A Phase II Trial of Nifurtimox for Refractory or Relapsed Neuroblastoma or Medulloblastoma.
Phase: PHASE2
Conditions: Neuroblastoma, Medulloblastoma
Sponsor: Giselle Sholler

 
 
 
 
 
 
 
 
 
Pr ot oc ol Nif urti m o x P h ase II  
 
V 0 7 0 6  
 
 
 
 
 
 
 
A P h ase II Tri al of Nif urti m o x f or Refr act or y or Rel a pse d 
Ne ur o bl ast o m a or Me d ull o bl ast o m a.  
 
 
 
 
 
 
Versi o n 9 . 0  Dece m ber  0 4, 2 0 15 
 
 
 
 
 
 
N C T 0 0 6 0 1 0 0 3
NCT00601003

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 2 of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
S T U D Y C O M MI T T E E  
 
S T U D Y C H AI R:  
 
St u d y C hair:      
 
 
Giselle S h oller, M D  
N M T R C C hair  
1 0 0 Mic hi ga n Street  N E   M C 2 7 2          
Gra n d Ra pi ds, MI 4 9 5 0 3 
Tel:  ( 6 1 6) 2 6 7 - 0 3 3 2  
Fa x: ( 6 1 6) 3 9 1 - 2 7 8 5 
giselle.s h oller @ hele n de v osc hil dre ns. or g  
 
S T U D Y VI C E C H AI R : 
 
Willia m Fer g us o n, M D 
Pe diatric He mat ol o g y - O nc ol o g y 
Car di nal Gle n n o n C hil dre n’s Me dical Ce nter/ Sai nt L o uis U ni versit y Sc h o ol of Me dici ne  
1 4 6 5 S. Gra n d Bl v d. 
Sai nt L o uis, M O 6 3 1 0 4 
P h o ne: ( 3 1 4)- 5 7 7- 5 6 3 8 
Fa x: ( 3 1 4) 2 6 8- 4 0 8 1 
E mail: fer g us ws @sl u.e d u  
 
 
S A F E T Y O F FI C E R:  
 
Gi na K. Ha n na, P har m D. 
P har macist   
8 0 5 Ma g n olia Cree k Circle 
Orla n d o, F L 3 2 8 2 8 
P h: 3 5 2- 2 5 6- 2 4 6 7 
E- mail:  gi na. ha n na @ g mail.c o m 
 
S E NI O R S T A TI S TI CI A N:  
Ta ka As hi ka ga, P h. D. 
Me dical Bi ostatistics  
& Bi oi nf or matics Facilit y  
U V M C olle ge of Me dici ne  
2 7 Hills B uil di n g 
1 0 5 Carri ga n Dri ve 
B urli n gt o n, V T 0 5 4 0 5  
P h o ne ( 8 0 2) 6 5 6- 2 5 2 6 
Fa x ( 8 0 2) 6 5 6- 0 6 3 2 
E mail Ta ka mar u. As hi ka ga @ u v m.e d u  
 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 3 of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
S T U D Y C O M MI T T E E M E M B E R S  
 
Ja mes Wallace, M D 
De pt. of Ra di ol o g y 
U V M C olle ge of Me dici ne/ F A H C  
1 1 1 C olc hester A ve 
B urli n gt o n, V T 0 5 4 0 1  
P h o ne: 8 0 2- 8 4 7- 3 5 0 6 
E mail: ja mes. wallace @ vt me d net. or g  
 
Willia m R o berts, M D  
Pe diatric He mat ol o g y/ O nc ol o g y 
Ra d y C hil dre n's H os pital Sa n Die g o 
3 0 2 0 C hil dre ns Wa y M C 5 0 3 5 
Sa n Die g o, C A 9 2 1 2 3- 4 2 8 2 
P h o ne: 8 5 8- 9 6 6- 5 8 1 1 
Fa x: 8 5 8- 9 6 6 - 8 0 3 5 
E mail: wr o berts @c hs d. or g  
 
Terrill F. Sa x o n, P h D 
C hair, Ass ociate Pr ofess or  
De pt. of E d ucati o nal Ps yc h ol o g y 
Office: B urles o n 2 1 8 A 
Ba yl or U ni versit y  
Wac o, Te xas 7 6 7 9 8  
P h o ne: ( 2 5 4) 7 1 0- 6 1 0 1 
E mail: Terrill _ Sa x o n @ ba yl or.e d u 
 
Ge ne vie ve Ber ge n da hl, R N  
Cli nical Pr o gra m Direct or  
N M T R C  
1 0 0 Mic hi ga n Street  N E   M C 2 7 2          
Gra n d Ra pi ds, MI 4 9 5 0 3  
Tel: ( 6 1 6) 2 6 7- 0 3 3 5  
E- Mail: Ge ne vie ve. ber ge n da hl @ hele n de v osc hil dre ns. or g 
 
Al yssa Va n der Werff  
Cli nical Pr o gra m C o or di nat or  
N M T R C  
1 0 0 Mic hi ga n Street  N E   M C 2 7 2          
Gra n d Ra pi ds, MI 4 9 5 0 3  
Tel:  ( 6 1 6) 2 6 7 -0 3 2 7   
Fa x: ( 6 1 6) 3 9 1 -2 7 8 5  
E- Mail:  Al yssa. Va n der Werff @  hele n de v osc hil dre ns. or g   
 
 
 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 4 of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
 
 
 
Ti m ot h y Hi g gi ns, M D 
Ra di ol o gist 
Fletc her Alle n Healt h Care  
Mai n Ca m p us - Patric k 1  
1 1 1 C olc hester A ve n ue 
B urli n gt o n, V T 0 5 4 0 1  
P h: 8 0 2- 8 4 7- 3 5 9 2 
 
 
Data Safet y a n d M o nit ori n g B oar d:  
 
 
Gi na K. Ha n na, P har m D.  
P har macist   
8 0 5 Ma g n olia Cree k Circle 
Orla n d o, F L 3 2 8 2 8 
P h: 3 5 2- 2 5 6- 2 4 6 7 
E- mail:  gi na. ha n na @ g mail.c o m 
 
 
 
Wi nst o n H u h, M D  
Assista nt Pr ofess or,  
De part me nt of Pe diatrics Patie nt Care,  
Di visi o n of Pe diatrics,  
T he U ni versit y of Te xas M D A n ders o n Ca ncer Ce nter,  
H o ust o n, T X  7 7 0 3 0  
 
 
T o m Geller, M D  
Pe diatric He mat ol o g y - O nc ol o g y 
Car di nal Gle n n o n C hil dre n’s Me dical Ce nter/  
Sai nt L o uis U ni versit y Sc h o ol of Me dici ne 
1 4 6 5 S. Gra n d Bl v d. 
Sai nt L o uis, M O 6 3 1 0 4 
P h o ne: ( 3 1 4)- 5 7 7- 5 6 3 8 
Fa x: ( 3 1 4) 2 6 8- 4 0 8 1 
 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 5 of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
T A B L E O F C O N T E N T S  
S E C TI O N   
  
  
  
  
  
  
  
  
        P A G E   
 
 
 
T A B L E O F C O N T E N T S  ............................................................................................................................... 5 
 
0BS T U D Y C O M MI T T E E  .................................................................................................................................. 7 
 
1. 0  
1BP R O T O C O L C O N C E P T  ...................................................................................................................... 8 
 
2. 0  
O BJ E C TI V E S ....................................................................................................................................... 8 
2. 1  3BPri mar y O bjecti ve:  ..................................................................................................................... 8 
2. 2  Sec o n dar y O bjecti ves:  ................................................................................................................ 9 
 
3. 0  
B A C K G R O U N D A N D P R E LI MI N A R Y D A T A  ................................................................................. 9 
3. 1  Cli nical bac k gr o u n d  ................................................................................................................... 9 
3. 2  Precli nical  bac k gr o u n d  ............................................................................................................. 1 0  
3. 3  Nif urti m o x I n d uces A p o pt osis of Ne ur o blast o ma Cells i n vitr o a n d i n vi v o . .......................... 1 1  
3. 4  Nif urti m o x is C yt ot o xic t o Me d ull o blast o ma Cells i n vitr o a n d i n vi v o  .................................. 1 2  
3. 5  P har mac o ki netic St u dies of Nif urti m o x  ................................................................................... 1 2  
3. 6 Assa y Pr oce d ure:  ...................................................................................................................... 1 2  
3. 7  H P L C se parati o n:  ..................................................................................................................... 1 3  
 
4. 0  
S U BJ E C T E LI GI BI LI T Y A N D S T U D Y D E SI G N  ............................................................................ 1 4  
4. 1  Eli gi bilit y:  ................................................................................................................................ 1 4  
4. 2  Stratificati o n  ............................................................................................................................. 1 5  
4. 3  S u bject Re gistrati o n  ................................................................................................................. 1 5  
 
5. 0  
T R E A T M E N T P L A N  ......................................................................................................................... 1 5  
5. 1  Nif urti m o x D osi n g - C ycles 1 - 6 ................................................................................................ 1 5  
5. 2  C o m bi nati o n T hera p y: .............................................................................................................. 1 6  
 
6. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S:  ............................................................................................... 1 7  
6. 1  Sa m ple Size Disc ussi o n  ........................................................................................................... 1 7  
6. 2  Statistical A nal ysis A p pr oac hes  ............................................................................................... 1 9  
 
7. 0  
D O S E A DJ U S T M E N T S  ..................................................................................................................... 1 9  
7. 1 Nif urti m o x D ose M o dificati o ns  ............................................................................................... 1 9  
7. 2 T o p oteca n/ C ycl o p h os p ha mi de D ose M o dificati o ns:  ................................................................ 2 0  
 
8. 0  
S U P P O R TI V E C A R E A N D C O N C O MI T A N T T H E R A P Y  ............................................................. 2 1  
 
9. 0  
R E Q UI R E D O B S E R V A TI O N S  ......................................................................................................... 2 2  
 
1 0. 0    P H A R M A C O KI N E TI C S T U DI E S  .................................................................................................... 2 5  
 
1 1. 0    M O NI T O RI N G O F P O T E N TI A L A D V E R S E N E U R O L O GI C A L E F F E C T S  ................................. 2 7  
 
1 2. 0  
O F F S T U D Y C RI T E RI A  ............................................................................................................... 2 9  
 
1 3. 0  
154BE V A L U A TI O N/ R E S P O N S E C RI T E RI A.  .................................................................................... 2 9  
 
1 4. 0  
S A F E T Y M O NI T O RI N G  .............................................................................................................. 3 3  
 
1 5. 0  
A D V E R S E E V E N T R E P O R TI N G  ................................................................................................ 3 4  
 
1 6. 0  
S E RI O U S A D V E R S E E V E N T R E P O R TI N G  .............................................................................. 3 4  
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 6 of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
1 7. 0  
A G E N T I N F O R M A TI O N  ............................................................................................................. 3 5  
 
1 7. 1 Nif urti m o x. ............................................................................................................................. 3 5  
 
1 7. 2 C ycl o p h os p ha mi de  ................................................................................................................. 3 7  
 
1 7. 3 T o p oteca n  ............................................................................................................................... 3 8  
 
1 7. 4   Fil grasti m  .............................................................................................................................. 3 9  
 
1 7. 5  Pe gfil grasti m  .......................................................................................................................... 4 0  
 
1 8. 0  
BI O L O GI C A L S T U DI E S ( O pti o nal)  ............................................................................................ 4 1  
 
1 8. 2  B o ne Marr o w Sa m ple I nstr ucti o ns (f or all partici pati n g sites):  ............................................. 4 2  
 
1 9. 0  
R E F E R E N C E S  ............................................................................................................................... 4 5  
 
 
A p pe n di x I:  Str uct ure d I nter vie w f or A d verse Ne ur ol o gic E ve nts  .............................................................. 4 6  
 
 
A p pe n di x II: R E Q UI R E D O B S E R V A TI O N S  ............................................................................................. 4 7  
 
 
A p pe n di x III: Q O L Q uesti o n naires ............................................................................................ ................... 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 7 of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
0B 
 
 
I N V E S TI G A T O R SI G N A T U R E S H E E T 
 
I ha ve rea d t he attac he d pr ot oc ol a n d a gree t hat it c o ntai ns all t he necessar y details f or 
perf or mi n g t he st u d y. 
 
I will pr o vi de c o pies of t he pr ot oc ol a n d of t he precli nical a n d cli nical i nf or mati o n 
(I n vesti gat or’s Br oc h ure) o n t he test article, w hic h was f ur nis he d t o me b y t he 
Ne ur o blast o ma a n d Me d ull o blast o ma Tra nslati o nal Researc h C o ns orti u m ( N M T R C), t o 
all me m bers of t he st u d y tea m res p o nsi ble t o me w h o partici pate i n t he st u d y.  I will 
disc uss t his material wit h t he m t o ass ure t hat t he y are f ull y i nf or me d re gar di n g t he test 
article a n d t he c o n d uct of t he st u d y. 
 
O nce t he pr ot oc ol has bee n a p pr o ve d b y t he I nstit uti o nal Re vie w B oar d 
(I R B)/I n de pe n de nt Et hics C o m mittee (I E C), I will n ot m o dif y t his pr ot oc ol wit h o ut 
o btai ni n g t he pri or a p pr o val of t he N M T R C a n d of t he I R B/I E C.  I will s u b mit t he 
pr ot oc ol m o dificati o ns a n d/ or a n y i nf or me d c o nse nt f or m (I C F) m o dificati o ns t o t he 
N M T R C a n d t he I R B/ I E C, a n d a p pr o val will be o btai ne d before a n y m o dificati o ns are 
i m ple me nte d. 
 
I u n dersta n d t he pr ot oc ol a n d will w or k acc or di n g t o it, t he pri nci ples of G o o d Cli nical 
Practice ( G C P) [c urre nt I nter nati o nal C o nfere nce of Har m o nizati o n (I C H) g ui deli nes], 
a n d t he Declarati o n of Helsi n ki ( 1 9 6 4) i ncl u di n g all a me n d me nts u p t o a n d i ncl u di n g t he 
Sc otla n d re visi o n ( 2 0 0 0) a n d n otes of clarificati o n a d de d i n 2 0 0 2 a n d 2 0 0 4. 
 
 
 
 
 
 
I n vesti gat or's Si g nat ure 
 
Date  
 
 
 
I n vesti gat or’s Pri nte d Na me 
 
 
 
 
 
I n vesti gati o nal Site Na me 
 
 
 
 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 8 of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
A P h ase II Tri al of Nif urti m o x f or Refr act or y or Rel a pse d 
Ne ur o bl ast o m a or Me d ull o bl ast o m a.  
 
1. 0  
1BP R O T O C O L C O N C E P T  
T here is c urre ntl y n o c urati ve treat me nt f or c hil dre n wit h rela pse d/refract or y 
ne ur o blast o ma, a n d f or t hese c hil dre n t he 5- year  s ur vi val rate is < 1 0 %.  Alt h o u g h 
t here ha ve bee n re p orts t hat t he s ur vi val rate of c hil dre n wit h c he m ose nsiti ve 
rela pse d me d ull o blast o ma ca n a p pr oac h 4 0 % f oll o wi n g i nte nsi ve c he m ot hera p y 
c o m bi ne d wit h a ut ol o g o us ste m cell s u p p ort, m ore rece nt data l o o ki n g at s ur vi val 
of all patie nts rela psi n g after m o der n c o m bi nati o n c he m ot hera p y a n d ra diati o n is 
als o o n t he or der of 1 0- 1 5 %.  As s uc h, ne w t hera pe utic a p pr oac hes are nee de d t o 
treat t hese c hil dre n.   
 
T his p hase II cli nical trial is s pecificall y desi g ne d t o assess t he a nti ne o plastic  
effect of t he a nti parasitic dr u g nif urti m o x w he n gi ve n i n c o m bi nati o n wit h 
c ycl o p h os p ha mi de a n d t o p oteca n t o c hil dre n wit h rela pse d or refract or y 
ne ur o blast o ma or me d ull o blast o ma.  
 
A rece ntl y c o m plete d p hase I trial of nif urti m o x i n s u bjects wit h 
rela pse d/refract or y ne ur o blast o ma esta blis he d a ma xi m u m t olerate d d ose of 3 0 
m g/ k g/ da y.   Precli nical w or k has s h o w n t hat si n gle-a ge nt nif urti m o x has b ot h i n 
vitr o a n d i n viv o c yt ot o xicit y a gai nst b ot h ne ur o blast o ma a n d me d ull o blast o ma 
cell li nes a n d xe n o graft m o dels.  I n t he p hase I st u d y, nif urti m o x was i nitiall y 
gi ve n al o ne, a n d t he n c o m bi ne d wit h t o p oteca n a n d c ycl o p h os p ha mi de; res p o nses 
were see n i n b ot h p hases of t hera p y .  
T he prese nt st u d y is a p hase II trial of nif urti m o x wit h t he a d diti o n of sta n da r d 
d oses of c ycl o p h os p ha mi de, a n d t o p oteca n, i n s u bjects wit h eit her ne ur o blast o ma 
or me d ull o blast o ma t hat is i n first or s u bse q ue nt rela pse, or refract or y t o sta n dar d 
i nitial t hera p y.  O ur pri mar y o bjecti ve is t o e val uate t he efficac y of nif urti m o x i n 
c o m bi nati o n wit h t hese c he m ot hera p y a ge nts.  O ur sec o n dar y ai ms will be t o: 
•  e val uate t he pea k ser u m le vels of nif urti m o x i n t hese s u bjects a n d 
c orrelate pea k le vel wit h res p o nse; 
•  c orrelate t u m or ge n o mic a nal ysis wit h res p o nse; 
•  e val uate q ualit y of life of s u bj ects recei vi n g t his dr u g c o m bi nati o n; 
 
2. 0  O B J E C TI V E S   
2. 1.  3BPri mar y O bjecti ve :  
2. 1. 1.  
4BTest t he efficac y ( best res p o nse) a n d safet y  of nif urti m o x i n c hil dre n wit h 
rela pse d or refract or y ne ur o blast o ma or me d ull o blast o ma, i n c o m bi nati o n 
wit h c ycl o p h os p ha mi de/t o p oteca n 
2. 1. 2.  
5BE val uate Mea n Ti me t o Pr o gressi o n  
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 9 of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
2. 2.  Sec o n dar y O bjecti ves : 
2. 2. 1.  
7 BE val uate t he  correlati o n bet wee n  t he p har macol o gic ser u m le vels of 
n if urti m o x wit h t u m or res p o nse. 
2. 2. 2.  
8BQ ualit y of life a n d ne ur oc o g niti ve e val uati o n/ q uesti o n naire. 
2. 2. 3.  
9BBi ol o g y st u dies t o i ncl u de: ge n o mic a nal ysis of cells pre - a n d p ost- 
treat me nt, c orrelati o n of i n vitr o res p o nse t o i n vi v o res p o nse, fl o w 
c yt o metr y of t u m or b ur de n i n b o ne marr o w a n d bi o mar ker de vel o p me nt. 
 
3. 0  B A C K G R O U N D A N D P R E LI MI N A R Y D A T A  
 
3. 1.  Cli nical bac k gr o u n d 
T his P hase II trial is desi g ne d t o e val uate t he a nti-t u m or efficac y of 
nif urti m o x i n c hil dre n wit h ne ur o blast o ma a n d me d ull o blast o ma. 
N if urti m o x is a s y nt hetic nitr of ura n c o m p o u n d t hat has bee n use d safel y 
si nce t he 1 9 7 0’s f or t he treat me nt of C ha gas’ Disease i n b ot h a d ults a n d 
c hil dre n.  T he efficac y a n d t o xicit y of nif urti m o x i n a c o h ort of 6 2 
c hil dre n wit h C ha gas’ Disease has rece ntl y bee n re vie we d 2.  I n 2 0 0 2, a 
patie nt wit h pr o gressi ve refract or y ne ur o blast o ma w h o was bei n g treate d 
wit h c ycl o p h os p ha mi de a n d t o p oteca n  ac q uire d C ha gas ’ Disease fr o m a 
bl o o d tra nsf usi o n, a n d was starte d o n t he rec o m me n de d d ose of nif urti m o x 
( 1 5- 2 0 m g/ k g/ da y); her t u m or s u bse q ue ntl y re gresse d1.  S u bse q ue ntl y 6 
m ulti pl y rela pse d ne ur o blast o ma s u bjects were treate d wit h nif urti m o x ( 2 0  
m g/ k g/ da y) c o m bi ne d wit h c ycl o p h os p ha mi de a n d t o p oteca n t hr o u g h 
c o m passi o nate release.  Fi ve of t he si x s u bjects s h o we d a res p o nse t o 
treat me nt a n d t w o of t hese s u bjects attai ne d a c o m plete re missi o n o n t his 
t hera p y a n d re mai n wit ho ut e vi de nce of disease f or m ore t ha n o ne year 
after be gi n ni n g nif urti m o x.   
 
A P hase I trial of nif urti m o x i n c hil dre n wit h m ulti pl y rela pse d/refract or y 
ne ur o blast o ma has bee n c o m plete d.  T he pri mar y o bjecti ve was t o 
deter mi ne t he ma xi m u m t olerate d d ose of t his me dicati o n , w hic h  was 
f o u n d t o be 3 0 m g/ k g/ da y di vi de d i n 3 d oses.  T he n o n- d ose-li miti n g 
t o xicities were mai nl y na usea a n d ne ur o pat h y. T he d ose li miti n g t o xicities 
of t w o patie nts at 4 0 m g/ k g/ da y were a gra de 3 p ul m o nar y he m orr ha ge 
a n d a gra de 3 ne ur o pat h y (re versi ble). T he P hase I trial als o e val uate d 
t u m or res p o nse.  
 
F o urtee n patie nts were e val ua ble f or efficac y f oll o wi n g nif urti m o x 
treat me nt al o ne. Acc or di n g t o R E CI S T criteria, 6 patie nts dis pla ye d sta ble 
disease, a n d 8 ha d pr o gressi ve disease. I n a d diti o n t o R E CI S T cr iteria, 
patie nts were als o e val uate d f or a cli nical res p o nse as defi ne d b y 
ra di ol o gical sta ble disease wit h eit her a 5 0 % decrease i n uri nar y 
catec h ola mi nes, cleara nce of b o ne marr o w disease, or res ol uti o n of MI B G 
acti vit y. A cli nical res p o nse was see n i n 2  ( 3 3 %) of t he 6 patie nts wit h 
sta ble disease. Of t hese patie nts, o ne ha d res ol uti o n of b o ne marr o w 
disease, w hic h was c o nfir me d o n s u bse q ue nt b o ne marr o w bi o psies, a n d 
o ne ha d greater t ha n 5 0 % decrease i n uri nar y catec h ola mi nes. 
Of t he te n patie nts t hat we re e val ua ble f or efficac y after 3 c ycles wit h 
nif urti m o x, c ycl o p h os p ha mi de a n d t o p oteca n, 3 s h o we d a partial res p o nse, 
5 ha d sta ble disease, a n d 2 ha d pr o gressi ve disease acc or di n g t o R E CI S T 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 1 0  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
criteria. Of t he 5 patie nts wit h sta ble disease, a cli nical res p o nse was see n 
i n 3 ( 6 0 %) of t he m. O ne patie nt c o nti n ue d t o ha ve cleara nce of b o ne 
marr o w disease a n d a greater t ha n 5 0 % decrease i n uri nar y 
catec h ola mi nes. T he ot her t w o patie nts ha d a decrease i n uri nar y 
catec h ola mi nes b y o ver 5 0 %. T w o patie nts were n o n- e val ua ble f or t heir 
res p o nse t o c o m bi nati o n t hera p y. O ne patie nt die d fr o m pr o gressi ve 
disease pri or t o recei vi n g c o m bi nati o n t hera p y, a n d o ne patie nt ref use d 
f urt her treat me nt. T he mea n pr o gressi o n- free s ur vi val f or all 1 4 patie nts 
w h o be ga n treat me nt was 9 . 1 m o nt hs ( me dia n 4. 5 m o nt hs). T he mea n 
pr o gressi o n-free s ur vi val varie d de pe n di n g u p o n t he n u m ber of pre vi o us 
c he m ot hera p y re gi me ns. I n patie nts t hat ha d recei ve d < 3 pre vi o us 
c he m ot hera p y re gi me ns, t he mea n pr o gressi o n-free s ur vi val was 1 2. 5 
m o nt hs ( me dia n 1 4. 0 m o nt hs), w hile i n patie nts t hat ha d u n der g o ne > 3 
pri or c he m ot hera p y re gi me ns, t he mea n pr o gressi o n- free s ur vi val was 7. 6 
m o nt hs ( me dia n 7. 6 m o nt hs). T he Ma ntel p val ue f or t his a nal ysis was 
0. 3 9. Gi ve n t he e xte nsi ve pri or treat me nt t hese s u bjects ha d recei ve d, 
t hese res ults are e nc o ura gi n g a n d f or m t he basis of t he pr o p ose d st u d y 
utilizi n g a nif urti m o x d ose of 3 0 m g/ k g/ da y. 
 
T he c o m bi nati o n of c ycl o p h os p ha mi de a n d t o p oteca n was  c h ose n f or 
c o m bi nati o n t hera p y beca use it has s h o w n efficac y i n t he treat me nt of 
rela pse d ne ur o blast o ma a n d me d ull o blast o ma; in a n earlier  p hase II st u d y 
e val uati n g t his c o m bi nati o n c o n d ucte d b y t he Pe diatric O nc ol o g y Gr o u p, 
t here was a 3 4 % res p o nse rate  a m o n g patie nts wit h rela pse d 
ne ur o blast o ma.  We h y p ot hesize t hat t her e will be greater res p o nse i n 
c o m bi nati o n wit h nif urti m o x.   
 
M ulti ple palliati ve ra diati o n t hera p y re gi me ns ha ve bee n utilize d i n 
c hil dre n wit h pai nf ul b o n y metastases fr o m ne ur o blast o ma. N o s yste matic 
re vie w of t hese sc he d ules has bee n d o ne, b ut it has bee n o ur o bser vati o n 
t hat s h ort c o urses of ra diati o n ( o ne t o t hree da y s) ma y w or k as well as  
m ore pr ol o n ge d sc he d ules ( u p t o t hree wee ks) a n d will be sta n dar dize d as 
s u p p orti ve care f or b o ne pai n. 
 
3. 2.  Precli nical bac k gr o u n d 
Nif urti m o x is a nitr o heter oc yclic c o m p o u n d c o ntai ni n g a nitr o gr o u p t hat 
is esse ntial f or its efficac y.  Nif urti m o x has bee n s h o w n t o e xert its 
c yt ot o xic effect s pecificall y b y ge nerati n g free ra dicals. T he nitr o gr o u p 
ca n be re d uce d t o t he nitr o a ni o n ra dical i n cell -free s yste ms b y i nteracti n g 
wit h c yt oc hr o me P- 4 5 0 re d uctase, xa nt hi ne o xi dase, asc or bate, a n d 
catec h ola mi nes.  Nitr o  a ni o ns ca n t he n re d uce o x y ge n t o t he s u per o xi de 
a ni o n ra dical a n d h y dr o ge n per o xi de.  I n C ha gas’ disease, t he nitr o a ni o n 
free ra dicals a n d o x yra dicals ha ve been s h o w n t o be c yt ot o xic f or t he 
parasite T. cr uzi.    T he re d ucti o n of t he nitr o gr o u p n ot o nl y ge nerates 
a ni o n ra dicals, b ut i nteracti o n wit h catec h ola mi nes 3 a p pears als o t o 
ge nerate se mi q ui n o ne free ra dicals t hat e xacer bate da ma ge t o f u ncti o nall y 
i m p ortant bi o m olec ules, lea di n g t o a p o pt osis of ne ur o blast o ma cell li nes.  
Ne ur o blast o ma cells are k n o w n t o c o ntai n hi g h le vels of catec h ola mi nes, 
t here b y p ote ntiall y lea di n g t o relati vel y s pecific tar geti n g of t hese cells.  

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 1 1  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
T he i m p orta nce of t he i nteracti o n bet wee n nif urti m o x a n d catec h ola mi nes 
i n ne ur o blast o ma cell li nes was c o nfir me d b y t he re d ucti o n of c yt ot o xicit y 
b y pretreat me nt wit h A M P T, a t yr osi ne h y dr o x ylase i n hi bit or t hat re d uces 
t he t otal a m o u nt of catec h ola mi ne st ore d i n cells, als o re d uces nif urti m o x-
i n d uce d c yt ot o xicit y.  I n a d diti o n, t he e n ha nce d se nsiti vit y of s y m pat hetic 
ne ur o ns — b ut n ot par asy m pat hetic ne ur o ns or n o n- ne ur o nal cells—t o 
nif urti m o x s u p p orts t his c o ncl usi o n ( S h oller, i n s u b missi o n).     
 
3. 3.  Nif urti m o x I n d uces A p o pt osis of Ne ur o blast o ma C ells i n vitr o a n d i n vi v o.      
We teste d t he effect of nif urti m o x o n gr o wt h of C H L A- 9 0, L A 1- 5 5 n, L A-
N 2, S M S K C N R, a n d S Y 5 Y ne ur o blast o ma cells i n c ult ure.  Nif urti m o x 
i n hi bite d t he gr o wt h of all fi ve cell li nes i n a c o nce ntrati o n- de pe n de nt 
ma n ner.  After 2 da ys of e x p os ure t o 2 0 mc g/ ml of nif urti m o x, t he n u m ber 
of cells is decrease d t o 5. 9 % of ve hicle -treate d c o ntr ols i n C H L A- 9 0 
( p < 0. 0 0 1), 3 1. 3 % i n L A 1- 5 5 n ( p < 0. 0 0 1), 3 2. 9 % i n L A- N 2 ( p < 0. 0 0 1), 
3. 6 % i n S M S- K C N R ( p < 0. 0 0 1), a n d 1. 8 % i n S Y 5 Y ( p < 0. 0 0 1).   T he 
c o nce ntrati o n re q uire d t o reac h 5 0 % i n hi biti o n of gr o wt h (I C 5 0) f or t hese 
cell li nes was esti mate d t o be 1 2. 1 8 mc g/ ml f or C H L A- 9 0, 1 3. 6 2 mc g/ ml 
f or L A 1- 5 5 n, 1 7. 1 7 mc g / ml f or L A-N 2 ,  1 0. 9 8 mc g / ml f or S M S-K C N R 
a n d 9. 1 5 mc g/ ml f or S Y 5 Y.   I n c o ntrast, c yt ot o xic effects were  n ot 
o bser ve d o n n or mal e pit helial cells i n c ult ure e x p ose d t o nif urti m o x. 
 
C o nc urre nt wit h t he decrease i n cell via bilit y, nif urti m o x treat me nt 
pr o d uces m or p h ol o gi cal c ha n ges c o nsiste nt wit h a p o pt osis  a n d t hese 
m or p h ol o gic c ha n ges occ ur i n a d ose- de pe n de nt ma n ner.   E x p os ure t o 1 
µ g/ ml of nif urti m o x ca use d a decrease i n a x o n le n gt h c o m pare d t o c o ntr ol 
u ntreate d cells, a n d at 1 0 µ g/ ml nif urti m o x t his effect was i ncre ase d 
si g nifica ntl y wit h r o u n di n g of cells. At 2 0  µ g/ ml nif urti m o x, 
ne ur o blast o ma cells  were r o u n de d u p a n d fl oati n g wit h o nl y a fe w cells 
re mai ni n g a d here nt t o t he plate.   
 
 
I n a d diti o n t o its effects i n vitr o, nif urti m o x was als o a ble t o re d uce t he 
gr o wt h of ne ur o blast o ma t u m ors i n a xe n o graft m o del.   N u de mice 
(n u/ n u ) were i njecte d i n t he left fla n k wit h S M S K C N R cells a n d all o we d 
t o f or m pal pa ble t u m ors f or 1 0- 1 4 da ys.  T he mice were t he n fe d 5 g f o o d 
pellets dail y wit h or wit h o ut 1 5 0  m g/ k g nif urti m o x.  T here were n o si g ns 
of dr u g- relate d t o xicit y at t his d ose sc he d ule, w hic h res ults i n ser u m le vels 
a p pr o xi matel y e q ui vale nt t o a d ose of 1 2 m g/ k g i n h u ma ns.  After 2 8 da ys 
of treat me nt ( w he n c o ntr ol mice reac he d ma xi m u m t u m or size of 3. 0c m 3) 
t he mice were sacrifice d a n d t heir t u m ors were e xcise d a n d wei g he d.  
Treat me nt wit h nif urti m o x res ulte d i n i n hi biti o n of t u m or gr o wt h: t he 
a vera ge t u m or wei g ht i n c o ntr ol mice was 1. 1 5 gra ms c o m pare d t o a n 
a vera ge wei g ht of 0. 3 gra ms i n mice recei vi n g nif urti m o x ( p = 0. 0 3 ). 
I m m u n o hist oc he mical stai ni n g s h o we d t hat t u m ors treate d wit h nif urti m o x 
ha d decrease d cell pr oliferati o n as e vi de nce d b y decrease i n Ki 6 7 p ositi ve 
stai ni n g ( 7 5. 3 % vers us 9 3. 2 %, p < 0. 0 0 1) a n d decrease i n mit otic i n de x 
( 3 3. 5 vers us 5 0. 2, p = 0. 0 1 2) as well as a n i ncrease i n a p o pt osis as 
e vi de nce d b y a n i ncrease i n t he p y k n otic i n de x ( 6 3. 7 vers us 3 9. 5, 
p = 0. 0 2 2). 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 1 2  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
 
3. 4.  Nif urti m o x  is C yt ot o xic t o Me d ull o blast o ma C ells i n vitr o a n d i n vi v o       
We teste d t he effect of nif urti m o x o n gr o wt h of D 2 8 3 a n d D A O Y 
me d ull o blast o ma cells i n c ult ure.  Nif urti m o x i n hi bit e d t he gr o wt h of 
t hese li nes i n a c o nce ntrati o n- de pe n de nt ma n ner.  After 2 da ys of e x p os ure 
t o 2 0 mc g/ ml of nif urti m o x, t he n u m ber of cells is decrease d t o 7. 0 % of 
ve hicle-treate d c o ntr ols i n D 2 8 3 ( p < 0. 0 0 1) a n d 4 0 % i n D A O Y ( p < 0. 0 0 1). 
 
A m o use xe n o graft m o del was use d t o m ore f ull y e val uate t he effect of 
n if urti m o x.  N u de mice were i njecte d stere ota xicall y i n t he cere bell u m 
wit h 1 0 5 D 2 8 3 cells a n d fe d f o o d wit h or wit h o ut nif urti m o x 
( 1 5 0 m g/ k g/ da y) f or 7 wee ks p ost-s ur ger y. T he a ni mals were t he n 
sacrifice d, a n d t he t u m ors re m o ve d a n d e val uate d b y 
i m m u n o hist oc he mistr y. I n viv o t u m or gr o wt h was i n hi bite d b y nif urti m o x, 
a n d hist ol o gic e val uati o n of t he t u m ors s h o we d t hat nif urti m o x treat me nt 
res ulte d i n a n i ncrease i n t he a p o pt otic rate.  
  
3. 5.  P har mac o ki netic St u dies of Nif urti m o x  
Des pite meta b olis m st u dies i n rats a n d d o gs dati n g t o 1 9 7 2, t here a p pears 
t o be little p u blis he d data re gar di n g p har mac o ki netics of nif urti m o x i n 
h u ma ns.  T he pr o d uct br oc h ure refers t o li mite d P K st u dies i n healt h y 
a d ult v ol u nteers a n d patie nts wit h re nal fail ure w h o recei ve d si n gle d oses 
i n t he ra n ge of 1 0- 1 5 m g/ k g.  After a n oral d ose t he ti me t o pea k plas ma 
c o nce ntrati o n was a b o ut 2. 5 h o urs, t he C ma x  was 0. 7 5 1 µ g/ ml ( 7 5 1 n g/ ml) 
a n d t he T 1/ 2 was a p pr o xi matel y 3. 5 h o urs.  T here was lar ge i nter- patie nt 
varia bilit y wit h pea k c o nce ntrati o ns ra n gi n g bet wee n 3 5 6- 1 0 9 3 n g/ ml. 
 
A n H P L C assa y f or ser u m has bee n p u blis he d ( Pa ul os et al, J o ur nal of 
C hr o mat o gra p h y 4 3 3: 3 5 9- 3 6 2, 1 9 8 8) a n d t h e s pecifics are o utli ne d bel o w.  
T he se nsiti vit y usi n g detecti o n at 4 0 0 n m a n d se parati o n o n a C 1 8 c ol u m n 
was re p orte d t o be 0. 0 7 7 µ g/ ml ( 7 7 n g/ ml) ser u m , w hic h is a p pr o xi matel y 
2 0 % of t he l o west pea k le vel re p orte d i n t he st u dies n ote d a b o ve.  
F urt her m ore, wit h a T 1/ 2 of  ∼ 3. 5 h o urs a n d TI D d osi n g, t he assa y a p pears 
se nsiti ve e n o u g h t o d o at least li mite d P K st u dies o n c hil dre n as s mall as 
1 0 k g: 1 t o 2 ml bl o o d sa m ples o btai ne d at 2 ti me p oi nts ( baseli ne a n d 1 8 0 
mi n utes p ost- a d mi nistrati o n) w o ul d re q uire a t otal v ol u me of n o m ore t ha n 
4 ml .  
 
3. 6.  Assa y Pr oce d ure  (a da pte d fr o m Pa ul os et al):   
A 5 0 µ l ali q u ot of nitr of uraz o ne s ol uti o n ( 3 0 µ g/ ml) is a d de d t o 1. 0 ser u m 
sa m ple as a n i nter nal sta n dar d.  Ser u m pr otei ns are preci pitate d wit h 0. 6 
ml 1 M  perc hl oric aci d , a n d the preci pitate re m o ve d b y ce ntrif u gati o n f or 
1 0 mi n utes at 1 0 0 0 x g.  T he li q ui d p hase i s as pirate d a n d t he aci d 
ne utralize d wit h 2 0 0 µ l of 1 M s o di u m h y dr o xi de. T he nif urti m o x 
(t o get her wit h t he nitr of uraz o ne sta n dar d) is e xtracte d i nt o a n or ga nic 
p hase of 3. 5 ml dic hl or o met ha ne f or 1 h o ur.  A 3 ml ali q u ot of t he or ga nic 
p hase is e va p orate d t o dr y ness at 4 0o C, t he resi d ue diss ol ve d i n 2 0 0 µ l 
H P L C m o bile p hase b uffer, of w hic h 2 0 µ l ali q u ots are use d f or eac h 
H P L C se parati o n.  

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 1 3  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
 
3. 7.  H P L C se parati o n:  
C hr o mat o gra p h y is d o ne o n a 1 5 c m, 3. 9 m m I D u B o n da pa k C 1 8 c ol u m n.  
T he m o bile p hase is met ha n ol- S ore nse n p h os p hate b uffer, p H 7. 0 ( 5 0: 5 0, 
v/ v).  T he c hr o mat o gra p h y was d o ne at a rate of 1 ml/ mi n.  T he sta n dar d 
el utes at a p pr o xi matel y 2 mi n utes a n d t he dr u g at 3 mi n utes. 
 
T h is assa y was re p orte d t o be li near o ver t he ra n ge of 0. 0 7 7- 2. 3 µ g/ ml 
( 7 7- 2 3 0 0 n g/ ml) a n d t he re pr o d uci bilit y base d u p o n a p o ole d ser u m 
sa m ple assa ye d re petiti vel y o ver a 2- wee k peri o d s h o we d a n i nter-da y 
c oefficie nt of variati o n of o nl y 4 %. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 1 4  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
4. 0  S U B J E C T E LI GI BI LI T Y A N D S T U D Y D E SI G N  
4. 1.  Eli gi bilit y:  
I ncl usi o n Criteri a: 
4. 1. 1.  
20BA ge: 0 -2 1 years at t he ti me of dia g n osis. 
4. 1. 2.  
21BDia g n osis: Hist ol o gic verificati o n at eit her t he ti me  of ori gi nal dia g n osis 
or rela pse of ne ur o blast o ma or me d ull o blast o ma . 
4. 1. 3.  
2BDisease Stat us: Refract or y or first or m ulti ple rela pse d ne ur o blast o ma, or 
me d ull o blast o ma t hat has rela pse d after, or is refract or y t o, a 
c he m ot hera p y- c o ntai ni n g treat me nt re gi me n.  
4. 1. 4.  Meas ura ble disease, i ncl u di n g at least o ne of t he f oll o wi n g: 
Meas ura ble t u m or  > 1 0 m m b y C T or M RI   
P ositi ve b o ne marr o w bi o ps y/as pirate.   
F or ne ur o blast o ma s u bjects o nl y, a p ositi ve MI B G  
F or me d ull o blast o ma s u bjects o nl y, p ositi ve C S F c yt ol o g y 
4. 1. 5.  C urre nt disease state m ust be o ne f or w hic h t here is c urre ntl y n o k n o w n 
c urati ve t hera p y.  
4. 1. 6.  
29BA ne gati ve uri ne pre g na nc y test is re q uire d f or fe male s u bject s of c hil d 
beari n g p ote ntial ( o nset of me nses or ≥1 3 years of a ge).  
4. 1. 7.  
30BB ot h male a n d fe male st u d y s u bjects nee d t o a gree t o use o ne of t he m ore 
effecti ve birt h c o ntr ol met h o ds d uri n g treat me nt a n d f or si x m o nt hs after 
treat me nt is st o p pe d. T hese met h o ds i ncl u de t otal a bsti ne nce ( n o se x), oral 
c o ntrace pti ves (“t he pill”), a n i ntra uteri ne de vice (I U D), le v o n or gestr ol 
i m pla nts ( N or pla nt), or me dr o x y pr o gester o ne acetate i njecti o ns ( De p o-
pr o vera s h ots). If o ne of t hese ca n n ot be use d, c o ntrace pti ve f oa m wit h a 
c o n d o m is rec o m me n de d.   
4. 1. 8.  
31BOr ga n F u ncti o n Re q uire me nts 
S u bjects m ust h a ve a de q uate li ver f u ncti o n as defi ne d b y A S T or 
A L T < 1 0 x u p per li mit of n or mal  
S u bjects wit h o ut b o ne marr o w metastases m ust ha ve a de q uate 
b o ne marr o w f u ncti o n, defi ne d as A N C > 5 0 0/ µ l 
4. 1. 9.  
34BI nf or me d C o nse nt: All s u bjects a n d/ or le gal g uar dia ns m ust si g n i nf or me d 
writte n c o nse nt.  Asse nt, w he n a p pr o priate, will be o btai ne d acc or di n g t o 
i nstit uti o nal g ui deli nes 
35BE xcl usi o n Criteri a : 
4. 1. 1 0.  36BLife e x pecta nc y < 2 m o nt hs or La ns k y sc ore < 5 0 %  
4. 1. 1 1.  S u bjects t hat wei g h Less t ha n 3. 5 k g 
4. 1. 1 2.  37BI n vesti gati o nal Dr u gs: S u bjects w h o  are c urre ntl y recei vi n g a n ot her  
i n vesti gati o nal dr u g are e xcl u de d fr o m partici pati o n. 
4. 1. 1 3.  38BA nti -ca ncer A ge nts: S u bjects w h o are c urre ntl y recei vi n g ot her a ntica ncer  
a ge nts are n ot eli gi ble.  S u bjects m ust ha ve f ull y rec o vere d fr o m t he 
effects of pri or c he m ot hera p y ( he mat ol o gical a n d b o ne marr o w 
s u p pressi o n effects), ge nerall y at least 3 wee ks fr o m t he m ost rece nt 
a d mi nistrati o n ( 6 wee ks f or nitr os o ureas).  
4. 1. 1 4.  39BI nfecti o n: S u bjects w h o ha ve a n u nc o ntr olle d i nfecti o n are n ot eli gi ble  
u ntil t he i nfecti o n is j u d ge d t o be well c o ntr olle d i n t he o pi ni o n of t he 
i n vesti gat or. 
4. 1. 1 5.  40BS u bjects w h o , i n t he o pi ni o n of t he i n vesti gat or, ma y n ot be a ble t o 
c o m pl y wit h t he safet y m o nit ori n g re q uire me nts of t he st u d y, or i n w h o m 
c o m plia nce is li kel y t o be s u b o pti mal, s h o ul d b e e xcl u de d . 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 1 5  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
4. 2.  Stratificati o n  
Str at u m I – First  rela pse d a n d refract or y ne ur o blast o ma 
Str at u m II - M ulti pl y rela pse d ne ur o blast o ma 
Str at u m III - Rela psed /refract or y me d ull o blast o ma 
 
4. 3.  S u bject Re gistrati o n  
4. 3. 1.  
43BAll sites will c o m plete a “ S u bject Re gistrati o n F or m.” T h is f or m will t he n 
be sca n ne d or fa xe d t o t he Researc h  C o or di nat or at t he Ne ur o blast o ma a n d 
Me d ull o blast o ma Tra nslati o nal Researc h C o ns orti u m ( N M T R C) .   
4. 3. 2.  
4BEac h s u bject will be gi ve n a u ni q ue i de ntifier n u m ber.  T his u ni q ue 
i de ntifier will be ke pt o n a “ S u bject I de ntificati o n L o g” at eac h site. 
 
5. 0  T R E A T M E N T P L A N  
5. 1.  Nif urti m o x D osi n g - C ycles 1 - 6 
5. 1. 1.  Ne ur o blast o ma ( Strat u m 1 a n d II s u bjects) - Nif urti m o x will be 
a d mi nistere d at 3 0  m g/ k g/ da y i n t hree di vi de d d oses f or e ver y da y of t he 
st u d y.   
5. 1. 2.  Me d ull o blast o ma ( Strat u m III s u bjects) - Nif urti m o x will be a d mi nistere d 
at 2 0 m g/ k g/ da y i n t hree di vi de d d oses f or e ver y da y of t he st u d y.   
5. 1. 3.   
5. 1. 4.  Nif urti m o x d oses will be r o u n de d t o t he nearest w h ole ta blet ( eac h ta blet 
is pr o vi de d as 1 2 0 m g/ta blet) . T here will be n o d ose i nterr u pti o ns u nless 
t o xicit y s u per ve nes (see Secti o n 7 . 0). 
 
5. 1. 4. 1. F or s u bjects ≤ 1 0 k g or < 1 year of a ge Nif urti m o x c o ntact t he 
N M T R C f or d osi n g. 
    
5. 1. 4. 2. Nif urti m o x ma y be gi ve n b y G t u be or N G t u be.  
5. 1. 4. 3. Nif urti m o x s h o ul d be gi ve n wit h f o o d 
5. 1. 4. 4. Nif urti m o x ma y be cr us he d or c ut a n d gi ve n i n f o o d if s u bject is 
u na ble t o s wall o w  
5. 1. 4. 5. If s u bjects v o mits after gi vi n g Nif urti m o x d ose:  
  −If less t ha n or e q ual t o 3 0 mi n utes si nce d ose- re peat d ose   
  −If o ver 3 0 mi n utes si nce d ose- d o N O T re peat d ose 
 
5. 1. 5.  Nif urti m o x D osi n g C alc ulati o n E xa m ple ( ne ur o blast o ma d ose use d as 
e xa m ple) :   
 
Patie nt wei g ht ( k g) x 3 0 = _ _ _ _ _ _ ÷ 1 2 0 = _ _ _ _ _ _ # of pills per 
da y.  R o u n d n u m ber of pills per da y t o nearest w h ole ta blet t he n 
di vi de i nt o 3 e ve n ( w he n p ossi ble) or u ne ve n d oses.  
E xa m ple: S u bject wei g hs 2 7 k g.  2 7 k g x 3 0 m g/ k g/ da y = 
8 1 0 m g/ da y.  Di vi de 8 1 0 m g/ da y b y 1 2 0 m g/ta blet = 6. 7 5 ta blets per 
da y.  R o u n d u p t o 7 ta blets per da y, t he n di vi de i nt o 3 d oses.  
S u bject s h o ul d get 3 ta bs i n a m, 2 ta bs i n after n o o n, 2 ta bs at ni g ht 
t o e q ual 7 ta bs per da y.  
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 1 6  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
5. 1. 6.   Nif urti m o x D osi n g M o dificati o n f or S u bject Wei g ht C ha n ges :  
54BNif urti m o x d ose s h o ul d be a dj uste d at eac h refill f or wei g ht c ha n ges, 
or s o o ner at t he be gi n ni n g of eac h c ycle if a n oticea ble c ha n ge i n 
wei g ht occ urs.  
 
 
5. 2.  C o m bi nati o n T hera p y :  
5. 2. 1.  T he c o m bi nati o n of c ycl o p h os p ha mi de, a n d t o p oteca n, al o n g wit h t he 
nif urti m o x, will be use d i n eac h c ycle.  
  
5. 2. 2.  Nif urti m o x will be gi ve n orall y t hree ti mes per da y  per secti o n 5. 1. 
 
5. 2. 3.  Eac h c ycle of c o m bi nati o n c he m ot hera p y will be gi ve n o ver 5 c o nsec uti ve 
da ys as f oll o ws:  
 
5. 2. 3. 1. Pre h y drati o n wit h 5 0 0 ml/ m 2 D 5 W ½ N S  I V o ver 3 0- 6 0 mi n utes, 
al o n g wit h a ntie metic t hera p y as per treati n g p h ysicia n prefere nce;  
 
5. 2. 3. 2. C ycl o p h os p ha mi de, 2 5 0 m g/ m 2/ d ose pre pare d per i nstit uti o nal 
sta n dar ds i n n or mal sali ne, I V, i nf use d o ver 3 0 mi n utes; 
 
5. 2. 3. 3. T o p oteca n, 0. 7 5 m g/ m 2/ d ose, pre pare d per i nstit uti o nal sta n dar ds i n 
n or mal sali ne,  I V, i nf use d o ver 3 0 mi n utes; 
 
5. 2. 4.  T his 2 1 da y c ycle ( +/- 3 da ys)  of nif urti m o x, c ycl o p h os p ha mi de, a n d 
t o p oteca n will be re peate d f or a t otal of 6 ti mes. 
 
5. 2. 5.  S u bjects wit h o ut b o ne marr o w metastases m ust ha ve a de q uate b o ne 
marr o w f u ncti o n,  defi ne d as A N C > 5 0 0/ µ l bef ore starti n g a n y 
c he m ot hera p y. S u bjects wit h d oc u me nte d b o ne marr o w i n v ol ve me nt w h o 
ha ve ot her wise rec o vere d fr o m pri or c yt ot o xic t hera p y ar e eli gi ble t o 
c o nti n ue t hera p y.  If s u bjects ha ve bee n ne gati ve f or b o ne marr o w 
metastases, b ut d o n ot ha ve a de q uate b o ne marr o w f u ncti o n (as descri be d 
a b o ve), t he n t he b o ne marr o w ma y be rec hec ke d. If t here is n o b o ne 
marr o w i n v ol ve me nt t he n wait t o see if A N C rec o vers; fil grasti m or 
pe gfil grasti m  ca n be use d t o sti m ulate marr o w. If t he y ha ve n ot rec o vere d 
wit hi n 2 wee ks s u bject will be ta ke n off pr ot oc ol t hera p y, b ut ma y re mai n 
o n nif urti m o x u n der t his I N D a n d be m o nit ore d per secti o n 9. 8 
 
 
5. 3.  S u bjects wit h  a pri or hist or y of seiz ures will be rec o m me n de d t o start o n a n a nti-
seiz ure me dicati o n pri or t o starti n g o n Nif urti m o x.  
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 1 7  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
5. 4.  At c o m pleti o n of c ycle 6 (last c ycle), s u bjects t hat are be nefiti n g fr o m t he st u d y 
dr u g ma y c o nti n ue t o recei ve nif urti m o x u n der t his I N D,  as si n gle a ge nt or i n 
c o m bi nati o n t hera p y at treati n g p h ysicia n’s discreti o n. If s u bjects e x perie nce 
pr o gressi o n or i nt olera nce at a n y p oi nt t hereafter t he y will be c o ns i dere d resista nt 
t o nif urti m o x a n d g o off st u d y.  Treati n g p h ysicia ns will c o nti n ue t o re p ort 
t o xicities as descri be d bel o w a n d will re p ort res p o nse t o treat me nt as s u bjects are 
e val uate d. 
 
 
5. 5.  If s u bjects are t olerati n g nif urti m o x, b ut are u na ble t o c o nti n ue o n st u d y f or 
reas o ns ot her t ha n pr o gressi o n or d ose li miti n g t o xicities (e. g. platelet or A N C 
c o u nts n ot rec o vere d wit hi n 2 wee ks of ne xt c ycle start), s u bjects ma y re mai n o n 
nif urti m o x u n der t he c urre nt I N D a n d c o nti n ue t o be m o nit ore d f or dr u g safet y 
a nd ma xi mal res p o nse t o nif urti m o x.  
 
 
6. 0  S T A TI S TI C A L C O N SI D E R A TI O N S:  
 
 
6. 1.  Sa m ple  Size Disc ussi o n  
T he sa m ple size disc ussi o n f oc uses o n t he pri mar y efficac y o utc o me 
meas ure d b y t he pr o p orti o n of s u bjects w h o, d uri n g t he 6 c ycles of 
treat me nt, ac hie ve a best t u m or res p o nse of eit her c o m plete res p o nse ( C R) 
or partial res p o nse ( P R) as defi ne d bel o w.  A n a bs ol ute differe nce i n 
res p o nse rates c o m pare d t o c he m ot hera p y al o ne of ~ 1 5 % t o 2 0 % w o ul d be 
c o nsi dere d cli nicall y si g nifica nt. Eac h strat u m of t his trial will c o m pare a 
n ull h y p ot hesis pr o p orti o n wit h a n alter nati ve h y p ot hesis pr o p orti o n a n d 
will use a directi o nal 5 % T y pe I err or le vel.  Eac h strata  will use a n 8 0 % 
p o wer le vel. Strat u m I c o nsists of ne ur o blast o ma s u bjects i n first rela pse, 
a n d t he n ull res p o nse rate ( C R + P R) is ta ke n t o be 3 0 % w hile t he 
alter nati ve res p o nse rate ( C R + P R) is ta ke n t o be 5 0 % as defi ne d 
a b o ve.  Strat u m  II c o nsists of m ulti pl y rela pse d or refract or y 
ne ur o blast o ma s u bjects a n d t he n ull res p o nse rate is ta ke n t o be 2 0% w hile 
t he alter nati ve res p o nse rate is ta ke n t o be 4 0 %.   Strat u m III c o nsists of 
m ulti pl y rela pse d or refract or y me d ull o blast o ma s u bjects, f or w h o m t he 
n ull h y p ot hesis res p o nse rates are als o 5 % a n d s o t he alter nati ve res p o nse 
rate is 2 0%.   Pre vi o us sa m ple size j ustificati o ns f oc use d u p o n a si n gle 
sa m ple size deter mi nati o n f or all t hree strata.  Strat u m I a n d II will be 
m o difie d t o i m ple me nt a t w o -sta ge mi ni ma x desi g n t o acc o m m o date a n 
i nteri m l o o k a n d st o p pi n g f or f utilit y d ue t o t he larger sa m ple size nee d 
w hile Strat u m III will retai n t he ori gi nal si n gle sta ge desi g n gi ve n t hat t he 
c urre nt sa m ple size accr ual is alrea d y at 2 0 s u bjects per strat u m.  
  
 
Strat u m I  
 
A sa m ple size of n = 3 9 s u bjects will be re q uire d t o test t he 30 % vs. 5 0 % 
res p o nse rate h y p ot heses f or t he Strat u m I s u bject gr o u p usi n g a t w o-sta ge 
mi ni ma x desi g n wit h a n i nteri m l o o k w he n t he first 1 9 e val ua ble s u bjects 
are accr ue d a n d t he fi nal l o o k w he n 3 9 e val ua ble s u bjects are accr ue d. T he 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 1 8  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
t w o-sta ge decisi o n r ule f or t his desi g n bec o mes: 
 
Sta ge 1:  Acce pt t he n ull h y p ot hesis if t he res p o nse rate is less t ha n  
or e q ual t o 6/ 1 9 f or t he 1st 1 9 s u bjects.  Ot her wise c o nti n ue t o 
sta ge 2. 
T he pr o ba bilit y of st o p pi n g f or f utilit y at Sta ge 1 is 0. 6 7 
w he n  t he n ull h y p ot hesis is tr ue a n d 0. 1 0 5 w he n t he 
alter nati ve is tr ue. 
  
Sta ge 2:  Acce pt t he n ull h y p ot hesis if t he res p o nse rate is less t ha n 
or e q ual t o 1 6 / 3 9.  Ot her wise  reject t he n ull h y p ot hesis. 
T he size of t he T y pe I err or rate is 4. 5 % w hile t he act ual p o wer 
is 8 0. 4 %.   
 
 
Strat u m I I 
 
A sa m ple size of n = 3 3 s u bjects will be re q uire d t o test t he 2 0 % vs. 4 0 % 
res p o nse rate h y p ot heses f or t he Strat u m II s u bject gr o u p usi n g a t w o-
sta ge mi ni ma x desi g n wit h a n i nteri m l o o k w he n t he first 1 8 e val ua ble 
s u bjects are accr ue d a n d t he fi nal l o o k w he n 3 3 e val ua ble s u bjects are 
accr ue d. T he t w o -sta ge decisi o n r ule f or t his desi g n bec o mes: 
 
Sta ge 1:  Acce pt t he n ull h y p ot hesis if t he res p o nse rate is less t ha n  
or e q ual t o 4/ 1 8 f or t he 1st 1 8 s u bjects.  Ot her wise c o nti n ue t o  
sta ge 2. 
T he pr o ba bilit y of st o p pi n g f or f utilit y at Sta ge 1 is 0. 7 2 w he n t he 
n ull h y p ot hesis is tr ue  
 
Sta ge 2:  Acce pt t he n ull h y p ot hesis if t he res p o nse rate is less t ha n 
or e q ual t o 1 0/ 3 3.  Ot her wise  reject t he n ull h y p ot hesis. 
T he siz e of t he T y pe I err or rat e is 4. 6 % w hile t he act ual p o wer 
is 8 0. 1%.    
 
Strat u m III  
 
A sa m ple size of n = 2 1 will be re q uire d t o test t he 5 % vs. 2 0 % res p o nse 
rate h y p ot heses f or t he Strat u m III s u bject gr o u ps usi n g a si n gle sta ge 
desi g n.   
 
 
T otal patie nts  
 
Ass u mi n g t hat a p pr o xi mat el y 5 % of Strat u m I s u bjects will be n o n -
e val ua ble, t he act ual sa m ple size nee de d will be n = 4 1. Ass u mi n g t hat 
a p pr o xi matel y 1 0 % of Strat u m II s u bjects will be n o n -e val ua ble, t he n t he 
act ual sa m ple size nee de d will be n = 3 6.   Ass u mi n g t hat a p pr o xi matel y 
1 0 % of Strat u m III s u bjects will be n o n -e val ua ble, t he n a sa m ple size of n 
= 2 3 eac h will be re q uire d f or Strata III.  

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 1 9  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
 
 
6. 2.  Statistical A nal ysis A p pr oac hes  
Statistical a nal ysis of t he pri mar y o utc o me will be c o n d ucte d f or eac h of 
t he t hree s u bject strata se paratel y Strat u m I  a n d II data will utilize a t w o -
sta ge mi ni ma x a nal ysis as o utli ne d i n t he sa m ple size j ustificati o n.  
Strat u m  III data will be a nal yze d o nl y w he n t he f ull sa m ple size f or t hat 
strat u m has bee n ac hie ve d. T he n u m ber of s u bjects wit h c o m plete ( C R) 
a n d partial ( P R) res p o nses, sta ble disease ( S D), a n d pr o gressi ve disease 
( P D), will be s u m marize d relati ve t o t he t otal n u m ber of e val ua ble 
s u bjects.  A n e xact bi n o mial m o del will be use d t o test t he n ull a n d 
alter nati ve h y p ot heses as s pecifie d i n t he sa m ple size disc ussi o n a b o ve 
usi n g t he state d directi o nal 5 % si g nifica nce le vel.  I n a d diti o n, e xact 9 5 % 
c o nfi de nce i nter vals f or t he pri mar y efficac y o utc o me  usi n g t he bi n o mial 
m o del will be o btai ne d t o s u p ple me nt t he p- val ue calc ulati o ns a n d  t o assist 
i n t he i nter pretati o n of t he o bser ve d res ults at t he c o m pleti o n of t he f ull 6 
c ycles of treat me nt.  F urt her e xa mi nati o n of baseli ne a n d treat me nt -relate d 
meas ures ass ociate d wit h t he pri mar y efficac y o utc o me ( C R + P R) rate will 
utilize a l o gistic r e gressi o n m o del w here t he o utc o me of i nterest will be 
t he gr o u p of s u bjects ac hie vi n g a C R or P R vs. ot her s u bjects.   
 
Statistical a nal ysis of t he sec o n dar y o utc o me meas ures , s uc h as q ualit y of 
life data, will utilize a wit hi n -s u bjects a p pr oac h gi ve n t he re peate d 
meas ures str uct ure of t he data as c ollecte d o ver t he m ulti ple o bser vati o nal 
ti me p oi nts.  Ti me t o e ve nt a nal ysis usi n g Ka pla n- Meier pl ots a n d C o x 
re gressi o n m o dels will be use d t o e xa mi ne t he l o n ger ter m occ urre nce of 
cli nical o utc o mes  (s uc h as s ur vi val) a n d t he i nfl ue nce of p ote ntial 
c o variates.  T he p ote ntial f or missi n g data i n a n y l o n git u di nal st u d y is 
rec o g nize d.  T h us, a se nsiti vit y a nal ysis of t he i m pact of missi n g data will 
be c o n d ucte d usi n g a m ulti ple i m p utati o n a p pr oac h if data ca n be ass u me d 
t o be missi n g at ra n d o m or c o m pletel y at ra n d o m.   T hese res ults will be 
c o m pare d t o m o deli n g res ults base d u p o n li near mi xe d m o del res ults 
wit h o ut use of i m p utati o ns. 
 
7. 0  D O S E A D J U S T M E N T S   
7. 1.  Nif urti m o x D ose M o dificati o ns   
7. 1. 1.  A n y Gra de 5 t o xicit y attri b uta ble t o Nif urti m o x  t hat occ urs wit hi n 3 0 da ys 
of ta ki n g st u d y dr u g, will re q uire a D S M B meeti n g t o be hel d wit hi n 7 
da ys of re p orti n g t he t o xicit y.  U ntil t he ti me t hat t he D S M B meets, n o 
ne w s u bjects ma y be e nr olle d o n st u d y.  T he c o m mittee will e val uate t he 
relati o ns hi p of t he nif urti m o x t o t he t o xicit y. 
7. 1. 2.  A n y s u bjects w h o de m o nstrate Gra de 3 or 4 C N S/ P N S t o xicit y attri b uta ble 
t o Nif urti m o x will ha ve nif urti m o x hel d.  If s y m pt o ms res ol ve wit hi n 1 4 
da ys, s u bjects ma y res u me nif urti m o x at a re d uce d dose of 2 0 m g/ k g/ da y 
( 1 5 m g/ k g/ da y f or me d ull o blast o ma). F or s u bjects t hat restart at t he 
re d uce d d ose: if t he y de m o nstrate a sec o n d Gra de 3 or 4 C N S/ P N S 
t o xicit y attri b uta ble t o Nif urti m o x at t his p oi nt t he y will ha ve nif urti m o x 
hel d a gai n. A gai n, if s y m pt o ms res ol ve wit hi n 1 4 da ys, s u bjects ma y 
res u me nif urti m o x at a re d uce d d ose of 1 5 m g/ k g/ da y ( 1 0 m g/ k g/ da y f or 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 2 0  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
me d ull o blast o ma). If t he s y m pt o ms d o n ot i m pr o ve t o a Gra de 2 or less 
wit hi n 1 4 da ys t he y will be re m o ve d fr o m st u d y. F or s u bjects t hat resta rt 
at t he 1 5 m g/ k g/ da y ( 1 0 m g/ k g/ da y f or me d ull o blast o ma) re d uce d d ose: if 
t he y de m o nstrate a t hir d Gra de 3 or 4 C N S/ P N S t o xicit y attri b uta ble t o 
Nif urti m o x a gai n at t his p oi nt t he y will be re m o ve d fr o m st u d y. 
7. 1. 3.  A n y s u bject w h o de m o nstrates Gra de 2 C N S/ P N S t o x icit y attri b uta ble t o 
Nif urti m o x ma y ha ve nif urti m o x hel d, at t he discreti o n of t heir treati n g 
p h ysicia n or t he PI, d uri n g a n e val uati o n of t he s y m pt o ms f or a peri o d u p 
t o 7 da ys ma xi m u m.  
7. 1. 4.  S u bjects w h o de vel o p a n y ot her Gra de 4 t o xicit y attri b uta ble t o nif urti m o x 
( ot her t ha n he mat ol o gical t o xicit y or fe brile ne utr o pe nia) will ha ve t he 
dr u g hel d a n d will be f oll o we d u ntil res ol uti o n of t o xicit y t o ≤ Gra de 2.  If 
s y m pt o ms r es ol ve t o ≤ Gra de 2 wit hi n 7 da ys, s u bjects ma y res u me 
nif urti m o x at a re d uce d d ose of 2 0 m g/ k g/ da y ( 1 5 m g/ k g/ da y f or 
me d ull o blast o ma).  If s y m pt o ms d o n ot res ol ve t o ≤ Gra de 2 wit hi n 7 
da ys, s u bjects will be re m o ve d fr o m st u d y a n d m o nit ore d u ntil t o xicit y is 
≤ Gra de 2.  If s u bject e x perie nces a sec o n d Gra de 4 t o xicit y attri b uta ble t o 
nif urti m o x t he y will ha ve t he dr u g hel d a n d will be f oll o we d u ntil 
res ol uti o n of t o xicit y t o ≤ Gra de 2.  If s y m pt o ms res ol ve t o ≤ Gra de 2 
wit hi n 7 da ys, s u bjects ma y res u me nif urti m o x at a re d uce d d ose of 
1 5 m g/ k g/ da y ( 1 0 m g/ k g/ da y f or me d ull o blast o ma).  If s y m pt o ms d o n ot 
res ol ve t o ≤ Gra de 2 wit hi n 7 da ys, s u bjects will be re m o ve d fr o m st u d y 
a n d m o nit ore d u ntil t o xicit y is ≤ Gra de 2. If s u bject e x perie nces a t hir d 
Gra de 4 t o xicit y attri b uta ble t o nif urti m o x  ( ot her t ha n he mat ol o gical 
t o xicit y or fe brile ne utr o pe nia) at t he re d uce d d ose le vel of 1 5 m g/ k g/ da y 
( 1 0 m g/ k g/ da y f or me d ull o blast o ma), t he y will be off st u d y.  T here will be 
n o d ose re- escalati o ns all o we d.  
7. 2.  T o p oteca n/ C ycl o p h os p ha mi de D ose M o dificati o ns: 
7. 2. 1.  S u bjects w h o de vel o p a n y Gra de 4 t o xicit y t hat is attri b uta ble t o 
c ycl o p h os p ha mi de or t o p oteca n ot her t ha n t he c o m m o nl y a ntici pate d 
he mat ol o gic or i nfecti o us t o xicities will be re m o ve d fr o m st u d y b ut ma y 
c o nti n ue o n nif urti m o x u n der t he c urre nt I N D as l o n g as n o t u m or 
pr o gressi o n is d oc u me nte d.   T hese s u bjects will c o nti n ue t o be e val ua ble 
f or t o xicit y. 
7. 2. 2.  S u bjects e x perie nci n g pr ol o n ge d ( greater t ha n 7 da ys) Gra de  4 
he mat ol o gic t o xicities attri b uta ble t o c ycl o p h os p ha mi de or t o p oteca n ma y 
ha ve t heir c ycl o p h os p ha mi de a n d t o p oteca n d ose re d uce fr o m recei vi n g 
dr u g o n Da ys 1 t hr o u g h 5 of eac h c ycle t o o nl y recei vi n g dr u g o n da ys 1 
t hr o u g h 3 of eac h c ycle. 
7. 2. 3.  Pri or t o starti n g eac h c ycle, t he A N C s h o ul d be > 5 0 0/ µ l (e xce pt i n 
s u bjects wit h d oc u me nte d b o ne marr o w i n v ol ve me nt); see Sec. 5. 2. 5, 8. 3,  
8. 4 a n d 8. 5 f or g ui deli nes if c o u nts are i na de q uate. 
7. 2. 4.  S u bjects e x perie nci n g he mat uria i n e xcess of s p ora dic as y m pt o matic 
micr osc o pic he mat uria ma y ha ve M E S N A a d de d t o t heir 
c he m ot hera p y/ h y drati o n fl ui ds (s u g geste d t otal M E S N A d ose is 6 0 % of 
c ycl o p h os p ha mi de d ose).  S u bjects wit h gr oss he mat uria, cl ots, or d ys uria 
des pite h y drati o n/ M E S N A will ha ve t o p oteca n/c ycl o p h os p ha mi de 
disc o nti n ue d.  
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 2 1  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
 
8. 0  S U P P O R TI V E C A R E A N D C O N C O MI T A N T T H E R A P Y  
 
8. 1.  C o nc urre nt a ntica ncer t hera p y ot her t ha n c ycl o p h os p ha mi de or t o p oteca n ma y 
n ot be a d mi nistere d t o s u bjects o n st u d y E X C E P T f or ra diati o n t o relie ve 
metastatic b o ne pai n as l o n g as t here are ot her meas ura ble areas of disease t o 
f oll o w f or sec o n dar y e n d p oi nt.  
8. 1. 1.  Ra diati o n t hera p y ma y be gi ve n t o sites of pai nf ul b o ne metastases. Pri or 
t otal b o d y irra diati o n t o d oses < 2 0 G y will be per missi ble, h o we ver a n y 
pri or f ocal ra diati o n t hera p y t o t he s y m pt o matic site will e xcl u de t he 
s u bject fr o m t his sta n dar dize d ra diati o n t hera p y pla n. S u bjects will be 
treate d wit h t hree fracti o ns of 3 G y eac h. T he ra diati o n d ose ma y be 
prescri be d t o a p oi nt or v ol u me at t he discreti o n of t he treati n g ra diati o n 
o nc ol o gist. M ulti ple sites ma y be i ncl u de d a n d treate d per t he trial. 
8. 1. 2.  Re -treatme nt ra diati o n t hera p y tec h ni q ues a n d d ose sc he d ules will be d o ne 
at t he discreti o n of t he treati n g ra diati o n  o nc ol o gist.  
 
8. 2.  Pr o p of ol: I n a past st u d y wit h nif urti m o x, a p ossi ble i nteracti o n bet wee n pr o p of ol 
a n d nif urti m o x was  o bser ve d i n t w o s u bjects.  T here is ver y li mite d i nf or mati o n 
b ut a te m p oral relati o ns hi p was n ote d wit h ti mi n g of me dicati o ns a n d a d verse 
e ve nt occ urre nce  ( ne ur ot o xicit y), t he i nf or mati o n is n ot c o ncl usi ve at t his ti me. 
D ue t o t his p ossi ble i nteracti o n, t he f oll o wi n g g ui deli nes f or pr o p of ol use w hile 
ta ki n g nif urti m o x s h o ul d be f oll o we d: 
H ol d nif urti m o x f or 2 4 h o urs pri or t o pr ol o n ge d a nest hesia wit h pr o p of ol 
of > 1 h o ur.  If Nif urti m o x ca n n ot be hel d pri or t o a pr oce d ure (f or 
e xa m ple e mer ge nc y sit uati o ns), a n d alter nati ve a ge nt s h o ul d be 
c o nsi dere d.  S h ort d urati o n pr o p of ol use ( < 1 h o ur) has n ot elicite d a n y 
u nt o war d res p o nses i n past st u d y s u bjects , a n d t heref ore d oes n ot re q uire 
a n y c ha n ge i n nif urti m o x use pri or t o pr oce d ure.   
 
8. 3.  M etr o ni daz ole : D uri n g t he c o urse of t his st u d y; a p ossi ble i nteracti o n bet wee n 
metr o ni daz ole a n d nif urti m o x has bee n  o bser ve d i n t w o s u bjects.  T here is ver y 
li mite d i nf or mati o n b ut a te m p oral relati o ns hi p was n ote d wit h ti mi n g of 
me dicati o ns a n d a d verse e ve nt occ urre nce ( se vere ne ur ot o xicit y). D ue t o t his 
p ossi ble i nteracti o n, t he f oll o wi n g g ui deli nes f or metr o ni daz ole use w hile ta ki n g 
nif urti m o x s h o ul d be f oll o we d: 
M etr o ni daz ole  s h o ul d n ot be use d w hile ta ki n g Nif urti m o x.  If a n ot her 
alter nati ve a ge nt ca n n ot be use d t he n h ol d nif urti m o x d uri n g 
metr o ni daz ole use.  Nif urti m o x ma y be restarte d 4 8 h o urs after c o m pleti o n 
of last d ose of metr o ni daz ole. 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 2 2  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
8. 4.  S u p p orti ve c are:  A p pr o priate a nti bi otics, bl o o d pr o d ucts, a ntie metics, 
i ntra ve n o us fl ui ds, a n d ge neral s u p p orti ve care are t o be use d as dee me d 
cli nicall y necessar y b y treati n g p h ysicia n.  
8. 5.  F or Me d ull o bl ast o m a S u bjects - If, at start of c he m ot hera p y, platelet c o u nt is ≤ 
5 0, 0 0 0/ µ l, platelet tra nsf usi o n rec o m me n de d t o re d uce t he ris k of C N S blee di n g. 
8. 6.  If t he start of t he ne xt c ycle of c he m ot hera p y is dela ye d b y > 1  wee k after  t he 
a ntici pate d start date , t he n fil grasti m or pe gfil grasti m  s h o ul d be gi n 2 4- 4 8 h o urs 
after t he c o m pleti o n of da y 5 c he m ot hera p y a n d c o nti n ue u ntil ne utr o p hil 
rec o ver y (a d mi nistere d  per treati n g i nstit uti o n’s g ui deli nes) .  
8. 7.  S u bject s w h o ha ve a seiz ure t hat is li kel y t o be sec o n dar y t o nif urti m o x t o xicit y 
will be starte d o n t he a nti -seiz ure me dicati o n o xcar baze pi ne .  If t his me dicati o n 
is n ot t olerate d a n ot her a nti-seiz ure me dicati o n ma y be prescri be d i n c o ns ultati o n 
wit h ne ur ol o g y. 
8. 8.  S u bjects w h o de vel o p a Gra de 2 or hi g her na usea or a n a versi o n t o s wall o wi n g 
t he nif urti m o x ta blets ma y s plit t he ta blets i n 2 a n d place t he m i n a Size 0 
Gelca p, i n or der t o ma ke t he m easier t o t olerate.  
8. 9.  F or pai n sec o n dar y t o t u m or s welli n g, de xa met has o ne at a d ose of 5 m g/ m 2 BI D 
ma y be a d de d t o re gi me n. 
 
 
9. 0  R E Q UI R E D O B S E R V A TI O N S  
 
9. 1.  Pri or  t o st u d y e ntr y ( wit hi n 7 da ys of start of t hera p y): 
− P h ysical e xa m i ncl u di n g ne ur ol o gical e xa m a n d Cli nical T otal 
Ne ur o pat h y Scale ( T N Sc)  
− Uri ne catec h ola mi nes  (f or ne ur o blast o ma o nl y) 
− Uri ne pre g na nc y test f or fe male s u bject s of c hil d beari n g p ote ntial 
( o nset of me nses or ≥1 3 years of a ge)  
− C B C wit h differe ntial  
− E lectr ol ytes, B U N, C reati ni ne,  
− L D H, A S T, A L T, B ilir u bi n, Ferriti n  
− Ne ur ol o gic str uct ure d i nter vie w (see a p pe n di x I) a n d baseli ne 
meas ures o n t he B RI E F a n d P C S Q o L: D T q uesti o n naire as well as t he 
P C S Q o L: M T D q uesti o n naire (as o utli ne d i n secti o n 1 1. 0). 
 
9. 2.  Pri or  t o st u d y e ntr y ( wit hi n 3 0 da ys of start of t hera p y)-  m ust  be d o ne after last 
pre vi o us c he m o d ose:  
− C T or M RI of meas ura ble disease sites  
− MI B G sca n ( n ot re q uire d if s u bject’s disease is pre vi o usl y deter mi ne d 
t o be n ot MI B G a vi d or f or s u bjects wit h me d ull o blast o ma) 
− B o ne marr o w as pirate a n d bi o ps y (re q uire d f or ne ur o blast o ma 
s u bjects, o pti o nal f or me d ull o blast o ma. ( S h o ul d be str o n gl y 
c o nsi dere d f or me d ull o blast o ma s u bjects t hat ha ve l o w platelet a n d 
A N C c o u nts, a n d sl o w rec o veries of c o u nts). E xtra b o ne marr o w 
sa m ples t o be se nt (if s u bject a grees t o bi ol o g y p orti o n of st u d y) per 
secti o n 1 8. 2.  
− C S F cell c o u nt a n d c yt ol o g y ( me d ull o blast o ma s u bjects o nl y) 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 2 3  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
9. 3.  Da y s 1 a n d 4 of C ycle 1:  P har mac o ki netic st u dies are t o be dra w n pri or t o t he 
s u bject ta ki n g t heir 1st d ose of Nif urti m o x d ose a n d a gai n 3 h o urs f oll o wi n g t he 
o bser ve d m or ni n g d ose. See secti o n 1 0. 0 f or s pecific P K c ollecti o n a n d ha n dli n g 
i nf or mati o n. 
 
9. 4.  Eac h wee k ( +/ - 3 da y wi n d o w) f or first 2 1 da ys:   
− P h ysical e xa m i ncl u di n g ne ur ol o gical e xa m  
− C B C wit h diffe re ntial  
− Electr ol ytes, B U N, creati ni ne  
− L D H, A S T, A L T, bilir u bi n  
 
9. 5.  Pri or t o e ver y 2 1 da y treat me nt c ycle ( +/- 3 da y wi n d o w  f or c ycle start) wit hi n 7 
da ys of start of ne xt c ycle:  
− P h ysical E xa m i ncl u di n g ne ur ol o gical e xa m 
− C B C wit h differe ntial  
− Electr ol ytes, B U N, creati ni ne  
− L D H, A S T, A L T, bilir u bi n  
− Uri ne catec h ola mi nes (f or ne ur o blast o ma s u bject s).   
 
Treati n g p h ysicia n ma y o btai n a d diti o nal st u dies at t heir discreti o n.  
 
9. 6.  A d diti o nal st u dies  at t he e n d of C ycles 2 a n d 4 :  
− M RI/ C T re -e val uati o n of disease sites  
− MI B G sca n (f or MI B G a vi d ne ur o blast o ma s u bjects o nl y) 
− B o ne marr o w bi o ps y a n d as pirate (if p ositi ve at st u d y e ntr y) 
− C S F f or cell c o u nt a n d c yt ol o g y ( me d ull o blast o ma o nl y a n d if p ositi ve 
at st u d y e ntr y)  
− Ne ur ol o gical str uct ure d i nter vie w (see A p pe n di x 1) , Cli nical T otal 
Ne ur o pat h y Scale ( T N Sc), a n d meas ures o n t he B RI E F a n d 
P C S Q o L: D T q uesti o n naire (as o utli ne d i n secti o n 1 1. 0 of pr ot oc ol). 
− A d diti o nal i ma gi n g or st u dies ma y be d o ne if cli nicall y i n dicate d b y 
s y m pt o ms, e xa m, or t u m or mar kers 
 
9. 7.  At t he E n d of Pr ot oc ol T hera p y ( C ycle 6) or at Earl y Wit h dra wal:  
− P h ysical E xa m i ncl u di n g ne ur ol o gical e xa m a n d Cli nical T otal 
Ne ur o pat h y Scale ( T N Sc)  
− C B C wit h differe ntial  
− Electr ol ytes, B U N, creati ni ne  
− L D H, A S T, A L T, Bilir u bi n  
− Uri ne catec h ola mi nes (f or ne ur o blast o ma s u bjects) Ne ur ol o gical 
str uct ure d i nter vie w (see A p pe n di x 1) 
− Meas ures o n t he B RI E F a n d P C S Q o L : D T q uesti o n naire (as o utli ne d i n 
secti o n 1 1 . 0 of pr ot oc ol). 
− M RI/ C T re -e val uati o n of disease sites  
− MI B G sca n (f or MI B G a vi d ne ur o blast o ma s u bjects o nl y) 
− B o ne marr o w bi o ps y a n d as pirate (if p ositi ve at st u d y e ntr y) 
− C S F f or cell c o u nt a n d c yt ol o g y ( me d ull o blast o ma o nl y a n d if p ositi ve 
at st u d y e ntr y)  

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 2 4  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
− If t he s u bject wit h dra ws earl y, sca ns nee d n ot be re peate d if rece ntl y 
perf or me d u nless cli nicall y i n dicate d.  A d diti o nal i ma gi n g or st u dies 
ma y be d o ne if cli nicall y i n dicate d b y s y m pt o ms, e xa m, or t u m or 
mar kers. Treati n g p h ysicia n ma y o btai n a d diti o nal st u dies at t hei r 
discreti o n.  
 
9. 8.   F oll o w u p f or s u bjects re mai ni n g o n Nif urti m o x b ut off pr ot oc ol t hera p y 
( O P T F): 
  
9. 8. 1.  Wit hi n 7 da ys of start of eac h  c ycle ( +/- 3 da y wi n d o w f or c ycle start): 
− P h ysical E xa m i ncl u di n g ne ur ol o gical e xa m 
− C B C wit h differe ntial  
− Electr ol ytes, B U N, creati ni ne  
− L D H, A S T, A L T, bilir u bi n  
− Uri ne catec h ola mi nes (f or ne ur o blast o ma s u bjects).   
− Treati n g p h ysicia n ma y o btai n a d diti o nal st u dies at t heir discreti o n.  
 
 
9. 8. 2.  Mi ni m u m of e ver y t hree c ycles ( or s o o ner if i n dicate d) : 
− M RI/ C T re -e val uati o n of disease sites  
− MI B G sca n (f or MI B G a vi d ne ur o blast o ma s u bjects o nl y) 
− B o ne marr o w bi o ps y a n d as pirate (if p ositi ve at st u d y e ntr y) 
− C S F f or cell c o u nt a n d c yt ol o g y ( me d ull o blast o ma o nl y a n d if p ositi ve 
at st u d y e ntr y)  
− Treati n g p h ysicia n ma y o btai n a d diti o nal st u dies at t h eir discreti o n.  
 
 
9. 9.  
L o n g ter m f oll o w u p  f or s u bjects t hat are off st u d y ( ha ve st o p pe d ta ki n g 
nif urti m o x) :  
 
9. 9. 1.  S u bject s will be f oll o we d at 3 0 da ys ( + 7 da ys) past last d ose of st u d y dr u g 
as f oll o ws: 
− P h ysical  e xa m i ncl u di n g ne ur ol o gical e xa m 
− C B C wit h differe ntial  
− E lectr ol ytes, B U N, creati ni ne 
− L D H, A S T, A L T, bilir u bi n  
− Uri ne catec h ola mi nes (f or ne ur o blast o ma s u bjects)  
− Ne ur ol o gic str uct ure d i nter vie w (see a p pe n di x I)  
 
9. 9. 2.  S u bjects will be f oll o we d f or l o n g ter m s urvi val b y c o ntact wit h pare nt or 
treati n g i nstit uti o n t o c o nfir m s ur vi val at t he f oll o wi n g ti me p oi nts (ti me 
fr o m last d ose of st u d y dr u g): 
− 2 m o nt hs  
− 3 m o nt hs  
− 5 m o nt hs  
− 7 m o nt hs  
− 9 m o nt hs  
− 1 year 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 2 5  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
 
 
9. 1 0.  
Sca n S u b missi o n: All re q uire d st u d y sca ns ( C T’s, M RI’s, a n d MI B G’s) 
will be re vie we d b y ce ntral ra di ol o g y at t he U ni versit y of Ver m o nt a n d 
Fletc her Alle n Hea lt h Care acc or di n g t o secti o n 1 3. 0.  All st u d y re q uire d 
sca ns s h o ul d be se nt o n disc t o: 
 
Al yssa Va n der Werff  
Cli nical Pr o gra m C o or di nat or  
N M T R C  
1 0 0 Mic hi ga n A ve n ue N E   M C 2 7 2          
Gra n d Ra pi ds, MI 4 9 5 0 3  
T el:  ( 6 1 6) 2 6 7 -0 3 2 7   
Fa x: ( 6 1 6) 3 9 1 -2 7 8 5  
E- Mail:  Al yssa. Va n der Werff @  hele n de v osc hil dre ns. or g   
 
 
1 0. 0  P H A R M A C O KI N E TI C S T U DI E S  
1 0. 1.  
O n Da ys 1 a n d 4 of c ycle 1 P K s peci me ns will be c ollecte d.  
1 0. 1. 1.  T he s u bject will h ol d ( n ot ta ke) t heir 1st d ose of nif urti m o x o n da ys o ne 
a n d f o ur u ntil arri vi n g t o t he cli nic a n d pre- d ose bl o o d s peci me n is 
c ollecte d. 
1 0. 1. 2.  Pre -d osi n g P K sa m ple will be c ollecte d a n d pr ocesse d as per Secti o n 1 0. 3 
a n d 1 0. 4 
1 0. 1. 3.  O nce t he pre- n if urti m o x s peci me n is c ollecte d t he s u bject will ta ke t heir 
prescri be d m or ni n g d ose of n if urti m o x.  If gel ca ps ules are bei n g use d, t he 
nif urti m o x s h o ul d N O T be place d i n t he Gel Ca ps ules f or t his d ose. 
1 0. 1. 4.  T hree h o urs f oll o wi n g ( +/- 1 5 mi n utes) t he s u bject’s m or ni n g d ose of 
nif urti m o x, t he ne xt P K sa m ple will be c ollecte d.  
1 0. 1. 5.  T he date a n d ti me of all s peci me n c ollecti o ns a n d of t he d ose of 
nif urti m o x will be n ote d i n t he s u bject’s c hart. 
 
 
1 0. 2.  
P K S a m ple re q uire me nts:  
O ne 2 cc w h ole bl o o d s peci me n will be c ollecte d i n a ser u m se parat or  t u be 
( S S T). 
 
1 0. 3.  
S peci me n H a n dli n g:  
1 0. 3. 1.  S peci me n will be c ollecte d wit h al u mi n u m f oil wra p pe d ar o u n d t he t u be i n 
or der t o pr otect t he sa m ple fr o m li g ht deteri orati o n.  
1 0. 3. 2.  F oll o wi n g c ollecti o n t he s peci me n  will t o be all o we d t o cl ot at r o o m 
te m perat ure for n o less t ha n t we nt y t o t hirt y mi n utes. 
1 0. 3. 3.  S peci me n will be  s p u n i n a ce ntrif u ge at 1, 0 0 0- 1, 3 0 0 g f or 1 0- 1 5 mi n utes 
1 0. 3. 4.  F oll o wi n g ce ntrif u gati o n t he ser u m fr o m t he S S T will  be ali q u ote d i nt o a 
plastic scre w ca p pe d cr y o vial.  
1 0. 3. 5.  S peci me ns m ust be la bele d wit h t he s u bject’s i nitials, u ni q ue st u d y 
i de ntifier, a n d date a n d ti me of s peci me n c ollecti o n. 
1 0. 3. 6.  S peci me n will t he n be st ore d i n a - 7 0° C. freezer u ntil rea d y t o be s hi p pe d.  
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 2 6  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
1 0. 4.  
S peci me n s hi p pi n g : 
1 0. 4. 1.  All s peci me ns will be s hi p pe d o n dr y ice f oll o wi n g t he fe deral I A T A 
hazar d o us S peci me n S hi p pi n g G ui deli nes 
1 0. 4. 2.  S peci me ns s h o ul d be batc h s hi p pe d (after a p pr o xi matel y 5 s u bjects) o n a 
M o n da y- T h urs da y (la b d oes n ot acce pt Sat ur da y deli veries) .   
1 0. 4. 3.  S peci me ns will be s hi p pe d t o  t he f oll o wi n g a d dress :  
 
Pi n g Z h a o  
Pe diatric O nc ol o g y Tra nslati o nal Researc h La b orat or y  
C o o pers La n di n g 
1 3 4 5 M o nr oe A ve, S uite 1 2 1 
Gra n d Ra pi ds, MI 4 9 5 0 5 
Tel: 6 1 6- 4 8 6 - 8 6 4 5 
Pi n g.z ha o @ hele n de v osc hil dre ns. or g  
 
 
 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 2 7  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
1 1. 0  M O NI T O RI N G O F P O T E N TI A L A D V E R S E N E U R O L O GI C A L E F F E C T S   
Pre vi o usl y descri be d ne ur o p har mac ol o gical a n d t o xic ol o gical pr o perties of 
nif urti m o x ma n date cl ose m o nit ori n g f or p ote ntial a d verse ne ur ol o gic effects. 
Nif urti m o x is k n o w n t o cr oss t he bl o o d- brai n barrier, raisi n g t he p ossi bilit y of 
a d verse C N S effects a s well as peri p heral ne ur ot o xicit y. T he s y m pt o ms t o be 
m o nit ore d are g ui de d b ot h b y pri or re p orte d a d verse be ha vi oral/s u bjecti ve effects 
( w hic h mi g ht be ne ur ol o gicall y me diate d), as well as p ote ntial si de effects 
res ulti n g fr o m t he catec h ola mi ner gic ne ur oto xicit y of t he st u d y dr u g. P ote ntial 
catec h ola mi ner gic tar gets i ncl u de s y m pat hetic a dre ner gic ne ur o ns of t he a dre nal 
me d ulla, ne ur o ns of t he l oc us cer ule us i n t he me d ulla, a n d d o pa mi ner gic ne ur o ns 
of t he basal ga n glia. C ollecti vel y, t hese ne ur o ns m o d ulate a ut o n o mic 
(s y m pat hetic) car di o vasc ular f u ncti o n, m ot or c o ntr ol, atte nti o n, re war d s yste ms of 
t he brai n, a n d ne ur o-e n d ocri ne f u ncti o n (e. g., pr olacti n release).   
 
Alt h o u g h s o me dr u g i nf or mati o n s u m maries me nti o n peri p heral ne ur o pat h y as a 
p ossi ble si de eff ect of nif urti m o x, t hese refere nces a p pear t o reflect pl a usi ble 
ne ur o pat hic s y m pt o ms ( n u m b or wea k ha n ds, feet) rat her t ha n s pecific cli nical or 
la b orat or y e vi de nce of peri p heral ne ur o pat h y ( de presse d te n d o n jer ks, a b n or mal 
electr o p h ysi ol o gical fi n di n gs).  A re vie w of t he literat ure di d n ot re veal a n y pri or 
defi niti ve e vi de nce of nif urti m o x -i n d uce d ne ur o pat h y. H o we ver, t o xicit y ma y 
bec o me e vi de nt at t he hi g her dr u g d oses t o be st u die d i n t his pr ot oc ol; t heref ore, 
i nter val ne ur ol o gical e xa mi nati o ns a n d q uesti o ns re gar di n g t o xicit y will be 
directe d t o detecti n g nif urti m o x -relate d ne ur o pat h y. Beca use o ne p ote ntial site of 
C N S ne ur ot o xicit y is t he l oc us cer ule us — a brai nste m n ucle us ass ociate d wit h 
re g ulati o n of atte nti o n a n d ar o usal —e xec uti ve f u ncti o n will be assesse d (e. g., 
“ be ha vi or re g ulati o n” a n d “ metac o g niti o n” ) wit h t he Be h avi or R ati n g I n dex of 
Exec utive F u ncti o n ( B RI E F).  
T he Be h avi or R ati n g I nve nt ory of Exec utive F u ncti o n  ( B RI E F) is desi g ne d t o 
assess e xec uti ve f u ncti o ni n g i n c hil dre n a n d a d olesce nts a ges 5- 1 8. It c o nsists of 
t w o p ossi ble rati n g f or ms - a pare nt a n d a teac her q uesti o n naire - w hic h re q uire 
1 0- 1 5 mi n utes t o a d mi nister a n d 1 5- 2 0 mi n utes t o sc ore. We will o nl y be usi n g 
t he pare nt c o m plete d q uesti o n naire i n t his st u d y. T he B RI E F is s uite d f or b ot h 
h o me a n d sc h o ol setti n gs. T he B RI E F is usef ul i n e val uati n g c hil dre n wit h a wi de 
s pectr u m of de vel o p me ntal a n d ac q uire d ne ur ol o gical c o n diti o ns s uc h as lear ni n g 
disa bilities, Atte nti o n -Deficit/ H y peracti vit y  Dis or der ( A D H D), Tra u matic Brai n 
I nj ur y ( T BI), L o w Birt h Wei g ht, T o urette’s S y n dr o me, a n d Per vasi ve 
De vel o p me ntal Dis or ders/ A utis m.  
Eac h B RI E F q uesti o n naire c o ntai ns 8 6 ite ms i n 8 n o n o verla p p pi n g cli nical scales 
a n d 2 vali dit y scales. T hese t he oreticall y a n d statisticall y deri ve d scales f or m t w o 
br oa de r i n de xes: 
 
1) Be ha vi oral Re g ulati o n: I n hi bit, S hift, E m oti o nal C o ntr ol  
2) Metac o g niti o n: I nitiate, W or ki n g Me m or y, Pla n/ Or ga nize, Or ga nizati o n 
of Materials, M o nit or  
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 2 8  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
Assessi n g Q u ality of Life ( Q o L) 
T he q ua lit y of life ( Q o L) of c hil dre n/fa milies i n treat me nt is a n i m p orta nt 
c o nsi derati o n i n cli nical dr u g trials. F or t he c hil d, s ocial-e d ucati o nal be ha vi or ca n 
be affecte d b y c o g niti ve a bilities a n d ne ur ot o xicities a n d t he ot her si de- effects of 
treat me nt dr u gs. H o w Q o L is affecte d b y a s pecific st u d y dr u g is als o of i nterest 
gi ve n t hat Q o L is use d b y pare nts, p h ysicia ns a n d s u bject s as a meas ure of dr u g 
efficac y. T w o q uesti o n naires will be use d t o meas ure t he Q o L effects of t he st u d y 
dr u g(s) o n s u bjects a n d t hei r fa milies. 
 
T w o se parate q uesti o n naires will be use d t o e xa mi ne t w o as pects of Q o L: ( 1) 
H o w s u bjects’ Q o L is affecte d b y nif urti m o x (a n d wit h c o m bi nati o ns of 
a d diti o nal a ge nts/t hera pies), a n d ( 2), h o w t he pare nts of pe diatric ca ncer patie nts 
percei ve t he i m p orta nce of vari o us Q o L effects w hile ma ki n g treat me nt decisi o ns 
f or t heir c hil d. F or t he f or mer, t he Pe di atric C a ncer S urvey: P are nt Assess me nt of 
C hil dre n’s Q u ality of Life D uri n g Tre at me nt  ( P C S Q o L: D T). T he sec o n d as pect of 
Q o L will be assesse d wit h Pe di atric C a ncer S urvey: F or P are nts M aki n g 
Decisi o ns  ( P C S Q o L: M T D). 
 
T he pr o p ose d pla n a n d sc he d ule f or m o nit ori n g of a d verse ne ur ot o xic effects 
i ncl u des ( 1) serial ne ur ol o gic e xa mi nati o n, ( 2) iterati ve str uct ure d i nter vie ws ( See 
A p pe n di x 1 f or “ Str uct ure d I nter vie w f or A d verse Ne ur ol o gic E ve nts” f or m) a n d 
( 3) B RI E F assess me nts a n d t w o Q o L q uesti o n naires ( A p pe n di x 3). 
 
 
 
Ne ur ol o gic 
E xa m  
Str uct ure d 
I nter vie w 
B RI E F  
P C S Q o L: D T  
 
P C S Q o L: M T D  
Baseli ne  
√ 
√ 
√^  
√^  
√^  
E n d of Wee k 1  
√ 
 
 
 
 
E n d of Wee k 2  
√ 
 
 
 
 
E n d of e ver y C ycle  
√ 
 
 
 
 
E n d of C ycles 2 & 4  
 
√ 
√^  
√^  
 
E n d of Pr ot oc ol 
T hera p y/ Earl y 
Wit h dra wal  
√ 
√ 
√^  
√^  
 
3 m o nt h f oll o w u p  
 
 
 
 
 
6 m o nt h f oll o w u p  
 
 
 
 
 
9 m o nt h f oll o w u p  
 
 
 
 
 
1 Year f oll o w u p  
 
 
 
 
 
N ote . B RI E F: Be h avi or R ati n g I n dex of Exec utive F u ncti o n ( B RI E F); P C S Q o L: D T: P are nt Assess me nt of 
C hil dre n's Q u ality of Life D uri n g Tre at me nt ; P C S Q o L: M T D: F or P are nts M aki n g Tre at me nt Decisi o ns . 
^  T he B RI E F a n d Q O L q uesti o n naires will be c o m plete d b y t he pare nts  
 
 
T he ne ur ol o gic e xa m a n d Cli nical T otal Ne ur o p at h y  Scale ( T N Sc) will be perf or me d b y 
a pe diatric ne ur ol o gist or o nc ol o gist w h o is e x perie nce d at perf or mi n g ne ur ol o gical 
e xa ms o n c hil dre n i n t he a ntici pate d a ge gr o u p. S o me s pecific feat ures of t he e xa m t o be 
rec or de d i ncl u de dee p te n d o n refle xes, p u pil size, le n gt h- de pe n de nt se ns or y c ha n ges, a n d 
tre m or/ ot her a b n or mal s p o nta ne o us m o ve me nts.   
 
A n o utli ne of t he str uct ure d i nter vie w t o be c o n d ucte d is i ncl u de d i n A p pe n di x I of t his 
pr ot oc ol.  

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 2 9  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
 
1 2. 0  S U B J E C T WI T H D R A W A L A N D T RI A L DI S C O N TI N U A TI O N  
 
 
1 2. 1.  
Criteri a f or S u bject Off -T her a p y  
S u bjects will be re m o ve d fr o m t he st u d y t hera p y f or t he f oll o wi n g reas o ns:  
•  Pr o gressi ve ne o plastic disease  
•  S u bject or g uar dia n wit h dra ws c o nse nt t o c o nti n ue i n t he trial  
•  S u bject  de vel o ps  a n  i nterc urre nt  ill ness  t hat  precl u des  f urt her  p artici pati o n,  or  re q uires  a 
pr o hi bite d c o nc o mita nt treat me nt  
•  T he I n vesti gat or wit h dra ws t he s u bject i n t he s u bject’s best i nterests  
•  S u bject  is  l ost  t o  f oll o w -u p  ( defi ne d  as  t he  i na bilit y  t o  c o ntact  t he  s u bject  o n  3  se parate 
occasi o ns o ver a peri o d of 2 wee ks)  
•  A d mi nistrati ve reas o ns (e. g., t he s u bject is tra nsferre d t o h os pice care)  
•  A n  a d verse  e ve nt,  w hic h  i n  t he  o pi ni o n  of  t he  I n vesti gat or,  precl u des  f urt her  trial 
partici pati o n or f ulfills t he pr ot oc ol re q uire me nts f or wit h dra wal  
•  Deat h  
 
1 2. 2.  
Criteri a f or S u bject Off -St u d y  
S u bjects ma y be wit h dra w n fr o m t he st u d y c o m pletel y w hic h i ncl u des wit h dra wal fr o m s u r vi val 
f oll o w-u p f or t he f oll o wi n g reas o ns:  
•  C o m pleti o n of all st u d y re q uire me nts  
•  S u bject or g uar dia n wit h dra ws c o nse nt t o c o nti n ue i n t he trial (if t his occ urs, n o f urt her st u d y 
visits or data ma y be c ollecte d)  
•  S u bject  is  l ost  t o  f oll o w -u p  ( defi ne d  as  t he  i na bilit y  t o  c o ntact  t he  s u bject  o n  3  se parate 
occasi o ns o ver a peri o d of 2 wee ks)  
•  Deat h  
 
 
1 3. 0   154BE V A L U A TI O N/ R E S P O N S E  C RI T E RI A . 
1 3. 1.  Res p o nse Assess me nt:  Eac h s u bject will be classifie d acc or di n g t o t heir “ best 
res p o nse” f or t he p ur p oses of a nal ysis of treat me nt effect. Best res p o nse is 
deter mi ne d fr o m t he se q ue nce of t he o bjecti ve stat uses descri be d bel o w.  
1 3. 2.  Res p o nse Criteri a F or P atie nts wit h S oli d T u m ors - T his st u d y will use  t he 
( R E CI S T) Res p o nse E val uati o n Criteria i n S oli d T u m or fr o m t he N CI.    
1 3. 3.  Me as ur a ble dise ase:  The prese nce of at least o ne lesi o n t hat ca n be 
acc uratel y meas ure d i n at least o ne di me nsi o n wit h t he l o n gest dia meter at 
least 1 0 m m. 
1 3. 3. 1.  
Meas ura ble Disease Res p o nse will be assesse d at e n d of C ycle 2 
e n d of c ycle 4, a n d e n d of pr ot oc ol t hera p y.  
1 3. 3. 2.  
F or patie nts wit h Meas ura ble Disease: T his st u d y will use  t he 
( R E CI S T) Res p o nse E val uati o n Criteria i n S oli d T u m or fr o m t he 
N CI.  
1 3. 3. 3.  
Serial meas ure me nt s of lesi o ns are t o be d o ne wit h C T or M RI. 
T he sa me met h o d of assess me nt is t o be use d t o c haracterize eac h 
i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w- u p. 
1 3. 3. 4.  
Q ua ntificati o n  of Disease B ur de n T he s u m of t he l o n gest dia meter 
( L D) f or all tar get lesi o ns will be calc ulate d a n d re p orte d as t he 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 3 0  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
disease meas ure me nt.  F or t his e val uati o n, all sca ns will u n der g o 
ce ntral re vie w at t he U ni versit y of Ver m o nt. 
C o m plete Res p o nse  ( C R): Disa p peara nce of all tar get lesi o ns. 
P arti al Res p o nse  ( P R): At least a 3 0 % decrease i n t he disease 
meas ure me nt, ta ki n g as refere nce t he disease meas ure me nt 
d o ne t o c o nfir m meas ura ble disease at st u d y e ntr y . 
St a ble Dise ase  ( S D): Neit her s ufficie nt decrease t o q ualif y f or 
P R or s ufficie nt i ncrease t o q ualif y f or P D fr o m st u d y e ntr y. 
Pr o gressi ve Dise ase  ( P D):  At least a 2 0 % i ncrease i n t he s u m 
of t he l o n gest dia meters of all tar get lesi o ns c o m pare d t o  st u d y 
e ntr y, t he a p peara nce of u ne q ui v ocal ne w lesi o ns, or la b orat or y 
e vi de nce of cli nical pr o gressi o n ( e. g., s prea d t o b o ne marr o w 
or i ncreasi n g catec h ola mi nes).  
 
 
 
1 3. 4.  Res p o nse Criteri a f or P atie nts wit h B o ne M arr o w Dise ase :  
 
1 3. 4. 1.  T h ose patie nts wit h m or p h ol o gic e vi de nce of ne ur o blast o ma b y r o uti ne H 
a n d E stai ni n g ( N S E stai ni n g o nl y is n ot e val ua ble) will be e val ua ble t o 
assess b o ne marr o w res p o nse.  
 
C o m plete res p o nse:  N o t u m or cells detecta ble b y r o uti ne 
m or p h ol o g y o n t w o s u bse q ue nt bilateral b o ne marr o w as pirates 
a n d bi o psies d o ne at least t hree wee ks a part after st u d y e ntr y.  
Pr o gressi ve dise ase : T u m or see n o n m or p h ol o g y o n t w o 
c o nsec uti ve b o ne marr o ws d o ne at least t hree wee ks a part i n 
patie nts w h o ha d N O t u m or i n b o ne marr o w at st u d y e ntr y. ( N ote: 
Patie nt ma y be declare d as pr o gressi ve disease i n b o ne marr o w 
after o nl y o ne dia g n ostic b o ne marr o w at t he discreti o n of t he 
treati n g p h ysicia n after disc ussi o n wit h t he st u d y c hair.) 
St a ble dise ase : Persiste nce of  a n a m o u nt of t u m or i n t he b o ne 
marr o w b y m or p h ol o g y t hat d oes n ot meet criteria f or eit her 
c o m plete res p o nse or pr o gressi ve disease.  
 
 
1 3. 5.  Res p o nse Criteri a f or P atie nts wit h MI B G P ositi ve Lesi o ns  
 
1 3. 5. 1.  Patie nts w h o ha ve a p ositi ve MI B G sca n at t he sta rt of t hera p y will be 
e val ua ble f or  MI B G res p o nse.  T he use of 1 2 3I f or MI B G i ma gi n g is 
rec o m me n de d f or all sca ns. If t his ra di ois ot o pe is u na vaila ble at t he 
treati n g i nstit uti o n, t he use of t he sa me ra di ois ot o pe f or all MI B G sca ns 
f or a n i n di vi d ual patie nt is str o n gl y e nc o ura ge d. All MI B G’s will be 
perf or me d at t he researc h i nstit uti o n a n d ce ntrall y re vie we d at t he 
U ni versit y of Ver m o nt. 
 
T he f oll o wi n g criteria will be use d t o re p ort MI B G res p o nse b y t he 
researc h i nstit uti o n o n t he e n d of c o urse re p ort f or ms:  
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 3 1  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
C o m plete res p o nse  = c o m plete res ol uti o n of all MI B G p ositi ve 
lesi o ns 
 
P arti al res p o nse  = res ol uti o n of at least o ne MI B G p ositi ve lesi o n, 
wit h persiste nce of ot her MI B G p ositi ve lesi o ns. 
 
St a ble dise ase  = n o c ha n ge i n MI B G sca n i n n u m ber of p ositi ve 
lesi o ns (i ncl u des patie nts w h o ha ve sa me n u m ber of p ositi ve 
lesi o ns b ut decrease d i nte nsit y) 
 
Pr o gressi ve dise ase  = De vel o p me nt of ne w MI B G p ositi ve lesi o ns 
 
 
 
 
 
 
1 3. 6.  Ce ntr al Re vie w  
 
1 3. 6. 1.  T he res p o nse of MI B G lesi o ns will be assesse d o n ce ntral re vie w usi n g t he 
C urie scale as o utli ne d bel o w. Ce ntral re vie w res p o nses will be use d t o 
assess efficac y f or st u d y e n d p oi nt. N O T E: T his sc ori n g is N O T re q uire d t o 
be d o ne b y t he researc h i nstit uti o n f or e n d of c o urse res p o nse assess me nts. 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 3 2  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
1 3. 6. 2.  T he b o d y is di vi de d i nt o 9 a nat o mic sect ors f or oste o me d ullar y lesi o ns, 
wit h a 1 0t h ge neral sect or all ocate d f or a n y e xtra- osse o us lesi o ns. I n eac h 
re gi o n, t he lesi o ns are sc ore d as f oll o ws. T he a bs ol ute e xte nsi o n s c ore is 
gra de d as: 0 = n o site per se g me nt, 1 = 1 site per se g me nt, 2 = m ore t ha n 
o ne site per se g me nt, 3 = massi ve i n v ol ve me nt ( > 5 0 % of t he se g me nt). 
T he a bs ol ute sc ore is o btai ne d b y a d di n g t he sc ore of all t he se g me nts. See 
dia gra m of sect ors bel o w:  
 
1 3. 6. 3.  T he rel ati ve sc ore  is calc ulate d b y di vi di n g t he a bs ol ute sc ore at eac h 
ti me b y t he c orres p o n di n g pretreat me nt o verall sc ore. T he relati ve sc ore of 
eac h patie nt is calc ulate d at eac h res p o nse assess me nt a n d classifie d as 
bel o w : 
C o m plete res p o nse: all areas of u pta ke o n MI B G sca n c o m pletel y 
res ol ve d. 
P arti al res p o nse : Relati ve sc ore < 0. 2 (lesi o ns al m ost 
disa p peare d) t o < 0. 5 (lesi o ns str o n gl y re d uce d). 
St a ble dise ase : Relati ve sc ore > 0. 5 (lesi o ns wea kl y b ut 
si g nifica ntl y re d uce d) t o > 0. 9 (lesi o ns n ot re d uce d). 
  
  
 
P r o gressi ve Dise ase : Ne w Lesi o ns o n MI B G sca n.  
 
 
1 3. 7.  Defi niti o n of O ver all Res p o nse f or E ac h P atie nt  ( Ce ntr al Re vie w) 
 
1 3. 7. 1.  T his will be utilize d as a basis t o i nte grate res p o nse at all sites defi ne d as 
meas ura ble i n t his st u d y, i ncl u di n g C T/ M RI lesi o ns w hic h meet R E CI S T 
criteria, MI B G p ositi ve lesi o ns, a n d b o ne marr o w disease. T hese criteria 
will be use d t o defi ne t he o verall res p o nse f or t he patie nt i n b ot h strata i n 
t he statistical a nal ysis. 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 3 3  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
1 3. 7. 2.  C o m plete Res p o nse ( C R)  
Disa p peara nce of all tar get lesi o ns. N o e vi de nce of t u m or at a n y 
site (c hest, a b d o me n, li ver, b o ne, b o ne marr o w, n o des, etc.), a n d 
H V A/ V M A n or mal.  
 
1 3. 7. 3.  P arti al Res p o nse ( P R)  
At least a 3 0 % decrease i n t he disease meas ure me nt f or C T/ M RI  
tar get lesi o ns, ta ki n g as refere nce t he disease meas ure me nt d o ne t o 
c o nfir m meas ura ble disease i n tar get lesi o ns at st u d y e ntr y. B o ne 
marr o w wit h C R. MI B G wit h eit her P R/ C R i n b o ne lesi o ns; MI B G 
ma y be S D or C R i n s oft tiss ue lesi o ns c orres p o n di n g t o lesi o ns o n 
C T/ M RI. H V A/ V M A ma y still be ele vate d.  
 
1 3. 7. 4.  Pr o gressi ve Dise ase ( P D)  
A n y o ne of t he f oll o wi n g: 
a) At least a 2 0 % i ncrease i n t he disease meas ure me nt f or C T/ M RI 
tar get lesi o ns, ta ki n g as refere nce t he s mallest disease 
meas ure me nt rec or de d si nce t he start  of treat me nt.  
b) A p peara nce of o ne or m ore ne w lesi o ns or ne w sites of t u m or. 
c) P D as defi ne d a b o ve f or eit her b o ne marr o w or MI B G lesi o ns.  
 
1 3. 7. 5.  St a ble dise ase ( S D)  
T he patie nt will be classifie d as sta ble disease if t here are n o ne w 
lesi o ns; n o ne w sites of disease , a n d t he y d o n ot fit t he criteria f or 
P D/ P R/ C R as a b o ve.  
 
 
 
 
1 4. 0  S A F E T Y M O NI T O RI N G  
1 4. 1.  T o xicit y data m ust be s u b mitte d t o t he St u d y C hair at t he e n d of eac h c ycle of 
t hera p y. 
1 4. 2.  Gi na Ha n na, P har m D will ser ve as t he Safet y Officer f or t his pr ot oc ol . T he 
Safet y Officer will re vie w all t o xicit y data at eac h D S M B meeti n g or s o o ner if 
t here is a safet y c o ncer n. 
1 4. 3.  T he N M T R C V 0 7 0 6  m o nit ori n g Pla n will be f oll o we d f or t his pr ot oc ol. 
 
 
 
 
 
 
 
 
 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 3 4  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
1 5. 0  A D V E R S E E V E N T R E P O R TI N G  
 
1 5. 1.  Nif urti m o x is s u p plie d t hr o u g h a n I N D a n d t heref ore res p o nsi bilit y t o t he 
F D A i ncl u des: 
1 5. 1. 1.  Re p orti n g a n y u ne x pecte d fatal or life- t hreate ni n g a d verse e x perie nce 
ass ociate d wit h use of t he dr u g b y tele p h o ne, fa x, or o ver ni g ht mail, n o 
later t ha n 7 cale n dar da ys after i nitial recei pt of i nf or mati o n. 
1 5. 1. 2.  Re p orti n g a n y a d verse e x perie nce ass ociate d wit h use of t he dr u g t hat is 
b ot h seri o us a n d u ne x pecte d i n writi n g n o later t ha n 1 5 cale n dar da ys after 
i nitial recei pt of i nf or mati o n. 
1 5. 1. 3.  S u b mitti n g a n n ual pr o gress re p orts. 
1 5. 1. 4.  Fe brile ne utr o pe nia is a n e x pecte d res ult  of t o p oteca n/c ycl o p h os p ha mi de 
a n d s o d o es n ot  nee d t o be re p orte d. 
1 5. 2.  A “ Data F or m f or Rec or di n g A d verse E ve nts” will be pr o vi de d t o rec or d n o n-
seri o us A d verse E ve nts.  All Gra de 3 ( C T C A E Versi o n 3. 0) or hi g her A E’s 
(e xce pt he mat ol o gic) will nee d t o be ca pt ure d.  
1 5. 3.  T he D S M B c haire d b y t he safet y officer will re g ularl y meet per N M T R C 
p olic y a n d D S M B c harter t o re vie w all safet y re p orts a n d deter mi ne w het her 
pr ot oc ol m o dificati o ns are warra nte d .  
 
 
1 6. 0   S E RI O U S A D V E R S E E V E N T R E P O R TI N G  
 
1 6. 1.  All Seri o us A d verse E ve nt s (S A E’s ) t hat occ ur at partici pati n g sites m ust  be 
re p orte d t o t he c o or di nati n g site wit hi n 2 4 h o urs of disc o ver y a n d 
c o or di nati n g ce nters m ust disse mi nate t his i nf or mati o n t o t he ot her sites as 
s o o n as p ossi ble.   
All seri o us, u ne x pecte d e ve nts a n d Gra de  4 a n d Gra de 5 t o xicities, b ot h 
e x pecte d a n d u ne x pecte d , m ust be re p orte d t o t he St u d y C hair ( w h o will t he n 
re p ort it t o t he Safet y Officer) wit hi n 2 4 h o urs of disc o ver y. T he partici pati n g 
site will t he n be res p o nsi ble f or s u b mitti n g all re q uire d Me d watc hes t hat occ ur 
at t heir sites t o t he F D A (a n d pr o vi di n g a c o p y t o t he c o or di nati n g site st u d y 
c hair), a n d s u b mitti n g pa per w or k t o all t heir o w n l ocal I R B re q uire me nts.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 3 5  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
1 6. 2.  
Rel ate d ness t o St u d y Dr u g  
T he I n vesti gat or m ust atte m pt t o deter mi ne if a n a d verse e ve nt is i n s o me wa y relate d t o t he use 
of  t he  st u d y  dr u g  a n d  defi ne  a n  attri b uti o n  cate g or y.  T his  relati o ns hi p  s h o ul d  be  descri be d  as 
f oll o ws: 
 
R E L A TI O N S HI P  
A T T RI B U TI O N  
D E S C RI P TI O N  
U nr el at e d t o 
i n v e sti g ati o n al 
a g e nt/i nt er v e nti o n  
 
U nr el at e d  
T h e A E i s cl e arl y N O T r el at e d t o t h e 
i nt er v e nti o n. 
T he e ve nt is clearl y d ue t o ca uses disti nct fr o m t he use of 
t he st u d y dr u g, s uc h as a d oc u me nte d pre-e xisti n g 
c o n diti o n, t he effect of a c o nc o mita nt me dicati o n, or a ne w 
c o n diti o n w hic h, base d o n t he pat h o p h ysi ol o g y of t he 
c o n diti o n, a n d t he p har mac ol o g y of t he st u d y dr u g, w o ul d 
be u nrelate d t o t he use of t he st u d y dr u g.  
U nli k el y  
T h e A E i s d o u btf ull y r el at e d t o t h e i nt er v e nti o n. 
A d verse e ve nt d oes n ot ha ve te m p oral relati o ns hi p t o 
i nter ve nti o n, c o ul d rea dil y ha ve bee n pr o d uce d b y t he 
s u bject’s cli nical state, c o ul d ha ve bee n d ue t o 
e n vir o n me ntal or ot her i nter ve nti o ns, d oes n ot f oll o w 
k n o w n patter n of res p o nse t o i nter ve nti o n, d oes n ot 
rea p pear or w orse n wit h rei ntr o d ucti o n of i nter ve nti o n. 
R el at e d t o  
i n v e sti g ati o n al 
a g e nt/i nt er v e nti o n  
 
P o s si bl e  
T h e A E m a y b e r el at e d t o t h e i nt er v e nti o n. 
T he e ve nt f oll o ws a reas o na ble te m p oral se q ue nce fr o m 
a d mi nistrati o n of t he st u d y dr u g a n d t he e ve nt f oll o ws a 
k n o w n res p o nse patter n t o t he st u d y dr u g B U T t he e ve nt 
c o ul d ha ve bee n pr o d uce d b y a n i nterc urre nt me dical 
c o n diti o n w hic h, base d o n t he pat h o p h ysi ol o g y of t he 
c o n diti o n, a n d t he p har mac ol o g y of t he st u d y dr u g, w o ul d 
be u nli kel y relate d t o t he use of t he st u d y dr u g O R t he 
e ve nt c o ul d be t he effect of a c o nc o mi ta nt me dicati o n. 
Pr o b a bl e  
T h e A E i s li k el y r el at e d t o t h e i nt er v e nti o n. 
T he e ve nt f oll o ws a reas o na ble te m p oral se q ue nce fr o m 
a d mi nistrati o n of t he st u d y dr u g, t he e ve nt f oll o ws a 
k n o w n res p o nse patter n t o t he st u d y dr u g A N D t he e ve nt 
ca n n ot ha ve bee n reas o na bl y e x plai ne d b y a n i nterc urre nt 
me dical c o n diti o n O R t he e ve nt ca n n ot be t he effect of a 
c o nc o mita nt me dicati o n. 
D efi nit e  
T h e A E i s cl e arl y r el at e d t o t h e i nt er v e nti o n. 
T he e ve nt f oll o ws a reas o na ble te m p oral se q ue nce fr o m 
a d mi nistrati o n of t he st u d y dr u g, t he e ve nt f oll o ws a 
k n o w n res p o nse patter n t o t he st u d y dr u g a n d base d o n t he 
k n o w n p har mac ol o g y of t he st u d y dr u g, t he e ve nt is 
clearl y relate d t o t he effect of t he st u d y dr u g.  T he a d verse 
e ve nt i m pr o ves u p o n disc o nti n uati o n of t he st u d y dr u g  a n d 
rea p pears u p o n re peat e x p os ure. 
 
 
 
1 7. 0  A G E N T I N F O R M A TI O N  
1 7. 1.   193B193BNif urti m o x - See att ac he d pr o d uct br oc h ure.   
1 7. 1. 1.  F or m ul ati o n a n d St a bilit y : T he dr u g is st a ble at r o o m te m per at ure, 
a n d is li g ht se nsiti ve.  
1 7. 1. 2.  G ui deli nes f or A d mi nistr ati o n : See secti o ns u n der 5. 1. 
1 7. 1. 3.  S u p plie r: T he dr u g will be pr o vi de d t o e ac h site b y B a yer i n pill f or m.  
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 3 6  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
Ris ks a n d si de effects rel ate d t o nif urti m o x:  
T h ose i n dic ati n g nee d f or me dic al atte nti o n:  
  
C o m m o n  
Occ asi o n al  
R are  
H a p pe ns t o 2 1 -1 0 0 
c hil dre n o ut of e ver y 1 0 0  
H a p pe ns t o 5 -2 0 
c hil dre n o ut of e ver y 
1 0 0  
H a p pe ns t o < 5 c hil dre n o ut of 
e ver y 1 0 0 
W hile t a ki n g 
nif urti m o x:  
  
S ki n R as h, he a d ac he or 
verti g o ( dizzi ness)  
Ce n tral ner v o us s yste m  
t o xicit y i ncl u di n g dis orie ntati o n 
(c o nf usi o n ), dist ur ba nces of 
e q uili bri u m s uc h as ata xia 
(cl umsi ness or u nstea di ness), 
a n d n ysta g m us ( u nc o ntr olle d 
bac k -a n d-f ort h a n d/ or r olli n g 
e ye m o ve me nts ); e xcitati o n, 
f or getf ul ness, i ns o m nia (tr o u ble 
i n slee pi n g ), irrita bilit y, 
ps yc h osis ( m o o d or me ntal 
c ha n ges ), seiz ures 
(c o n v ulsi o ns), m uscle 
wea k ness, per i p heral 
ne ur o pat h y ( n u m b ness, 
ti n gli n g, pai n, or wea k ness i n 
ha n ds or feet)  a n d tre m ors; a 
hi g h e osi n o p hil c o u nt, fe ver, 
i m p ote nce ( decrease d se x ual 
dri ve or a bilit y), or a l o w w hite 
bl o o d cell c o u nt wit h a ris k of  
i nfecti o n ca n occ ur wit h hi g h 
d oses  
Us uall y disa p pear 
s p o nta ne o usl y after 
wit h dra wal of t he 
me dicati o n.  
L ate:  
T here are n o k n o w n late si de effects of Nif urti m o x at t his ti me.  
A n y ti me after 
c o m pleti o n of 
treat me nt 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 3 7  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
Ris ks a n d si de effects rel ate d t o n if urti m o x 
T h ose i n dic ati n g nee d f or me dic al atte nti o n o nl y if t he y c o nti n ue or are b ot hers o me: 
  
C o m m o n  
Occasi o nal  
Rare  
Ha p pe ns t o 2 1 -1 0 0 c hil dre n 
o ut of e ver y 1 0 0  
Ha p pe ns t o 5 -2 0 c hil dre n 
o ut of e ver y 1 0 0  
Ha p pe ns t o < 5 c hil dre n o ut of 
e ver y 1 0 0 
W hile ta ki n g 
n if urti m o x: 
Gastr oi ntesti nal dist ur ba nces, 
s uc h as a n ore xia wit h wei g ht 
l oss (l oss of a p petite), 
e pi gastric pai n (a b d o mi nal or 
st o mac h pai n), na usea a n d/ or 
v o miti n g occ ur i n 2 0 -8 0 % of 
patie nts.   
Hea dac he or verti g o 
( dizzi ness) occ ur i n 1 0- 
1 2 % of patie nts.  
  
 
 
1 7. 2.   C ycl o p h os p h a mi de  N S C # 0 2 6 2 7 1 
1 7. 2. 1.  S o urce a n d P h ar m ac ol o g y : A n al k ylati n g a ge nt, relate d t o nitr o ge n 
m ustar d, w hic h is bi oc he micall y i nert u ntil it is meta b olize d t o its acti ve 
c o m p o ne nts b y t he li ver p h os p ha mi dases. It is n o n- p hase- s pecific. T he 
dr u g a n d its meta b olites are e xcrete d e xcl usi vel y b y t he ki d ne y after 
pare nteral a d mi nistrati o n. T he plas ma half -life ra n ges fr o m 4 t o 6. 5 h o urs.  
1 7. 2. 2.  F or m ul ati o n a n d St a bilit y :  See pac ka ge insert.  
1 7. 2. 3.  G ui deli nes f or A d mi nistr ati o n :   T he cycl o p h os p ha mi de will be 2 5 0 
m g/ m 2/ d ose pre pare d per i nstit uti o nal sta n dar ds i n n or mal sali ne a n d 
a d mi nistere d i ntra ve n o usl y o ver 3 0 mi n utes. See secti o ns u n der 5. 2. 
17 2 4  
201BT o xicit y : 
 
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  
Occ 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 
A n ore xia ( L), 
na usea ( L),  
v o miti n g( L)  
Metallic taste ( L),  
I na p pr o priate 
A D H 1  
Tra nsie nt bl urre d 
visi o n 1 car diac 
t o xicit y wit h 
arr h yt h mias 1 
m y ocar dial 
necr osis 2( L) 
Pr o m pt:  
Wit hi n 2 - 3 wee ks, 
pri or t o t he ne xt 
c o urse 
M yel os u p pressi o n 
( L), 
al o pecia ( L) 
 
He m orr ha gic 
c ystitis ( L) 
 
 
Del a ye d:  
A n y ti me later 
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 
I m m u n os u p pressi o n, 
g o na dal 
d ysf u ncti o n /sterilit y 
( L) 
 
 
 
 
 
 
P ul m o nar y 
fi br osis 3( L) 
L ate:  
A n y ti me aft er 
c o m pleti o n of 
treat me nt 
 
 
Sec o n dar y 
mali g na nc y, 
bla d der fi br osis 
 
1 Less c o m m o n wit h l o wer d oses. 3 Ris k i ncre ase d wit h c hest r a di ati o n.  
2 O nly wit h very hi g h d oses. ( L) T o xicity m ay als o occ ur l ater.  

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 3 8  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
 
1 7. 2. 5.  S u p plier : C o m merciall y a vaila ble. See pac ka ge i nsert f or f urt her 
i nf or mati o n. 
 
1 7. 3.   T o p otec a n  N S C # 6 0 9 6 9 9 
1 7. 3. 1.  S o urce a n d P h ar m ac ol o g y : T o p oteca n A S is a se mis y nt hetic a nal o g ue of 
ca m pt ot heci n, a n al kal oi d deri ve d fr o m t he ca m pt ot heci n tree w hic h gr o ws 
wi del y t hr o u g h o ut Asia. T he dr u g is a s pecific T o p ois o merase -I i n hi bit or. 
T o p oteca n i nterferes wit h t he re pair acti vit y of t o p ois o merase I b y 
sta bilizi n g t he f or mati o n of a c o vale ntl y b o n de d D N A-T o p ois o merase I 
c o m ple x. T h us, t he 5'- p h os p h or yl ter mi n us of t he e nz y me catal yze d si n gle 
stra n d D N A 
brea k re mai ns b o u n d t o t he t yr osi ne of t he e nz y me t here b y 
i nterferi n g wit h re plicati o n. T he dr u g e xists as t w o s pecies i n 
e q uili bri u m i n a q ue o us s ol uti o ns. O ne is a m ore acti ve cl ose d-ri n g 
lact o ne a n d t he ot her a less acti ve o pe n ri n g f or m. Aci dic 
c o n diti o ns fa v or t he cl ose d ri n g lact o ne f or m w hile basic a n d 
p h ysi ol o gic p H fa v ors t he o pe n ri n g f or m. I n h u ma n plas ma t he 
lact o ne f or m is a b o ut 2 1 % b o u n d t o plas ma pr otei n. T he dr u g is 
e xcrete d 3 9 % i n uri ne a n d t he re mai n der i n t he st o ol, t h e latter is 
pres u ma bl y via biliar ye xcreti o n. I n rats, o ver 9 0 % of t he 
ra di oacti vit y fr o m [ 1 4 C]t o p oteca n was rec o vere d i n st o ol a n d uri ne 
i n t he first 9 6 h o urs. T he half life f or t he lact o ne f or m is 1 8 0 
mi n utes. 
1 7. 3. 2.  F or m ul ati o n a n d St a bilit y:  See pac ka ge insert . 
1 7. 3. 3.  G ui deli nes f or A d mi nistr ati o n : T o p oteca n at a d ose of 0. 7 5 m g/ m 2 will 
be pre pare d per i nstit uti o nal sta n dar ds i n n or mal sali ne a n d a d mi nistere d  
i ntra ve n o usl y,  i nf use d o ver 3 0 mi n utes. See secti o ns u n der 5. 2. 
1 7. 3. 4.  T o xicit y : 
 
 
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 
Occ 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 usea, v o miti n g, 
diarr hea ( L), 
m uc ositis ( L), fl u -
li ke s y m pt o ms ( L), 
hea dac he, ras h ( L), 
ele vate d 
tra nsa mi nases, 
ele vate d al kali ne 
p h os p hatase, 
ele vate d bilir u bi n 
A b d o mi nal pai n, 
ri g ors 
 
Pr o m pt:  
Wit hi n 2 - 3 wee ks, 
pri or t o ne xt c o urse  
M yel os u p pressi o n,  
al o pecia 
 
 
 
Del a ye d:  
A n yti me later 
 
Ast he nia  
 
Micr osc o pic 
he mat uria  

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 3 9  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
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 
L ate:  
A n yti me aft er 
c o m pleti o n of 
t hera p y 
 
 
 
 
( L) T o xicity m ay als o occ ur l ater. 
1 7. 3. 5.  S u p plier : C o m merciall y a vaila ble. See pac ka ge i nsert f or f urt her 
i nf or mati o n. 
 
1 7. 4.  Fil gr a sti m N S C # 6 1 4 6 2 9 
1 7. 4. 1.  S o urce a n d P h ar m ac ol o g y : Fil grasti m is a h u ma n gra ul oc yte c ol o n y 
sti m ulati n g fact or ( G- C S F), pr o d uce d b y rec o m bi na nt D N A tec h n ol o g y. 
Fil grastri m is a 1 7 5 a mi n o aci d pr otei n wit h a m olec ular wei g ht of 1 8, 8 0 0 
dalt o ns ma n ufact ure d b y rec o m bi na nt D N A tec h n ol o g y utilizi n g E. c oli 
bacte ria i nt o w hic h has bee n i nserte d t he h u ma n gra n ul oc yte c ol o n y 
sti m ulati n g fact or ge ne. It differs fr om t he nat ural pr otei n i n t hat t he N- 
a mi n o aci d i n met hi o ni ne a n d t he pr otei n is n ot gl yc os ylate d.  G- C S F is a 
li nea ge s pecific c ol o n y-sti m ulati n g fact or whic h re g ulates t he pr o d ucti o n 
of ne utr o p hils wit hi n t he b o ne marr o w a n d affects ne u tro p hil pr o ge nit or 
pr oliferati o n, differe ntiati o n a n d selecte d e n d- cell f u ncti o nal acti vati o n( 
i ncl u di n g e n ha nce d p ha g oc ytic a bilit y, pri mi n g of t he cell ular meta b olis m 
ass ociate d wit h res pirat or y b urst, a nti b o d y de pe n de nt killi n g, a n d t he 
i ncrease d e x pressi o n of s o me f u ncti o ns ass ociate d wit h cell s urface 
a nti ge n).  T he eli mi nati o n half- life is si milar f or s u bc uta ne o us a n d 
i ntra ve n o us a d mi nistrati o n, a p pr o xi matel y 3. 5 h o urs.  T he ti me t o pea k 
c o nce ntrati o n wit h a d mi nistere d s u bc uta ne o usl y is 2 t o 8 h o urs. 
1 7. 4. 2.  F or m ul ati o n a n d St a bilit y : See p ac ka ge insert.  
1 7. 4. 3.  G ui deli nes f or A d mi nistr ati o n : Fil grasti m or pe gfil grasti m s h o ul d be gi n 
2 4- 4 8 h o urs after t he c o m pleti o n of da y 5 c he m ot hera p y if nee de d, a n d 
c o nti n ue u ntil ne utr o p hil rec o ver y.  Pe g fil grasti m ma y be s u bstit ute d at t he 
discreti o n of t he treati n g p h ysicia n. 
 
1 7. 4. 4.  T o xicit y : 
Ris ks a n d si de effects rel ate d t o fil gr asti m i ncl u de t h ose w hic h are: 
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  
Occ 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  
•  Ac hi n g or pai n i n t he 
b o nes 
 
•  L ocal irritati o n at t he site of 
t he i njecti o n 
•  Hea dac he    
•  Hi g her t ha n n or mal le vels of 
li ver e nz y mes a n d uric aci d 
i n t he bl o o d 
•  A l o w n u m ber of platelets i n 
t he bl o o d w hic h ma y ca use 
y o u t o br uise a n d blee d 
•  Aller gic reacti o ns w hic h 
ca n be life t hreate ni n g 
wit h s h ort ness of breat h, 
l o w bl o o d press ure, ra pi d 
heart rate, hi ves a n d facial 
s welli n g. T his reacti o n is 
ver y rare a n d has bee n  
ass ociate d mai nl y wit h 
i ntra ve n o us 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 4 0  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
m ore easil y  
•  L o w fe ver 
•  E nlar ge me nt of t he s plee n 
w hic h ma y ca use pai n i n t he 
a b d o me n or left s h o ul der 
•  W orse ni n g of s ki n ras hes 
•  Hi g her t ha n n or mal w hite 
bl o o d c o u nt 
a d mi nistrati o n.  
•  If y o u are k n o w n t o ha ve 
sic kle cell disease, 
fil grasti m ma y ca use a 
sic kle cell crisis 
•  R u pt ure of t he s plee n 
•  Diffic ult y breat hi n g a n d 
l u n g da ma ge t hat ma y be 
d ue t o t he w hite bl o o d 
cells t hat are sti m ula te d b y 
fil grasti m tra veli n g t o t he 
l u n gs w he n t he y are 
i nfla me d or i nfecte d. 
 
1 7. 4. 5.  S u p plier:  C o m merciall y a vaila ble. See pac ka ge i nsert f or f urt her 
i nf or mati o n. 
 
1 7. 5.  Pe gfil gr asti m ( pe g yl ate d fil gr asti m, S D/ 0 1, Ne ul ast a ®) ( 0 7 2 0 0 6 
1 7. 5. 1.  S o urce a n d P h ar m ac ol o g y :. Pe gfil grasti m is t he pe g ylate d f or m of 
rec o m bi na nt met hi o n yl h u ma n G-C S F(fil grasti m). Pe gfil grasti m is 
pr o d uce d b y c o vale ntl y bi n di n g a 2 0- kil o dalt o n ( k D) 
m o n o met h o x y p ol yet h yle ne gl yc ol m olec ule t o t he N- ter mi nal met hi o n yl 
resi d ue of fil grasti m. T he m olec ular wei g ht of pe gfil grasti m is 3 9 k D. G-
C S F is a li nea ge s pecific c ol o n y -sti m ulati n g fact or w hic h re g ulates t he 
pr o d ucti o n of ne utr o p hils wit hi n t he b o ne marr o w a n d affects ne utr o p hil 
pr o ge nit or pr oliferati o n, differe ntiati o n, a n d selecte d e n d- cell f u ncti o nal 
acti vati o n (i ncl u di n g e n ha nce d p ha g oc ytic a bilit y, pri mi n g of t he cell ular 
meta b olis m ass ociate d wit h res pirat or y b urst, a nti b o d y de pe n de nt killi n g, 
a n d t he i ncrease d e x pressi o n of s o me f u ncti o ns ass ociate d wit h cell 
s urface a nti ge ns). After s u bc uta ne o us i njecti o n t he eli mi nati o n half- life of 
pe gfil grasti m ra n ges fr o m 1 5 t o 8 0 h o urs a n d t he ti me t o pea k 
c o nce ntrati o n ra n ges fr o m 2 4 t o 7 2 h o urs. Ser u m le vels are s ustai ne d i n 
m ost patie nts d uri n g t he ne utr o pe nic peri o d p ostc he m ot hera p y, a n d be gi n 
t o decli ne after t he start of ne utr o p hil rec o ver y, c o nsiste nt wit h ne utr o p hil-
de pe n de nt eli mi nati o n. 
1 7. 5. 2.  F or m ul ati o n a n d St a bilit y : See pac ka ge i nsert. 
1 7. 5. 3.  G ui deli nes  f or A d mi nistr ati o n: Fil grasti m or pe gfil grasti m s h o ul d be gi n 
2 4- 4 8 h o urs after t he c o m pleti o n of da y 5 c he m ot hera p y if nee de d, a n d 
c o nti n ue u ntil ne utr o p hil rec o ver y.  Pe gfil grasti m ma y be s u bstit ute d at t he 
discreti o n of t he treati n g p h ysicia n. 
 
 
 
 
 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 4 1  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
1 7. 5. 4.  T o xicit y : 
 
Ris ks a n d si de effects rel ate d t o pe gfil gr asti m i ncl u de t h ose w hic h:  
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  
Occ 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  
•  Ac hi n g or pai n i n t he 
b o nes 
 
•  L ocal irritati o n at t he site of 
t he i njecti o n 
•  Hea dac he    
•  Hi g her t ha n n or mal le vels of 
li ver e nz y mes a n d uric aci d 
i n t he bl o o d 
•  A l o w n u m ber of platelets i n 
t he bl o o d w hic h ma y ca use 
y o u t o br uise a n d blee d 
m ore easil y  
•  L o w fe ver 
•  E nlar ge me nt of t he s plee n 
w hic h ma y ca use pai n i n t he 
a b d o me n or left s h o ul der 
•  W orse ni n g of s ki n ras hes 
•  Hi g her t ha n n or m al w hite 
bl o o d c o u nt 
•  Aller gic reacti o ns w hic h 
ca n be life t hreate ni n g 
wit h s h ort ness of breat h, 
l o w bl o o d press ure, ra pi d 
heart rate, hi ves a n d facial 
s welli n g. T his reacti o n is 
ver y rare a n d has bee n 
ass ociate d mai nl y wit h 
i ntra ve n o us 
a d mi nistrati o n. 
•  If yo u are k n o w n t o ha ve 
sic kle cell disease, 
fil grasti m ma y ca use a 
sic kle cell crisis 
•  R u pt ure of t he s plee n 
•  Diffic ult y breat hi n g a n d 
l u n g da ma ge t hat ma y be 
d ue t o t he w hite bl o o d 
cells t hat are sti m ulate d b y 
fil grasti m tra veli n g t o t he 
l u n gs w he n t he y are 
infla me d or i nfecte d.  
1 7. 5. 5.  S u p plier:  C o m merci all y a v ail a ble. See p ac k a ge i nsert f or f urt her 
i nf or m ati o n. 
 
1 8. 0  BI O L O GI C A L S T U DI E S  ( O pti o n al) 
1 8. 1.  
T u m or c ollecti o n a n d esta blis h me nt of pri mar y ne ur o blast o ma a n d 
me d ull o blast o ma cell li nes i n c ult ure  (t o be perf or me d at t he t he 
Ne ur o blast o ma Tra nslati o nal Researc h  La b ). 
1 8. 1. 1.  Via ble, fres h t u m or > 0. 2 gra ms fr o m t u m or bi o ps y or 2 cc fr o m b o ne 
marr o w as pirate s h o ul d be place d i n R P MI tiss ue c ult ure me dia usi n g 
sterile tec h ni q ue f or cell li ne ge nerati o n.  Cells s h o ul d be la bele d wit h 
s u bjects i nitials a n d st u d y n u m ber. 
*If t here is n ot a de q uate tiss ue a vaila ble t he n cells will be o btai ne d 
fr o m t he c yt o ge netics la b orat or y after c o m pleti o n of t heir testi n g. 
1 8. 1. 2.  If e xcess tiss ue is a vaila ble, t he n s na p fr oze n t u m or tiss ue a p pr o xi matel y 
5 m m i n size s h o ul d be wra p pe d i n f oil, s na p fr oze n i n li q ui d nitr o ge n a n d 
st ore d at - 2 0º C.  Tiss ue sa m ples will be c o de d.  Fi xe d tiss ue re mai ni n g 
fr o m dia g n ostic e val uati o n ma y be use d.  
1 8. 1. 3.  T u m or cells will be gr o w n t o 7 0 % c o nfl ue nc y a n d tra nsferre d t o 
Ne ur o basal me dia wit h E G F a n d F G F.   
1 8. 1. 4.  Cell li nes will be mai ntai ne d i n c ult ure f or bi ol o g y st u dies.  T hese will 
i ncl u de deter mi ni n g t he gr o wt h c ur ves a n d res p o nsi ve ness of cells deri ve d 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 4 2  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
fr o m t hese t u m ors t o a variet y of gr o wt h fact ors, c yt o ki nes, ne ur otr o p hic 
fact ors, a n d c yt ot o xic a ge nts (s uc h as nif urti m o x).  We will st u d y t he 
ge nes e x presse d b y t hese cells usi n g re verse -tra nscri ptase p ol y merase 
c hai n reacti o n ( R T - P C R), N ort her n bl ot a nal ysis, real ti me P C R, a n d D N A 
a n d m R N A micr o arra ys bef ore a n d after treat me nt wit h nif urti m o x a n d 
ot her a ge nts.  F urt her st u d y of t he pr otei ns e x presse d b y t hese cells will be 
d o ne usi n g i m m u n oc yt oc he mistr y a n d Wester n bl otti n g. Fl o w c yt o metr y 
will be use d t o detect resi d ual ne ur o blast o ma i n b o ne marr o w sa m ples. 
 
1 8. 2.  
B o ne M arr o w S a m ple I nstr ucti o ns  (f or all p artici p ati n g sites): 
1 8. 2. 1.  If s u bject a grees t o o pti o nal bi ol o g y p orti o n of st u d y, b o ne marr o w 
sa m ples s h o ul d be se nt at t he f oll o wi n g ti me p oi nts: 
All patie nts - E nr oll me nt 
F or B o ne Marr o w P ositi ve patie nts o nl y ; als o se n d sa m ples at: E n d 
of C ycle 2, E n d of C ycle 4, a n d E n d of Pr ot oc ol T hera p y (e n d of 
c ycle 6) . 
 
1 8. 2. 2.  S a m ple C ollecti o n -  
 
Se n d gree n t o p (s o di u m he pari n) t u be (s) t o eac h of t he f oll o wi n g sites wit h 
a mi ni m u m of 2cc a n d prefera bl y 5cc of b o ne marr o w  as pirate i n 
t he m.  B ot h ca n be s hi p pe d r o o m te m perat ure- b ut nee d t o be se nt o ut 
sa me da y pri orit y o ver ni g ht ( m ust get t here wit hi n 2 4 h o urs of t he 
dra w ).   S hi p me nts are o nl y acce pte d M o n da y t hr o u g h Fri da y, s o B o ne 
Marr o w dra w nee ds t o be d o ne a n d s hi p pe d o ut o n M o n da y t hr o u g h 
T h urs da y o nl y please. Please n otif y eac h site (at e -mail a d dress liste d 
bel o w of pe n di n g s hi p me nt arri vals). Please e ncl ose “ B o ne Marr o w 
S hi p me nt Tra ns missi o n F or m” wit h eac h s hi p me nt - o ne f or eac h site.  
 
 
1 8. 2. 3.  S a m ple S hi p me nt A d dresses:  
 
O ne sa m ple will g o t o:  
Pi n g Z h a o  
S pectr u m Healt h, C o o per’s La n di n g 1 3 4 5 M o nr oe A ve ; S uite 1 2 1  
Gra n d Ra pi ds, MI 4 9 5 0 5  
Pi n g.z ha o @ hele n de v osc hil dre ns. or g  
 
T he ot her sa m ple will g o t o:  
S pectr u m Healt h Fl o w C yt o metr y La b  
 
Le m me n -H olt o n Ca ncer Pa vili o n    
1 4 5 Mic hi ga n Street  N E S uite 6 2 0 1 
Gra n d Ra pi ds, MI 4 9 5 0 3 
p h o ne: 6 1 6- 4 8 6- 6 2 3 3 
 
 
1 8. 3.  
Bi o m ar ker De vel o p me nt  
Bi o mar kers are o bjecti vel y meas ure d a n d e val uate d i n dicat ors of n or mal 
bi ol o gical pr ocesses, pat h o ge nic pr ocesses, or p har mac ol o gic res p o nses t o 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 4 3  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
a t hera pe utic i nter ve nti o n. I n o nc ol o g y, t here is partic ular i nterest i n t he 
m olec ular c ha n ges u n derl yi n g t he o nc o ge nic pr ocesses t hat ma y i de ntif y 
ca ncer s u bt y pes a n d t he sta ge of disease, assess t he e xte nt of t u m or 
gr o wt h, pr o vi de s urr o gate meas ures of disease pr o gressi o n or metastasis, 
or pre dict res p o nses t o i n vesti gati o nal pr o d ucts. T hese i n vesti gati o ns ma y 
be usef ul i n de vel o pi n g mar kers t o i de ntif y disease s u bt y pes, g ui de 
t hera p y a n d/ or pre dict disease pr o gressi o n.  I n a d diti o n t o testi n g t he 
safet y a n d effecti ve ness of t he i n vesti gati o nal pr o d uct i n t his st u d y, we 
ma y atte m pt t o de vel o p bl o o d a n d/ or t u m or test(s) desi g ne d t o i de ntif y 
s u bjects m ost li kel y t o be nefit fr o m t he i n vesti gati o nal pr o d uct. A 5cc 
bl o o d sa m ple will be dra w n f or bi o mar ker de vel o p me nt at scree ni n g, c ycle 
2, c ycle 4, a n d at e n d of st u d y, a n d at t he safet y f oll o w- u p visits.  
 
T o st u d y t he effects of h u ma n ge n o mic ( p he n ot y pic) variati o n o n dr u g 
res p o nse, we pla n t o c o n d uct e x pl orat or y p har mac o ge n o mic st u dies as part 
of t his st u d y. M olec ular a nal yses o n bi ol o gical sa m ples o btai ne d fr o m 
s u bjects o n t his st u d y ma y be use d t o i de ntif y res p o nse patter ns t o 
nif urti m o x, i de ntif y ca ncer s u bt y pes, sta ge disease, assess t he a m o u nt of 
t u m or gr o wt h or pre dict disease pr o gressi o n or metastasis. T hese 
m olec ular a nal yses will n ot i ncl u de e x pl orat or y p har mac o ge netic a nal ysis.  
 
All s u bjects will be as ke d t o p r o vi de paraffi n t u m or bl oc ks ( or a mi ni m u m 
of 2 0 u nstai ne d sli des, if a vaila ble) fr o m t he pri mar y a n d/ or metastatic 
t u m or t hat are arc hi ve d. I n a d diti o n, all s u bjects will be as ke d t o pr o vi de 
e xisti n g s na p fr oze n t u m or sa m ples. 
 
C orres p o n di n g pat h ol o g y re p orts s h o ul d als o be pr o vi de d. As a n o pti o nal 
part of t his st u d y, s u bjects ma y be as ke d t o u n der g o tiss ue sa m pli n g b y 
c ore bi o ps y of a l ocall y a d va nce d or metastatic lesi o n f or e x pl orat or y 
bi o mar ker a nal yses pri or t o t he start of st u d y treat me nt. T he t u m or tiss ue 
bi o psies m ust be accessi ble wit h mi ni mal m or bi dit y t o t he s u bject b y a 
perc uta ne o us c ore nee dle bi o ps y eit her wit h or wit h o ut t he ai d of a C T 
sca n or ultras o u n d g ui da nce. Bi o ps y s peci me ns will be o btai ne d usi n g 
sta n dar d sterile s ur gical tec h ni q ues. All t u m or bi o ps y sa m ples s h o ul d ha ve 
a p orti o n of t he bi o ps y stai ne d wit h he mat o x yli n a n d e osi n a n d re vie we d 
b y a pat h ol o gist t o c o nfir m t he prese nce a n d esti mate t he perce nta ge of 
t u m or tiss ue. T he p ur p ose of t his a nal ysis is t o de vel o p a n a p pr oac h f or t he 
i de ntificati o n a n d vali dati o n of tra nscri pts t hat ma y pre dict w hic h s u bjects 
are li kel y t o res p o n d t o nif urti m o x. 
 
1 8. 4.  
P h ar m ac o ge netic St u dies  
D N A will be c ollecte d a n d e xtracte d fr o m bl o o d a n d t u m or sa m ples t o be 
utilize d f or e x pl orat or y p har mac o ge netic a nal ysis. T hese 
p har mac o ge netics a nal yses are differe nt fr o m t he bl o o d a n d t u m or 
a nal ysis f or bi o mar ker de vel o p me nt as descri be d a b o ve beca use t he y are 
f oc use d o n e val uati n g differe nt i n herite d or disease-i n d uce d ge ne f or ms i n 
t u m or D N A t hat ma y i nfl ue nce t he differe nt res p o nses s u bjects ha ve t o t he 
sa me dr u g. T he g oals of t hese e x pl orat or y st u dies are t o i de ntif y p ote ntial 
ge netic mar kers t hat ma y hel p i n t he i n vesti gati o n of ca ncer a n d/ or 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 4 4  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
s u bjects w h o ma y ha ve t he best p ossi ble res p o nse t o nif urti m o x. T he 
c urre nt pla n is t o c o n d uct e x pl orat or y p har mac o ge netic st u dies o n t u m or 
tiss ue t o e val uate f or m utati o ns of ge nes (e. g. M Y C N) i n a n atte m pt t o 
deter mi ne if t he prese nce of a n y of t hese m utati o ns/rearra n ge me nts 
c orrelates wit h res p o nse.  
 
A d diti o nal ge ne cate g ories f or a nal yses ma y i ncl u de t u m or s u p press or 
ge nes (e. g. p 5 3, P T E N), o nc o ge nes (e. g., N- m yc, M E T), cell a d hesi o n, 
i n vasi o n a n d metastasis ge nes (e. g., α v β 3,  C D H 1, M M P’s), ge nes 
i n v ol ve d i n re g ulati n g cell gr o wt h a n d t he cell c ycle (e. g., c ycli n D 1, 
G H R H ), i m m u ne f u ncti o n-relate d a n d t u m or a nti ge n ge nes (e. g., T N F, 
S C Y A 2, K L K 3), dr u g meta b olis m a n d tra ns p ort ge nes (e. g., C Y P 3 A 4/ 5, 
P X R, G S T M 1, A B C B 1), a n d ge nes i n v ol ve d i n a n gi o ge nesis (e. g., HI F 1 α   
V E G F, F G F R 3). T h ose rele va nt t o st u d y dr u g acti o n i ncl u de a p o pt osis 
ge nes (e. g., B C L 2, I A Ps, T N F S F 6) a n d t he p utati ve dr u g 
tar gets/ pat h wa ys. 
 
1 8. 5.  
S a m ple St or a ge a n d Destr ucti o n  
Bl o o d a n d t u m or sa m ples c ollecte d f or bi o mar ker de vel o p me nt a n d 
p har mac o ge netic st u dies a n d a n y ot her c o m p o ne nts fr o m t he cells ma y be 
st ored f or u p t o 2 0 years t o researc h scie ntific q uesti o ns relate d t o ca ncer 
a n d/ or nif urti m o x. T he s u bject retai ns t he ri g ht t o ha ve t he sa m ple material 
destr o ye d at a n y ti me b y c o ntacti n g t he pri nci pal i n vesti gat or. T he 
PI/s p o ns or will be t he e xcl usi ve o w ner of a n y data, disc o veries, or 
deri vati ve materials fr o m t he sa m ple materials a n d is res p o nsi ble f or t he 
destr ucti o n of t he sa m ple(s) at t he re q uest of t he researc h s u bject t hr o u g h 
t he pri nci pal i n vesti gat or or at t he e n d of t he st ora ge peri o d. If a 
c o m merci al pr o d uct is de vel o pe d fr o m t his researc h pr oject, t he 
PI/s p o ns or will o w n t he c o m mercial pr o d uct. T he s u bject will ha ve n o 
c o m mercial ri g hts t o s uc h pr o d uct a n d will ha ve n o c o m mercial ri g hts t o 
t he data, i nf or mati o n, disc o veries, or deri vati ve materials gai ne d or 
pr o d uce d fr o m t he sa m ple. 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 4 5  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
 
1 9. 0  R E F E R E N C E S  
 
1.  S h oller, G S, Kal k u nte, S, Gree nla w, C, Mc Carte n, K, F or ma n, E, A nti- T u m or 
acti vit y of Nif urti m o x o bser ve d i n a patie nt wit h Ne ur o blast o ma. J Pe diatr 
He mat ol O nc ol. 2 0 0 6 Oct; 2 8( 1 0): 6 9 3- 6 9 5 
 
2.  S olari A, Ortiz S, S ot o A, Ara nci bia C, Ca m pilla y R, C o ntreras M, Sali nas P, 
R ojas A, Sc he n o ne H, Treat me nt of Tr y pa n os o ma cr uzi- i nfecte d c hil dre n wit h 
Nif urti m o x: a 3 year f oll o w- u p b y P C R. J o ur nal of A nti micr o bial C he m ot hera p y. 
2 0 0 1; 4 8: 5 1 5- 5 1 9 
 
3.  Ra ma kris h na Ra o, D N, Mas o n, R, Ge nerati o n of Nitr o A ni o ns of S o me 5-
Nitr of ura ns, 2 - a n d 5- Nitr oi mi daz oles b y N ore pi ne p hri ne, D o pa mi ne, a n d 
Ser ot o ni n.  J. Bi ol. C he m. 1 9 8 7; 2 6 2( 2 4): 1 1 7 3 1- 1 1 7 3 6  
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 4 6  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
A p pe n di x I:  Str uct ure d I nter vie w f or A d verse Ne ur ol o gic E ve nts  
 
St u d y I D #:: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
I nitials: _ _ _ _ _ _ _ _ _ 
 
Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _    
  
C ycle #: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Pr o vi der c o m pleti n g f or m Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Please c o m plete wit h t he fa mil y.  
 
T o xicit y  
Gra de  
 
N o ne  
1  
2  
3  
4  
Hea dac he?  
 
 
 
 
 
Li g ht Se nsiti vit y?  
 
 
 
 
 
St o mac h u pset?  
 
 
 
 
 
V o miti n g?  
 
 
 
 
 
I m bala nce? 
 
 
 
 
 
Dizzi ness/ Li g ht hea de d ness?  
 
 
 
 
 
Pai n i n li m bs?  
 
 
 
 
 
C ol d ha n ds/feet?  
 
 
 
 
 
S peec h har d t o u n dersta n d?  
 
 
 
 
 
Dis orie ntati o n/c o nf usi o n?  
 
 
 
 
 
E xcessi ve slee pi ness? 
 
 
 
 
 
Diffic ult y or c ha n ge i n slee p r o uti ne?  
 
 
 
 
 
U n us ual m o ve me nts?  
 
 
 
 
 
Tre m or?  
 
 
 
 
 
U n us ual cr yi n g, irrita bilit y?  
 
 
 
 
 
C ha n ge i n his/ her i nterest i n t o ys, pla y?  
 
 
 
 
 
C ha n ge i n a p petite?  
 
 
 
 
 
C ha n ge i n h o w his/ her e yes m o ve?  
 
 
 
 
 
C ha n ge i n a bilit y t o c he w or s wall o w?  
 
 
 
 
 
Seiz ure or ot her s u d de n c ha n ge i n le vel of 
a ware ness?  
 
 
 
 
 
 
 
I n eac h case of a p ositi ve, pare nts will be as ke d t o gra de t he se verit y of t he si g n or 
s y m pt o m i n a ma n ner t hat will all o w us t o cate g orize t he si g n/s y m pt o m as class 1- 5 * 
acc or di n g t o t he classificati o n s yste m as f oll o ws:  
 
Gra de  
Pare nt’s Q ualitati ve Descri pti o n of t he a d verse si g n/s y m pt o m  
Gra de 1  
Prese nt o nl y as a si g n, n ot a pr o ble m i n a n y se nse  
Gra de 2  
C hil d c o m plai ns, b ut still t he s y m pt o m is  n ot i nterferi n g wit h 
c hil d’s us ual acti vities  
Gra de 3  
I nterferi n g wit h c hil d’s us ual acti vities 
Gra de 4  
Si g nifica ntl y a n d per vasi vel y effecti n g t he c hil d’s dail y life  
[ * A gra de of 5 i n t he classificati o n c orres p o n ds t o Deat h a n d s o will clearl y n ot be t he 
classificati o n res ulti n g fr o m pare nt i nter vie w.]  

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 4 7  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
A p pe n di x II: R E Q UI R E D O B S E R V A TI O N S  
 
Ti me P oi nt:  
Prest u d y 
C ycle 1, w k 
2 
C ycle 1, w k 
3 
Pri or t o 
eac h 
c ycle‡ 
E n d of c ycles 
2 a n d 4 ¶ 
E n d of Pr ot oc ol 
T hera p y 
or Earl y 
Wit h dra wal  
3 0 Da y 
F oll o w- u p 
P h ysical E xa m  
X  
X  
X  
X  
 
X  
X  
Ne ur o e xa m  
X  
X  
X  
X  
 
X  
X  
Ne ur o i nter vie w / T N Sc 
X  
 
 
 
X  
X  
X  
B RI E F assess me nt  
X  
 
 
 
X  
X  
 
P C S Q o L: M T D  
X  
 
 
 
 
 
 
P C S Q o L: D T  
X  
 
 
 
X  
X  
 
Uri ne pre g na nc y test †  
X  
 
 
 
 
 
 
C bc/ diff  
X  
X  
X  
X  
 
X  
X  
L ytes, B U N, Creat  
X  
X  
X  
X  
 
X  
X  
L D H, A S T, A L T, Bili  
X  
X  
X  
X  
 
X  
X  
Ferriti n  
X  
 
 
 
 
 
 
H V A/ V M A ( N B o nl y)  
X  
 
 
X  
 
X  
X  
C T or M RI  
X  
 
 
 
X  
X  
 
MI B G *  
X  
 
 
 
X  
X  
 
B o ne marr o w  
X  
 
 
 
 X #  
X #  
 
C S F cell 
c o u nt/c yt ol o g y  
X §  
 
 
 
  X § #  
X § #  
 
* = MI B G n ot re q uire d if s u bject’s ne ur o blast o ma was pre vi o usl y deter mi ne d t o be n ot MI B G a vi d or f or s u bjects wit h me d ull o blast o ma 
# =  Re peat o nl y if p ositi ve at st u d y e ntr y 
† =  O nl y f or fe male s u bjects of c hil d beari n g p ote ntial ( ≥1 3 years of a ge) 
‡ = testi n g t o occ ur wit hi n 7 da ys of t he start of eac h c ycle ( +/- 3 da ys) 
¶ = testi n g t o occ ur wit hi n 7 da ys of c o m pleti n g c ycle ( +/- 3 da ys)  
§ = Me d ull o blast o ma s u bjects o nl y 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 4 8  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
A p pe n di x III:  Q o L Q uesti o n n aires  
 
 
 
 
 
 
 
 
I D # _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P ar e nt A s s e s s m e nt of C hil dr e n' s Q u alit y of Lif e D uri n g Tr e at m e nt  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
 
 
 
 
  
G E N E R A L DI R E C TI O N S  
  
 
 
 
 
  
  
  
  
  
  
 
 
 
 
W he n a c hil d is u n der g oi n g ca ncer treat me nt, it us uall y has maj or effects o n 
t he c hil d's q ualit y of life a n d t he lifest yle of t he fa mil y. We are i ntereste d i n 
lear ni n g h o w t hese effects c ha n ge as a res ult of bei n g i n certai n ca ncer 
treat me nts/trials. O n t he ne xt pa ges t here are q uesti o ns a n d state me nts 
descri bi n g a ra n ge of effects y o ur c hil d/fa mil y mi g ht e x perie nce d uri n g 
treat me nt.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
P L E A S E P R O VI D E T H E F O L L O WI N G I N F O R M A TI O N:  
  
  
  
  
  
  
  
  
  
  
  
Y o ur n a m e:  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Y o ur r el ati o n s hi p t o c hil d:  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
C hil d' s n a m e:  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
C hil d' s Di a g n o si s:  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
C hil d' s c urr e nt a g e:  
  
  
  
( y e ar s) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
T o d a y' s D at e:  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
P C S Q o L: D T 1. 0 N ot t o b e r e pr o d u c e d wit h o ut p er mi s si o n.   C o p yri g ht © 2 0 0 7. T F S a x o n, P h D, & G S  S h oll er, M D. All ri g ht s r e s er v e d 0 1/ 0 7  

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 4 9  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
 
 
 
 
 
 
1. D oes y o ur c hil d c o m plai n of pai n? Yes _ _ _  
N o _ _ _  
 
If yes, h o w ofte n d oes he/s he c o m plai n per da y? _ _ _ _ _ _ _ _ _ _ 
 
2. Is y o ur c hil d c urre ntl y ta ki n g pai n me dicati o ns? Yes _ _ _  
N o _ _ _  
 
If yes, please c hec k me dicati o n(s) bei n g use d a n d i n dicate d ose a n d fre q ue nc y. 
 
Me dicati o n  
D ose/ T y pe (e. g., oral, I V, patc h, P C A)  
H o w ofte n per da y?  
_ _ _ dila u di d  
 
 
_ _ _ m or p hi ne  
 
 
_ _ _fe nta n yl  
 
 
_ _ _ met ha d o ne  
 
 
_ _ _ T yle n ol  
 
 
_ _ _ T yle n ol  wit h c o dei ne 
 
 
_ _ _i b u pr ofe n / M otri n 
 
 
_ _ _ deca dr o n  
 
 
_ _ _ ot her pai n me dici ne  
 
 
 
 
 
 
3. D o t hese me dicati o ns c o ntr ol y o ur c hil d’s pai n? Yes _ _ _  
N o _ _ _  
 
4. Besi des me dici nes, d o y o u use ot her met h o ds t o c o ntr ol pai n? Yes _ _ _  
N o _ _ _  
 
If yes, please descri be: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
5. D oes y o ur c hil d re q uire T P N or N G/ G -b utt o n n utriti o n? Yes _ _ _  
N o _ _ _  
 
6. D oes y o ur c hil d ta ke a n a p petite sti m ula nt (e. g., Me gace)? Yes _ _ _  N o _ _ _  
 
7 . D oes y o ur c hil d atte n d sc h o ol? Yes _ _ _ 
N o _ _ _  
 
If n o, d oes y o ur c hil d ha ve a t ut or/ h o me teac her? Yes _ _ _  
N o _ _ _  
 
 
If yes, h o w ma n y da ys ha ve b ee n misse d i n t he last 2 wee ks? _ _ _ _ _ _ _ 
 
 
Reas o ns f or missi n g sc h o ol:  
 
 
_ _ _l o w bl o o d c o u nts  
 
 
_ _ _ pai n c o ntr ol  
 
 
_ _ _ na usea  
 
 
_ _ _ u na ble t o wal k  
 
 
_ _ _ ot her –  please descri be: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
8. Has y o ur c hil d ha d a seiz ure i n t he last 2 wee ks? Yes _ _ _  
N o _ _ _  
 
If yes, ( 1) date of last seiz ure _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
( 2) n u m ber of seiz ures i n last t w o wee ks _ _ _ _ _ _ _ _ _ _ _ 
 
9 . Is y o ur c hil d c urre ntl y o n a nti-seiz ure me dicati o n? Yes _ _ _ N o _ _ _  
 
If yes, ( 1) h o w l o n g a g o di d he/s he be gi n usi n g t he me dicati o n? _ _ _ _ _ __ _ _ _ _  
 
 
( 2) ha ve t here bee n seiz ures si nce starti n g t he me dicati o n? Yes _ _ _ 
N o _ _ _  
 
1 0 . Has y o ur c hil d bee n h os pitalize d i n t he past t w o wee ks? Yes _ _ _ 
N o _ _ _  
 
If yes, ( 1) w hat was t he le n gt h of t he h os pitalizati o n? _ _ _ _ _ _ _ _ _ 
 
 
( 2) descri be t he reas o n(s) f or the h os pitalizati o n: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 5 0  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
  
DI R E C TI O N S: Bel o w are state me nts descri bi n g a ra n ge of 
effects y o ur c hil d/fa mil y mi g ht e x perie nce d uri n g 
treat me nt. F or eac h state me nt, please circle t he res p o nse 
( o nl y o ne) t hat best descri bes t he fre q ue nc y of w hat has 
ha p pe ne d t o y o ur c hil d/fa mil y d uri n g t he last 2 m o nt hs t o 
t he prese nt ti me. 
Ver y 
Fre q ue ntl y  Fre q ue ntl y  Occasi o nall y  
Rarel y  
Ver y 
Rarel y  
Ne ver  
  
  
  
  
  
1. M y c hil d e x perie nces refl u x. 
5 
4 
3 
2 
1 
0 
 
2. M y c hil d ta kes a ntie metic me dicati o ns (f or na usea) 
s uc h as Z ofra n, Vistaril or K ytril. 
5 
4 
3 
2 
1 
0 
 
3. M y c hil d e x perie nces na usea f or l o n g peri o ds of 
ti me. 
5 
4 
3 
2 
1 
0 
 
4. M y c hil d re q uires wee kl y re d bl o o d cell 
tra nsf usi o ns. 
5 
4 
3 
2 
1 
0 
 
5. M y c hil d re q uires wee kl y platelet tra nsf usi o ns.  
5 
4 
3 
2 
1 
0 
 
6. M y c hil d re q uires s ocial is olati o n d ue t o l o w w hite 
cell c o u nts (l o w i m m u nit y).  
5 
4 
3 
2 
1 
0 
 
7. M y c hil d re q uires 7 -1 0 da ys of s u b -c uta ne o us 
i njecti o ns of a dr u g t hat will hel p his/ her w hite bl o o d 
cells rec o ver.  
5 
4 
3 
2 
1 
0 
 
8. M y c hil d has t o wear a mas k o n his/ her face i n 
cr o w ds d ue t o l o w i m m u nit y.  
5 
4 
3 
2 
1 
0 
 
9. I ha ve n otice d m y c hil d's ha n ds tre m bli n g 
(tre m ors). 
5 
4 
3 
2 
1 
0 
 
1 0. M y c hil d e x perie nces “ ne ur o pat hic” pai n –  
c hr o nic pai n ass ociate d wit h da ma ge d ner ves t hat is 
diffic ult t o treat.  
5 
4 
3 
2 
1 
0 
 
1 1. M y c hil d's atte nti o n s pa n see ms s h orter t ha n it 
use d t o.  
5 
4 
3 
2 
1 
0 
 
1 2. M y c hil d tal ks i n his/ her slee p.  
5 
4 
3 
2 
1 
0 
 
1 3. M y c hil d has ni g ht mares.  
5 
4 
3 
2 
1 
0 
 
1 4. I ha ve n otice d t hat m y c hil d is f or getf ul.  
5 
4 
3 
2 
1 
0 
 
1 5. M y c hil d gets i nfecti o ns.  
5 
4 
3 
2 
1 
0 
 
1 6. M y c hil d has s ore b u m ps o n his/ her hea d.  
5 
4 
3 
2 
1 
0 
 
1 7. M y c hil d nee ds ster oi ds f or pai n a n d s welli n g 
(e. g. deca dr o n). 
5 
4 
3 
2 
1 
0 
 
1 8. M y c hil d has n o a p petite.  
5 
4 
3 
2 
1 
0 
 
1 9. M y c hil d has m o ut h s ores.  
5 
4 
3 
2 
1 
0 
 
2 0. M y c hil d has tr o u ble s wall o wi n g.  
5 
4 
3 
2 
1 
0 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 5 1  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
2 1. M y c hil d cries.  
5 
4 
3 
2 
1 
0 
 
2 2. M y c hil d  has diarr hea.  
5 
4 
3 
2 
1 
0 
 
2 3. M y c hil d is c o nsti pate d.  
5 
4 
3 
2 
1 
0 
 
2 4. M y c hil d is n ot a ble t o wal k o n his/ her o w n.  
5 
4 
3 
2 
1 
0 
 
2 5. M y c hil d ta kes a nti bi otics (e. g., va nc o m yci n) f or 
e xte n de d peri o ds of ti me ( oral/I V).  
5 
4 
3 
2 
1 
0 
 
2 6. M y c hil d v o mits.  
5 
4 
3 
2 
1 
0 
 
2 7. M y c hil d is let har gic.  
5 
4 
3 
2 
1 
0 
 
2 8. M y c hil d has tr o u ble uri nati n g.  
5 
4 
3 
2 
1 
0 
 
2 9. M y c hil d slee ps a l ot.  
5 
4 
3 
2 
1 
0 
 
3 0. M y c hil d has a diffic ult ti me ta ki n g pills orall y.  
5 
4 
3 
2 
1 
0 
 
3 1. M y c hil d ca n n ot c o nce ntrate.  
5 
4 
3 
2 
1 
0 
 
3 2. M y c hil d c o m plai ns of pai n.  
5 
4 
3 
2 
1 
0 
 
3 3. M y c hil d see ms u n ha p p y. 
5 
4 
3 
2 
1 
0 
 
3 4. M y c hil d is n ot a ble t o pla y a n d d o t hi n gs he/s he 
wa nts t o d o.  
5 
4 
3 
2 
1 
0 
 
3 5. M y c hil d d oes n ot s mile/la u g h m uc h.  
5 
4 
3 
2 
1 
0 
 
3 6. I belie ve m y c hil d has a p o or q ualit y of life.  
5 
4 
3 
2 
1 
0 
 
3 7. M y c hil d ca n n ot ri de his/ her bi ke/ tric ycle. 
5 
4 
3 
2 
1 
0 
 
3 8. M y c hil d is u na ble t o d o t hi n gs he/s he wa nts t o d o 
o n his/ her o w n.  
5 
4 
3 
2 
1 
0 
 
3 9. M y c hil d slee ps p o orl y.  
5 
4 
3 
2 
1 
0 
 
4 0. M y c hil d is sa d beca use we ha ve t o tra vel/ be 
se parate d fr o m o ur ot her fa mil y me m bers. 
5 
4 
3 
2 
1 
0 
 
4 1. M y c hil d ca n n ot r u n.  
5 
4 
3 
2 
1 
0 
 
 
 
 
 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 5 2  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
 
 
 
 
 
 
 
 
I D # _ _ _ _ _ _ _ _ _ _ _
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F or P ar e nt s M a ki n g Tr e at m e nt D e ci si o n s  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
 
 
 
 
  
G E N E R A L DI R E C TI O N S  
  
 
 
 
 
  
  
  
  
  
  
 
 
 
 
W he n a c hil d  is u n der g oi n g ca ncer treat me nt, it us uall y has maj or effects o n t he c hil d's 
q ualit y of life a n d t he lifest yle of t he fa mil y.  Pare nts wei g h t hese effects as treat me nt 
decisi o ns are ma de.  We are i ntereste d i n lear ni n g w hat fact ors are i m p orta nt t o y o u as 
y o u ma ke t hese treat me nt decisi o ns f or y o ur c hil d.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
 
 
 
 
O n t he ne xt pa ges t here are state me nts a b o ut w hat c o ul d ha p pe n t o y o ur c hil d d uri n g 
treat me nt.  F or eac h state me nt, please circle t he res p o nse ( o nl y o ne) t hat best descri bes 
t he i m p orta nce of eac h o ne as y o u c o nsi der treat me nt o pti o ns f or y o ur c hil d. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
P L E A S E P R O VI D E T H E F O L L O WI N G I N F O R M A TI O N:  
  
  
  
  
  
  
  
  
  
  
  
Y o ur n a m e:  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Y o ur r el ati o n s hi p t o c hil d:  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
C hil d' s n a m e:  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
C hil d' s c urr e nt a g e:    
  
  
  
  
  
  
  
C hil d' s di a g n o si s ( cir cl e o n e):  
M e d ull o 
bl a st o m a  
Fir st R el a p s e 
N e ur o bl a st o m a  
R el a p s e d 
N e ur o bl a st o m a 
(i n cl u d e s 
r efr a ct or y N B) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
D at e of fir st 
r el a p s e: 
  
  
  
( y e ar s) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
H a s H o s pi c e b e e n R e c o m m e n d e d t o y o u ? ( cir cl e o n e)  
y e s  
n o  
  
  
  
  
  
  
  
  
  
  
  
  
  
T o d a y' s D at e:  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
P C S Q o L: M T D 1. 0 N ot t o b e r e pr o d u c e d wit h o ut p er mi s si o n.   C o p yri g ht © 2 0 0 7. T F S a x o n, P h D, & G S S h oll er, M D. All ri g ht s r e s er v e d 0 1/ 0 7  
 
 
 
  

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 5 3  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
DI R E C TI O N S: Bel o w are state me nts a b o ut p ossi ble 
effects of treat me nt o n y o ur c hil d a n d fa mil y d uri n g 
ca ncer treat me nt. Circle t he n u m ber ( o nl y o ne) t hat 
s h o ws h o w i m p orta nt t his effect is t o y o u as y o u 
ma ke treat me nt decisi o ns f or y o ur c hil d.  
Ver y 
I m p orta nt  I m p orta nt M o deratel y 
I m p orta nt 
Of  Little 
I m p orta nce  U ni m p orta nt  
  
  
  
  
  
1. Y o ur c hil d’s hair is li kel y t o fall o ut.  
4 
3 
2 
1 
0 
 
2. Y o ur c hil d is li kel y t o bec o me na use o us a n d re q uire 
a ntie metic me dicati o ns s uc h as Z ofra n, Vistaril or K ytril.  
4 
3 
2 
1 
0 
 
3. Y o ur c hil d is li kel y t o feel na usea f or l o n g peri o ds of 
ti me. 
4 
3 
2 
1 
0 
 
4. Y o ur c hil d will li kel y re q uire fre q ue nt re d bl o o d cell 
tra nsf usi o ns. 
4 
3 
2 
1 
0 
 
5. Y o ur c hil d will li kel y re q uire wee kl y platelet 
tra nsf usi o ns. 
4 
3 
2 
1 
0 
 
6. Y o ur c hil d will be a ble t o recei ve treat me nt dr u gs i n 
cli nic. 
4 
3 
2 
1 
0 
 
7. Y o ur c hil d will li kel y re q uire s ocial is olati o n f oll o wi n g 
treat me nt dr u gs d ue t o l o w w hite cell c o u nts (l o w 
i m m u nit y). 
4 
3 
2 
1 
0 
 
8. Y o ur c hil d will re q uire 7 -1 0 da ys of i njecti o ns of a dr u g 
t hat will hel p his/ her w hite bl o o d cells rec o ver. 
4 
3 
2 
1 
0 
 
9. Y o ur c hil d ma y ha ve t o wear a mas k o n his/ her face i n 
cr o w ds d ue t o l o w i m m u nit y f oll o wi n g treat me nt.  
4 
3 
2 
1 
0 
 
1 0. Y o ur c hil d ma y ha ve heari n g l oss f oll o wi n g t he 
i nf usi o n of s o me treat me nt dr u gs. 
4 
3 
2 
1 
0 
 
1 1. Y o ur c hil d ma y re q uire narc otic pai n me dici nes (e. g., 
m or p hi ne, dila u di d, met ha d o ne).  
4 
3 
2 
1 
0 
 
1 2. F oll o wi n g treat me nt wit h s o me dr u gs, y o ur c hil d ma y 
e x perie nce “ ne ur o pat hic” pai n – c hr o nic pai n ass ociate d 
wit h da ma ge d ner ves t hat is diffic ult t o treat.  
4 
3 
2 
1 
0 
 
1 3. Y o ur c hil d ma y miss  ma n y da ys of sc h o ol d ue t o l o w 
i m m u nit y or h os pitalizati o n. 
4 
3 
2 
1 
0 
 
1 4. Y o ur c hil d’s per ma ne nt teet h ma y be a d versel y affecte d 
b y s o me treat me nt dr u gs.  
4 
3 
2 
1 
0 
 
1 5. Y o ur c hil d’s p ort will m ost li kel y be accesse d a n d re -
accesse d fre q ue ntl y.  
4 
3 
2 
1 
0 
 
1 6. Y o ur c hil d ma y re q uire a ne w p ort.  
4 
3 
2 
1 
0 
 
1 7. Y o ur c hil d ma y re q uire a PI C li ne or fe m oral li ne as a 
te m p orar y meas ure i n t he e ve nt of a n i nfecte d p ort. 
4 
3 
2 
1 
0 
 
1 8. Y o ur c hil d ma y ac q uire a n i nfecti o n i n his p ort.  
4 
3 
2 
1 
0 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 5 4  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
1 9. Y o u ma y ha ve t o rel ocate i n defi nitel y t o a n ot her cit y t o 
recei ve treat me nt. 
4 
3 
2 
1 
0 
 
2 0. Y o ur c hil d ma y nee d ster oi ds f or pai n a n d s welli n g 
(e. g.,  deca dr o n). 
4 
3 
2 
1 
0 
 
2 1. Y o ur c hil d will m ost li kel y l ose wei g ht a n d s uffer 
a n ore xia (st o p eati n g).  
4 
3 
2 
1 
0 
 
2 2. Y o ur c hil d ma y ha ve t o tra vel t o a n ot her cit y/state t o d o 
sca ns, bi o psies a n d ot her tests o n t he treat me nt pr ot oc ol. 
4 
3 
2 
1 
0 
 
2 3. Y o ur c hil d will m ost li kel y nee d a n N G/ G -b utt o n f or 
n utriti o n.  
4 
3 
2 
1 
0 
 
2 4. Y o ur c hil d will m ost li kel y be a ble t o recei ve c o nti n ue d 
treat me nt o n t his cli nical trial at y o ur h o me i nstit uti o n. 
4 
3 
2 
1 
0 
 
2 5. Y o u ma y ha ve t o tra vel t o a n ot her cit y/state t o recei ve 
treat me nt. 
4 
3 
2 
1 
0 
 
2 6. Y o ur c hil d will m ost li kel y re q uire n utriti o n t hr o u g h 
her p ort ( T P N)  
4 
3 
2 
1 
0 
 
2 7. Y o ur c hil d ma y de vel o p m o ut h s ores d uri n g or after 
t hera p y. 
4 
3 
2 
1 
0 
 
2 8. Y o ur c hil d is li kel y t o de vel o p diarr hea d uri n g t hera p y.  
4 
3 
2 
1 
0 
 
2 9. Y o ur c hil d is li kel y t o be o n a nti bi otics f or e xte n de d 
peri o ds of ti me ( oral/I V).  
4 
3 
2 
1 
0 
 
3 0. Y o ur  c hil d is li kel y t o v o mit d uri n g t hera p y.  
4 
3 
2 
1 
0 
 
3 1. Y o ur c hil d ma y fre q ue ntl y feel let har gic a n d slee p y.  
4 
3 
2 
1 
0 
 
3 2. T hera pe utic a ge nts use d o n a cli nical trial ma y be n o n -
F D A a p pr o ve d f or use i n c hil dre n or of y o ur c hil d's ca ncer.  
4 
3 
2 
1 
0 
 
3 3. Y o ur c hil d ma y e x perie nce refl u x a n d ot her u p per GI 
pr o ble ms (es o p ha geal strict ures) as a res ult of t hera p y.  
4 
3 
2 
1 
0 
 
3 4. Y o ur i ns ura nce c o m pa n y ma y be less c o o perati ve f or 
s o me cli nical trial dr u gs a n d e x peri me ntal t hera pies. 
4 
3 
2 
1 
0 
 
3 5. It ma y  be necessar y f or y o u t o ac q uire te m p orar y 
h o usi n g near y o ur treati n g i nstit uti o n.  
4 
3 
2 
1 
0 
 
3 6. Y o ur c hil d ma y re q uire I V me dicati o n i n t he cli nic.  
4 
3 
2 
1 
0 
 
3 7. Y o ur c hil d ma y nee d t o ta ke a nti -seiz ure me dicati o n 
4 
3 
2 
1 
0 
 

Nif urt i m o x P hase II: Nif urti m o x f or Ne ur o blast o ma a n d Me d ull o blast o ma V 0 7 0 6 
Pa ge 5 5  of 5 5  
A me n d me nt  # 9 . 0    Versi o n:  Dece m ber 0 4 , 2 0 15  
3 8. Y o ur c hil d c o ul d recei ve c o m bi nati o n t hera p y ( m ulti ple 
a ge nts use d at t he sa me ti me) i nstea d of si n gle a ge nt 
t hera p y. 
4 
3 
2 
1 
0 
 
3 9. Y o ur c hil d ma y re q uire h os pital a d missi o n f or I V 
me dicati o ns.  
4 
3 
2 
1 
0 
 
4 0. Y o ur c hil d ma y ha ve t o lear n t o ta ke pills orall y.  
4 
3 
2 
1 
0