Understanding Mechanisms of Acquired Resistance to BIBW2992
Phase: NA
Conditions: Non-small Cell Lung Cancer, EGFR Mutations
Sponsor: Massachusetts General Hospital



C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
Pr ot oc ol Versi o n D ate:   Oct o ber 2 0 1 3 
N CI Pr ot oc ol #: N/ A 
D F/ H C C L oc al Pr ot oc ol #: 1 0- 0 9 2 
Titl e:  U n derst a n di n g mec h a nis ms of ac q uire d resist a nce t o BI B W 2 9 9 2: a pil ot st u d y  
Pri nci p al I n vesti g at or:   
Lecia V. Se q uist, M D, M P H 
Massac h usetts Ge neral H o s pital Ca ncer Ce nter 
5 5 Fr uit Street, P O B 2 1 2 
B ost o n, M A  0 2 1 1 4 
P h o ne: 6 1 7. 7 2 6. 7 8 1 2 
Fa x: 
 
E mail: L V Se q uist @ part ners. or g  
C o or di n ati n g Ce nter:  M G H 
C o-I n vesti g at ors:  
M G H:   Jeffre y E n gel ma n, M D, P h D 
 
 
 Pa n os
 Fi dias,
 M D
 
 
 
 Re becca
 Heist,
 M D,
 M P H
 
 
 
 I n ga
 Le n nes,
 M D
 
 
 
 Alice
 S ha w,
 M D,
 P h D
 
 
 
 Je n nifer
 Te mel,
 M D
 
              C hrist o p her Azz oli, M D 
St atistici a n:  Al o na M uzi ka ns k y, M G H      
P r oj e ct M a n a g e r: 
  
R es p o nsi bl e R es e a r c h N u rs e:  
 
R es p o nsi bl e D at a M a n a g e r: 
 
A ge nt(s):   BI B W 2 9 9 2 (I N D # 1 1 0 7 2 0) – B oe hri n ger I n gel hei m P har mace uticals, I nc.   

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3 
 
I N D # 1 1 0 7 2 0 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
S C H E M A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T KI- n aï ve N S C L C 
P atie nts wit h E G F R 
M ut ati o ns, n = 2 0 
 
M a n d at or y t u m or 
bi o ps y f or S N a Ps h ot  
BI B W 2 9 9 2 4 0- 5 0 m g P O Q D u ntil o bjecti ve t u m o r pr o gressi o n 
M a n d at or y 
re pe at t u m or 
bi o ps y f or 
S N a Ps h ot
Seri al bl o o d s a m ples f or C T C a n al ysis 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3 
 
I N D # 1 1 0 7 2 0 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
T A B L E O F C O N T E N T S 
1.  
O B J E C TI V E S .................................................................................................................... .................................. 4 
1. 1  
St u dy De si g n ................................................................................................................................................. 4 
1. 2  
Pri m ary O bjective ............................................................................................................. ........................... 4 
1. 3  
Sec o n d ary O b jectives .......................................................................................................... ......................... 4 
2.  
B A C K G R O U N D .................................................................................................................... .............................. 4 
2. 1  
St u dy A ge nt ................................................................................................................... ................................ 4 
2. 2  
St u dy Dise ase.................................................................................................................. .............................. 9 
2. 3  
M olec ul ar Tec h ni q ues B ack gr o u n d ............................................................................................... ............. 1 1 
2. 4  
St u dy R a ti o n ale ........................................................................................................................................... 1 3 
3.  
P A R TI CI P A N T S E L E C TI O N ......................................................................................................... ................. 1 3 
3. 1  
Eli gi bility Cr iteri a ...................................................................................................................................... 1 3 
3. 2  
E x cl usi o n Crit eri a ............................................................................................................ ........................ 1 4 
3. 3  
I ncl usi o n of W o me n, Mi n orities a n d Other U n derre prese nte d P o p ul ati o ns .............................................. 1 5  
4.  
R E GI S T R A TI O N P R O C E D U R E S ....................................................................................................... ........... 1 5 
4. 1  
Ge ner al G ui deli nes f or D F/ H C C a n d D F/ P C C I n stit uti o ns ....................................................................... 15  
4. 2  
R e gistr ati o n Pr o c ess f or D F/ H C C a n d D F/ P C C I n stit uti o ns ................................................................... 1 5 
4. 3  
G e n er al G ui d eli n es f or Ot h er P arti ci p ati n g I nstit uti o ns ..................................................................... 1 6  
4. 4  
R e gistr ati o n Pr ocess f or Ot her P artici p ati n g I nstit uti o ns ..................................................................... ... 1 6 
5.  
S T U D Y T R E A T M E N T ............................................................................................................... ...................... 1 7 
5. 1  
Overvie w ...................................................................................................................... ............................... 1 7 
5. 2  
I de ntific ati o n of t he I nvesti g ati o n a l A ge nt .................................................................................................. 1 8 
5. 3  
A d mi nistr ati o n of  BI B W 2 9 9 2 ..................................................................................................................... 1 8 
5. 4  
I n divi d u al P atie nt D ose Esc al ati o n t o  5 0 m g ............................................................................................. 1 9 
5. 5  
D ose M o d ific ati on ............................................................................................................. ......................... 2 0 
5. 6  
C o m pli a nce a n d Acc o u nt a bility ................................................................................................. ................. 2 1 
5. 7  
P ack a gi n g, L a beli n g, Re-s u p ply, a n d St or a ge ................................................................................... ......... 2 1 
5. 8  
Pr e-tr e at m e nt Crit eri a ........................................................................................................ ...................... 2 2 
5. 9  
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p ortive C are G ui deli nes .......................................................... 2 2  
5. 1 0  
D ur ati o n of T her a py ........................................................................................................... ......................... 2 4 
5. 1 1  
D ur ati o n of F oll o w U p ......................................................................................................... ...................... 2 4 
6.  
S A F E T Y A S S E S S M E N T S A N D A D V E R S E E V E N T S .................................................................................. 2 4  
6. 1  
Overvie w ...................................................................................................................... ............................... 2 4 
6. 2  
Defi niti o n of Ter ms ........................................................................................................... .......................... 2 5 
6. 3  
Pr oce d ures f or A E a n d S A E Rec or di n g a n d Re p or ti n g .............................................................................. 2 7 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2 
Oct o ber 2 0 1 3 
 
  
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntial. D o n ot di scl ose or use e xce pt as a ut h orize d.  
6. 4  
M o nit ori n g of A dverse Eve nts a n d Peri o d of O bserv a ti o n ......................................................................... 2 8 
6. 5  
C o ntr ace pti o n a n d Pre g n a ncy ................................................................................................... ................. 2 9 
7.  
M O L E C U L A R A N D C O R R E L A TI V E S T U DI E S ......................................................................................... 3 1  
7. 1  
Re pe at Bi o psies f or M olec ul ar Testi n g ......................................................................................... .............. 3 1 
7. 2  
Circ ul ati n g T u m o r Cell St u dies .................................................................................................................. 3 2 
8. 
E F FI C A C Y A S S E S S M E N T ........................................................................................................... ................... 3 3 
8. 1  
Defi niti o n of Ter ms ........................................................................................................... .......................... 3 3 
8. 2  
Res p o nse Criteri a ............................................................................................................. .......................... 3 5 
8. 3  
D ur ati o n of Res p o nse .......................................................................................................... ....................... 3 8 
8. 4  
Pr o gressi o n- Fr ee S urviv al ..................................................................................................... .................... 3 8 
8. 5  
Over all S u rviv al .......................................................................................................................................... 3 8 
9.  
S T U D Y C A L E N D A R ........................................................................................................................................ 3 9  
1 0.  
D A T A A N D S A F E T Y M O NI T O RI N G .................................................................................................... ... 4 1 
1 0. 1  
D at a Re p o rtin g ................................................................................................................ ........................... 4 1 
1 0. 2  
S afety Mee ti n gs ........................................................................................................................................... 4 1 
1 0. 3  
M o nit o ri n g .................................................................................................................................................. 4 2 
1 1.  
R E G U L A T O R Y C O N S I D E R A TI O N S ....................................................................................................... 4 2 
1 1. 1  
Pr ot oc ol Revie w a n d A me n d m e nts ................................................................................................ ............. 4 2 
1 1. 2  
I nf or me d C o nse nt ....................................................................................................................................... 4 2 
1 1. 3  
Et hics a n d G o o d Cli n ic al Pr actice ( G C P) ....................................................................................... .......... 4 2 
1 1. 4  
St u dy D oc u me nt ati o n ........................................................................................................... ....................... 4 3 
1 1. 5  
Rec or ds Re te nti o n ....................................................................................................................................... 4 3 
1 2.  
S T A TI S TI C A L C O N SI D E R A TI O N S .................................................................................................... ..... 4 4 
1 2. 1  
St u dy Desi g n/ E n d p oi nts ........................................................................................................ ...................... 4 4 
1 2. 2  
S a m ple Size/ P o wer C alc ul ati o n f or t he Pri m ar y E n d p oi nt ........................................................................  4 5 
1 2. 3  
D at a t o Be A n alyze d ........................................................................................................... ........................ 4 5 
1 2. 4  
P atie nt Di s p ositi o n ..................................................................................................................................... 4 5 
1 2. 5  
P atie nt C h ar ac teristics ............................................................................................................................... 4 6 
1 2. 6  
S afety of Tre at me nt ........................................................................................................... .......................... 4 6 
1 2. 7  
A n alysis of Re s p o nse R ate .......................................................................................................................... 4 6 
1 2. 8  
A n alysis of Pr o gressi o n- Fre e a n d Over all S urviv al ............................................................................. ...... 4 6 
1 2. 9  
A n alysis of Re pe at Bi o psy C o m plic ati o ns a n d Res u lts ............................................................................... 4 6 
1 2. 1 0  
A n alysis of Circ ul ati n g T u m o r Cells .......................................................................................................... 4 6 
1 3.  
P U B LI C A TI O N  P L A N ................................................................................................................................. 4 7 
1 4.  
R E F E R E N C E S .................................................................................................................... .......................... 4 8 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2 
Oct o ber 2 0 1 3 
 
  
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntial. D o n ot di scl ose or use e xce pt as a ut h orize d.  
1 5.  
A P P E N DI C E S .................................................................................................................... ........................... 5 1 
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3 
 
I N D # 1 1 0 7 2 0 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
4 
1.  O B J E C TI V E S 
 
1. 1  St u d y Desi g n 
 
T his is a pil ot st u d y e xa mi ni n g t he feasi bilit y  of usi n g a m olec ular e n d p oi nt, s pecificall y 
ac q uisiti o n of t he T 7 9 0 M E G F R re sista nce m utati o n, as t he pri mar y e n d p oi nt f or a cli nical trial. 
T he st u d y will c o nsist of 2 0 t yr osi ne ki nase i n hi b it or ( T KI)- naï ve patie nts wit h m utati o ns i n t he 
e pi der mal gr o wt h fact or rece pt or ( E G F R). Patie nts will be treate d wit h t he irre versi ble pa n- Er b B 
T KI c o m p o u n d BI B W 2 9 9 2, w hic h i n pre-cli nical st u dies i n hi bits  t he ac q uire d resista nce T 7 9 0 M 
m uta nt allele a n d t heref ore has t he p ote ntial t o  dela y t he e mer ge nce of t his c o m m o n resista nce 
mec ha nis m. H o we ver, it re mai ns u n k n o w n if BI B W 2 9 9 2 ca n o verc o me t he T 7 9 0 M m utati o n i n 
patie nts. All patie nts will i nitia ll y be treate d wit h BI B W 2 9 9 2 at 4 0 m g dail y, t h o u g h as i n ot her 
st u dies wit h t his c o m p o u n d, d ose escalati o n t o 5 0 m g will be per mitte d f or i n di vi d ual patie nts after 
o ne c ycle if t here are mi ni mal a d verse e ve nts  at 4 0 m g. Patie nts will c o nti n ue BI B W 2 9 9 2 u ntil 
pr o gressi o n, a n d t u m or tiss ue bi o ps y f or c o m pre he nsi ve ge n o mic pr ofili n g is ma n dat or y at t he ti me 
of ac q uire d resista nce. T he pri mar y e n d p oi nt will be t o deter mi ne t he pr o p orti o n of patie nts wit h 
T 7 9 0 M resista nce m utati o ns at t he ti me of pr o gre ssi o n. Serial a nal yses of circ ulati n g t u m or cells 
( C T Cs) will als o be perf or me d t o e x pl ore t he utilit y of t his platf or m t o assess e v ol vi n g ca ncer cell 
ge n ot y pes as resista nce de vel o ps. 
 
1. 2  Pri m ar y O bjecti ve 
 
1.  T o deter mi ne t he pr o p orti o n of patie nts t hat  ha ve a T 7 9 0 M m utatio n o n t heir pr o gressi o n 
bi o ps y a n d t o c o m pare t his wit h p u blis he d data  f or first- ge nerati o n E G F R t yr osi ne ki nase 
i n hi bit ors 
 
1. 3  Sec o n d ar y O bjecti ves 
 
1.  T o esti mate t he res p o nse rate 
2.  T o esti mate t he pr o gressi o n-free a n d o verall s ur vi val 
3.  T o descri be t he safet y of o btai ni n g re peat t u m or bi o psies f or ge n ot y pe a nal ysis 
4.  T o descri be ot her mec ha nis ms of resista n ce ( besi des T 7 9 0 M) o bser ve d o n t he pr o gressi o n 
bi o psies  
5.  T o e x pl ore t he res ults of e x peri me ntal C T C- deri ve d ge n ot y pe asse sse d fr o m serial bl o o d 
sa m ples ta ke n d uri n g t hera p y wit h BI B W 2 9 9 2 a n d t o c o m pare C T C- deri ve d res ults wit h t h ose 
fr o m t he pr o gressi o n bi o psies 
2.  B A C K G R O U N D 
 
2. 1  St u d y A ge nt 
2. 1. 1  Scie ntific B ac k gr o u n d 
 
BI B W 2 9 9 2 is a hi g hl y selecti ve a n d p ote nt l o w m olec ular wei g ht, irre versi ble i n hi bit or of t he er b B-
fa mil y of t yr osi ne ki nase rece pt ors E G F R (er b B 1 / H E R 1) a n d H E R 2 (er b B 2). T he p ote nc y of BI B W 
2 9 9 2 was deter mi ne d i n e nz y matic assa ys usi n g rec o m bi na nt h u ma n wil d-t y pe E G F R (I C 5 0 0. 5 n M) 
a n d H E R 2 (I C 5 0 1 4 n m) (ref. i n vesti gat or’s br oc h ure ). A pa nel of rec o m bi na nt h u ma n ki nases teste d 
i n parallel was n ot i n hi bite d, de m o nstrati n g t he hi g h tar get s pecificit y of BI B W 2 9 9 2. M olec ular 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
5
m o deli n g re veale d t hat BI B W 2 9 9 2 bi n ds c o vale ntl y a n d wit h hi g h a ffi nit y t o C ys 7 7 3 wit hi n t he 
catal ytic cleft of t he A T P- bi n di n g p o c ket of t he E G F rece pt or. It has bee n re p orte d t hat t his s pecific 
m olec ular i nteracti o n res ults i n irre versi ble i n hi biti o n of t he E G F R t yr osi ne ki nase d o mai n. 1 
E x peri me ntal data fr o m i n vitr o was h o ut st u dies c o nfir me d t he irre versi ble bi n di n g of BI B W 2 9 9 2 t o 
its m olec ular tar get. I n c o nstit uti vel y E G F R- o vere x pressi n g A 4 3 1 h u ma n e pi der m oi d ca ncer cells, 
BI B W 2 9 9 2 i n hi biti o n of E G F R-si g na li n g laste d f or u p t o 7 h o urs after re m o val of t he c o m p o u n d fr o m 
t he cell c ult ures (ref. i nvesti gat or’s br oc h ure). I n  c o ntrast, A 4 3 1 cells e x p ose d t o re versi ble E G F R 
T KIs re gai ne d f ull rece pt or f u ncti o n al m o st i m me diatel y after i n hi bit or was h o ut. 
 
T he efficac y a n d p ote nc y of BI B W 2 9 9 2 was de m o nstrate d i n vitr o i n rece pt or p h os p h or ylati o n a n d 
cell pr oliferati o n assa ys i n va ri o us h u ma n ca ncer cell m o dels.2 
 
T he s pecific acti vit y of BI B W 2 9 9 2 wa s deter mi ne d i n t w o i n de pe n de nt i n vitr o assa y s yste ms: i) 
E G F-i n d uce d E G F R a ut o p h os p h or ylati o n usi n g i m m u n o preci pitati o n a n d Wester n bl ot a n d ii) 
cl o n o ge nic, a nc h ora ge-i n de pe n de nt cell gr o wt h i n a s oft-a gar assa y s yste m. 2 T he a nti pr oliferati ve 
effects o bser ve d wit h BI B W 2 9 9 2 c o m pare fa v ora bl y t o acti vit y data p u blis he d f or gefiti ni b i n t he 
sa me N S C L C cell m o dels. 3 I n a d diti o n, BI B W 2 9 9 2 s u p presse d E G F R p h os p h or ylati o n a n d 
cl o n o ge nic gr o wt h i n t he gefiti ni b resista nt N CI- H 1 9 7 5 m o del, s u g gesti ng t hat t u m o ur cells har b ori n g 
t he T 7 9 0 M E G F R T KI resista nce m utati o n re mai n se nsiti ve t o t his irre versi ble E G F R s mall m olec ule 
i n hi bit or.4 
 
I n vitr o acti vit y of BI B W 2 9 9 2 i n h u ma n ca ncer ce ll m o dels is n ote d i n Ta ble 1 bel o w. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3 
 
I N D # 1 1 0 7 2 0 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
6 
 
 
T he i n viv o acti vit y of BI B W 2 9 9 2 a gai nst E G F R was i n vest i gate d i n a n A 4 3 1 s u bc uta ne o us xe n o graft 
m o del (ref i n vesti gat or’s br oc h ur e). Dail y oral treat me nt wit h BI B W 2 9 9 2 at d oses of 2 0 m g/ k g 
res ulte d i n a n al m ost c o m plete i n hi biti o n of t u m or gr o wt h o ver a peri o d of 2 5 da ys. Si milar a nti-t u m or 
acti vit y was o bser ve d i n N CI- N 8 7 t u m or beari n g mice treate d wit h BI B W 2 9 9 2 at si milar 
c o nce ntrati o ns. I n t hese i n viv o st u dies, BI B W 2 9 9 2 plas ma c o nce ntrati o ns of 8 0- 2 8 5 n M 
c orres p o n di n g t o a n A U C 0- 2 4 of 5 8 9- 3 1 9 8 n M * h were  re q uire d f or a nti-t u mor acti vit y. All BI B W 
2 9 9 2 d oses s h o w n t o be effecti ve i n m o us e xe n o graft m o dels were well t olerate d. 
2. 1. 2  P h ar m ac ol o g y a n d T o xic ol o g y Pr ofile 
 
T he a bs ol ute bi oa vaila bilit y of BI B W 2 9 9 2 after oral i n gesti o n was 4 5 % i n rats wit h a me dia n t ma x  
reac he d after 4 h o urs a n d a ter mi nal half-life (t 1/ 2) of 4. 5 h o urs.  I n rats t he e x p os ure was d ose 
pr o p orti o nal a n d n o ge n der-relate d effects or c o m p o u n d acc u m ulati o n was o bser ve d. BI B W 2 9 9 2 is 
pri maril y e xcrete d via t he feces. N o rele va nt i n hi biti o n of c yt oc hr o me P 4 5 0 is oe nz y mes was f o u n d. I n 
vitr o BI B W 2 9 9 2 is h o we ver a C Y P 3 A 4 s u bstrate. Si nce t his is n ot c o nsi dere d a d o mi na nt meta b olic 
pat h wa y, i n viv o dr u g- dr u g i nteracti o ns  wit h C Y P 3 A 4 i n d ucers or i n hibit ors are n ot e x pecte d (ref 
i n vesti gat or’s br oc h ure). 
 
I n viv o BI B W 2 9 9 2 was meta b olize d o nl y t o a mi n or e xte nt a n d t he meta b olis m was g o ver ne d b y 
a d d uct f or mati o n t o pr otei ns or n ucle o p hilic s mall m olec ules. It was f o u n d t hat meta b olis m is of 
s u b or di nate r ole f or BI B W 2 9 9 2 a n d t hat e nz y me-catal yze d meta b olic re acti o ns pla y a ne gli gi ble r ole 
f or t he meta b olis m of BI B W 2 9 9 2 i n viv o. O nl y a p pr o x. 2 % of t he d oses were meta b olize d b y F M O 3 
i n viv o. T he C Y P 3 A 4- de pe n de nt N- de met h ylati o n was e ve n t o o l o w t o be q ua ntitati vel y detecte d i n 
h u ma n v ol u nteers. T heref ore, i ntri nsic (e. g. ge netic pr e dis p ositi o n) or e xtri nsic (e. g. b y c o me dicati o ns) 
T a ble 1 
I n vitr o acti vit y of BI B W 2 9 9 2 i n h u m a n t u m o ur cell m o dels  
 
e x pressi n g wil d t y pe or m ut ate d E G F R  
Cell 
li ne  
Ori gi n  
E G F R st at us  
BI B W 2 9 9 2 I C 5 0  
Gefiti ni b I C 5 0  
 
 
 
 
E G F R- p h os-
p h or ylati o n 1  
Pr oliferati o n i n 
vitr o 2  
E G F R-
p h os p h or ylati o n 1  
Pr oliferati o n i n 
vitr o 3  
N CI- 
H 1 6 6 6  
N S C L C   
Wil d-t y pe  
7 n M   
1 6 n M   
1 0 0 n M   
4 μ M  
N CI- 
H 3 2 5 5  
N S C L C  
L 8 5 8 R- m utati o n  
6 n M   
0. 7 n M   
5 0 n M   
6 3 n M  
N CI- 
H 1 9 7 5  
N S C L C  
L 8 5 8 R- m utati o n 
a n d T 7 9 0-
resista nce 
m utati o n  
9 3 n M   
9 9 n M   
resista nt   
resista nt  
1 E G F i n d uce d a ut o- p h os p h or ylati o n of E G F R  
2 cl o n o ge nic a nc h ora ge-i n de pe n de nt s oft a gar assa y 
3 M T S assa y ( R 0 6- 1 3 8 8)  

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3 
 
I N D # 1 1 0 7 2 0 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
7 
effects o n t he acti vit y of F M O 3 or C Y P 3 A 4 i n viv o are e x pecte d t o be of little, if a n y, rele va nce f or t he 
p har mac o ki netics of BI B W 2 9 9 2. 
 
T he h u ma n A D M E data c o nfir me d t h e res ults of t he precli nical [ 1 4C] A D M E st u dies a n d all 
meta b olites of t he h u ma n [ 1 4C] A D M E st u d y were o bser ve d i n t he rat or t he mi ni pi g. I n ac ute 
t o xic ol o g y st u dies, oral a dmi nistrati o n of si n gle d oses i n rats a n d mice i n dicate d a l o w ac ute t o xic 
p ote ntial of BI B W 2 9 9 2. C ha n ges i n re nal a n d he patic f u ncti o n occ urre d o nl y at d oses t hat were 1 0- 3 0 
f ol d a b o ve t he le vels re q uire d f or a ntit u m o ur acti vit y. BI B W 2 9 9 2 ha d effects o n gastr oi ntesti nal 
f u ncti o n t hat were d ose- de pe n de nt a n d i n hi g h d oses, lea di n g t o pr of o u n d in hi biti o n. N o ac ute t o xic 
effects o n t he ce ntral ner v o us  s yste m were detecte d. 
 
I n oral re peate d d ose st u dies f or u p t o 2 6 wee ks i n rats a n d mi ni pi gs, t he mai n tar get or ga ns were t he 
gastr oi ntesti nal tract (rats a n d mi ni pi gs), ki d ne ys (rat), a n d t he s ki n (rat s). I n t he gastr oi ntesti nal tract, 
i ncreasi n g s yste mic e x p os ure was ass ociate d wit h d ose- de pe n de nt atr o p h y of t he e pit heli u m a n d 
c o nc o mita nt f ocal er osi o ns/ u lcerati o ns i n t he st o mac h of rats a n d mi ni pi gs. Cli nicall y t his res ulte d i n 
diarr hea i n b ot h s pecies a n d fecal occ ult bl o o d i n a si n gle mi ni pi g. I n ra t ki d ne ys pa pillar y necr osis a n d 
dilate d t u b ules were f o u n d. Si milar pat h ol o gic fi n di n gs, i.e., pa pillar y necr osis  i n rats a n d d o gs ha ve 
bee n descri be d pre vi o usl y f or t he E G F R-s mall m olec ule i n hi bit or gefiti ni b. H o we ver, ne p hr ot o xicit y 
has n ot bee n re p orte d as a si de-effect of gefiti n i b t hera p y i n h u ma ns. A sec o n dar y pat h o p h ysi ol o gic 
effect o n re nal f u ncti o n i n BI B W  2 9 9 2-treate d a ni mals d ue t o diarr hea-i n d uce d de h y drati o n a n d 
e maciati o n has t o als o be c o nsi d ere d. C uta ne o us alterati o ns, i.e., e pit helial atr o p h y were o bser ve d i n 
rats. H o we ver, BI B W 2 9 9 2 is n ot irritati n g t o i ntact s ki n i n al bi n o ra b bits a n d t he effects o bser ve d i n 
rats are m ost li kel y relate d t o t he s pecific p har mac o d y na mic mec ha nis m of E G F R-i n hi biti o n (ref 
i n vesti gat or’s br oc h ure). A variet y of or ga ns i ncl u di n g t he aer o di gesti ve tract a n d re pr o d ucti ve or ga ns 
were affecte d b y e pit helial atr o p h y. T hese atr o p hic c h a n ges were n ot se vere a n d f ull y re verse d d uri n g a 
2- wee k rec o ver y peri o d. Mi n or car d i o vasc ular effects (i ncrease d blo o d press ure a n d heart rate) a n d a 
d ose- de pe n de nt decrease of Q T ti me i n t he elec tr ocar di o gra m ( E C G) occ urre d i n BI B W 2 9 9 2-treate d 
mi ni pi gs. T hese data n o n ot i n dicate a ris k f or Q T- pr ol o n gati o n relate d arr h yt h mia. BI B W 2 9 9 2 ha d n o 
pr o-arr h yt h mic p ote ntial, as deter mi ne d b y t he e ffects o n H E R G- me diate d p otassi u m c urre nt or o n 
g ui nea pi g pa pillar y m uscle acti o n p ote ntial c o nfi g urati o n. BI B W 2 9 9 2 de m o nstrate d m uta ge nic 
p ote ntial i n bacteria b u t ha d n o ge n ot o xic p ote ntial i n viv o e ve n at hi g hl y t o xic/let hal d oses i n a ni mals. 
Beca use of its s pecific p har mac o d y na mic m ec ha nis m of acti o n, BI B W 2 9 9 2 is p ote ntiall y 
e m br y o/fet ot o xic a n d/ or terat o ge nic.  
2. 1. 3  BI B W 2 9 9 2 Cli nic al  Tri al Pr o gr a m 
 
T he m ost u p t o date trial a n d safe t y i nf or mati o n ca n be f o u n d i n t he c urre nt versi o n of t he I n vesti gat or 
Br oc h ure. 
 
BI B W 2 9 9 2 s h o we d m o deratel y fast a bs or pti o n wit h me dia n t ma x  val ues bet wee n 1 h t o 6 h after 
a d mi nistrati o n. T he g Mea n ter mi nal half-life (t 1/ 2) of BI B W 2 9 9 2 mai nl y ran ge d bet wee n 1 3 h t o 5 7 h. 
I n ge neral, t he ma xi m u m bl o o d c o nce ntrati o n ( Cma x ) a n d t he i nte gral of t he c o nce ntrati o n ti me c ur ve 
( A U C) of BI B W 2 9 9 2 i ncrease d i n a d ose- pr o p orti o nal wa y. 
 
T he ma xi m u m t olerate d d ose ( M T D) of BI B W 2 9 9 2 wa s i de ntifie d as 5 0 m g o nce dail y i n p hase I 
c o nti n u o us d osi n g m o n ot hera p y trials. T he 5 0 m g d ose is c urre ntl y use d i n t he p hase II b/III trial 
1 2 0 0. 2 3 i n N S C L C patie nts pr o gressi n g o n erl oti ni b or gefiti ni b, as ma xi m u m E G F R i n hi biti o n is 
re q uire d i n t his last-li ne p o p ulati o n e nric he d f or t he prese nce of resista nce m utati o ns. F or a m ore 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
8
se nsiti ve p o p ulati o n wit h E G F R acti vati n g m utati o n, a starti n g d ose of 4 0 m g is e x pecte d t o be 
s ufficie nt. I n p hase I cli nical trials of BI B W 2 9 9 2, d ura ble res p o nses ( > 2 0 m o nt hs) were see n at dail y 
d oses of 4 0 m g a n d less. 
 
I n t his trial, a starti n g d ose of 4 0 m g will be use d i n or der t o o pti m ize t he efficac y/t o xicit y bala nce i n 
t he ver y se nsiti ve p o p ulati o n of T KI- naï ve patie nts wit h E G F R m utati o ns. Varia bilit y is e x pecte d i n 
t he i nci de nce a n d se verit y of a d verse e ve nts a n d t o e ns ure ma xi m u m E G F R i n hi biti o n, d ose escalati o n 
t o 5 0 m g will be all o we d after t he first c o urse of treat me nt ( 2 8 da ys) i n patie nts wit h mi ni mal 
treat me nt-relate d a d verse e ve nts. T his d ose escalati o n strate g y has bee n use d bef ore, partic ularl y i n t he 
o n g oi n g lar ge i nter nati o nal p hase III ra n d o mize d trial of BI B W 2 9 9 2 vers us c he m ot hera p y i n patie nts 
wit h E G F R m utati o ns ( L U X- L u n g 3).  
 
T he A d verse E ve nts ( A Es) o bser ve d t o date i n P has e I a n d P hase II trials are c o nsiste nt wit h t h ose 
re p orte d f or ot her E G F R t yr osi ne kinase i n hi bit ors ( d ose de pe n de nt diarr hea a n d s ki n-relate d a d verse 
e ve nts i ncl u di n g ras h a n d ac ne). Ot her A Es were i n t he e x pecte d ra n ge f or patie nts wit h a d va nce d 
ca ncer disease (ref i n vesti gat or’s br oc h ure). I n t he BI B W 2 9 9 2 P has e I m o n ot hera p y trials, t he m ost 
fre q ue nt dr u g-relate d a d verse e ve nts were ass ociate d wit h gastr oi ntesti nal dis or ders ( diarr hea, na usea, 
v o miti n g, st o matitis), s ki n a n d s u bc uta ne o us tiss ue di s or ders (ras h, dr y s ki n, pr urit us, ac neif or m ras h, 
a n d ac ne), ge neral dis or ders a n d a d mi nistrati o n s ite c o n diti o ns (fati g ue, m uc osal i nfla m mati o n), 
res pirat or y dis or ders (e pista xis, t y picall y gra de 1), a n d meta b olis m a n d n utriti o nal dis or ders (a n ore xia, 
de h y drati o n). 
 
Diarr hea is t he si n gle m ost ofte n re p orte d gastr o i ntesti nal A E. A n i ncrease d i nci de nce of diarr hea 
gra de 3 has bee n o bser ve d i n p hase  II m o n ot hera p y trials (startin g d ose of 5 0 m g q d). Pr o m pt a n d 
pr oacti ve ma na ge me nt of diarr hea t o get her wit h ti mel y treat me nt pa us e a n d d ose re d ucti o n is cr ucial t o 
re d uce t he se verit y of diarr hea a n d its p ote ntial c o m plicati o ns s uc h as de h y drati o n lea di n g t o ser u m 
electr ol yte c ha n ges ( h y p o natrae mia, h y p o kalae mia a n d h y p o ma g nesae mia) a n d/ or re nal i m pair me nt. 
 
Na usea a n d v o miti n g are t he ot her c o m m o nl y re p orte d gastr oi ntesti nal  a d verse e ve nts a n d ca n be 
ge nerall y ma na ge d s uccessf ull y wit h t he use of a ntie metics. 
 
S ki n relate d a d verse e ve nts prese n t i n a n u m ber of f or ms, i.e., ras h (i ncl u di n g er yt he mat o us, mac ul o-
pa p ular, pa p ular, etc.), ac ne, der matitis ac neif or m, dr y s ki n, s ki n reacti o n a n d pr uritis. F ollic ulitis as 
well as nail c ha n ges (i ncl u di n g par o n yc hia) are ot her re p orte d ma nife stati o ns of s ki n-relate d a d verse 
e ve nts wit h BI B W 2 9 9 2. Earl y a n d a de q uate ma na ge me nt of s ki n-relate d a d ve rse e ve nts ca n re d uce 
t he fre q ue nc y a n d t he se verit y of t he m. 
 
F urt her A Es i ncl u de d oral disc o mf ort (st o matitis, m o ut h ulcerati o n, oral pai n, dr y m o ut h, s oft tiss ue 
dis or der) a n d m uc osal i nfla m mati o n. C o nj u ncti vitis a n d r hi n orr hea as a res ult of i nfla m mati o n i n t he 
m uc osal me m bra nes ha ve bee n re p orte d. M uc osal a n d s ki n dr y ness ca n lea d t o e pista xis, w hic h has t o 
date bee n o bser ve d at C T C A E Gra de 1. A n ore xia, fa ti g ue a n d ast he nia are als o fre q ue ntl y o bser ve d. 
 
Of 2 2 e val ua ble patie nts wit h N S C L C fr o m P hase I trials wit h BI B W 2 9 9 2, t here ha ve bee n f o ur 
partial res p o nses ( P Rs) ( 3 c o nfir me d a n d 1 u nc o nfir me d P R) ra n gi n g i n d urati o n fr o m 5 m o nt hs t o 2 4 
m o nt hs. All 4 patie nts were n o n-s m o ki n g Ca ucasia n wit h  a de n ocarci n o ma of t he l u n g. I n t w o of t hese 
t hree patie nts wit h c o nfir me d P R, E G F R seq ue nci n g has s h o w n e x o n 1 9 i n-fra me deleti o ns. 
 
T he efficac y a n d safet y of BI B W 2 9 9 2 i n N S C L C patie nts wit h E G F R m utati o ns is u n der e val uati o n i n 
a p hase II trial ( L U X- L u n g 2). I n t his trial, patie nts wit h Sta ge III B/I V l u n g a de n ocarci n o ma wit h 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
9
E G F R m utati o n i n e x o ns 1 8- 2 1 a n d fa il ure of o ne li ne of s yste mic c he m ot hera p y were treate d wit h 
BI B W 2 9 9 2 at a d ose of 5 0 m g o nce dail y u ntil disease pr o gressi o n. 5 T he trial u n der we nt t w o maj or 
a me n d me nts. T he first was t o decrease t he starti ng d ose t o 4 0 m g o nce dail y a n d t he sec o n d was t o 
all o w i ncl usi o n of c he m ot hera p y- n aï ve patie nts. 1 2 9 patie nts were e n r olle d. Preli mi nar y res ults were 
prese nte d i n A u g ust 2 0 0 9 at t he W orl d C o n gress o n L u n g Ca ncer. T he res p o nse rate was 6 3 % i n t he 
first-li ne patie nts a n d 6 6 % i n t he sec o n d-li ne patie nts. Diarr hea a n d s ki n-relate d a d verse e ve nts ha ve 
bee n t he mai n si de effects b ut ha ve bee n ma na gea b le wit h a p pr o priate d ose i nterr u pti o n/re d ucti o n. T he 
i nci de nce of gra de 3 diarr hea was l o wer at 4 0 m g (4. 3 %) t ha n at 5 0 m g ( 3 0 %). S ur vi val data are n ot 
yet mat ure f or a nal ysis. 
 
A gl o bal, ra n d o mize d, p hase III trial ( L U X- L u n g 3) is c urre ntl y o n g oi n g a n d is assessi n g t he 
pr o gressi o n-free s ur vi val differe nce bet wee n first- li ne BI B W 2 9 9 2 a n d first-li ne c he m ot hera p y wit h 
cis plati n a n d pe metre xe d i n N S C L C patie nts wit h E G F R m utati o ns. 
 
2. 2  St u d y Dise ase 
2. 2. 1  N o n- S m all Cell L u n g C a ncer, E G F R M ut ati o ns, a n d T yr osi ne Ki n ase I n hi bit ors 
 
N o n-s mall cell l u n g ca ncer ( N S C L C) is t he m ost c o m m o n ca use of ca ncer m ortalit y i n me n a n d 
w o me n i n t he U. S. A p pr o xi matel y 1 7 0, 0 0 0 A merica ns will be dia g n ose d wit h N S C L C t his year a n d 
a p pr o xi matel y half of t he m will ha ve a d va nce d or metastatic disease at prese ntati o n, w hic h is n ot 
c ura ble. C he m ot hera p y a n d bi ol o gicall y tar gete d a ge nts ca n e xte n d s ur vi val m o destl y f or t hese 
patie nts; h o we ver, disc o ver y of n o vel wa ys t o pr ol o n g t he disease c o urse is a t o p researc h pri orit y. 
 
T he e pi der mal gr o wt h fact or rece pt or ( E G F R) si g nali n g pat h wa y pla ys a ce ntral r ole i n t he ne o plastic 
tra nsf or mati o n of N S C L C a n d pr o motes ca ncer cell s ur vi val, meta stasis, a n d a n gi o ge nesis. T he 
pre d o mi na nce of E G F R si g nali n g i n N S C L C ma kes t he pat h wa y a n attracti ve ca n di date f or t he 
de vel o p me nt of tar gete d t hera pe utics. I n t he last si x years, t he F D A has ap pr o ve d t w o dr u gs i n t his 
class f or sal va ge treat me nt of N S C L C, gefiti ni b (Iressa ®, f or merl y k n o w n as Z D 1 8 3 9) a n d erl oti ni b 
( Tarce va ®, f or merl y k n o w n as O SI- 7 7 4). B ot h are s mall m olec ule orall y- bi oa vaila ble t yr osi ne ki nase 
i n hi bit ors ( T KIs) of t he E G F R T K d o mai n. Erl oti ni b i m pr o ves s ur v i val c o m pare d t o place b o w he n 
a d mi nistere d after fail ure of first li ne or sec o n d li ne c he m ot hera p y f or a d va nce d N S C L C a n d is 
c urre ntl y a p pr o ve d f or t hat i n dicati o n. 6 Gefiti ni b recei ve d accelerate d a p pr o val f or sal va ge treat me nt of 
N S C L C base d o n res p o nse t o treat me nt a n d s y m pt o m i m pr o ve me nt i n p hase II cli nical trials. A 
ra n d o mize d place b o-c o ntr olle d trial faile d t o de m o nstrate a s ur vi val be nefit a n d gefiti ni b is n o w o nl y 
a vaila ble i n t he U S if partici pati n g i n a cli nical trial, t h o u g h it is wi del y use d else w here i n t he w orl d. 7 
 
O ur gr o u p a n d ot hers descri be d s o matic m utati o ns i n t he E G F R  ge ne t hat se nsitize N S C L C t u m ors t o 
T KIs, prese nt i n a b o ut 1 0 % of u nselecte d U S patie n ts wit h N S C L C b ut i n u p t o 5 0 % of ne ver-s m o ki n g 
N S C L C patie nts. 8- 1 1 Acti vati n g E G F R m utati o ns pri maril y c o nsist of o verla p pi n g deleti o n m utati o ns i n 
t he L R E A re gi o n of e x o n 1 9 or t he p oi nt s u bstit uti o n m utati o n L 8 5 8 R i n e x o n 2 1, t h o u g h t here are 
se veral ot her rare acti vati n g m utatio ns descri be d i n t he literat ure. 1 2 E G F R m utati o ns c o nfer a state of 
“ o nc o ge ne a d dicti o n” o n t he m olec ular bi ol o g y of t he t u m or, s uc h t hat t he critical d o w nstrea m 
si g nali n g pat h wa ys are s olel y c o ntr olle d b y E G F R an d are t heref ore hi g hl y s u sce pti ble t o cell deat h b y 
bl oc ka de of E G F R. 1 3, 1 4O ur gr o u p has pre vi o usl y de m o nstrate d t hat patie nts wit h a d va nce d N S C L C 
a n d E G F R m utati o ns treate d wit h first-li ne gefi niti b ha ve a me dia n pr o gressi o n free s ur vi val of 9. 2 
m o nt hs, a n d me dia n o verall  s ur vi val of 1 7. 5 m o nt hs. 1 5 T his st u d y is c o nsiste nt wit h ot her trials usi n g 
E G F R- T KI treat me nt i n patie nts wit h m utati o ns, w h ic h de m o nstrate res p o nse rates > 5 0 % a n d ti me t o 
pr o gressi o n of > 9 m o nt hs 1 6- 2 0   

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
1 0
 
S uc h a “ ge n ot y pe- directe d” treat me nt strate g y has n o w bee n pr o ve n effecti ve i n 2 ra n d o mize d trials. 
T he I P A S S st u d y was c o n d ucte d i n Asia w her e E G F R m utati o n i nci de nce is hi g her. 2 1 All patie nts were 
n o n-s m o kers or f or mer li g ht s m o kers ( q uit at least 1 5 years pri or a n d ≤ 1 0 pac k years hist or y) a n d all 
ha d ne wl y- dia g n ose d a d va nce d a de n ocarci n o ma. Patie nts were ra n d o ml y assi g ne d t o fr o nt-li ne 
gefiti ni b or fr o nt-li ne c he m ot hera p y wit h car b o plati n a n d pacl ita xel. T he st u d y utilize d a n o n-
i nferi orit y desi g n p o were d t o de m onstrate t hat t he 9 5 % c o nfi de nce i nter val ( CI) f or t he hazar d rati o 
( H R) f or P F S of gefiti ni b c o m pare d t o c he m ot herap y la y e ntirel y bel o w t he tar get of 1. 2. T he o verall 
P F S H R was 0. 7 4 ( 9 5 % CI 0. 6 5- 0. 8 5), s h o wi n g t hat gefiti ni b was n ot o nl y n o n-i nferi or, b ut was 
act uall y s u peri or t o c he m ot hera p y. E ve n m ore ill ust rati ve was t he m olec ular s u b- gr o u p a nal ysis. E G F R 
m utati o n stat us was a vaila ble f or 3 6 % of patie nts a n d t he m utati o n- p ositi ve rate was 6 0 % i n t his 
cli nicall y-e nric he d st u d y. F or m u tati o n- p ositi ve patie nts t he res ults fa v ore d gefti ni b e ve n m ore 
str o n gl y, wit h a P F S H R of 0. 4 8 (9 5 % CI 0. 3 6- 0. 6 4). C o n versel y, f or m utati o n- ne gati ve patie nts, 
c he m ot hera p y was a better treat me nt wit h a P F S H R  of 2. 9 5 ( 9 5 % CI 2. 0 5- 3. 9 8). I n ot her w or ds, f or 
patie nts k n o w n t o har b or a n E G F R m utati o n, gefi ti ni b was m ore effecti ve t ha n car b o plati n a n d 
paclita xel wit h re gar ds t o P F S, b ut f or patie nts w h o fit t he “cli nical p he n ot y pe” of a T KI-res p o n der, t he 
ge n ot y pe tr u m pe d t he p he n ot y pe a n d T KI t hera p y di d n ot ha ve a g o o d o utc o me. T his la n d mar k st u d y 
ar g ues t hat patie nts wit h a m o derate c ha nce of ha r b ori n g a n E G F R m utati o n s h o ul d u n der g o m olec ular 
testi n g at t he ti me of dia g n osis, a n d if a n E G F R m utati o n is i de ntifie d, t hera p y wit h a n E G F R T KI 
s h o ul d be str o n gl y c o nsi dere d.  
 
T he ot her rece nt ra n d o mize d st u d y re gar di n g a ge n ot y pe- directe d treat me nt strate g y was p u blis he d i n 
a bstract f or m o nl y t h us far a n d is  a s maller st u d y, b ut all patie nts e nr olle d were p ositi ve f or a n E G F R 
m utati o n s o t he m olec ular res ults are n ot a s u b gr o u p a nal ysis b ut t he e ntire st u d y c o h ort. 2 2 T his trial 
c o nsiste d of Ja pa nese patie nts wit h ne wl y dia g n os e d a d va nce d a de n ocarci n o ma wit h E G F R m utati o ns 
ra n d o mize d t o fr o nt-li ne gefiti ni b or fr o nt-li ne c he m ot hera p y wit h car b o plati n a n d paclita xel. T he 
pri mar y e n d- p oi nt was a gai n P F S a n d t he st u d y was p o w ere d f or 3 2 0 patie nts a n d a n a ntici pate d H R of 
0. 6 9, fa v ori n g gefiti ni b. A n i nteri m a nal ysis after 2 0 0 pa tie nts de m o nstrate d a benefit f or gefiti ni b wit h 
H R 0. 3 6 ( 9 5 % CI 0. 2 5- 0. 5 1). 
 
I n s u m, t hese st u dies s u g gest t hat patie nts har b ori n g a n E G F R m utati o n derive si g nifica nt cli nical 
be nefit fr o m treat me nt wit h E G F R- T KIs. As a res u lt, E G F R T KI t hera p y is t he e mer gi n g sta n dar d of 
care treat me nt f or t his p o p ulatio n, i ncl u di n g as fr o nt li ne t hera p y. T he E ur o pea n U ni o n’s me dici ne 
a d mi nistrati o n rece ntl y gra nte d a p pr o val of gefiti ni b s pecificall y f or patie nts har b ori n g a n E G F R 
m utati o n a n d se veral o nc ol o g y care g ui deli nes i n t he U S are bei n g m o difie d t o i ncl u de E G F R m utati o n 
scree ni n g a n d c o nsi derati o n of a n E G F R T KI f or t hese patie nts.  
2. 2. 2  De vel o p me nt of Resist a nce,  T 7 9 0 M, a n d BI B W 2 9 9 2 
O ne cli nical o bstacle t o E G F R T KI t hera p y is t hat a ll patie nts t hat be nefit fr o m T KI treat me nt ulti matel y 
de vel o p dr u g-resista nce ma nifesti n g as pr o gressi o n of t h eir ca ncer. O n a vera ge t his  occ urs after a me dia n 
of 9- 1 2 m o nt hs. 1 5- 1 9, 2 1, 2 3 T here is vast cli nical p ote ntial i n u n dersta n di n g t he mec ha nis ms of T KI 
resista nce a n d de vel o pi n g strate gies t o re verse or pre ve nt it. 
 
T w o mai n mec ha nis ms of ac q uire d resista nce ha ve bee n i de ntifie d. T he first is a sec o n dar y E G F R 
m utati o n, T 7 9 0 M, t hat re n ders gefiti ni b a n d erl oti ni b i neffecti ve i n hi bit ors of E G F R ki nase acti vit y, 
a n d t he sec o n d is a m plificati o n of t he M E T o nc o ge ne , w hic h acti vates Er b B 3- de pe n de nt acti vati o n of 
PI 3 K i n de pe n de nt of E G F R. 2 4- 2 7 E G F R T 7 9 0 M has bee n detecte d b ot h fr o m t u m ors of E G F R m uta nt 
N S C L C patie nts w h o ha ve de vel o pe d cli nical resist a nce t o gefiti ni b or erl oti ni b a n d fr o m i n vitr o 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
1 1
gefiti ni b-resista nt E G F R m uta nt cell li nes. 2 4- 2 6, 2 8, 2 9 T o date, t he E G F R T 7 9 0 M m utati o n is f o u n d i n 
r o u g hl y 5 0 % of t u m ors ( 2 4 of 4 8) fr o m patie nts t hat ha ve de vel o pe d ac q uire d re sista nce t o gefiti ni b or 
erl oti ni b. 2 6, 2 8, 2 9 
 
T he E G F R T 7 9 0 M m utati o n occ urs i n  a n a nal o g o us p ositi o n t o k n o w n resista nce m utati o ns t o i mati ni b 
i n ot her ki nases ( T 3 1 5I i n A B L, T 67 4I i n P D G F R A, a n d T 6 7 0I i n KI T). 3 0- 3 2 T he c o nser ve d t hre o ni ne 
resi d ue a m o n g t hese differe nt ki nases, l ocate d near t he ki nase acti ve site, is ofte n referre d t o as t he 
“ gate kee per” m utati o n. I n A B L, t he T 3 1 5I m utati o n ca uses a steric hi n dra nce a n d ca uses i mati ni b 
bi n di n g. 3 0, 3 3 I n E G F R, t he T 7 9 0 M m utati o n i ncreases t he rece pt or’s affi nit y f or A T P, t here b y 
decreasi n g t he p ote nc y of t he A T P-c o m petiti ve i n hi bit ors, gefiti ni b a n d erl oti ni b. 3 4  
 
Ca ncers t hat bec o me resista nt t o ki nase i n hi bit ors t hr o u g h a sec o n dar y m utati o n ar e still li kel y t o be 
de pe n de nt o n t he acti vate d ki nase f or t heir gr o wt h a n d s ur vi val. T h us, alter nati ve strate gies of 
i n hi biti n g E G F R T 7 9 0 M ma y be t hera pe uticall y efficaci o us. T his has pr o m pte d t he precli nical a n d 
cli nical de vel o p me nt of sec o n d- ge nerati o n irre versi ble E G F R i n hi bit ors, s uc h as BI B W 2 9 9 2, w hic h 
ha ve s h o w n acti vit y i n gefiti ni b -resista nt precli nical m o dels of N S C L C c o ntai ni n g E G F R T 7 9 0 M.3 5- 3 7 
T hese irre versi ble T KIs are a ble t o i n hi bit E G F R p h os p h or ylati o n a n d lea d t o gr o wt h i n hi biti o n of cell 
li nes a n d xe n o graft m o dels c o ntaini n g E G F R T 7 9 0 M. Irre versi ble E G F R i n hi bit ors are als o A T P 
mi metics si milar t o gefiti ni b a n d erl oti ni b, b ut u nli k e gefiti ni b or erl oti ni b, t he y c o vale ntl y bi n d C ys-
7 9 7 of E G F R. H o w t he irre versi ble nat ure of t hese a ge nts all o ws t he m t o i n hi bit E G F R 
p h os p h or ylati o n is u nclear. It is p ossi ble t hat b y c o vale ntl y bi n di n g t o E G F R, t he l ocal c o nce ntrati o n 
of t hese a ge nts near t he acti ve site i ncreases b y se veral or ders of ma g nit u de (c o m pare d wit h gefiti ni b 
or erl oti ni b), t h us pr o vi di n g a m ea ns of i n hi biti n g E G F R p h os p h or yla ti o n des pite t he prese nce of a 
T 7 9 0 M m utati o n. 
 
W hile t he pre-cli nical e vi de nce f or acti vit y of BI B W 2 9 9 2 i n N S C L C wit h b ot h acti vati n g E G F R 
m utati o ns a n d T 7 9 0 M is pr o misi n g, it re mai ns u n k n o w n if BI B W 2 9 9 2 ca n o verc o me t he T 7 9 0 M 
m utati o n i n l u n g ca ncer patie nts. T h is st u d y will deter mi ne if treat ment wit h BI B W 2 9 9 2 pre ve nts t he 
ac q uisiti o n of a T 7 9 0 M resista nce m utati o n 
 
2. 3  
M olec ul ar Tec h ni q ues B ac k gr o u n d 
2. 3. 1  S N a Ps h ot Ge n ot y pi n g Pl atf or m 
 
Rece ntl y, M G H i m ple me nte d a m ulti ple x m olec ular dia g n ostics platf or m ( S Na Ps h ot). T his assa y 
utilizes f or mali n-fi xe d paraffi n-e m be d de d tiss ue t o q uic kl y a n d ec o n o micall y i de ntif y 5 8 c o m m o nl y 
m utate d l oci i n 1 3 ke y o nc o ge nes: E G F R, K- R A S,  N- R A S, A P C, B R A F, F L T 3, J A K 2, Kit, N otc h, 
PI 3 K, P T E N, T P 5 3, a n d beta-cate n i n. T he D N A of i nterest is a mplifie d usi n g m ulti ple xe d P C R. 
Ge n ot y pes are deter mi ne d usi n g a si n gle- base e xte ns i o n se q ue nci n g reacti o n, i n w hic h allele-s pecific 
pr o bes i nterr o gate l oci of  i nterest a n d are e xte n de d b y fl u oresce ntl y la bele d di de o x y n ucle oti des. T he 
allele-s pecific pr o bes ha ve differe nt sizes a n d are s u bse q ue ntl y res ol ve d b y electr o p h oresis a n d 
a nal yze d b y a n a ut o mate d D N A se q ue ncer. A m p lificati o ns of E G F R, H E R 2, a n d M E T a n d 
tra nsl ocati o ns i n A L K are assesse d usi n g m ultic ol or FI S H assa ys. T he S Na Ps h ot pr ofile has bee n 
vali date d a n d is perf or me d i n a C LI A-certifie d la b. It is use d i n place of r o uti ne E G F R a n d K- R A S 
m utati o n testi n g at o ur ce nter, as  it pr o vi des a d diti o nal i nf or matio n t hat ma y be use d t o i de ntif y 
s pecific ge netic a b n or malities t hat c orrelate wit h t u m or res p o nse t o  n o vel treat me nts.  
 
Bi o psies perf or me d f or t his st u d y at c olla b orati n g ce nters will u n der g o m olec ular a nal ysis at M G H. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
1 2
2. 3. 2  Circ ul ati n g T u m or Cell ( C T C)- C hi p 
 
T he a bilit y t o metastasize is o ne  of t he hall mar ks of mali g na nc y, a n d t h o u g h its mec ha nis ms are n ot 
f ull y descri be d, circ ulati n g t u m or cell ( C T C) distri b uti o n t hr o u g h t he bl o o dstrea m a p pears t o be a vital 
ste p i n t he pr ocess.3 8, 3 9 S uccessf ul ca pt ure a n d c haracterizati o n of C T Cs has tre me n d o us p ote ntial as a 
ve hicle t o better u n dersta n d t he bi ol o g y of t he metastatic pr ocess, a n d pr o vi des a n a ve n ue t o e x pl ore 
n u mer o us cli nical a p plicati o ns via n o n-i n vasi ve, patie nt-s pecific ge n o mic a nal ysis. U nli ke t u m or-
deri ve d cells i n b o ne marr o w, w hic h ca n be d or ma nt a n d l o n g-li ve d, C T Cs ha ve  a s h ort half-life ( < 1 
da y) a n d t heir prese nce i n dicates a rece nt i nfl u x fr o m a n acti ve pr oliferati n g t u m or.4 0 He nce, C T Cs 
ma y reflect t he cli nical stat us of ca ncer patie nts i n a d y na mic fas hi o n, a n d c o ul d p ote ntiall y be usef ul 
i n t he earl y detecti o n of res p o nse t o t hera p y.  
 
At t he M G H Ca ncer Ce nter, i n vesti g at ors ha ve de vel o pe d a de vice call e d a “ C T C-c hi p” t o ca pt ure a n d 
q ua ntif y C T Cs fr o m patie nt bl o o d sa m ples. T he C T C-c hi p is a micr ofl ui dic platf or m i n w hic h w h ole 
bl o o d tra vels t hr o u g h a f orest of micr o n-size d E p C A M a nti b o d y-c oate d micr o p osts u n der precisel y 
c o ntr olle d la mi nar fl o w c o n diti o ns. T he arra n ge me nt  a n d fl o w d y na mics of t he micr o p ost arra y g ui des 
t he cells ge ntl y t hr o u g h t he c hi p an d facilitates fre q ue nt i nteracti o ns wit h t he E p C A M a nti b o d y-c oate d 
micr o p osts, res ulti n g i n ca pt ure of via ble C T Cs dire ctl y t o t he p osts. We ha ve de m o nstrate d t hat t he 
C T C-c hi p ca n attai n s uccessf ul ca pt ure of a n a vera g e of 1 0 0 via ble C T Cs per m L of w h ole bl o o d fr o m 
9 9 % of teste d a d va nce d N S C L C pati e nts, a n d t hat detecti o n of E G F R m utati o ns fr o m is olate d C T Cs is 
feasi ble a n d c orrelates wit h t u m or tiss ue sa m ple testi n g.4 1, 4 2 F urt her m ore, we s h o we d t hat usi n g a n 
ultrase nsiti ve allele-s pecific assa y (t he S A R M S assa y, b y D X S) t o l o o k f or E G F R m utati o ns i n t he 
dia g n ostic t u m or tiss ue sa m ples, we i de ntifie d a si g nifica nt pr o p orti o n of patie nts t hat ha d b ot h 
acti vati n g E G F R m utati o ns a n d l o w le vels of det ecta ble T 7 9 0 M. T h o u g h t he T 7 9 0 M di d n ot precl u de a 
res p o nse t o E G F R T KI t hera p y, it di d c orrelate wit h a si g nifica ntl y s h orter pr o gressi o n-free s ur vi val 
( 7. 7 m o nt hs wit h detecta ble T 7 9 0 M c om pare d t o 1 6. 5 m o nt hs wit h o ut, p < 0. 0 0 1). 4 2 T his is c o nsiste nt 
wit h ot her st u dies s u g gesti n g t hat  T 7 9 0 M is prese nt at l o w le vels i n ma n y E G F R m uta nt ca ncers, 
t heref ore t hera p y wit h a n E G F R T KI t hat ca n n ot i n hi bit T 7 9 0 M all o ws m ore ra pi d selecti ve gr o wt h of 
t he resista nt cl o ne.4 3  
 
D ue t o t he nat ure of t his tec h n ol o g y ( nee ds t o be a nal yze d wit hi n h o urs of bl o o d dra w), o nl y patie nts 
e nr olle d o n t his st u d y at M G H will be a ble  t o s u b mit sa m ples f or C T C a nal ysis.  
2. 3. 3  I nter ve nti o n al R a di ol o g y Re pe at Bi o psies 
 
T he M G H De part me nt of Ra di ol o g y pr o vi des s u b-s pecialize d care base d o n or ga n s yste m. T he 
T h oracic I ma gi n g a n d I nter ve nti o nal Ra di ol o g y secti o n is direct e d b y Dr. J o- A n ne S he par d a n d 
i ncl u des 1 3 pr o vi ders, 6 of w h o m perf or m l u n g bi o psies o n a re g ular basis, t otali n g a p pr o xi matel y 2 6 0 
pr oce d ures per year. T he t h oracic ser vice has a 4-sl ice m ulti- detect or C T sca n ner s pecificall y de dicate d 
t o t h oracic i nter ve nti o nal pr oce d ures. T he A b d o mi nal I ma gi n g a n d I n ter ve nti o nal Ra di ol o g y secti o n is 
directe d b y Dr. Peter M ueller a n d i ncl u des 2 0 pr o vi ders, perf or mi n g a p pr o xi matel y 5 0 0 0 pr oce d ures 
per year. T he a b d o mi nal ser vice has 3 fl u or osc o pic u nits, 2 helical C T sca n ners, a n d 2 ultras o u n d u nits 
s pecificall y de dicate d t o a b d o mi nal i nter ve nti o n.   
 
Si nce 2 0 0 3, a t otal of 1 7 1 9 l u n g/c hest bi o psies ha ve bee n perf or me d at M G H. C o m plicati o ns ha ve 
i ncl u de d p ne u m ot h ora x i n 3 1 5 ( 1 8. 3 %), p ne u m ot h ora x re q uiri n g c hest t u be i n 4 3 ( 2. 5 %), a n d 
he m o pt ysis i n 4 5 ( 2. 6 %). M ortalit y is ver y rare b ut ma y occ ur i n patie nts wit h si g nifica nt c o-
m or bi dities. Si nce 2 0 0 3 l u n g bi o psies ha ve res ulte d i n deat h f or o nl y 1 patie nt ( 0. 6 %). T hese 
c o m plicati o n rates are c o m para ble t o t h ose re p orte d b y ot her maj or aca de mic ce nters.  

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
1 3
 
O ver a 1 0- year peri o d, 3 5 5 9 li ver bi o psies ha ve b ee n perf or me d u n der C T or ultras o u n d g ui da nce at 
M G H b y t he GI/ G U i nter ve nti o nal ra di ol o g y ser vice; 1 6 3 7 f ocal li ver bi o psies ( w here a f ocal mass 
was sa m ple d) a n d 1 9 2 2 n o nf ocal ( w here li ver pare nc h y ma was sa m ple d f or diff use he patic disease). 
C o m plicati o ns are cate g orize d b y t he S ociet y of I nter v e nti o nal Ra di ol o g y criteria i nt o t hree cate g ories: 
1) mi n or: n o i nter ve nti o n nee de d or o ver ni g ht a d missi o n f or o bser vati o n o nl y; 2) maj or: re q uires 
t hera p y, > 4 8 h o ur h os pital a d missi o n, prol o n ge d h os pitalizati o n; or 3) deat h. 4 4 O ver a 1 0- year peri o d, 
t here were 3 2 c o m plicati o ns ( 0. 9 %): 1 3 mi n or ( 0. 3 %), 1 7 maj or ( 0. 5 %), a n d 2 deat hs ( 0. 0 6 %). O verall, 
t he c o m plicati o n rate of bi o psies at M G H b y i nter ve nti o nal ra di ol o g y is l o w. 
 
I nter ve nti o nal ra di ol o g y ser vices at c olla b orati n g i nstit uti o ns ha ve  si milar e x perie nce a n d safet y 
rec or ds. 
2. 4  
St u d y R ati o n ale 
 
As disc usse d a b o ve, N S C L C patie nts wit h E G F R m utati o ns are hi g hl y  li kel y t o res p o n d well t o E G F R 
T K i n hi biti o n wit h eit her first- ge nerati o n E G F R  T KIs (erl oti ni b, gefti ni b) or wit h t he sec o n d-
ge nerati o n irre versi ble i n hi bit or BI B W 2 9 9 2, b ut re sista nce ulti matel y de vel o ps. Fift y perce nt of 
resista nce t o first- ge nerati o n T KIs is d ue t o t he de vel o p me nt of a sec o n dar y E G F R m utati o n i n e x o n 
2 0, t he p oi nt m utati o n T 7 9 0 M. T h o u g h i n itiall y vie we d as a cl o nal p o p ulati o n arisi n g i n res p o nse t o 
T KI t hera p y, ne wer researc h s u g gests t hat T 7 9 0 M is prese nt i n a s mall fracti o n of cells pri or t o 
treat me nt wit h first- ge nerati o n T KIs ( n ot detecta ble wit h sta n dar d bi- directi o nal se q u e nci n g). Si nce t he 
n o vel irre versi ble pa n- H E R i n hi bit or BI B W 2 9 9 2 is  hi g hl y acti ve i n l u n g ca ncers har b ori n g acti vati n g 
E G F R m utati o ns a n d ca n i n hi bit t h e E G F R T 7 9 0 M m oiet y i n pre-cli n ical st u dies, a ke y q uesti o n is 
w het her BI B W 2 9 9 2 ca n s u p press t he de vel o p me nt of cli nical resista nce via T 7 9 0 M i n l u n g ca ncer 
patie nts. T he o bjecti ves of t his  pil ot st u d y are t o esti mate t he effecti ve ness of BI B W 2 9 9 2 at 
s u p pressi n g t he de vel o p me nt of t he T 7 9 0 M resista nce m utati o n i n l u n g ca ncer patie nts. We will o btai n 
a ma n dat or y re peat t u m or bi o ps y at t he ti me of c li nical pr o gressi o n a n d deter mi ne t he pr o p orti o n of 
patie nts t hat ha ve a T 7 9 0 M m utati o n. T h is rate of m utati o n will be c o m pare d t o t he 5 0 % hist orical data 
o bser ve d after de vel o p me nt of resista nce t o  re versi ble first- ge nerati o n E G F R T KIs. 
 
3.  P A R TI CI P A N T S E L E C TI O N 
 
3. 1  
Eli gi bilit y Criteri a 
 
Partici pa nts m ust meet t he f oll o wi n g criteria  o n scree ni n g e xa mi nati o n t o be eli gi ble t o 
partici pate i n t he st u d y: 
 
3. 1. 1  Partici pa nts m ust ha ve hist ol o gicall y or c yt ol o gicall y c o nfir me d sta ge III B, I V, or 
rec urre nt n o n-s mall cell l u n g ca ncer 
 
3. 1. 2  A s o matic m utati o n i n e pi der ma l gr o wt h fact or rece pt or ( EG F R) m ust be prese nt as 
d oc u me nte d b y a C LI A-certifie d la b orat or y.  
 
3. 1. 3  T here m ust be ra di o gra p hic meas ura ble or e val ua ble disease  
 
3. 1. 4  Partici pa nts m ust be willi n g, at t he ti me of si g ni n g c o nse nt, t o a gree t o a f ut ure bi o ps y of 
t heir t u m or tiss ue at t he ti me of disease pr o gressi o n, pr o vi de d s uc h a bi o ps y is safe a n d 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
1 4
feasi ble at t hat ti me. T his bi o ps y will be s u bjecte d t o ge ne tic a nal yses t o atte m pt t o 
i de ntif y t he mec ha nis m of ac q uire d dr u g resista nce. 
 
3. 1. 5  Perf or ma nce stat us m ust be 0, 1 or 2 o n t he Easter n C o o pe rati ve O nc ol o g y Gr o u p scale4 5 
 
3. 1. 6  A ge m ust be ≥ 1 8 years 
 
3. 1. 7  Partici pa nts m ust ha ve n or mal or ga n a n d marr o w f u ncti o n as defi ne d bel o w: 
 A bs ol ut e n e utr o p hil c o u nt >  1, 5 0 0/ mc L 
 Pl at el ets >  1 0 0, 0 0 0/ mc L 
 A S T ( S G O T)/ A L T ( S G P T) <  3 X i nstit uti o n al u p p er limit of n or mal ( U L N) or, 
if li v er met ast ases pr es e nt ≤ 5 X U L N 
 T ot al bilir u bi n ≤ 1. 5 X U L N 
    Cr e ati ni n e ≤ 1. 5 X U L N or cr e ati ni ne cl e ar a nce > 6 0 m L/ mi n/ 1. 7 3 m2 f or 
s u bj e cts wit h cr e ati ni ne l e vels ≥ 1. 5 x U L N                  . 
3. 1. 8  T he effects of BI B W 2 9 9 2 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 me n m u st a gree t o use a de q uate c o ntrace pti o n 
( h or m o nal or barrier met h o d of birt h c o ntr ol; a bsti ne nce) 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 treati n g p h ysicia n 
i m me diatel y. 
 
 
 
3. 1. 9  Partici pa nts m ust ha ve t he a bilit y t o u n de rsta 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. 
 
3. 2  
E x cl usi o n C rit e ri a 
 
Partici pa nts w h o e x hi bit a n y of t he f oll o wi n g c o n d iti o ns at scree ni n g will n ot be eli gi ble f or 
a d missi o n i nt o t he st u d y. 
 
3. 2. 1  Pri or E G F R t yr osi ne ki nase i n hi bit or t hera p y (i ncl u di n g gefiti ni b, erl oti ni b, or a n y 
e x peri me ntal E G F R T KI a ge nts) 
 
3. 2. 2  K n o w n brai n metastases, u nless t he y ha ve u n der g o ne defi niti ve t hera p y a n d are 
ne ur ol o gicall y sta ble at t he ti me of st u d y e ntr y 
 
3. 2. 3  Sta n dar d c he m ot hera p y or ra diati o n ≤ 2 wee ks of starti n g BI B W 2 9 9 2, or e x peri me ntal 
s yste mic ca ncer t hera p y ≤ 4 wee ks of starti n g BI B W 2 9 92. N ote t hat pri or palliati ve 
ra diati o n t o b o n y disease, C N S disease, or a limite d t h oracic area is o nl y all o we d if t here 
is meas ura ble or pr o gressi ve disease o utsi de t he fiel d of ra diati o n. 
 
3. 2. 4  A n ot her mali g na nc y wit hi n t he last 3 years (e xce pt n o n- mela n o ma s ki n ca ncer or a n o n-
i n vasi ve/i n sit u ca ncer) 
 
3. 2. 5  K n o w n pre-e xisti n g a n d cli nicall y acti ve i nterstitial l u n g disease 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
1 5
 
3. 2. 6  Si g nifi ca nt g astr oi nt esti n al dis or ders wit h diarr h e a as a maj or s y m pt o m (e. g. Cr o h n’s 
dis e as e, mal a bs or pti o n, et c) 
 
3. 2. 7  Hist or y of cli ni c all y r el e v a nt car di o vas c ul ar a b n or m aliti es s u c h as u n c o ntr oll e d 
h y p ert e nsi o n, c o n g esti v e h e art f ail ur e N Y H A cl assifi c ati o n of 3, u nst a bl e a n gi n a or 
p o orl y c o ntr oll e d arr h yt h m i a, or m y o c ar di al i nfar cti o n wit hi n 6 m o nt hs. 
 
 
3. 2. 8  A n y ot h er c o n c o mit a nt s eri o u s ill n ess or or ga n s yst e m d ysf u n cti o n w hi c h i n t h e 
o pi ni o n of t h e i n v esti g at or w o ul d eit her c o m pr o mis e pa ti e nt s afet y or i nt erf er e wit h 
t h e e v al u ati o n of t h e s afet y of t h e st u d y dr u g. 
 
3. 2. 9  Pr e g n a n c y or br e ast f e e di n g.  
 
3. 2. 1 0  I n a bilit y t o c o m pl y wit h t he pr ot oc ol 
 
3. 2. 1 1  Partici pa nts ma y n ot be recei vi n g a n y ot her i n vesti gati o nal a ge nts d uri n g t he c o urse of 
BI B W 2 9 9 2 t hera p y. 
 
3. 2. 1 2  Hist or y of aller gic reacti o ns attri b ute d t o c o m p o u n ds of si milar c he mical or bi ol o gic 
c o m p ositi o n t o BI B W 2 9 9 2 . 
 
3. 2. 1 3  Lif e e x p e ct a n c y < 1 2 wee ks 
3. 3  
I ncl usi o n of W o me n, Mi n orities a n d Ot her U n derre prese nte d P o p ul ati o ns 
 
L u n g ca ncer affects me n a n d w o me n, a n d pe o ple of all race a n d s oci oec o n o mic class. We d o n ot 
e x pect t he i ncl usi o n a n d e xcl us i o n criteria t o ne gati vel y affect e nr oll me nt of u n derre prese nte d 
p o p ulati o ns. 
 
4.  R E GI S T R A TI O N P R O C E D U R E S 
 
4. 1  
Ge ner al G ui deli nes f or D F / H C C a n d D F/ P C C I nstit uti o ns 
 
I nstit uti o ns will r e gist er eli gi bl e p arti ci p a nts wit h t h e D F/ H C C Q u alit y Ass ur a n ce Offi ce 
f or Cli ni cal Tri als ( Q A C T) c e ntr al r e gistr ati o n s yst e m. R e gistr ati o n m ust o c c ur pri or t o 
t h e i niti ati o n of t h er a p y. A n y partici pa nt n ot r e gist er e d t o t h e pr ot o c ol b ef or e tr e at m e nt 
b e gi ns will b e c o nsi d er e d  i n eli gi bl e a n d r e gistr ati o n will be de ni e d.  
 
A m e m b er of t h e st u d y t e a m will c o nfir m eli g i bilit y crit eri a a n d c o m pl et e t h e pr ot o c ol-
s p e cifi c eli gi bilit y c h e c klist. 
  
F oll o wi n g r e gistr ati o n, p arti ci p a nts m a y b e gi n pr ot o c ol tr e at m e nt. Iss u es t h at w o ul d 
c a us e tr e at m e nt d el a ys s h o ul d b e dis c uss e d wit h t h e Pri n ci p al I n vesti gat or. If a partici pa nt 
d oes n ot recei ve pr ot oc ol t hera p y f oll o wi n g re gistrati o n, t he partici pa nt’s pr ot oc ol stat us m ust 
be c ha n ge d. N otif y t he Q A C T Re gistrar of parti c i p a nt st at us c h a n g es as s o o n as p ossi bl e. 
 
4. 2  R e gist r ati o n P r o c ess f or D F/ H C C a n d D F/ P C C I nstit uti o ns 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
1 6
 
T he Q A C T re gistrati o n staff is accessi ble o n M o n da y t hr o u g h Fri da y, fr o m 8: 0 0 A M t o 5: 0 0 
P M Easter n Sta n dar d Ti me. I n e mer ge nc y sit uat i o ns w he n a partici pa nt m ust be gi n treat me nt 
d uri n g off- h o urs or h oli da ys, call t he Q A C T  re gistrati o n li ne at 
 a n d f oll o w t he 
i nstr ucti o ns f or re gisteri n g partici pa nts after h o urs. 
   
T he re gistrati o n pr oce d ures are as f oll o ws: 
 
1.  
O btai n writte n i nf or me d c o nse n t fr o m t he partici pa nt pri or t o t he perf or ma nce of a n y 
st u d y relate d pr oce d ures or assess me nts. 
 
2.  
C o m plete t he pr ot oc ol-s pecific eli gi bilit y c hec klist usi n g t he eli gi bilit y assess me nt 
d oc u me nte d  i n  t he  partici pa n t’s  me dical/researc h  rec or d.  T o  be  eli gi ble  f or 
re gistr ati o n t o t he st u d y, t he p artici p a nt m ust meet e ac h i ncl usi o n a n d e xcl usi o n 
criteri a liste d o n t he eli gi bilit y c hec klist.  
 
3.  
Fa x t he eli gi bilit y c hec klist(s) a n d all pa ge s of t he c o nse nt f or m(s) t o t he Q A C T at 
 
  
E xce pti o n:  D F/ P C C Affiliate sites m ust fa x t he e ntire si g ne d c o nse nt f or m i ncl u di n g 
HI P A A Pri vac y A ut h orizati o n a n d t he eli gi b ilit y c hec klist t o t he Net w or k Affiliate 
Office. T he Net w or k Affiliate Office will re gister t he partici p a nt wit h t he Q A C T. 
  
4.  
T he Q A C T Re gistrar will (a) vali date eli gi b ilit y, ( b) re gister t he partici pa nt o n t he 
st u d y, a n d (c) ra n d o mize t he partici pa nt w he n a p plica ble. 
  
5.  
T he  Q A C T  Re gistrar  will  se n d  a n  e mail  c o nfir mati o n  of  t he  re gistrati o n  a n d/ or  
ra n d o mizati o n t o t he pers o n i nitiati n g t he re gistrati o n i m me diatel y f oll o wi n g t he 
re gistrati o n a n d/ or ra n d o mizati o n. 
 
4. 3  G e n e r al G ui d eli n es f o r Ot h e r P a rti ci p ati n g I nstit uti o ns 
 
Eli gi bl e p arti ci p a nts will b e  e nt er e d o n st u d y c e ntr all y at t h e M ass a c h us etts G e n er al 
H os pit al C a n c er C e nt er b y t h e St u d y C o or di n at o r. S e e s e cti o n 4. 4 as f or f ull i nstr u cti o ns. 
A c o p y of t h es e i nstr u cti o ns c a n als o b e f o u n d i n A p p e n di x 3 ( M u lti- C e nt er D at a S af et y 
M o nit ori n g Pl a n).  
 
F oll o wi n g r e gistr ati o n, p arti ci p a nts s h o ul d b e gi n pr ot o c ol tr e at m e nt wit hi n 7 2 h o urs or as 
s o o n as p ossi bl e. Iss u es t h at w o ul d c a us e tr e at m e nt d el a ys s h o ul d b e dis c uss e d wit h t h e 
Pri n ci p al I n vesti gat or. If a partici pa nt d oes n ot  recei ve pr ot oc ol t hera p y f oll o wi n g 
re gistrati o n, t he partici pa nt’s pr ot oc ol stat us m ust be c ha n ge d. T he St u d y C o or di nat or s h o ul d 
be n otifi e d of p arti c i pa nt st at us c ha n ges as s o o n as p ossi ble. 
 
E xce pt i n ver y u n us ual circ u msta nces, eac h partici pati n g i nstit uti o n will or der t he st u d y 
a g e nt(s) dir e ctl y fr o m t h e s u p pli er. A p arti ci p ati n g sit e m a y or d er t h e a g e nt(s)  o nl y after 
t he i nitial I R B a p pr o val f or t he site has bee n f or war de d b y t he C o or di nati n g Ce nter t o t he 
s u p plier. 
 
4. 4  
R e gist r ati o n Pr ocess f or Ot her P artici p ati n g I nstit uti o ns 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
1 8
T his st u d y e xa mi nes first li ne BI B W 2 9 9 2, a n irre versi b le d ual ki nase i n hi bit or, i n patie nts wit h 
a d va nce d N S C L C a n d E G F R m utati o ns. T he pri mar y e n d p oi nt is defi ni n g t he pr o p orti o n of patie nts 
wit h T 7 9 0 M o n a re peat t u m or tiss ue bi o ps y ta ke n at t he ti me of cli nical pr o gressi o n.  
5. 2  
I de ntific ati o n of t he I n vesti g ati o n al A ge nt 
 
S u bst a nce (I N N): BI B W 2 9 9 2 
P har mace utical f or m:  
Fil m-c oate d ta blets 
S o urce:  
B oe hri n ger I n gel hei m P har ma G m b H & C o. K G 
U nit stre n gt h:  
5 0 m g, 4 0 m g, 3 0 m g a n d 2 0 m g fil m-c oate d ta bl ets (t he d ose of 
BI B W 2 9 9 2 i n t he fil m-c oate d ta blet s is relate d t o t he free base 
e q ui vale nt of BI B W 2 9 9 2) 
Dail y D ose:  
Starti n g d ose 4 0 m g wit h i n di vi d ual d ose escala ti o n t o 5 0 m g if 
t olerate d 
D urati o n of use:  
C o nti n u o us dail y d os i n g u ntil pr o gressi o n, u nacce pta ble a d verse 
e ve nts or ot her reas o n n ecessitati n g wit h dra wal. F or 
a d mi nistrati ve p ur p oses treat me nt is di vi de d i nt o c ycles w hic h 
are eac h 4 wee ks ( 2 8 da ys) i n d urati o n. 
R o ute of a d mi nistrati o n:   
Oral (s wall o we d) 
Fre q ue nc y:  
O nce dail y, o n a n e m pt y st o mac h 
 
Treat me nt will be a d mi nistere d o n a n o ut patie nt basi s. N o i n vesti gati o nal or c o m mercial a ge nts or 
t hera pies ot her t ha n BI B W 2 9 9 2 ma y be a d mi nistere d wit h t he i nte nt t o treat t he partici pa nt’s 
mali g na nc y w hile t he y are partici pati n g o n t his trial. 
5. 3  
A d mi nistr ati o n of BI B W 2 9 9 2 
 
F or a d mi nistrati ve p ur p oses treat me nt will be di vi de d i nt o treat me nt c ycles, w hic h are eac h 4 wee ks 
( 2 8 da ys) i n d urati o n. Patie nts will ta ke a si n gle oral d ose of 4 0 m g BI B W 2 9 9 2 eac h da y f or t he first 
c ycle ( 2 8 da ys).  
 
T he me dicati o n s h o ul d be ta ke n at t he sa me ti me eac h  da y ( ± 2 h o urs) o n a n e m pt y st o mac h, w hic h is 
defi ne d as at least o ne h o ur bef o re f o o d i nta ke a n d at least t hree h o urs after fo o d i nta ke. T he ta blet 
s h o ul d be s wall o we d wit h a glass of water. BI B W 2 9 9 2 ta blets are fil m-c oate d a n d t heref ore s h o ul d 
n ot be c he we d or cr us he d. 
5. 3. 1  Misse d/ V o mite d D ose 
If a patie nt i na d verte ntl y d oes n ot ta ke BI B W 2 9 9 2 at t heir us ual ti me, he or s he ma y ta ke t heir dail y 
d oses a n yti me as l o n g as it is at least 1 2 h o urs bef ore  t he ne xt d ose is d ue t o be ta ke n. BI B W 2 9 9 2 s h o ul d 
be ta ke n o n a n e m pt y st o mac h, at least o ne h o ur bef ore f o o d i nta ke a n d at leas t t hree h o urs after f o o d 
i nta ke. T he dail y treat me nt sc he d ule will be res u me d t he ne xt  da y wit h t he patie nt ta ki n g t he sc he d ule d 
d ose at t he us ual ti me. If a n e ntire dail y d ose is s ki p pe d, t he patie nt s h o ul d res u me treat me nt t he 
f oll o wi n g da y wit h t heir re g ular d ose. N o “ ma ke- u p d ose” or i ncrease d d osi n g s h o ul d occ ur. If a d ose is 
v o mite d wit hi n 1 h o ur of a d mi nist rati o n, me dicati o ns t o c o ntr ol na usea a n d v o miti n g s h o ul d be use d, a n d 
t he d ose ca n be re peate d. Patie nts s h o ul d re p ort all v o mite d, misse d or dela ye d d oses t o t he st u d y staff 
a n d will be pr o vi de d wit h a me di cati o n diar y w hic h s h o ul d be t ur ne d i n at e ver y visit. 
5. 3. 2  I n a bilit y t o S w all o w Pills 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
1 9
BI B W 2 9 9 2 s h o ul d n ot be c he we d or cr us he d. If patie nts are tr ul y u na ble t o s wall o w t he ta blets after a n 
eff ort t o c o nf or m t o t he pr ot oc ol, t he st u d y dr u g ma y be diss ol ve d a n d s wall o we d after dis persi n g t he 
BI B W 2 9 9 2 ta blets acc or di n g t o t he f o ll o wi n g pr oce d ure: Place t he ta blet i nt o a glass co ntai ni n g 5 0 m L 
is ot o nic s o di u m c hl ori de s ol uti o n. Stir u ntil t he ta blet is br o ke n u p i nt o ver y fi ne particles (a b o ut 1 5 
mi n utes). Dri n k t he s us pe nsi o n i m me diatel y or a d mi nister  via a gastric t u be if a p plica ble. Ri nse t he glass 
wit h a n ot her 5 0 ml of is ot o nic s o di u m c hl ori de s o l uti o n a n d dri n k or a d mi nister t he s u p ple me ntar y 
s ol uti o n via t he gastric-t u be a gai n (t o pic k u p a n y dr u g re mai ni n g i n t he glass/ gastric-t u be). Is ot o nic 
s o di u m c hl ori de m ust be prescri be d b y t he i n vesti gat or if t his pr ot oc ol is t o be use d, a n d pr os pecti ve 
patie nt-s pecific per missi o n t o use t he diss ol vi n g pr ot oc ol m ust be o btai ne d fr o m t he l ocal I R B. 
5. 4  
I n di vi d u al P atie nt D ose Esc al ati o n t o 5 0 m g 
 
D uri n g t he first c ycle of t hera p y at 4 0  m g dail y, if t he patie nt e x perie nces ≥ Gra de 1 diarr hea, s ki n-
relate d a d verse e ve nts or m uc ositis or a n y dr u g-relate d e ve nt ≥ Gra de 2, t he d ose of BI B W 2 9 9 2 
s h o ul d be c o nti n ue d at 4 0 m g ( u nless d ose re d ucti o n is necessar y - see secti o n 5. 5). F or a descri pti o n 
of C T C A E gra di n g of t o xicities, see A p pe n di x 2. 
 
If n o ne of t he a b o ve e ve nts are e x perie nce d d uri n g t he first c ycle of treat me nt, t he d ose f or C ycle 2 
s h o ul d be i ncrease d t o 5 0 m g eac h da y. T he patie nt s h o ul d re mai n o n 5 0 m g f or s u bse q ue nt treat me nt 
c ycles, u nless d ose re d ucti o n is necessar y (see secti o n 5. 5). 
 
D ose escalati o n is pr o hi bite d i n a n y sit uati o n ot her t h a n t hat descri be d a b o ve. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
2 0
5. 5  D ose M o dific ati o n  
 
I n t he e ve nt of mil d ( grade 1 or tra nsie nt gra de 2) treat me nt-re late d t o xicities, BI B W 2 9 9 2 ma y be hel d 
f or u p t o 1 4 da ys a n d t he n restarte d at t he sa me d ose at t he i n vesti gat or’s discre ti o n. If t o xicit y is m ore 
se vere, meeti n g t he criteria o utli ne d bel o w, t he treat me nt wit h BI B W 2 9 9 2 s h o ul d be ha n dle d 
acc or di n g t o t he sc he d ule i n Ta ble 2.  
 
T a bl e 2. D os e R e d u cti o n S c h e m e 
 
A E t y pe a n d gr a de  
A cti o n 
D os e r e d u cti o n s c h e m e 
E ve nts relate d t o st u d y dr u g;  
• A n y dr u g rel ate d  A E 
C T C A E Gra de ≥3.  
• C T C A E Gra de ≥2 diarr hea 
persisti n g f or 2 or m ore 
c o nsec uti ve da ys ( 4 8 h o urs) 
des pite a de q uate a nti-
di arr he al 
me dicati o n/ h y drati o n.  
 
• C T C A E Gra de ≥2 na usea 
a n d/ or v o miti n g persisti n g 
f or 7 or m ore c o nsec uti ve 
da ys des pite a nti-e metic 
treat me nt/ h y drati o n.  
 
• C T C A E Gra de ≥2 
w orse ni n g of re nal f u ncti o n 
as meas ure d b y ser u m 
cr eati ni ne, ne wl y de vel o pe d 
pr otei n uria, or ne wl y 
de vel o pe d decrease i n 
gl o mer ular filtrati o n rate of 
m ore t ha n 5 0 % fr o m 
baseli ne.  
 
 
 
 
H ol d treat me nt wit h 
BI B W 2 9 9 2 u ntil 
patie nt has rec o vere d t o 
C T C A E Gra de ≤ 1 or 
baseli ne 1 . Res u me 
treat me nt at re d uce d 
d ose acc or di n g t o 
sc he d ule o p p osite. If 
pati e nt has n ot 
rec o vere d t o C T C A E 
Gra de ≤ 1 or baseli ne1 
wit hi n 2 8 da ys st u d y 
treat me nt s h o ul d be 
per ma ne ntl y 
disc o nti n ue d 2 . 
 
 
 
If patie nt was recei vi n g 5 0 
m g, res u me treat me nt at a 
d ose of 4 0 m g.  
 
If patie nt was recei vi n g 4 0 
m g, res u me treat me nt at a 
d ose of 3 0 m g.  
 
If patie nt was recei vi n g 3 0 
m g, res u me treat me nt at a 
d ose of 2 0 m g.  
 
If patie nt was recei vi n g 2 0 
m g, disc o nti n ue BI B W 
2 9 9 2.  
1 Baseli ne is defi ne d as t he C T C A E gra de at t he start of treat me nt 
2 I n t he e ve nt t hat t he patie nt is deri vi n g o b vi o us cli nical be nefit i n t he o pi ni o n of t he i n vesti gat or, b ut has n ot rec o vere d 
wit hi n 2 8 da ys of h ol di n g dr u g, t he f urt her treat me nt of t he patie nt ma y occ ur o nl y after c o ns ultati o n wit h t he pri nci pal 
i n vesti gat or a n d o btai ni n g per missi o n f or pr ot oc ol de viati o n fr o m t he I R B. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
2 1
 
I m p orta nt n otes re gar di n g d ose re d ucti o n: 
 
 If t he patie nt meets o ne of t he A E criteria o utli ne d i n t he left c ol u m n of ta ble 2, d ose re d ucti o n 
m ust occ ur after h ol di n g t he dr u g a n d all o wi n g t o xicities t o res ol ve t o C T C A E gra de 1 or 
baseli ne. 
 
 I n a d diti o n, patie nts m ust disc o nti n ue treat me nt if t he y e x perie nce deteri orati o n i n left 
ve ntric ular car diac f u ncti o n ( L V E F) t o C T C A E Gra de ≥3. 
 
 I n t he e ve nt of a pr ol o n ge d (≥7 c o nsec uti ve da ys) Gra de 2 dr u g-re late d e ve nt n ot liste d i n ta ble 
2, w hic h is p o orl y t olerate d b y t he patie nt, t h e i n vesti gat or ma y c h o ose t o h ol d BI B W 2 9 9 2 f or 
u p t o 2 8 da ys t o all o w t he patie nt t o rec o ve r, f oll o we d b y a d ose re d ucti o n acc or di n g t o t he 
sc he d ule i n ta ble 2. 
 
 I n t he e ve nt of a n a d verse e ve nt t hat is n ot relate d t o treat me nt or  a seri o us a d verse e ve nt t hat is 
n ot relate d t o treat me nt, or a n ot her reas o n at t he i n vesti gat or’s  discreti o n, t he i n vesti gat or ma y 
c h o ose t o pa use t he me dicati o n f or u p t o 7 da ys t o all o w t he patie nt t o rec o ver. N o ma n dat or y 
d ose re d ucti o n nee d occ ur i n t his case.  
5. 6  
C o m pli a nce a n d Acc o u nt a bilit y 
 
A dr u g diar y will be pr o vi de d t o eac h patie nt t hat  c orres p o n ds t o eac h c ycle of t hera p y. C o m plete d 
dr u g diaries will be c ollecte d o n a re g ular basis, c o m pare d wit h ret ur n e d pill c o u nts, a n d e val uate d f or 
c o m plia nce. At t h e e n d of t h e st u d y, u n us e d s u p p li es of BI B W 2 9 9 2 s h o ul d b e d estr o y e d a c c or di n g 
t o i nstit uti o n al p oli ci es. 
5. 7  
P ac k a gi n g, L a beli n g, Re-s u p pl y, a n d St or a ge 
 
BI B W 2 9 9 2 will be s u p plie d as fil m-c oate d ta blets.  A vaila ble d osa ge stre n gt hs will be 2 0 m g, 3 0 m g, 
4 0 m g a n d 5 0 m g. Ta blets will be s u p plie d i n H D P E, c hil d-resista nt, ta m per-e vi de nt b ottles. B ottles 
will be la bele d acc or di n g t o l ocal re g ulati o ns a n d will i ncl u de t he f oll o wi n g as a mi ni m u m: 
• St u d y n u m ber  
• Pr o d uct na me (e. g., BI B W 2 9 9 2) 
• C o nte nts of t he b ottle (e. g., 3 0 ta blets) 
• Ta blet stre n gt h 
• Batc h n u m ber 
• Use- b y date 
• St ora ge i nf or mati o n 
• I nstr ucti o ns f or use 
• S p o ns or na me a n d a d dress 
• A state me nt t hat t he me dicati o n is f or cli nical trial use o nl y 
• A ca uti o n state me nt 
 
A ne w b ottle of me dicati o n will be dis pe nse d o n da y 1 of eac h c ycle, re gar dless of t he n u m ber of 
ta blets re mai ni n g i n t he b ottle fr o m t he pre vi o us c ycle. T he patie nt will i nitiall y recei ve o ne b ottle of 
4 0 m g ta blets a n d i n t he e ve nt t hat d ose i ncrease or re d ucti o n is necessar y t he patie nt will ret ur n t o t he 
cli nic a n d ne w me dicati o n will be dis pe nse d. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
2 2
 
BI B W 2 9 9 2 m ust be st ore d i n t he ori gi nal pac ka g i n g. Fil m-c oate d ta blets are h u mi dit y se nsiti ve a n d 
t heref ore b ottles m ust be ke pt ti g htl y cl ose d. Ta blets will be st ore d at t he st u d y site i n a li mite d access 
area a n d m ust n ot be st ore d a b o ve 2 5º C.  
 
5. 8  
P r e-t r e at m e nt C rit e ri a 
 
5. 8. 1  C ycle 1, D a y 1 
 
Patie nts will be eli gi ble f or treat me n t wit h BI B W 2 9 9 2 at t he start of pr ot oc ol t hera p y if t he y meet all 
st u d y eli gi bilit y criteria. 
5. 8. 2  S u bse q ue nt C ycles 
 
Patie nts will be eli gi ble f or retreat me nt wit h BI B W 2 9 9 2 e ver y 2 8 da ys, pr o vi de d t hat a n y treat me nt-
relate d t o xicities re q uiri n g treat me nt dela y (see Secti o n 5. 5) ha ve res ol ve d t o ≤ gra de 1 or baseli ne 
wit hi n 2 8 da ys. If retreat me nt criteria are n ot met wit hi n t his peri o d, t he s u bject m ust be wit h dra w n 
fr o m t he st u d y. 
 
Patie nts ma y c o nti n ue o n st u d y treat me nt i n defi nitel y, i n t he a bse nce of meeti n g o ne of t he criteria f or 
disc o nti n uati o n fr o m st u d y treat me nt (see Secti o n 5. 1 0). 
 
5. 9  
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p orti ve C are G ui deli nes 
 
Patie nts s h o ul d n ot recei ve a n y a d diti o nal e x pe ri me ntal a nti-ca ncer treat me nt, c he m ot hera p y, 
i m m u n ot hera p y, h or m o ne treat me nt ( wit h t he e xce ptio n of me gestr ol acetate) or ra di ot hera p y (e xce pt 
palliati ve s h ort-c o urse ra di ot he ra p y t o n o n-tar get lesi o ns) bet wee n i nf or me d c o nse nt a n d t he e n d of 
treat me nt visit. 
 
Ot her s u p p orti ve me dicati o ns ma y be us e d as per i nstit uti o nal g ui deli nes. 
5. 9. 1  S u g geste d M a n a ge me nt of Di arr he a 
 
Cl ose m o nit ori n g a n d pr oacti ve ma na ge me nt of di arr hea is esse ntial f or s uccessf ul treat me nt of 
patie nts wit h BI B W 2 9 9 2. Earl y a n d a p pr o priate i nter ve nti o n ca n pr e ve nt t he de vel o p me nt of m ore 
se vere diarr hea. I n m ost cases, l o pera mi de (I mo di u m) c o ntr ols diarr hea ca use d b y BI B W 2 9 9 2.  
T he rec o m me n dati o ns f or ma na ge me nt are as f oll o ws: 
 If a n y diarr hea is e x perie nce d ( C T C A E Gra de 1), t w o 2 m g l o pera mi de ta blets (t otal d ose 4 
m g) s h o ul d be ta ke n i m me diatel y, f oll o we d b y o ne 2 m g ta blet wit h e ver y l o ose b o wel 
m o ve me nt, u p t o a ma xi m u m dail y d ose of 8 ta blets ( 1 6 m g). 
 
 Ot her a nti- diarr heal me dicati o ns t hat c o ul d be use d i ncl u de: L o m otil ( 5 m g, f o ur ti mes a da y), 
or ti nct ure of o pi u m ( 1 5- 2 0 dr o ps orall y e ver y 4 h o urs) or octre oti de ( 1 5 0 t o 3 0 0 g S Q t wice a 
da y). 
 
 Oral h y drati o n is i m p orta nt re gar dless of se ve rit y of diarr hea; a p pro priate re h y drati o n ( 1. 5 
L/ m 2/ da y pl us e q ui vale nt of act ual fl ui d l oss) a n d electr ol yte re place me nt s h o ul d be 
rec o m me n de d i n t he e ve nt of C T C A E Gra de 2 a n d Gra de 3 diarr hea. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
2 3
 
 F or C T C A E Gra de 3 diarr hea or C T C A E Gra de 2 diarr hea lasti n g ≥ 2 da ys ( 4 8 h o urs) des pite 
a de q uate a nti diarr heal treat me nt, BI B W 2 9 9 2 m ust be hel d u ntil rec o ver y t o C T C A E ≤ Gra de 
1. U p o n rec o ver y, BI B W 2 9 9 2 s h o ul d be res u me d at a re d uce d d ose acc or di n g t o t he d ose 
re d ucti o n sc he me o utli ne d i n Secti o n 5. 5 
 
 If des pite o pti mal s u p p orti ve care a n d a treat me nt pa use, diarr hea d oes n ot res ol ve t o C T C 
Gra de ≤1 wit hi n 2 8 da ys, t he patie nt s h o ul d be  re m o ve d fr o m pr ot oc ol t hera p y. 
5. 9. 2  S u g geste d M a n a ge me nt of R as h 
 
A pr oacti ve a n d earl y a p pr oac h t o ma na ge me nt of ras h is cr ucial. Ra s h ca n be ma na ge d b y a variet y of 
treat me nt o pti o ns t o relie ve s y m pt o ms a n d re d uce t he ras h. T he rec o m me n dati o ns f or ma na ge me nt are 
as f oll o ws: 
 
 Ge ner al/ Pre ve nti o n : strict s u n pr otecti o n; use of a s u nscree n of S u n Pr otecti o n Fact or 1 5 ( S P F 
1 5) or hi g her, prefera bl y c o ntai ni n g zi nc o xi de ; use of a t hic k, alc o h ol-free e m ollie nt crea m. 
 
 C T C A E Gr a de 1 r as h : mil d ras h ma y n ot nee d treat me nt. H o we ver, if treat me nt is c o nsi dere d 
necessar y, m oist urizi n g l oti o ns , t o pical h y dr oc ortis o ne ( 1 % or 2. 5 %) crea m a n d/ or cli n da m yci n 
1 % gel ca n be use d. 
 
 C T C A E Gr a de 2 r as h : relief fr o m maj or s y m pt o ms ca use d b y C T C A E Gra de 2 s ki n-relate d 
a d verse e ve nts s h o ul d be ac hie ve d b y a c o m bi na ti o n of l ocal a n d s yste mic t hera pies i ncl u di n g: 
1) S yste mic a nti bi otics ( d o x yc ycli ne or mi n oc ycli ne etc.). 
2) T o pical treat me nt ( h y dr oc ortis o ne 2. 5 % cr ea m, cli n da m yci n 1 % gel, pi mecr oli m us 
1 % crea m). 
 
A n d / or 
 
1) A nti hista mi nes ( di p he n h y dra mi ne, etc.) 
2) Oral pre d nis o ne (s h ort ter m i.e., < 1 4 da ys  treat me nt) ma y be a d de d at i n vesti gat or’s 
discreti o n. 
 
S yste mic a n d t o pical treat me nt s h o ul d be i nitiat e d at t he start of C T C A E Gra de 2 ras h a n d 
c o nti n ue u ntil i m pr o ve me nt or res ol uti o n t o C T C A E Gra de ≤1. As a b o ve, treat me nt ma y be 
hel d f or u p t o 7 da ys a n d restarte d at t he sa me d os e at t he discreti o n of t h e i n vesti gat or. If gra de 
2 ras h persists f or ≥ 7 da ys des pite treat me nt a n d is p o orl y t olerate d b y t he patie nt, treat me nt 
s h o ul d be hel d f or u p t o 2 8 da ys f oll o we d b y a re d ucti o n i n t he d ose of BI B W 2 9 9 2 acc or di n g 
t o t he d ose re d ucti o n sc he me i n Ta ble 2, see Secti o n 5. 5. 
 
 C T C A E Gr a de 3 ( or gre ater) r as h: ma y be treate d i n a ma n ner si milar t o C T C A E Gra de 2 
ras h. I n t he e ve nt of C T C A E Gra de ≥3 ras h, treat me nt wit h BI B W 2 9 9 2 s h o ul d be hel d u ntil 
rec o ver y t o C T C A E Gra de ≤1. Treat me nt s h o ul d be res u me d at a re d uce d d ose (see Secti o n 
5. 5). If C T C A E Gra de ≥3 ras h d oes n ot res ol ve t o C T C A E Gra de ≤1 wit hi n 2 8 da ys of st o p pi n g 
BI B W 2 9 9 2 treat me nt a n d des pite o pti mal s u p p orti ve  care, t he patie nt s h o ul d be re m o ve d fr o m 
st u d y. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
2 4
5. 9. 3  S u g geste d M a n a ge me nt of I n terstiti al L u n g Dise ase 
 
Alt h o u g h q uite rare, i nterstitial l u n g disease (I L D) is a class effect of E G F R T KIs a n d ca n be life 
t hreate ni n g. T heref ore, patie nts s h o ul d be m o nit ore d closel y f or s y m pt o ms c o nsiste nt wit h I L D, s uc h as 
ne w o nset d ys p nea wit h o ut a n o b vi o u s ca use. C hest C T s h o ul d be o btai ne d t o l o o k f or i nterstitial fi br otic 
c ha n ges if I L D is s us pecte d. I n t he e ve nt t hat I L D is s us pecte d, dr u g  treat me nt s h o ul d be disc o nti n ue d 
a n d t he patie nt s h o ul d recei ve a p pr o priate me dical ma na ge me nt a n d s u p p orti ve care. Alt h o u g h t here is 
n o esta blis he d treat me nt, s yste mic c ortic oster oi ds are ofte n a d mi nistere d. BI B W 2 9 9 2 s h o ul d n ot be 
restarte d i n t h ose patie nts s us pecte d of ha vi n g dr u g-relate d I L D a n d t he s u bject s h o ul d be re m o ve d fr o m 
t he st u d y. 
 
5. 1 0  D ur ati o n of T her a p y 
 
D ur ati o n of t h er a p y will d e p e n d o n  i n di vi d u al r es p o ns e, e vi d e n c e of dis e as e pro gr essi o n a n d 
t ol er a n c e. I n t h e a bs e n c e of tr e at m e nt d el a ys d u e t o a d v ers e e v e nts, tr e at m e nt m a y b e gi v e n 
c o nti n u o usl y u ntil o n e of t h e f oll o wi n g crit eri a a p pli es: 
 
   Dis e as e pr o gr essi o n b y R E CI S T crit eri a (s e e S e cti o n 8. 3) N ote t hat if a patie nt has  
pr o gressi o n b y R E CI S T b ut is still deri vi n g cli nical be nefit a n d t h ere is n ot li kel y t o be har m 
fr o m c o nti n ui n g treat me nt, patie nts ma y co nti n ue t hera p y u ntil n o l o n ger cli nicall y 
be nefitti n g, after disc ussi o n wit h a n d a p pr o val b y t he S p o ns or, Dr. Se q uist. 
 
R etr e at m e nt crit eri a ar e n ot m et wit hi n t h e s p e cifi e d ti m e fr a m e (s e e S e cti o n 5. 5) 
 
I nt er c urr e nt ill n ess t h at pr e v e nts f urt h er a d mi nistr ati o n of tr e at me nt, 
 
U n a c c e pt a bl e a d v ers e e v e nt(s), 
 
P arti ci p a nt d e ci d es t o wit h dr a w fr o m t h e st u d y, or 
 
G e n eral or s p e cifi c c h a n g es i n t he parti ci p a nt's c o n diti o n r e n d er t he p arti ci pa nt 
u nacce pta ble f or f urt her treat me nt i n t he o pi ni o n of t he treati n g i n vesti gat or . 
 
Deat h 
 
L ost t o f oll o w- u p 
 
5. 1 1  D ur ati o n of F oll o w U p  
 
P arti ci p a nts will b e  f oll o w e d f or s ur vi v al aft er r e m o v al fr o m st u d y u ntil d e at h. Partici pa nts 
re m o ve d fr o m st u d y f or u nacce pta ble a d verse e ve nts will be f oll o we d f or safet y u ntil res ol uti o n or 
sta bilizati o n of t he a d verse e ve nt. 
  
 
6.  S A F E T Y A S S E S S M E N T S A N D A D V E R S E E V E N T S 
 
6. 1  
O ver vie w 
 
Safet y meas ure me nts t hat will be use d i n t he st u d y i ncl u de p h ysical e xa mi nati o ns, peri o dic e ye 
e xa mi nati o ns, a n d cli nical la b orat or y tests ( he mat olo g y, bl o o d c he mistries, creati ni ne a n d li ver 
f u ncti o n tests). T o xicities will be defi ne d a n d gra de d usi n g Versi o n 4. 0 of t he N CI C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E ) w hic h is l ocate d o n t he C T E P we bsite at: 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o ni c _a p plicati o ns/ctc. ht m.  
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
2 5
T he a d verse e ve nts e x pecte d wit h BI B W 2 9 9 2 are s u m marize d i n Secti o n 2. 1 of  t he pr ot oc ol a n d are 
catal o ge d t h or o u g hl y i n t he Liste d A d verse E ve nts secti o n of t he I n ve sti gat or’s Br oc h ure, w hic h is o n 
file wit h t he Pri nci pal I n vesti gat or. 
 
If p ossi ble, s y m pt o ms fr o m a d verse e ve nts s h o ul d be ma na ge d a g gressi vel y wit h s u p p orti ve care. See 
Secti o n 5. 9 f or s pecific rec o m me n dati o ns a b o ut ma na gi n g ras h, diarr hea a n d i nterstitial l u n g disease.  
 
All a d verse e ve nts e x perie nce d b y partici pa nts will be c ollecte d fr o m t he ti me of si g ni n g i nf or me d 
c o nse nt, t hr o u g h t he peri o d of treat me nt, u ntil t he fi nal st u d y visit a n d re peat t u m or tiss ue bi o ps y occ ur 
(see Secti o n 9). Partici pa nts c o ntin ui n g t o e x perie nce t o xicit y at t he p ost- bi o ps y off-st u d y visit ma y be 
c o ntacte d f or a d diti o nal assess me nts u ntil t he t o xic it y has res ol ve d or is dee me d irre versi ble. 
 
6. 1. 2  Hist or y a n d P h ysic al E x a mi n ati o n 
 
T he rele va nt i nter val hist or y s h o ul d be o btai ne d d uri n g scree ni n g a n d at t he start of eac h c ycle. I nter val 
hist ories s h o ul d i ncl u de elicitati o n of i nteri m ill nesses a n d a d verse e ve nts. If a s u bject re mai ns o n 
st u d y treat me nt f or m ore t ha n 8 c ycles, t hese assess me nts ma y occ ur e ver y ot her m o nt h, see Secti o n 9. 
 
A pr o ble m-f oc use d p h ysical e xa mi nati o n ( P E) will be perf or me d d uri n g scree ni n g, at t he start of eac h 
c ycle, o n da ys 8 a n d 1 5 of c ycle 1, a n d at t he ti m e of st u d y disc o nti n uati o n. If a s u bject re mai ns o n 
st u d y treat me nt f or m ore t ha n 8 c ycles, t hese assess me nts ma y occ ur e ver y ot her m o nt h, see Secti o n 9. 
E ver y P E s h o ul d i ncl u de meas ure me nt of b o d y we i g ht, vital si g ns, a n d e val uati o n of t he E C O G 
perf or ma nce sc ore (see A p pe n di x 1). Bl o o d press ure m u st be rec or de d at eac h visit. Meas ure me nt of 
hei g ht nee d o nl y occ ur at t he scree ni n g P E. 
 
 
6. 1. 3  L a b or at or y E x a mi n ati o ns 
 
La b orat or y e xa mi nati o ns t o be perf or me d d uri n g scree ni n g i ncl u de he m o glo bi n, w hite bl o o d cell c o u nt 
i ncl u di n g ne utr o p hil c o u nt (s u m of p ol yse g me nte d gra n ul oc ytes a n d ba n d f or ms) , platelets, bilir u bi n, 
al kali ne p h os p hatase, A L T, A S T, bl o o d urea ni tr o ge n ( B U N), creati ni ne, calci u m, electr ol ytes 
(s o di u m, p otassi u m), a n d a uri ne pre g na nc y test (f or w o me n of c hil d- beari n g a ge).   
 
La b orat or y e xa mi nati o ns are t o be perf or me d at t he start of eac h c ycle of treat me nt, o n da ys 8 a n d 1 5 
of c ycle 1, a n d at t he ti me of  st u d y disc o nti n uati o n i ncl u de hem o gl o bi n, w hite bl o o d cell c o u nt 
i ncl u di n g ne utr o p hil c o u nt (s u m of p ol yse g me nte d gra n ul oc ytes a n d ba n d f or ms) , platelets, bilir u bi n, 
al kali ne p h os p hatase, A L T, A S T, bl o o d urea nitr o ge n ( B U N), creati ni ne, calci u m a n d electr ol ytes 
(s o di u m, p otassi u m). 
6. 2  
Defi niti o n of Ter ms  
6. 2. 1  A d verse E ve nt ( A E) 
 
A n a d verse e ve nt ( A E) is a n y u n desira ble si g n, s y m pt o m or me dical c o n diti o n or e x perie nce t hat 
de vel o ps or w orse ns i n se verit y after si g ni n g i nf o r me d c o nse nt or a n y pr oce d ure s pecifie d i n t he 
pr ot oc ol, e ve n if t he e ve nt is n ot c o nsi dere d t o be re late d t o t he st u d y.  
 
A b n or mal la b orat or y val ues or dia g n o stic test res ults c o nstit ute ad verse e ve nts o nl y if t he y i n d uce 
cli nical si g ns or s y m pt o ms or re q uire treat me nt or f urt her dia g n ostic tests.  

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
2 6
6. 2. 2  Seri o us a d verse e ve nt ( S A E) 
 
A seri o us a d verse e ve nt ( S A E) is a n y a d verse e ve nt,  occ urri n g at a n y d ose a n d re gar dless of ca usalit y 
t hat:  
 Res ults i n deat h 
 Is life-t hreate ni n g. Life-t hreate nin g mea ns t hat t he pers o n was at i m me diate ris k of deat h fr o m 
t he reacti o n as it occ urre d, i.e., it d oes n ot i ncl u de a reac ti o n w hic h h y p ot heticall y mi g ht ha ve 
ca use d deat h ha d it occ urre d i n a m ore se ver f or m. 
 Re q uires or pr ol o n gs i n patie nt h os pitalizati o n (i.e., t he e ve n t re q uire d at least a 2 4- h o ur 
h os pitalizati o n or pr ol o n ge d a h os pitaliza ti o n be y o n d t he e x pecte d le n gt h of sta y). 
H os pitalizati o n a d missi o ns a n d/ or s ur gical o perati o ns sc he d ule d t o occ u r d uri n g t he st u d y peri o d, 
b ut pla n ne d pri or t o st u d y e ntr y ar e n ot c o nsi dere d S A Es if t he ill ness or disease e xiste d bef ore 
t he pers o n was e nr olle d i n t he trial, pr o vi de d t hat it di d n ot deteri orate i n a n u ne x pecte d ma n ner 
d uri n g t he trial (e. g., s ur ger y pe rf or me d earlier t ha n pla n ne d). 
 Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y. Disa bilit y is defi ne d as a s u bsta ntial 
disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life f u ncti o ns. 
 Is a c o n ge nital a n o mal y or birt h defect; or 
 Is a n i m p orta nt me dical e ve nt w he n, base d u p o n a p pr o priate me dical j u d g me nt, it ma y je o par dize 
t he partici pa nt a n d re q uire me dical or s ur gical i nter ve nti o n t o pr e ve nt o ne of t he o utc o mes liste d 
a b o ve. E xa m ples of s uc h me dical  e ve nts i ncl u de aller gic bro nc h os pas m re q uiri n g i nte nsi ve 
treat me nt i n a n e mer ge nc y r o o m or at h o me; blo o d d yscrasias or c o n v ulsi o n s t hat d o n ot res ult i n 
i n patie nt h os pitalizati o n, or t he de velo p me nt of dr u g de pe n de nc y or dr u g a b use. 
 
E ve nts n ot c o nsi dere d t o be seri o us a d verse e ve nts are h os pitalizati o ns f or: 
 r o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass ociate d wit h a n y deteri orati o n i n 
c o n diti o n, or f or electi ve pr oce d ures 
 A b n or mal la b val ues t hat d o n ot re q uire treat me nt 
  treat me nt pla n ne d bef ore si g ni n g i nf or me d co nse nt f or a pre-e xisti n g c o n diti o n t hat di d n ot 
w orse n  
 e mer ge nc y o ut patie nt treat me nt f or a n e ve nt n ot f u lfilli n g t he seri o us criteria o utli ne d a b o ve a n d 
n ot res ulti n g i n i n patie nt a d missi o n 
 res pite care 
6. 2. 3  E x pecte d A d verse E ve nts 
 
A d verse e ve nts ca n be ' E x pecte d' or ' U ne x pecte d’. E x pecte d a d verse e ve nts are t h ose t hat ha ve bee n 
pre vi o usl y i de ntifie d as res ulti n g fr o m a d mi nistrati o n of t he a ge nt. F or t he p ur p oses of t his st u d y, a n 
a d verse e ve nt is c o nsi dere d e x pecte d  w he n it a p pears i n t he I n vesti gat or’s Br oc h ure  
6. 2. 4  U ne x pecte d a d verse e ve nt 
 
 
F or t he p ur p oses of t his st u d y, a n a d verse e ve nt is c o nsi dere d u ne x pecte d  w he n it varies i n nat ure, 
i nte nsit y or fre q ue nc y fr o m i nf or mati o n pro vi de d i n t he I n vesti gat or’s Br oc h ure.   
6. 2. 5  Attri b uti o n 
 
Attri b uti o n is t he rela ti o ns hi p bet wee n a n a d verse e ve nt or seri o us a d verse e ve nt a n d t he st u d y 
treat me nt. Attri b uti o n will be assi g ne d as f oll o ws: 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
2 7
 
 Defi nite – T he A E is clearl y relate d  t o t he st u d y treat me nt. 
 Pr o ba ble – T he A E is li kel y relate d  t o t he st u d y treat me nt. 
 P ossi ble – T he A E ma y be relate d  t o t he st u d y treat me nt.  
 U nli kel y - T he A E is d o u btf ull y relate d  t o t he st u d y treat me nt. 
 U nr el at e d - T h e A E is  cl e arl y N O T r el at e d t o t h e st u d y tr e at m e nt. 
6. 3  
Pr oce d ures f or A E a n d S A E Rec or di n g a n d Re p orti n g 
 
Re p orti n g or partici pati n g i n vesti gat ors will assess t h e occ urre nce of A Es a n d S A Es at all partici pa nt 
e val uati o n ti me p oi nts d uri n g t he st u d y.  
 
All A Es a n d S A Es w het her re p orte d b y t he partic i pa nt, disc o vere d d urin g q uesti o ni n g, directl y 
o bser ve d, or detecte d b y p h ysical e xa m i nati o n, la b orat or y test or ot her mea ns, will be rec or de d i n t he 
partici pa nt’s me dical rec or d a n d o n t he a p pr o priate st u d y-s pecific case re p ort f or ms. Eac h rec or de d A E 
or S A E will be descri be d b y its d urati o n (i.e., start a n d e n d dates), i nte nsit y treat me nt re q uire d, gra de, 
s us pecte d relati o ns hi p t o t he i n vesti gati o nal pr o d uct (ca usalit y), o utc o me a n d acti o ns ta ke n wit h 
i n vesti gati o nal pr o d uct. 
 
T he descri pti o ns a n d gra di n g scales f o u n d i n t he C T E P N CI C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts ( C T C A E) versi o n 4. 0 will be uti lize d f or A E re p orti n g. T he C T C A E versi o n 4. 0 is 
l ocate d o n t he C T E P we bsite at: 
 htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o ni c a p plicati o ns/ctc. ht m.  
All a p pr o priate treat me nt areas s h o ul d ha ve access t o a c o p y of t he C T E P Acti ve Versi o n of C T C A E. 
 
T o e ns ure c o nsiste nc y of A E a n d S A E ca usalit y a ssess me nts, i n vesti gat ors sh o ul d a p pl y t he f oll o wi n g 
ge neral g ui deli ne: 
 Y E S 
T here is a pla usi ble te m p oral relati o ns hi p bet w ee n t he o nset of t he A E a n d a d mi nistrati o n of 
t he i n vesti gati o nal pr o d uct, a n d t he A E ca n n ot be rea dil y e x plai ne d b y t he patie nt’s cli nical 
state, i nterc urre nt ill ness, or c o nc o mita nt t hera pies; a n d/ or t he A E f oll o ws a k n o w n patter n of 
res p o nse t o t he i n vesti gati o nal pr o d uct; a n d/ or t he A E a bates or res ol v es u p o n disc o nti n uati o n 
of t he i n vesti gati o nal pr o d uct or d ose re d ucti o n a n d, if a p plica ble, rea p pears u p o n re-c halle n ge. 
 N O 
E vi de nce e xists t hat t he A E has a n eti ol o g y ot her t ha n t h e i n vesti gati o nal pr o d uct (e. g., 
pree xisti n g me dical c o n diti o n, u n der l yi n g disease, i nterc urre nt ill ness, or c o nc o mita nt 
me dicati o n); a n d/ or t he A E has n o pla usi ble te m p oral relati o ns hi p t o a d mi nistrati o n of t he 
i n vesti gati o nal pr o d uct (e. g., ca ncer dia g n ose d 2 da ys after first d ose of st u d y dr u g).  
 
Eac h partici pati n g i n vesti gat or is  re q uire d t o a bi de b y t he re p orti n g re q uire me nts set b y t he D F/ H C C. 
T he st u d y m ust be c o n d ucte d i n c o m plia nce wit h F D A re g ulati o ns, l ocal  safet y re p orti n g re q uire me nts, 
a n d re p orti n g re q uire me nts of t he pr i nci pal i n vesti gat or. S pecific rep orti n g re q uire me nts are detaile d 
bel o w. 
6. 3. 1  Seri o us A d verse E ve nt Re p orti n g 
6. 3. 1. 1  Re p orti n g t o t he I nstit uti o n al Re vie w B o ar d 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
2 8
 
All seri o us a d verse e ve nts t hat occ u r, d uri n g treat me nt, or wit hi n 2 8 days of t he last d ose of treat me nt 
m ust be re p orte d t o t he D F CI O ffice f or H u ma n Researc h St u dies (O H R S).  E ve nts t hat occ ur after 
c o nse nt b ut bef ore st u d y e nr oll me nt/re gistrati o n a n d r ecei vi n g st u d y treat me nt d o n ot nee d t o be 
re p orte d.  T his i ncl u des e ve nts meeti n g t he criteria o utli ne d i n Secti o n 6. 2. 2, as well as t he f oll o wi n g: 
 
 Gra de 2 ( m o derate) a n d Gra de 3 (se vere) e ve n ts t hat are u ne x pecte d a n d at least p ossi bl y 
relate d/ass ociate d wit h t he i nter ve nti o n. 
 
 All Gra de 4 (life-t hreate ni n g or di sa bli n g) e ve nts t hat are u ne x pecte d or n ot s pecificall y liste d 
i n t he pr ot oc ol as n ot re q uiri n g re p orti n g. 
 
 All Gra de 5 (fatal) e ve nts w hile t h e partici pa nt is e nr olle d a n d ac ti vel y partici pati n g i n t he trial 
O R w he n t he e ve nt occ urs wit hi n 2 8 da ys of t he last st u d y i nter ve nti o n.  
 
N ote : If t he partici pa nt is i n l o n g ter m f oll o w u p, re p ort t he deat h at t he ti me of c o nti n ui n g 
re vie w.  
 
Partici pati n g i n vesti gat ors m ust re p ort eac h seri o us a d verse e ve nt wit hi n 2 4 h o urs of lear ni n g of t he 
occ urre nce. I n t he e ve nt t hat t he partici pati n g i n vesti gat or d oes n ot bec o me a ware of t he seri o us 
a d verse e ve nt i m me diatel y (e. g., partici pa nt s o u g ht treat me nt else w here), t he partici pati n g i n vesti gat or 
is t o re p ort t he e ve nt wit hi n 2 4 h o urs after lear ni n g of it a n d d oc u me nt t he ti me of his or her first 
a ware ness of t he a d verse e ve nt.   
Wit hi n t he f oll o wi n g 2 4- 4 8 h o urs, t h e partici pati n g i n vesti gat or m ust pr o vi de f oll o w- u p i nf or mati o n o n 
t he seri o us a d verse e ve nt. F oll o w- u p i nf or mati o n sh o ul d descri be w het her t he e ve nt has res ol ve d or 
c o nti n ues, if a n d h o w t he e ve nt was treate d, a n d w h et her t he partici pa nt will c o nti n ue or disc o nti n ue 
st u d y partici pati o n. 
6. 3. 1. 2  Re p orti n g t o B oe hri n ger I n gel hei m ( BI) 
 
All A Es re p orte d as a n e x pe dite d Safet y Re p ort t o t he F D A, all ot her Seri o us a d verse e ve nts a n d N o n-
seri o us A Es occ urri n g at t he sa me ti me a n d/ or w hich are me dicall y relate d t o t he S A E m ust als o be 
re p orte d t o B oe hri n ger I n gel hei m usi n g t he BI S A E f or m per t he ti meli nes i n dicate d i n t he 
P har mac o vi gila nce A gree me nt. 
 
6. 3. 1. 3  Re p orti n g t o H os pit al  Ris k M a n a ge me nt 
 
Partici pati n g i n vesti gat ors will re p ort t o t heir l ocal Ris k Ma na ge me nt office a n y s u bject safet y re p orts 
or se nti nel e ve nts t hat re q uire re p orti n g acc or di n g t o i nstit uti o nal p olic y. 
 
6. 3. 2  N o n- Seri o us A d verse E ve nt Re p orti n g  
 
N o n-seri o us a d verse e ve nts will be re p orte d o n t he t o xicit y Case Re p ort F or ms.   
6. 4  
M o nit ori n g of A d verse E ve nts a n d Peri o d of O bser v ati o n 
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
2 9
All a d verse e ve nts, b ot h seri o us a n d n o n-seri o us, a n d deat hs t hat ar e e nc o u ntere d fr o m si g ni n g of t he 
i nf or me d c o nse nt, t hr o u g h o ut t he st u d y, a n d wit hi n 2 8 da ys of t he last st u d y i nter ve nti o n s h o ul d be 
f oll o we d t o t heir res ol uti o n, or u ntil t he partici pati n g i n vesti gat or assesses t he m as sta ble, or t he 
partici pati n g i n vesti gat or deter mi nes  t he e ve nt t o be irre versi ble, or t he partici pa nt is l ost t o f oll o w- u p. 
T he prese nce a n d res ol uti o n of A Es a n d S A Es ( wit h dates) s h o ul d be d oc u me nte d o n t he a p pr o priate 
case re p ort f or m a n d rec or de d i n t h e partici pa nt’s me dical rec or d t o facilitate s o urce data verificati o n.  
 
F or s o me S A Es, t he st u d y s p o ns or or desi g nee ma y f oll o w- u p b y tele p h o ne, fa x, a n d/ or m o nit ori n g 
visit t o o btai n a d diti o nal case deta ils dee me d necessar y t o a p pr o priatel y e val uate t he S A E re p ort (e. g., 
h os pital disc har ge s u m mar y, c o ns ulta nt  re p ort, or a ut o ps y re p ort).  
 
Partici pa nts s h o ul d re p ort a n y seri o us p ost-st u d y e ve nt(s) t hat mi g ht reas o na bl y be relate d t o 
partici pati o n i n t his st u d y, i ncl u di n g a n y u na ntici pate d deat h or  a d verse e ve nt occ urri n g after a 
partici pa nt has disc o nti n ue d or te r mi nate d st u d y partici pati o n t hat ma y reas o na bl y be relate d t o t he 
st u d y.   
6. 5  
C o ntr ace pti o n a n d Pre g n a nc y 
 
Fe male patie nts w h o are n ot of c hil d beari n g p ote ntial d ue  t o bei n g p ost me n o pa usal ( 2 years wit h o ut 
me nses) or s ur gical sterilizati o n ( o o p h orect o m y, h ystere ct o m y a n d/ or t u bal li gati o n) d o n ot nee d t o use 
c o ntrace pti o n. All ot her fe male pa tie nts are c o nsi dere d t o ha ve c hil d beari n g p ote ntial a n d s h o ul d use 
a de q uate c o ntrace pti o n t hr o u g h o ut t he st u d y (fr o m scr ee ni n g u ntil e n d of st u d y pa rtici pati o n or 2 8 da ys 
after last d ose of trial me di cati o n, w hic he ver is later). 
 
Acce pta ble met h o ds of c o ntrace pti o n f or fe male s i ncl u de h or m o nal c o ntrace pti o n a n d d o u ble barrier 
met h o d. D o u ble barrier met h o d of c o nt race pti o n is defi ne d as t w o barrier met h o ds use d si m ulta ne o usl y 
eac h ti me t he patie nt has i nterc o urse. Acce pte d barrier met h o ds i ncl u de dia p hra g m, fe male c o n d o m, 
cer vical ca p, male c o n d o m a n d I U D (t he dia p hra g m a n d cer vical ca p m ust be use d i n c o nj u ncti o n wit h 
s per mici dal jell y/crea m). If h or m o nal c o ntrace pti ves are use d, at least o ne ba rrier met h o d s h o ul d als o 
be use d. Part ner vasect o m y, nat ural 'r h yt h m' a n d s per mici dal jell y/crea m are n ot  acce pta ble as met h o ds 
of c o ntrace pti o n. 
 
Male patie nts s h o ul d use a de q uate c o ntrace pti o n t hr o u g h o ut t he st u d y (e. g. c o n d o m a n d s per mici dal 
jell y). 
 
Fe male patie nts m ust ha ve a ne gati ve pre g na nc y test ( β - H C G test i n uri ne or ser u m) pri or t o 
c o m me nci n g st u d y treat me nt. If a patie nt is f o u n d t o be pre g na nt d uri n g st u d y pa rtici pati o n, t his s h o ul d 
be ha n dle d as f oll o ws: 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3 
 
I N D # 1 1 0 7 2 0 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
3 0 
 
 
Ti mi n g of 
Pre g n a nc y 
Acti o n 
Pri or t o starti n g st u d y 
me dicati o n 
Patie nt s h o ul d be wit h dra w n fr o m t he st u d y i m me diatel y. 
N o re p orti n g necessar y. 
D uri n g st u d y 
tre at me nt 
Treat me nt m ust be st o p pe d i m me diatel y a n d t he pre g na nc y 
s h o ul d be re p orte d i m me diatel y usi n g t he pre g na nc y f or m.  
If t he i n vesti gat or wis hes t o give a n y f urt her tr eat me nt wit h st u d y 
me dicati o n, t his m ust be disc us se d a n d a gree d wit h B oe hri n ger 
I n gel hei m. 
T he pre g na nc y s h o ul d be f oll o we d u p t o fi nal o utc o me i ncl u di n g 
a n y pre mat ure ter mi nati o n.  O nl y re p orts of pre mat ure 
ter mi nati o n s h o ul d be re p orte d t o t he B oe hrin ger I n gel hei m o n t he 
BI S A E f or m. 
I n a d diti o n, a n y e ve nt lea di n g t o t he ter mi natio n of pre g na nc y 
(i.e. s p o nta ne o us, accide ntal, or i n d uce d a b orti o n; as well as 
miscarri a ge, i ntra uteri ne fetal de mise/ deat h) m ust be re p orte d as 
a n S A E. 
D uri n g f oll o w- u p 
(after 
fi nis hi n g treat me nt 
b ut bef ore e n d of 
st u d y partici pati o n), 
or wit hi n 2 8 da ys of 
last d ose of st u d y 
me dicati o n (e ve n if 
n o l o n ger 
partici pati n g i n 
st u d y) 
T he pre g na nc y s h o ul d be ca pt u re d usi n g t he pre g na nc y f or m. 
T he pre g na nc y s h o ul d be f oll o we d u p t o fi nal o utc o me i ncl u di n g 
a n y pre mat ure ter mi nati o n.  O nl y re p orts of pre mat ure 
ter mi nati o n s h o ul d be re p orte d t o B oe hri n ger I n gel hei m o n t he BI 
S A E f or m. 
I n a d diti o n, a n y e ve nt lea di n g t o t he ter mi natio n of pre g na nc y 
(i.e. s p o nta ne o us, accide ntal, or i n d uce d a b orti o n; as well as 
miscarri a ge, i ntra uteri ne fetal de mise/ deat h) m ust be re p orte d as 
a n S A E. 
 
 
 
 
 
 
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
3 1
7.  M O L E C U L A R A N D C O R R E L A TI V E S T U DI E S  
7. 1  
Re pe at Bi o psies f or M olec ul ar Testi n g 
 
It is e x p e ct e d t h at all p ati e nts will u n d er g o a r e p e at t u m or tiss ue bi o ps y at t h e ti m e of r e m o v al 
fr o m st u d y tr e at m e nt. I d e all y, t h e l esi o n t o b e bi o psi e d s h o ul d b e n e w or gr o wi n g o n BI B W 2 9 9 2 
t h er a p y. T h e p ur p os e of t his bi o ps y is t o ass ess f or t h e pr es e n c e or a bs e n c e of t h e r esist a n c e 
m ut ati o n T 7 9 0 M. T his is t h e pri m ar y e n d- p oi nt of t h e st u d y. I n m ost c as es, t h e r e p e at bi o ps y will 
b e at t h e ti m e of cli ni c al pr o gr essi o n. If a p ati e nt is b ei n g r e m o v e d fr o m tr e at m e nt f or r e as o ns 
ot h er t h a n cli ni c al pr o gr essi o n ( e. g. wit h dr a w al of c o ns e nt, i nt ol er a n c e of si d e  eff e cts, et c) t h e n a 
r e p e at bi o ps y is d esir a bl e b ut n ot r e q uir e d. 
7. 1. 1  Re q uire me nts f or Re pe at Bi o ps y 
 F or T h oracic I R Bi o psies: Eac h patie nt m ust be  assesse d f or ris k a n d a p pr o ve d b y t h oracic 
i nter ve nti o nal ra di ol o g y as ha vi n g a ca n di date lesio n t hat meas ures at le ast 8 m m o n a c hest C T 
sca n a n d is a p pr o priate f or perc uta ne o us bi ps y. Ris k assess me nt i ncl u des a n e val uati o n of t he 
e xte nt of e m p h yse ma a n d p ul m o nar y fi br osis, ris k of pr oce d ure-relate d p ne u m ot h ora x as esti mate d 
b y t he l ocati o n of t he lesi o n a n d t he prese nce of b ull o us disease i n t he tar gete d pat h of t he bi o ps y 
nee dle, a n d C T e vi de nce of p ul m o nar y arterial h y perte nsi o n or  si g nifica nt car diac disease. L u n g 
bi o psies will n ot be perf or me d i n patie nts wit h c hr o nic l u n g disease re q uiri n g s u p ple me ntal o x y ge n 
at h o me or i n patie nts wit h k n o w n m o derate or se vere p ul m o nar y arterial h y perte nsi o n, val v ular 
disease or car di o m y o pat h y. 
 F or A b d o mi nal I R Bi o psies: E ac h patie nt m ust be assesse d f or ris k a n d a p pr o ve d b y GI/ G U 
i nter ve nti o nal ra di ol o g y as ha vi n g a ca n di date lesio n t hat is a p pr o priate f or perc uta ne o us bi o ps y. 
Ris k assess me nt i ncl u des a n e val uati o n of t he ris k of blee di n g a n d ris k of perf orati o n of visceral 
str uct ures gi ve n t he l ocati o n of t he tar get lesi o n. 
 N o as piri n, n o n-ster oi dal a nti-i n fla m mat or y dr u gs ( N S AI D S), or ot her a nti- platelet me dicati o n is 
all o we d f or 7 da ys pri or t o bi o ps y. 
 N o l o w m olec ular wei g ht he pari n is a ll o we d f or 1 2 h o urs pri or t o bi o ps y.  
 Pr ot hr o m bi n ti me m ust be < 1 4 sec o n ds, assesse d wit hi n 2 wee ks of bi o ps y or wit hi n 7 2 h o urs of 
bi o ps y if o n c hr o nic warfari n or  ot her a nti-c oa g ulati o n t hera p y. 
 Platelet c o u nt m ust be  > 7 5, 0 0 0, assesse d wit hi n 2 wee ks of bi o ps y 
 Patie nts w h o ha ve a b o n y metastatic site as t he pla n ne d site f or re peat bi o ps y, u nless t here is a 
si g nifica nt s oft tiss ue c o m p o ne nt t hat ca n be sa m pled, as t he decalcif yi n g material use d t o pr ocess 
osse o us bi o psies de nat ures D N A a n d t he material is  t heref ore n ot s uita ble f or m olec ular a nal ysis.  
 Si g nifica nt c o- m or bi dit y or ort h o pe dic c o n diti o n t hat ma y i m pe de o pti mal p ositi o ni n g d uri n g 
bi o ps y a n d/ or p ost- bi o ps y rec o ver y 
 Patie nts m ust ha ve a n a de q uate fa mil y/care gi ver  s u p p ort s yste m t o e nsure s ufficie nt o bser vati o n 
after t he o ut patie nt bi o ps y. If patie nt d ose n ot ha ve a s u p p ort s yste m, arra n ge me nts will be ma de 
f or o ver ni g ht a d missi o n after t he bi o ps y t o o bser ve f or p ote ntial c o m plicati o ns.  

U n derst a n di n g resist a nce t o BI B W 2 9 9 2 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
3 2
7. 1. 2  Pr oce d ure f or Re pe at Bi o ps y 
O nce t he case is a p pr o ve d b y i nter ve nti o nal ra di ol o g y f or its a p pr o priate ness f or bi o ps y t he bi o ps y will 
be sc he d ule d a n d perf or me d i n t he us ual ma n ner. T h e lesi o n will be i de ntifie d b y eit her ultras o u n d or 
C T i ma gi n g. T he i nter ve nti o nal ra di ol o gist will select a safe pat h t o t he lesi o n. A n i ntra ve n o us ca n n ula 
will be place d a n d se dati o n will be a d mi nistere d as  per r o uti ne cli nical pr ot oc ol. T y pical se dati o n 
me dicati o ns i ncl u de a c o m bi nati o n of i ntra ve n o us mi daz ola m a n d fe nta n yl. S u bc uta ne o us li d ocai ne 
will be a d mi nistere d a n d t he n a 1 7- 1 9 ga u ge metal ca n n ula will be i nserte d perc uta ne o usl y i nt o t he 
lesi o n wit h vis ual c o nfir mati o n b y eit her C T or ultras o u n d. T he i nter v e nti o nal ra di ol o gist will atte m pt 
t o o btai n t w o or m ore 1- 2 c m l o n g 1 8- 2 0- ga u ge c ore bi o ps y sa m ples a n d t hree ore m ore 2 2 ga u ge fi ne 
nee dle as pirates of tiss ue usi n g a c utti n g c ore bi o ps y nee dle or 2 2 ga u ge nee dle. T he n or mal 
de part me ntal pre- pr oce d ural d oc u me ntati o n, pr oce d ure n ote d oc u me ntati o n a n d p ost- pr oce d ure 
o bser vati o n a n d disc har ge al g orit h ms will be perf or me d as per sta n dar d practice. N ote: bi o psies ma y 
be o btai ne d at t he l ocati o n of c olla b o rati n g i n vesti gat ors, i.e. patie nts are n ot re q uire d t o tra vel t o M G H 
f or t heir bi o psies. T hese ce nters s h o ul d f oll o w t he proce d ures as o utli ne d i n t he pr ot oc ol or call Dr. 
Se q uist at M G H t o disc uss a n y maj or variati o ns i n bi o ps y practice fr o m t he pr ot oc ol d oc u me nt. 
7. 1. 3  M olec ul ar Assess me nt of Re pe at Bi o ps y Tiss ue 
Re peat bi o ps y t u m or tiss ue will be ha n dle d u n der t he f oll o wi n g pr oce d ures. O ne sli de will be r o ute d t o 
a nat o mic pat h ol o g y, t o c o nfir m t hat t he lesi o n bi o p sie d is mali g na nt a n d a p pears as e x pecte d fr o m a 
hist ol o gic sta n d p oi nt gi ve n t he pres u m pti ve dia g n osis. T he maj orit y of t he sa m ple will u n der g o 
ge n ot y pi n g a nal ysis wit h t h e S Na Ps h ot platf or m as descri be d i n Secti o n 2. 3. 1. N ote: if t he bi o ps y is 
ta ke n at a n ot her h os pital besi des Massac h usetts Ge neral H os pital, a nat o mic c o nfir mati o n of t he dia g n osis 
s h o ul d still occ ur at t he h os pital perf or mi n g t he bi o ps y ( usi n g as little material as p ossi ble). T he rest of 
t he material will be f or mali n-fi xe d a n d paraffi n-e m be d de d, a n d s h o ul d be r o ute d t o Dr. Se q uist at M G H 
f or a nal ysis wit h t he S Na Ps h ot platf or m. Sa m ples s h o ul d be s hi p pe d wit h a re q uisiti o n f or m (see 
A p pe n di x 4) t o: 
 
T he pri mar y use of t he material o btai ne d fr o m re peat bi o psies will be t o asse ss T 7 9 0 M stat us fr o m 
resista nt s peci me ns. We will als o deter mi ne if t here is M E T a m plificati o n, a n ot her vali date d mec ha nis m 
of ac q uire d resista nce. H o we ver, w h e n t here is s ufficie nt tiss ue, we will perf or m ot her e x pl orat or y 
ge n o mic, pr ote o mic a n d e x pressi o n pr ofili n g a n d atte m pt t o de vel o p patie nt-s pecific t u m or m o dels i n 
vitr o a n d i n viv o. T he esta blis h me nt of s uc h mo dels will all o w us t o f u ncti o nall y vali date or ref ute t he 
h y p ot hesize d mec ha nis ms of resista nce t o BI B W 2 9 9 2. We ha ve ha d s uccess wit h t hese tec h ni q ues i n t he 
past a n d will perf or m t hese st u dies  i n c olla b orati o n wit h Dr. B o R ue da w h o has a n esta blis he d trac k 
rec or d of de vel o pi n g xe n o graft t u m or m o dels a n d cell li nes fr o m patie nt s peci me ns.  Left o ver material 
will be ret ur ne d t o t he par tici pati n g i nstit uti o n at t he c o m pleti o n of t he st u d y.  
7. 1. 4  F oll o w- U p after Re pe at Bi o ps y 
All s u bjects will be see n i n cli nic f o r f oll o w- u p a n d assess me nt of bi o ps y-relate d c o m plicati o ns at 7 
da ys p ost- bi o ps y ( ± 2 da ys) a n d a gai n at ≥ 3 0 da ys p ost- bi o ps y. 
7. 2  
Circ ul ati n g T u m or Cell St u dies 
Bl o o d sa m pl es f or C T C a nal ysis will be c o llecte d at t he f oll o wi n g ti me p oi nts. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
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C O N FI D E N TI A L 
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3 3
 
 Da y 1, pri or t o t hera p y 
 Da y 1, t hree h o urs after d ose 
 Da y 8 
 Da y 1 5 
 C ycle 2, da y 1 
 C ycle 3, da y 1 
 C ycle 4, da y 1 
 C ycle 5, da y 1 
 T he n e ver y 2 c ycles 
 At t he ti me of pr o gressi o n (e n d of st u d y visit) 
 
C T Cs will be assesse d fr o m eac h peri p heral bl o o d usi n g t he C T C- C hi p (see Secti o n 2. 3. 2). T his assa y 
will be perf or me d u n der t he s u per visi o n of Dr. Da niel Ha ber. Bl o o d sa m ples will be sa me- da y 
c o uriere d t o t he Ha ber La b i n t he C harlest o w n Na v y Yar d at M G H. Bl o o d sa m ples will be st ore d o n a 
r oc ki n g platf or m t o pre ve nt cell settli n g a n d will be pr ocesse d wit hi n 2 4 h o urs of bl o o d dra w. W h ole 
bl o o d will be passe d t hr o u g h t he C T C-c hi p usi n g st a n dar d pr oce d ures as pre vi o usl y p u blis he d 4 1. 
Ca pt ure d C T Cs will be fi xe d o n t he C T C-c hi p a n d stai ne d t o i de ntif y D N A c o nte nt, e pit helial cells a n d 
n o ns pecificall y b o u n d le u k oc ytes. Cells stai ni n g p os iti ve f or n uclear c o nte nt a n d p ositi ve f or 
c yt o kerati n will be c o u nte d as C T Cs. T he n u m ber of  C T Cs per milliliter of bl o o d will be deter mi ne d 
b y c o m pre he nsi ve i ma ge a nal ysis, sca n ni n g t he e ntire  c hi p a n d i de ntif yi n g C T Cs base d o n cell size, 
m or p h ol o g y a n d fl u oresce nce stai ni n g. T he ass ociati o n of C T C n u m bers wit h ra di o gra p hic disease 
res p o nse a n d rec urre nce will be assesse d. 
 
Ca pt ure d C T Cs will t he n be l yse d a n d D N A c o nte n t will be c ollecte d. Allele-s pecific se nsiti ve 
met h o ds will be use d t o deter mi ne t he T 7 9 0 M stat us  of t he ca pt ure d cells, as pre vi o usl y p u blis he d.4 2 If 
s ufficie nt material is a vaila ble, e x pl orat or y a nalyses will als o be perf or me d s uc h as w h ole ge n o me 
a m plificati o n of D N A a n d a nal ysis wit h t he S Na P s h ot platf or m. C T C- base d ge n ot y pes will t he n be 
c orrelate d wit h t u m or- deri ve d ge n ot y pes.  
8.  E F FI C A C Y A S S E S S M E N T  
 
Alt h o u g h r es p o ns e is n ot t h e pri m ar y e n d p oi nt of t h is tri al, p arti ci p a nts wit h m e as ur a bl e a n d/ or 
n o n- m e as ur a bl e dis e as e will b e ass e ss e d b y R E CI S T v ersi o n 1. 1 crit eri a. F or t h e p ur p os es of t his 
st u d y, p arti ci p a nts s h o ul d b e r e e v al u at e d e ver y 8 w e e ks. I n a d diti o n t o a b as eli n e s c a n, 
c o nfir m at or y s c a ns s h o ul d als o b e o bt ai n e d 4- 8 w e e ks f oll o wi n g i niti a l d o c u m e nt ati o n of a n 
o bj e cti v e r es p o ns e. 
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y usi n g t he crit eri a pr o p os e d b y t h e 
R es p o ns e E v al u ati o n Crit eri a i n S o li d T u m ors ( R E CI S T) g ui d eli n e.4 6  C h a n g es i n t h e di a m et er 
( u ni di me nsi o n al me as ur e me nt) of t h e t u m or l esi o ns ar e us e d  i n t h e R E CI S T crit eria.  
8. 1  
Defi niti o n of Ter ms 
8. 1. 1  E v al u a ble C o h orts  
E v al u a bl e f or t o xi cit y . All p arti ci p a nts w h o r e c ei v e at l e ast o n e d os e of st u d y tr e at m e nt will b e 
e v al u a bl e f or t o xi cit y fr o m t h e ti m e of t h eir first tr e at me nt. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
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E v al u a bl e f or o bj e cti v e r es p o ns e . O nl y t h os e p arti ci p a nts w h o h av e m e as ur a bl e dis e as e pr es e nt 
at b as eli n e, h a v e r e c ei v e d  at l e ast o n e c y cl e of t h er a p y, a n d h a v e h a d t h eir dis eas e re-e val uat e d 
will b e c o nsi der e d e v al u a bl e f o r r es p o nse. T h ese p arti ci p a nts will h a v e t h eir r es p o ns e cl assifi e d 
a c c or di n g t o t h e d efi niti o ns st at e d b el o w. ( N ot e: P arti ci p a nts w h o e x hi bit o bj e cti v e dis e as e 
pr o gr essi o n or di e pri or t o t h e e n d of c y cl e 1 will als o b e c o nsi d er e d e v al u a bl e.) 
8. 1. 2  Dise ase P ar a meters 
M e as ur a bl e dis e as e . M e as ur a bl e dis e as e is t h e pr es e n c e of at l e ast o n e ( 1) l esi o n t h at c a n 
b e acc uratel y meas ure d i n  at l east o ne di me nsi o n wit h l o n gest dia meter > 1 0 m m wit h s pir al C T 
s c a n. All t u m or me as ur e me nts m ust b e r e c or d e d i n milli m et ers ( or deci mal fracti o ns of ce nti meters). 
M ali g n a nt l y m p h n o d es . T o b e c o nsi d er e d p at h ol o gi c all y e nl ar g e d a n d me as ur a bl e, a l y m p h n o d e 
m ust b e > 1 5 m m i n s h ort a xis w h e n a ss ess e d b y C T s c a n ( C T s c a n sli c e t hi c k n ess r e c o m m e n d e d 
t o b e n o gr e at er t h a n 5 m m). At b as eli n e a n d i n f oll o w- u p, o nl y t he s h ort a xis will  b e m e as ur e d 
a n d f oll o w e d. 
R e mi n d er:  A l esi o n i n a pr e vi o usl y irr a di at e d ar e a is n ot eli gi bl e f or m e as ur a bl e dis e as e 
u nl ess t h er e is o bj e cti v e e vi d e n c e of pr o gr essi o n of t h e l esi o n  pri or t o st u d y e nr oll m e nt. 
L esi o ns i n pr e vi o usl y irr a di at e d ar e as m ust b e cl e arl y i d e ntifi e d as s u c h. 
  
N o n- me as ur a bl e dis e as e .  
All ot her l esi o ns ( or sit es of dis ease), i n cl u di n g s mall lesi o ns (l o n gest dia meter < 1 0 m m or 
pat h ol o gical l y m p h n o des wit h >  1 0 t o < 1 5 m m s h ort a xis, ar e c o nsi d er e d n o n- m e as ur a bl e dis e as e. 
B o n e l esi o ns, le pt o me ni n geal disease, ascites, ple ural/ pericar dial eff usi o ns, l y m p ha n gitis 
c utis/ p ul m o nis, i nfla m mat or y breast disease, a b d o mi nal masses i de ntifie d b y p h ysical e xa m t hat are 
n ot meas ura ble b y re pr o d uci ble i ma gi n g tec h ni q ues, a n d c ystic lesi o ns are all c o nsi dere d n o n-
meas ura ble. 
T ar g et l esi o ns .  
All m e as ur a bl e l esi o ns u p t o a m a xi m u m of 2 l esi o ns p er or g a n a n d 5 l esi o ns i n t ot al, 
r e pr es e nt ati v e of all i n v ol v e d or g a ns, s h o ul d b e i d e ntifi e d as t ar g et l esi o ns a n d r e c or d e d a n d 
m e as ur e d at b as eli n e. L esi o ns m ust b e a c c ur at el y m e as ur e d i n 1 di m e ns i o n wit h a mi ni m u m si z e 
of 1 0 m m b y C T or M RI (sli c e t hi c k n ess n o gr e at er t h a n 5 m m), 2 0 m m b y c h est  x-r a y. N o d es 
m ust h a v e a s h ort a xis >  1 5 m m. T h e s h ort a xis s h o ul d b e i n cl u d e d i n t h e s um of t h e l esi o ns i n t h e 
c al c ul ati o n of r es p o ns e. N o d es t h at s hri n k t o < 1 0 m m ar e c o nsi d er e d n or m al. T ar g et l esi o ns 
s h o ul d b e s el e ct e d o n t h e b asis of t h eir si z e, b e  r e pr es e nt ati v e of all t h e i n v ol v e d or g a ns, a n d 
s h o ul d b e l esi o ns t h at c a n b e f oll o w e d wit h r e pr o d u ci bl e r e p e at e d m e as ur e m e nts.  
L ytic b o ne lesi o ns or mi xe d l ytic- blastic lesi o ns, wit h i de ntifi a ble s oft tiss ue c o m p o ne nts , t hat ca n be 
e val uate d b y cr oss secti o na l i ma gi n g tec h ni q ues s uc h as C T or M RI ca n be c o nsi dere d tar get lesi o ns if 
t he s oft tiss ue c o m p o ne nt meets t he defi niti o n of meas ura bility as defi ne d a b o ve. C ystic lesi o ns 
t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d as tar get lesi o ns. H o we ver, if n o n-c ystic 
lesi o ns are prese nt, t hese are preferre d f or selecti o n as tar get lesi o ns. Lesi o ns i n pre vi o usl y irra diate d 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
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C O N FI D E N TI A L 
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areas or areas s u bject t o ot her l oc o-re gi o nal t hera p y are us uall y n ot  c o nsi dere d meas ura ble u nless t here 
has bee n de m o nstrate d pr o gr essi o n of t hat lesi o n.  
N o n-tar get lesi o ns .  
All ot h er l esi o ns, i n cl u di n g s m all l esi o ns < 1 0  m m or p at h ol o gi c al l y m p h n o d es m e as uri n g > 1 0 
m m  t o  <  1 5  m m  i n  s h ort  a xis,  as  w ell  as  tr ul y  n o n- m e as ur a bl e  l esi o ns,  w hi c h  i n cl u d e  
l e pt o m e ni n g e al  dis e as e,  as cit es,  pl e ur al  or  p eri c ar di al  eff usi o n,  i nfl a m m at or y  br e ast  dis e as e,  
l y m p h a n giti c i n v ol v e m e nt of s ki n or l u n g, a b d o mi n al m ass es i d e ntifi e d b y p h ysi c al e x a m t h at ar e 
n ot m e as ur a bl e b y r e pr o d u c i bl e i m a gi n g t e c h ni q u es. 
8. 1. 3: Met h o ds f or E v al u ati o n of Me as ur a ble Dise ase 
All meas ure me nts s h o ul d be ta ke n a n d rec or de d i n me tric n otati o n, usi n g a r uler, cali pers, or di gital 
meas ure me nt t o ol. All baseli ne e val uati o ns s h o ul d be perf or me d as cl osel y as p ossi ble t o t he be gi n ni n g 
of treat me nt a n d ne ver m ore t ha n 4 wee k s bef ore t he be gi n ni n g of t he treat me nt. 
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haracterize eac h i de ntifie d 
a n d re p orte d lesi o n at baseli ne a n d d uri n g f o ll o w- u p. I ma gi n g- base d e val uati o n is preferre d t o 
e val uati o n b y cli nical e xa mi nati o n w he n b ot h met h o ds  ha ve bee n use d t o assess t he a nti-t u m or effect 
of a treat me nt. 
Cli nical lesi o ns . Cli nical lesi o ns will o nl y be c o nsi dere d meas ura ble w h e n t he y are s u p erfi ci al ( e. g., 
s ki n n o d ul es a n d p al p a bl e l y m p h n o d es). F or t h e c as e of s ki n lesi o ns, d oc u me ntati o n b y c ol or 
p h ot o gra p h y, i ncl u di n g a r uler t o esti mate t he size of t he lesi o n, is rec o m me n de d. 
C hest x-ra y . Lesi o ns o n c hest x-ra y are acce pta ble as meas ura ble lesi o ns w he n t he y are clearl y 
defi ne d a n d s urr o u n de d b y aerate d l u n g; h o we ver, C T is prefera ble. 
C o n ve nti o nal C T a n d M RI . T hese tec h ni q ues s h o ul d be perf or me d wit h c uts of 1 0 m m or less i n slice 
t hic k ness c o nti g u o usl y. S piral C T s h o ul d be perf or me d usi n g a 5 m m c o nti g u o us rec o nstr ucti o n 
al g orit h m. T his a p plies t o t u m ors of t he c hest, a b d o m e n, a n d p el vis. H e a d a n d n e c k t u m ors a n d t h os e 
of e xtr e miti es us u all y r e q uir e s pecifi c pr ot o c ols. 
8. 2  
Res p o nse Criteri a 
8. 2. 1  E v al u ati o n of T ar get Lesi o ns 
C o m plete R es p o ns e ( C R) : 
 Dis a p p e ar a n c e of all t ar g et l esi o ns. A n y p at h ol o gi cal l y m p h n o d e m ust h a v e r e d u cti o n i n s h ort a xis 
t o < 1 0 m m 
Partial Res p o nse ( P R) :  
 At least a 3 0 % decrease i n t he s u m of t he di a m et ers of t ar g et l esi o ns, t a ki n g as r ef er e n c e t h e 
b as eli n e s u m di a m et ers.  Pr o gressi ve Disease ( P D):   

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
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C O N FI D E N TI A L 
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 At l e ast a 2 0 % i n cr e ase i n t h e s u m of t h e di a met ers of t ar g et l esi o ns, t a ki n g as r ef er e n c e t h e 
s m all e st s u m o n st u d y wit h at l e a st a 5 m m a b s ol ut e i n cr e a s e i n t h e s u m of all 
l e si o n s. T h e a p p e ar a n c e of o n e or m or e n e w l e si o n s * d e n ot e s di s e a s e pr o gr e s si o n. 
* Defi niti o n of Ne w Lesi o n : T he fi n di n g of a ne w lesi o n s h o ul d be u ne q ui v ocal (i.e. n ot d ue t o 
differe nce i n sca n ni n g tec h ni q ue, i ma gi n g m o dalit y, or fi n di n gs t h o u g ht t o re prese nt s o met hi n g ot her 
t ha n t u m or (e x: ne w b o ne lesi o ns may be heali n g or flare of pre-e x isti n g lesi o ns). H owe ver, a lesi o n 
i de ntifie d o n a f oll o w- u p sca n i n a n a nat o mical l ocati o n t hat was n ot sca n ne d at baseli ne is 
c o nsi dere d ne w a n d will i n dicate P D. If a ne w lesi o n is e q ui v ocal ( beca use of s mall size, etc.), 
f oll o w- u p e val uati o n will clarif y if it tr ul y re prese nts ne w disease a n d if P D is c o nfir me d, 
pr o gressi o n s h o ul d be declare d usi n g t he date of  t he i nitial sca n o n w hic h t he lesi o n was disc o vere d. 
St a bl e Dis e ase ( S D):   
 N eit h er s uffi ci e nt s hri n k a g e t o q u alif y f or P R n or s uffi ci e nt i n cr e as e t o q u alif y f or P D, t a ki n g as 
r ef er e n c e t h e s m all est s u m di a m et ers w hile o n st u d y. 
U n k n o w n ( U N):  Assess me nt of tar get lesi o ns ca n n ot be ma de d ue t o i ns ufficie nt or u ne val ua ble data. 
I n t his case, a c o ncise e x pla nati o n m ust be gi ve n. 
N ote : If t u m or res p o nse data is missi n g f or tar get lesi o ns, t he o verall assess me nt m ust be U N u nless 
t here is ne w disease t hat w o ul d res ult i n a n o verall assess me nt of P D. H o we ver, if t here is missi n g or 
u ne val ua ble data f or n o n-ta r get lesi o ns, b ut data is a vaila ble f or all tar get le si o ns, t he o verall res p o nse 
f or t hat ti me p oi nt will be assi g ne d base d o n t he s u m L D of all tar get lesi o ns. A d diti o nall y, t he 
assess me nt of C R ca n n ot be ma de if t her e is missi n g or  u ne val ua ble data f or n o n-tar get lesi o ns. I n t his 
case, t he o verall asse ss me nt w o ul d be P R. 
8. 2. 2  E v al u ati o n of N o n- T ar get Lesi o ns 
C o m pl et e Res p o ns e ( C R):  Disa p peara nce of all n o n-tar get lesio ns. All l y m p h n o d es m ust b e n o n-
p at h ol o gi c al i n si z e ( < 1 0 m m s h ort a xis). 
I n c o m pl et e R es p o ns e/ St a bl e Dis e as e ( S D): Persiste nce of o ne or m ore n o n-tar get lesi o ns. 
Pr o gr essi v e Dis e as e ( P D):  A p p e ar a n c e of o n e or m or e n e w l esi o ns * ( n e w l esi o ns m ust b e > 
sli c e t hi c k n ess) a n d/ or u ne q ui v ocal pr o gressi o n of e xisti n g n o n-tar get lesi o ns. O v er all l e v el of 
s u bst a nti al w ors e ni n g t h at m erits dis c o nti n u ati o n of t h er a p y. A us ef ul t est t h at c a n b e a p pli e d 
w h e n  ass essi n g  n o n-t ar g ets  f or  u n e q ui v o c al  pr o gr essi o n  is  t o  c o nsi d er  if  t h e  i n cr e as e  i n  
o v er all  dis e as e  b ur d e n  b as e d  o n  t h e  c h a n g e  i n  n o n- m e as ur a bl e  dis e as e  is  c o m p ar a bl e  i n  
m a g nit u d e t o t h e i n cr e as e t h at  w o ul d b e r e q uir e d t o d e cl are P D f or m e as ur a bl e dis e as e. 
U n k n o w n ( U N):  Assess me nt of n o n-tar get lesi o ns ca n n ot be ma de d ue t o i ns ufficie nt or u ne val ua ble 
data. I n t his case, a c o ncise e x pla nati o n m ust be gi ve n. 
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
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3 7
* Defi niti o n of Ne w Lesi o n : T he fi n di n g of a ne w lesi o n s h o ul d be u ne q ui v ocal (i.e. n ot d ue t o 
differe nce i n sca n ni n g tec h ni q ue, i ma gi n g m o dalit y, or fi n di n gs t h o u g ht t o re prese nt s o met hi n g ot her 
t ha n t u m or (e x: ne w b o ne lesi o ns may be heali n g or flare of pre-e xis ti n g lesi o ns). If a ne w lesi o n is 
e q ui v ocal ( beca use of s mall size, et c.), f oll o w- u p e val uati o n will cl arif y if it tr ul y re prese nts ne w 
disease a n d if P D is c o nf ir me d, pr o gressi o n s h o ul d be declare d usi n g t he date of t he i nitial sca n o n 
w hic h t he lesi o n was disc o vere d.  
8. 2. 3  E v al u ati o n of Best O ver all Res p o nse 
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he tr e at me nt u ntil dis e as e 
pr o gr essi o n/r e c urr e n c e (t a ki n g as r ef er e n c e f or pr o gressi ve disease t he s mallest meas ure me nts 
rec or de d si nce t he treat me nt st art e d). T h e p arti ci p a nt's b est r es p o ns e assi g n m e nt will d e p e n d o n t h e 
ac hie ve me nt of b ot h meas ure me n t a n d c o nfir mati o n criteria. 
T a ble 3. E v al u ati o n of Best  O ver all Res p o nse F or P atie nts wit h Me as ur a ble Dise ase  
 
T ar get 
Lesi o ns 
N o n- T ar get 
Lesi o ns 
Ne w 
Lesi o ns 
O v e r all 
Res p o nse 
Best O ver all Res p o nse f or 
w he n C o nfir m ati o n is 
Re q uire d: 
C R
 C R
 N o
 C R
 
> 4 w ks c o nfir mati o n 
C R 
N o n- C R/ N o n- P D 
N o
 P R
 
> 4 w ks c o nfir mati o n 
C R  N ot
 
e val uate
d  
N o
 P R
P R 
N o n- C R/ N o n-
P D/ N ot 
e val uate d 
N o
 P R
 
S D
 N o n- C R/ N o n-
P D/ N ot 
e val uated  
N o
 S D
 
D oc u me nte d at least o nce 
> 4 w ks fr o m b as eli ne 
P D
 A n y   
Yes or N o 
P D  
N o pri or S D, P R or C R 
A n y  P D *
 
Yes or N o 
P D
A n y  A n
y  Y es
  P D
* 
I n e xce pti o nal cir c u mst a n c es, u n e q ui v o c al pr o gr essi o n i n n o n-t ar g et lesi o ns ma y b e 
a c c e pte d as dis e as e pr o gr essi o n. 
 
N ote :   Partici pa nts wit h a gl o b al d et eri or ati o n of h e alt h st at us r e q uiri n g dis c o nti n u ati o n of 
tr e at m e nt wit h o ut o bj e cti v e e vi d e n c e of dis e as e pr o gr essi o n at t h at ti m e s h o ul d b e 
r e p ort e d as "sy m pt o m atic deteri or ati o n". E v er y eff ort s h o ul d b e ma d e t o d o c u me nt t h e 
o bj ecti ve pr o gr essi o n e v e n after disc o nti n uati o n of treat me nt. 
 
T a ble 4. E v al u ati o n of  Best O ver all Res p o nse F or P atie nts wit h N o n- Me as ur a ble Dise ase 
 
N o n- T ar get Lesi o ns 
Ne w 
Lesi o ns 
O v e r all Res p o nse 
C R 
N o
 C R
 

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C O N FI D E N TI A L 
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3 8
N o n- C R/ n o n- P D 
N o
 N o n C R/ n o n- P D
 
N ot all e val uate d 
N o
 N ot
 
e val uate d
 
U ne q ui v ocal P D  
Yes or N o 
P D 
A n y
 Yes
 
P D
 
N o n- C R/ n o n- P D is preferre d o ver sta ble disease f or n o n-tar get disease si nce S D is 
i ncreasi n gl y use d a n e n d p oi nt f or assess me nt of efficac y i n s o me trials s o t o assi g n t his 
cate g or y w he n n o lesi o ns ca n be  meas ure d is n ot a d vise d.  
8. 3  
D ur ati o n of Res p o nse 
D ur ati o n  of  o v er all  r es p o ns e :  T he  d ur ati o n  of  o v er all  r es p o ns e  is  m eas ur e d  fr o m  t h e  ti me  
meas ure me nt criteria are met f or C R or P R ( w hic he v er is first rec or de d) u nt il t he first date t hat 
rec urre nce or P D is o bjecti vel y d oc u me nte d, t a ki n g as r ef er e n c e f or P D t h e s mall est me as ur e m e nts 
r e c or d e d si nce t he treat me nt starte d. 
D ur ati o n of o v er all c o m pl et e r es p o ns e: T he d urati o n of o verall C R is meas ure d fr o m t he ti me 
meas ure me nt criteria are first m et f or C R u ntil t h e first d at e t h at r e c urr e nt dis e as e is o bj e cti v el y 
d oc u me nte d. 
D ur ati o n of st a bl e dis e as e : St a bl e dis e as e is m e as ur e d fr o m t h e st art of t h e treat me nt u ntil t he 
criteria f or pr o gressi o n are met, ta ki n g as refere nce t he s mallest meas ure me nts rec or de d si nce t he 
treat me nt starte d. 
8. 4  
Pr o gressi o n- Free S ur vi v al 
 
Pr o gressi o n- Free S ur vi val ( P F S) is defi ne d as t he d u rati o n of ti me fr o m start of treat me nt t o ti me of 
o bjecti ve disease pr o gressi o n or deat h  
8. 5  
O ver all S ur vi v al 
 
O verall s ur vi val ( O S) is defi ne d as t he d urati o n of ti me fr o m start of treat me nt t o deat h. 

test (if a p plica ble). St u dies  t o be  d o ne  at t he start of  eac h c y cle of  treat me nt i ncl u de C B C , 
L F Ts, B U N, Cr, calci u m, a n d electr ol ytes.  
f  
f  T u m or Me as ure me nt – Baseli ne sca ns ca n be perf or me d u p t o 2 8 da ys pri or t o start of 
treat me nt. F oll o w- u p sca ns s h o ul d be perf or me d wit hi n 1 0 da ys of t he start of c ycles 3, 5, 7, 
9, etc. T his ca n als o be t h o u g ht of as f oll o wi n g c y cles 2, 4, 6, 8, etc. 
g  
Circ ul ati n g T u m or Cell Ass a y –  Sa m ples f or C T C a nal ysis will be dra w n Da y 1 pri or t o t hera p y, 
Da y 1 t hree h o urs after d ose, Da y 8, Da y 1 5, C y cle 2 da y 1, C ycle 3 da y 1, C ycle 4 da y 1, 
C ycle 5 da y 1, t he n e ver y 2 c ycles, a n d at e n d of st u d y visit, see Secti o n 7. 2 
      C T C c ollecti o n at M G H o nl y. 
h  Assess me nt of Re q uire me nts f or Re pe at Bi o ps y – T o be perf or me d at t he ti me of 
pr o gressi o n, see Secti o n 7. 1. 1. I ncl u des i nter ve nti o nal ra di ol o g y re vie w of fil ms f or bi o ps y, 
h ol di n g of a nti- platelet a n d a nti-c oa g ul ati o n me dicati o ns, assess me nt of P T, P L Ts. Re pe at 
bi o ps y  s h o ul d be perf or me d as i n Secti o n 7. 1 an d s u b mitte d f or m olec ular a nal ysis a n d t he 
patie nt s h o ul d be see n f or a f oll o w- u p visit t o assess p ost- bi o ps y c o m plicati o ns at 7 da ys ( ± 
2 da ys) a n d at ≥ 3 0 da ys p ost- bi o ps y 
i  
S ur vi v al f oll o w- u p - After disc o nti n uati o n fr o m t he st u d y f or a n y reas o n, w here p ossi ble 
t he patie nt, patie nt’s fa mil y, or t he patie nt’s c urre nt p h ysicia n m ust be c o ntacte d e ver y 1 2 
wee ks f or s ur vi val i nf or mati o n u ntil deat h. All s u bse q ue nt c he m ot h era p y, ra diati o n, s ur gical 
or ot her a nti-ca ncer t hera pies are t o be c oll ecte d u ntil deat h. A state me nt of deat h f or m 
s h o ul d be s u b mitte d at a n y p oi nt d uri n g t he st u d y w he n a patie nt has die d.  I n a d diti o n, a n y 
patie nt w h o disc o nti n ue d st u d y treat me nt  f or reas o ns ot her t ha n o bjecti ve disease 
pr o gressi o n s h o ul d c o nti n ue, w here p ossi ble, t o  ha ve o bjecti ve t u m or assess me nts e ver y 8-
1 2 wee ks i n or der t o c ollect i nf or mati o n o n pr o gressi o n of disease. 
 
 
 
 
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3 
 
I N D # 1 1 0 7 2 0 
C O N FI D E N TI A L 
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4 1 
1 0.  D A T A A N D S A F E T Y M O NI T O RI N G  
1 0. 1  D at a Re p orti n g 
1 0. 1. 1  Met h o d  
T h e Q A C T will c oll e ct, ma n a g e, a n d m o nit or d at a f or t his st u d y.  
1 0. 1. 2  D at a  S u b missi o n  
T he sc he d ule f or c o m pleti o n a n d s u b missi o n of case re p ort f or ms ( pa per or 
electr o nic) t o t he Q A C T is as f oll o ws: 
F or m 
S u b missi o n Ti meli ne 
Eli gi bilit y C h e c klist  
C o m pl et e pri or t o re gistrati o n wit h Q A C T 
O n St u d y F or m 
Wit hi n 1 4 d a ys of r e gistr ati o n 
B as eli n e Ass ess me nt F or m  
Wit hi n 1 4 da ys of r e gistr ati o n 
Tr eat me nt F or m 
Wit hi n 1 0 da ys of t he last da y of t he c ycle 
A d verse E ve nt Re p ort F or m  
Wit hi n 1 0 da ys of t he last da y of t he c ycle 
Res p o nse Assess me nt F or m 
Wit hi n 1 0 da ys of t he c o m pleti o n of t he c ycle 
re q uire d f or res po nse e val uati o n 
Off Treat me nt/ Off St u d y F or m
Wit hi n 1 4 da ys of c o m pleti n g treat me nt or 
bei n g ta ke n off st u d y f or a n y reas o n 
F oll o w u p/ S ur vi val F or m  
Wit hi n 1 4 da ys  of t he pr ot oc ol defi ne d f oll o w 
u p visit date or call 
1 0. 2  S afet y Meeti n gs 
 
T he D F/ H C C Data a n d Safet y M o nit ori n g C o m mitt ee ( D S M C) will re vie w a n d m o nit or t o xicit y 
a n d accr ual data fr o m t his trial. T he c o m mittee is c o m p ose d of cli nical s pecialists wit h 
e x perie nce i n o nc ol o g y a n d w h o ha ve n o direct re lati o ns hi p wit h t he st u d y. I nf or mati o n t hat 
raises a n y q uesti o ns a b o ut partici pa nt safet y will be a d dresse d wit h t he Pri nci pal I n vesti gat or a n d 
st u d y tea m. 
 
T he D S M C will meet q uarterl y a n d/ or m ore ofte n if  re q uire d t o re vie w t o xicit y a n d accr ual data.  
I nf or mati o n t o be pr o vi de d t o t he c o m mittee ma y i ncl u de:  u p-t o- date partici pa nt accr ual; c urre nt 
d ose le vel i nf or mati o n; D L T i nf or mati o n; all gra d e 2 or hi g her u ne x pecte d  a d verse e ve nts t hat 
ha ve bee n re p orte d; s u m mar y of all deat hs occ urr i n g wit hi n 3 0 da ys f or P hase I or II pr ot oc ols; 
f or ge ne tra nsfer pr ot oc ols, s u m mar y of all deat hs w hile bei n g treate d a n d d uri n g acti ve f oll o w-

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
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C O N FI D E N TI A L 
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4 2
u p; a n y res p o nse i nf or mati o n; a u dit res ults, a n d a s u m mar y pr o vi de d b y t he st u d y tea m. Ot her 
i nf or mati o n (e. g. sca ns, la b orat or y val ues) will be pr o vi de d u p o n re q uest.  
1 0. 3  M o nit ori n g  
 
I n v ol ve me nt i n t his st u d y as a partici pati n g in vesti gat or i m plies acce pta nce of p ote ntial a u dits 
or i ns pecti o ns, i ncl u di n g s o ur ce data verificati o n, b y re prese n tati ves desi g nate d b y t he D F/ H C C 
O verall Pri nci pal I n vesti gat or ( or Pr ot oc ol C hair) or D F/ H C C. T he p ur p ose of t hese a u dits or 
i ns pecti o ns is t o e xa mi ne st u d y-relate d acti vities an d d oc u me nts t o deter mi ne w het her t hese 
acti vities were c o n d ucte d a n d data were rec o r de d, a nal yze d, a n d acc uratel y re p orte d i n 
acc or da nce wit h t he pr ot oc ol, i nstit uti o nal p o lic y, G o o d Cli nical Practice ( G C P), a n d a n y 
a p plica ble re g ulat or y re q uire me nts.   
 
All data will be m o nit ore d f or ti meli ness of  s u b missi o n, c o m plete ness, a n d a d here nce t o 
pr ot oc ol re q uire me nts. M o nit ori n g will be gi n at t he ti me of partici pa nt re gistrati o n a n d will 
c o nti n ue d uri n g pr ot oc ol perf or ma nce a n d c o m pleti o n.  
1 1.  R E G U L A T O R Y C O N SI D E R A TI O N S 
1 1. 1  Pr ot oc ol Re vie w a n d A me n d me nts 
T his pr ot o c ol, t h e pr o p os e d i nf or m e d c o ns e nt a n d all f or ms of p arti ci p a nt i nf or m ati o n r el at e d 
t o t h e st u d y ( e. g., a d v ertis e m e nts us e d t o r e cr uit p arti ci p a nts) a n d a n y ot h er n e c ess ar y 
d o c u m e nts m ust b e s u b mitt e d, r e vi e w e d a n d a p pr o v e d b y a pr o p er l y c o nstit ut e d I R B 
g o v er ni n g e a c h st u d y l o c ati o n.  
A n y c h a n g es m a d e t o t h e pr ot o c ol m ust b e s u b mitt e d as a me n d me nts a n d m ust b e a p pr o v e d 
b y t h e I R B pri or t o i m pl e m e nt ati o n. A n y c h a n g es i n st u d y c o n d u ct m ust b e r e p ort e d t o t h e 
I R B. T h e D F/ H C C O v er all Pri n ci p al I n v esti gat or will diss e mi n at e pr ot o c ol a me n d m e nt 
i nf or m ati o n t o all p arti ci p ati n g i n v esti g at ors.  
All d e cisi o ns of t h e I R B c o n c er ni n g t h e c o n d u ct of t h e st u d y m ust b e ma d e i n writi n g. 
1 1. 2  I nf or me d C o nse nt 
 
All p arti ci p a nts m ust b e pr o v i d e d a c o ns e nt f or m d es cri bin g t his st u d y a n d pr o vi di n g 
s uffi ci e nt i nf or m ati o n f or p art i ci p a nts t o m a k e a n i nf or m e d d e cisi o n a b o ut t h eir 
p arti ci p ati o n i n t his st u d y. T h e f or m al c o ns e nt of a p arti ci pa nt, usi n g t h e I R B a p pr o v e d 
c o ns e nt f or m, m ust b e o bt ai n e d b ef or e t h e p arti ci p a nt is i n v ol v e d i n a n y st u d y-r el at e d 
pr o c e d ur e. T h e c o ns e nt f or m m ust b e si g n e d a n d d at e d b y t h e p arti ci p a nt or t h e 
p arti ci p a nt’s l e g all y a ut h ori z e d r e pr es e nt ati v e,  a n d b y t h e p ers o n o bt ai ni n g t h e c o ns e nt. T h e 
p arti ci p a nt m ust b e gi v e n a c o p y of t h e si g n e d a n d d at e d c o ns e nt d o c u m e nt. T h e ori gi n al 
si g n e d c o p y of t h e c o ns e nt d o c u m e nt m ust b e r et ai ne d i n t he me dical rec or d or researc h file.  
1 1. 3  Et hics a n d G o o d Cli nic al Pr actice ( G C P) 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
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C O N FI D E N TI A L 
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T his st u d y is t o b e c o n d u ct e d a c c or di n g t o t h e f oll o wi n g c o nsi d er ati o ns, w hi c h 
r e pr es e nt g o o d a n d s o u n d r es e ar c h pr a cti c e: 
 
E 6 G o o d Cli ni c al Pr a cti c e:  C o ns oli d at e d G ui d a n c e 
w w w.f d a. g o v/ d o w nl o a ds/ R e g ul at or yI nf or mati o n/ G u i d a n c es/ U C M 1 2 9 5 1 5. p df  
 
U S C o d e of F e d er al R e g ul ati o ns ( C F R) g o v er ni n g cli ni c al st u d y c o n d u ct a n d 
et hi c al pri n ci pl es t h at h a v e t h eir or i gi n i n t h e D e cl arati o n of H elsi n ki 
o  Titl e 2 1 P art 1 1 – El e ctr o ni c R e c or ds; El e ctr o ni c Si g n at ur es 
w w w. a c c ess. g p o. g o v/ n ar a/ cfr/ w ai si d x 0 2/ 2 1 cfr 1 1 0 2. ht ml 
o  Titl e 2 1 P art 5 0 – Pr ot e cti o n of H u m a n S u bj e cts 
w w w. a c c ess. g p o. g o v/ n ar a/ cfr/ w ai si d x _ 0 2/ 2 1 cfr 5 0 _ 0 2. ht ml  
o  Titl e 2 1 P art 5 4 – Fi n a n ci al Dis c l os ur e b y Cli ni cal I n v esti g at ors 
w w w. a c c ess. g p o. g o v/ n ar a/ cfr/ w ai si d x _ 0 2/ 2 1 cfr 5 4 _ 0 2. ht ml  
o  Titl e 2 1 P art 5 6 – I ns tit uti o n al R e vi e w B o ar ds 
w w w. a c c ess. g p o. g o v/ n ar a/ cfr/ w ai si d x 0 2/ 2 1 cfr 5 6 0 2. ht ml  
o  Titl e 2 1 P art 3 1 2 – I n v esti g ati o n al N e w Dr u g A p pli c ati o n 
w w w. a c c ess. g p o. g o v/ n ar a/ cfr/ w aisi d x _ 0 2/ 2 1 cfr 3 1 2 _ 0 2. ht ml   
 
St at e l a ws 
 
D F/ H C C r es e ar c h p oli ci es a n d pr o c e d ur es        
htt p:// w w w. df h c c. h ar v ar d. e d u/ cli ni c al-r es e ar c h-s u p p ort/ cli ni c al-r es e ar c h- u nit-
cr u/ p oli ci es- a n d- pr o c e d ur es/   
It is u n d erst o o d t h at d e vi ati o ns fr o m t he pr ot o c ol s h o ul d b e a v oi d e d, e x c e pt w h e n 
n e c ess ar y t o eli mi n at e a n i m m e di at e h a z ar d t o a r es e ar c h p arti ci p a nt. I n s u c h c as e, 
t h e d e vi ati o n m ust b e r e p ort e d t o t h e I R B a c c or di n g t o t h e l o c al  r e p orti n g p oli c y.  
1 1. 4  St u d y D oc u me nt ati o n 
 
T he i n vesti gat or m ust pre pare a n d mai ntai n a de q uate a n d acc urate case hist ories desi g ne d t o 
rec or d all o bser vati o ns a n d ot her data perti ne nt t o t he st u d y f or eac h researc h partici pa nt. T his 
i nf or mati o n e na bles t he st u d y t o be f ull y d oc u me nte d a n d t he st u d y data t o be s u bse q ue ntl y 
verifie d. 
 
Ori gi nal s o urce d oc u me nts s u p p orti n g e ntries i n t h e case re p ort f or ms i ncl u de b ut are n ot li mite d 
t o h os pital rec or ds, cli nical c harts, la b orat or y a n d p har mac y rec or ds, rec or de d data fr o m 
a ut o mate d i nstr u me nts, micr ofic hes, p h ot o gra p hi c ne gati ves, micr ofil m or ma g netic me dia, 
a n d/ or x-ra ys.  
1 1. 5  Rec or ds Rete nti o n 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
4 4
 
All st u d y-r el at e d d o c u m e nts m ust  b e r et ai n e d f or t h e m a xi m u m p eri o d r e q uir e d b y a p pli c a bl e 
f e d er al r e g ul ati o ns a n d g ui d eli nes or i nstit uti o n al p oli ci es.  
1 2.  S T A TI S TI C A L C O N SI D E R A TI O N S  
1 2. 1  St u d y Desi g n/ E n d p oi nts 
 
T his is a pil ot st u d y e xa mi ni n g t he feasi bilit y of  usi n g ac q uisiti o n of a resista nce m utati o n as t he 
pri mar y e n d p oi nt f or a cli nical tr ial. N S C L C patie nts wit h E G F R m utati o ns are hi g hl y li kel y t o 
res p o n d well t o E G F R T K i n hi biti o n wit h eit her first- ge nerati o n E G F R T KIs (erl oti ni b, gefti ni b) 
or wit h t he sec o n d- ge nerati o n irre versi ble i n hi bit or BI B W 2 9 9 2, b ut resista nce ulti matel y 
de vel o ps, see Bac k gr o u n d. C urre nt literat ure c o nsiste ntl y esti mates t hat fift y perce nt of 
resista nce t o first- ge nerati o n T KIs is d ue t o t he de vel o p me nt of a sec o n dar y E G F R m utati o n i n 
e x o n 2 0, t he p oi nt m utati o n T 7 9 0 M. Si nce t he n o vel  irre versi ble pa n- H ER i n hi bit or BI B W 2 9 9 2 
is hi g hl y acti ve i n l u n g ca ncers har b ori n g acti vati n g E G F R m utati o ns a n d ca n i n hi bit t he E G F R 
T 7 9 0 M m oiet y i n pre-cli nical st u dies, a ke y q uesti o n is w het her BI B W 2 9 9 2 ca n s u p press t he 
de vel o p me nt of cli nical resista nce via T 7 9 0 M i n l u n g ca ncer patie nts.  
 
T he st u d y will c o nsist of 2 4 T KI- naï ve patie nts wit h m utati o ns i n E G F R. Gi ve n o ur relati vel y 
lar ge p o p ulati o n of referral patie nts at D F/ H C C wit h E G F R m utatio ns a n d t he c olla b orati o n wit h 
a fe w select ot her ce nters, T his sa m ple size was fe lt t o be feasi ble t o e nr oll wit hi n a t hree year 
ti me peri o d. Eac h s u bject will be e x pecte d t o re mai n o n t hera p y f or a p pr o xi matel y 1 0 m o nt hs. 
T heref ore wit hi n 3. 5 years it is e x pecte d t hat we will c o m plete at least 1 6 of t he pr o gressi o n 
bi o psies. 
 
All patie nts will i nitiall y be treate d wit h BI B W 2 9 9 2 at 4 0 m g dail y, t h o u g h as i n ot her st u dies 
wit h t his c o m p o u n d, d ose escalati o n t o 5 0 m g w ill be per mitte d f or i n di vi d ual patie nts after o ne 
c ycle if t here are mi ni mal a d verse e ve nts at  4 0 m g. T u m or tiss ue bi o ps y f or c o m pre he nsi ve 
ge n o mic pr ofili n g is ma n dat or y at t he ti me of ac q uire d resista nce (cli nical pr o gressi o n). T he 
pri mar y e n d p oi nt will be t o deter mi ne t he pr o p orti o n of patie nts wit h T 7 9 0 M resista nce 
m utati o ns at t he ti me of pr o gressi o n. T he data c o llecte d will be vital i n deter mi ni n g t he o pti mal 
strate g y f or f ut ure st u dies c o m pari n g t he efficac y of BI B W 2 9 9 2 t o first- ge nerati o n E G F R T KIs. 
 
T he pri mar y o bjecti ve is: 
1.  T o deter mi ne t he pr o p orti o n of patie nts t hat  ha ve a T 7 9 0 M m utatio n o n t heir pr o gressi o n 
bi o ps y a n d t o c o m pare t his wit h p u blis he d data  f or first- ge nerati o n E G F R t yr osi ne ki nase 
i n hi bit ors 
 
T he sec o n dar y o bjecti ves are: 
1.  T o esti mate t he res p o nse rate 
2.  T o esti mate t he pr o gressi o n-free a n d o verall s ur vi val 
3.  T o descri be t he safet y of o btai ni n g re peat t u m or bi o psies f or ge n ot y pe a nal ysis 
4.   T o descri be ot her mec ha nis ms of resist a nce ( besi des T 7 9 0 M) o bser ve d o n t he pr o gressi o n 
bi o psies 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
4 5
5.  T o e x pl ore t he res ults of e x peri me ntal C T C- deri ve d ge n ot y pe assesse d fr o m serial bl o o d 
sa m ples ta ke n d uri n g t hera p y wit h BI B W 2 9 9 2 a n d t o c o m pare C T C- deri ve d res ults wit h 
t h ose fr o m t he pr o gressi o n bi o psies 
1 2. 2  S a m ple Size/ P o wer C alc ul ati o n f or t he Pri m ar y E n d p oi nt 
 
Base d o n pri or data t he rate of T 7 9 0 M at t he ti me of pr o gressi o n o n first- ge nerati o n E G F R T KIs 
( gefit ni b/erl oti ni b) is 5 0 %.2 6, 2 8, 2 9 
 
T he n ull h y p ot hesis is t hat BI B W  2 9 9 2 t hera p y yiel ds t he sa me rate of T 7 9 0 M at t he ti me of 
pr o gressi o n ( 5 0 %).  
 
It is e x pecte d t hat a p pr o xi matel y 6 of t he patie nts will n ot u n der g o a re peat bi o ps y, des pite 
c o nse nti n g t o t he bi o ps y at t he ti me of e nr oll me n t. Reas o ns f or n ot ha vi n g a bi o ps y ma y i ncl u de 
patie nt wit h dra wal of c o nse nt or n ot ha vi n g a lesi o n t hat is safe a n d feasi ble t o bi o ps y at t he ti me 
of pr o gressi o n. T heref ore, p o wer calc ulati o ns were perf or me d ass u mi n g t here w o ul d be 1 8 
bi o psies perf or me d.  
 
Wit h 1 8 bi o psies a n d a si g nifica nce le vel of 0. 0 5, a n d usi n g a o ne-si de d bi n o mial test, we ca n 
ac hie ve 8 6 % p o wer t o detect t he alter nati ve h y p ot hesis t hat BI B W 2 9 9 2 t hera p y yiel ds a 2 0 % 
rate of T 7 9 0 M at t he ti me of pr o gressi o n. T he alter nate h y p ot hesis i m plies t hat BI B W 2 9 9 2 ma y 
be better at s u p pressi n g T 7 9 0 M as a m ec ha nis m of ac q uire d dr u g resista nce.  
1 2. 3  D at a t o Be A n al yze d 
E v al u a bl e f or t h e pri m ar y e n d p oi nt ( a c q uisiti o n of T 7 9 0 M): All p ati e nts w h o u n d er g o a 
r e p e at bi o ps y will b e e v al u a bl e f or a c q uisiti o n of T 7 9 0 M. If t h e r es ults of t his t est ar e n ot 
i nt er pr et a bl e d u e t o t e c h ni c al f ail ur e of t h e ass a y, T 79 0 M will b e ass u m e d t o b e pr es e nt (t h e 
m or e c o ns er v ati v e ass u m pti o n i n  t er ms of aff e cti n g t h e pri mary e n d p oi nt). P a ti e nts t h at d o 
n ot u n d er g o a r e p e at bi o ps y will n ot b e i n cl u d e d i n t h e pri m ar y e n d p oi nt a n al ysis. 
E v al u a bl e f or t o xi cit y . All p arti ci p a nts w h o r ec ei v e at l e ast o n e d os e of st u d y tr e at m e nt will 
b e e v al u a bl e f or t o xi cit y fr o m t h e ti m e of t h eir first tr e at m e nt. 
 
E v al u a bl e f or o bj e cti v e r es p o ns e . O nl y t h os e p arti ci p a nts wh o h a v e m e as ur a bl e dis e as e 
pr es e nt at b as eli n e, h a v e r e c ei v e d at l e ast o n e c y cl e of t h er a p y, a n d h a v e h a d t heir dise as e 
r e- e v al u at e d will be c o nsi d er e d e valu a bl e f or r es p o ns e. T hese p arti ci p a nts will h a v e t h eir 
r es p o ns e cl assifi e d a c c or di n g t o t h e d efi niti o ns st at e d b el o w. ( N ot e: P arti ci p a nts w h o 
e x hi bit o bj e cti v e dis e as e pr o gr essi o n or di e pri or t o  t h e e n d of c y cl e 1 will als o b e c o nsi d er e d 
e v al u a bl e.) 
1 2. 4  P atie nt Dis p ositi o n 
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
4 6
A detaile d descri pti o n of patie nt dis p os iti o n will be pr o vi de d. It will i ncl u de: 
 A defi niti o n of patie nt e nr oll me nt 
 A s u m mar y of data re gar di n g patie n t disc o nti n uati o n of st u d y treat me nt 
 A s u m mar y of data re gar di n g patie nt i ncl usi o n a n d e xcl usi o n i n efficac y a n d safet y 
a nal yses 
1 2. 5  P atie nt C h ar acteristics 
 
Patie nt c haracteristics will i ncl u de a s u m mar y of t he f oll o wi n g: 
 Patie nt de m o gra p hics 
 Baseli ne disease c haracteristics 
 Baseli ne t u m or m olec ular c haracteristics 
 Si g nifica nt me dical hist or y a n d c o- m or bi dities 
 C o nc o mita nt t hera pies 
 Ot her c haracteristic s as a p pr o priate 
1 2. 6  S afet y of Tre at me nt 
 
A s u m mar y of t he a d verse e ve nts a n d t heir attri b ute d relate d ness t o treat me nt will be pr o vi de d. 
1 2. 7  A n al ysis of Res p o nse R ate 
 
Res p o nse rate will be assesse d as per R E CI S T, see Secti o n 8. 3. Res ults will be re p orte d wit h 
9 5 % c o nfi de nce i nter vals. 
1 2. 8  A n al ysis of Pr o gressi o n- Free a n d O ver all S ur vi v al 
Pr o gressi o n- Free S ur vi val ( P F S) will  be defi ne d as t he d urati o n of ti me fr o m start of treat me nt t o 
ti me of o bjecti ve disease pr o gressi o n or deat h. O verall s ur vi val ( O S) wi ll be defi ne d as t he 
d urati o n of ti me fr o m start of treat me nt u ntil deat h. A nal ysis will be perf or me d usi n g t he 
Ka pla n- Meier met h o d. 
1 2. 9  A n al ysis of Re pe at Bi o ps y  C o m plic ati o ns a n d Res ults 
 
C o m plicati o ns arisi n g fr o m re peat t u m or bi o psies f or ge netic a nal yses will be rec or de d at t he t w o 
p ost- bi o ps y re q uire d visits or at a n y ot her ti me t hat t he y bec o me a p pare nt a n d will be re p orte d 
a n n uall y t o t he I R B as part of t he c o nti n ui n g re vie w a p plicati o n ( u nless t he y meet S A E re p orti n g 
criteria, i n w hic h case t he y will be re p orte d i m me diatel y). At t he e n d of t he st u d y, t he 
c o m plicati o ns will be s u m marize d a n d prese nte d t o get her wit h t he rest of t he st u d y data i n a 
descri pti ve fas hi o n.  
 
Ot her m olec ular fi n di n gs fr o m t he t u m or re peat bi o psies at t he ti me of c li nical pr o gressi o n will 
be prese nte d i n a descri pti ve f or mat. 
1 2. 1 0  A n al ysis of Circ ul ati n g T u m or Cells 
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
4 7
C T C sa m ples will be use d i n e x pl orat or y a nal yses, see Secti o n 7. 2. Res ults of C T C st u dies will 
be prese nte d i n a descri pti ve fas hi o n a n d will be h y p ot hesis- ge nerati n g o nl y. 
1 3.  P U B LI C A TI O N P L A N 
 
At t he e n d of t he st u d y, t he res ults will be a nal yze d a n d a ma n uscri pt s u b mitte d f or peer re vie w 
wit hi n 2 4 m o nt hs of t he e n d of data c ollecti o n. As t his is a pil ot st u d y, t here is n o ot her pre-
s pecifie d pla n f or t he ti mi n g of p u blic release of data. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
4 8
 
1 4.  R E F E R E N C E S  
 
1.   
Fr y D W, Bri d ges AJ, De n n y W A, et al. S pecific, irre versi ble i nacti vati o n of t he 
e pi der mal gr o wt h fact or rece pt or a n d er b B 2, b y a ne w class of t yr osi ne ki nase i n hi bit or. 
Pr oc N atl Ac a d Sci U S A. Se p 2 9 1 9 9 8; 9 5( 2 0): 1 2 0 2 2- 1 2 0 2 7. 
2.   
S olca F, Sc h weifer N, Ba u m A, R u d ol p h D, A mels ber g A. BI B W 2 9 9 2, a n irre versi ble 
d ual E G F R/ H E R 2 ki nas i n hi bit or s h o ws ac ti vit y i n L 8 5 8 R/ T 7 9 0 M m uta nts. Pa per 
prese nte d at: A A C R- N CI- E O R T C I nter nati o na l C o nfere nce o n M olec ular Tar gets a n d 
Ca ncer T hera pe utics; N o ve m ber 1 4- 1 8, 2 0 0 5, 2 0 0 5; P hila del p hia, P A. 
3.   
M u k o hara T, E n gel ma n J A, Ha n na N H, et al. Differe ntial effects of gefiti ni b a n d 
cet u xi ma b o n n o n-s mall-cell l u n g ca ncers beari n g e pi der mal gr o wt h fact or rece pt or 
m utati o ns. J N atl C a ncer I nst. A u g 1 7 2 0 0 5; 9 7( 1 6): 1 1 8 5- 1 1 9 4. 
4.   
I n u kai M, T o y o o ka S, It o S, et al. Prese nce of e pi der mal gr o wt h fact or rece pt or ge ne 
T 7 9 0 M m utati o n as a mi n or cl o ne  i n n o n-s mall cell l u n g ca ncer. C a ncer Res. A u g 1 5 
2 0 0 6; 6 6( 1 6): 7 8 5 4- 7 8 5 8. 
5.   
Ya n g C- H, S hi h J Y, S u W C, et al. BI B W 2 9 9 2, a n o vel irre ve rsi ble E G F R/ H E R 2 
t yr osi ne ki nase i n hi bit or, i n c he m o naï vepatie nts wit h a de n ocarci n o ma of t he l u n g a n d 
acti vati n g E G F R m utati o ns ( L U X- L u n g 2). Pa per prese nte d at: W orl d C o n gress o n L u n g 
Ca ncer, 2 0 0 9; Sa n Fra ncisc o, C A. 
6.   
S he p her d F A, R o dri g ues Pereira J, Ci ulea n u T, et al. Erl oti ni b i n pre vi o usl y treate d n o n-
s mall-cell l u n g ca ncer. N E n gl J Me d. J ul 1 4 2 0 0 5; 3 5 3( 2): 1 2 3- 1 3 2. 
7.   
I R E S S A ( Z D 1 8 3 9, gefiti ni b) Ta blets Briefi n g D oc u me nt. O nc ol o gy Dr u gs A dvis ory 
C o m mittee ( O D A C) . Was hi n gt o n D C: Fe deral Dr u g A d mi nistrati o n; 2 0 0 5. 
8.   
P ha m D, Kris M G, Riel y GJ, et al. Use of ci garette-s m o ki n g hist or y t o esti mate t he 
li keli h o o d of m utati o ns i n e pi der mal gr o wt h fact or rece pt or ge ne e x o ns 1 9 a n d 2 1 i n l u n g 
a de n ocarci n o mas. J Cli n O nc ol. A pr 1 0 2 0 0 6; 2 4( 1 1): 1 7 0 0- 1 7 0 4. 
9.   
L y nc h TJ, Bell D W, S or della R, et al. Acti vati n g m utati o ns i n t he e pi der mal gr o wt h 
fact or rece pt or u n derl yi n g res p o nsi ve ness of n o n-s mall-cell l u n g ca ncer t o gefiti ni b. N 
E n gl J Me d. Ma y 2 0 2 0 0 4; 3 5 0( 2 1): 2 1 2 9- 2 1 3 9. 
1 0.   
Paez J G, Ja n ne P A, Lee J C, et al. E G F R m utati o ns i n l u n g ca ncer: c orrelati o n wit h 
cli nical res p o nse t o gefiti ni b t hera p y. Scie nce. J u n 4 2 0 0 4; 3 0 4( 5 6 7 6): 1 4 9 7- 1 5 0 0. 
1 1.   
Pa o W, Miller V, Za k o ws ki M, et al. E GF rece pt or ge ne m utati o ns are c o m m o n i n l u n g 
ca ncers fr o m " ne ver s m o kers" a n d are ass ociate d  wit h se nsiti vit y of t u m ors t o gefiti ni b 
a n d erl oti ni b. Pr oc N atl Ac a d Sci U S A. Se p 7 2 0 0 4; 1 0 1( 3 6): 1 3 3 0 6- 1 3 3 1 1. 
1 2.   
S har ma S V, Bell D W, Settle ma n J, Ha ber D A. E pi der mal gr o wt h fact or rece pt or 
m utati o ns i n l u n g ca ncer. N at Rev C a ncer. Mar 2 0 0 7; 7( 3): 1 6 9- 1 8 1. 
1 3.   
Se q uist L V, Bell D W, L y nc h TJ, Ha ber D A. M olec ular pre dict ors of res p o nse t o 
e pi der mal gr o wt h fact or rece pt or a nta g o nists i n n o n-s mall-cell l u n g ca ncer. J Cli n O nc ol. 
Fe b 1 0 2 0 0 7; 2 5( 5): 5 8 7- 5 9 5. 
1 4.   
E n gel ma n J A, Ja n ne P A. Mec ha nis ms of ac q uire d resista nce t o e pi der mal gr o wt h fact or 
rece pt or t yr osi ne ki nase i n hi bit ors i n n o n-s mall cell l u n g ca ncer. Cli n C a ncer Res. Ma y 
1 5 2 0 0 8; 1 4( 1 0): 2 8 9 5- 2 8 9 9. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
4 9
1 5.   
Se q uist L V, Marti ns R G, S pi gel D, et al. First-li ne gefiti ni b i n patie nts wit h a d va nce d 
n o n-s mall-cell l u n g ca ncer har b ori n g s o matic E G F R m utati o ns. J Cli n O nc ol. Ma y 2 0 
2 0 0 8; 2 6( 1 5): 2 4 4 2- 2 4 4 9. 
1 6.   
S u na ga N, T o miza wa Y, Ya na gita ni N, et al. P hase II pr os pecti ve st u d y of t he efficac y of 
gefiti ni b f or t he treat me nt of sta ge III/ I V n o n-s mall cell l u n g ca ncer wit h E G F R 
m utati o ns, irres pecti ve of pre vi o us c he m ot hera p y. L u n g C a ncer. J u n 2 0 0 7; 5 6( 3): 3 8 3- 3 8 9. 
1 7.   
Asa hi na H, Ya maza ki K, Ki n os hita I, et al. A p hase II trial of gefiti ni b as first-li ne 
t hera p y f or a d va nce d n o n-s mall cell l u n g ca ncer wit h e pi der mal gr o wt h fact or rece pt or 
m utati o ns. Br J C a ncer. Oct 2 3 2 0 0 6; 9 5( 8): 9 9 8- 1 0 0 4. 
1 8.   
Y os hi da K, Yata be Y, Par k J Y, et al. Pr os pecti ve vali dati o n f or pre dicti o n of gefiti ni b 
se nsiti vit y b y e pi der mal gr o wt h fact or rece ptor ge ne m utati o n i n patie nts wit h n o n-s mall 
cell l u n g ca ncer. J T h or ac O nc ol. Ja n 2 0 0 7; 2( 1): 2 2- 2 8. 
1 9.   
I n o ue A, S uz u ki T, F u k u hara T, et al. Pr os pecti ve p hase II st u d y of gefiti ni b f or 
c he m ot hera p y- nai ve patie nts wit h a d va nce d  n o n-s mall-cell l u n g ca ncer wit h e pi der mal 
gr o wt h fact or rece pt or ge ne m utati o ns. J Cli n O nc ol. J ul 2 0 2 0 0 6; 2 4( 2 1): 3 3 4 0- 3 3 4 6. 
2 0.   
va n Za n d wij k N, Mat h y A, B oerri gter L, et al. E G F R a n d K R A S m utati o ns as criteria f or 
treat me nt wit h t yr osi ne ki nase i n hi bit ors: retr o- a n d pr os pecti ve o bser vati o ns i n n o n-
s mall-cell l u n g ca ncer. A n n O nc ol. Ja n 2 0 0 7; 1 8( 1): 9 9- 1 0 3. 
2 1.   
M o k T S, W u Y L, T h o n g prasert S, et al. Gefiti ni b or car b o plati n- paclita xel i n p ul m o nar y 
a de n ocarci n o ma. N E n gl J Me d. Se p 3 2 0 0 9; 3 6 1( 1 0): 9 4 7- 9 5 7. 
2 2.   
K o ba yas hi K, I n o ue A, Mae m o n d o M, et al. First-li ne gefiti ni b vers us first-li ne 
c he m ot hera p y b y car b o plati n ( C B D C A) pl us paclita xel ( T X L) i n n o n-s mall cell l u n g 
ca ncer ( N S C L C) patie nts ( pts ) wit h E G F R m utati o ns: A p hase III st u d y ( 0 0 2) b y N ort h 
East Ja pa n Gefiti ni b St u d y Gr o u p. J Cli n O nc ol. 2 0 0 9; 2 7( 1 5s):s u p pl a bst 8 0 1 6. 
2 3.   
Pas- Ares L, Sa nc hez J M, Garcia- Velasc o A, et al. pr os pecti ve p hase II trial of erl oti ni b i n 
a d va nce d n o n-s mall cell l u n g ca n cer ( N S C L C) patie nts ( p) wit h m utati o ns i n t he t yr osi ne 
ki nase ( T K) d o mai n of t he e pi der mal gr o wt h fact or rece pt or ( E G F R). Pa per prese nte d at: 
A merica n S ociet y of Cli nical O nc ol o g y, 2 0 0 6; Atla nta, G A. 
2 4.   
K o ba yas hi S, B o g g o n TJ, Da yara m T, et al. E G F R m utati o n a n d resi sta nce of n o n-s mall-
cell l u n g ca ncer t o gefiti ni b. N E n gl J Me d. Fe b 2 4 2 0 0 5; 3 5 2( 8): 7 8 6- 7 9 2. 
2 5.   
Pa o W, Miller V A, P oliti K A, Riel y GJ, S om war R, Za k o ws ki M F. Ac q uire d resista nce 
of l u n g a de n ocarci n o mas t o gefiti ni b or erl oti n i b is ass ociate d wit h a sec o n d m utati o n i n 
t he E G F R ki nase d o mai n. P L o S Me d. Fe b 2 2, 2 0 0 5 2 0 0 5; 2( 3):e 7 3. 
2 6.   
E n gel ma n J A, Zej n ulla h u K, Mits u d o mi T, et al. M E T a m plificati o n lea ds t o gefiti ni b 
resista nce i n l u n g ca ncer b y acti vati n g E R B B 3 si g nali n g. Scie nce. Ma y 1 8 
2 0 0 7; 3 1 6( 5 8 2 7): 1 0 3 9- 1 0 4 3. 
2 7.   
Bea n J, Bre n na n C, S hi h J Y, et al. M E T a m plificati o n occ urs w it h or wit h o ut T 7 9 0 M 
m utati o ns i n E G F R m uta nt l u n g t u m ors wit h ac q uire d resista nce t o ge fiti ni b or erl oti ni b. 
Pr oc N atl Ac a d Sci U S A. Dec 2 6 2 0 0 7; 1 0 4( 5 2): 2 0 9 3 2- 2 0 9 3 7. 
2 8.  
K osa ka T, Yata be Y, E n d o h H, et al. A nal ys is of e pi der mal gr o wt h fact or rece pt or ge ne 
m utati o n i n patie nts wit h n o n-s mall cell l u n g ca n cer a n d ac q uire d resista nce t o gefiti ni b. 
Cli n C a ncer Res. Oct 1 2 0 0 6; 1 2( 1 9): 5 7 6 4- 5 7 6 9. 
2 9.   
Bala k M N, G o n g Y, Riel y GJ, et al. N o vel D 7 6 1 Y a n d c o m m o n sec o n dar y T 7 9 0 M 
m utati o ns i n e pi der mal gr o wt h fact or rece pt or- m uta nt l u n g a de n ocarci n o mas wit h 
ac q uire d resista nce t o ki nase i n hi bit ors. Cli n C a ncer Res. N o v 1 2 0 0 6; 1 2( 2 1): 6 4 9 4- 6 5 0 1. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
5 0
3 0.   
S ha h N P, Ni c oll J M, Na gar B, et al. M ulti ple B C R- A B L ki nase d o mai n m utati o ns c o nfer 
p ol ycl o nal resista nce t o t he t yr o si ne ki nase i n hi bit or i mati ni b ( S TI 5 7 1) i n c hr o nic p hase 
a n d blast crisis c hr o nic m yel oi d le u ke mia. C a ncer Cell. A u g 2 0 0 2; 2( 2): 1 1 7- 1 2 5. 
3 1.   
Ta m b ori ni E, B o na di ma n L, Grec o A, et al. A ne w m utati o n i n t he KI T A T P p oc ket 
ca uses ac q uire d resista nce t o i mati ni b i n a gastr oi ntesti nal str o mal t u m or patie nt. 
G astr oe nter ol o gy. J ul 2 0 0 4; 1 2 7( 1): 2 9 4- 2 9 9. 
3 2.   
C o ols J, De A n gel o DJ, G otli b J, et al. A t yr osi ne ki nase create d b y f usi o n of t he 
P D G F R A a n d FI P 1 L 1 ge nes as a t hera pe utic tar get of i mati ni b i n i di o pat hic 
h y pere osi n o p hilic s y n dr o me. N E n gl J Me d. Mar 2 7 2 0 0 3; 3 4 8( 1 3): 1 2 0 1- 1 2 1 4. 
3 3.   
Weis ber g E, Ma nle y P W, C o wa n-Jac o b S W, H oc h ha us A, Griffi n J D. Sec o n d ge nerati o n 
i n hi bit ors of B C R- A B L f or t he treat me nt of i mati ni b-resista nt c hr o nic m yel oi d 
le u kae mia. N at Rev C a ncer. Ma y 2 0 0 7; 7( 5): 3 4 5- 3 5 6. 
3 4.   
Y u n C H, Me n g wasser K E, T o ms A V, et al. T he T 7 9 0 M m utati o n i n E G F R ki nase ca uses 
dr u g resista nce b y i ncreasi n g t he affi nit y f or A T P. Pr oc N atl Ac a d Sci U S A. Fe b 1 2 
2 0 0 8; 1 0 5( 6): 2 0 7 0- 2 0 7 5. 
3 5.   
K wa k E L, S or della R, Bell D W, et al. Irre versi ble i n hi bit ors of t he E G F rece pt or ma y 
circ u m ve nt ac q uire d resista nce t o gefiti ni b. Pr oc N atl Ac a d Sci U S A. Ma y 2 4 
2 0 0 5; 1 0 2( 2 1): 7 6 6 5- 7 6 7 0. 
3 6.   
E n gel ma n J A, Zej n ulla h u K, Gale C M, et al. P F 0 0 2 9 9 8 0 4, a n irre versi ble pa n- E R B B 
i n hi bit or, is effecti ve i n l u n g ca ncer m o dels wit h E G F R a n d E R B B 2 m utati o ns t hat are 
resista nt t o gefiti ni b. C a ncer Res. Dec 1 5 2 0 0 7; 6 7( 2 4): 1 1 9 2 4- 1 1 9 3 2. 
3 7.   
Li D, A m br o gi o L, S hi ma m ura T, et al. BI B W 2 9 9 2, a n irre versi ble E G F R/ H E R 2 
i n hi bit or hi g hl y effecti ve i n precli nical l u n g ca ncer m o dels. O nc o ge ne. A u g 7 
2 0 0 8; 2 7( 3 4): 4 7 0 2- 4 7 1 1. 
3 8.   
Els hi mali YI, Gr o d y W W. T he cli nical si g nifica nce of circ ulati n g t u m or cells i n t he 
peri p heral bl o o d. Di a g n M ol P at h ol. Dec 2 0 0 6; 1 5( 4): 1 8 7- 1 9 4. 
3 9.   
Paterli ni- Brec h ot P, Be nali N L. Circ ulati n g t um or cells ( C T C) detecti o n: Cli nical i m pact 
a n d f ut ure directi o ns. C a ncer Lett. Fe b 1 9 2 0 0 7. 
4 0.   
Patel H, Le Marer N, W hart o n R Q, et al. Cleara nce of circ ulati n g t u m or cells after 
e xcisi o n of pri mar y c ol orectal ca ncer. A n n S ur g. Fe b 2 0 0 2; 2 3 5( 2): 2 2 6- 2 3 1. 
4 1.   
Na grat h S, Se q uist L V, Ma hes wara n S, et al. Is olati o n of rare  circ ulati n g t u m o ur cells i n 
ca ncer patie nts b y micr oc hi p tec h n ol o g y. N at ure. Dec 2 0 2 0 0 7; 4 5 0( 7 1 7 3): 1 2 3 5- 1 2 3 9. 
4 2.   
Ma hes wara n S, Se q uist L V, Na grat h S, et al. Detecti o n of m utati o ns i n E G F R i n 
circ ulati n g l u n g-ca ncer cells. N E n gl J Me d. J ul 2 4 2 0 0 8; 3 5 9( 4): 3 6 6- 3 7 7. 
4 3.   
E n gel ma n J A, M u k o hara T, Zej n ulla h u K, et al. Allelic dil uti o n o bs c ures detecti o n of a 
bi ol o gicall y si g nifica nt resista nce m uta ti o n i n E G F R-a m plifie d l u n g ca ncer. J Cli n I nvest. 
Oct 2 0 0 6; 1 1 6( 1 0): 2 6 9 5- 2 7 0 6. 
4 4.   
O mar y R A, Bett ma n n M A, Car della J F, et al. Q ualit y i m pr o ve me nt g ui deli nes f or t he 
re p orti n g a n d arc hi vi n g of i nter ve nti o nal ra di ol o g y pr oce d ures. J V asc I nterv R a di ol. Se p 
2 0 0 2; 1 3( 9 P t 1): 8 7 9- 8 8 1. 
4 5.   
O ke n M M, Creec h R H, T or me y D C, et al. T o xicit y a n d res p o nse criteria of t he Easter n 
C o o perati ve O nc ol o g y Gr o u p. A m J Cli n O nc ol. Dec 1 9 8 2; 5( 6): 6 4 9- 6 5 5. 
4 6.   
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d 
t u m o urs: re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J C a ncer. Ja n 2 0 0 9; 4 5( 2): 2 2 8- 2 4 7. 
 
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
5 1
1 5.  A P P E N DI C E S 
A p p e n di x 1: P e rf o r m a n c e St at us C rit e ri a 
 
 
E C O G Perf or m a nce St at us Sc ale 
 
Gr a d e
 D es cri pti o n
 
0 
N or m al a cti vit y. F ull y a cti v e, a bl e  t o c arr y o n all pr e- dis e as e 
p erf or m a n c e wit h o ut r estri cti o n. 
1 
S y m pt o ms, b ut a m b ul at or y. R e stri ct e d i n p h ysi c all y 
str e n u o us a cti vit y, b ut a m b ul at or y a n d a bl e t o c arr y o ut w or k 
of a li g ht or s e d e nt ar y n at ur e ( e. g., li g ht h o us e w or k, offi c e 
w or k). 
2 
I n b e d < 5 0 % of t he ti m e. A m b ul at or y a n d c a p a bl e of all 
s elf- c ar e, b ut u n a bl e t o c arr y o ut a n y w or k a cti viti es. U p a n d 
a b o ut m or e t h a n 5 0 % of w a ki n g h o urs. 
3 
I n b e d > 5 0 % of t h e ti m e. C a p a ble of o nl y li mit e d s elf- c ar e, 
c o nfi n e d t o b e d or c h air m or e t h a n 5 0 % of w a ki n g h o urs. 
4 
1 0 0 % b e dri d d e n. C o m pl et el y di s a bl e d. C a n n ot c arr y o n a n y 
s elf- c ar e. T ot all y c o nfi n e d t o b e d or c h air. 
5
 D e a d.
 
 
 
 
A p pe n di x 2: C T C Gr a di n g I nf or m ati o n 
 
T he descri pti o ns a n d gra di n g scales f o u n d i n t he C T E P N CI C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts ( C T C A E) versi o n 4. 0 will be ut ilize d f or A E re p orti n g. T he C T C A E versi o n 4. 0 
is l ocate d o n t he C T E P we bsite at: 
 htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o ni c a p plicati o ns/ctc. ht m.  
A li n k t o t his we bsite will be i ncl u de d as part of t he electr o nic o nc ol o g y pr ot oc ol s yste m at 
D F/ H C C. 
 
 
 
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
5 2
A p pe n di x 3: D a n a- F ar ber/ H ar v ar d C a ncer Ce nter M ulti- Ce nter D at a a n d S afet y 
M o nit ori n g Pl a n f or Pr ot oc ol # 1 0- 0 9 2 
 
 
T a ble of C o nte nts 
 
1. 0    I ntr o d ucti o n 
 
  5 6 
1. 1   P ur p ose 
1. 2   D at a a n d S afet y M o nit ori n g Pl a n C o m p o ne nts 
5 6 
2. 0      Ge ner al R oles a n d Res p o nsi bilities 
5 7  5 7 
  
2. 1   Pr ot oc ol C h air 
 
5 7 
 
2. 2   C o or di n ati n g Ce nter  
 
5 8 
 
2. 3   P artici p ati n g I nstit uti o n  
 
5 8 
 
3. 0  Pr ot oc ol De vel o p me nt 
 
5 9  
 
3. 1   Acti v ati o n of a Pr ot oc ol  
 
5 9 
 
3. 2   C o or di n ati n g Ce nter S u p p ort F u ncti o n 
5 9 
 
4. 0   Pr ot oc ol M a n a ge me nt 
 
6 0 
 
4. 1 Pr ot oc ol Distri b uti o n  
 
6 0 
 
4. 2 Pr ot oc ol Re visi o ns a n d Cl os ures 
6 0  
 
4. 3 I nf or me d C o nse nt Re q uire me nts 
6 1 
 
4. 4 I R B D oc u me nt ati o n  
 
6 1 
 
4. 5 I R B Re – A p pr o v als  
 
6 1 
 
4. 6 P artici p a nt C o nfi de nti alit y a n d A ut h oriz ati o n 
6 2  
 
4. 7 P artici p a nt Re gistr ati o n a n d R a n d o miz ati o n 
6 2 
 
4. 8 D F/ H C C M ulti-ce nter Pr ot oc ol C ase N u m ber 
6 3  
 
4. 9 D F/ H C C M ulti-ce nter Pr ot oc ol Re gistr ati o n P olic y 
6 3 
 
4. 1 0 Sc he d ule of D at a S u b missi o n 
6 4 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
5 3
 
4. 1 1 D at a F or m Re vie w  
 
6 4 
 
4. 1 2 Missi n g a n d Deficie nt Me m or a n d u m 
6 5 
 
5. 0 Re q uisiti o ni n g I n vesti g ati o n al Dr u g  6 6
 
     
 6. 0   S afet y Assess me nts a n d T o xicit y M o nit ori n g 6 7
 
  
      
6. 1 Seri o us A d verse E ve nts  
 
6 7 
 
6. 2 G ui deli nes f or Re p orti n g Seri o us A d verse E ve nts 
6 7  
 
6. 3 G ui deli nes f or Pr ocessi n g I N D S afet y Re p orts 
6 7 
 
 
 
 
7. 0 Pr ot oc ol Vi ol ati o ns a n d De vi ati o ns   
6 8  
          
7. 1 Defi niti o ns   
 
6 8 
 
7. 2 Re p orti n g Pr oce d ures  
 
6 8 
 
8. 0 M o nit ori n g: Q u alit y C o ntr ol   
 
6 9 
 
 
 
8. 1 O n g oi n g M o nit ori n g of Pr ot oc ol C o m pli a nce 
6 9 
 
8. 2 E v al u ati o n of P artici p ati n g I nstit uti o n Perf or m a nce 
6 9 
 
9. 0 A u diti n g: Q u alit y Ass ur a nce   
 
7 1 
 
9. 1 D F/ H C C S p o ns ore d Tri als  
 
7 1 
 
9. 2 P artici p ati n g I nstit uti o n  
 
7 1 
 
9. 3 C o or di n ati n g Ce nter  
 
7 1 
 
9. 4 S u bst a n d ar d Perf or m a nce  
 
7 1  
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3 
 
I N D # 1 1 0 7 2 0 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
5 4 
1. 0  I N T R O D U C TI O N 
 
T he Da na- Far ber/ Har var d Ca ncer Ce nter M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n 
( D F/ H C C D S M P) o utli nes t he pr oce d ures f or a D F/ H C C M ulti- Ce nter re searc h pr ot oc ol.  
 
1. 1  P ur p ose 
T o esta blis h sta n dar ds t hat will e ns ure t hat a Da na- Far ber/ Har var d Ca ncer Ce nter ( D F/ H C C) 
M ulti-ce nter pr ot oc ol will c o m pl y wit h Fe de ral re g ulati o ns; G o o d Cli nical Practice ( G C P) 
G ui deli nes; a n d Healt h I ns ura nce P orta bilit y a n d Acc o u nta bil it y Act ( HI P A A) re q uire me nts 
i n acc or da nce wit h t he C T E P M ulti-ce nter G ui deli nes.        
 
1. 2  M ulti- Ce nter D at a a n d S afet y M o nit ori n g Pl a n  C o m p o ne nts 
 
T he M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n i ncl u des t he f oll o wi n g c o m p o ne nts: 
 
D F/ H C C M ulti-ce nter Pr ot oc ol :  O ne or m ore o utsi de i nstituti o ns c olla b orati n g wit h Da na-
Far ber/ Har var d Ca ncer Ce nter o n a researc h  pr ot oc ol w here D F/ H C C is t he Lea d I nstit uti o n. 
D F/ H C C i ncl u des Da na- Far ber/ Part ners Ca ncer Care ( D F/ P C C) Net w or k Cli nical Trial 
Affiliates.  
 
Le a d I nstit uti o n:  O ne of t he  Da na- Far ber/ Har var d Ca ncer Ce nter sites ( D F CI, M G H, 
BI D M C, C H B, B W H) will be t he Lea d I n stit uti o n a n d will be res p o nsi ble f or t he 
c o or di nati o n, de vel o p me nt, s u b missi o n, a n d a p pr o va l of a pr ot oc ol as well as its s u bse q ue nt 
a me n d me nts per t he D F CI I R B a n d a p plica ble  re g ulat or y g ui deli nes ( C T E P, F D A, O B A 
etc.).  T he Lea d I nstit uti o n is t he h o me of t he O verall PI.   
 
D F/ H C C C o ntr act Pri nci p al I n vesti g at or :  I n vesti gat or l ocate d at t he Lea d I nstit uti o n w h o 
will be c har ge d wit h t he res p o nsi bilit y of t h e a d mi nistrati o n of t he D F/ H C C Pr oject. T his 
m ost ofte n will be t he Pr ot oc ol C hair, b ut oc casi o nall y t his ma y be t he o verall gra nt or 
c o ntract h ol der, as a p plica ble. 
 
Pr ot oc ol C h air:  T he  Pr ot oc ol C hair is t he Pri nci pal I n vesti gat or f or t he D F/ H C C pr ot oc ol 
s u b mitte d as t he Lea d I nstit uti o n.  F or a p plica ble pr ot oc ols, t he Pr ot oc ol C hair will be t he 
si n gle liais o n wit h a n y re g ulat or y a ge ncies (i.e. C T E P Pr ot oc ol a n d I nf or mati o n Office 
( PI O), F D A, O B A etc.).  
 
P artici p ati n g I nstit uti o n:  A Partici pati n g I nstit uti o n is a n i nstit uti o n t hat desires t o 
c olla b orate wit h D F/ H C C a n d c o m mits t o accr ui n g partici pa nts t o a D F/ H C C pr ot oc ol.  T he 
Partici pati n g I nstit uti o n ac k n o wle d ges t he Pr ot oc ol C hair as ha vi n g t he ulti mate a ut h orit y 
a n d res p o nsi bilit y f or t he o verall c o n d uct of t he st u d y.    
 
C o or di n ati n g Ce nter: I n g e n er al, t h e L e a d I nstit uti o n is t h e C o or di n ati n g C e nt er f or t h e 
D F / H C C M ulti- c e nt er Pr ot o c ol. T h e C o or di n ati n g C e nt er will pr o vi d e t h e 
a d mi nistr ati v e s u p p ort t o t h e Pr ot o c ol C h a ir i n or d er t h at h e /s h e m a y f ulfill t h e 
r es p o nsi biliti es o utli n e d i n t h e D S M P an d as s p e cifi e d i n a p pli c a bl e r e g ul at or y 
g ui d eli n es (i. e. C T E P M ulti- C e nt er G ui d eli n es).  I n a d diti o n t o t h e L e a d I nstit uti o n, t h e 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
5 5
Q u alit y Ass ur a n c e Offi c e f or Cli ni c al Tri als ( Q A C T) pr o vi d es s u p p ort s er vi c es t o assist 
t h e Pr ot o c ol C h air.  
 
Cli nic al Tri als Office: T he cli nical trials offices of t he D F/ H C C c o ns orti u m me m bers 
s u p p ort i n vesti gat ors a n d t heir st u d y tea ms wit h t he c o or di nati o n, s u b missi o n a n d o n g oi n g 
c o n d uct of researc h pr ot oc ols i n v ol vi n g h u ma n s u bjects.  S pecificall y, t hese offices s u p p ort 
f o ur c ore ser vice areas i ncl u din g; pre-re vie w of PI  i nitiate d pr ot oc ols; assista nce i n t he 
pre parati o n a n d ma na ge me nt of I n vesti gati o na l Ne w Dr u g (I N D) a p plicati o ns a n d s u bse q ue nt 
re q uire d re p orti n g t o t he F D A; re g ulat or y c o ns ultati o n a n d g ui da nce i n t he i nter pretati o n of 
l ocal, fe deral, a n d I C H/ G C P g ui deli nes a n d p olicies; a n d t he orie ntati o n a n d o n g oi n g trai ni n g 
s u p p ort of cli nical researc h pers o n nel.  
 
D F/ H C C Q u alit y Ass ur a nce Office f or Cli nic al Tri als: T he D F/ H C C Q A C T is a u nit t hat 
has bee n de vel o pe d t o c o m p ut erize, ma na ge, a n d Q C & Q A data a n d D F/ H C C trials.  T he 
D F/ H C C Q A C T is l ocate d a d mi nistrati vel y i n t h e office of t he Se ni or Vice Presi de nt f or 
Cli nical Researc h, at Da na- Far ber Ca ncer I n stit ute.  T he Q A C T uses D F/ H C C c o m p uterize d 
i nstit uti o nal data bases f or partici pa nt re gistratio ns a n d f or t he ma na ge me nt of trial data as 
well as a set of q ualit y ass ura nce pr o gra ms desi g ne d t o a u dit D F/ H C C trials.   
 
2. 0  G E N E R A L R O L E S A N D R E S P O N SI BI LI TI E S 
I n acc or da nce wit h t he C T E P M ulti-ce nter G ui deli nes, t he Pr ot oc ol C hair, C o or di nati n g 
Ce nter ( Lea d I nstit uti o n or desi g nee), a n d t he Partici pati n g I nstit uti o ns will all a gree t o t he 
ge neral res p o nsi bilities as f oll o ws (s pecific pr oce d ures f or t hese ge neral res p o nsi bilities are 
detaile d i n t he D S M P): 
 
2. 1  Pr ot oc ol C h air ( D F/ H C C Pri nci p al I n vesti g at or) 
 
T he Pr ot oc ol C hair, Dr. Lecia Se q uist  will acce pt res p o nsi bilit y f o r all as pects of t he 
M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n t o: 
 O versee t he c o or di nati o n, de vel o p me n t, s u b missi o n, a n d a p pr o val of t he 
pr ot oc ol as well as s u bse q ue nt a me n d me nts.  
 E ns ure t hat t he i n vesti gat ors, st u d y tea m me m bers, a n d Partici pati n g I nstit uti o ns 
are q ualifie d a n d a p pr o priatel y res o ur ce d t o c o n d uct t he pr ot oc ol.   
 S u b mit t he M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n as a n i ncl usi o n t o t he 
pr ot oc ol. 
 Ass ure all Partici pati n g I nstit uti o ns are usi n g t he c orrect vers i o n of t he pr ot oc ol. 
 E ns ure t hat eac h partici pati n g i n vesti g at or a n d st u d y tea m recei ves a de q uate 
pr ot oc ol trai ni n g a n d/ or a Site I nitiati o n Visit pri or t o e nr olli n g s u bjects. 
 F or i nter nati o nal trials, ass ure t hat t h e pr ot oc ol is pr o vi de d t o Partici pati n g 
I nstit uti o ns i n t he pri mar y lan g ua ge s p o ke n at t he site.    
 M o nit or pr o gress a n d o verall c o n d uct of t he st u d y at all Partici pati n g 
I nstit uti o ns.  
 C o m m u nicate re g ularl y wit h eac h Site I n vesti gat or 
 E ns ure all D F CI I R B, D F/ H C C a n d ot he r a p plica ble (i.e. F D A) re p orti n g 
re q uire me nts are met.  
 Re vie w data a n d m ai ntai n ti mel y s u b missi o n of data f or st u d y a nal ysis.  

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
5 6
 Act as t he si n gle liais o n wit h F D A f o r t his i n vesti gat or- hel d I N D trial 
 
 
2. 2   C o or di n ati n g Ce nter ( Le a d I nstit uti o n) 
 
T he C o or di nati n g Ce nter is t he D F/ H C C Lea d I nstit uti o n’s st u d y tea m or desi g nee (i.e 
Me dical M o nit or, Cli nical Researc h Or ga nizati o n). T he D F/ H C C Lea d I nstit uti o n, 
Massac h usetts Ge neral H os pital Ca ncer Ce nt er, will e ns ure t hat all Partici pati n g 
I nstit uti o ns wit hi n t he M ulti- Ce nter Pr ot oc ol de m o nstrate t h eir i nte nt a n d ca pa bilit y of 
c o m pl yi n g wit h Fe deral Re g ulati o ns, G C Ps a n d HI P A A re q uire me nts. T o assist t he 
Pr ot oc ol C hair i n meeti n g his/ her res p o nsi b ilities as re q uire d b y t he D S M P, t he D F/ H C C 
Lea d I nstit uti o n’s st u d y tea m or desi g n ee will ass u me t he f oll o wi n g ge neral 
res p o nsi bilities: 
 Assist i n pr ot oc ol re vie w. 
 Mai ntai n c o pies of F W A a n d I nstit uti o nal Re vie w B oar d (I R B) a p pr o vals fr o m 
all Partici pati n g I nstit uti o ns. 
 Mai ntai n F D A c orres p o n de nce 
 Mai ntai n u p date d r oster  of partici pa nts.  
 Verif y eli gi bilit y. 
 Verif y res p o nse. 
 C ollect data o n pr ot oc ol s pecific C R Fs. 
 Pre pare all s u b mitte d data f or re vie w b y t he Pr ot oc ol C hair. 
 Mai ntai n d oc u me ntati o n of Seri o us A d verse E ve nt ( S A E) re p orts s u b mitte d b y 
Partici pati n g I nstit uti o ns a n d s u b mit t o Pr ot oc ol C hair f or ti mel y re vie w.   
 Distri b ute Seri o us A d verse E ve nt safet y  re p orts ( b ot h I N D Safet y re p orts a n d 
pr ot oc ol s pecific S A Es).  
 M o nit or  at  Partici pati n g  I nstit uti o ns  ei t her  b y  o n-site  i ns pecti o n  of  selecte d  
partici pa nt  rec or ds  a n d/ or  wit h  s o urce  d oc u me nts  a n d  researc h  rec or ds  
s u b mitte d t o t he Lea d I nstit uti o n.  
    
I n a d diti o n t o t he Lea d I nstit uti o n, t he D F/ H C C Q ualit y Ass ura nce Office f or Cli nical 
Trials pr o vi des t he f oll o wi n g s u p p ort ser vi ces t o assist t he Pr ot oc ol C hair: 
 De vel o p pr ot oc ol s pecific cas e re p ort f or ms ( C R F/e C R F S). 
 Q A/ Q C data of pr ot oc ol s pecific C R Fs.  
 Pr o vi de Ce ntral Partici pa nt Re gistrati o n. 
 Verif y  t hat  eli gi bilit y  has  bee n  c o nfir me d  b y  t he  i n vesti gat or  a n d  t hat  
a p pr o priate c o nse nt has bee n o btai ne d.  
 Pr o vi de a u diti n g ser vices (f u n di n g a n d Q A C T a p pr o val re q uire d). 
 
2. 3   P artici p ati n g I nstit uti o n 
 
Eac h Partici pati n g I nstit uti o n will pr o vi de t o  t he C o or di nati n g Ce nter a list of t he ke y 
pers o n nel assi g ne d t o t he r ole f or o versi g ht of  data ma na ge me nt at t heir site. All sites 
m ust ha ve office s pace, office e q ui p me nt,  a n d i nter net access t hat meet HI P A A 
sta n dar ds. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
5 7
T he ge neral res p o nsi bilities f or eac h Part ici pati n g I nstit uti o n are as f oll o ws: 
 
 C o m mit t o accr ual t o t he Lea d I n stit uti o n’s ( D F/ H C C) pr ot oc ol. 
 S u b mit pr ot oc ol a n d/ or a me n d m e nts t o t heir l ocal I R B. 
 Mai ntai n a re g ulat or y bi n der. 
 U p date C o or di nati n g Ce nter wit h res earc h staff c ha n ges o n a ti mel y basis. 
 Re gister partici pa nts t hr o u g h t he C o or di nati n g Ce nter.  
 S u b mit s o urce d oc u me nts, researc h rec o r ds, a n d C R Fs per pr ot oc ol s pecific 
s u b missi o n g ui deli nes t o t he C o or di nati n g Ce nter. 
 S u b mit  Seri o us  A d verse  E ve nt  re p orts  t o  l ocal  I R B  a n d  directl y  t o  t he  
C o or di nati n g Ce nter.  
 S u b mit de viati o ns a n d vi olati o ns t o l ocal I R B a n d t he C o or di nati n g Ce nter. 
 Sec ure i n vesti gati o nal a ge nts per fe dera l g ui deli nes a n d pr ot oc ol re q uire me nts. 
 F or  pr ot oc ols  usi n g  i n vesti gati o nal  a ge nts,  t he  Partici pati n g  I nstit uti o n  will  
or der  t heir  o w n  i n vesti ga ti o nal  a ge nts  re gar dless  of t he  s u p plier  (i.e.  N CI,  
p har mace utical c o m pa n y) 
 
 
3. 0 P R O T O C O L D E V E L O P M E N T 
 
3. 1 Acti v ati o n of a Pr ot oc ol 
 
T he Pr ot oc ol C hair is res p o nsi ble f or t he c o or di nati o n, de vel o p me nt, a n d a p pr o val of t he 
pr ot oc ol as well as its s u bse q ue nt a me n d me nts, a n d re p orti n g S A Es, vi olati o ns a n d 
de viati o ns per D F CI I R B g ui deli nes a n d F D A G ui deli nes.  F urt her, t he Pr ot oc ol C hair 
will be t he si n gle liais o n wit h F D A. 
 
T o meet t hese re q uire me nts, t he Pr ot oc ol C hair will be res p o nsi ble f or t he f oll o wi n g 
mi ni m u m sta n dar ds: 
 
 I ncl usi o n of t he D F/ H C C M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n i n t he 
pr ot oc ol as a n a p pe n di x. 
 I de ntif y, q ualif y a n d i nitiate Partici pati n g I nstit uti o ns a n d o btai n accr ual 
c o m mit me nts.  
 C o m mit t o t he pr o visi o n t hat t he pr ot oc ol  will n ot be re writte n or m o difie d b y 
a n y o ne ot her t ha n t he Pr ot oc ol C hair. 
 E ns ure t hat t here is o nl y o ne versi o n of  t he Pr ot oc ol a n d t hat all Partici pati n g 
I nstit uti o ns use t he c orrect versi o n.  
 O versee t he de vel o p me nt of data c ollecti o n f or ms (case re p ort f or ms) t hat are of 
c o m m o n f or mat f or use at all t h e Partici pati n g I nstit uti o ns.  
 
 3. 2 C o or di n ati n g Ce nter S u p p ort F u ncti o n 
  
T he D F/ H C C Lea d I nstit uti o n’s st u d y staff or desi g nee will pr o vi de a d mi nistrati ve a n d 
clerical s u p p ort t o t he Pr ot oc ol C hair f or t he de vel o p me nt a n d distri b uti o n of t he 
pr ot oc ol.  

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
5 8
 
T he tas ks t o be perf or me d b y t he D F/ H C C Lea d I nstit uti o n’s st u d y staff or desi g nee 
i ncl u de: 
 Mai ntai n Re g ulat or y d oc u me nts f or all Partici pati n g I nstit uti o ns.  
 Re vie w of t he pr ot oc ol a n d c o nse nt t o c hec k f or l o gistics, s pelli n g, a n d 
c o nsiste nc y.  Pr o vi de t he Pr ot oc ol C h air a list of q ueries relate d t o a n y 
i nc o nsiste ncies. 
 Pr o vi de necessar y a d mi nistrati ve secti o ns, i ncl u di n g para gra p hs relate d t o 
re gistrati o n l o gistics, data ma na ge me nt sc he d ules, a n d m ulti-ce nter g ui deli nes.  
 Mai nte na nce of c o ntact list of all Partici pati n g I nstit uti o ns i n t he D F/ H C C 
M ulti-ce nter Pr ot oc ol a n d t h e distri b uti o n of u p dates t o t he sites as nee de d.  
 Deri vati o n of t he st u d y cale n dar, if a p plica ble. 
  Assista nce i n pre parati o n a n d mai nte na nce of case re p ort f or ms. 
 C o n d uct re g ular c o m m u nicati o ns wit h all Partici pati n g I nstit uti o ns (c o nfere nce 
call, e mails, etc)   
 Mai ntai n d oc u me ntati o n of all c o m m u nicati o ns.  
 
 
4. 0 P R O T O C O L M A N A G E M E N T 
 
T he C o or di nati n g Ce nter is res p o nsi ble f or ass uri n g t hat eac h Partici pati n g I nstit uti o n has t he 
a p pr o priate ass ura nce o n file wit h t he Offi ce of H u ma n Researc h Pr otecti o n ( O H R P).   
A d diti o nall y, t he C o or di nati n g Ce nt er m ust mai ntai n c o pies of all I R B a p pr o vals, f or eac h 
Partici pati n g I nstit uti o n.  
 
4. 1 Pr ot oc ol Distri b uti o n 
 
T he C o or di nati n g Ce nter will distri b ute t he fi nal a p pr o ve d pr ot oc ol a n d a n y s u bse q ue nt 
a me n de d pr ot oc ols t o all Part ici pati n g I nstit uti o ns.    
 
4. 2 Pr ot oc ol Re visi o ns a n d Cl os ures 
 
T he Partici pati n g I nstit uti o ns will recei v e p h o ne, fa x, mail or e- mail n otificati o n of 
pr ot oc ol re visi o ns fr o m t he Lea d I nstit uti o n or desi g nee.  It is t he i n di vi d ual Partici pati n g 
I nstit uti o n’s res p o nsi bilit y t o n otif y its I R B of t hese re visi o ns. 
 
N o n life-t hre ate ni n g re visi o ns: Partici pati n g I nstit uti o ns will  recei ve writte n n otificati o n 
of pr ot oc ol re visi o ns re gar di n g n o n life-t hreate ni n g e ve nts fr o m t he Lea d I nstit uti o n or 
desi g nee. N o n-life-t hreate ni n g pr ot oc ol  re visi o ns s h o ul d be I R B a p pr o ve d a n d 
i m ple me nte d wit hi n 9 0 da ys fr o m recei pt of t he n otificati o n. 
 
Re visi o ns f or life-t hre ate ni n g C a uses: Partici pati n g I nstit uti o ns  will recei ve tele p h o ne 
n otificati o n fr o m t he Lea d I nstit uti o n or desi g nee c o ncer ni n g pr ot oc ol  re visi o ns re q uire d 
t o pr otect li ves wit h f oll o w- u p b y fa x, mail or e- mail.  Life-t hreate ni n g pr ot oc ol re visi o ns 
will be i m ple me nte d i m me diatel y f oll o we d b y I R B re q uest f or a p pr o val 
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
5 9
Pr ot oc ol Cl os ures a n d Te m p or ar y H ol ds: Partici pati n g I nstit uti o ns will recei ve fa x, e-
mail, or p h o ne n otificati o n of pr ot oc ol cl os ures a n d te m p orar y h ol ds fr o m t he Lea d 
I nstit uti o n or desi g nee. Cl os ures a n d h ol ds will be effecti ve i m me diatel y.  I n a d diti o n, t he 
Lea d I nstit uti o n or desi g nee will u p date t he Partici pati n g I nstit uti o ns o n a n o n g oi n g basis 
a b o ut pr ot oc ol accr ual data s o t hat t he y w ill be a ware of i m mi ne nt pr ot oc ol cl os ures. 
 
4. 3  I nf or me d C o nse nt Re q uire me nts 
 
 
 
T he D F/ H C C a p pr o ve d i nf or me d c o nse nt d oc u me nt will ser ve as a te m plate f or t he 
i nf or me d c o nse nt fr o m partici pati n g i nstit uti o ns. As best a p ossi ble, t he te m plate s h o ul d 
be f oll o we d wit h t he s pecificati o ns o utli ne d i n t he D F/ H C C g ui da nce d oc u me nt o n 
M o del C o nse nt La n g ua ge.   
 
Partici pati n g sites are t o se n d t heir versi o n of t he i nf or me d c o nse nt d oc u me nt a n d HI P A A 
a ut h orizati o n, if a se parate d oc u me nt, t o t he Lea d Site f or t heir re visi o n pri or t o 
s u b missi o n t o t he partici pati n g site's I R B.  
 
T he Pri nci pal I n vesti gat or ( PI) at eac h Partic i pati n g I nstit uti o n will i de ntif y t he p h ysicia n 
me m bers of t he st u d y tea m w h o will be o btai ni n g c o nse nt a n d si g ni n g t he c o nse nt f or m 
f or t hera pe utic pr ot oc ols. It is D F/ H C C p olic y t h at o nl y atte n di n g p h ysici a ns c a n 
o bt ai n i nf or me d c o nse nt a n d re-c o nse n t t o dr u g a n d/ or de vice tri als.   
 
 
4. 4 I R B D oc u me nt ati o n 
 
T he f oll o wi n g m ust be o n file wit h t he D F/ H C C  Lea d I nstit uti o n or desi g nee a n d m ust be 
s u b mitte d a n d a p pr o ve d b y t he D F CI I R B pri or t o partici pa nt re gistrati o n: 
 
 A p pr o val Letter of t he i nstit uti o n's I R B   
 C o p y of t he I nf or me d C o nse nt F or m a p pr o ve d b y t he Partici pati n g I nstit uti o n’s 
I R B  
 I R B a p pr o val f or all a me n d me nts 
 
It is t he Partici pati n g I nstit uti o n's res p o nsi bilit y t o n otif y its I R B of pr ot oc ol a me n d me nts.  
Partici pati n g I nstit uti o ns will ha ve 9 0 da ys  fr o m recei pt t o pr o vi de t he D F/ H C C Lea d 
I nstit uti o n t heir I R B a p pr o val f or A me n d me nts t o a pr ot oc ol.    
 
4. 5 I R B Re- A p pr o v al 
          
A n n ual I R B re-a p pr o val fr o m t he Partici pati n g I nstit uti o n is re q uire d i n or der t o c o nti n ue 
researc h a n d re gister partici pa nts o nt o a pr ot oc ol.  T here is n o grace peri o d f or c o nti n ui n g 
a p pr o vals. 
 
Pr ot oc ol re gistrati o ns will n ot be c o m plete d if  a re-a p pr o val letter is n ot recei ve d b y t he 
D F/ H C C Lea d I nstit uti o n fr o m t h e Partici pati n g I nstit uti o ns o n or bef ore t he a n ni versar y 
of t he pre vi o us a p pr o val date.   

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
6 0
 
 
4. 6 P artici p a nt C o nfi de nti alit y a n d A ut h oriz ati o n St ate me nt 
 
T he HI P P A of 1 9 9 6 c o ntai ns, as o ne of its si x maj or c o m p o ne nts, t he re q uire me nt t o 
create pri vac y sta n dar ds f or healt h care i nf or ma ti o n t hat is use d or discl ose d i n t he c o urse 
of treat me nt, pa y me nt or healt h care o perati o ns.  T he ori gi nal Pri vac y R ule, as it has 
c o me t o be k n o w n, was p u blis he d i n Dece m be r 2 0 0 0.  T he Fi nal R ule was p u blis he d o n 
A u g ust 1 4, 2 0 0 2, w hic h m o difie d t he pri vac y r ule i n si g nifica nt wa ys vis-à- vis researc h. 
 
I n or der f or c o vere d e ntities t o use or discl ose pr otecte d healt h i nf or mati o n d uri n g t he 
c o urse of a D F/ H C C M ulti- C e nter Pr ot oc ol, t he st u d y pa rtici pa nt m ust si g n a n 
A ut h orizati o n.  T his A ut h orizati o n ma y or ma y n ot be se parate fr o m t he I nf or me d 
C o nse nt.  T he D F/ H C C M ulti- Ce nter Pr ot oc ol, wit h t he a p pr o val fr o m t he D F CI I R B a n d 
if a p plica ble N CI/ C T E P, will pr o vi de a n I nf or me d C o nse nt te m plate, w hic h c o vere d 
e ntities ( D F/ H C C M ulti- Ce nter Pr ot oc ol Pa rtici pati n g I nstit uti o ns) m ust use.  
 
T he D F/ H C C M ulti- Ce nter Pr ot oc ol will use all eff orts t o li mit its use of pr otecte d healt h 
i nf or mati o n i n its trials.  H o we ver, beca use of t he nat ure of t hese trials, certai n pr otecte d 
healt h i nf or mati o n m ust be c ollecte d per Na ti o nal Ca ncer I nstit ute re q uire me nts. T hese 
are t he pri mar y reas o ns w h y D F/ H C C has c h ose n t o use A ut h orizati o ns, si g ne d b y t he 
partici pa nt i n t he trial, rat her t ha n li mite d data sets wit h data use a gree me nts.   
 
4. 7 P artici p a nt Re gistr ati o n a n d R a n d o miz ati o n  
T o re gister a partici pa nt, please refer t o page 1 8, secti o n 4. 4 f or details re gar di n g t he 
re gistrati o n pr ocess. 
 
 
4. 8 D F/ H C C M ulti-ce nter Pr ot oc ol C ase N u m ber 
 
O nce eli gi bilit y has bee n esta blis he d a n d t h e partici pa nt s uccessf ull y re gistere d, t he 
partici pa nt is assi g ne d a fi ve di git pr ot oc ol case n u m ber.  T his n u m ber is u ni q ue t o t he 
partici pa nt o n t his trial a n d m ust be use d  f or Q A C T C R F/e C R F c o m pleti o n a n d writte n 
o n all data a n d Q A C T c orres p o n de nce f or t he partici pa nt.  
 
4. 9 D F/ H C C M ulti-ce nter Pr ot oc ol Re gistr ati o n P olic y 
 
4. 9. 1 I niti ati o n of T her a p y : Partici pa nts m ust be re gistere d wit h t he D F/ H C C Q A C T 
bef ore recei vi n g treat me nt.  Treat me nt ma y n ot be i nitiate d u ntil t he Partici pati n g 
I nstit uti o n recei ves a fa xe d or e- maile d c o p y of t he partici pa nt’s Re gistrati o n 
C o nfir mati o n me m o fr o m t he D F/ H C C Q A C T. T hera p y m ust be i nitiate d per 
pr ot oc ol g ui deli nes.  T he Pr ot oc ol C hair a n d D F CI I R B m ust be n otifie d of a n y 
e xce pti o ns t o t his p olic y .  
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
6 1
4. 9. 2  Eli gi bilit y E xce pti o ns:  T he D F/ H C C Q A C T will ma ke n o e xce pti o ns t o t he 
eli gi bilit y re q uire me nts f or a pr ot oc ol wit h o ut pri or D F CI I R B a p pr o val.  T he 
D F/ H C C Q A C T re q uires eac h i nstit uti o n t o f u ll y c o m pl y wit h t his re q uire me nt. 
 
4. 9. 3  Verific ati o n of Re gi str ati o n, D ose Le vels, a n d Ar m Desi g n ati o n: A re gistrati o n 
c o nfir mati o n me m o f or partici pa nts re gi stere d t o D F/ H C C M ulti- Ce nter Pr ot oc ol 
will be fa xe d or e maile d t o t he re gisteri n g i nstit uti o n wit hi n o ne w or ki n g da y of t he 
re gistrati o n. Treat me nt ma y n ot be i nitiate d u ntil t he site recei ves a fa xe d or e-
maile d  c o p y of t he re gistrati o n c o nfir mati o n me m o.  
 
4. 9. 4  C o nfi de nti alit y:  All d oc u me nts, i n vesti gati ve re p orts, or i nf or mati o n relati n g t o t he 
partici pa nt are strictl y c o nfi de ntial. W he n e ver reas o na bl y feasi ble, a n y partici pa nt 
s pecific re p orts (i.e. Pat h ol o g y Re p orts, M RI Re p orts, O perati ve Re p orts, etc.) 
s u b mitte d t o t he Lea d I nstit uti o n or desi g nee m ust ha ve t he partici pa nt’s f ull na me 
& s ocial sec urit y n u m ber “ blac ke d o ut” a n d t he assi g ne d D F/ H C C Q A C T case 
n u m ber a n d pr ot oc ol n u m ber  writte n i n ( wit h t he e xce pti o n of t he si g ne d i nf or me d 
c o nse nt d oc u me nt). Partici pa nt i nitials ma y o nl y be i ncl u de d or retai ne d f or cr oss 
verificati o n of i de ntificati o n. 
  
 
4. 1 0 Sc he d ule of D at a S u b missi o n 
T he D F/ H C C Q A C T de vel o ps a set of eit her  pa per or electr o nic case re p ort f or ms, 
( C R F/e C R Fs) f or use wit h t he D F/ H C C M ulti- Ce nter Pr ot oc ol.  Q A C T pr o vi des a we b 
base d trai ni n g f or e C R F users.  T hese f or ms are desi g ne d t o c ollect data f or eac h st u d y.  
N ote:  It is necess ary t o se n d o nly O N E co py of all p a per C ase Re p ort F or ms, if 
a p plic a ble.  
   
4. 1 0. 1 Eli gi bilit y C hec klist 
 
P ur p ose - O utli nes pr ot oc ol-s pecific eli gi bilit y criteria a n d i ncl u des t he f oll o wi n g:  
              
Partici pa nt De m o gra p hics (a d dress, zi p c o de , se x, race, et h nicit y, i nitials, date of 
birt h)  
1)  Para meters f or eli gi bilit y  
2)  Para meters f or e xcl usi o n  
 
 
4. 1 0. 2 O n-st u d y F or m(s) 
 
P ur p ose -  d oc u me nts t he f oll o wi n g ite ms: 
 De m o gra p hic data 
 Pri or t hera p y 
 Past me dical a n d s ur gical hist or y 
 Descri pti o n of partici p a nt’s p h ysical stat us at  pr ot oc ol re gistrati o n 
 Disease site s pecific data 
 
4. 1 0. 3 B aseli ne Assess me nt F or m(s)  

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
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P ur p ose – D oc u me nts o bjecti ve a n d s u bjecti ve di sease stat us as defi ne d b y t he 
pr ot oc ol . Rec or ds all perti ne nt ra di o gra p hic a n d la b orat or y m eas ure me nts of disease 
utilize d i n deter mi ni n g res p o nse e val uati o ns.  
 
4. 1 0. 4   Tre at me nt F or m(s) 
 
P ur p ose - Rec or ds t he f oll o wi n g i nf or mati o n relate d t o t he ti me t he partici pa nt 
recei ves pr ot oc ol treat me nt: 
 Partici pa nt, Pr ot oc ol i nf or mati o n  
 Pr ot oc ol treat me nt a n d s u p p orti v e t hera p y per treat me nt c ycle 
 Pr ot oc ol s pecific la b orat or y val ues per treat me nt c ycle 
 All me dicati o ns ot her t ha n pr ot oc ol c he m ot hera p y a ge nts use d t o treat 
c o nc o mita nt   dia g n oses, if a p plica ble 
 
4. 1 0. 5  A d verse E ve nt Re p ort F or m(s) 
 
P ur p ose – D oc u me nts a d verse e ve nts t hat occ u r w hile t he partici pa nt is recei vi n g 
treat me nt a n d f or u p t o 3 0 da ys after t he last d ose of treat me nt.  All a d verse e ve nts 
are t o be gra de d b y n u m ber usi n g t he t o xicit y gra di n g scale re q uire d b y t he 
pr ot oc ol. T his f or m is n ot f or I R B s u b missi o n, b ut f or rec or di n g t he A E i n t he 
rese arc h d at a b ase. 
 
4. 1 0. 6  Res p o nse Assess me nt F or m(s)  
 
P ur p ose – D oc u me nts o bjecti ve a n d s u bjecti ve res p o nse as defi ne d b y t he pr ot oc ol. 
Rec or ds all perti ne nt ra di o gra p hic a n d la b or at or y meas ure me nts of disease utilize d 
i n deter mi ni n g res p o nse e val uati o ns.  
 
4. 1 0. 7   Off Tre at me nt a n d Off St u d y F or m(s)  
 
P ur p ose - T he Off Treat me nt a n d Off St u d y F or ms are  s u b mitte d w he n t he 
partici pa nt is re m o ve d fr o m t he st u d y or has c o m plete d all pr ot oc ol treat me nt.  
N ote: If t he partici pa nt dies w hile o n pr ot oc ol , t he Off St u d y F or m is t he last f or m 
s u b mitte d. 
 
4. 1 0. 8   F oll o w u p  / S ur vi v al F or m 
 
P ur p ose - S u m marizes partici pa nt stat us at a gi ve n p oi nt i n ti me after bei n g 
re m o ve d fr o m treat me nt.  
 
 
 4. 1 1 D at a F or m Re vie w 
 
W he n data f or ms arri ve at t he D F / H C C Q A C T, t he y are re vie we d f or: 
   
 
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
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C o m plete ness:  
Is all t he i nf or mati o n pr o vi de d as re q uire d per pr ot oc ol? 
 
Pr ot oc ol Tre at me nt C o m pli a nce:   
Are t he dr u g d osa ge a n d sc he d ule c orrect?  
  
A d verse E ve nts ( T o xicities):  
Di d t he partici pa nt e x perie nce a d verse e ve nts (t o xicities or si de effects) ass ociate d wit h 
t he treat me nt? Was t he treat me nt dela ye d d ue t o t he a d verse e ve nt? W hat was t he m ost 
se vere de gree of t o xicit y e x perie nce d b y t he partici pa nt?  
 
N otati o ns c o ncer ni n g a d verse e ve nts will a d dr ess relati o ns hi p t o pr ot oc ol treat me nt f or 
eac h a d verse e ve nt gra de.  All a d verse e v e nts e nc o u ntere d d uri n g t he st u d y will be 
e val uate d acc or di n g t o t he N C I C o m m o n T o xicit y Criteria assi g ne d t o t he pr ot oc ol a n d 
all a d verse e ve nts m ust be n ote d o n t he pa rtici pa nt's A d verse E ve nt ( T o xicit y) F or ms. 
 
Res p o nse:   
Di d t he partici pa nt ac hie ve a res p o nse?  W hat  le vel of res p o nse di d t he y ac hie ve?  O n 
w hat date di d t he partici pa nt ac hie ve t he re s p o nse a n d h o w was t he res p o nse deter mi ne d? 
 
Res p o nse criteria are defi ne d i n t he pr ot oc ol .  A t u m or assess me nt m ust be perf or me d 
pri or t o t he start of treat me nt a n d w hile t he partici pa nt is o n treat me nt as s pecifie d b y t he 
pr ot oc ol.   
 
O bjecti ve res p o nses m ust ha ve d oc u me ntati o n s uc h as p h ysical meas ure me nts, x-ra ys, 
sca ns, or la b orat or y tests.   
 
A s u bjecti ve res p o nse is o ne t h at is percei ve d b y t he partic i pa nt, s uc h as re d ucti o n i n 
pai n, or i m pr o ve d a p petite. 
 
 
4. 1 2  Missi n g a n d Deficie nt Me m or a n d u m  
 
Data s u b missi o ns are m o nit ore d f or ti meli ness a n d c o m plete ness of s u b missi o n. 
Partici pati n g I nstit uti o ns are n otifie d of t heir data s u b missi o n deli n q ue ncies i n 
acc or da nce wit h t he f oll o wi n g p olicies a n d pr oce d ures: 
 
I nc o m plete or Q uesti o na ble Data 
 
If st u d y f or ms are recei ve d wit h missi n g or q uesti o na ble data, t he s u b mitti n g i nstit uti o n 
will recei ve a writte n q uer y fr o m t he D F/ H C C Q A C T Data A nal yst.  Res p o nses t o t he 
q uer y s h o ul d be c o m plete d a n d ret ur ne d wit hi n 1 4 da ys.  Res p o nses ma y be ret ur ne d o n 
t he writte n q uer y or o n a n a me n de d case re p ort f or m. I n b ot h i nsta nces t he q uer y m ust be 
attac he d t o t he s pecific data bei n g re-s u b mitte d i n res p o nse.   
 
Missi n g F or ms  

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
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If st u d y f or ms are n ot s u b mitte d o n sc he d ule, t he Partici pati n g I nstit uti o n will recei ve a 
Missi n g F or m Re p ort fr o m t he D F/ H C C Q A C T n o ti n g t he missi n g f or ms.  T hese re p orts 
are c o m pile d b y t he D F/ H C C Q A C T a n d distri b u te d a mi ni m u m of t hree ti mes a year.  
 
 
5. 0  R E Q UI SI TI O NI N G I N V E S TI G A TI O N A L D R U G 
 
 
Partici pati n g  I nstit uti o ns  s h o ul d  or der  t h eir  o w n  a ge nt  fr o m  B oe hri n ger  I n gel hei m  
P har marce uticals,  I nc.’s  c o ntracte d  distri b ut or  f or  t his  trial,  Al mac.  T he  Al mac  S u p plies  
Or der F or m a n d c o m plete i nstr ucti o ns will be gi ve n t o eac h site i n t h e start- u p materials.  
 
 
 
6. 0 S A F E T Y A S S E S S M E N T S A N D T O XI CI T Y M O NI T O RI N G 
 
All partici pa nts recei vi n g i n vesti gati o nal a ge nts  will be e val uate d f or safet y.   T he safet y 
para meters i ncl u de all la b orat or y tests a n d he mat ol o gical a b n or malities, p h ysical 
e xa mi nati o n fi n di n gs, a n d s p o nta ne o us re p orts  of a d verse e ve nts re p orte d t o t he 
i n vesti gat or b y partici pa nts.  All t o xicities e nc o u ntere d d uri n g t he st u d y will be e val uate d 
acc or di n g t o t he N CI criteria s pecifie d i n t he pr ot oc ol a n d rec or de d pri or t o eac h c o urse of 
t hera p y.  Life-t hreate ni n g t o xicities s h o ul d be re p orte d i m me diatel y t o t he Pr ot oc ol C hair 
a n d I nstit uti o nal Re vie w B oar d (I R B).  
 
A d diti o nal safet y assess me nts a n d t o xicit y m o nit ori n g will be o utli ne d i n t he pr ot oc ol. 
 
6. 1 Seri o us A d verse E ve nts 
 
A seri o us a d verse e ve nt ( S A E) is a n y a d verse dr u g e x perie nce at a n y d ose t hat res ults i n 
a n y of t he f oll o wi n g o utc o mes: deat h, a life-t hreate ni n g a d verse dr u g e x perie nce, 
i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pita lizati o n, a persiste nt or 
si g nifica nt disa bilit y/i nca pacit y, or a c o n genital a n o mal y/ birt h defect.  I m p orta nt 
me dical e ve nts t hat ma y n ot res ult i n deat h, be life-t hreat e ni n g, or re q uire 
h os pitalizati o n ma y be c o ns i dere d seri o us w he n, based u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o par dize t he partici pa nt or ma y re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n.  E xa m ples of s uc h 
me dical e ve nts i ncl u de aller gic br o nc h os pa s m re q uiri n g i nte nsi ve treat me nt i n a n 
e mer ge nc y r o o m or at h o me, bl o o d d yscrasias  or c o n v ulsi o ns i n a partici pa nt w h o has 
ne ver ha d seiz ure acti vit y i n t he past t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he 
de vel o p me nt of dr u g de pe n de nc y or a b use. 
 
6. 2 G ui deli nes f or Re p orti n g Seri o us A d verse E ve nts  
 
G ui deli nes f or re p orti n g Seri o us  A d verse E ve nts ( S A Es):  
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
6 6
 
Neit her t he F D A n or t he I C H G C P g ui deli nes defi ne t he ter ms “ pr o t oc ol vi olati o n” or 
“ pr ot oc ol de viati o n.”  All D F/ H C C Pr ot oc ol C hai rs m ust a d here t o t h ose p olicies set b y t he 
D F CI I R B, t he defi niti o ns f or pr ot oc ol vi olati o n a n d de viat i o n as descri be d b y t he D F CI 
I R B will be a p plie d f or re p orti n g p ur p oses f or all I nstit uti o ns Partici pati n g i n t he D F/ H C C 
M ulti-ce nter Pr ot oc ol.  
   
7. 1  Defi niti o ns 
 
Pr ot oc ol De vi ati o n: A n y de part ure fr o m t he defi ne d pr oce d ures set f ort h i n t he I R B-
a p pr o ve d pr ot oc ol w hic h is pr os pectively a p pr ove d  pri or t o its i m ple me ntati o n. 
 
Pr ot oc ol E xce pti o n:   A n y pr ot oc ol de viati o n t hat relates t o t he eli gi bilit y criteria, e. g. 
e nr oll me nt of a s u bject w h o d oes n ot m eet all i ncl usi o n/e xcl usi o n criteria. 
 
 
 
Pr ot oc ol Vi ol ati o n: A n y pr ot oc ol de viati o n t hat was n ot  pr os pecti vel y a p pr o ve d b y t he 
I R B pri or t o its i nitiati o n or i m ple me ntati o n.    
 
7. 2 Re p orti n g Pr oce d ures 
 
T he Pr ot oc ol C h air:  is res p o nsi ble f or e ns uri n g t hat clear d oc u me ntati o n is a vaila ble 
i n t he me dical rec or d a n d/ or re g ulat or y d oc u me nts t o descri be all pr ot oc ol e xce pti o ns, 
de viati o ns  a n d vi olati o ns.  
T he Pr ot oc ol C hair will als o be res p o ns i ble f or e ns uri n g t hat all pr ot oc ol 
vi olati o ns/ de viati o ns are pr o m ptl y re p orte d per D F CI I R B g ui deli nes.  
 
P artici p ati n g I nstit uti o ns : Pr ot oc ol de viati o ns re q uire pr os pecti ve a p pr o val fr o m 
D F CI I R B. T he Partici pati n g i nstit uti o n m u st s u b mit t he de viati o n re q uest t o t he 
Pr ot oc ol C hair or desi g nee, w h o will s u b m it t he de viati o n re q uest t o t he D F CI I R B. 
U p o n D F CI I R B a p pr o val t he de viati o n s h o ul d be s u b mitte d t o t he Partici pati n g 
I nstit uti o n’s o w n I R B, per its i nstit uti o nal p olic y. 
A c o p y of t he Partici pati n g I nstit uti o n’s I R B re p ort a n d deter mi nati o n will be f or war de d 
t o t he D F/ H C C Lea d I nstit uti o n or desi g nee b y mail, facsi mile, or via e- mail wit hi n 1 0 
b usi ness da ys after t he ori gi nal s u b missi o n.  
 
All pr ot oc ol vi olati o ns m ust be se nt t o t he D F/ H C C Lea d I nstit uti o n Pr ot oc ol C hair or 
desi g nee i n a ti mel y ma n ner.  
 
C o or di n ati n g Ce nter:   U p o n recei pt of t he vi olati o n/ de viati o n re p ort fr o m t he 
Partici pati n g I nstit uti o n, t he D F/ H C C L ea d I nstit uti o n or desi g nee will s u b mit t he 
re p ort t o t he Pr ot oc ol C hair f or re vie w. S u bse q ue ntl y, t he Partici pati n g I nstit uti o n’s 
I R B vi olati o n/ de viati o n re p ort will be s u b mitted t o t he D F CI I R B f or re vie w per D F CI 
I R B re p orti n g g ui deli nes. D F/ H C C will f or ward all vi olati o n re p orts t o C T E P via a n 
i nter nal D F/ H C C pr ocess, as a p plica ble. 
 
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
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8. 0 M O NI T O RI N G: Q U A LI T Y C O N T R O L 
 
T he q ualit y c o ntr ol pr ocess f or a cli nical trial re q uires verificati o n of pr ot oc ol c o m plia nce a n d 
data acc urac y. As t he C o or di nati n g Ce nter, t he D F / H C C Lea d I nstit uti o n or desi g nee wit h t he ai d 
of t he Q A C T pr o vi des q ualit y c o ntr ol o versi g ht f or t he D F/ H C C M ulti-ce nter Pr ot oc ol. 
 
8. 1   O n g oi n g M o nit ori n g of Pr ot oc ol C o m pli a nce  
 
T he D F/ H C C Lea d I nstit uti o n will i m ple me nt m o nit ori n g acti vities fr o m t he ti me bef ore 
t he cli nical p hase of t he pr ot oc ol be gins c o nti n ui n g t hr o u g h t o t he ti me of st u d y 
c o m pleti o n t o e ns ure t hat Partici pati n g I nstit uti o ns are c o m pl yi n g wit h re g ulat or y a n d 
pr ot oc ol re q uire me nts, data q ualit y, a n d s u bjec t safet y. T he Partici pati n g I nstit uti o ns will 
be re q uire d t o s u b mit s u bject s o urce d oc u me nts t o t he D F/ H C C Lea d I nstit uti o n or 
desi g nee f or m o nit ori n g. Als o, t he Partici pati n g I nstit uti o n ma y be s u bject t o o n-site 
m o nit ori n g c o n d ucte d b y t he D F/ H C C Lea d I nstit uti o n or desi g nee.  
 
T he Lea d I nstit uti o n will pr o vi de re g ular a n d o n g oi n g c o m m u nicati o n t o Partici pati n g 
I nstit uti o ns a b o ut st u d y related i nf or mati o n t hat ma y i ncl u de ; partici pati o n i n re g ular 
Lea d I nstit uti o n i ni tiate d telec o nfere nces, distri b uti o n of a n o n g oi n g “ Ne wsletter” 
hi g hli g hti n g o verall pr ot oc ol pr o gress a n d i m p orta nt a n n o u nce me nts, a n d c ollecti n g 
s o urce d oc u me nts fr o m Partici pati n g I nstit uti o ns, at s pecific data p oi nts, t hat s u p p ort t he 
pri mar y a n d or sec o n dar y e n d p oi nts.  
 
 Re dacte d s o urce d oc u me nts t o be se nt t o t he Lea d I nstit uti o n (list d oes n ot i ncl u de 
baseli ne s o urce alrea d y s u b mitte d) f or m o nit ori n g:  
    - Da y 1 M D/ N P/ R N n otes at start of eac h ne w c ycle.  D oc u me ntati o n of a d verse  
         e ve nt/ gra de t o be i ncl u de d 
    - Re-sta gi n g e xa ms/re p orts (c ycle 3, 5, 7, etc)  
    - U p o n pr o gressi o n, pat h ol o g y res ults fr o m repeat bi o ps y.  Please, refer t o pa ge 3 3,  
     secti o n 7. 1. 2 a n d 7. 1. 3 a n d A p pe n di x 4 f or f urt her details re gar di n g t he re peat   
       bi o ps y.   
All data s u b mitte d t o t he D F/ H C C Q A C T will be m o nit ore d f o r ti meli ness of s u b missi o n, 
c o m plete ness, a n d a d here nce t o pr ot oc ol re q uire me nts. T he Lea d I nstit uti o n or desi g nee a n d 
if a p plica ble Q A C T Data A nal ysts assi g ne d t o t he Prot oc ol will perf or m t he o n g oi n g 
pr ot oc ol data c o m plia nce m o nit ori n g wit h t h e s u p p ort of t he Partici pati n g I nstit uti o n’s 
C o or di nat ors, t he Pri nci pal I n vesti g at ors, a n d t he Pr ot oc ol C hair.  
 
8. 2  E v al u ati o n of P artici p ati n g I nstit uti o n Perf or m a nce 
 
8. 2. 1 Eli gi bilit y C hec klist:   
 
Eli gi bilit y criteria are c hec ke d o n a pr ot oc ol-s pecific eli gi bilit y c h ec klist a n d fa xe d t o 
t he D F/ H C C Q A C T pri or t o re gistrati o n o n pr ot oc ol.  T he c hec klist a n d i nf or me d 
c o nse nt d oc u me nt are re vie we d b y a D F/ H C C Q A C T Pr ot oc ol Re gistrar bef ore t he 
partici pa nt ca n be re gistere d o n a pr ot oc ol.  T he D F/ H C C Q A C T ca n n ot ma ke 
e xce pti o ns t o t he eli gi bilit y re q uire me nts. 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
6 8
 
8. 2. 2 Accr u al of Eli gi ble P artici p a nts:  
 
A n n ual accr ual rates f or eli gi ble partici pa nts  e nr olle d o nt o t hera pe utic cli nical trials 
are calc ulate d f or eac h i nstit uti o n.  Partici pati n g I nstit uti o ns are e x pecte d t o mai ntai n 
t he mi ni m u m a n n ual a vera ge accr ual as defi ne d b y t he pr ot oc ol gra nt or c o ntract.  
 
 
9. 0 A U DI TI N G: Q U A L I T Y A S S U R A N C E 
 
A u diti n g is a met h o d of Q ualit y Ass ura nce . T he mai n f oc us i n a u diti n g is t o meas ure if t he 
sta n dar ds a n d pr oce d ures set are bei n g f oll o wed. A u diti n g is t he s yste matic a n d i n de pe n de nt 
e xa mi nati o n of all trial relate d acti vities a n d d oc u m e nts.  A u dits deter mi ne if e val uate d acti vities 
were a p pr o priatel y c o n d ucte d a n d t he data were ge nerate d, rec or de d a n d a nal yze d, a n d 
acc uratel y re p orte d per t he pr ot oc ol, Sta n dar d O perati n g Pr oce d ures ( S O Ps), G o o d Cli nical 
Practice ( G C P) a n d t he C o de  of Fe deral Re g ulati o ns. 
 
9. 1 D F/ H C C S p o ns ore d Tri als  
 
O ne a u dit o n-site will be sc he d ule b y t he Q A C T ass u mi n g at least t hree s u bjects ha ve 
bee n treate d o n pr ot oc ol at t h e site. A p pr o xi matel y 3- 4 s u bjec ts w o ul d be a u dite d at t he 
site o ver a 2 da y peri o d.  If violati o ns w hic h i m pact s u bject sa fet y or t he i nte grit y of t he 
st u d y are f o u n d, m ore s u bject rec or ds ma y be a u dite d.  
 
9. 3 P artici p ati n g I nstit uti o n 
 
It is t he Partici patin g I nstit uti o n’s res p o nsi bilit y t o n o tif y t he D F/ H C C Lea d I nstit uti o n of 
all sc he d ule d a u dit dates (i nter nal or N CI) a n d re-a u dit dates (if a p plica ble), w hic h 
i n v ol ve t he D F/ H C C M ulti- Ce nter Pr ot oc ol. All i nstit uti o ns will f or war d a c o p y of fi nal 
a u dit a n d/ or re-a u dit re p orts a n d c orrecti ve acti o n pla ns (if a p plica ble) t o t he D F/ H C C 
Lea d I nstit uti o n or desi g nee wit hi n 1 2 wee ks after t he a u dit date.  
 
9. 4 C o or di n ati n g Ce nter ( Le a d I nstit uti o n or desi g nee)   
 
T he Pr ot oc ol C hair will re vie w all D F/ H C C M ulti- Ce nter Pr ot oc ol Fi nal A u dit re p orts 
a n d c orrecti ve acti o n pla ns if a p plica ble. T he Lea d I nstit uti o n or desi g nee m ust f or war d 
t hese re p orts t o t he D F/ H C C Q A C T per D F/ H C C p olic y f or re vie w b y t he D F/ H C C 
A u dit C o m mittee. Base d u p o n t he a u dit asse ss me nts t he D F/ H C C A u dit C o m mittee c o ul d 
acce pt or c o n diti o nall y acce pt t he a u dit rati n g a n d fi nal re p ort. C o n diti o nal a p pr o val 
c o ul d re q uire t he Pr ot oc ol C hair t o i m ple me nt rec o m me n dati o ns or re q uire f urt her 
f oll o w- u p.  F or u nacce pta ble a u dits, t he A u dit C o m mittee w o ul d f or war d t he fi nal a u dit 
re p ort a n d c orrecti ve acti o n pla n t o t he D F CI I R B as a p plica ble. 
 
9. 5 S u b- St a n d ar d Perf or m a nce  
 

U n derst a n di n g resist a nce t o BI B W 2 9 9 2  
 
 
Oct o ber 2 0 1 3  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
 
6 9
T he Pr ot oc ol C hair, D F CI I R B a n d t he N CI f o r C T E P trials, is c har ge d wit h c o nsi deri n g 
t he t otalit y of a n i nstit uti o n’s perf or ma nce i n c o nsi deri n g i nstit uti o nal partici pati o n i n t he 
D F/ H C C M ulti- Ce nter Pr ot oc ol. 
 
9. 5. 1 C orrecti ve Acti o ns 
 
Partici pati n g I nstit uti o ns t hat fail t o  meet t he perf or ma nce g oals of accr ual, 
s u b missi o n of ti mel y acc urate data, a d here nce t o pr ot oc ol re q uire me nts, a n d 
c o m plia nce wit h state, fe deral, a n d G o o d Cli nical Practice g ui deli nes, will be 
rec o m me n de d f or a si x- m o nt h pr o bati o n peri o d. S uc h i nstit uti o ns m ust res p o n d 
wit h a c orrecti ve acti o n pla n a n d m ust de m o nstrate d uri n g t he pr o bati o n peri o d t hat 
deficie ncies ha ve bee n c orrecte d, as e vi de nce d b y t he i m pr o ve d perf or ma nce 
meas ures. Partici pati n g I nstit uti o ns t hat fail t o de m o nstrate si g nifica nt i m pr o ve me nt 
will be c o nsi dere d b y t he Pr ot oc ol C hair f or re v ocati o n of partici pati o n.