
m ar k ers  ar e  i niti all y  a b o v e t h e  u p p er  n or m al li mit, t h e y  m ust  n or m ali z e f or  a 
p ati e nt t o  b e  c o nsi d er e d i n  c o m pl et e  cli ni c al r es p o ns e.   S p e cifi c  g ui d eli n es f or 
b ot h  C A- 1 2 5 r es p o ns e (i n r e c urr e nt  o v ari a n  c a n c er)  a n d  P S A r es p o ns e (i n 
r e c urr e nt  pr ost at e  c a n c er)  h a v e  b e e n  p u blis h e d [J N CI   9 6: 4 8 7- 4 8 8,  2 0 0 4; J  Cli n 
O n c ol   1 7,  3 4 6 1- 3 4 6 7,  1 9 9 9; J  Cli n  O n c ol   2 6: 1 1 4 8- 1 1 5 9,  2 0 0 8].  I n  a d diti o n, t h e 
G y n e c ol o gi c  C a n c er I nt er gr o u p  h as  d e v el o p e d  C A- 1 2 5  pr o gr essi o n  crit eri a 
w hi c h  ar e t o  b e i nt e gr at e d  wit h  o bj e cti v e t u m or  ass ess m e nt f or  us e i n first- li n e 
tri als i n  o v ari a n  c a n c er [J N CI   9 2: 1 5 3 4- 1 5 3 5,  2 0 0 0]. 
C yt ol o g y,  H ist ol o g y   T h es e t e c h ni q u es  c a n  b e  us e d t o  diff er e nti at e  b et w e e n 
p arti al r es p o ns es ( P R)  a n d  c o m pl et e r es p o ns es ( C R) i n r ar e  c as es ( e. g., r esi d u al 
l esi o ns i n t u m or t y p es, s u c h  as  g er m  c ell t u m ors,  w h er e  k n o w n r esi d u al  b e ni g n 
t u m ors  c a n r e m ai n).  
T h e  c yt ol o gi c al  c o nfir m ati o n  of t h e  n e o pl asti c  ori gi n  of  a n y  eff usi o n t h at  a p p e ars 
or  w ors e ns  d uri n g tr e at m e nt  w h e n t h e  m e as ur a bl e t u m or  h as  m et  crit eri a f or 
r es p o ns e  or st a bl e  dis e as e is  m a n d at or y t o  diff er e nti at e  b et w e e n r es p o ns e  or 
st a bl e  dis e as e ( a n  eff usi o n  m a y  b e  a si d e  eff e ct  of t h e tr e at m e nt)  a n d  pr o gr essi v e 
dis e as e.  
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  7 2  of  9 7  
 
 
 R es p o ns e  Crit eri a  –  E v al u ati o n  of  T ar g et  L esi o ns  
T a bl e  8 :  R es p o ns e  Crit eri a - T ar g et  L esi o ns  
C o m pl et e  R es p o ns e ( C R)   Dis a p p e ar a n c e  of  all t ar g et l esi o ns.   A n y 
p at h ol o gi c al l y m p h  n o d es ( w h et h er t ar g et  or  n o n-
t ar g et)  m ust  h a v e r e d u cti o n i n s h ort  a xis t o  < 1 0 
m m  
P arti al  R es p o ns e ( P R)   
At l e ast  a  3 0 %  d e cr e as e i n t h e s u m  of t h e 
di a m et ers  of t ar g et l esi o ns, t a ki n g  as r ef er e n c e t h e 
b as eli n e s u m  di a m et ers  
Pr o gr essi v e  Dis e as e ( P D)   At l e ast  a  2 0 % i n cr e as e i n t h e s u m  of t h e 
di a m et ers  of t ar g et l esi o ns, t a ki n g  as r ef er e n c e t h e 
s m all est s u m  o n st u d y (t his i n cl u d es t h e  b as eli n e 
s u m if t h at is t h e s m all est  o n st u d y).  I n  a d diti o n 
t o t h e r el ati v e i n cr e as e  of  2 0 %, t h e s u m  m ust als o 
d e m o nstr at e  a n  a bs ol ut e i n cr e as e  of  at l e ast  5 
m m.  ( N ot e:  t h e  a p p e ar a n c e  of  o n e  or  m or e  n e w 
l esi o ns is  als o  c o nsi d er e d  pr o gr essi o ns). 
St a bl e  Dis e as e ( S D)   
N eit h er s uffi ci e nt s hri n k a g e t o  q u alif y f or  P R  n or 
s uffi ci e nt i n cr e as e t o  q u alif y f or  P D, t a ki n g  as 
r ef er e n c e t h e s m all est s u m  di a m et ers  w hil e  o n 
st u d y 
 
 R es p o ns e  Crit eri a  –  E v al u ati o n  of  N o n- T ar g et  L esi o ns   
T a bl e  9 :  R es p o ns e  Crit eri a - N o n -T ar g et  L esi o ns  
C o m pl et e  R es p o ns e ( C R)  
Dis a p p e ar a n c e  of  all  n o n -t ar g et l esi o ns  a n d 
n or m ali z ati o n  of t u m or  m ar k er l e v el.   All l y m p h 
n o d es  m ust  b e  n o n- p at h ol o gi c al i n si z e ( < 1 0  m m 
s h ort  a xis) 
N ot e:  If t u m or  m ar k ers  ar e i niti all y  a b o v e t h e 
u p p er  n or m al li mit, t h e y  m ust  n or m ali z e f or  a 
p ati e nt t o  b e  c o nsi d er e d i n  c o m pl et e  cli ni c al 
r es p o ns e. 
N o n -C R/  N o n -P D   
P ersist e n c e  of  o n e  or  m or e  n o n -t ar g et l esi o n(s) 
a n d/ or  m ai nt e n a n c e  of t u m or  m ar k er l e v el  a b o v e 
t h e  n or m al li mits 
Pr o gr essi v e  Dis e as e ( P D)  
A p p e ar a n c e  of  o n e  or  m or e  n e w l esi o ns  a n d/ or 
u n e q ui v o c al  pr o gr essi o n   of  e xisti n g  n o n-t ar g et 
l esi o ns.  U n e q ui v o c al  pr o gr essi o n  s h o ul d  n ot 
n or m all y tr u m p t ar g et l esi o n st at us.  It  m ust  b e 
r e pr es e nt ati v e  of  o v er all  dis e as e st at us  c h a n g e, 
n ot  a si n gl e l esi o n i n cr e as e.      
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  7 3  of  9 7  
 
 E v al u ati o n  of  B est  O v er all  R es p o ns e 
T h e  b est  o v er all r es p o ns e is t h e  b est r es p o ns e r e c or d e d fr o m t h e st art  of t h e 
tr e at m e nt  u ntil  dis e as e  pr o gr essi o n/r e c urr e n c e (t a ki n g  as r ef er e n c e f or 
pr o gr essi v e  dis e as e t h e s m all est  m e as ur e m e nts r e c or d e d si n c e t h e tr e at m e nt 
st art e d).   T h e  p ati e nt's  b est r es p o ns e  assi g n m e nt  will  d e p e n d  o n t h e  a c hi e v e m e nt 
of  b ot h  m e as ur e m e nt  a n d  c o nfir m ati o n  crit eri a. 
F or  P ati e nts  wit h  M e as ur a bl e  Dis e as e (i. e.,  T ar g et  Dis e as e):  
T a bl e  1 0 :  B est  O v er all  R es p o ns e - M e as ur a bl e  Dis e as e  
T a r g et  L esi o ns   
N o n -T a r g et 
L esi o ns  
N e w 
L esi o ns  
O v e r all 
R es p o ns e  
B est  O v e r all  R es p o ns e 
w h e n  C o nfi r m ati o n is 
R e q ui r e d *  
C R  
C R   
N o   
C R   
> 4  w ks.  C o nfir m ati o n * *  
C R  
N o n -
C R/ N o n -P D  
N o  
P R  
 
> 4  w ks.  C o nfir m ati o n * *  
C R   
N ot  e v al u at e d   
N o   
P R  
P R  
N o n -
C R/ N o n -
P D/ n ot 
e v al u at e d  
N o  
P R  
S D  
N o n -
C R/ N o n -
P D/ n ot 
e v al u at e d  
N o  
S D   
d o c u m e nt e d  at l e ast  o n c e 
> 4  w ks. fr o m  b as eli n e * *  
P D  
A n y   
Y es  or  N o   
P D  
 
n o  pri or  S D,  P R  or  C R  
A n y  
P D * * *   
Y es  or  N o   
P D  
A n y  
A n y   
Y es   
P D  
*       S e e  R E CI S T  1. 1  m a n us cri pt f or f urt h er  d et ails  o n  w h at is  e vi d e n c e  of  a  n e w l esi o n.  
* *     O nl y f or  n o n -r a n d o mi z e d tri als  wit h r es p o ns e  as  pri m ar y  e n d p oi nt. 
* * *  I n  e x c e pti o n al  cir c u mst a n c es,  u n e q ui v o c al  pr o gr essi o n i n  n o n -t ar g et l esi o ns  m a y  b e  a c c e pt e d  as 
dis e as e  pr o gr essi o n.  
 
N ot e :  
P ati e nts  wit h  a  gl o b al  d et eri or ati o n  of  h e alt h st at us r e q uiri n g  dis c o nti n u ati o n  of  tr e at m e nt 
wit h o ut  o bj e cti v e  e vi d e n c e  of  dis e as e  pr o gr essi o n  at t h at ti m e s h o ul d  b e r e p ort e d  as 
“ s y m pt o m ati c  d et eri or ati o n. ”   E v er y  eff ort s h o ul d  b e  m a d e t o  d o c u m e nt t h e  o bj e cti v e 
pr o gr essi o n  e v e n  aft er  dis c o nti n u ati o n  of tr e at m e nt.  
 
F or  P ati e nts  wit h  N o n -M e as ur a bl e  Dis e as e (i. e.,  N o n -T ar g et  Dis e as e)  
T a bl e  1 1 :  B est  O v er all  R es p o ns e - N o n  M e as ur a bl e  Dis e as e  
N o n -T a r g et  L esi o ns   
N e w  L esi o ns  
O v e r all  R es p o ns e  
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 v al u at e d   
N o  
n ot  e v al u at e d  
U n e q ui v o c al  P D   
Y es  or  N o  
P D  
A n y  
Y es  
P D  
*  ‘ N o n -C R/ n o n -P D’ is  pr ef err e d  o v er ‘st a bl e  dis e as e’ f or  n o n -t ar g et  dis e as e  si n c e  S D is 
i n cr e asi n gl y  us e d  as  a n  e n d p oi nt f or  ass ess m e nt  of  effi c a c y i n s o m e tri als s o t o  assi g n t his 
c at e g or y  w h e n  n o  l esi o ns  c a n  b e  m e a s ur e d is  n ot  a d vis e d 
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  7 4  of  9 7  
 
 D ur ati o n  of  R es p o ns e 
D ur ati o n  of  o v er all r es p o ns e:   T h e  d ur ati o n  of  o v er all r es p o ns e is  m e as ur e d fr o m 
t h e ti m e  m e as ur e m e nt  crit eri a  ar e  m et f or  C R  or  P R ( w hi c h e v er is first r e c or d e d) 
u ntil t h e first  d at e t h at  r e c urr e nt  or  pr o gr essi v e  dis e as e is  o bj e cti v el y  d o c u m e nt e d 
(t a ki n g  as r ef er e n c e f or  pr o gr essi v e  dis e as e t h e s m all est  m e as ur e m e nts r e c or d e d 
si n c e t h e tr e at m e nt st art e d).  
T h e  d ur ati o n  of  o v er all  C R is  m e as ur e d fr o m t h e ti m e  m e as ur e m e nt  crit eri a  ar e 
first  m et f or  C R  u ntil t h e first  d at e t h at  pr o gr essi v e  dis e as e is  o bj e cti v el y 
d o c u m e nt e d.   
D ur ati o n  of st a bl e  dis e as e :   St a bl e  dis e as e is  m e as ur e d fr o m t h e st art  of t h e 
tr e at m e nt  u ntil t h e  crit eri a f or  pr o gr essi o n  ar e  m et, t a ki n g  as r ef er e n c e t h e 
s m all est  m e as ur e m ents r e c or d e d si n c e t h e tr e at m e nt st art e d, i n cl u di n g t h e 
b as eli n e  m e as ur e m e nts.  
 Pr o gr essi o n- Fr e e  S ur vi v al ( P F S)  
P F S is  d efi n e d  as t h e  d ur ati o n  of ti m e fr o m st art  of tr e at m e nt t o ti m e  of 
pr o gr essi o n  or  d e at h,  w hi c h e v er  o c c urs first.  
 Ot h er  R es p o ns e  P ar a m et ers  
F or  ot h er r es p o ns e  p ar a m et ers, r ef er t o  S e cti o n  1 5. 0 f or  d et ails.  
 
 A D V E R S E  E V E N T S  
S af et y  ass ess m e nts  will  c o nsist  of  m o nit ori n g  a n d r e c or di n g  pr ot o c ol- d efi n e d  a d v ers e  e v e nts 
( A Es)  a n d s eri o us  a d v ers e  e v e nts ( S A Es) t h at  ar e  c o nsi d er e d r el at e d t o tr ast u z u m a b 
e mt a nsi n e  a n d  vi n or el bi n e,  all  e v e nts  of  d e at h,  a n d  a n y st u d y s p e cifi c iss u e  of  c o n c er n. 
T h es e  will i n cl u d e  b ut  n ot  b e li mit e d t o:  m e as ur e m e nt  of  pr ot o c ol -s p e cifi e d  h e m at ol o g y, 
cli ni c al  c h e mistr y,  a n d  uri n al ysis  v ari a bl es;  m e as ur e m e nt  of  pr ot o c ol- s p e cifi e d  vit al si g ns; 
a n d  ot h er  pr ot o c ol- s p e cifi e d t ests t h at  ar e  d e e m e d  criti c al t o t h e s af et y  e v al u ati o n  of 
tr ast u z u m a b  e mt a nsi n e  w h e n  gi v e n i n  c o m bi n ati o n  wit h  vi n or el bi n e. 
 P u r p os e  
A d v ers e  e v e nt  d at a  c oll e cti o n  a n d r e p orti n g,  w hi c h  ar e r e q uir e d  as  p art  of  e v er y  cli ni c al 
tri al,  ar e  d o n e t o  e ns ur e t h e s af et y  of  p ati e nts  e nr oll e d i n t h e st u di es,  as  w ell  as t h os e 
w h o  will  e nr oll i n f ut ur e st u di es  usi n g si mil ar  a g e nts.   A d v ers e  e v e nts  ar e r e p ort e d i n  a 
r o uti n e  m a n n er  at s c h e d ul e d ti m es  d uri n g  a tri al.   A dditi o n all y,  c ert ai n  a d v ers e  e v e nts 
m ust  b e r e p ort e d i n  a n  e x p e dit e d  m a n n er f or ti m eli er  m o nit ori n g  of  p ati e nt s af et y  a n d 
c ar e.   
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  7 5  of  9 7  
 
 A d v e rs e  E v e nt  
A d v ers e  E v e nt ( A E):  C a n  b e  a n y  u nf a v or a bl e  a n d  u ni nt e n d e d si g n ( e. g.,  a n  a b n or m al 
l a b or at or y fi n di n g), s y m pt o m,  or  dis e as e t e m p or all y  ass o ci at e d  wit h t h e  us e  of  a  dr u g, 
m e di c al tr e at m e nt,  or  pr o c e d ur e  wit h o ut j u d g m e nt  a b o ut  c a us alit y.   A n  a d v ers e  e v e nt 
c a n   aris e fr o m  a n y  us e  a n d fr o m  a n y r o ut e  of  a d mi nistr ati o n, f or m ul ati o n,  or  d os e 
i n cl u di n g  a n  o v er d os e.  T his i n cl u d es  a n y  n e wl y  o c c urri n g  e v e nt  or  a  pr e vi o us  c o n diti o n 
t h at  h as i n cr e as e d i n s e v erit y  or fr e q u e n c y si n c e i niti ati o n  of  a  dr u g,  m e di c al tr e at m e nt, 
or  pr o c e d ur e.  
A b n or m al  Fi n di n gs 
I n  a n y  cli ni c al  ass ess m e nt,  a  v al u e  o utsi d e t h e  n or m al  or r ef er e n c e r a n g e (s u c h  as  a 
cli ni c al l a b or at or y,  vit al si g n,  or  E C G)  will  n ot  b e r e p ort e d  or  ass ess e d  as  a n  A E  u nl ess 
t h at  v al u e is  c o nsi d er e d t o  b e  of  cli ni c al si g nifi c a n c e  b y t h e i n v esti g at or.   A  v al u e  of 
cli ni c al si g nifi c a n c e is  o n e t h at l e a ds t o  dis c o nti n u ati o n  or  d el a y i n  pr ot o c ol tr e at m e nt, 
d os e  m o difi c ati o n, t h er a p e uti c i nt er v e nti o n *,  or is  c o nsi d er e d t o  b e  a  cli ni c all y 
si g nifi c a nt  n e w fi n di n g  or  c h a n g e fr o m  b as eli n e  b y t h e i n v esti g at or.  
* Tr a nsf usi o n s u p p ort  a d mi nist er e d t o  offs et  cli ni c al s y m pt o ms  of  a n e mi a  or 
t hr o m b o c yt o p e ni a  will  n ot  b e  c o nsi d er e d t h er a p e uti c i nt er v e nti o n. 
Si g ns  a n d  S y m pt o ms 
Si g ns/s y m pt o ms r es ulti n g fr o m  a n  u n d erl yi n g  cli ni c al  di a g n osis s h o u l d  b e  d o c u m e nt e d 
as  o n e  c o m pr e h e nsi v e  A E.  If  n o  u n d erl yi n g  cli ni c al  di a g n osis  c a n  b e i d e ntifi e d,  e a c h 
si g n/s y m pt o m s h o ul d  b e r e p ort e d  as  a s e p ar at e i n d e p e n d e nt  e v e nt.  ( A  n e w  or 
w ors e ni n g  e v e nt r es ulti n g fr o m  a n  u n d erl yi n g  cli ni c al  di a g n osis  or  a r e a cti o n t o 
c o n c urr e nt  m e di c ati o ns s h o ul d  b e  d o c u m e nt e d  as  a s e p ar at e i n d e p e n d e nt  A E  u nl ess it is 
wit hi n t h e  n or m al r a n g e  of fl u ct u ati o n f or t h at  p ati e nt.)    
Gr a d e  C h a n g es/ Fl u ct u ati o ns 
A Es  will  b e r e p ort e d  at t h e  m a xi m u m  gr a d e/s e v erit y  e x p eri e n c e d f or t h e  d ur ati o n   of t h e 
e v e nt.    S h o ul d  o n e  p arti c ul ar  e v e nt  w arr a nt f urt h er i n v esti g ati o n,  a d diti o n al  d et ails  m a y 
b e  c oll e ct e d  at t h e  dis cr eti o n  of t h e  Pri n ci p al I n v esti g at or.    
Pr o gr essi o n  of  Dis e as e 
Pr o gr essi o n  of  dis e as e, if  d o c u m e nt e d i n  a c c or d a n c e t o st a n d ar d  of  c ar e, s h o ul d  n ot  b e 
r e p ort e d  as  a n  A E. 
T ests  a n d  Pr o c e d ur es  
T ests  a n d  pr o c e d ur es s h o ul d  n ot  b e r e p ort e d  as  A Es.   T h e  u n d erl yi n g  cli ni c al  di a g n osis 
( or si g n/s y m pt o m i n t h e  e v e nt  a n  u n d erl yi n g  cli ni c al  di a g n osis is  n ot  k n o w n) r e q uiri n g 
t esti n g  or  a  pr o c e d ur e, s h o ul d  b e r e p ort e d  as  a n  a d v ers e  e v e nt if it  m e ets  crit eri a f or 
r e p orti n g. 
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  7 6  of  9 7  
 
 
 S e ri o us  A d v e rs e  E v e nts  (s e e  als o  A p p e n di x  A) 
S eri o us  A E ( S A E)  m e a ns  a n y  u nt o w ar d  m e di c al  o c c urr e n c e t h at  o c c urs  at  a n y  d os e:  
1.   R es ults i n  d e at h.  
2.   Is lif e-t h r e at e ni n g.  
T h e t er m  "lif e -t hr e at e ni n g " i n t h e  d efi niti o n  of  "s eri o us " r ef ers t o  a n  e v e nt i n  w hi c h 
t h e  p ati e nt  w as  at ris k  of  d e at h  at t h e ti m e  of t h e  e v e nt; it  d o es  n ot r ef er t o  a n  e v e nt 
w hi c h  h y p ot h eti c all y  mi g ht  h a v e  c a us e d  d e at h if it  w er e  m or e s e v er e).  
3.   R e q ui r es i n p ati e nt  h os pit ali z ati o n  o r  p r ol o n g ati o n  of  p r es e nt  h os pit ali z ati o n.  
El e cti v e  h os pit ali z ati o n t o si m plif y  pr ot o c ol tr e at m e nt/ e v al u ati o ns  or t o tr e at  a 
b as eli n e  c o n diti o n t h at  di d  n ot  w ors e n fr o m  b as eli n e  will  n ot  b e  c o nsi d er e d  a n  S A E.    
4.   R es ults i n  p e rsist e nt  o r s i g nifi c a nt  dis a bilit y/i n c a p a cit y.  
Dis a bilit y is  d efi n e d  as  a s u bst a nti al  disr u pti o n  of  a  p ers o n’s  a bilit y t o  c o n d u ct 
n or m al lif e f u n cti o ns. 
5.   Is  a  c o n g e nit al  a n o m al y/ bi rt h  d ef e ct .  
6.   Is  a m e di c all y i m p o rt a nt  e v e nt.  
A  m e di c all y i m p ort a nt  e v e nt  m a y  n ot  b e i m m e di at el y lif e t hr e at e ni n g  or r es ult i n 
d e at h  or  h os pit ali z ati o n  b ut  m a y j e o p ar di z e t h e  p ati e nt  or  m a y r e q uir e i nt er v e nti o n 
t o  pr e v e nt  o n e  of t h e  ot h er  o ut c o m es list e d i n t h e  d efi niti o n  a b o v e,  or i n v ol v es 
s us p e ct e d tr a ns missi o n  vi a  a  m e di ci n al  pr o d u ct  of  a n i nf e cti o us  a g e nt.    E x a m pl es 
of s u c h  m e di c al  e v e nts i n cl u d e  all er gi c  br o n c h os p as m r e q uiri n g i nt e nsi v e tr e at m e nt 
i n  a n  e m er g e n c y r o o m  or  at  h o m e,  bl o o d  d ys cr asi as  or  c o n v ulsi o ns t h at  d o  n ot r es ult 
i n i n p ati e nt  h os pit ali z ati o n,  or t h e  d e v el o p m e nt  of  dr u g  d e p e n d e n c y  or  dr u g  a b us e; 
a n y  or g a nis m,  vir us,  or i nf e cti o us  p arti cl e ( e. g.,  pri o n  pr ot ei n tr a ns mitti n g 
Tr a ns missi bl e  S p o n gif or m  E n c e p h al o p at h y),  p at h o g e ni c  or  n o n p at h o g e ni c, is 
c o nsi d er e d  a n i nf e cti o us  a g e nt.   
Cl arifi c ati o n s h o ul d  b e  m a d e  b et w e e n t h e t er ms  s eri o us  a n d s e v er e b e c a us e t h e y  A R E 
N O T s y n o n y m o us.   T h e t er m  s e v er e is  oft e n  us e d t o  d es cri b e t h e i nt e nsit y (s e v erit y)  of 
a s p e cifi c  e v e nt ( as i n  mil d,  m o d er at e,  or s e v er e  m y o c ar di al i nf ar cti o n); t h e  e v e nt its elf, 
h o w e v er,  m a y  b e  of r el ati v el y  mi n or  m e di c al si g nifi c a n c e (s u c h  as  a s e v er e  h e a d a c h e).  
T his is  N O T t h e s a m e  a s s eri o us,  w hi c h is  b as e d  o n  p ati e nt/ e v e nt  o ut c o m e  or  a cti o n 
crit eri a  d es cri b e d  a b o v e  a n d is  us u all y  ass o ci at e d  wit h  e v e nts t h at  p os e  a t hr e at t o  a 
p ati e nt’s lif e  or f u n cti o ni n g.   A s e v er e  A E  d o es  n ot  n e c ess aril y  n e e d t o  b e  c o nsi d er e d 
s eri o us.   F or  e x a m pl e,  p ersist e nt  n a us e a  of s e v er al  h o urs  d ur ati o n  m a y  b e  c o nsi d er e d 
s e v er e  n a us e a  b ut  n ot  a n  S A E.   O n t h e  ot h er  h a n d,  a str o k e r es ulti n g i n  o nl y  a  mi n or 
d e gr e e  of  dis a bilit y  m a y  b e  c o nsi d er e d  mil d  b ut  w o ul d  b e  d efi n e d  as  a n  S A E  b as e d  o n 
t h e  a b o v e  n ot e d  crit eri a.   S eri o us n ess ( n ot s e v erit y) s er v es  as  a  g ui d e f or  d efi ni n g 
r e g ul at or y r e p orti n g  o bli g ati o ns.   


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  7 7  of  9 7  
 
 A d v e rs e  E v e nt  C oll e cti o n  P e ri o d  
All  a d v ers e  e v e nts t h at  o c c ur  aft er i nf or m e d  c o ns e nt is  o bt ai n e d  a n d  wit hi n  ≤  3 0  d a ys  of 
t h e l ast  d os e  of st u d y t h er a p y (or st u d y  dis c o nti n u ati o n/t er mi n ati o n,  w hi c h e v er is 
e arli er ),  will  b e r e p ort e d  a n d f oll o w e d  u ntil r es ol uti o n.   R es ol uti o n is  d efi n e d  as  a r et ur n 
t o  b as eli n e st at us  or t h e st a bili z ati o n  of  a n  e v e nt  wit h t h e  e x p e ct ati o n t h at it  will r e m ai n 
c hr o ni c.   Aft er t his  p er i o d, i n v esti g at ors s h o ul d  o nl y r e p ort  S A Es t h at  ar e  attri b ut e d t o 
pri or st u d y tr e at m e nt.   
 A d v e rs e  E v e nt  R e p o rti n g  R e q ui r e m e nts  
T h e i nf or m ati o n t o  b e r e p ort e d i n  A Es  will  b e  ass ess e d  b y  a n d  assi g n e d s e v erit y  usi n g 
t h e  N ati o n al  C a n c er I nstit ut e  C o m m o n  T er mi nol o g y  Crit eri a f or  A d v ers e  E v e nts ( N CI 
C T C A E),  V ersi o n  4. 0 3.    T h e  N CI  C T C A E  pr o vi d es  d es cri pti v e t er mi n ol o g y  a n d  a 
gr a di n g s c al e f or  e a c h  a d v ers e  e v e nt list e d.   A  c o p y  of t h e  N CI  C T C A E  v 4. 0 3  c a n  b e 
d o w nl o a d e d fr o m t h e  C T E P  h o m e  p a g e 
(htt p:// e vs. n ci. ni h. g o v/ft p 1/ C T C A E/ A b o ut. ht ml ).    
I nf or m ati o n t o  b e r e p ort e d i n t h e  d es cri pti o n  of  e a c h  a d v ers e  e v e nt  m a y  b e i n cl u d e d, 
b ut is  n ot li mit e d t o:  
1.   Cli ni c al  Di a g n osis  of t h e  e v e nt  as  d et e r mi n e d  b y  N CI  C T C A E,  V ersi o n  4. 0 3 
d es cri pti v e t er mi n ol o g y.  If  n o  cli ni c al   di a g n osis  c a n  b e i d e ntifi e d,  e a c h 
si g n/s y m pt o m s h o ul d  b e r e p ort e d  as  a s e p ar at e i n d e p e n d e nt  e v e nt. 
2.   D at e  of  o ns et  of t h e  A E (st art  d at e).  
3.   D at e  of r es ol uti o n  of t h e  A E ( e n d  d at e).  
4.   S e v erit y  of t h e  e v e nt  d et er mi n e d  b y  N CI  C T C A E,  V ersi o n  4. 0  gr a di n g s c al e.     
5.   R el ati o ns hi p  of t h e  A E t o st u d y t h er a p y.   C at e g ori z e d  as f oll o ws: 
D efi nit e   
T h e  a d v ers e  e v e nt is  cl e arl y r el at e d  t o t h e i n v esti g ati o n al  a g e nt(s) 
Pr o b a bl e   
T h e  a d v ers e  e v e nt is  li k el y r el at e d t o t h e i n v esti g ati o n al  a g e nt(s) 
P ossi bl e   
T h e  a d v ers e  e v e nt  m a y  b e r el at e d  t o t h e i n v esti g ati o n al  a g e nt(s) 
U nli k el y   
T h e  a d v ers e  e v e nt is  d o u btf ull y r el at e d  t o t h e i n v esti g ati o n al  a g e nt(s) 
U nr el at e d   T h e  a d v ers e  e v e nt is  cl e arl y  n ot r el at e d  t o t h e i n v esti g ati o n al  a g e nt(s) 
6.   W h et h er  or  n ot t h e  A E is  S eri o us  or  N ot  S eri o us  as  d efi n e d i n  S e cti o n  1 4 . 3  S eri o us 
A d v ers e  E v e nts.  
 
 
 
 
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  7 8  of  9 7  
 
7.   W h et h er t h e  A E is  S us p e ct e d  a n d/ or  U n e x p e ct e d.  
S us p e ct e d  
A n y  A E f or  w hi c h t h er e is  a r e as o n a bl e  p ossi bilit y t h at t h e  dr u g  c a us e d 
t h e  A E.  F or t h e  p ur p os es  of  e x p e dit e d s af et y r e p orti n g, ‘r e as o n a bl e 
p ossi bilit y’  m e a ns t h er e is  e vi d e n c e t o s u g g est  a  c a us al r el ati o ns hi p 
b et w e e n t h e  dr u g  a n d t h e  A E. 
U n e x p e ct e d  
A n y  A E f or  w hi c h t h e  n at ur e  or s e v erit y  of t h e  e v e nt is  n ot  c o nsi st e nt 
wit h t h e  a p pli c a bl e  pr o d u ct i nf or m ati o n,  e. g., t h e I n v esti g at or’s 
Br o c h ur e  or  P a c k a g e I ns ert. 
8.   A cti o n t a k e n  as  a r es ult  of t h e  A E.   
9.   O ut c o m e.  
 A d diti o n al  G e n e r al  G ui d eli n es f o r  C o nsist e nt  C a us alit y  Ass ess m e nts  
T o  e ns ur e  c o nsist e n c y  of  A E  a n d  S A E  c a us alit y  ass ess m e nts, i n v esti g at ors s h o ul d 
a p pl y t h e f oll o wi n g  g e n er al  g ui d eli n e(s): 
Y es  
T h er e is  a  pl a usi bl e t e m p or al r el ati o ns hi p  b et w e e n t h e  o ns et  of t h e  S A E  or  A E  a n d 
a d mi nistr ati o n  of t h e tr ast u z u m a b  e mt a nsi n e,  a n d t h e  S A E  or  A E  c a n n ot  b e r e a dil y 
e x p l ai n e d  b y t h e s u bj e ct’s  cli ni c al st at e, i nt er c urr e nt ill n ess,  or  c o n c o mit a nt t h er a pi es; 
a n d/ or t h e  S A E  or  A E f oll o ws  a  k n o w n  p att er n  of r es p o ns e t o t h e tr ast u z u m a b 
e mt a nsi n e;  a n d/ or t h e  S A E  or  A E  a b at es  or r es ol v es  u p o n  dis c o nti n u ati o n  of t h e 
tr ast u z u m a b  e mt a nsi n e  or  d os e r e d u cti o n ( a p pli c a bl e t o  p h as e II  p orti o n  o nl y)  a n d, if 
a p pli c a bl e, r e a p p e ars  u p o n r e- c h all e n g e.  
N o  
E vi d e n c e  e xists t h at t h e  S A E  or  A E  h as  a n  eti ol o g y  ot h er t h a n t h e tr ast u z u m a b 
e mt a nsi n e ( e. g.,  pr e e xisti n g  m e di c al  c o n diti o n,  u n d erl yi n g  di s e as e, i nt er c urr e nt ill n ess, 
or  c o n c o mit a nt  m e di c ati o n);  a n d/ or t h e  S A E  or  A E  h as  n o  pl a usi bl e t e m p or al 
r el ati o ns hi p t o tr ast u z u m a b  e mt a nsi n e  a d mi nistr ati o n ( e. g.,  c a n c er  di a g n os e d  2  d a ys 
aft er first  d os e  of st u d y  dr u g).  
E x p e ct e d  a d v ers e  e v e nts  ar e t h os e  a d v ers e  e v e nts t h at  ar e list e d  or  c h ar a ct eri z e d i n t h e 
c urr e nt I n v esti g at or  Br o c h ur e, i n cl u d e d  at t h e  e n d  of t h e  c urr e nt  pr ot o c ol.  
U n e x p e ct e d   a d v ers e  e v e nts  ar e t h os e  n ot list e d i n t h e  c urr e nt I n v esti g at or  Br o c h ur e 
(I. B.)  or  n ot i d e ntifi e d.  T his i n cl u d es  a d v ers e  e v e nts f or  w hi c h t h e s p e cifi cit y  or 
s e v erit y is  n ot  c o nsist e nt  wit h t h e  d es cri pti o n i n t h e  P.I.  or I. B.  F or  e x a m pl e,  u n d er t his 
d efi niti o n,  h e p ati c  n e cr osis  w o ul d  b e  u n e x p e ct e d if t h e  P.I.  or I. B.  o nl y r ef err e d t o 
el e v at e d  h e p ati c  e n z y m es  or  h e p atit is. 
 E x p e dit e d  A d v e rs e  E v e nt  R e p o rti n g  R e q ui r e m e nts  
All  A Es, r e g ar dl ess if s eri o us  or  n ot,  will  b e  d es cri b e d i n t h e s o ur c e  d o c u m e nts, 
r e p ort e d  o n t h e  a p pli c a bl e  A E  p a g e  of t h e  C R Fs,  a n d  e nt er e d i nt o V el os .   H o w e v er, 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  7 9  of  9 7  
 
c ert ai n  a d v ers e  e v e nts  m ust  als o  b e r e p ort e d i n  a n  e x p e dit e d  m a n n er f or  m or e ti m el y 
m o nit ori n g  of  p ati e nt s af et y  a n d  c ar e.   A p p e n di x  A  pr o vi d es i nf or m ati o n  a b o ut  t h es e 
e x p e dit e d r e p orti n g  r e q uir e m e nts. 
 Alt e r n at e  D efi niti o ns  
T h e  alt er n at e  d efi ni ti o ns s h o w n  b el o w i n  T a bl e  1 2 s h o ul d  b e  us e d  O N L Y  w h e n t h e 
r e p ort e d  A E is  n ot i n t h e  a b o v e r ef er e n c e d  gr a di n g s c al e.   
T a bl e  1 2 :  A d v ers e  E v e nt  Gr a di n g ( S e v erit y)  S c al e 
G r a d e   S e v e rit y  
Alt e r n at e  D es c ri pti o n ( a) 
1 
Mil d ( a p pl y  e v e nt -s p e cifi c    
N CI  C T C A E  gr a di n g  crit eri a)  
 
As y m pt o m ati c  or  mil d s y m pt o ms;  cli ni c al  or  
di a g n osti c  o bs er v ati o ns  o nl y; i nt er v e nti o n 
n ot i n di c at e d  
2 
M o d er at e ( a p pl y  e v e nt -s p e cifi c 
N CI  C T C A E  gr a di n g  crit eri a)  
Mi ni m al, l o c al  or  n o ni n v asi v e  i nt er v e nti o n 
i n di c at e d; li miti n g  a g e- a p pr o pri at e 
i nstr u m e nt al  A D L( b) 
3 
S e v er e ( a p pl y  e v e nt -s p e cifi c 
N CI  C T C A E  gr a di n g  crit eri a)  
S e v er e  or  m e di c all y si g nifi c a nt  b ut  n ot 
i m m e di at el y lif e-t hr e at e ni n g;  h os pit ali z ati o n 
or  pr ol o n g ati o n  of  h os pit ali z ati o n i n di c a t e d; 
dis a bli n g; li miti n g s elf  c ar e  A D L ( c) 
4 
V er y s e v er e, lif e t hr e at e ni n g,  
or  dis a bli n g ( a p pl y  e v e nt-
s p e cifi c  N CI  C T C A E  gr a di n g 
crit eri a)  
Lif e -t hr e at e ni n g  c o ns e q u e n c es; 
ur g e nt i nt er v e nti o n i n di c at e d 
5   
D e at h r el at e d t o  A E  
 
K e y:  A D L  =  a cti viti es  of  d ail y  li vi n g;  A E  =  a d v ers e  e v e nt;  C T C A E  =  C o m m o n 
T er mi n ol o g y  Crit eri a f or  A d v ers e  E v e nts;  N CI  =  N ati o n al  C a n c er I nstit ut e.  
N ot e :  R e g ar dl ess  of s e v erit y, s o m e  e v e nts  m a y  als o  m e et r e g ul at or y s eri o us n ess 
crit eri a.   R ef er t o  t h e d efi niti o n  of  a s eri o us  A E (s e e  S e cti o n  1 4. 3 ) 
a  Us e t h es e  alt er n ati v e  d efi niti o ns f or  Gr a d e  1,  2,  3,  a n d  4  e v e nts  O N L Y  w h e n t h e 
o bs er v e d  or r e p ort e d  A E is  n ot i n t h e  N CI  C T C A E listi n g. 
b  I nstr u m e nt al  A D L r ef ers t o  pr e p ari n g  m e als, s h o p pi n g f or  gr o c eri es  or  cl ot h es,  usi n g 
t h e t el e p h o n e,  m a n a gi n g  m o n e y,  et c. 
c S elf - c ar e  A D L r ef er t o  b at hi n g,  dr essi n g  a n d  u n dr essi n g, f e e di n g s elf,  usi n g t h e 
t oil et, t a ki n g  m e di c ati o ns,  a n d  n ot  b e dri d d e n.   
 
 
 
 S T A TI S TI C A L  C O N SI D E R A TI O N S  
 P ati e nt  e n r oll m e nt  a n d f oll o w -u p  
B as e d  o n t h e  esti m at e d  n u m b er  of  p ot e nti all y  eli gi bl e  p ati e nts s e e n  at  U ni v ersit y  of 
Mi a mi,  e nr oll m e nt  p eri o d f or t his  p h as e I/II st u d y is  esti m at e d t o  b e  a b o ut  2  y e ars.  T h e 
e x p e ct e d  a c cr u al  p eri o d  f or t h e  p h as e I  c o m p o n e nt  of st u d y is  a b o ut  6  m o nt hs  a n d f or 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  8 0  of  9 7  
 
t h e  p h as e II  a b o ut  1. 5  y e ars.  T o  g at h er  d at a  o n  dis e as e r el a ps e/ pr o gr essi o n  a n d s ur vi v al, 
all  p ati e nts  will  b e  u n d er f oll o w  u p f or  a  mi ni m u m  of  3   y e ars,  u nl ess t h e y  wit h dr a w 
c o ns e nt  or  di e  wit hi n t h at ti m e.  T h us,  e x p e ct e d t ot al st u d y  d ur ati o n is  4. 5 t o  5  y e ars. 
I n  g e n er al,  p ati e nt  e nr oll m e nt  d uri n g  p h as e I  will  b e s p a c e d  at l e ast  3 w e e ks  a p art t o 
all o w f or  e v al u ati o n  of  D L T.  Si m ult a n e o us  e nr oll m e nt is  o nl y  p er mitt e d if t h e first 
p ati e nt t o r e c ei v e  a  d os e l e v el  d o es  n ot  e x p eri e n c e  D L T  wit hi n  2  c y cl es,  p ati e nts  2  a n d 
3  m a y  b e  e nr oll e d si m ult a n e o usl y  at t h e s a m e  d os e l e v el.  
 A n al ysis s ets  
All st u d y - eli gi bl e  p ati e nts  w h o st art t h e  pr o p os e d tr e at m e nt  will  b e  c o nsi d er e d 
e v al u a bl e f or  p ur p os es  of  a n al y zi n g  d at a  o n s af et y  a n d t o xi cit y.   F or t h e  p h as e I 
c o m p o n e nt  of st u d y, if  a  p ati e nt  wit h dr a ws fr o m st u d y  d uri n g t h e tr e at m e nt f or r e as o ns 
ot h er t h a n t o xi cit y, t h e n t h e  n e xt  p ati e nt s h all  b e tr e at e d  at t h e s a m e  d os e  as t h e 
wit h dr a w n  p ati e nt.  A n al ysis  of  effi c a c y  e n d p oi nts f or t h e  p h as e II, t h at is,  P F S, 
tr e at m e nt r es p o ns e ( C R,  P R,  P D,  or  S D),  a n d  O S  will  b e  b as e d  o n  3 5  p ati e nts  e nr oll e d 
o n t h e  p h as e II  p orti o n  of t h e st u d y.  
 E x cl usi o ns 
P ati e nts  w h o  ar e  e nr oll e d  o n st u d y  b ut  n ot tr e at e d  wit h  at l e ast  2  c y cl es ( d o  n ot st art 
tr e at m e nt  wit h  vi n or el bi n e  a n d tr ast u z u m a b  e mt a nsi n e)  ar e  n ot  c o nsi d er e d  e v al u a bl e 
a n d  will  b e  e x cl u d e d fr o m  all  effi c a c y  a n al ys es.   R e as o ns f or s u c h  e x cl usi o ns  will  b e 
c h ar a ct eri z e d,  b ut  c o ul d i n cl u d e r e as o ns s u c h  as:  c o ns e nt  wit h dr a w n  or  eli gi bilit y 
s u bs e q u e ntl y  n ot  c o nfir m e d.  A n y  p ati e nt  w h o i niti at es tr e at m e nt  a n d is l at er f o u n d t o  b e 
i n eli gi bl e f or t h e st u d y  will  b e  wit h dr a w n fr o m tr e at m e nt (st o p r e c ei vi n g st u d y 
tr eat m e nt)  a n d  e x cl u d e d ( n ot  e v al u a bl e) fr o m t h e  m ai n  a n al ys es  of s af et y  a n d tr e at m e nt 
effi c a c y.   S u c h  p ati e nts,  h o w e v er,  w o ul d  b e f oll o w e d f or  o v er all s ur vi v al.   T h e 
e x p eri e n c e  of  a n y tr e at e d  p ati e nts  w h o  ar e  n ot  “st u d y  eli gi bl e ”  will  b e  c h ar a ct eri z e d 
s e p ar at el y fr o m t h at  of  e v al u a bl e  p ati e nts,  w h os e  e x p eri e n c e  will r e pr es e nt t h e  m ai n 
b asis f or  e v al u ati n g t h e  pr o p os e d  c o m bi n e d tr e at m e nt  eff e ct i n t his tri al.  
 St u d y si z e j ustifi c ati o n  
T h e  o bj e cti v e  of t h e  p h as e I  c o m p o n e nt  of st u d y is t o  d et er mi n e r e c o m m e n d e d  d os e 
p h as e II  d os e  of  vi n or el bi n e  wit h  tr ast u z u m a b  e mt a nsi n e.  P ati e nts  will  b e tr e at e d  at  o n e 
of  4 - 5  d os e l e v els  a c c or di n g t o t h e st a n d ar d  d os e  es c al ati o n/ d e-es c al ati o n s c h e m e 
d et ail e d i n  S e cti o n  7. 1. I n  a c c or d a n c e  wit h t his s c h e m e, t h e r e c o m m e n d e d  p h as e II  d os e 
of  vi n or el bi n e  wit h  tr ast u z u m a b  e mt a nsi n e ( vi n or el bi n e  o n  d a y  1  a n d  8  a n d  
tr ast u z u m a b  e mt a nsi n eo n  d a y  1)  will  b e  est a blis h e d  as t h e  hi g h est  d os e l e v el t est e d f or 
w hi c h  n o  m or e t h a n  1  o ut  of  6  p ati e nts  e x p eri e n c es  D L T.  T h e  n u m b er  of  p ati e nts f or 
p h as e I  c o m p o n e nt  will  b e  b et w e e n  1 5  a n d  2 1  ass u mi n g f o ur  d os e l e v els  ar e t est e d. 
T h e  o bj e cti v e  of t h e  p h as e II  c o m p o n e nt  of st u d y is t o  o bt ai n  pr eli mi n ar y  e vi d e n c e  of 
t h e t h er a p e uti c  effi c a c y  of  a  c o m bi n ati o n r e gi m e n  c o nsisti n g  of  vi n or el bi n e  a n d 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  8 1  of  9 7  
 
tr a nst u z u m a b e mt a nsi n e  i n  H E R 2- p ositi v e  M B C  p ati e nts.  T h e  pri m ar y  e n d p oi nt is 
pr o gr essi o n-fr e e s ur vi v al ( P F S).  S e c o n d ar y  e n d p oi nts  ar e  o bj e cti v e r es p o ns e r at e, 
cli ni c al  b e n efit r at e,  a n d  o v er all s ur vi v al.   A n al ysis  of t h es e  e n d p oi nts  will  b e  b as e d  o n 
all  e v al u a bl e  p at i e nts  as  d efi n e d i n  S e cti o n  3. 0.   T h e st u d y tr e at m e nt  will  b e  of f urt h er 
i nt er est if t h e  m e di a n  P F S is ≥ 1 2    m o nt hs,  a n d  will  b e  c o nsi d er e d i n eff e cti v e if t h e 
m e di a n  P F S is  ≤ 9  m o nt hs.  Wit h  3 5  p ati e nts  a n d  a si g nifi c a n c e l e v el  of  1 0 %, st atisti c al 
p o w er  of t h e st u d y  will  b e  8 1. 1 %,  ass u mi n g  n o  p ati e nts  ar e  dr o p p e d  o ut.    
 Pl a n n e d st atisti c al  a n al ysis   
D e m o gr a p hi c  a n d  b as eli n e  c h ar a ct eristi cs :  P ati e nt  d e m o gr a p hi cs  a n d  dis e as e 
c h ar a ct eristi cs  will  b e s u m m ari z e d  usi n g  d es cri pti v e st atisti cs:  c o u nts  a n d  p er c e nt a g es , 
r a n g e,  m e di a n,  m e a n,  a n d st a n d ar d  d e vi ati o n,  as  a p pr o pri at e. 
S af et y :   T o xi citi es  will  b e t a b ul at e d  b y t y p e,  gr a d e,  d ur ati o n,  a n d  attri b uti o n t o 
tr e at m e nt.  A  p ati e nt-l e v el s u m m ar y  b y  w orst  gr a d e t o xi cit y  will  b e i n cl u d e d. 
Effi c a c y :  Pr eli mi n ar y  e vi d e n c e  of tr e at m e nt  effi c a c y  will  b e  ass ess e d  b y  pr o gr essi o n -
fr e e s ur vi v al ( P F S)  a n d tr e at m e nt r es p o ns e ( C R,  P R,  S D,  or  P D)  b y  R E CI S T 1. 1  crit eri a 
– s e e  a p p e n di x  B.  I n  a d diti o n, t h e  e x p eri e n c e  of  p ati e nts i n  e a c h  c at e g or y  will  b e 
s u m m ari z e d b y  d es cri pti v e st atisti cs ( m e di a n  a n d r a n g e) f or ti m e t o  o ns et  of r es p o ns e 
or  pr o gr essi o n,  a n d  d ur ati o n  of  b e n efit if  a c hi e v e d.  T h e  K a pl a n- M ei er  m et h o d  will  b e 
us e d t o  esti m at e  pr o gr essi o n -fr e e s ur vi v al  a n d  o v er all s ur vi v al  a n d  c orr es p o n di n g 
m e di a ns.  P oi n t  esti m at es  wit h  c orr es p o n di n g  9 5 %  c o nfi d e n c e i nt er v als f or t h e 
pr o p orti o n  of  pr o gr essi o n- fr e e/s ur vi vi n g  p ati e nts  will  b e  gi v e n f or s el e ct e d ti m es, s u c h 
as  6,  1 2,  1 8,  2 4  a n d  3 6  m o nt hs f oll o wi n g t h e i niti ati o n  of tr e at m e nt,  as  w ell  as f or 
m e di a n ti m es.   F or   p ur p os es  of t h es e  a n al ys es,  pr o gr essi o n-fr e e s ur vi v al ( P F S) will  b e 
m e as ur e d fr o m  d at e  fr o m first tr e at m e nt r e c ei v e d  o n st u d y t o  d at e  of  d o c u m e nt e d 
dis e as e  pr o gr essi o n,  or  d e at h  d u e t o  c a n c er,  w hi c h e v er  o c c urs first.   P ati e nts  w h o  d o  n ot 
e x p eri e n c e  pr o gr e ssi o n  a n d t h os e  w h o  di e fr o m  c a us es  ot h er t h a n  c a n c er  will  b e 
c e ns or e d  at t h e  d at e  of l ast  k n o w n  pr o gr essi o n fr e e  d at e.   O v er all s ur vi v al  ( O S) will  b e 
m e as ur e d fr o m  d at e  fr o m first tr e at m e nt r e c ei v e d  o n st u d y t o  d at e  of  d e at h fr o m  a n y 
c a us e.  S ur vi v al ti m e  will  b e  c e ns or e d  at t h e  d at e  of l ast  c o nt a ct f or  p ati e nts  w h o r e m ai n 
ali v e.  
 
 D A T A  R E P O R TI N G  
D at a  m ust  b e s u b mitt e d  a c c or di n g t o t h e  pr ot o c ol r e q uir e m e nts f or  all  p ati e nts r e gist er e d.  
P ati e nts f or  w h o m  d o c u m e nt ati o n is i n a d e q u at e t o  d et er mi n e  eli gi bilit y  will  g e n er all y  b e 
d e e m e d i n eli gi bl e.   
 D at a  a n d  S af et y  M o nit o ri n g  
T h e  S yl v est er  C o m pr e h e nsi v e  C a n c er  C e nt er ( S C C C)  D at a  a n d  S af et y  M o nit ori n g 
C o m mitt e e ( D S M C)  will  m o nit or t his  cli ni c al tri al  a c c or di n g t o t h e  C a n c er  C e nt er’s 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  8 2  of  9 7  
 
D S M  Pl a n .  I n its  o v ersi g ht  c a p a cit y, t h e  D S M C  b e ars r es p o nsi bilit y f or s us p e n di n g  or 
t er mi n ati n g t his st u d y.   D S M C  o v ersi g ht  of t h e  c o n d u ct  of t his tri al i n cl u d es  o n g oi n g 
r e vi e w  of  a c cr u al  a n d  a d v ers e  e v e nt ( A E)  d at a,  a n d  p eri o di c r e vi e w  of t h e st u d y 
t h er a p y.  T h e  g ui d eli n es  a p p e ari n g i n  t his s e cti o n  ar e  off er e d f or  D S M C  c o nsi d er ati o n 
i n  ass essi n g  A Es, a n d r es p o ns e t o st u d y  tr e at m e nt.  I n  a d diti o n, t h e  D S M C  will r e vi e w 
r e p orts fr o m  all  a u dits, sit e  visits,  or st u d y r e vi e ws  p ert ai ni n g t o t his  cli ni c al tri al  a n d 
t a k e  a p pr o pri at e  a cti o n.   T h e  S C C C  D S M  Pl a n t o  w hi c h t his st u d y is s u bj e ct  c a n  als o 
b e f o u n d  at  w w w.s yl v est er. or g .  
 E arl y st o p pi n g  g ui d eli n es f or  p h as e II  c o m p o n e nt  of st u d y 
N O T E :  D uri n g  p h as e I  c o m p o n e nt, t o xi cit y  will  b e  m o nit or e d  b y r es e ar c h t e a m 
f oll o wi n g  es c al ati o n/ d e-es c al ati o n r ul es  pr es e nt e d i n  S e cti o n  7. 2. 
W e  pr o p os e t h e  f oll o wi n g  g ui d eli n es f or t h e  D S M C i n its r e vi e w  of  a c c u m ul ati n g  d at a 
o n t o xi cit y  a n d r es p o ns e t o tr e at m e nt  d uri n g t h e  p h as e II  c o m p o n e nt  of st u d y.   T h e 
pr o p os e d  g ui d eli n es  w er e  d e v el o p e d  usi n g  B a y esi a n  m et h o ds,  w hi c h  c a n  b e  a p pli e d  at 
a n y st a g e  of  e nr oll m e nt  wit h o ut  a d v a n c e s p e cifi c ati o n  of t h e  n u m b er  of i nt eri m 
a n al ys es t o  b e  p erf or m e d,  or t h e  n u m b er  of  p ati e nts  e v al u a bl e f or t o xi cit y,  or r es p o ns e, 
at t h e ti m e s u c h  ass ess m e nts  ar e  m a d e.   
U n d er t h e  B a y esi a n  m et h o d,  w e  assi g n  a  pri or  pr o b a bilit y (l e v el  of  b e li ef  at t h e st art  of 
t h e tri al) t o  a r a n g e  of  p ossi bl e  v al u es f or t h e tr u e t o xi cit y r at e.   As  d at a  o n tr e at e d 
p ati e nts  b e c o m e  a v ail a bl e,  e a c h  of t h es e  pr o b a bilit y  distri b uti o ns is r e vis e d  a n d t h e 
r es ulti n g  p ost eri or  pr o b a bilit y  b e c o m es t h e  b asis f or r e c o m me n di n g  eit h er  e arl y 
t er mi n ati o n  or  c o nti n u ati o n  of t h e st u d y.  I n t h e s e cti o ns t h at f oll o w,  w e  pr o vi d e 
s p e cifi c st o p pi n g  g ui d eli n es  b as e d  o n  p ost eri or  pr o b a biliti es f or  m o nit ori n g t o xi cit y  a n d 
effi c a c y  o v er t h e  c o urs e  of t his tri al.   U n d erl yi n g  ass u m pti o ns f or t h e  pri or  distri b uti o ns 
ar e  als o  pr es e nt e d.  
 S af et y:  E arl y  St o p pi n g  D u e t o  T o xi cit y  
( As  d es cri b e d i n  S e cti o n  1 0. 1) If  a tr e at m e nt-r el at e d ( p ossi bl e,  pr o b a bl e,  or  d efi nit e) 
d e at h  o c c urs,  e nr oll m e nt  will  b e s us p e n d e d  a n d  c o nti n u ati o n  of t h e st u d y  will  b e 
r e ass ess e d  b y t h e  D S M C. 
F or t h e  p ur p os es  of s af et y  m o nit ori n g,  w e  d efi n e  u n a c c e pt a bl e t o xi cit y t o  b e  a n y  of t h e 
f oll o wi n g tr e at m e nt-r el at e d ( p ossi bl e,  pr o b a bl e,  or  d efi nit e)  a d v ers e  e v e nts: 
•  Gr a d e  3  n e ur o p at h y  w hi c h  d o es  n ot r es ol v e t o  gr a d e  2  or l ess  wit hi n t w o  c y cl es 
of tr e at m e nt  
•  Gr a d e  4  n e utr o p e ni a  w hi c h  d o es  n ot r es ol v e t o  gr a d e  2  or l ess  wit hi n  1 4  d a ys 
•  Gr a d e  3  el e v ati o n  of li v er f u n cti o n t ests ( L F Ts) t h at  d o es  n ot r es ol v e t o  gr a d e  2 
or l ess  wit hi n  1 4  d a ys 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  8 3  of  9 7  
 
•  R e - o c c urr e n c e  of  gr a d e  4  n e utr o p e ni a  or  gr a d e  3  el e v ati o n  of  L F Ts  d es pit e  2 
d os e  m o difi c ati o ns  or  o n e  d os e  m e di c ati o n  a n d  o n e  pr ot o c ol s p e cifi e d  d os e 
d el a y.  
•  Gr a d e  3 l eft  v e ntri c ul ar s yst oli c  d ysf u n cti o n t h at  d o es  n ot r es ol v e t o  gr a d e  2  or 
l ess  wit hi n  o n e  c y cl e  of tr e at m e nt 
N O T E :  Gr a d e  5 ( d e at h)  n ot rel at e d t o tr e at m e nt  will  n ot  b e  c o nsi d er e d  u n a c c e pt a bl e 
a d v ers e  e v e nt.  
U n a c c e pt a bl e t o xi cit y is  e x p e ct e d t o  o c c ur i n  n o  m or e t h a n  1 0 %  of  p ati e nts  wit hi n t h e 
p h as e II  c o m p o n e nt  of t h e st u d y i n t h e  w h ol e  c o h ort ( u p t o  3 5 p ati e nts). I n  ot h er  w or ds 
n o  m or e t h a n  4  p ati e nts.  If t h er e is  e vi d e n c e t h at t h e tr u e r at e  of t his t o xi cit y  e x c e e ds 
2 0 % (i. e.  m or e t h a n  7  p ati e nts), t h e n t h e st u d y s h o ul d  b e s us p e n d e d  or  p ossi bl y 
t er mi n at e d  e arl y.   S p e cifi c all y,  w e s u g g est  as  a  g ui d eli n e f or  e arl y t er mi n ati o n  a 
p ost eri or  pr o b a bilit y  of  9 0 %  or  hi g h er t h at t h e tr u e r at e  e x c e e ds  2 0 %.  T a bl e  1 3  d et ails 
s p e cifi c i nst a n c es  w h er e t his  g ui d eli n e is  m et. I n t his s etti n g,  e arl y t er mi n ati o n  d u e t o 
e vi d e n c e  of  e x c essi v e t o xi cit y  w o ul d  b e  w arr a nt e d.   
T a bl e  1 3  E arl y  St o p pi n g  G ui d eli n es  d u e t o t o xi cit y f or  p h as e II  
E a rl y  St o p pi n g  G ui d eli n es  d u e t o t o xi cit y f o r  p h as e II.  
P ati e nts  wit h   
u n a c c e pt a bl e t o xi cit y  
P ati e nts  e v al u at e d   
f or t o xi cit y 
O bs er v e d   
t o xi cit y r at e  ≥ 
3  
3 t o  4  
7 5 %  
4  
5 t o  6  
6 7 %  
5  
7 t o  9  
5 6 %  
6  
1 0  t o  1 1 
5 5 %  
7  
1 2 t o  1 4  
5 0 %  
8  
1 5 t o  1 7  
4 7 %  
9  
1 8 t o  1 9  
4 7 %  
1 0  
2 0 t o  2 2  
4 5 %  
1 1  
2 3 t o  2 5  
4 4 %  
1 2  
2 6 t o  2 8  
4 3 %  
1 3  
2 9 t o  3 1  
4 2 %  
1 4  
3 2 t o  3 3  
4 2 %  
1 5  
3 5  
4 2 %  


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  8 4  of  9 7  
 
E a rl y  St o p pi n g  G ui d eli n es  d u e t o t o xi cit y f o r  p h as e II.  
P ati e nts  wit h   
u n a c c e pt a bl e t o xi cit y  
P ati e nts  e v al u at e d   
f or t o xi cit y 
O bs er v e d   
t o xi cit y r at e  ≥ 
U n a c c e pt a bl e t o xi cit y:  a n y  of t h e f oll o wi n g  t r e at m e nt-r el at e d ( p ossi bl e,  p r o b a bl e,  o r 
d efi nit e)  a d v ers e  e v e nts:  
•   Gr a d e  3  or  hi g h er  n o n- h e m at ol o gi c t o xi cit y,  e x cl u di n g f ati g u e,  or t o xi cit y  attri b ut e d 
t o  a n dr o g e n  d e pri v ati o n; 
•   Gr a d e  4  or  hi g h er  h e m at ol o gi c  t o xi cit y,  e x cl u di n g l y m p h o p e ni a, l e u c o p e ni a,  a n d 
n e utr o p e ni a l asti n g  ≤   7  d a ys,  a n d  a n e mi a. 
o    I n  p atie nts  wit h  G r a d e  4  n e ut r o p e ni a ,  a f oll o w  u p  C B C  will  b e  c h e c k e d 
wit hi n  7  d a ys.  H o w e v er, if  C B C r es ults  c a n n ot  b e  o bt ai n e d  d u e t o  p ati e nt  n o n-
c o m pli a n c e  or s a m pl e  err ors  a n d  a s u bs e q u e nt  C B C r es ults s h o w r es ol uti o n  of 
Gr a d e  4  n e utr o p e ni a, t his  will  b e r e p ort e d  a n d  n ot  c o nsi d er e d  u n a c c e pt a bl e 
t o xi cit y. 
 
 E arl y  St o p pi n g  D u e t o  L a c k  of  Effi c a c y:  M o nit ori n g t h e  O v er all  R es p o ns e  R at e  
( O R R) 
W hil e  b ot h  dr u gs  ar e  hi g hl y  a cti v e i n  M B C (s e e s e cti o ns  1. 3,  1. 4  a n d  1. 5 )  a n d  w e 
e x p e ct s y n er g y, it is  n ot  a nti ci p at e d t h at  t his st u d y  will  b e st o p p e d  d u e t o l a c k  of 
effi c a c y.  H o w e v er, t h e  D S M C s h o ul d  c o nsi d er st o p pi n g t h e st u d y  e arl y if  a c c u m ul ati n g 
d at a s u g g est t h at t h e tr u e  O R R is  n o  b ett er t h a n  1 5 %.   T a bl e  1 4 s h o ws s p e cifi c i nst a n c es 
w h er e t his  g ui d eli n e is  m et, t h us s u g g est i n g  e arl y t er mi n ati o n  d u e t o  e vi d e n c e t h at 
tr e at m e nt is i n eff e cti v e.   
T a bl e  1 4  E arl y  St o p pi n g  G ui d eli n es f or l a c k  of  effi c a c y  
E a rl y  St o p pi n g  G ui d eli n es f o r l a c k  of  effi c a c y.  
N o.  of  P ati e nts  wit h 
r es p o ns e 
P ati e nts  e v al u at e d   
f or r es p o ns e * 
O bs er v e d  
o v er all  r es p o ns e r at e  ≤ 
0  
1 1 t o  2 1  
0 %  
1  
2 2 t o  3 0  
5 %  
2  
3 1 t o  3 5  
6 %  
 *  E v al u a bl e  a n d  ass ess e d f or r es p o ns e  u n d er i n cl usi o n  crit eri a.   
 
F or  e x a m pl e, if  1 1 t o  2 1  e v al u a bl e  p ati e nts  h a v e  b e e n  ass ess e d f or r es p o ns e  a n d  n o n e 
h as  a c hi e v e d  crit eri a f or r es p o ns e, t h e n r e c o m m e n d ati o n s h o ul d  b e  m a d e t o st o p t h e 
st u d y  e arl y f or l a c k  of  effi c a c y.   Li k e wis e, if  o nl y  o n e r es p o n d er  a m o n g t h e first  2 2 t o 
3 0  e v al u a bl e  p ati e nts,  t h e n r e c o m m e n d ati o n s h o ul d  b e  m a d e t o st o p t h e st u d y  e arl y f or 
l a c k  of  effi c a c y.   


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  8 5  of  9 7  
 
P ost eri or  pr o b a biliti es  us e d t o  d eri v e t h e st o p pi n g  g ui d eli n es s h o w n  a b o v e  ar e 
c al c ul at e d  u n d er  a  pri or  b et a  distri b uti o n  wit h  p ar a m et ers  β 1 = 0. 8  a n d  β 2 = 1. 2,  w hi c h 
c orr es p o n ds t o  a n  e x p e ct e d  o v er all  r es p o ns e r at e  of  4 0 %  b as e d  o n  v er y li mit e d 
i nf or m ati o n, r o u g hl y  e q u al t o  h a vi n g st u di e d  2  p ati e nts.   E q ui v al e ntl y, t his  pri or 
distri b uti o n i m pli es t h at t h er e  o nl y  2 5. 3 %  c h a n c e t h at t h e tr u e   o v er all r es p o ns e r at e 
( OR R) is  n o  b ett er t h a n  1 5 %.  
 
 N o  E arl y  St o p pi n g f or  B ett er t h a n  E x p e ct e d  Tr e at m e nt  Effi c a c y  
W e  d o  n ot i nt e n d t o st o p t h e st u d y  e arl y if t h e  pr o p os e d  tr e at m e nt  a p p e ars t o  b e  o v erl y 
eff e cti v e.  U n d er s u c h  cir c u mst a n c e,  c o nti n u ati o n  of t h e tri al  will  yi el d  a d diti o n al 
i nf or m ati o n r e g ar di n g t h e  m a g nit u d e  of t h e tr u e  o bj e cti v e o v er all  r es p o ns e r at e  a n d 
pr o gr essi o n-fr e e s ur vi v al.  M or e o v er, if r es ults fr o m t his st u d y  ar e  pr o misi n g, f urt h er 
st u di es  will  b e  n e e d e d t o f ull y  ass ess t h e  b e n efits  a n d ris ks  of  vi n or el bi n e  wit h 
tr ast u z u m a b  e mt a nsi n e i n  pr e-tr e at e d  H E R 2- p ositi v e  M B C. 
 
  S T U D Y  M O NI T O RI N G  
T his st u d y  will  b e  a u dit e d  a n d/ or  m o nit or e d  ( as  a p pli c a bl e)  a c c or di n g t o t h e  U ni v ersit y  of 
Mi a mi r e q uir e m e nts.   S e e  als o  htt p:// ur es e ar c h. mi a mi. e d u/r e g ul at or y -c o m pli a n c e -
s er vi c es/r c q a  a n d htt p://r es e ar c h. m e d. mi a mi. e d u/ cli ni c al -r es e ar c h/ cr ors.   
 I N V E S TI G A T O R  R E S P O N SI BI LI TI E S  
 I n v esti g at o r  R es p o nsi bilit y/ P e rf o r m a n c e 
T h e i n v esti g at or  will  e ns ur e t h at t his st u d y is  c o n d u ct e d i n  a c c or d a n c e  wit h  all 
r e g ul ati o ns  g o v er ni n g t h e  pr ot e cti o n  of  h u m a n s u bj e cts.  T h e i n v esti g at or  will  e ns ur e 
t h at  all  w or k  a n d s er vi c es  d es cri b e d i n  or  ass o ciat e d  wit h t his  pr ot o c ol  will  b e 
c o n d u ct e d i n  a c c or d a n c e  wit h t h e i n v esti g ati o n al  pl a n,  a p pli c a bl e r e g ul ati o ns,  a n d t h e 
hi g h est st a n d ar ds  of  m e di c al  a n d  cli ni c al r es e ar c h  pr a cti c e.  
 C o nfi d e nti alit y  
T h e i n v esti g at or  m ust  e ns ur e t h at  e a c h s u bj e ct’s  a n o n y mit y  will  b e  m ai nt ai n e d  a n d  e a c h 
s u bj e ct’s i d e ntit y  will  b e  pr ot e ct e d fr o m  u n a ut h ori z e d  p arti es.   A  n u m b er  will  b e 
assi g n e d t o  e a c h s u bj e ct  u p o n st u d y  e ntr y  a n d t h e  n u m b er  a n d t h e s u bj e ct’s i niti als  will 
b e  us e d t o i d e ntif y t h e s u bj e ct f or t h e  d ur ati o n  of t h e s t u d y.   T h e i n v esti g at or  will 
m ai nt ai n  all  d o c u m e nts r el at e d t o t his st u d y i n stri ct  c o nfi d e n c e.  
 I nf o r m e d  C o ns e nt  a n d  P e r missi o n t o  Us e  P r ot e ct e d  H e alt h I nf o r m ati o n   
It is t h e r es p o nsi bilit y  of t h e i n v esti g at or t o  o bt ai n  writt e n i nf or m e d  c o ns e nt fr o m  e a c h 
su bj e ct  p arti ci p ati n g i n t his st u d y  aft er  a d e q u at e  e x pl a n ati o n, i n l a y l a n g u a g e,  of t h e 
m et h o ds,  o bj e cti v es,  a nti ci p at e d  b e n efits,  a n d  p ot e nti al  h a z ar ds  of t h e st u d y.   T h e 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  8 6  of  9 7  
 
i n v esti g at or  m ust  als o  e x pl ai n t h at t h e s u bj e ct is  c o m pl et el y fr e e t o r ef us e t o  e nt er t h e 
st u d y  or t o  dis c o nti n u e  p arti ci p ati o n  at  a n y ti m e (f or  a n y r e as o n)  a n d r e c ei v e  alt er n ati v e 
c o n v e nti o n al t h er a p y  as i n di c at e d.   Pri or t o st u d y  p arti ci p ati o n,  e a c h s u bj e ct  will si g n  a n 
I R B  a p pr o v e d i nf or m e d  c o ns e nt f or m  a n d r e c ei v e  a  c o p y  of s a m e ( a n d i nf or m ati o n 
l e afl et, if  a p pr o pri at e).   F or s u bj e cts  n ot  q u alifi e d  or  a bl e t o  gi v e l e g al  c o ns e nt,  c o ns e nt 
m ust  b e  o bt ai n e d fr o m  a  p ar e nt, l e g al  g u ar di a n,  or  c ust o di a n.  T h e i n v esti g at or  or 
d esi g n e e  m ust  e x pl ai n t o t h e s u bj e ct  b ef or e  e nr oll m e nt i nt o t h e st u d y  t h at f or 
e v al u ati o n  of st u d y r es ults, t h e s u bj e ct’s  pr ot e ct e d  h e alt h i nf or m ati o n  o bt ai n e d  d uri n g 
t h e st u d y  m a y  b e s h ar e d  wit h t h e st u d y s p o ns or, r e g ul at or y  a g e n ci es,  a n d t h e I R B.  It is 
t h e i n v esti g at or’s ( or  d esi g n e e’s) r es p o nsi bilit y t o  o bt ai n  p er missi o n t o  us e  pr ot e ct e d 
h e alt h i nf or m ati o n  p er  HI P A A fr o m  e a c h s u bj e ct,  or if  a p pr o pri at e, t h e s u bj e cts’  p ar e nt 
or l e g al  g u ar di a n. 
 S o u r c e  D o c u m e nt ati o n  a n d I n v esti g at o r  Fil es  
T h e i n v esti g at or  m ust  m ai nt ai n  a d e q u at e  a n d  a c c ur at e r e c or ds t o f ull y  d o c u m e nt t h e 
c o n d u ct  of t h e st u d y  a n d t o  e ns ur e t h at st u d y  d at a  c a n  b e s u bs e q u e ntl y  v erifi e d.   T h es e 
d o c u m e nts s h o ul d  b e  cl assifi e d i nt o t w o s e p ar at e  c at e g ori es:  ( 1) i n v esti g at or st u d y fil e 
a n d ( 2) s u bj e ct  cli ni c al s o ur c e  d o c u m e nts t h at  c orr o b or at e  d at a  c oll e ct e d  o n t h e  C R F’s.  
S u bj e ct  cli ni c al s o ur c e  d o c u m e nts  m a y i n cl u d e  h os pit al/ cli ni c  p ati e nt r e c or ds; 
p h ysi ci a n's  a n d  n urs e's  n ot es;  a p p oi nt m e nt  b o o k;  ori gi n al l a b or at or y,  E C G,  E E G, 
r a di ol o g y,  p at h ol o g y,  a n d s p e ci al  ass ess m e nt r e p orts;  p h ar m a c y  dis p e nsi n g r e c or ds; 
s u bj e ct  di ari es; si g n e d i nf or m e d  c o ns e nt f or ms;  a n d  c o ns ult a nt l ett ers.   W h e n t h e  C R F 
or  a n y f or m is  us e d  as t h e s o ur c e  d o c u m e nt, t his  m ust  b e  cl e arl y st at e d i n t h e 
i n v esti g at or st u d y fil e.  Mi ni m all y, t h e f oll o wi n g  b e  d o c u m e nt e d i n s o ur c e  d o c u m e nts: 
•   M e di c al  hist o r y/ p h ysi c al  c o n diti o n  a n d  di a g n osis  of t h e s u bj e ct  b ef or e i n v ol v e m e nt 
i n t h e st u d y s uffi ci e nt t o  v erif y  pr ot o c ol  e ntr y  crit eri a 
•   St u d y  n u m b er,  assi g n e d s u bj e ct  n u m b er,  a n d  v erifi c ati o n t h at  writt e n i nf or m e d 
c o ns e nt w as  o bt ai n e d ( e a c h r e c or d e d i n  d at e d  a n d si g n e d  n ot es  o n t h e  d a y  of  e ntr y 
i nt o t h e st u d y) 
•   Pr o gr ess  n ot es f or  e a c h s u bj e ct  visit 
•   D o c u m e nt ati o n  of tr e at m e nt 
•   L a b or at or y t est r es ults  
•   A d v ers e  e v e nts ( a cti o n t a k e n  a n d r es ol uti o n) 
•   C o n diti o n  a n d r es p o ns e  of s u bj e ct  u p o n  c o m pl eti o n  of  or  e arl y t er mi n ati o n  fr o m 
t h e st u d y 
 R e c o r di n g  a n d  P r o c essi n g  of  D at a  
If  usi n g  h ar d  c o pi es  of  C R F’s, st u d y  c e nt er  p ers o n n el  will  c o m pl et e i n di vi d u al  C R F’s 
i n i n k.   All  c orr e cti o ns t o  e nt er e d  d at a  will  b e  m a d e  b y  dr a wi n g  a si n gl e li n e t hr o u g h 
t h e i nf or m ati o n t o  b e  c orr e ct e d  with o ut  o bs c uri n g it.   All  c orr e cti o ns  will  b e i niti al e d, 
d at e d  a n d  e x pl ai n e d, if  n e c ess ar y.   T h e  us e  of  “ w hit e- o ut ”  or  o bs c uri n g  c orr e cti o n t a p e 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  8 7  of  9 7  
 
will  b e  pr o hi bit e d.   A  C R F is r e q uir e d f or  e v er y  p ati e nt  w h o r e c ei v e d  a n y  a m o u nt  of 
st u d y tr e at m e nt.   T h e i n v esti g at or  will  e ns ur e t h at t h e  C R F’s  ar e  a c c ur at e,  c o m pl et e, 
l e gi bl e  a n d ti m el y.  S e p ar at e s o ur c e r e c or ds  ar e r e q uir e d t o s u p p ort  all  C R F  e ntri es 
e x c e pt t h os e f or  w hi c h  us e  of t h e  C R F  as s o ur c e  d o c u m e nt is  cl e arl y  all o w e d  p er  n ot e 
i n t h e i n v esti g at or st u d y fil e. 
D at a  m ust  b e s u b mitt e d  a c c or di n g t o t h e  pr ot o c ol r e q uir e m e nts f or  A L L  p ati e nts 
r e gist er e d.   P ati e nts f or  w h o m  d o c u m e nt ati o n is i n a d e q u at e t o  d et er mi n e  eli gi bilit y  will 
g e n er all y  b e  d e e m e d i n eli gi bl e.   
D at a  m ust  b e s u b mitt e d  a c c or di n g t o t h e  pr ot o c ol r e q u ir e m e nts f or  A L L  p ati e nts 
r e gist er e d.   P ati e nts f or  w h o m  d o c u m e nt ati o n is i n a d e q u at e t o  d et er mi n e  eli gi bilit y  will 
g e n er all y  b e  d e e m e d i n eli gi bl e.   
A list  of f or ms t o  b e s u b mitt e d,  as  w ell  as  e x p e ct ati o n  d at es  m a y  b e f o u n d i n  A p p e n di x 
B.  
 R e p o rts t o  S p o ns o r 
A n y lit er at ur e  arti cl es t h at  ar e  a r es ult  of t h e st u d y s h o ul d  b e s e nt t o  G e n e nt e c h.  C o pi es 
of s u c h r e p orts s h o ul d  b e  m ail e d t o t h e  assi g n e d  Cli ni c al  O p er ati o ns  c o nt a ct f or t h e 
st u d y:  E m ail: str a uss.r oss @ g e n e. c o m  or  F a x:   9 7 3- 2 5 2- 7 6 1 8.    
 N o n -P r ot o c ol  R es e a r c h  
N o i n v esti g ati v e  pr o c e d ur es  ot h er t h a n t h os e  d es cri b e d i n t his  pr ot o c ol  will  b e 
u n d ert a k e n  o n t h e  e nr oll e d s u bj e cts  wit h o ut t h e  a gr e e m e nt  of t h e I R B. 
 Et hi cs  
T h e i n v esti g at or  a gr e es t o  c o n d u ct t h e st u d y i n  c o m pli a n c e  wit h t h e  pr ot o c ol,  c urr e nt 
g o o d  cli ni c al  pr a cti c es,  a n d  all  a p pli c a bl e (l o c al,  F D A) r e g ul at or y  g ui d eli n es  a n d 
st a n d ar d  of  et hi cs. 
U M  Et hi cs  Pr o gr a ms’  R es e ar c h  Et hi cs  C o ns ult ati o n  S er vi c e ( R E C S) is  a fr e e r es o ur c e 
f or  U M  R es e ar c h ers.   S e e t h e w e bsit e f or f urt h er i nf or m ati o n : 
htt p:// w w w. mi a mi. e d u/i n d e x. p h p/ et hi cs/ pr oj e cts/r e cs/   
 
 Ess e nti al  d o c u m e nts f o r t h e  c o n d u ct  of  a  cli ni c al t ri al  
Ess e nti al  d o c u m e nts  ar e t h os e  d o c u m e nts  wit h i n di vi d u all y  a n d  c oll e cti v el y  p er mit 
e v al u ati o n  of t h e  c o n d u ct  of  a tri al  a n d t h e  q u alit y  of t h e  d at a  pr o d u c e d.  T h e f oll o wi n g 
d o c u m e nts s h o ul d  b e  o n fil e:  1)  C V’s  a n d li c e ns e  of  all I n v esti g at ors;  2 ) I R B 
d o c u m e nt ati o n/ c orr es p o n d a n c e  a n d  3 )  D o c u m e nt ati o n  of I R B  c ertifi c ati o n 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  8 8  of  9 7  
 
R E F E R E N C E S  
1.   S E E R  St at  F a ct  S h e ets:  Br e ast  C a n c er.  S ur v eill a n c e,  E pi d e mi ol o g y,  a n d  E n d  R es ults ( S E E R) 
Pr o gr a m ( w w w.s e er. c a n c er. g o v)  S E E R * St at  D at a b as e: I n ci d e n c e  - S E E R  9  R e gs  R es e ar c h 
D at a,  N o v  2 0 1 4  S u b ( 1 9 7 3- 2 0 1 2)  < K atri n a/ Rit a  P o p ul ati o n  A dj ust m e nt > -  Li n k e d  T o  C o u nt y 
Attri b ut es  -  T ot al  U. S.,  1 9 6 9- 2 0 1 3  C o u nti es,  N ati o n al  C a n c er I nstit ut e,  D C C P S,  S ur v eill a n c e 
R es e ar c h  Pr o gr a m,  S ur v eill a n c e  S yst e ms  Br a n c h, r el e as e d  A pril  2 0 1 5,  b as e d  o n t h e 
N o v e m b er  2 0 1 4 s u b missi o n. 
2.   Sl a m o n  DJ,  Cl ar k  G M,  W o n g  S G,  et  al.  H u m a n  br e ast  c a n c er:  c orr el ati o n  of r el a ps e  a n d 
s ur vi v al  wit h  a m plifi c ati o n  of t h e  H E R - 2/ n e u  o n c o g e n e. S ci e n c e .  1 9 8 7;  2 3 5( 4 7 8 5): 1 7 7- 8 2. 
3.   Sl a m o n  DJ,  L e yl a n d-J o n es  B,  S h a k  S,  et  al.   Us e  of  C h e m ot h er a p y  pl us  a  M o n o cl o n al 
A nti b o d y  a g ai nst  H E R 2 f or  M et ast ati c  Br e ast  C a n c er  T h at  O v er e x pr ess es  H E R 2.  N  E n gl  J 
M e d .  2 0 0 1;  3 4 4: 7 8 3- 7 9 2. 
4.   B as el g a J,  C ort es J,  Ki m  S,  et  al.  P ert u z u m a b  pl us  Tr ast u z u m a b  pl us  D o c et a x el f or 
M et ast ati c  Br e ast  C a n c er.  N  E n gl  J  M e d .  2 0 1 2;  3 6 6: 1 0 9- 1 1 9. 
5.   M art y  M,  C o g n etti  F,  M ar a ni n c hi  D,  et  al.   R a n d o mi z e d  P h as e II  Tri al  of t h e  Effi c a c y  a n d 
S af et y  of  Tr ast u z u m a b  C o m bi n e d  Wit h  D o c et a x el i n  P ati e nts  Wit h  H u m a n  E pi d er m al 
Gr o wt h  F a ct or  R e c e pt or  2 – P ositi v e  M et ast ati c  Br e ast  C a n c er  A d mi nist er e d  As  First -Li n e 
Tr e at m e nt:  T h e  M 7 7 0 0 1  St u d y  Gr o u p.  J  C li n O n c ol.   2 0 0 5;  2 3( 1 9):  4 2 6 5- 4 2 7 4. 
6.   S p e ct or  N L,  Xi a  W,  B urris  3 r d H,  et  al.  St u d y  of t h e  bi ol o gi c  eff e cts  of l a p ati ni b,  a r e v ersi bl e 
i n hi bit or  of  Er b B 1  a n d  Er b B 2 t yr osi n e  ki n as es,  o n t u m or  gr o wt h  a n d s ur vi v al  p at h w a ys i n 
p ati e nts  wit h  a d v a n c e d  m ali g n a n ci es.  J  Cli n  O n c ol.   2 0 0 5;  2 3:  2 5 0 2 – 2 5 1 2.  
7.   G e y er  C E,  F orst er J M,  Li n d q uist  D,  et  al.  L a p ati ni b  pl us  C a p e cit a bi n e f or  H E R 2- P ositi v e 
A d v a n c e d  Br e ast  C a n c er.  N  E n gl  J  M e d .  2 0 0 6;  3 5 5: 2 7 3 3- 2 7 4 3. 
8.   Bl a c k w ell  K L,  B urst ei n  HJ,  St or ni ol o  A,  et  al.  R a n d o mi z e d  St u d y  of  L a p ati ni b  Al o n e  or i n 
C o m bi n ati o n  wit h   Tr ast u z u m a b i n  W o m e n wit h  Er b B 2- P ositi v e,  Tr ast u z u m a b- R efr a ct or y 
M et ast ati c  Br e ast  C a n c er.  J  C li n O n c ol.   2 0 1 0;  2 8( 7):1 1 2 4- 1 1 3 0. 
9.   L e wis  P hilli ps  G D,  G u a n g mi n  L,  D u g g er  D,  et  al.   T ar g eti n g  H E R 2 -P ositi v e  Br e ast  C a n c er 
wit h  Tr ast u z u m a b - D M 1,  a n  A nti b o d y – C yt ot o xi c  Dr u g  C o nj u g at e. C a n c er  R es .  2 0 0 8;  6 8; 
9 2 8 0. 
1 0.  B urris  H, III,  R u g o  H,  V u k elj a  S.,  et  al.  P h as e II st u d y  of t h e  a nti b o d y  dr u g  c o nj u g at e 
tr ast u z u m a b- D M 1 f or t h e tr e at m e nt  of  h u m a n  e pi d er m al  gr o wt h f a ct or r e c e pt or  2 ( H E R 2)-
p ositi v e  br e ast  c a n c er  aft er  pri or  H E R 2 -dir e ct e d t h er a p y.  J  Cli n  O n c ol.  2 0 1 1;  2 9: 3 9 8 – 4 0 5. 
1 1.  J u nttill a  T,  P ars o ns  L G,  P hilli ps  G L,  et  al.   Tr ast u z u m a b -D M 1 ( T -D M 1) r et ai ns  all t h e 
m e c h a nis ms  of  a cti o n  of tr ast u z u m a b  a n d  effi ci e ntl y i n hi bits  gr o wt h  of l a p ati ni b i ns e nsiti v e 
br e ast  c a n c er.  Br e ast  C a n c er  R es  Tr e at .  2 0 1 1;  1 2 8( 2): 3 4 7- 5 6. 
1 2.  H ur vit z  S A,  Diri x  L,  K o csis J,  et  al.  P h as e II r a n d o mi z e d st u d y  of tr ast u z u m a b  e mt a nsi n e 
v ers us tr ast u z u m a b  pl us  d o c et a x el i n  p ati e nts  wit h  h u m a n  e pi d er m al  gr o wt h f a ct or r e c e pt or 
2- p ositi v e  m et ast ati c  br e ast  c a n c er.  J  Cli n  O n c ol .  2 0 1 3;  3 1( 9): 1 1 5 7- 6 3. 
1 3.  V er m a  S,  Mil es  D,  Gi a n ni  L,  et  al.  Tr ast u z u m a b  e mt a nsi n e f or  H E R 2- p ositi v e  a d v a n c e d 
br e ast  c a n c er.  N  E n gl  J  M e d .  2 0 1 2;  3 6 7( 1 9): 1 7 8 3- 9 1. 
1 4.  C a n o b bi o  L,  B o c c ar d o  F,  P ast ori n o  G,  et  al.  P h as e II st u d y  of  N a v el bi n e i n  a d v a n c e d  br e ast 
c a n c er.  S e mi n  O n c ol.   1 9 8 9;  1 6: 3 7- 4 0. 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  8 9  of  9 7  
 
1 5.  F u m ol e a u  P,  C h e v alli er  B,  K er br at  P,  et  al.  A  m ulti c e nt er  p h as e II st u d y  of t h e  effi c a c y  a n d 
s af et y  of  d o c et a x el  as first li n e tr e at m e nt  of  a d v a n c e d  br e ast  c a n c er.  R e p ort  of t h e  Cli ni c al 
S cr e e ni n g  Gr o u p  of t h e  E O R T C.  A n n  O n c ol.   1 9 9 6;  7: 1 6 5- 7 1. 
1 6.  G ar ci a - C o n d e J,  Ll u c h  A,  C ass a d o  A,  et  al. P h as e II tri al  wit h  vi n or el bi n e i n t h e  a d v a n c e d 
br e ast  c a n c er  u ntr e at e d.  Br e ast  C a n c er  R es  Tr e at .  1 9 9 2;  2 3: 1 4 2( A bs  5 2).  
1 7.  Br u n o  S,  Lir a- P u ert o  V,  T e x eir a  L,  et  al.  P h as e II tri al  wit h  vi n or el bi n e i n t h e tr e at m e nt  of 
a d v a n c e d  br e ast  c a n c er.  Pr o c  E C C O  6 .  1 9 9 1 ( A bs  2 6 8 a).  
1 8.  T er e n zi a ni  M,  D e mi c h eli  R,  Br a m bill a  C,  et  al.  Vi n or el bi n e:  a n  a cti v e,  n o n  cr oss r esist a nt 
dr u g i n  a d v a n c e d  br e ast  c a n c er.  R es ults fr o m  a  p h as e II st u d y.  Br e ast  C a n c er  R es  Tr e at . 
1 9 9 6;  3 9: 2 8 5- 2 9 1. 
1 9.  Di er as  V,  E xtr a J M,  B ellis a nt  E,  et  al.  Effi c a c y  a n d  T ol er a n c e  of  Vi n or el bi n e  a n d 
Fl u or o ur a cil  C o m bi n ati o n  as  First- Li n e  C h e m ot h er a p y  of  A d v a n c e d  Br e ast  C a n c er:  R es ults 
of  a  P h as e II  St u d y  Usi n g  a  S e q u e nti al  Gr o u p  M et h o d.  J  Cli n  O n c ol.   1 9 9 6;  1 4: 2 0 9 7- 3 1 0 4. 
2 0.  N ol e  F,  d e  Br a u d  F,  A a pr o  M,  et  al.  A.  P h as e I –II  st u d y  of  vi n or el bi n e i n  c o m bi n ati o n  wit h 
5-fl u or o ur a cil  a n d f oli ni c  a ci d  as first- li n e  c h e m ot h er a p y i n  m et ast ati c  br e ast  c a n c er:  a 
r e gi m e n  wit h  a l o w s u bj e ctiv e t o xi c  b ur d e n.  A n n  O n c ol.   1 9 9 7;  8: 8 6 5 – 8 7 0. 
2 1.  Bl aj m a n  C,  B al bi a ni  L,  Bl o c k J,  et  al.  A  pr os p e cti v e, r a n d o mi z e d  p h as e III tri al  c o m p ari n g 
c o m bi n ati o n  c h e m ot h er a p y  wit h  c y cl o p h os p h a mi d e,  d o x or u bi ci n,  a n d  5-fl u or o ur a cil  wit h 
vi n or el bi n e  pl us  d o x or u bi ci n i n t h e  tr e at m e nt  of  a d v a n c e d  br e ast  c ar ci n o m a. C a n c er . 1 9 9 9; 
8 5: 1 0 9 1- 1 0 9 7. 
2 2.  A n d ers o n  M,  Li d bri n k  E,  Bj err e  K,  et  al.  P h as e III  R a n d o mi z e d  St u d y  C o m p ari n g  D o c et a x el 
Pl us  Tr ast u z u m a b  Wit h  Vi n or el bi n e  Pl us  Tr ast u z u m a b  As  First- Li n e  T h er a p y  of  M et ast ati c 
or  L o c all y  A d v a n c e d  H u m a n  E pi d er m al  Gr o wt h  F a ct or  R e c e pt or  2 – P ositi v e  Br e ast  C a n c er: 
T h e  H E R N A T A  St u d y.  J  C li n O n c ol.  2 0 1 1;  2 9( 3):  2 6 4- 2 7 1. 
2 3.  M at h e  G,  R ei z e nst ei n  P.  P h as e I  p h ar m a c ol o gi c st u d y  of  a  n e w  Vi n c a   al k al oi d:  N a v el bi n e. 
C a n c er  L ett .  1 9 8 5;  2 7: 2 8 5 – 9 3. 
2 4.  S ori o  R,  R o bi e u x I,  G alli gi o ni  E,  et  al.  P h ar m a c o ki n eti cs  a n d t ol er a n c e  of  vi n or el bi n e i n 
el d erl y  p ati e nts  wit h  m et ast ati c  br e ast  c a n c er.  E ur  J  C a n c er .  1 9 9 7;  3 3( 2): 3 0 1 – 3. 
2 5.  V o g el  C,  O’ R o ur k e  M,  Wi n er  E.  Vi n or el bi n e  as first-li n e  c h e m ot h er a p y f or  a d v a n c e d  br e ast 
c a n c er i n  w o m e n  6 0  y e ars  of  a g e  or  ol d er.  A n n  O n c ol.   1 9 9 9;  1 0( 4): 3 9 7- 4 0 2. 
2 6.  W e b er  B L,  V o g el  C, J o n es  S. I ntr a v e n o us  vi n or el bi n e  as first- li n e  a n d s e c o n d-li n e t h er a p y i n 
a d v a n c e d  br e ast  c a n c er.  J  Cli n  O n c ol.  1 9 9 5;  1 3( 1 1): 2 7 2 2- 3 0. 
2 7.    B urst ei n  HJ,  H arris  L N,  M ar c o m  P K.  Tr ast u z u m a b  a n d  Vi n or el bi n e  as  First-Li n e  T h er a p y 
f or  H E R 2-O v er e x pr essi n g  M et ast ati c  Br e ast  C a n c er:  M ulti c e nt er  P h as e II  Tri al  wit h  Cli ni c al 
O ut c o m es,  A n al ysis  of  S er u m  T u m or  M ar k ers  as  Pr e di cti v e  F a ct ors,  a n d  C ar di a c 
S ur v eill a n c e  Al g orit h m . J  Cli n  O n c ol .  2 0 0 3;  2 1( 1 5): 2 8 8 9- 2 8 9 5.  
2 8.  J a h a n z e b  M,  Br ufs k y  A,  Er b a n J,  L e wis  D,  Li m e nt a ni  S.  D os e- d e ns e  n e o a dj u v a nt tr e at m e nt 
of  w o m e n  wit h  br e ast  c a n c er  utili zi n g  d o c et a x el,  vi n or el bi n e  a n d tr ast u z u m a b  wit h  gr o wt h 
f a ct or s u p p ort [ a bstr a ct]. J  Cli n  O n c ol.   2 0 0 5;  2 3:s 2 6. 
2 9.  P e gr a m  M D,  K o n e c n y  G E,  O’ C all a g h a n  C,  et  al.  R ati o n al  c o m bi n ati o ns  of tr ast u z u m a b  wit h 
c h e m ot h er a p e uti c  dr u gs  us e d i n t h e tr e at m e nt  of  br e ast  c a n c er.  J  N atl  C a n c er I nst.   2 0 0 4; 
9 6: 7 3 9 – 4 9. 
3 0.  B urst ei n  HJ,  K es h a vi a h  A,  B ar o n  A D,  et  al.  Tr ast u z u m a b  pl us  vi n or el bi n e  or t a x a n e 
c h e m ot h er a p y  f or  h er 2-o v er e x pr essi n g  m et ast ati c  br e ast  c a n c er: t h e tr ast u z u m a b  a n d 
vi n or el bi n e  or t a x a n e st u d y.  C a n c er.   2 0 0 7;  1 1 0: 9 6 5 – 7 2. 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  9 0  of  9 7  
 
3 1.  R or b ert  N,  L e yl a n d-J o n es  B,  As m ar  L,  et  al.  R a n d o mi z e d  p h as e III st u d y  of tr ast u z u m a b, 
p a clit a x el,  a n d  c ar b o pl ati n  c o m p ar e d  wit h tr ast u z u m a b  a n d  p a clit a x el i n  w o m e n  wit h  H E R- 2-
o v er e x pr essi n g  m et ast ati c  br e ast  c a n c er.  J  Cli n  O n c ol.   2 0 0 6;  2 4( 1 8): 2 7 8 6- 9 2. 
3 2.  Li vi n gst o n e  R B,  B arl o w  W E,  K as h JJ,  et  al.  S W O G  S 0 2 1 5:  a  p h as e II st u d y  of  d o c et a x el  a n d 
vi n or el bi n e  pl us fil gr asti m  wit h  w e e kl y tr ast u z u m a b f or  H E R 2 - p ositi v e, st a g e I V  br e ast 
c a n c er.  Br e ast  C a n c er  R es  Tr e at .  2 0 1 1;  1 3 0( 1): 1 2 3- 3 1. 
 
 
 
 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  9 1  of  9 7  
 
A P P E N DI X  A:  E X P E DI T E D  A D V E R S E  E V E N T ( A E)  R E P O R TI N G  R E Q UI R E M E N T S  
 
F or  all  A Es t h at  m e et  crit eri a f or  e x p e dit e d r e p orti n g, t h e  P ri n ci p al I n v esti g at or ( PI) is  o bli g at e d 
t o  p urs u e  a n d  pr o vi d e f oll o w- u p r e p orti n g i nf or m ati o n  u ntil t h e  e v e nt  h as r es ol v e d  or  u ntil  a n 
a c c e pt a bl e  m e di c al  e n d p oi nt  h as  b e e n r e a c h e d  (i. e. f or t h e  d ur ati o n s p e cifi e d i n t h e  pr ot o c ol), or 
t h e  p ati e nt is l ost t o f oll o w- u p. 
 
T h e  PI  a n d  all  a p pli c a bl e r es e ar c h st u d y t e a m  m e m b ers s h o ul d  b e c o m e f a mili ar  wit h t h e s af et y 
pr ofil e  of t h e i n v esti g ati o n al  a g e nt(s)  a n d/ or i nt er v e nti o n  at t h e st art  of t h e st u d y  a n d f or t h e 
d ur ati o n  of t h e r es e ar c h,  e. g.  b y r e vi e wi n g t h e I n v esti g at or’s  Br o c h ur e (I B)  a n d  a n y  S af et y 
R e p orts r el e as e d ,  b y t h e  S p o ns or  as  a p pli c a bl e.   
 
A.   I R B  E x p e dit e d  R e p orti n g 
a.   All I n v esti g at ors s h o ul d  als o  b e  a w ar e  of l o c al I nstit uti o n al r e q uir e m e nts f or  A E 
r e p orti n g.   F or  m or e i nf or m ati o n r e g ar di n g t h e I R B  p oli c y,  pl e as e r ef er t o t h e  U M 
H S R O’s I n v esti g at or  M a n u al:  htt p:// hsr o. m e d. mi a mi. e d u/ d o c u m e nts/ H R P- 1 0 3  -
_I N V E S TI G A T O R _ M A N U A L _ 4. 1 1. 2 0 1 4. d o c x  a n d t h e  U M  H S R O  S O P  o n  N e w 
I nf or m ati o n ( H R P- 0 2 4) 
htt ps:// e pr ost. m e d. mi a mi. e d u/ e Pr ost/ D o c/ 0/ H LJ 5 O TJ V Q E H 4 1 9 E 0I 6 Q P T 3 B 1 9 9/ H R P
-0 2 4 % 2 0 -% 2 0 S O P % 2 0 -% 2 0 N e w % 2 0I nf or m ati o n. d o c x  
b.   All  A Es t h at  ar e s eri o us,  u n a nti ci p at e d  a n d  p ossi bl y  r el at e d  will  b e r e p ort e d t o t h e 
I R B  wit hi n t e n ( 1 0)  w or ki n g  d a ys  of  b ei n g  m a d e  k n o w n t o t h e  PI.   
c.   E v e nts t h at  ar e  m or e fr e q u e nt t h a n  a nti c ip at e d  or  m or e s e v er e t h a n  e x p e ct e d  m ust  b e 
r e p ort e d t o t h e I R B  wit hi n t e n ( 1 0)  w or ki n g  d a ys  of  b ei n g  m a d e  k n o w n t o t h e  PI. 
d.   All   u n a nti ci p at e d  d e at hs  m ust  b e r e p ort e d t o t h e I R B  wit hi n  2 4  h o urs  of  b ei n g  m a d e 
k n o w n t o t h e  PI. 
B.   S p o ns or  E x p e dit e d  R e p orti n g  –  G e n e nt e c h, I n c.   
a.   T h e  PI  is  als o r e q uir e d t o  c o m pl y  wit h  all r e p orti n g r e q uir e m e nts  as s u p pli e d  b y t h e 
I n v esti g ati o n al  Dr u g  S p o ns or(s).  
 
b.   I n v esti g at ors  m ust r e p ort  all  S A Es  wit hi n t h e ti m eli n es  d es cri b e d  b el o w.  T h e 
c o m pl et e d  M e d w at c h/ c as e r e p ort s h o ul d  b e f a x e d i m m e di at el y  u p o n  c o m pl eti o n t o 
G e n e nt e c h  D r u g  S af et y   at: ( 6 5 0)  2 2 5  4 6 8 2 O R  ( 6 5 0)  2 2 5  4 6 3 0. Pl e as e  us e t h e 
“ G e n e nt e c h  S af et y  R e p orti n g  F a x  C o v er  S h e et ”  pr o vi d e d  at t h e  e n d  of t h e  pr ot o c ol. 
 
 
c.   R el e v a nt f oll o w- u p i nf or m ati o n s h o ul d  b e s u b mitt e d t o  G e n e nt e c h  D r u g  S af et y  as 
s o o n  as it  b e c o m es  a v ail a bl e  a n d/ or  u p o n r e q u est. 


C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  9 2  of  9 7  
 
 
d.   S eri o us  A E r e p orts t h at  ar e r el at e d t o t h e tr ast u z u m a b  e mt a nsi n e  a n d  A Es  of  S p e ci al 
I nt er est (r e g ar dl ess  of  c a us alit y)  will  b e tr a ns mitt e d wit hi n fift e e n ( 1 5)  c al e n d ar  d a ys 
of t h e  A w ar e n ess  D at e . 
 
e.   S eri o us  A E r e p orts t h at  ar e  u nr el at e d t o t h e tr ast u z u m a b  e mt a nsi n e  will  b e tr a ns mitt e d 
wit hi n t hirt y ( 3 0)  c al e n d ar  d a ys  of t h e  A w ar e n ess  D at e. 
 
f.  A d diti o n al  R e p orti n g  R e q uir e m e nts i n cl u d e t h e f oll o wi n g: 
•  All  N o n-s eri o us  A d v ers e  E v e nts  ori gi n ati n g fr o m t h e  St u d y  will  b e f or w ar d e d i n  a 
q u art erl y r e p ort.  
•   Pr e g n a n c y : If  a f e m al e s u bj e ct  b e c o m es  pr e g n a nt  w hil e r e c ei vi n g t h e st u d y  dr u g(s) or 
wit hi n   9 0   d a ys   aft er  t h e  l ast   d os e   of  st u d y   dr u g,   a  r e p ort  s h o ul d   b e   c o m pl et e d   a n d  
e x p e diti o usl y s u b mitt e d.  A n y r e p orts  of  pr e g n a n c y f oll o wi n g t h e st art  of  a d mi nistr ati o n 
wit h t h e tr ast u z u m a b  e mt a nsi n e  will  b e tr a ns mitt e d  wit hi n t hirt y ( 3 0)  c al e n d ar  d a ys  of t h e 
A w ar e n ess  D at e .  F oll o w-u p t o  o bt ai n t h e  o ut c o m e  of t h e  pr e g n a n c y s h o ul d  als o  o c c ur.  
A b orti o n,  w h et h er  a c ci d e nt al, t h er a p e uti c,  or s p o nt a n e o us, s h o ul d  al w a ys  b e  cl assifi e d  as 
s eri o us,  a n d  e x p e diti o usl y r e p ort e d  as  a n  S A E.   Si mil arl y,  a n y  c o n g e nit al  a n o m al y/ birt h 
d ef e ct i n  a  c hil d  b or n t o  a f e m al e s u bj e ct  e x p os e d t o t h e tr ast u z u m a b  e mt a nsi n e s h o ul d  b e 
r e p ort e d as  a n  S A E.  
  
A d diti o n al i nf or m ati o n  o n  a n y tr ast u z u m a b  e mt a nsi n e -e x p os e d   pr e g n a n c y a n d i nf a nt  will 
b e r e q u est e d  b y  R o c h e  Dr u g  S af et y  at s p e cifi c ti m e  p oi nts (i. e.  aft er  h a vi n g r e c ei v e d t h e 
i niti al r e p ort,  at t h e  e n d  of t h e s e c o n d tri m est er,  2  w e e ks  after t h e  e x p e ct e d  d at e  of  d eli v er y, 
a n d  at  3,  6,  a n d  1 2  m o nt hs  of t h e i nf a nt’s lif e). 
 
g.   P ost- St u d y  A d v ers e  E v e nts:  T h e i n v esti g at or s h o ul d  e x p e diti o usl y r e p ort  a n y  S A E 
o c c urri n g  aft er  a s u bj e ct  h as  c o m pl et e d  or  dis c o nti n u e d st u d y  p arti ci p ati o n if 
attri b ut e d t o  pri or tr ast u z u m a b  e mt a nsi n e  e x p os ur e. If t h e i n v esti g at or s h o ul d  b e c o m e 
a w ar e  of t h e  d e v el o p m e nt  of  c a n c er  or  a  c o n g e nit al  a n o m al y i n  a s u bs e q u e ntl y 
c o n c ei v e d  offs pri n g  of  a f e m al e s u bj e ct  w h o  p arti ci p at e d i n t h e st u d y, t his s h o ul d 
( als o)  b e r e p ort e d  as  a n  S A E. 
h.   A Es  of  S p e ci al I nt er est  ( A E SIs):  A Es  of  S p e ci al I nt er est  ar e  d efi n e d  as  a  p ot e nti al 
s af et y  pr o bl e m, i d e ntifi e d  as  a r es ult  of s af et y  m o nit ori n g  of t h e  pr o d u ct.  T h e 
tr ast u z u m a b  e mt a nsi n e  E v e nts  of  S p e ci al I nt er est  ar e: 
•  C ar di a c  e v e nts 
•  T hr o m b o c yt op e ni a ( Gr a d e  ≥  3)  
•  H e p ati c  e v e nts ( Gr a d e  ≥  3  A S T,  A S L T  or t ot al  bilir u bi n  el e v ati o ns  or r u g-
I n d u ct e d  Li v er i nj ur y ( n o n-s eri o us  a n d s eri o us)) 
• I nf usi o n  Ass o ci at e d  R e a cti o ns,  H y p ers e nsiti vit y 
•  E m br y of et al  T o xi cit y  or  Birt h  D ef e cts 
 




C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  9 4  of  9 7  
 
A P P E N DI X  C:  P E R F O R M A N C E  S T A T U S  S C A L E S  
 
 
 
As  p u blis h e d i n  A m  J  Cli n  O n c ol :  O k e n  M M,  Cr e e c h  R H,  T or m e y  D C,  H ort o n J,  D a vis  T E, 
M c F a d d e n  E T,  C ar b o n e  P P.  T o xi cit y  a n d  R es p o ns e  Crit eri a  of t h e  E ast er n  C o o p er ati v e 
O n c ol o g y  Gr o u p.  A m J  Cli n  O n c ol  1 9 8 2; 5: 6 4 9- 6 5 5.  T h e  E ast er n  C o o p er ati v e  O n c ol o g y  Gr o u p, 
R o b ert  C o mis,  M D,  Gr o u p  C h air.  
 
 




C O N FI D E N TI A L  
 
V ersi o n  N u m b er : 3. 0 
e Pr ost #  2 0 1 5 1 0 5 5 
 
V ersi o n  D at e:  2 8 N O V 2 0 1 7 
P a g e  9 6  of  9 7  
 
A P P E N DI X  E :  A L G O RI T H M  F O R  C O N TI N U A TI O N  &  DI S C O N TI N U A TI O N  O F 
T R A S T U Z U M A B  E M T A N SI N E  B A S E D  O N  L E F T  V E N T RI C U L A R  E J E C TI O N 
F R A C TI O N  A S S E S S M E N T S I N  P A TI E N T S