Phase I Trial of Endoxifen Gel Versus Placebo Gel in Women Undergoing Breast Surgery
Phase: PHASE1
Conditions: Breast Ductal Carcinoma In Situ, Breast Lobular Carcinoma In Situ, Stage 0 Breast Cancer AJCC v6 and v7, Stage I Breast Cancer AJCC v7, Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage II Breast Cancer AJCC v6 and v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7, Stage III Breast Cancer AJCC v7, Stage IIIA Breast Cancer AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 1 –  
C O V E R P A G E  
  
  
  
  
 
D C P P r ot oc ol #:   
N W U 2 0 1 7- 0 9- 0 1 
 
L oc al P r ot oc ol #:   N CI 2 0 1 7- 0 9- 0 1 
 
P H A S E I T RI A L O F E N D O XI F E N G E L V E R S U S P L A C E B O G E L I N W O M E N U N D E R G OI N G 
B R E A S T S U R G E R Y    
 
C o ns orti u m  N a me:    
 
N ort h wester n Ca ncer Pre ve nti o n C o ns orti u m 
 
Or g a niz ati o n N a me:  
N ort h wester n U ni versit y  
N a me of C o ns orti u m Pri nci p al  
See ma A. K ha n, M. D. 
I n vesti g at or:    
  
 
3 0 3 E. S u peri or, S uite 4- 1 1 1  
 
 
C hica g o, I L 6 0 6 1 1 
 
 
T el: ( 3 1 2) 5 0 3 - 4 2 3 6 
 
 
Fa x: ( 3 1 2) 5 0 3 - 2 5 5 5 
 
  
E-mail: s k ha n @ n m. or g  
 
  
  
 
Or g a niz ati o n N a me:  
 
N ort h wester n U ni versit y  
P r ot oc ol Pri nci p al   
  
See ma A. K ha n, M. D. 
I n vesti g at or a n d P r ot oc ol C h air: Pr ofess or of S ur ger y  
 
  
3 0 3 E. S u peri or, S uite 4- 1 1 1 
 
  
C hica g o, I L 6 0 6 1 1 
 
 
T el: ( 3 1 2) 5 0 3 - 4 2 3 6 
 
 
Fa x: ( 3 1 2) 5 0 3 - 2 5 5 5 
 
  
E-mail: s k ha n @ n m. or g  
 
Or g a niz ati o n:    
  
 
Me m orial Sl oa n -Ketteri n g Ca ncer Ce nter  
I n vesti g at or:    
  
 
Melissa Pile ws kie, M . D. 
  
  
  
  
 
E vel y n H. La u der Breast Ce nter  
  
  
  
  
  
3 0 0 East 6 6t h Street  
  
  
  
  
  
Ne w Y or k, N Y 1 0 0 6 5 
  
  
  
  
 
T el: 6 4 6 - 8 8 8- 4 5 9 0 
  
  
  
  
  
Fa x: 6 4 6- 8 8 8- 4 9 2 1 
  
  
  
  
  
E-mail: pile ws k m @ ms kcc. or g  
 
Or g a niz ati o n:    
  
 
Ce dars -Si nai Me dical Ce nter  
I n vesti g at or:    
  
 
Sc ott Karla n, M . D. 
  
  
  
  
  
Sa ul a n d J o yce Bra n d ma n Breast Ce nter i n t he Sa m uel Osc hi n  
  
  
  
  
 
Ca ncer Ce nter  
  
  
  
  
  
3 1 0 N. Sa n Vice nte Bl v d., R o o m 3 1 4 
  
  
  
  
  
West H oll y w o o d, C A 9 0 0 4 8- 1 8 1 0 
  
  
  
  
 
T el: ( 3 1 0) 4 2 3- 9 3 3 1   
  
  
  
  
 
Fa x: ( 3 1 0) 4 2 3- 9 3 3 9 
  
  
  
  
  
E-mail: Karla n S @cs hs. or g   
 
Or g a niz ati o n:  
 
N ort h wester n U ni versit y  
St atistici a n:  
 
Mas ha K oc her gi ns k y , P h. D. 
 
 
6 8 0 N. La ke S h ore Dr., S uite 1 4 0 0  

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 2 –  
 
  
C hica g o, I L 6 0 6 1 1                                                        
T ele p h o ne: ( 3 1 2) 5 0 3- 4 2 2 4 
    
 
Fa x: ( 3 1 2) 9 0 8- 9 5 8 8 
 
 
E mail: m k oc her g @ n ort h wester n.e d u  
 
I N D S p o ns or:   
N CI/ Di visi o n of Ca ncer Pre ve nti o n  
I N D #    
 
 
A ge nt(s) / S u p plier: 
Nati o nal Ca ncer I nstit ute  
N CI C o ntr act #  
H H S N 2 6 1 2 2 0 1 2 0 0 0 3 5I  
P r ot oc ol Te m pl ate:  
Versi o n 8. 5 0 8/ 3 1/ 2 0 1 6 
 
P r ot oc ol Versi o n D ate:  Ma y 1 1 , 2 0 2 0 
 
P r ot oc ol Re visi o n or    
A me n d me nt #     
Versi o n 6. 5 
 
 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 3 –  
S C H E M A  
 
N W U 2 0 1 7- 0 9- 0 1: P h ase I tri al of e n d o xife n gel vers us pl ace b o gel i n w o me n u n der g oi n g 
bre ast s ur ger y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
1: Mastect o m y f or sta ge 0 -III breast ca n cer t h era p y or pr o p h yla xis ( B R C A m utati o n carriers, w o me n wit h str o n g    
                    fa mil y hist or y or l o b ular carci n o ma i n sit u or ot h er c o n diti o ns w h ere pr o p h ylactic mast ect o m y h as b ee n electe d)  
 
2: If m ore t h a n o n e s u bject e x p erie n ces d ose -li miti n g t o xicit y i n C o h ort 1, t h e c o h ort will b e e xte n d e d t o i n cl u d e a n  
    
                    a d diti o n al 6 s u bjects: 1 0 m g d ail y 3 E n d o xife n gel ( 4) vs. place b o gel ( 2).  
 
3: 1 0 m g d ail y , a p plie d 5 m g p er breast  
  
4: 2 0 m g d ail y, a p plie d 1 0  m g p er breast  
  
5: Alt h o u g h n o m ore t h a n o n e s u bject e x perie n ce d d ose -li miti n g t o xicit y i n C o h ort 2, i nteri m a n al ysis s h o we d m ore  
                    s ki n irritati o n a n d n o p er me ati o n  a d va nta ge wit h hi g h er d ose. T h eref ore, 1 0  m g d ail y d osa ge will b e use d  f or  
                    C o h ort 3.  
   
 
6: All s u bjects will u n d er g o mast ect o m y at 2 1 -2 8 d a ys. If s ur ger y n ee ds t o b e d ela ye d, a n a d diti o n al 7 d a ys of  
   
                    treat me nt is all o we d.     
 
 
W o me n sc he d ule d f or mastect o m y
1  
Scree ni n g Visit 1 –  c o nse nt, baseli ne tests, B E S S Q, s ki n p h ot os  
2: 1 Ra n d o mizati o n i n C o h orts 1 a n d 2. A ll s u bjects i n C o h ort 3 
will recei ve acti ve a ge nt wit h o ut ra n d o mizati o n .  
A ma xi m u m of 3 8  s u bjects will be e nr olle d. 
 
         C o h ort 1 2: 1 0 m g d ail y 3 E n d o xife n gel ( 8) vs. place b o  gel  ( 4) 
         C o h ort 2:  2 0 m g d ail y 4 E n d o xife n gel ( 8) vs. place b o  gel  ( 4) 
         C o h ort 3: 1 0 m g 5 E n d o xife n gel ( 8)  
 
 
Dail y treat me nts t o b ot h breasts f or 2 1 -2 8 da ys 6  
W ee kl y p h o ne calls f or c o m plia nce  a n d A E assess me nt  
St u d y Visit 1: E n d of st u d y tre at me nt tests, B E S S Q, s ki n p h ot os  
St u d y Visit 2: Mastect o m y pr oce d ure  
St u d y Visit 3: 7 -1 4 da y p ost -o p visit    
Fi nal p h o ne call/e mail/te xt messa ge at 6 0 da ys  
 
E n d p oi nts  
1)  S ki n t o xicit y e val uati o n usi n g C T C A E v 4  
2)   Dr u g c o nce ntrati o n i n breast tiss ue a n d bl o o d  
3)  Breast tiss ue bi o mar kers of e n d o xife n effect  
4)  C oa g ulati o n pr otei ns mea s ures of s yste mic estr o ge nicit y in plas ma  
5)  F ut ure st u dies of dr u g met a b olis m ge nes i n ger mli ne D N A fr o m   
     peri p heral bl o o d ( B uff y C o at) f or D N A/ R N A is olati o n  ( o pti o nal) 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 4 –  
T A B L E O F C O N T E N T S  
 
C O V E R P A G E .............................................................................................................................................. 1 
S C H E M A  ...................................................................................................................................................... 3 
1.  
O BJ E C TI V E S  ..................................................................................................................................... 6 
1. 1  
Pri mar y O bj ecti ve  ........................................................................................................................................ 6 
1. 2  
Sec o n dar y O bj ecti ves  .................................................................................................................................. 6 
2.  
B A C K G R O U N D ................................................................................................................................. 6 
2. 1  
Nee d f or ne w a p pr oac hes f or w o me n wit h d uct carci n o ma i n sit u a n d t h ose at hi g h ris k  ........................... 6 
2. 2  
E n d o xife n  ..................................................................................................................................................... 7 
2. 3  
Rati o nale  ...................................................................................................................................................... 9 
3.  
S U M M A R Y O F S T U D Y P L A N  ...................................................................................................... 1 0 
4.  
P A R TI CI P A N T S E L E C TI O N  .......................................................................................................... 1 2 
4. 1  
I ncl usi o n Criteria ....................................................................................................................................... 1 2  
4. 2  
E x cl usi o n Criteria  ...................................................................................................................................... 1 3  
4. 3  
I ncl usi o n of W o me n a n d Mi n orities .......................................................................................................... 1 4  
4. 4  
Recr uit me nt a n d Rete nti o n Pla n  ................................................................................................................ 1 4  
5.  
A G E N T A D MI NI S T R A TI O N  .......................................................................................................... 1 5 
5. 1  
D ose Re gi me n a n d D ose Gr o u ps  ............................................................................................................... 1 5  
5. 2  
St u d y A ge nt A d mi nistrati o n  ...................................................................................................................... 1 6  
5. 3  
R u n -i n Pr oce d ures ..................................................................................................................................... 1 6  
5. 4  
C o ntrai n dicati o ns  ....................................................................................................................................... 1 6  
5. 5  
C o nc o mita nt Me dicati o ns  .......................................................................................................................... 1 6  
5. 6  
D ose M o dificati o n  ..................................................................................................................................... 1 7  
5. 7  
A d here nce/ C o m plia nce  .............................................................................................................................. 1 7  
6.  
P H A R M A C E U TI C A L I N F O R M A TI O N  ......................................................................................... 1 7 
6. 1  
St u d y A ge nt (I N D  
, N CI, Di visi o n of Ca ncer Pre ve nti o n)  ............................................................ 1 7  
6. 2  
Re p orte d A d verse E ve nts a n d P ote ntial Ris ks  ........................................................................................... 1 7  
6. 3  
A vaila bilit y  ................................................................................................................................................ 2 0  
6. 4  
A ge nt Distri b uti o n  ..................................................................................................................................... 2 0  
6. 5  
A ge nt Acc o u nta bilit y  ................................................................................................................................. 2 0  
6. 6  
P ac ka gi n g a n d La beli n g  ............................................................................................................................. 2 0  
6. 7  
St ora ge  ....................................................................................................................................................... 2 0  
6. 8  
Re gistrati o n/ Ra n d o mizati o n  ...................................................................................................................... 2 1  
6. 9  
Bli n di n g a n d U n bli n di n g Met h o ds  ............................................................................................................. 2 1  
6. 1 0  A ge nt Destr ucti o n/ Dis p osal  ....................................................................................................................... 2 2  
7.  
C LI NI C A L E V A L U A TI O N S A N D P R O C E D U R E S  ...................................................................... 2 2 
7. 1  
Sc he d ule of E ve nts  .................................................................................................................................... 2 2  
7. 2  
B aseli ne T esti n g/ Pre -st u d y E val uati o n ...................................................................................................... 2 3  
7. 3  
E val uati o n D uri n g St u d y I nter ve nti o n  ....................................................................................................... 2 4 
7. 4  
E val uati o n at C o m pleti o n of St u d y I nter ve nti o n  ....................................................................................... 2 5  
7. 5  
P ost -i nter ve nti o n F oll o w-u p P eri o d  ........................................................................................................... 2 5  
8.  
C RI T E RI A F O R E V A L U A TI O N A N D E N D P OI N T D E FI NI TI O N ............................................... 2 6 
8. 1  
Pri mar y E n d p oi nt  ....................................................................................................................................... 2 6  
8. 2  
Sec o n dar y E n d p oi nts  ................................................................................................................................. 2 6  
8. 3  
Off -A ge nt Criteria  ..................................................................................................................................... 2 8  
8. 4  
Off -St u d y Criteria  ...................................................................................................................................... 2 8  
8. 5  
St u d y T er mi nati o n  ..................................................................................................................................... 2 8  
9.  
C O R R E L A TI V E/ S P E CI A L S T U DI E S  ............................................................................................ 2 8 
9. 1  
Rati o nale f or Met h o d ol o g y Selecti o n  ........................................................................................................ 2 8  
9. 2  
C o m para ble Met h o ds  ................................................................................................................................. 2 9  
1 0.  
S P E CI M E N M A N A G E M E N T  ......................................................................................................... 3 0 
1 0. 1  La b orat ories  ............................................................................................................................................... 3 0  
1 0. 2  C ollecti o n a n d Ha n dli n g Pr oce d ures  ......................................................................................................... 3 1  
1 0. 3  S hi p pi n g I nstr ucti o ns  ................................................................................................................................. 3 1  

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 5 –  
1 0. 4  Tiss ue B a n ki n g  .......................................................................................................................................... 3 1  
1 1.  
R E P O R TI N G A D V E R S E E V E N T S  ................................................................................................. 3 1 
1 1. 1  A d verse E ve nts  .......................................................................................................................................... 3 1  
1 1. 2  Seri o us A d verse E ve nts  ............................................................................................................................. 3 3  
1 2.  
S T U D Y M O NI T O RI N G  ................................................................................................................... 3 4 
1 2. 1  Data Ma na ge me nt  ...................................................................................................................................... 3 4  
1 2. 2  Cas e Re p ort F or ms  .................................................................................................................................... 3 5  
1 2. 3  S o urce D oc u me nts  ..................................................................................................................................... 3 5  
1 2. 4  Data a n d Safet y M o nit ori n g Pla n  ............................................................................................................... 3 5  
1 2. 5  S p o ns or or F D A M o nit ori n g  ...................................................................................................................... 3 5  
1 2. 6  Rec or d Rete nti o n  ....................................................................................................................................... 3 5  
1 2. 7  Cli nical S u p pl y A gree me nt  ........................................................................................................................ 3 6  
1 3.  
S T A TI S TI C A L C O N SI D E R A TI O N S  .............................................................................................. 3 7 
1 3. 1  St u d y Desi g n/ Descri pti o n  .......................................................................................................................... 3 7  
1 3. 2  Ra n d o mizati o n/ Stratificati o n  ..................................................................................................................... 3 7  
1 3. 3  Accr ual a n d Feasi bilit y  .............................................................................................................................. 3 7  
1 3. 4  Pri mar y O bj ecti ve, E n d p oi nt(s), A nal ysis Pla n  ......................................................................................... 3 8  
1 3. 5  Sec o n dar y O bj ecti ves, E n d p oi nts, A nal ysis Pla ns  ..................................................................................... 3 8  
1 3. 6  Re p orti n g  a n d E xcl usi o ns  .......................................................................................................................... 3 8  
1 3. 7  E val uati o n of T o xicit y  ............................................................................................................................... 3 9  
1 3. 8  E val uati o n of Res p o nse  ............................................................................................................................. 3 9  
1 3. 9  I nteri m A nal ysis......................................................................................................................................... 3 9  
1 3. 1 0  A ncillar y St u dies  ....................................................................................................................................... 3 9  
1 4.  
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  ................................................................ 3 9 
1 4. 1  F or m F D A 1 5 7 2  ......................................................................................................................................... 3 9  
1 4. 2  Ot her Re q uire d D oc u me nts  ....................................................................................................................... 3 9  
1 4. 3  I nstit uti o nal Re vie w B oar d A p pr o val ........................................................................................................ 4 0  
1 4. 4  I nf or me d C o nse nt ...................................................................................................................................... 4 0  
1 4. 5  S u b missi o n of Re g ulat or y D o c u me nts  ....................................................................................................... 4 1  
1 4. 6  Ot her  .......................................................................................................................................................... 4 1  
1 5.  
FI N A N CI N G, E X P E N S E S, A N D/ O R I N S U R A N C E  ...................................................................... 4 1 
R E F E R E N C E S  ........................................................................................................................................... 4 2 
C O N S E N T F O R M  ...................................................................................................................................... 4 5 
A P P E N DI X A  ............................................................................................................................................. 5 7 
A P P E N DI X B  ............................................................................................................................................. 5 8 
A P P E N DI X C  ............................................................................................................................................. 59  
A P P E N DI X D  ............................................................................................................................................. 6 1 
A P P E N DI X E  ............................................................................................................................................. 6 4 
A P P E N DI X F .............................................................................................................................................. 6 6 
A P P E N DI X G  ............................................................................................................................................. 74  
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 6 –  
1. 
O B J E C TI V E S  
 
1. 1 
P ri m ar y O bjecti ve  – T he pri mar y o bj ecti ve is t o esta blis h t he der mal t olera bilit y a n d safet y of 
  
e n d o xife n ( E N X) gel a d mi nistere d t o picall y t o b ot h breasts at t w o d oses: 1 0  m g d ail y  ( 5 m g per 
 
breast)  a n d 2 0 m g dail y ( 1 0 m g per breast)  i n c o m paris o n t o ve hicle place b o gel, usi n g o bj ecti ve 
 
assess me nt s base d o n C T C A E criteria.  
 
1. 2 
Sec o n d ar y O bjecti ves  
 
1. 2. 1  
T o m eas ure t he breast tiss ue c o nce ntrati o ns of ( E) a n d ( Z) is o mers of N- des met h yl- 4-
  
h y dr o x yta m o xife n ( EN X ) a n d 4- h y dr o x yta m o xife n ( 4-O H T)  at eac h d ose  ( 1 0 m g per da y a n d 2 0 
 
m g per da y) .  
1. 2. 2    T o m eas ure t he plas ma c o nce ntrati o ns of  ( E) a n d ( Z) is o mers E N X  a n d 4-O H T at eac h d ose  ( 1 0 
  
m g per da y a n d 2 0 m g per da y).  
1. 2. 3  
T o m eas ure plas ma h or m o ne le vels f or ster oi d h or m o nes (estra di ol, pr o gester o ne, 
  
de h y dr oe pia n dr oste ne di o ne [ D H E A], a n dr oste ne di o ne, test oster o ne) i n c o m paris o n t o ve hicle 
  
place b o gel. 
1. 2. 4  
T o m eas ure ser u m estr o ge nic  res p o nse t o t o pical E N X  gel t hera p y i n c o m paris o n t o ve hicle 
  
place b o gel (se x h or m o ne bi n di n g gl o b uli n a n d I G F pat h wa y pr otei ns).  
1. 2. 5 
T o a ssess c ha n ges i n c oa g ulati o n para meters ( Fact or VIII, Fact or I X, v W F, Pr otei n S) i n res p o nse 
 
t o E N X gel t hera p y i n c o m paris o n t o ve hicle place b o gel. 
1. 2. 6  
Usi n g pre- a n d p ost- t hera p y tiss ue sa m ples, t o e x pl ore t he p ote ntial t hera pe utic effects of t he t w o 
 
d oses of E N X  gel  i n c o m paris o n t o ve hicle place b o gel: a) b y I H C, Ki 6 7 la belli n g (f or cell 
  
pr oliferati o n), estr o ge n rece pt or ( E R), pr o gester o ne rece pt or ( P R) e x pressi o n (f or estr o ge n 
  
bl oc ka de); b) b y e x pressi o n of a pa nel of ge nes re p orte d t o c ha n ge wit h E N X  e x p os ure ( usi n g 
 
na n ostri n g assa ys ).  
1. 2. 7 
Ba n k  ger mli ne D N A f or f ut ure p o ole d a nal yses of p ol y m or p his ms i n ta m o xife n meta b olizi n g 
  
e nz y mes i n c o m paris o n t o ve hicle place b o gel ( o pti o nal). 
1. 2. 8 
T o assess s y m pt o ms relate d t o use of e n d o xife n gel  i n c o m paris o n t o ve hicle place b o gel, as 
 
assesse d b y t he  Breast Ca ncer Pre ve nti o n Trial ( B C P T) Ei g ht S y m pt o m Scale  ( B E S S) 
  
q uesti o n naire. 
 
2. 
B A C K G R O U N D  
 
2. 1 
Nee d f or ne w a p pr o ac hes f or w o me n wit h d uct c arci n o m a i n sit u a n d t h ose at hi g h 
ris k  
 
Des pite lar ge P hase III cli nical trials t hat ha ve esta blis he d t he s uccess of selecti ve estr o ge n rece pt or 
m o d ulat ors ( S E R Ms) f or breast ca ncer pre ve nti o n [ 1- 4] a n d t hera p y of d uct carci n o ma i n sit u ( D CI S)[ 5, 
6] , t he acce pta nce of ta m o xife n ( T A M) b y w o me n at hi g h ris k f or breast ca ncer has bee n l o w [ 7- 9]. 
Reas o ns i ncl u de q ualit y of life i m pair me nts, t he p ossi bilit y of seri o us si de effects, a n d rel ucta nce b y 
healt h y w o me n t o ta ke oral me dicati o n f or pre ve nti o n.  H o we ver, breast ca ncer pre ve nti o n re q uires o nl y 
t hat t he breast be e x p ose d t o t he dr u g; s yste mic e x p os ure is b ot h u n necessar y a n d har mf ul. F or e xa m ple, 5 
years of s yste mic e x p os ure wit h oral T A M lea ds t o be nefits t o t he breast a n d b o ne, b ut wit h c osts t o 
q ualit y of life, a n d healt h  [ 1 0- 1 2].  A n alter nati ve t o oral deli ver y is t hat of tra ns der mal deli ver y of dr u gs 
t hr o u g h t he breast s ki n; its a d va nta ges i ncl u de l o w s yste mic e x p os ure, t he a v oi da nce of fast he patic 
meta b olis m, a n d si m plicit y of a p plicati o n t hat will all o w disse mi nati o n acr oss t he gl o be. T heref ore, l ocal 
tra ns der mal t hera p y ( L T T) t o t he breast is li kel y t o i m pr o ve t he t olera bilit y a n d t he acce pta nce of 
p har mac ol o gical ca ncer pre ve nti o n re gi me ns b y w o me n.   
E xisti n g d at a o n L T T t o t he bre ast  are s u m marize d i n refere nce 1 3 [ 1 3], b ut i n brief a 
de vel o pi n g b o d y of e vi de nce s u g gests t hat s mall li p o p hilic m olec ules s uc h as 4 - h y dr o x yta m o xife n ( 4-

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 7 –  
O H T), tela prist o ne acetate ( T P A), E N X  a n d dicl ofe nac ca n be l ocall y c o nce ntrate d i n t he breast w he n 
a p plie d t o t he breast s ki n  [ 1 4- 1 7]. I n t he case of 4- O H T t here is cli nical data s u p p orti n g g o o d rete nti o n of 
dr u g i n t he breast wit h l o w s yste mic e x p os ure, lac k of first- pass he patic meta b olis m, a n d bi ol o gic ef fect 
o n breast ca ncer cells [ 1 5, 1 6]. F or dicl ofe nac t o o, we ha ve s h o w n rete nti o n i n t he breast wit h tra ns der mal 
deli ver y t hr o u g h t he breast ( b ut n ot t he a b d o mi nal) s ki n  [ 1 7], a n d f or T P A a n d E N X o ur precli nical 
st u dies de m o nstrate g o o d der mal per meati o n wit h hi g h c o nce ntrati o ns ac hie ve d i n t he ma m mar y gla n d 
w here t he dr u g was a p plie d tra ns der mall y  [ 1 7]. T he s u m of t hese cli nical a n d precli nical st u dies usi n g 
selecti ve estr o ge n rece pt or m o d ulat ors ( S E R Ms) a n d a C O X i n hi bit or y a ge nt lea d t o t he pr o p ositi o n t hat 
L T T t o t he breast is a via ble o pti o n f or w o me n re q uiri n g a nti-t u m or t hera p y deli vere d o nl y t o t he breast 
(i.e., w he n t here is n o re q uire me nt f or s yste mic t hera p y).    
T he u ni q ue fe at ures of t he bre ast pre dict t he s uccess of L T T ; t hese i ncl u de t he e m br y ol o gical 
ori gi n of t he breast as a s ki n a p pe n da ge (a m o difie d eccri ne gla n d) [ 1 8]  wit h a well - de vel o pe d i nter nal 
l y m p hatic circ ulati o n[ 1 9], a n d t he prese nce of a s u bc uta ne o us a n d retr o- ma m mar y fatt y e n vel o pe. 
Pre vi o us st u dies of L T T, i ncl u di n g o ur rece ntl y c o m plete d pre- o perati ve trial ( N W U 0 7 - 9- 0 3) testi n g 4-
h y dr o x yta m o xife n ( 4- O H T) gel i n w o me n wit h d uctal carci n o ma i n sit u ( D CI S), s u g g est t hat deli ver y is 
l ocal wit h mi ni mal s yste mic e x p os ure, a n d g o o d bi ol o gical effect[ 1 5, 1 6, 2 0]. Gi ve n rece nt e nc o ura gi n g 
data o n E N X , t he ot her maj or meta b olite of ta m o xife n (see bel o w), we perf or me d preli mi nar y testi n g of 
its der mal per meati o n . O ur res ults s u g geste d t hat E N X is i n fact m ore s uita ble t ha n 4-O H T f or 
tra ns der mal deli ver y[ 2 1], a n d le d us t o s u b mit a pr o p osal t o P R E V E N T/ D C P f or t he de vel o p me nt of a 
tra ns der mal f or m ulati o n of E N X. Base d o n o ur precli nical data wit h a n alc o h olic gel f or m ulati on of E N X  
c o ntai ni n g oleic aci d 0. 5 % ( v/ v), tra ns der mal gel s of 0. 5 % a n d 1 % ( w/ v) E/ Z E N X , G M P gra de,  ha ve  
n o w bee n f or m ulate d b y i n vesti gat ors of t he P R E V E N T Pr o gra m, a n d t o xicit y st u dies are u n der wa y, wit h 
pr ojecte d c o m pleti o n i n J u ne of 2 0 1 7 . T he ac q uisiti o n of precli nical t o xicit y data, as o utli ne d bel o w, n o w 
p ositi o ns us t o pr o p ose a P hase I safet y a n d p har mac o ki netic trial i n w o me n pla n ni n g mastect o m y. T his 
will  e na ble f ut ure cli nical trials i n w o me n at hi g h ris k f or breast ca ncer, a n d t h ose wit h D CI S.  
 
2. 2  
E n d o xif e n 
 
E N X  is p artic ul arl y well s uite d f or de vel o p me nt as a bre ast L T T a ge nt. Li ke 4-O H T, t he bi n di n g 
affi nities of E N X are 2 5 -f ol d greater f or E R α a n d 5 6-f ol d greater f or E R β t ha n t hat of T A M [ 2 2, 2 3].   It 
has bee n re p orte d t hat E N X a n d 4- O H T 
ha ve si milar a nti -pr oliferati ve acti vit y 
a n d selecti ve i n hi bit or y effects o n E R α  
tar get ge nes w he n a d mi n istere d at e q ual 
c o nce ntrati o ns i n breast ca ncer cells 
[ 2 2, 2 4] a n d b ot h E N X a n d 4 -O H T 
i n d uce si milar c ha n ges i n gl o bal ge ne 
e x pressi o n patter ns i n M C F-7 breast 
ca ncer cells [ 2 3].  H o we ver, rece nt data 
ha ve s u g geste d t hat mec ha nis m of E N X 
acti o n ma y differ fr o m 4 -O H T. W u et 
al. de m o nstrate d t hat u nli kel y 4 -O H T, E N X  tar gets E Rα  f or pr oteas o mal de gra dati o n si milar to t hat of t he 
f ul vestra nt (I CI 1 8 2 7 8 0), E R- d o w n re g ulat or- [ 2 5]. F urt her m ore, Ha wse et al., ha ve re p orte d t hat E N X -
me diate d recr uit me nt of E R α t o k n o w n tar get ge nes a n d gl o bal ge ne e x pressi o n patter n differs  fr o m t hat 
of 4- O H T a n d f ul vestra nt i n M C F cells  [ 2 6]. T his res ult c o ntrasts  t o Li m‘s earlier fi n di n g w hic h E N X 
re g ulates ge ne e x pressi o n si milar t o 4- O H T. B ot h st u dies ha ve use d differe nt c o ncertati o n of estr o ge n a n d 
dr u g c o ncertati o n i n c ult ure. T heref ore a h u ma n st u d y will be usef ul  t o i n vesti gate p ote ntial differe nces  i n 
mec ha nis m of  acti o n bet wee n E N X a n d 4 -O H T.  T he s pecific t o xicit y pr ofile of E N X is u n der st u d y, b ut 
res ults fr o m t he Ma y o gr o u p s u g gest t hat, i n ter ms of uteri ne wei g ht, l u mi nal e pit helial cell hei g ht, a n d 
cell pr oliferati o n i n t he str o ma a n d l u mi nal e pit heli u m of t h e uter us, E N X has si milar uter otr o p hic effects 
t o T A M w he n a d mi nistere d orall y t o rats [ 2 7].  If it s hares t he t o xicit y of t he pare nt dr u g T A M  a n d its 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 8 –  
der mal per meati o n is  e q ui vale nt t o t hat of 4 -O H T ( or better), E N X is a n e xcelle nt ca n di date f or L T T.  
A d diti o nall y, t he c he mical str uct ure of E N X w o ul d re n der it m ore s uita ble f or tra ns der mal deli ver y. It is 
s maller a n d m ore p olar t ha n 4-O H T; o ne met h yl gr o u p at a tertiar y a m i ne is re place d wit h a h y dr o ge n, 
res ulti n g i n a sec o n dar y a mi ne, w hic h is m ore h y dr o p hilic t ha n t he tertiar y a mi ne of 4- O H T.  Wit h t he 
a d diti o n of a per meati o n e n ha ncer s uc h as oleic aci d ( O A) w hic h ma kes t he strat u m c or ne u m fl ui dic  [ 2 8, 
2 9] a n d et ha n ol, w hic h gi ves a c o nti n u o us dri vi n g f orce [ 3 0, 3 1], E N X m o ves faster t hr o u g h t he s ki n t ha n 
4- O H T  [ 2 1]. T he a mi ne gr o u p of E N X ma y pr o vi de a fa v ora ble bala nce of h y dr o p hilic a n d h y dr o p h o bic 
pr o perties, ma ki n g E N X tra verse t he strat u m c or ne u m m ore easil y.    
 
Or al E N X  is well t olerate d i n a P hase I trial c o n d ucte d b y G oetz a n d c ollea g ues ( pers o nal 
c o m m u nicati o n). T he d ose escalati o n was halte d at  oral d oses u p t o 16 0  m g dail y  a n d t he l o n gest d urati o n 
of t hera p y bei n g 1 8 m o nt hs ( pr ot oc ol 8 8 2 1; N C T 0 1 3 2 7 7 8 1) d ue t o ac hie vi n g stea d y -state ser u m 
c o nce ntrati o ns of 4 µ M rat her t ha n f or t o xicit y . T he maj or t o xicit y c o nsiste d of Gra de 2 h ot flas hes . T he 
st u d y i ncl u de d d ose fi n di n g gr o u ps of 3 patie nts at eac h d ose a n d e x pa nsi o n c o h orts of 5 patie nts at 4 0, 
8 0, a n d 1 0 0 m g dail y. A m o n g t hese 3 7 Sta ge I V breast ca ncer patie nts treate d wit h oral d oses ra n gi n g 
fr o m 2 0 m g t o 1 0 0 m g dail y, Gra de 2  h ot flas hes occ urre d i n 5/ 3 7 ( 1 3. 5 %). T here were als o re p orts of 
fati g ue ( 3/ 3 7 or 8 %) a n d a n xiet y ( 1 patie nt) a n d irrita bilit y ( 1 patie nt). A variet y of ot her e ve nts were als o 
o bser ve d i n t his pre-treate d, Sta ge I V ca ncer p o p ulati o n, w hic h i ncl u de d h y pertri gl yceri de mia ( 1 patie nt), 
seiz ure ( 1 patie nt), t hr o m b oe m b olis m ( 1 patie nt), li m b e de ma ( 1 patie nt), a ne mia a n d h y p oal b u mi ne mia 
( 1 patie nt), slee p dist ur ba nce ( 2 patie nts), parest hesia ( 1 patie nt) a n d h y p o p h os p hate mia ( 1 patie nt). T his 
a ge nt is n o w bei n g c o m pare d wit h  oral ta m o xife n i n a P hase II trial i n  l ocall y a d va nce d or metastatic 
patie nts  (A 0 1 1 2 0 3), w here t he E N X  d ose is 8 0 m g dail y. O ur pre vi o us cli nical data wit h 4 -O H T gel a n d 
tra ns der mal dicl ofe nac, b ot h s h o w l o w circ ulati n g dr u g le vels wit h tra ns der mal deli ver y. T heref ore, we 
e x pect t hat s yste mic effects a n d t olera bilit y will be m ore fa v ora ble t ha n wit h t he oral a ge nt; ne vert heless, 
we will m o nit or t hese usi n g t he B E S S q uesti o n naire, as i n o ur pre vi o us st u dies.  
 
Tr a ns der m al d ose selecti o n : O ur i n vitr o ( h u ma n s ki n) [ 2 1]  a n d i n vi v o (r o de nt) data[ 1 7] de m o nstrates 
t hat E N X i n a 6 0 % ( v/ v) alc o h olic gel wit h 0. 5 %( v/ v) oleic aci d, pe netrates well a n d c o nce ntrates best i n 
t he ma m mar y gla n d t o w hic h it is a p plie d. ( Z) E N X citrate salt ( > 9 7 %)  fr o m Ji na P har mace uticals [ 3 2, 
3 3] was use d f or o ur i n vi v o a ni mal  st u d y.  Briefl y, i n a n o n-G L P  ( G o o d La b orat or y Practice) st u d y, we 
ra n d o mize d n u de rats i nt o f o ur gr o u ps: n o treat me nt, oral T A M ( 3 m g/ k g/ da y), 4-O H T gel ( 1 m g/ k g/ da y), 
E N X gel ( 1 m g/ k g/ da y), a n d treate d t he m dail y. T here were n o de at hs, n o wei g ht l oss, a n d n o ski n 
irrit ati o n at t he e n d of t he ex peri me nt.  Gj er de et al. ha ve re p orte d d ose -de pe n de nt i ncreases i n 
c o nce ntrati o ns of E N X f oll o wi n g a d mi nistrati o n of oral T A M, [ 3 4]. E N X c o nce ntrati o n i n n or mal breast 
tiss ue was n ot deter mi ne d; h o we ver, it is safe t o ass u me t hat t hese t o o will rise wit h i ncreasi n g oral (a n d 
tra ns der mal) d ose. O ur res ults fr o m a pre-s ur gical p hase II b trial of tra ns der mal 4- H y dr o x yta m o xife n 
vers us oral ta m o xife n i n w o me n wit h D CI S of t he breast ( N W U 0 7 - 9- 0 2) s h o we d t hat w o me n ta ki n g oral 
T A M 2 0 m g/ da y f or at least 6 wee ks ac hie ve d me dia n E N X c o nce ntrati o n of 8 n g/ g i n ma m mar y a di p ose 
tiss ue [ 1 6]. O ur precli nical data s h o we d t hat dail y oral T A M ( 3 m g/ k g/ da y) f or 6 wee ks ac hie ve d t he 
ma m mar y c o nce ntrati o n of 4- O H T a n d E N X of me dia n 4 ~ 5 n g/ g eac h i n rats  [ 1 7]. Plas ma E N X 
c o nce ntrati o n of w o me n treate d wit h 2 0 m g d ose of oral T A M dail y ( N W U 0 7- 9- 0 2) was 6 n g/ m L ( 1 6 
n M) [ 1 6]. Plas ma E N X c o nce ntrati o n of oral T A M-treate d rats ( 3 m g/ k g/ da y d ose) was 3 n g/ m L ( 8 n M), 
b ut 1. 8 n g/ m L ( 5 n M ) i n E N X-gel treate d rats ( 1 m g/ k g/ da y d ose)  [ 1 7]. T he h u m a n e q uiv ale nt d ose 
( H E D) of 3 m g/ k g/ d ay of or al T A M i n r ats is 0. 4 8 m g/ k g/ d ay or 2 8. 8 m g/ d ay per 6 0 k g w o me n a n d t he 
H E D of 1 m g/ k g/ d ay of 4- O H T or E N X gel i n r ats is 0. 1 6 m g/ k g/ d ay or  1 0 m g/ d ay  per 6 0 k g w o me n.  
P K – P D m o deli n g b y G o n g et al. s h o ws t u m or gr o wt h i n hi biti o n ( T GI) i n d ose-ra n gi n g e x peri me nts of 
oral ( Z) E N X i n M C F 7 xe n o graft beari n g mice  [ 3 5].  T heref ore, o ur a n d ot hers precli nical data s u g gest 
t hat o ur rat d ose of ( Z) E N X 1 m g/ k g/ da y (H E D 0. 1 6 m g/ k g/ d ay or 1 0 m g/ d ay per 6 0 k g w o me n ) is i n 
t he efficaci o us ra n ge, a n d gi ve n t he e x pecte d hi g h ma m mar y c o nce ntrati o ns, c o ul d p ote ntiall y be l o were d 
t o reac h t he mi ni mal effecti ve d ose. 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 9 –  
D ur ati o n of e x p os ure : t he p ur p ose of t his first-i n- h u ma n st u d y of E N X  gel f or m ulate d f or tra ns der mal 
E N X deli ver y  i n t he U S is t o esta blis h s ki n safet y a n d t o d oc u me nt der mal per meati o n. F or t hese 
p ur p oses, a d urati o n of 2 1- 2 8 da ys of e x p os ure will be s ufficie nt t o s h o w t hat t here is n o si g nifica nt s ki n 
irritati o n ca use d b y E N X, t he carrier gel, or t he oleic aci d use d f or per meati o n e n ha nce me nt. St u dies of 
si milar a ge nts ( 4- O H T gel a n d tela prist o ne gel) a p plie d t o t he breast s ki n ha ve s h o w n e xcelle nt s ki n 
t olera bilit y, a n d if t his E N X  gel f or m ulati o n s h o ws si milar res ults, we will t he n pla n st u dies wit h l o n ger 
e x p os ure. 
 
E N X  ( E: Z = 5 0: 5 0) gel pr o d ucts - 0. 5 % a n d 1 % ( w/ v), GM P  gr a de: T he N CI P R E V E N T pr o gra m has 
de ve l o pe d E N X tra ns der mal alc o h olic gel pr o d ucts wit h 0. 5 % oleic aci d as a per meati o n e n ha ncer. ( Z) 
E N X free -base i n s oli d f or m is sta ble ( data n ot s h o w n) a n d relati vel y sta ble i n et ha n ol wit h a Ma x 
s ol u bilit y of ~ 5 0 m g/ m L ( Et O H). L o n g ter m sta bilit y testi n g ( ~ 6 m o nt h) was perf or me d o n t he 0. 5 % a n d 
1. 0 % ( w/ v) E/ Z E N X mi xt ure f or m ulati o n.  O verall, b ot h f or m ulati o ns a p pear sta ble o ver ti me  (less t ha n 
3 % de gra dati o n).  A t otal v ol u me of  eac h gel pr o d uct is 9 0 m L.  O ne p u m p deli vers eac h d ose i n 1 m L or 
0. 8 9 8 5 g of gel pr o d uct. Eac h p u m p ( 1 m L) c o ntai ns 5 m g or 1 0 m g of ( E/ Z) E N X mi xt ure per breast 
w hic h c o ntai n 2. 5 m g or 5 m g ( Z) E N X per breast. C o nsi deri n g t he a p plicati o n t o b ot h breasts, t he fi nal 
dail y gel d oses will c o ntai n 5 m g or 1 0 m g of ( Z) E N X.  
 
2. 3 
R ati o n ale 
 
2. 3. 1 H y p ot heses 
O ur pri m ary hy p ot hesis  is t hat E N X  gel at 2 0 m g dail y ( 1 0 m g per breast) will be safe a n d t olera ble as 
assesse d o bjecti ve l y usi n g C T C A E criteria , i n c o m paris o n t o t he place b o gr o u p.   
O ur  seco n d ary  hy p ot heses  i ncl u de 1) t he breast tiss ue c o nce ntrati o ns of E N X  at will reac h t he 
c o nce ntrati o ns ac hie ve d i n o ur pri or st u d y of oral ta m o xife n vers us 4- O H T gel  ( 5. 8 n g/ g tiss ue) [ 3 6].   2) 
T he plas ma c o nce ntrati o ns of E N X  at eac h d ose ( 1 0 m g per da y a n d 20 m g per da y) will be si g nifica ntl y 
l o wer t ha n t h ose see n i n w o me n o n oral ta m o xife n. 3) Plas ma h or m o nes (estra di ol, pr o gester o ne, D H E A, 
a n dr oste ne di o ne, test oster o ne)  will n ot be c ha n ge d b y E N X gel use. 4) Cha n ges i n ser u m estr o ge nicit y 
(se x h or m o ne bi n di n g gl o b uli n a n d I G F pat h wa y pr otei ns) will be mi ni mal, if a n y . 5) Cha n ges i n 
c oa g ulati o n para meters ( Fact or V, Fact or VIII, v o n Wille bra n d fact or, Pr otei n S) will be mi ni mal, if a n y. 
6) Bi ol o gic e n d p oi nts s uc h as Ki 6 7 la beli n g i n de x, E R, a n d P R e x pres si o n, a n d e x pressi o n of a pa nel of 
ge nes re p orte d t o c ha n ge wit h E N X  e x p os ure , will be c o nsiste nt wit h a t hera pe utic effect of E N X  gel .  7)  
P ol y m or p his ms i n ta m o xife n meta b olizi n g e nz y mes will n ot affect breast tiss ue E N X  c o nce ntrati o n. T his 
h y p ot hesis will n ot be teste d i n t he c urre nt st u d y, b ut ger mli ne D N A will be ba n ke d f or f ut ure p o ole d 
a nal yses of  tra ns der mall y vers us orall y a d mi nistere d ta m o xife n a n d meta b olites relati ve t o meta b olic 
efficie nc y f or oral ta m o xife n . Ba n ki n g of ger mli ne D N A f or f ut ure p o ole d a nal yses will be o pti o nal f or 
partici pa nts.  8) S y m pt o ms re p orte d wit h t he use of E N X gel will be si milar bet wee n treate d a n d place b o 
gr o u ps. 
 
2. 3. 2  
T he rati o nale f or e val uati n g t his a ge nt i n w o me n wit h D CI S a n d t h ose at hi g h ris k f or breast 
ca ncer  has bee n prese nte d a b o ve i n Secti o n 2 ( Bac k gr o u n d). H o we ver, t he tar get p o p ulati o n f or t he 
prese nt st u d y is w o me n w h o are sc he d ule d f or mastect o m y, eit her f or ris k re d ucti o n, or f or breast ca ncer 
or D CI S t hera p y. T h us w o me n wit h i n vasi ve breast ca ncer , w ho ha ve n ot recei ve d ne o-a dj u va nt 
treat me nt, will be i ncl u de d e ve n t h o u g h t he y are n ot t he ulti mate tar get p o p ulati o n f or tra ns der mal E N X  
gel t hera p y. T his is j ustifie d si nce t he pri mar y g oal is t o test s ki n safet y of t his a ge nt, a n d tra ns der mal 
per meati o n,  b ot h of w hic h ca n be well-acc o m plis he d i n a mastect o m y p o p ulati o n. W o me n wit h i n vasi ve 
ca ncer pla n ni n g t hera pe utic mastect o m y are u nli kel y t o  be har me d if t he y partici pate si nce t he d urati o n 
of i nter ve nti o n is s h ort, will n ot dela y t hera pe utic s ur ger y, a n d p oses mi ni mal ris k t o t he patie nt’s 
e ve nt ual ca ncer t hera p y w hic h will pr ocee d p ost -o perati vel y as cli nicall y i n dicate d. L iterat ure re vie w a n d 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 1 0 –  
perti ne nt precli nical, pil ot, a n d preli mi nar y a n d/ or u n p u blis he d data t o s u p p ort c o n d uct of t he trial is 
prese nte d i n Secti o n 2 ( Bac k gr o u n d).  
 
2. 3. 3  
We are pr o p osi n g t he first cli nical trial  of E N X  gel f or tra ns der mal deli ver y  i n t he U S. Alt h o u g h a 
si milar a ge nt, 4-O H T, is well t olerate d a n d safe, a P hase I st u d y d oc u me nti n g safet y a n d i n vi v o h u ma n 
s ki n per meati o n of E N X  gel is nee de d. C o m p o ne nts of e xci pie nts f or E N X gel trial c o nsist of oleic aci d 
[ 0. 5 % ( v/ v) or 0. 5 % ( w/ w)], et h yl alc o h ol [ 6 0% ( v/ v)  or 5 3 % ( w/ w)] , p h os p hate b uffer at p H 7. 0 [ 4 0 % 
( v/ v) or 4 4 % ( w/ w), a n d h y dr o x y pr o p yl cell ul ose [1. 5 % ( w/ v) or 1. 6 7 % ( w/ w)]  (see T a ble 1 B i n 
A p pe n di x G) .  T his gel f or m ulati o n is si milar t o t he c o m p o ne nts of place b o gel use d i n se veral 4- O H T  
h y dr oalc o h olic gel trials ( base d o n 4-O H T i n vesti gat or’s br oc h ure, Asce n d T hera pe utics I nc). Gelli n g 
material  ( h y dr o x y pr o p yl cell ul ose) a n d diss ol uti o n met h o d ( p h os p hate b uffer at ne utral p H) are t he sa me.  
Mai n differe nces are t hat o ur gel f or m ulati o n c o ntai ns less alc o h ol a n d uses oleic aci d , 0. 5 %, as a s ki n 
per meati o n e n ha ncer . Oleic aci d (cis- 9-octa dece n oic aci d) is a l o n g-rec o g nize d usef ul per meati o n 
e n ha ncer. Its utilit y is li kel y relate d t o its be nt cis-c o nfi g urati o n, w hic h a p pears t o dist ur b t he i ntercell ular 
li pi d pac ki n g of t he strat u m c or ne u m, t here b y re d uci n g its barrier f u ncti o n [ 3 7, 3 8]. Oleic aci d ( O A) as a 
dietar y s u bsta nce is G e nerall y R ec o g nize d as Safe ( G R A S), a n d is prese nt at c o nce ntrati o ns of u p t o 7 0 % 
i n oli ve oil a n d pea n ut oil. It is use d i n si x F D A-a p pr o ve d t o pical a n d tra ns der mal f or m ulati o ns ( ge neric 
test oster o ne gel, i mi q ui m o d crea m a n d ot hers). I nf or mati o n of i nacti ve i n gre die nts f or a p pr o ve d dr u gs is 
p u blicl y a vaila ble at  t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) we bsite li n ks (see T a ble s 2- 5 i n A p pe n di x 
G). T he F D A) all o ws a ma xi m u m a m o u nt  of O A  i n u nit d ose u p t o 2 5% ( w/ w) as a n i nacti ve i n gre die nt 
i n to pical  f or m ulati o ns. F or t he tra ns der mal patc h, O A d ose  s h o ul d n ot e xcee d 2 2 m g per da y. O ur 
f or m ulati o n c o ntai ns O A, 0. 5 % ( w/ w) w hic h it is clearl y at t he l o w e n d of t he ra n ge of a p pr o ve d pr o d ucts. 
Sec o n dl y, t he F D A all o w s et h yl alc o h ol < 7 0 % ( w/ w) f or tra ns der mal/t o pical r o ute. O ur f or m ulati o n 
c o ntai ns et h yl alc o h ol, 5 3 % ( w/ w) w hic h is less tha n a n o ver -t he-c o u nter healt hcare a ntise ptic , 6 1 % 
( w/ w) et h yl alc o h ol ( A va gar d, 3 M I nc.) (see T a ble 3 a n d Fi g ure 1 i n A p pe n di x G). Fi nall y , 
h y dr o x y pr o p yl cell ul ose a n d p h os p hate b uffer ha ve bee n wi del y use d t o t o pical/tra ns der mal dr u gs alrea d y 
a p pr o ve d b y t he F D A (see T a ble s 4 a n d 5 i n A p pe n di x G). Base d o n t h is F D A safet y i nf or mati o n, we 
str o n gl y belie ve t hat place b o gel will n ot ha ve ris k p ote ntial t o patie nts if it is a p plie d as directe d.   
 
2. 3. 4 R ati o n ale f or t o b acc o a n d alc o h ol use q uesti o n n aires: increasi n g e vi de nce s u g gests t hat t o bacc o 
a n d alc o h ol use are ris k fact ors i n t he de vel o p me nt of i ntrae pit helial ne o plasia a n d ca ncer. I n a d diti o n, 
t o bacc o a n d alc o h ol use ma y a d versel y affect a ge nt i nter ve nti o n, f or e xa m ple b y alteri n g t he safet y pr ofile 
o r meta b olis m of a dr u g. Sta n dar dize d assess me nts of t o bacc o a n d alc o h ol use d uri n g cli nical trials will 
ai d i n u n dersta n di n g t he p ote ntial relati o ns hi p bet wee n t he use of t hese pr o d ucts a n d cli nical e n d p oi nts or 
ca ncer pre ve nti o n bi o mar kers. T heref ore, N CI, D C P is i ncl u di n g a ssess me nt of t o bacc o a n d alc o h ol use at 
baseli ne a n d at st u d y Visit 1 , t o deter mi ne t he p ote ntial i m pact of t o bacc o a n d alc o h ol use o n 1) treat me nt 
t o xicit y a n d s y m pt o m b ur de n, a n d 2) t he efficac y of treat me nt i nter ve nti o n.  
 
3. 
S U M M A R Y  O F S T U D Y P L A N  
 
3. 1  
I n t his d o u ble- bli n d, ra n d o mize d P hase I trial, a ma xi m u m of 3 8 partici pa nts w h o are pla n ni n g 
mastect o m y ( u nilateral or bilateral, f or t hera p y or ris k -re d ucti o n) will be accr ue d i nt o eac h of t hree 
c o h orts. T he st u d y a ge nt is tra ns der mal  E N X  gel vers us place b o gel a p plie d t o t he breast s ki n, starti n g 
wit h  1 0 m g  E N X  gel  dail y a n d pr ocee di n g t o 2 0  m g dail y ( 5 m g a n d 1 0 m g t o eac h breast at eac h d ose 
le vel). T he E N X gel  a n d place b o gels c o ntai n  6 0 % ( v/ v) or 4 7. 4 % ( w/ v) alc o h olic s ol uti o n wit h 0. 5 % 
( v/ v) or 0. 4 5 % ( w/ v) oleic aci d.  T h e trial will be c o n d ucte d i n t he pre -s ur gical wi n d o w setti n g, e nr olli n g 
w o me n w h o nee d u nilateral or bilateral mastect o m y, wit h a treat me nt peri o d c o nsisti n g of a 2 8 da ys  ± 7 
da ys , lea di n g u p t o t he da y of mastect o m y. Accr ual will occ ur at N W U, M S K C C, a n d at Ce dars Si nai L os 
A n geles ( C S -L A).  
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 1 1 –  
3. 2. 1 
We pla n ne d  a 2: 1  (E N X : place b o) ra n d o mizati o n i n c o h ort 1 a n d c o h ort 2, w hile all c o h ort 3 
s u bj ects w o ul d recei ve acti ve gel at t he fi nal d ose, b ut w o ul d cease t hera p y 3 da ys pri or t o s ur ger y. Of t he 
t wel ve C o h ort 1 s u bjects, ei g ht recei ved E N X  gel 1 0 m g dail y ( 5 m g per breast) a n d f o ur  recei ved 
place b o. Si nce n o s u bj ect e x perie nce d d ose -li miti n g t o xicit y ( D L T) i n C o h ort 1, we pr ocee de d t o C o h ort 
2, w here 1 2 s u bj ects a g ai n were ra n d o mize d 2: 1. Ei g ht recei ve d E N X  gel 2 0 m g d ail y  ( 1 0 m g per breast) , 
a n d f o ur recei ve d place b o gel. We i nitiall y pla n ne d t hat if n o m ore t ha n o ne s u bject e x perie nces D L T, we 
w o ul d pr ocee d t o C o h ort 3, w here ei g ht s u bj ects w o ul d recei ve E N X  gel at 2 0 m g dail y ( 1 0 m g per 
breast) , b ut st o p gel a p plicati o n 3 da ys pri or t o s ur ger y.  A n i nteri m a nal ysis was c o n d ucte d after 
c o m pleti o n of C o h ort 2 a n d disc usse d o n A pril 1 3, 2 0 2 0. Alt h o u g h o nl y o ne s u bj ect i n C o h ort 2 
e x perie nce d D L T, we o bser ve d m o re s ki n irritati o n i n C o h ort 2 partici pa nts. There was n o per meati o n  
a d va nta ge wit h t he hi g her d osa ge. T heref ore, we deci de d  t o use a 1 0 m g dail y d ose f or C o h ort 3. Si nce 
dr u g c o nce ntrati o n i n t he breasts was  varia ble i n t he i nteri m a nal ysis, all C o h ort 3 s u bj ects will c o nti n ue 
dail y  a p plicati o n of st u d y dr u g u ntil t he da y pri or t o s ur ger y, i n or der t o better assess t he dr u g distri b uti o n 
i n t he breast. We e x pect a t otal of 8 s u bjects will c o m plete C o h ort 3, t heref ore a t otal of 3 2 s u bjects will 
c o m plete t he  st u d y. 
 
3. 2. 2  
Defi niti o n of D ose -Li miti n g T oxicity ( D L T) : f or t he p ur p oses of t his a ge nt, a n d t he a ntici pate d 
nee d f or l o n g -ter m t olera bilit y, we ha ve use d Gra de 2 or greater s ki n t o xicit y as t he D L T, usi n g C T C A E 
criter ia f or t he para meters s h o w n i n Ta ble 1. T he Gra de 2  or greater  reacti o n s h o ul d occ ur at t he 
a p plic ati o n site  f or 4 8 h o urs or l o n ger a n d be defi nitel y, pr o ba bl y, or p ossi bl y relate d t o t he st u d y dr u g t o 
be a ca use f or partici pa nt wit h dra wal.  After c o ns ultati o n wit h t he N CI D C P me dical m o nit or, a partici pa nt 
will be u n bli n de d i n t he e ve nt of a D L T . 
 
 
3. 3 
Partici pa nts will be gi ve n 1 ca nister of st u d y a ge nt , eac h c o ntai ni n g 9 0 m L of acti ve gel or 
place b o, at t he baseli ne visit .  Partici pa nts will ta ke st u d y a ge nt f or 2 1- 2 8  da ys.  T he st u d y will be 
ter mi nate d w he n 1) m ore t ha n 2 s u bjects e x perie nce Gra de 2 or greater t o xicit y (at a p plicati o n site f or 4 8 
h o urs or l o n ger , a n d defi nitel y , pr o ba bl y, or p ossi bl y relate d t o st u d y dr u g) i n C o h ort 1 a n d its e x pa nsi o n; 
or 2) ei g ht s u bjects c o m plete partici pati o n i n C o h ort 3.  
 
3. 4  
N o r u n-i n peri o d is pla n ne d. 
 
3. 5 
Ti me p oi nts f or perf or mi n g st u d y assess me nts f or pri mar y e n d p oi nt 
 
3. 5. 1 
Wee kl y p h o ne calls t o assess dr u g t olera bilit y, wit h s pecial e m p hasis o n s ki n reacti o ns if a n y.  If 
s ki n reacti o ns are re p orte d b y s u bj ects bet wee n st u d y visits , t he partici pa nt will be as ke d t o ta ke a 
p h ot o gra p h (a si n gle fr o ntal vie w of b ot h breasts, i n g o o d li g ht ).  T he partici pa nt will be pr o vi de d a 
pers o nalize d li n k via e mail, w here t he y ca n u pl oa d t he p h ot o gra p hs t o a sec ure R E D Ca p site. Dr . C h oi 
will ha ve access t o t his site a n d will e val uate t he p h ot os, a n d gra de t he m usi n g C T C A E criteria  usi n g t he 
para meters o utli ne d i n Ta ble 1 . If s he feels, or t he partici pa nt re q uests, a c o ns ultati o n, t his will be 
arra n ge d t o occ ur wit hi n t he ne xt 4 8 h o urs ( or 7 2 h o urs if t his ha p pe ns t o occ ur o ver a wee ke n d). T he N U 
der mat ol o gist is Dr. Je n nifer Na m C h oi; at M S K C C Dr. Mari o Lac o ut ure ; at Ce dars Dr. S usa n 
Ra biza de h . Pri or t o sc he d uli n g a c o ns ultati o n, Dr. La c o ut ure a n d Dr. Ra biza de h ma y  als o be gra nte d 
access t o p h ot os fr o m partici pa nts at t heir i nstit uti o ns t hr o u g h R E D Ca p.   
 
3. 5. 2 
Baseli ne a n d e n d - of-i nter ve nti o n p h ot os a n d s ki n t o xicit y assess me nt usi n g C T C A E criteria.  
T he p h ot o gra p hs will be ta ke n b y t he c o or di nat or as a  sta n dar dize d si n gle fr o ntal vie w of b ot h breasts (t he 
vie w will i ncl u de fr o m t he b ott o m of t he nec k t o bel o w t he breasts, a n d fr o m t he lateral si de of o ne breast 
t o t he lateral si de of t he ot her breast), a n d si de vie ws of eac h breast. T he y will be u pl oa de d t o N O TI S a n d 
vie we d b y Dr. C h oi f or sc ori n g. 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 1 2 –  
3. 6 
Me as ure me nts t ake n t o meet sec o n d ary st u dy o bjectives   
 
Scree ni n g Visit 1: At e ntr y f or c o nse nt, re vie w of eli gi bilit y, i nstr ucti o ns o n h o w t o a p pl y st u d y a ge nt, 
baseli ne s y m pt o m assess me nt, c o nc o mita nt me dicati o n re vie w, bl o o d dra w f or cli nical a n d researc h la bs , 
uri ne or ser u m pre g na nc y test i n w o me n of c hil d beari n g p ote ntial, last me nstr ual peri o d, B E S S 
q uesti o n naire, breast s ki n p h ot os, C T C A E criteria assess me nt,  a n d dis pe nsi n g st u d y  a ge nt.  
 
St u dy Visit 1 : Da y bef ore s ur ger y. S y m pt o m a n d a d verse e ve nt assess me nt, c o nc o mita nt me dicati o n 
re vie w, last me nstr ual peri o d, B E S S q uesti o n naire, breast s ki n p h ot os, C T C A E criteria assess me nt, a n d 
st u d y a ge nt c o m plia nce.   
 
St u dy Visit 2: Da y of  s ur ger y. Bl o o d dra w f or cli nical a n d researc h la bs, uri ne or ser u m pre g na nc y test i n 
w o me n of c hil d beari n g p ote ntial, p h ysical e xa m, me dical hist or y, a n d tiss ue f or researc h. St u d y visit 1 
a n d 2 ma y be c o m bi ne d o n da y of s ur ger y.  
 
St u dy Visit 3 : P ost - o perati ve visit. S y m pt o m a n d a d verse e ve nt assess me nt, c o nc o mita nt me dicati o n 
re vie w, last me nstr ual peri o d, breast s ki n p h ot os, a n d C T C A E criteria assess me nt . 
 
3. 7  
C li nical pr oce d ures, la b tests a n d ot her meas ure me nts ta ke n t o m o nit or effects a n d safet y of st u d y 
a ge nt .  
•  
S ki n e val uati o n t hr o u g h hist or y, p h ysical e xa mi nati o n ( d oc u me nte d b y s ki n p h ot o gra p hs a n d 
C T C A E criteria ).  T his will be perf or me d at st u d y e ntr y a n d at t he e n d of i nter ve nti o n.  
•  
Cli nical b l o o d tests pre a n d p ost i nter ve nti o n  t o esta blis h g o o d he mat ol o gic, re nal, a n d li ver 
f u ncti o n. 
•  
Researc h bl o o d tests pre a n d p ost i nter ve nti o n t o e val uate effects o n c oa g ulati o n pat h wa y pr otei ns 
a n d mar kers of s yste mic estr o ge nicit y.  
•  
Uri ne pre g na nc y test i n w o me n wit h c hil d beari n g p ote ntial ( pre a n d p ost i nter ve nti o n) 
•  
Breast size a n d b o d y mass i n de x ( B MI) pre i nter ve nti o n.  
•  
E xa mi nati o n of breast tiss ue a n d plas ma sa m ples f or dr u g c o nce ntrati o n (at t he e n d of 
i nter ve nti o n) a n d a ntiestr o ge nic effects of E N X  gel (c o m pari n g sa m ples o btai ne d pri or t o a n d 
f oll o wi n g i nter ve nti o n).  
 
3. 8  
D urati o n of st u d y: u p t o 7 da ys  bet wee n c o nse nt a n d start of i nter ve nti o n, 2 1 - 2 8 da ys of 
i nter ve nti o n, 7- 1 4 da ys after e n d of i nter ve nti o n. F or partici pa nts w h o nee d t o dela y s ur ger y, a n a d diti o nal 
7 da ys of t hera p y will be all o we d.  T h us t he mi ni m u m p eri o d o n-st u d y will be f o ur wee ks a n d t he 
ma xi m u m will be se ve n wee ks.  
 
4. 
P A R TI CI P A N T S E L E C TI O N 
 
4. 1 
I ncl usi o n Criteri a 
 
4. 1. 1 
W o me n sc he d ule d f or u nilateral or bilateral mastect o m y f or breast ca ncer t hera p y, pat h ol o g y 
c o nfir me d sta ge 0 -III (i ncl u di n g d uctal carci n o ma i n sit u), or pr o p h yla xis (B R C A 1/ 2  m utati o n carriers, 
w o me n wit h str o n g fa mil y hist or y or l o b ular carci n o ma i n sit u or ot her c o n diti o ns w here pr o p h ylactic 
mastect o m y has bee n electe d).  
 
4. 1. 2  
A ge ≥1 8 years (si nce breast ca ncer is n ot a pe diatric disease a n d n o safet y data are a vaila ble f or 
E N X  use i n c hi ldre n).  
 
4. 1. 3 
E C O G perf or ma nce stat us ≤1 ( Kar n ofs k y ≥7 0 %; see A p pe n di x A) . 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 1 3 –  
 
4. 1. 4 
Partici pa nts m ust ha ve a de q uate he patic a n d re nal f u ncti o n tests, as defi n e d bel o w. U p per li mits 
of n or mal ( U L N) refer t o t h ose e xisti n g at eac h accr ui n g i nstit uti o n.  
 
T otal bilir u bi n  … … … … … … … < 1. 5 X U L N  
  
(i n w o me n wit h pri or d oc u me nte d bilir u bi n ele vati o ns c o nsiste nt wit h Gil bert’s s y n dr o me, t otal 
  
bilir u bi n u p t o 3 X U L N will be all o we d). 
 
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  
 
Creati ni ne … … … … … … … …... < 2 X U L N  
 
Al kali ne p h os p hatase  … … … …  < 2. 5 X U L N  
  
Bl o o d Urea Nitr o ge n. … … …. ….< 2 X U L N  
 
4. 1. 5   A bilit y t o u n dersta n d a n d t he willi n g ness t o si g n a writte n i nf or me d c o nse nt d oc u me nt w hic h  
 i ncl u des a re q uire me nt t o a p pl y st u d y a ge nt t o se nsiti ve b o d y parts dail y.  
 
4. 1. 6    W illi n gness  a n d a bilit y t o sc he d ule mastect o m y 2 1- 2 8 da ys  f oll o wi n g start of st u d y a ge nt. 
W o me n wit h breast i m pla nts ma y partici pate.  
 
4. 1. 7  
Willi n g ness  t o a v oi d e x p osi n g breast s ki n t o nat ural or artificial s u nli g ht (i.e. ta n ni n g be ds) f or 
t he d urati o n of st u d y a ge nt d osi n g.  
 
4. 1. 8  
Ne gati ve uri ne or ser u m  pre g na nc y test res ult, f or partici pa nts of c hil d beari n g p ote ntial .  Fe male 
of c hil d - beari n g p ote ntial is a n y w o ma n (re gar dless of se x ual orie ntati o n, w het her s he has u n der g o ne a 
t u bal li gati o n, or re mai ns celi bate b y c h oice) w h o meets t he f oll o wi n g criteria: has n ot u n der g o ne a 
h ysterect o m y or bilateral o o p h orect o m y; A N D  has ha d a me nstr ual peri o d at a n y ti me i n t he prece di n g 1 2 
c o nsec uti ve m o nt hs).  
 
4. 1. 9  
T he effects of t o pical E N X gel o n t he de vel o pi n g h u ma n fet us are u n k n o w n. F or t his reas o n, 
w o me n of c hil d- beari n g p ote ntial a n d t heir male part ners m ust a gree t o use eff ecti ve f or ms of birt h 
c o ntr ol (a bsti ne nce is n ot a n all o we d met h o d) pri or t o st u d y e ntr y a n d f or t he d urati o n of st u d y 
partici pati o n. S h o ul d a w o ma n bec o me pre g na nt or s us pect s he is pre g na nt w hile partici pati n g i n t his 
st u d y, s he s h o ul d i nf or m her st u d y ph ysicia n i m me diatel y.  
 
4. 2 
E xcl usi o n Criteri a  
 
4. 2. 1 
T he prese nce of gr oss s ki n i n vasi o n/ ulcerati o n b y t he breast ca ncer, or i nfla m mat or y c ha n ges 
wit h s ki n e de ma A N D er yt he ma.  N ote: Pa get’s disease is per mitte d.  
 
4. 2. 2 
W o me n recei vi n g a “ ni p ple dela y” pr oce d ure pri or t o mastect o m y.  
 
4. 2. 3   W o me n wit h s ki n diseases ( ps oriasis, ecze ma) . 
 
4. 2. 4   A hist or y of t hr o m b oe m b olic dis o r der. 
 
4. 2. 5  
E n d o metrial i ntrae pit helial ne o plasia (als o k n o w n as at y pical h y per plasia) or a hi g h ris k of 
uteri ne ca ncer , defi ne d here as k n o w n carriers of L y nc h s y n dr o me m utati o ns ( M L H 1, M S H 2, M S H 6, 
P M S 2) . 
 
4. 2. 6 
Partici pa nts ma y n ot ha ve recei ve d a n y ot her i n vesti gati o nal a ge nts i n t he pre vi o us 3 m o nt hs.  
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 1 4 –  
4. 2. 7 
Hist or y of aller gic reacti o ns attri b ute d t o c o m p o u n ds of si milar c he mic al or bi ol o gic c o m p ositi o n 
t o ta m o xife n.  
 
4. 2. 8 
T a ke n ta m o xife n or ot her selecti ve estr o ge n/ pr o gester o ne rece pt or m o d ulat ors ( S E R Ms/ S P R Ms) 
wit hi n t w o years pri or t o e nteri n g st u d y or bee n re q uire d t o disc o nti n ue S E R M t hera p y d ue t o 
t hr o m b oe m b olic or uteri ne t o xicit y.  
 
4. 2. 9  
U nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o, o n g oi n g or acti ve i nfecti o n, 
s y m pt o matic c o n gesti ve heart fail ure, u nsta ble a n gi na pect oris, car diac arr h yt h mia, or ps yc hiatric 
ill ness/s ocial sit uatio ns t hat w o ul d li mit c o m plia nce wit h st u d y re q uire me nts. 
 
4. 2. 1 0 Hist or y of pri or breast ca ncer -s pecific t hera p y wit hi n t he pre vi o us 2 years (c he m ot hera p y, 
ra diati o n, a nti-H E R 2 a ge nts, e n d ocri ne a ge nts, e ver oli m us, C D K 4 -6 i n hi bit ors) . Pre vi o us u nilateral 
ra diati o n of t he c o ntralateral si de i n w o me n sc he d ule d f or mastect o m y is all o we d.  St u d y gel will be 
a p plie d t o b ot h breasts. 
 
4. 2. 1 1 Hist or y of pri or mastect o m y.   
 
4. 2. 1 2 Pre g na nt or breastfee di n g.  
 
4. 2. 1 3   Patie nts recei vi n g ne oa dj u va nt c he m ot hera p y wit h c urati ve i nte nt.  
 
4. 2. 1 4   Me n are e xcl u de d fr o m t his st u d y si nce breast ca ncer is me n is rare a n d t here are n o data 
re gar di n g s ki n pe netrati o n of t o pical breast ca ncer pre ve nti o n a ge nts t hr o u g h male c hest wall s ki n ( w hic h 
is t hic ker a n d harrier t ha n fe male c hest wall s ki n).    
 
4. 2. 1 5   C urre nt users of ot her t o pical me dicati o ns o n t he breast s ki n m ust be willi n g a n d a ble t o 
disc o nti n ue use f or t he d urati o n of partici pati o n. B o d y l oti o n a n d ot her n o n- me dici nal t o pical c o m p o u n ds 
ma y be a p plie d > 4 h o urs after st u d y gel a p plicati o n. 
 
4. 3 
I ncl usi o n of W o me n a n d Mi n orities 
 
Fe male me m bers of all races a n d et h nic gr o u ps are eli gi ble f or t his trial.  Me n are n ot eli gi ble, si nce  
breast ca ncer is me n is rare, t here are n o data re gar di n g s uccess of breast ca ncer  pre ve nti o n me dicati o ns i n 
me n, a n d me n are n ot i ncl u de d i n breast ca ncer pre ve nti o n a ge nt g ui deli nes. A d diti o nall y, t here are n o 
data re gar di n g s ki n pe netrati o n of t o pical breast ca ncer pre ve nti o n a ge nts t hr o u g h male c hest wall s ki n 
( w hic h is t hic ker a n d hairier t ha n fe male c hest wall s ki n).   
 
4. 4 
Recr uit me nt a n d Rete nti o n Pl a n  
 
Partici pa nts will be recr uite d at t he L y n n Sa ge Breast Ce nter of N ort h wester n U ni versit y ( N U), t he Breast 
Ser vice of Me m orial Sl oa n Ketteri n g Ca ncer Ce nter ( M S K C C), a n d t he Sa ul a n d J o yce Bra n d ma n Breast 
Ce nter of Ce dars- Si nai Me dical Ce nter ( C S M C); all w o me n u n der g oi n g mastect o m y f or a n y reas o n will 
be a p pr oac he d.  T he PI at eac h site a n d/ or desi g nate d staff will disc uss t he trial wit h g y nec ol o gists, 
pri mar y care p h ysicia ns, a n d o nc ol o gists of all disci pli nes at eac h ce nter.  Als o, patie nts will be pre -
scree ne d t hr o u g h cli nic visit lists. N U has re q ueste d a wai ver of c o nse nt fr o m t he CI R B t o s u p p ort 
scree ni n g of cli nic sc he d ules of me dical o nc ol o gists ( or s ur gical o nc ol o gists etc.) a n d re vie w of me dical 
rec or ds/re gistr y data t o i de ntif y p ote ntiall y eli gi ble partici pa nts t o c o ntact a b o ut st u d y partici pati o n. O nce 
e nr olle d, patie nts will be u n der t he s u per visi o n of t he Pri nci pal I n vesti gat or at eac h site ( Dr. See ma K ha n 
at N U, Dr. Meli ssa Pile ws kie at M S K C C, a n d Dr. Sc ott Karla n at C S M C).  Dr. K ha n will be res p o nsi ble 
f or t he o verall c o n d uct of t he st u d y.  I n di vi d uals c o m pleti n g t he st u d y will be rei m b urse d f or i nci de ntal 

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e x pe nses ass ociate d wit h t hese st u dies . S u bjects  will be rei m b urs e d $ 1 0 0 after c o m pleti o n of Scree ni n g 
Visit 1, $ 1 0 0 after c o m pleti o n of St u d y Visit 1 ( w hic h ma y be c o m bi ne d wit h St u d y Visit 2 da y of 
s ur ger y), a n d $ 1 0 0 after c o m pleti o n of St u d y Visit 3. S u bj ects w h o are re q uire d t o ret ur n t o t he office f or 
a pre g na nc y test visit will recei ve a n a d diti o nal $ 1 0 0.  Pa y me nts will be ma de at t he c o ncl usi o n of t he 
partici pati o n. T he da y -t o-d a y ma na ge me nt of patie nts will be u n der t he directi o n of Cli nical Researc h 
Office at eac h of t he Ca ncer Ce nters w here t he st u d y is t o be c o n d ucte d ( N U, M S K C C, a n d C S M C). 
 
A n u m ber of c o nti n ge nc y o pti o ns ca n be c o nsi dere d if recr uit me nt is bel o w pr ojecti o ns, 
1)  T he st u d y c o ul d be a me n de d t o i ncl u de w o me n pla n ni n g breast-c o nser vi n g s ur ger y. T his will still 
all o w t he assess me nt of s ki n safet y, a n d  a n assess me nt of dr u g per meati o n, al beit m ore li mite d.  
2)  Pr ot oc ol m o dificati o n c o ul d be c o nsi dere d t o i n vite w o me n u n der g oi n g s ur gical resecti o n of 
at y pical/ hi g h ris k lesi o ns t o partici pate. T his will be a tar get p o p ulati o n f or e ve nt ual de pl o y me nt 
of t his a ge nt, a n d t heref ore w o ul d be a rele va nt gr o u p t o i ncl u de if t he pr ot oc ol is e x pa n de d t o 
pr oce d ures less t ha n mastect o m y.  
3)  P re vi o us st u dies of 4-O H T gel ha ve de m o nstrate d stea d y state wit h 2 wee ks of t hera p y, a n d 
t heref ore t he treat me nt peri o d c o ul d be s h orte ne d t o 2- 4 wee ks .  
 
5. 
A G E N T A D MI NI S T R A T I O N 
 
I nter ve nti o n will be a d mi nistere d o n a n o ut p atie nt basis. Re p orte d A Es a n d p ote ntial ris ks are descri be d 
i n Secti o n 6. 2.  
 
5. 1 
D ose Re gi me n a n d D ose Gr o u ps   
 
 
 
T his is a P hase 1 trial wit h a 2: 1 ra n d o mizati o n  t o acti ve or place b o E N X  gel a p plie d t o t he breast s ki n, 
bilaterall y. T he st u d y a ge nt a n d place b o will be s u p plie d b y Nati o nal Ca ncer I nstit ute, Di visi o n of Ca ncer 
Pre ve nti o n ( N CI -D C P ) a n d will be dis pe nse d i n metere d ca nisters t hat deli ver 1 ml of gel per p u m p (see 
m ore detail i n 2. 2 st u d y a ge nt). Briefl y, E N X gel pr o d ucts wit h st u d y a ge nt were ma n ufact ure d t o deli ver 
5 m g or 1 0 m g of E N X  mi xt ure ( E/ Z = 5 0: 5 0) i n 1 m L ( = 0. 8 9 8 5 g) of gel per p u m p. T heref ore, o ne p u m p 
will deli ver eac h d ose 5 m g or 1 0 m g  of (E/ Z) E N X per breast. C o nsi deri n g t he a p plicati o n t o b ot h 
breasts, t he fi nal dail y gel d oses will be 1 0  m g or 2 0 m g of E N X  gel . I n C o h ort 1, acti ve gel s u bjects will 
a p pl y 1 0 m g E N X  gel dail y ( 5 m g  gel i n 1 p u m p t o eac h breast) a n d i n C o h ort 2 acti ve gel s u bjects will 
a p pl y 20 m g  E N X gel dail y ( 1 0 m g i n 1 p u m p t o eac h breast).  T he last da y of st u d y a ge nt a d mi nistrati o n 
will be t he da y bef ore s ur ger y .  I n C o h ort 3, t here is n o ra n d o mizati o n, all 8 s u bjects will a p pl y1 0 m g 
E N X gel dail y ( 5 m g gel i n 1 p u m p t o eac h breast) u ntil t he da y bef ore s ur ger y. S ki n healt h of t he breasts 
will be esta blis he d at baseli ne, a n d s ki n t o xicit y will be m o nit ore d wee kl y t hr o u g h p h o ne calls, a n d at t he 

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e n d of i nter ve nti o n t hr o u g h p h ysical e xa mi nati o n, a n d d oc u me nte d b y p h ot o gra p hs. S u bjects wit h acti ve 
s ki n disease o n t he breast ( ps oriasis or ecze ma) are e xcl u de d, as are t h ose wit h ulcerate d ca ncers. S u bjects 
will be a d vise d t o n ot e x p ose breast s ki n t o direc t s u n or ta n ni n g be ds, t o n ot s h o wer/ bat he f or at least 4 
h o urs f oll o wi n g gel a p plicati o n, a n d t o a v oi d c o ntact of breast s ki n wit h ot her i n di vi d uals f or at least 4 
h o urs after a p plicati o n.  After 4 h o urs, if c o ntact is li kel y, t he breast ma y be clea nse d w it h a was hcl ot h, or 
b y bat hi n g/s h o weri n g.  
T he d urati o n of i nter ve nti o n is 2 1 - 2 8 da ys. If re q uire d, beca use of a dela y i n s ur ger y, u p t o e xtra 7 da ys of 
treat me nt will be all o we d.  
 
5. 2 
St u d y A ge nt A d mi nistr ati o n  
 
5. 2. 1 
All partici pa nts will recei ve eit her acti ve gel or place b o gel eac h da y a n d will be bli n de d t o t heir 
ra n d o mizati o n stat us. T he st u d y gel will be self-a d mi nistere d. All s u bjects i n C o h ort 3 will recei ve acti ve 
dr u g. 
 
5. 2. 2 
O ne 9 0 ml ca nister  of gel pr o d ucts c o ntai ni n g place b o or st u d y a ge nt will be distri b ute d t o eac h 
partici pa nt at t he baseli ne visit. Eac h partici pa nt will a p pl y t he gel dail y t o b ot h breasts f or 2 1- 2 8 da ys. 
O ne p u m p ( 1 m L) of place b o or acti ve gel pr o d ucts will be a p pl ie d t o b ot h  breast s o nce a da y. T he last 
da y of gel a p plic ati o n will be t he da y pri or t o t he da y of s ur ger y . 
 
5. 2. 3 
T he gel ( E N X / place b o) s h o ul d be a p plie d i n t he m or ni n g after dail y s h o wer (i n or der t o mi ni mize 
p ote ntial tra nsfer t o t he part ner at ni g ht).  Partici pa nts will be i nstr ucte d o n a p plicati o n of t he dr u g t o t he 
breast s d uri n g t he i nitial st u d y visit, a n d will a p pl y it eac h m or ni n g after a s h o wer, all o w it t o dr y f or o ne 
mi n ute a n d dress as us ual.  If t he y f or get t o a p pl y t he gel i n t he m or ni n g, a d mi nistrati o n later i n t he da y is 
acce pta ble, as l o n g as the s ki n has bee n was he d si nce t he last a p plicati o n. If a d ose is misse d a n d a p plie d 
late, 1 2 h o urs s h o ul d ela pse bef ore a p plicati o n of t he ne xt d ose. Partici pa nts will be i nstr ucte d n ot t o 
bat he, s wi m, or s h o wer f or at least 4 h o urs after gel a p plicati o n.  C o ntact of ot her i n di vi d uals wit h t he 
treate d breasts is u nli kel y t o be ass ociate d wit h si g nifica nt tra nsfer of dr u g; c o ntact is per mitte d after t he 
treate d area has bee n was he d wit h s oa p a n d water a n d was hi n g is all o wa ble after a mi ni m u m of 4 h o urs 
p ost-a p plicati o n.   
 
5. 2. 4  
T he da y of s ur ger y, partici pa nts s h o ul d refrai n fr o m a p pl yi n g a n y st u d y a ge nt, a n d be s ure t o 
bat he, s h o wer, or was h t heir breasts bef ore c o mi n g t o s ur ger y, t o a v oi d t he p ossi bilit y of rece ntl y a p plie d 
gel c o nta mi nati n g t he sa m ples ta ke n f or dr u g assa ys.   
 
5. 3 
R u n -i n Pr oce d ures  
 
N o r u n-i n pr oce d ures are pla n ne d. 
 
5. 4  
C o ntr ai n dic ati o ns 
 
Preca uti o ns re gar di n g s u n/ta n ni n g - be d e x p os ure, bat hi n g, a n d c o ntact wit h ot hers are descri be d i n Secti o n 
5. 1.  
 
5. 5 
C o nc o mit a nt Me dic ati o ns  
 
All me dicati o ns ( prescri pti o n a n d o ver-t he-c o u nter), vita mi n a n d mi neral s u p ple me nts, a n d/ or her bs ta ke n 
b y t he partici pa nt will be d oc u me nte d o n t he c o nc o mita nt me dicati o n C R F a n d will i ncl u de: 1) start a n d 
st o p date, d ose a n d r o ute of a d mi nistrati o n, a n d i n dicati o n. Me dicati o ns ta ke n f or a pr oce d ure (e. g., 
bi o ps y) s h o ul d n ot  be i ncl u de d.  

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5. 6  
D ose M o dific ati o n 
 
N o d ose m o dificati o ns are pla n ne d, ot her t ha n t h ose o utli ne d i n t he st u d y sc he ma.  H o we ver, st u d y a ge nt 
will be disc o nti n ue d if t he partici pa nt e x perie nces a  d ose -li miti n g t o xicit y.  
 
5. 7 
A d here nce/ C o m pli a nce  
 
5. 7. 1  
C o m plia nce is defi ne d as a p plicati o n of 8 0 % of d oses d uri n g t he i nter ve nti o n peri o d (e. g. o ver 2 8 
da ys, 2 2 d oses m ust be a p plie d, or o ver 2 1 da ys, 1 7 d oses m ust be a p plie d). A d diti o nall y d uri n g t he last 
t hree da ys  of  pla n ne d treat me nt, n o d oses s h o ul d be misse d.  
 
5. 7. 2 
C o m plia nce will be m o nit ore d b y wei g hi n g t he gel ca nister w he n dis pe nse d, a n d w he n ret ur ne d at 
t he e n d of t he i nter ve nti o n. Partici pa nts will eit her mai ntai n a pa per st u d y diar y or use a we b-a p p t hat ca n 
be accesse d b y eit her s mart - p h o ne or c o m p uter/ta blet. C o m plia nce will als o be c hec ke d d uri n g wee kl y 
p h o ne calls.  
 
5. 7. 3 
Parti ci pa nts w h o d o n ot utilize t he p h o ne we bsite/a p plicati o n will recei ve re mi n ders f or st u d y 
me dicati o n i nta ke via e mail or te xt messa ges, se nt b y t he st u d y staff d uri n g t he first wee k of st u d y a n d 
f urt her if nee de d. T he st u d y staff will se n d e mails or te xt messa ge o n cell ular p h o ne; partici pa nts will be 
e nc o ura ge d t o res p o n d t o t hese messa ges i n dicati n g if d ose has bee n ta ke n. T hese res p o nses will be use d 
t o assess c o m plia nce a n d will be re vie we d at wee kl y p h o ne c o ntact. F or partici pa nts w h o miss m ore t ha n 
o ne d ose i n a wee k, t he e mail/te xt re mi n ders will c o nti n ue f urt her i nt o d osi n g peri o d. 
 
Partici pa nt w h o d o utilize t he p h o ne we bsite/a p plicati o n will be c o ntacte d b y t he st u d y c o or di nat or if t he 
partici pa nt misses t w o or m ore da ys of e ntr y.  T hese res p o nses will be use d t o assess c o m plia nce a n d will 
be re vie we d at wee kl y p h o ne c o ntact.  
 
6. 
P H A R M A C E U TI C A L I N F O R M A TI O N  
 
6. 1  
St u d y A ge nt (I N D  
, N CI, Di visi o n of C a ncer Pre ve nti o n)    
 
E N X  Gel  
( E/ Z)-E N X  ([ E/ Z]- 4- h y dr o x y- N- des met h ylta m o xife n h y dr oc hl ori de), a 1: 1 race mic mi xt ure, is pr o vi de d 
as a 0. 5 % ( w/ v, 5 m g/ m L) a n d a 1. 0 % ( w/ v, 1 0 m g/ m L) h y dr oalc o h olic gel. Gel e xci pie nts i ncl u de 6 0 % 
et ha n ol, 1. 5 % ( w/ v) h y dr o x y pr o p yl cell ul ose ( Kl ucel H F), a n d 0. 5 % oleic aci d i n p h os p hate b uffer at p H 
7. 0. T he gel is pr o vi de d i n a p u m p wit h eac h p u m p acti o n e x pelli n g 1 m L of gel c o ntai ni n g 5 or 1 0 m g of 
E N X fr o m t he 0. 5 % a n d 1. 0 % mi xt ures, res pecti vel y.  
 
Pl ace b o Gel  
Matc hi n g place b o gel c o ntai ns t he sa me e xci pie nts a n d is pr o vi de d i n t he sa me p u m p f or mat.  
 
6. 2 
Re p orte d A d verse E ve nts a n d P ote nti al Ris ks  
 
( E/ Z)-E N X  gel , a 1: 1 race mic mi xt ure, is bei n g pr o vi de d i n a t o pical h y dr oalc o h olic gel f or tra ns der mal 
a d mi nistrati o n t o t he breasts f or l ocalize d treat me nt. ( Z) E N X is a hi g hl y acti ve meta b olite of ta m o xife n, 
~ 1 0 0 ti mes m ore acti ve, a n d t h us t his a n d a n ot her cl osel y- relate d meta b olite ( Z) 4-h y dr o x yta m o xife n ( 4 
O H T) are t h o u g ht t o pr o vi de t he b ul k of ta m o xife n’s p har mac ol o gical acti vit y. C o nse q ue ntl y, ta m o xife n 
is n o w vie we d as a pr o dr u g. E N X is f or me d i n t w o ste ps fr o m ta m o xife n, b y c yt oc hr o me P 4 5 0 ( C Y P) 
3 A 4 a n d C Y P 2 D 6, a n d t he n c o nj u gate d b y p hase II e n z y mes i n t he li ver t o i nacti ve f or ms b y s ulfati o n or 

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gl uc ur o ni dati o n [ 3 9]. I nterc o n versi o n of ( Z) - t o ( E)- E N X is of or ms occ urs s p o nta ne o usl y a n d 
bi directi o nall y i n a n a q ue o us e n vir o n me nt, i ncl u di n g me dia a n d bi ol o gical fl ui ds, t h o u g h o xi dati ve 
c o n diti o ns a n d ele vate d tem perat ures i ncrease is o merizati o n  [ 4 0]. ( E) is o mers of 4- O H T a n d E N X ha ve 
m uc h l o wer bi n di n g affi nities f or t he estr o ge n rece pt or ( E R) c o m pare d wit h t heir ( Z) is o mer versi o ns, 
~ 2 0 0 ti mes l o wer affi nit y; t h us, e ve n i n t he prese nce of e q ual a m o u nts of ( E)- E N X, ( Z) - E N X a nta g o nis m 
d o mi nates E R p har mac ol o gical acti vit y [ 4 1].  
 
T his pr ot oc ol will be t he first t o treat w o me n wit h t o pical d oses of E N X  gel  i n t he U S. H o we ver, w o me n 
ha ve pre vi o usl y bee n e x p ose d t o s yste mic E N X fr o m oral ta m o xife n d osi n g as a sec o n dar y c o nse q ue nce 
of its meta b olis m a n d fr o m oral ( Z)- E N X, a n i n vesti gati o nal breast ca ncer a ge nt u n der e val uati o n b y N CI, 
Di visi o n of Ca ncer Treat me nt a n d Dia g n osis ( D C T D). F or t he latter, i n N CI-s p o ns ore d st u di es 
( N C T 0 1 3 2 7 7 8 1, N C T 0 1 2 7 3 1 6 8, a n d N C T 0 2 3 1 1 9 3 3) w o me n wit h E R-p ositi ve breast ca ncer are bei n g 
treate d wit h oral ( Z)- E N X ca ps ules, t o a v oi d t he meta b olic re q uire me nt of C Y P 2 D 6 f or ta m o xife n si nce 
s o me w o me n ha ve C Y P 2 D 6 m uta nt alleles a n d t h us are ge n ot y picall y u na ble t o pr o perl y or efficie ntl y 
meta b olize ta m o xife n t o its m ore acti ve meta b olites  [ 4 2]. T he h u ma n safet y pr ofile of oral ( Z)-E N X 
ca ps ules fr o m t he D C T D I N D is s u m marize d bel o w, t h o u g h t o pical d osi n g of E N X gel is a ntici pate d t o 
res ult i n m uc h l o wer s yste mic E N X s o a d verse e ve nts ( A Es) ma y be si g nifica ntl y fe wer a n d of l o wer 
gra de. T o s u p p ort t o pical h u ma n d osi n g of E N X  gel , a ni mal t o xic ol o g y st u dies ha ve bee n c o m plete d a n d 
are descri be d bel o w. Fi nall y, t o pical d osi n g of t he cl osel y- relate d m olec ule 4- O H T i n a h y dr oalc o h olic 
gel has bee n c o n d ucte d i n w o me n f or vari o us differe nt i n dicati o ns s uc h as breast ca ncer [ 1 5, 3 6]a n d 
mastal gia ( breast pai n) [ 4 3] . T hese st u dies re veale d t hat t o pical 4 O H T gel was well-t olerate d t h o u g h 
s o me tra nsie nt a n d mil d s ki n A Es occ urre d s uc h as er yt he ma a n d pr uritis; t o pical E N X gel ma y e x hi bit a 
si milar safet y pr ofile. 
 
Or al ( Z) -E N X  - H u m a n S af et y P r ofile  
 
U n der t he D C T D I N D, w hi c h is cr oss -refere nce d b y N CI, D C P’s I N D, w o me n wit h metastatic breast 
ca ncer ha ve bee n treate d wit h ca ps ules of oral ( Z) - E N X. T he d ose escalati o n st u d y di d n ot i de ntif y a 
ma xi m u m t olerate d d ose ( M T D) d ue t o l o w t o xicit y of t he a ge nt a n d i nstea d d ose escalati o n was st o p pe d 
at 1 6 0 m g/ da y si nce t his d ose ac hie ve d t he tar get plas ma stea d y -state c o nce ntrati o n ( Css) of  > 4 µ M ( Z) -
p E N X. A nti -t u m or acti vit y has bee n o bser ve d ( data c ut- off date 0 9/ 3 0/ 2 0 1 4), wit h si x partial res p o nses i n 
5 5 e val ua ble patie nts. C o m m o n A Es i n or der of fre q ue nc y ha ve bee n ( data c ut- off date 0 9/ 3 0/ 2 0 1 4): h ot 
flas hes ( 4 3 %), l y m p h oc yte c o u nt decrease d ( 2 0 %), a ne mia ( 1 9 %), fati g ue ( 1 7 %), na usea ( 1 4 %), platelet 
c o u nt decrease d ( 1 3 %), ala ni ne a mi n otra nsferase i ncrease d ( A L T, 1 2 %), as partate a mi n otra nsferase 
i ncrease d ( A S T, 1 2 %), irrita bilit y ( 1 2 %), w hite bl o o d cell c o u nt decrease d ( 1 2 %), e de ma li m b ( 1 0 %), 
h y pertri gl yceri de mia ( 1 0 %), a n ore xia ( 9 %), a n d hi g h c h olester ol ( 9 %). Se vere A Es were: A L T ( gra de 3), 
h y pertri gl yceri de mia ( gra de 4), a n d t hr o m b oe m b olic e ve nts ( o ne eac h gra de 3 a n d 4). 
 
T o pic al ( E/ Z) -E N X  - N o ncli nic al S afet y P r ofile  < < Fi nal res ults pe n di n g o n g oi n g st u dies > > 
 
E N X has u n der g o ne precli nical a ni mal testi n g s p o ns ore d b y N CI, D C P a n d D C T D t o s u p p ort h u ma n 
cli nical st u dies. T hese st u dies i ncl u de m ulti ple r o utes of a d mi nistrati o n t o f ull y u n dersta n d t he s yste mic 
a n d l ocal t o xicit y pr ofiles. 2 8 - Da y t o xic ol o g y st u dies of oral E N X or si n gle-is o mer ( Z)-E N X ha ve bee n 
c o m plete d i n rats a n d d o gs. A 2 8 - da y der mal t o xicit y st u d y of E N X a p plie d t o ma m mar y gla n ds is 
u n der wa y i n mi ni pi gs (res ults pe n di n g). E N X is n ot p h ot ot o xic base d o n a ne gati ve i n vitr o ne utral re d 
st u d y. Fi nall y, a n i m m u n ot o xicit y st u d y, der mal dela ye d h y perse nsiti vit y, is u n der wa y i n g ui nea pi gs 
(res ults pe n di n g).  
 
Oral ( Z) -E N X d oses ≤2 0 0 m g/ k g/ da y were well -t olerate d w he n a d mi nistere d f or f o ur da ys t o fe male rats. 
Oral ( Z) -E N X a d mi nistere d dail y t o rats f or 2 8 da ys res ulte d i n let halit y at d oses ≥8 0 m g/ k g/ da y ( ≥4 8 0 
m g/ m 2/ da y). T he M T D was 2 0 m g/ k g/ da y ( 1 2 0 m g/ m 2/ da y). Cli nical si g ns of t o xicit y (a b d o mi nal 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol  V ersi o n 6. 5,  M a y  1 1,  2 0 2 0  
 
– 1 9 –  
dist e nti o n,  d ys p n e a,  h u n c h e d  p ost ur e,  a n d  dis c h ar g e fr o m t h e  n os e/ m o ut h)  o c c urr e d  m ai nl y i n r ats 
a d mi nist er e d  ≥ 8 0  m g/ k g/ d a y.  C h a n g es i n  cli ni c al  p at h ol o g y  p ar a m et ers  w er e  n ot e d i n  al k ali n e 
p h os p h at as e ( A L P),  al b u mi n,  A L T,  A S T,  c al ci u m,  a n d t ot al  pr ot ei n;  d e cr e as e d  ut eri n e  w ei g ht  als o 
o c c urr e d.  Li v er, l u n g,  h e ar t,  ki d n e y,  g astr oi nt esti n al ( GI), s k el et al  m us cl e,  a n d r e pr o d u cti v e tr a ct t o xi cit y 
w er e  d os e -li miti n g.  Wit h t h e  e x c e pti o n  of  o v ari a n  c ysts  a n d  histi o c yti c i nfiltr ati o n  of t h e l u n g,  or al ( Z)-
E N X t o xi cit y  a p p e ar e d t o  b e r e v ersi bl e  aft er  a  2 8 -d a y r e c o v er y  p er i o d.  
 
Or al  2 8 -d a y  d osi n g  of r ats  wit h t h e r a c e mi c ( E/ Z) - E N X  mi xt ur e  at l o w er  d os es,  1,  2 0,  or  4 0  m g/ k g/ d a y  vs. 
si n gl e is o m er ( Z)- E N X  at  4 0  m g/ k g/ d a y r es ult e d i n r e d u c e d  b o d y  w ei g ht  g ai n  a n d/ or  b o d y  w ei g ht l oss i n 
m al es  a n d f e m al es  at  all l e v els  of tr e at m e nt, t h o u g h  n o  d efi niti v e,  d os e -r el at e d  alt er ati o ns i n  cli ni c al 
p at h ol o g y  p ar a m et ers  or  cli ni c al  o bs er v ati o ns  w er e  n ot e d.  N o  d efi niti v e  m a cr o - or  mi cr os c o pi c  p at h ol o g y 
o bs er v ati o ns  o c c urr e d i n  m al e r ats  at  a n y  d os e l e v el,  w hil e t h e  o v ar y  w as i d e ntifi e d  as  a  t ar g et  or g a n i n 
f e m al es f oll o wi n g  d os es  of  2 0  a n d  4 0  m g/ k g/ d a y ( E/ Z)- E N X  a n d  of  4 0  m g/ k g/ d a y ( Z)-E N X.  Mi cr os c o pi c 
p at h ol o g y fi n di n gs i n di c at e d t h at  o v ari a n t o xi cit y  h a d  n ot r e v ers e d  1 5  d a ys f oll o wi n g  c ess ati o n  of  d osi n g.  
 
Or al ( Z) - E N X  at  3 0  m g/ k g/ d a y r es ult e d i n  d os e-li miti n g  e m esis i n f e m al e  d o gs  aft er  4  c o ns e c uti v e  d a ys 
d uri n g  a  2 8- d a y  c y cl e.  R e pr o d u cti v e tr a ct t o xi cit y  w as  o bs er v e d i n f e m al es ( v a gi n al  e pit h eli u m 
h y p er pl asi a)  a n d  m al es ( atr o p h y  of t h e  pr ost at e  a n d t est es,   d e pl eti o n  of s p er m at o z o a i n t h e  e pi di d y mi d es) 
a n d t h y mi c  atr o p h y i n  b ot h s e x es.  R e pr o d u cti v e tr a ct l esi o ns  w er e  n ot r e v ersi bl e  aft er  a  2 8- d a y r e c o v er y 
p eri o d.  A  n o  o bs er v e d  a d v ers e  eff e ct l e v el ( N O A E L)  w as  n ot  est a blis h e d.  T h e  M T D  w as  > 3 0  m g/ k g/ d a y 
( > 6 0 0  m g/ m 2/ d a y).  Wit h r es p e ct t o  b o d y s urf a c e  ar e a, t h e  M T D i n  d o gs ( > 6 0 0  m g/ m 2/ d a y)  w as  at l e ast 
fi v e-f ol d  gr e at er t h a n t h e r at  M T D ( 1 2 0  m g/ m 2/ d a y).  
 
E N X  d os e- d e p e n d e ntl y i n hi bit e d  h u m a n  p ot assi u m  c h a n n els i n  a  p at c h- cl a m p st u d y  wit h  a  5 0 % i n hi bit or y 
c o n c e ntrati o n (I C 5 0)  of  1. 6  M  w hi c h  w as si mil ar t o t h e I C 5 0  v al u e  of  1. 2  μ M f or t a m o xif e n  w hi c h is 
k n o w n  c a us e  a d v ers e  c ar di o v as c ul ar  eff e cts s u c h  as  Q T  pr ol o n g ati o n  a n d t ors a d es  d e  p oi nt es  [ 4 4].  
 
T o pi c al ( E/ Z) - 4- H y d r o x yt a m o xif e n - H u m a n  S af et y  P r ofil e  
 
D u e t o its si mil arit y t o  E N X  g el, t h e  h u m a n s af et y  pr ofil e  of t o pi c al  4 -O H T  g el  m a y  b e  a  g ui d e f or  A Es. 
T o pi c al  4 - O H T i n  al c o h ol s ol uti o n  or  g el  h as  b e e n  a d mi nist er e d t o  > 4 5 0  pr e-  a n d  p ost m e n o p a us al 
w o m e n. I n  p h as e  1 s af et y  a n d  P K st u di es, t o pi c al  4- O H T  w as  pr o vi d e d t o  w o m e n  at  d os es r a n gi n g fr o m 
0. 2 5 – 1  m g/ br e ast/ d a y f or t hr e e  w e e ks  u p t o t hr e e  m o nt hs.  T o pi c al  4 -O H T  w as  w ell t ol er at e d  wit h  o nl y 
dr u g-r el at e d  mil d  pr urit us  b ei n g  o bs er v e d i n  a f e w  p ati e nts.  T o pi c al  4  O H T r es ult e d i n s u bst a nti al  br e ast 
tiss u e  u pt a k e  wit h  mi ni m al  m et a b olis m  a n d  v er y l o w s yst e mi c  pl as m a  c o n c e ntr ati o ns.  
 
P h as e  2 st u di es  of t o pi c al  4 - O H T  u p t o  4  m g/ d a y f or  u p t o si x  m o nt hs  w as  w ell-t ol er at e d,  a bs or b e d,  a n d 
p h ar m a c ol o gi c al l y  a cti v e i n  br e asts f or r e d u ci n g  br e ast  p ai n ( m ast al gi a),  br e ast  d e nsit y ( a  br e ast  c a n c er 
ris k f a ct or),  a n d  br e ast  c a n c er  c ell  pr olif er ati o n i n  w o m e n  wit h  d u ct al  c ar ci n o m a i n sit u ( D CI S)  a n d 
l o c all y  a d v a n c e d  br e ast  c a n c er. I n  a  pl a c e b o- c o ntr oll e d, si x-m o n t h  p h as e  2 st u d y  of  4- O H T t o pi c al  g el i n 
pr e m e n o p a us al  w o m e n  wit h  c y cli c al  br e ast  p ai n, t h e  m ost  c o m m o n  A Es s e e n i n  4- O H T - vs.  pl a c e b o -
tr e at e d  w o m e n ( 4  m g/ d a y)  w er e:  h e a d a c h e ( 2 0 %  vs.  1 0 %),  n as o p h ar y n gitis ( 1 1 %  vs.  1 2 %),  a p pli c ati o n 
sit e r e a cti o n ( 4 %  vs.  0%),  a n d  p h ar y n gitis ( 4 %  vs.  0 % [ 3 6 ].  T h es e  e v e nts  w er e  all  mil d t o  m o d er at e  a n d 
s o m e  h e a d a c h es  a n d  a p pli c ati o n sit e r e a cti o ns ( a p pli c ati o n sit e  b ur ni n g, it c hi n g)  w er e  d e e m e d  dr u g-
r el at e d.  A d diti o n al  dr u g-r el at e d  A Es s e e n i n  4-O H T -tr e at e d  w o m e n  w er e  d e cr e as e d  a p p etit e,  e xf oli ati v e 
d er m atitis,  a n d  h y p ot e nsi o n.  N o si g nifi c a nt  c h a n g es i n  h e m at ol o gi c  p ar a m et ers, li v er f u n cti o n, r e n al 
f u n cti o n,  el e ctr ol yt es,  or s er u m  gl u c os e  w er e  o bs er v e d. 
 
I n  a  N CI,  D C P-s p o ns or e d  pr es ur gi c al st u d y  of  w o m e n  wit h  D CI S,  6 –1 0  w e e ks of t o pi c al  4 -O H T  g el  at  4 
m g/ d a y ( 2  m g t o  e a c h  br e ast)  or  or al t a m o xif e n  at  2 0  m g/ d a y r es ult e d i n si mil ar  4- O H T  br e ast l e v els  a n d 
si mil ar r e d u cti o ns i n  br e ast t u m or  c ell  pr olif er ati o n [ 3 6].  S yst e mi c l e v els  of  4  O H T  w er e  m ar k e dl y l o w er 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 2 0 –  
(fi ve-f ol d) wit h t o pical 4- O H T gel c o m pare d wit h oral ta m o xife n. 4-O H T t o pical gel was well -t olerate d 
a n d t he m ost c o m m o n A Es t hat were eit her si milar or less fre q ue nt i n 4 -O H T - vs. ta m o xife n-treate d 
w o me n were: h ot fl us h ( 5 0 % vs. 5 0 %), breast pai n ( 4 2 % vs. 6 4 %), fati g ue ( 3 3 % vs. 2 9 %), a n d 
h y per hi dr osis ( 2 5 % vs. 4 3 %). O nl y t hree A Es were ele vate d i n 4- O H T -treate d w o me n c o m pare d wit h 
ta m o xife n-treate d w o me n: pr uritis ( 1 7 % vs. 0 %), v ul v o va gi nal dr y ness ( 1 7 % vs. 0 %), a n d wei g ht 
i ncrease d ( 1 7 % vs. 0 %).  
 
6. 3 
A v ail a bilit y  
 
T o pical ( E/ Z )-E N X  gel, 0. 5 % a n d 1. 0 %, a n i n vesti gati o nal a ge nt, a n d matc hi n g place b o gel are s u p plie d 
t o i n vesti gat ors b y N CI , D C P.  
 
6. 4 
A ge nt Distri b uti o n  
 
A ge nts will o nl y be release d b y N CI, D C P after d oc u me ntati o n of I R B a p pr o val of t he D C P-a p pr o ve d 
pr ot oc ol a n d c o nse nt is pr o vi de d t o D C P a n d t he c ollecti o n of all Esse ntial D oc u me nts is c o m plete (see 
D C P we bsite f or descri pti o n of Esse ntial D oc u me nts).  
 
N CI, D C P -s u p plie d a ge nts ma y be re q ueste d b y t he I n vesti gat or ( or t heir a ut h orize d desi g nees) at eac h 
Or ga nizati o n. D C P g ui deli nes re q uire t hat t he a ge nt be s hi p pe d directl y t o t he i nstit uti o n or site w here t he 
a ge nt will be pre pare d a n d a d mi nistere d. D C P d oes n ot per mit t he tra nsfer of a ge nts bet wee n i nstit uti o ns 
( u nless pri or a p pr o val fr o m D C P is o btai ne d). D C P d oes n ot a ut o maticall y s hi p a ge nts; t he site m ust 
ma ke a re q uest. A ge nts are re q ueste d b y c o m pleti n g t he D C P Cli nical Dr u g Re q uest f or m ( NI H - 9 8 6) (t o 
i ncl u de c o m plete s hi p pi n g c o ntact i nf or mati o n) a n d fa xi n g or maili n g t he f or m t o t he D C P a ge nt 
re p osit or y c o ntract or: 
 
J o h n C o o ki n ha m 
M RI Gl o bal 
D C P Re p osit or y 
1 2 2 2 Ozar k Street 
N ort h Ka nsas Cit y, M O 6 4 1 1 6 
P h o ne: ( 8 1 6) 3 6 0- 3 8 0 5 
F A X:  ( 8 1 6) 7 5 3- 5 3 5 9 
E mer ge nc y T ele p h o ne: ( 8 1 6) 3 6 0- 3 8 0 0 
 
6. 5  
A ge nt Acc o u nt a bilit y  
 
T he I n vesti gat or, or a res p o nsi ble part y desi g nate d b y t he I n vesti gat or, m ust mai ntai n a caref ul rec or d of 
t he i n ve nt or y a n d dis p ositi o n of all a ge nts recei ve d fr o m D C P usi n g t he N CI Dr u g Acc o u nta bilit y Rec or d 
F or m ( D A R F). T he I n vesti gat or is re q uire d t o mai ntai n a de q uate rec or ds of recei pt, dis pe nsi n g a n d fi nal 
dis p ositi o n of st u d y a ge nt. T his res p o nsi bilit y has bee n dele gate d t o eac h accr ual site’s p har mac y . I ncl u de 
o n recei pt rec or d fr o m w h o m t he a ge nt was recei ve d a n d t o w h o m st u d y a ge nt was s hi p pe d, date, q ua ntit y 
a n d batc h or l ot n u m ber. O n dis pe nsi n g rec or d, n ote q ua ntities a n d dates st u d y a ge nt was dis pe nse d t o a n d 
ret ur ne d b y eac h partici pa nt.  
 
6. 6  
P ac k a gi n g a n d L a bel i n g 
 
T o pical ( E/ Z )-E N X  gel, 0. 5 % a n d 1. 0 %, a n d matc hi n g place b o gel will be pac ka ge d b y N CI, D C P .  
 
6. 7  
St or a ge  

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 2 1 –  
 
I n eac h i nstit uti o nal researc h p har mac y, t he gel m ust be st ore d i n a l oc ke d a n d sec ure area at r o o m 
te m perat ure, 5 9‐8 6 ° F ( 1 5 ‐3 0 ° C) a n d pr otect fr o m li g ht a n d m oist ure. Partici pa nts will be i nstr ucte d t o 
st ore t heir st u d y a ge nt i n a l ocati o n n ot accessi ble b y c hil dre n, at r o o m te m perat ure, a n d pr otecte d fr o m 
li g ht a n d m oist ure.  
 
6. 8  
Re gistr ati o n/ R a n d o miz ati o n 
 
1.  A st u d y c o or di nat or m ust u pl oa d i nt o t he N ort h wester n Cli nical Trials Ma na ge me nt S yste m, a si g ne d 
a n d c o m plete i nf or me d c o nse nt al o n g wit h HI P A A a ut h orizati o n a n d a c o m plete d eli gi bilit y f or m f or 
eac h partici pa nt i de ntifie d as eli gi ble t o be e ntere d i nt o t he st u d y.   
2.  All partici pa nts m ust be re gistere d i n t he N ort h wester n U ni versit y R o bert H. L urie C o m p re he nsi ve 
Ca ncer Ce nter Cli nical Trials Ma na ge me nt S yste m ( C T M S).  Partici pa nts m ust n ot start pr ot oc ol 
treat me nt pri or t o re gistrati o n i n t he L urie Ca ncer Ce nter  C T M S.  
3.  After re gistrati o n i n t he C T M S, partici pa nts will be assi g ne d a partici pa nt i de ntificati o n n u m ber a n d a 
ra n d o mizati o n n u m ber w he n a p plica ble.  
4.  A n N C P C Q ualit y Ass ura nce M o nit or will s u b mit t he f oll o wi n g i nt o t he R E D Ca p Ra n d o mizati o n 
I nf or mati o n F or m: ( 1) St u d y N u m ber, ( 2) Site, ( 3) P har macist E mail(s), ( 4) Partici pa nt I D [ PI D], ( 5) 
Partici pa nt I nitials, a n d ( 6) Ra n d o mizati o n Date.  
5.  A n A ut o matic Treat me nt Assi g n me nt N otificati o n e mail will be se nt t o t he researc h p har macist(s) 
c o ntai ni n g: ( 1) St u d y N u m ber, ( 2) Site, ( 3) Partici pa nt I D [ PI D], ( 4) Partici pa nt I nitials, ( 5) 
Ra n d o mizati o n Date, a n d ( 6) Treat me nt Assi g n me nt. 
6.  T he cli nical researc h c o or di nat or(s) will recei ve a C o nfir mati o n of Re gistrati o n c o ntai ni n g t he PI D 
via e mail.  
7.  T he f oll o wi n g pe o ple will ha ve a c o p y of t he u n- bli n de d ra n d o mizati o n l o g: t he st u d y statisticia n at 
N U, t he Q ualit y Ass ura nce T ea m at N U, a n d t he I n vesti gati o nal P har macists at eac h site . T he 
f oll o wi n g pe o ple will ha ve access t o t he R E D Ca p st u d y pr oj ect co ntai ni n g ra n d o mizati o n 
i nf or mati o n: t he st u d y statisticia n at N U a n d t he Q ualit y Ass ura nce T ea m at N U. T he st u d y 
statisticia n will set u p ra n d o mizati o n bl oc ks.  
 
W he n p ossi ble, t he st u d y c o or di nat or will n otif y a n N C P C Q ualit y Ass ura nce M o nit or a n d/ or se n d a n 
e mail t o nc pc @ n ort h wester n.e d u  pri or t o re gisteri n g a partici pa nt. Pri or n otificati o n is re q uire d f or 
partici pa nt ra n d o mizati o ns o utsi de t he n or mal b usi ness h o urs of M o n da y - Fri da y 9: 0 0a m- 5: 0 0 p m C T.   
 
6. 9  
B li n di n g a n d U n bli n di n g Met h o ds 
 
St u d y partici pa nts will recei ve a prescri pti o n, bli n de d, fr o m t he i n vesti gati o nal p har mac y.  T he bli n d will 
be mai ntai ne d t hr o u g h t he eff ort of t he p har mac o d y na mics a nal yst a n d t he p har mac y.  U n bli n di n g will 
occ ur w he n it is  dee me d me dicall y necessar y  or i n t he e ve nt of a D L T  a n d will o nl y ta ke place after 
c o ns ultati o n wit h t he N CI, D C P Me dical M o nit or: 
 
Na me:    
Marj orie Perl off, M D  
A d dress:  
Di visi o n of Ca ncer Pre ve nti o n  
  
 
Nati o nal Ca ncer I nstit ute  
  
  
9 6 0 9 Me dical Ce nter Dri ve, 5 E 5 4 4 
  
  
R oc k ville, M D 2 0 8 5 0 
T el:   
  
( 2 4 0) 2 7 6- 7 0 9 7 ( d uri n g n or mal b usi ness h o urs) 
Cell:     
( 2 4 0) 7 3 1- 1 7 7 2 
Fa x:   
  
( 2 4 0) 2 6 7- 7 8 2 8 
E mail:     
perl off m @ mail. ni h. g o v 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 2 2 –  
 
After h o urs c o ns ultati o n will be pr o vi de d b y Dr. See ma K ha n, at tele p h o ne 3 1 2- 5 0 3- 4 2 3 6 or cell p h o ne 
3 1 2- 3 0 7- 3 6 4 6.   
 
6. 1 0 
A ge nt Dest r ucti o n/ Dis p os al  
 
D C P -s u p plie d a ge nts: at t he c o m pleti o n of i n vesti gati o n, all u n use d st u d y a ge nt will be ret ur ne d t o N CI, 
D C P Re p osit or y acc or di n g t o t he D C P “ G ui deli nes f or A G E N T R E T U R N S” a n d usi n g t he D C P f or m 
“ Ret ur n Dr u g List”.  
 
7. 
C LI NI C A L E V A L U A TI O N S A N D P R O C E D U R E S  
 
7. 1 
Sc he d ule of E ve nts  
 
S C H E D U L E O F E V E N T S  
 
Pr oce d ure  
Scree ni n g 
Visit 1 1 
 
D a y 8 ± 3, 
1 5 ± 3, 2 2 ± 3 
( 1st d a y of 
st u d y dr u g 
= d a y 1)  
St u d y 
Visit 1 
( d a y 
bef ore 
s ur ger y) 6 
St u d y 
Visit 2  
D a y 2 2 t o 
2 9 ( d a y of 
s ur ger y) 8 
St u d y Visit 3 
D a y 2 9 -5 0 ( 7-
1 4 d a ys  after 
s ur ger y) 
P h o ne, 
e m ail, or 
te xt 
F oll o w -U p 
D a y 6 0 ± 7  
Assess Eli gi bilit y  
X  
 
 
 
 
 
I nf or me d C o nse nt 
X  
 
 
 
 
 
Re gistrati o n  
X  
 
 
 
 
 
Ra n d o mizati o n  
X  
 
 
 
 
 
Me dical Hist or y  
X  
 
 
X 7 
 
 
E C O G P erf or ma nce 
Stat us  
X  
 
 
 
 
 
Last Me nstr ual P eri o d  
X  
 
X  
 
X  
X  
P h ysical E xa m  
X  
 
 
X 7 
 
 
Vital Si g ns/ Hei g ht 
a n d W ei g ht  
X  
 
 
X  
X  
 
B o d y Mass I n de x  
X  
 
 
 
 
 
Br east c u p size  
X  
 
 
 
 
 
Breast s ki n p h ot os  
X  
 
X 9  
 
X 1 0  
 
B E S S Q uesti o n naire  
X  
 
X  
 
 
 
T o bacc o a n d Alc o h ol 
Use Q uesti o n naires  
X  
 
X  
 
 
 
C T C A E s ki n t o xicit y  
X  
X  
X  
 
X  
 
Cli nical La bs ( L F Ts 
a n d Re nal f u ncti o n 
tests) 
X  
 
 
X  
 
 
Uri ne or Ser u m 
Pre g na nc y T est  
X 2 
 
 
X 5  
 
 
Researc h bl o o d 
s peci me n c ollecti o n 
X  
 
 
X  
 
 
Tiss ue pr oc ure me nt 
f or researc h p ur p oses3 
X  
 
 
X  
 
 
C o nc o mita nt 
Me dicati o ns  
X  
X  
X  
 
X  
 
Dis pe nse St u d y A ge nt 
a n d diar y 4 
X  
 
 
 
 
 
C ollect St u d y A ge nt  
 
 
X  
 
 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 2 3 –  
Pr oce d ure  
Scree ni n g 
Visit 1 1 
 
D a y 8 ± 3, 
1 5 ± 3, 2 2 ± 3 
( 1st d a y of 
st u d y dr u g 
= d a y 1)  
St u d y 
Visit 1 
( d a y 
bef ore 
s ur ger y) 6 
St u d y 
Visit 2  
D a y 2 2 t o 
2 9 ( d a y of 
s ur ger y) 8 
St u d y Visit 3 
D a y 2 9 -5 0 ( 7-
1 4 d a ys  after 
s ur ger y) 
P h o ne, 
e m ail, or 
te xt 
F oll o w -U p 
D a y 6 0 ± 7  
Re vie w A ge nt 
Diar y/ Rec or d  
 
 
X  
 
 
 
A d verse E ve nts 
assess me nt  
 
X  
X  
 
X  
 
T ele p h o ne/ E mail 
C o ntact  
 
X  
 
 
 
X  
1Scree n 1 will occ ur wit hi n 6 wee ks pri or t o re gistrati o n.  
2Re q uire d wit hi n 5 da ys pri or t o starti n g st u d y treat me nt f or fe males of c hil d - beari n g p ote ntial. W o me n of 
c hil d-beari n g p ote ntial w h ose Scree ni n g Visit 1 occ urs > 5 da ys pri or t o starti n g st u d y a ge nt, will ha ve a 
se parate office visit t o c o n d uct a sec o n d pr e g na nc y test wit hi n 5 da ys of starti n g st u d y a ge nt. 
3Tiss ue will be o btai ne d fr o m t he dia g n ostic c ore nee dle bi o ps y ( D C N B ) as well as t he s ur gical resecti o n 
s peci me n f or st u d y e n d p oi nts. T h o u g h t here is n o p h ysical c ollecti o n of tiss ue at Scree ni n g Visit 1, 
release f or ac q uisiti o n of D C N B tiss ue will be c o m plete d at t his visit. 
4Partici pa nts w h o are u na ble t o pic k u p t he st u d y me dicati o n will recei ve it via mail or c o urier deli ver y 
re q uiri n g si g nat ure t o c o nfir m recei pt. 
5Uri ne or ser u m pre g na nc y test is r o uti nel y perf or me d f or fe males of c hil d- beari n g p ote ntial pri or t o t he 
s ur ger y. 
6St u d y Visits 1 a n d 2 ma y be c o m bi ne d o n t he sa me da y if feasi ble a n d c o n ve nie nt (i.e. s ur ger y start ti me 
all o ws c o m pleti o n of St u d y Visit 1 tas ks pri or t o s ur ger y start ti me). If t his is n ot p ossi ble, St u d y Visit 1 
will occ ur o n t he da y pri or t o s ur ger y.  
7S o urce d oc u me nt will be a nest hesi ol o gist or s ur ge o n pre- o p hist or y a n d p h ysical. Ma y ha ve bee n 
perf or me d o n da y of s ur ger y or wit hi n 2 8 da ys pri or.  
8P artici pa nts w h o re q uire a dela y i n s ur ger y will be all o we d t o c o nti n ue treat me nt f or u p t o 7 a d diti o nal 
da ys.  
9 S t u d y Visit 1 s ki n p h ot os will be ta ke n o nl y i n partici pa nt e x perie nci n g s ki n t o xicit y, a n d will f oc us o n 
t he area s h o wi n g t he s ki n t o xicit y. 
1 0 St u d y Visit 3  s ki n p h ot os will be ta ke n o nl y i n partici pa nts w h o ha d d oc u me nte d s ki n t o xicit y at St u d y 
Visit 1, a n d will f oc us o n t he area s h o wi n g t he s ki n t o xicit y.    
 
7. 2 
B aseli ne Testi n g/ Pre -st u d y E v al u ati o n 
 
7. 2. 1 Scree ni n g Visit 1  
T he f oll o wi n g will be c ollecte d:  
1.  I nf or me d C o nse nt 
2.  Me dical Hist or y per treati n g p h ysicia n  
3.  E C O G perf or ma nce stat us  
4.  Pri or a n d c o nc o mita nt me dicati o n re vie w  
5.  Vital si g ns assess me nt  
6.  P h ysical E xa m per treati n g p h ysicia n wit hi n 6 wee ks of re gistrati o n  
7.  Cli nical la bs f or re nal a n d he patic f u ncti o n i ncl u di n g t otal bilir u bi n, A S T, A L T, al kali ne 
p h os p hatase, bl o o d urea nitr o ge n, a n d creati ni ne t o be c ollecte d wit hi n 6 wee ks pri or t o 
re gistrati o n  
8.  Bl o o d c ollecti o n f or researc h p ur p oses:  
a. T w o 3 m L Bl ue T o p t u be (citrate) f or c oa g ulati o n pa nel.  
b.  T w o 1 0 m L La ve n der t o p t u bes ( K 2E D T A) t o o btai n plas ma f or h or m o ne le vel 
meas ure me nt (estra di ol, pr o gester o ne, a n d a n dr o ge ns [ D H E A ( de h y dr oe pia n dr oster o ne), 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 2 4 –  
a n dr oste ne di o ne, a n d test oster o ne]) a n d meas ure me nt of I G F -1, I G F B P - 3, a n d S H B G. 
B uff y c oat ( w hite bl o o d cells ( W B C)) will be sa ve d f or D N A/ R N A is olati o n f or f ut ure  
p o ole d a nal yses if t he s u bject c o nse nts t o t his o pti o nal st u d y.  
9.  S ki n s y m pt o ms per C T C A E criteria ( T a ble 1) 
1 0.  Re vie w of c o nf or ma nce wit h I ncl usi o n / E xcl usi o n criteria 
1 1.  B E S S q uesti o n naire ( A p pe n di x D)   
1 2.  T o bacc o a n d Alc o h ol Use Q uesti o n naires  
1 3.  Breast s ki n p h ot os  
1 4.  Breast c u p size  
1 5.  B o d y Mass I n de x ( B MI)  
1 6.  C ollecti o n of last me n str ual peri o d date f or pre me n o pa usal partici pa nts 
1 7.  Uri ne or ser u m pre g na nc y test f or w o me n wit h c hil d- beari n g p ote ntial  
1 8.  Re gistrati o n a n d ra n d o mizati o n  
1 9.  Dis pe nsi n g st u d y me dicati o n (f or partici pa nts  w h o are n ot a ble t o pic k it u p, t he st u d y me dicati o n 
will be deli vere d via mail or c o urier re q uiri n g si g nat ure f or c o nfir mati o n of recei pt).  Partici pa nts 
of c hil d - beari n g p ote ntial will be gi n d osi n g wit hi n 5 da ys of a ne gati ve pre g na nc y test. 
2 0.  Partici pa nt  diar y ( A p pe n di x B a n d C) will be re vie we d a n d dis pe nse d al o n g wit h t he st u d y 
me dicati o n.  
2 1.  Tiss ue will be o btai ne d fr o m t he D C N B as well as t he s ur gical resecti o n s peci me n f or st u d y e n d 
p oi nts. T h o u g h t here is n o p h ysical c ollecti o n of tiss ue at Scree ni n g Visit 1, release f or 
ac q uisiti o n of D C N B tiss ue will be c o m plete d at t his visit.  
 
T he a m o u nt of st u d y a ge nt t hat will be distri b ute d t o t he partici pa nt at t he scree ni n g visit will be 1 
ca nister of acti ve or place b o gel . T he y will ret ur n it at St u d y Visit 1 (t he e ve ni n g bef ore or t he m or ni n g of 
s ur ger y). 
 
7. 3  
E v al u ati o n D uri n g St u d y I nter ve nti o n 
 
7. 3. 1  
Wee kl y p h o ne calls f or m o nit ori n g of t o xicit y a n d c o m plia nce.  ( Da ys 8 ± 3, 1 5 ± 3, 2 2 ± 3) 
All partici pa nts will be f oll o we d d uri n g i nter ve nti o n via wee kl y tele p h o ne calls b y t he cli nical researc h 
staff t o assess c o m plia nce a n d a d verse e ve nts.  T he st u d y staff will call o n da ys 8, 1 5, 2 2 fr o m t he first 
da y of st u d y me dicati o n ( ± 3 da ys). If t hese da ys are n o n -b usi ness da ys, t he calls will be ma de o n t he ne xt 
cl osest b usi ness da y. E mails ma y be s u bstit ute d f or t he wee kl y p h o ne calls.  Please refer t o A p pe n di x E 
f or s u g geste d state me nts f or partici pa nt c o m m u nicati o ns.  
 
At t hese p h o ne calls, t he f oll o wi n g wit h be c ollecte d: 
1.  C o nc o mita nt me dicati o n re vie w  
2.  A d verse e ve nts – T o assess a d verse e ve nts p artici pa nts will be as ke d n o n- lea di n g q uesti o ns, 
f oll o we d b y t he q uesti o ns i n A p pe n di x E as nee de d, t o d oc u me nt if t he y ha ve e x perie nce d a n y of 
t he f oll o wi n g s y m pt o ms: 
a. S ki n s y m pt o ms base d o n Ta ble 1, e x plai ne d t o partici pa nts usi n g plai n la n g ua ge 
b.  H ot flas hes  
c. Va gi nal disc har ge  
d.  Uteri ne s p otti n g/ Uteri ne blee di n g 
3.  A d diti o nall y, a n y ot her s y m pt o m e x perie nce d b y partici pa nts will be rec or de d t o assess a d verse 
e ve nts.  
 
7. 3. 2  
St u d y staff will als o call partici pa nts f o ur da ys pri or t o s ur ger y t o re mi n d partici pa nts t o c o nti n ue 
st u d y a ge nt f or t he last t hree da ys pri or to s ur ger y. If a re mi n der call falls o n a n o n-b usi ness da y, t he call 
will be ma de o n t he ne xt cl osest b usi ness da y. Re mi n der calls ma y be s u bstit ute d f or e mails a n d ma y be 
c o m bi ne d wit h wee kl y p h o ne calls f or m o nit ori n g t o xicit y a n d c o m plia nce.  

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 2 5 –  
   
7. 4  
E v al u ati o n at C o m pleti o n of St u d y I nter ve nti o n 
 
St u d y Visits 1 a n d 2 ma y be c o m bi ne d o n t he sa me da y if feasi ble a n d c o n ve nie nt (i.e. s ur ger y start ti me 
all o ws c o m pleti o n of St u d y Visit 1 tas ks pri or t o s ur ger y start ti me. If t his is n ot p ossi ble, St u d y Visit 1 
will occ ur o n t he da y pri or t o s ur ger y.  Partici pa nts will fast fr o m mi d ni g ht o n t he e ve ni n g pri or t o 
s ur ger y.   
 
7. 4. 1 
St u d y Visit 1  (Da y bef ore s ur ger y, ca n occ ur o n t he da y of s ur ger y if feasi ble f or partici pa nt  t o 
arri ve earl y) 
1.  B E S S q uesti o n naire ( A p pe n di x D)   
2.  T o bacc o a n d Alc o h ol Use Q uesti o n naires  
3.  S ki n s y m pt o ms per C T C A E criteria ( T a ble 1). 
4.  B reast s ki n p h ot os, ta ke n o nl y i n partici pa nts e x perie nci n g s ki n t o xicit y, a n d will f oc us o n t he 
area s h o wi n g t he s ki n t o xicit y.  
5.  C ollecti o n  of last me nstr ual peri o d date f or pre me n o pa usal partici pa nts 
6.  C o nc o mita nt me dicati o ns a n d a d verse e ve nts assess me nt  
7.  C o m plia nce assess me nt ( wei g hi n g gel dis pe nsers) a n d c ollecti o n of st u d y a ge nt  
8.  C ollecti o n of st u d y diar y.  
 
7. 4. 2 St u d y Visit 2  ( Da y of s ur ger y, da y 2 2- 2 9) 
O n arri val t he f oll o wi n g pr oce d ures/e val uati o ns will be perf or me d:  
1.  Uri ne or ser u m pre g na nc y test (f or s u bj ects of c hil d beari n g p ote ntial) - per sta n dar d of care pri or 
t o t he s ur ger y. 
2.  Me dical hist or y per treati n g p h ysicia n  
3.  P h ysical e xa m . T he s o urce d oc u me nt f or t his ma y be a nest hesia or s ur ger y H & P, c o m plete d 
wit hi n 2 8 da ys pri or t o s ur ger y.  
4.  Vital si g ns assess me nt per a nest hesia assess me nt or pre - o perati ve n ursi n g e val uati o n  
5.  Cli nical la bs f or re nal a n d he patic f u ncti o n i ncl u di n g t otal bilir u b i n, A S T, A L T, al kali ne 
p h os p hatase, bl o o d urea nitr o ge n a n d creati ni ne 
6.  Bl o o d c ollecti o n f or researc h p ur p oses:  
a. T w o 3 m L Bl ue T o p t u be (citrate) f or c oa g ulati o n pa nel.  
b.  T w o 1 0 m L La ve n der t o p t u bes ( K 2E D T A) t o o btai n plas ma f or h or m o ne le vel 
meas ure me nt (estra di ol, pr o gester o ne, a n d a n dr o ge ns [ D H E A ( de h y dr oe pia n dr oster o ne), 
a n dr oste ne di o ne, a n d test oster o ne]) a n d meas ure me nt of I G F -1, I G F B P - 3, a n d S H B G. 
B uff y c oat will be sa ve d f or D N A/ R N A is olati o n f or f ut ure p o ole d a nal yses  if t he s u bject 
c onse nts t o t his o pti o nal st u d y.  
7.  Bl o o d c ollecti o n s h o ul d occ ur pri or t o c o m pleti o n of t he mastect o m y (i.e. if bl o o d is n ot dra w n 
pri or t o t he patie nt e nteri n g t he o perati n g r o o m, it ca n be dra w n i n t he O R).  
8.  Tiss ue will be o btai ne d fr o m t he D C N B as well as t he s ur gical resecti o n s peci me n f or st u d y e n d 
p oi nts. 
 
7. 5 
P ost -i nter ve nti o n F oll o w-u p Peri o d  
 
7. 5. 1 
St u d y V isit 3 ( P ost- o p visit i n t he breast s ur ger y cli nic, da y 2 9- 50) ( T he i nte nt is t o ha ve t his visit 
7- 1 4 da ys after st u d y visit 2 ): 
1.  Vital si g ns assess m e nt  
2.  C o nc o mita nt me dicati o n f oll o w -u p assess me nt f or t h ose ta ke n pri or t o s ur ger y.  N o ne w 
c o nc o mita nt me dicati o ns will be rec or de d u nless t he y pertai n t o a d verse e ve nts t hat occ urre d 
pri or t o s ur ger y.  

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 2 7 –  
 
2.  Plas ma c o nce ntrati o n of dr u g: ( E) a n d ( Z) is o mers of N- des met h yl - 4- h y dr o x yta m o xife n ( E N X)  
a n d 4-h y dr o x yta m o xife n ( 4 -O H T) t o be  perf or me d b y Dr. Mi g uel M uzzi o usi n g L C/ M S/ M S as 
p u blis he d b y us pre vi o usl y[ 1 6, 1 7] . Bl o o d will be c ollecte d wit h a ntic oa g ula nt K 2- E D T A.  
3.  Plas ma h or m o ne le vels f or ster oi d h or m o nes: estra di ol, pr o gester o ne, de h y dr oe pia n dr oster o ne 
( D H E A), a n dr oste ne di o ne a n d test oster o ne t o be meas ure d b y L C/ M S/ M S usi n g met h o ds 
de vel o pe d f or pri or st u dies b y o ur gr o u p [ 4 5]. Bl o o d will be c ollecte d wit h a ntic oa g ula nt K 2-
E D T A.  
4.  Pl as m a c o nce ntr ati o ns of I G F- 1/I G F B P - 3 a n d S H B G: I G F- 1 a n d its bi n di n g pr otei ns I G F B P- 3, 
a n d S H B G[ 1 6, 4 6] t o be meas ure d b y E LI S A assa ys at N ort h wester n U ni versit y, C o m pre he nsi ve 
Meta b olic C ore. Bl o o d will be c ollecte d wit h a ntic oa g ula nt K 2- E D T A.  
5.  Pl as m a levels of c o a g ul ati o n c asc a de pr otei ns : f o ur bl o o d c oa g ulati o n pr otei n assa ys [fact or VIII, 
fact or I X, v o n Wille bra n d fact or ( v W F), a n d Pr otei n S] usi n g plas ma sa m ples t o be perf or me d at 
He m ostasis La b orat or y, N ort h wester n Me m orial H os pital. Bl o o d will be c ollecte d wit h 
a ntic oa g ula nt citrate. 
6.  
E N X -res p o nse 
e n d p oi nts i n bre ast tiss ue s a m ples: Ki 6 7 
la beli n g i n de x, P R a n d E R e x pressi o n, 
a n d e x pressi o n of a pa nel of ge nes 
re p orte d t o c ha n ge wit h E N X  e x p os ure, 
will be meas ure d i n breast tiss ue 
sa m ples o btai ne d at dia g n ostic c ore 
nee dle bi o ps y ( C N B) perf or me d pri or t o 
st u d y e ntr y, a n d c o m pare d t o t he 
meas ure me nts i n p ost -t hera p y s ur gical 
sa m ples. B ot h Ki 6 7 re d ucti o n a n d i ncrease i n P R e x pressi o n are ass ociate d wit h ta m o xife n 
res p o nse [ 4 7]. I n a d diti o n, we will meas ure e x pressi o n of ge nes selecte d fr o m t h ose m o d ulate d b y 
4- O H T [ 4 8] a n d t h ose affecte d b y E N X  [ 2 6] i n M C F 7 breast ca ncer cells. Ha wse et al., ha ve 
re p orte d t hat E N X treat me nt o p p ose d t he e x pressi o n of 2 8 ge nes m o d ulate d b y estra di ol al o ne i n 
M C F 7 cell c ult ure [ 2 6].  Of t hese, 1 2 ge nes were re g ulate d b y b ot h 4- O H T a n d E N X b ut n ot b y 
f ul vestra nt, a n d 6 ge nes were u ni q uel y m o d ulate d b y E N X b ut n ot b y 4-O H T or f ul vestra nt. O n 
t he ot her ha n d, t he y als o re p orte d t hat E N X m o d ulates 1 7 7 ge nes t hat are i n de pe n de nt fr o m its 
effect i n o p p osi n g estr o ge n si g nali n g, s u g gesti n g t hat t he m olec ular mec ha nis m of E N X acti o ns 
differ fr o m t h ose of 4- O H T a n d f ul vestra nt [ 2 6].  Our rece ntl y o pe ne d 4 -O H T gel st u d y will 
pr o vi de a n o p p ort u nit y t o c o m pare ge ne e x pressi o n pr ofiles i n res p o nse t o E N X a n d 4- O H T  i n 
t u m or sa m ples. At t he e n d of t he i nter ve nti o n peri o d, t he mastect o m y s peci me n will be sa m ple d 
t o o btai n tiss ue f or t hese meas ure me nts. We will use Na n o Stri n g n C o u nter ® assa ys ( Na n o Stri n g 
I nc., Seattle, C A) as a researc h platf or m t o e val uate differe ntial e x pressi o n of 1 0 0 ge nes. We will 
i ncl u de t he 5 0 ge nes of t he Pr osi g na Breast Ca ncer Pr o g n ostic Ge ne Si g nat ure Assa y (f or merl y 
calle d t he P A M 5 0 test): 1) t o defi ne t u m or s u bt y pes (l u mi nal A/ B, Basal, etc.) of c ore bi o ps y 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 2 8 –  
s peci me n ( baseli ne), 2) t o e val uate differe ntial e x pressi o n of pr oliferati o n ge nes ( C E N P F, A N L N, 
C D C 2 0, C C N B 1, C E P 5 5, M Y B L 2, M KI 6 7) b y i nter ve nti o n. A d diti o nal 5 0 ge nes will be selecte d 
fr o m ge nes c o m m o nl y res p o n di n g t o b ot h 4-O H T  a n d E N X treat me nts as well as ge nes u ni q uel y 
m o d ulate d b y E N X n ot b y 4- O H T i n M C F 7 cells as H o wse et al . re p orte d [ 2 6]. T he Pat h ol o gist 
will mar k t he t u m or area o n t he H & E sli de s f or macr o- dissecti o n. K ha n la b orat or y will perf or m 
macr o - dissecti o n a n d t otal R N A e xtracti o n R N A r o m F F P E secti o ns of dia g n ostic c ore bi o ps y 
bl oc k a n d t hera pe utic s ur gical bl oc k wit h p urificati o n kit ( Qia ge n or R oc he kit) . Total R N A 
q ualit y a n d q ua ntit y will be meas ure d b y Q u bit a n d Bi oa nal yzer a nal ysis ( N U ge n o mics c ore). 
R N A sa m ples will be st ore d at - 8 0° C.   T he R N A sa m ples ( mi n i m u m 1 2 0 n g R N A ali q u ot per 
sa m ple) will be s hi p pe d t o Na n o Stri n g hea d q uarter ( Seattle, C A) as o ne batc h wit h dr y ice. T he 
m R N A ge ne e x pressi o n pr ofili n g usi n g 1 0 0 n g will be perf or me d wit h Na n o Stri n g  n C o u nter ® 
assa ys Na n o Stri n g n C o u nter assa y b y Na n o Stri n g c o m pa n y staff at Na n o Stri n g hea d q uarters.   
7.   P ol y m or p his ms i n ta m o xife n meta b olizi n g e nz y mes will n ot be assesse d i n t he c urre nt st u d y, b ut 
ger mli ne D N A will be ba n ke d f or f ut ure p o ole d a nal yses of tra ns der mall y vers us orall y 
a d mi nistere d ta m o xife n a n d meta b olites relati ve t o meta b olic efficie nc y f or oral ta m o xife n.  
S u bj ects will be gi ve n t he o pti o n t o c o nse nt t o t his f ut ure st u d y.  
  
  
8. 3 
Off -A ge nt Criteri a  
 
Partici pa nts ma y st o p ta ki n g st u d y a ge nt f or t he f oll o wi n g reas o ns: c o m plete d t he pr ot oc ol- prescri be d 
i nter ve nti o n, a d verse e ve nt or seri o us a d verse e ve nt, i na de q uate a ge nt s u p pl y, n o nc o m plia nce, 
c o nc o mita nt me dicati o ns, or me dical c o ntrai n dicati o n. Partici pa nts will c o nti n ue t o be f oll o we d, if 
p ossi ble, f or safet y reas o ns a n d i n or der t o c ollect e n d p oi nt data acc or di n g t o t he sc he d ule of e ve nts.   
 
All partici pa nts i ncl u de d i n t he st u d y w h o recei ve d a ge nt ma y  be assesse d f or res p o nse t o i nter ve nti o n, 
Partici pa nts w h o c o m plete less t ha n 8 0 % of t he pla n ne d d ose or di d n ot ta ke t he last 3 re q uire d d oses will 
be c o nsi dere d n o n -c o m plia nt a n d will n ot be e val ua ble f or sec o n dar y e n d p oi nts; Partici pa nts t hat recei ve 
a ge nt b ut wit h dra w wit h o ut i nitiati n g treat me nt will be re place d a n d will n ot be f oll o we d or e val ua ble f or 
D L Ts.  
 
8. 4 
Off -St u d y Criteri a  
 
P artici pa nts ma y g o ‘ off -st u d y’ f or t he f oll o wi n g reas o ns: t he pr ot oc ol i nter ve nti o n a n d a n y pr ot oc ol-
re q uire d f oll o w- u p peri o d is c o m plete d, A E/ S A E , l ost t o f oll o w- u p, n o n-c o m plia nce, c o nc o mita nt 
me dicati o n, me dical c o ntrai n dicati o n, wit h dra w c o nse nt, deat h, deter mi nati o n of i neli gi bilit y (i ncl u di n g 
scree n fail ure), pre g na nc y, partici pa nt wit h dra wal, or p h ysicia n decisi o n.   
 
8. 5 
St u d y Ter mi n ati o n  
 
N CI, D C P as t he st u d y s p o ns or has t he ri g ht t o disc o nti n ue t he st u d y at a n y ti me.  
 
9. 
C O R R E L A TI V E/ S P E CI A L S T U DI E S  
 
9. 1  
R ati o n ale f or Met h o d ol o g y Selecti o n 
 
T he tec h ni q ues f or e n d p oi nt assess me nt, meas ure me nt of dr u gs, meta b olites a n d dr u g effects ha ve bee n 
esta blis he d i n pri or st u dies[ 1 7, 3 6] . T he c urre nt st u d y will c o ntri b ute t o t he c urre nt k n o wle d ge base b y 
pr o vi di n g critical der mal safet y, p har mac o ki netic a n d p har mac o d y na mic data o n a p ote ntiall y m ore 
effecti ve ta m o xife n meta b olite t ha n t he pre vi o usl y teste d 4 - O H T; a n d b y pr o vi di n g preli mi nar y data o n 
t he a nti-t u m or a n d a nti-t u m ori ge nic efficac y of E N X .   

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 2 9 –  
 
Bre ast Tiss ue a n d Pl as m a dr u g c o nce ntr ati o n: T he f oll o wi n g fact ors s h o ul d be use d t o assess a ssa y 
perf or ma nce i n h u ma n plas ma a n d breast tiss ue matrices:  selecti vit y, li nearit y, precisi o n, acc urac y, 
rec o ver y a n d sta bilit y, f oll o wi n g t he F D A’s G ui da nce f or I n d ustr y: Bi oa nal ytical Met h o d Vali dati o n 
[ U. S. De part me nt of Healt h a n d H u ma n Ser vices, F o o d a n d Dr u g A d mi nistrati o n, Ce nter f or Dr u g 
E val uati o n a n d Researc h ( C D E R), Ce nter f or Veteri nar y Me dici ne ( C V M), Ma y 2 0 0 1.] Assa ys of ( E) a n d 
( Z) is o mers of N- des met h yl- 4- h y dr o x yta m o xife n ( E N X)  a n d 4- h y dr o x yta m o xife n ( 4-O H T) will be 
perf or me d b y Dr. Mi g uel M uzzi o usi n g L C/ M S/ M S as p u blis he d b y us pre vi o usl y[ 1 6] [ 1 7].  
 
I H C f or Ki 6 7, estr o ge n rece pt or ( E R ), a n d pr o gester o ne rece pt or ( P R) a n al ysis:  ot her met h o ds f or 
meas ure me nt of pr oliferati o n are a vaila ble b ut Ki 6 7 la beli n g i n de x ( KI 6 7 -LI) is t he m ost vali date d a n d 
wi del y use d met h o d of meas uri n g pr oliferati o n i n s h ort-ter m i nter ve nti o n st u dies, a n d als o m ost s uite d t o 
t he s mall tiss ue sa m ples t hat will be a vaila ble f or baseli ne assess me nt (i.e. c ore nee dle bi o psies). I H C is 
als o a well -esta blis he d a n d re pr o d uci ble tec h ni q ue f or meas ure me nt of h or m o ne rece pt ors. T a m o xife n 
a n d E N X  ha ve de m o nstrate d gr o wt h s u p pressi o n of esta blis he d E R + ma m mar y D CI S a n d i n vasi ve 
carci n o ma i n b y re d ucti o n i n Ki 6 7 [ 3 6, 4 9] a n d hi g h P R e x pressi o n c orrelate d t o t he effecti ve ness  of 
a dj u va nt ta m o xife n i n pre me n o pa usal E R + breast ca ncer patie nts[ 5 0, 5 1]. We ha ve als o c o nsi dere d 
w het her or n ot t o perf or m laser ca pt ure micr o dissecti o n of t u m or a n d be ni g n breast tiss ue i n or der t o 
e xcl u de str o ma, b ut deci de d a gai nst t his si nce c ha n ges i n str o ma ma y al s o be perti ne nt a n d L C M greatl y 
i ncreases t he c ost a n d c o m ple xit y of t he st u dies. 
 
Pl as m a h or m o ne le vels f or ster oi d h or m o nes:  estra di ol, pr o gester o ne, de h y dr oe pia n dr oster o ne 
( D H E A), a n dr oste ne di o ne a n d test oster o ne t o be meas ure d b y L C/ M S/ M S usi n g met h o ds de vel o pe d f or 
pri or st u dies b y o ur gr o u p [ 4 5]. T hese are detaile d i n t he P K/ Bi o mar ker S u p ple me nt.  
 
Pl as m a c o nce ntr ati o ns of I G F- 1/I G F B P -3 a n d S H B G : I G F- 1 a n d its bi n di n g pr otei ns I G F B P- 3, a n d 
S H B G  [ 1 6, 4 6] t o be meas ure d b y e nz y me-li n ke d i m m u n os or be nt assa y ( E LI S A ) assa ys at N ort h wester n 
U ni versit y, C o m pre he nsi ve Meta b olic C ore.  E LI S A kits will be p urc hase d fr o m R & D s yste ms I nc. a n d 
perf or me d usi n g t he ma n ufact urer’s pr ot oc ols. T hese are detaile d i n t he P K/ Bi o mar ker S u p ple me nt. 
 
Pl as m a le vels of c o a g ul ati o n c asc a de pr otei ns:  f o ur bl o o d c oa g ulati o n pr otei n assa ys [fact or VIII, fact or 
I X, v o n Wille bra n d fact or ( v W F), a n d Pr otei n S] usi n g plas ma sa m ples t o be perf or me d at He m ostasis 
La b orat or y, N ort h wester n Me m orial H os pital.  T hese are detaile d i n t he P K/ Bi o mar ker S u p ple me nt.  
 
R N A e x pressi o n ass a y : I n a d diti o n, we will meas ure m R N A e x pressi o n of a pa nel t o be deri ve d fr o m 
e xisti n g data o n ge ne e x pressi o n c ha n ges i n d uce d b y E N X  a n d 4-O H T  [ 2 6, 4 8], a nd m o difie d acc or di n g 
t o t he best data a vaila ble at t he ti me t hat t he fi nal set of tiss ues bec o me a vaila ble. We will use Na n o Stri n g 
n C o u nter a nal ysis ( Na n ostri n g T ec h n ol o gies, Seattle, W A) ; t his is a well -esta blis he d a n d re pr o d uci ble 
tec h ni q ue f or deter mi nati o n of differe ntial m R N A e x pressi o n. T hese are detaile d i n t he P K/ Bi o mar ker 
S u p ple me nt. 
 
Ge n ot y pi n g ass a y f or dr u g met a b olis m e nz y me p ol y m or p his m a n al ysis:  Ge n ot y pi n g assa y is a well -
esta blis he d , r o b ust a n d re pr o d uci ble tec h ni q ue f or deter mi nati o n of p ol y m or p his m of ge nes.   K ha n la b 
has s uccessf ull y d o ne ge n ot y pi n g assa ys f or st u d y of si n gle n ucle oti de p ol y m or p his ms ( S N P) of e nz y mes 
i n v ol ve d i n ster oi d h or m o ne bi os y nt hesis ( N CI 0 6 B 1 N A F h or m o ne st u d y pr oject). We ha ve use d 
T a q Ma n ® S N P ge n ot y pi n g assa y kits fr o m t he Life T ec h n ol o gies I nc. Wit h 4. 5 milli o n S N P assa ys 
a vaila ble, i ncl u di n g 3. 5 milli o n Ha p Ma p S N Ps, 7 0, 0 0 0 c S N Ps a n d 1 6 0, 0 0 0 vali date d assa ys, Ta q Ma n ® 
S N P ge n ot y pi n g assa ys ma ke it eas y t o perf or m h u ma n a n d m o use S N P ge n ot y pi n g st u dies wit h t he 
precisi o n of T a q Ma n ® rea ge nt -base d c he mistr y. [ 5 2] 
 
9. 2 
C o m p ar a ble Met h o ds  

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 3 0 –  
 
Pr o p ose d met h o ds re prese nt sta n dar d tec h n ol o g y f or dr u g a n d h or m o ne c o nce ntrati o n meas ure me nt i n 
plas ma a n d tiss ue; f or I H C, a n d f or bl o o d c oa g ulati o n pr otei n pr ofili n g as well as I G F-1/I G F B P - 3 a n d 
S H B G pr otei ns i n plas ma sa m ples. Ge ne e x pressi o n will be e xa mi ne d usi n g N a n ostri n g, w hic h is a 
relati vel y ne w b ut n o w fairl y sta n dar d met h o d f or meas uri n g ge ne e x pressi o n i n paraffi n e m be d de d 
sa m ples. 
 
1 0. 
S P E CI M E N M A N A G E M E N T  
 
1 0. 1  
L a b or at ories 
 
1 0. 1. 1 Cli nical La b orat ories attac he d t o N ort h wester n U ni versit y, Me m orial Sl oa n Ketteri n g Ca ncer 
Ce nter, a n d Ce dars- Si nai Me dical Ce nter will be res p o nsi ble f or perf or mi n g bl o o d la b orat or y a nal ysis f or 
partici pa nt scree ni n g eli gi bilit y.  
A d dresses of Cli nical La b orat ories:  
 
N ort h wester n U ni versit y Mai n La b  
2 5 1 E H ur o n 
C hica g o, I L 6 0 6 1 1 
 
 
Me m orial Sl oa n Ketteri n g De part me nt of La b orat or y Me dici ne, Mai n  
1 2 7 5 Y or k A ve 
Ne w Y or k N Y  1 0 0 6 5  
 
Ce dars -Si nai Me dical Ce nter  
De part me nt of Pat h ol o g y a n d La b orat or y Me dici ne 
8 7 0 0 Be verl y B L V D, R o o m 3 7 1 9 
L os A n geles, C A  9 0 0 4 8 
 
1 0. 1. 2 Researc h Assa y La b orat ories are as f oll o ws  
 
T he Pat h ol o g y C ore Facilit y ( P C F) at t he R o bert H. L urie C o m pre he nsi ve Ca ncer Ce nter of N ort h wester n 
U ni versit y will recei ve ser u m, plas ma a n d breast tiss ue sa m ples fr o m all partici pati n g st u d y sites (e xce pt 
f or ser u m pre g na nc y tests, w hic h will be pr ocesse d b y t he cli nical la b orat ories at eac h accr ual site). T he 
distri b uti o n of sa m ples t o a p pr o priate ce ntral la bs f or assa ys as liste d bel o w will be perf or me d b y t he 
Pat h ol o g y C ore Facilit y, as directe d b y Dr . K ha n’s la b orat or y pers o n nel. Details of s hi p pi n g are pr o vi de d 
i n secti o n 1 0. 3. 
 
Dr u g c o nce ntr ati o n ass ays  of tiss ue a n d plas ma sa m ples a n d plas ma ster oi d h or m o ne assa ys will be 
perf or me d b y t he la b orat or y of Dr. Mi g uel M uzzi o at t he Illi n ois I nstit ute of Researc h (II T RI), usi n g 
L C/ M S/ M S pr ot oc ols esta blis he d f or o ur pri or st u dies [ 1 6, 1 7];[ 4 5].  
 
Cell pr olifer ati o n a n d pr o gester o ne rece pt or I H C at baseli ne a n d after treat me nt will be perf or me d i n t he 
Pat h ol o g y C ore Facilit y of t he R o bert H. L urie C o m pre he nsi ve Ca ncer Ce nter. 
 
Pl as m a h or m o ne levels f or ster oi d h or m o nes: estra di ol, pr o gester o ne, de h y dr oe pia n dr oster o ne ( D H E A), 
a n dr oste ne di o ne a n d test oster o ne t o be meas ure d b y L C/ M S/ M S i n t he la b orat or y of Dr. Mi g uel M uzzi o 
at t he Illi n ois I nstit ute of Researc h (II T RI) . 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 3 1 –  
Pl as m a c o nce ntr ati o ns of I G F- 1/I G F B P - 3 a n d S H B G: I G F- 1 a n d its bi n di n g pr otei ns I G F B P- 3, a n d 
S H B G  [ 1 6, 4 6] t o be meas ure d b y E LI S A assa ys at N ort h wester n U ni versit y, C o m pre he nsi ve Meta b olic 
C ore.  
 
Pl as m a levels of c o a g ul ati o n c asc a de pr otei ns : f o ur bl o o d c oa g ulati o n pr otei n assa ys [ Fact or VIII, fact or 
I X, v o n Wille bra n d fact or ( v W F), a n d Pr otei n S] usi n g plas ma sa m ples t o be perf or me d at He m ostasis 
La b orat or y, N ort h wester n Me m orial H os pital. 
 
1 0. 2 
C ollecti o n a n d H a n dli n g Pr o ce d ures  
  
 
All partici pati n g sites will recei ve s pecific i nstr ucti o ns f or c ollecti o n, pr ocessi n g a n d s hi p me nt of sa m ples 
a n d s peci me n t o t he P C F at N U.  
 
Refer t o S peci me n Ma n ual.  
 
1 0. 3 
S hi p pi n g I nstr ucti o ns  
 
All sa m ples will be s hi p pe d i n c o m plia nce wit h t he I nter na ti o nal Air Tra ns p ort Ass ociati o n (I A T A) 
Da n ger o us G o o ds Re g ulati o ns. 
 
Refer t o S peci me n Ma n ual.  
 
1 0. 4 
Tiss ue B a n ki n g  
 
Bi ol o gic s peci me ns c ollecte d d uri n g t he c o n d uct of eac h cli nical trial t hat are n ot use d d uri n g t he c o urse 
of t he st u d y will be c o nsi dere d deli vera bles u n der t he c o ntract a n d t h us t he pr o pert y of t he N CI. At st u d y 
c o m pleti o n, N CI reser ves t he o pti o n t o eit her retai n or reli n q uis h o w ners hi p of t he u n use d bi ol o gic 
s peci me ns. If N CI retai ns o w ners hi p of s peci me ns, t he C o ntract or s hall c ollect, verif y a n d tra nsfer t he 
re q ueste d bi ol o gic s peci me ns fr o m t he site t o a N CI-s pecifie d re p osit or y or la b orat or y at N CI’s e x pe nse.   
 
1 1. 
R E P O R TI N G A D V E R S E E V E N T S   
 
D E FI NI TI O N: A E mea ns a n y u nt o war d me dical occ urre nce ass ociate d wit h t he use of a dr u g i n h u ma ns, 
w het her or n ot c o nsi dere d dr u g relate d. A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n), 
s y m pt o m, or disease te m p orall y ass ociate d wit h partici pati o n i n a st u d y, w het her or n ot relate d t o t hat 
partici pati o n. T his i ncl u des all deat hs t ha t occ ur w hile a partici pa nt is o n a st u d y. 
 
Please n ote t hat all a b n or mal cli nical la b orat or y val ues t hat are deter mi ne d t o be of cli nical si g nifica nce 
base d o n a p h ysicia n’s assess me nt are t o be re p orte d as A Es. T h ose la bs deter mi ne d t o be of n o cli nical 
si g nifica nce or of u n k n o w n cli nical si g nifica nce ( per t he p h ysicia n’s assess me nt) s h o ul d n ot be re p orte d 
as A Es. A n y la b val ue of u n k n o w n cli nical si g nifica nce s h o ul d c o nti n ue t o be i n vesti gate d/f oll o we d - u p 
f urt her f or a fi nal deter mi nati o n, if p ossi ble. 
 
A list of A Es t hat ha ve occ urre d or mi g ht occ ur ca n be f o u n d i n § 6. 2 Re p orte d A d verse E ve nts a n d 
P ote ntial Ris ks , as well as t he I n vesti gat or Br oc h ure or pac ka ge i nsert.  
 
1 1. 1 
A d verse E ve nts  
 
1 1. 1. 1  Re p orta ble A Es 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 3 3 –  
 
Gr a de  
Se verit y  
Descri pti o n  
1  
Mil d  
Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns o nl y; 
i nter ve nti o n n ot i n dicate d. 
2  
M o d erate  
M o derate; mi ni mal, l o cal or n o ni n vasi ve i nter ve nti o n i n dicate d;  
li miti n g a ge-a p pr o priate i nstr u me ntal acti vities of d ail y li vi n g ( A D L) *.  
3  
Se v ere  
Se vere or me dicall y si g nifi ca nt b ut n ot i m me diatel y life -t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g self -
care A D L * *.  
4  
Life -t hreate ni n g 
Life -t hreate ni n g c o nse q u e n ces; ur ge nt i nter ve nti o n i n dicate d. 
5  
Fatal  
Deat h relate d t o A E.  
   
A D L  
 
*I nstr u me ntal A D L refers t o pre pari n g meals, s h o p pi n g f or gr oceries or cl ot hes, usi n g t he tele p h o ne, 
ma na gi n g m o ne y, etc. 
 
* * Self-care A D L refers t o bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he t oilet, ta ki n g 
me dicati o ns, a n d n ot be dri d de n. 
 
1 1. 1. 4 Assess me nt of relati o ns hi p of A E t o treat me nt  
  
 
T he p ossi bilit y t hat t he A E  is relate d t o st u d y a ge nt will be classifie d as o ne of t he f oll o wi n g: n ot relate d, 
u nli kel y, p ossi ble, pr o ba ble, a n d defi nite. 
  
1 1. 1. 5  F oll o w- u p of A Es 
 
All A Es, i ncl u di n g la b a b n or malities t hat i n t he o pi ni o n of t he i n vesti gat or are cli nicall y si g nifica nt, will 
be f oll o we d acc or di n g t o g o o d me dical practices a n d d oc u me nte d as s uc h.  
 
1 1. 2 
Seri o us A d verse E ve nts   
 
1 1. 2. 1 D E FI NI TI O N : Re g ulati o ns at 2 1 C F R § 3 1 2. 3 2 (re vise d A pril 1, 2 0 1 4) defi nes a n S A E as a n y  
u nt o war d me dical occ urre nce t hat at a n y d ose h as o n e or m or e of t h e f oll o wi n g o ut c o mes : 
 
• 
Dea t h 
•  
A life-t hreate nin g A E  
•  In patie nt h os pitalizati o n or pr o lo n gati o n of e xisti n g  h os pitalizati o n 
•  
A p ersistent  or sig n ificant i n capa cit y or s u bsta ntial disr u pti o n of t he a bilit y t o perf or m n or mal life 
f u ncti o ns 
•  
A c o n ge nital a n o maly or birt h de fect 
• 
I m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life-t hreate ni n g or res ult i n deat h 
or h os pitalizati o n s h o ul d als o be c o nsi dere d seri o us w he n, base d u p o n a p pr o priate 
me dical j u d g me nt, t he y ma y j e o par dize t he patie nt a n d ma y re q uire i nter ve nti o n t o 
pre ve nt o ne of t he ot her o utc o mes. 
 
T he pla n ne d mastect o m y pr oce d ure will n ot be c o nsi dere d t o be a n S A E. 
 
1 1. 2. 2  Re p orti n g S A Es t o D C P 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 3 4 –  
1 1. 2. 2. 1  
T he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns will re p ort S A Es o n t he D C P 
S A E Re p ort F or m f o u n d at htt p:// pre ve nti o n.ca ncer. g o v/cli nical -trials/cli nical-trials-
ma na ge me nt/ pr ot oc ol-i nf or mati o n- office/ pi o-i nstr ucti o ns-a n d-t o ols/ 2 0 1 2-c o ns ortia . 
 
1 1. 2. 2. 2   
C o ntact t he D C P Me dical M o nit or  b y p h o ne wit hi n 2 4 h o urs of k n o wle d ge of t he e ve nt.  
 
Na me:    
Marj orie Perl off, M D  
A d dress:  
Di visi o n of Ca ncer Pre ve nti o n  
  
 
Nati o nal Ca ncer I nstit ute  
  
  
9 6 0 9 Me dical Ce nter Dri ve, 5 E 5 4 4 
  
  
R oc k ville, M D 2 0 8 5 0 
T el:   
  
( 2 4 0) 2 7 6- 7 0 9 7 ( d uri n g n or mal b usi ness h o urs) 
Cell:     
( 2 4 0) 7 3 1- 1 7 7 2 
E mail:     
perl off m @ mail. ni h. g o v 
 
I ncl u de t he f oll o wi n g i nf or mati o n w he n calli n g t he Me dical M o nit or : 
•  
Date a n d ti me of t he S A E  
•  
Date a n d ti me of t he S A E re p ort 
•  
Na me  of re p orter 
•  
Call bac k p h o ne n u m ber 
•  
Affiliati o n/I nstit uti o n c o n d ucti n g t he st u d y  
•  
D C P pr ot oc ol n u m ber 
•  
Title of pr ot oc ol  
•  
Descri pti o n of t he S A E, i ncl u di n g attri b uti o n t o dr u g 
 
1 1. 2. 2. 3  
T he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns will e mail  writte n S A E re p orts 
t o t he f oll o wi n g pe o ple wit hi n 4 8 h o urs of lear ni n g of t he e ve nt usi n g t he filla ble P D F S A E Re p ort F or m:  
 
•  
T he N CI/ D C P Me dical M o nit or  
•  
D C P’s Re g ulat or y C o ntract or C C S Ass ociates, I nc. ( C C S A; p h o ne: 6 5 0- 6 9 1- 4 4 0 0) at 
safet y @ccsai nc.c o m 
•  
N ort h wester n Ca ncer Pre ve nti o n C o ns orti u m ( N C P C, p h o ne: 3 1 2- 5 0 3- 7 8 2 0 ) at 
nc pc @ n ort hester n.e d u  
  
1 1. 2. 2. 4   T he D C P Me dical M o nit or  a n d C C S A re g ulat or y a n d safet y staff will deter mi ne w hic h S A Es 
re q uire F D A s u b missi o n as I N D safet y re p orts . 
 
1 1. 2. 2. 5   T he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns will c o m pl y wit h a p plica ble 
re g ulat or y re q uire me nts relate d t o re p orti n g S A Es t o t he I R B/I E C.  
 
1 1. 2. 3  F oll o w- u p of S A E 
 
Site staff s h o ul d se n d f oll o w - u p re p orts as re q ueste d w he n a d diti o nal i nf or mati o n is a vaila ble. A d diti o nal 
i nf or mati o n s h o ul d be e ntere d o n t he D C P S A E Re p ort F or m i n t he a p pr o priate f or mat. F oll o w- u p 
i nf or mati o n s h o ul d be se nt t o D C P, C C S A, a n d N C P C as s o o n as a vaila ble.  S u bjects w h o e x perie nce a n 
S A E wi ll be f oll o we d f or 3 0 da ys or u ntil res ol uti o n.  
 
1 2. 
S T U D Y M O NI T O RI N G  
 
1 2. 1  
D at a M a n a ge me nt 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 3 5 –  
 
Data will be ma na ge d b y t he st u d y statisticia n, Dr. K oc her gi ns k y , acc or di n g t o sta n dar d o perati n g 
pr oce d ures, w hic h meet t he g ui deli nes of D C P Re q uire me nts f or Data Ma na ge me nt a n d w hic h f oll o w t he 
Data Ma na ge me nt Pla n t hat N ort h wester n U ni versit y has o n file wit h t he Di visi o n of Ca ncer Pre ve nti o n, 
N CI.   S o urce data verificati o n will be perf or me d b y t he De part me nt of Cli nical Researc h Ser vices.   T he 
C o ns ortia 2 0 1 2 Data Ma na ge me nt Pla n, s u b mitte d as part of a c o ntract a gree me nt wit h t he N CI 
( H H S N 2 6 1 2 0 1 2 0 0 0 3 5I), was a p pr o ve d.  
  
1 2. 2 
C ase Re p ort F or ms  
 
Partici pa nt data wil l be c ollecte d usi n g pr ot oc ol-s pecific case re p ort f or ms ( C R Fs) de vel o pe d fr o m t he 
sta n dar d set of D C P C he m o pre ve nti o n C R F T e m plates a n d utilizi n g N CI-a p pr o ve d C o m m o n Data 
Ele me nts ( C D Es). T he a p pr o ve d C R Fs will be use d b y N ort h wester n U ni versit y t o create  t he electr o nic 
C R Fs (e -C R Fs) scree ns i n t he R o bert H. L urie C o m pre he nsi ve Ca ncer Ce nter Cli nical Trials Ma na ge me nt 
S yste m ( C T M S). Site staff will e nter data i nt o t he e - C R Fs f or tra ns missi o n t o D C P acc or di n g t o D C P 
sta n dar ds a n d pr oce d ures. 
 
1 2. 3 
S o urce D oc u me nts  
 
All s o urce d oc u me nts will be c ollecte d a n d st ore d i n t he Cli nical Researc h Office of t he site w here t he 
partici pa nt was accr ue d.  A n y data rec or de d directl y o n C R Fs t hat c o nstit ute n o pri or writte n or electr o nic 
rec or d of data, will be s pecifically i de ntifie d as s o urce data.  B E S S  q uesti o n naire c o m plete d i n pers o n 
ma y be c o m plete d directl y o n t he electr o nic C R F a n d nee d n ot be tra nscri be d fr o m se parate s o urce 
d oc u me ntati o n.  
 
1 2. 4  
D at a a n d S af et y M o nit ori n g Pl a n 
 
A c o m pre he nsi ve Data Safet y a n d M o nit ori n g Pla n has bee n s u b mitte d b y N ort h wester n U ni versit y, 
a p pr o ve d b y t he D C P, a n d is o n file t here.  A n y f ut ure c ha n ges will be f or war de d f or re vie w.   
 
1 2. 5  
S p o ns or or F D A M o nit ori n g 
 
T he N CI, D C P ( or t heir desi g nee), p har mace utical c olla b orat or ( or t heir desi g nee), or F D A ma y 
m o nit or/a u dit vari o us as pects of t he st u d y. T hese m o nit ors will be gi ve n access t o facilities, data bases, 
s u p plies a n d rec or ds t o re vie w a n d verif y data perti ne nt t o t he st u d y.  
 
1 2. 6 
Rec or d R ete nti o n  
 
Cli nical rec or ds f or all partici pa nts, i ncl u di n g C R Fs, all s o urce d oc u me ntati o n (c o ntai ni n g e vi de nce t o 
st u d y eli gi bilit y, hist or y a n d p h ysical fi n di n gs, la b orat or y data, res ults of c o ns ultati o ns, etc.), as well as 
I R B rec or ds a n d ot her re g ulat or y d oc u me ntati o n will be retai ne d b y t he I n vesti gat or i n a sec ure st ora ge 
facilit y i n c o m plia nce wit h Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A), Office of 
H u ma n Researc h Pr otecti o ns ( O H R P), F o o d a n d Dr u g A d mi nistrati o n ( F D A) re g ulati o ns a n d g ui da nces, 
a n d N CI/ D C P re q uire me nts, u nless t he sta n dar d at t he site is m ore stri n ge nt. T he rec or ds f or all st u dies 
perf or me d u n der a n I N D will be mai ntai ne d, at a mi ni m u m, f or t w o years after t he a p pr o val of a Ne w 
Dr u g A p pl icati o n ( N D A). F or N CI/ D C P, rec or ds will be retai ne d f or at least t hree years after t he 
c o m pleti o n of t he researc h. N CI will be n otifie d pri or t o t he pla n ne d destr ucti o n of a n y materials. T he 
rec or ds s h o ul d be accessi ble f or i ns pecti o n a n d c o p yi n g b y a ut h orize d pers o ns of t he F o o d a n d Dr u g 
A d mi nistrati o n. If t he st u d y is d o ne o utsi de of t he U nite d States, a p plica ble re g ulat or y re q uire me nts f or 
t he s pecific c o u ntr y partici pati n g i n t he st u d y als o a p pl y. 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 3 6 –  
 
1 2. 7 
Cli nic al S u p pl y A gree me nt  
 
T he a ge nt s, E N X  gel a n d place b o gel, are s u p plie d b y D C P, N CI, w here t he y were de vel o pe d b y 
i n vesti gat ors i n t he P R E V E N T Pr o gra m.  T heref ore, t he f oll o wi n g o bli gati o ns/ g ui deli nes, i n a d diti o n t o 
t he pr o visi o ns i n t he “I ntellect ual Pr o pert y O pti o n t o C olla b orat or c o ntai ne d wit hi n t he ter ms of a war d, 
a p pl y t o t he use of A ge nt(s) i n t his st u d y: 
 
1 2. 7. 1 A ge nt(s) ma y n ot be use d f or a n y p ur p ose o utsi de t he sc o pe of t his pr ot oc ol, n or ca n A ge nt(s) be 
tra nsferre d or lice nse d t o a n y part y n ot partici pati n g i n t he cli nical st u d y. C olla b orat or(s) data f or 
A ge nt(s) are c o nfi de ntial a n d pr o prietar y t o C olla b orat or(s) a n d s hall be mai ntai ne d as s uc h b y t he 
i n vesti gat ors. T he pr ot oc ol d oc u me nts f or st u dies utilizi n g i n vesti gati o nal a ge nts c o ntai n c o nfi de ntial 
i nf or mati o n a n d s h o ul d n ot be s hare d or distri b ute d wit h o ut t he per missi o n of t he N CI. If a patie nt 
partici pati n g o n t he st u d y or partici pa nt’s fa mil y me m ber re q uests a c o p y of t his pr ot oc ol, t he i n di vi d ual 
s h o ul d si g n a c o nfi de ntialit y a gree me nt. A s uita ble m o del a gree me nt ca n be d o w nl oa de d fr o m t he D C P 
we bsite.  
 
1 2. 7. 2 F or a cli nical pr ot oc ol w here t here is a n I n vesti gati o nal A ge nt use d i n c o m bi nati o n wit h (a n) ot her 
i n vesti gati o nal A ge nt(s), eac h t he s u bject of differe nt c olla b orati ve a gree me nts, t he access t o a n d use of 
data b y eac h C ol la b orat or s hall be as f oll o ws ( data pertai ni n g t o s uc h c o m bi nati o n use s hall herei nafter be 
referre d t o as " M ulti-part y Data”).  
 
1 2. 7. 3 N CI m ust pr o vi de all C olla b orat ors wit h pri or writte n n otice re gar di n g t he e xiste nce a n d nat ure of 
a n y a gree me nts g o ver n i n g t heir c olla b orati o n wit h NI H, t he desi g n of t he pr o p ose d pr ot oc ol, a n d t he 
e xiste nce of a n y o bli gati o ns t hat w o ul d te n d t o restrict N CI's partici pati o n i n t he pr o p ose d c o m bi nati o n 
pr ot oc ol. 
 
1 2. 7. 4 Eac h C olla b orat or s hall a gree t o per mit use of t he M ul ti-Part y Data fr o m t he cli nical trial b y a n y 
ot her C olla b orat or s olel y t o t he e xte nt necessar y t o all o w sai d ot her C olla b orat or t o de vel o p, o btai n 
re g ulat or y a p pr o val, or c o m mercialize its o w n i n vesti gati o nal a ge nt. 
 
1 2. 7. 5 A n y C olla b orat or ha vi n g t he ri g h t t o use t he M ulti-Part y Data fr o m t hese trials m ust a gree i n 
writi n g pri or t o t he c o m me nce me nt of t he trials t hat it will use t he M ulti -Part y Data s olel y f or 
de vel o p me nt, re g ulat or y a p pr o val, a n d c o m mercializati o n of its o w n i n vesti gati o nal a ge nt.  
 
1 2. 7. 6 Cli nical Trial Data a n d Res ults a n d Ra w Data de vel o pe d u n der a c olla b orati ve a gree me nt will be 
ma de a vaila ble e xcl usi vel y t o C olla b orat or(s), t he N CI, a n d t he F D A, as a p pr o priate. All data ma de 
a vaila ble will c o m pl y wit h HI P A A re g ulati o ns.  
 
1 2. 7. 7 W he n a C olla b orat or wis hes t o i nitiate a data re q uest, t he re q uest s h o ul d first be se nt t o t he N CI, 
w h o will t he n n otif y t he a p pr o priate i n vesti gat ors of C olla b orat or's wis h t o c o ntact t he m.  
 
1 2. 7. 8 A n y ma n uscri pts re p orti n g t he res ults of t his cli nical trial m us t be pr o vi de d t o D C P f or i m me diate 
deli ver y t o C olla b orat or(s) f or a d vis or y re vie w a n d c o m me nt pri or t o s u b missi o n f or p u blicati o n. 
C olla b orat or(s) will ha ve 3 0 da ys ( or as s pecifie d i n t he C S A) fr o m t he date of recei pt f or re vie w. 
C olla b orat or s hall ha ve t he ri g ht t o re q uest t hat p u blicati o n be dela ye d f or u p t o a n a d diti o nal 3 0 da ys i n 
or der t o e ns ure t hat C olla b orat or’s c o nfi de ntial a n d pr o prietar y data, i n a d diti o n t o C olla b orat or(s)’s 
i ntellect ual pr o pert y ri g hts, are pr otecte d. C o pies of a bstracts m ust be pr o vi de d t o D C P f or f or war di n g t o 
C olla b orat or(s) f or c o urtes y re vie w as s o o n as p ossi ble a n d prefera bl y at least t hree da ys pri or t o 
s u b missi o n, b ut i n a n y case, pri or t o prese ntati o n at t he meeti n g or p u blicati o n i n t he pr ocee di n gs. Press 
releases an d ot her me dia prese ntati o ns m ust als o be f or war de d t o D C P pri or t o release. C o pies of a n y 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 3 7 –  
ma n uscri pt, a bstract, a n d/ or press release/ me dia prese ntati o n s h o ul d be se nt t o t he Pr ot oc ol I nf or mati o n 
Office at N CI  D C P PI O @ mail. ni h. g o v .  
  
  
 
 
T he Pr ot oc ol I nf or mati o n Office will f or war d ma n uscri pts t o t he D C P Pr oject Officer f or distri b uti o n t o 
t he C olla b orat or(s). N o p u blicati o n, ma n uscri pt or ot her f or m of p u blic discl os ure s hall c o ntai n a n y of 
C olla b orat or’s c o nfi de ntial/ pr o prietar y i nf or mati o n. 
 
1 3. 
S T A TI S TI C A L C O N SI D E R A TI O N S  
 
1 3. 1 
St u d y Desi g n/ Descri pti o n  
 
We pla n a ra n d o mize d, d o u ble -bli n d, P hase I trial wit h a c o ntr ol ar m a n d a treat me nt ar m, wit h d ose 
escalati o n fr o m 1 0 m g E N X  gel  dail y  ( 5 m g per breast)  t o 2 0 m g dail y  ( 1 0 m g per breast) . D ose-li miti n g 
t o xicit y is defi ne d as t he occ urre nce of Gra de 2 or greater  s ki n res p o nse f or a n y of t he C T C A E para meters 
liste d i n Ta ble 1.  
 
C o h orts 1 a n d 2 will be ra n d o mize d 2: 1 ( E N X  gel a n d place b o). C o h ort 3 will c o ns ist o nl y of acti vel y 
treate d s u bjects. We pla n ne d t hat t he sa m ple size ma y r a n ge u p t o 3 8, de pe n di n g o n t he fre q ue nc y of D L T, 
a n d h o w earl y i n eac h c o h ort D L T wa s o bser ve d. After c o m pleti o n of C o h ort 2 ( wit h accr ual of 1 2 s u bjects 
eac h i n C o h ort 1 a n d 2), we will n o w accr ue 8 s u bjects i n C o h ort 3 , wit h a fi nal accr ual of 3 2 s u bjects. All 
s u bj ects w h o recei ve a n y st u d y dr u g will be e val ua ble f or t he pri mar y e n d p oi nt of der mal t o xicit y.  
 
We c h o ose a 2: 1 ra n d o mize d desi g n wit h a place b o ar m wit h eac h d ose i n  or der t o est a blis h v ari a bility of 
me as ure me nts w he n n o tre at me nt is a p plie d, a n d yet t o pr o vi de treat me nt t o as ma n y s u bjects as p ossi ble.  
Ra n d o mizati o n  is  d o u ble  bli n de d,  a n d  t he  gel  use d  i n  t he  treat me nt  a n d  c o ntr ol  gr o u ps  has  si milar  
a p peara nce, c o nsi ste nc y, a n d c he mical c o m p ositi o n, e xce pt f or t he prese nce of E N X  i n t he acti ve gel. T he 
st u d y will e m pl o y i nte nt t o treat pri nci ples. Alt h o u g h f or mal statistical c o m paris o n will be li mite d b y t he 
s mall sa m ple size (as ca n be t he case f or P hase I trials), the place b o gr o u p will be use d t o i nter pret s u bjecti ve 
s y m pt o ms s uc h as s ki n irritati o n or pr uritis. C o m bi ni n g place b o gr o u ps will yiel d a t otal of n = 8, t h us 
pr o vi di n g sta n dar d err or of t he esti mate of S D/s qrt( 8) a n d 0. 5/s qrt/( 8). 
 
1 3. 2  
R a n d o miz ati o n/ Str atific ati o n  
 
Ra n d o mizati o n list will be pr o vi de d b y st u d y statisticia n a n d ma de a vaila ble t o t he accr ual -site 
p har macists . Neit her stratificati o n n or bl oc ki n g will be use d f or de m o gra p hic fact ors. I nteri m a nal ysis f or 
t o xicit y is b uilt i nt o t he desi g n of t his escalati o n st u d y (see t he sc he ma). Efficac y deter mi nati o n will be 
d o ne f or eac h of t w o d oses a n d place b o gr o u ps wit h p ur p ose of gai ni n g all t he i nf or mati o n a vaila ble.  
 
1 3. 3  
Accr u al a n d Fe asi bilit y  
 
Ass u mi n g 3 8 w o me n  f or all c o h orts, we a ntici pate recr uiti n g 1 4 at N U, a n d 1 2 eac h at M S K C C a n d C S-
L A. W o me n of all races a n d et h nicities will be recr uite d. T he d urati o n of accr ual is e x pecte d t o be 1 2 - 1 4 
m o nt hs at a rate of 3 s u bjects per m o nt h ( o ne s u bj ect per site per m o nt h).  T he a ntici pate d ti meli ne is 
s h o w n bel o w. 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 3 8 –  
 
 
1 3. 4 
Pri m ar y O bjecti ve, E n d p oi nt(s) , A n al ysis Pl a n 
 
D at a A n al yses Pl a ns   T he pri mar y pla n is t o esti mate a n d pr o vi de c o nfi de nce i nter vals ( CIs) f or t he 
i nci de nce of s ki n irritati o n i n patie nts treate d at eac h d ose le vel, as well as i n t he place b o, usi n g C T C A E 
criteria liste d i n T a ble 1. It is e x pecte d a wealt h of i nf or mati o n o n para meters of i nterest will be ac q uire d 
fr o m place b o gr o u p, s h ort of f or mal testi n g.  
 
1 3. 5 
Sec o n d ar y O bjecti ves, E n d p oi nts, A n al ysis Pl a ns  
 
Sec o n d ary o bjectives:   
1) C o m paris o n of breast tiss ue c o nce ntrati o ns of E N X  at eac h d ose will be d o ne usi n g vis ualizati o n, 
gra p hics a n d b y pr o vi di n g a p pr o priate c o nfi de nce i nter val ( CI).  
2)  Plas ma c o nce ntrati o ns of E N X  at eac h d ose ( 1 0 m g per da y a n d 2 0 m g per da y), will be re p orte d as 
o bser ve d c o nce ntrati o ns wit h a p pr o priate CIs.  
3- 5) R elate t o c o m par is o n of t he plas ma le vels f or ster oi d h or m o nes, plas ma estr o ge nic res p o nse pr otei ns, 
a n d plas ma c oa g ulati o n para meters.  T o assess treat me nt-relate d c ha n ges, t he 9 5 % CI of t he mea n 
differe nce p ost- pre a n d a test of t he ce ntral para meter = 0 will be pr o vi de d  as i n t he pre vi o us o bjecti ve.  
6) T o  assess tiss ue bi ol o gic res p o nse t o E N X gel treat me nt. T hese will be c o m pare d as pre - a n d p ost-
t hera p y val ues , t o e xpl ore t he p ote ntial t hera pe utic effects of t he t w o d oses of E N X : a) b y I H C f or Ki 6 7, 
E R, a n d P R e x pressi o n; b) b y na n ostri n g assa ys, usi n g a pa nel of ge nes re p orte d t o c ha n ge wit h E N X  
e x p os ure. F or b ot h I H C a n d ge ne e x pressi o n, val ues f or “ pre” a n d f or “ p o st” meas ure me nts will be 
s u btracte d fr o m eac h ot her a n d CIs f or t he mea n differe nce will be pr o vi de d. A n o n para metric test of t he 
ce ntral para meter bei n g zer o will be perf or me d.  
7)  T o ba n k ger mli ne D N A f or f ut ure p o ole d a nal yses of p ol y m or p his ms i n ta m o xife n meta b olizi n g 
e nz y mes, statistical a nal ysis will be use d as nee de d  ( o pti o nal). 
8 ) A nal ysis of s y m pt o ms as re p orte d i n t he B E S S q uesti o n naire: T his uses sc ores w here t he l o west 
descri bes  “ n o s y m pt o m” a n d t he hi g hest reflects “e xtre mel y” or “al wa ys”.  T he hi g h sc ores are a d verse. 
W he n s u btracti n g p ost -pre meas ures, ne gati ve val ues s u g gest i m pr o ve me nt o ver ti me, w hile p ositi ve 
s u g gest w orse ni n g. We will pr o vi de gra p hical dis pla ys of t hese differe nces as hist o gra ms wit h x-a xis 
v al ues - 5, - 4, … 0, … 4, 5 a n d e m pirical mass f u ncti o n o n t he t o p. T o c o m pare t he d ose gr o u ps (l o w, 
hi g h) a n d si n g ular d ose vers us place b o , if a p pr o priate, we will use t he n o n para metric t w o sa m ple 
Wilc o x o n- Ma n n -W hit ne y test, wit h c orrecti o ns f or ties . T he stu d y was n ot s pecificall y p o were d f or s uc h 
a nal ysis, a n d res ulti n g o ne a n d t w o si de d p- val ues will be c o nsi dere d descri pti ve statistics usef ul f or 
f ut ure a nal yses. A vera ge, me dia n a n d ra n ge of sc ores f or eac h n ote d gr o u p will be pr o vi de d as descri pti ve 
meas ures of l ocati o n a n d varia nce. We will use m ulti ple i m p utati o n via n o n- para metric pr o ba bilit y 
i nte gral tra nsf or mati o n[ 5 3] t o i m p ute missi ng data as a p pr o priate.   
 
All tests will be t w o -si de d. We will use m ulti ple i m p utati o n via n o n-para metric pr o ba bilit y i nte gral 
tra nsf or mati o n ( Hele n o ws ki, P h D Dissertati o n, 2 0 1 1) t o i m p ute missi n g data as a p pr o priate.   
 
1 3. 6 
Re p orti n g  a n d E xcl usi o ns  
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 3 9 –  
C o m p lia nce is defi ne d as c o ns u m pti o n of 8 0 % of t he prescri be d d ose o ver t he w h ole st u d y peri o d, a n d  of 
all of t he last 3 re q uire d d oses. W here i nf or mati o n is a vaila ble, data o n n o n -c o m plia nt patie nts will be 
c o nsi dere d f or d ose-res p o nse a nal ysis. Missi n g data will be treate d via m ulti ple i m p utati o ns as descri be d 
i n pre vi o us secti o ns.  
 
1 3. 7  
E v al u ati o n of T o xicit y 
 
All partici pa nts will be e val uate d f or t o xicit y as descri be d i n t he pr ot oc ol.  D ose -Li miti n g T o xicit y ( D L T)  
is defi ne d as Gra de 2 or greater s ki n t o xicit y, usi n g C T C A E criteria f or t he para meters s h o w n i n T a ble 1. 
T he Gra de 2 or greater reacti o n s h o ul d occ ur at t he a p plicati o n site f or 4 8 h o urs or l o n ger a n d be 
defi nitel y , pr o ba bl y, or p ossi bl y relate d t o t he st u d y dr u g.  
 
1 3. 8  
E v al u ati o n of Re s p o nse 
 
All partici pa nts i ncl u de d i n t he st u d y w h o recei ve d a ge nt will be assesse d f or res p o nse t o i nter ve nti o n, 
e ve n if t here are maj or pr ot oc ol de viati o ns.   
 
All of t he partici pa nts w h o met t he eli gi bilit y criteria ( wit h t he e xce pti o n of t h ose w h o di d n ot recei ve 
st u d y a ge nt) will be i ncl u de d i n t he mai n a nal ysis. All c o ncl usi o ns re gar di n g efficac y will be base d o n all 
eli gi ble partici pa nts. 
 
S u b -a nal yses ma y be perf or me d o n t he s u bsets of partici pa nts, e xcl u di n g t h ose f or w h o m maj or pr ot oc ol 
de viati o ns ha ve bee n i de ntifie d (e. g., earl y deat h d ue t o ot her reas o ns, earl y disc o nti n uati o n of 
i nter ve nti o n, maj or pr ot oc ol vi olati o ns, etc.). H o we ver, s u b-a nal yses will n ot ser ve as t he basis f or 
dra wi n g c o ncl usi o ns c o ncer ni n g efficac y, a n d t he reas o ns f or e xcl u di n g partici pa nts fr o m t he a nal ysis 
s h o ul d be clearl y re p orte d. F or all meas ure me nts of res p o nse, t he 9 5 % c o nfi de nce i nter vals will be 
pr o vi de d. 
 
1 3. 9 
I nteri m A n al ysis 
 
I nteri m a nal yses a n d st o p pi n g r ules are t h ose i n here nt i n t o xicit y e val uati o n a n d d ose escalati o n / de-
escalati o n. Earl y ter mi nati o n ma y occ ur if t he l o west d ose is f o u n d t o xic.  
 
1 3. 1 0 A ncill ar y St u dies  
 
A ncillar y st u dies will be perf or me d as nee de d a n d a s p ossi ble.  P o wer a nal yses ha ve n ot bee n perf or me d 
f or t he prese nt ti me lac k of k n o wle d ge of para meters a n d effect sizes i n v ol ve d. B o nferr o ni c orrecti o n f or 
m ulti ple c o m paris o ns will be a p plie d as p ossi ble i n gi ve n c o nte xt.  
 
1 4. 
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  
 
1 4. 1  
F or m F D A 1 5 7 2 
 
Pri or t o i nitiati n g t his st u d y, t he Pr ot oc ol Lea d I n vesti gat or at t he Lea d or Partici pati n g Or ga nizati o n(s)  
will pr o vi de a si g ne d F or m F D A 1 5 7 2 stati n g t hat t he st u d y will be c o n d ucte d i n c o m plia nce wit h 
re g ulati o ns f or cli nical i n vesti gati o ns a n d listi n g t he i n vesti gat ors, at eac h site t hat will partici pate i n t he 
pr ot oc ol. All pers o n nel directl y i n v ol ve d i n t he perf or ma nce of pr oce d ures re q uire d b y t he pr ot oc ol a n d 
t he c ollecti o n of data s h o ul d be liste d o n F or m F D A 1 5 7 2. 
 
1 4. 2 
Ot her Re q uire d D oc u me nts  

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 4 0 –  
 
1 4. 2. 1  C urre nt ( wit hi n t w o years) C V or bi os ketc h f or all st u d y pers o n nel liste d o n t he F or m F D A 1 5 7 2 
a n d Dele gati o n of Tas ks f or m f or t he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns. C Vs or 
bi os ketc hes d o n ot nee d t o be u p date d f or partici pati n g st u d y staff after dr u g s hi p me nt a ut h orizati o n 
( D S A).   
 
1 4. 2. 2 C urre nt me dical lice nses ( w here a p plica ble) f or all st u d y pers o n nel liste d o n F or m F D A 1 5 7 2 a n d 
Dele gati o n of T as ks f or m f or t he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns. 
 
1 4. 2. 3  La b certificati o n ( e. g., C LI A, C A P) a n d la b n or mal ra n ges f or all la bs liste d o n F or m F D A 1 5 7 2 
f or t he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns. 
 
1 4. 2. 4  D oc u me ntati o n of G o o d Cli nical Practice trai ni n g f or all st u d y pers o n nel liste d o n t he F D A F or m 
1 5 7 2 a n d Dele gati o n of T as ks f or m f or t he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns. 
 
1 4. 2. 5  D oc u me ntati o n of Fe deral wi de Ass ura nce ( F W A) n u m ber f or t he Lea d Or ga nizati o n a n d all 
Partici pati n g Or ga nizati o ns.  
 
1 4. 2. 6  Si g ne d I n vesti gat or’s Br oc h ure/ Pac ka ge I nsert ac k n o wle d ge me nt f or m  
 
1 4. 2. 7  Dele gati o n of T as ks f or m  f or t he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns si g ne d b y 
t he Pri nci pal I n vesti gat or f or eac h site a n d i nitiale d b y all st u d y pers o n nel liste d o n t he f or m 
 
1 4. 2. 8  Si g ne d a n d date d N CI, D C P Fi na ncial Discl os ure  F or m f or all st u d y pers o n nel liste d o n F or m 
F D A 1 5 7 2 f or t he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns 
 
1 4. 3  I nstit uti o n al Re vie w B o ar d A p pr o v al 
 
Pri or t o i nitiati n g t he st u d y a n d recei vi n g a ge nt, t h e I n vesti gat ors at t he Lea d Or ga nizati o n a n d t he 
Partici pati n g Or ga nizati o n(s) m ust o btai n writte n a p pr o val t o c o n d uct t he st u d y fr o m t he a p pr o priate I R B. 
S h o ul d c ha n ges t o t he st u d y bec o me necessar y, pr ot oc ol a me n d me nts will be s u b mitte d t o t he D C P PI O 
acc or di n g t o D C P A me n d me nt G ui deli nes. T he D C P-a p pr o ve d a me n de d pr ot oc ol m ust be a p pr o ve d b y 
t he I R B pri or t o i m ple me ntati o n 
 
1 4. 4 
I nf or me d C o nse nt 
 
All p ote ntial st u d y partici pa nts will be gi ve n a c o p y of t he I R B -a p pr o ve d I nf or me d C o nse nt t o re vie w. 
T he i n v esti gat or will e x plai n all as pects of t he st u d y i n la y la n g ua ge a n d a ns wer all q uesti o ns re gar di n g 
t he st u d y. If t he partici pa nt deci des t o partici pate i n t he st u d y, he/s he will be as ke d t o si g n a n d date t he 
I nf or me d C o nse nt d oc u me nt. T he st u d y a ge nt(s) will n ot be release d t o a partici pa nt w h o has n ot si g ne d 
t he I nf or me d C o nse nt d oc u me nt. S u bj ects w h o ref use t o partici pate or w h o wit h dra w fr o m t he st u d y will 
be treate d wit h o ut prej u dice.  
 
Partici pa nts m ust be pr o vi de d t he o pti o n t o all o w t he use of bl o o d sa m ples, ot her b o d y fl ui ds, a n d tiss ues 
o btai ne d d uri n g testi n g, o perati ve pr oce d ures, or ot her sta n dar d me dical practices f or f urt her researc h 
p ur p oses. If a p plica ble, state me nt of t his o pti o n ma y be i ncl u de d wit hi n t he i nf or me d c o nse nt d oc u me nt 
or ma y be pr o vi de d as a n a d de n d u m t o t he c o nse nt. A M o del C o nse nt F or m f or Use of Tiss ue f or 
Researc h is a vaila ble t hr o u g h a li n k i n t he D C P we bsite.  
 
Pri or t o st u d y i nitiati o n, t he i nf or me d c o nse nt d oc u me nt m ust be re vie we d a n d a p pr o ve d b y N CI, D C P, 
t he C o ns orti u m Lea d Or ga nizati o n, a n d t he I R B at eac h Or ga nizati o n at w hic h t he pr ot oc ol will be 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 4 1 –  
i m ple me nte d. A n y s u bse q ue nt c ha n ges t o t he i nf or me d c o nse nt m ust be a p pr o ve d b y N CI, D C P, t he 
C o ns orti u m Lea d Or ga nizati o n’s I R B, a n d t he n s u b mitte d t o eac h or ga nizati o n’s I R B f or a p pr o val pri or 
t o i nitiati o n. 
 
1 4. 5  
S u b missi o n of Re g ul at or y D oc u me nts 
 
All re g ulat or y d oc u me nts are c ollecte d b y t he C o ns ortia Lea d Or ga nizati o n a n d re vie we d f or 
c o m plete ness a n d ac c urac y. O nce t he C o ns ortia Lea d Or ga nizati o n has recei ve d c o m plete a n d acc urate 
d oc u me nts fr o m a partici pati n g or ga nizati o n, t he C o ns orti u m Lea d Or ga nizati o n will f or war d t he 
re g ulat or y d oc u me nts t o D C P’s Re g ulat or y C o ntract or: 
 
 
Pa per D oc u me nt/ C D - R O M S u b missi o ns: 
 
Re g ulat or y Affairs  De part me nt  
 
C C S Ass ociates , I nc. 
  
2 0 0 1 Gate wa y Pl, S uite 3 5 0 W 
 
Sa n J ose , C A 9 5 1 1 0 
 
P h o ne: 6 5 0 - 6 9 1- 4 4 0 0 
  
Fa x: 6 5 0- 6 9 1- 4 4 1 0 
 
  
E- mail S u b missi o ns: 
 
re g ulat or y @ccsai nc.c o m 
 
Re g ulat or y d oc u me nts t hat d o n ot re q uire a n ori gi nal si g nat ure ma y be se nt electr o nicall y t o t he 
C o ns orti u m Lea d Or ga nizati o n f or re vie w, w hic h will t he n be electr o nicall y f or war de d t o D C P ’s 
Re g ulat or y C o ntract or. 
 
1 4. 6 
Ot her  
 
T his trial will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, G o o d Cli nical Practice ( G C P), a n d t he 
a p plica ble re g ulat or y re q uire me nts.  
 
1 5. 
FI N A N CI N G, E X P E N S E S,  A N D/ O R I N S U R A N C E  
 
T he pr ot oc ol s h o ul d descri be a ny ex pe nses i nc urre d by t he st u dy p artici p a nt a n d/ or t heir i ns ur a nce 
c arrier. T his i ncl u des a ny i nj uries t he p artici p a nt m ay h ave rel ate d t o t heir p artici p ati o n i n t he st u dy. 
 
T o c o ver e x pe nses relate d t o tra vel, c hil d -care, l oss of w or k ti me a n d ot her si milar iss ues, partici pa nts 
will recei ve  $ 1 0 0 after c o m pleti o n of Scree ni n g Visit 1, $ 1 0 0 after c o m pleti o n of St u d y Visit 1 ( w hic h 
ma y be c o m bi ne d wit h St u d y Visit 2 da y of s ur ger y), a n d $ 1 0 0 after c o m pleti o n of St u d y Visit 3. 
Partici pa nts w h o are re q uire d t o ret ur n t o t he office f or a n a d diti o nal pre g na nc y test will recei ve a n 
a d diti o nal $ 1 0 0.  It is p ossi ble t hat i nj ur y ma y res ult fr o m partici pati n g i n t his st u d y.  A n y  e x pe nses 
i nc urre d as a res ult of researc h relate d i nj ur y will be t he res p o nsi bilit y of t he st u d y partici pa nt a n d/ or t heir 
i ns ura nce carrier. 
 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 4 2 –  
R E F E R E N C E S  
 
1.  
Fis her B, C osta nti n o J P, Wic ker ha m D L et al. T a m o xife n f or pre ve nti o n of breast ca ncer: Re p ort 
of t he Nati o nal S ur gical A dj u va nt Breast a n d B o wel Pr oj ect P - 1 St u d y. J. Natl. Ca ncer I nst. 1 9 9 8; 9 0: 
1 3 7 1- 1 3 8 8. 
2.  
Fis her B, C osta nti n o J P, Wic ker ha m D L et al . T a m o xife n f or t he pre ve nti o n of breast ca ncer: 
c urre nt stat us of t he Nati o nal S ur gical A dj u va nt Breast a n d B o wel Pr oject P - 1 st u d y. J. Natl. Ca ncer I nst. 
2 0 0 5; 9 7: 1 6 5 2- 1 6 6 2. 
3.  
V o gel V G, C osta nti n o J P, Wic ker ha m D L et al. U p date of t he Nati o nal S ur gical A dj u va nt Breast 
a n d B o wel Pr oject St u d y of T a m o xife n a n d Ral o xife ne ( S T A R) P- 2 Trial: Pre ve nti n g breast ca ncer. 
Ca ncer Pre v. Res ( P hila) 2 0 1 0; 3: 6 9 6- 7 0 6. 
4. 
C uzic k J, F or bes J F, Sesta k I et al. L o n g -ter m res ults of ta m o xife n pr o p h yla xis f or breast ca ncer--
9 6- m o nt h f oll o w- u p of t he ra n d o mize d I BI S-I trial. J. Natl. Ca ncer I nst. 2 0 0 7; 9 9: 2 7 2- 2 8 2. 
5.  
Wa p nir I L, Di g na m JJ, Fis her B et al. L o n g- ter m o utc o mes of i n vasi ve i psilateral breast t u m or 
rec urre nces after l u m pect o m y i n N S A B P B- 1 7 a n d B- 2 4 ra n d o mize d cli nical trials f or D CI S. J Natl 
Ca ncer I nst 2 0 1 1; 1 0 3: 4 7 8 - 4 8 8. 
6. 
Fis her B, Di g na m J, W ol mar k N et al. T a m o xife n i n treat me nt of i ntra d uctal breast ca ncer: 
Nati o nal S ur gical A dj u va nt Breast a n d B o wel Pr oject B - 2 4 ra n d o mise d c o ntr olle d trial. La ncet 1 9 9 9; 3 5 3: 
1 9 9 3- 2 0 0 0. 
7. 
R oetz hei m R G, Lee J H, F ul p W et al. Acce pta nce a n d a d here nce t o c he m o pre ve nti o n a m o n g 
w o me n at i ncrease d ris k of breast ca ncer. Breast 2 0 1 5; 2 4: 5 1- 5 6. 
8. 
Mel ni k o w J, Pater niti D, Azari R et al. Prefere nces of W o me n E val uati n g Ris ks of T a m o xif e n 
( P O W E R) st u d y of prefere nces f or ta m o xife n f or breast ca ncer ris k re d ucti o n. Ca ncer 2 0 0 5; 1 0 3: 1 9 9 6-
2 0 0 5. 
9.  
Fla na ga n M R, Re n di M H, Ga di V K et al. A dj u va nt E n d ocri ne T hera p y i n Patie nts wit h D uctal 
Carci n o ma I n Sit u: A P o p ulati o n- Base d Retr os pecti ve A na l ysis fr o m 2 0 0 5 t o 2 0 1 2 i n t he Nati o nal Ca ncer 
Data Base. A n n S ur g O nc ol 2 0 1 5; 2 2: 3 2 6 4- 3 2 7 2. 
1 0. 
Cella D, La n d S R, C ha n g C H et al. S y m pt o m meas ure me nt i n t he Breast Ca ncer Pre ve nti o n Trial 
( B C P T) ( P-1): ps yc h o metric pr o perties of a ne w meas ure of s y m pt o ms  f or mi dlife w o me n. Breast Ca ncer 
Res Treat 2 0 0 8; 1 0 9: 5 1 5- 5 2 6. 
1 1.  
C uzic k J. C he m o pre ve nti o n of breast ca ncer. Breast Ca ncer 2 0 0 8; 1 5: 1 0- 1 6. 
1 2.  
Da y R, Ga nz P A, C osta nti n o J P et al. Healt h- relate d q ualit y of life a n d ta m o xife n i n breast ca ncer 
pre ve nti o n : a re p ort fr o m t he Nati o nal S ur gical A dj u va nt Breast a n d B o wel Pr oject P- 1 St u d y. 
J. Cli n. O nc ol 1 9 9 9; 1 7: 2 6 5 9- 2 6 6 9. 
1 3.  
Lee O, K ha n S A. N o vel r o utes f or a d mi nisteri n g c he m o pre ve nti o n: l ocal tra ns der mal t hera p y t o 
t he breasts. Se mi n O nc ol 2 0 1 6; 4 3: 1 0 7- 1 1 5. 
1 4. 
Ma u vais -J a vis P, Ba u d ot N, Castai g ne D et al. tra ns- 4-H y dr o x yta m o xife n c o nce ntrati o n a n d 
meta b olis m after l ocal perc uta ne o us a d mi nistrati o n t o h u ma n breast. Ca ncer Res 1 9 8 6; 4 6: 1 5 2 1- 1 5 2 5. 
1 5.  
R o ua net P, Li nares- Cr uz G, Dra vet F et al. Ne oa dj u va nt perc uta ne o us 4- h y dr o x yta m o xife n 
decreases breast t u m oral cell pr oliferati o n: a pr os pecti ve c o ntr olle d ra n d o mize d st u d y c o m pari n g t hree 
d oses of 4 -h y dr o x yta m o xife n gel t o oral ta m o xife n. J. Cli n. O nc ol 2 0 0 5; 2 3: 2 9 8 0 - 2 9 8 7. 
1 6. 
Lee O, Pa ge K, I va ncic D et al. A Ra n d o mize d P hase II Pres ur gical Trial of Tra ns der mal 4 -
H y dr o x yta m o xife n Gel vers us Oral T a m o xife n i n W o me n wit h D uctal Carci n o ma I n Sit u of t he Breast. 
Cli n. Ca ncer Res. 2 0 1 4; 2 0: 3 6 7 2- 3 6 8 2. 
1 7. 
Lee O, I va ncic D, All u S et al. L ocal tra ns der mal t hera p y t o t he breast f or breast ca ncer 
pre ve nti o n a n d D CI S t hera p y: precli nical a n d cli nical e val uati o n. Ca ncer C he m ot her P har mac ol 2 0 1 5; 7 6: 
1 2 3 5- 1 2 4 6. 
1 8. 
Ac ker ma n A B, Kessler G, G y orfi T et al. C o ntrar y vie w: t he breast is n ot a n or ga n per se, b ut a 
disti ncti ve r e gi o n of s ki n a n d s u bc uta ne o us tiss ue. A m.J. Der mat o pat h ol. 2 0 0 7; 2 9: 2 1 1- 2 1 8. 
1 9.  
S ua mi H, Pa n W R, Ma n n G B, T a yl or GI. T he l y m p hatic a nat o m y of t he breast a n d its 
i m plicati o ns f or se nti nel l y m p h n o de bi o ps y: a h u ma n ca da ver st u d y. A n n. S ur g. O nc ol. 2 0 0 8; 1 5: 8 6 3-

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 4 3 –  
8 7 1. 
2 0.  
P uj ol H, Gira ult J, R o ua net P et al. P hase I st u d y of perc uta ne o us 4- h y dr o x y-ta m o xife n wit h 
a nal yses of 4 - h y dr o x y-ta m o xife n c o nce ntrati o ns i n breast ca ncer a n d n or mal breast tiss ue. Ca ncer 
C he m ot her. P har mac ol. 1 9 9 5; 3 6: 4 9 3- 4 9 8. 
2 1. 
Lee O, I v a ncic D, C hattert o n R T et al. I n vitr o h u ma n s ki n per meati o n of e n d o xife n: p ote ntial f or 
l ocal tra ns der mal t hera p y f or pri mar y pre ve nti o n a n d carci n o ma i n sit u of t he breast. Breast 
Ca ncer: T ar gets a n d T hera p y 2 0 1 1; 3: 6 1- 7 0. 
2 2. 
Li m Y C, Desta Z, Fl oc k hart D A, S kaar T C. E n d o xife n ( 4- h y dr o x y- N- des met h yl- ta m o xife n) has 
a nti-estr o ge nic effects i n breast ca ncer cells wit h p ote nc y si milar t o 4 - h y dr o x y-ta m o xife n. Ca ncer 
C he m ot her. P har mac ol. 2 0 0 5; 5 5: 4 7 1- 4 7 8. 
2 3.  
Li m Y C, Li L, Desta Z et al. E n d o xife n, a sec o n dar y meta b olite of ta m o xife n, a n d 4 -O H -
ta m o xife n i n d uce si milar c ha n ges i n gl o bal ge ne e x pressi o n patter ns i n M C F-7 breast ca ncer cells. 
J. P har mac ol. E x p. T her. 2 0 0 6; 3 1 8: 5 0 3- 5 1 2. 
2 4.  
J o h ns o n M D, Z u o H, Lee K H et al. P har mac ol o gical c haracterizati o n of 4- h y dr o x y- N- des met h yl 
ta m o xife n, a n o vel acti ve meta b olite of ta m o xife n. Breast Ca ncer Res Treat. 2 0 0 4; 8 5: 1 5 1- 1 5 9. 
2 5. 
W u X, Ha wse J R, S u bra ma nia m M et al. T he ta m o xife n meta b olite, e n d o xife n, is a p ote nt 
a ntiestr o ge n t hat tar gets estr o ge n rece pt or al p ha f or de gra dati o n i n breast ca ncer cells. Ca ncer Res 2 0 0 9; 
6 9: 1 7 2 2- 1 7 2 7. 
2 6. 
Ha wse J R, S u bra ma nia m M, Cice k M et al. E n d o xife n's m olec ular mec ha nis ms of acti o n are 
c o nce ntrati o n de pe n de nt a n d differe nt t ha n t hat of ot her a nti-estr o ge ns. P L o S. O ne. 2 0 1 3; 8: e 5 4 6 1 3. 
2 7.  
Sc h wei kart K M, El dri d ge S R, Saf gre n S L et al. C o m parati ve uter otr o p hic effects of e n d o xife n 
a n d ta m o xife n i n o variect o mize d S pra g ue- Da wle y rats. T o xic ol Pat h ol 2 0 1 4; 4 2: 1 1 8 8- 1 1 9 6. 
2 8. 
Fa n g J Y, H wa n g T L, Le u Y L. Effect of e n ha ncers a n d retar ders o n per c uta ne o us a bs or pti o n of 
fl ur bi pr ofe n fr o m h y dr o gels. I nt.J. P har m. 2 0 0 3; 2 5 0: 3 1 3- 3 2 5. 
2 9.  
Y u B, D o n g C Y, S o P T et al. I n vitr o vis ualizati o n a n d q ua ntificati o n of oleic aci d i n d uce d 
c ha n ges i n tra ns der mal tra ns p ort usi n g t w o- p h ot o n fl u oresce nce micr osc o p y. J.I n vest Der mat ol. 2 0 0 1; 
1 1 7: 1 6- 2 5. 
3 0.  
O gis o T, Pa k u T, I wa ki M, T a ni n o T. Perc uta ne o us pe netrati o n of fl u orescei n is ot hi oc ya nate-
de xtra ns a n d t he mec ha nis m f or e n ha nce me nt effect of e n ha ncers o n t he i ntercell ular pe netrati o n. 
Bi ol. P har m. B ull. 1 9 9 5; 1 8:  1 5 6 6- 1 5 7 1. 
3 1.  
Willia ms A C, Barr y B W. Pe netrati o n e n ha ncers. A d v. Dr u g Deli v. Re v. 2 0 0 4; 5 6: 6 0 3- 6 1 8. 
3 2. 
A h ma d A, Ali S M, A h ma d M U et al. Orall y a d mi nistere d e n d o xife n is a ne w t hera pe utic a ge nt 
f or breast ca ncer. Breast Ca ncer Res. Treat. 2 0 1 0; 1 2 2: 5 7 9- 5 8 4. 
3 3.  
A h ma d A, S ha ha b u d di n S, S hei k h S et al. E n d o xife n, a ne w c or nerst o ne of breast ca ncer t hera p y: 
de m o nstrati o n of safet y, t olera bilit y, a n d s yste mic bi oa vaila bilit y i n healt h y h u ma n s u bjects. 
Cli n. P har mac ol. T her. 2 0 1 0; 8 8: 8 1 4- 8 1 7. 
3 4. 
Gjer de J, Ga n di ni S, G uerrieri- G o nza ga A et al. Tiss ue distri b uti o n of 4- h y dr o x y- N-
des met h ylta m o xife n a n d ta m o xife n - N- o xi de. Breast Ca ncer Res. Treat. 2 0 1 2; 1 3 4: 6 9 3- 7 0 0. 
3 5.  
G o n g I Y, T eft W A, L y J et al. Deter mi nati o n of cli nicall y t hera pe utic e n d o xife n c o nce ntrati o ns 
ba se d o n efficac y fr o m h u ma n M C F 7 breast ca ncer xe n o grafts. Breast Ca ncer Res. Treat. 2 0 1 3; 1 3 9: 6 1 -
6 9. 
3 6. 
Lee O, Pa ge K, I va ncic D et al. A ra n d o mize d p hase II pres ur gical trial of tra ns der mal 4 -
h y dr o x yta m o xife n gel vers us oral ta m o xife n i n w o me n wit h d ucta l carci n o ma i n sit u of t he breast. Cli n 
Ca ncer Res 2 0 1 4; 2 0: 3 6 7 2- 3 6 8 2. 
3 7. 
Al berti I, Kalia Y N, Nai k A et al. I n vi v o assess me nt of e n ha nce d t o pical deli ver y of ter bi nafi ne 
t o h u ma n strat u m c or ne u m. J C o ntr ol Release 2 0 0 1; 7 1: 3 1 9- 3 2 7. 
3 8. 
L oftss o n T, G u d m u n ds d ottir T K, Fri dri ks d ottir H et al. Fatt y aci ds fr o m c o d- li ver oil as s ki n 
pe netrati o n e n ha ncers. P har ma zie 1 9 9 5; 5 0: 1 8 8- 1 9 0. 
3 9.  
J or da n V C. Ne w i nsi g hts i nt o t he meta b olis m of ta m o xife n a n d its r ole i n t he treat me nt a n d 
pre ve nti o n of breast ca ncer. Ster oi ds 2 0 0 7; 7 2: 8 2 9- 8 4 2. 
4 0. 
El ki ns P, C ole ma n D, B ur gess J et al. C haracterizati o n of t he is o meric c o nfi g urati o n a n d 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 4 4 –  
i m p urities of ( Z)-e n d o xife n b y 2 D N M R, hi g h res ol uti o n L C M S, a n d q ua ntitati ve H P L C a nal ysis. J 
P har m Bi o me d A nal 2 0 1 4; 8 8: 1 7 4- 1 7 9. 
4 1.  
Katze nelle n b o ge n B S, N or ma n MJ, Ec kert R L et al. Bi oacti vities, estr o ge n rece pt or i nteracti o ns, 
a n d plas mi n o ge n acti vat or -i n d uci n g acti vities of ta m o xife n a n d h y dr o x y-ta m o xife n is o mers i n M C F- 7 
h u ma n breast ca ncer cells. Ca ncer Res 1 9 8 4; 4 4: 1 1 2- 1 1 9. 
4 2.  
G oetz M P, Ka mal A, A mes M M. Ta m o xife n p har mac o ge n o mics: t he r ole of C Y P 2 D 6 as a 
pre dict or of dr u g res p o nse. Cli n P har mac ol T her 2 0 0 8; 8 3: 1 6 0- 1 6 6. 
4 3. 
Ma nsel R, G o yal A, Nest o ur E L et al. A p hase II trial of Afi m o xife ne ( 4 - h y dr o x yta m o xife n gel) 
f or c yclical mastal gia i n pre me n o pa usal w o me n. Breast Ca ncer Res. Treat. 2 0 0 7; 1 0 6: 3 8 9- 3 9 7. 
4 4.  
C hae YJ, Lee KJ, Lee HJ et al. E n d o xife n, t he acti ve meta b olite of ta m o xife n, i n hi bits cl o ne d 
h E R G p otassi u m c ha n nels. E ur J P har mac ol 2 0 1 5; 7 5 2: 1- 7. 
4 5. 
C hattert o n R T, M u zzi o M, Hei nz R et al. Met h o d ol o gical c o nsi derati o ns i n estr o ge n assa ys of 
breast fl ui d a n d breast tiss ue. Ster oi ds 2 0 1 5; 9 9: 1 0 3- 1 0 7. 
4 6.  
B o na n ni B, Serra n o D, Ga n di ni S et al. Ra n d o mize d bi o mar ker trial of a nastr oz ole or l o w- d ose 
ta m o xife n or t heir c o m bi nati o n i n s u bjects wit h breast i ntrae pit helial ne o plasia. Cli n Ca ncer Res 2 0 0 9; 
1 5: 7 0 5 3- 7 0 6 0. 
4 7.  
C ha n g J, P o wles TJ, Allre d D C et al. Pre dicti o n of cli nical o utc o me fr o m pri mar y ta m o xife n b y 
e x pressi o n of bi ol o gic mar kers i n breast ca ncer patie nts. Cli n. Ca ncer Res. 2 0 0 0; 6: 6 1 6- 6 2 1. 
4 8.  
Bar ker S, Mal o uitre S D, Gl o ver H R et al. C o m paris o n of effects of 4- h y dr o x y ta m o xife n a n d 
tril osta ne o n oestr o ge n-re g ulate d ge ne e x pressi o n i n M C F-7 cells: u p -re g ulati o n of oestr o ge n rece pt or 
beta. J. Ster oi d Bi oc he m. M ol. Bi ol. 2 0 0 6; 1 0 0: 1 4 1- 1 5 1. 
4 9.  
Ye o B, D o wsett M. Ne oa dj u va nt e n d ocri ne t hera p y: Patie nt selecti o n, treat me nt d urati o n a n d 
s urr o gate e n d p oi nts. Breast 2 0 1 5; 2 4 S u p pl 2: S 7 8- 8 3. 
5 0.  
Ste n da hl M, R y de n L, N or de ns kj ol d B et al. Hi g h pr o gester o ne rece pt or e x pr essi o n c orrelates t o 
t he effect of a dj u va nt ta m o xife n i n pre me n o pa usal breast ca ncer patie nts. Cli n Ca ncer Res 2 0 0 6; 1 2: 
4 6 1 4- 4 6 1 8. 
5 1.  
Jirstr o m K, Ste n da hl M, R y de n L et al. A d verse effect of a dj u va nt ta m o xife n i n pre me n o pa usal 
breast ca ncer wit h c ycli n D 1 ge ne a m plificati o n. Ca ncer Researc h. 6 5.( 1 7): 8 0 0 9.- 1 6., 2 0 0 5. 
5 2. 
De la Ve ga F M, Lazar u k K D, R h o des M D, We nz M H. Assess me nt of t w o fle xi ble a n d 
c o m pati ble S N P ge n ot y pi n g platf or ms: T a q Ma n S N P Ge n ot y pi n g Assa ys a n d t he S N Ple x Ge n ot y pi n g 
S yste m. M utat Res 2 0 0 5; 5 7 3: 1 1 1- 1 3 5. 
5 3. 
Hele n o ws ki I B, De mirtas H. M ulti ple i m p utati o n of c o nti n u o us data via a se mi para metric 
pr o ba bilit y i nte gral tra nsf or mati o n. J Bi o p har m Stat 2 0 1 4; 2 4: 3 5 9- 3 7 7. 
 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 4 5 –  
C O N S E N T F O R M  
 
St u d y Title  f or St u d y P artici p a nts:  
A st u d y testi n g if e n d o xife n, a n acti ve f or m of t a m o xife n , c a n be deli vere d t o t he bre ast t hr o u g h t he 
bre ast s ki n .  
 
Offici al St u d y Title  f or I nter net Se arc h o n htt p:// w w w. Cli nic al Tri als. g o v :  
N W U 2 0 1 7- 0 9- 0 1 P h a se I tri al of e n d o xife n gel vers us pl ace b o gel i n w o me n u n der g oi n g 
bre ast s ur ger y . 
 
P r ot oc ol v 6. 5 ( 0 5/ 1 1 / 2 0 2 0) 
 
I ntr o d ucti o n  
 
T his is a cli nical trial, a t y pe of researc h st u d y . Cli nical trials i ncl u de o nl y pe o ple w h o c h o ose t o ta ke part 
i n t he researc h. Please ta ke y o ur ti me t o ma ke y o ur decisi o n a b o ut v ol u nteeri n g. Y o u ma y disc uss y o ur 
decisi o n wit h y o ur frie n ds a n d fa mil y. Y o u ca n als o disc uss t his st u d y wit h y o ur healt h care tea m. If y o u 
ha ve a n y q uesti o ns, y o u ca n as k y o ur st u d y d oct or f or m ore of a n e x pla nati o n. Y o u s h o ul d o nl y a gree t o 
partici pate i n t his st u d y w he n y o u are c o mf orta ble e n o u g h wit h t he i nf or mati o n s o t hat y o u ca n ma ke a n 
i nf or me d decisi o n a b o ut j oi ni n g.  
 
W h a t is t he us u al a p pr o ac h t o m y bre ast c a ncer or hi g h ris k c o n diti o n  f or 
bre ast c a ncer ?   
Y o u are bei n g as ke d t o partici pate beca use y o u are pla n ni n g t o u n der g o s ur ger y t o re m o ve o ne or b ot h 
breasts beca use of a ca ncer dia g n osis or t o pre ve nt breast ca ncer. Y o ur s ur gical a n d me dical treat me nt, 
will be deci de d b y y o u a n d y o ur d oct ors. T he me dicati o n bei n g teste d i n t his trial is n ot mea nt t o treat 
y o ur c o n diti o n, a n d it will n ot i nterfere wit h y o ur us ual treat me nt eit her. T he st u d y treat me nt will ta ke 
place pri or t o y o ur sc he d ule d s ur ger y.   
 
W h at are m y ot her c h oices  if I d o n ot t a ke p art i n t his st u d y?  
If y o u deci de n ot t o ta ke part i n t his st u d y, y o u ha ve ot her c h oices. F or e xa m ple: 
•  
y o u ma y c h o ose t o ha ve s ur ger y wit h o ut a n y me dical treat me nt bef ore s ur ger y. 
•  
y o u ma y c h o ose t o ta ke part i n a differe nt st u d y, if o ne is a vaila ble,  
•  
or y o u ma y c h o ose t o d o n ot hi n g.  
 
W h y is t his st u d y bei n g d o ne ?  
T he p ur p ose of t his st u d y is t o test t he safet y of a me dicate d gel c o ntai ni n g e n d o xife n (a n acti ve f or m of 
ta m o xife n) a p plie d t o t he s ki n of t he breast at differe nt d oses t o fi n d o ut w hat effects, if a n y, it has o n 
pe o ple a n d t heir ris k of breast ca ncer. T here will be u p t o 3 2 w o me n  ta ki n g part i n t his st u d y. B y 
de vel o pi n g met h o ds t o treat t he breast wit h a gel a p plie d t o t he s ki n, we h o pe t o greatl y re d uce t he dr u g 
d ose t o t he rest of t he b o d y, a n d t heref ore decrease si de -effects of dr u gs ta ke n f or pre ve nti o n of breast 
ca ncer.  I n t his st u d y, we will test if e n d o xife n gel ca n be a p plie d t o t he breast s ki n wit h o ut ca usi n g s ki n 
irritati o n, c o m pare d t o a place b o gel (t hat c o ntai ns n o e n d o xife n). T he e n d o xife n gel will be teste d at t w o 
d oses i n t his st u d y ( 1 0  m g e n d o xife n dail y or 2 0 m g dail y) . We will als o c o m pare t he a m o u nt of t he dr u g 
t hat reac hes t he breast at eac h of t hese d oses.  
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 4 6 –  
T he use of e n d o xife n (t he st u d y dr u g) i n t his st u d y is i n vesti gati o nal, mea ni n g t hat it is n ot a p pr o ve d b y t he 
F o o d a n d Dr u g A d mi nistrati o n ( F D A). E n d o xife n gi ve n b y m o ut h ( orall y) is c urre ntl y bei n g e xa mi ne d i n 
cli nical trials f or breast ca ncer, w here it is a ntici pate d t o be as g o o d as or  better t ha n ta m o xife n, si nce it is 
t he acti ve f or m of ta m o xife n. T his  will be t he first st u d y i n t he U S of t o pical e n d o xife n gel.  All w o me n w h o 
pa rtici pate i n t his st u d y will recei ve e n d o xife n gel or place b o gel f or a b o ut 2 8 da ys  pri or t o s ur ger y. T he 
researc hers i n t his st u d y w o ul d li ke t o c o m pare h o w partici pa nts  will t olerate e n d o xife n gel a p plie d t o t he 
breast s ki n at t he 1 0 m g or t he 2 0 m g d ose , h o w m uc h gets i nt o t he breast at eac h d ose le vel, a n d h o w m uc h 
gets i nt o t he bl o o d.   
 
T he st u d y i n vesti gat ors h o pe t o e nr oll u p  t o 3 2 w o me n at N ort h wester n U ni versit y, Me m orial Sl oa n 
Ketteri n g Ca ncer Ce nter, a n d Ce dars- Si nai Me dical Ce nter.  
 
W h at are t he st u d y gr o u ps ?  
T his st u d y is a P hase I st u d y, w hic h mea ns t hat t he g oal is t o st u d y if e n d o xife n gel a p plie d t o t he breast 
s ki n is well t olerate d. T he st u d y has t hree gr o u ps. Differe nt d oses of e n d o xife n gel or place b o gel ( gel 
wit h n o me dici ne i n it) will be gi ve n t o se veral st u d y partici pa nts. W hat y o u recei ve will de pe n d o n w he n 
y o u e nr oll o n t he st u d y  a n d w hat gr o u p y o u are p ut i nt o.  O nce y o u are p ut i nt o a gr o u p y o u ca n n ot s witc h 
t o a n ot her gr o u p.  
 
T he first t w o gr o u ps ( d ose esc al ati o n p art) :     
If y o u are i n o ne of t he first t w o gr o u ps, a c o m p uter will ra n d o ml y assi g n y o u t o recei ve e n d o xife n gel or 
place b o gel. T his is d o ne beca use n o o ne k n o ws if e n d o xife n gel will be t olerate d better or w orse t ha n t he 
place b o gel. If y o u are i n o ne of t he first t w o gr o u ps, y o u ha ve t wice t he li keli h o o d t o recei ve e n d o xife n 
gel c o m pare d t o place b o gel. Neit her y o u n or y o ur d oct or will k n o w if y o u are recei vi n g e n d o xife n gel or 
place b o gel . Y o ur d oct or ca n n ot c h o ose w hic h gel y o u recei ve. A p har macist will al wa y s k n o w e xactl y 
w hat  gel  eac h partici pa nt is recei vi n g a n d will be a ble t o tell y o ur me dical tea m if nee de d f or y o ur care.  
 
If y o u are i n o ne of t he first t w o gr o u ps …. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I n t he first gr o u p, se veral st u d y partici pa nts will recei ve en d o xife n gel at a l o w d ose.  If t he gel d oes n ot 
ca use b ot hers o me si de effects, it will be gi ve n t o t he sec o n d gr o u p of st u d y partici pa nts at a hi g her d ose. 
If t he l o w d ose ca uses b ot hers o me si de effects i n t w o or m ore w o me n i n t he first gr o u p, it will be gi ve n t o 
a d diti o nal st u d y p artici pa nts at t he sa me d ose t o get a better i dea of h o w ofte n t he gel is b ot hers o me.  I n 
t his wa y, we h o pe t o deter mi ne t he safest/ best t olerate d d ose of e n d o xife n. O nce t his d ose of en d o xife n is 
f o u n d, t he n t he ne xt part of t he st u d y will be gi n wit h t he t hir d gr o u p.  
 
 
R a n d o mize  
( T he c o m p uter 
will r a n d o mly 
assi g n y o u)  
E n d o xife n Gel  d aily 
u ntil d ay bef ore s ur gery  
( 1 6 w o me n) 
Y o u a gree t o 
t a ke p art i n t he 
st u dy 
Pl ace b o Gel d aily u ntil 
d ay bef ore s ur ger y  
( 8 w o m e n) 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 4 7 –  
 
T he t hir d gr o u p ( d ose e x p a nsi o n p art ): 
If y o u are i n t he t hir d gr o u p, y o u will recei ve e n d o xife n gel. I n t his gr o u p, ei g ht partici pa nts will recei ve 
t he safest/ best t olerate d d ose of t he acti ve st u d y dr u g. T here will be n o place b o i n t he t hir d gr o u p.   
 
If y o u are i n t he t hir d gr o u p …. 
 
 
 
 
 
 
 
 
 
H o w l o n g will I be i n  t his st u d y ?  
Y o u will recei ve t he st u d y dr u gs f or 3- 4 wee ks  ( 2 1-2 8 da ys)  bef ore y o ur breast s ur ger y. E ve n if y o u d o 
n ot fi nis h t he st u d y, y o ur d oct or will c o nti n ue t o watc h y o u f or si de effects a n d f oll o w y o ur c o n diti o n f or 
o ne or t w o wee ks after s ur ger y.  
 
W h at e xtr a tests a n d pr oce d ures will I h a ve if I t a ke p art i n t his st u d y ?  
If y o u a gree t o partici pate, y o u will be re q uire d t o si g n t his c o nse nt bef ore y o u ha ve a n y tests or pr oce d ures 
t hat are d o ne o nl y f or t his st u d y. Y o u will be as ke d t o c o me t o t he_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (site s pecific a d dress).  
T here are 3 mai n  parts t o t his st u d y:  Scree ni n g , Treat me nt , a n d F oll o w-U p . 
 
Bef ore y o u be gi n t he st u d y: Scree ni n g  
Scree ni n g is a peri o d d uri n g w hic h tests a n d e xa ms will be d o ne t o deter mi ne if y o u are eli gi ble t o 
partici pate i n t he treat me nt part of t he st u d y.  S o me of t he tests a n d e xa ms ma y ha ve bee n rece ntl y d o ne b y 
o ne of y o ur d oct ors a n d mi g ht n ot nee d t o be re peate d.  T hese tests a n d assess me nts ma y be d o ne o n o ne 
da y or t w o da ys. S o me bl o o d tests will be d o ne f or researc h p ur p oses o nl y a n d will n ot c ha n ge t he wa y 
y o ur disease is treate d. Y o ur st u d y d oct or will disc uss t his wit h y o u.   
 
T he f oll o wi n g tests will be re q uire d t o fi n d o ut if y o u ca n be i n t he st u d y: 
1.  
Re vie w of y o ur me dical hist or y a n d a p h ysical e xa m 
2.  
Uri ne or ser u m pre g na nc y test (f or w o me n w h o are a ble t o bec o me pre g na nt) 
3.  
Assess me nt of y o ur a bilit y t o c o m plete y o ur dail y acti vities  
4.  
Bl o o d tests (a b o ut 2 teas p o o ns or 1 0 m L will be c ollecte d) t o see h o w y o ur li ver a n d ki d ne ys are 
f u ncti o ni n g 
5.  
De -i de ntifie d pict ures of y o ur breasts will be ta ke n as a baseli ne bef ore st u d y gel is a p plie d. T he 
p h ot o will o nl y be of y o ur nec k t o a b d o me n wit h n o facial i de ntificati o n.  
 
If t he e xa ms a n d tests s h o w t hat y o u ca n c o nti n ue t o ta ke part i n t he st u d y, a n d y o u c h o ose t o, t he n y o u will 
nee d t he f oll o wi n g e xtra pr oce d ures.  T hese are n ot part of t he us ual a p pr oac h f or y o ur c o n diti o n.  
•  
C o m pleti o n of a q uesti o n naire t o deter mi ne w hat s y m pt o ms y o u are alrea d y e x perie nci n g 
•  
C ollecti o n of bl o o d f or researc h p ur p oses (a t otal of a b o ut 2 ta bles p o o ns or 2 6 m L) 
 
Y o ur i nitial st u d y visit f or scree ni n g will last a p pr o xi matel y 6 0 t o 9 0 mi n utes. If y o u are f o u n d t o be eli gi ble , 
y o u will recei ve t he st u d y dr u g, w hic h  ma y be gi ve n t o y o u t hat sa me da y if y o u are a ble t o pic k it u p 
a p pr o xi matel y 5 -6 h o urs later or t he ne xt da y. If y o u are u na ble t o wait, or t o ret ur n t he ne xt da y, t he dr u g 
will be maile d t o y o u.  
Y o u a gree t o 
t a ke p art i n t he 
st u dy 
E n d o xife n Gel  d ail y u ntil  
d a y  bef ore s ur ger y  
( 8 w o me n) 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 4 8 –  
 
If y o u are a ble t o bec o me pre g na nt, it is i m p orta nt t hat y o u are n ot pre g na nt w he n e nteri n g t he st u d y or 
w hile ta ki n g t his st u d y dr u g. F or t his reas o n, y o u will nee d t o ha ve a ne gati ve pre g na nc y test wit hi n 5 da ys 
p ri or t o starti n g t he st u d y dr u g.  If y o ur Scree ni n g Visit d oes n ot occ ur wit hi n fi ve da ys of starti n g t he st u d y 
dr u g, y o u will nee d t o ret ur n t o t he office f or a n ot her pre g na nc y test.   
 
Re mi n ders t o t ake y o ur st u dy dr u g:  Y o u will ha ve t he o pti o n of recei vi n g e mail or te xt messa ges fr o m 
researc h staff t o re mi n d y o u a b o ut t he st u d y me dicati o n d uri n g t he first wee k of st u d y treat me nt peri o d. 
We e nc o ura ge y o u t o res p o n d t o i n dicate if t he d ose has bee n ta ke n. If y o u are ha vi n g tr o u ble 
re me m beri n g, t hese re mi n ders ca n be e xte n de d be y o n d t he first wee k. Re mi n der messa ges t o use t he 
st u d y gel me dicati o n will als o be se nt d uri n g t he last wee k of st u d y treat me nt as it is ver y i m p orta nt t hat 
y o u n ot miss a n y d ose d uri n g t his wee k s o t hat we are a ble t o f ull y use all data c ollecte d.  
 
Tre at me nt  
D uri n g t he treat me nt p orti o n of t his st u d y, i nstr ucti o ns t o a p pl y t he st u d y me dicati o n will be re vie we d wit h 
y o u b y t he st u d y staff. O nce y o u recei ve t he me dicati o n, y o u will nee d t o st ore t he m i n y o ur h o me i n a 
place pr otecte d fr o m li g ht, heat a n d m oist ure.  
 
De pe n di n g u p o n t he gr o u p t o w hic h y o u are ra n d o mize d y o u will rec ei ve o ne of t he f oll o wi n g treat me nts:  
 
1.  E n d o xife n gel or place b o gel 1 0 m g dail y  ( 5 m g per breast) 
2.  E n d o xife n gel or place b o gel 2 0 m g dail y ( 1 0 m g per breast) 
3.  E n d o xife n gel wit h n o p ossi bilit y of place b o ( 5 m g per breast) 
 
Y o u will be gi ve n a st u d y diar y t o fill o ut a n d d oc u me nt eac h d ose of st u d y me dicati o n t hat y o u ta ke. Y o u 
will  ha ve t he o pti o n of usi n g a p h o ne a p plicati o n/ we bsite or usi n g a pa per st u d y diar y.  We will s h o w y o u 
h o w t o use t he p h o ne a p plicati o n/ we bsite a n d it will n ot c o ntai n a n y of y o ur pers o nal i nf or mati o n.  Y o u 
s h o ul d mar k a n y misse d or s ki p pe d d oses i n t his diar y, as well as a n y si de effects t hat y o u are e x perie nci n g.  
 
Y o u will use t he gel f or 3 t o 4 wee ks  (2 1 t o 2 8 da ys ) pri or t o y o ur s ur ger y. T he last da y t hat y o u will ta ke 
y o ur st u d y dr u g will be t he m or ni n g of t he da y bef ore y o ur s ur ger y  if y o u are i n gr o u ps 1 or 2. If y o u are 
i n Gr o u p 3, the last da y t hat y o u will ta ke y o u r st u d y dr u g will be t he m or ni n g of t he t hir d da y pri or t o y o ur 
s ur ger y. F or e xa m ple, if y o ur s ur ger y is o n M o n da y, y o ur last d ose will be o n t he pri or Fri da y m or ni n g.  
Y o u will nee d t o s h o wer, bat he, or was h y o ur breasts t he m or ni n g of s ur ger y, bef ore y o u lea ve f or t he 
h os pital.  
 
If y o u c h o ose t o use t he pa per diar y i nstea d of t he p h o ne a p plicati o n/ we bsite, t he st u d y pers o n nel will se n d 
e mail re mi n ders t o y o u e ver y da y d uri n g t he first wee k a n d last wee k of t he st u d y. If y o u c h o ose t o use t he 
p h o ne a p plicati o n/ we bsite, t he st u d y pers o n nel will c o ntact y o u if y o u miss t o e nter y o ur i nf or mati o n f or 2 
da ys.  Re gar dless of w het her y o u use t he pa per diar y or t he p h o ne a p p, st u d y pers o n nel will c o ntact y o u 
e ver y wee k b y p h o ne t o c hec k o n y o ur pr o gress a n d a ns wer a n y q uesti o ns re gar di n g t he i nta ke/a p plicati o n 
of st u d y me dicati o n. Y o u will als o be as ke d q uesti o ns a b o ut p ote ntial si de effects of t he st u d y me dicati o n. 
T hese p h o ne calls will last a p pr o xi matel y 1 0 mi n utes.  If y o u prefer, t he st u d y c o or di nat or ma y e mail y o u 
i nstea d of calli n g y o u wee kl y.  Please let y o ur st u d y c o or di nat or k n o w h o w y o u prefer t o be c o ntacte d.   
 
Y o u will ha ve a st u d y visit o n t he da y bef ore s ur ger y, w he n y o ur st u d y treat me nt will e n d. If y o u ca n 
arri ve earlier t ha n y o ur sc he d ule d ti me o n t he da y of s ur ger y, it ma y be p ossi ble t o d o t his visit o n t he 
sa me da y of y o ur s ur ger y. D uri n g t his visit, y o u will ha ve a q ualit y of life s ur ve y.  T he st u d y diar y will be 
re vie we d a n d c ollecte d a n d all u n use d st u d y me dicati o n will be c ollecte d at t his visit. 
 
O n t he da y of y o ur s ur ger y, t he baseli ne tests will be re peate d. T hese tests i ncl u de a me dical hist or y a n d 
p h ysical e xa m, bl o o d tests (a b o ut 2 teas p o o ns or 1 0 m L will be c ollecte d) f or li ver a n d ki d ne y f u ncti o n a n d 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 4 9 –  
bl o o d dra w f or researc h p ur p oses (a b o ut 2   ta bles p o o ns or 2 6 m L will be c ollecte d). Y o u will fast starti n g 
at mi d ni g ht bef ore t his visit. P lease ta ke y o ur us ual me dici nes (if a n y) wit h a si p of water o n t he m or ni n g 
of t he s ur ger y.  T his visit will last a p pr o xi matel y 6 0 t o 9 0 mi n utes. Y o u will t he n pr ocee d t o ha ve y o ur 
s ur ger y, as y o u w o ul d if y o u were n ot partici pati n g i n t he st u d y; y o ur s ur gical treat me nt will n ot be c ha n ge d 
i n a n y wa y. O nce t he breast is re m o ve d, it will be deli vere d t o t he pat h ol o gist w h o will e xa mi ne y o ur tiss ue 
a n d i de ntif y w hat is nee de d f or dia g n osis t o g ui de treat me nt. I n a d diti o n, sa m pl es of t he s ur gical s peci me n 
n ot nee de d f or y o ur dia g n osis will be re m o ve d t o meas ure st u d y dr u g c o nce ntrati o ns a n d breast ca ncer 
mar kers.  
 
I n a d diti o n, tiss ue fr o m t he pre-s ur gical bi o ps y will be teste d a n d t he res ults c o m pare d wit h tiss ues re m o ve d 
at s ur ger y t o see t he effects of e n d o xife n gel treat me nt.   
 
As part of t his st u d y y o u will als o be as ke d t o a ns wer q uesti o ns a b o ut y o ur t o bacc o a n d alc o h ol use, b ot h 
bef ore y o u be gi n t he st u d y a n d a gai n at St u d y Visit 1. Researc hers wa nt t o see if t o bacc o a n d a lc o h ol use 
affects t he si de effects pe o ple mi g ht get w hile o n t his st u d y, or if t o bacc o a n d alc o h ol use m o difies t he 
effects of t he st u d y a ge nts.   F or t he t o bacc o a n d alc o h ol use q uesti o ns, y o u ca n deci de t o n ot a ns wer s o me 
or all of t he q uesti o ns. Y o ur decisi o n will n ot affect w het her y o u ca n partici pate i n t he st u d y, a n d it will 
n ot affect y o ur relati o ns hi p wit h y o ur d oct or or t he st u d y staff. 
 
F oll o w u p  
T he f oll o w u p visit f or t he st u d y will be at y o ur p ost -o p visit i n t he cli nic t o re vie w y o ur pr o gress.  T h is visit  
will be 1- 2 wee ks  after t he s ur ger y a n d at t his ti me, i nf or mati o n a b o ut a n y si de effects, me dicati o ns, a n d 
t he last me nstr ual peri o d (if y o u are ha vi n g peri o ds), will be c ollecte d. If y o u are still ha vi n g peri o ds, a fi nal 
p h o ne call o ne m o nt h after y o ur s ur ger y will be ma de t o rec or d t he date of y o ur last me nstr ual peri o d.   
 
W h at  p ossi ble  ris ks c a n I e x pect fr o m t a ki n g p art i n t his st u d y ?  
If y o u c h o ose t o ta ke part i n t his st u d y, t here is a ris k t hat y o u ma y:  
•  
L ose ti me at w or k or h o me a n d s pe n d m ore ti me i n t he h os pital or d oct or’s office t ha n us ual 
(t here are t w o st u d y visits t hat ma y n ot c oi nci de wit h y o ur cli nical care visits, b ut we will tr y as 
m uc h as p ossi ble t o mi ni mize e xtra visits) . 
•  
Be as ke d se nsiti ve or pri vate q uesti o ns w hic h y o u n or mall y d o n ot disc uss, f or e xa m ple a b o ut 
y o ur t o bacc o a n d alc o h ol use.  
•  
T here is a ris k s o me o ne c o ul d get access t o t he pers o nal i nf or mati o n i n y o ur me dical rec or ds or 
ot her i nf or mati o n researc hers ha ve ke pt a b o ut y o u. S o me o ne mi g ht be a ble t o trace t his 
i nf or mati o n bac k t o y o u. T he researc hers belie ve t he c ha nce t hat s o me o ne will i de ntif y y o u is 
ver y s mall, b ut t he ris k ma y c ha n ge i n t he f ut ure as pe o ple c o me u p wit h ne w wa ys of traci n g 
i nf or mati o n. T he researc hers belie ve t he c ha nce t hese t hi n gs will ha ppe n is ver y s mall, b ut ca n n ot 
pr o mise t hat t he y will n ot occ ur.  
•  
T here ca n als o be a ris k i n fi n di n g o ut ne w ge netic i nf or mati o n a b o ut y o u. Ne w healt h 
i nf or mati o n a b o ut i n herite d traits t hat mi g ht affect y o u or y o ur bl o o d relati ves c o ul d be f o u n d 
d uri n g a st u d y.  
 
T he e n d o xife n gel use d i n t his st u d y is hi g hl y u nli kel y t o affect h o w differe nt parts of y o ur b o d y w or k, 
s uc h as y o ur li ver, a n d bl o o d. T he c ha nces of t his ha p pe ni n g are e xtre mel y l o w, gi ve n w hat we k n o w 
a b o ut ta m o xife n a n d its acti ve f or ms, t hr o u g h ma n y years of cli nical trials a n d cli nical e x perie nce. T he 
st u d y d oct or will be testi n g y o ur bl o o d a n d will let y o u k n o w if c ha n ges occ ur t hat ma y affect y o ur healt h.  
 
T here is als o a ris k t hat y o u c o ul d ha ve si de effects.  
Here are i m p orta nt p oi nts a b o ut si de effects: 
•  
T he st u d y d oct ors d o n ot k n o w w h o will o r will n ot ha ve si de effects. 

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Here are i m p orta nt p oi nts a b o ut h o w y o u a n d t he st u d y d oct or ca n ma ke si de effects less of a pr o ble m: 
•  
T ell t he st u d y d oct or if y o u n otice or feel a n yt hi n g differe nt s o t he y ca n see if y o u are ha vi n g a 
si de effect. 
•  
T he st u d y d oct or ma y be a ble t o treat s o me si de effects.  
 
T he ta bles bel o w s h o w t he m ost c o m m o n si de effects t hat we k n o w a b o ut, base d o n e x perie nce wit h t hese 
cl osel y relate d dr u gs: oral e n d o xife n, oral ta m o xife n a n d t o pical 4- h y dr o x yta m o xife n gel, s o me of w hic h 
ma y  be seri o us.  W o me n i n t he U S ha ve n ot bee n treate d wit h t o pical e n d o xife n gel bef ore. T here mi g ht 
be ot her si de effects t hat we d o n ot yet k n o w a b o ut. If i m p orta nt ne w si de effects are f o u n d, t he st u d y 
d oct or will disc uss t hese wit h y o u. 
 
P ossi ble si de effects of e n d o xife n gel 
C O M M O N, S O M E M A Y B E S E RI O U S  
I n 1 0 0 pe o ple, m ore tha n 2 0 ma y ha ve:  
•  
H ot flas hes, h ot fl us h  
•  
Tire d ness  
•  
Ni g htti me s weati n g  
•  
Hea dac he  
 
O C C A SI O N A L, S O M E M A Y B E S E RI O U S  
I n 1 0 0 pe o ple, fr o m 4 t o 2 0 ma y ha ve: 
•  
Na usea  
•  
Irrita bilit y 
•  
Slee p dist ur ba nce  
•  
Pr urit us  
•  
Va gi nal disc har ge  
•  
Va gi nal dr y ness  
•  
Wei g ht gai n  
 
R A R E, S O M E M A Y B E  S E RI O U S  
I n 1 0 0 pe o ple 3 or fe wer ma y ha ve: 
•  
S ki n reacti o n f oll o wi n g a p plicati o n of t o pical dr u g  (i.e., feeli n g c ol d/ic y i n t he s ki n f oll o we d b y 
te m p orar y war mi n g)  
 
Re pr o d ucti ve ris ks: Y o u s h o ul d n ot get pre g na nt or breastfee d w hile i n t his st u d y . T he e n d o xife n gel use d 
i n t his st u d y c o ul d be da ma gi n g t o a n u n b or n ba b y. C hec k wit h t he st u d y d oct or a b o ut w hat t y pes of birt h 
c o ntr ol, or pre g na nc y pre ve nti o n, t o use w hil e i n t his st u d y. 
 
Ris ks of t he bl o o d tests: Br uisi n g, s ore ness, or rarel y, i nfecti o n ma y occ ur as a res ult of t he nee dle stic ks 
t o o btai n bl o o d fr o m y o u.  
 
W h at p ossi ble  be nefit s c a n I e x pect fr o m t a ki n g p art i n t his st u d y ? 
 
Partici pati n g i n t his st u d y is u nli kel y t o hel p y o ur c o n diti o n. T his st u d y ma y hel p us lear n t hi n gs t hat 
c o ul d hel p pe o ple i n t he f ut ure. 
 
C a n I st o p t a ki n g p art i n t his st u d y ?  

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Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
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Yes. Y o u ca n deci de t o st o p at a n y ti me. If y o u deci de t o st o p f or a n y reas o n, it is i m p orta nt t o let t he 
st u d y d oct or k n o w as s o o n as p ossi ble s o y o u ca n st o p safel y. If y o u st o p, y o u ca n deci de w het her or n ot 
t o let t he st u d y d oct or c o nti n ue t o pr o vi de y o ur me dical i nf or mati o n t o t he or ga nizati o n r u n ni n g t he st u d y. 
 
F or t he t o bacc o a n d alc o h ol use q uesti o ns, y o u ca n deci de t o n ot a ns wer s o me or all of t he q uesti o ns. 
Y o ur decisi o n will n ot affect w het her y o u ca n partici pate i n t he st u d y, a n d it will n ot affect y o ur 
relati o ns hi p wit h y o ur d oct or or t he st u d y staff. 
 
T he st u d y d oct or will tell y o u a b o ut a n y ne w i nf or mati o n or c ha n ges i n t he st u d y t hat c o ul d affect y o ur 
healt h or y o ur willi n g ness t o c o nti n ue i n t he st u d y. 
 
T he st u d y d oct or ma y ta ke y o u o ut of t he st u d y: 
•  
If y o ur healt h c ha n ges.  
•  
If t he st u d y is n o l o n ger i n y o ur best i nterest. 
•  
If ne w i nf or mati o n bec o mes a vaila ble. 
•  
If y o u d o n ot f oll o w t he st u d y r ules. 
•  
If t he st u d y is st o p pe d earl y f or a n y reas o n b y t he s p o ns or, I R B or F D A. 
 
W h at are m y ri g hts i n t his st u d y ?  
T a ki n g part i n t his st u d y is y o ur c h oice. N o matter w hat decisi o n y o u ma ke, a n d e ve n if y o ur decisi o n 
c ha n ges, t here will be n o pe nalt y t o y o u. Y o u will n ot l ose me dical care or a n y le gal ri g hts. 
 
F or q uesti o ns a b o ut y o ur ri g hts w hile i n t his st u d y, c all t he N ati o n al C a ncer I nstit ute Ce ntr al 
I nstit uti o n al Re vie w B o ar d at 8 8 8- 6 5 7- 3 7 1 1 .  
 
W h at are t he c osts of t a ki n g p art i n t his st u d y ?  
T he st u d y gel (e n d o xife n gel or place b o ) will be s u p plie d at n o c har ge w hile y o u ta ke part i n t his st u d y. 
T he c ost of st u d y-s pecific bi o psies a n d e xa ms, tests, a n d a n y ot her pr oce d ures will be pai d f or b y t h e 
st u d y. 
 
S o me c osts ass ociate d wit h y o ur care ma y be c o nsi dere d sta n dar d of care, a n d will be bille d t o y o u or 
y o ur i ns ura nce c o m pa n y. Y o u will ha ve t o pa y f or a n y c osts (i ncl u di n g de d ucti bles a n d c o- pa y me nts) n ot 
c o vere d b y y o ur healt h i ns urer  if t hese are re q uire d f or treat me nt of y o ur breast c o n diti o n. 
 
Bef ore y o u deci de t o be i n t he st u d y, y o u s h o ul d c hec k wit h y o ur healt h pla n or i ns ura nce c o m pa n y t o 
fi n d o ut e xactl y w hat t he y will pa y f or.  
 
T o c o ver y o ur e x pe nses relate d t o tra vel, c hil d -care, l oss of w or k ti me a n d ot her si milar iss ues, y o u will 
recei ve $ 1 0 0 after  y o ur i nitial scree ni n g visit 1, $ 1 0 0 after St u d y Visit 1 ( w hic h ma y be c o m bi ne d wit h 
St u d y Visit 2 da y of s ur ger y), a n d $ 1 0 0 after c o m pleti o n of St u d y Visit 3 after y o ur s ur ger y. If y o u nee d 
t o ret ur n t o t he office o n a se parate visit f or a pre g na nc y test, y o u will recei ve a n a d diti o nal $ 1 0 0.   
 
W h at h a p pe ns if I a m i nj ure d or h urt bec a use I t o o k p art i n t his st u d y ?  
If y o u feel y o u ha ve bee n i nj ure d or h urt as a res ult of ta ki n g part i n t he st u d y, it is i m p orta nt t hat y o u tell 
t he st u d y d oct or i m me diatel y. Y o u will get me dical treat me nt if y o u are i nj ure d or h urt as a res ult of 
ta ki n g part i n t his st u d y.  
 
T he st u d y s p o ns ors will n ot offer t o pa y f or me dical treat me nt f or i nj ur y. Y o ur i ns ura nce c o m pa n y ma y 

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n ot be willi n g t o pa y f or st u d y-relate d i nj ur y. If y o u ha ve n o i ns ura nce c o vera ge, y o u w o ul d be 
res p o nsi ble f or a n y c osts. E ve n t h o u g h y o u are i n a st u d y, y o u kee p all of y o ur le gal ri g hts t o recei ve 
pa y me nt f or i nj ur y ca use d b y me dical err ors.  
 
W h o will see m y me dic al i nf or m ati o n ?  
 
Y o ur pri vac y is ver y i m p orta nt t o us a n d we will ma ke e ver y eff ort t o pr otect it . Y o ur i nf or mati o n ma y be 
gi ve n o ut if re q uire d b y la w. F or e xa m ple, certai n states re q uire d oct ors t o re p ort t o healt h b oar ds if t he y 
fi n d a disease li ke t u berc ul osis. H o we ver, we will d o o ur best t o ma ke s ure t hat a n y i nf or mati o n t hat is 
release d will n ot be a ble t o i de ntif y y o u. S o me of y o ur healt h i nf or mati o n, a n d/ or i nf or mati o n a b o ut y o ur 
s peci me n, fr o m t his st u d y will be ke pt i n a ce ntral data base f or researc h. Y o ur na me or c o ntact 
i nf or mati o n will n ot be p ut i n t he data base. 
 
T here are or ga nizati o ns t hat ma y i ns pect y o ur rec or ds. T hese or ga nizati o ns are r e q uire d t o ma ke s ure y o ur 
i nf or mati o n is ke pt pri vate. S o me of t hese or ga nizati o ns are: 
•  
T he st u d y s p o ns or ( Nati o nal Ca ncer I nstit ute).  
•  
T he I nstit uti o nal Re vie w B oar d,  I R B, is a gr o u p of pe o ple w h o re vie w t he researc h wit h t he 
g oal of pr otecti n g t he pe o ple w h o ta ke part i n t he st u d y. 
•  
T he F o o d a n d Dr u g A d mi nistrati o n a n d t he Nati o nal Ca ncer I nstit ute i n t he US.  
•  
T he Nati o nal Ca ncer I nstit ute will o btai n i nf or mati o n f or t his cli nical trial u n der data c ollecti o n 
a ut h orit y Title 4 2 U. S. C. 2 8 5. 
 
W here c a n I get m ore i nf or m ati o n ?  
T he Nati o nal Ca ncer I nstit ute will o btai n i nf or mati o n fr o m t his cli nical trial u n der data c ollecti o n 
a ut h orit y Title 4 2 U. S. C. 2 8 5. 
 
Y o u m ay visit t he N CI we bsite at htt p://c a ncer. g ov/  f or m ore i nf or m atio n a b o ut st u dies or ge ner al 
i nf or m ati o n a b o ut c a ncer. Y o u m ay als o c all t he N CI C a ncer I nf or m ati o n Service t o get t he s a me 
i nf or m ati o n at: 1- 8 0 0- 4-C A N C E R ( 1 - 8 0 0- 4 2 2- 6 2 3 7).  
 
A descri pti o n of t his cli nical trial will be a vaila ble o n htt p:// w w w. Cli nical Trials. g o v , as re q uire d b y U S 
la w. T his we bsite will n ot i ncl u de i nf or mati o n t hat ca n i de ntif y y o u. At m ost, t he we bsite will i ncl u de a 
s u m mar y of t he res ults. Y o u ca n searc h t his we bsite at a n y ti me. 
 
W h o c a n a ns wer m y q uesti o ns a b o ut t his st u d y ?  
Y o u ca n tal k t o t he st u d y d oct or a b o ut a n y q uesti o ns or c o ncer ns y o u ha ve a b o ut t his st u d y or t o re p ort 
si de effects or i nj uries. C o ntact t he st u d y d oct or _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (i nsert n a me of st u dy d oct or[s]) at 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (i nsert tele p h o ne n u m ber). 
 
T his secti o n is a b o ut o pti o n al st u dies y o u c a n c h o ose t o t a ke p art i n.  
T his part of t he c o nse nt f or m is a b o ut o pti o nal st u dies t hat y o u ca n c h o os e t o ta ke part i n. Y o u 
will n ot get healt h be n efits fr o m a n y of t hese st u di es. T he res earc hers lea di n g t his o pti o nal st u d y 
h o pe t he res ults will hel p ot her pe o ple wit h ca ncer i n t he f ut ure. 
 
T he res ults will n ot be a d de d t o y o ur me dical rec or ds, a n d y o u or y o ur st u d y d oct or ma y n ot k n o w t he 
res ults. Y o u will n ot b e bille d f or t hese o pti o nal st u dies.  
 
Y o u ca n still ta ke part i n t he mai n st u d y e ve n if y o u sa y ‘ n o’ t o a n y or all of t hese st u dies. If y o u si g n u p 
f or b ut ca n n ot c o m plete a n y of t he st u dies f or a n y reas o n, y o u ca n still ta ke part i n t he mai n st u d y. 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
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Circ le y o ur c h oice of “ yes” or “ n o” f or eac h of t he f oll o wi n g st u dies.  
 
O pti o n al S a m ple C ollecti o ns f or L a b or at or y St u dies a n d/ or  Bi o b a n ki n g f or 
P ossi ble  F ut ure St u dies  
 
Researc hers are tr yi n g t o lear n m ore a b o ut ca ncer, dia betes, a n d ot her healt h pr o ble ms. M uc h of t his 
researc h is d o ne usi n g sa m ples fr o m y o ur bi o psies, bl o o d, uri ne, or ot her fl ui ds. T hr o u g h t hese st u dies, 
researc hers h o pe t o fi n d ne w wa ys t o pre ve nt, detect, treat, or c ure healt h pr o ble ms.  
 
S o me of t hese st u dies ma y be a b o ut ge nes . Ge nes ca rr y i nf or mati o n a b o ut feat ures t hat are f o u n d i n y o u 
a n d i n pe o ple  w h o are relate d t o y o u. Researc hers are i ntereste d i n t he wa y t hat ge nes affect h o w y o ur 
b o d y res p o n ds t o treat me nt. 
 
If y o u c h o ose t o ta ke part, a sa m ple of bl o o d, a n d tiss ue fr o m y o ur breast will be c ollecte d.  T he 
researc hers as k y o ur per missi o n t o st ore a n d use y o ur sa m ples a n d healt h i nf or mati o n f or me dical 
researc h. T he researc h t hat ma y be d o ne is u n k n o w n at t his ti me. St ori n g sa m ples f or f ut ure st u dies is 
calle d “ bi o ba n ki n g” . T he Bi o ba n k is bei n g r u n b y t he Di visi o n of Ca ncer Pre ve nti o n a n d s u p p orte d b y t he 
Nati o nal Ca ncer I nstit ute.  
 
W H A T I S I N V O L V E D ?  
If y o u a gree t o ta ke part, here is w hat will ha p pe n ne xt: 
1)  A sa m ple fr o m t he tiss ue t hat was c ollecte d at t he ti me of y o ur s ur ger y wil l be se nt t o t he 
Bi o ba n k.  
2) Y o ur sa m ple s a n d s o me relate d i nf or mati o n ma y be st ore d i n t he Bi o ba n k, al o n g wit h sa m ples a n d 
i nf or mati o n fr o m ot her pe o ple w h o ta ke part. T he sa m ples will be st ore d at N ort h wester n U ni versit y  
u ntil t he e n d of t he st u d y, w he n t he y ma y be tra nsferre d t o t he Nati o nal I nstit utes of Healt h. 
3) Q ualifie d researc hers ca n s u b mit a re q uest t o use t he materials st ore d i n t he Bi o ba n k. A researc h 
c o m mittee will re vie w eac h re q uest. T here will als o be a n et hics re vie w t o e ns ure t hat t he re q uest is 
necessar y a n d pr o per. Researc hers will n ot be gi ve n y o ur na me or a n y ot her i nf or mati o n t hat c o ul d 
directl y i de ntif y y o u.  
4) Neit her y o u n or y o ur st u d y d oct or will be n otifie d if/w he n researc h is c o n d ucte d usi n g y o ur 
sa m ples a n d will n ot be gi ve n a n y res ults of t his researc h . 
5) S o me of y o ur ge netic a n d healt h i nf or mati o n ma y b e place d i n ce ntral data bases t hat ma y be 
p u blic, al o n g wit h i nf or mati o n fr o m ma n y ot her pe o ple. I nf or mati o n t hat c o ul d directl y i de ntif y y o u 
will n ot be i ncl u de d.  
 
W H A T A R E T H E P O S SI B L E RI S K S ?  
1)  T here is a ris k t hat s o me o ne c o ul d get access t o t he pers o nal i nf or mati o n i n y o ur me dical rec or ds 
or ot her i nf or mati o n we ha ve st ore d a b o ut y o u.  
2)  T here is a ris k t hat s o me o ne c o ul d trace t he i nf or mati o n i n a ce ntral data base bac k t o y o u . E ve n 
wit h o ut y o ur na me or ot her i de ntifiers, y o ur ge netic i nf or mati o n is u ni q ue t o y o u. T he researc hers 
belie ve t he c ha nce t hat s o me o ne will i de ntif y y o u is ver y s mall, b ut t he ris k ma y c ha n ge i n t he 
f ut ure as pe o ple c o me u p wit h ne w wa ys of traci n g i nf or mati o n.  
 
 
  
A ne w Fe deral  la w, calle d t he Ge netic  I nf or mati o n N o n discri mi nati o n  Act  ( GI N A), ge nerall y  
 
ma kes  it ille gal f or healt h  i ns ura nce c o m pa nies, gr o u p  healt h  pla ns,  a n d m ost  e m pl o yers  t o 

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Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 5 4 –  
 
discri mi nate  a gai nst  y o u  base d  o n y o ur ge netic  i nf or mati on. T his  la w ge nerall y  will  pr otect  y o u  
 
i n t he f oll o wi n g wa ys:    
•  
Healt h  i ns ura nce c o m pa nies a n d gr o u p healt h  pla ns ma y  n ot re q uest y o ur ge netic  
i nf or mati o n t hat we  get  fr o m t his researc h.  
 
•  
Healt h  i ns ura nce c o m pa nies a n d gr o u p healt h  pla ns ma y  n ot use y o ur ge netic  
i nf or mati o n w he n  ma ki n g  d ecisi o ns  re gar di n g y o ur eli gi bilit y or pre mi u ms.   
 
 
E m pl o yers wit h  1 5 or m ore  e m pl o yees  ma y  n ot use y o ur  ge netic  i nf or mati o n t hat we  get  fr o m 
t his researc h w he n  ma ki n g  a decisi o n  t o hire,  pr o m ote, or fire y o u  or w he n  setti n g t he ter ms of 
y o ur e m pl o y me nt. All  healt h  i ns ura nce c o m pa nies a n d gr o u p healt h  pla ns  m ust  f oll o w t his la w b y 
Ma y  2 1, 2 0 1 0. All  e m pl o yers wit h  1 5 or m ore  e m pl o yees  m ust  f oll o w t his la w as of  N o ve m ber 
2 1, 2 0 0 9. 
  
  
 
Be  a ware t hat t his ne w Fe deral  la w d oes n ot pr otect  y o u  a gai nst  ge netic  discri mi nati o n  b y 
c o m pa nies t hat sell life i ns ura nce, disa bilit y  i ns ura nce, or l o n g-ter m care i ns ura nce.  
 
3)  T here are la ws a gai nst t he mis use of ge netic i nf or mati o n, b ut t he y ma y n ot gi ve f ull pr otecti o n. 
Ne w healt h i nf or mati o n a b o ut i n herite d traits t hat mi g ht affect y o u or y o ur bl o o d relati ves c o ul d 
be f o u n d d uri n g a st u d y. T he researc hers belie ve t he c ha nce t hese t hi n gs will ha p pe n is ver y 
s mall, b ut ca n n ot pr o mise t hat t he y will n ot occ ur. 
 
 
H O W WI L L I N F O R M A TI O N A B O U T M E B E K E P T P RI V A T E ?  
Y o ur pri vac y is ver y i m p orta nt t o t he researc hers a n d t he y will ma ke e ver y eff ort t o pr otect it . Here are 
j ust a fe w of t he ste ps t he y will ta ke: 
1)  W he n y o ur sa m ple(s) is se nt t o t he researc hers, n o i nf or mati o n i de ntif yi n g y o u (s uc h as y o ur 
na me or s ocial sec urit y n u m ber ) will be se nt. Sa m ples will be i de ntifie d b y a u ni q ue st u d y c o de 
o nl y.  
2)  T he list t hat li n ks t he u ni q ue c o de t o y o ur na me will be ke pt se parate fr o m y o ur sa m ple a n d 
healt h i nf or mati o n . A n y Bi o ba n k a n d ( _ _ _ _ _ _ _ _ _ _ _ _ _ _ _i nsert n a me of cli nic al tri als 
or g a niz ati o n)  staff wit h access t o t he list m ust si g n a n a gree me nt t o kee p y o ur i de ntit y 
c o nfi de ntial. 
3)  Researc hers t o w h o m ( _ _ _ _ _ _ _ _ _ _ _ _ _ _i nsert n a me of cli nic al tri als or g a niz ati o n) se n ds y o ur 
sa m ple a n d i nf or mati o n will n ot k n o w w h o y o u are. T he y m ust als o si g n a n a gree me nt t hat t he y 
will n ot tr y t o fi n d o ut w h o y o u are.  
4)  I nf or mati o n t hat i de ntifies y o u will n ot be gi ve n t o a n y o ne, u nless re q uire d b y la w. 
5)  If researc h res ults are p u blis he d, y o ur na me a n d ot her pers o nal i nf or mati o n will n ot be use d. 
 
W H A T A R E T H E P O S SI B L E B E N E FI T S ? 
 
Y o u will n ot be nefit fr o m ta ki n g part.  Y o ur sa m ples ma y be hel pf ul t o researc h w het her y o u d o or d o n ot 
ha ve ca ncer.  T he researc hers,  usi n g t he sa m ples fr o m y o u a n d ot hers, mi g ht ma ke disc o veries t hat c o ul d 
hel p pe o ple i n t he f ut ure.  
 
A R E T H E R E A N Y C O S T S O R P A Y M E N T S ?  
T here are n o c osts t o y o u or y o ur i ns ura nce. Y o u will n ot be pai d f or ta ki n g part; h o we ver, y o u ma y 
recei ve s o me f u n ds t o defra y s o me of t he c ost of partici pati n g (e. g., par ki n g, c hil d care). If a n y of t he 
researc h lea ds t o ne w tests, dr u gs, or ot her c o m mercial pr o d ucts, y o u will n ot s hare i n a n y pr ofits. 
 
W H A T I F I C H A N G E M Y MI N D ?  

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– 5 5 –  
 
If y o u deci de y o u n o l o n ger wa nt y o ur sa m ples t o be use d, y o u ca n call t he st u d y d oct or, 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _,  (i nsert n a me of st u dy d oct or f or m ai n tri al) at _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (i nsert 
tele p h o ne n u m ber of st u dy d oct or f or m ai n tri al) w h o will let t he researc hers k n o w . T he n, a n y sa m ple t hat 
re mai ns i n t he ba n k will n o l o n ger be use d. Sa m ples or relate d i nf or mati o n t hat ha ve alrea d y bee n gi ve n 
t o or use d b y researc hers will n ot be ret ur ne d. 
 
W H A T I F I H A V E M O R E Q U E S TI O N S ?  
If y o u ha ve q uesti o ns a b o ut t he use of y o ur sa m ples f or researc h, c o ntact t he st u d y d oct or, 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _, (i nsert n a me of st u dy d oct or f or m ain tri al) , at _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (i nsert 
tele p h o ne n u m ber of st u dy d oct or f or m ai n tri al). 
 
Please circle y o ur a ns wer t o s h o w w het her or n ot y o u w o ul d li ke t o ta ke part i n eac h o pti o n. 
 
S A M P L E S  A N D I N F O R M A TI O N  F O R F U T U R E R E S E A R C H S T U DI E S:  
 
M y sa m ples  a n d relate d i nf or mati o n ma y be ke pt i n a Bi o ba n k f or use i n f ut ure healt h researc h. 
 
 
Y E S   
 
N O          
 
 
M y sa m ples  f or D N A ma y be ke pt i n a Bi o ba n k f or use i n f ut ure healt h researc h.  
 
 
Y E S   
 
N O          
 
T he i nf or mati o n fr o m m y t o bacc o a n d alc o h ol use q uesti o n naires ma y be use d i n f ut ure healt h 
researc h. 
 
 
Y E S   
 
N O  
 
I a gree t hat m y st u d y d oct or, or t heir re prese ntati ve, ma y c o ntact me or m y p h ysicia n t o see if I 
wis h t o partici pate i n ot her researc h i n t he f ut ure. 
 
 
Y E S   
 
N O   
 
I a gree t hat m y st u d y d oct or, or t heir re prese ntati ve, ma y c o ntact me or m y d oct or t o see if I wis h 
t o lear n a b o ut t he res ults fr o m t his st u d y. 
 
Y E S    
N O  
        
T his is t he e n d of t he secti o n a b o ut o pti o nal st u dies.  
 
 
 
 
M y Si g n at ure A greei n g t o T a ke P art i n t he M ai n St u d y  
I ha ve rea d t his c o nse nt f or m or ha d it rea d t o me. I ha ve disc usse d it wit h t he st u d y d oct or a n d m y 
q uesti o ns ha ve bee n a ns were d . I will be gi ve n a si g ne d c o p y of t his f or m. I a gree t o ta ke part i n t he mai n 
st u d y a n d a n y a d diti o nal st u dies w here I circle d ‘ yes’.   

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_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
  
_ _ _ _ _ _ _ _ _ _ 
S u bj ect’s Na me ( pri nte d) a n d Si g nat ure    
  
  
  
 
Date  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
  
_ _ _ _ _ _ _ _ _ _ 
Na me ( pri nte d) a n d Si g nat ure of Pers o n O btai ni n g C o nse nt  
  
 
Date  

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

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Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 5 8 –  
A P P E N DI X B 
St u d y Di ar y  
Pr ot oc ol N u m ber 
S u bj ect I D  
Na me  
 
Site  
Start date  
             E n d Date  
 
 
Da y _ _ of St u d y  
  
  
  
  
 
Date   
  
 
Ti me  
 
Di d y o u ha ve a n y h ot flas hes i n t he past 2 4 h o urs?  
 
yes   
n o 
 
If yes, h o w ma n y  
  
  
  
  
  
1- 5  
  
6- 1 0  
  
1 1- 1 5 
 
Di d y o u ha ve ni g ht s weats i n t he past 2 4 h o urs?    
 
yes   
n o 
 
Di d y o u a p pl y y o ur st u d y gel as directe d, a t otal of 2 c o m plete 
p u m ps ( 1 c o m plete p u m p per br east)?    
  
 
yes   
n o 
 
Di d y o u discar d a n y d oses of gel?  
  
  
 
yes       n o  
 
D i d y o u e x perie nce a n y s ki n irritati o n?                                           yes        n o 
 
 
 
Si g nat ure/ Date  
 
 
Da y _ _ of St u d y  
  
  
  
  
 
Date   
  
 
Ti me    
 
Di d y o u ha ve a n y h ot flas hes i n t he past 2 4 h o urs?  
 
yes   
n o 
 
If yes, h o w ma n y  
  
  
  
  
  
1- 5  
  
6- 1 0  
  
1 1- 1 5 
 
Di d y o u ha ve ni g ht s weats i n t he past 2 4 h o urs?    
 
yes   
n o 
 
Di d y o u a p pl y y o ur st u d y gel as directe d, a t otal of 2 c o m plete  
p u m ps ( 1 c o m plete p u m p per br east)  
  
  
 
yes   
n o 
 
Di d y o u discar d a n y d oses of gel?  
  
  
 
yes       n o  
 
Di d  y o u e x perie nce a n y s ki n irritati o n?                                           yes        n o 
 
 
 
 
Si g nat ure/ Date  
 
T o be re peate d, f or eac h da y, u ntil e n d of 
i nter ve nti o n 

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Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 5 9 –  
 
 
A P P E N DI X C  
G E L A P P LI C A TI O N I N S T R U C TI O N S:  
 
1.  Fla m ma ble: d o n ot a p pl y near fire, fla me or heat , or w hile s m o ki n g 
 
2.  A p pl y t he gel t o y o ur o w n breasts after bat hi n g, prefera bl y i n t he m or ni n g a n d at a p pr o xi matel y t he 
sa me ti me eac h da y. 
 
3.  T o a p pl y, re m o ve t he ca p fr o m t he ca nister . W he n y o u use a ca nister  f or t he first ti me, y o u m ust pri me 
it b y pressi n g t he p u m p f ull y se veral ti mes u ntil gel is dis pe nse d ( p oi nt t he s p o ut t o war d a si n k or 
waste bas ket a n d d o n ot use t he first d ose, w hic h ma y b e i nc orrect). 
 
4.  O nce t he ca nister  is pri me d, place  it o n a har d s urface a n d place t he pal m of o ne  ha n d u n der t he p u m p 
t o catc h t he gel. Be s ure t o press d o w n c o m pletel y o n t he p u m p a n d release it c o m pletel y t o dis pe nse 
o ne d ose of gel. 
 
5.  A p pl y a t otal of t w o c o m plete p u m ps per da y,  o ne d ose of gel ( o ne c o m plete  p u m p) t o e ac h bre ast 
per d a y  ( d osa ge is i n dicate d o n t he ca nister la bel). D o n ot a p pl y m ore or less t ha n o ne d ose t o eac h 
breast. Be s ure t o release t he p u m p c o m pletel y bet wee n b ot h act uati o ns. 
 
6.  If y o u acci de ntall y p u m p t wice f or o ne breast, please discar d t his d ose a n d tr y a gai n t o get o ne p u m p. 
If y o u press d o w n o n t he p u m p a n d t he gel d oes n ot f ull y la n d i n y o ur ha n d, please discar d t his d ose 
a n d tr y a gai n . If y o u d o discar d p u m pe d d oses, please rec or d t his o n y o ur st u d y diar y. T here are e xtra 
d oses i n t he p u m p t o all o w f or pri mi n g a n d err ors. 
 
7.  S prea d t he gel e ve nl y o ver t he e ntire s urface of y o ur breast, wit h o ut r u b bi n g. 
 
8.  Was h y o ur ha n ds i m me diatel y after a p pl yi n g t he gel.  
 
9.  All o w t he gel o n y o ur breasts t o air dr y f or 2 mi n utes a n d t he n i m me diatel y c o ver wit h cl ot hi n g (t he 
gel is c ol orless a n d will n ot stai n y o ur cl ot hi n g). O nce dr y, t he gel is n o l o n ger fla m ma ble. D o n ot 
e x p ose y o ur bare breasts t o s u nli g ht at a n y ti me. 
 
1 0.  D o n ot a p pl y a n y ot her crea m, l oti o n or m oist urizer t o y o ur breasts at a n y ti me d uri n g t he st u d y. 
 
1 1.  D o n ot was h y o ur breasts or i m merse i n water ( bat h , s wi m) f or at least 4 h o urs f oll o wi n g a p plicati o n 
of t he gel. If t his is n ot p ossi ble, dela y a p plicati o n of t he gel t hat da y u ntil after i m mersi o n, a n d be s ure 
t o f oll o w all t he a b o ve i nstr ucti o ns. If y o u re g ularl y s wi m i n t he m or ni n g, it is better t o a p pl y t he gel 
after war ds, after y o ur s h o wer.  
 
1 2.    After use, re place t he ca p o n t he ca nister. 
 

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– 6 0 –  
R E C O M M E N D A TI O N S:  
 
1.  
Be s ure t o a p pl y after b at hi n g or s h o weri n g, e ac h d a y  d uri n g t he st u d y a n d prefera bl y i n t he 
m or ni n g. 
 
2.  
If y o u f or get t o a p pl y a d ose, d o n ot d o u ble t he d ose t o “catc h u p”. If y o ur ne xt d ose is sc he d ule d 
wit hi n t he ne xt 1 2 h o urs, it is best j ust t o wait; if it is m ore t ha n 1 2 h o urs u ntil y o ur ne xt d ose, a p pl y 
t he d ose y o u misse d a n d res u me y o ur n or mal d osi n g after t hat. 
 
3.  
F or t he d urati o n of t he st u d y, a v oi d c o ntact bet wee n t he a p plicati o n area a n d t he s ki n of ot her 
i n di vi d uals (i.e. y o ur c hil d, y o ur se x ual part ner, or ot her pers o ns). If necessar y, s ki n c o ntact is 
all o wa ble after t he breasts ha ve bee n was he d. As n ote d a b o ve, y o u m ust wait at least   4  h o urs 
f oll o wi n g a p plicati o n bef ore was hi n g t he a p plicati o n area, ot her wise, dela y a p plicati o n u ntil after 
was hi n g a n d c o ntact.  
 
4.  
D o n ot i n gest or s wall o w t he gel. F or e xter nal use o nl y.  
 
5.  
If t he p u m p d oes n’t c o me bac k u p c orrectl y or if t here’s n o gel deli vere d w he n y o u press d o w n o n 
t he p u m p, d o n ot use t his ca nister  a n d n otif y y o ur d oct or i m me diatel y. 
 
6.  
After t he e n d of st u d y treat me nt, be s ure t o ta ke bac k t o y o ur d oct or all  t he gel ca nister s y o u ha ve 
bee n gi ve n (e ve n if e m pt y or n ot use d). T his is ver y i m p ort a nt f or t he s uccess of t he st u d y . 
 
S T O R A G E I N S T R U C TI O N S:  
 
1.  
Kee p y o ur gel ca nister s at r o o m te m perat ure. 
 
2.  
Kee p t he gel ca nister s o ut of t he reac h of c hil dre n. 
 
S P E CI A L I N S T R U C TI O N S F O R T H E D A Y B E F O R E S U R G E R Y  
 
1.  
T he d a y B E F O R E s ur ger y , y o u s h o ul d ta ke y o ur us ual m or ni n g d ose of t he gel a p plicati o n.  T his will be y o ur 
last d ose of t he st u d y dr u g.  B e s ure t o f oll o w all was hi n g i nstr ucti o ns a b o ve.   
 
2.  
T he d a y of s ur ger y, d o n ot a p pl y t he gel.   B e s ure t o ta ke a s h o wer, bat he, or was h y o ur  breasts t he m or ni n g 
of s ur ger y bef ore y o u get t o t he h os pital.   
 
D E LI V E R Y I N S T R U C TI O N S  
 
N ote: y o u r i nstit uti o n ma y or ma y n ot all o w f or Fe d E x/ U P S/c o urier deli ver y of gel dis pe nsers.  If y o u are ha vi n g t he 
dis pe nsers deli vere d via Fe d E x, U P S, or a n ot her c o urier, y o u M U S T be prese nt t o si g n f or t he pac ka ge t he first d a y 
it arri ves.  If y o u are u na ble t o si g n f or t he pac ka ge d uri n g t he day, y o u ha ve t he o pti o n of re q uesti n g t hat t he pac ka ge 
be hel d f or pic k u p.   
 
F or m ore i nf or mati o n ( Fe d E x), see: htt p:// w w w.fe de x.c o m/ us/ser vices/ h ol d at l ocati o n fi n d l oc ati o ns ht ml.   
F or m ore i nf or mati o n ( U P S), see htt ps:// w w w. u ps.c o m/c o nt e nt/ us/e n/re gister/reas o ns/ m y u ps. ht ml .  
 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 6 4 –  
A P P E N DI X E  
 
Please use t he f oll o wi n g s u g geste d state me nts f or partici pa nt c o m m u nicati o ns.  
 
F or E m ail, P h o ne or Te xt Re mi n ders d uri n g t he first wee k ( a n d s u bse q ue ntl y 
if nee de d) ple ase use t he s u g geste d st ate me nt: 
 
“ Hell o m y na me is [i nsert na me ] fr o m [site na me/ de part me nt], re gar di n g N W U 2 0 1 7- 0 9- 0 1 T o p E N D  
researc h st u d y.  Please re me m ber t o a p pl y y o ur st u d y gel a n d c o m plete y o ur partici pa nt diar y. If y o u ha ve 
a n y q uesti o ns please call [i nsert n a me], Researc h C o or di nat or at ( x x x) x x x- x x x.”  
 
 
F or P h o ne C alls t o assess c o m pli a nce, t o xicit y, a n d c h a n ges i n me dic ati o n 
ple ase use t he s u g geste d st ate me nts:  
 
“ Hell o m y na me is [i nsert n a me], Researc h C o or di nat or at ( x x x) x x x- x x x fr o m [site na me/ de part me nt]. I 
wa nte d t o c hec k i n wit h y o u briefl y a b o ut t he N W U 2 0 1 7- 0 9- 0 1 T o p E N D st u d y. Is t his a g o o d ti me t o 
tal k?” 
 
  
If n o: “ W he n w o ul d be a better ti me f or me t o call y o u?” 
 
        If yes: “ As part of y o ur st u d y f oll o w u p, I a m calli n g y o u t o briefl y assess y o ur st u d y c o m plia nce  
  
a n d s y m pt o ms. Si nce we  last s p o ke o n < < date > >, ha ve  y o u  misse d y o ur  st u d y me dicati o n o n a n y 
 
da ys? ”  
 
 
If yes: “ H o w ma n y da ys di d y o u miss y o ur st u d y me dicati o n? O n w hat dates di d y o u miss y o ur 
  
st u d y me dicati o n?” 
 
      “ Si nce we  last s p o ke, ha ve  t here bee n  a n y c ha n ges  t o y o ur  c urre nt me dicati o ns? F or  e xa m ple, a 
 
c ha n ge  i n d ose,   st o p pi n g a me dicati o n, or starti n g a ne w  me dicati o n.”  
 
If yes: “ Please tell me w hat has c ha n ge d.” 
 
       “ Si nce we last s p o ke o n < < date > >, ha ve y o u n ote d a n y c ha n ges i n t he s ki n of y o ur breast?”    
  
If t he p artici p a nt re p orts yes, If t he p artici p a nt re p orts yes, t he n utilize t he pl ai n l a n g u a ge 
  
g ui de bel o w t o ask m ore pr o bi n g q uesti o ns as nee de d.  
 
  
Plai n La n g ua ge G ui de f or assessi n g s ki n a p plicati o n A Es 
1.  Is y o ur breast s ki n dr y fr o m gel a p plicati o n? If yes, is it re d or itc h y? 
2.  D o y o u ha ve pai n o n y o ur breast s ki n? If yes, h o w se vere?  
3.  Is y o ur s ki n itc h y fr o m gel a p plicati o n? If yes, h o w se vere? Are y o u ta ki n g a n y me dici ne f or 
it? 
4.  D o y o u ha ve ras h o n y o ur breast s ki n? If yes, h o w bi g is t he affecte d area? Are y o u ta ki n g 
a n y me dici ne f or it? Ca n y o u please se n d us a pict ure of y o ur ras h?  
5.  D o y o u ha ve hi ves o n t he breast s ki n w here y o u ha ve a p plie d t he gel ? If yes, h o w bi g is t he 
affecte d area? Are y o u ta ki n g a n y me dici ne f or it?  
 
       “ Si nce we last s p o ke o n < < date > >, ha ve y o u e x perie nce d a n y ot her s y m pt o ms?  
 
       “ Please re me m ber t o a p pl y y o ur st u d y gel a n d fill o ut t he st u d y diar y. T ha n k y o u f or y o ur ti me.” 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 6 5 –  
F or Re mi n der P h o ne C alls f o ur d a ys pri or t o s ur ger y, ple ase use t he f oll o wi n g 
s u g geste d st ate me nt.  
“ Hell o m y na me is [i nsert na me ] fr o m [site na me/ de part me nt], re gar di n g N W U 2 0 1 7- 0 9- 0 1 T o p E N D 
researc h st u d y.  T his messa ge is f or [i nsert na me]. Please re me mber t o c o nti n ue a p pl yi n g y o ur st u d y a ge nt 
f or t he last 3 da ys pri or t o s ur ger y a n d c o m plete y o ur partici pa nt diar y. Y o ur last gel a p plicati o n s h o ul d 
be o n t he da y bef ore y o ur s ur ger y. If y o u ha ve a n y q uesti o ns please call [i nsert n a me], Researc h 
C o or di nat or at ( x x x) x x x- x x x.”  
 
 
 
 
F or t he L ast P h o ne C all t o pre me n o p a us al w o me n, ple ase use t he f oll o wi n g 
s u g geste d st ate me nt: 
“ Hell o m y na me is [i nsert na me ] fr o m [site na me/ de part me nt], re gar di n g N W U 2 0 1 7- 0 9- 0 1 T o p E N D 
researc h st u d y. Is t his a g o o d ti me t o tal k?” 
 
  
If n o: “ W he n w o ul d be a better ti me f or me t o call y o u?” 
 
        If yes: “ Ha ve y o u ha d a peri o d si nce we last met? If s o, w hat was t he start date?”  
 
        “ T ha n k y o u f or y o ur ti me a n d f or partici pati n g i n t his st u d y.” 
 
 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 6 6 –  
A P P E N DI X F 
Alc o h ol a n d T o b acc o Use Assess me nt  
A L C O H O L A S S E S S M E N T – B A S E LI N E  
 
I nstr ucti o ns: 
F or t he f oll o wi n g q uesti o ns a b o ut dri n ki n g alc o h olic be ver a ges, a dri n k me a ns a 1 2 oz. beer, a 5 oz. 
gl ass of wi ne, or o ne a n d a h alf o u nces of li q u or. 
 
1.  I n y o ur e ntire life, ha ve y o u ha d at least 1 2 dri n ks of a n y ki n d of alc o h olic be vera ge?  
 Yes  
 N o ( E n d) 
 Ref use d ( E n d) 
 D o n’t k n o w/ N ot s ure 
 
2.  I n t he past 1 2 m o nt hs, o n a vera ge, h o w ofte n di d y o u dri n k a n y t y pe of alc o h olic be vera ge?  
_ _ _ _ _ _ _ _ ( E nter t he n u m ber of da ys y o u dra n k base d o n t he ti mefra me c hec ke d bel o w.  E nter 0 if y o u 
ne ver dra n k a n d s ki p t o Q uesti o n 6.)   
 Wee k  
 M o nt h 
 Year  
 Ref use d  
 D o n’t k n o w/ N ot s ure 
 
3.  I n t he past 1 2 m o nt hs, o n t h ose da ys t hat y o u dra n k alc o h olic be vera ges, o n a vera ge, h o w ma ny dri n ks 
di d y o u ha ve per da y?  
_ _ _ _ _ _ _ _ ( E nter t he a vera ge n u m ber of dri n ks per da y) 
 
 Ref use d  
 D o n’t k n o w/ N ot s ure 
 
4.  I n t he past 1 2 m o nt hs, o n h o w ma n y da ys di d y o u ha ve 5 or m ore dri n ks of a n y alc o h olic be vera ge?  
_ _ _ _ _ _ _ _ _ ( E nter t he n u m ber of da ys y o u ha d 5 or m ore dri n ks, or e nter 0 if n o ne.) 
 
 Ref use d  
 D o n’t k n o w/ N ot s ure 
 
5.  Was t here e ver a ti me or ti mes i n y o ur life w he n y o u dra n k 5 or m ore dri n ks of a n y ki n d of alc o h olic 
be vera ge al m ost e ver y da y?  
 Yes  
 N o  
 Ref use d  
 D o n’t k n o w/ N ot s ure 
 
6.  If y o u d o n ot c urre ntl y dri n k alc o h olic be vera ges, b ut di d i n t he past, h o w l o n g has it bee n si nce y o u 
last dra n k re g ularl y?  
 Wit hi n t he past m o nt h ( 0 t o 1 m o nt h a g o) 
 Bet wee n 1 a n d 3 m o nt hs ( 1 t o 3 m o nt hs a g o) 
 Bet wee n 3 a n d 6 m o nt hs ( 3 t o 6 m o nt hs a g o) 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 6 7 –  
 Bet wee n 6 a n d 1 2 m o nt hs ( 6 t o 1 2 m o nt hs a g o) 
 Bet wee n 1 a n d 5 years ( 1 t o 5 years a g o)  
 Bet wee n 5 a n d 1 5 years ( 5 t o 1 5 years a g o) 
 M ore t ha n 1 5 years a g o  
 D o n’t k n o w/ N ot s ure 
 Ne ver dra n k re g ularl y  
 
7.  At t he hea viest p oi nt, eit her n o w or i n t he past, o n t he da ys w he n y o u dra n k, a b o ut h o w ma n y dri n ks 
di d y o u dri n k a da y o n t he a vera ge?  
_ _ _ _ _ _ _ _ _ _ ( E nter t he n u m ber of dri n ks a da y) 
  
 Ref use d  
 D o n’t k n o w/ N ot s ure 
 
8.  H o w ma n y years ha ve y o u bee n dri n ki n g ( or di d dri n k) re g ularl y?  
_ _ _ _ _ _ years 
 
 Ref use d  
 D o n’t k n o w/ N ot s ure  
 
9.  At w hat a ge di d y o u be gi n dri n ki n g re g ularl y?  
_ _ _ _ _ _ years of a ge 
 
 Ref use d  
 D o n’t k n o w/ N ot s ure  
 
1 0.  W hat t y pe(s) of alc o h ol d o y o u dri n k? ( Mar k A L L t hat a p pl y) 
 Wi ne  
 Li q u or 
 Beer  
 Wi ne c o oler  
 
 
C o or di nat or Si g nat ure _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   Date _ _ _ _ / _ _ _ _ / _ _ _ _ _ _ _ _ 
 
( M M/ D D/ Y Y Y Y) 
 
 
 
 
 
 
 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 6 8 –  
A P P E N DI X F 
Alc o h ol a n d T o b acc o Use Assess me nt  
T O B A C C O A S S E S S M E N T – B A S E LI N E  
 
Secti o n A. B asic Ci g arette Use I nf or m ati o n 
 
1. Ha ve y o u s m o ke d at least 1 0 0 ci garettes ( 5 pac ks = 1 0 0 ci garettes) i n y o ur e ntire life?  
Yes   
 
 N o → S ki p t o Secti o n B  
 D o n’t k n ow/ N ot s ure → S ki p t o Secti o n B  
 
2. H o w ol d were y o u w he n y o u first s m o ke d a ci garette (e ve n o ne or t w o p uffs)? 
_ _ _ _ _ _ _ Years ol d   
 
3. H o w ol d were y o u w he n y o u first be ga n s m o ki n g ci garettes re g ularl y?   
_ _ _ _ _ _ _ Years ol d   
  C hec k here if y o u ha ve ne ver s m o ke d ci garettes re g ularl y.  
 
4. H o w ma n y t otal years ha ve y o u s m o ke d ( or di d y o u s m o ke) ci garettes? D o n ot c o u nt a n y ti me y o u ma y 
ha ve sta ye d off ci garettes.  
_ _ _ _ _ _ Years (If y o u s m o ke d less t ha n o ne year, write “ 1.”)   
 
5. O n  a vera ge w he n y o u ha ve s m o ke d, a b o ut h o w ma n y ci garettes d o y o u ( or di d y o u) s m o ke a da y?  ( A 
pac k us uall y has 2 0 ci garettes i n it).   
_ _ _ _ _ N u m ber of ci garettes per da y 
 
6. D o y o u N O W  s m o ke ci garettes?  
 E ver y da y  
 S o me da ys 
 Not at all → S ki p t o q uesti o n 8  
 
7.  H o w s o o n after y o u wa ke u p d o y o u s m o ke y o ur first ci garette?  
  Wit hi n 3 0 mi n utes 
  After 3 0 mi n utes 
 
8. H o w l o n g has it bee n si nce y o u last s m o ke d a ci garette (e ve n o ne or t w o p uf fs)? 
First c heck w hic h o ne of t he f oll o wi n g c h oices a p plies t o y o u. T he n, if a p plic a ble, write a n u m ber o n t he 
li ne f or h o w m a ny d ays, weeks, m o nt hs, or ye ars it h as bee n si nce y o ur l ast ci g arette. 
 I s m o ke d a ci garette t o da y (at least o ne p uff) 
 1-7 da ys → N u m ber of da ys si nce last ci garette  _ _ _ _ _ _ _ _  
 Less t ha n 1 m o nt h → N u m ber of wee ks si nce last ci garette  _ _ _ _ _ _ _ _ _  
 Less t ha n 1 year → N u m ber of m o nt hs si nce last ci garette  _ _ _ _ _ _ _ _ _ _  
 M ore t ha n 1 year → N u m ber of years si nce last ci garette  _ _ _ _ _ _ _ _ _ _ _  
 D o n’t k n o w/ D o n’t re me m ber  
 
 
 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 6 9 –  
Secti o n B. Use of Ot her F or ms of T o b acc o  
9.  Ha ve y o u e ver use d ot her f or ms of t o bacc o, n ot i ncl u di n g ci garettes?  
      
 Yes  
 N o → S ki p t o Secti o n C  
 
1 0. H o w ofte n d o y o u/ di d y o u use ot her f or ms of t o bacc o?  
 E ver y da y → N u m ber of ti mes per da y  _ _ _ _ _ _ _ _  
 S o me da ys → N u m ber of da ys _ _ _ _ _ _ _ per  
 Wee k  
 M o nt h 
Year  
 
1 1. W hic h of t he f oll o wi n g pr o d ucts ha ve y o u e ver use d re g ularl y? 
 C hec k all t h at a p ply  
 Ci garettes  
 E-ci garettes or ot her electr o nic nic oti ne deli ver y s yste m  
 Tra diti o nal ci gars, ci garill os or filtere d ci gars  
 Pi pes  
 Water pi pe  
 H o o ka h 
 Cl o ve ci garettes or krete ks  
 Bi dis  
 S m o keless t o bacc o, li ke di p, c he w, or s n uff 
 S n us 
 Paa n wit h t o bacc o, g ut ka, zar da, k hai ni 
 Ot her, Please s pecif y: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
1 2. If y o u d o n ot c urre ntl y use ot her f or ms of t o bacc o, b ut di d i n t he past, h o w l o n g has it bee n si nce y o u 
last use d ot her f or ms of t o bacc o re gularl y?  
 Wit hi n t he past m o nt h ( 0 t o 1 m o nt h a g o) 
 Bet wee n 1 a n d 3 m o nt hs ( 1 t o 3 m o nt hs a g o) 
 Bet wee n 3 a n d 6 m o nt hs ( 3 t o 6 m o nt hs a g o) 
 Bet wee n 6 a n d 1 2 m o nt hs ( 6 t o 1 2 m o nt hs a g o) 
 Bet wee n 1 a n d 5 years ( 1 t o 5 years a g o)  
 Bet wee n 5 a n d 1 5 years ( 5 t o 1 5 years a g o) 
 M ore t ha n 1 5 years a g o  
 D o n’t k n o w/ N ot s ure 
 Ne ver use d ot her f or ms of t o bacc o re g ularl y 
 
Secti o n C. Sec o n d -H a n d S m o ke E x p os ure  
1 3. Are y o u c u rre ntl y li vi n g wit h a s m o ker?   
Yes   
 
 N o  
 
1 4. I n t he past 3 0 da ys, ha ve y o u li ve d  i n a place w here ot her pe o ple s m o ke d ci garettes i n d o ors?  
Yes   
 
 N o  
 
1 5. I n t he past 3 0 da ys, ha ve y o u w or ke d i n a place w here ot her pe o ple s m o ke d ci garettes i n d o ors? 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 7 0 –  
Yes   
 
 N o  
 
1 6. T hi n ki n g of all y o ur  c hil d h o o d a n d a d ult years, ha ve y o u e ver li ve d  i n a place w here ot her pe o ple 
s m o ke d ci garettes i n d o ors? 
 Yes   
I n t otal, f or a b o ut h o w ma n y years? _ _ _ _ _ _ _ If less t ha n 1, write “ 1.”   
 N o  
 
1 7. T hi n ki n g of all t he years y o u ha ve w or ke d,  ha ve y o u e ver w or ke d  i n a place w here ot her pe o ple s m o ke d 
ci garettes i n d o ors?    
Yes  
→ I n t otal, f or a b o ut h o w ma n y years? _ _ _ _ _ _ _ If less t ha n 1, write “ 1.”    
 N o  
 
 
C o or di nat or Si g nat ure  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   Date  _ _ _ _ / _ _ _ _ / _ _ _ _ _ _ _ _ 
 
( M M/ D D/ Y Y Y Y) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 7 1 –  
A P P E N DI X F 
Alc o h ol a n d T o b acc o Use Assess me nt  
A L C O H O L A S S E S S M E N T - F O L L O W -U P  
I nstr ucti o ns: 
F or t he f oll o wi n g q uesti o ns a b o ut dri n ki n g alc o h olic be ver a ges, a dri n k me a ns a 1 2 oz. beer, a 5 oz. 
gl ass of wi ne, or o ne a n d a h alf o u nces of li q u or. 
 
1. D uri n g t he past 3 0 da ys, di d y o u dri n k a n y alc o h olic be vera ges?  
 Yes  
 N o ( E n d) 
 Ref use d ( E n d) 
 D o n’t k n o w/ N ot s ure 
 
2. D uri n g t he past 3 0 da ys, h o w ma n y da ys per wee k or per m o nt h di d y o u dri n k a n y alc o h olic be vera ges, 
o n t he a vera ge?  
_ _ _ _ _ _ _ _ ( E nter n u m ber of da ys y o u dra n k base d o n t he ti mefra me c hec ke d bel o w.  E nter 0 if y o u di d 
n ot dri n k.)  
 Wee k  
 M o nt h 
 Ref use d  
 D o n’t k n o w/ N ot s ure 
 
3. O n t he da ys w he n y o u dra n k, o n a vera ge, a b o ut h o w ma n y dri n ks di d y o u ha ve?  
_ _ _ _ _ _ _ _ ( E nter t he a vera ge n u m ber of dri n ks y o u ha d per da y.) 
 
 Ref use d  
 D o n’t k n o w/ N ot s ure 
 
4. I n t he past 3 0 da ys, o n h o w ma n y da ys di d y o u ha ve 5 or m ore dri n ks per da y?  
_ _ _ _ _ _ _ _ _ _ _ _ _ N u m ber of ti mes  
 
  N o ne  
  D o n ot k n o w/ N ot s ure 
 
 
C o or di nat or Si g nat ure _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   Date _ _ _ _ / _ _ _ _ / _ _ _ _ _ _ _ _ 
  
( M M/ D D/ Y Y Y Y) 
 
 
 
 
 
 
 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 7 2 –  
A P P E N DI X F 
Alc o h ol a n d T o b acc o Use Assess me nt  
T O B A C C O A S S E S S M E N T - F O L L O W -U P  
 
1 . D o y o u N O W  s m o ke ci garettes?  
 E ver y da y  
 S o me da ys 
 N ot at all → S ki p t o Q uesti o n 3.  
 
2. O n a vera ge, w he n y o u s m o ke d, a b o ut h o w ma n y ci garettes d o y o u ( or di d y o u) s m o ke a da y? ( A pac k 
us uall y has 2 0 ci garettes i n it).     
_ _ _ _ _ N u m ber of ci garettes per da y 
 
3. H o w l o n g has it bee n si nce y o u last s m o ke d a ci garette (e ve n o ne or t w o p uffs)?    
First c heck w hic h o ne of t he f oll o wi n g c h oices a p plies t o y o u. T he n, if  a p plic a ble, write a n u m ber o n t he 
li ne f or h o w m a ny d ays, weeks, m o nt hs, or ye ars it h as bee n si nce y o ur l ast ci g arette. 
 I s m o ke d a ci garette t o da y (at least o ne p uff) 
 1-7 da ys → N u m ber of da ys si nce last ci garette _ _ _ _ _ _ _ _  
 Less t ha n 1 m o nt h → N u m ber of wee ks si nce last ci garette _ _ _ _ _ _ _ _ _  
 Less t ha n 1 year → N u m ber of m o nt hs si nce last ci garette _ _ _ _ _ _ _ _ _ _  
 M ore t ha n 1 year → N u m ber of years si nce last ci g arette _ _ _ _ _ _ _ _ _ _ _ 
 D o n’t k n o w/ D o n’t re me m ber  
 
4 . Si nce y o ur last visit, ha ve y o u use d ot her f or ms of t o bacc o, n ot i ncl u di n g ci garettes?  
 Yes  
  N o ( E n d)  
 
5. H o w ofte n d o y o u/ di d y o u use ot her f or ms of t o bacc o?  
 E ver y da y → N u m ber of ti mes per da y _ _ _ _ _ _ _ _  
 S o me da ys → N u m ber of da ys _ _ _ _ _ _ _ per  
 Wee k  
 M o nt h 
Year  
 
6. Si nce y o ur last visit, w hic h of t he f oll o wi n g pr o d ucts ha ve y o u use d?  C hec k all t h at a p ply  
 Ci garettes  
 E-ci garettes or ot her electr o nic nic oti ne deli ver y s yste m  
 Tra diti o nal ci gars, ci garill os or filtere d ci gars  
 Pi pes  
 Water pi pe  
 H o o ka h 
 Cl o ve ci garettes or krete ks  
 Bi dis  
 S m o keless t o bacc o, li ke di p, c he w, or s n uff 
 S n us 
 Paa n wit h t o bacc o, g ut ka, zar da, k hai ni 
Ot her, S pecif y _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 

N W U 2 0 1 7 -0 9 -0 1  
Pr ot o c ol V ersi o n 6. 5, Ma y 1 1, 2 0 2 0  
 
– 7 3 –  
7. If y o u d o n ot c urre ntl y use ot her f or ms of t o bacc o, b ut di d i n t he past, h o w l o n g has it bee n si nce y o u last 
use d ot her f or ms of t o bacc o re g ularl y?  
 Wit hi n t he past m o nt h ( 0 t o 1 m o nt h a g o) 
 Bet wee n 1 a n d 3 m o nt hs ( 1 t o 3 m o nt hs a g o) 
 Bet wee n 3 a n d 6 m o nt hs ( 3 t o 6 m o nt hs a g o) 
 Bet wee n 6 a n d 1 2 m o nt hs ( 6 t o 1 2 m o nt hs a g o) 
 Bet wee n 1 a n d 5 years ( 1 t o 5 years a g o)  
 Bet wee n 5 a n d 1 5 years ( 5 t o 1 5 years a g o) 
 M ore t ha n 1 5 years a g o  
 D o n’t k n o w/ N ot s ure 
 Ne ver use d ot her f or ms of t o bacc o re g ularl y 
 
T he f oll o wi n g i nstr ucti o ns pertai n t o q uesti o ns 8 - 1 0.  D uri n g eac h of t he f oll o wi n g ti me fra mes, please 
i n dicate w het her y o u s m o ke d ci garettes e ver y da y, s o me da ys, or n ot at all. 
 
8.  D uri n g st u d y treat me nt 
 S m o ke d e ver y da y  
 S m o ke d s o me da ys  
 Di d n ot s m o ke at all  
 D o n’t k n o w/ n ot s ure 
 N ot a p plica ble  
 
9.  After t he e n d of st u d y treat me nt 
      
 S m o ke d e ver y da y  
 S m o ke d s o me da ys  
 Di d n ot s m o ke at all  
 D o n’t k n o w/ n ot s ure 
 N ot a p plica ble (I ha ve n ot c o m plete d t he st u d y treat me nt)  
  
 
1 0.  Si nce y o ur last visit t o t his cli nic  
      
 S m o ke d e ver y da y  
 S m o ke d s o me da ys  
 Di d  n ot s m o ke at all  
 D o n’t k n o w/ n ot s ure 
      
 N ot a p plica ble ( T his is m y first visit t o t his cli nic)  
 
 
C o or di nat or Si g nat ure _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   Date _ _ _ _ / _ _ _ _ / _ _ _ _ _ _ ( M M/ D D/ Y Y Y Y)