Clinical trial NCT00601003
Conditions: Neuroblastoma Medulloblastoma
Sponsor: Giselle Sholler
Start date: 2008-01-14; Completion date: 2022-10-28
Enrollment: 112 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine whether nifurtimox in combination with cyclophosphamide and topotecan are effective in the treatment of relapsed or refractory neuroblastoma and medulloblastoma.

Detailed description:
This study is being done to test the effect of a drug, nifurtimox, against neuroblastoma and medulloblastoma in children. Nifurtimox is a drug that has been used in South America for many years to treat a parasitic disease known as Chagas Disease. It is not approved by the Food and Drug Administration for routine use in neuroblastoma or medulloblastoma in the United States, but limited early observations suggest that nifurtimox may have anti tumor activity for neuroblastoma and medulloblastoma.

From the preliminary trials of nifurtimox we have determined a safely tolerated dose of nifurtimox to use in neuroblastoma patients (30mg/kg/day). The dose determined in the Phase I study to be safe, will be the dose used for this study. From clinical experience in South America, we know that children can tolerate nifurtimox when given by mouth, and it appears to have no long-term side effects when used to treat Chagas Disease. Based on our laboratory and animal studies, we believe that drug levels similar to those used to treat Chagas Disease may shrink/kill neuroblastoma cells, especially when combined with other chemotherapy drugs. We do not know whether nifurtimox will shrink/kill tumor cells effectively in children. Therefore, the major goal of the study is to learn if nifurtimox in combination with other chemotherapy drugs is effective in shrinking/killing neuroblastoma and medulloblastoma cells.

Arms: arm 1: None
Interventions: intervention 1: Nifurtimox intervention 2: Cyclophosphamide intervention 3: Topotecan
Intervention descriptions: intervention 1: 30mg/kg/day PO divided into TID dosing q day intervention 2: 250 mg/m2/dose in normal saline, IV, infused over 30 minutes on days 1-5 of each cycle. intervention 3: 0.75mg/m2/dose, in normal saline, IV, infused over 30 minutes on days 1-5 of each cycle.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
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 
 
 

ICF_001.pdf: 
Official Title:  A Phase II Trial of Nifurtimox for Refractory or Relapsed Neuroblastoma or 
Medulloblastoma. 
NCT00601003
IRB-Approved Date:  1/19/16


Nifurtimox Version: 12/7/2015 
Page 1 of 21 
 
 
 
 
 
 
 
 
Permission to Take Part in a Human Research Study & 
HIPAA Authorization for Release of Health Information for 
Research Purposes 
 
 
Title of research study: A Phase II Trial of Nifurtimox for Refractory or Relapsed 
Neuroblastoma or Medulloblastoma 
Sponsor: The Neuroblastoma and Medulloblastoma Translational Research Consortium 
(NMTRC) 
Investigator: Deanna Mitchell, MD 
“You” refers to you, or you and your child 
“We” refers to Helen DeVos Children’s Hospital 
 
You are being asked to volunteer in this research study because you have recurrent or 
unresponsive neuroblastoma or recurrent medulloblastoma that cannot be cured by any 
other known treatment. 
 
What you should know about a research study? 
 Someone will explain this research study to you. 
 You volunteer to be in a research study. 
 Whether or not you take part is up to you. 
 You can choose not to take part in the research study. 
 You can agree to take part now and later change your mind. 
 Whatever you decide it will not be held against you. 
 Feel free to ask all the questions you want before you decide. 
 
Who can I talk to? 
If you have questions, concerns, or complaints, or think the research has hurt you talk to the 
investigator or members of the research team at 
. 
 
This research has been reviewed and approved by the Spectrum Health Institutional Review 
Board.  You may talk to them at 
 or 
 for any of the 
following: 
Patient name 
DOB 
MRN 
Physician 
FIN 
SH IRB Approved On: 01/19/16 
Do Not Use After: 08/03/16


Nifurtimox Version: 12/7/2015 
Page 2 of 21 
 
 Your questions, concerns, or complaints are not being answered by the investigator or 
research team. 
 You cannot reach the investigator or research team. 
 You want to talk to someone besides the investigator or research team. 
 You have questions about your rights as a research participant. 
 You want to get information or provide input about this research. 
 
Why are we doing this research? 
This study is being done to test the effect of a drug, Nifurtimox, against neuroblastoma and 
medulloblastoma in children.  Nifurtimox is a drug that has been used in South America for 
many years to treat a parasitic disease known as Chagas Disease.  Nifurtimox is not 
approved by the Food and Drug Administration for routine use in treating neuroblastoma or 
medulloblastoma in the United States, but early observations suggest that Nifurtimox may 
have anti-tumor properties.  To participate in this study, you must be 0 to 21 years old, have 
adequate liver function, and have recurrent neuroblastoma or medulloblastoma.   
 
From clinical experience in South America, we know that children can tolerate Nifurtimox 
when given by mouth, and it appears to have no long-term side effects when used to treat 
Chagas Disease.  Based on laboratory and animal studies, we believe that drug levels 
similar to those used to treat Chagas Disease may shrink/kill neuroblastoma cells, especially 
when combined with other chemotherapy drugs.  
 
The purpose of this study is to see whether Nifurtimox, when taken in combination with other 
chemotherapy drugs, will shrink/kill neuroblastoma or medulloblastoma cells.  The study will 
also look at the side effects when taken in this manner. 
 
The chemotherapy drugs that have been recommended for this study are approved by the 
US Food and Drug Administration (FDA) and have been used in the past to treat patients 
with 
neuroblastoma 
and 
medulloblastoma. 
These 
chemotherapy 
drugs 
are 
cyclophosphamide, topotecan, and zoledronic acid. 
 
How long will I be in the research? 
We expect that you will be in this research study for about 18 months.  You will have 6 
months of treatment and then your disease status will be monitored at set intervals for an 
additional 12 months after your treatment is done.   
 
If you respond well to the study treatment, your study doctor may decide to keep you on 
Nifurtimox for longer than 6 cycles.  The number of additional cycles will be determined by 
your doctor.  If you stay on Nifurtimox, you will be in the study for longer than 18 months, and 
your disease status will be monitored for 12 months following the last dose.  
 
How many people will be studied? 
It is anticipated that approximately 100 patients will participate between multiple study sites.  
We expect to enroll four to six patients a year at Helen DeVos Children’s Hospital. 
 
 
 
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Page 3 of 21 
 
What happens if I say yes, I want to be in this research? 
If you agree to be in the study, and the exams, tests and procedures show that you can be in 
the study, your study treatment will take place in the outpatient clinic according to the 
following schedule: 
 
You will participate in six individual cycles of therapy.  During these cycles you will take 
Nifurtimox three times per day by mouth every day of the study.  You will also receive 
intravenous (IV) cyclophosphamide and topotecan.  Cyclophosphamide and topotecan will 
be given through your vein with an IV or through your central line.  Each drug will be given 
over 30-60 minutes, for 5 days in a row at the beginning of each 21 day cycle.  Study visits 
will occur as described below, and all required tests are described in detail later in this 
section of the consent form. 
 
You must be seen at your study institution clinic during the entire Week 1 of Cycle 1. All 
required radiology scans (MIBG’s and MRI/CT’s), must be done at the study institution 
unless otherwise approved by the Sponsor. If Helen DeVos Children’s Hospital is not your 
home institution, all other care (except for the study procedures described below) can be 
done at your home institution at the discretion of your study doctor. 
 
Treatment Description 
Before study entry: 
After consent form is signed, certain tests and assessments must be completed before you 
can start study treatment.  If you have had any of these tests recently, you may not need to 
have them done again.  Your study doctor will tell you if any tests need to be repeated.   
 
The following tests must be done within 30 days of starting study treatment: 
 CT or MRI of measurable disease sites 
 MIBG scan (if you have had an avid/ positive scan before. MIBG not required for 
patients with medulloblastoma.) 
 Bone Marrow Aspirate and Biopsy (required for neuroblastoma subjects, may not be 
necessary for medulloblastoma subjects) 
 Lumbar 
Puncture 
for 
cerebral 
spinal 
fluid 
(CSF) 
collection 
and 
testing 
(medulloblastoma subjects only) 
 
The following tests must be done within 7 days of starting study treatment: 
 Complete physical exam, including neurological exam and a Clinical Total Neuropathy 
Scale (TNSc) 
 Urine catecholamines (neuroblastoma subjects only) 
 Urine pregnancy test for all female subjects age 13 and older 
 Labs: CBC with differential, electrolytes, kidney function tests (BUN and creatinine), 
and liver function tests (LDH, AST, ALT, Ferritin) 
 Neurologic structured interview and  questionnaires  
 Additional imaging or studies may be done if your doctor thinks they are needed 
 
Cycle 1: 
You will be closely monitored during the first cycle.  Each cycle requires you to visit the clinic 
5 days in a row to get your IV chemotherapy, but the first cycle is a bit different.  We are not 
sure how long your study visits will take.  There are special blood draws done on Day 1 and 
SH IRB Approved On: 01/19/16 
Do Not Use After: 08/03/16


Nifurtimox Version: 12/7/2015 
Page 4 of 21 
 
Day 4 that might require you to stay longer than usual, and there are two additional visits 
required during the first cycle.  Cycle 1 visits include: 
 Day 1 
o IV Chemotherapy (all IV chemotherapy will be given in clinic) 
o Nifurtimox pill count 
o Blood draw before first dose of Nifurtimox 
o Blood draw 3 hours after first dose of Nifurtimox 
 Day 2 
o IV Chemotherapy 
 Day 3 
o IV Chemotherapy 
 Day 4 
o IV Chemotherapy 
o Blood draw before first dose of Nifurtimox 
o Blood draw 3 hours after first dose of Nifurtimox 
 Day 5 
o IV Chemotherapy 
 Day 8 (+/- 3 day visit window) 
o Physical exam, including neurological exam 
o Labs: as described in the “Before Study Entry” section above 
 Day 15 (+/- 3 day visit window) 
o Same as Day 8 visit 
 Days 1-21  
o Nifurtimox will be taken by mouth 3 times a day, as directed  
 
Before each of the remaining cycles (2-6) the following tests need to be completed: 
 Physical exam, including neurological exam 
 Labs as previously described 
 Urine Catecholamines (neuroblastoma subjects only) 
 
Cycles 2 and 4: 
 Day 1: Pill count and drug diary collection 
 Days 1-5 
o IV Chemotherapy 
 Days 1-21  
o Nifurtimox will be taken by mouth 3 times a day, as directed  
 Before next cycle starts: 
o CT or MRI of disease sites 
o MIBG (previously avid/positive neuroblastoma subjects only) 
o Lumbar Puncture for CSF collection and testing (medulloblastoma subjects 
only, and only if positive at study entry) 
o Neurologic structured interview, TNSc, and two questionnaires 
o Additional imaging or studies may be done if your doctor thinks they are 
needed 
 
Cycles 3, 5 and 6: 
 Day 1: Pill count and drug diary collection 
 Days 1-5 
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o IV Chemotherapy 
 Days 1-21  
o Nifurtimox will be taken by mouth 3 times a day, as directed  
 
During each cycle after your 5 days of IV chemotherapy are done, you may start 
subcutaneous injections (shot under the skin) of filgrastim or pegfilgrastim to help your body 
make white blood cells if your body can’t make them on its own.   
 
To keep track of missed Nifurtimox doses, you will be asked to fill out a drug diary at home 
for each cycle of treatment.  The diary asks you to check off each dose you take, and make 
note of any missed doses (including the reason why the dose was missed).  Diary pages will 
be collected at the end of each cycle. 
 
You may have leftover Nifurtimox pills at the end of each cycle.  You will be asked to bring 
any leftover Nifurtimox to your appointment at the end of each cycle.  
 
End of Study Treatment (completion of cycle 6) or Early Withdrawal: 
 Remaining supply of Nifurtimox must be turned in 
 Pill count and drug diary collection 
 Physical and neurological exam and TNSc 
 Labs as previously described 
 Urine catecholamines (neuroblastoma subjects only) 
 Neurologic structured interview and two questionnaires 
 CT or MRI re-evaluation of disease sites 
 MIBG (previously avid/positive neuroblastoma subjects only) 
 Bone Marrow biopsy and aspirate (if positive at study entry) 
 Lumbar Puncture for CSF collection and testing (medulloblastoma subjects only, 
and only if positive at study entry) 
If you withdraw from the study early, CT/MRI and/or MIBG scans don’t need to be repeated 
unless your doctor thinks they are necessary. 
 
After your last dose of Nifurtimox: 
You will come to the clinic for a follow-up visit 30-37 days after your last dose of Nifurtimox.  
The following procedures will be done at this visit: 
 Physical exam, including a neurological exam 
 Neurologic Structured Interview 
 Labs as described in the “Before Study Entry” section 
 Urine catecholamines (neuroblastoma subjects) 
 
In addition, we will collect information about the status of your disease periodically for a year 
after your last dose of Nifurtimox.  We will either meet with you during routine follow-up 
appointments or we will contact you by phone at the following intervals: 
 2 months 
 3 months 
 5 months 
 7 months 
 9 months 
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 1 year 
Continuation on Nifurtimox: 
If you respond well to the treatment and you complete all 6 cycles, your doctor may 
recommend that you continue taking Nifurtimox, either by itself or in combination with other 
drugs (which may or may not include cyclophosphamide and topotecan).   Your doctor will 
decide how many extra cycles you will need.   
 
The following tests and exams are required within 7 days of starting each cycle: 
 Physical exam, including a neurological exam 
 Labs as described in the “Before Study Entry” section 
 Urine catecholamines (neuroblastoma patients) 
 Additional imaging or studies may be done if your doctor thinks they are needed 
 
The following tests and exams are required every three cycles (or sooner, if needed): 
 CT or MRI re-evaluation of disease sites 
 MIBG (previously avid/positive neuroblastoma subjects only) 
 Bone Marrow biopsy and aspirate (if positive at study entry) 
 Lumbar Puncture for CSF collection and testing (medulloblastoma subjects only, 
and only if positive at study entry) 
 
Tests/Evaluations: 
If you decide to be in this study, you will have various tests and evaluations performed 
throughout your study treatment.  These tests and evaluations will help monitor your disease, 
progress, and potential side effects.  Most of these exams, tests and procedures are part of 
regular cancer care and may be done even if you do not join this study.  If you have had 
some of them recently, they may not need to be repeated.  Additional tests, procedures, or 
evaluations may also be included in your care, as determined by your physician.   
Optional Biologic Studies: 
Along with this study, we are doing additional neuroblastoma and medulloblastoma research 
using extra blood and bone marrow collected during the screening phase.  Extra bone 
marrow samples will be collected during your routine bone marrow procedures while you are 
in the treatment phase, and extra blood will be collected periodically at the time of routine 
blood draws.   
 
If you have a procedure to remove a portion of your tumor while you are in the study, a 
leftover sample will be sent for optional testing if you choose to take part.  If you have 
archived tumor samples available from a previous surgery, we may also send a part of the 
tissue if you opt to take part.    You will not be asked to undergo a surgical procedure of any 
kind to obtain a piece of tumor for the purposes of the optional biologic studies.   
 
We are also asking all participants for permission to store any leftover specimens in a 
laboratory for use in future cancer and/or Nifurtimox research.  Your participation in the 
additional biologic studies and the leftover specimen storage are optional.  More information 
about the biologic studies can be found in the “Optional Biologic Studies Consent” section of 
this form.   
 
SH IRB Approved On: 01/19/16 
Do Not Use After: 08/03/16


Nifurtimox Version: 12/7/2015 
Page 7 of 21 
 
Blood samples will be taken from you throughout your treatment to evaluate your progress 
and measure blood counts.  If you already have a central line, blood will be taken from your 
central line.  Otherwise, blood will be drawn from your vein.  The amount of blood drawn will 
vary based upon the test/s performed.  Problems associated with drawing blood from a 
central line include infections and clotting.  If blood is taken from your vein, you may 
experience discomfort, pain, swelling and/or bruising.  Sometimes bleeding can occur at the 
place where blood is drawn.  Fainting and infection can also occur, but they are rare. 
 
You will be asked to also have extra research-related blood tests done called 
pharmacokinetic studies.  The pharmacokinetic studies will involve having additional blood 
samples drawn at specific intervals.  Approximately ½ teaspoon of blood would be collected 
at each interval.  These blood samples will be tested in a laboratory to determine the level of 
Nifurtimox in the blood.  This information will be used to better understand the metabolism 
(break down) of Nifurtimox.  This information along with any information about side effects 
will be used to determine what doses are most effective when using Nifurtimox.  The blood 
samples for the pharmacokinetics studies will be drawn right before taking the morning dose 
of Nifurtimox and then at 3 hours following the morning dosing on the first and fourth day of 
treatment during the first and third cycles only.  Whenever possible, these tests will be 
obtained from a central venous line.  You will not have to pay for these pharmacokinetic 
studies.   
If you agree to participate in the optional biologic studies, about 1 teaspoon of extra blood will 
be collected when you have routine blood draws at the following intervals: 
 Screening visit 
 Cycles 2 and 4 
 End of study visit 
 Follow-up visits 
 
Urine collections will be needed to measure certain substances that your body gets rid of in 
the urine.  These may be 12 to 24 hour urine collections.  Infants and children who are not 
toilet-trained must have a urinary catheter (flexible sterile rubber tube passed into the 
bladder) in place 12-24 hours to collect a urine sample.  The most common risk of catheter 
placement is infection.  Rarely, injury can occur to the urethra (the tube that leads to the 
bladder).   
 
Bone Marrow tests (bone marrow aspirations and/or biopsies) are performed to check for 
some tumors.  This is done to evaluate the degree of disease present in the bone marrow.  
These tests involve removing a sample of bone marrow from the center of a bone.  Bone 
marrow is the place where blood cells are made.  A bone marrow test is a procedure that 
takes only a few minutes.  This test is often performed while the child is sedated (made 
sleepy) to minimize any fear or discomfort.  A bone marrow test is usually done in a 
treatment room with the child lying flat on a table.  For a bone marrow aspiration, a medicine 
is injected into the skin over the hip bone to make it feel numb, and a small, sharp needle is 
inserted into the bone to remove 1 to 2 teaspoons of bone marrow (which looks like blood).  
For a bone marrow biopsy, another special needle is used to remove a tiny piece of bone.  
After the needle is removed, a small bandage is applied. At this time, you may experience 
intense pressure with brief periods of pain. Pain following the procedure is mild and should 
resolve within a few days.  One risk of this procedure is the remote possibility of infection.  
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Bruising is possible with some tenderness at the needle insertion site.  You will be asked to 
sign a separate consent form for this procedure.   
 
If you have your bone marrow tested during your study treatment, we will collect extra marrow 
(between 1-3 teaspoons) for special research testing of neuroblastoma cells, if they are 
present.  Collecting extra bone marrow for the special research is optional.  The optional study 
is described on the “Additional Optional Tumor Biology Consent” page of this consent form.  
You will be asked to sign the page if you wish to participate in the optional part of the study.   
 
Magnetic Resonance Imaging scans (MRI scans) and/or Computed Axial Tomography (CT 
scan) will also be performed to evaluate your disease.  An MRI is a scan using sound waves 
that produces very detailed pictures of parts of the body, such as the brain and spinal cord.  
A CT scan is the process of using computers to make a three-dimensional image from flat x-
ray pictures, one slice at a time.  The scans will show the doctors where a tumor is and how 
much is present.  A special IV dye (a solution that allows the specific body part studied to 
show up better when scanned) must be given for some MRI scans.  For many young 
children, sedation medicine (medicine to make you sleepy) must be given for scans that take 
a long time, because they must hold very still to get clear pictures.  Your doctor will explain 
these radiology tests in greater detail. The test itself is not painful; though there may be some 
discomfort from the need to remain still.  If IV dye is used, it can cause a reaction to people 
who are allergic, and may increase kidney dysfunction in people with kidney problems. You 
will be asked to sign a separate consent form for this procedure if sedation is needed.   
   
A lumbar puncture, sometimes called an LP or spinal tap, is a test done to get samples of 
spinal fluid (the clear liquid that surrounds the brain and spinal cord).  The spinal fluid is 
checked for cancer cells. A lumbar puncture is a procedure that takes only a few minutes.  
This test is often performed while the child is sedated (made sleepy) to minimize any fear or 
discomfort.  It is usually done in a treatment room with the child lying in a curled position on 
his/her side on a table.  After a small area of skin over the lower back is cleaned and injected 
with a tiny amount of medicine to make it feel numb, a small, sharp needle is inserted in the 
lower back to remove about 1-3 teaspoons of spinal fluid.  After the needle is removed, a 
small bandage is applied.  There is possibility of local pain at the needle insertion site.  There 
is a small risk of bleeding, headache and very rarely, infection.  The chance of permanent 
neurological (brain, spinal cord, and nerve) damage is extremely low.  You will be asked to 
sign a separate consent form for this procedure.   
 
Nuclear medicine scans (MIBG scan) are tests that use a tiny amount of radioactive tracer 
given IV to get pictures of certain body parts, such as bones (a bone scan) or the lymph 
nodes (a gallium scan).  The tracer is usually given a few hours before the pictures are 
taken.  You must lie still, so some form of sedation (medicine to make you sleepy) may be 
needed.  Allergic reactions to the radioactive tracer are rare.  The level of radiation exposure 
with these procedures is low.   You may be asked to sign a separate consent form for this 
procedure.   
 
A Clinical Total Neuropathy Scale (TNSc) will be done periodically to check for any changes 
in your reflexes, strength, movements and how sensitive you are to touch.  The neurological 
exam tells us how Nifurtimox might be affecting these things. 
 
Neurological structured interviews will be performed.  Your doctor will ask you to rate any 
neurological symptoms (such as headache, light sensitivity, upset stomach).  The purpose of 
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the interview is to find out if you are having any side effects that may be related to taking 
Nifurtimox, and how serious the side effects might be. 
 
Questionnaires will be given to you at study visits for you to complete.  There are three 
different questionnaires that will be used to tell us what your Quality of Life (QoL) is like: 
 BRIEF (Behavior Rating Inventory of Executive Function) assessment: 
o This survey helps us get information about the way you behave and think 
o There are 86 statements describing different behaviors.  Your parent will be 
asked to answer whether each behavior is Never (a problem), Sometimes a 
problem,  or Always a problem 
 PCSQoL:MTD (Pediatric Cancer Survey: For Parents Making Treatment Decisions: 
o This survey will ask your parent to answer questions about how important 
quality of life is when making treatment decisions 
 PCSQoL:DT (Pediatric Cancer Survey: Parent Assessment of Children’s Quality of 
Life During Treatment):  
o This survey will ask your parent to answer questions about how your quality of 
life changes during treatment.    
 
If you wish to take part in this study, we expect that you will: 
 Keep your study appointments.  If you cannot keep an appointment, contact your 
study doctor or research study staff to reschedule as soon as you know that you will 
miss the appointment. 
 Tell your study doctor or research staff about any medications you are taking. 
 Fill out your drug diary pages and turn them in at the end of each cycle or the 
beginning of the next cycle. 
 Tell your study doctor or research study staff about any side effects, doctor visits, or 
hospitalization that you may have whether or not you think they are related to the 
study therapy. 
 
What happens if I say no, I do not want to be in this research? 
You may decide not to take part in the research and it will not be held against you.  A refusal 
to participate will involve no penalty or loss of benefits to which you are otherwise entitled. 
 
Instead of being in this research study, your choices may include: Enrollment in another 
clinical trial that you may qualify for, standard chemotherapy treatment, or radiation.  An 
additional alternative is to accept no further therapy, with palliative care to help you feel more 
comfortable, an option that would probably result in continued progression of the disease. 
Please discuss these options with your regular doctor as well as other trusted personal and 
family advisors. Your treating physician will discuss any potential risks or complications 
associated with alternative treatments with you. 
 
Important risks and possible benefits of these alternatives:  
Because there are no known curative choices for relapsed neuroblastoma and 
medulloblastoma, alternative therapies could possibly lead to more or less side effects, and 
may decrease your chance of being cured.  The risk of no further therapy is that your HRM 
will get worse, and the benefit to choosing no further therapy will be receiving fewer 
interventions. Your treating physician will discuss the comparative risks and benefits for the 
treatments available for your type of HRM. 
 
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What happens if I say yes, but I change my mind later? 
You can agree to take part in the research now and stop at any time it will not be held 
against you. 
Discontinuing participation will not result in penalty or loss of benefits to which you are 
otherwise entitled.  
 
If you decide to leave the research, contact your study doctor immediately so you can talk 
about alternative treatment options.  You will be asked to come back to the clinic 30-37 days 
after your last dose of Nifurtimox for a follow-up visit.  The reason for this visit is to make sure 
you are safe, and to make sure you are not having any problems from stopping the 
Nifurtimox.  The following procedures will be done at this visit: 
 Physical exam, including a neurological exam 
 Neurologic Structured Interview 
 Labs as described in the “Before Study Entry” section 
 Urine catecholamines (neuroblastoma subjects) 
 
In addition, we will collect information about the status of your disease periodically for a year 
after your last dose of Nifurtimox.  We will either meet with you during routine follow-up 
appointments or we will contact you by phone at the following intervals: 
 2 months 
 3 months 
 5 months 
 7 months 
 9 months 
 1 year 
 
If you stop being in the research, already collected data may not be removed from the study 
database. You will be asked whether the investigator can continue to collect data from your 
routine medical care. If you agree, this data will be handled the same as research data. 
 
Could being in this study be bad for me? 
There may be some risks in this research study that we do not know at this time.  If we learn 
things, such as new findings, that we think might affect your desire to continue to participate 
in this study, we will tell you. If major risks are discovered after the study is finished, the 
sponsor may attempt to contact you. 
 
There might be other side effects that we do not know about yet because Nifurtimox has not 
been widely used to treat tumors in children.  These side effects could be dangerous or life 
threatening.  Side effects of Nifurtimox usually get better if the treatment is stopped, but there 
is the potential that side effects may persist even after stopping the drug.  With drugs like 
cyclophosphamide and topotecan, there is the risk of death due to side effects.  You should 
talk to your study doctor about any side effects that you have while taking part in the study. 
 
The possible side effects of the study treatment are listed in the following tables: 
 
 
 
 
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Risks and side effects related to Nifurtimox: 
 
Common 
Occasional 
Rare 
Seen in 21-100 
kids out of 100 
Seen in 5-20 
kids out of 
100 
Seen in less than 5 kids out of 100 
While taking 
Nifurtimox: 
 Gastrointestinal 
disturbances, such 
as anorexia with 
weight loss (loss of 
appetite), 
epigastric pain 
(abdominal or 
stomach pain), 
nausea and/or 
vomiting occur in 
20-80% of 
patients.   
Skin rash, 
headache or 
vertigo 
(dizziness) 
Central nervous system  toxicity including 
disorientation (confusion ), disturbances of 
equilibrium such as ataxia (clumsiness or 
unsteadiness), and nystagmus 
(uncontrolled back-and-forth and/or rolling 
eye movements ); excitation, 
forgetfulness, insomnia (trouble sleeping ), 
irritability, psychosis (mood or mental 
changes ), seizures (convulsions), muscle 
weakness, peripheral neuropathy 
(numbness, tingling, pain, or weakness in 
hands or feet)  and tremors; a high 
eosinophil count (a kind of white blood 
cell), fever, impotence (decreased sexual 
drive or ability), or a low white blood cell 
count with a risk of  infection can occur 
with high doses  
. 
Late: Any time 
after end of 
treatment 
There are no known late side effects of nifurtimox at this time. 
 
Risks and side effects related to Cyclophosphamide: 
Likely 
Less Likely 
Rare But Serious 
 
Loss of appetite 
 
Nausea  
 
Vomiting  
 
Fewer white blood cells 
in the blood. 
○ A low number of 
white blood cells 
may make it easier 
to get infections. 
 
Hair loss 
 
Decreased ability of the 
body to fight infection  
 
Absence  or decrease 
in the number of  sperm 
which may be 
temporary or 
permanent which may 
decrease the ability to 
have children 
 
 
 Abnormal hormone function 
which may lower the level of 
salt in the blood  
 Abdominal pain 
 Diarrhea 
 Fewer red blood cells and 
platelets in the blood 
○ A low number of red 
blood cells may make 
you feel tired and weak. 
○ A low number of platelets 
may cause you to bruise 
and bleed more easily. 
 Bleeding and inflammation of 
the urinary bladder 
 Absence  or decrease 
monthly periods which may 
be temporary or permanent 
and which may decrease the 
ability to have children 
 
Heart muscle damage which 
may occur with very high doses 
and which may be fatal 
 
Abnormal heart rhythms 
 
Damage and scarring of lung 
tissue which may make you 
short of breath 
 
A new cancer or leukemia 
resulting from this treatment. 
 
Damage or scarring of urinary 
bladder tissue 
 
Severe allergic reaction which 
can be life threatening with 
shortness of breath, low blood 
pressure, rapid heart rate chills 
and fever 
 
Infertility which is the inability to 
have children 
 
 
 
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Risks and side effects related to Filgrastim (G-CSF) or Pegfilgastim include: 
Likely 
Less Likely 
Rare but serious 
Aching or 
pain in the 
bones 
 
 
Pain, redness, itching, and 
hardening of the skin and bruising 
at the site of the injection 
 
Headache 
 
Higher than normal levels of liver 
enzymes in the blood which may 
indicate liver irritation or damage 
 
Increase of uric acid in the blood 
 
A low number of platelets in the 
blood which may cause you to 
bruise and bleed more easily 
 
Low fever 
 
Enlargement of the spleen (an 
organ in the abdomen/belly which 
stores blood cells) which may cause 
pain in the abdomen or left shoulder 
 
Higher than normal white blood 
count 
 
Skin condition marked by fever and 
painful skin lesions that appear 
mainly on the face, neck, back and 
arms  
 
Rash or worsening of rash1 
 
Inflammation of blood vessels in the 
skin leading to a raised purple rash 
and bruising has been seen mainly 
in patient who are treated for a long 
time1 
Overall reddening with feelings of 
warmth2 
 
Allergic reactions which can be life 
threatening with shortness of 
breath, low blood pressure, rapid 
heart rate, hives, itching, and facial 
swelling.  
 
Serious allergic reaction which can 
be life threatening with rapid build-
up of fluid under the skin, in the 
lining of the intestine, and possibly 
in the throat or swelling of the 
tongue which could make it difficult 
to breath2 
 
If you are known to have sickle cell 
disease, filgrastim or pegfilgrastim 
may cause a sickle cell crisis. 
 
Severe damage to the spleen (an 
organ in the abdomen/belly which 
stores blood cells) which could lead 
to pain and loss of blood into the 
abdomen (belly) and maybe life 
threatening 
 
Difficulty breathing and lung 
damage that may be due to the 
white blood cells that are stimulated 
by filgrastim or pegfilgrastim 
traveling to the lungs when they are 
inflamed or infected. 
 
A blood disorder or leukemia that 
has only been seen in patients with 
certain immune disorders who are 
treated for a very long time1 
1 Reported with filgrastim 
2 Reported with pegfilgrastim 
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Risks and side effects related to Topotecan: 
Likely 
Less Likely 
Rare But Serious 
 
Diarrhea  
 
Nausea 
 
Vomiting  
 
Constipation 
 
Fewer white blood cells, red 
blood cells and platelets in 
the blood. 
o A low number of white 
blood cells can make it 
easier to get infections 
o A low number of red 
blood cells can make you 
feel tired and weak 
o A low number of platelets 
causes you to bruise and 
bleed more easily 
 
Fever including fever with a 
low white blood cell count 
which could indicate infection 
and may require 
hospitalization and treatment 
with antibiotics 
 
Pain which may be in your 
abdomen, back or bones 
 
A feeling of weakness and/or 
tiredness 
 
Temporary hair loss 
 
 
Loss of appetite 
 
Elevation in the blood of 
certain enzymes or bilirubin 
found in the liver which 
could indicate liver irritation 
or damage 
 
Headache 
 
Rash, hives, itching or a red 
bumpy rash 
 
A mild lowering of the blood 
pressure which usually 
does not require treatment 
 
Inflammation and/or sores 
in the mouth, throat and/or 
esophagus 
 
An infection in the blood 
which will require admission 
to the hospital and 
treatment with antibiotics 
 
Numbness and tingling in 
the fingers and toes 
 
Small amount of blood 
and/or protein in the urine 
or an elevation in blood 
creatinine which may 
indicate mild kidney 
damage 
 
Shortness of breath 
 
Muscle or joint aches and 
pains 
 
Chest pain 
 
Shaking chills 
 
Severe allergic 
reaction which can be 
life threatening with 
shortness of breath, 
low blood pressure and 
a rapid heart rate 
 
Severe allergic 
reaction which can be 
life threatening with 
rapid build-up of fluid 
under the skin, in the 
lining of the intestine 
and possibly in the 
throat or swelling of the 
tongue which could 
make it difficult to 
breath. 
 
Bleeding into the tumor 
which may cause 
damage depending on 
the location of the 
tumor 
 
Possible Drug Interactions with Nifurtimox 
Propofol is a drug that is used for sedation (anesthesia).  You may receive propofol if you 
have surgery, or a procedure that requires you be sedated such as a bone marrow 
aspiration, CT Scan, or MRI scan. 
 
In a previous study using Nifurtimox in this population, there have been some possible 
incidences of what seems to be an interaction between Nifurtimox and extended use of 
propofol (greater than 1 hour).  We are currently recommending that for any procedure that 
will use propofol for greater than 1 hour, the study drug (Nifurtimox) be held for 24 hours prior 
to the procedure. If the Nifurtimox cannot be held for 24 hours prior to a procedure that might 
use extended length (greater than 1 hour) of propofol, we would request an alternative 
medicine be used for sedation.  This will be at your treating physician’s discretion. We have 
not seen any incidences of increased side effects with short duration use of propofol (less 
than 1 hour) at this time.  
 
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Although the risk of seizures using Nifurtimox alone, in otherwise healthy people, at the 
20mg/kg dose level is rare (less than 5 in 100 people), in the Phase I study, we noticed an 
increased risk of seizures as the Nifurtimox dose level increased.  We observed a 1 in 3 
chance of a seizure while on the higher dose level (40mg/kg/day of Nifurtimox) in our study 
patients.   
 
If you have a history of seizures, it is recommended that you start on an anti-seizure 
medication prior to starting this study.  You can discuss this with the study doctor during 
screening.  If you experience a seizure while on study, we ask that you contact your 
physician immediately.   You will then receive an MRI to try to determine if there is a specific 
cause, other than the Nifurtimox, for the seizure.  We would then most likely start you on an 
anti seizure medication, as long as you continue on the Nifurtimox, to prevent any further 
seizures. 
 
Under Michigan law, an HIV and hepatitis test may be done on you (or your child) without 
your consent if a healthcare worker is exposed to your (or your child’s) blood or other bodily 
fluids. If the results of an HIV or hepatitis test indicate that you (or your child) are HIV or 
hepatitis positive, you will be told about these results and given information about the 
disease, treatment resources, and other options. 
 
 
Possible Drug Interactions between Nifurtimox and Metronidazole 
Metronidazole is a drug that is used to treat diarrhea caused by infection with Clostridium 
difficile, a spore-forming bacterium. 
 
During the course of this study there have been two incidences of severe neurotoxicity that 
may have been possibly related to an interaction between metronidazole and nifurtimox. 
Although it has not been absolutely determined that it was this combination of drugs that 
caused the symptoms, due to the possibility that it was the combination, we are requesting 
that these two drugs not be used together. Please discuss any planned metronidazole use 
with your study doctor.   
 
 
Pregnancy/Birth Control:  
If you are or become pregnant during this study, there may be additional risks to you, or to 
your baby.  Some of these risks may be known, but some risks may not be known and may 
not be foreseeable.  Because the risks to embryo/fetus/unborn babies and babies who are 
breast feeding may not be known or foreseeable, pregnant women and nursing mothers are 
not allowed to join this study. If you are a woman who can get pregnant, you should not 
become pregnant during this study. 
 
Both male and female study subjects, of child-bearing age, need to agree to use one of the 
more effective birth control methods during treatment and for six months after treatment is 
stopped.  These methods include total abstinence (no sex), oral contraceptives (“the pill”), an 
intrauterine device (IUD), levonorgestrol implants (Norplant), or medroxyprogesterone 
acetate injections (Depo-provera shots).  If one of these cannot be used, contraceptive foam 
with a condom is recommended. 
 
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If you think you are pregnant or if you become pregnant during the study, you must tell the 
study doctor right away.  It is important to tell your doctor because there may be risks to you 
or your baby if you continue in the study. 
 
Women who can get pregnant must have a negative urine pregnancy test before being 
allowed to join in this study.   
 
In addition to these risks, this research may hurt you in ways that are unknown. If we learn of 
new risks that we think might affect your desire to stay in the research we will tell you.  It is 
possible, if major risks are discovered after the study is finished, the sponsor may attempt to 
contact you. 
 
 
 
Will I need to pay for any of the tests or procedures in the study? 
Taking part in this research study may lead to added costs to you. You or your health 
insurance company will be responsible for the costs of all standard medical care (including 
physician visits, tests, procedures, evaluations) and/or hospitalizations.  You or your health 
insurance will be billed for this procedure.  If your insurance company requires any co-
payment or deductible, you will be responsible for making that payment.   
While you are a participant in this study, Nifurtimox will be provided at no cost by Bayer 
Pharmaceuticals, the manufacturer of Nifurtimox.  You will not have to pay for the 
pharmacokinetic studies, or the blood tests monitoring the blood level of Nifurtimox. 
 
Will being in this study help me in any way? 
It is possible that treatment with the study medication may result in improvement of your 
disease; however, this has not yet been proven.  You may not benefit from your participation 
in this study. The information we learn in this study may help us to better understand your 
disease or illness and may help develop new ways to diagnose and treat it. 
 
What happens to the information you collect? 
Efforts will be made to limit your personal information, including research study and medical 
records, to people who have a need to review this information. We cannot promise complete 
confidentiality. Organizations that may inspect and copy your information for quality 
assurance and data analysis include: 
 
The Investigator and his/her research staff 
 
Spectrum Health and its affiliates 
 
The Spectrum Health Institutional Review Board (IRB) and staff 
 
Representatives from  the Food and Drug Administration (FDA) or other 
governmental regulatory agencies 
 
Bayer Pharmaceuticals (the manufacturer of Nifurtimox), 
 
Representatives from Helen DeVos Children’s Hospital-Spectrum Health, 
 Representatives from the Neuroblastoma and Medulloblastoma Translational 
Research Consortium (NMTRC) and its affiliates. 
 
Your primary care provider 
 
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Some of these organizations may be given direct access to your medical records for 
verification of the research procedures/date involved.  By signing this document you are 
authorizing this access. 
 
The information collected for this study that is sent to the sponsor is the property of the 
sponsor, and you will not be able to get it back. Your information is protected by keeping your 
information in a safe place, limiting the people who have access to your information, and 
limiting how the information may be used.  Each subject will be given a unique identifier 
number.  This unique identifier will be kept on a “Subject Identification Log” at each site.  
Details about permitted uses and disclosures of your information are described under the 
HIPAA Authorization section of this document.  We may publish the results of this research. 
However, we will keep your name and other identifying information confidential. 
 
Federal law provides additional protections of your personal information. These are 
described in a later section. 
 
 
Can I be removed from the research without my OK? 
The person in charge of the research study or the sponsor can remove you from the 
research study without your approval.  Possible reasons for removal include if he or she 
believes it is in your best interest, if you do not follow the study requirements, or if the study 
is stopped.   
 
If you are removed from the study without your OK, you will be asked to come back to the 
clinic 30 days after your last dose of Nifurtimox for a follow-up visit.  The reason for the visit 
is to make sure you are safe and that you are not having any problems from stopping the 
Nifurtimox.  The following procedures will be done at this visit: 
 Physical exam, including a neurological exam 
 Neurologic Structured Interview 
 Labs as described in the “Before Study Entry” section 
 Urine catecholamines (neuroblastoma patients) 
We will contact your treating physician periodically for a year after your last dose of 
Nifurtimox to collect data on your disease status.    
 
What if I’m injured or made sick from the research? 
If you are injured or made sick from taking part in this research study, medical care will be 
provided. No funds have been set aside to pay you in the event of a research related injury.  
Contact the investigator for more information. By signing this consent form you will not be 
waiving any of your legal rights which you otherwise would have if you were not participating 
in a research study. 
 
What else do I need to know? 
You will not be paid for participating in this study. 
 
This study is or will be listed in an online registry.  U.S. law requires this.  A registry is a place 
where information is collected.  You can see this registry at the website www.ClinicalTrials.gov.  
The U.S. government runs this website.  You and anyone else can visit this website at 
anytime.  You can get information about this study and other studies on this website.  Your 
personal information will NOT be shown on the website. 
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Dr. Giselle Sholler, a sub-Investigator at Helen DeVos Children’s Hospital, serves as the 
Chair of the Neuroblastoma and Medulloblastoma Translational Research Consortium (the 
sponsor of this trial), and may benefit financially based on the trial outcome.  Therefore, Dr. 
Sholler has agreed to not take part in patient enrollment and informed consent for this trial.  
Should you have any concerns or questions regarding this statement please feel free to 
speak further with the research team or you may call the Spectrum Health Institutional 
Review Board at 
. 
 
HIPAA Authorization for Release of Health Information for Research Purposes 
The information we are asking to use and share is called “Protected Health Information.”  It is 
protected by a federal law called the Privacy Rule of the Health Insurance Portability and 
Accountability Act (HIPAA).  In general, we cannot use or share your health information for 
research without your permission. 
 
 
What will be done with my information? 
This information will be collected and entered in a database along with the information from 
other people taking part in this study.   
 
Why am I being asked to release it? 
Your health information will be used to determine if Nifurtimox, either alone or in combination 
with other chemotherapy drugs, will shrink neuroblastoma or Medulloblastoma cells.  
 
What will be released? 
To complete this research study, we will need to collect and release (disclose) information 
about you.   
This information may include:    
 Your date of birth, name, contact information, medical record number, and insurance 
information. 
 Existing and ongoing medical records and medical history. 
 New health information collected for purposes of this study. 
 
Who will use it or share it? 
 The investigator and his/her research staff  
 Spectrum Health and its affiliates 
 The Spectrum Health Institutional Review Board (IRB) and its staff 
 The Food and Drug Administration (FDA) 
 The Sponsor of the research: Neuroblastoma and Medulloblastoma Translational 
Research Consortium (NMTRC) and its affiliates 
 Bayer Pharmaceuticals (the manufacturer of Nifurtimox) 
 Other collaborating institutions 
 Agencies that accredit the hospital or the research program 
 
Once your protected health information has been disclosed it is possible that anyone who 
receives that information may re-disclose it. Because some of these individuals who receive 
your protected health information may not be required by law to keep your information 
confidential, we cannot guarantee that your information will not be released or made 
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available to another party once it leaves Spectrum Health. Therefore, we share your 
information only if necessary and we use all reasonable efforts to request that those 
individuals who receive your information take steps to protect your privacy. 
 
How long will my health information be used? 
This authorization has no expiration date.  
 
Can I stop my protected health information from being used? 
You can tell us to stop using and sharing health information that can be traced to you at any 
time.  We will stop, except in very limited cases if needed to comply with law, protect your 
safety, or make sure the research was done properly.  If you have any questions about this 
please ask. If you want us to stop, you must tell us in writing.  Write Dr. Deanna Mitchell at 
the following address: 
 
Deanna Mitchell, MD 
 
 
 
 
 
What happens if I do not want you to collect and release my information? 
If you decide not to authorize release of your health information as part of this study, your 
decision will in no way affect your medical care or cause you to lose any benefits to which 
you are entitled.  You cannot participate in this research study if you do not authorize the use 
or release of your PHI. 
 
When will it be destroyed? 
We do not know when your information will no longer be used therefore the information will 
be kept for an indefinite length of time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SH IRB Approved On: 01/19/16 
Do Not Use After: 08/03/16


Nifurtimox Version: 12/7/2015 
Page 19 of 21 
 
ADDITIONAL OPTIONAL TUMOR BIOLOGY CONSENT 
 
This part of the study is optional.  You can still be in the Nifurtimox study if you decide you 
don’t want to be in this part of the study.  If you agree to allow your samples to be stored for 
future research, your blood, bone marrow and tumor samples will be stored in a safe and 
confidential area for up to 20 years.  You have the option to remove your samples from the 
laboratory at any time.  If in future, if you ask that your stored samples be destroyed, it is 
important to know that any research that has already been done on the samples cannot be 
changed.  No matter what you decide to do, it will not affect the care that you will get. 
 
Because these tests are for research only, usually your study doctor or you will not know the 
results. It is very unlikely that the research testing might find important information about your 
current or future health. If this unlikely event happens, the researchers may contact your 
doctor about what the research test results might mean. Only your doctor will be notified and 
the information will not become part of your medical record. Your doctor may discuss this 
unexpected finding with you, and may recommend that you see a genetic counselor and/or 
repeat testing in a clinical (not research) laboratory if needed. It is possible that your doctor 
may decide that no action is needed. 
 
I agree to have my blood, bone marrow and tumor samples, obtained as part of my regular 
care, sent to a special neuroblastoma/medulloblastoma laboratory for research studies that 
will not directly impact my treatment, but the results of these research studies may benefit 
future children with neuroblastoma or medulloblastoma.  
 
YES_______        NO_______   (initials)       Date_____/______/_________ 
 
 
I agree to have any leftover blood, bone marrow and tumor samples from the above optional 
biology studies saved in a neuroblastoma/medulloblastoma laboratory to be used for cancer 
and/or Nifurtimox research in the future. 
 
YES_______        NO_______   (initials)       Date_____/______/_________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SH IRB Approved On: 01/19/16 
Do Not Use After: 08/03/16


Nifurtimox Version: 12/7/2015 
Page 20 of 21 
 
Signature Block for Minor Participants: 
Your signature below documents your permission for the child named below to take part in 
this research and to the use and disclosure of this child’s protected health information. You 
will receive a signed copy of this complete form. 
 
 
Printed name of child 
 
 
 
Signature of parent or guardian 
 
Date 
 
 Parent 
 Guardian (See note below) 
Printed name of parent or guardian 
Note on permission by guardians: An individual may provide permission for a child only if that individual can 
provide a written document indicating that he or she is legally authorized to consent to the child’s general 
medical care. Attach the documentation to the signed document. 
 
 
 
 
Signature of person obtaining consent  
 
Date 
 
 
 
Printed name of person obtaining consent  
 
 
 
 
 
Signature Block for Capable Adult Participant: 
Your signature below documents your permission to take part in this research and to the 
use and disclosure of your protected health information.  You will receive a signed copy of 
this complete form. 
 
 
 
Signature of participant 
 
Date 
 
 
Printed name of participant 
 
 
 
Signature of person obtaining consent 
 
Date 
 
 
 
Printed name of person obtaining consent 
 
 
 
 
 
  
 
 
 
 
 
SH IRB Approved On: 01/19/16 
Do Not Use After: 08/03/16


Nifurtimox Version: 12/7/2015 
Page 21 of 21 
 
Signature Block for Non-English Speaking: Short Form 
Your signature below documents your permission to take part in this research and to the 
use and disclosure of your protected health information. You will receive a signed copy of 
this complete form. 
 
 
 
Signature of participant 
 
Date 
 
 
Printed name of participant 
 
 
 
Signature of person obtaining consent 
 
Date 
 
 
 
Printed name of person obtaining consent 
 
 
 
 
I certify that I have interpreted, to the best of my ability, in the participant’s stated primary language, all oral 
presentations made by all of those present during the informed consent discussion. 
 
 
 
Signature of Interpreter 
 
Date 
 
 
Printed name of Interpreter 
 
 
 
SH IRB Approved On: 01/19/16 
Do Not Use After: 08/03/16