Conditions: Brain Tumors
Keywords: Recurrent or refractory medulloblastoma/PNET CNS germ cell tumors Ependymomas AT/RT High grade glioma Other malignant brain tumors
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 46
Healthy volunteers: no

Brief summary:
The purpose of this study is to:

Find out how safe and effective (by monitoring the good and/or bad effects) treatment with high dose temozolomide, thiotepa and carboplatin with stem cell rescue followed by 13-cis-retinoic acid has on children and adolescents with recurrent/refractory brain tumors

Find out how the body uses 13-cis-retinoic acid by studying the your blood levels and proteins in the blood that break down the 13-cis-retinoic acid

Determine how well 13-cis-retinoic acid penetrates into the spinal fluid.

Detailed description:
Researchers have used high doses of combination chemotherapy followed by a stem cell rescue to treat recurrent brain tumors with moderate success. High dose chemotherapy with stem cell rescue has resulted in long term survival of about 25% in patients with several different types of recurrent brain tumors. Stem cells are cells in the bone marrow that produce blood cells. The stem cells are collected from the blood of the patient before the high dose chemotherapy. Patients are given high doses of chemotherapy to kill every brain tumor cell, but in the process the cells of the bone marrow are also killed. The previously collected stem cells are then infused into the patient to rescue the bone marrow and allow for healthy blood cells to re-populate and grow in the bone marrow. Initial studies used the drug etoposide along with carboplatin and thiotepa for the high dose chemotherapy. Patients had severe side effects, especially severe mouth-sores, thought mainly due to the etoposide, and some patients died from these side effects.

Recent studies have shown that a new drug, temozolomide, is active against some types of brain tumors. When it was given as a single drug to children with solid tumors, the side effects were considered to be tolerable. Temozolomide is given by mouth. In this study, researchers want to give high dose chemotherapy that includes the drugs temozolomide in place of etoposide, along with thiotepa and carboplatin. Patients will then be given their own stem cells back to rescue the bone marrow from the chemotherapy. A preliminary trial using this new drug combination was performed and has shown that patients tolerate this drug combination, even at the very high doses that will be used in this protocol.

Another drug that is being used in pediatric cancer treatment is called 13-cis-retinoic acid. This drug is closely related to vitamin A. It is taken by mouth. Cancer cells are immature cells that have not "grown up" into adult cells that do work in the body. 13-cis-retinoic acid is thought to act on some types of cancer cells to make them mature into cells that function in the body. It has also been shown in the laboratory to cause some brain tumor cells to undergo apoptosis. It has been used in other types of pediatric cancers and research is just beginning to use it for treatment of recurrent brain tumors. In this study researchers want to give you 13-cis-retinoic acid for 6 months after you recover from the high dose chemotherapy with stem cell rescue.

Arms:
arm 1: None

Interventions: intervention 1: temozolomide, thiotepa, carboplatin, 13-cis-retinoic acid
Intervention descriptions: intervention 1: 13-cis-retinoic acid, when absorbed, may be subject to first-pass metabolism and subsequent plasma (and tumor) concentrations will depend on the rate of metabolism to the inactive 4-oxo metabolite.

Protocol document:
Prot_SAP_ICF_000.pdf: 
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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T A B L E O F C O N T E N T S  
 
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 S pe cifi c Ai ms  
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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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Pati e nt Eli gi bilit y  
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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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9. 0  
E val u ati o n of R es p o nse a n d Rela pse Crit eria  
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Dr u g I nf or mati o n a n d T o xi citi es  
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1 1. 0  
M o dificati o n f or T o xi cit y  
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1 2. 0  
S u p p orti v e Car e G ui d eli n es  
 
2 9  
 
1 3. 0  
S t u d y M o nit ori n g 
 
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1 4. 0  
Crit eria f or Re m o val fr o m St u d y a n d Off St u d y Crit eria  
 
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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 8. 0    R efere n c es           
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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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3  
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.  
•  
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. 
•  
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) .    
•  
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