Clinical trial NCT01074177
Conditions: Non-small Cell Lung Cancer EGFR Mutations
Keywords: BIBW 2992 NSCLC
Sponsor: Massachusetts General Hospital
Start date: 2011-02-01; Completion date: 2017-03-01
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In this research study we are looking to see how effective BIBW 2992 is at suppressing the development of the T790M mutation in non-small cell lung cancer (NSCLC) patients. Epidermal growth factor receptors (EGFR) are proteins found on the surface of some cancer cells that promote a growth signal. Some cancer drugs for NSCLC work to block this signal from reaching its target on the cancer cells which in turn may slow or stop the cancer from growing. However, many times patients with EGFR mutations will stop responding to these cancer drugs and develop drug-resistance because they have developed a specific EGFR mutation called T790M. BIBW 2992 may prevent the T790M mutation from becoming active and therefore slow disease progression.

Detailed description:
* Participants will take tablets of BIBW 2992 once a day during each cycle. Each cycle is 28 days (4 weeks).
* Participants will come to the clinic on Day 1, 8 and 15 of Cycle 1. For Cycle 2 through 8, they will need to come to the clinic on Day 1. After Cycle 8, they will have study visits every 2 months.
* The following tests and procedures will be performed at these clinic visits: physical examination, routine blood tests, research blood samples, EKG (every fourth cycle starting cycle 5), ECHO or MUGA (every fourth cycle starting cycle 5), an assessment of the tumor by CT or MRI scan (every 8 weeks).
* Participants may continue to participate in this research study as long as their tumor does not grow and their disease does not worsen and they do not have any severe side effects.
* Participants will have a tumor biopsy performed at the end of their participation in this study if their tumor is growing or if they have a new tumor. The purpose of this biopsy is to assess for the presence or the absence of the mutation T790M.

Arms: arm 1: BIBW 2992 Taken orally once a day
Interventions: intervention 1: BIBW 2992
Intervention descriptions: intervention 1: Taken orally once a day

Protocol documents:
Prot_SAP_000.pdf: 


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. 
 
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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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 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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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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 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
 


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 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  
 
 
Oct o ber 2 0 1 3  
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. 
 
 
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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. 
 
 
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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.