Clinical trial NCT02448537
Conditions: Metastatic Sarcoma
Keywords: Metastatic Sarcoma Unresectable Sarcoma PM01183
Sponsor: Massachusetts General Hospital
Start date: 2015-08-01; Completion date: 2019-04-01
Enrollment: 42 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is investigating a drug called PM01183 alone and in combination with chemotherapy drugs called gemcitabine or doxorubicin as a possible treatment for metastatic or unresectable Sarcoma.

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

PM01183 is a new drug that is believed to bind DNA cause double strands of DNA to break. This drug has been studied in previous research studies, and these suggest that it may slow or stop the growth of cancers. The FDA (the U.S. Food and Drug Administration) has not approved PM01183 as a treatment for any disease.

In this research study, the investigators are trying to assess the effects, good or bad, that PM01183, administered either alone or in combination with gemcitabine or doxorubicin has on metastatic or unresectable sarcoma.

Arms: arm 1: Anthracycline-naïve patients will receive combination of PM01183 and Doxorubicin per cycle.

* PM01183 predetermined dose daily via IV per cycle
* Doxorubicin predetermined dose daily via IV per cycle arm 2: Prior anthracycline exposure and without prior gemcitabine exposure

* PM01183 predetermined dose given twice via IV per cycle
* Gemcitabine predetermined dose given twice via IV per cycle arm 3: Patients who have received at least both prior anthracycline and prior gemcitabine

-PM01183 predetermined dose once via IV per cycle
Interventions: intervention 1: PM01183 intervention 2: Doxorubicin intervention 3: Gemcitabine
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 




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I N D  S p o ns o r:   
Gr e g or y  M.  C ot e  M D  P h D 
M ass a c h us etts  G e n er al  H o s pit al  C a n c er  C e nt er 
3 2  Fr uit  Str e et 
B ost o n,  M ass a c h us etts  
0 2 1 1 4  


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S C H E M A 


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T A B L E  O F  C O N T E N T S 
S C H E M A ........................................................................................................................ ................. 3 
1. 
O BJ E C TI V E S .................................................................................................................... ....... 6 
1. 1   St u d y  D esi g n ............................................................................................................... 6  
1. 2   Pri m ar y  O bj e cti v es ...................................................................................................... 6  
1. 3   S e c o n d ar y  O bj e cti v es .................................................................................................. 6  
2. 
B A C K G R O U N D .................................................................................................................... .. 7 
2. 1   St u d y  Dis e as e(s).......................................................................................................... 7  
2. 2   P M 0 1 1 8 3 ..................................................................................................................... 7  
2. 3   Ot h er  A g e nt(s)  ........................................................................................................... 1 5 
2. 4   R ati o n al e ................................................................................................................... 1 6  
3.  P A R TI CI P A N T  S E L E C TI O N ................................................................................................ 1 6  
3. 1   Eli gi bilit y  Crit eri a ..................................................................................................... 1 7  
3. 2   E x cl usi o n  Crit eri a ..................................................................................................... 1 8  
3. 3   I n cl usi o n  of  W o m en  a n d  Mi n oriti es ......................................................................... 1 9  
4.   R E GI S T R A TI O N  P R O C E D U R E S ........................................................................................ 1 9  
4. 1   G e n er al  G ui d eli n es f or  D F/ H C C  a n d  D F/ P C C I nstit uti o ns ...................................... 1 9  
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 nstit uti o ns .................................... 1 9  
5.   T R E A T M E N T  P L A N ............................................................................................................. 2 0  
5. 1   Tr e at m e nt  R e gi m e n ................................................................................................... 2 0  
5. 2   Pr e- Tr e at m e nt  Crit eri a .............................................................................................. 2 1  
5. 3   A g e nt  A d mi nistr ati o n ................................................................................................ 2 5  
5. 4   G e n er al  C o n c o mit a nt  M e di c ati o n  a n d  S u p p orti v e  C ar e  G ui d eli n es ......................... 2 6  
5. 5   Crit eri a f or  T a ki n g  a  P arti ci p a nt  Off  Pr ot o c ol  T h er a p y ............................................ 2 8  
5. 6   D ur ati o n  of  F oll o w  U p .............................................................................................. 2 9  
5. 7   Crit eri a f or  T a ki n g  a  P arti ci p a nt  Off  St u d y .............................................................. 2 9  
6. 
Crit eri a f or tr e at m e nt  c o nti n u ati o n  a n d  D O SI N G  D E L A Y S/ D O S E  M O DI FI C A TI O N S ...... 2 9 
6. 1   Str at u m  A  D a y  1( c y cl es  2- 6)  a n d  St r at u m  B  D a y  1 ( c y cl e  2  a n d  b e y o n d): 
Crit eri a f or  Tr e at m e nt  C o nti n u ati o n ...................................................................... 2 9  
6. 2   Str at u m  B  D a y  8 ( C y cl e  1  a n d s u bs e q u e nt  c y cl es):  Crit eri a f or  Tr e at m e nt 
C o nti n u ati o n, .......................................................................................................... 3 0  
6. 3   Str at u m  C,  or  Str at a  A  a n d  B if  o n  P M 0 1 1 8 3  M o n ot h er a p y  at  a n y  p oi nt,  D a y 
1:  Crit eri a f or  Tr e at m e nt  C o nti n u ati o n .................................................................. 3 0  
6. 4   D os e  M o difi c ati o n .................................................................................................... 3 1  
7. 
A D V E R S E  E V E N T S  R E P O R TI N G  R E Q UI R E M E N T S: ..................................................... 3 2  
7. 1   D efi niti o ns................................................................................................................. 3 2  
8. 
P H A R M A C E U TI C A L I N F O R M A TI O N ............................................................................... 3 8  
8. 1   P M 0 1 1 8 3 ................................................................................................................... 3 8  


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8. 2   D o x or u bi ci n .............................................................................................................. 4 1  
8. 3   G e m cit a bi n e .............................................................................................................. 4 1  
9.   S T U D Y  C A L E N D A R ............................................................................................................ 4 1  
1 0.   M E A S U R E M E N T  O F  E F F E C T........................................................................................... 4 6  
1 0. 1   A ntit u m or  Eff e ct  –  S oli d  T u m ors ........................................................................... 4 6  
1 1.   D A T A  R E P O R TI N G /  R E G U L A T O R Y  R E Q UI R E M E N T S .............................................. 5 3  
1 1. 1   D at a  R e p orti n g ........................................................................................................ 5 3  
1 1. 2   D at a  S af et y  M o nit ori n g ........................................................................................... 5 4  
1 2.   S T A TI S TI C A L  C O N SI D E R A TI O N S.................................................................................. 5 4  
1 2. 1   St u d y  D esi g n/ E n d p oi nts.......................................................................................... 5 5  
1 2. 2   S a m pl e  Si z e,  A c cr u al  R at e  a n d  St u d y  D ur ati o n ..................................................... 5 6  
1 2. 3   M o nit ori n g  Pl a n ...................................................................................................... 5 6  
1 2. 4   C o nfi d e nti alit y ........................................................................................................ 5 7  
1 2. 5   E v al u ati o n  of  T o xi cit y ............................................................................................ 5 7  
1 3.   P U B LI C A TI O N  P L A N ........................................................................................................ 5 7  
A P P E N DI X  B   I N F O R M A TI O N  O N  P O S SI BL E  D R U G I N T E R A C TI O N S ........................... 5 9  
R E F E R E N C E S .................................................................................................................... .......... 6 1 
 
 
 


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1.
O B J E C TI V E S
St u d y  H y p ot h esis: 
P M 0 1 1 8 3,  as  a si n gl e  a g e nt  or i n  c o m bi n ati o n  wit h  eit h er  d o x or u bi ci n  or  g e m c it a bi n e 
c h e m ot h er a p y,  will l e a d t o  o bj e cti v e r es p o ns e  a n d/ or   d ur a bl e  dis e as e  c o ntr ol i n  p ati e nts  wit h 
m et ast ati c  a n d / or  u nr es e ct a bl e s ar c o m a. 
1. 1  
St u d y  D esi g n 
W e  pr o p os e  a t hr e e str at a  p h as e  II st u d y  of  P M 0 1 1 3 8  a d mi nister e d  eit h er  al o n e  or i n 
c o m b i n ati o n  wit h  c h e m ot h er a p y ( d o x or u bi ci n  or  g e m cit a bi n e)  wit h t he  pri m ar y  e n d p oi nt  of 
dis e as e  c o ntr ol r at e ( D C R;  D C R  =  o bj e cti v e r es p o ns e r at e  pl us st a bl e  dis e as e r at e  at  2 4  w e e ks).    
St r at u m  A:   A nt hr a c y cli n e- n aï v e  p ati e nts  will r e c ei v e t h e  c o m bi n ati o n  of  P M 0 1 1 8 3  a n d 
d o x or u bi ci n  e v er y  2 1  d a ys f or  u p t o  a t ot al  of  6  c y cl es;  p ati e nts  w h o  e x hi bit  dis e as e  c o ntr ol  or 
o bj e cti v e r es p o ns e  aft er  6  c y cl es  of t h e  c o m bi n ati o n  will  c o nti n u e  o n si n gl e- a g e nt  P M 0 1 1 8 3  u ntil 
dis e as e  pr o gr essi o n  or  u n a c c e pt a bl e t o xi cit y.   
St r at u m  B:   P ati e nts  wit h  pri or  a nt hr a c y cli n e  e x p os ur e ( or  a  c o ntr ai n di c atio n t o  a nt hr a c y cli n es) 
a n d  wit h o ut  pri or  g e m cit a bi n e  e x p os ur e  wi ll r e c ei v e t h e  c o m bi n ati o n  of  P M 0 1 1 8 3  a n d 
g e m cit a bi n e  o n  d a y  1  a n d t h e  c o m bi n ati o n  of  P M 0 1 1 8 3  a n d  g e m cit a bi n e  o n  d a y  8  of  a  2 1  d a y 
c y cl e  u ntil  dis e as e  pr o gr essi o n  or  u n a c c e pt a bl e t o xi cit y.  P ati e nts  w h o st o p  g e m cit a bi n e f or 
u n a c c e pt a bl e t o xi cit y  m a y  c o nti n u e  o n si n gl e- a g e nt  P M 0 1 1 8 3 ( a c c or di n g t o t h e si n gl e  a g e nt 
d osi n g str at e g y i n  Str at u m  C)  u ntil  dis e as e  pr o gr essi o n  or  u n a c c e pt a bl e t o xi cit y. 
St r at u m  C:   P ati e nts  w h o  h a v e r e c ei v e d  pri or  a nt hra c y cli n e ( or  h a v e  a  c o ntr ai n di c ati o n t o 
a nt hr a c y cli n es)  A N D  pri or  g e m cit a bi n e ( or  h a v e  a  c o ntr ai n di c ati o n t o  g e m cit a bi n e)  will r e c ei v e 
P M 0 1 1 8 3  as  a si n gl e  a g e nt  e v er y  2 1  d a ys  u ntil  dis e as e  pr o gr essi o n  or  u n a c c e pt a bl e t o xi cit y. 
I m a gi n g  will  b e  o bt ai n e d  e v er y  6  w e e ks f or t h e first  8  c y cl es.  I m a gi n g fr e q u e n c y  will  d e cr e as e 
t o  e v er y  9  w e e ks t h er e aft er.   
1. 2  
P ri m a r y  O bj e cti v es 
 
T o  d et er mi n e t h e  Dis e as e  C o ntr ol  R at e ( D C R  =  O v er all  R es p o ns e  R at e [ O R R]  +  St a bl e
Dis e as e [ S D]  at  2 4  w e e ks)  of  P M 0 1 1 8 3  al o n e  a n d  D C R  of  P M 0 1 1 8 3 i n  c o m bi n ati o n  wit h
c h e m ot h er a p y i n s ar c o m as
1. 3  
S e c o n d a r y  O bj e cti v es
 
T o f urt h er  c h ar a ct eri z e t h e  cli ni c al  a cti vit y   of  P M 0 1 1 8 3  al o n e  or  wit h  c h e m ot h er a p y  b y:
O R R,  pr o gr essi o n fr e e s ur vi v al ( P F S )  a n d  o v er all s ur vi v al ( O S)  at t w o  y e ars
 
T o  e x pl or e t h e  c orr el ati o n  of  D C R,  O R R,  P F S  a n d  O S t o  dis e as e s u bt y p e






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tr a b e ct e di n) s h o w e d s y n er gisti c  a cti vit y i n  c o m bi n ati o n  wit h  P M 0 1 1 8 3 i n  diff er e nt  c ell li n es. I n 
h e m at ol o gi c al  c ell li n es,  n o si g nifi c a nt s y n er gi es  w er e  i d e ntifi e d  wit h  1 0 st an d ar d  a nti n e o pl asti c 
a g e nts.  H o w e v er,  c o m bi n ati o ns  of  P M 0 1 1 8 3  wit h  c yt ar a bi n e,  d a u n or u bi ci n,  m et h otr e x at e, 
g e m cit a bi n e  or tr a b e ct e di n s h o w e d  hi nts  of s y n er gis m i n s p e cifi c  c ell li n e  m o d els. 
2. 2. 3  
I n  Vi v o  A nti- n e o pl asti c  A cti vit y 
I n  vi v o,  P M 0 1 1 8 3  als o  e x hi bits  a ntit u m or  a cti vit y  a g ai nst  diff er e nt  m uri n e  m o d els  of 
x e n o gr aft e d  h u m a n- d eri v e d t u m or t y p es. 
I n  a  p a n el  of  6  h u m a n t u m or   x e n o gr afts  gr o w n i n  at h y mi c  mi c e a si n gl e  b ol us i ntr a v e n o us (i. v.) 
i nj e cti o n  of  P M 0 1 1 8 3  at t h e  m a xi m u m t ol er at e d  d os e ( 0. 3  m g/ k g [ 0. 9  m g/ m2])  d e m o nstr at e d 
st atisti c all y si g nifi c a nt  a ntit u m or a cti vit y ( p < 0. 0 5)  a g ai nst  br e as t,  c ol o n,  g astri c,  a n d  ki d n e y 
x e n o gr afts,  b ut  n ot i n  o v ar i a n  a n d  pr ost at e t u m ors. 
I ntr a v e n o us  a d mi nistr ati o n  of  P M 0 1 1 8 3 at  a  d os e  of  0. 2  m g/ k g/ d a y ( 0. 6  m g/ m 2/ d a y) f or  3 
c o ns e c uti v e  w e e ks i n t h e  M 5 0 7 6 s ar c o m a  m o d el t h at  s p o nt a n e o usl y  m et ast asi z es i n t h e li v er  of 
C 5 7 Bl/ 6 f e m al e t u m or  b e ari n g  mi c e s h o w e d  m a r gi n al  a cti vit y  o n t h e  pri m ar y t u m or,  b ut 
st atisti c all y si g nifi c a ntl y r e d u c e d t h e  n u m b er  of li v er  m et ast as es  c o m p ar e d t o  pl a c e b o-tr e at e d 
a ni m als ( M e di a n < 5  a n d  1 2 4 f or  P M 0 1 1 8 3  a n d  pl a c e b o  gr o u ps, r es p e cti v el y). 
F or  a d diti o n al  pr e cli ni c al  P K  a n d s af et y  p h ar m a c ol o g y  d at a  pl e as e r ef er t o t h e  P M 0 1 1 8 3 
I n v esti g at or’s  Br o c h ur e (I B). 
2. 2. 4  
P M 0 1 1 8 3  C LI NI C A L  S T U DI E S 
As  of  1 5 J a n u ar y  2 0 1 4,  3 6 6  p ati e nts ( 3 3 1  wit h  s oli d t u m ors  a n d  3 5  wit h  a d v a n c e d  a c ut e 
l e u k e mi a)  h a d  b e e n tr e at e d  wit h  P M 0 1 1 8 3 i n  cli nic al tri als  wit hi n t h e  cli ni c al  d e v el o p m e nt 
pr o gr a m  of t his  c o m p o u n d:  1 9 8  p ati e nts i n  p h as e I  tri als ( 3 5  wit h  a d v a n ce d  a c ut e l e u k e mi a)  a n d 
1 6 8  p ati e nts i n  p h as e II tri als.  
O nl y t h e first-i n- h u m a n ( Fi M)  p h as e I tri al ( P M 1 1 8 3- A- 0 0 1- 0 8)  h a s  b e e n  c o m pl et e d.  T his  p h as e 
I tri al  e v al u at e d i ntra v e n o us (i. v.)  P M 0 1 1 8 3  w h e n i nf us e d  o v er  1  h o ur ( h)  e v er y t hr e e  w e e ks 
( q 3 w k) i n  3 1  p ati e nts  wit h  a d v a n c e d  a n d r efr a ct or y s oli d t u m ors.  A m o n g t h es e,  1 5 ( 4 8. 4 %) 
p ati e nts  w er e tr e at e d  at t h e  d efi n e d r e c o m m e n d e d  d os e ( R D).  T h e  R D f or  p h as e II st u di es  w as 
d efi n e d  at  a  P M 0 1 1 8 3  d os e  of  4  m g/ m 2  q 3 w k  w hi c h  w as f o u n d  e q ui v al e nt  b y  p h ar m a c o ki n eti c 
a n al ysis t o  7  m g fl at  d os e ( F D)  q 3 w k i n t his  st u d y.  Tr e at m e nt  at t he  R D  w as  g e n er all y  w ell 
t ol er at e d  wit h st a n d ar d  a nti e m eti c  pr o p h yl a xis. T h e  m ost r el e v a nt t o xi cit y  at t h e  R D  w as 
r e v ersi bl e, s h ort-l asti n g  m y el osu p pr essi o n.  O n e  p ati e nt  h a d  a  gr a d e  4 t hr o m b o c yt o p e ni a, t h e  o nl y 
d os e-li miti n g t o xi cit y ( D L T)  at t h e  R D.  N o si g ns  of  c u m ul ati v e t o xi cit y  w er e  o bs er v e d. 
A ntit u m or  a cti vit y  w as  o bs er v e d  at t h e  R D.  T h e  p h ar m a c o ki n eti c ( P K)  a n al ysis s h o w e d  hi g h 
i nt er- p ati e nt  v ari a bilit y ( >  5 0 % i n t h e  ar e a  u n der t h e  c ur v e [ A U C]),  a n d li n e arit y  a cr oss  all 
e x pl or e d  d os es.  Li n e ar r e gr es si o n  a n al ysis s h o w e d  c orr el ati o n   b et w e e n  n e utr o p e ni a  a n d  A U C 
(r 2 = 0. 4 5 2). 
T h e  ot h er si x  p h as e I tri als  ar e  o n g oi n g.  T w o  of t h e m ( P M 1 1 8 3- A- 0 0 5- 1 1  a n d  P M 1 1 8 3- A- 0 0 4-
1 0) h a v e  cl os e d r e cr uit m e nt  aft er  pl a n n e d  a c cr u al. I n t h es e  o n g oi n g  p h as e I tri als,  P M 0 1 1 8 3 is
b ei n g  e v al u at e d  as si n gl e  a g e nt i n s oli d t u m ors ( P M 1 1 8 3- A- 0 0 5- 1 1)  a n d i n  a c ut e
r el a ps e d/r efr a ct or y  a d ult l e u k e mi a ( P M 1 1 8 3- A-0 0 2- 1 0),  as  w ell  as i n  c o m bi n ati o n  wit h


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d o x or u bi ci n ( P M 1 1 8 3- A- 0 0 3- 1 0),  g e m cit a bi n e ( P M 1 1 8 3- A- 0 0 4- 1 0),  c a p e cit a bi n e ( P M 1 1 8 3- A-
0 0 6- 1 2),  a n d  w e e kl y  p a clit a x el,  wit h  or  wit h o ut  b e v a ci z u m a b ( P M 1 1 8 3- A- 0 0 7- 1 3) i n  p ati e nts
wit h s el e ct e d s oli d t u m ors.  A ntit u m or  a cti vit y  h a s  b e e n  c o nsist e ntl y  o bs er v e d  a cr oss  all st u di es
as  d es cri b e d  b el o w.
F o ur  p h as e II  cli ni c al tri als  ar e  o n g oi n g.  T w o  of t h e m ( P M 1 1 8 3- B- 0 0 1- 1 0  a n d  P M 1 1 8 3- B- 0 0 2-
1 0) h a v e  cl os e d r e cr uit m e nt  aft er  pl a n n e d  a c cr u al. I n t h es e  o n g oi n g  p h as e II tri als,  P M 0 1 1 8 3 is
b ei n g  e v al u at e d  as s e c o n d-li n e tr e at m e nt i n   a d v a n c e d  p a n cr e ati c  c a n c er ( P M 1 1 8 3- B- 0 0 1- 1 0),
pl ati n u m-r esist a nt  a n d  pl ati n u m-r efr a ct or y   o v ari a n  c a n c er ( P M 1 1 8 3- B- 0 0 2- 1 1),  B R C A  1/ 2-
ass o ci at e d  or  u ns el e ct e d  br e ast  c a n c er ( P M 1 1 8 3- B- 0 0 3- 1 1),  a n d i n  n o n-s m all  c ell l u n g  c a n c er,
eit h er  al o n e  or i n  c o m bi n ati o n  wit h  g e m cit a bi n e ( P M 1 1 8 3- B- 0 0 4- 1 3).
2. 2. 4. 1  
Si n gl e  a g e nt  P M 1 1 8 3  P h as e I st u d y: 
T h e  Fi M st u d y ( P M 1 1 8 3- A- 0 0 1- 0 8)  w as  c o n d u ct e d i n   p ati e nts  wit h  a d v a n c e d  a n d r efr a ct or y 
s oli d t u m ors  a n d  e v al u at e d  P M 0 1 1 8 3 i ntr a v e n o usl y (i. v.) i nf us e d  o v er  1  h o ur  e v er y t hr e e  w e e ks 
( q 3 w k).  T hirt y-t hr e e  p ati e nts  w er e i n cl u d e d  a n d  3 1  p ati e nts r ec ei v e d  at l e ast  o n e  d os e  of 
P M 0 1 1 8 3.  A m o n g t h es e,  1 5  p ati e nts  w er e tr e at e d  at  t h e  d efi n e d  R D: si x  d uri n g  es c al ati o n  a n d 
ni n e i n t h e s u bs e q u e nt  c o h ort  e x p a ns i o n  usi n g  a fl at  d os e (s e e  b el o w).  
T h e st u d y f oll o w e d  a n  a c c el er at e d titr ati o n  d esi g n t h at  all o w e d t h e  P M 0 1 1 8 3  d os e t o  b e s af el y 
i n cr e as e d  b y  2 0 0-f ol d, fr o m  0. 0 2  m g/ m2 t o  5  m g/ m2  q 3 w k,  w hi c h  w as f o u n d t o  b e t h e  M T D. 
T w o  of t hr e e  p ati e nts  h a d  d os e-li miti n g t o xi citi es ( D L Ts)  at t h e  m a xi m u m t ol er at e d  d os e ( M T D); 
b ot h  p ati e nts  h a d tr a nsi e nt  gr a d e  4 tr a ns a mi n as e i n cr e as es,  a n d  o n e  p ati e nt  als o  h a d  m ulti pl e 
t o xi citi es i n cl u di n g f ati g u e,  diarr h e a,  n a us e a  a n d  n e utr o p e ni a,  n o n e  of  w hi c h  w as i n di vi d u all y 
c o nsi d er e d  a  D L T  b ut  o v er all l e d t o tr e at m e nt   dis c o nti n u ati o n.  T h e  M T D  w as t h e n r e d u c e d  b y 
2 0 %, t o  4  m g/ m 2  w hi c h  w as  d efi n e d  as t h e  R D.  O v er all, o nl y  o n e  of  1 5  e v al u a bl e  p ati e nts tr e at e d 
at t h e  R D ( 7 %)  h a d  a  D L T:  gr a d e  4 t hr o m b o c yt o p e ni a).  
Pri m ar y  a nti e m eti c  pr o p h yl a xis  w as  n ot r e q uir e d f or  p ati e nts tr e at e d  u p t o  1. 3  m g/ m 2  of 
P M 0 1 1 8 3.  Mil d  n a us e a  a n d  v o miti n g  w er e  o bs er v e d  i n  p ati e nts tr e at e d  at  a  d os e  of  2. 6  m g/ m2. 
As  a r es ult, st a n d ar d  a nti e m eti c   pr o p h yl a xis  w as  m a n d at or y i n  all s u bs e q u e ntl y tr e at e d  p ati e nts, 
p arti c ul arl y t h os e tr e at e d  at t h e  M T D  a n d t h e  R D.  
T h e  m ost r el e v a nt t o xi cit y f o u n d i n t h e  Fi M  w a s r e v ersi bl e  m y el os u p pr essi o n,  m ai nl y  c o nsisti n g 
of  gr a d e  3/ 4  n o n-f e bril e  n e utr o p e ni a ( F N) i n  5 3. 3 %  of  p ati e nts.  Gr a d e  4  n e utr o p e ni a  w as s h ort-
l asti n g ( m e di a n:  3  d a ys; r a n g e,  1- 4)  wit h  n a dir  o c c urri n g  at  D 1 3 ( m e di a n  v al u e) (r a n g e  1 0- 1 5 
d a ys).  O nl y  o n e  of  1 5  p ati e nts ( 5 1  c y cl es)  at t h e  R D f ail e d t o  r e c o v er  n e utr o p hil  c o u nts  b y  D 2 2 
a n d  h a d  a  P M 0 1 1 8 3-r el at e d  d os e  d el a y.   
Tr e at m e nt  w as  g e n er all y  w ell t ol er at e d i n t h e  e x p a nsi o n  c o h ort tr e at e d  at t h e  R D.  N o  u n e x p e ct e d 
t o xi citi es  o c c urr e d i n t his st u d y,  a n d t h er e  w er e  n o si g ns of  c u m ul ati v e t o xi cit y  d es pit e si x 
p ati e nts ( 1 9 %) r e c ei vi n g  at l e ast si x  c y cl es.   
R e g ar di n g  a ntit u m or  a cti vit y  at t h e  R D, t h er e  w e r e  o n e  c o nfir m e d  P R i n  a  p a n cr e ati c  c a n c er 
p ati e nt, t hr e e  S D  ≥   4  m o nt hs i n t w o  p ati e nts  wit h s oft tiss u e s ar c o m a ( S T S)  a n d  o n e  p ati e nt  wit h 
m ali g n a nt  m el a n o m a.  
T h e  p ati e nt  p o p ul ati o n i n t his st u d y  w as  hi g hl y s el e ct e d,  p arti c ul arl y   at t h e  R D.  All  p ati e nts  w er e 
< 7 5  y e ars  of  a g e,  h a d  a n  E C O G  P S s c or e  of  0  or   1,  a n d  b as eli n e  al b u mi n l e v els  > 3. 3  g/ dl, t h us 
r efl e cti n g  a n  e x c ell e nt  m et a b oli c  a n d  n utriti o n al st at us f or  a  p h as e I st u d y  p o p ul ati o n.  


Pr ot o c ol  #: 1 5- 0 8 3 
V ersi o n  D at e: 2/ 5/ 2 0 1 6 
 
1 1 
P h ar m a c o ki n eti c  a n al ysis  of  P M 0 1 1 8 3 s h o w e d  hi g h  i nt er- p ati e nt  v ari a bility ( >  5 0 % i n  A U C)  a n d 
li n e arit y  a cr oss  all  d os es  e x pl or e d.  P M 0 1 1 8 3  cl e ar a n c e  w as  n ot f o u n d t o  b e r el at e d t o  B S A; 
h e n c e, t h e  R D ( ori gi n all y  4  m g/ m 2  q 3 w k)  w as t h e n r o u n d e d t o  a  F D  of  7  m g i n t h e  R D  e x p a nsi o n 
c o h ort ( n = 9).   Li n e ar r e gr essi o n  a n al ysis s h o w e d  a str o n g  c orr el ati o n  b et w e e n  n e utr o p e ni a  a n d 
s yst e mi c  e x p os ur e ( A U C) (r 2= 0. 4 5 2). 
 
2. 2. 4. 2  
P M 1 1 8 3- A- 0 0 3- 1 0 ( P M 0 1 1 8 3/ D o x or u bi ci n  C o m bi n ati o n): 
T h e  pri m ar y  o bj e cti v e  of t his  o n g o i n g  cli ni c al st u d y is t o  d et er mi n e  a s af e  R D f or  p h as e II 
st u di es  wit h t his  c o m bi n ati o n.  S e c o n d ar y  o bj e cti v e s i n cl u d e t o  ass ess s af et y, t o  a n al y z e  p ossi bl e 
P K  dr u g- dr u g i nt er a cti o ns,  a n d t o  e v al u at e t h e  a ntit u m or  a cti vit y  o bs er v e d i n  p ati e nts  wit h 
s el e ct e d  a d v a n c e d s oli d t u m ors.  T h e  d os e  of  D O X r e m ai ns fi x e d  at  5 0  m g/ m 2 q 3 w k,  u p t o  a 
m a xi m u m  c u m ul ati v e  d os e ( M C D)  of  4 5 0  m g/ m 2 t hr o u g h o ut t h e st u d y.  O n c e t his  M C D is 
r e a c h e d,  P M 0 1 1 8 3  a d mi nistr ati o n  m a y  c o nti n u e  al o n e  at its f ull si n gl e- a g e nt  R D ( 7  m g  F D 
q 3 w k)  as l o n g  as s ust ai n e d  cli ni c al  b e n efit is  o bs er v e d.  T h e  D O X  d os e  c al c ul ati o n is  c a p p e d  at  2 
m 2  of  B S A.  A n  a m e n d m e nt t o t h e  ori gi n al  pr oto c ol s et  a  m a xi m u m  a g e  of  7 5  y e ars  a n d  all o w e d 
t h e  a d diti o n  of  pri m ar y  gr o wt h f a ct or  pr o p h yl a xis t o  a  pr osp e cti v e  c o h ort  of  p ati e nts. 
At  d at a  c ut off (J a n u ar y  1 5,  2 0 1 4),  4 5  p ati e nts  h a v e  b e e n i n cl u d e d  a n d tr e at e d  wit h t h e 
c o m bi n ati o n  a cr oss f o ur  diff er e nt  d os e l e v els.  D at a fr o m  4 1  p ati e nts ( 1 3  wit h  C S F  pr o p h yl a xis 
a n d  2 8  wit h o ut  C S F  pr o p h yl a xis)  ar e  a v ail a bl e f or  a n al ysis, i n cl u di n g  ni n e tr e at e d  wit h si n gl e-
a g e nt  P M 0 1 1 8 3.  As  of  c ut off,  1 0  p ati e nts  h a v e  c o nti n u e d tr e at m e nt  wit h  P M 0 1 1 8 3  al o n e  aft er 
D O X  dis c o nti n u ati o n. 
T h e  M T D is  d efi n e d  at  5  m g  of  P M 0 1 1 8 3  c o m bi n e d  wit h t h e fi x e d  D O X  d os e ( 5 0  m g/ m 2)  b ot h 
o n  D 1  q 3 w k r e g ar dl ess  of  C S F s u p p ort.  At t his  d o s e l e v el, t hr e e  of s ev e n  p ati e nts ( 4 3 %)  wit h 
C S F  a n d t w o  of fi v e ( 4 0 %)  wit h o ut  C S F  h a d  D L Ts:  F N ( n = 3),  gr a d e  3  di arr h e a  wit h  gr a d e  3 
c olitis ( n = 1),  a n d  n e utr o p e ni c s e pti c s h o c k  wit h  gr a d e  4  t hr o m b o c yt o p e ni a ( n = 1).  T h e 
i m m e di at el y l o w er  D L ( P M 0 1 1 8 3  4  m g  a n d  D O X)  w as t h e n  e x p a n d e d.  D L Ts  w er e f o u n d i n 
n o n e  of t hr e e  p ati e nts  wit h  C S F  at t his  d os e l e v e l,  a n d i n  o n e  of t e n (1 0 %)  p ati e nts  wit h o ut  C S F 
( F N);  as  a r es ult,  P M 0 1 1 8 3 4  m g  F D  a n d  D O X  5 0  m g/ m 2  w as  d efi n e d  as t h e  R D f or t his 
c o m bi n ati o n. 
Pri m ar y  C S F  pr o p h yl a xis  di d  n ot  a ll o w f urt h er  d os e  es c al ati o n i n t his st u d y.  F N  w as  d el a y e d t o 
C y cl e  2 i n s o m e  p ati e nts, i nst e a d  of  C y cl e  1  wit h o ut  C S F  pr o p h yl a xis,  b u t t h e i n ci d e n c e  of  F N 
di d  n ot s e e m t o  h a v e  b e e n si g nifi c a ntl y  pr e v e n t e d.  D L Ts  o c c urri n g  at t h e  M T D r e g ar dl ess  of 
C S F  pr o p h yl a xis  w er e  n ot  e x cl usi v el y r el a t e d t o  n e utr o p e ni a a n d  als o i n cl u d e d  n o n-
h e m at ol o gi c al t o xi citi es ( gr a d e  3  di arr h e a)  a n d  gr a d e  4 t hr o m b o c yt o p e ni a.  T h us,  R D  w as  n ot 
f urt h er  e x p a n d e d  wit h  pri m ar y  CS F  pr o p h yl a xis.  As  of  c ut off, t h e  R D is  b ei n g  e x p a n d e d f or 
s el e ct e d t u m or t y p es  d u e t o t h e  pr o misi n g  a nti t u m or  a cti vit y  o bs er v e d i n s m all  c ell l u n g  c a n c er 
( S C L C)  as s e c o n d li n e,  e n d o m etri al  c a n c er  an d  n e ur o e n d o cri n e t u m ors ( N E T).  A c c or di n g t o 
est a blis h e d  g ui d eli n es,  pri m ar y  C S F  pr o p h yl a xis s h o ul d  b e  a d mi nist er e d  w h e n  at l e ast  a  2 0 % ris k 
of  F N is  ass o ci at e d  wit h  a n y  p a rti c ul ar r e gi m e n.  At  c ut off,  F N  w as  o bs er v e d  at t h e  R D i n t w o  of 
t e n  p ati e nts i n t h e  c o h ort  wit h o ut  C S F  pr o p h yl a xis,  b ut i n  o n e  of t hr e e  p ati e nts i n t h e  c o h ort  wit h 
C S F  pr o p h yl a xis;  h e n c e,  m or e  d at a  ar e  n e e d e d t o  dr a w  d efi niti v e   c o n cl usi o ns r e g ar di n g  pri m ar y 
C S F  pr o p h yl a xis r e q uir e m e nts  at t his  p oi nt. 
As  m e nti o n e d  a b o v e,  a  pr ot o c ol  a m e n d m e nt  est a blis h e d t h e  m a xi m u m  a g e li mit i n  7 5  y e ars  ol d. 


Pr ot o c ol  #: 1 5- 0 8 3 
V ersi o n  D at e: 2/ 5/ 2 0 1 6 
 
1 2 
A m o n g t h e i niti al fi v e  p ati e nts tr e at e d  b ef or e  t h e  pr ot o c ol  a m e n d m e nt i n st u d y  P M 1 1 8 3- A- 0 0 3-
1 0  at  D L 1 ( P M 0 1 1 8 3  3. 5  m g  F D  a n d  D O X  5 0  m g/ m 2), t w o  D L Ts ( b ot h  F N) o c c urr e d i n t h e  o nl y 
t w o  p ati e nts  ol d er t h a n  7 5  y e ars.  
M ost  n o n- h e m at ol o gi c al tr e at m e nt-r el at e d  A E s  o bs er v e d  at t h e  R D f or t h e  P M 0 1 1 8 3  +  D O X 
c o m bi n ati o n  w er e  mil d  or  m o d er at e.  T h e  m ost  fr e q u e ntl y r e p ort e d w er e f ati g u e,  n a us e a, 
c o nsti p ati o n  a n d  al o p e ci a.  N o  n o n- h e m at ol o gi c al  gr a d e  4  e v e nts  o c c urr e d  at t h e  R D.  S e v er e 
r el at e d  A Es  at t h e  R D  o nl y r e a c h e d  gr a d e  3 a n d  c o m pris e d f e bril e  n e utr o p e ni a  a n d  m u c os al 
i nfl a m m ati o n ( m u c ositis). 
Gr a d e  3/ 4  n e utr o p e ni a  w as t h e  m ost  c o m m o n  h e m a t ol o gi c al t o xi cit y  at t h e  R D, r e g ar dl ess  of 
C S F  pr o p h yl a xis.  Alt h o u g h it  o c c urr e d sli g htl y l ess fr e q u e ntl y  wit h  C S F  pr o p h yl a xis, t his 
a p pr o a c h  w as  n ot  pr e v e nti v e  e n o u g h t o  all o w  d os e  es c al ati o n t o  c o nti n u e s a f el y.  Ot h er t o xi citi es 
at t h e  R D  w er e l ess  c o m m o n  a n d  o c c urr e d irr es p e cti v el y  of  C S F  pr o p h yl a xis,  as  e x p e ct e d:  gr a d e 
3  a n e mi a  w as f o u n d i n t w o  p ati e nts  wit h  C S F  a n d  o n e  wit h o ut  C S F,  a n d  gr a d e  3 
t hr o m b o c yt o p e ni a i n  o nl y  o n e  p ati e nt  wit h  C S F.  N e v ert h el ess,  as  o n e  of t h e  D L Ts ( gr a d e  4 
t hr o m b o c yt o p e ni a)  o bs er v e d  at t h e  M T D i n t he  c o h ort  wit h o ut  C S F  w as  n ot  ass o ci at e d t o 
n e utr o p e ni a, t h e  R D  wit h  C S F  pr o p h yl a xis  w as  n ot f urt h er  e x p a n d e d.  M ost  bi o c h e mi c al 
a b n or m aliti es  w er e  u nr e m ar k a bl e i n  m ost  p ati e nts  a n d  w er e  mil d  or  m o d er at e. 
Pr eli mi n ar y  effi c a c y r es ults fr o m  3 3  p ati e nts  ar e  a v ail a bl e  at  c ut off.  A n   O R R  of  3 9 % ( 9 5 %  CI, 
2 3- 5 8 %), i n cl u di n g f o ur  p ati e nts  wit h  C R  a n d  ni n e  wit h  P R,  w as  a c hi e v e d.  A d diti o n all y,  S D 
l asti n g ≥   4  m o nt hs  w as  o bs er v e d i n si x ( 1 8 %)  p ati e nts  wit h  S T S ( n = 2),  S C L C,  bl a d d er, 
e n d o m etri al  a n d  H C C ( n = 1  e a c h).  T h er ef or e,  pr eli m i n aril y r es ults  a v ail a bl e  at  c ut off s h o w e d t h at 
5 8 %  of  p ati e nts  e x p eri e n c e d  eit h er  r es p o ns e  or  pr ol o n g e d  dis e as e st a bili z ati o n  as  cli ni c al  b e n efit 
t o tr e at m e nt  wit h t h e  P M 0 1 1 8 3/ D O X c o m bi n ati o n i n t his st u d y.  
At  c ut off,  at l e ast  1 0  p ati e nts  h a d  c o n ti n u e d tr e at m e nt  wit h  P M 0 1 1 8 3  al o n e  aft er  D O X 
dis c o nti n u ati o n.   
B est t u m or r es p o ns e  as  p er  R E CI S T  v. 1. 1  w it h  P M 0 1 1 8 3  +  D O X i n st u d y  P M 1 1 8 3- A- 0 0 3- 1 0. 
 
 
T u m o r t y p e 
T ot al 
S C L C  
Bl a d d e r  
S T S  
O v a ri a n  
G ast ri c  
E n d o m et ri al B r e ast  
N E T  
Ot h e r 
n  
%  
n  
%  
n  %  
n  
%  
n  
%  
n  
%  
n  %  
n  %  
n  
%  
n  
% 
C R 
.  
.  
.  
.  
1  1 7  
1  
1 0 0  
.  
.  
1  
3 3  
1  5 0  
.  .  
.  
.  
4  
1 2 
P R 
5  
4 2  
1  
2 5  
.  .  
.  
.  
.  
.  
1  
3 3  
1  5 0  
1  5 0  
.  
.  
9  
2 7 
S D  ≥   4 
m o nt hs 
1  
8  
1  
2 5  
2  3 3  
.  
.  
.  
.  
1  
3 3  
.  .  
.  .  
1  
5 0  
6  
1 8 
S D  <  4 
m o nt hs 
.  
.  
.  
.  
.  .  
.  
.  
1  
1 0 0  
.  
.  
.  .  
1  5 0  
.  
.  
2  
6 
P D 
6  
5 0  
2  
5 0  
3  5 0  
.  
.  
.  
.  
.  
.  
.  .  
.  .  
1  
5 0  
1 2  3 6 
T ot al 
1 2  1 0 0  4  
1 0 0  
6  1 0 0  
1  
1 0 0  
1  
1 0 0  
3  
1 0 0  
2  1 0 0  
2  1 0 0  
2  
1 0 0  
3 3  1 0 0 
All  S C L C  p ati e nts  w h o  a c hi e v e d  P R r e c ei v e d  P M 0 1 1 8 3  +  D O X  as s e c o n d-li n e tr e at m e nt. 
C R,  c o m pl et e r es p o ns e;  D O X,  d o x or u bi ci n;  N E T,  n e ur o e n d o cri n e t u m or;  P D,  pr o gr essi v e  dis e as e;  P R,  p arti al r es p o ns e;  R E CI S T,  R es p o ns e 
E v al u ati o n  Crit eri a I n  S oli d  T u m ors;  S C L C, s m all  c ell l u n g  c a n c er;  S D, st a bl e  dis e as e;  S T S, s oft tiss u e s ar c o m a. 
 
2. 2. 4. 3  
P M 1 1 8 3- A- 0 0 4- 1 0 ( P M 0 1 1 8 3  +  G e m cit a bi n e  C o m bi n ati o n) 
T his st u d y  ai m e d t o  d efi n e  a s af e  R D f or  p h as e  II st u di es f or t his  dr u g  c o m bi n ati o n,  a n d t o 
e x pl or e its t ol er a bilit y, f e asi bilit y  a n d  a ntit u m or  a cti vit y, i n  p ati e nts  wit h s p e cifi c s oli d t u m ors  u p 
t o  7 5- y e ars- ol d  of  a g e  a n d  wit h  E C O G  P S  0-1.  T h e st arti n g  d os e  w as  P M 0 1 1 8 3  2. 5  m g  F D  a n d 
G E M  8 0 0  m g/ m 2/ d a y,  b ot h  o n  D 1  a n d  D 8  q 3 w k.  T h e  G E M  d os e  c al c ul ati o n  w as  c a p p e d  at  a 


Pr ot o c ol  #: 1 5- 0 8 3 
V ersi o n  D at e: 2/ 5/ 2 0 1 6 
 
1 3 
B S A  of  2  m 2. 
R e cr uit m e nt is  cl os e d  pri or t o  c ut off (J a n u ar y   1 5,  2 0 1 4).  A t ot al  of  4 7  p ati e nts  w er e i n cl u d e d,  4 5 
w er e tr e at e d  a n d  ar e  a v ail a bl e f or  a n al ysis.  
D L 4 ( P M 0 1 1 8 3  3. 5  m g  F D  +  G E M  1 0 0 0  m g/ m 2/ d a y)  w as t h e  hi g h est  D L  e x pl or e d i n t his st u d y. 
Ni n e  p ati e nts  w er e i n cl u d e d  at t his  D L,  a n d  s e v e n  w er e  e v al u a bl e f or  D L Ts.  F o ur  of t h es e 
p ati e nts  h a d  D L Ts  d uri n g  C y cl e  1.  T h es e  c o nsist e d  of  n e utr o p e ni c i nf e cti o n;  F N; tr e at m e nt-
r el at e d  d os e  o missi o n  d u e t o  m y el os u p pr essi o n;  a n d  n e utr o p e ni c s e psis  wit h  gr a d e  4 
t hr o m b o c yt o p e ni a t h at r es ult e d i n  d e at h.  C o ns e q u e ntl y,  D L 3 ( P M 0 1 1 8 3  3. 5  m g  F D  +  G E M  8 0 0 
m g/ m 2/ d a y)  w as i niti all y  e x p a n d e d t o  ni n e  p ati e nts; t h er e  w er e t w o  D L Ts ( b ot h  F N),  a n d t h e 
c o h ort  w as f urt h er  e x p a n d e d i n  or d er t o  c o nfir m  f e asi bilit y  of t his  d os e.  Fi n all y, fi v e  of  2 1 
p ati e nts ( 2 4 %)  h a d  D L Ts:  F N  al o n e ( n = 3);  F N   a n d  gr a d e  4 t hr o m b o c yt o p e ni a ( n = 1);  a n d 
n e utr o p e ni c s e psis  a n d  gr a d e  4 t h r o m b o c yt o p e ni a t h at r es ult e d i n  d e at h ( n = 1).  Aft er  dis c ussi o n 
wit h t h e I n v esti g at ors, t his  d os e l e v el  w as  c o nsi d er e d  n ot f e asi bl e f or  p h as e II st u di es; t h e 
o bs er v e d r at e  of  n e utr o p e ni c f e v er  w o ul d  h a v e  r e q uir e d  pri m ar y  C S F  pr o p h yl a xis i n  a c c or d a n c e 
wit h  c urr e nt  g ui d eli n es,  w hi c h  w o ul d  h a v e  n ot  pr e v e nt e d t h e s e v er e t h r o m b o c yt o p e ni a  o bs er v e d 
i n s o m e  c as es.  T h er ef or e,  D L 3  w as  d efi n e d  as t h e  M T D  a n d t h e  n e xt l o w er  d os e l e v el ( D L 2, 
P M 0 1 1 8 3  3  m g  F D  +  G E M  8 0 0  m g/ m 2/ d a y)  w as f urt h er  e x p a n d e d t o  1 0  e v al u a bl e  p ati e nts. 
N o n e  of t h es e  p ati e nts  h a d  D L Ts;  t h er ef or e, t his  D L  w as  d efi n e d  as t h e  R D f or t his  c o m bi n ati o n. 
M ost tr e at m e nt-r el at e d  A Es  o bs er v e d  at t h e  R D  w er e  mil d  or  m o d e r at e.  T h e  m ost fr e q u e nt  w er e 
f ati g u e ( n = 8,  7 2. 7 %),  g astr oi nt esti n al  dis or d ers s u c h  as  n a us e a ( n = 6,  5 4. 5 %)  a n d  v o miti n g ( n = 4, 
3 6. 4 %),  d e cr e as e d  a p p etit e ( n = 3,  2 7. 3 %)  a n d r as h  ( n = 3,  2 7. 3 %).  N o  gr a d e  4  e v e nts  o c c urr e d  at 
t h e  R D;  gr a d e  3  e v e nts  c o m pris e d t w o  e pis o d es  of f ati g u e  a n d  o n e  of r as h.  N o  al o p e ci a r el at e d t o 
t h e  P M 0 1 1 8 3  +  G E M  c o m bi n ati o n  w as r e p ort e d. 
M y el os u p pr essi o n,  p arti c ul arl y  gr a d e  3/ 4  n e utr o p e ni a,  w as t h e  m ost r e m ar k a bl e  h e m at ol o gi c al 
t o xi cit y  at t h e  R D. It r e a c h e d  gra d e  4 i n fi v e  p ati e nts ( 4 5. 5 %).  Of  n ot e, i n  c o ntr ast t o  w h at 
h a p p e n e d  at t h e  M T D,  n o  gr a d e  4 t hr o m b o c yt o p e ni a  o c c urr e d  at t h e  R D:  gr a d e  3  e v e nts  o nl y 
o c c urr e d i n t w o  p ati e nts ( 1 8. 2 %).   A n ot h er s e v er e  h e m at ol o gi c al t o xi cit y  w as  gr a d e  3  a n e mi a 
( n = 5,  4 5. 5 %).  O n e  of  1 1  p ati e nts tr e at e d  at t h e R D ( 9. 1 %)  e x p eri e n c e d  a  si n gl e  e pis o d e  of  F N. 
M ost  bi o c h e mi c al  a b n or m aliti es  w er e  mil d  or  m o d er at e.  N o  gr a d e  4  a b n or m aliti es  o c c urr e d.  Of 
n ot e,  mil d  gr a d e  A L T/ A S T i n cr e as es  w er e  o bs er v e d  i n  all  p ati e nts  at t h e  R D, i n  c o ntr ast t o t h e 
fi n di n gs  wit h  ot h er  c o m bi n ati o ns  b ei n g t est e d.  O nl y  o n e  p ati e nt  at t h e  R D ( 9. 1 %) s h o w e d  gr a d e 
3  A L T i n cr e as e. 
At  c ut off,  3 8  of  4 5 tr e at e d  p ati e nts  w er e  e v al u a bl e f or  effi c a c y.  T h e  b est r es p o ns e  a c hi e v e d  wit h 
t h e  P M 0 1 1 8 3  +  G E M  c o m bi n ati o n i n t his st u d y is sh o w n i n t h e t a bl e  b el o w.   O v er all,  ni n e  of  3 8 
e v al u a bl e  p ati e nts r es p o n d e d t o t h e  c o m bi n a ti o n, f or  a n  O R R  of  2 4 % ( 9 5 %  CI,  1 1. 4 %- 4 0. 2 %). 
Fi v e  of t h e  ni n e r es p o ns es  o c c urr e d i n  p ati e nts  wit h  N S C L C, i n cl u di n g  o n e  C R. I n  a d diti o n, 
pr ol o n g e d  S D ( ≥   4  m o nt hs)  w as  a c hi e v e d i n  1 0  p ati e nts ( 2 6 %); t u m or t y p es  c o m pris e d  N S C L C 
( n = 4),  br e ast  c a n c er ( n = 3),  p a n cr e as  c a n c er, o v ari a n  c a n c er,  a n d  m es o t h eli o m a ( n = 1  e a c h). 
B est t u m or r es p o ns e  as  p er  R E CI S T  v. 1. 1  wit h  P M 0 1 1 8 3  +  G E M i n st u d y  P M 1 1 8 3- A- 0 0 4- 1 0. 
 
 
T u m o r t y p e 
T ot al 
N S C L C  
P a n c r e as  
B r e ast  
O v a ri a n  
M es ot h eli o m a  
Bili a r y t r a ct 
n  
%  
n  
%  
n  
%  
n  
%  
n  
%  
n  
%  
n  
% 
C R 
1  
6  
.  
.  
.  
.  
.  
.  
.  
.  
.  
.  
1  
3 
P R 
4  
2 4  
1  
1 7  
1  
1 7  
2  
4 0  
.  
.  
.  
.  
8  
2 1 


Pr ot o c ol  #: 1 5- 0 8 3 
V ersi o n  D at e: 2/ 5/ 2 0 1 6 
 
1 4 
 
T u m o r t y p e 
T ot al 
N S C L C  
P a n c r e as  
B r e ast  
O v a ri a n  
M es ot h eli o m a  
Bili a r y t r a ct 
n  
%  
n  
%  
n  
%  
n  
%  
n  
%  
n  
%  
n  
% 
S D  ≥   4  m o nt hs 
4  
2 4  
1  
1 7  
3  
5 0  
1  
2 0  
1  
5 0  
.  
.  
1 0  
2 6 
S D  <  4  m o nt hs 
4  
2 4  
1  
1 7  
1  
1 7  
.  
.  
1  
5 0  
2  
1 0 0  
9  
2 4 
P D 
4  
2 4  
3  
5 0  
1  
1 7  
2  
4 0  
.  
.  
.  
.  
1 0  
2 6 
T ot al 
1 7  
1 0 0  
6  
1 0 0  
6  
1 0 0  
5  
1 0 0  
2  
1 0 0  
2  
1 0 0  
3 8  
1 0 0 
C R,  c o m pl et e r es p o ns e;  G E M,  g e m cit a bi n e;   N S C L C,  n o n-s m all  c ell l u n g  c a n c er;  P D,  pr o gr essi v e  dis e as e;  P R,  p arti al r es p o ns e;  R E CI S T, 
R es p o ns e  E v al u ati o n  Crit eri a I n  S oli d  T u m ors;  S D, st a bl e  dis e as e. 
 
2. 2. 5  
S af et y  D at a: 
A v ail a bl e  d at a fr o m  o n g oi n g  p h as e II tri als s u g g est t h at,  b esi d es  m y el os u p pr essi o n,  ot h er 
t o xi citi es  of  P M 0 1 1 8 3  ar e  mil d t o m o d er at e  g astr oi nt esti n al ( GI)  A Es, i n  p arti c ul ar  n a us e a  a n d 
v o miti n g,  c o nsti p ati o n,  di arr h e a  a n d  a b d o mi n al  p a i n.  G astr oi nt esti n al  A Es  o c c asi o n all y r e a c h 
gr a d e  3,  b ut  n o  P M 0 1 1 8 3-r el at e d  gr a d e  4  e pis o d es  h a v e  o c c urr e d.  S e v er e  n a us e a  a n d/ or  v o miti n g 
s e e m t o  h a v e  o c c urr e d t o  d at e  m or e fr e q u e ntl y  i n  P R R O C  p ati e nts t h a n i n  M B C  or  p a n cr e ati c 
c a n c er  p ati e nts.  
T h e  hi g h er t h a n  e x p e ct e d s e v erit y  of  n a us e a/ v o miti n g  o bs er v e d i n s o m e  p ati e nts i n t h e  P R R O C 
st u d y ( P M 1 1 8 3- B- 0 0 2- 1 1)  c o ul d  b e i n s o m e  c as es  ass o ci at e d t o t h e  dis e as e  u n d er st u d y 
(i nt esti n al s u b- o c cl usi o n is  us u all y  o bs er v e d i n t h es e  p ati e nts).  T his  e v e nt  pr o b a bl y l e d t o t h e  us e 
of  a pr e pit a nt  d uri n g  C y cl e  2,  p arti c ul arl y i n t h os e  m or e s e v er el y  aff e ct e d i n  C y cl e  1 ( w h e n  us e  of 
a pr e pit a nt  w as f or bi d d e n).  T his r es ult e d i n   u n us u all y  pr ol o n g e d  a n d s e v er e  m y el os u p pr essi o n 
( p arti c ul arl y,  n e utr o p e ni a  a n d t hr o m b o c yt o p e ni a) i n  at l e ast f o ur  p ati e nts.  A  P K  a n al ysis t h at 
c o m p ar e d s yst e mi c  e x p os ur e t o  P M 0 1 1 8 3  d uri n g  C y cl e  1 ( wit h o ut  a pr e pit a nt)  a n d  C y cl e  2 ( aft er 
r e c ei vi n g  a pr e pit a nt) s h o w e d a  5 0 %  d e cr e as e i n  P M 0 1 1 8 3  cl e ar a n c e  d uri n g  C y cl e  2,  w hi c h i n 
t ur n r es ult e d i n  n e arl y  d o u ble  P M 0 1 1 8 3  A U C  v al u es.  T his  w as li k el y  d u e t o t h e  c o n c o mit a nt 
a pr e pit a nt  a d mi nistr ati o n.  T h er ef or e,  a pr e pit a nt  a d mi nist r ati o n is  c urr e ntl y  e x cl u d e d i n  al m ost  all 
o n g oi n g  cli ni c al tri als,  u n l ess  e x pli citl y  a n d s pe cifi c all y  a ut h ori z e d. 
G e n er al  dis or d ers r el at e d t o  P M 0 1 1 8 3 tr e at m e nt  m ai nl y  c o nsist e d  of f ati g u e/ ast h e ni a, i n  a b o ut 
t w o t hir ds  of  all  p ati e nts tr e at e d i n  p h as e II tri als.  Ot h er  A Es t h at  o c c urr e d  at l o w er fr e q u e n ci es 
w er e  p yr e xi a,  m u c os al i nfl a m m ati o n  a n d  p eri p h er al  e d e m a.  F ati g u e/ ast h e ni a is r el ati v el y 
pr e v al e nt i n  c a n c er  p ati e nts,  a n d is s o m eti m es r e l at e d t o t h e  n e arl y  u bi q uit o us  a n e mi a  c a us e d 
eit h er  b y  pri or t h er a pi es, t h e  dis e as e its elf,  or  m ost fr e q u e ntl y  h as  a  m u ltif a ct ori al  eti ol o g y.  T h es e 
g e n er al  dis or d ers,  wit h t h e  e x c e p ti o n  of  ast h e ni a,  w er e r ar el y s e v er e  a n d s e e m e d t o  h a v e 
r el ati v el y s p ar e d t h e  M B C  p ati e nts.  
P ot e nti all y s eri o us  or lif e-t hr e at e ni n g  A Es r el at e d t o  P M 0 1 1 8 3  w er e  r ar e  a n d  o c c urr e d i n l ess 
t h a n t hr e e  p ati e nts i n  e a c h  p h as e II tri al.  Of  n ot e, s e v er e r es pir ator y  dis or d ers ( d ys p n e a, 
p n e u m o nitis, r es pir at or y f ail ur e  a n d t a c h y p n e a)  o c c urr e d  m ai nl y  a m o n g  M B C  p ati e nts s o f ar. 
M y el os u p pr essi o n is  b y f ar t h e  m ost fr e q u e nt t o xi ci t y  o bs er v e d i n  p h as e II tri als.  T h e i n ci d e n c e 
of  gr a d e  3/ 4  n e utr o p e ni a i n cr e as e d fr o m  o v er  5 0 %  of  p ati e nts i n  p h a s e I st u di es t o  7 2. 5 % i n  all 
p h as e II st u di es,  y et t h e  o v er all  i n ci d e n c e  of  F N r e m ai ns j ust b el o w t h e  2 0 % t hr es h ol d i n  all 
p h as e II st u di es  as  of  c ut off ( w hil e i n s o m e s p e ci fi c s etti n gs, s u c h  as  o v ari a n  c a n c er, it is j ust 
a b o v e t his t hr es h ol d).  T h er ef or e, t h e  n e e d f o r  pri m ar y  C S F  pr o p h yl a xis  at t h e  R D f or si n gl e-
a g e nt  P M 0 1 1 8 3  q 3 w k  n e e ds t o  b e  a d e q u at el y  i n di vi d u ali z e d  at pr es e nt.  Gr a d e  3/ 4 
t hr o m b o c yt o p e ni a  als o s e e ms t o  h a v e i n cr e as e d i n fr e q u e n c y t o  n e arl y  o n e t hir d  of  p ati e nts,  as 
c o m p ar e d t o t h e  hi g hl y s el e ct e d  p h as e I  p ati e nt  p o p ul ati o n. 


Pr ot o c ol  #: 1 5- 0 8 3 
V ersi o n  D at e: 2/ 5/ 2 0 1 6 
 
1 5 
 
P o ol e d  a n al ysis  of t h e first t hr e e  P h as e  2 st u di es, i n cl u di n g  m or e t h a n  1 0 0  p ati e nts, i d e ntifi e d 
t h at  b o d y s urf a c e  ar e a st atisti c all y c orr el at e d t o t hr o m b o c yt o p e ni a.  T h er e  w as  als o  v ari a bilit y i n 
t h e i n ci d e n c e  of  n e utr o p e ni a  a n d f e bril e  n e utr o p e ni a  d e p e n di n g  o n t h e  p o p ul ati o n  of t h e  diff er e nt 
st u di es.  F or  e x a m pl e, i n t h e  pl ati n u m-r esist a nt  o v ari a n  c a n c er st u d y,  2 3 %  of t h e  p ati e nts  h a d 
f e bril e  n e utr o p e ni a.   H o w e v er, i n t h e  P h as e  2 i n  br e ast  c a n c er, l ess t h a n 5 %  of t h e  p ati e nts  h a d 
f e bril e  n e utr o p e ni a.  
 
2. 3  
Ot h er  A g e nt(s) 
 
D o x o r u bi ci n:  
D o x or u bi ci n ( A dri a m y ci n ®,  R u b e x ®,  a n d  D o xil ®) is  a n  a nt hr a c y cli n e  a nti bi o ti c t h at  e x erts its 
eff e cts  o n  c a n c er  c ells  vi a t w o  pri m ar y  m e c h a nis ms. ( 1) I nt er c al ati o n: I n its r ol e  as  a n 
i nt er c al ati n g  a g e nt t h e  dr u g  w ed g es  b et w e e n t h e  b as es  of  D N A  a n d  bl o c ks  D N A s y nt h esis  a n d 
tr a ns cri pti o n. ( 2)  E n z y m e i n hi biti o n:  T h e  dr u g i n hi bits t h e  a cti vit y  of  a n  e n z y m e, t o p ois o m er as e 
t y p e II.  T his l e a ds t o  br e a ks i n t h e  g e n o mi c  D N A.  B ot h  of t h es e  m e c h a nis ms r es ult i n  D N A 
disr u pti o n t h at  ulti m at el y  c a n l e a d t o t h e  d e at h  of t h e  c ell.   Si n gl e  a g e nt  d o x or u bi ci n is t h e 
st a n d ar d tr e at m e nt i n  p ati e nts  wit h  a d v a n c e d s oft tiss u e s ar c o m a. 1 9  T y pi c al i nstit uti o n al  d osi n g is 
u p t o  7 5  m g/ m 2  gi v e n  b y  b ol us  o v er  1- 3  d a ys  wit h  m a xi m u m lif e-ti m e  d os e  at  4 5 0  m g/ m2.   
 
G e m cit a bi n e : 
G e m cit a bi n e is  a  n u cl e osi d e  a n al o g u e t h at is  F D A  a p pr o v e d f o r s e v er al  m ali g n a n ci es i n cl u di n g 
b ut  n ot li mit e d t o l u n g  c a n c er,  br e ast  c a n c er,  p a n cr e as/ bili ar y t u m ors  a n d  s ar c o m as.   G e m cit a bi n e 
is  a  p yri mi di n e  a nti m et a b olit e.2 0  It  e x hi bits  c ell  p h as e s p e cifi cit y,  pri m aril y  killi n g  c ells 
u n d er g oi n g  D N A s y nt h esis ( S- p h as e )  a n d  bl o c ki n g t h e  pr o gr essio n t hr o u g h t h e  Gl/ S- p h as e 
b o u n d ar y.  T h e  c yt ot o xi c  eff e ct  of  g e m cit a bi n e is  at tri b ut e d t o  a  c o m bi n ati o n  of t w o  a cti o ns,  as 
f oll o ws.  First,  g e m cit a bi n e  dis p h os p h at e i n hi bits ri b o n u cl e as e r e d u ct as e,  w hi c h is r es p o nsi bl e f or 
c at al y zi n g t h e r e a cti o ns t h at   g e n er at e  d e o x y n u cl e osi d e tri ph os p h at es f or  D N A s y nt h esis. 
I n hi biti o n  of t his  e n z y m e  c a us es  a r e d u cti o n i n t h e  c o n c e ntr ati o ns  of  d e o x y n u cl e oti d es, i n cl u di n g 
d C T P.  S e c o n dl y,  g e m cit a bi n e tri p h os p h at e  c o m p et es  wit h  d C T P f or i n c or p or ati o n i nt o  D N A. 
R e d u cti o n i n t h e i ntr a c ell ul ar  c o n c e ntr ati o n  of  d C T P  b y t h e  di p h os p h at e  e n h a n c es i n c or p or ati o n 
of  g e m cit a bi n e tri p h os p h at e i nt o   D N A.  Aft er t h e  g e m cit a bi n e  n u cl e oti d e is i n c or p or at e d i nt o 
D N A  o nl y  o n e  a d diti o n al  n u cl e oti d e is  a d d e d t o t h e  gr o wi n g  D N A str a n ds  a n d t h er e is i n hi biti o n 
of f urt h er  D N A s y nt h esis.  G e m cit a bi n e i n d u c es i ntr a n u cl e os o m al   D N A fr a g m e nt ati o n 
c h ar a ct eristi c  of  pr o gr a m m e d  c ell  d e at h. 
 
T h e  us e  of  G e m cit a bi n e i n  p ati e nts  wit h l o c all y  a d v a n c e d  or  m et ast ati c s ar c o m a,  eit h er  as  a 
si n gl e  a g e nt  or i n  c o m bi n ati o n  wit h   ot h er  c yt ot o xi c  a g e nts,  h as  b e e n  e v al u at e d i n s e v er al  cli ni c al 
tri als.   A s e mi n al st u d y  p erf or m e d  at  M D  A n d erso n s h o w e d t h at i ntr a c ell ul ar  a c c u m ul ati o n  of 
g e m cit a bi n e tri p h os p h at e is  s at ur at e d  at  pl as m a  g e m cit a bi n e l e v els  of  1 0- 2 5  u M. 2 1   C yt ot o xi c 
a cti vit y  w as t h o u g ht t o  b e  m or e  a cti v e  wit h  l o n g er  e x p os ur e t o  dr u g,  w hi c h  m a xi mi z es t h e 
i ntr a c ell ul ar  a c c u m ul ati o n  of  g e m cit a bi n e.   T his h y p ot h esis  w as t est e d i n  p a n cr e ati c  c a n c er, 
w h er e s u bj e cts  w er e r a n d o mi z e d t o r e c ei v e  g e m cit a bi n e  at  1 0  m g/ m 2/ mi n  vs.  a  3 0  mi n ut e 
b ol us. 2 2   T h e i nf usi o n al tr e at m e nt  ar m  h a d  a  m e di a n s ur vi v al ti m e  of  8  m o nt hs  v ers us  5  m o nt hs 
i n t h e  c o ntr ol  ar m ( p =. 0 1 3).   Dr.  S hr e y as  P at el f urt h er  e v al u at e d i nf usi o n al  g e m cit a bi n e i n 
p ati e nts  wit h  a d v a n c e d s oft tiss u e s ar c o m as i n   a  p h as e II st u d y  w h er e p ati e nts r e c ei v e d t w o 


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1 6 
diff er e nt  d os e r at es. 2 3   5 6  p ati e nts r e c ei v e d  g e m cit a bi n e at  1 g/ m 2  o v er  3 0  mi n ut es.   9  p ati e nts 
r e c ei v e d st a n d ar d  b ol us  d osi n g i n  w e e k  1  an d i nf usi o n al  d osi n g  o v er  1 5 0  mi n ut es  o n  w e e k  2 t o 
e v al u at e  G T P l e v els i n  P B M Cs.   A  1. 4 f ol d i n cr e as e i n t h e  c o n c e ntr ati o n  of  G T P  w as s e e n i n t h e 
i nf usi o n al tr e at m e nt  ar m.   S e v er al  ot h er  p h as e II  a n d r etr os p e cti v e st u di es  h a v e  als o 
d e m o nstr at e d s af et y  a n d  effi c a c y  of i nf usi o n a l  g e m cit a bi n e, i n cl u di n g  a  S A R C st u d y t h at t est e d 
i nf usi o n al  g e m cit a bi n e   as  a si n gl e  a g e nt ( 1 2 0 0 m g/ m 2  o v er  1 2 0  mi n)  v ers us i n  c o m bi n ati o n  wit h 
d o c et a x el ( g e m cit a bi n e i nf us e d  at  9 0 0  m g/ m 2  o v er  9 0  mi n ut es). 2 4   
 
M y el os u p pr essi o n ( a n e mi a, l e u c o p e ni a,  n e utr o p e ni a)  is t h e  d os e-li miti n g t o xi cit y  ass o ci at e d  wit h 
G e m cit a bi n e.  C o m m o n t o xi citi es i n cl u d e  n a us e a  a n d  v o miti n g  us u all y  of  mil d t o  m o d er at e 
s e v erit y, tr a nsi e nt  el e v ati o ns  of s er u m tr a ns a mi n as es (s eri o us  h e p at o t o xi ct y i n cl u di n g li v er 
f ail ur e  a n d  d e at h  h a v e  b e e n r e p ort e d r ar el y i n  p ati e nts r e c ei vi n g  G e m cit a bi n e  al o n e  or i n 
c o m bi n ati o n  wit h  ot h er  p ot e nti all y  h e p at ot o xi c  dr u gs), f e v er,  a n d r as h.  A  c o m pr e h e nsi v e r e vi e w 
of  g e m cit a bi n e t h er a p y i n  m et ast ati c  s ar c o m a  c a n  b e s e e n  at  M a ki  et  al. 2 5   
I n s ar c o m as,  g e m cit a bi n e is  m ost  a cti v e i n c o m bi n ati o n  wit h  d o c et a x el,  d a c ar b a zi n e  a n d 
vi n or el bi n e. 1 4- 1 7  I nstit uti o n al  d osi n g st a n d ar ds  v ar y  b y r e gi m e n fr o m  8 0 0  m g/ m 2 t o  1 0 0 0  m g/ m2 
a d mi nist er e d  b y  w e e kl y  b ol us ( e. g.  d a ys  1  a n d  8  of  a  2 1  d a y  c y cl e).   
  
2. 4  
R ati o n al e 
 
T h e s ar c o m as  ar e  a  h et er o g e n o us  gr o u p  of  m a li g n a n ci es  e n c o m p assi n g  al m ost  5 0  diff er e nt 
s u bt y p es  of  c a n c er.   D es pit e  a d v a n c es i n s ur gi c al   a n d r a di ati o n t e c h ni q u es,  w h e n s ar c o m as r e c ur 
or  m et ast asi z e, t h e y  ar e  al m ost  u ni v ers all y  l et h al.  Si n gl e  a g e nt  or  c o m bi n ati o n  c h e m ot h er a p y 
r e gi m e ns, t h at  ar e  d o x or u bi ci n  or  g e m cit a bi n e- b as ed,  ar e t h e st a n d ar d  of  c ar e f or  S T S.  H o w e v er, 
r es p o ns e r at es  ar e  c o nsist e ntl y l ess t h a n  5 0 %  a n d  m e di a n  pr o gressi o n-fr e e  a n d  o v er all s ur vi v al 
r e m ai n  p o or  at  3  a n d  1 2  m o nt hs, r es p e cti v el y,  a nd  as s u c h,  n o v el t h er a pi es f or s ar c o m as  ar e 
n e e d e d.    P M 0 1 1 8 3 ( L ur bi n e ct e di n ), is  a s y nt h eti c all y  d eri v e d  n o v el  c h e mi c al  e ntit y t h at i n d u c es 
d o u bl e-str a n d  D N A  br e a ks t hr o u g h  bi n di n g t o  t h e  D N A  mi n or  gr o v e.   T h o u g h  P M 0 1 1 8 3 is  a n 
a n al o g u e  of tr a b e ct e di n i n  c ert ai n  as p e cts,  n o v el  str u ct ur al f e at ur es  h a v e  i m pr o v e d its t o xi cit y 
pr ofil e,  p ot e n c y  a n d  p h ar m a c o ki n eti cs s u c h t h at  ~ 4 -f ol d  hi g h er  d os es  a n d  ~ 1 5-f ol d  hi g h er  pl as m a 
e x p os ur e  ar e  a c hi e v e d r el ati v e t o tr a b e ct e di n.   A d diti o n all y,  P M 0 1 1 8 3  c a n  b e  a d mi nist er e d  as  a 
o n e- h o ur  o ut p ati e nt i nf usi o n  a n d  a p p e ars t o  h a v e  l ess ris k  of i n cr e asi n g s er u m tr a ns a mi n as e 
l e v els.   R e c e nt  p h as e I  a n d II  d at a  of  P M 0 1 1 8 3  eit h er  al o n e  or i n  c o m bi n ati o n  wit h  d o x or u bi ci n 
or  g e m cit a bi n e  c h e m ot h er a p y  h a v e s h o w n  pr o misi n g  e arl y  cli ni c al  a cti vit y  a n d  e x c ell e nt  cli ni c al 
t ol er a bilit y.   T h e  p ot e nti al  a cti vit y  of  P M 0 1 1 8 3 i n s ar c o m as r e m ai ns  p o orl y  d efi n e d,  b ut  v er y 
e arl y  a n d li mit e d  e x p eri e n c e s u g g est s  cli ni c al  a cti vit y.   Gi v e n t h e a d v a nt a g es  of t h e  e asi er  d osi n g 
a d mi nistr ati o n  a n d t h e  e arl y  a cti vit y  si g n als,  w e  b eli e v e t his  a g e nt  w arr a nts f urt h er i n v esti g ati o n 
as  effi ci e ntl y  as  p ossi bl e  i n s ar c o m a  p ati e nts.   
 
3.  P A R TI CI P A N T  S E L E C TI O N 
 
 L a b or at or y t ests r e q uir e d f or  eli gi bilit y  m ust  b e   c o m pl et e d  wit hi n  1 5  d a ys  pri or t o  d a y  1  of 
tr e at m e nt.  B as eli n e  m e as ur e m e nts  m ust  b e  d o c u me nt e d fr o m t ests  wit hi n  1 5  d a ys  of  d a y  1  of 
tr e at m e nt.  Di a g n osti c t ests, s u c h  as  M RIs  a n d  C T s c a ns,  m ust  b e  p erf or m e d  wit hi n  3 0  d a ys  of 
d a y  1  of tr e at m e nt.   
 


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1 7 
3. 1   
Eli gi bilit y  C rit e ri a  
 
3. 1. 1   P arti ci p a nts  m ust  h a v e  p at h ol o gi c all y  c o nfir m e d s oft-tiss u e s ar c o m a,  w hi c h is  m et ast ati c 
or  u nr es e ct a bl e, s ar c o m a  wit h  n o  c ur ati v e  m ulti m o d alit y  o pti o ns ( p at h ol o g y r e vi e w 
r e q uir e d f or  p ati e nts  wit h  p at h ol o g y  n ot  pr e vi o usl y r e vi e we d  at  D F CI,  B W H  or  M G H)  
  
3. 1. 2   P arti ci p a nts  m ust  h a v e  m e as ur a bl e  dis e as e  b y  R E CI S T  1. 1.   S e e  S e cti o n  1 1 f or t h e 
e v al u ati o n  of  m e as ur a bl e  dis e as e. 
 
3. 1. 3   N o  m or e t h a n t w o  pri or li n es  of  c h e m ot h er a p y f or  m et ast ati c s ar c o m a  ar e  all o w e d;  N e o-
a dj u v a nt/ a dj u v a nt  c h e m ot h er a p y  wit h  d efi niti v e t h er a p y (r a di ati o n, s ur g er y  or r a di ati o n 
a n d s ur g er y)  will  n ot  b e  c o u nt e d  as  o n e  of  t h es e  pri or li n es  of t h er a p y.  N o n- c yt ot o xi c 
t h er a pi es  will  n ot  b e  c o u nt e d  as  o n e of t h es e  pri or li n es  of t h er a p y.  
 
3. 1. 4   A g e   1 8  a n d  <  7 5  y e ars.  
 
3. 1. 5   E C O G  p erf or m a n c e st at us  ≤ 1 (s e e  A p p e n di x  A) 
 
3. 1. 6   Lif e  e x p e ct a n c y  of  gr e at er t h a n  3  m o nt hs   
 
3. 1. 7   P arti ci p a nts  m ust  h a v e  n or m al  or g a n  a n d  m arr o w f u n cti o n  as  d efi n e d  b el o w: 
 
  
H e m o gl o bi n  
>   9  g/ dl 
  
a bs ol ut e  n e utr o p hil  c o u nt   
≥   1, 5 0 0/ m c L 
  
pl at el ets  
≥   1 0 0, 0 0 0/ m c L 
  
t ot al  bilir u bi n 
<   1. 5  X  U L N  
  
A S T( S G O T)/ A L T( S G P T)   
≤ 3  X  U L N (i n cl u di n g  p ati e nts  wit h li v er  m et ast as es) 
  
cr e ati ni n e
  < 1. 5  X  U L N 
  
C P K 
<  2. 5  X  U L N 
  
Al b u mi n
  >   3  g/ dl 
 
3. 1. 8   W o m e n  of  c hil d b e ari n g  p ot e nti al   m ust  h a v e  a  n e g ati v e s er um  or  uri n e  pr e g n a n c y t est 
wit hi n  7  d a ys  pri or t o r e c ei vi n g st u d y  a g e nts. 
 
3. 1. 9   F or  p ati e nts i n str at u m  A,  a n  E C H O  or  M U G A  d e m o nstr ati n g  E F  >  5 0 % is r e q uir e d 
wit hi n  2 8  d a ys  pri or t o  st u d y  dr u g  a d mi nistr ati o n. 
 
3. 1. 1 0   P arti ci p a nts  m ust  b e  willi n g  a n d  a bl e t o   c o m pl y  wit h t h e st u d y s c h e d ul e d  visits, 
l a b or at or y t ests,  a n d  ot h er  pr o c e d ur es  o utli n e d i n t h e  pr ot o c ol. 
 
3. 1. 1 1   Pr e- m e n o p a us al  w o m e n  m ust  h a v e  a  n e g ati v e  pr e g n a n c y t est  b ef or e st u d y  e ntr y.  B ot h 
w o m e n  a n d  m e n  m ust  a gr e e t o  us e  a  m e di c all y  a c c e pt a bl e  m et h o d  of  c o ntr a c e pti o n 
t hr o u g h o ut t h e tr e at m e nt  p eri o d  a n d f or  at l e ast si x  w e e ks  aft er tr e at m e nt  dis c o nti n u ati o n. 
A c c e pt a bl e  m et h o ds  of  c o ntr a c e pti o n i n cl u d e i ntr a ut eri n e  d e vi c e (I U D),  or al 
c o ntr a c e pti v e, s u b d er m al i m pl a nt,  d o u bl e  b a rri er  a n d/ or  c o m pl et e  a bsti n e n c e ( n o n-
p eri o di c) . 
 


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3. 1. 1 2   W as h o ut  p eri o d  pri or t o  D a y  1  C y cl e  1: 
   >   3  w e e ks si n c e l ast  c h e m ot h er a p y or t h er a p e uti c r a di ati o n t h er a p y 
   >   4  w e e ks  or  3  h alf-li v es si n c e  pri or  a nti b o d y- b as e d t h er a p y,  w hi c h e v er is 
s h ort er  
   >   2  w e e ks si n c e  a n y  or al  a nti- n e o pl asti c  or  or al i n v esti g ati o n al  a g e nt 
   R es ol uti o n  of tr e at m e nt-r el at e d t o xi cit y t o  <   gr a d e  1;  al o p e ci a  a n d  c ut a n e o us 
t o xi cit y  ar e  all o w e d  <  gr a d e  2.   
   > 1  w e e k si n c e  p alli ati v e  R T  
 
3. 1. 1 3   A bilit y t o  u n d erst a n d  a n d t h e  willi n g n ess t o  si g n  a  writt e n i nf or m e d  c o ns e nt  d o c u m e nt. 
 
3. 2  
E x cl usi o n  C rit e ri a 
 
3. 2. 1   Pri or  e x p os ur e t o  P M 0 1 1 8 3 
 
3. 2. 2   P ati e nts  w h o  h a v e r e c ei v e d tr a b e ct e di n ( Y o n d e lis,  E T- 7 4 3)  or  p arti ci p at e d i n t h e  p h as e 
III  cli ni c al st u d y  of tr a b e ct e di n  N C T 0 1 3 4 3 2 7 7 pr e vi o usl y  will  n ot  b e  eli gi bl e.  
 
3. 2. 3   F or str at u m  A,  p ati e nts  m ust  n ot   h a v e r e c ei v e d  pri or  a nt hr ac y cli n e- b as e d t h er a p y ( pri or 
tr e at m e nt  wit h  n o n- a nt hr a c ycli n es is  p er mitt e d).   
 
3. 2. 4   F or str at u m  B  p ati e nts  m ust  h a v e r e c ei v e d  pr i or  a nt hr a c y cli n e- b as ed t h er a p y ( or  h a v e  a 
c o ntr ai n di c ati o n t o r e c ei vi n g t his tr e at m e nt)  a n d  m ust  n ot  h a v e r e c ei v e d  pri or 
g e m cit a bi n e 
 
3. 2. 5   F or str at u m  C,  p ati e nts  m ust  h a v e r e c ei v e d  pr i or  a nt hr a c y cli n e ( or  h av e  a  c o ntr ai n di c ati o n 
t o  a nt hr a c y cli n e)  A N D  g e m cit a bi n e- b as e d t h er a p y ( or  h a v e  a  c o ntr ai n di c ati o n t o 
g e m cit a bi n e).  
 
3. 2. 6   Pri or r a di ati o n tr e at m e nt  of  > 4 5  G y t o t h e  p el vis 
 
3. 2. 7   Pr e vi o usl y  u ntr e at e d  E wi n g  S a r c o m a  a n d r h a b d o m y os ar c o m a 
 
3. 2. 8   N o n-s oft tiss u e s ar c o m as, s u c h  as  ost e os ar c o m a  a n d  c h o n dr os ar c o m a  ar e  e x cl u d e d 
 
3. 2. 9   P arti ci p a nts  w h o  ar e r e c ei vi n g  a n y  ot h er i n v esti g ati o n al  a g e nts. 
 
3. 2. 1 0   A cti v e  h e p at o p at h y  of  a n y  ori gi n i n cl u di n g  a cti v e  h e p atitis  B  a n d  h e p atitis  C 
 
3. 2. 1 1   P arti ci p a nts  wit h  k n o w n  u n c o ntr oll e d  br ai n  m et ast as es  will  b e  e x cl u d e d fr o m t his 
cli ni c al. 
 
3. 2. 1 2   Hist or y  of  all er gi c r e a cti o ns  attri b ut e d t o  c o m p o u n ds  of si mil ar  c h e mi c al  or  bi ol o gi c 
c o m p ositi o n t o  P M 0 1 1 8 3  or tr a b e ct e di n ( Y o n d elis,  E T- 7 4 3). 
 


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3. 2. 1 3   U n c o ntr oll e d i nt er c urr e nt ill n ess i n cl u di n g,  b ut  n ot li mit e d t o,  o n g oi n g  or  a cti v e i nf e cti o n, 
s y m pt o m ati c  c o n g esti v e  h e art f ail ur e,  u nst a bl e  a n gi n a  p e ct oris,  c ar di a c  arr h yt h mi a, 
c hr o ni c i n d w elli n g  dr ai ns,  hist or y  of i nt ers titi al  p n e u m o nitis  or  p ul m o n ar y fi br osis  or 
ps y c hi atri c ill n ess/s o ci al sit u ati o ns t h at  w o ul d li mit  c o m pli a n c e  wit h st u d y r e q uir e m e nts.  
 
3. 2. 1 4   A cti v el y  br e astf e e di n g  w o m e n  u nl ess it is i n t err u pt e d  d uri n g tr e at m e nt  a n d  at l e ast  6 
w e e ks  aft er tr e at m e nt  dis c o nti n u ati o n.   
 
3. 2. 1 5   K n o w n  m y o p at h y  or  p ersist e nt  C P K  el e v ati o ns   > 2. 5  U L N i n t w o  diff er e nt  d et er mi n ati o ns 
p erf or m e d  o n e  w e e k  a p art.  
 
3. 2. 1 6   I m m u n o c o m pr o mis e d  p ati e nts, i n cl u di n g t h os e  wit h  HI V.   
 
3. 3  
I n cl usi o n  of  W o m e n  a n d  Mi n o riti es 
 
B ot h  m e n  a n d  w o m e n  of  all r a c es  a n d  et h ni c  gr o u ps  ar e  eli gi bl e f or t his tri al. 
 
4.  R E GI S T R A TI O N  P R O C E D U R E S 
 
4. 1  
G e n e r al  G ui d eli n es f o r  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 c e  Offi c e f or 
Cli ni c al  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 ns  m ust  o c c ur  pri or t o t h e 
i niti ati o n  of  pr ot o c ol t h er a p y.  A n y  p arti ci p a nt  n ot r e gist er e d t o t h e  pr ot o c ol  b ef or e  pr ot o c ol 
t h er a p y  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  b e  d e ni e d. 
 
A n i n v esti g at or  will  c o nfir m  eli gi bilit y  crit eri a   a n d  a  m e m b er  of t h e st u d y t e a m  will  c o m pl et e t h e 
Q A C T  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 t h er a p y. 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  O v erall  Pri n ci p al I n v e sti g at or ( PI). If  a  p arti ci p a nt 
d o es  n ot r e c ei v e  pr ot o c ol t h er a p y f oll o wi n g r e gistr ati o n, t h e  p art i ci p a nt’s r e gistr ati o n  o n t h e 
st u d y  m ust  b e  c a n c el e d.  N otif y t h e  Q A C T  R e gistr ar  of r e gistr ati o n  c a n c e ll ati o ns  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 o r  D F/ H C C  a n d  D F/ P C C I nstit uti o ns 
 
T h e  Q A C T r e gistr ati o n st aff is  a c c essi bl e  o n  M o n d a y t hr o u g h  Fri d a y, fr o m  8: 0 0  A M t o  5: 0 0  P M 
E ast er n  St a n d ar d  Ti m e. I n  e m er g e n c y sit u ati o ns  w h e n  a  p arti ci p a nt  m ust  b e gi n  pr ot o c ol t h er a p y 
d uri n g  off- h o urs  or  h oli d a ys,  c all t h e  Q A C T r e gi str ati o n li n e  at 
  a n d f oll o w t h e 
i nstr u cti o ns f or r e gist erin g  p arti ci p a nts  aft er  h o urs. 
 
T h e r e gistr ati o n  pr o c e d ur es  ar e  as f oll o ws: 
 
   O bt ai n  writt e n i nf or m e d  c o ns e nt fr o m t h e  p a rti ci p a nt  pri or t o t he  p erf or m a n c e  of  a n y 
pr ot o c ol s p e cifi c  pr o c e d ur es  or  ass ess m e nts.  
 


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   C o m pl et e t h e  Q A C T  pr ot o c ol-s p e cifi c  eli g i bilit y  c h e c klist  usi n g t h e  eli gi bilit y 
ass ess m e nt  d o c u m e nt e d i n t h e  p arti ci p a nt’s  m e di c al r e c or d  a n d/ or r es e ar c h  c h art.  T o  b e 
eli gi bl e f o r  r e gist r ati o n t o t h e  p r ot o c ol, t h e  p a rti ci p a nt  m ust  m e et  all i n cl usi o n  a n d 
e x cl usi o n  c rit e ri o n  as  d es c ri b e d i n t h e  p r ot o c ol  a n d  r efl e ct e d  o n t h e  eli gi bilit y 
c h e c klist. 
 
 
   F a x t h e  eli gi bilit y  c h e c klist(s)  a n d  all  p a g es  of t h e  c o ns e nt f or m(s) t o t h e  Q A C T  at 
  F or  P h as e I  pr ot o c ols,  att a c h  p arti ci p a nt  d os e l e v el  assi g n m e nt  c o nfir m ati o n 
fr o m t h e s p o ns or. 
 
   T h e  Q A C T  R e gistr ar  will ( a) r e vi e w t h e  eli gi bil it y  c h e c klist, ( b) r e gist er t h e  p arti ci p a nt 
o n t h e  pr ot o c ol,  a n d ( c) r a n d o mi z e t h e  p arti ci p a nt  w h e n  a p pli c a bl e. 
 
   A n  e m ail  c o nfir m ati o n  of t h e r e gistr ati o n  a n d/ or r a n d o mi z ati o n  will  b e s e nt t o t h e  O v er all 
PI, st u d y  c o or di n at or(s) fr o m t h e  L e a d  Sit e, tr e ati n g i n v esti g at or  a n d r e gist eri n g  p ers o n 
i m m e di at el y f oll o wi n g t h e r e gistr ati o n  a n d/ or r a n d o mi z ati o n. 
 
5.  T R E A T M E N T  P L A N 
 
5. 1  
T r e at m e nt  R e gi m e n 
 
St r at u m  A : ( A nt hr a c y cli n e- n aï v e  p ati e nts,  u nl ess  a  c o ntr ai n di c atio n t o  d o x or u bi ci n  e xists)  
   C y cl es  1- 6:   D o x or u bi ci n f oll o w e d  b y  P M 0 1 1 8 3  will  b e  a d mi nist er e d  o n  a n  o ut p ati e nt 
b asis  o n  d a y  1  of  a  2 1- d a y  c y cl e.   
 
Tr e at m e nt  will  c o nti n u e f or  a t ot al  of  6  c y cl es  u nl ess  P D  or  u n a c c e pt a bl e t o xi cit y.  
 
   C y cl es  7  a n d  b e y o n d ;  p ati e nts  w h o  e x hi bit  dis e as e  c o ntr ol  or r es p o ns e  aft er  6  c y cl es  m a y 
c o nti n u e  o n  P M 0 1 1 8 3 si n gl e- a g e nt  o n  d a y  1  of  a  2 1- d a y  c y cl e  
 
St r at u m  B : ( P ati e nts  wit h  pri or  a nt hra c y cli n e tr e at m e nt  or  c o ntr ai n di c ati o n,  b ut  wit h  n o  pri or 
tr e at m e nt  wit h  g e m cit a bi n e)   
   G e m cit a bi n e f oll o w e d  b y  P M 0 1 1 8 3  will  b e  a d mi ni st er e d  o n  a n  o ut p ati e nt  b asis  o n  d a y  1 
a n d  g e m cit a bi n e f oll o w e d  b y  P M 0 1 1 8 3  will  b e  a d mi nist er e d  8  of  a  2 1- d a y  c y cl e.   
 
St r at u m  C : ( P ati e nts  w h o  h a v e r e c ei v e d  b ot h  pri or  a nt hr a c y cli n e  a n d  pri or  g e m cit a bi n e,  u nl ess  a 
c o ntr ai n di c ati o n t o  eit h er  a n t hr a c y cli n es  or  g e m cit a bi n e e xists,  as  o utli n e d i n t h e 
i n cl usi o n/ e x cl usi o n  crit eri a i n s e cti o ns  3. 1/ 3. 2)   
   P M 0 1 1 8 3  as  a si n gl e  a g e nt  will  b e  a d mi nist er e d  o n  a n  o ut p ati e nt  b asis  o n  d a y  1  of  a  2 1-
d a y  c y cl e.  
 
R e p ort e d  a d v ers e  e v e nts  a n d  p ot e nti al ris ks  ar e  d es cri b e d i n  S e cti o n  7.   A p pr o pri at e  d os e 
m o difi c ati o ns  ar e  d es cri b e d i n  S e cti o n  6.   N o i n v e sti g ati o n al  or  c o m m er ci al  a g e nts  or t h er a pi es 
ot h er t h a n t h os e  d es cri b e d  b el o w  m a y  b e  a d mi nist er e d  wit h t h e i nt e nt t o tr e at t h e  p arti ci p a nt's 
m ali g n a n c y. 


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2 1 
 
Pr o p h yl a cti c  G C S F  will  b e  a d mi nist er e d  a c c or di n g t o t h e  g ui d eli n es i n s e cti o n  6. 4 .  D osi n g  a n d 
f or m ul ati o n  will  b e  p er i nstit uti o n st a n d ar d. 
 
B o d y s urf a c e  ar e a ( B S A)  will  b e  c al c ul at e d  usi n g t h e  D u b ois f or m ul a  o n  d a y  1  of  e a c h  c y cl e  or 
p er i nstit uti o n st a n d ar d  of  c ar e.   
 
5. 2  
P r e- T r e at m e nt  C rit e ri a 
 
Pri or t o  a n y st u d y r el at e d t esti n g,  p ati e nts  will si g n t h e i nf or m e d  c o ns e nt f or m  a n d  u n d er g o 
m e di c al  e v al u ati o n t o  est a blis h t h eir  b as eli n e  c o n diti o n  a n d  d et er mi n e  eli gi bilit y.  T h e f oll o wi n g 
st u di es  will  b e  o bt ai n e d  wit hi n  3 0  d a ys  of  e nr oll m e nt f or t h e  p ur p os e  of  b as eli n e  ass ess m e nt: 
 
C o m pl et e  m e di c al  hist or y  a n d  p h ysi c al  e x a mi n ati o n i n cl u di n g: 
   C o m pl et e  m e di c al  hist or y 
   D o c u m e nt ati o n st at us  of  dis e as e 
   D o c u m e nt ati o n  of  pri or t h er a pi es  
   D o c u m e nt ati o n  of  c urr e nt  m e di c ati o ns  
   C o m pl et e  p h ysi c al  e x a mi n ati o n, i n cl u di n g  vit al si g ns  a n d  ass ess m e nt  of  E C O G 
p erf or m a n c e st at us  
   Pr e- e xisti n g  c o n diti o ns  will  b e  ass ess e d  a n d  e v al u at e d  a c c or di n g t o t h e  N CI  C T C A E 
v 4. 0 3 t o  est a blis h t h e  p ati e n t’s  b as eli n e  c o n diti o n 
 
Dis e as e- S p e cifi c  L a b or at or y  T est s-  P at h ol o g y  a n d  T u m or I m a gi n g 
   C o nfir m i nstit uti o n al r e vi e w  of  di a g n osti c  p at h ol o gi c  m at eri al 
   B as eli n e t u m or i m a gi n g st u di es  will  b e  eit h er  C T  or  M RI.  T h e  m o d alit y  c h os e n f or  a n y 
i n di vi d u al  p ati e nt  will  b e t h e s a m e t hr o u g h o ut t h e  d ur ati o n  of t h e st u d y. 
 
T h e f oll o wi n g s cr e e ni n g t ests  will  b e  p erf or m e d  wit hi n  1 5  d a ys  pri or t o  D a y  1  of tr e at m e nt: 
   C B C  wit h  diff er e nti al 
   C h e mistri es: s o di u m,  p ot assi u m,  gl u c os e,  cr e ati ni n e, t ot al  bilir u bi n,  al k ali n e  p h os p h at as e 
[ A L P],  as p art at e tr a ns a mi n as e [ A S T],  al a ni n e tr a ns a mi n as e [ A L T],  ur e a  or  bl o o d  ur e a 
nitr o g e n [ B U N], t ot al  pr ot ei n,  al b u mi n,  C P K  
   I N R  a n d  A P T T 
   L D H 
   Uri n al ysis 
   Uri n e  or s er u m  pr e g n a n c y t est (f or  pr e m e n o p a us al  w o m e n) 
   E C G if  cli ni c all y i n di c at e d 
 
F or  Str at u m  A  a  pr e-tr e at m e nt  e c h o c ar di o gr a m  or   M U G A  m ust  b e  c o m pl et e d  wit hi n  2 8  d a ys 
pri or t o  d a y  1. 
 
5. 2. 1  
Str at u m  A:  P M 0 1 1 8 3  a n d  D o x or u bi ci n 
 
C y cl e  1,  D a y  1: 
P ati e nts  w h o  h a v e si g n e d t h e i nf or m e d  c o ns e nt f o r m,  c o m pl et e d t h e s cr e e ni n g  pr o c ess,  a n d  m et 


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2 2 
t h e  crit eri a f or  e nr oll m e nt  will  b e  e nt er e d i nt o t he tri al  a n d  assi g n e d  a n i d e ntifi c ati o n  n u m b er. I n 
a d diti o n t h e f oll o wi n g  will  b e  p erf or m e d: 
 
   C ertifi c ati o n t h at  p ati e nt  m e ets  all i n cl usi o n  a n d  e x cl usi o n  crit eri a  a n d is  a bl e t o  c o m pl y 
wit h  all r e q uir e m e nts  of t h e  cli ni c al tri al 
   R e vi e w  c o n c o mit a nt  m e di c ati o ns si n c e s cr e e ni n g 
   P erf or m  p h ysi c al  e x a mi n ati o n  wit h  vit al si g ns  (t e m p er at ur e,  h e art r at e,  bl o o d  pr ess ur e, 
o x y g e n s at ur ati o n, r es pir at or y r at e,  h ei g ht  a n d  w ei g ht)  a n d  E C O G  p erf or m a n c e st at us 
   L a b or at or y t esti n g  – t o  b e  d o n e  if s cr e e ni n g l a bs  w er e  d o n e  m or e t h a n  7  d a ys  pri or t o  D a y 
1.   P ati e nt  will  w ait f or t h e l a b r es ults  o n t his  d a y t o r e- c o nfir m l a b  p ar a m et ers f or 
eli gi bilit y. 
o   C B C  wit h  diff er e nti al 
o   C h e mistri es: s o di u m,  p ot assi u m,  c al ci u m,  p h os p h or us,  gl u c os e,  cr e ati ni n e, t ot al 
bilir u bi n,  al k ali n e  p h os p h at as e,  A S T,  A L T,  B U N, t ot al  pr ot ei n,  al b u mi n,  C P K, 
L D H 
o   Uri n e  or s er u m  pr e g n a n c y t est (f or  pr e m e n o p a us al  w o m e n) if  n ot  p erf or m e d 
wit hi n  7  d a ys  of  c y cl e  1  d a y  1 
   Tr e at m e nt:  D o x or u bi ci n  5 0  m g/ m 2 f oll o w e d  b y  P M 0 1 1 8 3  2  m g/ m2  
 
 
C y cl es  2- 6,  D a y  1: 
   Pl e as e s e e s e cti o n  6 f or  Crit eri a f o r  Tr e at m e nt  C o nti n u ati o n  a n d  d osi n g 
d el a ys/ m o difi c ati o ns.  
   R e vi e w  c o n c o mit a nt  m e di c ati o ns  
   P erf or m  p h ysi c al  e x a mi n ati o n  wit h  vit al si g ns  (t e m p er at ur e,  h e art r at e,  bl o o d  pr ess ur e, 
o x y g e n s at ur ati o n, r es pir at or y r at e,  h ei g ht  a n d  w ei g ht)  a n d  E C O G  p erf or m a n c e st at us 
   L a b or at or y t esti n g 
o   C B C  wit h  diff er e nti al 
o   C h e mistri es: s o di u m,  p ot assi u m,  c al ci u m,  p h os p h or us,  gl u c os e,  cr e ati ni n e, t ot al 
bilir u bi n,  al k ali n e  p h os p h at as e,  A S T,  A L T,  B U N, t ot al  pr ot ei n,  al b u mi n,  C P K, 
L D H 
   Tr e at m e nt:  D o x or u bi ci n  5 0  m g/ m 2 f oll o w e d  b y  P M 0 1 1 8 3  2  m g/ m2  
 
C y cl es  7  a n d s u bs e q u e nt,  D a y  1: 
   Pl e as e s e e s e cti o n  6 f or  Crit eri a f o r  Tr e at m e nt  C o nti n u ati o n  a n d  d osi n g 
d el a ys/ m o difi c ati o ns.  
   R e vi e w  c o n c o mit a nt  m e di c ati o ns  
   P erf or m  p h ysi c al  e x a mi n ati o n  wit h  vit al si g ns  (t e m p er at ur e,  h e art r at e,  bl o o d  pr ess ur e, 
o x y g e n s at ur ati o n, r es pir at or y r at e,  h ei g ht  a n d  w ei g ht)  a n d  E C O G  p erf or m a n c e st at us 
   L a b or at or y t esti n g 
o   C B C  wit h  diff er e nti al 
o   C h e mistri es: s o di u m,  p ot assi u m,  c al ci u m,  p h os p h or us,  gl u c os e,  cr e ati ni n e, t ot al 
bilir u bi n,  al k ali n e  p h os p h at as e,  A S T,  A L T,  B U N, t ot al  pr ot ei n,  al b u mi n,  C P K, 
L D H 
   Tr e at m e nt:  
o   P M 0 1 1 8 3:  


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2 3 
   3. 2  m g/ m 2  
 
5. 2. 2  
Str at u m  B:  P M 0 1 1 8 3  a n d  G e m cit a bi n e 
 
C y cl e  1  D a y  1  
 
P ati e nts  w h o  h a v e si g n e d t h e i nf or m e d  c o ns e nt f o r m,  c o m pl et e d t h e s cr e e ni n g  pr o c ess,  a n d  m et 
t h e  crit eri a f or  e nr oll m e nt  will  b e  e nt er e d i nt o t he tri al  a n d  assi g n e d  a n i d e ntifi c ati o n  n u m b er. I n 
a d diti o n t h e f oll o wi n g  will  b e  p erf or m e d: 
 
   C ertifi c ati o n t h at  p ati e nt  m e ets  all i n cl usi o n  a n d  e x cl usi o n  crit eri a  a n d is  a bl e t o  c o m pl y 
wit h  all r e q uir e m e nts  of t h e  cli ni c al tri al 
   R e vi e w  c o n c o mit a nt  m e di c ati o ns si n c e s cr e e ni n g 
   P erf or m  p h ysi c al  e x a mi n ati o n  wit h  vit al si g ns  (t e m p er at ur e,  h e art r at e,  bl o o d  pr ess ur e, 
o x y g e n s at ur ati o n, r es pir at or y r at e,  h ei g ht  a n d  w ei g ht)  a n d  E C O G  p erf or m a n c e st at us 
   L a b or at or y t esti n g  – t o  b e  d o n e  if s cr e e ni n g l a bs  w er e  d o n e  m or e t h a n  7  d a ys  pri or t o  D a y 
1.   P ati e nt  will  w ait f or t h e l a b r es ults  o n t his  d a y t o r e- c o nfir m l a b  p ar a m et ers f or 
eli gi bilit y. 
o   C B C  wit h  diff er e nti al 
o   C h e mistri es: s o di u m,  p ot assi u m,  c al ci u m,  p h os p h or us,  gl u c os e,  cr e ati ni n e, t ot al 
bilir u bi n,  al k ali n e  p h os p h at as e,  A S T,  A L T,  B U N, t ot al  pr ot ei n,  al b u mi n,  C P K, 
L D H 
o   Uri n e  or s er u m  pr e g n a n c y t est (f or  pr e m e n o p a us al  w o m e n) if  n ot  p erf or m e d 
wit hi n  7  d a ys  of  c y cl e  1  d a y  1 
   Tr e at m e nt:  G e m cit a bi n e  8 0 0  m g/ m 2 f oll o w e d  b y  P M 0 1 1 8 3  1. 6  m g/ m2 
 
C y cl e  1  D a y  8: 
   Pl e as e s e e s e cti o n  6 f or  Crit eri a f o r  Tr e at m e nt  C o nti n u ati o n  a n d  d osi n g 
d el a ys/ m o difi c ati o ns.  
   R e vi e w  c o n c o mit a nt  m e di c ati o ns  
   P erf or m  p h ysi c al  e x a mi n ati o n  wit h  vit al si g ns  (t e m p er at ur e,  h e art r at e,  bl o o d  pr ess ur e, 
o x y g e n s at ur ati o n, r es pir at or y r at e,  h ei g ht  a n d  w ei g ht)  a n d  E C O G  p erf or m a n c e st at us 
   L a b or at or y t esti n g 
o   C B C  wit h  diff er e nti al 
o   C h e mistri es: s o di u m,  p ot assi u m,  c al ci u m,  p h os p h or us,  gl u c os e,  cr e ati ni n e, t ot al 
bilir u bi n,  al k ali n e  p h os p h at as e,  A S T,  A L T,  B U N, t ot al  pr ot ei n,  al b u mi n,  C P K, 
L D H 
   Tr e at m e nt:  G e m cit a bi n e  8 0 0  m g/ m 2 f oll o w e d  b y  P M 0 1 1 8 3  1. 6  m g/ m2  
 
S u bs e q u e nt  c y cl es,  D a y  1 
   Pl e as e s e e s e cti o n  6 f or  Crit eri a f o r  Tr e at m e nt  C o nti n u ati o n  a n d  d osi n g 
d el a ys/ m o difi c ati o ns.  
   R e vi e w  c o n c o mit a nt  m e di c ati o ns  
   P erf or m  p h ysi c al  e x a mi n ati o n  wit h  vit al si g ns  (t e m p er at ur e,  h e art r at e,  bl o o d  pr ess ur e, 
o x y g e n s at ur ati o n, r es pir at or y r at e,  h ei g ht  a n d  w ei g ht)  a n d  E C O G  p erf or m a n c e st at us 
   L a b or at or y t esti n g 


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2 4 
o   C B C  wit h  diff er e nti al 
o   C h e mistri es: s o di u m,  p ot assi u m,  c al ci u m,  p h os p h or us,  gl u c os e,  cr e ati ni n e, t ot al 
bilir u bi n,  al k ali n e  p h os p h at as e,  A S T,  A L T,  B U N, t ot al  pr ot ei n,  al b u mi n,  C P K, 
L D H 
   Tr e at m e nt:  G e m cit a bi n e  8 0 0  m g/ m 2 f oll o w e d  b y  1. 6  m g/ m2  
 
S u bs e q u e nt  c y cl es,  D a y  8: 
   Pl e as e s e e s e cti o n  6 f or  Crit eri a f o r  Tr e at m e nt  C o nti n u ati o n  a n d  d osi n g 
d el a ys/ m o difi c ati o ns.  
   R e vi e w  c o n c o mit a nt  m e di c ati o ns  
   P erf or m  p h ysi c al  e x a mi n ati o n  wit h  vit al si g ns  (t e m p er at ur e,  h e art r at e,  bl o o d  pr ess ur e, 
o x y g e n s at ur ati o n, r es pir at or y r at e,  h ei g ht  a n d  w ei g ht)  a n d  E C O G  p erf or m a n c e st at us 
   L a b or at or y t esti n g 
o   C B C  wit h  diff er e nti al 
o   C h e mistri es: s o di u m,  p ot assi u m,  c al ci u m,  p h os p h or us,  gl u c os e,  cr e ati ni n e, t ot al 
bilir u bi n,  al k ali n e  p h os p h at as e,  A S T,  A L T,  B U N, t ot al  pr ot ei n,  al b u mi n,  C P K, 
L D H 
   Tr e at m e nt:  G e m cit a bi n e  8 0 0  m g/ m 2 f oll o w e d  b y  P M 0 1 1 8 3  1. 6  m g/ m2 
 
S u bs e q u e nt  c y cl es,  D a y  1, if  g e m cit a bi n e is  dis c o nti n u e d: 
   If  g e m cit a bi n e is  dis c o nti n u e d f or  g e m cit a bi n e-r el at e d t o xi cit y t h e  p ati e nt  m a y  c o nti n u e 
P M 0 1 1 8 3  M o n ot h er a p y  pr o vi d e d t h e y  m e et  crit er i a f or tr e at m e nt  c o nti n u ati o n  a n d  d osi n g 
d el a ys/ m o difi c ati o n r ul es. 
   Tr e at m e nt  of  P M 0 1 1 8 3  will f oll o w t h e  S u bs e q u e nt  C y cl e  D a y  1  g ui d eli n es f or  Str at u m  C 
P M O 1 1 8 3  M o n ot h er a p y i n s e cti o n  5. 2. 3 
 
5. 2. 3  
Str at u m  C:  P M 0 1 1 8 3  M o n ot h er a p y 
 
C y cl e  1  D a y  1  
 
P ati e nts  w h o  h a v e si g n e d t h e i nf or m e d  c o ns e nt f o r m,  c o m pl et e d t h e s cr e e ni n g  pr o c ess,  a n d  m et 
t h e  crit eri a f or  e nr oll m e nt  will  b e  e nt er e d i nt o t he tri al  a n d  assi g n e d  a n i d e ntifi c ati o n  n u m b er. I n 
a d diti o n t h e f oll o wi n g  will  b e  p erf or m e d: 
 
   C ertifi c ati o n t h at  p ati e nt  m e ets  all i n cl usi o n  a n d  e x cl usi o n  crit eri a  a n d is  a bl e t o  c o m pl y 
wit h  all r e q uir e m e nts  of t h e  cli ni c al tri al 
   R e vi e w  c o n c o mit a nt  m e di c ati o ns si n c e s cr e e ni n g 
   P erf or m  p h ysi c al  e x a mi n ati o n  wit h  vit al si g ns  (t e m p er at ur e,  h e art r at e,  bl o o d  pr ess ur e, 
o x y g e n s at ur ati o n, r es pir at or y r at e,  h ei g ht  a n d  w ei g ht)  a n d  E C O G  p erf or m a n c e st at us 
   L a b or at or y t esti n g  – t o  b e  d o n e  if s cr e e ni n g l a bs  w er e  d o n e  m or e t h a n  7  d a ys  pri or t o  D a y 
1.   P ati e nt  will  w ait f or t h e l a b r es ults  o n t his  d a y t o r e- c o nfir m l a b  p ar a m et ers f or 
eli gi bilit y. 
o   C B C  wit h  diff er e nti al 
o   C h e mistri es: s o di u m,  p ot assi u m,  c al ci u m,  gl u c os e,  cr e ati ni n e, t ot al  bilir u bi n, 
al k ali n e  p h os p h at as e,  A S T,  A L T,  B U N, t ot al  pr ot ei n,  al b u mi n,  C P K,  L D H 
o   Uri n e  or s er u m  pr e g n a n c y t est (f or  pr e m e n o p a us al  w o m e n) if  n ot  p erf or m e d 




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U nl ess  ot h er wis e s p e cifi e d  b y i nstit uti o n st a n d ar d  of  c ar e,  d osi n g  b y  m g/ m 2 s h o ul d  b e r e-
c al c ul at e d  o n  d a y  1  of  e a c h s c h e d ul e d  d o x or u bi ci n  p us h/i nf usi o n.  
 
D osi n g  will  b e  c a p p e d  at  2  m 2. 
 
C ar e is t o  b e t a k e n  w h e n  a d mi nist eri n g  d o x or u bi ci n  d u e t o its str o n g  v esi c a nt  pr o p erti es.  T h e  us e 
of  v ei ns  o v er j oi nts,  or i n  e xtr e miti es  wit h  c o m p r o mis e d  v e n o us  a n d/ or l y m p h ati c  dr ai n a g e  m ust 
b e  a v oi d e d,  a n d  us e  of  a  c e ntr al   v e n o us  c at h et er is r e c o m m e n d ed i n s u bj e cts  wit h  diffi c ult 
v e n o us  a c c ess.  D o x or u bi ci n  m ust  n ot  b e  mi x e d  wit h  ot h er  dr u gs,  or  wit h  h e p ari n.  D o x or u bi ci n 
m ust  b e  pr ot e ct e d fr o m s u nli g ht  ( n or m al r o o m li g ht  all o w e d). 
 
I n  c as e  of s us p e ct e d  e xtr a v as ati o n, t h e i nf usi o n  m ust  b e st o p p e d  a n d i m m e di at e  m e as ur es  m ust 
b e t a k e n  a c c or di n g t o i nstit uti o n al  g ui d eli n es.  Ti ss u e  n e cr osis r es ulti n g fr o m  e xtr a v as ati o n  m a y 
o c c ur  d a ys t o  w e e ks  aft er t h e  i n ci d e nt.  S u bj e cts  m ust  b e  o bser v e d f or  d el a y e d r e a cti o ns,  a n d 
pri or i nj e cti o n sit es  c ar ef ull y i ns p e ct e d. I n s e v er e  c as es,  a  pl asti c s ur g e o n  m a y  b e  c o ns ult e d. 
Er yt h e m at o us str e a ki n g ( a  hist a mi n e r el e as e  p h e n o m e n o n)  al o n g t h e  v ei n  pr o xi m al t o t h e 
i nj e cti o n sit e  m ust  b e  diff er e nti at e d fr o m  a n  e xtr a v as ati o n  e v e nt.  T his  “ d o x or u bi ci n fl ar e ” 
r e a cti o n  us u all y s u bsi d es  wit hi n  3 0  mi n ut es.  T h e i nj e cti o n  m a y  b e  c o nti n u e d at  a sl o w er  p a c e i n 
t h e s a m e sit e,  or it  m a y  b e  c h a n g e d t o  a n ot h er sit e.  A d mi nistr ati o n  of  di p h e n h y dr a mi n e  2 5- 5 0  m g 
I V  a n d  h y dr o c ortis o n e  1 0 0  m g I V i nt o t h e s a m e I V li n e  m a y  a c c el er at e  cle ari n g  of t h e r e a cti o n.  
 
 
5. 3. 3  
G e m cit a bi n e  
 
G e m cit a bi n e  will  b e  gi v e n  vi a I V  at  a fi x e d r at e  of  a p pr o xi m at el y  1 0  m g/ m 2/ mi n.     
 
U nl ess  ot h er wis e s p e cifi e d  b y i nstit uti o n st a n d ar d  of  c ar e,  d osi n g  b y  m g/ m 2 s h o ul d  b e r e-
c al c ul at e d  o n  d a y  1  a n d  d a y  8  of  e a c h s c h e d ul e d  g e m cit a bi n e tr e at m e nt.  
 
D osi n g  will  b e  c a p p e d  at  2  m 2. 
 
 
5. 4  
G e n e r al  C o n c o mit a nt  M e di c ati o n  a n d  S u p p o rti v e  C a r e  G ui d eli n es 
 
5. 4. 1  
Pr o p h yl a cti c  M e di c ati o n 
 
P ati e nts  m ust r e c ei v e st a n d ar d  a nti e m eti c  pr o p h yl a cti c  m e di c ati o ns  at l e ast  3 0  mi n ut es 
b ef or e  a d mi nistr ati o n  of  P M 0 1 1 8 3  as f oll o ws: 
   C orti c ost er oi d ( d e x a m et h as o n e I V/ p o  or  e q ui v al e nt  as  p er i nstit uti o n al st a n d ar ds) 
   S er ot o ni n ( 5- H T 3)  a nt a g o nists 
o   Str at u m  A:  o n d a ns etr o n  1 6  m g  I V/ p o  or  e q ui v al e nt 
o   Str at u m  B  a n d  C:  o n d a ns etr o n  8  m g I V/ p o  or  e q ui v al e nt 
   If  n e c ess ar y  e xt e n d e d  d osi n g  or a d diti o n al  a nti e m eti cs  ar e  all o w e d 
   A pr e pit a nt  a n d f os a pr e pit a nt  ar e  pr o hi bit e d 
   S e c o n d ar y  pr o p h yl a xis  G C S F is  o nl y  all o w e d  a c c or di n g t o t h e  g ui d eli n es i n 


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s e cti o n  6. 4.  
   
 
5. 4. 2  
All o w e d  M e di c ati o ns/ T h er a pi es  
 
A n y  m e di c ati o ns,  wit h t h e  e x c e pti o ns  n ot e d  b el o w,  w hi c h  ar e  c o nsi d er e d  n e c ess ar y f or t h e 
p ati e nt's  w elf ar e,  a n d  w hi c h  ar e  n ot  k n o w n t o i n t er a ct  wit h t h e st u d y  m e di c ati o n,  m a y  b e  gi v e n  at 
t h e  dis cr eti o n  of t h e I n v esti g at or,  pr o vi di n g t he  m e di c ati o ns, t h e  d os es,  d at es  a n d r e as o ns f or 
a d mi nistr ati o n  ar e r e c or d e d i n t h e  e C R F. 
 
I n  a d diti o n,  a n y  u n pl a n n e d  di a g n osti c, t h er a p e uti c  or s ur gi c al  pr o c e d ure  p erf or m e d  d uri n g t h e 
st u d y  p eri o d  m ust  b e r e c or d e d i n t h e  e C R F. 
 
All  m e di c ati o ns ( pr es cri pti o ns  or  o v er-t h e- c o u nt er  m e di c ati o ns)  c o nti n u e d  at  t h e st art  of t h e tri al 
or st art e d  d uri n g t h e st u d y  or  u nt il  3 0  d a ys fr o m t h e  e n d  of t he l ast  pr ot o c ol tr e at m e nt  a n d 
diff er e nt fr o m t h e st u d y  m e di c ati o n  m ust  b e  d o c u m e nt e d. 
 
C o ntr a c e pti o n 
P ati e nts  of  c hil d  b e ari n g  p ot e nti al  a n d t h eir  p art n ers,  w h o  ar e s e x u all y  a cti v e,  m ust  a gr e e t o t h e 
us e  of t w o  hi g hl y  eff e cti v e f or ms  of  c o ntr a c e pti o n t hr o u g h o ut t h eir  p arti c i p ati o n i n t h e st u d y  a n d 
f or  3  m o nt hs  aft er l ast d os e  of st u d y  dr u g(s).  
   C o n d o m  wit h s p er mi ci d e  a n d  o n e  of t h e f oll o wi n g: 
   Or al  c o ntr a c e pti v e  or  h or m o n al t h er a p y ( e. g.  h or m o n e i m pl a nts) 
   Pl a c e m e nt  of  a n i ntr a- ut eri n e  d e vi c e  
 
A c c e pt a bl e  n o n- h or m o n al  birt h  c o ntr ol  m et h o ds i n cl u d e:  
   T ot al s e x u al  a bsti n e n c e.   A b sti n e n c e  m ust  b e f or t h e t ot al  d ur ati o n  of t h e st u d y  a n d t h e 
dr u g  w as h o ut  p eri o d. 
   V as e ct o mis e d s e x u al  p art n er  pl us  m al e  c o n d o m.    Wit h  p arti ci p a nt  ass ur a n c e t h at  p art n er 
r e c ei v e d  p ost- v as e ct o m y  co nfir m ati o n  of  a z o os p er mi a 
   T u b al  o c cl usi o n  pl us  m al e  c o n d o m  wit h s p er mi ci d e 
   I ntr a ut eri n e  D e vi c e (I U D)  pl us  m al e  c o n d o m +s p er mi ci d e.   Pr o vi d e d  c oils  ar e  c o p p er-
b a n d e d 
A c c e pt a bl e  h or m o n al  m et h o ds: 
   Et o n o g estr el i m pl a nts ( e g, I m pl a n o n,  N or pl a n) + m al e  c o n d o m  wit h s p er mi ci d e 
   N or m al  a n d l o w  d os e  c o m bi n e d  or al  pills + m al e  c o n d o m  wit h s p er mi ci d e 
   N or el g estr o mi n/ et hi n yl  estr a di ol ( E E) tr a n s d er m al s yst e m + m al e  c o n d o m  wit h s p er mi ci d e 
   I ntr a v a gi n al  d e vi c e + m al e  c o n d o m  wit h s p er mi ci d e ( e g,  E E  a n d  et o n o g estr el)  
   C er a z ett e ( d es o g estr el) + m al e  c o n d o m  wit h s p er mi ci d e.   C er a z ett e is  c urr e ntl y t h e  o nl y 
hi g hl y  effi c a ci o us  pr o g est er o n e  b as e d  pill. 
 
 
5. 4. 3  
Pr o hi bit e d  M e di c ati o ns/ T h er a pi es 
 
B e c a us e t h er e is  a  p ot e nti al f or i nt er a cti o n  of  P M 0 1 1 8 3  wit h  ot h er  c o n c o mit a ntl y  a d mi nist er e d 
dr u gs t hr o u g h t h e  c yt o c hr o m e  P 4 5 0 s yst e m, t h e  c as e r e p ort f or m  m ust  c a pt ur e t h e  c o n c urr e nt  us e 


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of  all  ot h er  dr u gs,  o v er-t h e- c o u nt er   m e di c ati o ns,  or  alt er n ati v e t h era pi es.   T h e  O v er all  PI s h o ul d 
b e  al ert e d if t h e  p arti ci p a nt is  t a ki n g  a n y  a g e nt  k n o w n t o  aff e ct  or  wit h t h e  p ot e nti al t o  aff e ct 
s el e ct e d  C Y P 4 5 0 is o e n z y m es ( n ot a bl y   C Y P 2 C 8  a n d  C Y P 3 A 4).   A p p e n di x  B  pr es e nts  g ui d eli n es 
f or i d e ntif yi n g  m e di c ati o ns/s u bst a n c es t h at  c o ul d p ot e nti all y i nt er a ct  wit h t h e st u d y  a g e nt(s). 
 
A pr e pit a nt  a n d r el at e d  c o m p o u n ds  ar e  pr o hi bit e d.  
 
T h e  pl as m a  pr ot ei n  bi n di n g  of  P M 0 1 1 8 3 r a n g e d fr o m   8 8- 9 8 % i n  all s p e ci es t est e d.  I n  h u m a ns, 
9 7 %  of  P M 0 1 1 8 3  w as  b o u n d t o  pl as m a  pr ot ei ns i n d e p e n d e nt  of  dr u g  c o n c e ntr ati o n.   T h er e f or 
c a uti o n is r e c o m m e n d e d  w h e n  c o n c o mit a nt  m e di c a ti o ns  k n o w n t o  b e  hi g hl y  pr ot ei n- b o u n d  ar e 
a d mi nist er e d  wit h  P M 0 1 1 8 3.   
 
P alli ati v e r a di ati o n  will  b e  p er mitt e d  aft er  c y cl e  2  o nl y f or l o c ali z e d  p ai n  c o ntr ol  a n d  n ot  d u e t o 
u n e q ui v o c al r a di ol o gi c al  or  cli ni c all y  pr o gr essi v e  dis e as e.   St u d y  dr u g,  d o x or u bi ci n  a n d 
g e m cit a bi n e s h o ul d  b e t e m p or aril y  h el d  d uri n g t his  p eri o d.   D osi n g s h o ul d r es u m e  wit h t h e  n e xt 
s c h e d ul e d  c y cl e t h at is  at l e ast  7  d a ys  aft er r a di ati o n is  c o m pl et e.   
 
A d mi nistr ati o n  of  ot h e r  a nti- c a n c er  a g e nts 
P ati e nts  m ust  n ot r e c ei v e  a n y  ot h er  c o n c urr e nt   a nti- c a n c er t h er a p y, i ncl u di n g i n v esti g ati o n al 
a g e nts,  w hil e  o n st u d y tr e at m e nt.   P ati e nts  m a y  c o nti n u e t h e  us e  of  bis p h os p h o n at es f or  b o n e 
dis e as e  a n d  c orti c ost er oi ds f or t h e s y m pt o m ati c  c o ntr ol  of  br ai n  m et ast as es  pr o vi d e d t h e  d os e is 
st a bl e  b ef or e  a n d  d uri n g t h e st u d y  a n d t h e y  w er e  st art e d  at l e ast  4  w e e ks  pri or t o  b e gi n ni n g st u d y 
tr e at m e nt.  F ull  d et ails  of  all  of t h es e tr e at me nts  ar e r e c or d e d i n t h e  p ati e nt’s  n ot es  a n d 
a p pr o pri at e s e cti o n  of t h e  e C R F 
 
5. 5  
C rit e ri a f o r  T a ki n g  a  P a rti c i p a nt  Off  P r ot o c ol  T h e r 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 e s p o ns e,  e vi d e n c e  of  dis e as e  pr o 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 nt(s),  tr e at m e nt  m a y  c o nti n u e 
u ntil  o n e  of t h e f oll o wi n g  crit eri a  a p pli es: 
 
o   Dis e as e  pr o gr essi o n 
o   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 m e nt 
o   U n a c c e pt a bl e  a d v ers e  e v e nt(s)  d es pit e  d os e-r e d u cti o n. 
o   P arti ci p a nt  d e ci d es t o  wit h dr a w  fr o m t h e  pr ot o c ol t h er a p y 
o   G e n er al  or s p e cifi c  c h a n g es i n t h e  p arti ci p a nt's  c o n diti o n r e n d er t h e  p arti ci p a nt 
u n a c c e pt a bl e f or f urt h er tr e at m e nt i n t h e  j u d g m e nt  of t h e tr e ati n g i n v esti g at or 
 
P arti ci p a nts  will  b e r e m o v e d fr o m t h e  pr ot o c ol t h er a p y  w h e n  a n y  of t h es e  crit eri a  a p pl y.   T h e 
r e as o n f or r e m o v al fr o m  pr ot o c ol t h er a p y,  a n d t he  d at e t h e  p arti ci p a nt  w as r e m o v e d,  m ust  b e 
d o c u m e nt e d i n t h e  c as e r e p ort f or m ( C R F).  Alt er n ati v e  c ar e  o pti o ns  will  b e  dis c uss e d  wit h t h e 
p arti ci p a nt. 
 
A  Q A C T  Tr e at m e nt  E n d e d/ Off  St u d y  F or m  will  b e fill e d  o ut  w h e n  a  p arti ci p a nt is r e m o v e d fr o m 
pr ot o c ol t h er a p y.  T his f or m  c a n  b e f o u n d  o n  t h e  Q A C T  w e bsit e  or  o bt ai n e d fr o m t h e  Q A C T 
r e gistr ati o n st aff. 


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I n t h e  e v e nt  of  u n us u al  or lif e-t hr e at e ni n g  c o m pli c ati o ns, tr e ati n g i n v esti g at ors  m ust i m m e di at el y 
n otif y t h e  O v er all  PI,  Gr e g or y  M.  C ot e  M D  P h D  at 
.  
 
 
5. 6  
D u r 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  e v er y  6  m o nt hs  +/ -  1  m o nt h  aft er r e m o v al fr o m  pr ot o c ol t h er a p y 
u ntil  d e at h f or  o v er all s ur vi v al f or  2  y e ars  aft e r  dis c o nti n ui n g st u d y  dr u g(s).  T his  m a y i n cl u d e 
offi c e  visits  or  p h o n e  c all i n q uiri es if t h e  p ati e nt is  n ot  a v ail a bl e.  P arti ci p a nts r e m o v e d fr o m 
pr ot o c ol t h er a p y f or  u n a c c e pt a bl e  a d v ers e  e v e nt(s)  will  b e f oll o w e d  u ntil r es ol uti o n  or 
st a bili z ati o n  of t h e  a d v ers e  e v e nt  a n d/ or  d e at h. 
 
5. 7  
C rit e ri a f o r  T a ki n g  a  P a rti ci p a nt  Off  St u d y 
 
P arti ci p a nts  will  b e r e m o v e d fr o m st u d y  w h e n  a n y  of t h e f oll o wi n g  crit eri a  a p pl y: 
   L ost t o f oll o w- u p 
   Wit h dr a w al  of  c o ns e nt f or  d at a s u b missi o n 
   D e at h 
 
T h e r e as o n f or t a ki n g  a  p arti ci p a nt  off st u d y,  a n d t h e  d at e t h e  p arti ci p a nt  w as r e m o v e d,  m ust  b e 
d o c u m e nt e d i n t h e  c as e r e p ort f or m ( C R F). 
 
A  Q A C T  Tr e at m e nt  E n d e d/ Off  St u d y  F or m  will  b e fill e d  o ut  w h e n   a  p arti ci p a nt  c o m es  off st u d y. 
T his f or m  c a n  b e f o u n d  o n t h e  Q A C T  w e bsit e  or  o bt ai n e d fr o m t h e  Q A C T r e gistr ati o n st aff.  
 
 
6.  C RI T E RI A  F O R  T R E A T M E N T  C O N TI N U A TI O N  A N D  D O SI N G  D E L A Y S/ D O S E  M O DI FI C A TI O N S 
 
Crit eri a f or tr e at m e nt  c o nti n u ati o n  a n d  d os e  d el a ys  a n d  m o difi c ati o ns  will  b e  m a d e  as i n di c at e d 
i n t h e f oll o wi n g t a bl e(s).  D osi n g  c a n  b e r e d u c e d b as e d  o n t h e  cli ni c al j u d g m e nt  of t h e tr e ati n g 
i n v esti g at or if it is t h o u ght t o  b e i n t h e i nt er est   of t h e  p ati e nt.    
 
T h e  d es cri pti o ns  a n d  gr a di n g s c al es f o u n d i n  t h e r e vis e d  N CI  C o m m o n  T er mi n ol o g y  Crit eri a f or 
A d v ers e  E v e nts ( C T C A E)  v ersi o n  4. 0  will  b e  uti li z e d f or  d os e  d el a ys  a n d  d os e  m o difi c ati o ns.  A 
c o p y  of t h e  C T C A E  v ersi o n  4. 0 3  c a n  b e  d o w nl o a d e d fr o m t h e  C T E P  w e bsit e 
 htt p:// ct e p. c a n c er. g o v/ pr ot o c ol D e v el o p m e nt/ el e ctr o ni c  a p pli c ati o ns/ ct c. ht m .  
 
 
6. 1  
St r at u m  A  D a y  1( c y cl es  2- 6)  a n d  St r at u m  B  D a y  1 ( c y cl e  2  a n d  b e y o n d):  C rit e ri a f o r  T r e at m e nt 
C o nti n u ati o n 
   E C O G       
         
P S  <   1 
   a bs ol ut e  n e utr o p hil  c o u nt   
≥   1, 5 0 0/ m c L 
   H b     
≥   9  g/ d L (tr a nsf usi o n is  p er mitt e d) 
   pl at el ets  
≥   1 0 0, 0 0 0/ m c L (tr a nsf usi o n is  n ot  p er mitt e d) 
   t ot al  bilir u bi n    
<   1. 5 X  U L N  


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3 0 
   A S T/ A L T      
        
  
≤   3  X i nstit uti o n al  u p p er li mit  of  n or m al 
   Al b u mi n
  >   3. 0  g/ dl 
   cr e ati ni n e
  <   1. 5 X  U L N 
   C P K   <   Gr a d e  1 
   Ot h er  n o n- h e m at ol o gi c,  cli ni c all y si g nifi c a nt,  dr u g-r el at e d  A E’s  <   Gr a d e  1 
   If t h e  a b o v e  crit eri a  ar e  n ot  m et  o n  d a y  1  of  a n y f oll o wi n g tr e at m e nt  c y cl e, r e g ar dl ess  of 
t h e r e as o n, r e- ass ess m e nt f or tr e at m e nt  c o ntin u ati o n  eli gi bilit y  will  b e  p erf or m e d  e v er y 
4 8- 7 2  h o urs  at t h e  dis cr eti o n  of t h e tr e ati n g i n v e sti g at or.   Tr e at m e nt  will  b e  d el a y e d  u p t o 
a  m a xi m u m  of t hr e e  w e e ks  b e y o n d its  d u e  d at e  u ntil  a p pr o pri at e r e c o v er y.   P ati e nts  n ot 
m e eti n g r e-tr e at m e nt  crit eri a  aft er  a  m a xi m u m  of t hr e e- w e e k  d el a y  will  b e  wit h dr a w n 
fr o m t h e st u d y.   E x c e pti o ns  ar e  p er mitt e d i n t he  c as e  of  o bj e cti v e  cli ni c al  b e n efit  u p o n t h e 
a gr e e m e nt  of t h e  o v er all  PI.   
   S e e s e cti o n  6. 4  T a bl e  1 f or  d os e  m o difi c at i o n f or  h e m at ol o gi c  a n d  n o n- h e m at ol o gi c 
t o xi citi es.   
   D el a ys f or  n o n- cli ni c al r e as o ns  O R  n ot  cli ni c all y si g nifi c a nt  A Es  w h i c h  ar e  u nr el at e d  or 
u nli k el y r el at e d,  will  b e  p er mitt e d  u p o n  a gr e e m e nt  wit h t h e  o v er all  PI. 
6. 2  
St r at u m  B  D a y  8 ( C y cl e  1  a n d s u bs e q u e nt  c y cl es):  C rit e ri a f o r  T r e at m e nt  C o nti n u ati o n,  
   E C O G       
         
P S  <   2 
   a bs ol ut e  n e utr o p hil  c o u nt   
≥   1, 0 0 0/ m c L 
   H b     
≥   8  g/ d L (tr a nsf usi o n is  p er mitt e d) 
   pl at el ets  
≥   7 5, 0 0 0/ m c L (tr a nsf usi o n is  n ot  p er mitt e d) 
   t ot al  bilir u bi n    
<   1. 5 X  U L N  
   A S T/ A L T      
        
  
≤   5  X i nstit uti o n al  u p p er li mit  of  n or m al  
 ( < 
gr a d e  2  b y  C T C A E 4) 
   cr e ati ni n e
  <   1. 5 X  U L N  
   Al b u mi n
  >   3. 0  g/ dl 
   C P K    
<   Gr a d e  1 
   Ot h er  n o n- h e m at ol o gi c,  cli ni c all y si g nifi c a nt,  dr u g-r el at e d  A E’s  <   Gr a d e  2 
   If t h e  a b o v e  crit eri a  ar e  n ot  m et  o n  d a y  8, t he  p ati e nt s h o ul d  b e r e ass ess e d f or  eli gi bilit y 
wit hi n  7 2  h o urs. If  at t his  p oi nt t h e  p ati e nt still  d o es  n ot  m e et tr e at m e nt  crit eri a, 
r e g ar dl ess  of t h e r e as o n, t h e  p ati e nt  will n ot r e c ei v e t h e  d a y  8 i nf usi o n  a n d r es u m e 
tr e at m e nt  wit h  d os e r e d u cti o n  o n s c h e d ul e f or t h e s u bs e q u e nt  c y cl e  d a y  1  pr o vi d e d 
tr e at m e nt  crit eri a i n s e cti o n  6. 1  ar e  m et.   D a y  8 tr e at m e nt  d el a ys  will  n ot  c h a n g e t h e  n e xt 
c y cl e  d a y  1 s c h e d ul e,  pr o vi d e d t h e tr e at m e nt  crit eri a i n s e cti o n  6. 1  ar e  m et.  
   S e e s e cti o n  6. 4  T a bl e  1 f or  d os e  m o difi c at i o n f or  h e m at ol o gi c  a n d  n o n- h e m at ol o gi c 
t o xi citi es.   
   D el a ys f or  n o n- cli ni c al r e as o ns  O R  n ot  cli ni c all y si g nifi c a nt  A Es  w h i c h  ar e  u nr el at e d  or 
u nli k el y r el at e d,  will  b e  p er mitt e d  u p o n  a gr e e m e nt  wit h t h e  o v er all  PI.  
 
 
6. 3  
St r at u m  C,  o r  St r at a  A  a n d  B if  o n  P M 0 1 1 8 3  M o n ot h e r a p y  at  a n y  p oi nt,  D a y  1:  C rit e ri a f o r 
T r e at m e nt  C o nti n u ati o n 
   E C O G       
         
P S  <   1 
   a bs ol ut e  n e utr o p hil  c o u nt   
≥   1, 5 0 0/ m c L 
   H b     
≥   9  g/ d L (tr a nsf usi o n is  p er mitt e d) 


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V ersi o n  D at e: 2/ 5/ 2 0 1 6 
 
3 1 
   pl at el ets  
≥   1 0 0, 0 0 0/ m c L (tr a nsf usi o n is  n ot  p er mitt e d) 
   t ot al  bilir u bi n     
<  1. 5 X  U L N  
   A S T/ A L T      
        
  
≤   3  X i nstit uti o n al  u p p er li mit  of  n or m al 
   cr e ati ni n e
  <   1. 5 X  U L N 
   Al b u mi n
  >   3. 0  g/ dl 
   C P K    
<   Gr a d e  1 
   Ot h er  n o n- h e m at ol o gi c,  cli ni c all y si g nifi c a nt,  dr u g-r el at e d  A E’s  <   Gr a d e  2 
   If t h e  a b o v e  crit eri a  ar e  n ot  m et  o n  d a y  1  of  a n y f oll o wi n g tr e at m e nt  c y cl e, r e g ar dl ess  of 
t h e r e as o n, r e- ass ess m e nt f or tr e at m e nt  c o ntin u ati o n  eli gi bilit y  will  b e  p erf or m e d  e v er y 
4 8- 7 2  h o urs  at t h e  dis cr eti o n  of t h e tr e ati n g i n v e sti g at or.   Tr e at m e nt  will  b e  d el a y e d  u p t o 
a  m a xi m u m  of t hr e e  w e e ks  b e y o n d its  d u e  d at e  u ntil  a p pr o pri at e r e c o v er y.   P ati e nts  n ot 
m e eti n g r e-tr e at m e nt  crit eri a  aft er  a  m a xi m u m  of t hr e e- w e e k  d el a y  will  b e  wit h dr a w n 
fr o m t h e st u d y.   E x c e pti o ns  ar e  p er mitt e d i n t he  c as e  of  o bj e cti v e  cli ni c al  b e n efit  u p o n t h e 
a gr e e m e nt  of t h e  o v er all  PI.   
   S e e s e cti o n  6. 4  T a bl e  1 f or  d os e  m o difi c at i o n f or  h e m at ol o gi c  a n d  n o n- h e m at ol o gi c. 
   D el a ys f or  n o n- cli ni c al r e as o ns  O R  n ot  cli ni c all y si g nifi c a nt  A Es  w h i c h  ar e  u nr el at e d  or 
u nli k el y r el at e d,  will  b e  p er mitt e d  u p o n  a gr e e m e nt  wit h t h e  o v er all  PI.  
 
 
6. 4  
D os e  M o difi c ati o n 
 
N o n- h e m at ol o gi c t o xi citi es:  
   F or  a n y  c y cl e  d a y  1  d el a y l asti n g  m or e t h a n  o n e  w e e k,  or str at a  B  d a y  8  d el a y l asti n g 
m or e t h a n  7 2  h o urs,  d u e t o tr e at m e nt-r e l at e d t o xi cit y  d os e r e d u cti o n  m ust  b e 
i m pl e m e nt e d  a c c or di n g t o t h e str at e g y  b el o w i n  T a bl e  1. 
   F or  a n y tr e at m e nt-r el at e d,  cli ni c al si g nifi c a nt,  n o n- h e m at ol o gi c  gr a d e  > 3 t o xi cit y,  d os e 
r e d u cti o n  m ust  b e i m pl e m e nt e d  a c c or di n g t o t h e str at e g y i n  T a bl e  1. 
 
H e m at ol o gi c t o xi citi es:  
   F or  a n y  c y cl e  d a y  1  d el a y l asti n g  m or e t h a n  o n e  w e e k,  or str at u m  B  d a y  8  d el a y 
l asti n g  m or e t h a n  7 2  h o urs,  d u e t o  a tre at m e nt-r el at e d  h e m at ol o gi c t o xi cit y,  d os e 
r e d u cti o n  m ust  b e i m pl e m e nt e d 
   N e utr o p e ni a: 
o   As y m pt o m ati c  gr a d e  4  n e utr o p e ni a: t h e i n v esti g at or  m a y  eit h er  a d d  G C S F 
pr o p h yl a xis  p er i nstit uti o n  st a n d ar ds  or  d os e-r e d u c e  a c c or di n g t o  T a bl e  1.  
o   F e bril e  N e utr o p e ni a: r e q uir es  d os e r e d u cti o n  a c c or di n g t o  T a bl e  1  a n d  at 
t h e i n v esti g at or’s  dis cr eti o n G C S F  pr o p h yl a xis  m a y  b e  a d d e d  
   Ot h er tr e at m e nt-r el at e d,  cli n i c all y si g nifi c a nt,  Gr a d e  4  h e m at ol o gi c t o xi citi es  or 
Gr a d e  3 t hr o m b o c yt o p e ni a  wit h  c li ni c all y si g nifi c a nt  bl e e di n g: 
o   D os e r e d u cti o n is r e q uir e d  a c c or di n g t o  T a bl e  1 
 
 
 
T A B L E  1.  D os e  M o difi c ati o n  G ui d eli n es 
 
  


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V ersi o n  D at e: 2/ 5/ 2 0 1 6 
 
3 2 
  
P M 0 1 1 8 3   
P M 0 1 1 8 3  a n d  D o x or u bi ci n  
P M 0 1 1 8 3  a n d  G e m cit a bi n e  
  
  
P M 0 1 1 8 3  
D o x or u bi ci n  
P M 0 1 1 8 3  
G e m cit a bi n e  
I niti al D os e  
3. 2  m g/ m²   
2  m g/ m²  
5 0  m g/ m²  
1. 6  m g/ m²  
8 0 0  m g/ m²  
1 st D os e  R e d u cti o n  
2. 6  m g/ m²  
2  m g/ m²  
4 0  m g/ m²  
1  m g/ m²  
8 0 0  m g/ m²  
2 n d D os e  R e d u cti o n  
2  m g/ m²  
1. 2 5  m g/ m²  
4 0  m g/ m²  
1  m g/ m²  
6 0 0  m g/ m²  
 
  
 
   T w o  d os e r e d u cti o ns  ar e  all o w e d  p er  p a ti e nt f or t h e  d ur ati o n  of tr e at m e nt 
   N o  d os e  es c al ati o ns  ar e  all o w e d   
   If i n  Str at a  A  or  B  a  p arti ci p a nt  d e v el o ps  a s p e cifi c t o xi cit y  or i nt ol er a n c e f elt t o  b e 
r el at e d t o  d o x or u bi ci n  or t o  g e m cit a bi n e, t h e  p arti ci p a nt  m a y  c o nti n u e  o n si n gl e  a g e nt 
P M 0 1 1 8 3,  pr o vi d e d  ot h er tr e at m e nt  crit eri a  ar e  m et.  Crit eri a f or  Tr e at m e nt  C o nti n u ati o n 
i n t h es e  p ati e nts s h o ul d s u bs e q u e ntl y  b e f oll o w e d  a c c or di n g t o  Str at u m  C.  T h e  p ati e nt 
s h o ul d r e c ei v e t h e  Str at u m  C  P M 0 1 1 8 3  d os e l e v el  t h at  c orr el at es  wit h t h e  pr e vi o us  d os e 
l e v el  of  Str at a  A  or  B.   F or  e x a m pl e if t h e  p arti ci p a nt  c o m pl et es  6  c y cl es  of  d o x or u bi ci n 
at t h e  1 st  d os e r e d u cti o n l e v el  or st o ps  d o x or u bi ci n  at t h e  1 st  d os e r e d u cti o n l e v el t h e y 
s h o ul d st art  P M 0 1 1 8 3  m o n ot h er a p y  at t h e  1 st  d os e r e d u cti o n l e v el  of  Str at u m  C ( e. g  2. 6 
m g/ m 2)  
   Tr e at m e nt  d el a y is  p er mitt e d  u p t o  a  m a xi m u m  of t hr e e  w e e ks  b e y o n d  its  d u e  d at e  u ntil 
a p pr o pri at e r e c o v er y  of  A E’s list e d i n s e ct i o ns  6. 1,  6. 2  a n d  6. 3.   P ati e nts  n ot  m e eti n g r e-
tr e at m e nt  crit eri a  aft er  a  m a xim u m  of t hr e e- w e e k  d el a y  will  b e  wit h dr a w n fr o m t h e st u d y.  
E x c e pti o ns  ar e  p er mitt e d i n t h e  c as e  of  o bj e c ti v e  cli ni c al  b e n efit  u p o n t h e  a gr e e m e nt  of 
t h e  o v er all  PI.  
   D el a ys f or  n o n- cli ni c al r e as o ns  O R  n ot  cli ni c all y si g nifi c a nt  A Es  w h i c h  ar e  u nr el at e d  or 
u nli k el y r el at e d,  will  b e  p er mitt e d  u p o n  a gr e e m e nt  wit h t h e  o v er all  PI.  
 
7.  A D V E R S E  E V E N T S  R E P O R TI N G  R E Q UI R E M E N T S:  
 
7. 1  
D efi niti o ns  
7. 1. 1  A d v ers e  E v e nt ( A E) 
 
A n  A E is  a n y  u nt o w ar d  m e di c al  o c c urr e n c e i n  a  p ati e nt  or  cli ni c al  i n v esti g ati o n  p ati e nt 
a d mi nist er e d  a  p h ar m a c e uti c al  pr o d u ct  w hi c h  d o es   n ot  n e c ess aril y  h a v e  a  c a us al r el ati o ns hi p 
wit h t his tr e at m e nt.  
 
A n  A E  c a n t h er ef or e  b e  a n y  u nf a v or a bl e  a n d  u ni nt e n d e d si g n, ( e. g.,  a n  a b n or m al l a b or at or y 
fi n di n g),  or  a  dis e as e t e m p or all y ass o ci at e d  wit h t h e  us e  of  a  m e di ci n al  pr o d u ct,  w h et h er  or  n ot 
c o nsi d er e d r el at e d t o t h e  m e di ci n al  pr o d u ct. 
 
Ill n ess es  wit h  o ns et  d uri n g t h e st u d y  or  e x a c er b ati o ns  of  pr e- e xisti n g ill n ess es, i n cl u di n g  b ut  n ot 


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3 3 
li mit e d t o  cli ni c all y si g nifi c a nt  c h a n g es i n  p h ysi c al  e x a mi n ati o n fi n di n gs  a n d  a b n or m al  o bj e cti v e 
t ests/ pr o c e d ur es fi n di n gs ( e. g., X-r a y,  E C G) s h o ul d  b e r e c or d e d.  T h e  crit eri a f or  d et er mi ni n g 
w h et h er  a n  a b n or m al  o bj e cti v e t est fi n di n g s h o ul d  b e r e p ort e d  as  a n  A E  ar e  as f oll o ws: 
   T h e t est r es ult is  ass o ci at e d  wit h  cl i ni c all y si g nifi c a nt s y m pt o ms,  a n d/ or 
   T h e t est r es ult l e a ds t o  a  c h a n g e i n t h e st u d y  d osi n g  or  dis c o nti n u ati o n fr o m t h e  cli ni c al 
tri al, si g nifi c a nt  a d diti o n al  c o n c o mit a nt dr u g tr e at m e nt  or  ot h er t h er a p y,  a n d/ or 
   T h e t est r es ult l e a ds t o  a n y  of t h e  o ut c o m e s i n cl u d e d i n t h e  d efi niti o n  of  a  S A E (s e e 
d efi niti o n  b el o w),  a n d/ or 
   T h e t est r es ult is  c o nsi d er e d t o  b e  c li ni c all y r el e v a nt  b y t h e I n v esti g at or. 
 
“ Dis e as e  pr o gr essi o n ”  will  n ot  b e r e p ort e d  as  a n  A E ,  as t his i nf or m ati o n  will  b e  us e d f or  effi c a c y 
ass ess m e nt. 
 
7. 1. 2  
S eri o us  A d v ers e  E v e nt ( S A E) 
 
A  S A E is  a n y  a d v ers e  e x p eri e n c e  o c c urri n g  at  a n y  d os e t h at: 
   R es ults i n  d e at h (is f at al), 
   Is lif e-t hr e at e ni n g, 
   R e q uir es  or  pr ol o n gs i n p a ti e nt  h os pit ali z ati o n, 
   R es ults i n  p ersist e nt  or si g nifi c a nt  dis a bilit y  or i n c a p a cit y, 
   Is  a  c o n g e nit al  a n o m aly  or  birt h  d ef e ct,  
   Is  m e di c all y si g nifi c a nt,  or 
   Is  a n y s us p e ct e d tr a ns missi o n  of  a n i nfe cti o us  a g e nt  vi a  a  m e di ci n al  pr o d u ct.  
 
M e di c al  a n d s ci e ntifi c j u d g m e nt s h o ul d  b e  e x er cis e d i n  d e ci di n g  m e di c all y si g nifi c a nt  e v e nts; 
t his  crit eri o n s h o ul d  b e  a p pli e d t o  A Es t h at  m a y n ot  b e i m m e di at el y lif e-t hr e at e ni n g  or r es ult i n 
h os pit ali z ati o n  b ut  m a y j e o p ar di z e  t h e  p ati e nt  or  m a y r e q uir e i nt er v e nti o n t o  pr e v e nt  o n e  of t h e 
o ut c o m es list e d i n t h e  a b o v e  d efi niti o n. 
“ Dis e as e  pr o gr essi o n ”  as  a t er m  w ill  n ot  b e r e p ort e d  as  a  S A E. 
 
7. 1. 3  
D e at h  
 
D e at h  as s u c h is t h e  o ut c o m e  of  a  S A E  a n d s h o ul d  n ot  b e  us e d  as t h e  S A E t er m its elf.  T h e  c a us e 
of  d e at h s h o ul d  b e r e c or d e d  as t h e  S A E t er m i nst e a d.  W h e n  a v ail a bl e, t h e  a ut o ps y r e p ort  will  b e 
pr o vi d e d t o t h e  S p o ns or. 
Gr a d e  5 s h o ul d  b e  us e d f or  e v e nts  w hi c h l e a d  i m m e di at el y  a n d  dir e ctl y t o  d e at h,  a n d  gr a d e  4 
s h o ul d  b e  us e d  wit h  o ut c o m e  d e at h f or  e v e nts  w h i c h l e a d t o  d e at h  aft er a l o n g er ti m e  p eri o d,  a n d 
t h at  m a y  als o  b e li n k e d t o  a d diti o n al  m or bi diti es. 
 
7. 1. 4  
Lif e-t hr e at e ni n g  E v e nt 
 
A n y  e v e nt i n  w hi c h t h e  p ati e nt  w as  at ris k  of  d e at h  at t h e ti m e  of t h e  e v e nt is  c o nsi d er e d lif e-
t hr e at e ni n g; it  d o es  n ot r ef er t o  a n  e v e nt  w hi c h h y p ot h eti c all y  mi g ht  h a v e  c a us e d  d e at h if it  w er e 
m or e s e v er e. 
 


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3 4 
7. 1. 5  
H os pit ali z ati o n  or  Pr ol o n g ati o n  of  H os pit ali z ati o n  
 
A n y  A E r e q uiri n g  h os pit ali z ati o n  ( or  pr ol o n g ati o n  of  h os pit ali z ati on) t h at  o c c urs  or  w ors e ns 
d uri n g t h e  c o urs e  of  a  p ati e nt’s  p arti ci p ati o n i n  a  cli ni c al tri al  m ust  b e r e p ort e d  as  a  S A E  u nl ess 
e x e m pt e d fr o m  S A E r e p orti n g.  Pr ol o n g ati o n  of  h os p it ali z ati o n is  d efi n e d  as  a n y  e xt e nsi o n  of  a n 
i n p ati e nt  h os pit ali z ati o n  b e y o n d t he st a y  a nti ci p at e d/r e q uir e d  f or t h e i niti al  a d missi o n,  as 
d et er mi n e d  b y t h e I n v esti g at or  or tr e ati n g  p h ysi ci a n. 
 
H os pit ali z ati o ns t h at  d o  n ot  m e et  crit eri a f or  S A E r e p orti n g  ar e:  
a.   R e as o ns  d es cri b e d i n  pr ot o c ol [ e. g., i n v esti g ati o n al  m e di ci n al  pr o d u ct (I M P) 
a d mi nistr ati o n,  pr ot o c ol-r e q uir e d i nt er v e n ti o n/i n v esti g ati o ns,  et c.].  H o w e v er, 
e v e nts r e q uiri n g  h os pit ali z ati o ns  or  pr ol o n g a ti o n  of  h os pit ali z ati o n  as  a r es ult  of  a 
c o m pli c ati o n  of t h er a p y  a d mi nistr ati o n  or  cl i ni c al tri al  pr o c e d ures  will  b e r e p ort e d 
as  S A Es. 
b.   H os pit ali z ati o n  or  pr ol o n g e d  h os pit ali z ati o n f or t e c h ni c al,  pr a cti c al  or s o ci al 
r e as o ns, i n  a bs e n c e  of  a n  A E. 
c.   Pr e- pl a n n e d  h os pit ali z ati o ns:  a n y  pr e- pl a n n e d s ur g er y  or  pr o c e d ur e  m ust  b e 
d o c u m e nt e d i n t h e s o ur c e  d o c u m e nt ati o n.  O nl y if t h e  pr e- pl a n n e d s ur g er y  n e e ds 
t o  b e  p erf or m e d  e arli er  d u e t o  a  w ors e ni n g  of t h e  c o n diti o n, s h o ul d t his  e v e nt 
( w ors e n e d  c o n diti o n)  b e r e p ort e d  as  a  S A E.  
 
Ot h er sit u ati o ns t h at  M U S T  N O T  b e  c o nsi d er e d  as  h os pit ali z ati o ns  ar e t h e f oll o wi n g: 
d.   A n  e m er g e n c y  visit  d u e t o  a n  a c ci d e nt  w h er e t h e  p ati e nt is tr e at e d  a n d  dis c h ar g e d. 
e.   W h e n t h e  p ati e nt is  h el d  2 4  h o urs f or  o bs er v ati o n  a n d fi n all y is  n ot  a d mitt e d. 
f.  Pl a n n e d tr e at m e nts  at sit es  n ot  ass o ci at e d  t o  a  h os pit al  a n d  g e n er all y  c o nsi d er e d  as 
mi n or s ur gi c al  pr o c e d ur es (i. e., l as e r  e y e s ur g er y,  art hr os c o p y,  et c.). 
 
7. 1. 6  
U nlist e d/ U n e x p e ct e d  A d v ers e  E v e nt  
 
A n  A E, t h e  n at ur e  or s e v erit y  of  w hi c h is  n ot  c o nsist e nt  wit h t h e  a p pli c a bl e r ef er e n c e s af et y 
i nf or m ati o n. 
T h e  S p o ns or  a n d t h e  S p o ns or  d esi g n e e  will  us e  as t h e r ef er e n c e s af et y i nf or m ati o n f or t h e 
e v al u ati o n  of list e d n ess/ e x p e ct e d n ess t h e I B f o r l ur bi n e ct e di n ( P M 0 1 1 8 3)  a n d t h e  S u m m ar y  of 
Pr o d u ct  C h ar a ct eristi cs ( S m P C)  f or  d o x or u bi ci n  a n d  g e m cit a bi n e  as  d es cri b e d i n t h e  F D A 
p a c k a g e i ns ert. 
 
7. 1. 7  
A d v ers e  R e a cti o ns 
 
All  u nt o w ar d  a n d  u ni nt e n d e d r es p o n s es t o  a n i n v esti g ati o n al  m e di ci n al  pr o d u ct r el at e d t o  a n y 
d os e  a d mi nist er e d.  T his  d efi niti o n  c o v ers  als o  m e di c at i o n  err ors  a n d  us es  o utsi d e  w h at is 
f or es e e n i n t h e  pr ot o c ol, i n cl u di n g  o v er d os e, l a c k  of  effi c a c y,  mis us e  a n d  a b us e  of t h e  pr o d u ct. 
 
7. 1. 8  
A d v ers e  E v e nts  R el at e d t o t h e  St u d y  Dr u g 
 
A n  A E is  c o nsi d er e d r el at e d t o  a st u d y  dr u g/ I M P if t h e I n v esti g at or’s  ass ess m e nt  of  c a us al 
r el ati o ns hi p t o t h e I M P(s) is “ Y ( y es) ” (s e e  S e cti o n  7. 1. 1 0).  
 


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T h e I n v esti g at or  will  ass ess t h e  c a us al r e l ati o ns hi p  of t h e I M P(s) t o t h e  S A E. 
 
T h e  S p o ns or  m a y  als o  c o nsi d er r el at e d t o t h e  st u d y  dr u g(s)/I M P(s) t h os e  e v e nts f or  w hi c h t h e 
I n v esti g at or  ass ess es t h e  c a us al r el ati o ns hi p  wit h t h e I M P(s)  as  “ U k ( u n k n o w n) ”  w h e n it  c a n n ot 
r ul e  o ut  a r ol e  of t h e I M P(s) i n t h e  e v e nt. 
 
7. 1. 9  
E x p e dit e d  R e p orti n g 
 
T h e  S p o ns or is r es p o nsi bl e f or t h e  a p pr o pri at e  e x p e dit e d r e p orti n g  a c c or di n g t o t h e  a p pli c a bl e 
l e gisl ati o n. 
 
7. 1. 1 0  Ass ess m e nt  of  C a us al  R el ati o ns hi p t o t h e  St u d y  Dr u g 
 
T h e I n v esti g at or  m ust  pr o vi d e  a n  ass ess m e nt  of t h e  c a us al r el ati o ns hi p  of  e a c h  S A E t o t h e 
cli ni c al tri al I M P(s)  a c c or d i n g t o t h e f oll o wi n g s c al e: 
Y      T h er e is  a r e as o n a bl e  p ossi bilit y t h at t h e I M P(s)  c a us e d t h e  S A E. 
N      T h er e is  n o r e as o n a bl e  p ossi bilit y t h at t h e I M P(s)  c a us e d t h e  S A E  a n d  ot h er 
c a us es  ar e  m or e  pr o b a bl e. 
U k    ( U n k n o w n).  O nl y t o  b e  us e d i n s p e ci al sit u ati o ns  w h er e t h e I n v esti g at or  h as 
i ns uffi ci e nt i nf or m ati o n (i. e., t h e  p ati e nt  w as  n ot s e e n  at  his/ h er  c e nt er) if  n o n e  of 
t h e  a b o v e  c a n  b e  us e d. 
 
7. 2  A d v e rs e  E v e nts  R e p o rti n g  P r o c e d u r es 
7. 2. 1  
R e p orti n g  A d v ers e  E v e nts 
 
T h e  S p o ns or  will  c oll e ct  A Es  u ntil  3 0  d a ys  af t er  a d mi nistr ati o n  of t h e l ast  d os e  of st u d y 
dr u g(s)/I M P(s)  or  u ntil t h e st art  of  a  n e w  a ntit u m o r t h er a p y  or  u ntil t h e  d at e  of  d e at h,  w hi c h e v er 
o c c urs first.  All  A Es s us p e ct e d t o   b e r el at e d t o t h e stu d y  dr u g/I M P  m ust  b e f oll o w e d- u p  aft er t h e 
ti m e  of t h er a p y  dis c o nti n u ati o n  u ntil t h e  e v e nt  or its s e q u el a e r es ol v e  or st a bili z e  at  a n  a c c e pt a bl e 
l e v el t o t h e I n v esti g at or  a n d t h e  S p o ns or. 
 
All  A Es, i n cl u di n g  mis us e,  o v er d os e  a n d  a b us e,  m ust  b e r e c or d e d i n  E n glis h  usi n g  m e di c al 
t er mi n ol o g y i n t h e s o ur c e  d o c u m e nt  a n d t h e  C R F.  W h e n e v er  p ossi bl e, t h e I n v esti g at or  will 
r e c or d t h e  m ai n  di a g n osis i nst e a d  of t h e si g ns  a nd s y m pt o ms  n or m all y i n cl u d e d i n t h e  di a g n os es.  
 
I n v esti g at ors  m ust  ass ess s e v erit y ( gr a d e)  of t h e  e v e nt f oll o wi n g t h e  N CI- C T C A E  v.  4  a n d  assi g n 
a r el ati o ns hi p t o  e a c h st u d y  dr u g(s)/I M P(s);  a n d  p urs u e  a n d  o bt ai n i nf or m ati o n  a d e q u at e  b ot h t o 
d et er mi n e t h e  o ut c o m e  a n d t o  ass ess  w h et h er it   m e ets t h e  crit eri a f or cl assifi c ati o n  as  a  S A E 
r e q uiri n g i m m e di at e  n otifi c ati o n t o t h e  S p o ns or  a n d t h e  S p o ns or  d esi g n e e.  T h e I n v esti g at or  m ust 
pr o vi d e  a n y r el e v a nt i nf or m ati o n  as r e q u est e d  b y  t h e  S p o ns or  or t h e  S p o ns or  d esi g n e e i n  a d diti o n 
t o t h at  o n t h e  C R F. 
 
A b n or m al l a b or at or y t ests  o c c urri n g  d uri n g t h e st u d y s h o ul d  o nl y  b e  r e c or d e d i n t h e  A E s e cti o n 
of t h e  C R F if t h e  dis or d er: 
  Is  ass o ci at e d  wit h  cli ni c all y si g nifi c a nt s y m pt o ms,  a n d/ or 
  L e a ds t o  a  c h a n g e i n st u d y  d osi n g  or  dis c o nti n u ati o n fr o m t h e st u d y, si g nifi c a nt 
a d diti o n al  c o n c o mit a nt  dr u g tr e at m e nt  or  ot h er t h er a p y,  a n d/ or 




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3 7 
 
T h er ef or e,  pr e g n a n c y  a n d s us p e ct e d  pr e g n a n c y (i n c l u di n g  a  p ositi v e  pr e g n a n c y t est r e g ar dl ess  of 
a g e  or  dis e as e st at e)  of  p ati e nt  o c c urri n g  w hil e t h e  p ati e nt is  o n  st u d y  dr u g,  or  wit hi n  3 0  d a ys 
aft er t h e  a d mi nistr ati o n  of  t h e l ast  d os e  of t h e st u d y  dr u g(s)/I M P(s),  ar e  c o nsi d er e d i m m e di at el y 
r e p ort a bl e  e v e nts.  B e y o n d t his ti m efr a m e, t h e i n v esti g at or  will r e p ort  a n y  pr e g n a n c y if t h er e is 
a n y s us pi ci o n t h at t h e st u d y  dr u g(s)/I M P(s)  mi g ht  h a v e  a n i m p a ct  o n t h e  o c c urr e n c e  of t h e 
pr e g n a n c y. 
 
T h e I n v esti g at or  will r e p ort t h e f oll o wi n g  e v e nts  i m m e di at el y  a n d  al w a ys  wit hi n  2 4  h o urs fr o m 
first  k n o wl e d g e: 
   A n y  o c c urr e n c e  of  a  pr e g n a n c y  w h er e  a n y  ki n d  of  e x p os ur e t o t h e I M P(s) is s us p e ct e d. 
   P ossi bl e  e x p os ur e  of  a  pr e g n a nt  w o m a n. 
   All r e p orts  of  el e v at e d/ q u esti o n a bl e  or i n d et er mi n at e  b et a  h u m a n  c h ori o ni c 
g o n a d otr o pi ns ( β - h C Gs). 
 
I m m e di at el y  aft er  d et e cti n g  a c as e  of s us p e ct e d  pr e g n a n c y i n   a  p ati e nt, t h e  d e cisi o n  o n  h er 
c o nti n u e d  p arti ci p ati o n i n t h e  cli ni c al tri al  will  b e j oi ntl y t a k e n  b y t h e  p ati e nt, t h e I n v esti g at or 
a n d t h e  S p o ns or,  wit h t h e  p ati e nt’s  b est i nt er e st i n  mi n d.  A  d e cisi o n t o  c o nti n u e t h e  pr e g n a n c y 
will r e q uir e i m m e di at e  wit h dr a w al fr o m t h e tri al.  
 
A n y  pr e g n a n c y, s us p e ct e d  pr e g n a n c y,  or  p ositi v e  pr e g n a n c y t est  m ust  b e  r e p ort e d t o t h e  S p o ns or 
a n d t h e  S p o ns or  d esi g n e e i m m e di at el y  usi n g t h e  Pr e g n a n c y  R e p ort f or m. 
 
T h e I n v esti g at or  will f oll o w t h e  pr e g n a n c y  u ntil its  o ut c o m e,  a n d  m ust  n otif y t h e  S p o ns or  a n d 
t h e  S p o ns or  d esi g n e e t h e  o ut c o m e  of t h e  pr e g n an c y  wit hi n  2 4  h o urs  of first  k n o wl e d g e  as  a 
f oll o w- u p t o t h e i niti al r e p ort. 
 
F or  a n y  e v e nt  d uri n g t h e  pr e g n a n c y  w hi c h  m e ets  a s eri o us n ess  crit eri o n (i n cl u di n g f et al  or 
n e o n at al  d e at h  or  c o n g e nit al  a n o m al y) t h e I n v e sti g at or  will  als o f oll o w t h e  pr o c e d ur es f or 
r e p orti n g  S A Es ( c o m pl et e  a n d s e n d t h e  S A E f or m t o t h e  S p o ns or  a n d t h e  S p o ns or  d esi g n e e 
wit hi n  2 4  h o urs  of t h e I n v esti g at or’s  k n o wl e d g e  of t h e  e v e nt).  
 
All  n e o n at al  d e at hs t h at  o c c ur  w it hi n  3 0  d a ys  of  birt h s h o ul d b e r e p ort e d,  wit h o ut r e g ar d t o 
c a us alit y,  as  S A Es. I n  a d diti o n,  a n y i nf a nt  d e at h  at  a n y ti m e t h er e aft er t h at t h e I n v esti g at or 
s us p e cts is r el at e d t o t h e  e x p os ur e t o t h e st u d y  dr u g(s)/I M P(s) s h o ul d  als o   b e r e p ort e d t o t h e 
S p o ns or  a n d t h e  S p o ns or  d esi g n e e  b y f a csi mil e  w it hi n  2 4  h o urs  of t h e I nv esti g at ors’  k n o wl e d g e 
of t h e  e v e nt. 
 
7. 3  A d v e rs e  E v e nts  M o nit o ri n g 
 
S af et y r e vi e w  will  b e  p erf or m e d  b y t h e  S p o ns or   d esi g n e e  o n c e  S A E f or ms  h a v e  b e e n r e c ei v e d 
a n d t h e  C R Fs  el e ctr o ni c all y  c o m pl et e d  b y t h e I n v esti g at or.  
 
At  e v er y  m o nit ori n g  visit  p erf or m e d  b y t h e  d esi g n e d   cli ni c al r es e ar c h  m o nit or i n  c h ar g e  of t h e 
st u d y, t h e  c o nsist e n c y  b et w e e n t h e  C R F/ S A E  d at a  r e p ort e d t o t h e  S p o ns or /  S p o ns or  d esi g n e e  
a n d t h e  p ati e nt's s o ur c e  d at a  will  b e r e vi e w e d.  W h e n  a  dis cr e p a n c y is  f o u n d  d uri n g t h e r e vi e w, 








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( S e e t h e  N CI I n v esti g at or’s  H a n d b o o k f or  Pro c e d ur es f or  Dr u g  A c c o u nt a bilit y  a n d 
St or a g e.) 
 
8. 1. 9  
D est r u cti o n  a n d  R et u r n 
All  u n us e d  dr u g s u p pli e d  b y t h e  P h ar m a M ar  will  b e  pr o p erl y  d estr o y e d  at t h e st u d y sit e. 
D o c u m e nt ati o n  of t his  pr o c e d ur e  m ust  b e  pr o vi d e d t o  P h ar m a M ar  b y t h e  cli ni c al tri al 
m o nit or.  
 
8. 2  
D o x o r u bi ci n 
 
8. 2. 1  
F or m:  D o x or u bi ci n is  a  c o m m er ci all y   a v ail a bl e  c h e m ot h er a p y  a g e nt.  
8. 2. 2  
St or a g e,  d os a g e f or m  a n d  pr e p ar ati o n  will  b e  a c c or di n g t o i nstit uti o n al st a n d ar ds.  
 
8. 3  
G e m cit a bi n e 
 
8. 3. 1  
F or m:  G e m cit a bi n e  H Cl is  a  c o m m er ci all y  a v ail a bl e  n u cl e osi d e  a n al o g t h at  e x hi bits  a ntit u m or  a cti vit y. 
8. 3. 2  
St or a g e,  d os a g e f or m  a n d  pr e p ar ati o n  w ill  b e  a c c or di n g t o i nstit uti o n al st a n d ar ds 
 
 
9.  S T U D Y  C A L E N D A R 
 
B as eli n e  e v al u ati o ns  ar e t o  b e  c o n d u ct e d  wit hi n  1 5  d a ys  pri or t o  c y cl e  1  d a y  1.   B as eli n e  C T 
s c a ns,  or  M RIs  or  x-r a ys  m ust  b e  d o n e  < 3 0  d a ys  pri or t o  c y cl e  1  d a y  1.  I n t h e  e v e nt t h at t h e 
p arti ci p a nt’s  c o n diti o n is  d et eri or ati n g, l a b or at or y  e v al u ati o ns s h o ul d  b e r e p e at e d  wit hi n  4 8  h o urs 
pri or t o i niti ati o n  of t h e  n e xt  c y cl e  of t h er a p y. 
 
Ass ess m e nts  m ust  b e  p erf or m e d  pri or t o  a d mi nistr ati o n  of  a n y st u d y  a g e nt.  St u d y  ass ess m e nts 
s h o ul d  b e  wit hi n  + 3  d a ys  of t h e  pr ot o c ol-s p e cifi e d  d at e ,  u nl ess  ot h er wis e  n ote d.  F or  all str at a, 
d a y  1  of  a  gi v e n  c y cl e  c a n st art - 1  t o  + 2  d a ys t o  all o w f or s c h e d uli n g.  F or  Str at u m  B,  D a y  8  of  a 
gi v e n  c y cl e  c a n st art  u p t o  + 2  d a ys l at e t o  all o w f or s c h e d uli n g. 
 
 


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Str at u m  A 
 
 
    
C y cl e  1 
C y cl es  2- 6 f 
C y cl es  7  a n d 
s u bs e q u e nt  c y cl es f 
 
 
Pr e- 
St u d y k 
W k 
1 
W k 
2 
W k 
3 
W k 
1 
W k 
2 
W k 
3 
W k 
1 
W k 
2 
W k 
3 
Off  St u d y c 
P M 0 1 1 8 3  
    
X 
  
    
    X 
        
    X 
  
    
    
 
D o x or u bi ci n 
 
    X 
  
  
  X 
  
  
  
  
  
  
 
I nf or m e d 
 
c o ns e nt 
    
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
D e m o gr a p hi cs 
    
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
M e di c al 
 
hist or y 
    
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
C o n c urr e nt  m e ds 
X    
X----------------------------------------------------------------------- X   
P h ysi c al  e x a m 
X    
X    
X   
    
X    
X i 
  X 
  
  
  X 
 
Vit al si g ns m 
X 
  X 
 X 
  
 X 
 X i 
  X 
  
  
  X 
 
H ei g ht 
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
W ei g ht 
 
X 
    X 
  
    
    X 
        
    X 
  
    
    X 
 
E C O G  P erf or m a n c e st at us    
X    
X   
   
    
X   
   
    
X   
   
    
X 
C B C  w/ diff,  plts d 
X 
  X 
 X  
X 
  X 
    X i 
X i  X 
    X
l  
Xl  X 
 
S er u m  c h e mistr y a,  d  X
 
X
 
X
  
 
X
 
 
  X 
 X
l  
    X 
 
Uri n al ysis
  X
 
  
  
  
 
 
  
  
  
  
 
P T,  a P T T 
X   
   
   
   
 
 
  
  
  
  
 
E C G ( as i n di c at e d) j 
X 
  
  
  
  
  
  
  
  
  
 
 
A d v ers e  e v e nt  e v al u ati o n   
    
X---------------------------------------------------------------------- X    X 
R a di ol o gi c  e v al u ati o n g 
X 
R e p e at e d  e v er y  6  w e e ks f or t h e fi rst  8  c y cl es  a n d t h e n  e v er y  9 
w e e ks t h er e aft er.   D o c u m e nt ati o n (r a di ol o gi c)  m ust  b e 
pr o vi d e d f or  p arti ci p a nts r e m o v e d fr o m st u d y f or  pr o gr essi v e 
dis e as e. 
 
Uri n e  or s er u m  pr e g n a n c y 
t esti n g 
X b  
  
  
  
  
  
  
  
  
  
  
 
R e vi e w  of  P at h ol o g y h 
X  
  
  
  
  
  
  
  
  
  
  
  
 
E c h o c ar di o gr a m  or  M U G A j 
X 
  
  
  
 X  
  
  
X 
  
  
X 
a:    
Al b u mi n,  al k ali n e  p h os p h at as e, t ot al  bilir u bi n,  bi c ar b o n at e,  B U N,  c al ci u m,  c hl ori d e,  cr e ati ni n e,  gl u c os e,  L D H, 
p h os p h or us,  p ot assi u m, t ot al  pr ot ei n,  S G O T  [ A S T],  S G P T [ A L T], s o di u m,  C P K. 
b:   
S er u m  or  uri n e  pr e g n a n c y t est ( w o m e n   of  c hil d b e ari n g  p ot e nti al).  M ust  b e r ep e at e d if  n ot  wit hi n  7  d a ys  of  c 1 d 1. 
c:    
Off-st u d y  e v al u ati o n t o  b e  c o m pl et e d  3 0  +  7  d a ys fr o m l ast st u d y  dr u g  d os e.   
d:      l a b or at or y t esti n g  c a n  b e  p erf or m e d  u p t o  4 8 h  pri o r t o s c h e d ul e d  visit ( e x cl u di n g s cr e e ni n g l a b or at or y t esti n g) 
f:       d a y  1  of  a  gi v e n  c y cl e  c a n st art - 1 t o  + 2  d a ys t o  all o w f or s c h e d uli n g 
g:      s c a n  wi n d o w is  +/-  7  d a ys 
h:       o nl y r e q uir e d f or  p ati e nts  wit h  p at h ol o g y  n ot  pr e vi o usl y  r e vi e w e d  at  D F CI,  B W H  or  M G H 
i:        d uri n g t h e  c o m bi n ati o n  of  d o x or u bi ci n  a n d  P M 0 1 1 8 3  d a y  8  a n d  d a y  1 5 ( +/-  3  d a ys)  C B C/ diff r e q uir e d f or  c y cl es 
1  a n d  2,  o pti o n al t h er e aft er.  D uri n g t h e  c o m bi n ati o n  of   d o x or u bi ci n  a n d  P M 0 1 1 8 3  d a y  8 ( +/-  3  d a ys)  vit al si g ns 
a n d  p h ysi c al  e x a m is r e q uir e d f or  c y cl es  1  a n d  2,  o pti o n al t h er e aft er.   Pl e as e s e e f o ot n ot e  L f or  P M 0 1 1 8 3 
m o n ot h er a p y. 
j:        2 8  d a ys  wi n d o w f or t h e  e c h o c ar di o gr a m  or  M U G A b ef or e tr e at m e nt  d a y  1;   E C G r e q uir e d  o nl y  as  cli ni c all y 
i n di c at e d;  L V  ej e cti o n fr a cti o n  ass ess m e nt will  b e r e p e at e d  b ef or e  c y cl e  4  a n d  b ef or e  c y cl e  7  a n d t h e n  at  e n d  of 
st u d y 


Pr ot o c ol  #: 1 5- 0 8 3 
V ersi o n  D at e: 2/ 5/ 2 0 1 6 
 
4 3 
k:      s cr e e ni n g  d at a t o  b e  o bt ai n e d  wit hi n  1 5   d a ys  of tr e at m e nt   d a y  1;  b as eli n e r a di ol o gi c al e v al u ati o ns  wit hi n  3 0  d a ys 
of tr e at m e nt  d a y  1 
l:     f or t h e first  c y cl e  aft er  d o x or u bi ci n is  dis c o nti n u ed ( P M 0 1 1 8 3  m o n ot h er a p y)  d a y  8  a n d  d a y  1 5 ( +/-  3  d a ys)  c b c/ dif 
is r e q uir e d  a n d  d a y  8 ( +/-  3  d a ys)  c h e mistri es  ar e r e q uir e d; t h es e l a b or at or y  v al u es  ar e  o pti o n al f or f urt h er  c y cl es 
m:   o n  d a ys  w h er e l a bs  ar e  o pti o n al,  vit al si g ns  ar e  als o  o pti o n al   
 
 
 
 
Str at u m  B 
 
 
  
C y cl e
 
1
 
 
C y cl e  2  a n d 
s u bs e q u e nt  c y cl es f 
 
 
Pr e- 
St u d y j 
W k 
1 
W k 
2 
W k 
3 
W k 
1 
W k 
2 
W k 
3 
Off  St u d y c 
P M 0 1 1 8 3 
 
    
X 
  X 
  
    X 
    X 
  
    
 
G e m cit a bi n e 
 
    
X 
  X 
  
    X 
    X 
  
    
 
I nf or m e d 
 
c o ns e nt 
    
X 
  
  
  
  
  
  
  
  
  
 
D e m o gr a p hi cs 
    
X 
  
  
  
  
  
  
  
  
  
 
M e di c al 
 
hist or y 
    
X 
  
  
  
  
  
  
  
  
  
 
C o n c urr e nt  m e ds 
X    
X------------------------------------------- X    
P h ysi c al  e x a m 
X    
X    
X 
 
X 
  X 
  
X 
Vit al si g ns 
X    
X    
X 
 
X 
  X 
  
X 
H ei g ht 
 
X 
  
  
  
  
  
  
  
  
  
 
W ei g ht 
 
X 
    X 
  X 
  
    X 
    X 
  
    X 
 
E C O G  P erf or m a n c e st at us    
X    
X    
X   
    
X    
X   
    
X 
C B C  w/ diff,  plts d, k 
X 
  X 
 X 
 
X  
X 
  X 
  X i 
X 
S er u m  c h e mistr y a, d, k  X 
 
X 
 
X 
 
X
 
X 
  X 
  X i 
X 
Uri n al ysis
  X
 
  
  
  
 
 
  
 
P T,  a P T T 
X   
   
   
   
 
 
  
 
E C G ( as i n di c at e d) 
X   
   
   
   
   
   
   
 
A d v ers e  e v e nt  e v al u ati o n   
    
X------------------------------------------- X    
R a di ol o gi c  e v al u ati o n g 
X 
R e p e at e d  e v er y  6  w e e ks f or t h e first  8 
c y cl es  a n d t h e n  e v er y  9  w e e ks 
t h er e aft er.   D o c u m e nt ati o n (r a di ol o gi c) 
m ust  b e  pr o vi d e d f or  p arti ci p a nts 
r e m o v e d fr o m st u d y f or  pr o gr essi v e 
dis e as e. 
 
Uri n e  or s er u m  pr e g n a n c y 
t esti n g 
X b  
  
  
  
  
  
  
  
 
R e vi e w  of  P at h ol o g y h 
X 
  
  
  
  
  
  
  
  
  
 
a:    
Al b u mi n,  al k ali n e  p h os p h at as e, t ot al  bilir u bi n,  bi c ar b o n at e,  B U N,  c al ci u m,  c hl ori d e, 
cr e ati ni n e,  gl u c os e,  L D H,  p h os p h or us,  p ot assi u m,  t ot al  pr ot ei n,  S G O T [ A S T],  S G P T [ A L T], 
s o di u m,  C P K. 
b:   
S er u m  or  uri n e  pr e g n a n c y t est ( w o m e n  of  c h il d b e ari n g  p ot e nti al).  M ust  b e r e p e at e d if  n ot 
wit hi n  7  d a ys  of  c 1 d 1. 
c:        Off-st u d y  e v al u ati o n t o  b e  c o m p l et e d  3 0  +  7  d a ys fr o m l ast st u d y  dr u g  d os e 
d:      l a b or at or y t esti n g  c a n  b e  p erf or m e d  u p  t o  4 8 h  pri or t o s c h e d ul e d  visit ( e x cl u di n g s cr e e ni n g 


Pr ot o c ol  #: 1 5- 0 8 3 
V ersi o n  D at e: 2/ 5/ 2 0 1 6 
 
4 4 
l a b or at or y t esti n g) 
f:       d a y  1  of  a  gi v e n  c y cl e  c a n st art - 1 t o  + 2  d a ys t o  all o w f or s c h e d uli n g.  D a y  8  of  a  gi v e n  c y cl e 
c a n st art  u p t o  + 2  d a ys l at e t o  all o w f or s c h e d uli n g. 
g:      s c a n  wi n d o w is  +/-  7  d a ys   
h:       o nl y r e q uir e d f or  p ati e nts  wit h  p at h ol o g y  n ot  pr e vi o usl y  r e vi e w e d  at  D F CI,  B W H  or  M G H 
i         d a y  1 5  +/-  3  d a ys  bl o o d t ests r eq uir e d f or  c y cl es  1  a n d  2,  o pti o n al t h er e aft er 
j:      s cr e e ni n g  d at a t o  b e  o bt ai n e d  wit hi n 1 5   d a ys  of tr e at m e nt  d a y  1;  b as eli n e r a di ol o gi c al 
e v al u ati o ns  wit hi n  3 0  d a ys  of tr e at m e nt  d a y  1 
k:      if  g e m cit a bi n e is  dis c o nti n u e d: f or  t h e first  c y cl e  aft er  g e m cit a bi n e is  dis c o nti n u e d 
( P M 0 1 1 8 3  m o n ot h er a p y)  d a y  8  a n d  d a y  1 5 ( +/-  3  d ays)  c b c/ dif is r e q uir e d  a n d  d a y  8 ( +/-  3 
d a ys)  c h e mistri es  ar e r e q uir e d; t h es e l a b or at or y  v al u es  ar e  o pti o n al f or f urt h er  c y cl es   
 
 
 
 
Str at u m  C 
 
 
  
C y cl e
 
1
 
C y cl e  2  a n d 
s u bs e q u e nt  c y cl es f 
 
 
Pr e- 
St u d y j 
W k 
1 
W k 
2 
W k 
3 
W k 
1 
W k 
2 
W k 
3 
Off  St u d y c 
P M 0 1 1 8 3
 
 
X
 
  
  
X
 
  
  
 
I nf or m e d 
 
c o ns e nt 
    
X 
  
  
  
  
  
  
  
  
  
 
D e m o gr a p hi cs 
    
X 
  
  
  
  
  
  
  
  
  
 
M e di c al 
 
hist or y 
    
X 
  
  
  
  
  
  
  
  
  
 
C o n c urr e nt  m e ds 
X    
X-------------------------------------------- X    
P h ysi c al  e x a m 
X    
X    
X   
    
X    
X i  
    X 
 
Vit al si g ns 
X    
X    
X   
    
X    
X i  
    X 
 
H ei g ht 
 
X 
  
  
  
  
  
  
  
  
  
 
W ei g ht
  X
 
X
 
  
  
X
 
  
  
X
 
E C O G  P erf or m a n c e st at us    
X    
X   
   
    
X   
   
    
X 
C B C  w/ diff,  plts d 
X 
  X 
 X 
 
X   
X 
  X i  
Xi  
X 
S er u m  c h e mistr y a, d  X
 
X
 
X
  
 
X
  
  
 
X
 
Uri n al ysis
  X
 
  
  
  
 
 
  
 
P T,  a P T T 
X   
   
   
   
 
 
  
 
E C G ( as i n di c at e d) 
X   
   
   
   
   
   
   
 
A d v ers e  e v e nt  e v al u ati o n   
    
X-------------------------------------------- X    X 
R a di ol o gi c  e v al u ati o n g 
X 
R e p e at e d  e v er y  6  w e e ks f or t h e first  8 
c y cl es  a n d t h e n  e v er y  9  w e e ks 
t h er e aft er.   D o c u m e nt ati o n (r a di ol o gi c) 
m ust  b e  pr o vi d e d f or  p arti ci p a nts 
r e m o v e d fr o m st u d y f or  pr o gr essi v e 
dis e as e. 
 
Uri n e  or s er u m  pr e g n a n c y 
t esti n g 
X b  
 
 
R e vi e w  of  P at h ol o g y h 
X 
  
 
 
a:    
Al b u mi n,  al k ali n e  p h os p h at as e, t ot al  bilir u bi n,  bi c ar b o n at e,  B U N,  c al ci u m,  c hl ori d e, 
cr e ati ni n e,  gl u c os e,  L D H,  p h os p h or us,  p ot assi u m, t ot al  pr ot ei n,  S G O T [ A S T],  S G P T 


Pr ot o c ol  #: 1 5- 0 8 3 
V ersi o n  D at e: 2/ 5/ 2 0 1 6 
 
4 5 
[ A L T], s o di u m,  C P K. 
b:   
S er u m  or  uri n e  pr e g n a n c y t est ( w o m e n  of  c h il d b e ari n g  p ot e nti al).  M ust  b e r e p e at e d if  n ot 
wit hi n  7  d a ys  of  c 1 d 1. 
c:        Off-st u d y  e v al u ati o n t o  b e  c o m pl et e d  3 0  +  7  d a ys fr o m l ast st u d y  dr u g  d os e. 
d:      l a b or at or y t esti n g  c a n  b e  p erf or m e d  u p  t o  4 8 h  pri or t o s c h e d ul e d  visit ( e x cl u di n g s cr e e ni n g 
l a b or at or y t esti n g) 
f:       d a y  1  of  a  gi v e n  c y cl e  c a n st art - 1 t o  + 2  d a ys t o  all o w f or s c h e d uli n g 
g:      s c a n  wi n d o w is  +/-  7  d a ys 
h:       o nl y r e q uir e d f or  p ati e nts  wit h  p at h ol o g y  n ot  pr e vi o usl y  r e vi e w e d  at  D F CI,  B W H  or  M G H 
i:        d a y  8  ( +/-  3  d a ys)  p h ysi c al  e x a m  a n d  d a y  8 ( +/-  3  d a ys)  a n d  1 5 ( +/-  3  d a ys)  C B C/ diff 
r e q uir e d f or  c y cl es  1  a n d  2,  o pti o n al t h er e aft er.   
j:      s cr e e ni n g  d at a t o  b e  o bt ai n e d  wit hi n 1 5  d a ys  of tr e at m e nt  d a y  1;  b as eli n e r a di ol o gi c al 
e v al u ati o ns  wit hi n  3 0  d a ys  of tr e at m e nt  d a y  1 
 
 


Pr ot o c ol  #: 1 5- 0 8 3 
V ersi o n  D at e: 2/ 5/ 2 0 1 6 
 
4 6 
1 0.  M E A S U R E M E N T  O F  E F F E C T 
 
1 0. 1  
A ntit u m o r  Eff e ct  –  S oli d  T u m o rs 
 
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 f or r es p o ns e  e v er y  6  w e e ks f or 
t h e first  8  c y cl es  a n d t h e n  e v er y  9  w e e ks t h er e aft er.   
 
R es p o ns e  a n d  pr o gr essi o n  will  b e  e v al u at e d i n t his st u d y  usi n g t h e  n e w i nt er n ati o n al  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 oli d  T u m ors ( R E CI S T)  g ui d eli n e ( v ersi o n  1. 1) 
[E ur  J  C a   4 5: 2 2 8- 2 4 7,  2 0 0 9].   C h a n g es i n t h e l ar g est  dia m et er ( u ni di m e nsi o n al  m e as ur e m e nt)  of 
t h e t u m or l esi o ns  a n d t h e s h ort est  di a m et er i n t h e  c as e  of  m ali g n a nt l y m p h  n o d es  ar e  us e d i n t h e 
R E CI S T  crit eri a. 
 
1 0. 1. 1  D efi niti o ns  
 
E v al u a bl e f or  T ar g et  Dis e as e r es p o ns e.    O nl y t h os e  p arti ci p a nts  w h 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 h eir 
dis e as e r e- e v al u at e d  will  b e  c o nsi d er e d  e v al u a bl e f or t ar g et  dis e as e r es p o ns e.   T h es e 
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 eas e  pr o gr essi o n  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.) 
 
E v al u a bl e  N o n- T ar g et  Dis e as e  R es p o ns e .   P arti ci p a nts  w h o  h a v e l esi o ns  pr es e nt  at 
b as eli n e t h at  ar e  e v al u a bl e  b ut  d o  n ot  m e et t h e  d efi niti o ns  of  m e as ur a bl e  dis e as 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 e as e r e- e v al u at e d  will  b e 
c o nsi d er e d  e v al u a bl e f or  n o n-t ar g et  dis e as e.    T h e r es p o ns e  ass ess m e nt is  b as e d  o n t h e 
pr es e n c e,  a bs e n c e,  or  u n e q ui v o c al  pr o gr essi o n  of t h e l esi o ns.  
 
1 0. 1. 2  Dis e as e  P ar a m et ers  
 
M e as ur a bl e  dis e as e .   M e as ur a bl e l esi o ns  ar e  d efi n e d as t h os e t h at  c a n  b e  a c c ur at el y 
m e as ur e d i n  at l e ast  o n e  di m e nsi o n (l o n g est  di a m et er  t o  b e r e c or d e d)  as  ≥   2 0  m m  b y 
c h est  x-r a y  or  ≥ 1 0  m m  wit h  C T s c a n,  M RI,  or  c ali p ers  b y  cli ni c al  e x a m.   All t u m or 
m e as ur e m e nts  m ust  b e r e c or d e d i n  milli m et ers  ( or  d e ci m al fr a cti o ns  of  c e nti m et ers). 
 
M ali g n a nt l y m p h  n o d es.    T o  b e  c o nsi d er e d  p at h ol o gi c all y  e nl ar g e d  a n d  m e as ur a bl e,  a 
l y m p h  n o d e  m ust  b e ≥ 1 5  m m i n s h ort  a xis  w h e n  ass e ss e d  b y  C T s c a n ( C T s c a n sli c e 
t hi c k n ess r e c o m m e n d e d t o  b e  n o  gr e at er t h a n 5  m m).   At  b as eli n e  a n d i n f oll o w- u p,  o nl y 
t h e s h ort  a xis  will  b e  m e as ur e d  a n d f oll o w e d. 
 
N o n- m e as ur a bl e  dis e as e .   All  ot h er l esi o ns ( or sit es  of  dis e as e), i n cl u di n g s m all l esi o ns 
(l o n g est  di a m et er  < 1 0  m m  or p at h ol o gi c al l y m p h  n o d es  wit h  ≥ 1 0 t o  < 1 5  m m s h ort  a xis), 
ar e  c o nsi d er e d  n o n- m e as ur a bl e  dis e as e.   B o n e  l esi o ns, l e pt o m e ni n g e al  dis e as e,  as cit es, 
pl e ur al/ p eri c ar di al  eff usi o ns, l y m p h a n gitis  c uti s/ p ul m o nitis, i nfl a m m at or y  br e ast  dis e as e, 
a b d o mi n al  m ass es ( n ot f oll o w e d  b y  C T  or  M RI),  a n d  c ysti c l esi o ns  ar e  all  c o nsi d er e d 
n o n- m e as ur a bl e. 
 


Pr ot o c ol  #: 1 5- 0 8 3 
V ersi o n  D at e: 2/ 5/ 2 0 1 6 
 
4 7 
N ot e:  C ysti c l esi o ns t h at  m e et t h e  crit eri a f or r a di o gr a p hi c all y  d efi n e d si m pl e  c ysts 
s h o ul d  n ot  b e  c o nsi d er e d  as  m ali g n a nt l esi o ns ( n eit h er  m e as ur a b l e  n or  n o n- m e as ur a bl e) 
si n c e t h e y  ar e,  b y  d efi niti o n, si m pl e  c ysts. 
 
‘ C ysti c l esi o ns’ t h o u g ht t o r e pres e nt  c ysti c  m et ast as es  c a n  b e  c o nsi d er e d  as  m e as ur a bl e 
l esi o ns, if t h e y  m e et t h e  d efi niti o n  of  me as ur a bilit y  d es cri b e d  a b o v e.  H o w e v er, if  n o n-
c ysti c l esi o ns  ar e  pr es e nt i n t h e s a m e  p arti c i p a nt, t h es e  ar e  pr ef err e d f or s el e cti o n  as 
t ar g et l esi o ns. 
 
T ar g et l esi o ns.    All  m e as ur a bl e l esi o ns  u p t o  a  m a xi m u m  of  2 l esi o ns  p er  or g a n  a n d  5 
l esi o ns i n t ot al, r e pr es e nt ati v e  of  all i n v ol v e d  or g a ns, s h o ul d  b e i d e ntifi e d  as t a r g et 
l esi o ns  a n d r e c or d e d  a n d  m e as ur e d  at  b as eli n e.   T ar g et l esi o ns s h o uld  b e s el e ct e d  o n t h e 
b asis  of t h eir si z e (l esi o ns  w it h t h e l o n g est  di a m et er),  b e r e pr es e nt ati v e  of  all i n v ol v e d 
or g a ns,  b ut i n  a d diti o n s h o ul d  b e t h os e t h at l e n d t h e ms el v es  t o r e pr o d u ci bl e r e p e at e d 
m e as ur e m e nts. It  m a y  b e t h e  c as e t h at,  o n  o c c asi o n, t h e l ar g est l esi o n  d o es  n ot l e n d its elf 
t o r e pr o d u ci bl e  m e as ur e m e nt i n  w hi c h  cir c u mst a n c e t h e  n e xt l ar g est l esi o n  w hi c h  c a n  b e 
m e as ur e d r e pr o d u ci bl y s h o ul d  b e s el e ct e d.  A  s u m  of t h e  di a m et ers (l o n g est f or  n o n- n o d al 
l esi o ns, s h ort  a xis f or  n o d al l esi o ns) f or  all t ar g et l esi o ns  will  b e  c al c ul at e d  a n d r e p ort e d 
as t h e  b as eli n e s u m  di a m et ers. If l y m p h  n o d es  ar e t o  b e i n cl u d e d i n t h e s u m, t h e n  o nl y t h e 
s h ort  a xis is  a d d e d i nt o t h e s u m.  T h e  b as eli n e s u m  di a m et ers  will  b e  us e d  as r ef er e n c e t o 
f urt h er  c h ar a ct eri z e  a n y  o bj e cti v e t u m or r e gr essi o n i n t h e  m e as ur a bl e  di m e nsi o n  of t h e 
dis e as e.  
 
N o n-t ar g et l esi o ns .   All  ot h er l esi o ns ( or sit es  of  dis e as e) i ncl u di n g  a n y  m e as ur a bl e 
l esi o ns  o v er  a n d  a b o v e t h e  5 t ar g et l esi o ns s h o ul d  b e i d e ntifi e d  as n o n-t a r g et l esi o ns   a n d 
s h o ul d  als o  b e r e c or d e d  at  b as eli n e.  M e as ur e m e nts  of t h es e l esi o ns  ar e  n ot r e q uir e d,  b ut 
t h e  pr es e n c e,  a bs e n c e,  or i n r ar e  c as es u n e q ui v o c al  pr o gr essi o n  of  e a c h s h o ul d  b e  n ot e d 
t hr o u g h o ut f oll o w  u p.  
 
1 0. 1. 3  M et h o ds f or  E v al u ati o n  of  Dis e as e  
 
All  m e as ur e m e nts s h o ul d  b e t a k e n  a n d r e c or d e d  i n  m etri c  n ot ati o n  usi n g  a r ul er,  c ali p ers, 
or  a  di git al  m e as ur e m e nt t o ol.   All  b as eli n e  e v al u ati o ns s h o ul d  b e  p erf or m e d  as  cl os el y  as 
p ossi bl e t o t h e  b e gi n ni n g  of tr e at m e nt  a n d  n e v er  m or e t h a n  4  w e e ks  b ef or e t h e  b e gi n ni n g 
of t h e tr e at m e nt. 
 
T h e s a m e  m et h o d  of  ass ess m e nt  a n d t h e s a m e  t e c h ni q u e s h o ul d  b e  us e d t o  c h ar a ct eri z e 
e a c h i d e ntifi e d  a n d r e p ort e d l esi o n  at  b a s eli n e  a n d  d uri n g f oll o w- u p. I m a gi n g- b as e d 
e v al u ati o n is  pr ef err e d t o  e v al u ati o n  b y  cli n i c al  e x a mi n ati o n  u nl ess t h e l esi o n(s)  b ei n g 
f oll o w e d  c a n n ot  b e i m a g e d  b ut  ar e ass ess a bl e  b y  cli ni c al  e x a m.  
 
Cli ni c al l esi o ns.  Cli ni c al l esi o ns  will  o nl y  b e  c o nsi d er e d  m e as ur a bl e  w h e n t h e y  ar e 
s u p erfi ci al (e. g. , s ki n  n o d ul es  a n d  p al p a bl e l y m p h  n o d es)  a n d ≥ 1 0  m m i n  di a m et er  as 
ass ess e d  usi n g  c ali p ers ( e. g. , s ki n  n o d ul es).  I n t h e  c as e  of s ki n l esi o ns,  d o c u m e nt ati o n  b y 
c ol or  p h ot o gr a p h y, i n cl u di n g  a r ul er t o  esti m a t e t h e si z e  of t h e l esi o n, is r e c o m m e n d e d.  
 


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4 8 
C h est  x-r a y.   L esi o ns  o n  c h est  x-r a y  ar e  a c c e pt a bl e  as   m e as ur a bl e l esi o ns  w h e n t h e y  ar e 
cl e arl y  d efi n e d  a n d s urr o u n d e d  b y  a er at e d  l u n g;  h o w e v er,  C T is  pr ef er a bl e.  
 
C o n v e nti o n al  C T  a n d  M RI.   T his  g ui d eli n e  h as  d efi n e d  m e as ur a bilit y  of l esi o ns  o n  C T 
s c a n  b as e d  o n t h e  ass u m pti o n t h at  C T t hi c k n ess is  5 m m  or l ess. If  C T s c a ns  h a v e sli c e 
t hi c k n ess  gr e at er t h a n  5  m m, t h e  mi ni m u m si z e of  a  m e as ur a bl e l esi o n s h o ul d  b e t wi c e 
t h e sli c e t hi c k n ess.  M RI is  als o a c c e pt a bl e i n  c ert ai n sit u ati o ns ( e. g.  f or  b o d y s c a ns).   
 
Us e  of  M RI r e m ai ns  a  c o m pl e x iss u e.   M RI  h a s  e x c ell e nt  c o ntr ast, s p ati al,  a n d t e m p or al 
r es ol uti o n;  h o w e v er, t h er e  ar e  m a n y i m a g e  a cq uisiti o n  v ari a bl es i n v ol v e d i n  M RI,  w hi c h 
gr e atl y i m p a ct i m a g e  q u alit y, l esi o n  c o ns pi c u it y,  a n d  m e as ur e m e nt.   F urt h er m or e, t h e 
a v ail a bilit y  of  M RI is  v ari a bl e  gl o b all y.   As  wit h  C T,  if  a n  M RI is  p erf or m e d, t h e 
t e c h ni c al s p e cifi c ati o ns  of t h e s c a n ni n g s e q u e n c es  us e d s h o ul d  b e  o pti mi z e d f or t h e 
e v al u ati o n  of t h e t y p e  a n d sit e  of  dis e as e.   F u rt h er m or e,  as  wit h  C T, t h e  m o d alit y  us e d  at 
f oll o w- u p s h o ul d  b e t h e s a m e  as  w as  us e d at  b as eli n e  a n d t h e l esi o ns s h o ul d  b e 
m e as ur e d/ ass ess e d  o n t h e s a m e  p uls e s e q u e n c e.   It is  b e y o n d t h e s c o p e  of t h e  R E CI S T 
g ui d eli n es t o  pr es cri b e s p e cifi c  M RI  p uls e  s e q u e n c e  p ar a m et ers f or  all s c a n n ers,  b o d y 
p arts,  a n d  dis e as es.  I d e all y, t h e s a m e t y p e   of s c a n n er s h o ul d  b e  us e d  a n d t h e i m a g e 
a c q uisiti o n  pr ot o c ol s h o ul d  b e  f oll o w e d  as  cl os el y  as  p ossi bl e t o  pri or s c a ns.   B o d y s c a ns 
s h o ul d  b e  p erf or m e d  wit h  br e at h- h ol d  s c a n ni n g t e c h ni q u es, if  p ossi bl e. 
 
F D G- P E T.   W hil e  F D G- P E T r es p o ns e  ass ess m e nts n e e d  a d diti o n al st u d y, it is s o m eti m es 
r e as o n a bl e t o i n c or p or at e t h e  us e  of  F D G- PE T s c a n ni n g t o  c o m pl e m e nt  C T s c a n ni n g i n 
ass ess m e nt  of  pr o gr essi o n ( p arti c ul arl y  p ossi bl e ' n e w'  dis e as e).   N e w l esi o ns  o n t h e  b asis 
of  F D G- P E T i m a gi n g  c a n  b e i d e ntifi e d  a c c or di n g t o t h e f oll o wi n g  al g orit h m:  
( a)  N e g ati v e  F D G- P E T  at  b as eli n e,  wit h  a  p ositi v e  F D G- P E T  at f oll ow- u p is  a si g n  of 
P D  b as e d  o n  a  n e w l esi o n. 
( b)   N o  F D G- P E T  at  b as eli n e  a n d  a  p ositi v e F D G- P E T  at f oll o w- u p:  If t h e  p ositi v e 
F D G- P E T  at f oll o w- u p  c orr es p o n ds t o  a  n e w sit e   of  dis e as e  c o nfir m e d  b y  C T, t his is 
P D.  If t h e  p ositi v e  F D G- P E T  at f oll o w- u p is   n ot  c o nfir m e d  as  a  n e w sit e  of  dis e as e 
o n  C T,  a d diti o n al f oll o w- u p  C T  s c a ns  ar e  n e e d e d t o  d et er mi n e if t h er e is tr ul y 
pr o gr essi o n  o c c urri n g  at t h at sit e (if s o, t h e  d at e  of  P D  will  b e t h e  d at e  of t h e i niti al 
a b n or m al  F D G- P E T s c a n).  If t h e  p ositi v e  F D G- P E T  at f oll o w- u p  c orr es p o n ds t o  a 
pr e- e xisti n g sit e  of  dis e as e  o n  C T t h at is  n ot  pr o gr essi n g  o n t h e  b a sis  of t h e  a n at o mi c 
i m a g es, t his is  n ot  P D. 
( c)   F D G- P E T  m a y  b e  us e d t o  u p gr a d e  a r es p o ns e t o  a  C R i n  a  m a n n er si mil ar t o  a 
bi o ps y i n  c as es  w h er e  a r esi d u al r a di o gr a p hi c  a b n or m alit y is t h o u g ht t o r e pr es e nt 
fi br osis  or s c arri n g.   T h e  us e  of  F DG- P E T i n t his  cir c u mst a n c e s h o ul d  b e 
pr os p e cti v el y  d es cri b e d i n t h e  pr ot o c ol  a n d s u p p ort e d  b y  dis e as e-s p e cifi c  m e di c al 
lit er at ur e f or t h e i n di c ati o n.   H o w e v er, it  m ust  b e  a c k n o wl e d g e d t h at  b ot h  a p pr o a c h es 
m a y l e a d t o f als e  p ositi v e  C R  d u e t o  li mit ati o ns  of  F D G- P E T  a n d  bi o ps y 
r es ol uti o n/s e nsiti vit y. 
 
N ot e:   A ‘ p ositi v e’  F D G- P E T s c a n l esi o n  m e a ns  o n e  w hi c h is  F D G  a vi d  wit h  a n  u pt a k e 
gr e at er t h a n t wi c e t h at  of  t h e s urr o u n di n g tiss u e  o n t h e att e n u ati o n  c orr e ct e d i m a g e. 
 


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4 9 
P E T- C T.   At  pr es e nt, t h e l o w  d os e  or  att e n u ati o n  c orr e cti o n  C T  p orti o n  of  a  c o m bi n e d 
P E T- C T is  n ot  al w a ys  of  o pti m al  di a g n osti c  C T  q u alit y f or  us e  wit h  R E CI S T 
m e as ur e m e nts.   H o w e v er, if t h e sit e  c a n  d o c u m e nt t h at t h e  C T  p erf or m e d  as  p art  of  a 
P E T- C T is  of i d e nti c al  di a g n os ti c  q u alit y t o  a  di a g n osti c  C T ( wit h I V  a n d  or al  c o ntr ast), 
t h e n t h e  C T  p orti o n  of t h e  P E T- C T  c a n  b e us e d f or  R E CI S T  m e as ur e m e nts  a n d  c a n  b e 
us e d i nt er c h a n g e a bl y  wit h  c o n v e nti o n al  C T i n  a c c ur at el y  m e as uri n g  c a n c er l esi o ns  o v er 
ti m e.   N ot e,  h o w e v er, t h at t h e  P E T  p orti o n of t h e  C T i ntr o d u c es  a d diti o n al  d at a  w hi c h 
m a y  bi as  a n i n v esti g at or if it is  n o t r o uti n el y  or s eriall y  p erf or m e d.   
MI B G ( m et a-i o d o b e n z yl g u a ni di n e). T h e f oll o wi n g i s r e c o m m e n d e d, t o  a s s ur e  hi g h 
q u alit y i m a g e s  ar e  o bt ai n e d.  
P ati e nt  pr e p ar ati o n: I o di d e s,  u s u all y  S S KI  ( s at ur at e d  s ol uti o n  of  p ot a s si u m i o di d e), 
ar e  a d mi ni st er e d t o r e d u c e t h yr oi d al  a c c u m ul ati o n  of fr e e r a di oi o di n e,  pr ef er a bl y 
b e gi n ni n g t h e  d a y  pri or t o i nj e cti o n  a n d  c o nti n ui n g f or  3  a d diti o n al  d a y s ( 4  d a y s 
t ot al).  F or i nf a nt s  a n d  c hil dr e n,  o n e  dr o p t.i.d. i s  s uffi ci e nt, f or  a d ol e s c e nt s  2  dr o p s 
t.i. d.,  a n d f or  a d ult s  3  dr o p s t.i. d.  P arti ci p a nt s  a n d/ or  p ar e nt s  ar e  a s k e d  a b o ut  e x p o s ur e 
t o  p ot e nti al i nt erf eri n g  a g e nt s. If  n o n e i s  n ot e d,  a n i n d w elli n g i ntr a v e n o u s li n e i s 
e st a bli s h e d.  T h e  d o s e  of  MI B G i s  a d mi ni st er e d  b y  sl o w i ntr a v e n o u s i nj e cti o n  o v er  9 0 
s e c o n d s.  
I m a g e s fr o m t h e  h e a d t o t h e  di st al l o w er  e xtr e miti e s  s h o ul d  b e  o bt ai n e d.  
I- 1 2 3 MI B G  s ci nti gr a p h y i s  p erf or m e d t o  o bt ai n  b ot h  pl a n ar  a n d t o m o gr a p hi c i m a g e s.  
Pl a n ar:  A nt eri or  a n d  p o st eri or  vi e w s fr o m  t h e t o p  of t h e  h e a d t o t h e  pr o xi m al l o w er 
e xtr e miti e s  ar e  o bt ai n e d f or  1 0  mi n ut e s  at   2 4  h o ur s  a n d  o c c a si o n all y  at  4 8  h o ur s 
f oll o wi n g i nj e cti o n  of  1 0  m Ci/ 1. 7  s q u ar e  m et er s  of  b o d y  s urf a c e  ar e a ( ~ 1 5 0 μ Ci/ k g, 
m a xi m u m  1 0  m Ci).  A nt eri or  vi e w s  of t h e  di st al l o w er  e xtr e miti e s  ar e  a d e q u at e.  A 
l ar g e fi el d  of  vi e w  d u al  h e a d  g a m m a  c a m er a  wit h l o w  e n er g y  c olli m at or s i s  pr ef err e d.  
 
S P E C T:  M o st  p arti ci p a nt s r e c ei vi n g I- 1 2 3  MI B G  al s o  u n d er g o  S P E C T  at  2 4  h o ur s, 
u si n g  a  si n gl e  or  m ulti- h e a d e d  c a m er a  wit h  a l o w  e n er g y  c olli m at or.  T h e  c a m er a i s 
r ot at e d t hr o u g h  3 6 0  d e gr e e s,  1 2 0  pr oj e ctio n s  at  2 5  s e c o n d s  p er  st o p.  D at a  ar e 
r e c o n str u ct e d  u si n g filt er e d  b ac k  pr oj e cti o n s  wit h  a  B utt e r w ort h filt er  a n d  a  c ut  off 
fr e q u e n c y  of  0. 2- 0. 5.  S P E C T/ C T  m a y  b e  p erf orm e d  at i n stit uti o n s  wit h t hi s  c a p a cit y.  
 
Ultr as o u n d.   Ultr as o u n d is  n ot  us ef ul i n  ass ess m e nt  of l esi o n si z e  a n d s h o ul d  n ot  b e  us e d 
as  a  m et h o d  of  m e as ur e m e nt.  Ultr as o u n d  e x a m i n ati o ns  c a n n ot  b e r e pr o d u c e d i n t h eir 
e ntir et y f or i n d e p e n d e nt r e vi e w  at  a l at er  d at a  a n d,  b e c a us e t h e y  ar e  o p er at or  d e p e n d e nt, it 
c a n n ot  b e  g u ar a nt e e d t h at t h e s a m e t e c h ni q u e   a n d  m e as ur e m e nts  will  b e t a k e n fr o m  o n e 
ass ess m e nt t o t h e  n e xt. If  n e w l esi o ns  ar e i d e ntifi e d  b y  ultr as o u n d i n  t h e  c o urs e  of t h e 
st u d y,  c o nfir m ati o n  b y  C T  or  M RI is  a d vis e d. If  t h er e is  c o n c er n  a b o ut r a di ati o n  e x p os ur e 
fr o m  C T,  M RI  m a y  b e  us e d i nst e a d of  C T i n s el e ct e d i nst a n c es.  
 


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5 0 
E n d os c o p y,  L a p ar os c o p y.   T h e  utili z ati o n  of t h es e t e c h ni q u es f or  o bj e cti v e t u m or 
e v al u ati o n is  n ot  a d vis e d.  H o w e v er, s u c h t e c h ni q u es  m a y  b e  us ef ul t o  c o nfir m  c o m pl et e 
p at h ol o gi c al r es p o ns e  w h e n  bi o psi es  ar e  o bt ai n e d  or t o  d et er mi n e r el a ps e i n tri als  w h er e 
r e c urr e n c e f oll o wi n g  c o m pl et e r es p o ns e ( C R) or s ur gi c al r es e cti o n is  a n  e n d p oi nt. 
 
 
C yt ol o g y,  Hist ol o g y.   T h es e t e c h ni q u es  c a n  b e  us e d t o  diff er e nti at e  b et w e e n  p arti al 
r es p o ns es ( P R)  a n d  c o m pl et e r es p o ns es ( C R) i n r ar e  c as es ( e. g. , r esi d u al l esi o ns i n t u m or 
t y p es, s u c h  as  g er m  c ell t u m ors,  w h er e  k n o w n r esi d u al  b e ni g n t u m ors  c a n r e m ai n). 
 
T h e  c yt ol o gi c al  c o nfir m ati o n  of t h e  n e o pl asti c   ori gi n  of  a n y  eff usi o n t h at  a p p e ars  or 
w ors e ns  d uri n g tr e at m e nt  w h e n t h e  m e as ur a b l e t u m or  h as  m et  crit eri a f or r es p o ns e  or 
st a bl e  dis e as e is  m a n d at or y t o  diff er e nti a t e  b et w e e n r es p o ns e  or st a bl e  dis e as e ( a n 
eff usi o n  m a y  b e  a si d e  eff e ct  of t h e tr e at m e nt)  a n d  pr o gr essi v e  dis e as e. 
 
1 0. 1. 3. 1  
E v al u ati o n  of  T ar g et  L esi o ns 
 
C o m pl et e  R es p o ns e ( C R) :   Dis a p p e ar a n c e  of  all t ar g et l esi o ns.   A n y  p at h ol o gi c al 
l y m p h  n o d es ( w h et h er t ar g et  or  n o n-t ar g et) m ust  h a v e r e d u cti o n i n s h ort  a xis t o  < 1 0 
m m. 
 
P arti al  R es p o ns e ( P R) :   At l e ast  a  3 0 %  d e cr e as e i n t h e s u m  of t h e  di a m et ers  of t ar g et 
l esi o ns, t a ki n g  as r ef er e n c e t h e  b as eli n e s u m  di a m et ers. 
 
Pr o gr essi v e  Dis e as e ( P D) :   At l e ast  a  2 0 % i n cr e as e i n t h e s u m  of t h e  di a m et ers  of 
t ar g et l esi o ns, t a ki n g  as r ef er e n c e t he s m all est s u m  o n st u d y (t his i n cl u d es t h e 
b as eli n e s u m if t h at is t h e s m all est  o n st u d y) .  I n  a d diti o n t o t h e r el ati v e i n cr e as e  of 
2 0 %, t h e s u m  m ust  als o  d e m o nstr at e  a n  a bs ol u t e i n cr e as e  of  at l e ast  5  m m.  ( N ot e:  
t h e  a p p e ar a n c e  of  o n e  or  m or e  n e w l esio ns is  als o  c o nsi d er e d  pr o gr essi o ns). 
 
St a bl e  Dis e as e ( S D) :   N eit h er s uffi ci e nt s hri n k a g e t o  q u alif y f or  P R  n or s uffi ci e nt 
i n cr e as e t o  q u alif y f or  P D, t a ki n g  as r ef er e n c e t h e s m all est s u m  di a m et ers  w hil e  o n 
st u d y. 
 
1 0. 1. 3. 2  
E v al u ati o n  of  N o n- T ar g et  L esi o ns 
 
C o m pl et e  R es p o ns e ( C R) :   Dis a p p e ar a n c e  of  all  n o n-t ar get l esi o ns  a n d  n or m ali z ati o n 
of t u m or  m ar k er l e v el.   All l y m p h  n o d es  m ust  b e  n o n- p at h ol o gi c al i n si z e ( < 1 0  m m 
s h ort  a xis). 
 
N ot e:  If t u m or  m ar k ers  ar e i niti all y  a b o v e t h e  u p p er  n or m al li mit, t h e y  m ust 
n or m ali z e f or  a  p ati e nt t o  b e  c o nsi d er e d i n  c o m pl et e  cli ni c al r es p o ns e. 
 
N o n- C R/ N o n- P D:    P ersist e n c e  of  o n e  or  m or e  n o n-t ar g et l esi o n(s)  a n d/ or 
m ai nt e n a n c e  of t u m or  m ar k er  l e v el  a b o v e t h e  n or m al li mits. 
 
Pr o gr essi v e  Dis e as e ( P D) :   A p p e ar a n c e  of  o n e  or m or e  n e w l esi o ns  a n d/ or 


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u n e q ui v o c al  pr o gr essi o n   of  e xisti n g  n o n-t ar g et l esi o ns.  U n e q ui v o c al  pr o gr essi o n  
s h o ul d  n ot  n or m all y tr u m p t ar g et l esi o n st at us .  It  m ust  b e r e pres e nt ati v e  of  o v er all 
dis e as e st at us  c h a n g e,  n ot  a si n gl e l esi o n i n cr e as e.     
 
Alt h o u g h  a  cl e ar  pr o gr e ssi o n  of  “ n o n-t ar g et ” l esi o ns  o nl y is  e x c e pti o n al, t h e  o pi ni o n 
of t h e tr e ati n g  p h ysi ci a n s h o ul d  pr e v ail i n s u c h  cir c u mst a n c es,  a n d t h e  pr o gr essi o n 
st at us s h o ul d  b e  c o nfir m e d  at  a l at er  ti m e  b y t h e r e vi e w  p a n el ( or  Pri n ci p al 
I n v esti g at or). 
 
1 0. 1. 3. 3  
E v al u ati o n  of  N e w  L esi o ns 
 
T h e fi n di n g  of  a  n e w l esi o n s h o ul d  b e  u n e q ui v o c al (i. e.  n ot  d u e t o  diff er e n c e i n 
s c a n ni n g t e c h ni q u e, i m a gi n g  m o d alit y,  or  fi n di n gs t h o u g ht t o r e pr es e nt s o m et hi n g 
ot h er t h a n t u m or (f or  e x a m pl e, s o m e ‘ n e w’  b o n e l esi o ns  m a y  b e si m pl y  h e ali n g  or 
fl ar e  of  pr e- e xisti n g l esi o ns).  H o w e v er,  a l esi o n i d e ntifi e d  o n  a f oll o w- u p s c a n i n  a n 
a n at o mi c al l o c ati o n t h at  w as  n ot s c a n n e d  at  b as eli n e is  c o nsi d er e d  n e w  a n d  will 
i n di c at e  P D. If  a  n e w l esi o n is  e q ui v o c al ( b e c a us e  of s m all si z e  et c.), f oll o w- u p 
e v al u ati o n  will  cl arif y if it tr ul y r e pr es e nts  n e w  dis e as e  a n d if  P D is  c o nfir m e d, 
pr o gr essi o n s h o ul d  b e  d e cl ar e d  usi n g t h e  d at e  of t h e i niti al s c a n  o n  w hi c h t h e l esi o n 
w as  dis c o v er e d. 
 
1 0. 1. 3. 4  
E v al u ati o n  of  B est  O v er all  R es p o ns e 
 
T h e  b est  o v er all r es p o ns e is t h e  b est r es p o ns e r e c or d e d fr o m  t h e st art  of t h e tr e at m e nt 
u ntil  dis e as e  pr o gr essi o n/r e c urr e n c e (t a ki n g  as r ef er e n c e f or  pr o gr essi v e  dis e as e t h e 
s m all est  m e as ur e m e nts r e c or d e d si n c e t h e  tr e at m e nt st art e d).   T h e  p ati e nt's  b est 
r es p o ns e  assi g n m e nt  will  d e p e n d  o n t h e  a c hi e v e m e nt  of  b ot h  m e as ur e m e nt  a n d 
c o nfir m ati o n  crit eri a. 
 
F o r  P a rti ci p a nts  wit h  M e as u r a bl e  Dis e as e ( i. e.,  T a r g et  Dis e as e) 
 
T a r g et 
L esi o ns 
N o n- T a r g et 
L esi o ns 
N e w 
L esi o ns 
O v e r all 
R es p o ns e 
B est  O v e r all  R es p o ns e  w h e n 
C o nfi r m ati o n is  R e q ui r e d * 
C R 
  C R 
    N o 
 C R 
  > 4  w ks  C o nfir m ati o n * * 
C R 
  N o n- C R/ N o n-
P D 
N o 
  P R 
 
> 4  w ks  C o nfir m ati o n * * 
C R 
  N ot 
 
e v al u at e d 
 
N o 
 P R 
 
P R 
  N o n- C R/ N o n-
P D/ n ot 
e v al u at e d 
N o 
  P R 
 
S D 
  N o n- C R/ N o n-
P D/ n ot 
e v al u at e d 
N o 
  S D 
 
D o c u m e nt e d  at l e ast  o n c e  > 4 
w ks fr o m  b as eli n e * * 
P D    
A n y 
Y es  or  N o   
P D 
n o  pri or  S D,  P R  or  C R 
A n y   
P D * * *    
Y es  or  N o   
P D 
A n y 
  A n y 
    Y es 
 P D 
 


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  
S e e  R E CI S T  1. 1  m a n us cri pt f or f urt h er  d et ail s  o n  w h at is  e vi d e n c e  of  a  n e w l esi o n.  
* *         O nl y f or  n o n-r a n d o mi z e d tri als  wit h r es p o ns e  as  pri m ar y  e n d p oi nt. 
* * *      I n  e x c e pti o n al  cir c u mst a n c es,  u n e q ui v o c al  pr o gr essi o n i n  n o n-t ar g et l esi o ns  m a y  b e 
             a c c e pt e d  as  dis e as e  pr o gr essi o n. 
 
N ot e :   P arti ci p a 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 ui ri n g  dis c o nti n u ati o n  of 
tr e at m e nt  wit h o ut  o bj e cti v e  e vi d e n c e  of  dis e as e  pr o gr essi o n  at t h at ti m e s h o ul d  b e 
r e p ort e d  as  “s y m pt o m ati c  d et eri or ati o n. ”    E v er y  eff ort s h o ul d  b e  m a d e t o  d o c u m e nt t h e 
o bj e cti v e  pr o gr essi o n  e v e n  aft er  dis c o nti n u ati o n  of tr e at m e nt. 
 
F o r  P a rti ci p a nts  wit h  N o n- M e as u r a bl e  Dis e as e ( i. e.,  N o n- T a r g et  Dis e as e) 
 
N o n- T a r g et  L esi o ns    
N e w  L esi o ns 
O v e r all  R es p o ns e 
C R
  N o
   C R
 
N o n- C R/ n o n- P D
  N o
 
N o n- C R/ n o n- P D *
 
N ot  all  e v al u at e d 
N o 
n ot  e v al u at e d 
U n e q ui v o c al  P D 
Y es  or  N o 
P D 
A n y
  Y es
  P D
 
  
‘ N o n- C R/ n o n- P D’ is  pr ef err e d  o v er ‘st a bl e  dis eas e’ f or  n o n-t ar g et  dis e as e si n c e  S D is 
i n cr e asi n gl y  us e d  as  a n  e n d p oi nt f or  ass ess m e nt  of  effi c a c y i n s o m e tri als s o t o  assi g n 
t his  c at e g or y  w h e n  n o l esi o ns  c a n  b e  m e as ur e d is  n ot  a d vis e d 
 
1 0. 1. 4  D ur ati o n  of  R es p o ns e  
 
D ur ati o n  of  o v er all r es p o ns e :   T h e  d ur ati o n  of  o v er all r es p o ns e is  m e as ur e d fr o m t h e ti m e 
m e as ur e m e nt  crit eri a  ar e  m et f or  C R  or  P R ( w hi c h e v er is first r e c or d e d)  u ntil t h e first 
d at e t h at r e c urr e nt  or  pr o gr essi v e  dis e as e is   o bj e cti v el y  d o c u m e nt e d (t a ki n g  as r ef er e n c e 
f or  pr o gr essi v e  dis e as e t h e s m all est  m e as ur e m e nts r e c or d e d si n c e t h e tr e at m e nt st art e d,  or 
d e at h  d u e t o  a n y  c a us e.  P arti c i p a nts  wit h o ut  e v e nts r e p orte d  ar e  c e ns or e d  at t h e l ast 
dis e as e  e v al u ati o n). 
 
D ur ati o n  of  o v er all  c o m pl et e r es p o ns e :  T h e  d ur ati o n  of  o v er all  C R is  m e as ur e d fr o m t h e 
ti m e  m e as ur e m e nt  crit eri a  ar e first  m et f or  C R  u ntil t h e first  d at e t h at  pr o gr essi v e  dis e as e 
is  o bj e cti v el y  d o c u m e nt e d,  or  d e at h  d u e t o a n y  c a us e.  P arti ci p a nts  wit h o ut  e v e nts 
r e p ort e d  ar e  c e ns or e d  at t h e l ast  dis e as e  e v al u ati o n.  
 
 
D ur ati o n  of st a bl e  dis e as e :   St a bl e  dis e as e is  m e as ur e d fr o m t h e st art  of t h e tr e at m e nt 
u ntil t h e  crit eri a f or  pr o gr essi o n  ar e  m et, t a ki n g  as r ef er e n c e t h e s m all est  m e as ur e m e nts 
r e c or d e d si n c e t h e tr e at m e nt st art e d, i n cl u di n g t h e  b as eli n e  m e as ur e m e nts.  
 
1 0. 1. 5  Pr o gr essi o n- Fr e e  a n d  O v er all  S ur vi v al  
 
O v er all  S ur vi v al :  O v er all  S ur vi v al ( O S) is  d efi n e d as t h e ti m e fr o m   c y cl e  1  d a y  1 t o 
d e at h  d u e t o  a n y  c a us e,  or  c e ns or e d  at  d at e l ast  k n o w n  ali v e. 
 


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Pr o gr essi o n- Fr e e  S ur vi v al :  Pr o gr essi o n- Fr e e  S ur vi v al ( P F S) is  d efi n e d  as t h e ti m e fr o m 
c y cl e  1  d a y  1 t o t h e  e arli er  of  pr o gr essi o n  or   d e at h  d u e t o  a n y  c a us e.  P arti ci p a nts  ali v e 
wit h o ut  dis e as e  pr o gr essi o n  ar e  c e ns or e d  at  d at e  of l ast  dis e as e  e v al u ati o n. 
 
Ti m e t o  Pr o gr essi o n :  Ti m e t o  Pr o gr essi o n ( T T P) is  d efi n e d  as t h e ti m e fr o m  c y cl e  1  d a y  1 
t o  pr o gr essi o n,  or  c e ns or e d  at  d at e  of l ast dis e as e  e v al u ati o n f or t h os e  wit h o ut  pr o gr essi o n 
r e p ort e d. 
 
 
 
1 1.  D A T A  R E P O R TI N G /  R E G U L A T O R Y  R E Q UI R E M E N T S 
 
A d v ers e  e v e nt lists,  g ui d eli n es,  a n d i nstr u cti o ns f or  A E r e p orti n g  c a n  b e f o u n d i n  S e cti o n  7. 0 
( A d v ers e  E v e nts:  List  a n d  R e p orti n g  R e q uir e m e nts). 
 
1 1. 1  
D at a  R e p o rti n g 
 
1 1. 1. 1  M et h o d  
 
 T h e  Q A C T  will  c oll e ct,  m a n a g e,  a n d  p erf or m  q u alit y  c h e c ks  o n t h e  d at a f or t his st u d y. 
 
N ot e :  If  y o ur st u d y  h as  b e e n  assi g ne d t o  C D U S- C o m pl et e r e p orti n g,  all   a d v ers e  e v e nts 
( b ot h r o uti n e  a n d  e x p e dit e d) t h at  h a v e  oc c urr e d  o n t h e st u d y  a n d  m e et t h e  m a n d at or y 
C D U S r e p orti n g  g ui d eli n es  m ust  b e r e p ort e d  vi a t h e  m o nit ori n g  m et h o d i d e ntifi e d  a b o v e.  
If  y o ur st u d y  h as  b e e n  assi g n e d t o  CD U S- A b br e vi at e d r e p orti n g,  n o  a d v ers e  e v e nt 
r e p orti n g (r o uti n e  or  e x p e dit e d) is r e q uir e d t o  b e r e p ort e d  vi a  C D U S. 
 
1 1. 1. 2  R es p o nsi bilit y f or  D at a  S u b missi o n  
 
Pl e as e  us e t h e  a p pr o pri at e t e xt  b el o w,   w hi c h  c a n  b e  m o difi e d  as  n e c ess ar y. 
 
F or  n o n- C D U S/ C T M S s u b missi o ns:  I n v esti g ati v e sit es  wit hi n  D F/ H C C  or  D F/ P C C  ar e 
r es p o nsi bl e f or s u b mitti n g  d at a  a n d/ or  d at a f or ms t o t h e  Q A C T  a c c or di n g t o t h e s c h e d ul e 
s et  b y t h e  Q A C T. 
 
F or  C D U S  a n d  C M T S s u b missi o ns:   
P arti ci p a nt i nstit uti o ns  ar e r es p o nsi bl e f or s u b mitti n g  C D U S  d at a  a n d/ or  d at a f or ms t o 
eit h er t h e  C o or di n ati n g  C e nt er   or t o t h e  L e a d  Or g a ni z atio n  o n t h e st u d y  q u art erl y.   T h e 
d at e f or s u b missi o n t o t h e  C o or di n ati n g  C e nt er   or t o t h e  L e a d  Or g a ni z ati o n  will  b e s et  b y 
t h e m.   C D U S  d o es  n ot  a c c e pt  d at a s u b missi o ns fr o m t h e  p arti ci p a nt i nstit uti o ns  o n t h e 
st u d y.   W h e n s etti n g t h e  d at es,  all o w ti m e  f or  C o or di n ati n g  C e nt er  c o m pil ati o n,  O v er all 
PI r e vi e w,  a n d ti m el y s u b missi o n t o  C T E P  b y t h e  q u art erl y  d e a d li n es (s e e  S e cti o n 
1 2. 1. 1).   F or tri als  m o nit or e d  b y  C T M S,  a  q u art erl y r e p ort  of  d at a  will  b e  pr o vi d e d  b y 
T h er a d e x t o t h e  C o or di n ati n g  C e nt er. 
 
Eit h er t h e  C o or di n ati n g  C e nt er  or t h e  L e a d  Or g a ni z ati o n is r es p o nsi bl e f or  c o m pili n g  a n d 


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s u b mitti n g  C D U S  d at a t o  C T E P f or  all  p arti ci pa nt i nstit uti o ns  a n d f or  pr o vi di n g t h e  d at a 
t o t h e  O v er all  PI f or r e vi e w.   
 
1 1. 2  
D at a  S af et y  M o nit o ri n g 
 
T h e  D F/ H C C  D at a  a n d  S af et y  M o nit ori n g  C o m mitt e e ( D S M C)  will r e vi e w  a n d  m o nit or t o xi cit y 
a n d  a c cr u al  d at a fr o m t his st u d y.  T h e  c o m mitt e e is   c o m p os e d  of  cli ni c al s p e ci alists  wit h 
e x p eri e n c e i n  o n c ol o g y  a n d  w h o  h a v e  n o  dir e ct r e l ati o ns hi p  wit h t h e st u d y. I nf or m ati o n t h at 
r ais es  a n y  q u esti o ns  a b o ut  p arti ci p a nt s af et y  will  b e  a d dr ess e d  wit h t h e  O v er all  PI  a n d st u d y 
t e a m. 
 
T h e  D S M C  will r e vi e w  e a c h  pr ot o c ol  u p t o f o ur ti m es  a  y e ar  or  m or e  oft e n if r e q uir e d t o r e vi e w 
t o xi cit y  a n d  a c cr u al  d at a. I nf or m ati o n t o  b e  pro vi d e d t o t h e  c o m mitt e e  m a y i n cl u d e:  u p-t o- d at e 
p arti ci p a nt  a c cr u al;  c urr e nt  d os e l e v el i nf or m ati o n;  D L T i nf or m ati o n;  all  gr a d e  2  or  hi g h er 
u n e x p e ct e d  a d v ers e  e v e nts t h at  h a v e  b e e n r e p o rt e d; s u m m ar y  of  all  d e at hs  o c c urri n g  wit h  3 0 
d a ys  of i nt er v e nti o n f or  P h as e I  or  II  pr ot o c ols; f or  g e n e t h er a p y pr ot o c ols, s u m m ar y  of  all  d e at hs 
w hil e  b ei n g tr e at e d  a n d  d uri n g  a c ti v e f oll o w- u p;  a n y r es p o ns e i nf or m ati o n;  a u dit r es ults,  a n d  a 
s u m m ar y  pr o vi d e d  b y t h e st u d y t e a m.  Ot h er i nf or m ati o n ( e. g. s c a ns, l a b or at or y  v al u es)  will  b e 
pr o vi d e d  u p o n r e q u est.  
 
1 2.  S T A TI S TI C A L  C O N SI D E R A TI O N S 
 
W e  h a v e  d esi g n e d  a n  e x pl or at or y  p h as e II, t hr e e-str at u m st u d y f or t h e  pri m ar y  e n d p oi nt  of  D C R 
gr e at er t h a n  2 4  w e e ks.   P ati e nt s  will  b e str atifi e d  a m o n g t h e t h r e e str at a  b as e d  u p o n  hist or y  of 
pri or t h er a p y.   Str at u m  A  will  c o nsist  of  a nt h r a c y cli n e- n aï v e  p ati e nts  a n d  will r e c ei v e t h e 
c o m bi n ati o n r e gi m e n  of  P M 0 1 1 8 3  pl us  d o x or u bi ci n ( wit h  m ai nt e n a n c e  of  P M 0 0 1 1 8 3 if l o n g-
t er m  b e n efit  o c c urs  aft er  m a xi m al  c u m ul ati v e  d o x oru bi ci n is r e a c h e d).   Str at u m  B  will  c o nsist  of 
p ati e nts  wit h  pri or  a nt hr a c y cli n e t h er a p y  w h o  ar e  g e m cit a bi n e  n aï v e  a n d  will r e c ei v e t h e 
c o m bi n ati o n r e gi m e nt  of  P M 0 1 1 8 3  pl us  g e m cit a bi n e.   Str at u m  C  will  c o nsist  of  p ati e nts  w h o 
will r e c ei v e  P M 0 1 1 8 3  as  a si n gl e  a g e nt.   T h e tr u e  di s e as e  c o ntr ol r at e is  d efi n e d  as  a c hi e v e m e nt 
of  c o nfir m e d  o bj e cti v e r es p o ns e ( c o m pl et e r es p o ns e  or  p arti al r es p o ns e ),  or st a bl e  dis e as e t h at is 
c o nfir m e d  at l e ast  2 4  w e e ks fr o m st art  of st u d y  dr u g  a d mi nistr ati o n.   P ati e nts  wit h o ut st a bl e 
dis e as e,  dis e as e  pr o gr essi o n  wit hi n  2 4  w e e ks,  d e at hs  wit hi n  2 4  w e e ks,  or   wit h o ut  c o nfir m at or y 
s c a ns  at  2 4  w e e ks  p ost-st art  of st u d y  dr u g  will  b e  c o u nt e d  as f ail ur es.   
 
W e  will  e nr oll  2 0  e v al u a bl e  p ati e nts  b y i nt e nti o n t o tr e at i n  e a c h str at u m f oll o wi n g  a t w o-st a g e 
a p pr o a c h;  h o w e v er,  w e  will  e nr oll  p ati e nts t o t h e s e c o n d st a g e  b y  p erf or mi n g  a  c o n c urr e nt 
i nt eri m  a n al ysis.   P ati e nts  w h o  d o  n ot r e c ei v e  dru g f or  a n y r e as o n ( e. g.  wit h dr a w al  of  c o ns e nt) 
will  b e r e pl a c e d.  
 
 
 


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1 2. 1   St u d y  D esi g n/ E n d p oi nts 
 
   Pri m ar y  E n d p oi nt:   
o   T h e tr u e  dis e as e  c o ntr ol r at e is  d e fi n e d  as  a c hi e v e m e nt  of  c o nfir m e d 
o bj e cti v e r es p o ns e ( c o m pl et e r es p o ns e  or  p arti al r es p o ns e),  or st a bl e 
dis e as e t h at is  c o nfir m e d  at l e as t  2 4  w e e ks fr o m start  of st u d y  dr u g 
a d mi nistr ati o n 
 
   S e c o n d ar y  E n d p oi nts:  
o   O v er all r es p o ns e r at e ( O R R),  pr o gr essi o n fr e e s ur vi v al ( P F S )  at  2 4 
w e e ks,  o v er all s ur vi v al ( O S )  at  2 4  m o nt hs  
o   T o xi cit y  pr ofil e  of  P M 0 1 1 8 3  al o n e  or  wit h  c h e m ot h er a p y i n t his 
p ati e nt  p o p ul ati o n 
  
 
Str at u m  A ( P M 0 1 1 8 3  pl us  d o x or u bi ci n, f oll o w e d  b y  P M 0 1 1 8 3  m ai nt e n a n c e) 
 
At t h e first st a g e  a n al ysis  w e  will  ass ess  dis e as e  c o ntr ol r at e ( n ull:  2 1 %,  alt er n ati v e:  5 0 %);  w e 
will  n e e d t o  o bs er v e  at l e ast  3 r es p o ns es ( as  m e as ur e d  b y  D C R  at  2 4  w e e ks)  o ut  of  1 0  p ati e nts t o 
c o nti n u e t hr o u g h t h e s e c o n d st a g e.   At t h e s e c o n d  st a g e,  w e  will  ass ess  dis e as e  c o ntr ol r at e  a g ai n, 
a n d  w e  will  n e e d t o  o bs er v e  at l e ast  7 r es p o ns es   o ut  of  2 0  p ati e nts t o  a c c e pt t h e  c o m bi n ati o n 
tr e at m e nt  as  hi g hl y  pr o misi n g.   T h e  o v er all  p o w er f or tr u e  dis e as e  c o ntr ol r at e  at  2 4  w e e ks is 
9 1 %.   T h e  o v er all t y p e I  err or,  t h e  c h a n c e  of i n c orr e ctl y r ej e cti n g t h e  n ull  h y p oth esis, is  9 %.   T h e 
pr o b a bilit y  of st o p pi n g  at t h e first st a g e  u n d e r t h e  n ull  h y p ot h esis is  6 5 %.   T h e  o p er ati n g 
c h ar a ct eristi cs  of t his  d esi g n  ar e  c al c ul at e d  usi n g t h e  e x a ct  bi n o mi al  distri b uti o n. 
 
O v er all  o bj e cti v e r es p o ns e  r at e is  als o  of i nt er est i n t his tri al,  b ut t h e  o v er all  o bj e cti v e r es p o ns e 
r at e is li k el y l ess t h a n  5 0 % f or str at u m  A.  If t h ere  ar e  7  or  m or e  p ati e nts  wit h  c o m pl et e  or  p arti al 
r es p o ns e, t h e tr e at m e nt  will  als o  b e  c o nsi d er e d  pro misi n g.   T h er e is  at l e ast  5 8 %  pr o b a bilit y  of 
o bs er vi n g  7  or  m or e r es p o ns es i n  2 0 tr e at e d  p ati e nts if t h e tr u e  k n o w n r es p o ns e r at e is  4 0 %. 
 
Str at u m  B ( P M 0 1 1 8 3  pl us  g e m cit a bi n e) 
 
At t h e first st a g e  a n al ysis  w e  will  ass ess  dis e as e  c o ntr ol r at e ( n ull:  2 1 %,  alt er n ati v e:  5 0 %);  w e 
will  n e e d t o  o bs er v e  at l e ast  3 r es p o ns es ( as  m e as ur e d  b y  D C R  at  2 4  w e e ks)  o ut  of  1 0  p ati e nts t o 
c o nti n u e t hr o u g h t h e s e c o n d st a g e.   At t h e s e c o n d  st a g e,  w e  will  ass ess  dis e as e  c o ntr ol r at e  a g ai n, 
a n d  w e  will  n e e d t o  o bs er v e  at l e ast  7 r es p o ns es   o ut  of  2 0  p ati e nts t o  a c c e pt t h e  c o m bi n ati o n 
tr e at m e nt  as  hi g hl y  pr o misi n g.   T h e  o v er all  p o w er f or tr u e  dis e as e  c o ntr ol r at e  at  2 4  w e e ks is 
9 1 %.   T h e  o v er all t y p e I  err or,  t h e  c h a n c e  of i n c orr e ctl y r ej e cti n g t h e  n ull h y p ot h esis is  9 %.   T h e 
pr o b a bilit y  of st o p pi n g  at t h e first st a g e  u n d e r t h e  n ull  h y p ot h esis is  6 5 %.   T h e  o p er ati n g 
c h ar a ct eristi cs  of t his  d esi g n  ar e  c al c ul at e d  usi n g t h e  e x a ct  bi n o mi al  distri b uti o n. 
 
O v er all r es p o ns e r at e is  als o  a n i nt er est  of t his  tri al,  b ut t h e  o v er all r es p o ns e r at e is li k el y l ess 


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t h a n  5 0 % f or str at u m  B.  If t h er e  ar e  7  or  m or e  p ati e nts  wit h  c o m pl et e  or  p arti al r es p o ns e, t h e 
tr e at m e nt  will  als o  b e  c o nsi d er e d  pr o misi n g.   T h ere is  at l e ast  5 8 %  pr o b a bilit y  of  o bs er vi n g  7  or 
m or e r es p o ns es i n  2 0 tr e at e d  p ati e nts if  t h e tr u e  k n o w n r es p o ns e r at e is  4 0 %. 
 
Str at u m  C ( P M 0 1 1 8 3  m o n ot h er a p y) 
 
At t h e first st a g e  a n al ysis  w e  will  ass ess  dis e as e  c o ntr ol r at e ( n ull:  1 0 %,  alt er n ati v e:  3 0 %).  W e 
will  n e e d t o  o bs er v e  at l e ast  2 r es p o ns es ( as  m e as ur e d  b y  D C R  at  2 4  w e e ks)  o ut  of  1 2  p ati e nts t o 
c o nti n u e t hr o u g h t h e s e c o n d st a g e.   At t h e s e c o n d  st a g e,  w e  will  ass ess  dis e as e  c o ntr ol r at e  a g ai n, 
a n d  w e  will  n e e d t o  o bs er v e  at l e ast  4 r es p o ns es   o ut  of  2 0  p ati e nts t o  a c c e pt t h e  c o m bi n ati o n 
tr e at m e nt  as  hi g hl y  pr o misi n g.   T h e  o v er all  p o w er f or tr u e  dis e as e  c o ntr ol r at e  at  2 4  w e e ks is 
8 6 %.   T h e  o v er all t y p e I  err or,  t h e  c h a n c e  of i n c orr ectl y r ej e cti n g t h e  n u ll  h y p ot h esis is  1 2 %.  
T h e  pr o b a bilit y  of st o p pi n g  at t h e first st a g e  u n d er t h e  n ull  h y p ot h esis is  6 6 %.   T h e  o p er ati n g 
c h ar a ct eristi cs  of t his  d esi g n  ar e  c al c ul at e d  usi n g t h e  e x a ct  bi n o mi al  distri b uti o n. 
 
O v er all r es p o ns e r at e is  als o  a n i nt er est  of t his  tri al,  b ut t h e  o v er all r es p o ns e r at e is li k el y l ess 
t h a n  3 0 % f or str at u m  C.  If t h er e  ar e  4  or  m or e  p ati e nts  wit h  c o m pl et e  or  p arti al r es p o ns e, t h e 
tr e at m e nt  will  als o  b e  c o nsi d er e d  pr o misi n g.   T h ere is  at l e ast  3 7 %  pr o b a bilit y  of  o bs er vi n g  4  or 
m or e r es p o ns es i n  2 0 tr e at e d  p ati e nts if  t h e tr u e  k n o w n r es p o ns e r at e is  2 0 %. 
 
Pr o gr essi o n-fr e e  a n d  o v er all s ur vi v al  of  p ati e nts r e c ei vi n g  c o m bi n ati o n  P M 0 1 1 8 3  pl us 
D o x or u bi ci n,  c o m bi n ati o n  P M 0 1 1 8 3  pl us  G e m cit a bi n e,  or si n gl e  a g e nt  P M 0 1 1 8 3  will  b e 
d es cri b e d  usi n g t h e  m et h o d  of  K a pl a n  a n d  M ei er,  a n d  Gr e e n w o o d’s f or m ul a f or  9 0 %  c o nfi d e n c e 
i nt er v als f or  P F S  a n d  O S  at  2 4  w e e ks  will  b e r ep ort e d.  S e p ar at e  a n al ys es  will  b e  c o n d u ct e d 
b as e d  o n st u d y str at u m.  
 
1 2. 2  
S a m pl e  Si z e,  A c c r u al  R a t e  a n d  St u d y  D u r ati o n 
 
S a m pl e si z e:  2 0  p ati e nts  will  b e  e nr oll e d t o  e a c h str at u m f or  a t ot al  of  6 0  p ati e nts.  
 
A c cr u al  R at e: It is  esti m at e d  a c cr u al  will  b e  2- 5  p ati e nts  p er str at u m  p er  m o nt h.   T his  br o a d 
st u d y  d esi g n  will  all o w f or  eli gi bilit y  of  n e arl y  e v er y  p ati e nt i n  cli ni c t o  p arti ci p at e.   
 
St u d y  D ur ati o n:  2 4  m o nt hs 
 
 
1 2. 3  
M o nit o ri n g  Pl a n 
 
I n v ol v e m e nt i n t his st u d y  as  a  p arti ci p ati n g i n v esti g at or i m pli es  a c c e pt a n c e  of  p ot e nti al  a u dits  or 
i ns p e cti o ns, i n cl u di n g s our c e  d at a  v erifi c ati o n,  b y r e pr es e nt a ti v es  d esi g n at e d  b y t h e  Pri n ci p al 
I n v esti g at or  or  D F/ H C C.  T h e  p ur p ose  of t h es e  a u dits  or i ns p e cti o ns is t o  e x a mi n e st u d y-r el at e d 
a cti viti es  a n d  d o c u m e nts t o  d et er mi n e  w h et h er t h es e  a cti viti es  w er e  c o n d u ct e d  a n d  d at a  w er e 
r e c or d e d,  a n al y z e d,  a n d  a c c ur at el y r e p ort e d i n  a c c or d a n c e  wit h t h e  pr ot o c ol, i nstit uti o n al  p oli c y, 
G o o d  Cli ni c al  Pr a cti c e ( G C P),  a n d  a n y  a p pli c a bl e r e g ul at or y r e q uir e m e nts.  All  d at a  will  b e 
m o nit or e d f or ti m eli n ess  of s u b missi o n,  c o m pl et e n e ss,  a n d  a d h er e n c e t o  pr ot o c ol r e q uir e m e nts. 
M o nit ori n g  will  b e gi n  at t h e ti m e  of  p arti ci p a n t r e gistr ati o n  a n d  will  c o nti n u e  d uri n g  pr ot o c ol 
p erf or m a n c e  a n d  c o m pl eti o n. 


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5 7 
 
1 2. 4  
C o nfi d e nti alit y 
 
T h e  S p o ns or  m ai nt ai ns  c o nfi d e n ti alit y st a n d ar ds  b y  co di n g  e a c h  p ati e nt  e n r oll e d i n t h e st u d y 
t hr o u g h  assi g n m e nt  of  a  u ni q u e  p ati e nt i d e ntifi c ati o n  n u m b er.  P ati e nt  n a m es  ar e  n ot i n cl u d e d i n 
d at a s ets t h at  ar e tr a ns mitt e d  o utsi d e  of t h e  cli ni c al t e a m.  
P ati e nt  m e di c al i nf or m ati o n  o bt ai n e d  b y t his st u d y is  c o nfi d e nti al  a n d  m a y  b e  dis cl os e d t o t hir d 
p arti es  o nl y  as  p er mitt e d  b y t h e I nf or m e d  C o ns e nt  F or m.  
 
1 2. 5   E v al u ati o n  of  T o xi cit y 
 
T o xi cit y is  a n i m p ort a nt s e c o n d ar y  e n d p oi nt.   Wit h   2 0  p ati e nts i n  e a c h str at u m, t h er e is  at l e ast 
7 1 %  pr o b a bilit y  of  o bs er vi n g  o n e  or   m or e t o xi citi es  wit h  a tr u e r at e  as l o w  as  6 %.   Wit h  2 0 
tr e at e d  p ati e nts i n  e a c h str at u m, t h e  m a xi m u m  widt h  of  a  9 0 % t w o-si d e d  c o nfi d e n c e i nt er v al f or 
a n y  esti m at e d  a d v ers e  e v e nt  pr o p orti o n  ±  2 0 %. 
 
1 3.  P U B LI C A TI O N  P L A N 
 
T h e i n v esti g at ors  pl a n t o  p u blis h  wit hi n t w o  y e ars  of t h e l ast  p ati e nt   e nr oll e d  o n st u d y.  
 
 


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5 8 
 
A P P E N DI X  A   
P E R F O R M A N C E  S T A T U S  C RI T E RI A 
 
E C O G  P e rf o r m a n c e  St at us  S c al e 
K a r n ofs k y  P e rf o r m a n c e  S c al e 
Gr a d e 
  D es cri pti o ns 
 
P er c e nt 
 
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 0 0 
N or m al,  n o  c o m pl ai nts,  n o  e vi d e n c e 
of  dis e as e. 
9 0 
A bl e t o  c arr y  o n  n or m al  a cti vit y; 
mi n or si g ns  or s y m pt o ms  of  dis e as e. 
1 
S y m pt o ms,  b ut  a m b ul at or y.  
R estri 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). 
8 0 
N or m al  a cti vit y  wit h  eff ort; s o m e 
si g ns  or s y m pt o ms  of  dis e as e. 
7 0 
C ar es f or s elf,  u n a bl e t o  c arr y  o n 
n or m al  a cti vit y  or t o  d o  a cti v e  w or k.
2 
I n  b e d  < 5 0 %  of t h e 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. 
6 0 
R e q uir es  o c c asi o n al  assist a n c e,  b ut 
is  a bl e t o  c ar e f or  m ost  of  his/ h er 
n e e ds. 
5 0 
R e q uir es  c o nsi d er a bl e   assist a n c e  a n d 
fr e q u e nt  m e di c al  c ar e. 
3 
I n  b e d  > 5 0 %  of t h e ti m e.   C a p a bl e 
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 0 
Dis a bl e d, r e q uir es s p e ci al  c ar e  a n d 
assist a n c e. 
3 0 
S e v er el y  dis a bl e d,  h os pit ali z ati o n 
i n di c at e d.   D e at h  n ot i m mi n e nt. 
4 
1 0 0 %  b e dri d d e n.   C o m pl et el y 
dis 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. 
2 0 
V er y si c k,  h os pit ali z ati o n i n di c at e d. 
D e at h  n ot i m mi n e nt. 
1 0 
M ori b u n d, f at al  pr o c ess es 
pr o gr essi n g r a pi dl y. 
5 
  D e a d. 
 
0 
 D e a d. 
 
 
 
 
 
 
 
 
 
 
 
 


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A P P E N DI X  B   
I N F O R M A TI O N  O N  P O S SI B L E  D R U G  I N T E R A C TI O N S 
 
M E DI C A TI O N/ T H E R A P Y 
A L L O W E D 
   T h er a pi es f or  pr e- e xisti n g  a n d tr e at m e nt- e m er g e nt  m e di c al 
c o n diti o ns, i n cl u di n g  p ai n  m a n a g e m e nt. 
   Bl o o d  pr o d u cts  a n d tr a nsf usi o ns,  as  cli ni c all y i n di c at e d. 
   Bis p h os p h o n at es. 
   Er yt hr o p oi eti n  a c c or di n g t o  A S C O  g ui d eli n es. 
   S e c o n d ar y  G C S F  pr o p h yl a xis  will  b e  a d mi nist er e d  a c c or di n g t o 
t h e  g ui d eli n es i n s e cti o n  6. 4.   D osi n g   a n d f or m ul ati o n  will  b e  p er 
i nstit uti o n st a n d ar d.  D os e ti mi n g  m ust  b e  at l e ast  4 8  h o urs si n c e 
l ast st u d y  dr u g i nf usi o n 
   A nti c o a g ul ati o n t h er a p y f or t h e tr e at m e nt  or s e c o n d ar y 
pr o p h yl a xis  of  d e e p  v ei n t hr o m b osis.  
   L ut ei ni zi n g  h or m o n e-r el e asi n g  h or m o n e ( L H R H)  a g o nists, i n  pr e-
m e n o p a us al  w o m e n.   
   M e g estr ol  a c et at e f or  a p p etit e st i m ul ati o n if  a p pr o pri at e f or 
m a n a g e m e nt  of  e m er gi n g  w asti n g s y n dr o m e. 
M E DI C A TI O N/ T H E R A P Y 
P R O HI BI T E D 
   C o n c o mit a nt  a d mi nistr ati o n  of  a n y  ot h er  a nti n e o pl asti c t h er a p y  
   A n y  ot h er i n v esti g ati o n al  a g e nts. 
   I m m u n os u p pr essi v e t h er a pi es  ot h er t h a n  c orti c ost er oi ds.  
   I n  vitr o st u di es  h a v e s h o w n t h at  P M 0 1 1 8 3  h as t h e  p ot e nti al t o 
i n hi bit  c yt o c hr o m es  C Y P 2 C 8,  C Y P 2 B 6  a n d  C Y P 3 A 4.  T h e 
cli ni c al r el e v a n c e  of t his  p ot e nti al i nt er a cti o n is  u n k n o w n  at 
pr es e nt.  T h er ef or e,  c a uti o n s h o ul d  b e  e x er cis e d  w h e n  P M 0 1 1 8 3 is 
a d mi nist er e d  c o n c o mit a ntl y  wit h  C Y P 2 C 8,  C Y P 2 B 6  a n d 
C Y P 3 A 4 s u bstr at es,  p arti c ul arl y  t h os e  wit h  a  n arr o w t h er a p e uti c 
i n d e x . 
   A pr e pit a nt  or r el at e d  c o m p o u n ds. 
   R a di ot h er a p y, is  e x cl u d e d fr o m t h e  cli ni c al tri al  at t his ti m e. 
P alli ati v e r a di ati o n  will  b e  p er mitt e d  aft er  c y cl e  2  o nl y f or 
l o c ali z e d  p ai n  c o ntr ol  a n d  n ot  d u e t o  u n e q ui v o c al r a di ol o gi c al  or 
cli ni c all y  pr o gr essi v e  dis e as e.   St u d y  dr u g,  d o x or u bi ci n  a n d 
g e m cit a bi n e s h o ul d  b e t e m p or aril y  h el d  d uri n g t his  p eri o d.  
D osi n g s h o ul d r es u m e  wit h t h e  n e xt s c h e d ul e d  c y cl e t h at is  at 
l e ast  7  d a ys  aft er r a di ati o n is  c o m pl et e.   
I n  vitr o st u di es  usi n g  h u m a n li v er  mi cr os o m es  h a v e s h o w n t h at  P M 0 1 1 8 3  h as t h e  p ot e nti al t o i n hi bit  c yt o c hr o m e 
C Y P 2 B 6,  C Y P 2 C 8  a n d  C Y P 3 A 4.  M or e o v er, t h e  Ki  v al u es  c o m p ar e d  wit h t h e  a c hi e v e d  m a xi m u m  pl as m a 
c o n c e ntr ati o n ( C m a x )  v al u es  at r el e v a nt  d os es i n di c at e t h at t h e li keli h o o d  of  a  cli ni c all y r el e v a nt i n hi biti o n  of 
P M 0 1 1 8 3 is  p ossi bl e f or  C Y P 2 C 8 ([I]/ Ki > 0. 1)  a n d li k el y f o r  C Y P 3 A 4 ([I]/ Ki > 1).  T h e  m a g nit u d e  of t h e i nt er a cti o n 
is  u n k n o w n  at  pr es e nt.  T h er ef or e,  c a uti o n s h o ul d  b e  e x ercis e d  w h e n  P M 0 1 1 8 3 is  a d mi ni st er e d  c o n c o mit a ntl y  wit h 
C Y P 2 B 6,  C Y P 2 C 8  a n d  C Y P 3 A 4 s u bstr at es. 
A d diti o n all y,  i n  vitr o st u di es  wit h  h u m a n  mi cr os o m es  h a v e s h o w n t h at is of or ms  C Y P 2 D 6,  C Y P 2 E 1,  C Y P 3 A 4, 
C Y P 2 C 9  a n d  C Y P 2 C 1 9  p arti ci p at e i n  P M 0 1 1 8 3  m et a b olis m.  T h er ef or e,  c o n c o mit a nt  dr u gs  w hi c h i n d u c e  or i n hi bit 
a n y  of t h es e  c yt o c hr o m es,  es p e ci all y  C Y P 3 A 4  a n d  C Y P 2 C 1 9, s h o ul d  b e  a v oi d e d  w h e n e v er is  p ossi bl e.  A list  of 
c o m m o nl y  pr es cri b e d  dr u gs t h at  ar e i n hi bit ors, i n d u c ers  a n d s u bstr at es f or t h es e  e n z y m es  c a n  b e f o u n d  at t his 
w e bsit e: htt p:// m e di ci n e.i u p ui. e d u/ cli n p h ar m/ d dis/t a bl e. as p x  


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6 0 
A  p ot e nti all y si g nifi c a nt i nt er a cti o n  wit h  a pr e pit a nt is  s u g g est e d  b y  a v ail a bl e  d at a i n  p ati e nts  wit h  pl ati n u m-
r esist a nt/r efr a ct or y  o v ari a n  c a n c er.  P ati ents tr e at e d  wit h  a pr e pit a nt i n  C y cl e  2  h a d  P M 0 1 1 8 3  cl e ar a n c e r e d u c e d  b y 
5 0 %,  a p pr o xi m at el y,  c o m p ar e d  t o  C y cl e  1  e x p os ur e.  
  
 


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R E F E R E N C E S 
 
 
1.   
Si e g el  R,  M a J,  Z o u  Z, J e m al  A.  C a n c er  st atisti cs,  2 0 1 4.  C A  C an c er J  Cli n; 6 4: 9- 2 9. 
2.   
It ali a n o  A,  M at h o uli n- P elissi er  S,  C es n e  A L ,  et  al.  Tr e n ds i n s ur vi v al f or  p ati e nts 
wit h  m et ast ati c s oft-tiss u e s ar c o m a.  C a n c er; 1 1 7: 1 0 4 9- 5 4. 
3.    
K ar a v asilis  V,  S e d d o n  B M,  As hl e y  S,  Al- M u d eris  O,  Fis h er  C, J u ds o n I.  Si g nifi c a nt 
cli ni c al  b e n efit  of first-li n e  p alli ati v e  c h e m ot h er a p y i n  a d v a n c e d s oft-tiss u e s ar c o m a: 
r etr os p e cti v e  a n al ysis  a n d i de ntifi c ati o n  of  pr o g n osti c f a ct ors i n  4 8 8  p ati e nts.  C a n c er 
2 0 0 8; 1 1 2: 1 5 8 5- 9 1. 
4.   
S a ms o n  M K,  W ass er  L P,  B or d e n  E C,  et  al.  R a n d o mi z e d  c o m p aris o n  of 
c y cl o p h os p h a mi d e, i mi d a z ol e  c ar b o x a mi d e,  a n d  a dri a m y ci n  v ers us  c y cl o p h os p h a mi d e  a n d 
a dri a m y ci n i n  p ati e nts  wit h  a d v a n c e d st a g e  m ali g n a nt  m es ot h eli o m a:  a  S ar c o m a I nt er gr o u p 
St u d y. J  Cli n  O n c ol  1 9 8 7; 5: 8 6- 9 1. 
5.   
S a nt or o  A,  T urs z  T,  M o uri ds e n  H,  et  al.  D o x or u bi ci n  v ers us  C Y V A DI C  v ers us 
d o x or u bi ci n  pl us if osf a mi d e i n  first-li n e tr e at m e nt  of  a d v a n c e d s oft tiss u e s ar c o m as:  a 
r a n d o mi z e d st u d y  of t h e  E ur o p e a n  Or g a ni z ati o n f or  R es e ar c h  a n d  Tr e at m e nt  of  C a n c er  S oft 
Tiss u e  a n d  B o n e  S ar c o m a  Gr o u p. J  Cli n  O n c ol  1 9 9 5; 1 3: 1 5 3 7- 4 5. 
6.    
G ol dst ei n  D,  C h e u v art  B,  Tr u m p  D L,  et  al.  P h as e II tri al  of  c ar b o pl ati n i n s oft-tiss u e 
s ar c o m a.  A m J  Cli n  O n c ol  1 9 9 0; 1 3: 4 2 0- 3. 
7.   
P at el  S R,  V a d h a n- R aj  S,  P a p a d o p ol o us  N,  et  al.  Hi g h- d os e if osf a mi d e i n  b o n e  a n d 
s oft tiss u e s ar c o m as: r es ults  of  p h as e II  a n d  pil ot st u dies-- d os e-r es p o ns e  a n d s c h e d ul e 
d e p e n d e n c e. J  Cli n  O n c ol  1 9 9 7; 1 5: 2 3 7 8- 8 4. 
8.    
Br a m w ell  V H,  M o uri ds e n  H T,  S a nt or o  A,  et  al.  C y cl o p h os p h a mi d e  v ers us 
if osf a mi d e:  a r a n d o mi z e d  p h as e II tri al i n  a d ult s oft-tiss u e s ar c o m as.  T h e  E ur o p e a n  Or g a ni z ati o n 
f or  R es e ar c h  a n d  Tr e at m e nt  of  C a n c er [ E O R T C],  S oft  Tiss u e  a n d  B o n e  S ar c o m a  Gr o u p.  C a n c er 
C h e m ot h er  P h ar m a c ol  1 9 9 3; 3 1  S u p pl  2: S 1 8 0- 4. 
9.    
A nt m a n  K H,  R y a n  L,  Eli as  A,  S h er m a n  D,  Gri er  H E.  R es p o ns e t o if osf a mi d e  a n d 
m es n a:  1 2 4  pr e vi o usl y tr e at e d  p ati e nts  wit h  m et ast ati c  or  u nr es e ct a bl e  s ar c o m a. J  Cli n  O n c ol 
1 9 8 9; 7: 1 2 6- 3 1. 
1 0.   
v a n  O ost er o m  A T,  M o uri ds e n  H T,  Ni els e n  O S ,  et  al.  R es ults  of r a n d o mis e d st u di es  of 
t h e  E O R T C  S oft  Tiss u e  a n d  B o n e  S ar c o m a  Gr o up ( S T B S G)  wit h t w o  diff er e nt if osf a mi d e 
r e gi m e ns i n first-  a n d s e c o n d-li n e  c h e m ot h er a p y i n  a d v a n c e d s oft tiss u e s ar c o m a  p ati e nts.  E ur J 
C a n c er  2 0 0 2; 3 8: 2 3 9 7- 4 0 6. 
1 1.    
E d m o ns o n J H,  R y a n  L M,  Bl u m  R H,  et  al.  R a n d o mi z e d  c o m p aris o n  of  d o x or u bi ci n 
al o n e  v ers us if osf a mi d e  pl us  d o x or u bi ci n  or   mit o m y ci n,  d o x or u bi ci n,  a nd  cis pl ati n  a g ai nst 
a d v a n c e d s oft tiss u e s ar c o m as. J  Cli n  O n c ol  1 9 9 3; 1 1: 1 2 6 9- 7 5. 
1 2.    
A nt m a n  K,  Cr o wl e y J,  B al c er z a k  S P,  et  al .  A n i nt er gr o u p  p h as e III r a n d o mi z e d st u d y 
of  d o x or u bi ci n  a n d  d a c ar b a zi n e  wit h   or  wit h o ut if osf a mi d e  a n d  m es n a i n  a d v a n c e d s oft tiss u e 
a n d  b o n e s ar c o m as. J  Cli n  O n c ol  1 9 9 3; 1 1: 1 2 7 6- 8 5. 
1 3.    
Eli as  A,  R y a n  L,  S ul k es  A,  C olli ns J,  Ais n er J,  A nt m a n  K H.  R es p o ns e t o  m es n a, 
d o x or u bi ci n, if osf a mi d e,  a n d  d a c ar b a zi n e i n  1 0 8  p ati e nts  wit h  m et ast ati c  or  u nr es e ct a bl e s ar c o m a 
a n d  n o  pri or  c h e m ot h er a p y. J  Cli n  O n c ol  1 9 8 9; 7: 1 2 0 8- 1 6. 
1 4.    
H e nsl e y  M L,  M a ki  R,  V e n k atr a m a n  E,  et  al.  G e m cit a bi n e  a n d  d o c et a x el i n  p ati e nts 
wit h  u nr es e ct a bl e l ei o m y os ar c o m a: r es ults  of   a  p h as e II tri al. J  Cli n  O n c ol  2 0 0 2; 2 0: 2 8 2 4- 3 1. 
1 5.    
L e u  K M,  Ostr us z k a  LJ,  S h e w a c h  D,  et  al .  L a b or at or y  a n d  cli ni c al  e vi d e n c e  of 


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s y n er gisti c  c yt ot o xi cit y  of s e q u e nti al tr e at m e n t  wit h  g e m cit a bi n e f oll o w e d  b y  d o c et a x el i n t h e 
tr e at m e nt  of s ar c o m a. J  Cli n  O n c ol  2 0 0 4; 2 2: 1 7 0 6- 1 2. 
1 6.    
Dil e o  P,  M or g a n J A,  Z a hri e h  D,  et  al .  G e m cit a bi n e  a n d  vi n or el bi n e  c o m bi n ati o n 
c h e m ot h er a p y f or  p ati e nts  wit h  a d v a n c e d s oft tiss u e  s ar c o m as: r es ults  of  a  p h as e II tri al.  C a n c er 
2 0 0 7; 1 0 9: 1 8 6 3- 9. 
1 7.    
B a y J O,  R a y- C o q u ar d I,  F a y ett e J,  et  al .  D o c et a x el  a n d  g e m cit a bi n e  c o m bi n ati o n i n 
1 3 3  a d v a n c e d s oft-tiss u e s ar c o m as:  a r etr os p e cti v e  a n al ysis. I nt  J  C a n c er  2 0 0 6; 1 1 9: 7 0 6- 1 1. 
1 8.    
Br a m w ell  V H,  A n d ers o n  D,  C h ar ett e  M L .  D o x or u bi ci n- b as e d  c h e m ot h er a p y f or t h e 
p alli ati v e tr e at m e nt  of  a d ult  p ati e nts  wit h l o c all y   a d v a n c e d  or  m et ast ati c s oft tiss u e s ar c o m a. 
C o c hr a n e  D at a b as e  S yst  R e v  2 0 0 3: C D 0 0 3 2 9 3. 
1 9.    
M a ur el J,  L o p e z- P o us a  A,  d e  L as  P e n as  R,  et  al.  Effi c a c y  of s e q u e nti al  hi g h- d os e 
d o x or u bi ci n  a n d if osf a mi d e  c o m p ar e d  wit h st a n d a r d- d os e  d o x or u bi ci n i n  p ati e nts  wit h  a d v a n c e d 
s oft tiss u e s ar c o m a:  a n  o p e n-l a b el r a n d o mi z e d  p h a s e II st u d y  of t h e  S p a nis h  gr o u p f or r es e ar c h 
o n s ar c o m as. J  Cli n  O n c ol  2 0 0 9; 2 7: 1 8 9 3- 8. 
2 0.    
G o o d m a n  L S,  Gil m a n  A,  Br u nt o n  L L.   G o o d m a n  &  Gil m a n's  m a n u al  of 
p h ar m a c ol o g y  a n d t h er a p e uti cs.  N e w  Y or k:  M c Gr a w- Hill  M e di c al;  2 0 0 8. 
2 1.    
A b br u z z es e J L,  Gr u n e w al d  R,  W e e ks  E A,  et  al.  A  p h as e I  cli ni c al,  pl as m a,  a n d 
c ell ul ar  p h ar m a c ol o g y st u d y  of  g e m cit a bi n e. J  Cli n  O n c ol  1 9 9 1; 9: 4 9 1- 8. 
2 2.    
T e m p er o  M,  Pl u n k ett  W,  R ui z  V a n  H a p er e n  V,  et  al.  R a n d o mi z e d  p h as e II 
c o m p aris o n  of  d os e-i nt e ns e  g e m cit a bi n e: t hirt y- m i n ut e i nf usi o n  a n d fi x e d  d os e r at e i nf usi o n i n 
p ati e nts  wit h  p a n cr e ati c  a d e n o c ar ci n o m a. J  Cli n  O n c ol  2 0 0 3; 2 1: 3 4 0 2- 8. 
2 3.   
P at el  S R,  G a n d hi  V, J e n ki ns J,  et  al.  P h as e  II  cli ni c al i n v esti g ati o n  of  g e m cit a bi n e i n 
a d v a n c e d s oft tiss u e s ar c o m as  a n d  wi n d o w  e v al u ati o n  of  d os e r at e  o n  g e m cit a bi n e tri p h os p h at e 
a c c u m ul ati o n. J  Cli n  O n c ol  2 0 0 1; 1 9: 3 4 8 3- 9. 
2 4.    
M a ki  R G,  W at h e n J K,  P at el  S R,  et  al.  R a n d o mi z e d  p h as e II st u d y  of  g e m cit a bi n e  a n d 
d o c et a x el  c o m p ar e d  wit h  g e m cit a bi n e  al o n e i n  p ati e nts  wit h  m et ast ati c s oft tiss u e s ar c o m as: 
r es ults  of s ar c o m a  alli a n c e f or r es e ar c h t hr o u g h  c oll a b or ati o n st u d y  0 0 2 [ c orr e ct e d]. J  Cli n  O n c ol 
2 0 0 7; 2 5: 2 7 5 5- 6 3. 
2 5.    
M a ki  R G.  G e m cit a bi n e  a n d  d o c et a x el i n  m et a st ati c s ar c o m a:  p ast,  pr es e nt,  a n d f ut ur e. 
O n c ol o gist  2 0 0 7; 1 2: 9 9 9- 1 0 0 6.