NYU 05-40 PBMTC ONC-032P:High Dose Temozolomide,Thiotepa and Carboplatin With Autologous Stem Cell Rescue (ASCR) Followed by Continuation Therapy With 13-cis-retinoic Acid in Patients With Recurrent/Refractory Malignant Brain Tumors
Phase: PHASE2
Conditions: Brain Tumors
Sponsor: NYU Langone Health

2/ 1 8/ 2 0 1 1  versi o n 4 
P B M T C O N C -0 3 2: Hi g h d ose te m o z ol o mi d e, t hi ote p a a n d c a r b o pl ati n wit h a ut ol o g o us 
ste m cell resc ue ( A S C R) f oll o we d b y c o nti n u ati o n t he r a p y wit h 1 3 -cis-reti n oic aci d i n 
p atie nts wit h rec ur re nt/r efr a ct or y  m ali g n a nt b r ai n t u m ors.  
P ri nci p al I n v esti g at o r:  
S h ar o n G ar d ne r, M D  
Ne w Y o r k U ni v e rsit y M e dic al Ce nte r  
3 1 7 E. 3 4t h Str e et, 8t h Fl o o r  
Ne w Y o r k, N Y 1 0 0 1 6  
E m ail: S h ar o n. g ar d ne r @ n y u mc. o r g  
Tele p h o ne: ( 2 1 2) 2 6 3 - 84 0 0  
F a x: ( 2 1 2) 2 6 3 -8 4 1 0  
C o -Pri nc i p al I n vesti g at o rs: 
A n n e B e n d el, M. D.  
C hil dr e n’s H os pitals a n d Cli ni cs -M pls/ St. Pa ul  
2 5 2 5 C hica g o A v e n u e. S.  
S uit e 4 1 5 0  
Mi n n ea p olis, M N  5 5 4 0 4  
E mail: a n n e. b e n d el @ c hil dre ns h c. or g  
T ele p h o n e:( 6 1 2) 8 1 3 -5 9 4 0  
Fa x:( 6 1 3) 8 1 3 -6 3 2 5  
Mar k  Atlas, M. D.  
Sc h nei d er C hil dr e n's H os pital  
2 6 9 -0 1 7 6 t h A v e n u e, R m 2 5 5  
Ne w H y de Par k, N Y  1 1 0 4 0  
E mail: matlas @lij. e d u  
T ele p h o n e:( 7 1 8) 4 7 0 -3 4 6 0  
Fa x:( 7 1 8) 3 4 3 -4 6 4 2  
St u d y O pe r ati o ns Offic e:  
Ne w Y or k U ni v ersit y M e di cal C e nter  
N C T 0 0 5 2 8 4 3 7

 
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E x peri m e ntal D esi g n  
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Ba c k gr o u n d a n d Rati o nale  
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Treat m e nt Pla n  
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Re q uir e d O bser vati o ns  
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Ne ur o pat h ol o g y G ui deli nes/ S p eci me n S u b missi o n R e q ui r e me nts 
 
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Ne ur ora di ol o g y G ui d eli n es/ Ra di o gra p hi c S u b missi o n R e q uir e m e nts  
 
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E val u ati o n of R es p o nse a n d Rela pse Crit eria  
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S u p p orti v e Car e G ui d eli n es  
 
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S t u d y M o nit ori n g 
 
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Statistical C o nsi d erati o ns  
 
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Ge n d er a n d Et h ni c Ori gi n  
 
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1 7. 0      C o nse nt Pr oc e d ures  
 
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1 9. 0    A p p e n di x A:     A dj ust e d B o d y W ei g ht  
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           A p p e n di x B:     A d v erse E v e nt R e p orti n g G ui d eli n es  
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           A p p e n di x C:  
A d v erse E v e nt Assess m e nt F or m  
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           A p p e n di x D:     I nf or m e d C o nse nt  
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A p p e n di x E:      C oll ecti o n a n d S hi p m e nt of Bi ol o gi cal Sa m ples  
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1. 0  
S P E CI FI C AI M S  
 
 
1. 1  
Pri m ar y  
•  T o assess t h e e ve nt-fre e s ur vi val ( E F S) a n d o v erall s ur vi val ( O S) of pati e nts wit h r e c urre nt or refra ct or y 
m e d ull o blast o ma/ pri miti ve n e ur oe ct o d er mal t u m ors ( P N E T) wit h mi ni mal r esi d u al disease treate d wit h 
hi g h d ose t e m oz ol o mi d e, t hi ot e pa a n d car b o plati n wit h A S C R f oll o we d b y c o nti n u ati o n t h era p y wit h 1 3 -cis-
reti n oi c a ci d. 
1. 2  
Se c o n d ar y  
•  T o assess t h e E F S a n d O S of pati e nts wit h r e c urre nt or r efra ct or y c e ntral n er v o us s yst e m g er m c ell t u m or 
( C N S G C T), hi g h gra d e gli o ma, bra i nste m gli o ma, e p e n d y m o ma, at y pical t erat oi d/r ha b d oi d t u m or ( A T/ R T) 
a n d ot h er hi g h gra d e mali g na nt brai n t u m ors (e x cl u di n g hi g h gra d e gli o mas) wit h mi ni mal r esi d u al disease 
treat e d wit h hi g h d ose t e m o z ol o mi d e, t hi ot e pa a n d car b o plati n wit h A S C R f oll o we d b y c o nti n u ati o n t h era p y 
wit h 1 3 -cis -r eti n oi c a ci d. 
•  T o e val u ate t he t o xicit y of hi g h d ose t e m oz ol o mi d e, t hi ot e pa a n d car b o plati n wit h A S C R w h e n p erf or m e d 
i n a m ulti-i nstit uti o nal setti n g. 
•  T o e val u ate t he t o xicit y of 1 3 -cis -reti n oic a ci d f oll o wi n g hi g h d ose t em o z ol o mi de, t hi ot e pa a n d car b o plati n 
wit h A S C R.  
•  T o assess t h e i nt er-i n di vi d u al varia bilit y i n plas ma p har ma c o ki n eti cs of 1 3-cis-r eti n oi c a ci d a n d assess a 
si n gl e C S F 1 3-cis -r eti n oi c a ci d l e v el t o d et er mi n e if it is a p ot e ntial i n di cat or of C N S p e n etrati o n of t h e 
dr u g.  
•  T o i n v esti gat e t h e i nfl u e nc e of g e neti c variati o n i n e nz y m es i n v ol v e d i n t h e m eta b olis m of 1 3 -cis -reti n oi c 
a ci d o n t h e p har ma c o ki neti cs of t his a g e nt.  
•  T o relate i nt er -i n di vi d u al varia bilit y i n t h e p har ma c o ki n eti cs of 1 3-cis -r eti n oic a ci d a n d ge n eti c variati o n t o 
cli ni cal res p o nse as m eas ure d b y e ve nt -fre e s ur vi val a n d t o xicit y.  
 
2. 0  
E X P E RI M E N T A L D E SI G N  
 
T his is a p hase II st u d y of t e m o z ol o mi de, t hi ot e pa a n d car b o plati n wit h A S C R f oll o we d b y c o nti n u ati o n t h era p y 
wit h 1 3 -cis -r eti n oi c a ci d i n pati e nts wit h r e c urre nt or r efra ct or y brai n t u m ors wit h mi ni mal r esi d u al disease. 
Pati e nts will first u n d er g o t he c olle cti o n of a ut ol o g o us p eri p h eral bl o o d st e m c ells f oll o wi n g m o bilizati o n wit h 
fil grasti m a n d/ or c h e m ot h era p y.  C yt or e d u cti v e t h era p y will b e gin aft er a d e q u ate n u m b ers of st e m c ells ha ve 
be e n c oll e ct e d.  Pati e nts will re c ei v e t e m o z ol o mi d e orall y t wi ce dail y f or fi v e da ys f oll o we d b y t hi ot e pa a n d 
car b o plati n a d mi nist er e d i ntra v e n o usl y dail y f or t hre e da ys. A ut ol o g o us st e m c ells will be r ei nf use d t hr e e da ys 
f oll o wi n g t h e c o m pl eti o n of t h e c h e m ot h era p y. Patie nts w h o ha ve n ot alr ea d y r e cei v e d t h eir life ti m e ma xi m u m 
d ose of ra diati o n t h era p y ma y r e c ei ve a d diti o nal ra diati o n t h era p y f oll o wi n g re c o v er y fr o m t h e hi g h d ose 
c h e m ot h era p y. Pati e nts will b e gi n t h era p y wit h 1 3 -cis -r eti n oi c a ci d b et we e n da y + 4 2 a n d da y + 7 7 f oll o wi n g  
A S C R. T h e 1 3 -cis -reti n oi c a ci d will b e gi v e n dail y f or 1 4 da ys f oll o we d b y a 1 4 da y br ea k f or si x m o nt hs. 
 
P ati e nts will b e e n c o ura g e d t o ha v e bl o o d a n d C S F o btai n e d at s pe cifi c ti m e p oi nts ar o u n d t h e first c o urse of 
1 3 -cis -reti n oic a ci d t o d et er mi n e bl o o d a n d C S F p har ma c o ki neti cs of 1 3-cis -reti n oi c a ci d a n d g e neti c variati o n 
i n e n z y m es i n v ol v e d i n t h e m eta b olis m of 1 3-cis -r eti n oi c a ci d.  T her e will b e c e ntrali z e d r e vi e w of pat h ol o g y 
a n d res p o nse data.  
 
3. 0  
B A C K G R O U N D A N D R A TI O N A L E  
 
3. 1 
Pati e nts wit h re c urr e nt mali g na nt brai n t u m ors ha v e a dis mal pr o g n osis 1, 2, 3, 4, 5.  T h e use of c o n v e nti o nal 
d ose c h e m ot h era p y i n t hese patie nts ca n pr o d u c e o bj e cti v e ra di o gra p hi c r es p o nses, b ut al m ost i n varia bl y of 
d urati o n m eas ure d i n m o nt hs rat h er t ha n years. T h e use of hi g h d ose c h e m ot hera p y wit h a ut ol o g o us st e m c ell 
Ge neral Ba c k gr o u n d  

 
4  
resc u e f or t he tr eat m e nt of pati e nts wit h re c urr e nt mali g na nt brai n t u m ors has b e e n re p ort e d fr o m se v eral 
c e nters.  Re s p o nses ha ve b e e n o bser v e d i n pati e nts wit h r e c urr e nt m e d ull o bl ast o ma, P N E T, hi g h gra d e gli o ma 
a n d C N S G C T. 6, 7, 8, 9, 1 0   T h ese r e gi m e ns are m ost effi ca ci o us i n pati e nts wit h mi ni mal resi d u al t u m or b ur d e n at 
t h e ti m e of t he hi g h d ose c h e m ot hera p y. H o we v er, e ve nt -fr e e s ur vi val ra n gi n g fr o m a p pr o xi matel y 1 5 % 
(re c urre nt gli o blast o ma m ultif or m e) t o 3 0 % (r e c urr e nt m e d ull o blast o ma)7, 6  r e mai ns p o or a n d b e gs t h e q u esti o n 
w h et h er f urt h er c h e m ot h era p e uti c i nt e nsifi cati o n a n d t h e a d diti o n of ne w a g e nts c o ul d i n cr ease t h e  pr o p orti o n 
of pati e nts a c hie vi n g d ura bl e s ur vi val wit h o ut i n cr easi n g t h e earl y m or bi dit y a n d m ortalit y of s u c h tr eat m e nt.  
 
3. 2 
  
 
Alt h o u g h ma n y differe nt m y el oa blati ve pre parati v e r e gi m e ns ha v e b e e n utili z e d i n r e c urre nt C N S 
t u m ors, o ne of t h e m ost s u c c essf ul r e gi m e ns i n cl u d es hi g h d ose t hi ot e pa, car b o plati n a n d et o p osi d e.  T his 
re gi m e n was utili z e d i n C C G 9 8 8 3 a n d res ulte d i n a 3 0 % 3 y ear E F S f or pati e nts wit h re c urr e nt 
m e d ull o blast o ma/ P N E T, b ut it als o res ulte d i n si g nifi ca nt t o xicit y wit h a 1 3 % t o xi c d eat h rat e 7.  I n a n att e m pt t o 
p ote ntiall y de cr ease t h e t o xi cit y a n d p ossi bl y i m pr o v e t h e effica c y of t his r e gi m e n f or r e c urre nt C N S t u m ors, 
Gar d n er et. al ( N e w Y or k U ni v ersit y) ha v e s u bstit ut e d t e m oz ol o mi d e f or et o p osi d e i n c o m bi nati o n wit h 
t hi ot e pa a n d car b o plati n i n a p hase I d ose escalati o n st u d y.  D ose li miti n g t o xi cit y was se e n wit h a d ose of 
te m oz ol o mi d e of 2 0 0 m g/ m 2/ d ose bi d ( 4 0 0 m g/ m 2/ da y). T h e d ose li miti n g t o xicit y i n cl u d e d o n e pati e nt wit h 
se v er e m u c ositis a n d a se c o n d pati e nt wit h tra nsie nt e n c e p hal o pat h y. T he d ose of t e m o z ol o mi d e f or t h e p hase II 
st u d y is 3 5 0 m g/ m 2/ da y ( 1 7 5 m g/ m 2/ d ose) x 5 da ys.  
Rati o nal e f or t h e use of t e m o z ol o mi d e, t hi ote pa a n d car b o plati n  
T e m o z ol o mi d e is a n e w oral al k ylati n g a g e nt.  At p h ysi ol o gi c p H, t e m o z ol o mi d e s p o nta ne o us l y 
de gra des t o M TI C w hic h is t h e a cti v e cata b olite of da car ba zi n e ( D TI C). 1 1  T e m o z ol o mi de e x erts its pri mar y 
a cti vit y b y a d di n g a m et h yl gr o u p t o t h e O 6 -p ositi o n of g u a ni n e.  O 6 -al k yl g u a ni n e D N A al k yl tra nsferase ( A G T) 
re pairs t h e da ma g e ca use d b y met h ylati o n of g u a ni n e. T e m o z ol o mi d e, li k e t he nitr os o ur eas, is m ore effecti v e i n 
t u m ors wit h l o w l e vels of A G T.1 2  G ers o n et al. f o u n d t hat t he a d mi nistrati o n of t e m o z ol o mi d e i n a t wi c e dail y 
sc h e d ul e ra pi dl y d e pl et e d A G T i n a d ose d e pe n d e nt fas hi o n a n d pr e v e nte d its r e g e n erati o n.1 3    
T he C hil dr e n’s Ca n cer Gr o u p p erf or m e d a p hase I st u d y of t e m oz ol o mi d e i n p e diatri c pati e nts wit h 
re c urre nt s oli d t u m ors.1 4  T he d ose of t e m o z ol o mi d e was stratifi e d b y pri or cra ni os pi nal irra diati o n a n d was 
a d mi nist ere d orall y f or fi v e da ys wit h s u bse q u e nt c y cl es a d mi nist ere d e v er y 2 1 t o 2 8 da ys.  T he ma xi m u m 
t ol erat e d d ose was 2 1 5 m g/ m2/ da y f or patie nts wit h o ut pri or cra ni os pi nal irr a diati o n a n d 1 8 0 m g/ m2 / da y f or 
t h ose wit h pri or cra ni os pi nal irra diati o n.  T h e d ose li miti n g t o xiciti es wer e n e utr o p e nia a n d t hr o m b o c yt o p e nia.  
Alt h o u g h n o n o n he mat ol o gi c d ose li miti n g t o xi cit y o c c urre d, m or e t ha n half of t h e pati e nts ha d na usea a n d 
v o miti n g. T h e U nit e d Ki n g d o m has als o p u blis h e d r es ults of a p hase I st u d y of t e m o z ol o mi d e i n p e diatri c 
pati e nts wit h a d va n c e d ca n c er w h ere t he d ose li miti n g t o xi cit y was m y el os u p pr essi o n 1 5. 
T e m o z ol o mi d e has be e n f o u n d t o ha ve effi ca c y i n t h e tr eat m e nt of hi g h -gra de gli o mas i n a d ults.  I n a 
p hase II st u d y b y N e wla n ds et al, t e m o z ol o mi de was i nitiall y gi v e n at a d ose of 1 5 0 m g/ m 2/ da y f or fi ve da ys t o 
a d ult pati e nts wit h mali g na nt gli o mas. 1 6   T h e d ose was i ncr ease d t o 2 0 0 m g/ m 2/ da y f or 5 da ys i n s u bse q u e nt 
c o urses if t h er e was n o si g nifi ca nt m y el os u p pr essi o n n ot e d o n da y 2 2.  T he o bje cti v e res p o nse rate was 3 0 % i n 
2 7 patie nts wit h pri mar y disease tr eat e d wit h t w o c o urses of t e m oz ol o mi d e pri or t o ra di ot h era p y a n d 2 5 % i n 4 8 
pati e nts w h o were tr eat e d aft er t h eir disease ha d re c urr e d f oll o wi n g i nitial s ur g er y a n d ra di ot hera p y.  I n a 
m ulti c e nt er p hase II trial of t e m oz ol o mi d e i n a d ult pati e nts wit h a na plasti c astr o c yt o ma or a na plasti c 
oli g oastr o c yt o ma at first r ela pse, t h e o bj ecti ve r es p o nse rat e was 3 5 % ( 8 % c o m plete r es p o nse ( C R), 2 7 % partial 
res p o nse ( P R)) wit h a n a d diti o nal 2 6 % of pati e nts wit h sta bl e disease ( S D).1 7  F urt h er m ore, t h e C R, P R, a n d S D 
wer e ass o ciate d wit h healt h -relate d q u alit y-of -life b e n efits.  
T her e is s o m e e x p erie n c e usi n g t e m o z ol o mi d e i n p e diatric patie nts wit h mali g na nt brai n t u m ors, 
i n cl u di n g m e d ull o blast o ma/ P N E T.  Fri e d ma n et al. ha ve d e m o nstrat e d effi c a c y of t e m o z ol o mi de a gai nst 
m e d ull o blast o ma t u m or x e n o grafts 1 8.  A p e diatri c p hase II st u d y of te m o z ol o mi de i n r e c urre nt p e diatri c C N S 
t u m ors ( C C G A 0 9 7 0 1) s h o we d a cti vit y of t e m o z ol o mi d e i n re c urr e nt m e d ull o blast o ma/ P N E T r es ulti n g i n a C R 
i n 1/ 2 1, P R i n 3/ 2 1 a n d S D i n 1/ 2 1 pati e nts.  A si n gl e case r e p ort descri b es a c o m plete r es p o nse of 
le pt o me ni n geal r ec urr e n ce of m e d ull o blast o ma t o t e m oz ol o mi d e1 9. 
 
3. 3  Rati o nal e f or c o nti n u ati o n t h era p y wit h 1 3 -cis -reti n oic a ci d 

 
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Des pit e e nc o ura gi n g pr eli mi nar y r es ults wi t h m yel oa blati v e c he m ot h era p y f oll o we d b y ste m c ell tra ns pla nt, t h e 
maj orit y of pati e nts s u c c u m b t o t h eir t u m or d u e t o resi d u al mi cr osc o pi c dise ase t hat is r esista nt t o c h e m ot h era p y 
a n d ra diati o n t h era p y.  It w o ul d b e a p p eali n g t o fi n d a bi ol o gi cal a ge nt f or r e c urre nt brai n t u m ors t hat c o ul d b e 
utiliz e d p ost tra ns pla nt t o eli mi nat e or c ha n g e t h e a g gressi v e p ot e ntial of a n y mi ni mal resi d u al disease.  1 3 -cis -
reti n oi c a ci d is a well k n o w n bi ol o gi cal a g e nt t hat i n d u c es differ e ntiati o n a n d de cr eases pr oliferati on of 
ne ur o blast o ma c ell li n es.  1 3 -cis -reti n oi c a ci d has b ee n utili z e d cli ni call y i n a pr e vi o us n e ur o blast o ma tr eat m e nt 
st u d y, C C G 3 8 9 1, w h ere it was gi v e n p ost-tra ns pla nt o n a sc h e d ul e c o nsisti n g of si x 2 8 da y c y cl es, wit h 1 3-cis-
reti n oi c a ci d a d mi nist ered o n t h e first 1 4 da ys of ea c h 2 8 da y c y cl e.  Wit h t his re gi m e n, 1 3 -cis -r eti n oi c a ci d was 
well t ol erat e d wit h mil d t o xi citi es i n cl u di n g c h elitis, dr y s ki n, h y p ertri gl y c eri d e mia a n d h y p er cal c e mia, a n d was 
s h o w n t o i m pr o v e t h e E F S a n d O S of pati e nts wit h hi g h ris k n e ur o blast o ma. 2 0  
   T h er e is mi ni mal e x p eri e n ce usi n g 1 3 -cis -r eti n oi c a ci d i n brai n t u m ors.  B o uterfa et al. r e p ort e d i n hi biti o n of 
pr oliferati o n a n d mi grati o n of pri mar y c ult ur es of h u ma n gli o blast o ma m ultif or m e w he n e x p ose d t o r eti n oi ds 
i n cl u di n g 1 3 -cis -r eti n oi c a ci d.2 1 Y u n g et al. r e p ort e d a P hase II st u d y f or r ec urre nt mali g na nt gli o ma utili zi n g 
1 3 -cis-reti n oic a ci d at a d ose of 6 0-1 0 0 m g/ m 2/ da y f or 2 1 o ut of 2 8 da ys.  Of t h e f ort y-t hr e e pati e nts w h o 
re cei v e d m or e t ha n 4 wee ks of t h era p y, 7 % ha d a P R, 1 6 % ha d a mi n or r es p o nse a n d 3 0 % ha d sta ble disease 2 2 .   
A gra wal et al. fr o m N e w Y or k U ni v ersit y ( p ers o nal c o m m u nicati o n) ha ve f o u n d t hat m e d ull o blast o ma c ells 
e x pr ess R A R -al p ha b ut n ot R A R -beta b y west er n bl ot.  T h e y ha v e treat e d m ulti pl e esta blis h e d m e d ull o blast o ma 
c ell li nes a n d s h ort t er m m e d ull o blast o ma c ult ur es t o reti n oi ds a n d ha v e f o u n d t hat a p pr o xi mat el y 6 5 % r es p o n d.  
T he m e d ull o blast o ma c ell li ne D 2 8 3 M E D has b e e n reti n oi d se nsiti v e wit h a c o n c o mita nt d e cr ease i n H u 
e x pr essi o n, a mar k er of n e ur o nal differ e ntiati o n, s u g g esti n g t hat t h e a nti pr oliferati v e effe ct of r eti n oi ds ma y n ot 
be ass o ciat e d wit h differe ntiati o n al o n g a n e ur o nal pat h wa y.  Ols o n et al fr o m Fr e d H utc hi ns o n Ca n c er 
Researc h Ce nt er has l o o k e d at i n -vitr o r es p o nse of m e d ull o blas t o ma a n d e p e n d y m o ma c ells t o r eti n oi ds.2 3   H e 
f o u n d t hat m e d ull o blast o ma c ell li n es D 2 8 3 a n d D 3 4 1 u n d er we nt a p o pt osis i n 5 9-7 8 % of t h e c ells w h e n 
e x p ose d t o 1 3 -cis -r eti n oi c a ci d a n d all-tra ns r eti n oi c a ci d, w h er eas m e d ul o bl ast o ma cell li n es D A O Y a n d 
U W 2 2 8 s h o we d n o r es p o nse t o t h ese a g e nts. Ols o n als o n ot e d t hat a p o pt osis was i n hi bite d i n t h e fa c e of 
reti n oi c a ci d r e ce pt or a nta g o nists, s u g g esti n g t hat r eti n oi c a ci d r e c e pt or a cti vit y is criti cal t o t h e a cti vit y of 
reti n oi ds i n t h ese c ell li nes.  I nt er esti n gly, t h e s u bset of D 2 8 2 cells t hat di d n ot u n d er g o a p o pt osis de v el o pe d 
ne uriti c e xt e nsi o ns t h o u g ht c o nsist e nt wit h differe ntiati o n/ mat urati o n of t h e c ell. Ols o n has als o t est e d 1 0 fr es h 
pri mar y m e d ull o blast o ma t u m ors a n d f o u n d a hi g h rat e of a p o pt osis i n 8 of t he 1 0 t u m ors. H e has als o st u di e d 
reti n oi d e x p os ure t o 2 fr es h pri mar y e p e n d y m o ma t u m ors a n d n ote d n e ur o n al differ e ntiati o n i n t he c ells of b ot h 
t u m ors a n d a p o pt osis i n o n e of t h e t u m ors. 
 
3. 4  
3. 4. 1  
C o m pa ni o n Bi ol o g y St u d y  
      
I n v esti gati o n of t h e relati o ns hi p of 1 3-cis -r eti n oi c a ci d p har ma c o ki n eti cs a n d      
1 3 -cis-reti n oic a ci d p har ma c o ki n eti cs wer e pr e vi o usl y e xa mi n e d i n a p hase I st u d y utilizi n g 1 3-cis -r eti n oi c a ci d 
i n 3 1 pe diatric pati e nts wit h n e ur o blast o ma f oll o wi n g B M T. T his st u d y f o u n d si g nifi ca nt i nt er -pati e nt 
varia bilit y i n p ea k ser u m l e v els of 1 3 -cis -r eti n oi c a ci d.2 4, 2 5  Ma n y t hi n gs ma y affe ct t h e p har ma c o ki neti cs of 1 3 -
cis -r eti n oi c a ci d a n d t h er ef or e ma y i nfl u e n c e its effi ca c y. 1 3-cis -reti n oi c a ci d, w h e n a bs or be d, ma y b e s u bj ect t o 
first-pass m eta b olis m a n d s u bse q u e nt plas ma (a n d t u m or) c o nc e ntrati o ns will d e p e n d o n t h e rat e of m eta b olis m 
t o t h e i na cti v e 4-o x o m eta b olit e.  
p har ma c o g e neti c variati o n i n dr u g m eta b oli zi n g e n z y mes.  
     A n u m b er of c yt oc hr o m e P 4 5 0 ( C Y P) e nz y m es ha v e b e e n i de ntifi e d as pla y i n g a r ol e i n t h e m eta b olis m of 
1 3 -cis-reti n oic a ci d i n cl u di n g C Y P 2 C 8 a n d C Y P 3 A 7. G e n etic p ol y m or p his ms i n t h e C Y P 2 C 8 or C Y P 3 A 7 ge n e 
ha v e b ee n d escri b e d w hic h c o ul d u n derli e i n di vi d u al differe n c es i n 1 3 -cis -r eti n oi c a ci d m eta b olis m a n d 
bi oa vaila bilit y. 2 6, 2 7, 2 8, 2 9  A f urt h er as pe ct of 1 3 -cis -r eti n oi c a ci d m eta b olis m is gl u c ur o ni dati o n, of b ot h t he par e nt 
dr u g a n d of 4 -h y dr o x y -m eta b olit es. T his c o nj u gati o n ma y b e m e diate d b y U G T 1 A 1 or U G T 2 B 7, 3 0 b ot h 
e n z y m es t hat ar e s u bj ect t o g e n etic p ol y m or p his ms. 3 1 
     Alt h o u g h li mit e d st u di es ha ve b e e n d o n e o n t h e p har ma c o ki n eti cs of 1 3 -cis -r eti n oi c a ci d, t h er e ar e n o h u ma n 
data a n d mi ni mal a ni mal data c o nc er ni n g t h e pe n etrati o n of 1 3 -cis -r eti n oi c a ci d i nt o t h e c e ntral n er v o us s yst e m. 

 
6  
1 3 -cis-reti n oic a ci d is v er y li p o p hilic a n d is hi g hl y b o u n d ( > 9 9 %) t o plas ma pr otei ns.3 2 B e ca use of t hese 
feat ures, it is u n certai n h o w a c c urat el y C S F l e v els of 1 3-cis -r eti n oi c a ci d will pr e di ct p e netrati o n of t h e dr u g 
i nt o t h e brai n tiss u e. T here are n o st u di es i n h u ma ns or a ni mals i n r e gar ds t o C S F 1 3-cis -reti n oic a ci d l e v els. 
T her e ar e data i n rats re gar di n g t he p e n etrati o n of 1 3 -cis -reti n oic a ci d i nt o br ai n tiss u e. L e D o ze et al. m eas ur e d 
t h e p har ma c o ki n eti cs of 1 3-cis -r eti n oi c a ci d i n rat ser u m a n d brai n tiss u e a n d f o u n d 1 3-cis -r eti n oic a ci d 
per m eat e d i nt o t h e rat brai n. T h e brai n tiss u e l e v els of 1 3 -cis r eti n oi c a ci d wer e l o wer t ha n t h e plas ma l e v els, 
b ut c o n c e ntrati o n -ti m e pr ofil e se e n i n t h e brai n tiss u e parall el e d t hat se e n i n t h e ser u m.3 3 
     A c urr e nt U K st u d y ( U K C C S G St u d y P K 2 0 0 0 0 8) is i n v esti gati n g t h e v ariati o n i n 1 3 -cis -r eti n oi c a ci d 
p har ma c o ki n eti cs wit hi n a n d b et we e n c o urses of 1 3 -cis -r eti n oic a ci d w h e n gi v e n t o ne ur o blast o ma pati e nts 
f oll o wi n g a ut ol o g o us st e m cell tra ns pla nt. It has c urre ntl y re cr uit e d 2 8 pati e nts a n d pr eli minar y data i n di cat e 
t hat plas ma c o n c e ntrati o ns of 4-o x o -1 3 -cis -r eti n oi c a ci d, a n i na cti v e m eta b olit e of 1 3-cis -reti n oic ca n 
a cc u m ulat e t o e x ce e d t h e c o n c e ntrati o n of t h e pare nt c o m p o u n d d uri n g a 1 4 da y c o urse of tr eat m e nt. 3 4  T he data 
als o i n di cat e a n a p pr o xi mat e 1 0-f ol d variati o n i n 4-o x o -1 3 -cis -reti n oi c a ci d pea k plas ma c o n c e ntrati o ns 
bet wee n pati e nts r e c ei vi n g a sta n dar d d ose of 1 3 -cis -r eti n oi c a ci d. Be ca use 4-o x o -1 3 -cis -r eti n oi c a ci d is a 
reti n oi d br ea k d o w n pr o d u ct wit h littl e or n o a cti vit y, t his le v el of meta b olis m i n viv o ma y l ea d t o a di mi nis h e d 
effi ca c y of 1 3 -cis -r eti n oi c a ci d. 
     T he c urre nt st u d y is d esi g ne d t o b uil d o n data bei n g o btai n e d i n t he U K, c o n c er ni n g t h e i nter -i n di vi d u al 
varia bilit y of 1 3 -cis -r eti n oi c a ci d p har ma c o ki n eti cs a n d t he i nfl ue n c e of g e n eti c variati o n i n c yt o c hr o m e P 4 5 0 
e n z y m es o n t he meta b olis m of 1 3 -cis -r eti n oi c a ci d. T his will all o w d et er mi n ati o n of p ote ntial r elati o ns hi ps 
bet wee n i nter -i n di vi d u al p har ma c o ki n eti c varia bilit y, g e n etic variati o n i n e n z y m e a cti vit y a n d cli ni cal r es p o nse 
( 3 y ear e v e nt-fr e e s ur vi val) a n d t o xi cit y. R es ults fr o m t his st u d y will pr o vi d e a n i nsi g ht i nt o w h et her 
m o d ulati o n of 1 3 -cis -r eti n oi c a ci d d osi n g a cc or di n g t o s yst e mi c e x p os ure a n d/ or ge n ot y p e c o ul d be use d i n 
f ut ur e st u di es t o o pti mi z e t h e tr eatm e nt of ca nc ers. I n t his st u d y, p har ma c o ki neti c a n d p har ma c o ge n eti c 
sa m pli n g will b e carrie d o ut d uri n g a si n gle c o urse of 1 3-cis -r eti n oic a ci d tr e at m e nt. Fi v e ser u m sa m pl es ( pr e-
treat m e nt, a n d at 1, 2, 4 a n d 6 h o urs aft er oral a d mi nistrati o n of 1 3-cis -r eti noi c a ci d o n da y 1 4 of c y cl e 1) al o n g 
wit h a si n gle C S F sa m pl e ( 2 h o urs after a d mi nistrati o n of 1 3 -cis -r eti n oi c a ci d o n da y 1 4 of t h e first c o urse) will 
be c oll ecte d t o assess 1 3 -cis -r eti n oi c a ci d l e vels. A si n gle bl o o d sa m ple will be o btai n e d pre-tr eat me nt wit h 1 3 -
cis -r eti n oi c a ci d t o p erf or m ge n ot y p e a nal ysis f or e n z y m es t h o u g ht t o b e i n v ol ve d i n t he meta b olis m of 1 3-cis -
reti n oi c a ci d. All pati e nts ar e str o n gl y e n c o ura g e d t o parti ci pat e i n all as p e cts of t h e p har ma c o ki n eti c/ g e n ot y p e 
a nal ysis st u d y. M ost pati e nts ha ve t u m ors wit h a pr o p e nsit y f or C S F disse mi nati o n a n d t h us will r e q uir e a s pi nal 
ta p pr e-mai nte na nc e f or disease a nal ysis, w hi c h ca n b e c o or di nat e d wit h t he C S F p har ma c o ki neti c l e v el.   
 
4. 0  
P atie nt Eli gi bilit y  
 
4. 1  
Pati e nts wit h re c urr e nt or r ef ra ct or y m e d ull o blast o ma/ P N E T, C N S g er m c ell t u m ors, e p e n d y m o mas, 
A T/ R T , hi g h gra d e gli o ma a n d ot h er mali g na nt brai n t u m ors.  Brai nst e m gli o mas are eli gi bl e if r esi d u al 
disease is <  1. 5 c c a n d if t h e pati e nt is off d e ca dr o n.  
4. 2       Pati e nts m ust ha v e r e c urr e nt or r efra ct or y disease f oll o wi n g at l east o n e pri or c o urse of t h era p y a n d m ust 
ha v e mi ni mal r esi d u al disease d efi ne d as <  1. 5 c m 2  of e n ha n c e m e nt. Pati e nts wit h + C S F c yt ol o g y, 
li n ear or fi n e n o d ular l e pt o m e ni n g eal disease ar e eli gi bl e. 
4. 3  
Kar n ofs k y P erf or ma nc e Stat us or La ns k y P erf or ma nc e sc or e >  7 0 %.  
4. 4  
Pati e nts m ust ha v e a n a nti ci pat e d life e x p e cta n c y of gr eat er t ha n 1 2 wee ks t o be eli gi bl e f or t his st u d y.  
4. 5  
A d e q u at e he mat ol o gi c, re nal, li v er, a n d car dia c f u n cti o n as de m o nstrat e d b y la b orat or y va l u es 
perf or m e d wit hi n 2 1 da ys, i n cl usi ve, pri or t o a d mi nistrati o n of te m o z ol o mi d e.  
  
- A bs ol ut e n e utr o p hil c o u nt >  7 5 0/ m m 3  
  
- Plat el et c o u nt >  5 0, 0 0 0/ m m 3  
- H e m o gl o bi n >  1 0 g m/ d L ( Pati e nts ma y b e tra nsf use d t o raise t he h e m o gl o bi n a b o ve 1 0 g m/ dl)                           
  
- B U N a n d ser u m cr eati ni n e < 1. 5 ti mes u p p er li mit of la b orat or y n or mal  
  
- Cr eati ni n e cleara n ce or G F R >  7 0 cc/ mi n/ 1. 7 3 m 2    

 
7  
  
- T otal ser u m bilir u bi n < 1. 5 ti mes u p per li mit of la b orat or y n or mal  
  
- S G P T < 2. 5 ti m es u p p er li mit of la b orat or y n or mal  
4. 6  
Pati e nts m ust ha v e a n a de q u ate n u m b er of a ut ol o g o us st e m cells a vaila bl e d efi n e d as a mi ni m u m of 2 x 
1 0 6 C D 3 4 + cells/ k g a n d pr efera bl y at l east 5 x  1 0 6 C D 3 4 + c ells/ k g.  
4. 7  
A g e great er t ha n 6 m o nt hs of a g e a n d l ess t ha n 2 1 y ears.  
4. 8  
Pati e nts m ust ha v e r e c o v er e d fr o m a n y effe cts of maj or s ur g er y, c h e m ot h era p y or ra diati o n. Pati e nts 
ma y n ot ha v e r e cei v e d c he m ot h era p y ( e x cl u di n g nitr os ureas) wit hi n 2 1 da ys a n d ma y n ot ha ve r ec ei v e d 
ra diati o n t h era p y or nitr os ur eas wit hi n 4 2 da ys of starti n g tr eat m e nt. 
4. 9  
Pati e nts ma y ha ve r e cei v e d st er e ota cti c ra diati o n at t h e ti m e of r e c urre n c e as part of t h eir sal va g e 
treat m e nt. 
4. 1 0  
Pati e nts or l e gal g u ar dia ns m ust gi ve writt e n, i nf or me d c o nse nt.  
 
P atie nts  wit h a n y
 
 of t he f oll o wi n g c rite ri a ar e e xcl u de d fr o m t he st u d y:  
4. 1 1  
Pre vi o us m yel oa blati v e t h era p y  
4. 1 2  
Fre q u e nt v o miti n g or me di cal c o n diti o n t hat c o ul d i nt erfer e wit h oral m e di c ati o n i nta k e ( e. g., partial 
b o wel o bstr u cti o n)  
4. 1 3  
Pre vi o us or c o n c urr e nt  mali g na n ci es at ot h er sit es wit h t h e e x c e pti o n of s ur gicall y c ur e d car ci n o ma i n -
sit u of t he c er vi x a n d basal or s q u a m o us c ell car ci n o ma of t h e s ki n.  Pati e nts wit h pri or mali g na n ci es 
w hi c h ha v e n ot r e q uire d a nti -t u m or treat m e nt wit hi n t h e pr ec e di n g 2 4 m o nt hs ar e eli gi bl e. 
4. 1 4  
K n o w n HI V p ositi vit y or AI D S -r elat e d ill ness. 
4. 1 5  
Pre g na nt or n ursi n g w o m e n.  
4. 1 6  
W o m e n of c hil d b eari n g p ot e ntial w h o are n ot usi n g a n effecti ve met h o d of c o ntra c e pti o n.   
4. 1 7  
Me n w h o r ef use t o use a n effe cti v e met h o d of c o ntra c e pt i o n. 
4. 1 8  
I nstit uti o n al H u m a n Ri g hts C o m mitte e/I nstit uti o n al Re vie w B o ar d a p p r o v al:                        
                                  
A p pr o val f or t h e use of t his tr eat m e nt r e gi me n b y t h e i n di vi d u al’s H u ma n Ri g hts C o m mitte e or 
I nstit uti o nal Re vi e w Boar d (I R B) m ust b e o btai ne d i n a c c or da n c e wit h t h e i n di vi d u al i nstit uti o nal 
ass ura n c e p oli ci es of t h e U nit e d Stat es D H H S a n d m ust b e o n  fil e at t h e N e w Y or k U ni v ersit y P e diatri c 
O n c ol o g y Trials Offi c e pri or t o e nr oll m e nt of a n y pati e nt o n st u d y.  
 
4. 1 9  
P ati e nt Re gistr ati o n:  
 
 
Pati e nts will e nt er o n st u d y at t he ti m e pr ot oc ol t hera p y is pla n n e d t o b e gi n. Eli gi bl e pati e nts will be 
re gist er e d b y c o nta cti n g R osa C h u  i n t he P e diatri c O n c ol o g y Cli ni cal Trials Offic e at N e w Y or k 
U ni versit y M o n da y t hr o u g h Fri da y 9 a m -5 p m East er n Ti me at ( 2 1 2) 2 6 3 -9 9 2 4  e x c e pt h oli da ys. T h e 
i nf or mati o n r e q u est e d o n t h e pr ot o c ol eli gi bilit y f or m m ust be c o m pl et e d a n d t h e si g ne d i nf or m e d 
c o nse nt f or pr ot oc ol t hera p y m ust b e fa x e d t o ( 2 1 2) 2 6 3 -8 4 1 0 at t h e ti me of t his t ele p h o n e call f or 
re gistrati o n t o o c c ur. Pati e nts m ust b e r e gist er e d pri or t o starti n g pr ot oc ol t h era p y. A n e mail c o nfir mi n g 
eli gi bilit y will b e se nt t o t h e treati n g i nstit uti o n.  
 
 
 

 
8  
5. 0  
T R E A T M E N T P L A N  
 
5. 1  
P ost -rela pse/ Pr e-tra ns pla nt t h era p y:
T his t hera p y is n ot di ctat e d b y st u d y.  It ma y i n cl u d e s ur g er y a n d/ or c h e m ot hera p y. Ra diati o n t h era p y is 
all o we d b ut n ot r ec o m m e n d e d d uri n g r ei n d u cti o n b eca use of t h e p ot e ntial i n cr ease i n tra ns pla nt t o xi cit y.  
   
 
5. 2  
 
Pati e nts will u n d er g o l e u k a p h er esis pri or t o st u d y e ntr y.  Patie nts will b e re q uire d t o ha v e a n a de q u at e 
n u m b er of a ut ol o g o us st e m c ells a vaila bl e, d efi n e d as a mi ni m u m of 2 x 1 0 6 C D 3 4 + c ells/ k g a n d 
pr efera bl y at l east 5 x  1 0 6 C D 3 4 + c ells/ k g.  Pati e nts w h o will b e re c ei vi n g cra ni os pi nal ra diati o n 
t h era p y as part of t heir sal va g e treat m e nt s h o ul d att e m pt t o u n d er g o st e m c ell har v est pri or t o ra diati o n 
t h era p y.   
A ut ol o g o us P eri p h eral Bl o o d St e m C ell C oll e cti o n  
 
5. 3  
 
M y el oa blati ve C h e m ot h era p y --T e m o z ol o mi d e, T hi ot e pa, a n d Car b o plati n.  
5. 3. 1    C he m ot he r a p y will be d ose d ac c o r di n g t o a dj uste d b o d y wei g ht f o r all     
p atie nts wei g hi n g > 1 2 5 % i de al wei g ht f o r hei g ht. ( Se e a p pe n di x A f o r c alc ul ati n g a dj uste d b o d y 
wei g ht.)  
 
5. 3. 2   * N ote: T he c ar b o pl ati n will be d ose d usi n g t he r a w c r e ati ni ne cle ar a nc e. H o we v e r, if t he 
c o r r e cte d c r e ati ni ne cle ar a nc e is < 7 0 ml/ mi n/ 1. 7 3 m2 , neit he r t he c ar b o pl ati n n o r t he t hi ote p a will 
be gi v e n. T he st u d y PI s h o ul d be n otifie d i m me di atel y.  
 
5. 3. 3     P atie nts w h o h a v e a c o r r e cte d c r e ati ni ne cle ar a nc e > 
 
7 0 ml/ mi n/ 1. 7 3 m 2 b ut < 1 0 0 
ml/ mi n/ 1. 7 3 m 2  will r e c ei v e a l o we r d ose of c ar b o pl ati n a n d t hi ote p a t h a n p atie nts w h ose c o r r e cte d 
c r e ati ni ne cle ar a nc e is >   1 0 0 ml/ mi n/ 1. 7 3 m 2.  
5. 3. 4: T he d ose of te m o z ol o mi de will be t he s a me f o r all p atie nts w h ose c o r r e cte d c r e ati ni ne 
cle ar a nc e is > 
 
7 0 ml/ mi n/ 1. 7 3 m 2 . 
5. 3. 5:   D a ys -1 0, -9, -8, -7, a n d - 6 
T e m o z ol o mi d e will b e a d mi nist er e d orall y e v er y t wel v e h o urs (t otal of te n d oses) f or fi v e da ys o n da ys -
1 0 t hr o u g h -6. T h e d ose of t e m o z ol o mi de is 1 7 5 m g/ m 2/ d ose bi d ( or 5. 8 m g/ k g/ d ose bi d f or pati e nts < 3 
years of a g e) f or 5 da ys f or a t otal of 1 7 5 0 m g/ m 2 ( or 5 8 m g/ k g f or pati e nts < 3 y ears of a g e). T h e d ose 
of t e m o z ol o mi d e will b e r o u n d e d u p t o t h e n ear est 5 m g.  
 
5. 3. 6     D a ys -5, -4 a n d -3:  F o r p atie nts w h ose c o r r e cte d c r e ati ni ne cle ar a nc e is > 1 0 0 
ml/ mi n/ 1. 7 3 m 2: 
T hi ot e pa 3 0 0 m g / m2/ da y ( 1 0 m g/ k g/ da y f or patie nts < 3 y ears of a g e) will b e i nf use d i ntra v e n o usl y o ver 
t hr e e h o urs dail y f or t hre e da ys be gi n ni n g da y -5. Car b o plati n will b e i nf use d i ntra v e n o usl y o v er f o ur 
h o urs f oll o wi n g t h e t hi ot e pa dail y f or t hr e e da ys b e gi n ni n g da y -5. T h e d ose of Car b o plati n will b e 
cal c ulate d usi n g t h e Cal v ert f or m ula ( A U C = 7), s urfa c e ar ea ( 5 0 0 m g/ m 2) a n d wei g ht ( 1 6. 7 m g/ k g) a n d 
t h e l o west of t h e t hre e will b e use d. A cr eati ni n e cl eara nc e will b e m eas ure d pri or t o e ac h  d ose of 
Car b o plati n. T h e f oll o wi n g is t he e q u ati o n t o d et er mi ne t he d ose cal c ulat e d usi n g t h e Cal vert f or m ula.  
Pati e nts <  1 2 y ears of a g e:  
 
d ose = A U C x [ra w creati ni n e cl eara nc e ( ml/ mi n) + ( b o d y wt.( k g) x 0. 3 6)]  
Pati e nts > 1 2 y ears of a g e:  
 
d ose = A U C x (ra w cr eati ni ne cl eara n ce ( ml/ mi n) + 2 5)  
T he ma xi m u m d ose of car b o plati n will b e 1 0 5 0  m g as p er t h e F D A g ui deli n es.  
5. 3. 7  D a ys -5, -4 a n d -3: F o r p atie nts w h ose c o r r e cte d c r e ati ni ne cle ar a n c e is  
>  7 0 ml/ mi n/ 1. 7 3 m 2  a n d < 1 0 0 ml/ mi n/ 1. 7 3 m 2: 

 
9  
T hi ot e pa 2 0 0 m g/ m 2/ da y ( 6. 7 m g/ k g/ da y f or pati e nts < 3 years of a g e) will b e i nf use d i ntra v e n o usl y o ver 
t hr e e h o urs dail y f or t hre e da ys be gi n ni n g da y -5. Car b o plati n will b e i nf use d i ntra v e n o usl y o v er f o ur 
h o urs f oll o wi n g t h e t hi ot e pa dail y f or t hr e e da ys b e gi n ni n g da y -5. T h e d ose of Car b o plati n will b e 
cal c ulate d usi n g t h e Cal v ert f or m ula ( A U C = 4. 1), s urfa c e ar ea ( 3 0 0 m g/ m 2) a n d wei g ht (1 0 m g/ k g) a n d 
t h e l o west of t h e t hre e will b e use d. A cr eati ni n e cl eara nc e will b e m eas ure d pri or t o e ac h  d ose of 
Car b o plati n. T h e f oll o wi n g is t he e q u ati o n t o d et er mi ne  t he d ose cal c ulat e d usi n g t h e Cal vert f or m ula. 
Pati e nts <  1 2 y ears of a g e:  
 
d ose = A U C x [ra w creati ni n e cl eara nc e ( ml/ mi n) + ( b o d y wt.( k g) x 0. 3 6)]  
Pati e nts > 1 2 y ears of a g e:  
 
d ose = A U C x (ra w cr eati ni ne cl eara n ce ( ml/ mi n) + 2 5)  
T he ma xi m u m d ose of car b o plati n will b e 6 0 0  m g as p er t he F D A g ui d eli n es.  
5. 3. 8    T he r a p y Sc he me:  
Da y   
-1 0, -9, -8, -7, -6: T e m o z ol o mi d e 1 7 5 m g/ m 2/ d ose ( or 5. 8 m g/ k g) orall y bi d 
            Da y   
-5, -4, -3: F or pati e nts wit h a cr eati ni n e cleara n ce > 1 0 0 ml/ mi n/ 1. 7 3 m 2    T hi ote pa i ntra ve n o usl y 
3 0 0 m g/ m 2  ( or 1 0 m g/ k g) o v er 3 h o urs f oll o we d b y Car b o plati n i ntra v e n o usl y o v er 4 h o urs as cal c ulate d 
b y t he Cal vert f or m ula wit h A U C = 7 or 5 0 0 m g/ m 2 or 1 6. 7 m g/ k g. ( ma xi m u m d ose 1 0 5 0  m g)  
F or patie nts >  7 0 ml/ mi n/ 1. 7 3 m 2  a n d < 1 0 0 ml/ mi n/ 1. 7 3 m 2   
  
T hi ot e pa i ntra ve n o usl y 2 0 0 m g/ m 2 ( or 6. 7 m g/ k g) o v er 3 h o urs f oll o we d b y Car b o plati n i ntra v e n o usl y 
o v er 4 h o urs as cal c ulate d b y t h e Cal v ert f or m ula wit h A U C = 4. 1 or 3 0 0 m g/ m 2 or 1 0 m g/ k g.  ( ma xi m u m 
d ose 6 0 0 m g)  
Da y   -2: Rest  
Da y   
-1: Rest  
Da y   
 0: R ei nf usi o n a ut ol o g o us st e m c ells  
Da y  
+ 1: Fil grasti m 5 u g/ k g/ da y dail y s u b c uta n e o usl y ( or i ntra v e n o usl y o v er f o ur h o urs). It wil b e 
disc o nti n u e d w h e n t h e A N C > 1 0 0 0/ m m 3  f or t hr ee c o nsec uti v e da ys or > 1 0, 0 0 0/ m m3 f or o n e da y. 
5. 4  
 
Ra diati o n T h era p y  
Ra diati o n t h era p y ma y be gi v e n f oll o wi n g r e c o v er y fr o m t h e hi g h d ose c he m ot hera p y at t h e discr eti o n 
of t h e treati n g p h ysi cia n. Ra diati o n t hera p y s h o ul d start n o s o o n er t ha n 2 8 d a ys p ost st e m c ell r ei nf usi o n. 
Or ga n t o xi cit y wit hi n t h e ra diati o n fi el d s h o ul d ha v e r es ol v e d. It is hi g hl y  d esira bl e t o start ra diati o n 
t h era p y wit hi n 4 2 da ys aft er t h e ste m c ell r ei nf usi o n.   
 
 
5. 5  
Pati e nts will b e gi n 1 3 -cis -r eti n oi c a ci d as earl y as p ossi ble f oll o wi n g st e m c ell r ei nf usi o n b ut n ot bef or e 
da y 4 2. O n e of t h e pri n ci pal i n v esti gat ors m ust be n otifi e d if a patie nt is u na bl e t o b e gi n 1 3 -cis -r eti n oi c 
a ci d t h era p y b y da y 7 7. 1 3 -cis -r eti n oic aci d s h o ul d n ot be gi n u ntil at le ast 5 d a ys afte r t he r a di ati o n 
t he r a p y is c o m plete d. 1 3 -cis -reti n oi c a ci d ma y b e start e d if t he pati e nt has n or mal li v er ( < Gra de 2 
t o xi cit y) a n d ki d n e y f u n cti o n, tri gl yc eri d es < 2 x n or mal, n or mal cal ci u m, n o pr ot ei n uria or he mat uria.  
Pati e nts will r e c ei v e 1 3 -cis -r eti n oi c a ci d 1 6 0 m g/ m 2/ da y ( 5. 3 3 m g/ k g/ da y f or pati e nts < 1 2 k g) orall y 
di v i de d bi d f or 1 4 da ys f oll o we d b y a 1 4 da y r est f or a t otal of 6 c y cl es. R o u n d u p t o t h e n ear est 1 0 m g. 
Ca ps ules c o m e as 1 0, 2 0 a n d 4 0 m g si z es. Pati e nts s h o ul d i n g est t h e ca ps ules w h ol e if at all p ossi bl e. 
C hil dr e n ca n ofte n b e ta u g ht t o ta k e t h e ca ps ul es b y usi n g ca n d y of si milar siz e pri or t o t his p hase of 
t h era p y. A n alt er nati ve is t o p o k e a s mall h ol e i n t h e ca ps ul e a n d t h e n e m b e d it i n a fa v orit e f o o d or s oft 
ca n d y. T h e h ol e i n t h e ca ps ule all o ws it t o b e “ p o p p e d” a n d c h e we d. If n o n e of t h e a b o v e ar e s u c cessf ul 
t h e ca ps ul es ca n be car ef ull y a n d t otall y e m pti e d i nt o a ta bl es p o o n of hi g h fat f o o d s u c h as i ce crea m or 
pea n ut b utt er t o a d mi nist er. T ea c hi n g a c hil d t o s wall o w t h e e ntir e ca ps ul e, is feasi bl e a n d s h o ul d be 
e n c o ura g e d. U n der n o circ u msta n ces s h o ul d 1 3 -cis -reti n oi c a ci d b e r e m o v e d fr o m t h e ca ps ules f or m ore 
t ha n 1 h o ur pri or t o a d mi nist eri n g t o t h e pati e nt. 1 3-cis -r eti n oi c a ci d m ust n ot b e p ut i nt o a s ol uti o n f or 
a d mi nistrati o n as t his ca n r e d u c e effe cti v e dr u g l e v els a n d ca n ca use i n cr ease d tra ns -r eti n oic a ci d l e v els, 
lea di n g t o i ncr ease d t o xicit y. If a pati e nt d o es n ot m e et crit eria t o start 1 3-cis -r eti n oi c a ci d, call t h e 
pri nci pal i n v esti gat ors f or r ec o m m e n dati o ns.  
C o nti n u ati o n t h era p y wit h 1 3 -cis -r eti n oi c a ci d 

 
1 0  
5. 5. 1  
T o pi cal Vita mi n E s h o ul d b e a p pli e d t o li ps BI D d uri n g 1 3 -cis -r eti n oi c a ci d t h era p y if c h eilitis d e v el o ps. 
All pati e nts s h o ul d a v oi d dire ct s u n e x p os ur e w hil e o n 1 3 -cis -reti n oic a ci d t hera p y. T etra c y cli n e is 
pr o hi bite d d uri n g tr eat m e nt wit h is otreti n oi n d u e t o t h e i n cr ease d ris k of pse u d ot u m or cer e bri ( b e ni g n 
i ntra cra nial h y p ert e nsi o n). Vita mi n A a n d vita mi n A deri vati v es s h o ul d als o be a v oi d e d d uri n g 
is otr eti n oi n t h era p y. 
S u g geste d s u p p orti v e car e d uri n g 1 3 -cis -r eti n oi c a ci d t h era p y 
 
5. 5. 2  
Pri or t o ea c h c y cl e, a patie nt m ust ha v e:  
Crit eria t o b e gi n ea c h c ycle of 1 3 -cis -reti n oi c a ci d 
a. A L T < 5 x n or mal  
b.  S ki n t o xi cit y n o gr eat er t ha n gra d e 1  
c.  Ser u m tri gl yc eri d es < 3 0 0 m g/ dl  
d.  He mat uria a n d pr ot ei n uria < 1 + o n uri nal ysis. ( Tra ce h e mat uria a n d/ or pr otei n uria is all o we d)  
e.  Ser u m cr eati ni n e < 1. 5 m g/ dl  
f. Fe mal es of c hil d b eari n g p ot e ntial s h o ul d ha ve a ne gati v e pr e g na n c y test a n d v erificati o n of use of 
c o ntra c e pti o n.  
  
 
5. 6  
C o nc o mita nt M e di cati o n  
 
5. 6. 1  Pr o p h yla ctic a nti e m eti cs will b e a d mi nistere d at t he discreti o n of t he tr eati n g p h ysi cia n. T h e use of 
de xa m et has o ne f or a nti -e m eti c p ur p oses is disc o ura g e d be ca use of t h e c o n c er n of i n hi biti n g 
c h e m ot h era p y p e n etrati o n of t h e bl o o d brai n barri er.  
 
5. 6. 2  Pati e nts s h o ul d r e c ei v e P C P pr o p h yla xis d uri n g c o ns oli dati o n a n d a gai n f oll o wi n g st e m c ell r esc u e as 
per i nstit uti o n g ui deli nes.  
 
5. 6. 3    T etra c y cli n es a n d Vita mi n A ar e  pr o hi bit e d d uri n g tr eat m e nt wit h is otr eti n oi n.  
 
 6. 0  
R E Q UI R E D O B S E R V A TI O N S  
 
6. 1  
Pri or t o i nt e nsi v e c h e m ot hera p y a n d a ut ol o g o us st e m c ell r esc u e a n d wit hi n 2 1      
6. 1. 1 Ma g n eti c R es o na n c e I ma gi n g ( M RI) sca n of h ea d wit h  a n d wit h o ut           ga d oli ni u m.   
 
da ys of t h e start of 
te m oz ol o mi d e. 
6. 1. 2 M RI of t h e s pi n e wit h a n d wit h o ut ga d oli ni u m  
6. 1. 3 Baseli n e l u m bar C S F c yt ol o g y ( b y c yt os pi n e val u ati o n) f or pati e nts wit h       m e d ull o blast o ma, 
ot her P N E T’s, C N S G C T, A T/ R T a n d ot h er t u m ors w h e n cli ni call y i n di ca te d.                                                        
  
 
6. 1. 4 Baseli n e B U N, cr eati ni ne,, >  1 2 -h o ur cr eati ni n e cl eara n c e or G F R.  
6. 1. 5 Baseli n e A S T, A L T a n d bilir u bi n                                                                      
6. 1. 6 Baseli n e el e ctr ol yt es, cal ci u m, ma g nesi u m, a n d p h os p hate.                                      
6. 1. 7 Baseli n e h e m o gl o bi n, plat el et c o u nt, w hit e c ell c o u nt a n d differ e ntial.                                               
6. 1. 8 Ser u m or uri n e pr e g na nc y test f or p u b ertal girls                                                               

 
1 1  
6. 1. 9 A u di o gra m                                                                                                           
6. 1. 1 0 Baseli ne C S F a n d ser u m B -H C G a n d A F P i n pati e nts wit h C N S g er m c ell    
t u m ors         
6. 1. 1 1 Ot her t ests n e e d e d f or g o o d pati e nt car e i n cl u di n g baseli n e C X R,  e c h o car di o gra m, a n d 
p ul m o nar y f u n cti o n t ests are t o be d o n e at t h e  
p h ysi cia n’s discr eti o n.  
 
6. 2  
6. 2. 1 Dail y cr eati ni n e cl eara n c e (at l east 8 h o ur uri n e c oll e cti o n) f oll o wi n g t he first a n d se c o n d d ose of 
car b o plati n (i. e. pri or t o t he sec o n d a n d t hir d d ose of car b o plati n).  
M o nit ori n g D uri n g a n d F oll o wi n g I nt e nsi v e C h e m ot h era p y  
6. 2. 2 Bl o o d w or k i n cl u di n g c o m pl et e bl o o d c o u nt a n d c he mistri es s h o ul d b e d o n e as n ee d e d f or g o o d 
pati e nt car e.   
 
6. 3  
6. 3. 1 C S F a nal ysis if p ositi v e pre -tra ns pla nt t o assess c ell c o u nt a n d differe ntial, 
M o nit ori n g After Ste m C ell Tra ns pla nt  
pr otei n, a n d c yt ol o g y at da y 1 4 f oll o wi n g t h e first d ose o f 1 3-cis R A (t o c o or di nat e it wit h C S F 1 3 -cis -
R A l e v el), a n d at 6, 9 a n d 1 2 m o nt hs p osttra ns pla nt. If C S F c yt ol o g y is n e gati v e pr e -m yel oa blati v e 
c h e m ot h era p y, p ost tra ns pla nt l u m bar p u n ct ures are r e q uir e d o nl y as cli ni call y i n di cat e d. A l u m bar 
p u n ct ur e at da y 1 4 f oll o wi n g t h e first d ose of 1 3 -cis -R A (t o c o or di nat e it wit h C S F 1 3 -cis -R A l e vel) f or 
p har ma c o ki n eti c st u di es is str o n gl y e nc o ur a g e d b ut n ot r e q uir e d. ( S e e se cti o n 6. 4. 4 f or d etails.)   
6. 3. 2 Hea d M RI at t h e start of r eti n oi c a ci d (a p pr o xi mat el y 1. 5 -3 m o nt hs p ost tra ns pla nt), t he n e v er y 3 
m o nt hs t h er eaft er u ntil 2 years fr o m st e m c ell i nf usi o n; t h e n e v er y 4 m o nt hs f or 1 y ear, t h e n e v er y 6 
m o nt hs f or 1 y ear a n d a n n u all y t h ereafter.  
6. 3. 3 M RI of t h e s pi n e, if i nitiall y a b n or mal, s h o ul d be r e p eat e d at t h e start of r eti n oi c a ci d 
(a p pr o xi mat el y 1. 5-3 m o nt hs p ost tra ns pla nt), t h e n e v er y 3 m o nt hs t hereafter u ntil 2 years fr o m st e m 
c ell i nf usi o n; t h e n e v er y 4 m o nt hs f or 1 year, t h e n e v er y 6 m o nt hs f or 1 y ear a n d a n n u all y t h ereafter.  . If 
t h e M RI of t h e s pi n e was i nitiall y n or mal, re p eat sca ns f oll o wi n g st e m cell tra ns pla nt s h o ul d b e d o n e at 
t h e p h ysi cia n’s discr eti o n. 
6. 3. 4 A u di o gra m is r ec o m m e n d e d 3 m o nt hs a n d o n e y ear p ost tra ns pla nt; t h er eaft er a n n u all y o nl y if 
a b n or mal.  
6. 3. 5 Ser u m B H C G a n d A F P f or C N S g er m c ell t u m ors at t h e start of r eti n oi c a ci d (a p pr o xi mat el y 1. 5 -3 
m o nt hs p ost tra ns pla nt), t h e n e v er y 3 m o nt hs t h er eaft er u ntil 2 y ears fr o m st e m c ell i nf usi o n; t h e n e v er y 
4 m o nt hs f or 1 y ear, t he n e v er y 6 m o nt hs f or 1 y ear a n d a n n u all y t her eaft er i n pati e nts wit h a hist or y of 
p ositi v e mar k ers.  
6. 3. 6 C S F B H C G a n d A F P f or C N S g er m c ell t u m ors at da y 1 4 f oll o wi n g t h e start of 1 3 -cis -reti n oi c 
a ci d (a p pr o xi mat el y 1. 5 -3 m o nt hs p ost tra ns pla nt) a n d t h e n e v er y 3 m o nt hs p ost tra ns pla nt f or u p t o 1 
year i n pati e nts wit h p ositi v e mar k ers at ti m e of tra ns pla ntati o n.  If C S F mar k ers ar e ne gati v e pr e -
m yel oa blati v e c he m ot h era p y, re p eat l u m bar p u n ct ur e at da y 1 4 of t h e first c ycl e of 1 3 -cis -reti n oi c a ci d. 
  
6. 4  
M o nit ori n g D uri n g C o nti n u ati o n T h era p y wit h 1 3 -cis -R eti n oi c Aci d
6. 4. 1 P h ysi cal e xa m pri or t o ea c h c o urse of 1 3 -cis -reti n oi c a ci d. 
     
6. 4. 2 C B C, el e ctr ol yt es, B U N, creati ni n e, calci u m, p h os p h or us, ma g n esi u m, tri gl yc eri d es, A L T, 
bilir u bi n, uri nal ysis a n d pre g na n c y t est (f or w o me n of c hil d b eari n g p ot e ntial) pri or t o ea c h  c o urse of 
1 3 -cis-reti n oic a ci d. 
6. 4. 3 P har ma c o g e n etics of 1 3 -cis -reti n oi c a ci d. T hese st u dies ar e str o n gl y e nc o ur a g e d b ut n ot 
r e q uir e d.  
A si n gl e 5 ml bl o o d sa m pl e will b e ta k e n fr o m ea c h pati e nt pri or t o t h e first c o urse of 1 3 -cis -r eti n oi c a ci d 
treat m e nt, a n d tra nsferr e d t o a n E D T A t u b e a n d st or e d at  
-2 0 0C. D N A o btai n e d fr o m t his sa m pl e will b e g e n ot y p e d f or meta b oli zi n g e nz y m es t h o u g ht t o b e 
i n v ol v e d i n t h e m eta b olis m of 1 3-cis -R A, s u c h as C Y P 2 C 8 a n d C Y P 3 A 7, usi n g P C R te c h ni q u es 
esta blis he d at t h e N ort her n I nstit ut e f or Ca n c er R esearc h, N e wcastl e u p o n T y n e, U K.  T he sa m pl e s h o ul d 
be la bele d wit h t h e pati e nt’s u ni q u e pati e nt n u m b er (assi g ne d at t h e ti m e of e nr oll me nt b y t h e st u d y 

 
1 2  
o p erati o n offi c e at N Y U) , sa m pl e # (se e a p p e n di x E f or n u m beri n g sa m pl es), PI’s na m e a n d pr ot o c ol 
n u m b er w hi c h is P B M T C O N C 0 3 2.  
6. 4. 4 1 3 -cis-reti n oic a ci d p har ma c o ki n eti c sa m pli n g. T hese st u dies ar e str o n gl y e nc o ur a g e d b ut n ot 
r e q uir e d.  
Bl o o d a n d C S F sa m ples will b e ta k e n o n da y 1 4 of t h e first c o urse of 1 3 -cis -reti n oi c a ci d. 5 ml blo o d 
sa m ples will be ta k e n a n d i m m e diatel y tra nsferr e d t o f oil wra p p e d h e pari ni z e d t u b es at t h e f oll o wi n g 
ti m e-p oi nts: pr etr eat m e nt a n d 1, 2, 4 a n d 6 h o urs after oral a d mi nistrati o n of 1 3 -cis -reti n oic a ci d. Bl o o d 
sa m ples will be c e ntrif u g e d at a s p ee d of 2, 0 0 0 r p m at 4 0C f or 5 mi n utes a n d t h e plas ma se parate d, 
tra nsferr e d t o f oil wra p p e d t u b es (siz e of t u b e s h o ul d b e s u c h t hat t h e plas m a n earl y fills it, t h us 
pr e v e nti n g o xi dati o n of 1 3 -cis -r eti n oi c a ci d d uri n g st ora g e) a n d st or e d pr ote ct e d fr o m t h e li g ht at – 2 0 0C 
pri or t o tra ns p ortati o n t o Mi n n ea p olis. W h er e v er p ossi ble, p har ma c o ki n eti c sa m ples s h o ul d be ta k e n 
w h e n t h era p e uti c bl o o d sa m pl es ar e o btai n e d. Plas ma c o n c e ntrati o ns of 1 3 -cis -r eti n oi c a ci d, A T R A a n d 
t h e m eta b olit e 4-o x o -1 3 -cis -reti n oi c a ci d, will be d et er mi n e d b y H P L C a nal ysis as pr e vi o usl y 
descri b e d. 3 5  Ea c h sa m pl e s h o ul d b e la b el e d wit h t h e pati e nt’s u ni q u e patie nt n u m b er (assi g n e d at t h e 
ti m e of e nr oll m e nt b y t h e st u d y o p erati o n offi c e at N Y U), sa m pl e # (se e a p p e n di x E f or n u m b eri n g 
sa m ples), PI’s name a n d pr ot o c ol n u m b er w hic h is P B M T C O N C 0 3 2.  
 
A si n gl e C S F sa m ple ( 2 -5 ml) will be o btai n e d at t h e 2 h o ur p ost ti m e p oi nt o n da y 1 4 of t h e first c o urse 
of 1 3 -cis -r eti n oic a ci d. T h e pr e -mai nte na nc e C S F a nal ysis f or mali g na nt c ells s h o ul d b e d ela y e d u ntil 
d a y 1 4 of t h e first c o urse of 1 3 -cis -r eti n oi c a ci d t o c o or di nat e wit h t h e C S F p har ma c o ki n eti c ti m e p oi nt. 
T he C S F sa m pl e s h o ul d b e la b el e d wit h t he patie nt’s u ni q u e pati e nt n u m b er (assi g n e d at t he ti m e of 
e nr oll me nt b y t h e st u d y o p erati o n offi c e at N Y U) , sam pl e # (se e a p p e n di x E f or n u m b eri n g sa m pl es), 
PI’s na m e a n d pr ot o c ol n u m b er w hic h is P B M T C O N C 0 3 2.  
 
Se e se cti o n 6. 6 f or i nstr u cti o ns r e gar di n g s hi p pi n g t h e C S F a n d bl o o d sa m pl es.   
 
 
6. 5 T a ble 1: Re q uir e d O bse r v ati o ns a n d D at a C olle cti o n First Ye ar of T he r a p y  
 
* pati e nts wit h me d ull o bl ast o ma, P N E T, ger m c ell t u mors a n d w he n cli ni call y i n di cat e d.   
 
* * o nl y if p ositi ve pre-tra ns pl a nt 
 
O bs er vati o n  
Pre - 
B M T  
( wit hi n 
2 1 da ys)  
Da y  
– 5 # # 
Da y  
– 4 # #  
6 we e ks 
p ost-
B M T  
Da y  
+ 4 2- 1 8 0  
( d urin g 1 3-
cis-R A)  
3 mos 
p ost-
B M T  
6 mos 
p ost-
B M T  
9 mos 
p ost-
B M T  
1 year       
p ost- B M T  
P h ysi cal E xa m  
X  
 
 
 
X $  
 
 
 
X  
M RI Hea d w/ w o ga d oli ni u m  
X  
 
 
X  
 
X  
X  
X  
X  
M RI S pi ne w/ w o ga d oli ni u m  
X  
 
 
X * *     
 
X * *     
X * *     
    X * *  
    X * *  
L u mb ar C S F c yt ol o g y (cell c o u nt, 
c yt os pi n, pr ot ei n) * 
X  
 
 
 
X * *  
X * *     
X * *     
    X * *  
    X * *  
C B C wit h differe nti al a n d plat el ets  
X  
 
 
 
X $  
X  
X  
X  
X  
El ectr ol yt es, B U N, Cr., C a, P h os, M g  
X  
 
 
 
X $  
 
 
 
 
A S T, A L T, Bilir u bi n  
X  
 
 
 
X $  
 
 
 
 
Tri gl yceri de, uri nal ysis  
 
 
 
 
X $  
 
 
 
 
A u di o gra m  
X  
 
 
 
 
X  
 
 
X  
G F R or > 1 2 h o ur Creati ni ne Cl eara nce  
X  
 
 
 
 
 
 
 
 
> 8 h o ur Creati ni ne Cl eara nce  
 
X  
X  
 
 
 
 
 
 
S er u m/ uri ne pre g na nc y t est ^  
X  
 
 
 
X $  
 
 
 
 
S er u m β H C G/ α F P # 
X  
 
 
   X * *  
 
X * *  
X * *  
X * *  
X * *  
C S F β H C G/ α F P #, * * 
X  
 
 
   X * *  
 
X * *  
X * *  
X * *  
X * *  
Kar n ofs k y or La ns k y sc or e   
X  
 
 
 
 
 
 
 
X  

 
1 3  
^ P u b ert al girls  
 
# C S N ger m cell t u mors o nl y  
 
# # aft er C ar b o pl ati n d ose 
 
$Pri or t o eac h c o urse of cis -reti n oi c aci d 
 
 
 
 
 
 
6. 6 T a ble 2: A dj u ncti v e Reti n oic Aci d St u dies.  
T hese st u dies ar e str o n gl y e nc o ur a g e d b ut n ot r e q uir e d.  
 
O bser vati o n  
6 we e ks p ost -B M T  
Da y + 4 2 t o 1 8 0  
( d uri n g 1 3-cis -r eti n oi c a ci d) 
C S F cis -r eti n oi c a ci d l e v el 
 
X +  
1 3 -cis -reti n oic a ci d 
p har ma c o g e neti cs/ p har ma c o ki n eti cs  
X @  
X %  
( 5 ti me p oi nts) 
 
@ A si n gl e 5 ml bl o o d sa m pl e will b e ta k e n fr o m ea c h pati e nt pri or t o t h e first c o urse of 1 3 -cis -reti n oic a ci d 
treat m ent, a n d tra nsferr e d t o a n E D T A t u b e a n d st or e d at – 2 0 0C. T h e sa m pl e s h o ul d b e la b el e d wit h t h e 
pati e nt’s u ni q u e pati e nt n u m b er (assi g n e d at t h e ti m e of e nr oll m e nt b y t h e st u d y o perati o n offic e at N Y U) , 
sa m ple # (see a p p e n di x E f or n u m b eri n g sa m pl es), PI’s na m e a n d pr ot o c ol n u m b er w hi c h is P B M T C O N C 0 3 2.  
 
%  O n da y 1 4 of t h e first c o urse of 1 3 -cis -r eti n oi c a ci d, 5 ml bl o o d sa m pl es will b e ta k e n a n d i m m e diat el y 
tra nsferr e d t o f oil wra p p e d h e pari ni ze d t u b es at t h e f oll o wi n g ti m e-p oi nts: pretr eat m e nt a n d 1, 2, 4  a n d 6 h aft er 
oral a d mi nistrati o n of 1 3 -cis -r eti n oic a ci d.  Bl o o d sa m ples will be ce ntrif u g e d at a s p e e d of 2, 0 0 0 r p m at 4°C f or 
5 mi n ut es a n d t h e plas ma se parate d, tra nsferr e d t o f oil wra p p e d t u b es (si z e of t u b e s h o ul d b e s u c h t hat t h e 
plas ma n earl y fills  it, t h us pr e v e nti n g o xi dati o n of 1 3-cis -R A d uri n g st ora g e) a n d st or e d pr ot e ct e d fr o m t h e li g ht 
at -2 0 °C.  Ea c h sa m ple s h o ul d be la b el e d wit h t h e pati e nt’s u ni q u e pati e nt n u m ber (assi g n e d at t h e ti m e of 
e nr oll me nt b y t h e st u d y o p erati o n offi c e at N Y U) , sa m pl e # (se e a p p e n di x E f or n u m b eri n g sa m pl es), PI’s na m e 
a n d pr ot o c ol n u m b er w hi c h is P B M T C O N C 0 3 2.  
 
+  A si n gl e C S F sa m pl e ( 2 -5 mls) will be o btai n e d o n da y 1 4 at t h e 2 h o ur p ost oral a d mi nistrati o n of 1 3 -cis -
reti n oi c a ci d.  C S F sa m pl es s h o ul d b e tra nsferr e d t o wra p p e d t u bes n earl y fille d t o t h e t o p a n d st or e d pr ot e ct e d 
fr o m t h e li g ht at -2 0 °C. T he C S F sa m pl e s h o ul d b e la b el e d wit h t h e pati e nt’s u ni q u e pati e nt n u m b er (assi g n e d at 
t h e ti m e of e nr oll m e nt b y t h e st u d y o p erati o n offi c e at N Y U), sa m pl e # (se e a p p e ndi x E f or n u m b eri n g 
sa m ples), PI’s na me a n d pr ot o c ol n u m b er w hic h is P B M T C O N C 0 3 2.  
 
E x e c uti o n of a n a gr ee m e nt wit h C hil dr e n’s H os pitals a n d Cli ni cs of Mi n n es ota f or t h e r ei m b urse m e nt f or 
bi ol o gi cal sa m pl es ( Bl o o d a n d C S F) is r e q uire d pri or t o s hi p pi n g sa m pl es t o C hil dre n’s H os pitals a n d Cli ni cs of 
Mi n n es ota, Mi n nea p olis.  T o v erif y t h e stat us of t his a gre e m e nt b et we e n C hil dr e n’s H os pitals a n d Cli ni cs of 
Mi n n es ota a n d y o ur i nstit uti o n, please c o nta ct  Mar y La mers T k a c h ( mar y.la m ers @ c hil dr e ns m n. or g ) or L ezli e 
Ra bi ne ( l e zli e.ra bi n e @ c hil dr e ns m n. or g) eit h er via e mail or p h o ne: 6 1 2-8 1 3 -5 9 1 3   
 
Pl ease f oll o w t h e s hi p pi n g i nstr u cti o ns bel o w f or s hi p pi n g sa m ple ( Bl o o d a n d C S F).  Pa y m e nt is c o nti n g e nt 
u p o n a d h er e n c e t o t hese i nstr u cti o ns.  
    
•  La b el t h e sa m pl es wit h t h e f oll o wi n g f or mat:        
 

 
1 4  
P B T M C O N C 0 3 2  
PI’s Na m e  
  
  
 
Pati e nt St u d y #  
  
  
 
S a m pl e #   
 
•  Batc h a n d se n d all se v e n sa m pl es i n o n e s hi p me nt.  
•  I n cl u d e a c o p y of pa g e 1 of t he s hi p pi n g f or m (se e A p pe n di x E) wit h t h e s hi p me nt.  
•  N otif y M ar y L a m er s T k a c h ( m ar y.l a m er s @ c hil dr e n s m n. or g ) or L e zli e R a bi n e 
(l e zli e.r a bi n e @ c hil dr e n s m n. or g) eit h er vi a e m ail or p h o n e: 6 1 2-8 1 3 -5 9 1 3  pri or t o s hi p pi n g .  Pl e a s e 
pr o vi d e y o ur i n stit uti o n’ s n a m e, t h e p ati e nt( s) st u d y n u m b er( s), a n d t h e arri v al d at e.  S hi p m e nt s 
m a y o nl y arri v e M o n d a y - Fri d a y d uri n g r e g ul ar b u si n e s s h o ur s ( 8 a m -5 p m) .    
•   Shi p s a m pl e s o v er ni g ht o n 8 p o u n d s of dr y i c e.  Pl e a s e u s e F e d E x ( a c c o u nt # 3 1 4 -9 7 1 -2 4 8) t o 
s hi p s a m pl e s t o t h e f oll o wi n g a d dr e s s :       
 
Att n: M ar y L a m er s T k a c h or L e zli e R a bi n e  
C hil dr e n' s H o s pit al s a n d Cli ni c s of Mi n n e s ot a  
2 5 2 5 C hi c a g o A v e n u e S.  
C S C- 1 7 5  
Mi n n e a p oli s, M N   5 5 4 0 4  
 
 
 
 
 
Refer t o A p p e n di x E  f or s hi p pi n g f or m.  C o m pl et e t he f or m a n d i ncl u d e i n s hi p me nt t o C hil dr e n’s H os pitals a n d 
Cli nics of Mi n n es ota, Mi n n ea p olis.  
 
 

 
1 5  
6. 7 T a ble 3: Re q uir e d O bse r v ati o ns a n d D at a C olle cti o n 1 5 m o nt hs t o 3 ye ars p ost - BM T  
 
O bs er vati o n  
1 5 mos  
 p ost-B M T  
1 8 mos  
 p ost-
B M T  
2 1 mos  
 p ost-
B M T  
2 yrs  
 p ost-
B M T  
2 8 
mo nt hs 
 p ost-
B M T  
3 2 mo nt hs  
 p ost-
B M T  
3 yrs  
 p ost-
B M T  
M RI Hea d 
w/ w o 
ga d oli ni u m  
X  
X  
X  
X  
X  
X  
X  
M RI S pi ne 
w/ w o 
ga d oli ni u m  
   X * *  
    X * *   
    X * *  
    X * *  
   X * *  
   X * *  
    X * *  
S er u m 
H C G/ A F P # 
   X * *  
    X * *  
    X * *  
    X * *  
    X * *
  
 
   X * *  
    X * *  
Kar n ofs k y or 
La ns k y sc ore   
 
 
 
X  
 
 
X  
* * o nl y if p ositi ve pre-tra ns pl a nt or at t he p h ysi ci a n’s discreti o n if ne gati ve pre-tr a ns pl a nt. 
# C S N ger m cell t u mors o nl y  
 
 
7. 0   
N E U R O P A T H O L OG Y G UI D E LI N E S/ S P E CI M E N S U B MI S SI O N    R E Q UI R E M E N T S  
 
7. 1  
T he f oll o wi n g s p eci m e ns s h o ul d b e se nt fr o m tiss u e at t h e ti me of r ela pse. H o we v er, if n o tiss u e was 
o btai n e d at rela pse or if t h er e is i ns uffi cie nt tiss u e a vaila bl e, tiss u e fr o m i niti al dia g n osis is a c ce pta bl e 
f or s u b missi o n f or ce ntral r e vie w. T h e n e ur o pat h ol o gist at ea c h parti ci pati n g i nstit uti o n, at t h e 
c o m pl eti o n of r e vi e w of ea c h case ori gi nati n g at his/ h er i nstit uti o n, s h o ul d s u b mit t h e f oll o wi n g:  
 
- 
At l east o n e H & E fr o m ea c h bl o c k of t u m or  
- 
1 0 u nstai n e d sli d es fr o m o n e b est bl o c k  
- 
I nstit uti o nal n e ur o pat h ol o gists’s r e p ort 
 
7. 2  
T he sli d es a n d r e p ort s h o ul d be se nt t o:  
   
 
S har o n Gar d n er, M D  
  
 
St e v e n D. Hasse nfel d C hil dr e n’s C e nt er  
  
 
3 1 7 E. 3 4 t h Str e et  
  
 
Ne w Y or k, N Y  1 0 0 2 1  
  
 
T ele p h o n e: ( 2 1 2) 2 6 3 -8 5 2 0 or ( 2 1 2) 2 6 3 -8 4 0 0  
  
 
Be e p er: ( 9 1 7) 8 1 2 -0 5 2 6  
  
 
E mail: S har o n. gar d n er @ m e d. n y u. e d u  
  
 
Fa x: ( 2 1 2) 2 6 3 -8 4 1 0  
Pl ease c o nta ct Dr. Gar d n er f or t h e Air b or n e E x pr ess a cc o u nt i nf or mati o n pri or t o se n di n g t h e pat h ol o g y 
sa m ples. 
 
8. 0  
N E U R O R A DI O L O G Y S U B MI S SI O N R E Q UI R E M E N T S  
 
8. 1  
All pati e nts will ha v e c e ntral n e ur ora di ol o gical r e vie w. S u b mit t he f oll o wi n g st u di es wit h t h eir 
c orres p o n di n g r e p orts t o t h e a d dr ess b el o w:  
 
  
  
- Pr e -tra ns pla nt cra nial M RI wit h a n d wit h o ut c o ntrast 
  
  
- Pr e -tra ns pla nt s pi nal M RI wit h c o ntrast 
  
  
- 1 y ear p ost tra ns pla nt cra nial M RI wit h a n d wit h o ut c o ntrast  
  
  
- 1 y ear p ost tra ns pla nt s pi nal M RI wit h c o ntrast, if st u d y was p erf or m e d  
  
- Cra nial M RI at pr o gr essi o n (rela pse) wit h a n d wit h o ut c o ntrast if r ela p se o c c urs l ess t ha n o n e 
year p ost tra ns pla nt  

 
1 6  
  
- S pi nal M RI at pr o gr essi o n (rela pse) wit h c o ntrast if rela pse o cc urs l ess t ha n o n e y ear p ost 
tra ns pla nt 
8. 2  
I ma gi n g data ma y be se nt o n a C D or b y har d c o pi es of fil ms. T h e i ma gi n g data a n d r e p orts s h o ul d b e 
se nt t o:   
  
 
S har o n Gar d n er, M D  
  
 
St e v e n D. Hasse nfel d C hil dr e n’s C e nt er  
  
 
3 1 7 E. 3 4 t h Str e et  
  
 
Ne w Y or k, N Y  1 0 0 2 1  
  
 
T ele p h o n e: ( 2 1 2) 2 6 3 -8 5 2 0 or ( 2 1 2) 2 6 3 -8 4 0 0  
  
 
Be e p er: ( 9 1 7) 8 1 2 -0 5 2 6  
  
 
E mail: S har o n. gar d n er @ m e d. n y u. e d u  
  
 
Fa x: ( 2 1 2) 2 6 3 -8 4 1 0  
Pl ease c o nta ct D r. Gar d n er f or t h e F e de x  a c c o u nt i nf or mati o n pri or t o se n di n g t he ra di ol o g y st u dies. 
 
9. 0  
E V A L U A TI O N O F R E S P O N S E A N D R E L A P S E C RI T E RI A  
 
9. 1  
T u m or si z e o n e n ha n c e d M RI wit h ga d oli ni u m  
9. 1. 1  C o nti n ui n g C o m pl et e R es p o nse ( C C R): C o nti n ui n g a bse n c e of   
 
            
ra di o gra p hicall y i de ntifia ble t u m or o n c o m paris o n sca ns p erf or m e d at a mi ni m u m of 4 we e ks 
a part. 
  
 
9. 1. 1  C o m pl et e R es p o nse ( C R): C o m pl et e disa p p eara n c e of all k n o w n disease b y M RI  f or a mi ni m u m 
of 4 we e ks . 
 
9. 1. 2  Partial Res p o nse ( P R): Gr eat er t ha n 5 0 %  d e crease i n t u m or si ze d e m o nstra ble b y M RI  f or a 
mi ni m u m of 4 we e ks . 
 
9. 1. 3  Sta ble Disease ( S D): L ess t ha n 5 0 % d e cr ease or n o r e d u cti o n i n t u m or si z e de m o nstra bl e b y 
M RI.  Pati e nt fails t o q u alif y f or a C R, P R, or P D.  
 
9. 1. 4  Pr o gr essi v e disease ( P D): Dise ase i n pr e vi o usl y u ni n v ol ve d ar eas wit h o ut a c hi e vi n g a C R; 
cli ni cal or ra di ol o gi cal e vi d e n ce of i n crease d v ol u m e of > 2 5 % i n t u m or ar e a wit h ma xi m u m 
per p e n dic ular dia m et ers i n a n y site of r esi d u al disease as c o m par e d t o i m m e diat e pr e -st u d y ar ea. 
 
9. 1. 5  Rel a pse: A p p eara nc e or r ea p peara n ce of t u m or i n a n y sit e i n pati e nts w h o h a d r es p o n d e d 
c o m pl et el y t o t hera p y.  
 
9. 2  
C S F c yt ol o gi cal e xa mi nati o n of mali g na nt cells  
 
9. 2. 1  C R: C o m pl et e cl eara n c e of all mali g na nt c ells o n c yt os pi n a nal ysis of l u m bar C S F, if pr e vi o usl y 
p ositi v e.  
 
9. 2. 2  N o R es p o nse ( N R): I n c o m pl et e cleara nc e of mali g na nt c ells o n c yt os pi n a nal ysis of l u m bar C S F, if 
pr e vi o usl y p ositi v e.  
 
9. 2. 3  Rela pse: Pr ese n c e of mali g na nt c ells i n t h e C S F w he n it was pr e vi o usl y clear.  
 
9. 3  
E val u ati o n of e xtra cra nia l m etastases 
 

 
1 7  
T he pr ol o n g e d lat e n c y t o res ol uti o n of b o n e C T or M RI a b n or maliti es i n res p o nse t o t h era p y r e n d ers earl y 
e val u ati o n of r es p o nse i m p ossi bl e.  It is r e c o m m e n d e d t hat c o nsi d erati o n b e gi ve n t o bi o ps yi n g o n e or m ore 
ori gi nall y a b n or mal sites o n b o n e sca n at t hr e e m o nt hs fr o m marr o w r ei nf usi o n t o e val u at e r es p o nse t o t h era p y.  
 
9. 4  
O v erall rati n g of t u m or r es p o nses  
 
I n pati e nts wit h b ot h s oli d t u m or a n d C S F e val u a bl e f or r es p o nse, a C R will be d efi n e d as c o m pl ete r es p o nse of 
b ot h t u m or b ul k a n d C S F c ells.  Pr o gr essi v e disease i n eit h er l o cati o n (t u m or b ul k or C S F) will defi n e a n 
o v erall rati n g of P D.  
 
9. 5  
Rela pse  
 
Rela pse is d efi n e d as t he a p p eara n c e or r ea p p eara n c e of t u m or i n a n y sit e i n pati e nts w h o ha d r es p o n de d 
c o m pl et el y t o t hera p y.  
 
1 0. 0  
D R U G I N F O R M A TI O N A N D T O XI CI TI E S 
 
1 0. 1  
Te m o z ol o mi de  
  
 
1 0. 1. 1  A vaila bl e c o m m er ciall y ( S c heri n g C or p orati o n)  
 
1 0. 1. 2  F or m ulati o n: T e m o z ol o mi d e is s u p plie d as a ma c hi ne -fill e d, w hit e o pa q u e, pr eser vati v e-fr e e, t w o pie c e, 
har d g elati n ca ps ul e a vaila bl e i n 2 5 0 m g, 1 0 0 m g, 2 0 m g, a n d 5 m g str e n gt hs.  T h e 2 5 0 m g a n d 1 0 0 m g ca ps ul es 
are lar g er i n siz e t ha n t h e 2 0 m g a n d 5 m g.  T e m oz ol o mi d e ca ps ul es ar e pa c k a ge d i n 3 0 cc, 2 8 m m 4 8 0 T y pe 
1 a m b er glass b ottl es c o ntai ni n g 3 0 ca ps ul es of 5 m g, 2 0 m g, 1 0 0 m g or 2 5 0 m g str e n gt hs.  
  
 
1 0. 1. 3  St ora g e: T e m o z ol o mi d e ca ps ules s h o ul d be st or e d b et we e n 2 -3 0 o C i n a m ber glass b ottles.  
 
1 0. 1. 4  A d mi nistrati o n: T e m o z ol o mi d e is a d mi nist er e d orall y o n a n e m pt y st o ma c h.  T he dr u g is a p pr o xi matel y 
1 0 0 % bi oa vaila bl e. T he d ose s h o ul d b e r o u n d e d t o t h e near e st 5 m g.  T h e ca ps ules s h o ul d n ot b e br o k e n o p e n.  
H o we v er, f or y o u n g c hil dr e n w h o ca n n ot t ol erat e ca ps ules, t h e ca ps ul es ma y be o p e ne d b y t h e pare nt weari n g 
a p pr o priat e pr ot ecti ve gl o v es, a n d t h e c o nt e nts pla c e d i nt o a p pl e sa u c e or j ui c e, b ut N O T dair y pr o d u cts.  
Pati e nts m ust fast f or a mi ni m u m of o n e h o ur pri or t o t h e a d mi nistrati o n of e a c h d ose of t e m o z ol o mi d e, a n d 
c o nti n u e fasti n g f or o ne h o ur aft er t h e a d mi nistrati o n of ea c h d ose.  Water is p er mitte d d uri n g t his p eri o d of 
ti m e, h o we v er.  Li g ht, n o n-da ir y c o ntai ni n g m eals, ma y b e eat e n wit hi n 4 h o urs pri or t o ea c h d ose (j uic e, t oast, 
ja m). Patie nts w h o ar e o bese ( gr eat er t ha n 1 2 5 % a b o v e i d eal wei g ht f or h ei g ht) will ha ve t heir d oses base d o n 
a dj uste d b o d y wei g ht as d escri b e d i n A p p e n di x A.  
 
1 0. 1. 5  T o xi cities:  
 
C o m m o n  
H a p pe ns t o 2 1 -1 0 0 c hil d re n o ut 
of e v e r y 1 0 0  
Oc c asi o n al  
H a p pe ns t o 5 -2 0 c hil d re n o ut of e v e r y 1 0 0  
R a re  
H a p pe ns t o less t h a n 5 c hil d re n o ut of 
e v e r y 1 0 0  
m me di ate: Wit hi n 1-2 
ys of re c ei vi n g dr u g  
 
L oss of a p petite, n a us e a, v o miti n g, 
di a rr he a, c o nsti p ati o n, he a d ac he, r as h, 
itc hi n g, i nc re as e d ne e d t o uri n ate, u ri n a r y 
tr act i nfe cti o ns 
C o n v ulsi o ns, dizzi ness, diffic ult y w al ki n g, 
c o nf usi o n, diffic ult y s w all o wi n g, a n xiet y, 
p arti al p a r al ysis or we a k ness of o ne si de 
of t he b o d y, bl o o d cl ots w hic h m a y be  life-
t h re ate ni n g ( L) 
o m pt: Wit hi n 2 -3 
e ks, pri or t o ne xt 
u rs e  
De c re as e i n t he n u m be r of re d 
a n d w hite bl o o d c ells a n d 
pl atelets m a de i n t he b o ne 
m ar r o w 
M o ut h s ores, tire d ness, fl ui d b uil d u p i n 
le gs a n d ar ms 
P r ol o n ge d de c re as e i n t he n u m be r of re d 
a n d w hite bl o o d c ells a n d pl atelets m a de 
i n t he b o ne m a r r o w wit h a n i nc re as e d 
ris k of i nfe cti o n o r de at h, me m or y -l oss, 
u n a ble t o sle e p, de pressi o n, m us cle ac hes, 
bl u r re d or d o u ble visi o n  
l a ye d: A n yti me l ate r 
ri n g t he r a p y, e xcl u di n g 
 
H air l oss, li v e r d a m a ge  
 

 
1 8  
e a b o v e c o n diti o ns 
te: A n yti me afte r 
m pleti o n of t he r a p y  
 
 
C a nc e r  
 
 
1 0. 2  
T hi ote p a ( N, N, N, -Triet h yle net hi o p h os p h o r a mi de)  
 
 
1 0. 2. 1  A vaila bl e c o m m er ciall y ( L e d erle)  
 
1 0. 2. 2  F or m ulati o n: 1 5 m g vials i n p o w der f or m.  
 
1 0. 2. 3  St ora g e: Refri gerat e at  2- 8oC. 
 
1 0. 2. 4  Re c o nstit uti o n: R e c o nstit ut e 1 5 m g vial i n st eril e wat er t o gi v e a n is ot o nic s ol uti o n (si n ce p o w d er 
c o ntai ns 8 0 m g Na Cl a n d 5 0 m g Na H C O 3).  A 1 5 m g vial ma y b e dil ut e d i n 1 5. ml st eril e wat er, a n d t h e n a d d e d 
t o ot h er dil u e nts as ne e d e d, e. g., Na Cl, de xtr ose or d e xtr ose-Na Cl s ol uti o ns.  
 
1 0. 2. 5  Sta bilit y: R ec o nstit ut e d s ol uti o ns ar e sta bl e u n d er r efri g erati o n f or fi v e da ys wit h o ut l oss of p ot e nc y.  
 
1 0. 2. 6  A d mi nistrati o n: 3 0 0 m g/ m 2 ( or 1 0 m g/ k g f or c hil dr e n < 3 y ears of a g e) b y i ntra v e n o us i nf usi o n o v er 
t hr e e h o urs dail y f or t hre e da ys.  
 
1 0. 2. 7 T o xiciti es:  
 
 
C o m m o n  
H a p pe ns t o 2 1 - 1 0 0 c hil dre n o ut of e ve r y 
1 0 0  
O cc asi o n al  
H a p pe ns t o 5 - 2 0 c hil dr e n o ut of e ve r y 
1 0 0  
R ar e  
H a p pe ns t o < 5 c hil dr e n 
o ut of e ve r y 1 0 0  
I m me di ate: 
Wit hi n 1 - 2 d a ys of re cei vi n g 
dr u g  
N a use a, v o miti n g, l oss of a p petite  
P ai n at t he i njecti o n site, di zzi ness, 
he a d ac he  
Hi ves, s ki n r as h  
P r o m pt:  
Wit hi n 2 - 3 wee ks, pri or t o 
ne xt c o urse  
De cr e ase i n t he n u m be r of r e d a n d w hite 
bl o o d cells a n d pl atelets m a de i n t he 
b o ne m ar r o w 
 
At hi g h d oses use d bef or e m arr o w 
tr a ns pl a nts: m o ut h s ores, i nfl a m m ati o n  
of t he p ass a ge bet we e n t he t hr o at a n d 
st o m ac h 
At hi g h d oses use d bef or e m arr o w 
tr a ns pl a nts: i n a p pr o pri ate b e h a vi or, 
c o nf usi o n, dr o wsi ness, i nc re ase d li ver 
e nzy mes i n t he bl o o d, i nc re ase d 
bilir u bi n i n t he bl o o d, d ar ke ni n g of 
t he s ki n 
S u d de n hi g h fe ve r  
Del a ye d:  
A n yti me l ate r d uri n g t he r a p y, 
e xcl u di n g t he a b o ve c o n diti o ns 
A bse nc e of s pe r m or st o p pe d m o nt hl y 
pe ri o ds, i n a bilit y t o h a ve c hil dr e n 
 
 
L ate:  
A n yti me afte r c o m pl eti o n of 
t he r a p y 
 
 
 
( L) T oxicit y m ay als o oc c ur l ater. 
 
 
1 0. 3  
C ar b o pl ati n ( 1, 1 -c ycl o b ut a ne dic ar b o x yl ate ( 2 -)-0, 0') -pl ati n u m)  
 
1 0. 3. 1  A vaila bl e c o m m er ciall y  
 
1 0. 3. 2  F or m ulati o n: 1 5 0 m g pr e par e d as a w hit e l y o p hili ze d p o w d er wit h 1 5 0 m g of ma n nit ol i n a 2 0 ml a m b er 
vial f or i nje cti o n.  
 
1 0. 3. 3  St ora g e: I nta ct vials s h o ul d b e st or e d u n der r efri g erati o n at 2 - 8oC. 
 
1 0. 3. 4  Re c o nstit uti o n: 1 5 0 m g/ vial.  W h e n r e c o nstit ut e d wit h 9. 8 ml of st eril e water f or i nj ecti o n U. S. P., ea c h 
ml will c o ntai n 1 5 m g car b o plati n a n d 1 5 m g ma n nit ol at p H 4. 6 t o 7. 0.  

 
1 9  
 
1 0. 3. 5  Sta bilit y: W he n re c o nstit ut e d as dir e ct e d, t h e s ol uti o n of car b o plati n e x hi bits n o de c o m p ositi o n f or at 
least 2 4 h o urs at r o o m t e m p erat ur e.  Dil uti o n wit h sali ne s ol uti o n has b ee n ass ociat e d wit h i n cr ease d 
rates of d e c o m p ositi o n.  T he pr e parati o n c o ntai ns n o a nti ba ct erial preser vati ves a n d s h o ul d b e discar d e d 
ei g ht h o urs after r ec o nstit uti o n.  
 
1 0. 3. 6  A d mi nistrati o n: A U C = 7 or 5 0 0 m g/ m 2 or 1 6. 7 m g/ k g  (t h e l o west of t h e t hr e e) b y i ntra ve n o us i nf usi o n 
o v er f o ur h o urs. 1 0. 3. 7  T o xi cities:  
 
 
C o m m o n  
H a p pe ns t o 2 1 - 1 0 0 o ut of 
e ve r y 1 00 c hil dre n 
O cc asi o n al  
H a p pe ns t o 5 - 2 0 c hil dr e n o ut of 
e ve r y 1 00 
R ar e  
H a p pe ns t o < 5 c hil dr e n o ut of e ve r y 
1 0 0 
I m me di ate: 
Wit hi n 1 - 2 d a ys of 
r ec ei vi n g dr u g 
N a use a ( L), v o miti n g ( L)  
All er gi c r e acti o ns *( p ossi bl y 
se ve r e a n d life-t hre ate ni n g), 
r as h ( L) 
M et alli c t aste  
P r o m pt:  
Wit hi n 2 -3 wee ks, pri or 
t o n e xt c o urse 
L o w n u m be r of w hite bl o o d 
c ells a n d pl atelets 
(effe ct o n pl atelets m a y be 
gr e ater t h a n o n w hite bl o o d 
c ells)  
A b n or m al l e vels of c ert ai n s alts 
i n t he b o d y li ke s o di u m a n d 
p ot assi u m ( L) 
N u m b ness, ti n gli n g, cl u msi ness, 
d a m a ge t o t he li ver ( L), d a m a ge t o 
t he ki d ne y ( L), d a m a ge t o t he e ar 
c a usi n g he ari n g a n d b al a nc e 
pr o bl e ms( L) , h ai r l oss  
Del a ye d:  
A n y ti me l ate r d uri n g 
t he r a p y, e xcl u di n g t he 
a b o ve c o n diti o ns  
 
 
 
L ate:  
A n y  ti me afte r 
c o m pl eti o n of tr e at me nt  
 
 
A ne w l e u ke mi a c a use d b y t his 
tr e at me nt 
* T h e i n ci d e nc e of aller gic r e acti o ns t e n ds t o i n cre ase after r e pe at e d c o urses of tre at me nt (i ncr e ase d r at e of o cc urre n ce afte r si x c o urses n ote d i n a d ult 
p atie nts). 
( L) T oxicity m ay als o oc c ur l at er. 
 
1 0. 4  
Fil g r asti m  
 
1 0. 4. 1  A vaila bl e c o m m er ciall y.  
 
1 0. 4. 2  F or m ulati o n: A vaila bl e i n 3 0 0 u g/ ml a m p ul es c o ntai ni n g 3 0 0 u g or 4 8 0 u g.  
 
1 0. 4. 3  St ora g e: St or e u n d er r efri g erati o n at 2 - 8oC.  
 
1 0. 4. 4  Sta bilit y: A n y vial l eft at r o o m te m p erat ur e f or gr eater t ha n 2 4 h o urs s h o ul d b e discar de d.  
 
1 0. 4. 5    A d mi nistrati o n: A d mi nist er o nc e dail y, s u b c uta n e o usl y wit h o ut dil uti o n or if n e c essar y dil ute wit h 5 % 
de xtr ose i n water, pr efera bl y t o c o n ce ntrati o ns of 1 5 m c g/ ml or gr eat er f or I V a d mi nistrati o n. Dil uti o ns s h o ul d 
be pre par e d as cl ose t o t h e ti m e of a d mi nistrati o n as p ossi bl e ( u p t o 2 4 h o urs), si nc e t h e pr o d u ct is pr eser vati v e -
fr e e. W he n dil uti n g Fil grasti m t o 5-1 4 m c g/ ml i n D 5 W, it is n ec essar y at all ti m es t o a d d h u ma n ser u m al b u mi n, 
t o r ea c h a fi nal al b u mi n c o n c e ntrati o n of 2 m g/ ml. T h e d ose of Fil grasti m is 5 m c g/ k g.  
 

 
2 0  
1 0. 4. 6  T o xi cities:  
 
 
C o m m o n  
H a p pe ns t o 2 1 -1 0 0 c hil dre n 
o ut of e ve r y 1 0 0  
O cc asi o n al  
H a p pe ns t o 5 - 2 0 c hil dr e n o ut of e ve r y 
1 0 0  
R ar e  
H a p pe ns t o < 5 c hil dr e n o ut of e ve r y 1 0 0 
I m me di ate: 
Wit hi n 1 - 2 d a ys of 
r ec ei vi n g dr u g 
 
L oc al ir rit ati o n at i njecti o n site  
All er gi c r e acti o n, l o w fe ve r  
P r o m pt:  
Wit hi n 2 -3 wee ks, 
pri or t o t he ne xt 
c o urse 
 
Ac he or p ai n i nsi de t he b o nes, i ncr e ase d 
l e vels of li ver e nzy mes a n d uri c aci d i n 
t he bl o o d, l o w nu m be r of pl atelets i n t he 
bl o o d  
E nl ar ge me nt of t he s ple e n, w orse ni n g of 
pr e -e xisti n g s ki n r as hes, h air l oss 
Del a ye d:  
A n yti me l ate r 
d uri n g t her a p y, 
e xcl u di n g t he a b o ve 
c o n diti o ns 
 
 
I nfl a m m ati o n of a bl o o d vessel i n t he s ki n 
L ate:  
A n yti me afte r t he 
c o m pl eti o n of 
tr e at me nt 
 
 
 
 
1 0. 5     Is otr eti n oi n ( 1 3 cis-r eti n oic aci d, A C C U T A N E, A m neste e m) N S C # 3 2 9 4 8 1  
 
1 0. 5. 1  A vaila bl e c o m m er ciall y u n d er t he tra de na m e A C C U T A N E ( R o c h e La b orat ories) a n d A m n est e e m 
( Bert e k P har ma c e uti cals) i n 1 0 m g, 2 0 m g a n d 4 0 m g s oft g elati n ca ps ul es.  
 
1 0. 5. 2  F or m ulati o n a n d Sta bilit y: T h e 1 3 -cis is o m er of r eti n oi c a ci d will b e use d. T his is a yell o w -ora n ge 
cr ystalli n e p o w d er wit h a m ol e c ular wei g ht of 3 0 0. 4 4. A vaila bl e as a n oral g elati n ca ps ule i n 1 0 m g, 2 0 m g a n d 
4 0 m g si z es. W h e n t he d ose is ta k e n  i n a m et h o d ot h er t ha n si m pl y b ei n g s wall o we d, pr e par e t h e d ose 
i m m e diat el y pri or t o a d mi nistrati o n d u e t o la c k of sta bilit y data. 
 
1 0. 5. 3  A d mi nistrati o n: P O wit h f o o d or mil k t o e n ha n ce a bs or pti o n. T h e f oll o wi n g o pti o ns ma y b e offer e d t o 
ai d i n a d mi nistrati o n o f t h e ca ps ules t o c hil dre n u na bl e or u n willi n g t o s wall o w t h e ca ps ul es, i n or d er of 
pr efere n c e: 1) s wall o w ca ps ul e w h ole ( prefera bl e) O R 2) s oft e n ca ps ul e (i n war m wat er) bit e a n d s wall o w O R 
3) s oft e n ca ps ul e, bite a n d s u c k o ut c o nt e nts O R 4) s ofte n ca ps ul e, r e m o v e c o nte nts eit her wit h oral s yri n g e (a n d 
dra w it u p) or s q uis h o ut c o nt e nts i nt o a s mall m e di ci ne c u p a n d gi v e wit h fatt y f o o d. If at all p ossi bl e ha ve t he 
c hil d s u c k o n t h e e m pt y ca ps ul e i n h o p es of g etti n g m or e of t h e i nt e n de d d ose.  
 

 
2 1  
1 0. 5. 4  T o xi cities:  
 
 
C o m m o n  
H a p pe ns t o 2 1 - 1 0 0 
c hil dre n o ut of e ve r y 
1 0 0  
Oc c asi o n al  
H a p pe ns t o 5 -2 0 c hil dre n o ut of 
e ve r y 1 0 0  
R are  
H a p pe ns t o < 5 c hil dre n o ut of e ve r y 1 0 0  
I m m e di ate: 
Wit hi n 1 -2 d a ys of 
re c ei vi n g dr u g  
 
N a use a a n d v o miti n g  
A n a p h yl a xis, br o n c h os p as m  
Pr o m pt:  
Wit hi n 2 -3 we e ks, 
pri o r t o t h e n e xt 
c o u rse  
D r y s ki n ( L), dr y m o ut h 
( L), s woll e n a n d s ore 
li ps ( L), 
p h ot ose nsiti vit y, 
el e v at e d E S R, b ac k p ai n 
( L), a rt h r al gi a ( L), 
t ri gl yc e ri de el e v ati o n 
( L) 
R as h ( L), e ye i rrit ati o n/s ore n ess 
( L), j oi nt p ai ns ( L), b a c k pai n 
( L), e xtre m e ti re d n ess ( L), 
h e a d ac h e ( L), hi g h l e vels of f at i n 
t h e bl o o d ( L), hi g h le vels of li ve r 
e n z y mes i n t h e bl o o d ( L), hi g h 
l e vels of c al ci u m i n t h e bl o o d, 
c h ol este r ol el e v ati o n ( L) 
C h a n ges i n s ki n c ol or, u pset st o m ac h, 
di zzi n ess, fl ui d b uil d -u p  i n t he br ai n c a usi n g 
h e a d ac h e a n d n a use a/ v o miti n g a n d a n 
a b n or m alit y of t h e e yes, l o w n u m be rs of re d 
a n d w hit e bl o o d c ells, ele v ate d pl atel et 
c o u nts, ps y c hi atri c dis o r de rs i n cl u di n g 
a g gressi ve a n d/ or vi ol e nt be h a vi or, a 
c o n diti o n c alle d reti n oi c a ci d s y n d r o me wit h 
a n i n c re ase i n w hit e bl o o d c ells, f e v er, 
diffi c ult y bre at hi n g, l o w bl o o d p ress u re  
al o pe ci a, i ns o m ni a, a p petit e dist u r b a n c es, 
h y pe r gl yc e mi a,  let h ar g y, m al aise, 
p a rest h esi as, all e r gic v asc ulitis ( L), c hest 
p ai n, p a n c re atitis, h e ari n g i m p ai r m e nt, 
infl a m m at or y b o wel dise ase, vis u al 
dist u r b a n c es, i nfl a m m ati o n of t h e g u ms, 
dr yi n g of t h e res pi r at or y t r act wit h v oi c e 
alt e r ati o n, res pi r at or y i nf ecti o ns  
D el a ye d:  
A n y ti m e l ate r 
d u ri n g t h e r a p y, 
e x cl u di n g t he 
a b o ve c o n diti o ns  
 
S k el et al h y pe r ost osis  
E nl ar ge d se cti o ns of b o nes, de c re ase i n t h e 
de nsit y of b o ne c a usi n g we a ke n e d b o nes , 
r h a b d o m y ol ysis a b n o r m al m e nses, re n al 
dist u r b a n c es ( W B C i n u ri ne, pr ot ei n u ri a, 
h e m at u ri a, re n al c alc uli), c al cifi c ati o n of 
t e n d o n a n d li g a m e nts 
L at e:  
A n y ti m e afte r t h e 
c o m pl eti o n of 
t re at m e nt 
Bi rt h def ects t o u n b o r n  
C hil dre n if t a ke n  
d u ri n g pre g n a nc y  
 
 
 ( L) T o xi cit y m ay als o occ ur l at er. 
 
 
Reti n oi c  a ci d  ( R A)  ma y  pr o d u c e  birt h  malf or mati o ns  a n d  s h o ul d  n ot  b e  a d mi nist er e d  d uri n g  pr e g na n c y  or  t o 
w o me n w h o ma y b ec o m e pr e g na nt w hil e u n d er g oi n g treat m e nt. T her e is a n e xtr e mel y hi g h ris k t hat a d ef or m e d 
i nfa nt will r es ult if pr e g na n c y oc c urs w hil e ta ki n g R A i n a n y a m o u nt. Maj or h u ma n fetal a b n or maliti es r elat e d 
t o  R A  ha v e  b e e n  d o c u m e nte d,  i n cl u di n g  h y dr oc e p hal us,  mi cr o c e p hal us,  a b n or maliti es  of  t h e  e xt er nal  ear 
( mi cr o pi n na,  s mall  or  a bse nt  e xt er nal  a u dit or y  ca nals),  mi cr o p ht hal mia,  car di o vasc ular  a b n or maliti es,  fa cial 
d ys m or p hia, t h y m us gla n d a b n or maliti es, parat h yr oi d h or m o n e d efi ci e nc y, a n d cer e b ellar malf or mati o n. T h er e 
als o  is  a n  i n cr ease d  ris k  of  s p o nta n e o us  a b orti o n.  F or  fe mal e  pati e nts  of  c hil d -b eari n g  a g e,  effe cti v e 
c o ntra c e pti o n  m ust  b e  use d  f or  at  least  o n e  m o nt h  b ef or e  be gi n ni n g  R A  t hera p y,  d uri n g  t hera p y  a n d  f or  o ne 
m o nt h f oll o wi n g disc o nti n u ati o n of t h era p y. It is r e c o m m e n d e d t hat t w o r eli a bl e f or ms of c o ntra ce pti o n b e use d 
si m ulta n e o usl y u nl ess a bsti ne n c e is t h e c h ose n met h o d. If pre g na n c y d o es o c c ur d uri n g treat m e nt, t h e p h ysi cia n 
a n d t h e patie nt s h o ul d disc uss t h e d esira bilit y of c o nti n ui n g t he pr e g na nc y. All fe mal es of c hil d b eari n g a ge w h o 
will ha n dl e t h e dr u g t o a d mi nist er t o t h e pati e nt ar e a d vise d t o wear pr ote cti ve gl o v es.  
 
Is otr eti n oi n  m ust  be  pr esc ri be d  u n de r  t he  C o m mitte d  t o  Pr e g n a nc y  Pr e v e nti o n  Pr o g r a m  (i P L E D G E). 
P h ysi cia ns m ust c o m pl et e a o n e -ti me re gistrati o n wit h t he  ma n ufa ct urers  of Is otr eti n oi n i n  or der t o b e a bl e t o 
pr escri b e t h e dr u g. Ea c h p h ysi cia n ( or t h eir offi ce re pr ese ntati ve)/ p har ma cist a n d patie nt m ust b e r e gist er e d o n 
li n e @ htt p:// w w w.i ple d g e pr o gra m. c o m  (or call 1 -8 6 6 -4 9 5 -0 6 5 4 t o b e gi n t h e r e gistrati o n pr oc ess.)   
 
1 0. 6  
C olle cti o n a n d r ei nf usi o n of a ut ol o g o us ste m c ells i nf o r m ati o n a n d t o xicit y  
 

 
2 2  
1 0. 6. 1  Ge neral: L e u k a p heresis (f or t h e c oll e cti o n of p eri p h eral bl o o d st e m c ells) will be p erf or m e d usi n g a 
c o ntin u o us fl o w c ell se parat or ma c hi n e.  T his ma c hi n e is c o m m o nl y use d b y ma n y bl o o d ba n k fa ciliti es a n d 
se parat es w h ol e bl o o d i nt o s o m e of its c o m p o ne nts base d o n t h e differe n c es i n d e nsiti es.  
 
1 0. 6. 2  T o xi cities: A d v erse r ea cti o ns si milar t o t h ose se e n wit h r o uti n e b l o o d c oll ecti o n s u c h as 
li g ht h ea d e d n ess, fai nti n g, a n d v o miti n g ma y o c c ur.  Als o, c o m pli cati o ns u ni q u e t o t he p h er esis pr o ce d ur e 
i n cl u di n g: c hills (se c o n dar y t o e xtra c or p or eal c o oli n g of pati e nt bl o o d), v ol u m e d e pl eti o n or o v erl oa d, 
he m ol ysis, bl o o d cl otti n g, bl e e di n g, or air e m b olis m ma y o cc ur.  I n a d diti o n, i n pati e nts wei g hi n g less t ha n 4 0 
k g t he ma c hi n e will b e pri m e d wit h irra diat e d pa c k e d r e d bl o o d c ells re c o nstit ute d wit h sali n e or al b u mi n i n 
or d er t o pre v e nt h y p o v ol e mia.   C o nse q u e ntl y, t h ese pati e n ts will b e at a n i n cr ease d ris k of d e v el o pi n g 
tra nsf usi o n rea cti o ns or bl o o d-b or n e i nfe cti o ns.  H o we v er, t his e x p os ure will b e mi ni mal c o m par e d wit h t h e 
bl o o d tra nsf usi o n r e q uir e m e nts w hi c h t hese patie nts will i nc ur f oll o wi n g t h e i nte nsi v e c h e m ot h era p y p ha se of 
t h era p y. 
 
1 0. 6. 3  T he ris ks ass o ciat e d wit h r ei nf usi n g t h e c ells i ncl u d e uri n e disc ol orati o n, n a usea, v o miti n g, t h e o d or of 
t h e  pr eser vati v e  ( D M S O)  use d  t o  st ore  t h e  P B S C,  fe v er,  c hills,  a n d  i ncr ease d  bl o o d  pr ess ur e.    All  of  t h ese 
s y m pt o ms  are  t e m p orar y  a n d  us u all y  res ol v e  aft er  t h e  i nf usi o n  is  c o m pl et e.    As  wit h  a n y  e x p eri m e ntal 
pr o c e d ure, t h er e ma y b e u na ntici pat e d si d e effe cts.  
 
1 1. 0  M O DI FI C A TI O N F O R T O XI CI T Y  
 
1 1. 1  M o dificati o n d uri n g c yt or e d u cti o n  
T he cr eati ni n e cl eara n c e will b e deter mi n e d pri or  t o ea c h d ose of car b o plati n.  If t h e cr eati ni n e cl eara n c e 
dr o ps t o < 7 0 ml/ mi n/ 1. 7 3 m 2 , neit her t h e car b o plati n n or t h e t hi ot e pa will be a d mi nist er e d. 
 
1 1. 2  
M o dificati o n d uri n g 1 3 -cis -r eti n oi c a ci d t h era p y 
1 1. 2. 1 A d ose re d u cti o n of 2 5 % (t o 1 2 0 m g/ m 2/ da y or 4 m g/ k g/ da y if t h e c hil d wei g hs < 1 2 k g) f or s u bse q u e nt 
c y cles s h o ul d b e ma d e f or t h e o c c urre n c e of a n y Gra d e 3 or 4  t o xi citi es E X C L U DI N G: Gra d e 3 or 4 
he mat ol o gi c, Gra d e 3 h e patic, Gra de 3 na usea, Gra d e 3 v o miti n g, or Gra de 3 fe ver. If t he sa m e Gra d e 3 or 4 
t o xi cit y r e c urs at a 2 5 % d ose r e d u cti o n, t he n d e cr ease t h e d ose a n ot h er 2 0 % (t o 1 0 0 m g/ m2/ da y or 3. 3 3 
m g/ k g/ da y if t he c hil d wei g hs <  1 2 k g.) If t h e sa m e Gra d e 3 or 4 t o xi cit y r e c urs aft er t w o d ose r e d u cti o ns, t he n 
disc uss wit h o ne of t he pri n ci pal i n v esti gat ors b ef ore c o nti n ui n g t h era p y.  
 
1 1. 2. 2  It has b e e n r e p ort e d (rar el y) t hat s o m e pati e nts treat e d wit h 1 3-cis -reti n oi c a ci d d e v el o p ne w areas of 
a b n or mal u pta k e o n b o n e sca n, li k el y d u e t o i n cr ease d b o n e r es or pti o n. If s u c h c ha n g es o c c ur d uri n g r eti n oi c 
a ci d p hase i n a bse n c e of ot h er e vi d e n ce of t u m or r e c urre n c e, disc uss wit h t he st u d y c hair b ef ore r e p orti n g as 
disease pr o gr essi o n.  
 
 
1 1. 2. 3  If crit eria t o b e gi n t h e ne xt c y cl e ar e n ot m et b y t h e dat e t h e c ycle is d u e t o b e gi n, d ela y t h e c y cl e f or o n e 
we e k. If crit er ia ar e still n ot m et, h ol d t hera p y u ntil crit eria ar e m et, a n d treat at 2 5 % d ose r e d u cti o n ( 1 2 0 
m g/ m 2/ da y or 4 m g/ k g/ da y if t h e c hil d wei g hs < 1 2 k g). A n a d diti o nal d ose r e d u cti o n t o 1 0 0 m g/ m 2/ da y ( 3. 3 3 
m g/ k g/ da y if t he c hil d wei g hs < 1 2 k g) s h o ul d o c c ur if crit eria are n ot met wit hi n o n e we e k after d u e dat e f or 
s u bse q u e nt c y cl es. 
 
1 1. 2. 4  If t h e ser u m cr eati ni n e i n cr eases b y > 5 0 % i n a n y c y cl e of t h era p y, a cr eati ni ne cl eara n c e or G F R s h o ul d 
be d o n e pri or t o starti n g t he n e xt c y cl e, a n d a uri nal ysis. If t he creati n i n e cl e ara nc e a n d/ or G F R ar e < 5 0 
c c/ mi n/ 1. 7 3 m 2 , t h e n call o n e of t he pri n ci pal i n v esti gat ors f or a d ose a dj ust m e nt. 
 
1 1. 2. 5  If t h e patie nt d e v el o ps h e mat uria, pr ot ei n uria, a n d/ or h y pert e nsi o n d uri n g a n y c y cle of t hera p y, h ol d t h e 
m e dicati o n a n d c o nta ct o n e of t h e pri nci pal i n v esti gat ors.  

 
2 3  
 
1 1. 2. 6  F or l ocaliz e d c heilits, a p pl y t o pi cal vita mi n E t o t he li ps f or s u bse q u e nt c y cl es. If t his d o es n ot c o ntr ol 
s y m pt o ms s uffi cie ntl y t o all o w s uffi ci e nt oral i nta k e, t h e n d e crease t h e d ose b y 2 5 % t o 1 2 0 m g/ m 2/ da y or 4 
m g/ k g/ da y if t he c hil d wei g hs < 1 2 k g.  
 
1 1. 2. 7  If ser u m tri gl yc eri d es ar e > 3 0 0 m g/ dl w he n t h e n e xt c ycle is d u e, d ela y starti n g t h era p y f or t w o wee ks. 
If it is still > 3 0 0 m g/ dl, t h e n start t he patie nt o n m e di cal t h era p y f or ser u m tri gl y c eri de r e d u cti o n a n d b e gi n t he 
c y cle at t h e pr e vi o us cis-r eti n oi c a ci d d osa g e. If t h e ser u m tri gl y c eri des are < 3 0 0 m g/ dl b y t h e ti me t h e 
s u bse q u e nt c y cl e is d u e, t h e n c o nti n u e at t he sa m e d osa g e of cis-reti n oic a ci d. If t h e tri gl y c eri d es are still > 3 0 0 
m g/ dl aft er o n e c y cl e o n m e di cal t h era p y , t he n r e d u c e t h e cis-r eti n oic a ci d d osa g e b y 2 5 % f or s u bse q u e nt 
c y cles.  
 
1 2. 0      S U P P O R TI V E C A R E G UI D E LI N E S  
 
1 2. 1  
D uri n g hi g h d ose c h e m ot hera p y  
 
1 2. 1. 1 Pr ot e cti v e is olati o n p er l o cal i nstit uti o nal g ui d eli n es  
1 2. 1. 2 All bl o o d pr o d u cts t o b e irra diat e d wit h 1 5 0 0 c G y b ef or e bei n g gi v e n t o patie nt  
1 2. 1. 3 F u n gal pr o p h yla xis p er i nstit uti o nal g ui d eli n es.  
1 2. 1. 4 F or m e nstr u ati n g fe mal es re c o m m e n d: n ystati n va gi nal s u p p osit or y 1 0 0, 0 0 0 p v q da y. N ort ulate 5 m g p o 
q da y.  
1 2. 1. 5 Sta n dar d Hi c k ma n cat h eter care p er i nsti t uti o nal g ui d eli n es 
1 2. 1. 6 Da y -1 0 t o da y -2 b ef or e st e m cell r ei nf usi o n r ec o m m e n d: tri m et h o pri m ( 1 5 0 m g/ m 2/ da y) a n d 
s ulfa m et h o xa z ol e ( 7 5 0 m g/ m2/ d); di vi d e i nt o t w o d oses a n d gi v e q 1 2 h o urs f or P C P. F or patie nt all er gi c t o s ulfa 
dr u gs, p e nta mi di ne ma y b e u se d. 
1 2. 1. 7 Pr o p h yla xis a gai nst H S V, V Z V, a n d/ or C M V will b e gi v e n i n ser o p ositi v e patie nts p er i nstit uti o nal 
g ui d eli n es.  
1 2. 1. 8 D oc u m e nt e d or s us pe ct e d i nfe cti o ns d uri n g t h e c yt o p e ni c p hase will be tr eat e d wit h a p pr o priat e 
a nti bi oti cs, a nti -f u n gals, a n d/ or a nti virals as d et er mi n e d b y t h e treati n g p h ysicia n. 
 
1 2. 2  
Re c o m m e n d e d p ost tra ns pla nt i nstr u cti o ns  
  
 
1 2. 2. 1  W h e n t h e A N C >  5 0 0/ u L o n 3 r e peat e d d et er mi nati o ns, be gi n tri m et h o pri m ( 1 5 0 m g/ m 2/ da y) a n d 
s ulfa m et h o xa z ol e ( 7 5 0 m g/ m2/ d); di vi d e i nt o t w o d oses gi v e n 2 c o nse c uti v e da ys/ we e k u ntil m o nt h + 1 2. T h e 
tri met h o pri m/s ulfa m et h o xa z ol e s h o ul d n ot b e restart e d b ef or e da y + 2 8. 
 
1 2. 2. 2  Pati e nts s h o ul d ha v e i m m u n e f u n cti o n e val u ati o n at ni n e m o nt hs p ost st e m c ell r ei nf usi o n t o d et er mi n e 
w h e n t o b e gi n t h e r e -i m m u ni zati on pr o c ess as per l o cal i nstit uti o nal g ui d eli n es.    
 
 
 
1 3. 0     S T U D Y M O NI T O RI N G -S E RI O U S A D V E R S E E V E N T S  
 
1 3. 1  
A d v erse e v e nts will be gra d e d a c c or di n g t o t h e C T C A E crit eria, v ersi o n 3. 0. C T C A E v ersi o n 3. 0 ma y 
be d o w nl oa d e d fr o m t h e C T E P we b sit e ( htt p:// ct e p. ca n c er. g o v ).  
1 3. 2  
Gra de 3 a n d hi g h er a d v erse e v e nts will b e r e p ort e d t o t h e Pr ot o c ol C hair a n d O p erati o ns Offi c e wit hi n 
1 0 da ys of t h e o cc urr e n ce usi n g t h e f or m i n A p p e n di x C e x c e pt as s p e cifi e d i n se cti o n 1 3. 3.  
 
1 3. 3  
Gra de 4 a n d gra d e 5 a d verse e v e nts s p ecifi e d i n t h e ta bl e r e q uir e e x p e dit e d r e p orti n g.as d etaile d b el o w.  

 
2 4  
  
 
Attri b uti o n  
Gr a d e 4  
Gr a d e 5 #  
Pr ot o c ol -S p e cifi c 
R e q uir e m e nt s  
U n e x p e ct e d  E x p e ct e d  U n e x p e ct e d  E x p e ct e d  
  
U nr el at e d 
or 
U nli k el y  
  
  
A E R e p or t 
  
R e p ort t o St u d y C h air b y 
p h o n e wit hi n 2 4 h o ur s of 
o c c urr e n c e  a n d b y f a x or 
e m ail u si n g t h e f or m i n 
A p p e n di x C wit hi n 5 c al e n d ar 
d a y s.  
P o s si bl e, 
Pr o b a bl e, 
D efi nit e  
A E R e p ort  
  
A E R e p ort  
A E 
R e p ort  
 
#: T his i n cl u d es all deat hs wit hi n 3 0 da ys of t h e las t d ose of treat m e nt wit h a c o m mercial a g e nt re gar dl ess of 
attri b uti o n. A n y d eat h t hat o cc urs m or e t ha n 3 0 da ys aft er t h e last d ose of tr e at m e nt wit h a c o m m er cial a g e nt(s) 
a n d is attri b ut e d ( p ossi bl y, pr o ba bl y, or d efi nit el y) t o t h e a g e nt(s) a n d is n ot d u e t o ca n c er r e c urre n c e m ust be 
re p orte d a c c or di n g t o t h e i nstr u cti o ns a b o v e. 
 
 
1 3. 1     All seri o us a d v erse e v e nts ( d efi n e d b el o w), w het h er or n ot d e e me d dr u g -relat e d or e x p ecte d, m ust be 
re p orte d t o t he Pri n ci pal I n v esti gat ors a n d t h e O p erati o ns C e nt er wit hi n 1 0 d a ys of oc c urr e n c e. A seri o us 
a d v erse e ve nt is o ne t hat r es ults i n a n y of t h e f oll o wi n g o utc o m es:  
- D eat h  
- A life -t hr eat e ni n g a d verse dr u g e x p eri e n ce (t h e s u bj e ct was at i m me di ate ris k of d eat h fr o m t he 
a d v erse e ve nt as it o c c urre d)  
-A p ersiste nt or  si g nifi ca nt disa bilit y/i n ca pa cit y 
-Pr o gr essi o n of disease  
I n a d diti o n, i m p orta nt m e dical e v e nts (se e d efi niti o n b el o w), i n cl u di n g h e mat ol o gi cal, r e nal, 
car di o vasc ular, he pati c,   
 
 
1 3. 2    I m p orta nt m e di cal e ve nts t hat ma y n ot r es ult i n d eat h, b e life t hrea te ni n g or r e q uire h os pitalizati o n ma y 
be c o nsi d ere d a seri o us a d v erse dr u g e x p eri e nc e w h e n, base d u p o n me di cal j u d g m e nt, t h e y ma y 
je o par di z e t h e pati e nt a n d ma y r e q uir e m e dical or s ur gical i nt er ve nti o n.  
 
1 3. 3  Seri o us A d v erse E v e nts will be r e p ort e d i n a ti m el y ma n n er t o t h e Data Safet y  
M o nit ori n g B oar d a n d t o t he st u d y Pri n ci pl e I n v esti gat ors as p er P B M T C g ui d eli n es as o utli n e d i n 
A p p e n di x B.  
 
1 3. 4  
Parti ci pati n g c e nt ers will b e n otifie d of u n e x p ecte d fatal or life -t hreat e ni n g e ve nts b y t h e Pr ot oc ol C hair 
wit hi n 7 cal e n dar da ys aft er t h e Pr ot o c ol C hair’s i nitial r e c ei pt of t h e i nf or m ati o n.  
1 4. 0  
Crite ri a F o r Re m o v al Fr o m Pr ot o c ol A n d Off St u d y Crite ri a  
 
1 4. 1     Crit eria f or r e m o val fr o m pr ot o c ol  
1 4. 1. 1 Patie nt or par e ntal n o n -c o m plia n c e or re q u est t o wit h dra w fr o m    pr ot o c ol t h era p y. 
 
1 4. 1. 2 At t h e discr eti o n of t h e atte n di n g p h ysi cia n (r eas o n m ust b e s pe cifi e d)  
  
  
 
1 4. 1. 3 A n y pati e nt w h o d e v el o ps h y p erse nsiti vit y t o te m o z ol o mi d e.   
 
1 4. 2  Re m o val fr o m pr ot o c ol f oll o w -u p  

 
2 5  
Pati e nts ma y b e r e m o ve d fr o m pr ot o c ol  s p e cifie d f oll o w-u p u n d er t h e f oll o wi n g cir c u msta n c es:  
  
 
a) Deat h  
  
 
b) Pare nt re q u est  
  
 
c) E ntr y o nt o a n ot h er pr ot o c ol t h era p y  
 
1 5. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  
 
1 5. 1  Ac cr u al g oals will b e base d s olel y o n t h e n u m b er of patie nts e nr oll e d wit h t he dia g n oses  of rela pse d 
m e d ull o blast o ma or P N E T as we ha v e s o m e hist ori cal c o ntr ols o n w hic h t o base t h e a nal ysis.  Ot h er dia g n oses 
will b e a nal y z e d f or s ur vi val a n d t o xi cit y a n d r e p ort e d  
 
1 5. 2  
  F or t his st u d y, a 2 -sta g e Si m o n mi ni ma x d esi g n will b e use d.  F or a t otal of 3 6 s u bje cts, 1 7 will be 
a ccr u e d d uri n g sta g e 1 a n d 1 9 d uri n g sta g e 2.  Gi v e n t hat t h e “tr u e” r es p o nse pr o ba bilit y is 2 5 %, t h er e is a 
7 6. 5 3 % pr o ba bilit y of e n di n g t h e trial d uri n g sta g e 1.  A r es p o nse s hall b e d efi n e d as s ur vi val of t h e patie nt 
pr o gr essi o n -fr ee f or 1-y ear p ost -S C T.  H o we v er, if t he “tr u e” res p o nse pr o b a bilit y is 4 5 % t h e n t h er e is a 5. 9 6 % 
pr o ba bilit y t hat t h e trial will b e st o p p e d i n sta g e 1.    T h e al p ha l e vel of t h e d esi g n is 0. 0 4 a n d t h e p o wer is 0. 8.  
If 4 or fe wer r es p o nses are o bser ve d d uri n g t he first sta g e t he trial is st o p p e d earl y.  If after 1 7 pati e nts ar e 
e nr oll e d t h er e ar e fe wer t ha n 5 r es p o n d ers, t h e n f urt h er e nr oll m e nt will be s us p e n d e d u ntil t her e are eit her: 5 
d o c u m e nt e d r es p o n d ers at w hi c h ti me a c cr u al will b e r e -i nitiat e d or 1 3 d o c u m e nte d n o n-res p o n d ers at w hic h 
ti m e t h e st u d y will b e cl ose d. If 1 3 or fe wer res p o nses ar e o bser v e d b y t he e n d of t he trial, t h e n n o f urt h er 
i n vesti gati o n of t he dr u g c o m bi nati o n is warra nt e d.  Gi v e n a “ ba d” r es p o nse rate of 2 5 %, t h e e x p e ct e d sa m ple 
si z e f or t h e trial is 2 5. 1. 
 
 
1 5. 3  
Alt h o u g h 1 -year pr o gr essi o n -fr e e s ur vi val s h o ul d a p pr o xi mat e l o n g er s ur vi v al base d o n hist ori cal 
c o ntr ols, 3 -y ear pr o gressi o n -fr e e s ur vi val will b e esti mat e d usi n g t h e m et h o d of Ka pla n a n d M ei er. 
 
1 5. 4    St o p pi n g R ul es  
            T h e st u d y will be st o p p e d if 3 of t h e first 9 or 4 of t he first 2 0 pati e nts e nr oll e d (r e gar dl ess of dia g n osis) 
di e fr o m tra ns pla nt -r elat e d t o xicit y O R if aft er 2 0 pati e nts ar e e nr oll e d t he t o xi c m ortalit y rat e is > 2 0 %.  D eat hs 
fr o m pr o gr essi v e disease d o n ot a p pl y t o st o p pi n g r ul es.   
 
1 6. 0   Ge n de r a n d Et h nic O ri gi n  
 
T her e is n o c o m p elli n g e vi d e n c e t o s u g gest t hat o ut c o m e of tr eat m e nt f or r e c urre nt brai n t u m ors is de p e n d e nt 
o n g e n d er or et h ni cit y.  H e n ce, t h e st u d y si z e will n ot be a dj ust e d t o e ns ure hi g h p o wer t o d et e ct differ e n ces i n 
o utc o m e i n gr o u ps d efi n e d b y et h ni cit y or g e n d er.  
 
1 7. 0  
C O N S E N T P R O C E D U R E S  
 
T he i n v esti gati o nal nat ur e a n d o bj e cti v es of t his trial, t h e pr oc e d ures a n d tre at m e nts i n v ol v e d a n d t h eir att e n da nt 
ris ks, disc o mf orts a n d b e n efits, a n d p ot e ntial alter nati v e t h era pi es will b e caref ull y e x plai n e d t o t h e pati e nt or 
t h e pati e nt’s pare nts/l e gal g u ar dia ns (if h e/s h e is a c hil d), a n d a si g n e d i nf or m e d c o nse nt d o c u me nt will b e 
o btai n e d.  W h er e de e m e d a p pr o priat e b y t he tr eati n g p h ysi cia n a n d t h e c hil d’s par e nts/l e gal g u ar dia ns, t h e c hil d 
will als o b e i n cl u d e d i n all disc ussi o ns a b o ut t h e trial a n d ver bal asse nt t o partici pat e will b e o btai n e d.  
 

 
2 6  
1 8. 0     R E F E R E N C E S  
 
1.  
Alle n J C, Bl o o m J, Ertel I, et al: Brai n t u m ors i n c hil dr e n: C urr e nt c o o p erati ve a n d i nstit uti o nal 
c h e m ot h era p y trials i n n e wl y dia g n ose d a n d r e c urre nt disease. S e mi n O n c ol 1 3 : 1 1 0-1 2 2, 1 9 8 6.  
2.  
Lef k o wit z I B, Pa c k er RJ, Si e g el D R, et al: R es ults of tr eat m e nt of c hil dr e n wit h re c urr e nt 
m e d ull o blast o ma/ pri miti v e n e ur o e ct o d er mal t u m ors wit h l o m usti n e, cis plati n, a n d vi n cristi ne.  Ca n c er 
6 5 : 4 1 2-4 1 7, 1 9 9 0.  
3.  
T orres C F, R e bsa m e n S, Sil b er J H, et al: S ur v eilla n ce sca n ni n g of c hil dr e n wit h me d ull o blast o ma.  N 
E n gl J M e d 3 3 0 : 8 9 2-8 9 5, 1 9 9 4.  
4.  
M urra y J C, Kli n e N E, W o o S Y, et al: R e c urre nt me d ull o blast o ma i n c hil dre n p orte n ds a p o or pr o g n osis: 
A 2 5 y ear si n gle i nstit uti o n r e vi e w.  Pr o c e e di n gs of t h e Si xt h I nt er nati o nal S y m p osi u m o n P e diatri c 
Ne ur o -O n c ol o g y, H o ust o n, T X, Ma y 1 8 -2 1, 1 9 9 4, (a bstr 4 7).  
5.  
Alle n J C, B osl G, Wal k er R: C he m ot h era p y trials i n re c urr e nt pri mar y i ntra cra nial g er m c ell t u m ors. J 
Ne ur o o nc ol 3 : 1 4 7-1 5 2, 1 9 8 5.  
6.  
Gra ha m M L. H er n d o n J E 2 n d, Case y J R, et al: Hi g h-d ose c h e m ot h era p y wit h a ut ol o g o us st e m -c ell 
resc u e i n patie nts wit h r e c urr e nt a n d hi g h-ris k pe diatri c brai n t u m ors.  J Cli n O nc ol 1 5 : 1 8 1 4-1 8 2 3, 1 9 9 7.  
7.  
D u n k el IJ, B o y ett J M, Yat es A, et al: Hi g h -d ose car b o plati n, t hi ot e pa, a n d et o p osi d e wit h a ut ol o g o us 
st e m-c ell resc u e f or pati e nts wit h r ec urr e nt m e d ull o blast o ma. J Cli n O n c ol 1 6 : 2 2 2-2 2 8, 1 9 9 8.  
8.  
Kalifa C, Hart ma n n O, D e me o c q F, et al : Hi g h-d ose b us ulfa n a n d t hi ot e pa wit h a ut ol o g o us b o n e marr o w 
tra ns pla ntati o n i n c hil d h o o d mali g na nt brai n t u m ors: a p hase II st u d y.  B o ne Marr o w Tra ns pla nt 9 : 2 2 7-
2 3 3, 1 9 9 2.  
9.  
Fi nla y J L, G ol d ma n S, W o n g M C, et al. a n d t h e C hil dr e n’s Ca nc er Gr o u p: A pil ot st u d y of hi g h -d ose 
t hi ot e pa a n d et o p osi d e wit h a ut ol o g o us b o n e marr o w resc u e i n c hil dr e n a n d y o u n g a d ults wit h r e c urr e nt 
c e ntral ner v o us s yste m t u m ors.  J Cli n O n c ol 1 4 : 2 4 9 5-2 5 0 3, 1 9 9 6.  
1 0.  
B o uffet E, Bara n zelli M C, Patt e C, et al. a n d t h e S ociet e Fra n caise d’ O n c ol o gi e Pe diatri q u e ( S F O P): 
Hi g h d ose et o p osi d e a n d t hi ot e pa f or r efra ct or y a n d r e c urre nt mali g na nt i ntr a cra nial g er m c ell t u m o urs 
( C N S-G C T). 9 t h I nt er nati o nal S y m p osi u m o n P e diatri c N e ur o-O n c ol o g y 8 7, 2 0 0 0.  
1 1.  
Ne wla n ds E S, St e v e ns M F, W e d ge S R, et al: T e m o z ol o mi d e: A r e vi e w of its disc o v er y, c h e mi cal 
pr o p erties, pre -cli ni cal de v el o p m et na n d cli ni cal trials.  Ca nc er Treat Re v 2 3: 3 5 -6 1, 1 9 9 7.  
1 2.  
Gi bs o n N W, Hi c k ma n J A, Eri c ks o n L C, et al.: D N A cr oss -li n ki n g a n d c yt ot o xicit y i n n or mal a n d 
tra nsf or me d h u ma n c ells tr eat e d i n vitr o wit h 8-car ba m o yl - 3-( 2-c hl or o et h y)i mi da z o[ 5, 1 -d] -1, 2, 3, 5 -
tetra zi n-4( 3 H) -o n e.  Ca nc er R es 4 4 : 1 7 7 2-1 7 7 5, 1 9 8 4.  
1 3.  
Gers o n S L, S pir o T P, R ei d e n b er g P, et al: Ra pi d d e pl eti o n of O 6 -al k yl g u a ni ne D N A al k yltra nsferase 
wit h t wi c e dail y oral t e m o z ol o mi d e ( S C H 5 2 3 6 5) i n pati e nts wit h a d va nc e d ca n c er.  Pr o c A m S o c Cli n 
O n c ol. 3 2 n d a n n u al m e eti n g 1 5 : 1 7 8, 1 9 9 6. 
1 4.  
Nic h ols o n H S, Krail o M, A m es M M, S ei bel N L, R ei d J M, Li u -Mares W, Ve zi na L G, Etti n g er A G, 
Rea ma n G H: P hase I st u d y of te m o z ol o mi d e i n c hil dr e n a n d a d ol es ce nts wit h r e c urre nt s oli d t u m ors: a 
re p ort fr o m t h e C hil dr e n’s Ca n cer Gr o u p.  J Cli n O n c ol 1 6 : 3 0 3 7-4 3, 1 9 9 8.  
1 5.  
Estli n EJ, Las hf or d L, A bl ett S, Pri c e L, G o wi n g R, G h ol k ar A, K o hl er J, L e wis IJ, M orla n d B, 
Pi n k ert o n C R: P hase I st u d y of t e m o z ol o mi d e i n pa e d iatri c pati e nts wit h a d v a nc e d ca n c er.  U nit e d 
Ki n g d o m C hil dr e n’s Ca n c er St u d y Gr o u p.  Br J Ca n cer 7 8 : 6 5 2-6 1, 1 9 9 8.  
1 6.  
Ne wla n ds E S, O’ Reill y S M, Glaser M G, et al: T h e C hari n g Cr oss H os pital e x p eri e n c e wit h 
te m oz ol o mi d e i n pati e nts wit h gli o mas.  E ur J Ca n cer 3 2 A : 2 2 3 6-2 2 4 1, 1 9 9 6.  
1 7.  
Y u n g W, Pra d os M, Ya ya -T ur R, R ose nfel d S, Bra da M, Fri e d ma n H, Al bri g ht R, Ols o n J, C ha n g S, 
O’ Neill A: M ulti ce nt er P hase II trial of te m o z ol o mi d e i n patie nts wit h a na pl asti c astr o c yt o ma or 
a na plasti c oli g oastr o c yt o ma at first r ela pse.   J Cli n O n c ol 1 7 : 2 7 6 2-2 7 7 1, 1 9 9 9.  
1 8.  
Fri e d ma n H S, D ola n M E, P e g g A E et al: Acti vit y of t e m o z ol o mi d e i n t h e tr eat m e nt of ce ntral ner v o us 
s yst e m t u m or xe n o grafts.  Ca n c er R es 5 5: 2 8 5 3-2 8 5 7, 1 9 9 5.  
1 9.  
H o n g e n g S, Vis u dti b ha n A, D ha na c hai M et al:  Treat m e nt of l e pt o m e ni n g e al rela pse of 
m e d ull o blast o ma wit h t e m o z ol o mi d e.  J P e ds H e me/ O n c 2 4( 7): 5 9 1 -5 9 2, 2 0 0 2.  

 
2 7  
2 0.  
Matt ha y, K. K. et al. Treat m e nt of hi g h -ris k ne ur o blast o ma wit h i nt e nsi ve c h e m ot h era p y, ra di ot h era p y, 
a ut ol o g o us b o ne marr o w tra ns pla ntati o n a n d 1 3 -cis -r eti n oi c a ci d. N e w E n gl a n d J o ur nal of Me di ci n e, 
3 4 1: 1 1 6 5 -1 1 7 3, 1 9 9 9.  
2 1.  
B o ut erfa H, Pi c ht T, Kess D et al:  Reti n oi ds i n hi bit h u ma n gli o ma cell pr oliferati o n a n d mi grati o n i n 
pri mar y cell c ult ur es b ut n ot i n esta blis h e d c ell li n es.  N e ur os ur g 4 6( 2): 4 1 9 -4 3 0, 2 0 0 0.  
2 2.  
Y u n g W K, K yritsis A P, Gl eas o n MJ et al:  Treat m e nt of r e c urre nt mali g na nt gli o mas wit h hi g h d ose 1 3 -
cis-r eti n oi c a ci d.  Cli n Ca n c er R es 2( 1 2): 1 9 3 1-1 9 3 5, 1 9 9 6.   
2 3.       Halla ha n A R, Prit c har d JI, C ha n drarat na R A, et al. B M P -2 m e diat es reti n oi d -i n d u c e d a p opt osis i n 
m e d ull o blast o ma cells t hr o u g h a para cri ne effe ct. Nat M e d. A u g; 9( 8): 1 0 3 3 -1 0 3 8, 2 0 0 3.  
2 4.       K ha n A A, Villa bla n ca J G, R e y n ol ds C P, A vra mis VI.  P har ma c o ki n eti c st u di es of 1 3 -cis -r eti n oi c a ci d i n 
pe diatri c pati e nts wit h n e ur o blast o ma f oll o wi n g b o n e marr o w tra ns pla ntati o n.  Ca n c er C h e m ot her a n d 
P har ma c ol 3 9: 3 4 -4 1, 1 9 9 6.  
2 5.  
Villa bla n ca, J. G., K ha n A. A., A vra mis, V.I. et al:  P hase I trial of 1 3 -cis -r eti n oic a ci d i n c hil dre n wit h 
ne ur o blast o ma f oll o wi n g b o n e marr o w tra ns pla ntati o n.  J. Cli n. O n c ol.,  1 3: 8 9 4 -9 0 1, 1 9 9 5.  
2 6.    Marrill J, Ca pr o n C C, I dr es N, a n d C ha b ot G G, H u ma n c yt o c hr o m e P 4 5 0s i n v ol ve d i n t h e m eta b olis m 
of 9 -cis - a n d 1 3 -cis -r eti n oi c a ci ds: Bi oc h e mi cal P har ma c ol o g y, 6 3: 9 3 3-9 4 3 ( 2 0 0 2).  
2 7.    Dai D, Z el di n D C, Blais d ell J A, C ha nas B, C o utl e r SJ, G ha na y e m BI, a n d G ol dst ei n J A. P ol y m or p his ms 
i n  h u ma n  C y P 2 C 8  d ecrease  meta b olis m  of  t h e  a nti ca nc er  dr u g  palit a xel  a n d  ara c hi d o ni c  a ci d: 
P har ma c o g e n etics,  1 1: 5 9 7 -6 0 7 ( 2 0 0 1).  
2 8.    K u e hl P, Z ha n g J, Li n Y, La m ba J, Asse m M, S c h u et z J, Wat ki ns P B, Dal y  A,  Wri g ht o n  S A, Hall S D, 
Ma urel P, R elli n g M, Bri m er C, Yas u da K, Ve n k atara ma na n R, Str o m S, T h u m m el K, B o g us ki M S, a n d 
Sc h u et z  E.  S e q u e n c e  di versit y  i n  C Y P 3 A  pr o m oters  a n d  c hara ct eri zati o n  of  t h e  ge n eti c  basis  of 
p ol y m or p hic C Y P 3 A 5 e x pr essi o n. Nat ure G e n eti cs: 2 7: 3 8 3 -3 9 1 ( 2 0 0 1).  
2 9.    B ur k  O,  T e g u d e  H,  K o c h  I,  H ust ert  E,  W ol b ol d  R,  Gla eser  H,  Kl ei n  K,  Fr o m m  M F,  N u essl er  A K, 
Ne u ha us  P,  Za n g er  U M,  Ei c h el ba u m  M,  a n d  W oj n o ws ki  L.  M ol e c ular  m e c ha nis ms  of  p ol y m or p hi c 
C Y P 3 A &  e x pr essi o n  i n  a d ult  h u ma n  li v er  a n d  i nt esti n e.  J o ur nal  of  Bi ol o gi cal  C h e mistr y: 
1 0. 1 0 7 4/j bc. M 2 0 2 3 4 5 2 0 0 i n press ( we b citati o n) ( 2 0 0 2).  
3 0.  
Sa m o k ysz y n V M, Gall W E, Za wa da G et al.  4 -h y dr o x yr eti n oic a ci d, a n o v el s u bstrat e f or h u ma n li v er 
mi cr os o mal U D P -gl u c ur o n os yltra nsferase(s) a n d r ec o m bi na nt U G T 2 B 7:  J Bi ol C he m,  2 7 5: 6 9 0 8 -6 9 1 4 
( 2 0 0 0) 
3 1.    B has k er  C R,  M c Ki n n o n  W,  St o n e  A,  L o  A C T,  K u b ota  T,  Is hi za ki  T,  a n d  Mi n ers  J O.  Ge n eti c 
p ol y m or p his m  of  U D P -gl u c ur o n os yltra nsferase 2 B 7 ( U G T 2 B 7) at a mi n o  a ci d 2 6 8: et h ni c  di versit y of 
allel es a n d p ot e ntial  cli ni cal si g nifi ca nc e: P har ma c o g e n etics,  1 0: 6 7 9 -6 8 5 ( 2 0 0 0).  
3 2.    Wi e ga n d  U,  C h o u  R C.    P har ma c o ki n eti cs  of  oral  is oreti n oi n:  J o ur nal  of  t h e  A m eri ca n  Aca d e m y  of 
Der mat ol o g y, 3 9( 2): S 8 -S 1 2 ( 1 9 9 8).  
3 3.    Le D o ze  F, D e br u y n e D,  Al b essar d  F, Barr e L, Gilles  L D.   P har ma c o ki n eti cs of  All -tra ns r eti n oi c a ci d, 
1 3 -cis-reti n oic  a ci d  ,  a n d  fe nr eti ni d e  i n  plas ma  a n d  brai n  of  rat:    Dr u g  Meta b olis m  a n d  Dis p ositi o n.  
2 8( 2): 2 0 5 -2 0 8.  
3 4.  
Veal, G.J., Erri n gt o n, J., K oller, K. E. et al.  P har ma c o ki n eti cs a n d meta b olis m of 1 3 -cis -r eti n oi c a ci d i n 
c hil dr e n wit h n e ur o blast o ma:  Pr oc. A A C R, 4 4: 3 5 5 4 (a bstra ct) ( 2 0 0 3).  
3 5.  
Veal G.J., Erri n gt o n J., R e dfer n C. P. F., P ears o n A. D.J., a n d B o d d y A. V. I nfl u e n c e of is o m erisati o n o n 
t h e gr o wt h i n hi bit or y effe cts a n d c ell ular a cti vit y of 1 3-cis a n d all-tra ns reti n oi c a ci d i n n e ur o blast o ma 
c ells: Bi o c h e mi cal P har ma c ol o g y, 6 3: 2 0 7 -2 1 5 ( 2 0 0 2).  
 
 
 
 
 
 
 

 
2 8  
A p pe n di x A:  
 
 
M et h o d of C alc ul ati n g A dj uste d B o d y Wei g ht  
 
 
I B W = i d eal b o d y wei g ht 
 
Pati e nts o v er 1 8 y ears of a g e  
 
Male I B W = 5 0 k g + 2. 3 k g x n u m b e r of i n c h es o v er 5 fe et 
 
Fe mal e I B W = 4 5. 5 k g + 2. 3 k g x n u m ber of i n c h es o v er 5 fe et  
 
 
Pati e nts 1 -1 8 y ears of a g e  
 
a) Less t ha n 6 0 i n c h es  
 
I B W = ( ht2  x 1. 6 5)/ 1 0 0 0 w h er e ht = c m, I B W = k g  
 
b)  Great er t ha n or e q u al t o 6 0 i n c h es  
 
Males I B W = 3 9 k g + 2. 2 7 k g x  n u m b er of i n c h es o v er 5 fe et  
 
Fe mal e I B W = 4 2. 2 k g + 2. 2 7 k g x n u m b er of i nc h es o v er 5 feet  
 
 
 
T o c alc ul ate a dj uste d b o d y wei g ht:  
 
1)  Act u al b o d y wei g ht – I B W = E x c ess wei g ht 
 
2)  E x c ess wei g ht x 4 0 % = wei g ht a dj ust m e nt  
 
3)  A dj ust e d b o d y wei g ht = I B W + wei g ht a dj ust me n t 
 
 
 
 

 
2 9  
A p pe n di x B: G ui deli nes f or R e p orti n g A d verse E ve nts  
 
It is re c o g ni z e d t hat hi g h-d ose c he m ot hera p y wit h st e m c ell or b o ne marr o w resc ue is  
ass oci ate d wit h si g nifi ca nt t o xi citi es t hat are a n a nti ci pat e d c o nse q ue nc e of t hera p y rat her  
t ha n a n a d verse e ve nt. E xce pt w here ot her wise s pe cifi e d, t he N CI/ D C T C o m m o n 
T o xi cit y Criteria versi o n 3. 0 ( htt p://cte p. ca nc er. g o v/re p orti n g/ct c. ht ml) will be use d t o  
gra d e a d verse e ve nts, utili zi n g t he b o ne marr o w tra ns pl a nt -s pe cific a d verse e ve nt gra di n g 
criteria. 
 
C o m pl e x / m ulti c o m p o ne nt a d verse e ve nts will be gra de d usi n g t he a p pr o pri ate a d verse 
e ve nt re p orti n g sc ale (se e C T C A p pe n di x 6 – B M T C o m pl e x/ M ulti c o m p o ne nt E ve nts).  
R e p orti n g a d verse e ve nts will be i n a d diti o n t o re p orti n g of st u d y t o xicities as part of  
st u d y d at a re p orti n g re q uire me nts. 
A d verse e ve nts will be re p ort e d t o t he Pr ot oc ol C hair a n d t o t he P B M T C O perati o ns  
C e nter. E ve nts will be re p ort e d usi n g t he P B M T C “ S E RI O U S A D V E R S E E V E N T  
A S S E S S M E N T F O R P A TI E N T S E N R O L L E D O N P B M T C T RI A L S” f or m ( A p p e n di x 
C). E ve nts wil l be cl assifi e d usi n g t he f oll o wi n g crit eri a: 
 
He mat ol o gic T o xicit y  
T he f oll o wi n g m o difi e d crit eri a will be use d t o gra de s pe cifi e d he mat ol o gi c t o xicities.  
Ne ut r o p hils : 
Gra d e 3: Ne utr o p hils ≥1 0 0 b ut < 5 0 0/ ul f or d urati o n of 4 t o 8 we e ks.  
Gra d e 4: Ne utr o p hils < 1 0 0 f or > 4 we e ks or < 5 0 0/ ul f or d urati o n > 8 we e ks.  
Gra d e 5: De at h d ue t o i nfecti o n ass oci at e d wit h ne utr o p hils < 5 0 0/ ul.  
Gra d e 3 a n d hi g her ne utr o p hil t o xi citi es will  be re p ort e d t o t he Pr ot oc ol C hair a n d  
O perati o ns C e nt er as s pe cifi e d i n se cti o n 1 3. 0.  
Pl atelets:  
Gra d e 3: Pl at el ets ≥1 0, 0 0 0 b ut < 2 0, 0 0 0/ ul o n da y 1 0 0, i n d e pe n d e nt of tra nsf usi o ns 
f or 7 d a ys, wit h o ut ot her c o ntri b uti n g c a uses. 
Gra d e 4: Pl at el ets < 1 0, 0 0 0/ ul  o n d a y 1 0 0, i n d e pe n d e nt of tra nsf usi o ns f or 7 da ys,  
wit h o ut ot her c o ntri b uti n g ca uses.  
Gra d e 5: De at h d ue t o he m orr ha ge ass oci ate d wit h platelets < 2 0, 0 0 0/ ul.  
Gra d e 3 a n d hi g her t o xi citi es will be re p orte d t o t he Pr ot oc ol C hair a n d O perati o ns  
C e nter as s pe cifie d i n se cti o n 1 3. 0. 
 
T ra nsf usi o ns : 
Bl o o d tra nsf usi o ns will be re p ort e d w he n Gra de 3 or hi g her  
a c c or di n g t o C T C B M T g ui deli nes as s pe cifi e d i n se cti o n 1 3. 0.  
 
N o n -He m at ol o gic T o xicit y  
U nl ess ot her wise n ot e d, n o n -he mat ol o gi c t o xi cities will be gra de d b y t he C o m m o n  
T o xi cit y Criteria versi o n 3. 0.  
T he f oll o wi n g n o n -he mat ol o gic A d ve rse E ve nts will be re p o rte d t o t he Pr ot oc ol  
C h ai r a n d O pe rati o ns Ce nte r as s pe cifie d i n se cti o n 1 3. 0.  
 
C a r di o v asc ul a r : Gra d e 3 or hi g her usi n g t he st a n d ar d C T C sc ale 
Gra d e 2 or hi g h er vasc ul ar le a k s y n dr o mes.  
C o a g ul ati o n: Gra d e 3 or hi g her (t hr o m b oti c mi cr oa n gi o pat h y)  
De r m at ol o g y: Gra d e 3 or hi g her (ras h/ d es q ua mati o n)  
A n a p h yl actic re acti o ns : All t o be re p ort e d as seri o us a d verse e ve nts re gar dl ess of c a use. 
E n d oc ri ne: Gra d e 3 or hi g her usi n g t he st a n dar d C T C sc al e.  
G ast roi ntesti n al: V o miti n g: Gra de 4 or hi g her usi n g t he st a n dar d C T C sc al e.  
Di arr he a ass oci at e d wit h graft vers us h ost dise ase. Gra de 3 or hi g her usi n g t he C T C sc ale f or B M T st u di es.  
M uc ositis/st o matitis: Gra d e 3 or hi g her usi n g t he C T C sc al e f or st o matitis/ p har y n gitis/ m uc ositis f or B M T st u dies.  
T P N a d mi nist ere d f or m uc ositis will n ot be re p ort e d.  
He p atic: Bilir u bi n: Gra d e 3 or hi g her usi n g t he C T C sc al e f or G V H D.  

 
3 0  
S G O T/ S G P T: Gra de 3 or hi g her usi n g t he st a n d ar d C T C sc al e, a n d  o nl y if n ot ass o ci at e d wit h G V H D or V O D ( ot her wise 
it will be re p ort e d a cc or di n g t o t he criteri a f or t he a p pr o pri at e 
m ulti c o m p o ne nt e ve nt).  
V O D: Gra d e 3 or hi g her usi n g t he C T C sc ale f or c o m pl e x/ m ulti c o m p o ne nt e ve nts. Lifet hre at e ni n g ( Gra de 4) V O D will 
b e defi ne d as wei g ht gai n > 1 0 %, creati ni ne > 2, a n d O 2  
d e pe n d e nt. If 2 o ut of 3 fa ct ors prese nt, it will be c o nsi d ere d se vere. Wei g ht gai n will  
n ot be re p ort e d se parat e fr o m V O D.  
I nfe cti o n: O nl y i nfe cti o ns re q uiri n g h os pit aliz ati o n, d oc u me nt e d i n vasi ve f u n gal i nfe cti o ns re q uiri n g i ntra ve n o us t hera p y 
a n d a n y e pis o d es of se pti c s h oc k will be re p orte d. 
Met a b olic/ L a b o rat o r y : Gra d e 4 usi n g t he st a n dar d C T C sc al e. 
Ne urol o gic : Gra de 3 or hi g her usi n g t he st a n dar d C T C sc al e. 
P ul m o n a r y: Gra d e 3 or hi g her usi n g t he st a n d ar d C T C sc ale, e xc e pt Gra d e 2 F E V 1 a n d p ne u m ot h ora x will be re p ort e d. 
A b n or maliti es i n D L C O will n ot be re p orte d se paratel y b ut  
will be re p ort e d ac c or di n g t o t he ass oci at e d l e vel of p ul m o nar y d ysf u ncti o n.  
Re n al: Gra d e 3 or hi g her usi n g t he st a n d ar d C T C s c al e, a n d o nl y if n ot ass oci ate d wit h G V H D or V O D ( ot her wise it will 
be re p ort e d a c c or di n g t o t he crit eri a f or t he a p pr o pri at e m ultic o m p o ne nt e ve nt).  
Gra d e 3 or gre at er pr otei n uri a a n d re nal fail ure will be re p orte d.  
Ge nit o uri n a ry: C ystitis/ he mat uri a: Gra d e 3 or hi g her usi n g t he st a n dar d C T C sc ale.  
Bla d d er irri gati o n will be re p ort e d as Gra de 3.  
Ot her re q uire d treat me nt m o daliti es will be re p ort e d as gra d e 4.  
Pre g n a nc y: If a fe mal e pati e nt ( or t he se x ual part ner(s) of a  mal e patie nt) be c o mes  pre g na nt  w hil e re c ei vi n g  pr ot oc ol 
t hera p y, t he Pr ot oc ol C hair a n d O perati o ns C e nter s h o ul d be n otifie d i m me diatel y.  
G V H D: O nl y t he first i nci d e nt of Gra d e 3 or gre at er G V H D at a n y sit e will be re p ort e d.  
 
O T H E R A D V E R S E E V E N T S  
All ot her a d verse e ve nts will be re p ort e d a cc or di n g t o t he f oll o wi n g crit eria:  
P atie nts will be f oll o we d f or treat me nt -rel at e d t o xi cit y f or 1 0 0 da ys. Aft er 1 0 0 da ys 
patie nts will n ot be f oll o we d f or treat me nt -rel at e d t o xi cit y e xc e pt f or de at h, t he first 
e pis o d e of e xt e nsi ve c hr o ni c G V H D, rel a pse, or a n y ot her e ve nt, w hi c h is felt li k el y,  
pr o ba bl y, or d efi nitel y d ue t o t he st u d y treat me nt. E ve nts i n t hese c at e g ori es will  
c o nti n ue t o be re p ort e d u ntil t he st u d y cl oses t o f urt her f oll o w-u p. Pati e nt e ve nts t hat d o  
n ot me et t he a b o ve criteri a (e. g., h y per g l yc e mia fr o m st er oi d t hera p y) will n ot be re p ort e d 
t o t he I R B aft er 1 0 0 d a ys as t he y are c o m m o n i n t he p o p ul ati o n of b o ne marr o w 
tra ns pl a nt reci pie nts, b ut u nli kel y t o be dire ctl y relate d t o t he st u d y treat me nt. 
I n a d diti o n t o re p orti n g e ve nts t o t he Pr ot oc ol C hair a n d t he P B M T C O perati o ns C e nt er, 
a d verse e ve nts als o will be re p ort e d t o i nstit uti o nal re vi e w b oar ds. A d verse e ve nts,  
gra d es 1 -2, s pe cifie d i n t he c o nse nt as oc c asi o nal ( ha p pe ns t o bet we e n 5 -2 0 % of pati e nts)  
or c o m m o n ( ha p pe ns t o m ore t ha n 2 0 % of  pati e nts) will n ot be re p ort e d t o t he I R B.  
A d v e rse e v e nts, g r a de 3 o r 4 will be r e p o rte d t o t he i nstit uti o n al I R B usi n g t he  
c rite ri a set f o rt h i n t he a b o v e m o difie d B M T t o xicit y sc ale.  
 
 
 
 

 
3 1  
A p pe n di x C: P E DI A T RI C B L O O D A N D M A R R O W T R A N S P L A N T C O N S O R TI U M A D V E R S E 
E V E N T A S S E S S M E N T F O R P A TI E N T S E N R O L L E D O N P B M T C T RI A L S  
 
P L E A S E S U B MI T T HI S F O R M A S S P E CI FI E D I N T H E S T U D Y P R O T O C O L  
 
 
P r ot oc ol Titl e:   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
1. P ati e nt I nf or m ati o n  
 
1. P ati e nt I nf or m ati o n 
 
 
I n v esti g at o r:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _    D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
I nstit uti o n: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 

 
3 2  
Pr ot o c ol C hair R e vie w:  
 
Acti o n t o b e ta k e n:  
 
_ _ _ _ _ _ _ _ _ _  N o ne, c o nti n u e pr ot oc ol a p pr o val  
 
 
_ _ _ _ _ _ _ _ _ _   Pr ot o c ol s us p e n d e d p e n d i n g a d diti o nal r e vi e w 
 
 
_ _ _ _ _ _ _ _ _ _   Pr ot o c ol cl ose d  
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _      _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ur e of Pr ot o c ol C hair                                                                     Date  
 
Pl ease f or war d c o p y of t his f or m t o O p erati o ns C e nt er, Fa x ( 8 1 6) 8 5 5-1 7 0 0 wit hi n 7 da ys of r e cei pt.  
 
 
Pr ot o c ol M o nit or R e vi e w  
 
Assess me nt R e vie w:  
 
_ _ _ _ _ _ _ _ _  A gr e e wit h Pr ot o c ol C hair’s assess m e nt. N o f urt h er a cti o n r e q uire d.  
 
 
_ _ _ _ _ _ _ _ _  Disa gr e e wit h Pr ot o c ol C hair’s assess m e nt . F urt her a cti o n r e q uire d. (If f urt her a cti o n  
                    is r e q uir e d, pl ease d etail bel o w.) 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ur e of Pr ot o c ol M o nit or                                                             Dat e  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ur e of Pr ot o c ol M o nit or                                                             Dat e  
 
 
Pl ease  f or war d c o p y of t his f or m t o O p erati o ns C e nt er, Fa x ( 8 1 6) 8 5 5-1 7 0 0  wit hi n 5 da ys of r e cei pt.

 
3 3  
A p pe n di x D  
 
I N F O R M E D C O N S E N T T O P A R TI CI P A T E I N R E S E A R C H  
 
Hi g h d ose Te m o z ol o mi de, T hi ote p a a n d C ar b o pl ati n wit h A ut ol o g o us Ste m Cell Resc ue  
F oll o we d b y C o nti n u ati o n T he r a p y wit h 1 3 -Cis -r eti n oic Aci d  
i n P atie nts wit h Re c ur r e nt/ Refract o r y M ali g n a nt Br ai n T u m o rs  
 
O N C 0 3 2 P  
 
T his is a cli nical trial (a t y p e of r esear c h st u d y i n v ol vi n g h u ma n pati e nts). Cli ni cal trials i ncl u d e o nl y patie nts 
w h o c h o ose t o ta k e part. Pl ease ta k e y o ur ti m e t o ma k e y o ur d e cisi o n. Disc uss it wit h y o ur frie n ds a n d fa mil y.  
 
Y o u are b ei n g as k e d t o ta k e part i n t his st u d y be ca use y o u ha v e a brai n t u m or t hat has n ot res p o n d e d t o 
treat m e nt or has c o m e ba c k aft er treat m e nt. T his is call e d a r e c urre nt brai n t u m or. 
 
T his resear c h is part of a nati o n -wi d e st u d y c o or di nat e d b y t h e P e diatri c Bl o o d a n d Marr o w Tra ns pla nt 
C o ns orti u m.  
 
W H Y I S T HI S S T U D Y B EI N G D O N E ?  
 
T he c urr e nt sta n dar d tr eat m e nt f or c hil dr e n wit h re c urr e nt brai n t u m ors has be e n sta n dar d d ose c h e m ot hera p y. 
T he t u m or r es p o n ds b y s hri n ki n g, b ut r et ur ns a gai n i n m o nt hs.  
 
Researc h ers ha v e use d hi g h d oses of c o m bi nati o n c h e m ot h era p y f oll o we d b y a st e m c ell r esc u e t o tr eat 
re c urre nt brai n t u m ors wit h m o d erat e s u cc ess. Ste m c ells ar e c ells i n t he b o n e marr o w t hat pr o d u c e bl o o d c ells. 
T he st e m c ells ar e c oll ecte d fr o m t h e bl o o d of t h e pati e nt bef or e t h e hi g h d ose c he m ot h era p y. Pati e nts ar e gi v e n 
hi g h d oses of c he m ot h era p y t o kill e ver y brai n t u m or c ell, b ut i n t h e pr o cess t h e c ells of t h e b o n e marr o w ar e 
als o kill e d.  T h e pr e vi o usl y c oll e ct e d st e m c ells ar e t h e n i nf use d i nt o t he pati e nt t o r esc u e t he b o n e marr o w a n d 
all o w f or h ealt h y bl o o d c ells t o r e -p o p ulat e a n d gr o w i n t h e b o ne marr o w. I nitial st u di es use d t h e dr u g et o p osi d e 
al o n g wit h car b o plati n a n d t hi ot e pa f or t h e hi g h d ose c h e m ot h era p y. Pati e nts ha d se v er e si d e eff e cts, es p e ciall y 
se v er e m o ut h-s or es, t h o u g ht mai nl y d u e t o t he et o p osi de, a n d s o m e pati e nts di e d fr o m t h ese si de effe cts.  
 
Re c e nt st u dies ha v e s h o w n t hat a n e w dr u g, te m o z ol o mi d e, is a cti v e a gai nst s o me t y p es of brai n t u m ors. W he n 
it was gi ve n as a si n gl e dr u g t o c hil dr e n wit h s oli d t u m ors, t he si de effects wer e c o nsi d er e d t o be t ol era ble. 
T e m o z ol o mi d e is gi v e n b y m o ut h. I n t his st u d y, r esearc h ers wa nt t o gi v e hi g h d ose c h e m ot h era p y t hat i n cl u d es 
t h e dr u gs te m o z ol o mi d e i n pla c e of et o p osi d e, al o n g wit h t hi ot e pa a n d car b o plati n. Pati e nts will t he n b e gi ve n 
t h eir o w n st e m c ells ba c k t o r esc u e t he b o n e marr o w fr o m t h e c he m ot h era p y.  A pr eli mi nar y trial usi n g t his n e w 
dr u g c o m bi nati o n was p erf or m e d a n d has s h o w n t hat patie nts t ol erate t his dr u g c o m bi nati o n, e v e n  at t h e v er y 
hi g h d oses t hat will b e use d i n t his pr ot o c ol.  
 
A n ot h er dr u g t hat is b ei n g use d i n pe diatric ca n c er tr eat m e nt is call e d 1 3 -cis -r eti n oi c a ci d. T his dr u g is cl osel y 
relat e d t o vita mi n A. It is ta k e n b y m o ut h. Ca n c er c ells are i m mat ure c ells t h at ha ve n ot “ gr o w n u p” i nt o a d ult 
c ells t hat d o w or k i n t h e b o d y. 1 3 -cis -r eti n oi c a ci d is t h o u g ht t o a ct o n s o m e t y pes of ca n c er c ells t o ma ke t he m 
mat ure i nt o cells t hat f u ncti o n i n t he b o d y. It has als o bee n s h o w n i n t he l a b orat or y t o ca use s o me brai n t u mor cells t o u n der g o 
a p o pt osis. It has bee n use d i n ot her t y pes of pe di atri c ca ncers a n d researc h is j ust be gi n ni n g usi n g it f or treat me nt of re c u rre nt brai n 
t u mors. I n t his st u d y researc hers wa nt t o gi ve p ati e nts 1 3-cis-reti n oi c aci d f or 6 mo nt hs aft er t he y r ec o ver fr o m t he hi g h d os e 
c he mot her a p y wit h st e m c ell resc ue.  
 
I n s u m mar y, t h e p ur p ose of t his st u d y is t o: 
•  Fi n d o ut w hat effe cts ( g o o d a n d/ or ba d) tr eat m e nt wit h hi g h d ose t e m o z ol o mi d e, t hi ot e pa a n d car b o plati n 
wit h a st e m c ell resc u e f oll o we d b y 1 3 -cisr eti n oi c a ci d has o n c hil dr e n a n d a d olesc e nts wit h 
re c urre nt/refra ct or y brai n t u m ors 

 
3 4  
•  Fi n d o ut h o w t h e b o d y uses 1 3 -cisr eti n oi c a ci d b y st u d yi n g t h e pati e nt’s bl o o d l e v els a n d pr ot ei ns i n t h e 
bl o o d t hat br ea k d o w n t h e 1 3 -cisr eti n oi c a ci d  
•  Det er mi n e h o w well 1 3 -cisr eti n oi c a ci d pe n etrat es i nt o t h e s pi nal fl ui d.  
 
H O W M A N Y P E O P L E WI L L T A K E P A R T I N T H E S T U D Y ?  
 
It is e x p e ct e d t hat 7 5  pati e nts will ta k e part i n t his st u d y, nati o n wi d e, a n d “ X” pati e nts will b e e nr oll e d at t his 
i nstit uti o n. 
 
W H A T I S I N V O L V E D I N T H E S T U D Y ?  
 
Bef or e starti n g st u d y tr eat m e nt, y o u will ha v e r e c ei ve d c h e m ot h era p y t o d e crease t he si z e of t h e t u m or. Y o u 
a n d y o ur p h ysi cia n will ha v e d e ci de d t his tr eat m e nt bef or e e nt eri n g t his st u d y. D uri n g t his c h e m ot h era p y, y o u 
will ha v e y o ur st e m c ells c olle ct e d.  Aft er c oll e cti o n, t h e st e m cells ar e fr o z e n a n d st or e d u ntil t he y ar e n e e d e d 
aft er t h e hi g h d ose c h e m ot h era p y. A se parate c o nse nt will b e o btai n e d f or t h e c oll e cti o n of st e m c ells. T h e st e m 
c ell c oll e cti o n is n ot part of t his st u d y.  
 
Hi g h D ose C h e m o t h era p y – T e m o z ol o mi d e, T hi ot e pa, a n d Car b o plati n  
T he hi g h d ose c he m ot h era p y gi v e n d uri n g t his p hase is m y el oa blati v e. T his m ea ns t hat it d estr o ys t h e b o n e 
marr o w. If t h e st e m c ells were n ot gi v e n t o r esc u e t he b o ne marr o w, n e w bl o o d c ells w o ul d n ot b e a bl e t o 
de v el o p i n t h e b o d y.  
 
Vari o us m et h o ds will b e use d t o gi v e t h e dr u gs t o y o u. S o m e dr u gs will b e gi v e n b y ca ps ule, ta bl et or li q ui d 
t hr o u g h t h e m o ut h ( P O). Ot h er dr u gs will b e gi v e n usi n g a n e e dl e i nsert e d i nt o a v ei n (I V). Still ot h er dr u gs will 
be gi v e n wit h a ne e dl e i nsert e d dir e ctl y u n d er t h e s ki n ( S C).  
 
T he c he m ot h era p y is sc h e d ule d as a “ c o u nt d o w n” t o da y 0. O n da y 0 t h e st e m c ells are gi v e n ba c k t o y o u. T h e 
c h e m ot h era p y r e gi m e n f or t his st u d y is as f oll o ws:  
 
Da y:  T e m o z ol o mi d e  
T hi ot e pa  
Car b o plati n 
Da y 1 0   
X 
Da y 9   
X 
Da y 8   
X 
Da y 7   
X 
Da y 6   
X 
Da y 5   
 
X 
X 
Da y 4   
 
X 
X 
Da y 3   
 
X 
X 
Da y 2  
Rest  
Da y 1  
Rest  
Da y 0  
Peri p h eral Bl o o d St e m C ell/ B o n e Marr o w I nf usi o n  
 
•  T e m o z ol o mi d e  is gi v e n P O t wic e a da y 
•  T hi ot e pa  is gi v e n b y I V o v er 3 h o urs 
•  Car b o plati n  is gi v e n b y I V i nf usi o n o ver 4 h o urs i m m e diat el y aft er t he t hi ot e pa 
•  Fil grasti m ( G -C S F)  is a dr u g t o sti m ulat e t h e pr o d u cti o n of w hit e bl o o d cells. It will b e gi v e n I V or S C 
starti n g o n t h e da y after t h e st e m c ell i nf usi o n a n d c o nti n u e u ntil e n o u g h w hite bl o o d cells ar e pr e se nt i n t h e 
bl o o d t o fi g ht i nfecti o n. Us u all y t his will re q uir e 2 we e ks of G -C S F tr eat m e nt.  
 
C o nti n u ati o n T h era p y - 1 3 - Cis-r eti n oi c a ci d 
T his p hase of tr eat m e nt will b e gi n a b o ut 6 t o 1 0 we e ks after t h e st e m c ell r esc u e. Y o u will r ec ei v e t h e 1 3 -cis -
reti n oi c a ci d b y m o ut h t wi ce a da y. It is gi v e n f or 1 4 da ys f oll o we d b y a 1 4 da y rest peri o d. T his c y cl e is gi v e n 
6 ti m es f or a t otal of 6 m o nt hs of tr eat m e nt.  

 
3 5  
 
Y o u will be gi v e n a "r oa d ma p" w hic h is a cal e n dar of tr eat me nt. It will t ell y o u w hat da ys of t h e c y cl e t he 
s pe cifi c c h e m ot h era p y dr u gs ar e gi v e n. 
 
Sta n dar d t ests a n d pr o c e d ures  
T he f oll o wi n g t ests a n d pr oc e d ures are part of r e g ular ca n cer care a n d ma y b e d o n e e ve n if y o u d o n ot j oi n t h e 
st u d y. 
•  Hist or y a n d p h ysi cal e xa mi nati o n  
•  Fre q u e nt Bl o o d C o u nts  
•  Fre q u e n t la bs t o m o nit or bl o o d c he mistr y 
•  T ests t o m o nit or h eari n g  
•  T ests t o m o nit or h eart f u n cti o ni n g  
•  Uri n e t ests t o m o nit or ki d n e y f u n cti o ni n g  
•  S pi nal ta ps ma y b e d o n e t o c h ec k f or t u m or c ells i n t h e s pi nal fl ui d a n d m o nit or f or t u m or gr o wt h  
•  X- ra y, C T, a n d M RI scans t o e val u ate res p o nse t o tr eat m e nt  
•  Pre g na n c y t est f or all fe mal es of c hil d b eari n g a g e bef or e c h e m ot h era p y is gi ve n  
•  B o ne marr o w as pirat e/ bi o ps y  
•  Tra nsf usi o ns wit h r e d c ells a n d plat el ets. R e d bl o o d cell tra nsf usi o ns are gi v e n s o t hat y o u d o n ot de v el o p 
a ne mia. A ne mia o c c urs w h e n t h er e ar e n ot e n o u g h r e d bl o o d c ells pr o d u c e d t o carr y o x y ge n t o t he b o d y’s 
c ells. Y o u ma y als o r e c ei ve platel et tra nsf usi o ns. Plat el ets ar e bl o o d c ells t h at h el p y o ur bl o o d cl ot.  
 
Researc h st u d y t ests a n d pr o c e d ures  
T he f oll o wi n g t ests will be d o ne b e ca use y o u ar e part of t his st u d y. T hese tests are n ot part of sta n dar d care.  
 
Researc h ers wa nt t o st u d y h o w y o ur b o d y br ea ks d o w n a n d uses t h e 1 3 -cis -r eti n oi c a ci d. T his is d o n e b y 
m eas uri n g l e v els of t h e dr u g i n bl o o d sa m pl es a n d b y st u d yi n g e n z y m es ( pr ot ei ns i n t h e b o d y) t hat br ea k d o w n 
t h e dr u g. 
 
T his is a n o pti o nal part of t he st u d y. At t h e e n d of t h e c o nse nt, t h er e is ar e c he c k b o x es f or y o u t o c he c k Y E S if 
y o u wa nt t o ta k e part, or N O if y o u d o n ot.  
 
If y o u c h o ose t o parti ci pat e, 1 teas p o o n of bl o o d ( 5 ml) will b e dra w n fr o m y o ur c e ntral li ne at t h e f oll o wi n g 
ti m es d uri n g t h e first c y cl e of 1 3-cis -r eti n oi c a ci d: 
•  Bef or e t h e first d ose of 1 3 -cis -r eti n oi c a ci d 
•  O n t h e 1 4t h da y of 1 3 -cis -r eti n oi c a ci d, b ef or e t hat da y’s d ose, a n d 1, 2, 4 a n d 6 h o urs after t hat d ose.  
 
S o m e pati e nts will ha ve s pi nal ta ps d uri n g t h eir tr eat me nt t o m o nit or f or t u m or gr o wt h a n d t u m or c ells. F or 
t h ese pati e nts we w o ul d li k e t o c oll e ct e xtra s pi nal fl ui d d uri n g o n e r o uti n e s pi nal ta p t o m eas ure 1 3-cis -r eti n oi c 
a ci d i n t h e s pi nal fl ui d. T h e s pi nal ta p w o ul d b e d o n e o n t h e 1 4t h da y of first c y cl e of 1 3 -cis -reti n oic a ci d, t w o 
h o urs after t he m or ni n g d ose of 1 3 -cis -r eti n oi c a ci d.  T h e p ur p ose of t his as p e ct of t h e st u d y is t o d et er mi n e t h e 
le v el of 1 3-cis -r eti n oi c a ci d t hat pe n etrat es i nt o t he s pi nal fl ui d. 
 
H O W L O N G WI L L I B E I N T H E S T U D Y ?  
 
Y o u will be tr eat e d o n t his st u d y f or a b o ut 7 t o 8 m o nt hs. W e w o ul d li k e t o c o nti n u e t o e xa mi n e y o u b y 
perf or mi n g f oll o w -u p t ests t hat ma y i ncl u d e m e dical hist ori es, p h ysical e xa m s, bl o o d t ests, C T/ M RI sca ns, a n d 
s pi nal ta ps. W e w o ul d als o li k e t o c o nti n u e t o c oll e ct s o m e i nf or mati o n a b o ut h o w y o u are d oi n g f or as l o n g as 
y o u will all o w.  
 
Y o ur d o ct or ma y de ci d e t o ta k e y o u off t his st u d y if y o u d o n ot res p o n d t o t he tr eat m e nt or if  t he si de effects ar e 
t o o se v er e. Y o u ca n st o p parti ci pati n g at a n y ti m e. H o we ver, if y o u d eci d e t o st o p parti ci pati n g i n t h e st u d y, we 
e n c o ura g e y o u t o tal k wit h y o ur d o ct or. If y o u r ec ei v e hi g h d ose c h e m ot h era p y a n d d eci d e t o st o p partici pati o n 
i n t his st u d y wit h o ut re c ei vi n g a st e m c ell tra ns pla nt, t here is a p ot e ntial ris k t hat y o ur b o n e marr o w ma y n ot 

 
3 6  
c o nti n u e t o pr o d u c e t h e n ee d e d a m o u nt of bl o o d c ells. T his w o ul d r es ult i n a c o n diti o n calle d a plasti c a n e mia. 
A plasti c a n e mia ca n b e life t hr eat e ni n g.  
 
E v e n if y o u r e cei v e a ste m cell tra ns pla nt a n d y o ur b o n e marr o w c o nti n u es t o pr o d u ce t he n e e de d a m o u nt of 
bl o o d c ells, y o u ma y still d e v el o p a n i nfe cti o n. T h er ef ore, it is re c o m m e n d e d t hat y o u r e mai n u n d er me di cal car e 
u ntil y o ur i m m u ne s yst e m re c o vers fr o m t hera p y, e ve n if y o u ar e n o l o n ger parti ci pati n g i n t his st u d y. 
 
W H A T A R E T H E RI S K S O F T H E S T U D Y ?  
 
W hile o n t h e st u d y, y o u are at ris k f or si d e effe cts. Y o u s h o ul d disc uss t he m wit h y o ur d oct or. T h er e als o ma y 
be ot h er si d e effe cts t hat we ca n n ot pr e di c t. Ot her dr u gs will b e gi v e n t o ma k e si de effects l ess seri o us a n d l ess 
u nc o mf orta ble. Ma n y si d e effe cts g o a wa y s h ortl y after t h e c h e m ot hera p y dr u gs are st o p p e d, b ut i n s o m e cases 
si d e effe cts ca n b e seri o us or life-t hr eat e ni n g or l o n g lasti n g or p er ma n e nt. 
 
S o m e c he m ot h era p y dr u gs ca n da ma g e t h e bl o o d -pr o d u ci n g cells i n t h e b o n e marr o w. T his r es ults i n p eri o di c 
l o w bl o o d c o u nts i n b et we e n tr eat me nts, w hi c h ca n i n cr ease ris k f or seri o us i nfe cti o n, bl e e di n g or a n e mia. 
S o m e c he m ot h era p y ca n ca use na usea a n d v o miti n g. M e di cati o ns ca n b e gi v e n t o h el p pre v e nt t his. S o m e 
c h e m ot h era p y ca n affe ct t h e heart, l u n gs, ki d n e ys, li ver a n d/ or h eari n g. T ests will b e d o n e t o m o nit or t h e 
f u n cti o n of t h ese or ga n s yst e ms. 
 
Ris ks a n d p ossi bl e si d e effe cts r elat e d t o t h e c h e m ot hera p y we ar e st u d yi n g i n cl u d e t h e f oll o wi n g:  
 
C ar b o pl ati n 
 
C o m m o n  
Ha p pe ns t o 2 1- 1 0 0 o ut of 
e ver y 1 0 0 c hil dre n  
O cc asi o n al  
Ha p pe ns t o 5- 2 0 c hil dre n o ut 
of e ver y 1 0 0  
R are  
Ha p pe ns t o < 5 c hil dre n o ut of e ver y 1 0 0  
I m me di ate: 
Wit hi n 1 - 2 da ys of 
recei vi n g dr u g 
N a us ea ( L), v o miti n g ( L)  
All er gi c r eacti o ns *( p ossi bl y 
se vere a n d life-t hre at e ni n g), 
ras h ( L) 
Met alli c t ast e  
P r o m pt:  
Wit hi n 2 - 3 wee ks, 
pri or t o ne xt 
c o urse 
L o w n u mber of w hit e bl o o d 
cells a n d pl at el ets (effect o n 
pl at el ets ma y be great er t ha n 
o n w hit e bl o o d cells)  
A b n or mal l e vels of cert ai n 
salts i n t he b o d y li ke s o di u m 
a n d p ot assi u m ( L) 
N u mb ness, ti n gli n g, cl u msi ness, 
da ma ge t o t he li ver ( L), da ma ge t o t he 
ki d ne y ( L), da ma ge t o t he ear ca usi n g 
heari n g a n d bal a nce pr o bl e ms ( L), hair 
l oss 
L ate:  
A n y ti  me aft er 
c o mpl eti o n of 
treat me nt 
 
 
A ne w l e u ke mi a c a use d b y t his 
treat me nt 
 
* T he i nci d e nce of all er gi c re acti o ns t e n ds t o i ncre as e aft er re pe at e d c o urses of tre at me nt (i ncre as e d r at e of occ urre nce aft e r si x 
c o urses n ot ed i n a d ult p ati e nts). 
( L) T oxi cit y m ay als o oc c ur l at er. 
 
 
 
 
 
 
 
 
 
 
1 3- cis-reti n oi c aci d: 
 
C o m m o n  
Ha p pe ns t o 2 1- 1 0 0 
c hil dre n o ut of e ver y 1 0 0  
O cc asi o n al  
Ha p pe ns t o 5- 2 0 c hil dre n 
o ut of e ver y 1 0 0  
R are  
Ha p pe ns t o < 5 c hil dre n o ut of e ver y 1 0 0  
I m me di ate: 
Wit hi n 1 - 2 da ys 
of recei vi n g dr u g  
 
Na us ea a n d v o miti n g  
A na p h yl a xis, br o nc h os pas m  

 
3 7  
P r o m pt:  
Wit hi n 2 - 3 
we e ks, pri or t o 
t he ne xt c o urse 
Dr y s ki n ( L), dr y mo ut h 
( L), s w oll e n a n d s ore li ps 
( L), p h ot ose nsiti vit y, 
el e vat e d E S R, ba c k pai n 
( L), art hral gi a ( L), 
tri gl yc eri d e el e vati o n ( L) 
R as h ( L), e ye 
irrit ati o n/s ore ness ( L), 
j oi nt pai ns ( L), bac k pai n 
( L), e xtre me tire d ness 
( L), h ea dac h e ( L), hi g h 
l e vels of fat i n t he bl o o d 
( L), hi g h l e vels of li ver 
e nz y mes i n t he bl o o d ( L), 
hi g h le vels of cal ci u m i n 
t he bl o o d,  c h ol est er ol 
el e vati o n ( L)  
C ha n ges i n s ki n c ol or, u pset st o ma c h, di zzi ness, 
fl ui d b uil d- u p i n t he brai n ca usi n g hea dac he a n d 
na usea/ vo miti n g a n d a n a b n or malit y of t he e yes, 
l o w n u mbers of re d a n d w hit e bl o o d cells, 
el e vat e d pl at el et c o u nts, ps yc hi atri c dis or ders 
i ncl u di n g a g gr essi ve a n d/ or vi ol e nt be ha vi or, a 
c o n diti o n call e d reti n oi c aci d s y n dr o me wit h a n 
i ncrease i n w hit e bl o o d cells, fe ver, diffi c ult y 
breat hi n g, l o w bl o o d press ure , al o pe ci a, 
i ns o mni a, a p petit e dist ur ba nces, h y per gl yc e mi a, 
l et har g y, mal aise, parest hesi as, all er gi c vasc ulitis 
( L), c hest pai n, pa ncreatitis, heari n g i mp air me nt, 
i nfl a m mat or y b o wel disease, vis ual dist ur ba nces, 
i nfl a m mati o n of t he g u ms, dr yi n g of t he 
res pirat or y tr act wit h voice alt er ati o n, res pirat or y 
i nfecti o ns 
Del a ye d:  
A n y ti me l at er 
d uri n g t hera p y, 
e xcl u di n g t he 
a b o ve c o n d iti o ns 
 
S kel et al h y per ost osis  
E nl ar ge d se cti o ns of b o nes, decrease i n t he 
de nsit y of b o ne ca usi n g we a ke ne d b o nes, 
r ha b d o m y ol ysis a b n or mal me nses, re n al 
dist ur ba nces ( W B C i n uri ne, pr ot ei n uri a, 
he mat uri a, r e nal cal c uli), cal cifi c ati o n of t e n d o n 
a n d li ga me nts 
L ate:  
A n yti me afte r 
t h e c o m pl eti o n 
of tre at me nt  
Birt h defects t o u n b or n 
c hil dre n if t a ke n d uri n g 
pre g n a nc y  
 
 
( L) T oxi cit y m ay als o oc c ur l at er. 
A n ot e t o mot hers: 1 3- cis-reti n oi c aci d ca us es se vere birt h defects. If y o u ar e pre g na nt or t here is a n y c hance y o u mi g ht bec o me 
pre g n a nt, y o u must n ot i n gest t his dr u g  (all o w a n y of it t o get o n f o o d or get i n y o ur mo ut h). If y o u ha n dl e t he li q ui d fr o m t he 
ca ps ul es, y o u must was h y o ur h a n ds i m me di at el y aft er war ds or wear gl o ves.  
 
Tetr ac ycli ne must n ot be t a ke n d uri n g treat me nt wit h 1 3- cis-reti n oi c aci d d ue t o t he i ncrease d ris k of pse u d ot u mor cere bri ( be ni g n 
i ntracra ni al h y pert e nsi o n). Vit a mi n A a n d vit a mi n A deri vati ves s h o ul d als o be a voi de d d uri n g is otreti n oi n t hera p y.  
 
Te m oz ol o mi d e:  
 
C o m m o n  
Ha p pe ns t o 2 1- 1 0 0 c hil dre n 
o ut of e ver y 1 0 0  
O cc asi o n al  
Ha p pe ns t o 5- 2 0 c hil dre n 
o ut of e ver y 1 0 0  
R are  
Ha p pe ns t o l ess t ha n 5 c hil dre n 
o ut of e ver y 1 0 0  
I m me di ate: Wit hi n 1 -2 
da ys of r ecei vi n g dr u g  
 
L oss of a p petit e, na usea, 
v o miti n g, di arr hea, 
c o nsti pati o n, hea dac he, 
ras h, it c hi n g, i ncrease d 
nee d t o uri nat e, uri nar y 
tract i nfecti o ns 
C o n vulsi o ns, di zzi ness, diffi c ult y 
wal ki n g, c o nf usi o n, diffi c ult y 
s wall o wi n g, a n xiet y, p arti al 
paral ysis or wea k n ess of o ne si de 
of t he b o d y, bl o o d cl ots w hi c h 
ma y b e life -t hre at e ni n g ( L) 
P r o m pt: Wit hi n 2 -3 
we e ks, pri or t o ne xt 
c o urse 
Decre ase i n t he n u m b er of r e d 
a n d w hit e bl o o d cells a n d 
pl at el ets ma d e i n t he b o ne 
marr o w  
M o ut h s ores, tire d ness, 
fl ui d b uil d u p i n l e gs a n d 
ar ms  
Me mor y -l oss, u na bl e t o sl ee p, 
de pressi o n, muscl e ac hes, bl urre d 
or d o u bl e visi o n 
Del a ye d: A n yti me l at er 
d uri n g t hera p y, e xcl u di n g 
t he a b o ve c o n diti o ns 
 
Hair l oss, li ver da ma ge  
 
L ate: A n yti me aft er 
c o mpl eti o n of t hera p y  
 
 
C a ncer  
 
T hi ote p a: 
 
C o m m o n  
Ha p pe ns t o 2 1- 1 0 0 c hil dre n o ut of 
e ver y 1 0 0  
O cc asi o n al  
Ha p pe ns t o 5- 2 0 c hil dre n 
o ut of e ver y 1 0 0  
R are  
Ha p pe ns t o l ess t ha n 5 
c hil dre n o ut of e ver y 1 0 0  
I m me di ate: Wit hi n 1 -2 
da ys of r ecei vi n g dr u g  
Na usea, vo miti n g, l oss of a p petit e  
P ai n at t h e i nj ect sit e, 
di zzi ness, he a dac he  
Hi ves, s ki n ras h  
P r o m pt: Wit hi n 2 -3 
we e ks, pri or t o ne xt 
c o urse 
Decre ase t he n u mber of re d a n d 
w hit e bl o o d cells a n d plat el ets 
ma de i n t he b o ne marr o w 
At hi g h d oses use d bef ore marr o w 
tra ns pl a nts: mo ut h s ores, 
i nfl a m mati o n of t he passa ge 
bet we e n t he t hr oat a n d st o ma c h  
 
 
Del a ye d: A n yti me l at er 
d uri n g t hera p y, e xcl u di n g 
t he a b o ve c o n diti o ns 
A bse nc e of s per m or st o p pe d 
mo nt hl y peri o ds, i na bilit y t o ha ve 
c hil dre n 
 
 

 
3 8  
( L) T oxi cit y m ay als o oc c ur l at er. 
 
G- C S F:  
 
C o m m o n  
Ha p p e ns t o 2 1 -1 0 0 
c hil dre n o ut of e ver y 1 0 0  
Occasi o n al  
Ha p p e ns t o 5 -2 0 c hil dre n o ut of e ver y 1 0 0  
R are  
Ha p p e ns t o < 5 c hil dre n o ut of e ver y 
1 0 0  
I m m e diate: 
Wit hi n 1 -2 d a ys of 
recei vi n g dr u g 
 
L o cal irritati o n at i njecti o n site  
Aller gic r eacti o n, l o w fe ver  
Pr o m pt:  
Wit hi n 2 -3 wee ks, 
pri or t o t h e n e xt c o urs e  
 
Ac h e or p ai n i nsi d e t h e b o n es, i n creas e d 
le vels of li ver e n z y m es a n d uric aci d i n t h e 
bl o o d, l o w n u m b er of platelets i n t h e bl o o d  
E nlar ge m e nt of t h e s plee n, 
w ors e ni n g of pre -e xisti n g s ki n 
ras h es, h air l oss 
Dela y e d:  
A n yti m e later d uri n g 
t h era p y, e x cl u di n g t h e 
a b o ve c o n diti o ns 
 
 
I nfla m m ati o n of a bl o o d vess el i n t h e 
s ki n  
Late:  
A n yti m e after t h e 
c o m pleti o n of 
treat m e nt 
 
 
 
 
Re pr o d u cti v e ris ks : Be ca use t h e dr u gs a n d/ or ra diati o n t h era p y i n t his st u d y ca n affe ct a n u n b or n ba b y, y o u 
s h o ul d n ot b ec o m e pr e g na nt or fat h er a ba b y w hile o n t his st u d y. As k a b o ut c o u nseli n g a n d m or e i nf or mati o n 
a b o ut pr e ve nti n g pr e g na nc y. T h e a d mi nistrati o n of c h e m ot hera p y a n d ra diati o n descri b e d ma y ca use i nfertilit y 
( b ei n g l ess a ble t o pr o d u c e a via bl e e g g or s per m). We will tal k t o males w h o ha v e r ea c h e d p u b ert y a b o ut s p er m 
ba n ki n g.  
 
D uri n g a n d aft er t he i nf usi o n of t h e ste m c ells, y o u ma y e x perie n c e br eat hi n g diffi c ulties d u e t o cl u m ps of st e m 
c ells a n d/ or fat t hat b e c o me tra p p e d i n t h e l u n gs, I n a d diti o n, c o nta mi nati o n of t h e st e m c ells wit h ba ct eria a n d 
i ntr o d u cti o n of i nfe cti o n mi g ht o cc ur. 
 
W hile y o ur d oct ors a n d n urses are v er y e x p eri e n ce d at tr eati n g t h ese pr o bl e ms, it is p ossi bl e, t h o u g h u nli k el y 
t hat y o u c o ul d di e fr o m a n i nfe cti o n, bl e e di n g or a n ot h er c o m pli cati o n. It is als o p ossi bl e t hat y o ur b o n e marr o w 
ma y n ot r ec o ver aft er y o ur st e m c ells ar e gi v e n ba c k t o y o u. I n t h e e v e nt t hat t he b o ne marr o w d o es n ot r e c o v er, 
a d diti o nal st e m cells will b e gi v e n , if a vaila bl e.  
 
F or m or e i nf or mati o n a b o ut ris ks a n d si d e effe cts, as k y o ur d o ct or a n d r ea d y o ur c h e m ot h era p y dr u g s he ets t hat 
are atta c he d t o t his c o nse nt.  
 
A R E T H E R E B E N E FI T S T O T A KI N G P A R T I N T H E S T U D Y ?  
 
If y o u a gr e e t o ta k e part i n t his st u d y, t h er e ma y or ma y n ot b e dir e ct m e di cal b e n efit t o y o u. W e h o p e t h e 
i nf or mati o n l ear n e d fr o m t his st u d y will b e nefit ot h er patie nts i n t h e f ut ur e.  
 
W H A T O T H E R O P TI O N S A R E T H E R E ?  
 
I nst ea d of b ei n g i n t his st u d y, y o u ha v e t h ese o pti o ns: 
•  Sta n dar d c h e m ot hera p y  
•  N o t h era p y at t his ti me wit h car e t o h el p y o u fe el m or e c o mf orta bl e  
•  Ra diati o n t h era p y if y o u ha v e n ot alrea d y r ec ei v e d t h e ma x i m u m d ose 
•  Hi g h d ose c h e m ot h era p y wit h a ut ol o g o us st e m c ell resc u e usi n g a n ot h er hi g h d ose c h e m ot h era p y re gi m e n.  
 
Pl ease tal k t o y o ur d o ct or a b o ut t h ese a n d ot h er o pti o ns.  
 
W H A T A B O U T C O N FI D E N TI A LI T Y ?  
 

 
3 9  
Eff orts will b e ma d e t o k e e p y o ur p ers o nal i nf or mati o n c o nfi d e ntial. W e ca n n ot g u ara nt ee a bs ol ut e 
c o nfi d e ntialit y. Y o ur pers o nal i nf or mati o n ma y b e discl ose d if r e q uir e d b y l a w.  
 
Or ga nizati o ns t hat ma y i ns p ect a n d/ or c o p y y o ur r esearc h r e c or ds f or q u alit y ass ura n c e a n d data a nal ysis 
i n cl u d e gr o u ps s u c h as: 
 
Pe diatric Bl o o d a n d Marr o w Tra ns pla nt C o ns orti u m  
F o o d a n d Dr u g A d mi nistrati o n  
Nati o nal Ca n cer I nstit ut e  
C hil dr e n's H os pitals a n d Cli ni cs I nstit uti o nal R e vi e w B oar d  
Ne w Y or k U ni v ersit y H os pital I nstit uti o nal R e vi e w B oar d  
 
W H A T A R E T H E C O S T S ?  
 
T a ki n g part i n t his st u d y ma y l ea d t o a d d e d c osts t o y o u or y o ur i ns ura n c e c o m pa n y. Pl ease as k a b o ut a n y 
e x p e ct e d a d d e d c osts or i ns ura n ce pr o bl e ms. Staff will b e a bl e t o assist y o u wit h t his.  
 
I n t h e case of i nj ur y or ill n ess res ulti n g fr o m t his st u d y, e mer g e nc y m e di cal treat m e nt is a vaila bl e b ut will b e 
pr o vi d e d at t h e us u al c har g e. N o f u n ds ha v e b ee n set asi d e t o c o m p e nsat e y o u i n t h e e v e nt of i nj ur y. H o we v er 
b y si g ni n g t his f or m, y o u ar e n ot wai vi n g a n y ri g hts t hat y o u mi g ht ot h er wise ha v e.  
 
Y o u or y o ur i ns ura n c e c o m pa n y will be c har g e d f or c o nti n ui n g me di cal car e a n d/ or h os pitalizati o n.  
 
Y o u will r e cei v e n o pa y m e nt f or ta ki n g part i n t his st u d y.  
 
W H A T A R E M Y RI G H T S A S A P A R TI CI P A N T ?  
 
T a ki n g part i n t his st u d y is v ol u ntar y. Y o u ma y c h o ose n ot t o ta k e part or m a y l ea v e t h e st u d y at a n y ti m e. 
Lea vi n g t h e st u d y will n ot r es ult i n a n y p e nalt y or l oss of b e n efits t o w hi c h y o u ar e e ntitl e d.  
 
We will t ell y o u a b o ut n e w i nf or mati o n t hat ma y affect y o ur h ealt h, welfar e, or willi n g ness t o sta y i n t his st u d y.  
 
W H O M D O I C A L L I F I H A V E Q U E S TI O N S O R P R O B L E M S ?  
 
F or q u esti o ns a b o ut t h e st u d y or a r esearc h -r elat e d i nj ur y, c o nta ct t h e Pri nci pl e I n v esti gat or at y o ur I nstit uti o n. 
 
If y o u ha v e a n y q u esti o ns a b o ut y o ur ri g hts as a r esearc h parti ci pa nt or a n y c o m plai nts t hat y o u fe el y o u ca n n ot 
disc uss wit h t h e i n v esti gat ors, y o u ma y call t he Dir e ct or of y o ur I nstit uti o nal R e vie w B oar d.  
 
W H E R E C A N I G E T M O R E I N F O R M A TI O N ?  
 
Y o u ma y call t h e N CI's C a n c er I nf or m ati o n S ervic e  at 
1- 8 0 0 - 4-C A N C E R ( 1 -8 0 0 -4 2 2 -6 2 3 7) or T T Y: 1 -8 0 0 -3 3 2 -8 6 1 5  
 
Visit t h e N CI's We b site  at htt p:// w w w. nci. ni h. g o v/ ca n c eri nf o/  
 
Y o u will get a c o p y of t his f or m. Y o u ma y als o r e q u est a c o p y of t he pr ot o c ol (f ull st u d y pla n).  
 
SI G N A T U R E  
 
I a gr e e t o ta k e part i n t his st u d y. 
 

 
4 0  
Pl ease a ns wer t h e f oll o wi n g q u esti o ns b y c he c ki n g Y E S or N O a n d e nt eri n g y o ur i nitials  
 
# 1:  I gi v e m y c o nse nt f or t h e c oll e cti o n of bl o o d f or t he 1 3-cisr eti n oi c a ci d st u di es.  
 
# 1:  
  Y E S  
  N O   
 
 
 
i nitials 
 
# 2:  I gi v e m y c o nse nt f or t h e c oll e cti o n of e xtra s pi nal fl ui d f or t he 1 3-cisr eti n oi c a ci d st u di es.  
 
# 2:  
  Y E S  
  N O  
  D o es n’t a p pl y/ N ot ha vi n g s pi nal ta ps    
 
 
i nitials 
 
 
 
Parti ci pa nt  
Date  
 
 
Pati e nts 1 8 y ears of a g e or ol der are r e q uir e d t o si g n. Pati e nts l ess t ha n 1 8 m a y c h o ose t o si g n or t his ma y b e l eft 
bla n k.  
 
 
Pare nt/ G u ar dia n  
Date  
 
 
 
Pare nt/ G u ar dia n  
Date  
 
 
 
P h y si cia n/ P N P 
Date  
 
 
I R B #  
I R B A p pr o v e d:   
 
   
 

 
4 1  
  
  
  
  
  
  
  
 
 
A p p e n di x E: P B M T C O N C -0 3 2: C oll e cti o n a n d S hi p m e nt of Bi ol o gi c al S a m pl e s  
 
 T h e st u d y p arti ci p a nt c o n s e nt e d t o bi ol o gi c al p orti o n of P B M T C O N C -0 3 2 P  
 
P ati e nt St u d y N u m b er:  
 
D at e C o n s e nt e d:  
 
I n stit uti o n: 
 
PI at t h e I n stit uti o n:  
 
 
Pl e a s e c o m pl et e t h e f oll o wi n g f or m a n d s e n d wit h s a m pl e s t o C hil dr e n’ s H o s pit al s a n d Cli ni c s of Mi n n e s ot a, 
Mi n n e a p oli s (f or a d dr e s s a n d c o nt a ct i nf or m ati o n s e e s hi p pi n g i n str u cti o n s).  
 
A d mi ni str ati o n of 1 3 -ci s -R A:  
 
W ei g ht  
       
    S. A.  
 
* G F R/ Creati ni n e 
cleara n ce 
 
* Date of G F R/ Creati ni n e            
cleara n ce 
 
                                                                                                                                                                                                                                                                  
 
 
C a ps ules s wall o we d wit h mil k  
 
O R    C a ps ules s ni p p e d / mi x e d wit h ice -crea m  
 
 
Ot h er ( ple as e s p ecif y)  
       
 
St u d y d a y  
 
(e nter if n ot Da y 1 4 of 
treat m e nt) 
 
Treat m e nt c o urs e  
1, 2, 3, 4, 5, 6  
  (circle a ns wer) 
 
Pl e a s e c oll e ct t h e f oll o wi n g s a m pl e s a c c or di n g t o t h e i n str u cti o n s li st e d b el o w:  
 
 
D a y 1 4 Bl o o d Pr e p ar ati o n:  
•  
S a m pl e s s h o ul d, w h er e v er p o s si bl e, b e c oll e ct e d w h e n t h er a p e uti c bl o o d s a m pl e s ar e o bt ai n e d  
•  
C oll ect sa mpl es i n he pari ni ze d t u bes wr a p pe d wit h al u mi n u m f oil . 
•  
C e ntrif u ge ea c h bl o o d sa mple at 2, 0 0 0- 3, 0 0 0r p m at 4 oC f or 5 mi n ut es i n t he dar k i n or der t o se parat e pl as ma. 
•  
Tr a nsfer pl as ma t o f oil wra p pe d t u be (i de all y s uc h t hat pl as ma sa mpl e fills t he t u be) a n d freeze at - 2 00C pri or t o tra ns p ort. 
1 3 -cis -R A d os e ( m g)  
 
      Ti me of a d mi nistr ati o n  
       
Ti mi n g  
S a m ple #  
Ti mi n g  
S a m ple  
A m o u nt  
Ti me/ D at e 
T a k e n  
Ti me 
D ue  
P ri o r t o fi rst 
c o u rse of 1 3 -cis-
reti n oic aci d 
t re at me nt 
1 
6 we e ks p ost B M T 
( pri or t o first c o urse of 
1 3- cis-reti n oi c aci d) 
Bl o o d                  
(i n E D T A t u be        
- 2 00C pri or t o 
s hi p pi n g) 
5 ml  
 
 
D a y 1 4 of first 
c o u rse of 1 3 -cis-
reti n oic ac i d 
t re at me nt ( D a y 
+ 4 2 t o 1 8 0 p ost -
B M T)  
2 
Pre -oral a d mi nistrati o n 
of 1 3- cis-reti n oi c aci d 
Bl o o d 
5 ml  
 
 
3 
1 h o ur p ost treat me nt 
Bl o o d 
5 ml  
 
 
4 
2 h o urs p ost treat me nt 
Bl o o d 
5 ml  
 
 
5 
2 h o u rs p ost tre at me nt  
C S F  
 
2 -5 ml  
 
 
6  
4 h o urs p ost treat me nt  
Bl o o d  
5 ml 
 
 
7 
6 h o urs p ost treat me nt 
Bl o o d 
5 ml  
 
 
* D oc u me nt m ost c urre nt me as ure me nt 
pri or  t o 1 3 -cis -R A a d mi nistrati o n  

 
4 2  
 
D a y 1 4 C S F Pr e p ar ati o n:  
•  
Tr a n sf er C S F t o a f oil wr a p p e d t u b e a n d st or e at -2 0 0 C pri or t o tr a n s p ort.  
 
S hi p pi n g s a m pl e s t o C hil dr e n’ s H o s pit al s a n d Cli ni c s of Mi n n e s ot a, Mi n n e a p oli s:  
O n c e s a m pl e s h a v e b e e n r e c ei v e d, r ei m b ur s e m e nt will b e pr o c e s s e d.  R ei m b ur s e m e nt i s c o nti n g e nt o n 
t h e f oll o wi n g i n str u cti o ns:  
•  
La bel t he sa m pl es wit h t he f oll o wi n g f or mat:       
P B T M C O N C 0 3 2  
PI’s Na me  
  
  
  
  
  
  
 
P atie nt St u d y #  
  
  
  
  
  
  
 
S a m pl e #   
•  
B at c h a n d se n d all se ve n sa m pl es i n o ne s hi p me nt.  
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I ncl u d e a c o p y of t he s hi p pi n g f or m ( pre vi o us pa ge) wit h t he s hi p me nt. 
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N otif y M ar y L a m e r s T k a c h (m ar y.l a m er s @ c hil dr e n s m n. or g ) or L e zli e R a bi n e 
(l e zli e.r a bi n e @ c hil dr e n s m n. or g) eit h er vi a e m ail or p h o n e: 6 1 2-8 1 3 -5 9 1 3  at l e a st 2 4 h o ur s pri or t o 
s hi p pi n g .  Pl e a s e pr o vi d e y o ur i n stit uti o n’ s n a m e, t h e p ati e nt( s) st u d y n u m b er( s), a n d t h e arri v al d at e.  
S hi p m e nt s m a y o nl y arri v e M o n d a y - Fri d a y d uri n g r e g ul ar b u si n e s s h o ur s ( 8 a m -5 p m) .    
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S hi p s a m pl e s o v er ni g ht o n 8 p o u n d s of dr y i c e.  Pl e a s e u s e F e d E x ( a c c o u nt # 3 1 4 -9 7 1 -2 4 8) t o s hi p 
s a m pl e s t o t h e f oll o wi n g a d dr e s s:  
 
 
 
Att n: M ar y L a m er s T k a c h or L e zli e R a bi n e  
C hil dr e n' s H o s pit al s a n d Cli ni c s of Mi n n e s ot a  
2 5 2 5 C hi c a g o A v e n u e S.  
C S C -1 7 5  
Mi n n e a p oli s, M N   5 5 4 0 4