A Phase 1 Trial of the CD123 X CD3 DART Molecule Flotetuzumab (NSC#808294) in Children, Adolescents, and Young Adults With Relapsed or Refractory Acute Myeloid Leukemia
Phase: PHASE1
Conditions: Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia
Sponsor: Children's Oncology Group

 
V ersi o n  D at e:  0 7/ 0 8/ 2 0 
 
P a g e  1  
P E P N 1 8 1 2  
 
A  P H A S E  1  T RI A L  O F  T H E  C D 1 2 3  X  C D 3  D A R T ®  M O L E C U L E  F L O T E T U Z U M A B 
( N S C # 8 0 8 2 9 4, 
) IN  C HI L D R E N,  A D O L E S C E N T S,  A N D  Y O U N G  A D U L T S 
WI T H  R E L A P S E D  O R  R E F R A C T O R Y  A C U T E  M Y E L OI D  L E U K E MI A  
 
L e a d  O r g a ni z ati o n:  C O G  P e di at ri c  E a rl y  P h as e  Cli ni c al  T ri als  N et w o r k ( P E P -C T N)  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
F or  P E P -C T N  O p er ati o ns  a n d  D at a/ St atisti cs  C o nt a cts s e e:  htt p:// m e m b ers. c hil dr e ns o n c ol o g y gr o u p. or g  
A cti v at e d:   0 1/ 0 6/ 2 0  
V ersi o n  D at e:   
0 7/ 0 8/ 2 0  
Cl os e d:   
   0 4/ 0 8/ 2 2  
A m e n d m e nt  #:    
1  
 
 
 
 
 
 
T HI S  P R O T O C O L I S  F O R  R E S E A R C H  P U R P O S E S  O N L Y , A N D  S H O U L D  N O T  B E  C O PI E D , 
R E DI S T RI B U T E D  O R  U S E D  F O R  A N Y  O T H E R  P U R P O S E .  M E DI C A L  A N D  S CI E N TI FI C I N F O R M A TI O N 
C O N T AI N E D  WI T HI N  T HI S  P R O T O C O L I S  N O T I N C L U D E D  T O  A U T H O RI Z E  O R  F A CI LI T A T E  T H E 
P R A C TI C E  O F  M E DI CI N E  B Y  A N Y  P E R S O N  O R  E N TI T Y .  R E S E A R C H  M E A N S  A  S Y S T E M A TI C 
I N V E S TI G A TI O N, I N C L U DI N G  R E S E A R C H  D E V E L O P M E N T, T E S TI N G  A N D  E V A L U A TI O N , D E SI G N E D 
T O  D E V E L O P  O R  C O N T RI B U T E  T O  G E N E R A LI Z A B L E  K N O W L E D G E .  T HI S  P R O T O C O L I S  T H E 
R E S E A R C H  P L A N  D E V E L O P E D  B Y  T H E  C HI L D R E N ’S  O N C O L O G Y  G R O U P  T O I N V E S TI G A T E  A 
P A R TI C U L A R  S T U D Y  Q U E S TI O N  O R  S E T  O F  S T U D Y  Q U E S TI O N S  A N D  S H O U L D N O T  B E  U S E D  T O 
DI R E C T  T H E  P R A C TI C E  O F  M E DI CI N E  B Y  A N Y  P E R S O N  O R  T O  P R O VI D E I N DI VI D U A LI Z E D 
M E DI C A L  C A R E , T R E A T M E N T , O R  A D VI C E  T O  A N Y  P A TI E N T  O R  S T U D Y  S U B J E C T .  T H E 
P R O C E D U R E S I N  T HI S  P R O T O C O L  A R E I N T E N D E D  O N L Y  F O R  U S E  B Y  C LI NI C A L  O N C O L O GI S T S I N 
C A R E F U L L Y  S T R U C T U R E D  S E T TI N G S , A N D  M A Y  N O T  P R O V E  T O  B E  M O R E  E F F E C TI V E  T H A N 
S T A N D A R D  T R E A T M E N T .  A N Y  P E R S O N  W H O  R E Q UI R E S  M E DI C A L  C A R E I S  U R G E D  T O  C O N S U L T 
WI T H  HI S  O R  H E R  P E R S O N A L  P H Y SI CI A N  O R  T R E A TI N G  P H Y SI CI A N  O R  VI SI T  T H E  N E A R E S T  L O C A L 
H O S PI T A L  O R  H E A L T H C A R E I N S TI T U TI O N . 

                             
P E P N 1 8 1 2 
                                     
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 2 
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 
 
P E P N 1 8 1 2 
1  
S T U D Y C O M MI T T E E 
5  
A B S T R A C T 
7  
E X P E RI M E N T A L D E SI G N S C H E M A 
7  
1. 0   
G O A L S A N D O BJ E C TI V E S ( S CI E N TI FI C AI M S) 
8  
1. 1   
Pri mar y Ai ms 
8  
1. 2   
Sec o n dar y Ai ms 
8  
1. 3   
E x pl orat or y Ai ms 
8  
2. 0   
B A C K G R O U N D 
9  
2. 1   
I ntr o d ucti o n/ Rati o nale f or De vel o p me nt 
9  
2. 2   
Precli nical St u dies 
9  
2. 3   
Cli nical St u dies i n A d ults 
1 2  
2. 4   
Pe diatric St u dies 
1 3  
2. 5   
O ver vie w of Pr o p ose d Pe diatric St u d y 
1 3  
3. 0   
S C R E E NI N G A N D S T U D Y E N R O L L M E N T P R O C E D U R E S 
1 5  
3. 1   
C urre nt St u d y Stat us 
1 5  
3. 2   
I R B A p pr o val 
1 5  
3. 3   
Patie nt Re gistrati o n 
1 6  
3. 4   
Reser vati o n a n d C o ntact Re q uire me nts 
1 6  
3. 5   
I nf or me d C o nse nt/ Asse nt 
1 6  
3. 6   
Scree ni n g Pr oce d ures 
1 6  
3. 7   
Eli gi bilit y C hec klist 
1 6  
3. 8   
I nstit uti o nal Pat h ol o g y Re p ort 
1 6  
3. 9   
St u d y E nr oll me nt 
1 7  
3. 1 0   
D ose Assi g n me nt 
1 7  
4. 0   
P A TI E N T E LI GI BI LI T Y 
1 7  
4. 1   
I ncl usi o n Criteria 
1 7  
4. 2   
E xcl usi o n Criteria 
2 1  
5. 0   
T R E A T M E N T P R O G R A M 
2 2  
5. 1   
O ver vie w of Treat me nt Pla n 
2 2  
5. 2   
Criteria f or Starti n g S u bse q ue nt C ycles 
2 6  
5. 3   
D ose Escalati o n Sc he ma  
2 6  
5. 4   
Gra di n g of A d verse E ve nts 
2 7  
5. 5   
Defi niti o n of D ose- Li miti n g T o xicit y ( D L T) 
2 7  
6. 0   
D O S E M O DI FI C A TI O N S F O R A D V E R S E E V E N T S 
2 8  
6. 1   
D ose M o dificati o ns f or He mat ol o gical T o xicit y 
2 8  
6. 2   
D ose M o dificati o ns f or N o n- He mat ol o gical T o xicit y 
2 9  
6. 3   
D ose M o dificati o ns f or I nf usi o n- Relate d Reacti o ns a n d C yt o ki ne Release S y n dr o me  
2 9  
6. 4   
D ose M o dificati o ns f or Ca pillar y Lea k S y n dr o me 
3 4  
7. 0   
S U P P O R TI V E C A R E A N D O T H E R C O N C O MI T A N T T H E R A P Y 
3 5  
7. 1   
C o nc urre nt A ntica ncer T hera p y 
3 5  
7. 2   
I n vesti gati o nal A ge nts 
3 5  
7. 3   
S u p p orti ve Care 
3 5  

                             
P E P N 1 8 1 2 
                                     
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 3 
7. 4   
Gr o wt h Fact ors 
3 5  
7. 5   
C o nc o mita nt Me dicati o ns 
3 5  
8. 0   
E V A L U A TI O N S/ M A T E RI A L A N D D A T A T O B E A C C E S SI O N E D 
3 5  
8. 1   
Re q uire d Cli nical, La b orat or y a n d Disease E val uati o n 
3 5  
8. 2   
P har mac ol o g y ( Re q uire d) 
3 7  
8. 3   
I m m u n o ge nicit y St u d y ( Re q uire d) 
4 0  
8. 4   
Baseli ne C D 1 2 3 Site De nsit y Q ua ntificati o n ( O pti o nal) 
4 2  
8. 5   
N G S M R D C o m paris o n wit h Fl o w C yt o metr y M R D ( O pti o nal) 
4 2  
8. 6   
C D 3 T- L y m p h oc yte Q ua ntificati o n ( O pti o nal) 
4 4  
8. 7   
C yt o ki ne Pr o d ucti o n Meas ure me nt ( O pti o nal) 
4 4  
8. 8   
Pr ofili n g of t he T u m or Micr oe n vir o n me nt ( O pti o nal) 
4 5  
9. 0   
A G E N T I N F O R M A TI O N 
4 7  
9. 1   
Fl otet uz u ma b 
4 7  
9. 2   
C ytara bi ne                 ( 0 7/ 1 3/ 1 5) 
6 0  
9. 3   
Usef ul Li n ks a n d C o ntacts 
6 1  
1 0. 0   
C RI T E RI A F O R R E M O V A L F R O M P R O T O C O L T H E R A P Y A N D O F F S T U D Y 
C RI T E RI A 
6 1  
1 0. 1   
Criteria f or Re m o val fr o m Pr ot oc ol T hera p y 
6 1  
1 0. 2   
Off St u d y Criteria 
6 2  
1 1. 0   
S T A TI S TI C A L A N D E T HI C A L C O N SI D E R A TI O N S 
6 2  
1 1. 1   
Sa m ple Size a n d St u d y D urati o n 
6 2  
1 1. 2   
Defi niti o ns 
6 3  
1 1. 3   
D ose Escalati o n a n d Deter mi nati o n of M T D 
6 4  
1 1. 4   
I ncl usi o n of C hil dre n, W o me n a n d Mi n orities 
6 5  
1 1. 5   
P har mac o ki netic a n d C orrelati ve St u dies a n d Res p o nse A nal ysis 
6 6  
1 2. 0   
E V A L U A TI O N C RI T E RI A 
6 6  
1 2. 1   
C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) 
6 6  
1 2. 2   
Res p o nse Criteria f or Patie nts wit h Le u ke mia 
6 6  
1 2. 3   
C N S Le u ke mia at Dia g n osis 
6 8  
1 3. 0   
A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S 
6 9  
1 3. 1   
Ste ps t o Deter mi ne If a n A d verse E ve nt Is T o Be Re p orte d I n a n E x pe dite d Ma n ner  
6 9  
1 3. 2   
W he n t o Re p ort a n E ve nt i n a n E x pe dite d Ma n ner 
7 1  
1 3. 3   
E x pe dite d Re p orti n g Met h o ds 
7 2  
1 3. 4   
Defi niti o n of O nset a n d Res ol uti o n of A d verse E ve nts 
7 2  
1 3. 5   
Ot her Reci pie nts of A d verse E ve nt Re p orts 
7 2  
1 3. 6   
Sec o n dar y Mali g na nc y: 
7 3  
1 3. 7   
Re p orti n g Pre g na nc y, Fetal Deat h, a n d Deat h Ne o natal 
7 3  
1 4. 0   
R E C O R D S, R E P O R TI N G, A N D D A T A A N D S A F E T Y M O NI T O RI N G P L A N 
7 4  
1 4. 1   
Cate g ories of Researc h Rec or ds 
7 4  
1 4. 2   
C D U S  
7 4  
1 4. 3   
Data a n d Safet y M o nit ori n g Pla n 
7 4  
R E F E R E N C E S 
7 6  
A P P E N DI X I: P E R F O R M A N C E S T A T U S S C A L E S/ S C O R E S 
7 8  
A P P E N DI X II: C O R R E L A TI V E S T U DI E S G UI D E 
7 9  
A P P E N DI X III: T O XI CI T Y - S P E CI FI C G R A DI N G 
8 0  

                             
P E P N 1 8 1 2 
                                     
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 4 
A P P E N DI X I V- A: T H E R A P Y D E LI V E R Y M A P F O R C Y C L E 1, D O S E L E V E L 1  
8 1  
A P P E N DI X I V- B: T H E R A P Y D E LI V E R Y M A P F O R C Y C L E 1, D O S E L E V E L - 1 
8 5  
A P P E N DI X I V- C: T H E R A P Y D E LI V E R Y M A P F O R C Y C L E 1, D O S E L E V E L 2 
8 9  
A P P E N DI X V: T H E R A P Y D E LI V E R Y M A P F O R C Y C L E S 2 + 
9 3  
A P P E N DI X VI- A: P H A R M A C O KI N E TI C S T U D Y F O R M F O R P A TI E N T S O N D L 1 
9 7  
A P P E N DI X VI- B: P H A R M A C O KI N E TI C S T U D Y F O R M F O R P A TI E N T S O N D L- 1 
9 9  
A P P E N DI X VI- C: P H A R M A C O KI N E TI C S T U D Y F O R M F O R P A TI E N T S O N D L 2 
1 0 1  
A P P E N DI X VII: I M M U N O G E NI CI T Y S T U D Y F O R M 
1 0 3  
A P P E N DI X VIII: B A S E LI N E C D 1 2 3 SI T E D E N SI T Y Q U A N TI FI C A TI O N S T U D Y F O R M  
1 0 4  
A P P E N DI X I X: N G S M R D C O M P A RI S O N WI T H F L O W C Y T O M E T R Y M R D S T U D Y F O R M  
1 0 5  
A P P E N DI X X: C D 3 T- L Y M P H O C Y T E Q U A N TI FI C A TI O N S T U D Y F O R M 
1 0 6  
A P P E N DI X XI: C Y T O KI N E A N A L Y SI S 
1 0 7  
A P P E N DI X XII: T U M O R MI C R O E N VI R O N M E N T S T U D Y F O R M 
1 0 8  
A P P E N DI X XIII: C T E P A N D C T S U R E GI S T R A TI O N P R O C E D U R E S 
1 0 9  
A P P E N DI X XI V: R E Q UI R E M E N T S F O R P O T E N TI A L S A T E L LI T E P H A R M A C Y SI T E S  
1 1 2  
A P P E N DI X X V: P A TI E N T C LI NI C A L T RI A L W A L L E T C A R D 
1 1 3  
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 5 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
   
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
   
 
 
  
 
 
   
  
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
   
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
I N D S p o ns or: C O G  
 
 
F or P E P -C T N O perati o ns a n d Data/ Statistics  C o ntacts see: htt p: me m bers.c hil dre ns o nc ol o g y gr o u p. or g  
 
S E E S E C TI O N S 8. 2. 6 , 8. 3. 5 , 8. 4. 5 , 8. 5. 6 , 8. 7. 6 , A N D  8. 8. 6  F O R S P E CI M E N S HI P PI N G 
A D D R E S S E S  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 7 
T h is trial is c o vere d b y a Certificate of C o nfi de ntialit y fr o m t he fe deral g o ver n me nt, w hic h will hel p us 
pr otect t he pri vac y of o ur researc h s u bj ects.  T he Certificate pr otects a gai nst t he i n v ol u ntar y release of 
i nf or mati o n a b o ut s u bj ects c ollecte d d uri n g t he c o urse of o ur c o ver e d st u dies.  T he researc hers i n v ol ve d i n 
t he st u dies ca n n ot be f orce d t o discl ose t he i de ntit y or a n y i nf or mati o n c ollecte d i n t he st u d y i n a n y le gal 
pr ocee di n gs at t he fe deral, state, or l ocal le vel, re gar dless of w het her t he y are cri mi nal, a d mi nistrati ve, or 
le gislati ve pr ocee di n gs.  H o we ver, t he s u bject or t he researc her ma y c h o ose t o v ol u ntaril y discl ose t he 
pr otecte d i nf or mati o n u n der certai n circ u msta nces.  F or e xa m ple, if t he s u bj ect or his/ her g uar dia n re q uests 
t he release of i nf or mati o n i n writi n g, t he Certificate d oes n ot pr otect a gai nst t hat v ol u ntar y discl os ure.  
F urt her m ore, fe deral a ge ncies ma y re vie w o ur rec or ds u n der li mite d circ u msta nces, s uc h as a D H H S 
re q uest f or i nf or mati o n f or a n a u dit or pr o gra m e val uati o n or a n F D A re q uest u n der t he F o o d, Dr u g a n d 
C os metics Act. 
 
T he Certificate of C o nfi de ntialit y will n ot pr otect a gai nst ma n dat or y discl os ure b y t he researc hers of 
i nf or mati o n o n s us pecte d c hil d a b use, re p orta ble c o m m u nica ble diseases, a n d/ or p ossi ble t hreat of har m t o 
self or ot hers. 
 
A B S T R A C T 
P E P N 1 8 1 2 is a P hase 1 st u d y desi g ne d t o e val uate t he t o xicit y pr ofile of fl otet uz u ma b i n pe diatric patie nts 
wit h rela pse d/refract or y ac ute m yel oi d le u ke mia ( A M L). Fl otet uz u ma b is a bis pecific a nti b o d y desi g ne d t o 
tar get C D 3 a n d C D 1 2 3. Patie nts will recei ve a c o nti n u o us i nf usi o n of fl otet uz u ma b d ue t o t he fa v ora ble 
t o xicit y a n d efficac y pr ofile of t his a d mi nistrati o n sc he d ule i n a d ults wit h A M L. Patie nts ma y recei ve u p 
t o a t otal of 6 c ycles of fl otet uz u ma b u nless t he y are u na ble t o ac hie ve a partial res p o nse ( P R) after C ycle 
2 or are f o u n d t o ha ve pr o gressi ve disease at a n y ti me p oi nt. T he o bjecti ves of t his st u d y are t o deter mi ne 
t he ma xi m u m t olerate d d ose ( M T D) a n d rec o m me n de d P hase 2 d ose ( R P 2 D) of fl otet uz u ma b, as well as 
t o descri be t he t o xicities, p har mac o ki netics, a n d p har mac o d y na mics pr o perties of fl otet uz u ma b i n t he 
pe diatric p o p ulati o n. P E P N 1 8 1 2 i ncl u des c orrelati ve la b orat or y st u dies t o i de ntif y bi o mar kers t o pre dict 
t o xicities a n d res p o nse t o fl otet uz u ma b. 
 
 
E X P E RI M E N T A L D E SI G N S C H E M A 
 
 
* P atie nts s h o ul d recei ve a d ose of i ntrat hecal (I T) c ytara bi n e pri or t o t h e start of C ycl e 1 bet we e n Da ys - 6 a n d 0. P atie nts ma y 
recei ve a n o pti o nal d ose of I T c yt ara bi n e d uri n g s u bse q ue nt c ycl es o n Da y 1 or wit h b o ne marr o w e val u ati o ns at t he discreti o n of 
t he treati n g p h ysicia n.  
^ T he d urati o n of t h e o pti o nal treat me nt-fre e i nter val ( u p t o a ma xi m u m of 3 da ys) is at t h e treati n g p h ysicia n’s discreti o n. If n o 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 8 
treat me nt-fre e i nter val is c o nsi dere d necessar y, patie nts ma y pr ocee d i m me diatel y t o t h e ne xt c ycle of t h era p y as l o n g as t he y d o 
n ot ha ve pr o gressi ve disease. I n cases w her e t h e patie nt i m me diatel y pr ocee ds t o t h e ne xt c ycle of t hera p y, Da y 2 9 of t he pre vi o us 
c ycle will be Da y 1 of t h e s u bse q ue nt c ycle.  
 
A c ycle of t hera p y is 2 9 da ys. T he starti n g d ose will be 5 0 0 na n o gra ms/ k g/ da y ( D L 1) wit h d ose le vels f or 
s u bse q ue nt gr o u ps of patie nts as f oll o ws: 
 
D ose Le vel   
D ose ( n a n o gr a ms / k g/ d a y) 
-1  
3 0 0  
1 *  
5 0 0  
2  
7 0 0  
  * Starti n g D ose Le vel 
 
 
1. 0   
G O A L S A N D O B J E C TI V E S ( S CI E N TI FI C AI M S)  
 
1. 1   
P ri m ar y Ai ms 
 
 
T o assess t he safet y a n d t olera bilit y of fl otet uz u ma b a d mi nistere d b y 
c o nti n u o us I V i nf usi o n t o pe diatric pat ie nts < 2 1 years of a ge wit h rela pse d or 
refract or y A M L.  
 
 
T o esti mate t he ma xi m u m t olerate d d ose ( M T D) a n d/ or rec o m me n de d P hase 2 
d ose ( R P 2 D) of fl otet uz u ma b a d mi nistere d b y c o nti n u o us I V i nf usi o n  t o 
pe di atric patie nts < 2 1 years of a ge wit h rela pse d or refract or y A M L.  
 
1. 2   
Sec o n d ar y Ai ms 
 
 
T o c haracterize t he p har mac o ki netics of fl otet uz u ma b i n pe diatric patie nts 
wit h rela pse d of refract or y A M L.  
 
 
T o defi ne  preli m inaril y t he a nti-t u m or acti vit y of fl otet uz u ma b wit hi n t he 
c o nfi nes of a P hase 1 st u d y a n d c orrelate  p ote ntial acti vit y  wit h baseli ne 
di sease b ur de n at st u d y e ntr y.  
 
 
T o m o nit or a nti -dr u g a nti b o d y ( A D A) pr o d ucti o n a n d c haracterize t he 
i m m u n o ge nicit y of fl otet uz u ma b.  
 
1. 3   
E x pl or at or y Ai ms  
 
 
T o e val uate c ha n ges i n T -l y m p h oc yte p o p ulati o n n u m bers bef ore a n d after 
fl otet uz u ma b treat me nt.  
 
 
T o e val uate  t he t u m or micr oe n vir o n me nt a n d c yt o ki ne pr o d ucti o n b y i m m u ne 
effect or cells bef ore a n d after fl otet uz u ma b treat me nt.  
 
 
T o q ua ntif y C D 1 2 3 s urface e x pressi o n o n A M L cells at baseli ne a n d e val uate 
e x pressi o n as a p ote ntial bi o mar ker of fl otet uz u ma b res p o nse.  
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 9 
2. 0   
B A C K G R O U N D 
 
2. 1   
I ntr o d ucti o n/ R ati o n ale f or De vel o p me nt 
Des pite ma xi mal i nte nsificati o n of m ulti-a ge nt c yt ot o xic c he m ot hera p y, l o n g-ter m c ure 
rates f or c hil dre n wit h A M L re mai n a p pr o xi matel y 6 0 %. 1 T he de vel o p me nt of ne w A M L 
i m m u n ot hera pies is t h us of great i nterest, as t hese t hera pies ma y i m pr o ve o utc o mes or 
all o w re d ucti o n i n c yt ot o xic c he m ot hera p y a n d decrease l o n g-ter m t o xicities. D A R T 
m olec ules are bis pecific a nti b o d y- base d a ge nts t hat bi n d t w o disti nct a nti ge ns 
si m ulta ne o usl y. 
D A R Ts are si milar t o si n gle-c hai n bis pecific a nti b o dies, s uc h as 
bli nat u m o ma b, b ut i nstea d ha ve t w o i n de pe n de nt p ol y pe pti des eac h c o m p ose d of t he V H  
of o ne a nti b o d y i n ta n de m wit h t he V L  of t he ot her a nti b o d y attac he d b y a dis ulfi de bri d ge.2 
T his u ni q ue arc hitect ure i m pr o ves effect or- t o-tar get ( E: T) cell-t o-cell c o ntact a n d i n d uces 
greater i n vitr o tar get cell killi n g a n d T cell-s pecific acti vati o n.3 Fl otet uz u ma b is a C D 1 2 3 
x C D 3 D A R T desi g ne d t o tar get C D 1 2 3 + t u m or cells f or rec o g niti o n a n d eli mi nati o n b y 
C D 3 -e x pressi n g T l y m p h oc ytes. C D 1 2 3 (I L 3 R al p ha c hai n) is e x presse d at hi g h le vels o n 
t he maj orit y of A M L cells, as well at l o wer le vels o n n or mal plas mac yt oi d de n dritic cells 
( p D C), bas o p hils, m o n oc ytes, a n d e osi n o p hils.4 C D 1 2 3 o vere x pressi o n i n A M L has bee n 
ass ociate d wit h hi g her rates of c he m oresista nce a n d wit h hi g h-ris k ge netic alterati o ns, 
i ncl u di n g F L T 3  i nter nal ta n de m d u plicati o n (F L T 3 -I T D).5- 7 C D 1 2 3 is als o e x presse d at 
hi g h le vels o n le u ke mia ste m cells ( L S Cs), a s mall a n d d or ma nt cell ular p o p ulati o n t hat 
li kel y c o ntri b utes t o c he m oresista nce a n d le u ke mia pr o gressi o n.8, 9 C D 1 2 3 o vere x pressi o n 
c o m bi ne d wit h t he differe ntial C D 1 2 3 e x pressi o n o n L S Cs a n d pr o ba ble lac k of e x pressi o n 
b y n or mal he mat o p oietic ste m cells s u g gests t hat tar geti n g C D 1 2 3 ma y pr o vi de b ot h 
prefere ntial de b ul ki n g a n d m ore d ura ble re missi o n. 1 0, 1 1 T o t hat e n d, r o b ust a nti-le u ke mia 
efficac y has bee n o bser ve d i n precli nical m o dels of a d ult a n d c hil d h o o d A M L treate d wit h 
a variet y of C D 1 2 3-tar ge ted a ge nts, s uc h as f usi o n pr otei ns, m o n ocl o nal a nti b o dies, 
a nti b o d y- dr u g c o nj u gates, a n d c hi meric a nti ge n rece pt or ( C A R) T cell i m m u n ot hera pies. 1 1-
1 8 Se veral of t hese a ge nts ha ve a d va nce d t o P hase 1 cli nical trial e val uati o n i n a d ults wit h 
rela pse d 
or refract or y  
A M L 
(cli nicaltrials. g o v  
N C T 0 2 1 5 9 4 9 5,  
N C T 0 3 1 9 0 2 7 8, 
N C T 0 2 8 4 8 2 4 8, N C T 0 2 7 1 5 0 1 1), a n d cli nical res p o nses i n a s mall n u m ber of patie nts 
treate d  
wit h  
C D 1 2 3 i m m u n ot hera pies  
were rece ntl y re p orte d.1 9- 2 4 
Si g nifica nt 
m yel oa blati o n a n d car diac t o xicit y as o n tar get/ off t u m or effects ha ve n ot bee n re p orte d t o 
date, s u g gesti n g p ote ntial cli nical t olera bilit y of C D 1 2 3 tar gete d t hera pies.  
 
2. 2   
P recli nic al St u dies 
 
 
A nti -Le u ke mia  Acti vit y  of Fl otet uz u ma b  
Precli nical st u dies ha ve de m o nstrate d p ote nt acti vit y of fl otet uz u ma b a gai nst 
h u ma n A M L. I n vitr o i nc u bati o n of C D 1 2 3 + A M L cells wit h fl otet uz u ma b 
i n d uce d pr o n o u nce d T cell acti vati o n via i ncrease d C D 2 5 e x pressi o n, T cell 
pr oliferati o n, T cell ce ntral 
me m or y c o m part me nt e x pa nsi o n, c yt o ki ne 
pr o d ucti o n (I F N-  a n d I L- 6), a n d A M L cell killi n g vers us mi ni mal acti vit y 
a gai nst C D 1 2 3- c o ntr ol cells. 1 4 T his st u d y re p orte d t hat A M L cell killi n g was 
li kel y me diate d b y C D 8 + T cells via gra nz y me B a n d perf ori n c yt ot o xic 
pat h wa ys. A nti-le u ke mia acti vit y a p pear e d t o c orrelate directl y wit h t he le vel 
of C D 1 2 3 cell s urface e x pressi o n. 1 2 
 
D ose- de pe n de nt i n viv o i n hi biti o n of t u m or gr o wt h was als o de m o nstrate d i n 
A M L cell li ne xe n o graft m o dels. 1 2, 1 4. Fl otet uz u ma b was deli vere d c o nti n u o usl y 
f or u p t o a wee k via perit o neall y-i m pla nte d os m otic p u m ps i n i m m u n o deficie nt 
mice ( N S G/ β 2 m -/-) i nj ecte d i ntra der mall y wit h t he C D 1 2 3 + K G - 1a A M L cell 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 0  
li ne. T he mice were pre vi o usl y rec o nstit ute d i ntra ve n o usl y wit h n or mal h u ma n 
peri p heral bl o o d m o n o n uclear cells ( P B M Cs) t o pr o vi de a s o urce of h u ma n 
C D 3 + effect or cells. Si g nifica nt t u m or re gressi o n was o bser ve d at all teste d 
d oses of fl otet uz u ma b, w hereas n o acti vit y was o bser ve d i n a ni mals treate d wit h 
a C D 3 x 4 4 2 0 c o ntr ol D A R T ( Fi g ure 1 ).1 4 
 
 
 
Fi g ure 1: T u m or v ol u mes i n mice treate d wit h i ntra perit o neal fl otet uz u ma b ( M G D 0 0 6) 
b y c o nti n u o us i nf usi o n. Gra y area i n dicates c o nti n u o us deli ver y of fl otet uz u ma b or 
c o ntr ols. * i n dicates p < 0. 0 5 b y t w o- wa y A N O V A. 1 4 
 
I n a d diti o n, c y n o m ol g us m o n ke ys ( n = 4 8) ha ve bee n treate d wit h fl otet uz u ma b 
at vari o us d ose le vels a n d fre q ue ncies t o assess p ote ntial t olera bilit y i n n o n-
h u ma n pri mates a n d effects of fl otet uz u ma b u p o n n or mal tiss ues. N or mal 
C D 1 2 3 + cell de pleti o n i n t he peri p heral bl o o d was o bser ve d as earl y as 4 h o urs 
fr o m t he start of i nf usi o n a n d at d oses as l o w as 3 na n o gra ms/ k g/ da y. I n a ni mals 
t hat recei ve d i nterr u pte d d osi n g ( 4- da ys- o n/ 3- da ys- off sc he d ule), C D 1 2 3 + cell 
de pleti o n persiste d d uri n g t he 3- da ys- off peri o d. C D 1 2 3 + le u k oc yte n u m bers 
i n t he bl o o d ge nerall y ret ur ne d t o baseli ne o ver t he s u bse q ue nt 3 – 4 wee ks 
f oll o wi n g fl otet uz u ma b disc o nti n uati o n ( Fi g ure 2). Si milarl y, wit hi n t he b o ne 
marr o w, C D 1 2 3 + li nea ge- n e gati ve cells were decrease d at t he e n d of treat me nt 
i n M G D 0 0 6-treate d a ni mals c o m pare d t o t he ve hicle-treate d gr o u p a n d ret ur ne d 
t o baseli ne d uri n g t he rec o ver y peri o d.1 4  
 
 
Fi g ure 2: Precli nical st u d y of fl otet uz u ma b a d mi nistrati o n i n c y n o m ol g us m o n ke ys. 
Data de pict mea n n u m ber of C D 1 4-/ C D 1 2 3 + le u k oc ytes i n peri p heral bl o o d b y st u d y 
da y a n d gr o u p. Gr o u p 1 r ecei ve d ve hicle, 
Gr o u ps 2- 5 recei ve d 4- da y wee kl y 
fl otet uz u ma b i nf usi o ns reac hi n g tar get d oses of 1 0 0, 3 0 0, 6 0 0, a n d 1 0 0 0 
na n o gra ms/ k g/ da y, a n d Gr o u p 6 recei ve d a c o nti n u o us i nf usi o n of fl otet uz u ma b 
reac hi n g a tar get d ose of 1 0 0 0 na n o gra ms/ k g/ da y. Gra y area i n dicates deli ver y of 
fl otet uz u ma b or ve hicle.1 4 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 1  
 
 
A ni mal T o xic ol o g y  
O n tar get/ off t u m or t o xicities ha ve bee n re p orte d wit h vari o us le u ke mia 
i m m u n ot hera pies. 
C D 1 2 3 is 
e x presse d 
o n s o me 
n or mal 
c o m mitte d 
he mat o p oietic prec urs ors, s uc h as c o m m o n 
m yel oi d pr o ge nit ors ( C M P). 4 
A plasia of n or mal m yel oi d prec urs or cells is a p ote ntial o n tar get/ off t u m or 
t o xicit y of C D 1 2 3- base d i m m u n ot hera pies, as was o bser ve d i n o ne st u d y of 
A M L xe n o graft m o dels treate d wit h C D 1 2 3 C A R T cells. 1 7 I n t he n o n- h u ma n 
pri mate st u d y disc usse d a b o ve, c y n o m ol g us 
m o n ke ys were treate d wit h 
fl otet uz u ma b t o assess safet y. W hite bl o o d cell c o u nts a n d platelets s h o we d 
tra nsie nt fl uct uati o ns, b ut lar gel y re mai ne d wit hi n n or mal li mits t hr o u g h o ut t he 
st u d y at vari o us d ose sc he d ules a n d le vels. Re versi ble re d ucti o ns i n he mat ocrit 
we re als o o bser ve d at t he hi g hest d oses. B o ne marr o w m or p h ol o g y a n d 
cell ularit y re mai ne d u nc ha n ge d, a n d w hile b o ne marr o w C D 1 2 3 + prec urs or 
cells were re d uce d, he mat o p oietic ste m cells were n ot. After treat me nt 
cessati o n, t he maj orit y of he mat o p oietic para met ers ret ur ne d t o baseli ne, 
c o nsiste nt wit h re p o p ulati o n fr o m s pare d he mat o p oietic ste m cells w hic h 
e x press l o w or n o C D 1 2 3. 1 4 
 
C D 1 2 3 is als o e x presse d at l o w le vels o n e n d ot helial cells. 2 5 Ca pillar y lea k a n d 
e xacer bati o n of h y p ote nsi o n relate d t o c yt o ki ne release s y n dr o me ( C R S) are 
p ote ntial o n tar get/ of t u m or t o xicities. A n ot her precli nical st u d y s pecificall y 
e x pl ore d t his p ote ntial t o xicit y a n d re p orte d mi ni mal effects of C D 1 2 3 C A R T 
cells a gai nst pri mar y h u ma n e n d ot helial cells. 2 6  
 
Ot her u ni q ue t o xiciti es ass ociate d wit h bis pecific t hera pies i ncl u de i nf usi o n-
relate d reacti o ns (I R R) a n d C R S. T he pre dicte d mec ha nis m of acti o n of 
fl otet uz u ma b is t he creati o n of a n i m m u n ol o gical s y na pse bet wee n t he le u ke mic 
blast tar get cell a n d t he T cell, lea di n g t o T cell acti vati o n a n d killi n g of t he 
le u ke mic cell. Acti vati o n of T cells is ass ociate d wit h t he ela b orati o n of vari o us 
c yt o ki nes. I n vitr o precli nical testi n g of fl otet uz u ma b i nc u bate d wit h h u ma n 
P B M Cs de m o nstrate d 
m ost vi g or o us c yt o ki ne pr o d ucti o n of I F N- , b ut 
i ncrease d T N F-, I L- 2, I L- 6, I L- 4, a n d I L- 1 0 pr o d ucti o n was als o detecte d. 
T he se c yt o ki nes ha ve all bee n i m plicate d i n t he pat h o p h ysi ol o g y of c yt o ki ne 
release s y n dr o me ( C R S),2 7, 2 8 a c o m m o n a n d e x pecte d si de effect of a nti b o d y 
a n d cell ular i m m u n ot hera pies. I n precli nical n o n- h u ma n pri mate t o xic ol o g y 
st u dies, c y n o m ol g us maca q ues t olerate d a c o nti n u o us i nf usi o n of fl otet uz u ma b 
wit h 0. 1 u g/ k g/ da y escalate d 
wee kl y t o u p t o 1 u g/ k g/ da y. C R S  
was 
pre d o mi na ntl y a first- d ose effect t hat was miti gate d b y usi n g a wit hi n-s u bject 
d ose 
escalati o n 
strate g y.  
De pleti o n 
of 
circ ulati n g 
n or mal  
C D 1 2 3 + 
he mat o p oietic cells was o bser ve d as earl y as 7 2 h o urs after treat me nt i nitiati o n 
a n d persiste d t hr o u g h o ut t he i nf usi o n peri o d. 1 4  
 
 
Precli nical P har mac o ki netic St u dies  
F or mal p har mac o ki netic a nal yses ha ve bee n c o n d ucte d i n N O D/ S CI D mice 
a n d c y n o m ol g us m o n ke ys; i n ge neral, fl otet uz u ma b c o nce ntrati o ns a p pear t o 
be d ose- de pe n de nt. I n a n o n- h u ma n pri mate st u d y, 3 2 treat me nt- naï ve 
c yn o m ol g us m o n ke ys were treate d o n a wee kl y basis f or 5 wee ks wit h 
c o nti n u o us ve hicle or fl otet uz u ma b at escalati n g d oses ( 1 0 0, 3 0 0, 6 0 0, 1 0 0 0 
na n o gra ms/ k g/ da y). F oll o wi n g eac h d ose le vel, fl otet uz u ma b le vels a p peare d 
t o be li near a n d stati o nar y. Fl otet uz u ma b was ra pi dl y eli mi nate d fr o m plas ma 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 2  
wit h a n esti mate d eli mi nati o n half-life of  3. 5 h o urs, w hic h is c o m para ble t o 
that of bli nat u m o ma b i n h u ma ns. Peri p heral T cell c o u nts ra pi dl y decrease d 
d uri n g dr u g i nf usi o n a n d t he n i ncrease d sli g htl y a b o ve i nitial val ues (i.e., 
re b o u n d) o nce fl otet uz u ma b was eli mi nate d fr o m t he s yste m. Peri p heral 
C D 1 2 3 + cells were de plete d after t he first dr u g a d mi nistrati o n wit h t he l o west 
d ose i n all a ni mals, b ut wit h varia ble d urati o n of de pleti o n. A nti- dr u g 
a nti b o d y de vel o p me nt le d t o t he s u p pressi o n of T cell traffic ki n g, b ut di d n ot 
pre ve nt fl otet uz u ma b- me diate d C D 1 2 3 + cell de pleti o n. A p har mac o ki netic 
m o del was create d t o descri be t he ti me-c o urse of free dr u g plas ma 
c o nce ntrati o ns a n d was a ble t o re pr o d uce dr u g c o nce ntrati o n-ti me pr ofiles 
relia bl y i n a gr o u p of re prese ntati ve a ni mals after a 7- d a y i nf usi o n. 2 9 
 
2. 3   
Cli nic al St u dies i n A d ults 
 
 
P hase 1 Cli nical Trial  
Fl otet uz u ma b m o n ot hera p y is c urre ntl y u n der cli nical i n vesti gati o n i n a d ults 
wit h rela pse d or refract or y A M L (rr A M L) after treat me nt fail ure via t he p hase 
1 trial C P- M G D 0 0 6- 0 1 ( N C T 0 2 1 5 2 9 5 6; Macr o Ge ni cs). T his trial was 
pla n ne d t o e val uate u p t o 1 0 d ose le vels a n d/ or sc he d ules of fl otet uz u ma b 
m o n ot hera p y. I n t his st u d y, a ma xi mall y t olerate d d ose ( M T D) a n d 
rec o m me n de d P hase 2 d ose ( R P 2 D) was defi ne d as 5 0 0 na n o gra ms/ k g/ da y 
a d mi nistere d c o nti n u o usl y f or a 2 8 da y c ycle. 3 0 D ose-li miti n g t o xicit y of 
g ra de 3 I R R/ C R S occ urre d i n 3 of 9 a d ults ( n = 1 eac h f or C R S, s y nc o pe, a n d 
art hral gia/ m yal gia) treate d at 7 0 0 na n o gra ms/ k g/ da y. Data fr o m t he C P-
M G D 0 0 6- 0 1 trial de m o nstrate t olera bilit y of fl otet uz u ma b wit h a ste p- u p d ose 
re gi me n, w hic h utilizes l o wer- d ose fl otet uz u ma b at i nitiati o n f oll o we d b y a 
t w o-sta ge i ntra- patie nt escalati o n d uri n g t he first wee k a n d c o nti n u o us d osi n g 
at t he M T D f or t he f oll o wi n g 2 1 da ys. T his a p pr oac h has mi ni mize d i nf usi o n-
relate d reacti o ns (I R R)/ C R S w hile preser vi n g a nti-le u ke mia acti vit y. T he 
st u d y i nitiall y e x pl ore d a n i nter mitte nt d osi n g sc he d ule ( 4 da ys o n/ 3 da ys off) 
b ut, d ue t o safet y a n d efficac y c o ncer ns, t he trial has s u bse q ue ntl y bee n 
a me n de d t o treat all patie nts wit h c o nti n u o us 2 8- da y i nf usi o ns. At t he c ut- off 
date o n N o ve m ber 1, 2 0 1 8, 3 1 patie nts ha ve bee n treate d at t he R P 2 D. A nti-
le u ke mic acti vit y was re p orte d i n 1 8/ 2 7 ( 6 7 %) res p o nse-e val ua ble patie nts, 
wit h a n o verall res p o nse rate ( C R/ C Ri/ M L F [ m or p h ol o gic le u ke mia free 
state]/ P R) of 2 6 % ( 6/ 2 7) a n d a C R/ C Ri rate of 1 9 % ( 5/ 2 7). I nteresti n gl y, all 5 
of t he patie nts w h o ha d a C R/ C Ri were c o nsi dere d pri mar y c he m ot hera p y-
refract or y patie nts ( defi ne d as refract or y t o > 2 i n d ucti o n atte m pts, or first C R 
wit h i nitial C R < 6 m o nt hs) c o m pare d t o n o ne of t he patie nts wit h rela pse d 
A M L. 3 1  
 
T he m ost c o m m o n treat me nt-relate d a d verse e ve nt ( A E) o bser ve d i n treate d 
patie nts has bee n I R R/ C R S. M ost patie nts e x perie nce d mil d t o m o derate C R S 
( gra de 1 2 5 .8 %, gra de 2 5 8. 1 %) of s h ort d urati o n ( me dia n of 1 da y) a n d were 
c o nser vati vel y ma na ge d t o f ull res ol uti o n. Gra de ≥3 e ve nts occ urre d i n 4/ 3 1 
( 12. 9 %) of patie nts wit h a me dia n d urati o n of 2. 5 da ys. T we nt y- o ne patie nts 
(6 7 %) recei ve d at least o ne d ose of t he a nti-I L 6 rece pt or a nti b o d y 
t ociliz u ma b.3 1, 3 2  Gi ve n t he hi g h a ntici pate d i nci de nce of I R R/ C R S, ste p- u p 
d osi n g a n d C R S pr o p h yla xis wit h de xa met has o ne ha ve bee n i nstit ute d via 
pr ot oc ol a me n d me nts, w hic h ha ve decrease d t he i nci de nce of I R R/ C R S. Ot her 
A Es i ncl u de na usea ( 3 2. 3 %), peri p heral e de ma ( 2 9 %), diarr hea ( 2 5. 8 %), 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 3  
p yre xia ( 2 5. 8 %), C-reacti ve pr otei n i ncrease ( 1 9. 4 %), d ys p nea ( 1 6. 1 %), 
hea dac he ( 1 6. 1 %), h y p ote nsi o n ( 1 6. 1 %), a n d m yal gia ( 1 6. 1 %). He mat ol o gic 
A Es i ncl u de l y m p h oc yte c o u nt decrease ( 2 2. 6 %), a ne mia ( 1 9. 4 %), platelet 
c o u nt decrease ( 1 9. 4 %), w hite bl o o d cell c o u nt decrease ( 1 6. 1 %), a n d 
ne utr o p hil c o u nt decrease ( 1 2. 9 %).   
 
 
 
P hase 2 St u dies  
T here are c urre ntl y n o P hase 2 st u dies.  
 
 
P har mac ol o g y/ P har mac o ki netics/ C orrelati ve a n d Bi ol o gical St u dies  
Base d o n data fr o m t he o n g oi n g a d ult P hase 1 cli nical trial, fl otet uz u ma b has 
bee n f o u n d t o ha ve li near p har mac o ki netics wit h a hi g h v ol u me of distri b uti o n 
a n d cleara nce. 3 3  
 
I n re gar ds t o pre dicti n g C R S, of t he 3 0 patie nts treate d at t he R P 2 D, C R S 
se verit y s h o we d a relati o ns hi p wit h t he baseli ne fre q ue nc y of circ ulati n g 
C D 4 + cells w hile C 8 + cell fre q ue nc y, disease b ur de n, C D 1 2 3 e x pressi o n o n 
A M L blasts, m o n oc yte le vels or effect or- t o-tar get rati o n i n t he peri p heral 
bl o o d di d n ot s h o w a relati o ns hi p wit h C R S se verit y. A d diti o nall y, C R S 
se verit y was n ot c orrelate d wit h a nti-le u ke mic acti vit y. 3 2  
 
Ge ne e x pressi o n a nal ysis was perf or me d o n baseli ne b o ne marr o w sa m ples 
fr o m patie nts bei n g treate d o n t he a d ult P hase 1 cli nical trial. Base d o n t his 
a nal ysis, sa m ples were a ble t o be se parate d i nt o eit her i m m u ne-i nfiltrate d or 
i m m u ne- de plete d i m m u n ol o gic cl usters. C o m pare d t o rela pse d patie nts, t h ose 
patie nts wit h pri mar y refract or y A M L were m ore li kel y t o ha ve i m m u ne-
i nfiltrate d p he n ot y pes. I m m u ne-i nfiltrate d sa m ples c o ul d be f urt her s u b di vi de d 
i nt o i m m u ne-e nric he d a n d i m m u ne-e x ha uste d p he n ot y pes. C he m orefract or y 
patie nts 
were 
m ore li kel y t o be i m m u ne-e nric he d a n d h y p o met h ylati n g 
refract or y patie nts were m ore li kel y t o be i m m u ne-e x ha uste d wit h hi g her le vels 
of c hec k p oi nt e x pressi o n a n d T re g ulat or y cells. F urt her, res p o n ders t o 
fl otet uz u ma b s h o we d a si g nifica ntl y hi g her I F N- si g nali n g sc ore at baseli ne 
c o m pare d t o n o n-res p o n ders, c o nsiste nt 
wit h t he greater fre q ue nc y of 
res p o n ders i n pri mar y refract or y patie nts c o m pare d t o rela pse patie nts. 3 4  
 
2. 4   
P e di atric St u dies 
 
 
Pri or E x perie nce i n C hil dre n  
T here are c urre ntl y n o pe diatric st u dies p u blis he d or i n de vel o p me nt.  
 
2. 5   
O ver vie w of P r o p ose d Pe di atric St u d y 
T his is a P hase 1 st u d y usi n g a r olli n g si x desi g n 3 5 wit h o ne p ote ntial d ose escalati o n c o h ort. 
T he pri mar y ai m of t he st u d y is t o i de ntif y safe a n d t olera ble d osi n g of t he C D 1 2 3 x C D 3 
D A R T fl otet uz u ma b i n c hil dre n < 2 1 years of a ge wit h A M L i n sec o n d or greater rela pse, 
refract or y A M L after t w o or m ore c he m ot hera p y c ycles, first rela pse after pri mar y 
c he m ot hera p y-refract or y disease, or first rela pse after he mat o p oietic ste m cell 
tra ns pla ntati o n ( H S C T).  
 
Fl otet uz u ma b will be a d mi nistere d c o nti n u o usl y f or a t otal of 2 8 da ys ( N O T E:  i nf usi o n 
e n ds o n Da y 2 9). Ste p- u p d osi n g will be use d i n t he first 7 da ys of C ycle 1 t o mi ni mi ze 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 4  
I R R/ C R S, f oll o we d b y 2 1 da ys at t he a d ult rec o m me n de d p hase 2 d ose ( R P 2 D) ( 5 0 0 
na n o gra ms/ k g/ da y; d ose le vel 1, [ D L 1]). 3 1 If D L 1 is safe a n d t olera ble base d o n sta n dar d 
i m m u n ot hera p y D L T assess me nts 2 7, a n a d diti o nal c o h ort of patie nts will d ose-escalate 
fl otet uz u ma b t o 7 0 0 na n o gra ms/ k g/ da y ( D L 2). If fe wer t ha n 2 D L Ts occ ur at D L 2, t his 
will be c o nsi dere d t he R P 2 D. If t here are > 2 D L Ts at D L 2, D L 1 will be c o nsi dere d t he 
M T D of fl otet uz u ma b m o n ot hera p y. If fl otet uz u ma b m o n ot hera p y at D L 1 is n ot t olera ble, 
d ose de-escalati o n will occ ur t o 3 0 0 na n o gra ms/ k g/ da y ( D L- 1). If D L- 1 is dee me d 
t olera ble, t his d osi n g will be t he M T D. F urt her d ose de-escalati o n be y o n d D L- 1 will n ot 
be per mitte d a n d will li mit f urt her e x pl orati o n of fl otet uz u ma b i n t his patie nt p o p ulati o n.   
 
B o ne marr o w e val uati o n will be perf or me d o n Da y 2 9 ( +/ - 1 da y) as a n e x pl orat or y 
meas ure me nt of res p o nse. F oll o wi n g t he e n d of fl otet uz u ma b i nf usi o n o n Da y 2 9, patie nts 
will be all o we d a treat me nt-free i nter val of u p t o 3 da ys  t o all o w treat me nt res pite. T he 
d urati o n of t his treat me nt-free i nter val will be u p t o t he treati n g p h ysicia n’s discreti o n. 
H o we ver, patie nts ma y als o s ki p t he treat me nt-free i nter val a n d pr ocee d i m me diatel y t o 
t he ne xt c ycle of t hera p y w hile a waiti n g res ults fr o m res p o nse e val uati o n.  
 
If a patie nt e x perie nces pr o gressi ve disease at a n y ti me p oi nt, t he y m ust disc o nti n ue 
pr ot oc ol t hera p y. Patie nts wit h at least a partial res p o nse ( P R) f oll o wi n g C ycle 2 ma y 
c o nti n ue o n s u bse q ue nt c ycles of fl otet uz u ma b f or a t otal of u p t o 6 c ycles. Patie nts s h o ul d 
disc o nti n ue pr ot oc ol t hera p y if t he y ha ve n ot ac hie ve d at least a P R f oll o wi n g C ycle 2. N o 
pla n ne d ste p- u p d osi n g will occ ur d uri n g s u bse q ue nt c ycles u nless t here is a n i nf usi o n 
i nterr u pti o n of > 3 da ys bet wee n c ycles of fl otet uz u ma b. F or patie nts wit h n o e vi de nce of 
disease after C ycle 1, s u bse q ue nt c ycles s h o ul d be i nterr u pte d u ntil A N C ≥ 5 0 0 μ L a n d 
platelets ≥ 2 0, 0 0 0/ m m 3. Patie nts wit h persiste nt disease are per mitte d t o c o nti n ue 
fl otet uz u ma b re gar dless of A N C a n d platelet c o u nts.  
 
P har mac o ki netic sa m pli n g a n d m o nit ori n g f or A D As will be perf or me d i n all patie nts (see 
A p pe n di x VI - A, A p pe n di x VI- B , A p pe n di x VI- C , a n d A p pe n di x VII ). I n c o nse nti n g 
patie nts, c orrelati ve st u dies t o c haracterize t he t u m or micr oe n vir o n me nt will be o btai ne d, 
w hic h will i ncl u de peri p heral bl o o d st u dies a n d b o ne marr o w (see A p pe n di x X  a n d 
A p pe n di x XII ). C orrelati ve plas ma st u dies as a meas ure me nt of C R S a n d bi o mar kers of 
res p o nse will als o be o btai ne d i n c o nse nti n g patie nts (see A p pe n di x XI ). 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 5  
3. 0   
S C R E E NI N G A N D S T U D Y E N R O L L M E N T P R O C E D U R E S 
 
Patie nt e nr oll me nt f or t his st u d y will be facilitate d usi n g t he Sl ot- Reser vati o n S yste m i n 
c o nj u ncti o n wit h t he O nc ol o g y Patie nt E nr oll me nt Net w or k ( O P E N), a we b- base d re gistrati o n 
s yste m a vaila ble o n a 2 4/ 7 basis. It is i nte grate d wit h t he N CI Ca ncer Trials S u p p ort U nit ( C T S U) 
E nter prise S yste m f or re g ulat or y a n d r oster data a n d, u p o n e nr oll me nt, i nitializes t he patie nt 
p ositi o n i n t he R A V E data base. 
 
Access re q uire me nts f or O P E N :  
I n vesti gat ors a n d site staff will nee d t o be re gistere d wit h C T E P a n d ha ve a vali d a n d acti ve Ca ncer 
T hera p y E val uati o n Pr o gra m-I de ntit y a n d Access Ma na ge me nt ( C T E P-I A M) acc o u nt (c hec k at < 
htt ps://cte pc ore. nci. ni h. g o v/ia m/i n de x.js p  >) . T his is t he sa me acc o u nt ( user i d a n d pass w or d) use d 
f or cre de ntiali n g i n t he C T S U me m bers' we b site. T o perf or m re gistrati o ns i n O P E N, t he site user 
m ust ha ve bee n assi g ne d t he ' Re gistrar' r ole o n t he rele va nt Gr o u p or C T S U r oster. O P E N ca n be 
accesse d at htt ps:// o pe n.cts u. or g or fr o m t he O P E N ta b o n t he C T S U me m bers’ si de of t he we bsite 
at htt ps:// w w w.cts u. or g. 
3. 1   
C urre nt St u d y St at us  
I n vesti gat ors s h o ul d refer t o t h e C O G we bsite t o deter mi ne if t he st u d y is c urre ntl y o pe n 
f or accr ual.  If t he st u d y is liste d as acti ve, i n vesti gat ors s h o ul d t he n access t he St u dies 
Re q uiri n g Reser vati o ns pa ge t o e ns ure t hat a reser vati o n f or t he st u d y is a vaila ble. T o 
access t he St u dies Re q uiri n g Reser vati o ns pa ge:  
1. L o g i n t o htt ps:// o pe n.cts u. or g/ o pe n/ 
2.  Clic k t he Sl ot Reser v ati o n Ta b. T he Site P atie nt p a ge o pe ns.  
3.  Clic k t he Re p ort T a b. T he Sl ot Reserv ati o n Re p ort o pe ns. Av ail a ble Sl ots are 
det aile d per st u dy str at a. 
 
3. 2   
I R B A p pr o v al 
N CI Pe diatric CI R B a p pr o val or l ocal I R B a p pr o val of t his st u d y m ust be o btai ne d b y a 
site pri or t o e nr olli n g patie nts. Sites m ust s u b mit CI R B/I R B a p pr o vals t o t he N CI’s Ca ncer 
Trials S u p p ort U nit ( C T S U) Re g ulat or y Office a n d all o w 3 b usi ness da ys f or pr ocessi n g. 
T he C T S U I R B Certificati o n F or m ma y be s u b mitte d i n lie u of t he si g ne d I R B a p pr o val 
letter. All C T S U f or ms ca n be l ocate d o n t he C T S U we b pa ge ( w w w.cts u. or g). A n y ot her 
re g ulat or y d oc u me nts nee de d f or access t o t he st u d y e nr oll me nt scree ns will be liste d f or 
t he st u d y o n t he C T S U Me m ber’s We bsite u n der t he Re g ulat or y T a b. 
 
Sites partici pati n g o n t he N CI CI R B i nitiati ve a n d acce pti n g CI R B a p pr o val f or t he st u d y 
are n ot re q uire d t o s u b mit se parate I R B a p pr o val d oc u me ntati o n t o t he C T S U Re g ulat or y 
Office f or i nitial, c o nti n ui n g or a me n d me nt re vie w. T his i nf or mati o n will be pr o vi de d t o 
t he C T S U Re g ulat or y Office fr o m t he CI R B at t he ti me t he site’s Si g nat or y I nstit uti o n 
acce pts t he CI R B a p pr o val. T he Si g nat or y site ma y be c o ntacte d b y t he C T S U Re g ulat or y 
Office or as ke d t o c o m plete i nf or mati o n verif yi n g t he partici pati n g i nstit uti o ns o n t he 
st u d y. 
 
S u b mitti n g Re g ul at or y D oc u me nts: 
 
S u b mit re q uire d f or ms a n d d oc u me nts t o t he C T S U Re g ulat or y Office via t he Re g ulat or y 
S u b missi o n P ortal, w here t he y will be e ntere d a n d trac ke d i n t he C T S U R S S. 
 
Re g ulat or y S u b missi o n P ortal: w w w.cts u. or g ( me m bers’ area)  Re g ulat or y T a b 
 Re g ulat or y S u b missi o n 
W he n a p plica ble, ori gi nal d oc u me nts s h o ul d be maile d t o: 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 6  
C T S U Re g ulat or y Office 
1 8 1 8 Mar ket Street, S uite 3 0 0 0 
P hila del p hia, P A 1 9 1 0 3 
 
I nstit uti o ns wit h patie nts waiti n g t hat are u na ble t o use t he P ortal s h o ul d alert t he C T S U 
Re g ulat or y Office i m me diatel y at 1- 8 6 6- 6 5 1- 2 8 7 8 i n or der t o recei ve f urt her i nstr ucti o n 
a n d s u p p ort. F or ge neral ( n o n-re g ulat or y) q uesti o ns, call t he C T S U Ge neral Hel p des k at 
1 - 8 8 8- 8 2 3- 5 9 2 3 or c o ntact C T S U b y e mail at cts uc o ntact @ westat.c o m . 
 
St u d y ce nters ca n c hec k t he stat us of t heir re gistrati o n pac kets b y accessi n g t he Site 
Re gistrati o n Stat us pa ge o n t he C T S U Me m ber’s We bsite u n der t he Re g ulat or y T a b. ( N ote: 
Sites will n ot recei ve f or mal n otificati o n of re g ulat or y a p pr o val fr o m t he C T S U Re g ulat or y 
Office.) 
 
3. 3   
P atie nt Re gistr ati o n 
Pri or t o e nr oll me nt o n st u d y, patie nts m ust be assi g ne d a C O G patie nt I D n u m b er. T his 
n u m ber is o btai ne d via t he C O G Re gistr y i n t he O P E N s yste m o nce a ut h orizati o n f or t he 
release of pr otecte d healt h i nf or mati o n ( P HI) has bee n o btai ne d. 
 
3. 4   
Reser v ati o n a n d C o nt act Re q uire me nts 
Bef ore e nr olli n g a patie nt o n st u d y, a res er vati o n m ust be ma de t hr o u g h t he O P E N we bsite 
a n d t he St u d y C hair or Vice C hair s h o ul d be n otifie d. ( T he patie nt will nee d a C O G patie nt 
I D n u m ber i n or der t o o btai n a reser vati o n). Patie nts m ust be e nr olle d wit hi n 7 cale n dar 
da ys of ma ki n g a reser vati o n.  
 
Reser vati o ns ma y be o btai ne d 2 4- h o urs a da y t hr o u g h t he O P E N we bsite.  
 
3. 5   
I nf or me d C o nse nt/ Asse nt  
T he i n vesti gati o nal nat ure a n d o bj ecti ves of t he trial, t he pr oce d ures a n d treat me nts 
i n v ol ve d a n d t heir atte n da nt ris ks a n d disc o mf orts, a n d p ote ntial alter nati ve t hera pies will 
be caref ull y e x plai ne d t o t he patie nt or t he patie nt’s pare nts or g uar dia n if t he patie nt is a 
c hil d, a n d a si g ne d i nf or me d c o nse nt a n d asse nt will be o btai ne d acc or di n g t o i nstit uti o nal 
g ui deli nes. 
 
3. 6   
Scree ni n g P r oce d ures 
Dia g n ostic or la b orat or y st u dies perf or me d e xcl usi vel y t o deter mi ne eli gi bilit y f or t his trial 
m ust o nl y be d o ne after o btai ni n g writte n i nf or me d c o nse nt.  T his ca n be acc o m plis he d 
t hr o u g h o ne of t he f oll o wi n g mec ha nis ms: a) t he C O G scree ni n g pr ot oc ol, b) a n I R B-
a p pr o ve d i nstit uti o nal scree ni n g pr ot oc ol or c) t he st u d y-s pecific pr ot oc ol.  D oc u me ntati o n 
of t he i nf or me d c o nse nt f or scree ni n g will be mai ntai ne d i n t he patie nt’s researc h c hart. 
St u dies or pr oce d ures t hat were perf or me d f or cli nical i n dicati o ns ( n ot e xcl usi vel y t o 
deter mi ne eli gi bilit y) ma y b e use d f or baseli ne val ues e ve n if t he st u dies were d o ne bef ore 
i nf or me d c o nse nt was o btai ne d. 
 
3. 7   
Eli gi bilit y C hec klist 
Bef ore t he patie nt ca n be e nr olle d, t he res p o nsi ble i nstit uti o nal i n vesti gat or m ust si g n a n d 
date t he c o m plete d eli gi bilit y c hec klist.  A si g ne d c o p y of t he c hec klist will be u pl oa de d 
i nt o R A V E i m me diatel y f oll o wi n g e nr oll me nt. 
 
3. 8   
I nstit uti o n al P at h ol o g y Re p ort 
I m me diatel y f oll o wi n g e nr oll me nt, t he i nstit uti o nal pat h ol o g y re p ort f or t he dia g n osis 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 7  
u n der w hic h t he patie nt is bei n g e nr olle d m ust be u pl oa de d i nt o R A V E. T he re p ort m ust 
i ncl u de t he ass ociate d st u d y n u m ber a n d C O G patie nt re gistrati o n a n d accessi o n n u m bers. 
Pers o nal i de ntifiers, i ncl u di n g t he patie nt’s na me a n d i nitials m ust be re m o ve d fr o m t he 
i nstit uti o nal pat h ol o g y re p ort pri or t o s u b missi o n. 
 
3. 9   
St u d y E nr oll me nt 
Patie nts ma y be e nr olle d o n t he st u d y o nce all eli gi bilit y re q uire me nts f or t he st u d y ha ve 
bee n met. Patie nts w h o gi ve i nf or me d c o nse nt f or t he pr ot oc ol i n or der t o u n der g o 
scree ni n g f or eli gi bilit y are n ot c o nsi dere d e nr olle d a n d s h o ul d n ot be e nr olle d u ntil t he 
scree ni n g is c o m plete d a n d t he y are deter mi ne d t o meet all eli gi bilit y criteria. St u d y 
e nr oll me nt is acc o m plis he d b y g oi n g t o t he C T S U O P E N ( O nc ol o g y Patie nt E nr oll me nt 
Ne t w or k) htt ps:// o pe n.cts u. or g/ o pe n/ . F or q uesti o ns, please c o ntact t he St u d y Assi g ne d 
Researc h   
C o or di nat or,   
or   
t he   
C T S U   
O P E N   
hel p des k   
at 
htt ps:// w w w.cts u. or g/ C T S U C o ntact.as p x .  Patie nts m ust be e nr olle d bef ore treat me nt 
be gi ns.  T he date pr ot oc ol t hera p y is pr ojecte d t o start m ust be n o later t ha n fi ve ( 5) cale n dar 
da ys after t he date of st u d y e nr oll me nt. P atie nts m ust n ot recei ve a n y pr ot o c ol t her a p y 
pri or t o e nr oll me nt. T he o nl y e xce pti o n t o t his is f or i ntrat hecal c ytara bi ne, w hic h ca n be 
gi ve n wit hi n 1 wee k pri or t o a d mi nistrati o n of fl otet uz u ma b. If I T c ytara bi ne is gi ve n pri or 
t o e nr oll me nt, a se parate i nstit uti o nal c o nse nt m ust be o bt ai ne d.  
 
3. 1 0   
D ose Assi g n me nt 
T he d ose le vel will be assi g ne d via O P E N at t he ti me of st u d y e nr oll me nt. 
 
 
4. 0   
P A TI E N T E LI GI BI LI T Y 
 
All cli nical a n d la b orat or y st u dies t o deter mi ne eli gi bilit y m ust be perf or me d wit hi n 7 da ys pri or t o 
e nr oll me nt u nless ot her wise i n di cate d. La b orat or y val ues use d t o assess eli gi bilit y m ust be n o ol der 
t ha n se ve n ( 7) da ys at t he start of t hera p y.  La b orat or y tests nee d n ot  be re peate d if t hera p y starts 
wit hi n  se ve n ( 7) da ys of o btai ni n g la bs t o assess eli gi bilit y.  If a p ost-e nr oll me nt la b val ue is o utsi de 
t he li mits of eli gi bilit y, or la b orat or y val ues are ol der t ha n 7 da ys, t he n t he f oll o wi n g la b orat or y 
e val uati o ns m ust be re-c hec ke d wit hi n 4 8 h o urs pri or t o i nitiati n g t hera p y: C B C wit h differe ntial, 
bilir u bi n, A L T ( S G P T) a n d ser u m cre ati ni ne.  If t he rec hec k is o utsi de t he li mits of eli gi bilit y, t he 
patie nt ma y n ot recei ve pr ot oc ol t hera p y a n d will be c o nsi dere d off pr ot oc ol t hera p y. I ma gi n g 
st u dies, b o ne marr o w bi o ps y a n d/ or as pirate m ust be o btai ne d wit hi n 1 4 da ys pri or t o start of 
pr ot oc ol t hera p y (re peat t he t u m or i ma gi n g if necessar y).  
 
 
Clarificati o n i n ti mi n g w he n c o u nti n g da ys: As a n e xa m ple, please n ote t hat if t he patie nt’s last da y 
of pri or t hera p y is Se pte m ber 1 st, a n d t he pr ot oc ol re q uires waiti n g at least 7 da ys f or t hat t y pe of 
pri or t hera p y, t he n t hat patie nt ca n n ot be e nr olle d u ntil Se pte m ber 8 t h.   
 
I m p ort a nt n ote: T he eli gi bilit y criteri a liste d bel o w are i nter prete d liter all y a n d c a n n ot be 
w ai ve d ( per C O G p olic y p oste d 5/ 1 1/ 0 1).  All cli nic al a n d l a b or at or y d at a re q uire d f or 
deter mi ni n g eli gi bilit y of a p atie nt e nr olle d o n t his tri al m ust be a v ail a ble i n t he p atie nt’s 
me dic al or rese arc h rec or d w hic h will ser ve as t he s o urce d oc u me nt f or verific ati o n at t he 
ti me of a u dit. 
 
4. 1   
I ncl usi o n Criteri a 
 
 
A ge :   
Patie nts m ust be < 2 1 years of a ge at t he ti me of st u d y e nr oll me nt. 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 8  
 
 
Wei g ht: Patie nts m ust wei g h  >  1 7 k g * . 
 
* Wei g ht li mit is d ue t o c o nstrai nts relate d t o t he c o nce ntrati o n of t he c urre nt 
dr u g f or m ulati o n. If a ne w f or m ulati o n of fl otet uz u ma b bec o mes a vaila ble t o 
all o w d osi n g of s maller patie nts, t he pr ot oc ol will be a me n de d.  
 
 
Dia g n osis : Patie nts wit h re c urre nt  or refract or y A M L  are eli gi ble. Patie nts m ust 
ha ve hist ol o gic verificati o n of mali g na nc y at rela pse .   
 
 
Disease Stat us :  
i. 
Patie nts wit h le u ke mia m ust ha ve > M 2 marr o w b y m or p h ol o g y a n d/ or fl o w 
c yt o metr y a n d o ne of t he f oll o wi n g:  
a. Sec o n d or greater rela pse 
b.  Refract or y after 2 or m ore c he m ot hera p y c ycles 
c. First rela pse after pri mar y c he m ot hera p y-refract or y disease  
d.  First rela pse after H S C T 
ii. C N S disease: 
a. Patie nts m ust ha ve t he stat us of C N S 1 (see Secti o n 1 2. 3 ) a n d n o 
cli nical si g ns or ne ur ol o gic s y m pt o ms s u g gesti ve of C N S le u ke mia, 
s uc h as cra nial pals y. 
b.  Patie nts wit h C N S 3 or C N S 2 stat us ma y recei ve a ntece de nt i ntrat hecal 
c he m ot hera p y t o ac hie ve C N S 1 stat us pri or t o st u d y e ntr y (see Secti o n 
1 2. 3 ). 
c. Patie nts wit h a hist or y of C N S c hl or o mat o us disease are re q uire d t o 
ha ve n o ra di o gra p hic e vi de nce of disease pri or t o e nr oll me nt.  
 
 
T hera pe utic O pti o ns : Patie nt’s c urre nt disease state m ust be o ne f or w hic h t here 
is n o k n o w n c urati ve t hera p y or t hera p y pr o ve n t o pr ol o n g s ur vi val wit h a n 
acce pta ble q ualit y of life.  
  
 
Perf or ma nce Le vel : Patie nts m ust ha ve a perf or ma nc e stat us c orres p o n di n g t o 
E C O G sc ores of 0, 1, or 2. Use  Kar n ofs k y f or patie nts > 1 6 years of a ge a n d 
La ns k y f or 
patie nts 
 1 6 
years 
of 
a ge ( See 
A p pe n di x I  
a n d 
htt ps:// me m bers.c hil dre ns o nc ol o g y gr o u p. or g/ pr ot/refere nce _ materials.as p  
u n der Sta n dar d Secti o ns f or Pr ot oc ols). Use a p pr o priate sc ore f or st u d y 
p o p ulati o n. N O T E:  Patie nts w h o are u na ble t o wal k beca use of paral ysis, b ut 
w h o are u p i n a w heelc hair, will be c o nsi dere d a m b ulat or y f or t he p ur p ose of 
assessi n g t he perf or ma nce sc ore. 
 
 
Pri or T hera p y : 
 
4. 1. 7. 1  Patie nts m ust ha ve f ull y rec o vere d fr o m t he ac ute t o xic effects of all pri or 
a nti-ca ncer t hera p y a n d m ust meet t he f oll o wi n g mi ni m u m d urati o n fr o m 
pri or a nti-ca ncer directe d t hera p y pri or t o e nr oll me nt. If after t he re q uire d 
ti mefra me, t he n u merical eli gi bilit y criteria are met, e. g., bl o o d c o u nt 
criteria, t he patie nt is c o nsi dere d t o ha ve rec o vere d a de q uatel y. 
 
a. C yt ot o xic c he m ot hera p y or ot her a nti-ca ncer a ge nts k n o w n t o be 
m yel os u p pressi ve. See D V L h o me pa ge f or c o m mercial a n d P hase 1 
i n vesti gati o nal a ge nt classificati o ns. F or a ge nts n ot liste d, t he d urati o n 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 9  
of t his i nter val m ust be disc usse d wit h t he st u d y c hair a n d t he st u d y-
assi g ne d Researc h C o or di nat or pri or t o e nr oll me nt. 
 
 
≥ 1 4 da ys m ust ha ve ela pse d after t he c o m pleti o n of ot her 
c yt ot o xic t hera p y 
wit h t he e xce pti o n of h y dr o x y urea . 
A d diti o nall y, patie nts m ust ha ve f ull y rec o vere d fr o m all 
ac ute t o xic effects of pri or t hera p y. 
 
N O T E:  
C yt ore d ucti o n wit h h y dr o x y urea is rec o m me n de d 
t o be disc o nti n ue d ≥ 2 4 h o urs pri or t o t he start of 
pr ot oc ol t hera p y. 
 
    
N o waiti n g peri o d is re q uire d f or patie nts ha vi n g 
recei ve d i ntrat hecal 
c ytara bi ne,  
met h otre xate, 
a n d/ or h y dr oc ortis o ne.  
    
 
b.  A nti-ca ncer a ge nts n ot k n o w n t o be 
m yel os u p pressi ve (e. g. n ot 
ass ociate d wit h re d uce d platelet or A N C c o u nts): ≥ 7 da ys after t he 
last d ose of a ge nt. See D V L h o me pa ge f or c o m mercial a n d P hase 1 
i n vesti gati o nal a ge nt classificati o ns. F or a ge nts n ot liste d, t he d urati o n 
of t his i nter val m ust be disc usse d wit h t he st u d y c hair a n d t he st u d y-
assi g ne d Researc h C o or di nat or pri or t o e nr oll me nt.  
 
c. A nti b o dies: ≥ 2 1 da ys m ust ha ve ela pse d fr o m i nf usi o n of last d ose of 
a nti b o d y, a n d t o xicit y relate d t o pri or a nti b o d y t hera p y m ust be 
rec o vere d t o Gra de ≤ 1. 
 
d.  C ortic oster oi ds: See Secti o n 4. 2. 2. 1 . If use d t o m o dif y i m m u ne 
a d verse e ve nts  relate d t o pri or t hera p y, ≥ 1 4 da ys m ust ha ve ela pse d 
si nce last d ose of c ortic oster oi d. 
 
e. He mat o p oietic gr o wt h fact ors : ≥ 1 4 da ys after t he last d ose of a l o n g-
acti n g gr o wt h fact or (e. g. pe gfil grasti m) or 7 da ys f or s h ort-acti n g 
gr o wt h fact or. F or a ge nts t hat ha ve k n o w n a d verse e ve nts occ urri n g 
be y o n d 7 da ys after a d mi nistrati o n, t his peri o d m ust be e xte n de d 
be y o n d t he ti me d uri n g w hic h a d verse e ve nts are k n o w n t o occ ur.  T he 
d urati o n of t his i nter val m ust be disc usse d wit h t he st u d y c hair a n d t he 
st u d y-assi g ne d Researc h C o or di nat or. 
 
f. I nterle u ki ns, I nterfer o ns a n d C yt o ki nes ( ot her t ha n He mat o p oetic 
Gr o wt h Fact ors): ≥ 2 1 da ys after t he c o m pleti o n of i nterle u ki ns, 
i nterfer o n or c yt o ki nes ( ot her t ha n He mat o p oetic Gr o wt h Fact ors ) 
 
g.  Ste m cell I nf usi o ns ( wit h or wit h o ut T BI): 
 
All o ge neic ( n o n-a ut ol o g o us) b o ne marr o w or ste m cell tra ns pla nt, 
or ste m cell b o ost : ≥ 8 4 da ys after i nf usi o n a n d n o e vi de nce of 
G V H D. 
 
D o n or le u k oc yte i nf usi o n: > 4 2 da ys.  
 
 
A ut ol o g o us ste m cell i nf usi o n i ncl u di n g b o ost i nf usi o n:  ≥ 4 2 
da ys. 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 2 0  
h.  Cell ular T hera p y: ≥ 4 2 da ys after t he c o m pleti o n of a n y t y pe of 
cell ular t hera p y (e. g. m o difie d T cells, N K cells, de n dritic cells, etc.) 
 
i. 
X R T/ E xter nal Bea m Irra diati o n i ncl u di n g Pr ot o ns: ≥ 1 4 da ys after 
l ocal X R T; ≥ 8 4 da ys after T BI, cra ni os pi nal X R T or if ra diati o n t o  
5 0 % of t he pel vis; ≥ 4 2 da ys if ot her s u bsta ntial B M ra diati o n. 
 
j. 
Ra di o p har mace utical t hera p y (e. g., ra di ola bele d a nti b o d y, 1 3 1I-
MI B G): ≥ 4 2 da ys after s yste micall y a d mi nistere d 
ra di o p har mace utical t hera p y. 
 
k.  Patie nts m ust n ot ha ve recei ve d pri or e x p os ure t o fl otet uz u ma b. 
 
 
Or ga n F u ncti o n Re q uire me nts  
 
4. 1. 8. 1  A de q uate B o ne Marr o w F u ncti o n Defi ne d as: 
-  
Platelet c o u nt  2 0, 0 0 0/m m 3 ( ma y recei ve platelet tra nsf usi o ns).  
-  
He m o gl o bi n > 8. 0 g/ d L at baseli ne ( ma y recei ve R B C tra nsf usi o ns) 
 
T hese patie nts m ust n ot be k n o w n t o be refract or y t o re d cell or platelet 
tra nsf usi o n.  
 
4. 1. 8. 2  A de q uate Re nal F u ncti o n Defi ne d as: 
-   
Creati ni ne cleara nce or ra di ois ot o pe G F R  7 0 ml/ mi n/ 1. 7 3 m 2 or 
-  
A ser u m creati ni ne base d o n a ge/ ge n der as f oll o ws: 
 
A ge  
 
M a xi m u m Ser u m  
Cre ati ni ne ( m g/ d L)  
 
M ale  
Fe m ale  
1 t o < 2 years  
0. 6  
0. 6  
2 t o < 6 years  
0. 8  
0. 8  
6 t o < 1 0 years  
1  
1  
1 0 t o < 1 3 years  
1. 2  
1. 2  
1 3 t o < 1 6 years  
1. 5  
1. 4  
≥ 1 6 years  
1. 7  
1. 4  
T he t hres h ol d creati ni n e val u es i n t his Ta ble were deri ve d fr o m t he Sc h wartz 
f or m ula f or esti mati n g G F R ( Sc h wart z et al. J. P e ds, 1 0 6: 5 2 2, 1 9 8 5) utilizi n g 
c hil d le n gt h a n d stat ure data p u blis he d b y t h e C D C. 
 
4. 1. 8. 3  A de q uate Li ver F u ncti o n Defi ne d as: 
-  
Bilir u bi n (s u m of c o nj u gate d + u nc o nj u gate d)  1. 5 x u p per 
li mit of n or mal ( U L N) f or a ge re gar dless of baseli ne.  
-  
S G P T ( A L T )  3 x U L N. F or t he p ur p ose of t his st u d y, t he 
U L N f or S G P T is 4 5 U/ L re gar dless of baseli ne .  
-  
S G O T ( A S T ) < 3 x U L N . F or t he p ur p ose of t his st u d y, t he 
U L N f or S G P T is 5 0 U/ L re gar dless of baseli ne .  
-  
Ser u m al b u mi n  2 g/ d L. 
 
4. 1. 8. 4  A de q uate Car diac F u ncti o n Defi ne d As: 
-   
S h orte ni n g fracti o n of   2 7 % b y ec h ocar di o gra m, or 
-   
Ej ecti o n fracti o n of ≥ 5 0 % b y gate d ra di o n ucli de st u d y. 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 2 1  
 
4. 1. 8. 5  A de q uate Ne ur ol o gic F u ncti o n Defi ne d as: 
-   
Patie nts wit h seiz ure dis or der ma y be e nr olle d if o n a ntic o n v ulsa nts 
a n d well c o ntr olle d. 
-   
Ner v o us s yste m dis or ders ( C T C A E v 5 ) res ulti n g fr o m pri or t hera p y 
m ust be  Gra de 2 wit h t he e xce pti o n of d ecrease d te n d o n refle x 
( D T R). A n y Gra de of D T R is eli gi ble.  
 
 
I nf or me d C o nse nt: All patie nts a n d/ or t heir pare nts or le gall y a ut h orize d 
re prese ntati ves m ust si g n a writte n i nf or me d 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.  
 
 Access:  Per ma ne nt ce ntral access s h o ul d be esta blis he d wit h a ce ntral li ne . A 
ce ntral li ne  t hat c o ntai ns 2 l u me ns is preferre d.  
 
4. 2   
E xcl usi o n Criteri a 
 
 
Pre g na nc y or Breast -Fee di n g  
Pre g na nt or breast-fee di n g w o me n will n ot be e ntere d o n t his st u d y beca use 
t here is yet n o a vaila ble i nf or mati o n re gar di n g h u ma n fetal or terat o ge nic 
t o xicities. Pre g na nc y tests m ust be o btai ne d i n girls w h o are p ost- me narc hal. 
Males or fe males of re pr o d ucti ve p ote ntial ma y n ot partici pate u nless t he y ha ve 
a gree d t o use a n effecti ve c o ntrace pti ve met h o d f or t he d urati o n of st u dy 
t hera p y a n d f or 1 2 wee ks after fl otet uz u ma b disc o nti n uati o n.  
 
 
C o nc o mita nt  Me dicati o ns  
 
4. 2. 2. 1  C ortic oster oi ds:  Patie nts 
m ust be off ster oi ds ( u nless p h ysi ol o gic 
re place me nt d osi n g) f or at least 7 da ys pri or t o e nr oll me nt. If use d t o 
m o dif y i m m u ne a d verse e ve nts relate d t o pri or t hera p y, ≥ 1 4 da ys m ust 
ha ve ela pse d si nce last d ose of c ortic oster oi d ( See Secti o n 4. 1. 7. 1. d ). 
 
4. 2. 2. 2  I n vesti gati o nal Dr u gs:  Patie nts 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 n ot eli gi ble. 
 
4. 2. 2. 3  A nti-ca ncer A ge nts:  Patie nts w h o are c urre ntl y recei vi n g ot her a nti-ca ncer 
a ge nts are n ot eli gi ble [e xce pt h y dr o x y urea, w hic h ma y be c o nti n ue d u ntil 
2 4 h o urs pri or t o start of pr ot oc ol t hera p y]. 
 
4. 2. 2. 4  A nti- G V H D a ge nts p ost-tra ns pla nt :  
Patie nts w h o are recei vi n g c ycl os p ori ne, tacr oli m us or ot her a ge nts t o treat 
graft- vers us- h ost disease p ost b o ne marr o w tra ns pla nt are n ot eli gi ble f or 
t his trial. 
 
 
St u d y S pecific:  
 
4. 2. 3. 1  Patie nt has Fre nc h- A merica n- Britis h classificati o n ( F A B) t y pe 
M 3 
le u ke mia (ac ute pr o m yel oc ytic le u ke mia) or i de ntificati o n of t( 1 5; 1 7). 
 
4. 2. 3. 2  Patie nt has is olate d C N S i n v ol ve me nt or is olate d e xtra me d ullar y rela pse.  
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 2 2  
4. 2. 3. 3  Patie nt wit h k n o w n HI V i nfecti o n are eli gi ble if he or s he has a ne gati ve 
HI V ser ol o g y a n d a n u n detecta ble viral l oa d.  
 
4. 2. 3. 4  Patie nt k n o w n t o ha ve o ne of t he f oll o wi n g c o nc o mita nt ge netic 
s y n dr o mes: Bl o o m s y n dr o me, ata xia-tela n giectasia, Fa nc o ni a ne mia, 
K ost ma n n s y n dr o me, S h wac h ma n s y n dr o me or a n y ot her k n o w n b o ne 
marr o w fail ure s y n dr o me. Patie nts wit h D o w n s y n dr o me A R E eli gi ble f or 
t he st u d y.  
 
4. 2. 3. 5  Patie nts m ust n ot wei g h < 1 7 k g.  
 
4. 2. 3. 6  Patie nts m ust n ot ha ve recei ve d pri or t hera p y wit h a C D 1 2 3 directe d 
a nti b o d y or C D 1 2 3 directe d C A R T cells. 
 
 
I nfecti o n:  Patie nts w h o ha ve a n u nc o ntr olle d i nfecti o n are n ot eli gi ble. 
 
 
Patie nts w h o ha ve recei ve d a pri or s oli d or ga n tra ns pla ntati o n are n ot eli gi ble.  
 
 
Patie nts 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 are n ot eli gi ble. 
 
 
K n o w n h y perse nsiti vit y t o m uri ne, yeast, or rec o m bi na nt pr otei ns; p ol ys or bate 
8 0; rec o m bi na nt h u ma n ser u m al b u mi n; be nz yl alc o h ol; or a n y e xci pie nt 
c o ntai ne d i n t he fl otet uz u ma b dr u g f or m ulati o n. A d diti o nall y, t h ose patie nts 
w h o ha ve ha d a h y perse nsiti vit y  reacti o n t o et o p osi de t hat is c o nsi dere d li kel y 
relate d t o p ol ys or bate 8 0 are n ot eli gi ble.  
 
 
Patie nts m ust refrai n fr o m dri vi n g a m ot or ve hicle or o perati n g hea v y 
mac hi ner y w hile recei vi n g fl otet uz u ma b a n d f or 3 0 da ys fr o m t he date of last 
st u d y dr u g a d mi nistrati o n. 
 
 
5. 0   
T R E A T M E N T P R O G R A M 
 
5. 1   
O ver vie w of Tre at me nt Pl a n 
A c ycle of t hera p y is 2 9 da ys. F oll o wi n g t he e n d of fl otet uz u ma b i nf usi o n o n Da y 2 9, 
patie nts will be all o we d a treat me nt free i nter val of u p t o 3 da ys t o all o w res pite. T he 
d urati o n of t his treat me nt free i nter val will be u p t o t he treati n g p h ysicia n’s discreti o n. 
Kee pi n g i nterr u pti o ns t o < 3 da ys will re d uce t he c ha nce of disease re b o u n d a n d l o wer t he 
ris k f or rec urre nt C R S base d u p o n cli nical e x perie n ce i n fl otet uz u ma b-treate d a d ult 
patie nts. Alter nati vel y, t he treati n g p h ysicia n ma y o pt t o s ki p t he treat me nt-free i nter val 
a n d all o w t he patie nt t o pr ocee d i m me diatel y t o t he ne xt c ycle wit h o ut res pite, as l o n g as 
t he patie nt is e x perie nci n g cli nical be nefit. Cli nical be nefit ma y be defi ne d as a re d ucti o n 
i n le u ke mia relate d s y m pt o ms, a n d/ or a re d ucti o n i n tra nsf usi o n fre q ue nc y a n d/ or a 
re d ucti o n or cleara nce of peri p heral blasts. Patie nts wit h at least a P R f oll o wi n g C ycle 2 
ma y c o nti n ue o n s u bse q ue nt c ycles of fl otet uz u ma b f or a t otal of u p t o 6 c ycles, lasti n g 
a p pr o xi matel y 6 m o nt hs. Patie nts s h o ul d disc o nti n ue pr ot oc ol t hera p y if t he y ha ve n ot 
ac hie ve d at least a P R f oll o wi n g C ycle 2.  
 
D uri n g t he d ose escalati o n p orti o n of t he st u d y, fl otet uz u ma b will be a d mi nistere d b y 
c o nti n u o us i ntra ve n o us i nf usi o n f or a t otal of 2 8 da ys ( N O T E: i nf usi o n e n ds o n Da y 2 9). 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 2 3  
All d oses of fl otet uz u m a b i n t his st u d y are descri be d as n a n o gr a ms/ k g/ d a y. H o we ver, 
t he dr u g l a bels are e x presse d i n milli gr a ms/ m L. Ste p- u p d osi n g will be use d i n t he first 
7 da ys of C ycle 1 t o mi ni mize I R R/ C R S, f oll o we d b y 2 1 da ys at t he a d ult rec o m me n de d 
p hase 2 d ose ( R P 2 D) ( 5 0 0 na n o gra ms/ k g/ da y, D ose Le vel 1 [ D L 1]). If D L 1 is dee me d safe 
a n d t olera ble base d o n sta n dar d i m m u n ot hera p y D L T assess me nts ( Secti o n 5. 5 ), a n 
a d diti o nal c o h ort of patie nts will d ose-escalate t o fl otet uz u ma b at 7 0 0 na n o gra ms/ k g/ da y 
( D L 2). Ste p- u p d osi n g will occ ur d uri n g t he first 8 da ys of C ycle 1 f or t his c o h ort. If fe wer 
t ha n 2 D L Ts occ ur at D L 2, t his will be c o nsi dere d t he R P 2 D. If t here are > 2 D L Ts at D L 2, 
D L 1 will be c o nsi dere d t he M T D. If D L 1 is n ot t olera ble, d ose de-escalati o n will occ ur t o 
3 0 0 na n o gra ms/ k g/ da y ( D L- 1) wit h i nitial ste p- u p d osi n g d uri n g t he first 8 da ys of C ycle 
1 f or t his c o h ort. If D L- 1 is dee me d t olera ble, t his d osi n g will be t he M T D. F urt her d ose 
de-escalati o n will n ot be per mitte d a n d will li mit f urt her e x pl orati o n of fl otet uz u ma b i n 
t his patie nt p o p ulati o n. N o pla n ne d ste p- u p d osi n g will occ ur d uri n g s u bse q ue nt c ycles 
u nless t here is a n i nf usi o n i nterr u pti o n of m ore t ha n 3 da ys bet wee n c ycles of fl otet uz u ma b. 
If a n i nterr u pti o n lasts > 3 da ys, s u bse q ue nt c ycle d osi n g s h o ul d be disc usse d wit h t he st u d y 
c hair.  
 
B o ne marr o w e val uati o n will be perf or me d o n Da y 2 9 ( +/ - 1 da y) t o e val uate res p o nse.  
 
Dr u g d oses s h o ul d be a dj uste d base d o n t he patie nt’s wei g ht meas ure d wit hi n 7 da ys pri or 
t o t he be gi n ni n g of eac h c ycle. Fl otet uz u ma b c o nti n u o us i nf usi o n m ust be a d mi nistere d 
t hr o u g h a n I V li ne wit h a l o w pr otei n bi n di n g p ol yet hers ulf o ne ( P E S) 0. 2 micr o n i n-li ne 
filter. D ue t o t he ris k of C R S, sites s h o ul d ha ve s ufficie nt s u p pl y of t ociliz u ma b (e n o u g h 
t o treat a 7 0 k g patie nt x t hree 8 m g/ k g d oses) at all ti mes f or eac h patie nt o n t hera p y. 
Patie nts will r e mai n h os pitalize d f or t he d urati o n of C ycle 1 f or safet y m o nit ori n g. Patie nts 
ma y recei ve s u bse q ue nt c ycles as a n o ut patie nt if t he dr u g ca n be acc uratel y a n d safel y 
deli vere d (see A p pe n di x X I V), a n d at t he discreti o n of t he treati n g p h ysicia n a n d after 
disc ussi o n wit h t he st u d y c hair.  
 
Patie nts s h o ul d recei ve a si n gle d ose of I T c ytara bi ne pri or t o t he start of C ycle 1 bet wee n 
Da ys - 6 t o 0. Patie nts ma y recei ve I T c ytara bi ne o n Da y 1 of s u bse q ue nt c ycles or wit h 
b o ne marr o w e val uati o ns at t he discreti o n of t he treati n g p h ysicia n.  
 
I T C ytara bi ne A ge- base d d osi n g: 
A ge ( yrs)   
D ose 
< 1   
   
2 0 m g 
1- 1. 9 9    
3 0 m g 
2- 2. 9 9    
5 0 m g 
> 3   
   
7 0 m g 
 
 
I nf usi o n- Relate d Reacti o n/ C yt o ki ne Release S y n dr o me (I R R/ C R S) Pr o p h yla xis f or 
C ycle 1 :  
 
Acet a mi n o p he n : 1 0 – 1 5 m g/ k g/ d ose ( ma x: 6 5 0 m g/ d ose) I V or P O  
 
Wee k 1 Ste p- u p D osi n g: o nce dail y, 3 0 mi n utes pri or t o starti n g eac h ne w d ose, t he n q 4- 6 h 
pr n 
Fi nal D ose Escalati o n : 3 0 mi n utes pri or t o d ose escalati o n t o g oal d ose, t he n sc he d ule d q 8 h 
x 4 8 h o urs, t he n q 4- 6 h pr n 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 2 4  
Di p he n h y dr a mi ne : 0. 5 – 1 m g/ k g/ d ose ( ma x: 5 0 m g) I V or P O 
Wee k 1 Ste p- u p D osi n g : o nce dail y, 3 0 mi n utes pri or t o starti n g eac h ne w d ose, t he n q 6-
8 h pr n 
Fi nal D ose Escalati o n: 3 0 mi n utes pri or t o d ose escalati o n, t he n sche d ule d q 8 h x 4 8 h o urs, 
t he n q 6- 8 h pr n 
 
Hist a mi ne 2 Rece pt or A nt a g o nists: 
Ra niti di ne: 1 m g/ k g/ d ose I V ( ma x si n gle d ose: 5 0 m g) or 2 m g/ k g/ d ose P O ( ma x si n gle 
d ose: 1 5 0 m g); or e q ui vale ntl y d ose d H 2 rece pt or a nta g o nist (e. g., fa m oti di ne 0. 2 5 
m g/ k g/ d ose I V ( ma x si n gle d ose: 2 0 m g) or 0. 5 m g/ k g/ d ose P O ( ma x si n gle d ose: 4 0 m g)) 
Wee k 1 Ste p- u p D osi n g: 3 0 mi n utes pri or t o starti n g eac h ne w d ose, t he n ra niti di ne q 8 h 
(I V) or q 1 2 h ( P O) pr n O R fa m oti di ne q 1 2 h I V/ P O pr n 
Fi nal D ose Escalati o n: 3 0 mi n utes pri or t o d ose escalati o n, t he n sc he d ule d ra niti di ne q 8 h 
(I V) or q 1 2 h ( P O) O R fa m oti di ne q 1 2 h I V/ P O x 4 8 h o urs, t he n pr n (at sa me fre q ue nc y) 
 
De x a met h as o ne 
Wee k 1, Da y 1: 5 m g/ m
2/ d ose ( ma x si n gle d ose: 5 m g) I V or P O o nce, 3 0 mi n utes pri or t o 
starti n g fl otet uz u ma b, t he n 5 m g/ m 2/ d ose ( ma x si n gle d ose: 5 m g) I V or P O gi ve n 1 2 h o urs 
later x 1 (t otal dail y d ose: 1 0 m g/ m2) 
 
 
 
D L 1, C ycle 1  
 
D a y 
0  
1   
2   
3   
4   
5   
6   
7  
8 -
2 8  
2 9  
I T c yt ar a bi ne *  
X   
  
  
  
  
  
  
  
 
E n d of 
fl otet uz u ma b 
i nf usi o n 
Fl otet uz u m a b 3 0 
n a n o gr a ms / k g/ d a y 
  
X   
  
  
  
  
  
  
 
Fl otet uz u m a b 6 0 
n a n o gr a ms / k g/ d a y 
  
  
X   
  
  
  
  
  
 
Fl otet uz u m a b 1 0 0  
n a n o gr a ms / k g/ d a y 
  
  
  
X   
  
  
  
  
 
Fl otet uz u m a b 2 0 0  
n a n o gr a ms / k g/ d a y 
  
  
  
  
X   
  
  
  
 
Fl otet uz u m a b 3 0 0 
n a n o gr a ms / k g/ d a y 
  
  
  
  
  
X   
  
  
 
Fl otet uz u m a b 4 0 0  
n a n o gr a ms / k g/ d a y 
  
  
  
  
  
  
X   
  
 
Fl otet uz u m a b 5 0 0 
n a n o gr a ms / k g/ d a y 
  
  
  
  
  
  
  
X   
X  
* ca n be gi ve n bet wee n Da ys - 6 a n d 0 
 
 
D L -1, C ycle 1  
 
D a y 
0  
1   
2   
3   
4   
5   
6   
7   
8   
9 -2 8   
2 9  
I T c yt ar a bi ne *  
X   
  
  
  
  
  
  
  
  
 
E n d of 
fl otet uz u ma b 
i nf usi o n 
Fl otet uz u m a b 3 0 
n a n o gr a ms / k g/ d a y 
  
X   
  
  
  
  
  
  
  
 
Fl otet uz u m a b 6 0 
  
  
X   
X   
  
  
  
  
  
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 2 5  
n a n o gr a ms / k g/ d a y 
Fl otet uz u m a b 1 0 0  
n a n o gr a ms / k g/ d a y 
  
  
  
  
X   
X   
  
  
  
 
Fl otet uz u m a b 2 0 0 
n a n o gr a ms / k g/ d a y 
  
  
  
  
  
  
X   
X   
  
 
Fl otet uz u m a b 3 0 0 
n a n o gr a ms / k g/ d a y 
  
  
  
  
  
  
  
  
X   
X  
*  ca n be gi ve n bet wee n Da ys - 6 a n d 0 
 
 
D L 2, C ycle 1  
 
D a y 
0  
1   
2   
3   
4   
5   
6   
7   
8   
9 -2 8   
2 9  
I T c yt ar a bi ne *  
X   
  
  
  
  
  
  
  
  
 
E n d of 
fl otet uz u ma b 
i nf usi o n 
Fl otet uz u m a b 3 0 
n a n o gr a ms / k g/ d a y 
  
X   
  
  
  
  
  
  
  
 
Fl otet uz u m a b 1 0 0  
n a n o gr a ms / k g/ d a y 
  
  
X   
  
  
  
  
  
  
 
Fl otet uz u m a b 2 0 0  
n a n o gr a ms / k g/ d a y 
  
  
  
X   
  
  
  
  
  
 
Fl otet uz u m a b 3 0 0 
n a n o gr a ms / k g/ d a y 
  
  
  
  
X   
  
  
  
  
 
Fl otet uz u m a b 4 0 0  
n a n o gr a ms / k g/ d a y 
  
  
  
  
  
X   
  
  
  
 
Fl otet uz u m a b 5 0 0  
n a n o gr a ms / k g/ d a y 
  
  
  
  
  
  
X   
  
  
 
Fl otet uz u m a b 6 0 0  
n a n o gr a ms / k g/ d a y 
  
  
  
  
  
  
  
X   
  
 
Fl otet uz u m a b 7 0 0 
n a n o gr a ms / k g/ d a y 
  
  
  
  
  
  
  
  
X   
X  
      *ca n be gi ve n bet wee n Da ys - 6 a n d 0 
 
 
All C o h orts, C ycles 2 + 
 
 
D a y 1   
D a y 2 -2 8  
2 9  
I T c yt ar a bi ne * 
X  
 
E n d of 
fl otet uz u ma b 
i nf usi o n 
Fl otet uz u m a b at 
C ycle 1 t ar get d ose  
X  
X  
* Patie nts ma y recei ve a n o pti o nal d ose of I T c ytara bi ne d uri n g s u bse q ue nt c ycles o n Da y 1 or wit h b o ne 
marr o w e val uati o ns at t he discreti o n of t he treati n g p h ysicia n. 
 
If a tre at me nt-free i nter v al > 3 d a ys occ urs bet wee n a n y 2 c ycles, t he s u bse q ue nt c ycle will re q uire 
ste p- u p d osi n g. If a tre at me nt-free i nter v al > 3 d a ys occ urs bet wee n a n y 2 c ycles, t he St u d y C h air 
m ust be n otifie d a n d t he s u bse q ue nt c ycle d osi n g sc he d ule m ust be disc usse d.  
 
I T C ytara bi ne A ge- base d d osi n g: 
A ge ( yrs)   
D ose 
< 1   
   
2 0 m g 
1- 1. 9 9    
3 0 m g 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 2 6  
2 - 2. 9 9    
5 0 m g 
> 3   
   
7 0 m g 
 
I nf usi o n Relate d Reacti o n/ C yt o ki ne Release S y n dr o me Pr o p h yla xis pri or t o eac h 
s u bse q ue nt c ycle a n d f or pr ol o n ge d i nterr u pti o ns:  
 
Pr o p h yla xis is re q uire d pri or t o s u bse q ue nt c ycles if t he treat me nt-free i nter val is greater 
t ha n 2 4 h o urs. Pr o p h yla xis is als o rec o m me n de d f oll o wi n g a n y i nterr u pti o n i n c ycles t hat 
last > 2 4 h o urs. F or i nterr u pti o ns i n c ycles t hat last < 2 4 h o urs, pr o p h yla xis ca n be gi ve n at 
t he discreti o n of t he treati n g p h ysicia n.  
 
Acet a mi n o p he n : 1 0 – 1 5 m g/ k g/ d ose ( ma x: 6 5 0 m g/ d ose) I V or P O  
Da y 1: 3 0 mi n utes pri or t o starti n g fl otet uz u ma b i nf usi o n, t he n q 4- 6 h pr n 
 
Di p he n h y dr a mi ne : 0. 5 – 1 m g/ k g/ d ose ( ma x: 5 0 m g) I V or P O 
D a y 1: 3 0 mi n utes pri or t o fl otet uz u ma b i nf usi o n, t he n q 6- 8 h pr n 
 
R a niti di ne : 1 m g/ k g/ d ose I V ( ma x si n gle d ose: 5 0 m g) or 2 m g/ k g/ d ose P O ( ma x si n gle 
d ose: 1 5 0 m g); or e q ui vale ntl y d ose d H 2 rece pt or a nta g o nist (e. g., fa m oti di ne) 
Da y  1: 3 0 mi n utes pri or t o starti n g fl otet uz u ma b i nf usi o n, t he n q 8 h (I V) or q 1 2 h ( P O) pr n 
 
De x a met h as o ne 
Da y 1: 5 m g/ m 2/ d ose ( ma x si n gle d ose: 5 m g) I V or P O o nce 3 0 mi n utes pri or t o starti n g 
fl otet uz u ma b i nf usi o n, t he n 5 m g/ m2/ d ose ( ma x si n gle d ose: 5 m g) I V or P O gi ve n 1 2 h o urs 
later (t otal dail y d ose: 1 0 m g/ m2) 
 
5. 2   
Criteri a f or St arti n g S u bse q ue nt C ycles 
A c ycle ma y be re peate d e ver y 2 9 da ys, wit h a n o pti o nal < 3 da y res pite peri o d bet wee n 
eac h c ycle. T he o pti o nal < 3 da y res pite peri o d will be u p t o t he treati n g p h ysicia n’s 
discreti o n. If a patie nt has pr o gressi ve disease at a n y ti me p oi nt or is u na ble t o ac hie ve a 
P R f oll o wi n g C ycle 2, s u bse q ue nt pr ot oc ol t hera p y m ust be disc o nti n ue d. D ue t o a ris k f or 
disease re b o u n d a n d rec urre nt C R S, patie nts are all o we d t o pr ocee d t o s u bse q ue nt c ycles 
w hile a waiti n g disease e val uati o n at t he discreti o n of t he treati n g p h ysicia n. F or patie nts 
wit h n o e vi de n ce of disease after C ycle 1, s u bse q ue nt c ycles s h o ul d be i nterr u pte d u ntil 
A N C ≥ 5 0 0 μ L a n d platelets ≥ 2 0, 0 0 0/ m m 3. Patie nts wit h persiste nt disease are per mitte d 
t o c o nti n ue fl otet uz u ma b  re gar dless of A N C a n d platelet c o u nts. La b orat or y para meters 
as defi ne d i n t he eli gi bilit y secti o n, Secti o n 4. 0 , m ust be met, a n d t he patie nt m ust be 
eli gi ble t o c o nti n ue a ge nt a d mi nistrati o n per t he re q uire me nts i n Secti o n 6. 0 . 
 
5. 3   
D ose Esc al ati o n Sc he m a 
 
 
I nter-Patie nt Escalati o n  
T he starti n g d ose will be 5 0 0 na n o gra ms/ k g/ da y ( D L 1) wit h d ose le vels f or 
s u bse q ue nt gr o u ps of patie nts as f oll o ws: 
 
D ose Le vel  
D ose ( n a n o gr a ms / k g/ d a y) 
-1  
3 0 0  
1 *  
5 0 0  
2  
7 0 0  
* Starti n g D ose Le vel 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 2 7  
T here 
will be n o pla n ne d escalati o ns be y o n d 
D ose 
Le vel 2 ( 7 0 0 
na n o gra ms/ k g/ da y), as pre vi o us pe diatric P hase 1 st u dies ha ve rarel y defi ne d a 
M T D greater t ha n 1 6 0 % of t he a d ult M T D. If esti mate d cleara nce is hi g h i n t his 
pe diatric st u d y p o p ulati o n, we will c o nsi der a me n di n g t he pr ot oc ol t o all o w 
f urt her d ose escalati o n t o 9 0 0 na n o grams / k g/ da y.  
 
If t he M T D has bee n e xcee de d at t he first d ose le vel, t he n t he s u bse q ue nt c o h ort 
of patie nts will be treate d at a d ose of 3 0 0 na n o gra ms/ k g/ da y ( D ose Le vel - 1). 
If D ose Le vel - 1 is n ot well t olerate d, f urt her de-escalati o n will n ot occ ur. T he 
st u d y will be cl ose d t o accr ual. 
 
 
I ntra-Patie nt Escalati o n  
I ntra- patie nt d ose escalati o n will occ ur d uri n g t he first 7 da ys of C ycle 1 o n 
D ose  Le vel 1 a n d t he first 8 da ys of C ycle 1 o n D ose Le vels - 1 a n d 2 as 
descri be d i n Secti o n 5. 1 . I ntra- patie nt d ose escalati o n occ urri n g o utsi de of t his 
ti me peri o d is n ot all o we d.  
 
5. 4   
Gr a di n g of A d verse E ve nts 
A d verse e ve nts (t o xicities) will be gra de d acc or di n g t o t he N CI C o m m o n T er mi n ol o g y 
Criteria f or A d verse E ve nts ( C T C A E) versi o n 5. 0.  All a p pr o priate treat me nt areas s h o ul d 
ha ve access t o a c o p y of t he C T C A E versi o n 5. 0.  A c o p y of t he C T C A E versi o n 5. 0 ca n 
be  
d o w nl oa de d   
fr o m   
t he   
C T E P   
we bsite 
(htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m ).   
A n y 
s us pecte d or c o nfir me d d ose-li miti n g t o xicit y s h o ul d be re p orte d i m me diatel y ( wit hi n 2 4 
h o urs) t o t he St u d y C hair. 
 
5. 5   
Defi niti o n of D ose- Li miti n g T o xicit y ( D L T) 
D L T will be defi ne d as a n y of t he f oll o wi n g e ve nts t hat are p ossi bl y, pr o ba bl y or defi nitel y 
attri b uta ble t o pr ot oc ol t hera p y.  T he D L T o bser vati o n peri o d f or t he p ur p oses of d ose-
escalati o n will be t he first c ycle of t hera p y. 
 
D ose li miti n g he mat ol o gical a n d n o n- he mat ol o gical t o xicities are defi ne d differe ntl y.   
 
 
N o n -he mat ol o gical d ose -li miti n g t o xicit y 
5. 5. 1. 1  A n y Gra de 3 or greater n o n- he mat ol o gical t o xicit y at least p ossi bl y 
attri b uta ble t o pr ot oc ol t hera p y wit h t he s pecific e xcl usi o n of: 
 Al o pecia  
 Gra de 3 fati g ue, a n ore xia, na usea, v o miti n g, a n d diarr hea n ot 
re q uiri n g h os pitalizati o n, t u be-fee di n g, or use of T P N.  
 Gra de 3 li ver e nz y me ele vati o n, i ncl u di n g A L T/ A S T, occ urri n g 
after fl otet uz u ma b a d mi nistrati o n t hat ret ur ns t o Gra de < 1 or 
baseli ne wit hi n 7 da ys fr o m t he start of t hera p y. N ote:   F or t he 
p ur p oses of t his st u d y t he U L N f or A L T is defi ne d as 4 5 U/ L. 
 Gra de 3 or 4 fe ver, fe brile ne utr o pe nia, or i nfecti o n 
 Gr a de 3 or 4 is olate d electr ol yte a b n or malities t hat res ol ve wit h or 
wit h o ut i nter ve nti o n t o < Gra de 2 wit hi n 7 2 h o urs. Electr ol yte 
s u p ple me ntati o n is e nc o ura ge d. 
 Gra de 3 or 4 t u m or l ysis s y n dr o me t hat res ol ves wit hi n 7 da ys 
wit h o ut e n d- or ga n da ma ge. 
 Gra de 3 ras h t hat res ol ves ( wit h or wit h o ut s u p p orti ve care) t o < 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 2 8  
Gra de 2 wit hi n 7 da ys 
 Gra de 3 m uc ositis t hat res ol ves ( wit h or wit h o ut s u p p orti ve care) t o 
< Gra de 2 wit hi n 7 da ys 
 Earl y i nter ve nti o n wit h T P N or e nteral t u be fee di n g f or a n ore xia, 
na usea n ot attri b uta ble t o pr ot oc ol t hera p y, or c o ncer n f or p o or 
n utriti o nal stat us clearl y a n d i nc o ntr o verti bl y n ot attri b uta ble t o 
pr ot oc ol t hera p y will n ot be c o nsi dere d a D L T 
 Gra de 3 or greater pai n d ue t o le u ke mia, m uc ositis, t y p hlitis, 
i nfecti o n, or o b vi o us i nj ur y 
 Gra de 3 I R R (i ncl u di n g C R S) res ol vi n g t o < Gra de 2 wit hi n 7 2 
h o urs. C R S will be defi ne d b y A S B M T c o nse ns us gra di n g 3 6 
 Cases of H y’s la w ( > 3 x U L N of A L T/ A S T al o n g wit h > 2 x U L N i n 
t otal bilir u bi n wit h o ut e vi de nce of c h olestasis) will be c o nsi dere d a 
D L T if n o ot her reas o n ca n be f o u n d t o e x plai n t he o bser ve d i nj ur y 
(e. g. le u ke mia, i nfecti o n, a n ot her dr u g, etc.). 
 
5. 5. 1. 2  N o n- he mat ol o gical t o xicit y t hat ca uses a dela y of  1 4 da ys bet wee n 
treat me nt c ycles. 
 
5. 5. 1. 3  N ote: Aller gic reacti o ns t hat necessitate disc o nti n uati o n of st u d y dr u g will 
n ot be c o nsi dere d a d ose-li miti n g t o xicit y. 
 
 
He mat ol o gical d ose li miti n g t o xicit y  
He mat ol o gical d ose li miti n g t o xicit y will be defi ne d as fail ure t o rec o ver a 
peri p heral A N C > 5 0 0/ m m 3 a n d platelets > 2 0, 0 0 0/ m m3 b y 4 2 da ys after t he 
first treat me nt da y. Patie nts wit h detecta ble le u ke mia (i ncl usi ve of M R D) will 
be u ne val ua ble f or a he mat ol o gic D L T.  
 
5. 5. 2. 1  N ote:  Gra de 3 or 4 fe brile ne utr o pe nia will n ot be c o nsi dere d a d ose-
li miti n g t o xicit y. 
 
 
6. 0   
D O S E M O DI FI C A TI O N S F O R A D V E R S E E V E N T S 
 
T he St u d y C h air m ust be n otifie d of a n y d os a ge m o dific ati o n or use of m yel oi d gr o wt h f act or. 
 
6. 1   
D ose M o dific ati o ns f or He m at ol o gic al T o xicit y 
 
 
Patie nts w h o ha ve d ose -li miti n g t hr o m b oc yt o pe nia or ne utr o pe nia  s h o ul d 
recei ve s u bse q ue nt c ycles at t he ne xt l o wer d ose le vel.  
 
 
Patie nts w h o e x perie nce d ose -li miti n g t hr o m b oc yt o pe nia or ne utr o pe nia after 
o ne  d ose re d ucti o n m ust be re m o ve d fr o m pr ot oc ol t hera p y.  T he use of 
he mat o p oietic gr o wt h fact ors i s disc o ura ge d. H o we ver, gra n ul oc yte c ol o n y 
sti m ulati n g fact or ma y be use d o utsi de of C ycle 1 f or c ult ure pr o ve n 
bactere mia or i n vasi ve f u n gal i nfecti o n. T he St u d y C hair s h o ul d be n otifie d 
bef ore gr o wt h fact ors are i nitiate d.  
 
 
Patie nts w h o ha ve a d ose -li miti n g he mat ol o gical t o xicit y t hat d oes n ot res ol ve 
t o eli gi bilit y para meters wit hi n 5 6 da ys  of a n y c ycle i n t he a bse nce of 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 2 9  
detecta ble le u ke mia m ust be re m o ve d fr o m pr ot oc ol t hera p y. 
 
6. 2   
D ose M o dific ati o ns f or N o n- He m at ol o gic al T o xicit y 
 
 
Patie nts w h o ha ve a n y d ose -li miti n g n o n-he mat ol o gical t o xicit y (as defi ne d i n  
Secti o n 5. 5. 1 ) ma y c o nti n ue o n pr ot oc ol t hera p y u p o n meeti n g eli gi bilit y la b 
re q uire me nts or baseli ne b ut s h o ul d recei ve s u bse q ue nt d oses at t he ne xt 
l o wer d ose le vel.  
 
 
If a n o n -he m at ol o gical d ose -li miti n g t o xicit y rec urs after o ne d ose re d ucti o n, 
t he patie nt m ust be re m o ve d fr o m pr ot oc ol t hera p y. 
 
 
Patie nts w h o ha ve a d ose -li miti n g n o n-he mat ol o gical t o xicit y t hat d oes n ot 
res ol ve t o baseli ne or eli gi bilit y  wit hi n 2 1 da y s after t he pla n ne d start of t he 
ne xt treat me nt c ycle m ust be re m o ve d fr o m pr ot oc ol t hera p y.  
 
6. 3   
D ose M o dific ati o ns f or I nf usi o n- Rel ate d Re acti o ns a n d C yt o ki ne Rele ase S y n dr o me  
T he mec ha nis m of acti o n of fl otet uz u ma b is t he creati o n of a n i m m u n ol o gical s y na pse 
bet wee n t he le u ke mic blast beari n g C D 1 2 3 a n d T cells, lea di n g t o T cell acti vati o n a n d 
killi n g of t he le u ke mic cell. Acti vati o n of T cells is ass ociate d wit h t he ela b orati o n of 
vari o us c yt o ki nes i ncl u di n g I F N- , T N F-, I L- 2, I L- 6, I L- 4 a n d I L- 1 0. T his T cell 
acti vati o n a n d s u bse q ue nt c yt o ki ne pr o d ucti o n ca n lea d t o i nf usi o n relate d reacti o ns (I R Rs) 
or c yt o ki ne release s y n dr o me ( C R S). 
 
Patie nts s h o ul d be m o nit ore d cl osel y f or t he de vel o p me nt of I R Rs d uri n g fl otet uz u ma b 
i nf usi o n. Me dicati o ns a n d s u p p orti ve meas ures f or t he treat me nt of s uc h reacti o ns s h o ul d 
be a vaila ble f or i m me diate use f or a n i nf usi o n reacti o n d uri n g st u d y dr u g a d mi nistrati o n 
a n d ma y i ncl u de, b ut are n ot li mite d t o: s u bc uta ne o us e pi ne p hri ne, a nti hista mi nes, 
c ortic oster oi ds, I V fl ui ds, vas o press ors, o x y ge n, br o nc h o dilat ors, a n d a nti p yretics. 
Res uscitati o n e q ui p me nt a n d ot her s u p plies f or t he e mer ge nc y 
ma na ge me nt of a n 
aller gic/t o xic reacti o n m ust be a vaila ble. T he patie nt s h o ul d be treate d acc or di n g t o t he best 
a vaila ble l ocal practices a n d pr oce d ures. All s u p p orti ve meas ures c o nsiste nt wit h o pti mal 
patie nt care will be pr o vi de d t hr o u g h o ut t he st u d y acc or di n g t o i nstit uti o nal sta n dar ds. 
 
If p ossi ble, a ser u m sa m ple s h o ul d be o btai ne d at t he ti me of dia g n osis of C R S f or 
e val uati o n of circ ulati n g c yt o ki nes. F oll o w- u p sa m ples s h o ul d als o be o btai ne d at t he 
ti me of res ol uti o n of s y m pt o ms. A p plicati o n of a p pr o priate dia g n ostic or treat me nt 
pr oce d ures s h o ul d n ot be dela ye d or hi n dere d t o o btai n s uc h sa m ples. 
 
Ot her t y pes of a d verse reacti o ns ma y be o bser ve d d uri n g i nf usi o n t hat are n ot i nter prete d 
as relate d t o c yt o ki ne release, b ut ma y be relate d t o fl otet uz u ma b. S uc h reacti o ns s h o ul d 
be dia g n ose d, gra de d a n d ma na ge d acc or di n g t o best practices. Earl y a n d fre q ue nt 
c o ns ultati o n wit h t he st u d y me dical m o nit or is e nc o ura ge d. 
 
 
C R S Ma na ge me nt   
T he f oll o wi n g are treat me nt g ui deli nes ( w hic h ma y be m o difie d as nee de d b y 
t he res p o nsi ble i n vesti gat or acc or di n g t o t he best practices of me dici ne) f or 
C R S relate d t o fl otet uz u ma b. Earl y i nter ve nti o n at t h e first si g ns of C R S, 
i ncl u di n g p yre xia, tac h ycar dia, tac h y p nea a n d/ or h y p ote nsi o n i n t he a bse nce of 
alter nati ve eti ol o gies a n d i n c o nsiste nt te m p oral relati o ns hi p t o a d mi nistrati o n 
of fl otet uz u ma b, s h o ul d be u n derta ke n. 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 3 0  
 
C R S is a c o m m o nl y o bser ve d e ve nt d uri n g treat me nt wit h fl otet uz u ma b base d 
o n e x perie nce i n t he a d ult p o p ulati o n, wit h t he maj orit y of patie nts e x perie nci n g 
at least 1 e ve nt of Gra de 1 or 2. Base d o n c urre nt u n dersta n di n g gai ne d fr o m 
patie nts treate d wit h bli nat u m o ma b a n d C A R T cells, C R S is li kel y t o be a 
c o m m o n t o xicit y t hat ca n be ma na ge d t hr o u g h s u p p orti ve care a n d a nti-
c yt o ki ne i nter ve nti o ns t o all o w f or f ull acti vit y of T cells d uri n g t hera p y. A 
c o nse ns us gra di n g s yste m f or C R S has bee n pr o p ose d b y t he A merica n S ociet y 
f or Bl o o d a n d Marr o w Tra ns pla ntati o n w hic h will be utilize d f or t his st u d y 
( Ta ble 1).  
 
T a ble 1:    
   
A S B M T C R S C o nse ns us Gr a di n g 
 
C R S 
P ar a meter  
Gr a de 1   
Gr a de 2   
Gr a de 3   
Gr a de 4  
Fe ver *   
T e m perat ure >  
3 8 ̊ C  
T e m perat ure >  
3 8 ̊ C  
T e m perat ure >  
3 8 ̊ C  
T e m perat ure >  
3 8 ̊ C  
 
 
Wit h   
 
 
H y p ote nsi o n   
N o ne   
N ot 
re q uiri n g 
vas o press ors  
Re q uiri n g   
a 
vas o press or 
wit h or wit h o ut 
vas o pressi n  
Re q uiri n g 
m ulti ple 
vas o press ors 
(e xcl u di n g 
vas o pressi n)  
 
 
A n d/ or #  
 
 
H y p o xia   
N o ne   
Re q uiri n g l o w -
fl o w   
nasal 
ca n n ula # @  
or 
bl o w -b y  
s u p ple me ntal 
o x y ge n  
Re q uiri n g 
hi g h -fl o w nasal 
ca n n ula # @, 
face mas k, n o n-
re breat her 
mas k,   
or 
Ve nt uri  
mas k  
s u p ple me ntal 
o x y ge n  
Re q uiri n g 
p ositi ve 
press ure ( e.g. , 
C P A P, Bi P A P, 
i nt u bati o n a n d 
mec ha nical 
ve ntilati o n)  
 
Or ga n t o xicities ass ociate d wit h C R S ma y be gra de d acc or di n g t o C T C A E v 5. 0 b ut t he y d o n ot 
i nfl ue nce C R S gra di n g. 
 
* Fe ver is defi ne d as te m perat ure > 3 8° C n ot attri b uta ble t o a n y ot her ca use. I n patie nts w h o ha ve 
C R S t he n recei ve a nti p yretic or a ntic yt o ki ne t hera p y s uc h as t ociliz u ma b or ster oi ds, fe ver is n o 
l o n ger re q uire d t o gra de s u bse q ue nt C R S se verit y. I n t his case, C R S gra di n g is dri ve n b y 
h y p ote nsi o n a n d/ or h y p o xia. 
#C R S gra de is deter mi ne d b y t he m ore se vere e ve nt: h y p ote nsi o n or h y p o xia n ot attri b uta bl e t o 
a n y ot her ca use. F or e xa m ple, a patie nt wit h te m perat ure of 3 9. 5  ̊ C, h y p ote nsi o n re q uiri n g 1 
vas o press or, a n d h y p o xia re q uiri n g l o w-fl o w nasal ca n n ula is classifie d as gra de 3 C R S. 
 
@ L o w-fl o w nasal ca n n ula is defi ne d as o x y ge n deli vere d at < 6 L/ mi n ute. L o w fl o w als o i ncl u des 
bl o w- b y o x y ge n deli ver y, s o meti mes use d i n pe diatrics. Hi g h-fl o w nasal ca n n ula is defi ne d as 
o x y ge n deli vere d at > 6 L/ mi n ute. 
 
S o urce : Lee et al., 2 0 1 83 6 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 3 1  
C R S s h o ul d be ma na ge d as descri be d bel o w. E ver y atte m pt s h o ul d be 
ma de t o c o nti n ue t he i nf usi o n d uri n g ma na ge me nt of t he reacti o n. 
6. 3. 1. 1  Gra de 1 I nf usi o n Reacti o ns, I ncl u di n g C R S a n d I R R :  
 Sl o w t he i nf usi o n rate b y 2 0 %;  
 M o nit or t he patie nt f or w orse ni n g of c o n diti o n; 
 A d mi nister I V fl ui ds, di p he n h y dra mi ne I V, aceta mi n o p he n P O /I V 
f or fe ver, a n d o x y ge n a n d br o nc h o dilat ors f or mil d br o nc h os pas m, as 
a p pr o priate; 
 A d mi nister t ociliz u ma b ( 4- 8 m g/ k g [ ma x 8 0 0 m g/ d ose] I V) f or 
Gra de 1 I R R/ C R S t hat d oes n ot res ol ve wit hi n 2 h o urs wit h 
s u p p orti ve t hera p y, or is ass ociate d wit h a n y of t he f oll o wi n g si g ns 
a n d s y m pt o ms: 
o  T e m perat ure > 1 0 1. 5 oF ( 3 8. 6oC)  
o  Si g ns of pe n di n g res pirat or y c o m pr o mise as i n dicate d b y 
R R  > 2 0/ mi n or p ulse o xi metr y < 9 3 % i n t he a bse nce of 
s u p ple me ntal o x y ge n 
o  Decreases i n diast olic or s yst olic B P t o < 1 5 m m H g bel o w 
pretreat me nt baseli ne 
o  H R > 2 0 b p m a b o ve pre-treat me nt baseli ne 
o  N ote: is olate d c ha n ges i n he m o d y na mic para meters al o ne 
wit h o ut p ul m o nar y c o m pr o mise or fe ver s h o ul d n ot pr o m pt 
i m me diate use of t ociliz u ma b. 
 C ortic oster oi ds s h o ul d n ot be use d f or Gra de 1 I R R/ C R S. 
 C o nti n ue rate at 2 0 % re d ucti o n a n d i ncrease i nf usi o n rate t o t he 
or i gi nal rate b y i ncreasi n g t he i nf usi o n rate after sta bilizati o n or 
res ol uti o n of s y m pt o ms, as t olerate d. If m ulti ple d ose re d ucti o ns are 
re q uire d or if a m ore gra d ual i ncrease i n t he rate of i nf usi o n is 
desire d, d ose i ncreasi n g m ust be disc usse d wit h t he st u d y c hair.   
 
6. 3. 1. 2  Gra de 2 I nf usi o n Reacti o ns a n d I nf usi o n- Relate d E ve nts:  
 Sl o w t he i nf usi o n rate b y 5 0 %; 
 A d mi nister I V fl ui ds, di p he n h y dra mi ne I V, aceta mi n o p he n P O/I V 
f or fe ver, a n d o x y ge n a n d br o nc h o dilat ors f or br o nc h os pas m, as 
a p pr o priate a n d if n ot a d mi nistere d pre vi o usl y; 
 T ociliz u ma b s h o ul d be use d f or Gra de 2 I R R/ C R S t hat d oes n ot 
res ol ve wit h ot her meas ures wit hi n 2 h o urs, or t hat re q uires t he use 
of s u p ple me ntal o x y ge n > 4 L b y nasal ca n n ula or l o w d ose 
vas o press ors. 
o  T ociliz u ma b D osi n g:  
 
< 3 0 k g: 1 2 m g/ k g 
 
> 3 0 k g: 8 m g/ k g [ ma x 8 0 0 m g] 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 3 2  
 I n patie nts wit h C R S w h o res p o n d t o t ociliz u ma b, fe ver a n d 
h y p ote nsi o n ofte n res ol ve wit hi n 6 h o urs, a n d press ors a n d ot her 
s u p p orti ve care meas ures ca n be wea ne d q uic kl y t hereafter. I n s o me 
cases, h o we ver, s y m pt o ms ma y n ot c o m pletel y res ol ve, a n d 
c o nti n ue d a g gressi ve s u p p ort ma y be necessar y f or se veral da ys. If 
t he patie nt’s c o n diti o n d oes n ot i m pr o ve or sta bilize wit hi n 8 – 1 2 
h o urs of t he t ociliz u ma b d ose, a d mi nistrati o n of a sec o n d d ose of 
t ociliz u ma b a n d/ or a sec o n d i m m u n os u p pressi ve a ge nt, s uc h as 
a d diti o nal de xa met has o ne, s h o ul d be c o nsi dere d. T ociliz u ma b is 
ge nerall y n ot use d i n t he ma na ge me nt of C N S s y m pt o ms wit h o ut 
si g nifica nt he m o d y na mic i nsta bilit y or ot her life-t hreate ni n g 
s y m pt o mat ol o g y. 
 C ortic oster oi ds ma y be use d f or Gra de 2 I R R/ C R S t hat d oes n ot 
res p o n d t o ot her meas ures, i ncl u di n g t ociliz u ma b. De xa met has o ne is 
t he c ortic oster oi d of c h oice a d mi nistere d at a t otal dail y d ose of at 
least 0. 2 – 0. 4 m g/ k g/ da y ( ma xi m u m 2 4 m g per da y, i n a d diti o n t o 
de xa met has o ne a d mi nistere d d uri n g dail y d ose escalati o n ) 
a d mi nistere d prefera bl y i ntra ve n o usl y di vi de d 3 – 4 ti mes dail y f or at 
least 1 da y b ut n o m ore t ha n 4 da ys. T he d ose s h o ul d be st o p pe d or 
ta pere d as cli nicall y i n dicate d. 
 C o nti n ue rate at 5 0 % re d ucti o n a n d i ncrease i nf usi o n rate t o t he 
or i gi nal rate b y d o u bli n g t he i nf usi o n rate after sta bilizati o n or 
res ol uti o n of s y m pt o ms, as t olerate d. If m ulti ple d ose re d ucti o ns are 
re q uire d or if a m ore gra d ual i ncrease i n t he rate of i nf usi o n is 
desire d, d ose i ncreasi n g m ust be disc usse d wit h t he st u d y c hair.  
 M o nit or f or w orse ni n g c o n diti o n. 
 
6. 3. 1. 3  Gra de 3 I nf usi o n Reacti o ns a n d I nf usi o n- Relate d E ve nts:  
 St o p t he i nf usi o n, 
 T O A V OI D E X A C E R B A TI O N O F I N F U SI O N R E A C TI O N O R 
C R S: D O N O T F L U S H T H E T U BI N G – A S PI R A T E R E SI D U A L 
D R U G F R O M T H E P O R T L U M E N; 
 A d mi nister I V fl ui ds, di p he n h y dra mi ne I V, aceta mi n o p he n P O /I V 
f or fe ver, a n d o x y ge n a n d br o nc h o dilat ors f or mil d br o nc h os pas m, as 
a p pr o priate. 
 Pr o vi de a p pr o priate circ ulat or y s u p p ort i ncl u di n g vas o press ors as 
me dicall y i n dicate d; 
 A d mi nister t ociliz u ma b if n ot a d mi nistere d pre vi o usl y. If 
a d mi nistere d pre vi o usl y, a n a d diti o nal d ose ma y be use d f or 
pr ol o n ge d or rec urre nt e pis o des. 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 3 3  
 Gra de 3 C R S t hat is refra ct or y t o t ociliz u ma b s h o ul d be treate d wit h 
c ortic oster oi ds. De xa met has o ne is t he c ortic oster oi d of c h oice 
a d mi nistere d at a t otal dail y d ose of at least 0. 2 – 0. 4 m g/ k g/ da y 
( ma xi m u m 2 4 m g per da y) a d mi nistere d prefera bl y i ntra ve n o usl y 
di vi de d 3 – 4 ti mes dail y f or at least 1 da y b ut n o m ore t ha n 4 da ys. 
T he d ose s h o ul d be st o p pe d or ta pere d as cli nicall y i n dicate d. 
 If i nf usi o n reacti o n i m pr o ves t o ≤ gra de 2 wit hi n 7 2 h o urs, i nf usi o n 
ma y be res u me d at n o greater t ha n 5 0 % of t he ori gi nal rate o nce 
s y m pt o ms decrease t o Gra de 1. T he rate ma y t he n be escalate d t o t he 
ori gi nal rate after 3 0 mi n utes, as t olerate d. A m ore gra d ual i ncrease 
i n t he rate of i nf usi o n ma y be u n derta ke n after c o ns ultati o n wit h t he 
st u d y c hair; 
 If i nf usi o n reacti o n D O E S N O T i m pr o ve t o ≤ gra de 2 wit hi n 7 2 
h o urs or if t here are m ulti ple gra de 3 i nf usi o n reacti o ns, 
fl otet uz u ma b treat me nt m ust be per ma ne ntl y disc o nti n ue d; 
o  Re p ort as a n i m me diatel y re p orta ble e ve nt (I R E) 
i m me diatel y; 
o  Re p ort t he e ve nt as a seri o us a d verse e ve nt ( S A E) if 
a ppr o priate. 
 
6. 3. 1. 4  Gra de 4 I nf usi o n Reacti o ns a n d I nf usi o n- Relate d E ve nts  
 St o p t he i nf usi o n a n d disc o n nect t he i nf usi o n t u bi n g fr o m t he patie nt;  
 T O A V OI D E X A C E R B A TI O N O F I N F U SI O N R E A C TI O N O R 
C R S: D O N O T F L U S H T H E T U BI N G – A S PI R A T E R E SI D U A L 
D R U G F R O M T H E P O R T L U M E N; 
 A d mi nister I V fl ui ds, di p he n h y dra mi ne I V, aceta mi n o p he n P O /I V 
f or fe ver, a n d o x y ge n a n d br o nc h o dilat ors f or mil d br o nc h os pas m, as 
a p pr o priate. 
 Pr o vi de a p pr o priate ve ntilat or a n d circ ulat or y s u p p ort as me dicall y 
i n dicate d; 
 A ge nts i ncl u di n g t h ose liste d bel o w ha ve bee n descri be d i n t he 
ma na ge me nt of patie nts wit h se vere c o m plicati o ns of c yt o ki ne st or m 
a n d/ or se vere i m m u ne-relate d a d verse e ve nts, a n d ma y be re q uire d: 
o  Hi g her d oses of c ortic oster oi ds a n d/ or 
o  T ociliz u ma b (a nti- I L- 6 rece pt or): 
 
< 3 0 k g: 1 2 m g/ k g I V 
 
≥3 0 k g:   8 m g/ k g [ ma x 8 0 0 m g] I V, a n d/ or 
o  E ta nerce pt (a nti- T N F) 0. 8 m g/ k g  ( ma x: 5 0 m g/ d ose) s u b Q 
 N otif y t he S p o ns or’s Me dical M o nit or i m me diatel y; 
 Re p ort t he e ve nt as a n S A E. Patie nts w h o ha ve a Gra de 4 C R S 
s h o ul d n ot recei ve f urt her fl otet uz u ma b. 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 3 4  
6. 3. 1. 5  Gra de 5 I nf usi o n Reacti o ns a n d I nf usi o n- Relate d E ve nts:  
 N otif y t he S p o ns or’s Me dical M o nit or or desi g nee i m me diatel y; 
 Re p ort t he e ve nt as a n S A E. 
 
 
6. 4   
D ose M o dific ati o ns f or C a pill ar y Le a k S y n dr o me 
 
Ris k of ca pillar y lea k s y n dr o me ( C L S) has bee n ass ociate d wit h vari o us i m m u n ot hera pies, 
i ncl u di n g a nti b o d y- dr u g c o nj u gates, T cell-e n ga gi n g bis pecific a nti b o dies, a n d c hi meric 
a nti ge n rece pt or T cells. W hile C L S has n ot bee n o bser ve d wit h fre q ue nc y i n patie nts treate d 
wit h fl otet uz u ma b, ra pi d wei g ht gai n, decrease d al b u mi n, a n d s yste mic e de ma ha ve bee n 
re p orte d i n s o me patie nts. All e pis o des ha ve occ urre d d uri n g t he m ulti-ste p lea d-i n d osi n g 
peri o d a n d ha ve occ urre d c o nc o mita ntl y wit h s y m pt o ms a n d si g ns of c yt o ki ne release 
s y n dr o me (C R S ). 
 
Patie nts s h o ul d be m o nit ore d cl osel y f or t he de vel o p me nt of C L S d uri n g fl otet uz u ma b i nf usi o n 
wit h s pecific atte nti o n d uri n g t he lea d-i n d osi n g peri o d a n d/ or d uri n g C R S occ urre nce. Earl y 
si g ns a n d s y m pt o ms of C L S i ncl u de wei g ht gai n, ne w o nset or w orse ni n g e de ma, h y p ote nsi o n, 
a n d decrease d ser u m al b u mi n. Dail y wei g hts a n d strict ‘i ns a n d o uts’ (I/ Os) are str o n gl y 
rec o m me n de d d uri n g t he d ose escalati o n peri o d ( C ycle 1/ Da ys 1- 7 a n d be y o n d as cli nicall y 
i n dicate d). Me dicati o ns a n d s u p p orti ve meas ures f or t he treat me nt of s uc h rea cti o ns s h o ul d be 
a vaila ble f or i m me diate use, i ncl u di n g di uretics, c ortic oster oi ds, I V fl ui ds, vas o press ors, a n d 
s u p ple me ntal o x y ge n.  
 
C L S Ma na ge me nt 
T he f oll o wi n g are s u g geste d treat me nt g ui deli nes f or C L S relate d t o fl otet uz u ma b, w hic h ma y 
be m o difie d as nee de d b y treati n g p h ysicia ns/i n vesti gat ors acc or di n g t o t he best practices of 
me dici ne. Earl y i nter ve nti o n is rec o m me n de d at t he first cli nical si g ns of C L S i n t he a bse nce 
of clear alter nati ve eti ol o gies. 
 
 
Wei g ht gai n  
F or a n y wei g ht gai n ≥5 % fr o m t he pre vi o us treat me nt da y, c o nsi der al b u mi n 0. 5 – 1 
g/ k g/ d ose ( ma xi m u m d ose 2 5 g) u ntil b o d y wei g ht i ncrease has res ol ve d. If patie nt is 
n or m ote nsi ve or h y perte nsi ve, c o nsi der f ur ose mi de 1 
m g/ k g I V. F or 
wei g ht gai n 
u nres p o nsi ve t o fl ui d 
ma na ge me nt, c o nsi der a d mi nistrati o n of de xa met has o ne 5- 1 0 
m g/ m 2/ d ose ( ma x si n gle d ose 1 0 
m g) I V/ P O or e q ui vale nt c ortic oster oi d ( e. g. 
met h yl pre d nis ol o ne 1 m g/ k g/ d ose I V). I nterr u pti o n of  fl otet uz u ma b i nf usi o n ma y als o be 
c o nsi dere d. 
 
 
H y p ote nsi o n  
H y p ote nsi o n ca n be a si g n of C L S a n d/ or C R S. If a patie nt is n ote d t o be h y p ote nsi ve, his 
or her fl ui d stat us s h o ul d be ma na ge d as cli nicall y i n dicate d wit h i ntra ve n o us fl ui ds a n d 
vas o press ors. Al b u mi n or ot her c oll oi ds s h o ul d be c o nsi dere d f or patie nts w h ose perf usi o n 
is n ot rest ore d b y cr ystall oi d al o ne. F or h y p ote nsi o n u nres p o nsi ve t o fl ui d ma na ge me nt, 
de xa met has o ne 5- 1 0 
m g/ m 2/ d ose ( ma x si n gle d ose 1 0 
m g) I V/ P O or e q ui vale nt 
c ortic oster oi d (e. g, met h yl pre d nis ol o ne 1 m g/ k g/ d ose I V) s h o ul d be gi ve n. I nterr u pti o n of  
fl otet uz u ma b d osi n g s h o ul d als o be c o nsi dere d, partic ularl y i n patie nts wit h se vere 
h y p ote nsi o n re q uiri n g vas o press or me dicati o n s u p p ort. Please als o see C R S ma na ge me nt 
g ui deli nes i n Secti o n 6. 3. 1. 
  
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 3 5  
 
H y p oal b u mi ne mia  
F or a n y decrease i n al b u mi n ≥ 0. 5 g/ d L bel o w baseli ne le vel at t he start of t he c ycle, 
c o nsi der a d mi nistrati o n of al b u mi n 0. 5 – 1 g/ k g/ d ose ( ma xi m u m d ose 2 5 g); ma y be 
re peate d u p t o 3 ti mes dail y base d o n t he patie nt’s cli nical stat us. 
 
 
7. 0   
S U P P O R TI V E C A R E A N D O T H E R C O N C O MI T A N T T H E R A P Y 
 
7. 1   
C o nc urre nt A ntic a ncer T her a p y 
C o nc urre nt ca ncer t hera p y, i ncl u di n g c he m ot hera p y, ra diati o n t hera p y, i m m u n ot hera p y, or 
bi ol o gic t hera p y ma y N O T be a d mi nistere d t o patie nts recei vi n g st u d y dr u g. If t hese 
treat me nts are a d mi nistere d t he patie nt will be re m o ve d fr o m pr ot oc ol t hera p y. 
 
7. 2   
I n vesti g ati o n al A ge nts 
N o ot her i n vesti gati o nal a ge nts ma y be gi ve n w hile t he patie nt is o n st u d y. 
 
7. 3   
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, fl ui ds, electr ol ytes, a n d ge neral 
s u p p orti ve care are t o be use d as necessar y. Patie nts s h o ul d recei ve a de q uate h y drati o n d uri n g 
st u d y t hera p y, a n d t he a d diti o n of I V fl ui ds t o mai ntai n i ntra vasc ular v ol u me is rec o m me n de d 
f or at least 4 8 h o urs after t he start of t hera p y. Patie nts s h o ul d recei ve a p pr o priate P ne u m ocystis 
jir oveci p ne u m o nia pr o p h yla xis (e. g., tri met h o pri m-s ulfa met h o xaz ole) d uri n g st u d y 
partici pati o n. E m piric a nti-f u n gal ( e. g., cas p of u n gi n, fl uc o naz ole) a n d a nti bi otic pr o p h yla xis 
(e. g., le v ofl o xaci n) w he n A N C < 2 0 0 is str o n gl y e nc o ura ge d. 
 
See C O G S u p p orti ve Care G ui deli nes at htt ps://c hil dre ns o nc ol o g y gr o u p. or/i n de x. p h p/c o g-
s u p p orti ve-care- g ui deli nes. See Secti o n 7. 5  f or dr u gs t hat s h o ul d n ot be use d c o nc o mita ntl y 
d ue t o p ote ntial i nteracti o ns wit h fl otet uz u ma b. See bel o w f or rec o m me n dati o ns o n 
ma na ge me nt of s pecific t o xicities ass ociate d wit h fl otet uz u ma b.  
 
7. 4   
Gr o wt h F act ors 
Gr o wt h fact ors t hat s u p p ort platelet or w hite cell n u m ber or f u ncti o n ca n o nl y be 
a d mi nistere d i n acc or da nce wit h Secti o n 6. 1. 2 or f or c ult ure pr o ve n bactere mia or i n vasi ve 
f u n gal i nfecti o n. T he St u d y C hair s h o ul d be n otifie d bef ore gr o wt h fact ors are i nitiate d. 
 
7. 5   
C o nc o mit a nt Me dic ati o ns 
Beca use fl otet uz u ma b e m pl o ys a mec ha nis m of acti o n de pe n de nt u p o n t he e n ga ge me nt of 
T l y m p h oc ytes, t he use of c ortic oster oi ds ot her t ha n t h ose e m pl o ye d f or pre me dicati o n 
s h o ul d be li mite d. C hr o nic d oses of c ortic oster oi ds i n e xcess of 0. 2 5 m g/ k g ( ma x 1 0 m g) 
dail y of pre d nis o ne or e q ui vale nt are pr o hi bite d ot her t ha n f or t he ma na ge me nt of dr u g-
relate d a d verse e x perie nces. C ortic oster oi d pretreat me nt s h o ul d f oll o w t he rec o m me n de d 
d ose a n d sc he d ule (see Secti o n 5. 1 ).   
 
Vacci nati o ns ( wit h t he e xce pti o n of t he a n n ual i nacti vate d i nfl ue nza vacci ne) are 
pr o hi bite d d uri n g t he st u d y.  
 
 
8. 0   
E V A L U A TI O N S/ M A T E RI A L  A N D D A T A T O B E A C C E S SI O N E D 
 
8. 1   
Re q uire d Cli nic al, L a b or at or y a n d Dise ase E v al u ati o n 
All cli nical a n d la b orat or y st u dies t o deter mi ne eli gi bilit y m ust be perf or me d wit hi n 7 da ys 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 3 6  
pri or t o e nr oll me nt u nless ot her wise i n dicate d. La b orat or y val ues use d t o assess eli gi bilit y 
(see Secti o n 4. 0 ) m ust be n o ol der t ha n se ve n ( 7) da ys at t he start of t hera p y.  La b orat or y 
tests nee d n ot  be re peate d if t hera p y starts wit hi n  se ve n ( 7) da ys of o btai ni n g la bs t o assess 
eli gi bilit y.  If a p ost-e nr oll me nt la b val ue is o utsi de t he li mits of eli gi bilit y, or la b orat or y 
val ues are ol der t ha n 7 da ys, t he n t he f oll o wi n g la b orat or y e val uati o ns m ust be re-c hec ke d 
wit hi n 4 8 h o urs pri or t o i nitiati n g t hera p y: C B C wit h differe ntial, bilir u bi n, A L T ( S G P T) 
a n d ser u m creati ni ne.  If t he rec hec k is o utsi de t he li mits of eli gi bilit y, t he patie nt ma y n ot 
recei ve pr ot oc ol t hera p y a n d will be c o nsi dere d off pr ot oc ol t hera p y. I ma gi n g st u dies, b o ne 
marr o w as pirate, a n d bi o ps y m ust be o btai ne d wit hi n 1 4 da ys pri or t o start of pr ot oc ol 
t hera p y (re peat t he i ma gi n g if necessar y). 
 
S T U DI E S T O B E O B T AI N E D   
P re -St u d y   
D uri n g C ycle 
1  
P ri or t o S u bse q ue nt 
C ycles ^  
Hist or y  
X   
Wee kl y  
X  
P h ysical exa m wit h vital si g ns  
X   
Wee kl y  
X  
Hei g ht, wei g ht, B S A  
X  
 
X  
Perf or ma nce stat us 
X  
 
 
C B C, differe ntial, platelets  
X   
T wice Wee kl y 
(e ver y 3 t o 4 
da ys) 3 
Wee kl y
4 
P har mac o ki netics  
 
X 1 
X 1 
A nti -dr u g a nti b o d y ( A D A) 
 
X 1 0  
X 1 0  
Uri nal ysis  
X  
 
 
Electr ol ytes i ncl u di n g Ca + +  
X   
T wice wee kl y 
(e ver y 3 t o 4 
da ys) d uri n g 
Wee k 1, t he n 
w ee kl y 
X  
Creati ni ne, A L T, bilir u bi n , A S T 
X   
Wee kl y  
X  
Al b u mi n  
X  
 
X  
I ma gi n g ( C T or M RI) of c hl or o ma (if 
cli nicall y i n dicate d)  
X   
E n d of C ycle 1  
(if prese nt at 
baseli ne)  
E n d of eac h c ycle (if 
prese nt o n pre vi o us 
st u d y) 
B o ne marr o w as pirati o n   
X 5 , 6, 1 2, 1 3 
E n d of C ycle 1 5  
E n d of e ver y c ycle 
Pre g na nc y test 2 
X  
 
 
E C H O  or gate d ra di o n ucli de st u d y   
X  
 
X  
E K G  
X  
 
X  
Ne ur ol o gic exa m  
X  
 
X  
Ne xt -ge nerati o n se q ue nci n g ( N G S )  
M R D  a nal ysis 
Wit h b o ne 
marr o w 
e val uati o n 7 , 13 
Wit h b o ne 
marr o w 
e val uati o n 7  
Wit h b o ne marr o w 
e val uati o n 7 
Peri p heral T cell  q ua ntificati o n  
 
X 8 
X 8 
C yt o ki ne a nal ysis  
 
X 9  
X 9  
T u m or Micr oe n vir o n me nt Pr ofili n g   
X 1 1 , 1 3 
 
 
Fl o w c yt o metr y wit h mi ni mal resi d ual 
disease deter mi nati o n ( M R D) 1 4 
  
Wit h b o ne 
marr o w 
e val uati o n 
Wit h b o ne marr o w 
e val uati o n 
^   
St u dies ma y be o btai ne d wit hi n 7 2 h o urs pri or t o t he start of t he s u bse q ue nt c ycle. 
1   
P K sa m ples will be c ollecte d fr o m all patie nts d uri n g C ycle 1. T he P K sa m pli n g sc he d ule d uri n g C ycle 
1 will differ de pe n di n g o n d ose le vel assi g n me nt of t he patie nt. See Secti o n 8. 2  f or details. Bl o o d sa m ples 
will als o be c ollecte d 3 0 mi n ut es, 1 h o ur, 2 h o u rs, 4 h o urs, 8 ho u rs, a n d 2 4 h o urs after t he e n d of i nf usi o n 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 3 7  
o n t he patie nt’s last da y of pr ot oc ol t hera p y .  
2   
W o me n of c hil d beari n g p ote ntial re q uire a ne g ati ve pre g na nc y test pri or t o starti n g treat me nt; se x uall y 
acti ve patie nts m ust use a n acce pta ble met h o d of birt h c o ntr ol.  A bsti ne nce is a n acce pta ble met h o d of 
birt h c o ntr ol. 
3   If patie nts ha ve Gra de 4 ne utr o pe nia t he n C B Cs s h o ul d be c hec ke d at least e ver y ot her da y u ntil rec o ver y 
t o Gra de 3 or u ntil meeti n g t he criteria f or d ose li miti n g t o xi cit y. 
4   If patie nts de vel o p Gra de 4 ne utr o pe nia t he n C B Cs s h o ul d be c hec ke d e ver y 3 t o 4 da ys u ntil rec o ver y 
t o Gra de 3. 
5 
B o ne marr o w as pirate a n d cl ot secti o n/ bi o ps y. 
6 
In c o nse nti n g patie nts, C D 1 2 3 site de nsit y a nal ysis t o be se nt t o He mat ol o gics at baseli ne (s ee Secti o n 
8. 4 ).  
7   I n c o nse nti n g patie nts o nl y. S ee Secti o n 8. 5  f or details.  
8  
I n c o nse nti n g patie nts, bl o o d sa m ples will be c ollecte d o n C ycle 1 Da ys 1, 8, 1 4, 2 2, a n d 2 9 a n d o n Da y 
1 of s u bse q ue nt c ycles pri or t o i nf usi o n. See Secti o n 8. 6  f or details.  
9   I n c o nse nti n g patie nts, bl o o d s a m ples will be c ollecte d o n C ycle 1, Da y 1 ( pre-i nf usi o n) a n d o n C ycle 1, 
Da y 8 . A d diti o nall y, if patie nts e x perie nce I R R/ C R S, bl o o d sa m ples will be c ollecte d fr o m c o nse nti n g 
patie nts at t he ti me of I R R/ C R S a n d at t he ti me of I R R/ C R S res ol uti o n. See Secti o n 8. 7  f or details.  
1 0  
A D A sa m ples will be c ollecte d fr o m all patie nts o n C ycle 1, Da y 1 ( pre-i nf usi o n), C ycle 3, Da y 1 ( pre-
i nf usi o n), C ycle 5, Da y 1 ( pre-i nf usi o n). See Secti o n 8. 3  f or details.  
1 1  
I n c o nse nti n g patie nts, e xtra b o ne marr o w as pirate will be o btai ne d fr o m t he ma n dat or y b o ne marr o w 
bi o ps y pri or t o C ycle 1. See S ecti o n 8. 8  f or details.   
1 2  
C yt o ge netics a n d FI S H will be perf or me d o n t he c ollecte d b o ne marr o w as pirate (it is rec o m me n de d t hat 
c yt o ge netics/ FI S H be perf or me d b y a C O G-a p pr o ve d la b orat or y).  
1 3 
W he n p ossi ble, a d diti o nal ali q u ots of b o ne marr o w s h o ul d b e c ollecte d at t he ti me of t he scree ni n g b o ne 
marr o w f or o pti o nal ce ntral e val uati o ns. T he preferre d s peci me n s o urce is b o ne marr o w, b ut if a d diti o nal 
b o ne marr o w ca n n ot be o btai ne d, peri p heral bl o o d ma y be se nt i n t h ose patie nts w h o ha ve a n a bs ol ute 
blast c o u nt of at least 1, 0 0 0/ µl ( 2 m L of peri p heral bl o o d ma y be s u b mitte d f or eac h 1 m L of re q uire d 
marr o w). Alter nati vel y, fr oze n ali q u ots i n t h ose patie nts pre vi o usl y e nr olle d o n A P E C ca n be utilize d if 
per missi o n is gra nte d. See Secti o n  8. 4, Secti o n 8. 5 , a n d Secti o n 8. 8  f or details. 
1 4  
A nal yses t o be perf or me d at H e mat ol o gics. S hi p sa m ples t o t he a d dress liste d i n Secti o n 8. 4. 5 . 
 
 
8. 2   
 P h ar m ac ol o g y ( Re q uire d)  
 
 
 
Descri pti o n of St u dies a n d Assa y  
P har mac o ki netics ( P K) will be perf or me d t o det er mi ne t he P K of fl otet uz u ma b 
i n c hil dre n. Ser u m sa m ples will be c ollecte d a n d fl otet uz u ma b c o nce ntrati o n 
will be deter mi ne d b y a vali date d electr oc he mil u mi nesce nt ( E C L)- base d 
sa n d wic h assa y. Sa m ples will be a nal yze d b y Macr o Ge nics P har mace uticals. 
Bi oa nal ytical meas ures will be c o m bi ne d wit h res pecti ve i n di vi d ual patie nt 
d osi n g hist or y a n d de m o gra p hic i nf or mati o n. P har mac o metric a nal ysis will be 
perf or me d usi n g a n a p pr o priate m o del- base d a p pr oac h. P K para meters will be 
c orrelate d wit h t o xicit y para meters. P K e x p os ures will be c o m pare d bet wee n 
patie nts w h o ac hie ve C R/ C Ri a n d t h ose w h o d o n ot.  
 
 
Sa m pli n g Sc he d ule ( See A p pe n di x VI - A, A p pe n di x VI- B , a n d A p pe n di x VI-
C )  
T he P K sa m pli n g sc he d ule will var y acc or di n g t o t he d ose le vel assi g n me nt of 
t he patie nt. F or all patie nts bei n g treate d o n D L 1, bl o o d sa m ples will be 
c ollecte d at t he f oll o wi n g ti me p oi nts *:  
-   
C ycle 1, Da y 1: pri or t o start of i nf usi o n 
-   
C ycle 1, Da ys 3 – 7: 3 0 mi n utes pri or t o s yri n ge c ha n ge a n d d ose 
escalati o n 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 3 8  
-   
C ycle 1, Da y 8: 2 4 h o urs after Da y 7 s yri n ge c ha n ge a n d fi nal d ose 
escalati o n 
-   
C ycle 1, Da y 1 2, Da y 1 5, Da y 1 9, Da y 2 2, Da y 2 7, a n d Da y 2 9 ( pri or t o 
i nf usi o n e n di n g): a n y ti me 
  
 
F or all patie nts bei n g treate d o n D L- 1, bl o o d sa m ples will be c ollecte d at t he 
f oll o wi n g ti me p oi nts *:  
-   
C ycle 1, Da y 1: pri or t o start of i nf usi o n 
-   
C ycle 1, Da y 4, Da y 6, a n d Da y 8: 3 0 mi n utes pri or t o s yri n ge c ha n ge a n d 
d ose escalati o n 
-   
C ycle 1, Da y 9: 2 4 h o urs after Da y 8 s yri n ge c ha n ge a n d fi nal d ose 
escalati o n 
-   
C ycle 1, Da y 1 3, Da y 1 7, Da y 2 1, Da y 2 5, a n d Da y 2 9 ( pri or t o i nf usi o n 
e n di n g): a n y ti me 
 
F or all patie nts bei n g treate d o n D L 2, bl o o d sa m ples will be c ollecte d at t he 
f oll o wi n g ti me p oi nts *:  
-   
C ycle 1, Da y 1: pri or t o start of i nf usi o n 
-   
C ycle 1, Da ys 3 – 8: 3 0 mi n utes pri or t o s yri n ge c ha n ge a n d d ose 
escalati o n 
-   
C ycle 1, Da y 9: 2 4 h o urs after Da y 8 s yri n ge c ha n ge a n d fi nal d ose 
escalati o n 
-   
C ycle 1, Da y 1 3, Da y 1 7, Da y 2 1, Da y 2 5, a n d Da y 2 9 ( pri or t o i nf usi o n 
e n di n g): a n y ti me  
 
* All ti me p oi nts gi ve n are f or patie nts t hat f oll o w t he d osi n g sc he d ule e xactl y 
as o utli ne d i n Secti o n 5. 1 . F or patie nts t hat re q uire d ose i nterr u pti o ns d uri n g 
C ycle 1, P K sa m ples s h o ul d be dra w n acc or di n g t o w he n t he patie nt reac hes 
certai n d ose le vels (see A p pe n di x VI- A , A p pe n di x VI- B , a n d A p pe n di x VI-
C  f or details).  
 
Bl o o d sa m ples will als o be c ollecte d at t he f oll o wi n g ti me p oi nts o n t he 
patie nt’s last da y of pr ot oc ol t hera p y :  
-   
3 0 mi n utes, 1 ho u r, 2 h o urs, 4 ho u rs, 8 ho u rs, a n d 2 4 h o urs after t he e n d 
of i nf usi o n 
 
 
Sa m ple C ollecti o n a n d Ha n dli n g I nstr ucti o ns  
Bl o o d sa m ples ( 2 – 3 ml) will be c ollecte d i n S S T t u bes at a site dista nt fr o m 
t he i nf usi o n f or p har mac o ki netic e val uati o n. N O T E : Patie nts < 2 3 k g s h o ul d 
o nl y ha ve 2 ml of bl o o d dra w n per sa m ple. Sa m ples ca n n ot be dra w n fr o m t he 
2 n d l u me n of a m ulti-l u me n cat heter t hr o u g h w hic h dr u g is bei n g a d mi nist ere d. 
Rec or d t he e xact ti me t hat t he sa m ple is dra w n al o n g wit h t he e xact ti me t hat 
i nf usi o n be gi ns a n d e n ds. 
 
 
Sa m ple Pr ocessi n g  
1.  C ollect bl o o d i nt o a 2 –  3 m L S S T t u be a n d i n vert t he t u be se veral 
ti mes pri or t o all o wi n g bl o o d t o cl ot.  
2.  All o w bl o o d t o cl ot f or at least 6 0 mi n utes at r o o m te m perat ure.  
3.  Se parate ser u m wit hi n 6 0 – 9 0 mi n utes of c ollecti o n.  
4.  Ce ntrif u ge f or 1 0 mi n utes at r o o m te m perat ure at 1 1 0 0 – 1 3 0 0 x g 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 3 9  
5.  Tra nsfer ser u m e q uall y i nt o t w o 2 m L cr y o vials ( pri mar y a n d bac k 
u p)  
6.  I m me diatel y freeze at - 6 0 ̊ C t o - 8 0 ̊ C. 
 
 
Sa m ple La beli n g  
Eac h t u be m ust be la bele d wit h t he patie nt’s st u d y re gistrati o n n u m ber a n d t he 
st u d y I. D.  Data s h o ul d be rec or de d o n t he P har mac o ki netic St u d y F or m 
(A p pe n di x 
VI - A, A p pe n di x 
VI- B , a n d A p pe n di x 
VI- C ), 
w hic h 
m ust 
acc o m pa n y t he sa m ple(s). 
 
A d diti o nall y, 
Macr o Ge nics has sta n dar d na mi n g c o n ve nti o ns f or sa m ples. 
M G D 0 0 6 is fl otet uz u ma b. Sites s h o ul d use t he bel o w la beli n g c o n ve nti o ns f or 
la b sa m ples:  
 
Pre M G D 0 0 6 P K 1 ( pri mar y) 
Pre M G D 0 0 6 P K 2 ( bac k u p) 
U N S P K ( use t his f or u nsc he d ule d) 
 
F or all patie nts bei n g treate d o n D L 1, sa m ples are t o be la bele d via t he 
f oll o wi n g c o n ve nti o ns: 
 
S a m ple Ti me p oi nt  
L a bel N a mi n g C o n ve nti o n  
C ycle 1, Da y 1: pri or t o start of i nf usi o n  
Pre M G D 0 0 6 i nf usi o n  P K  
C ycle 1, Da y s 3 –  7 : 3 0 mi n utes pri or t o s yri n ge c ha n ge a n d d ose 
escalati o n 
3 0 mi n pre M G D 0 0 6 i nf usi o n 
(i ncl u de da y) P K  
C ycle 1, Da y 8 : 2 4 h o urs after Da y 7  s yri n ge c ha n ge a n d fi nal d ose 
escalati o n 
Da y 8  P K  
C yc le 1, Da y 1 2, Da y 1 5, Da y 1 9, Da y 2 2, Da y 2 7 , a n d Da y 2 9 
( pri or t o i nf usi o n e n di n g): a n y ti me 
Da y 1 2 P K, Da y 1 5  P K, etc.  
 
F or all patie nts bei n g treate d o n D L- 1, sa m ples are t o be la bele d via t he 
f oll o wi n g c o n ve nti o ns: 
 
S a m ple Ti me p oi nt  
L a bel N a mi n g C o n ve nti o n  
C ycle 1, Da y 1: pri or t o start of i nf usi o n  
Pre M G D 0 0 6 i nf usi o n  P K  
C ycle 1, Da y 4, Da y 6, a n d Da y 8: 3 0 mi n utes pri or t o s yri n ge 
c ha n ge a n d d ose escalati o n  
3 0 mi n pre M G D 0 0 6 i nf usi o n 
(i ncl u de da y) P K  
C ycle 1, Da y 9: 2 4 h o urs after Da y 8 s yri n ge c ha n ge a n d fi nal d ose 
escalati o n 
Da y 9 P K  
C ycle 1, Da y 1 3, Da y 1 7, Da y 2 1, Da y 2 5, a n d Da y 2 9 ( pri or t o 
i nf usi o n e n di n g): a n y ti me 
Da y 1 3 P K, Da y 1 7 P K, etc.  
 
F or all patie nts bei n g treate d o n D L 2, sa m ples are t o be la bele d via t he f oll o wi n g 
c o n ve nti o ns: 
 
S a m ple Ti me p oi nt  
L a bel N a mi n g C o n ve nti o n  
C ycle 1, Da y 1: pri or t o start of i nf usi o n   
Pre M G D 0 0 6 i nf usi o n  P K  
C ycle 1, Da ys 3 –  8: 3 0 mi n utes pri or t o s yri n ge  c ha n ge a n d d ose 
escalati o n 
3 0 mi n pre M G D 0 0 6 i nf usi o n 
(i ncl u de da y) P K  
C ycle 1, Da y 9: 2 4 h o urs after Da y 8 s yri n ge c ha n ge a n d fi nal d ose  
Da y 9 P K  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 4 0  
escalati o n 
C ycle 1, Da y 1 3, Da y 1 7, Da y 2 1, Da y 2 5, a n d Da y 2 9 ( pri or t o 
i nf usi o n e n di n g): a n y ti me   
Da y 1 3 P K, Da y 1 7 P K, etc.  
 
 
Bl o o d sa m ples will als o be c ollecte d at t he f oll o wi n g ti me p oi nts o n t he patie nt’s 
last da y of pr ot oc ol t hera p y ( E O T = e n d of treat me nt): 
 
S a m ple Ti me p oi nt  
L a bel N a mi n g C o n ve nti o n  
3 0 mi n utes, 1 h o ur, 2 h o urs, 4 h o urs, 8 h o urs, a n d 2 4 h o urs after t he 
e n d of i nf usi o n 
E O T  P K 3 0 mi n p ost, E O T P K  1 
hr p ost, etc.  
 
 
 
Sa m ple S hi p pi n g I nstr ucti o ns  
St ore sa m ples at - 7 0 ̊ C u ntil s hi p me nt. S hi p o n dr y ice t o Macr o Ge nics as eac h 
patie nt c o m pletes t he c ycle or at site’s discreti o n. If P K a n d i m m u n o ge nicit y 
sa m ples are s hi p pe d i n t he sa me s hi p pi n g c o ntai ner, place t he P K a n d 
i m m u n o ge nicit y sa m ples i n se parate cr y o b o xes wit hi n t he s hi p pi n g c o ntai ner. 
Pri or 
t o 
sa m ple 
s hi p me nt,  
please  
e mail 
 
 t o alert 
t he m of t he sa m ple s hi p me nt. S hi p t o t he f oll o wi n g a d dress:  
 
   
 
 
   
 
 
   
 
 
   
 
 
   
 
 
 
   
 
 
 
N O T E: Pri mar y a n d bac k- u p ali q u ots fr o m t he sa me ti me p oi nt s h o ul d N O T 
be se nt i n t he sa me s hi p me nt.  
 
8. 3   
I m m u n o ge nicit y St u d y ( Re q uire d)  
 
 
Descri pti o n of St u dies a n d Assa y  
Ser u m sa m ples will be c ollecte d a n d a nti-fl otet uz u ma b a nti b o dies will be 
detecte d usi n g a vali date d bri d gi n g i m m u n oassa y b y a Macr o Ge nics, I nc. 
bi oa nal ytical la b. I m m u n o ge nicit y will be c o m pare d bet wee n patie nts w h o 
ac hie ve C R/ C Ri a n d t h ose w h o d o n ot.  
 
 
Sa m pli n g Sc he d ule ( See A p pe n di x VII ) 
Bl o o d sa m ples will be c ollecte d at t he f oll o wi n g ti me p oi nts f or all patie nts :  
-   
C ycle 1, Da y 1: pre-i nf usi o n 
-   
C ycle 3, Da y 1: pre-i nf usi o n 
-   
C ycle 5, Da y 1: pre-i nf usi o n 
 
 
Sa m ple C ollecti o n a n d Ha n dli n g I nstr ucti o ns  
Bl o o d sa m ples ( 2 – 3 ml) will be c ollecte d i n S S T t u bes at a site dista nt fr o m 
t he inf usi o n f or i m m u n o ge nicit y e val uati o n. N O T E:  Patie nts < 2 3 k g s h o ul d 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 4 1  
o nl y ha ve 2 ml of bl o o d dra w n per sa m ple.  
 
 
Sa m ple Pr ocessi n g  
1.  C ollect bl o o d i nt o a 2 – 3 m L S S T t u be a n d i n vert t he t u be se veral ti mes 
pri or t o all o wi n g bl o o d t o cl ot 
2.  All o w bl o o d t o cl ot f or at least 6 0 mi n utes at r o o m te m perat ure. 
3.  Se parate ser u m wit hi n 6 0 – 9 0 mi n utes of c ollecti o n. 
4.  Ce nt rif u ge f or 1 0 mi n utes at r o o m te m perat ure at 1 1 0 0 – 1 3 0 0 x g. 
5.  Tr a nsfer ser u m e q uall y i nt o t w o 2 m L cr y o vials ( pri mar y a n d bac k u p). 
6.  I m me diatel y freeze at - 6 0 ̊ C t o - 8 0 ̊ C. 
 
 
Sa m ple La beli n g  
Eac h t u be m ust be la bele d wit h t he patie nt’s st u d y re gistrati o n n u m ber, t he 
st u d y I. D., a n d t he date a n d ti me t he sa m ple was dra w n.  Data s h o ul d b e 
rec or de d o n t he P har mac o ki netic St u d y F or m (A p pe n di x VII ), w hic h m ust 
acc o m pa n y t he sa m ple(s). 
 
A d diti o nall y, Macr o Ge nics has sta n dar d na mi n g c o n ve nti o ns f or sa m ples. Sites 
s h o ul d use t he bel o w la beli n g c o n ve nti o ns f or la b sa m ples:  
 
Pre M G D 0 0 6 A D A  
U N S A D A ( use t his f or u nsc he d ule d) 
 
F or all patie nts, sa m ples are t o be la bele d via t he f oll o wi n g c o n ve nti o ns: 
 
S a m ple Ti me p oi nt  
L a bel N a mi n g C o n ve nti o n  
C ycle 1, Da y 1: pre -i nf usi o n Pre M G D 0 0 6 i nf usi o n 
Pre M G D 0 0 6 A D A  
C ycle 3, Da y 1: pre -i nf usi o n Pre M G D 0 0 6 i nf usi o n C 3 
C 3 Pre M G D 0 0 6 A D A  
C ycle 5, Da y 1: pre -i nf usi o n Pre M G D 0 0 6 i nf usi o n C 5 
C 5 Pre M G D 0 0 6 A D A  
 
 
Sa m ple S hi p pi n g I nstr ucti o ns  
St ore sa m ples at - 7 0 ̊ C u ntil s hi p me nt. S hi p o n dr y ice t o Macr o Ge nics as eac h 
patie nt c o m pletes t he c ycle or at site’s discreti o n. If P K a n d i m m u n o ge nicit y 
sa m ples are s hi p pe d i n t he sa me s hi p pi n g c o ntai ner, place t he P K a n d 
i m m u n o ge nicit y sa m ples i n se parate cr y o b o xes wit hi n t he s hi p pi n g c o ntai ner. 
Pri or 
t o 
sa m ple 
s hi p me nt,  
please  
e mail 
 
 t o alert 
t he m of t he sa m ple s hi p me nt. S hi p t o t he f oll o wi n g a d dress:  
 
   
   
H ua Li 
   
   
Macr o Ge nics, I nc. 
   
   
1 5 2 3 5 S ha d y Gr o ve R oa d 
   
   
S uite 3 0 4 
   
   
R oc k ville, M D 2 0 8 5 0 – 3 2 3 4 
   
   
P h o ne: ( 3 0 1) 3 5 4- 2 6 1 6 
 
N O T E: Pri mar y a n d bac k- u p ali q u ots fr o m t he sa me ti me p oi nt s h o ul d N O T 
be se nt i n t he sa me s hi p me nt.  
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 4 2  
8. 4   
B aseli ne C D 1 2 3 Site De nsit y Q u a ntific ati o n ( O pti o n al)  
 
 
Descri pti o n of St u dies a n d Assa y  
Baseli ne b o ne marr o w sa m ples will be use d t o a nal yze C D 1 2 3 site de nsit y o n 
A M L cells t o ai d i n i de ntif yi n g bi o mar kers of t hera p y res p o nse a n d resista nce. 
C orrelati o n bet wee n c ha n ges i n C D 1 2 3 e x pressi o n a n d patie nt’s cli nical 
res p o nse t o fl otet uz u ma b as well as c yt o ge netic/ m olec ular feat ures will be 
descri be d. Sa m ples will be a nal yze d at He mat ol o gics, I nc.  
 
 
Sa m pli n g Sc he d ule ( See A p pe n di x VIII )  
A nal yses will be perf or me d o n t he b o ne marr o w sa m ples retrie ve d pri or t o 
C ycle 1.  
 
W h ile t he preferre d s peci me n is b o ne marr o w, if b o ne marr o w sa m ples ca n n ot 
be o btai ne d, peri p heral bl o o d ma y be se nt i n f or patie nts w h o ha ve a n a bs ol ute 
blast c o u nt > 1, 0 0 0/ µ L. 
 
 
Sa m ple C ollecti o n a n d Ha n dli n g I nstr ucti o ns  
B o ne marr o w sa m ples ( 5 m L) will be c ollecte d i n a preser vati ve-free s o di u m 
he pari n vac utai ner ( gree n t o p). 
 
I n cases w here t he s peci me n is e x pecte d t o ta ke m ore t ha n 2 4 h o urs t o arri ve, 
please a d d e q ual v ol u me of R P MI 1 6 4 0 me di u m t o t he marr o w s peci me n.  
 
If peri p heral bl o o d is o btai ne d, 1 0 m L of bl o o d will be c ollecte d i n a 
preser vati ve-free s o di u m he pari n vac utai ner ( gree n t o p).  
 
 
Sa m ple La beli n g  
Eac h t u be m ust be la bele d wit h t he patie nt’s st u d y re gistrati o n n u m ber, t he 
st u d y I. D., t he date a n d ti me t he sa m ple was dra w n, a n d m ust be clearl y la bele d 
as b o ne marr o w as pirate ( B M A), if a p plica ble. Data s h o ul d be rec or de d o n t he 
Baseli ne C D 1 2 3 Site De nsit y Q ua ntificati o n St u d y F or m ( A p pe n di x VIII ), 
w hic h m ust acc o m pa n y t he sa m ple(s).   
 
 
Sa m ple S hi p p i n g I nstr ucti o ns  
Sa m ples m ust be s hi p pe d t o He mat ol o gics, I nc. Seattle, W A at t he a d dress liste d 
bel o w. All s peci me ns m ust be s hi p pe d pri orit y o ver ni g ht. 
 
   
He mat ol o gics, I nc. 3 1 6 1 
   
Elli ot A ve. S uite 2 0 0 
   
Seattle, W A 9 8 1 2 1 
   
P h o ne: ( 8 0 0) 8 6 0- 0 9 3 4 or ( 2 0 6) 22 3 - 2 7 0 0 
  
Fa x: ( 2 0 6) 2 2 3- 5 5 5 0 
   
Wee ke n ds a n d After H o urs: ( 2 0 6) 2 6 4- 4 4 5 9 
 
8. 5   
N G S M R D C o m p aris o n wit h Fl o w C yt o metr y M R D ( O pti o n al) 
 
 
Descri pti o n of St u dies a n d Assa y  
M R D le vels at eac h b o ne marr o w e val uati o n ti me p oi nt will be meas ure d b y 
sta n dar d fl o w c yt o metr y a n d c o m pare d t o 
M R D meas ure d b y N G S. T he 
c orrelati o n bet wee n t he meas ure me nts wit h eac h tec h ni q ue will be descri be d t o 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 4 3  
ai d i n i de ntif yi n g bi o mar kers of t hera p y res p o nse a n d resista nce.  
 
 
Sa m pli n g Sc he d ule ( See A p pe n di x I X ) 
B o ne marr o w sa m ples will be c ollecte d fr o m c o nse nti n g patie nts at t he 
f oll o wi n g ti me p oi nt:  
-   
Wit h eac h b o ne marr o w e val uati o n 
 
W hile t he preferre d s peci me n is b o ne marr o w, if b o ne marr o w sa m ples ca n n ot 
be o btai ne d pri or t o C ycle 1, peri p heral bl o o d ma y be se nt i n f or patie nts w h o 
ha ve a n a bs ol ute blast c o u nt > 1, 0 0 0/ µ L. B o ne marr o w ma y be s u bstit ute d f or 
peri p heral bl o o d f or t he sa m ple ta ke n pri or t o C ycle 1 O N L Y. All ot her sa m ples 
m ust be b o ne marr o w.   
 
 
Sa m ple C ollecti o n a n d Ha n dli n g I nstr ucti o ns  
B o ne marr o w sa m ples ( 1 0 – 1 5 m L) will be c ollecte d i n gree n t o p s o di u m 
he pari n t u bes at t he ti me of b o ne marr o w e val uati o n.  
 
If peri p heral bl o o d is o btai ne d f or t he pri or t o C ycle 1 ti me p oi nt, 2 0 – 3 0 m L 
of bl o o d will be c ollecte d i n lar ge p ur ple E D T A t u bes. N O T E : Patie nts < 2 3 k g 
s h o ul d o nl y ha ve 2 0 m L of bl o o d dra w n per sa m ple.  
 
 
Sa m ple Pr ocessi n g  
St ore sa m ples at 4 ̊ C u ntil s hi p me nt.  
 
 
Sa m ple La beli n g  
Eac h t u be m ust be la bele d wit h t he patie nt’s st u d y re gistrati o n n u m ber, t he 
st u d y I. D., a n d t he date a n d ti me t he sa m ple was dra w n.  Data s h o ul d be 
rec or de d o n t he N G S M R D C o m paris o n wit h Fl o w C yt o metr y M R D St u d y 
F or m ( A p pe n di x I X), w hic h m ust acc o m pa n y t he sa m ple(s). 
 
 
Sa m ple S hi p pi n g I nstr ucti o ns  
F or q uesti o ns re gar di n g sa m ple c ollecti o n, pr ocessi n g, a n d s hi p pi n g, please 
e mail 
  
 
Sa m ples ma y be s hi p pe d at r o o m te m perat ure or wit h a n ice pac k. If sa m ples 
are t o be s hi p pe d wit h a n ice pac k, t he c ollecti o n t u bes are t o be wra p pe d i n 
pa per t o wels or ot her i ns ulati o n t o mi ni mize t u be freezi n g a n d direct c o ntact 
wit h t he ice pac k.  
 
Pri or t o sa m ple s hi p me nt, 
please 
e mail 
   
 
 t o alert t he m of t he sa m ple s hi p me nt.   
 
S hi p s a m ples t o t he f oll o wi n g a d dress:  
 
   
 
 
   
 
 
 
 
 
   
   
 
F oll o wi n g sa m ple s hi p me nt, se n d a n ot her e mail t o t he a d dresses liste d a b o ve 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 4 4  
wit h t he Fe d- E x trac ki n g n u m ber a n d c o p y t he P E P N 1 8 1 2 
Researc h 
C o or di nat or o n t he e mail.  
 
8. 6   
C D 3 T- L y m p h oc yte Q u a ntific ati o n ( O pti o n al) 
 
 
Descri pti o n of St u dies a n d Assa y  
Peri p heral bl o o d sa m ples will be c ollecte d fr o m c o nse nti n g patie nts t o ai d i n 
i de ntif yi n g bi o mar kers of res p o nse t hr o u g h fl o w c yt o metric a nal ysis of C D 3 + 
T-cells. C ha n ges i n T cell n u m ber will be descri be d a n d e x pl orat or y a nal ysis 
will be c o n d ucte d t o assess t heir c orrelati o n wit h cli nical feat ures i ncl u di n g 
occ urre nce of i nfecti o ns a n d res p o nse. Sa m ples will be a nal yze d l ocall y at t he 
treati n g i nstit uti o n.  
 
 
Sa m pli n g Sc he d ule ( See A p pe n di x X ) 
Bl o o d sa m ples will be c ollecte d fr o m c o nse nti n g patie nts at t he f oll o wi n g ti me 
p oi nts:  
-   
C ycle 1: Da y 1 pre-i nf usi o n, a n d Da ys 8, 1 5, 2 2, a n d 2 9 ( pri or t o t he e n d 
   
of i nf usi o n) 
-   
S u bse q ue nt c ycles, Da y 1: Pre-i nf usi o n  
 
 
Sa m ple C ollecti o n a n d Ha n dli n g I nstr ucti o ns  
Bl o o d sa m ples ( 2 – 3 ml) will be c ollecte d i n E D T A t u bes ( or i nstit uti o nal 
sta n dar d) a n d a nal yze d l ocall y via fl o w c yt o metr y acc or di n g t o i nstit uti o nal 
sta n dar ds. N O T E:  Patie nts < 2 3 k g s h o ul d o nl y ha ve 2 ml of bl o o d dra w n per 
sa m ple. Bl o o d sa m ples will be c ollecte d at a site dista nt fr o m t he i nf usi o n f or T 
cell q ua ntificati o n. Sa m ples ca n n ot be dra w n fr o m t he 2 n d l u me n of a m ulti-
l u me n cat heter t hr o u g h w hic h dr u g is bei n g a d mi nistere d. Rec or d t he e xact ti me 
t hat t he sa m ple is dra w n al o n g wit h t he e xact ti me t hat i nf usi o n be gi ns o n D a y 
1 of eac h c ycle. 
 
T he date a n d ti me of sa m ple c ollecti o n will be rec or de d o n t he C D 3 T-
L y m p h oc yte Q ua ntificati o n St u d y F or m ( A p pe n di x X ) a n d u pl oa de d i nt o 
R A V E. Q ua ntificati o n res ults will be c ollecte d i n R A V E per t he g ui da nce i n 
t he C R F pac ket.  
 
8. 7   
C yt o ki ne P r o d ucti o n Me as ure me nt ( O pti o n al)  
 
 
Descri pti o n of St u dies a n d Assa y  
Peri p heral bl o o d sa m ples will be c ollecte d fr o m c o nse nti n g patie nts t o i m pr o ve 
mec ha nistic u n dersta n di n g of p ote ntial t hera pe utic res p o nses a n d a d verse 
effects wit h fl otet uz u ma b t hera p y. Sa m ples will be a nal yze d t hr o u g h a q ualifie d 
E LI S A assa y b y Macr o Ge nics P har mace uticals.  
 
 
Sa m pli n g Sc he d ule ( See A p pe n di x XI ) 
Bl o o d sa m ples will be c ollecte d fr o m c o nse nti n g patie nts at t he f oll o wi n g ti me 
p oi nts:  
-   
C ycle 1, Da y 1: pre-i nf usi o n 
-   
C ycle 1, Da y 8 
 
A d diti o nall y, if patie nts e x perie nce I R R/ C R S, bl o o d sa m ples will be c ollecte d 
fr o m c o nse nti n g patie nts at t he f oll o wi n g ti me p oi nts:  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 4 5  
-   
At t he ti me of I R R/ C R S 
-   
At t he ti me of I R R/ C R S res ol uti o n  
 
 
Sa m ple C ollecti o n a n d Ha n dli n g I nstr ucti o ns  
Bl o o d sa m ples ( 2 – 3 ml) will be c ollecte d i n S S T t u bes at a site dista nt fr o m 
t he inf usi o n f or c yt o ki ne pr o d ucti o n meas ure me nt e val uati o n. N O T E:  Patie nts 
< 2 3 k g s h o ul d o nl y ha ve 2 ml of bl o o d dra w n per sa m ple.  
 
 
Sa m ple Pr ocessi n g  
1.  C ollect bl o o d i nt o a 2 – 3 m L S S T t u be. 
2.  All o w bl o o d t o cl ot f or at least 6 0 mi n utes at r o o m te m perat ure. 
3.  Se parate ser u m wit hi n 6 0 – 9 0 mi n utes of c ollecti o n. 
4.  Ce nt rif u ge f or 1 0 mi n utes at r o o m te m perat ure at 1 1 0 0 – 1 3 0 0 x g. 
5.  Tr a nsfer ser u m e q uall y i nt o t w o 2 m L ora n ge ca p pe d cr y o vials ( pri mar y 
a n d bac k u p). 
6.  I m me diatel y freeze at - 6 0 ̊ C t o - 8 0 ̊ C. 
 
 
Sa m ple La beli n g  
Eac h t u be m ust be la bele d wit h t he patie nt’s st u d y re gistrati o n n u m ber, t he 
st u d y I. D., a n d t he date a n d ti me t he sa m ple was dra w n.  Data s h o ul d be 
rec or de d o n t he C yt o ki ne A nal ysis St u d y F or m (A p pe n di x XI ), w hic h m ust 
acc o m pa n y t he sa m ple(s). 
 
A d diti o nall y, Macr o Ge nics has sta n dar d na mi n g c o n ve nti o ns f or sa m ples. Sites 
s h o ul d use t he bel o w la beli n g c o n ve nti o ns f or la b sa m ples:  
 
Pre M G D 0 0 6 C K 
Da y 8 C K 
Start I R R/ C R S C K 
E n d I R R/ C R S C K 
U N S C K ( use t his f or u nsc he d ule d) 
 
 
Sa m ple S hi p pi n g I nstr ucti o ns  
St ore sa m ples at - 7 0 ̊ C u ntil s hi p me nt. S hi p o n dr y ice t o 
Was hi n gt o n 
U ni versit y o nce all sa m ples ha ve bee n c ollecte d f or eac h patie nt. Pri or t o 
sa m ple s hi p me nt, please e mail 
 t o alert her of t he sa m ple 
s hi p me nt. S hi p t o t he f oll o wi n g a d dress:  
 
   
 
 
   
 
 
   
 
 
   
 
  
   
   
 
   
 
 
   
 
 
 
N O T E: Pri mar y a n d bac k- u p ali q u ots fr o m t he sa me ti me p oi nt s h o ul d N O T 
be se nt i n t he sa me s hi p me nt.  
 
8. 8   
P r ofili n g of t he T u m or Micr oe n vir o n me nt ( O pti o n al)  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 4 6  
 
 
De scri pti o n of St u dies a n d Assa y  
B o ne marr o w as pirate a n d bi o ps y will be c ollecte d fr o m c o nse nti n g patie nts t o 
ai d i n i de ntif yi n g bi o mar kers of res p o nse t hr o u g h ge ne e x pressi o n pr ofili n g, 
pr otei n a nal ysis, a n d patie nt- deri ve d xe n o graft m o deli n g. St u dies will be 
perf or me d via t he Tasia n La b at t he C hil dre n’s H os pital of P hila del p hia. 
 
 
Sa m pli n g Sc he d ule  
B o ne marr o w as pirate a n d bi o ps y will be c ollecte d fr o m c o nse nti n g patie nts at 
t he f oll o wi n g ti me p oi nts: 
-   
Pri or t o C ycle 1 
 
W hile t he preferre d s peci me n is b o ne marr o w, if b o ne marr o w sa m ples ca n n ot 
be o btai ne d, peri p heral bl o o d ma y be se nt i n f or patie nts w h o ha ve a n a bs ol ute 
blast c o u nt > 1, 0 0 0/ µ L  
 
I n a d diti o n t o t he b o ne marr o w as pirate or bl o o d sa m ple, 1 paraffi n-e m be d de d 
tiss ue bl oc k will be c ollecte d. If a bl oc k of tiss ue is u na vaila ble, 1 0 u nstai ne d 
sli des a n d 2 H & E stai ne d sli des ma y be c ollecte d i nstea d.  
 
 
Sa m ple C ollecti o n a n d Ha n dli n g I nstr ucti o ns  
B o ne marr o w sa m ples ( 1 0 – 1 5 m L) will be c ollecte d i n gree n t o p s o di u m 
he pari n t u bes at t he ti me of b o ne marr o w e val uati o n.  
 
If peri p heral bl o o d is o btai ne d, 2 0 – 3 0 m L of bl o o d will be c ollecte d i n gree n 
t o p s o diu m he pari n t u bes. N O T E:  Patie nts < 2 3 k g s h o ul d o nl y ha ve 2 0 m L of 
bl o o d dra w n per sa m ple.  
 
 
Sa m ple Pr ocessi n g  
St ore sa m ples at 4 ̊ C u ntil s hi p me nt.  
 
 
Sa m ple La beli n g  
Eac h t u be m ust be la bele d wit h t he patie nt’s st u d y re gistrati o n n u m ber, t he 
st u d y I. D., a n d t he date a n d ti me t he sa m ple was dra w n.  Data s h o ul d be 
rec or de d o n t he T u m or Micr oe n vir o n me nt St u d y F or m (A p pe n di x XII ), w hic h 
m ust acc o m pa n y t he sa m ple(s). 
 
 
Sa m ple S hi p pi n g I nstr ucti o ns  
F or q uesti o ns re gar di n g sa m ple c ollecti o n, pr ocessi n g, a n d s hi p pi n g, please 
e mail 
  
 
Sa m ples ma y be s hi p pe d at r o o m te m perat ure or wit h a n ice pac k. If sa m ples 
are t o be s hi p pe d wit h a n ice pac k, t he c ollecti o n t u bes are t o be wra p pe d i n 
pa per t o wels or ot her i ns ulati o n t o mi ni mize t u be freezi n g a n d direct c o ntact 
wit h t he ice pac k.  
 
Pri or t o sa m ple s hi p me nt, 
please 
e mail 
   
 
  
 
S hi p sa m ples t o t he f oll o wi n g a d dress:  
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 4 7  
   
 
 
   
 
 
 
 
 
   
   
 
F oll o wi n g sa m ple s hi p me nt, se n d a n ot her e mail t o t he a d dresses liste d a b o ve 
wit h t he Fe d- E x trac ki n g n u m ber a n d c o p y t he P E P N 1 8 1 2 
Researc h 
C o or di nat or o n t he e mail.  
 
 
9. 0   
A G E N T I N F O R M A TI O N 
 
9. 1  
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 4 8  
9. 1. 4. 2  
 
 
   
 
   
   
   
   
   
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
   
 
 
 
 
 
 
 
 
   
 
   
 
 
 
 
 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 4 9  
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 5 0  
  
 
 
  
 
 
 
.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
   
 
   
   
   
 
 
 
   
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
   
   
   
  
  
   
 
 
 
  
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 5 1  
 
   
   
   
   
  
   
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
9. 1. 6. 5  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
   
 
 
 
  
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 5 2  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 5 3  
 
 
 
  
 
 
   
 
 
 
   
   
   
   
   
   
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
ii. 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
  
 
 
   

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 5 4  
  
 
 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
 
  
 
 
 
    
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
  
    
 
 
 
    
 
 
 
 
  
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 5 5  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 5 6  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 5 7  
 
 
  
 
 
 
  
 
  
  
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
  
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
  
 
 
  
 
  
 
 
 
 
  
 
 
 
  
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 5 8  
  
  
 
 
   
 
 
 
   
   
   
   
   
 
   
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 5 9  
  
 
 
 
   
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
   
   
   
   
   
 
   
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
   
  
 
  
   
   
  
   
   
 
  
   
   
   
  
 
   
  
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 6 0  
 
 
 
  
 
9. 2   
C yt ar a bi ne   
   
   
   
   
   
   
   
         ( 0 7/ 1 3/ 1 5) 
( C yt osi ne ara bi n osi de, Ara- C, C yt osar ®) N S C # 6 3 8 7 8 
 
 
S o urce a n d P har mac ol o g y  
C ytara bi ne a p pears t o act t hr o u g h t he i n hi biti o n of D N A p ol y merase. A li mite d, 
b ut si g nifica nt, i nc or p orati o n of c ytara bi ne i nt o b ot h D N A a n d R N A has als o bee n 
re p orte d. It e x hi bits cell p hase s pecificit y, pri maril y killi n g cells u n der g oi n g D N A 
s y nt hesis ( S- p hase) a n d u n der certai n c o n diti o ns bl oc ki n g t he pr o gressi o n of cells 
fr o m t he G 1 p hase t o t he S- p hase. C ytara bi ne is meta b olize d b y de o x yc yti di ne 
ki nase a n d ot her n ucle oti de ki nases t o t he n ucle oti de tri p h os p hate ( Ara- C T P), a n 
effecti ve i n hi bit or of D N A p ol y merase. Ara- C T P is i nacti vate d b y a p yri mi di ne 
n ucle osi de dea mi nase, w hic h c o n verts it t o t he n o nt o xic uracil deri vati ve ( Ara- U). 
It a p pears t hat t he bala nce of ki nase a n d dea mi nase le vels ma y be a n i m p orta nt 
fact or i n deter mi ni n g se nsiti vit y or resista nce of t he cell t o c ytara bi ne. It has a n 
i nitial distri b uti ve p hase t½  of a b o ut 1 0 mi n utes, wit h a sec o n dar y eli mi nati o n 
p hase t ½  of a b o ut 1 t o 3 h o urs. Pea k le vels after i ntra m usc ular or s u bc uta ne o us 
a d mi nistrati o n of c ytara bi ne occ ur a b o ut 2 0 t o 6 0 mi n utes after i nj ecti o n a n d are 
l o wer t ha n I V a d mi nistrati o n. I ntrat hecall y a d mi nistere d d oses are meta b olize d 
a n d eli mi nate d m ore sl o wl y wit h a t ½  of a b o ut 2 h o urs. 
 
 
T o xicit y: (I ntrat hecal)  
 
 
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, fe ver, 
hea dac he  
Arac h n oi ditis  
Ras h, s o m n ole nce, 
me ni n gis m us, c o n v ulsi o ns, 
paresis  
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, ata xia  
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 n 
 
 
Necr otizi n g 
le u k oe nce p hal o pat h y, 
para ple gia, bli n d ness (i n 
c o m bi nati o n wit h X R T & 
s yste mic t hera p y) 
 
 
 
F or m ulati o n  
C ytara bi ne f or I nj ecti o n is a vaila ble as a preser vati ve free s ol uti o n 2 0 m g/ m L ( 5 
m L, 5 0 m L per vial) or 1 0 0 m g/ m L ( 2 0 m L vial). H y dr oc hl oric aci d a n d/ or s o di u m 
h y dr o xi de ma y be a d de d t o a dj ust t he p H. St ore i ntact vials of s ol uti o n at 1 5°- 3 0° C 
( 5 9°- 8 6° F). C ytara bi ne s ol uti o ns s h o ul d be pr otecte d fr o m li g ht. 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 6 1  
 
G ui deli nes f or A d mi nistrati o n  
See Treat me nt a n d D ose M o dificati o n secti o ns of t he pr ot oc ol. 
 
I ntr at hec al:  
   
   
   
F or i ntrat hecal a d mi nistrati o n, dil ute wit h 5- 1 0 m L ( or v ol u me per i nstit uti o nal  
   
   
   
practice) preser vati ve free 0. 9 % s o di u m c hl ori de i njecti o n, lactate d Ri n ger’s  
   
   
   
i njecti o n, Elli ot’s B s ol uti o n. T he v ol u me of C S F re m o ve d s h o ul d be e q ual t o at  
   
   
   
least ½ t he v ol u me deli vere d. 
 
Patie nt A ge 
( years) 
Rec o m me n de d 
v ol u me  
1 0 % C S F v ol u me  
C S F V ol u me *  
1 –  1. 9 9   
5 –  1 0 m L   
5 m L  
5 0 +  1 0 m L ( ba bies)  
2 –  2. 9 9   
5 –  1 0 m L   
8 m L  
8 0 +  2 0 m L ( y o u n ger c hil dre n)  
3 –  8. 9 9   
5 –  1 0 m L   
1 0 m L  
1 0 0 +  2 0 m L ( ol der c hil dre n)  
9 or greater   
5 –  1 0 m L   
1 3 m L  
1 3 0 +  3 0 m L (a d ults)  
* Riesel b ac h, R. E. et. al. S u b ar ac h n oi d distri b uti o n of dr u gs after l u m b ar i njecti o n; N E n gl J Me d.  1 9 6 2 Dec 2 0; 
2 6 7: 1 2 7 3- 8 
 
   
   
   
Of N ote: Lar ger v ol u mes a p pr o xi mati n g at least 1 0 % of t he C S F v ol u me,  
   
   
   
is o v ol u metric deli ver y, wit h t he patie nt re mai ni n g pr o ne after t he pr oce d ure ma y  
   
   
`   
facilitate dr u g distri b uti o n. T hese pr oce d ures ha ve n ot bee n vali date d i n cli nical  
   
   
   
trials. T he y are all o we d b ut n ot ma n date d f or patie nts o n C O G st u dies. 
 
I ntrat hecal c ytara bi ne mi xe d i n N S, lactate d Ri n ger’s i njecti o n, or Elli ot’s B 
   
s ol uti o n is sta ble f or 2 4 h o urs at 2 5º C b ut c o ntai ns n o preser vati ve a n d s h o ul d be 
   
a d mi nistere d as s o o n as p ossi ble after pre parati o n. 
 
 
S u p plier  
C o m merciall y a vaila bl e fr o m vari o us ma n ufact urers. See pac ka ge i nsert f or f urt her 
i nf or mati o n.  
 
9. 3   
Usef ul Li n ks a n d C o nt acts  
 C T E P F or ms, T e m plates, D oc u me nts: 
htt p://cte p.ca ncer. g o v/f or ms/   
 N CI C T E P I n vesti gat or Re gistrati o n: 
R C R Hel p Des k @ ni h. g o v   
 C T E P I de ntit y a n d Access Ma na ge me nt (I A M) acc o u nt: 
htt ps://cte pc ore. nci. ni h. g o v/ia m/   
 C T E P Ass ociate Re gistrati o n a n d I A M acc o u nt hel p: 
cte pre g hel p @cte p. nci. ni h. g o v   
 
I B C o or di nat or: 
I B C o or di nat or @ mail. ni h. g o v 
 
 
1 0. 0   
C RI T E RI A F O R 
R E M O V A L F R O M P R O T O C O L 
T H E R A P Y 
A N D 
O F F S T U D Y 
C RI T E RI A  
 
1 0. 1   
Criteri a f or Re m o v al fr o m P r ot oc ol T her a p y  
 
a)  
Cli nical (i ncl u di n g p h ysical e xa mi nati o n or ser u m t u m or mar kers) or ra di o gra p hic 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 6 2  
e vi de nce of pr o gressi ve disease ( See Secti o n 1 2 ). 
b)   
Ha ve n ot ac hie ve d at least a P R f oll o wi n g 2 s uccessi ve treat me nt c ycles. 
c)  
A d verse E ve nts re q uiri n g re m o val fr o m pr ot oc ol t hera p y ( See Secti o n 1 3 ). 
d)   
De vel o p me nt of a D L T f oll o wi n g 1 d ose re d ucti o n.  
e)  
A n i nf usi o n st o p or dela y of m ore t ha n 2 wee ks d ue t o A E or m ore t ha n 2 
disc o nti n uati o ns per c ycle d ue t o A E ( d oes n ot a p pl y f or pr ol o n gati o n of t he 
sc he d ule d treat me nt free peri o d of a c ycle). 
f)  
Ref usal of pr ot oc ol t hera p y b y patie nt/ pare nt/ g uar dia n 
g)   
N o n-c o m plia nce t hat i n t he o pi ni o n of t he i n vesti gat or d oes n ot all o w f or o n g oi n g 
partici pati o n. 
h)   
C o m pleti o n of 6 c ycles of t hera p y. 
i)  
P h ysicia n deter mi nes it is n ot i n t he patie nt’s best i nterest. 
j)  
Re peate d eli gi bilit y la b orat or y st u dies ( C B C wit h differe ntial, bilir u bi n, A L T ( S G P T) 
or  ser u m creati ni ne) are o utsi de t he para meters re q uire d f or eli gi bilit y pri or t o t he start 
o f fl otet uz u ma b ( See Secti o n 8. 1 ). 
k)   
St u d y is ter mi nate d b y S p o ns or. 
l)  
Pre g na nc y 
 
P atie nts w h o are re m o ve d fr o m pr ot oc ol t her a p y d uri n g C ycle 1 s h o ul d c o nti n ue t o 
h a ve t he re q uire d o bser v ati o ns i n Secti o n 8. 1  u ntil t he ori gi n all y pl a n ne d e n d of t he 
c ycle or u ntil all a d verse e ve nts h a ve res ol ve d per Secti o n 1 3. 4. 4 , w hic he ver h a p pe ns 
L A T E R. T h e o nl y e xce pti o n is wit h d oc u me nt ati o n of t he p atie nt’s wit h dr a w al of 
c o nse nt. P atie nts w h o are re m o ve d fr o m pr ot oc ol t her a p y i n s u bse q ue nt c ycles s h o ul d 
h a ve t he necess ar y o bser v ati o ns t o e ns ure a de q u ate cli nic al c are.  
 
Patie nts w h o are off pr ot oc ol t hera p y are t o be f oll o we d u ntil t he y meet t he criteria f or Off 
St u d y (see bel o w). O n g oi n g a d verse e ve nts, or a d verse e ve nts t hat e mer ge after t he patie nt 
is re m o ve d fr o m pr ot oc ol t hera p y, b ut wit hi n 3 0 da ys of t he last d ose of i n vesti gati o nal 
a ge nt, m ust be f oll o we d a n d re p orte d via R A V E a n d C T E P- A E R S (if a p plica ble).  F oll o w-
u p data will be re q uire d u nless c o nse nt is wit h dra w n. 
 
1 0. 2   
Off St u d y Criteri a 
 
a)  
T hirt y da ys after t he last d ose of t he i n vesti gati o nal a ge nt. 
b)   
T he patie nt d oes n ot recei ve pr ot oc ol treat me nt after st u d y e nr oll me nt. 
c)  
Deat h 
d)   
L ost t o f oll o w- u p 
e)  
Wit h dra wal of c o nse nt f or a n y re q uire d o bser vati o ns or data s u b missi o n. 
f)  
E nr oll me nt o nt o a n ot her C O G t hera pe utic (a nti-ca ncer) st u d y  
 
 
 
1 1. 0   
S T A TI S TI C A L A N D E T HI C A L C O N SI D E R A TI O N S 
 
1 1. 1   
S a m ple Size a n d St u d y D ur ati o n 
 
T his is a P hase 1 st u d y i n v ol vi n g a d ose escalati o n c o h ort usi n g a r olli n g si x desi g n wit h a 
pri mar y ai m of i de ntificati o n of safe a n d t olera ble d osi n g of t he C D 1 2 3 x C D 3 D A R T, 
fl otet uz u ma b, i n c hil dre n bet wee n < 2 1 years of  a ge wit h A M L i n sec o n d or greater rela pse, 
refract or y A M L after t w o or m ore c he m ot hera p y c ycles, or first rela pse after pri mar y 
c he m ot hera p y-refract or y disease. Pri or he mat o p oietic ste m cell tra ns pla ntati o n ( H S C T) is 
per mitte d.  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 6 3  
 
If D L 1 is safe a n d t olera ble base d o n sta n dar d i m m u n ot hera p y D L T assess me nts, a n 
a d diti o nal c o h ort of patie nts will d ose-escalate t o fl otet uz u ma b at 7 0 0 na n o gra ms/ k g/ da y 
( D L 2). If fe wer t ha n 2 D L Ts occ ur at D L 2, t his will be c o nsi dere d t he R P 2 D. If t here are 
> 2 D L Ts at D L 2, D L 1 will be c o nsi dere d t he M T D of fl otet uz u ma b m o n ot hera p y. If 
fl otet uz u ma b m o n ot hera p y at D L 1 is n ot t olera ble, d ose de-escalati o n will occ ur t o 3 0 0 
na n o gra ms/ k g/ da y ( D L- 1). If D L- 1 is dee me d t olera ble, t his d osi n g will be t he M T D. 
F urt her d ose de-escalati o n be y o n d D L- 1 will n ot be per mitte d a n d will li mit f urt her 
e x pl orati o n of fl otet uz u ma b i n t his patie nt p o p ulati o n.  B o ne marr o w e val uati o n will be 
perf or me d wit h bl o o d c o u nt rec o ver y fr o m C ycle 1 t hera p y as a n e x pl orat or y meas ure me nt 
of res p o nse. Patie nts wit h at least sta ble disease after C ycle 1 ma y c o nti n ue t o C ycle 2. 
Patie nts wit h at least a P R  f oll o wi n g C ycle 2 
ma y recei ve s u bse q ue nt c ycles of 
fl otet uz u ma b f or a t otal of u p t o 6 c ycles. 
 
A 
mi ni m u m of 4 e val ua ble patie nts a n d a 
ma xi m u m of 1 8 will be re q uire d f or 
deter mi nati o n of t he M T D/ R P 2 D. O nce t he M T D or R P 2 D has bee n defi ne d, u p t o 6 
a d diti o nal patie nts wit h A M L i n sec o n d or greater rela pse, refract or y A M L after t w o or 
m ore c he m ot hera p y c ycles, first rela pse after pri mar y c he m ot hera p y-refract or y disease, or 
first rela pse after H S C T wit h o ut restricti o ns o n he me e val ua bilit y ma y be e nr olle d t o 
ac q uire P K data i n a re prese ntati ve n u m ber of y o u n g patie nts (i.e. patie nts < 1 2 years ol d).  
Re vie w of t he e nr oll me nt rate i nt o pre vi o us C O G ne w a ge nt st u dies i n dicates t hat 1- 2 
patie nts per m o nt h are a vaila ble, w hic h will per mit c o m pleti o n of t he st u d y wit hi n 2 7 
m o nt hs.  A ma xi m u m of 2 7 patie nts is a ntici pate d all o wi n g f or t hree d ose le vels, P K 
e x pa nsi o n, a n d 1 0 % attriti o n. I n t he u nli kel y e ve nt t hat eac h d ose le vel is e x pa n de d t o 1 2 
patie nts, a n a bs ol ute 
ma xi m u m of 4 7 patie nts 
ma y be re q uire d all o wi n g f or 1 0 % 
i ne val ua bilit y, a n d t his w o ul d be c o m plete d wit hi n 4 7 m o nt hs. 
 
1 1. 2   
Defi niti o ns 
 
 E val ua ble F or A d verse E ve nts  
A n y patie nt w h o recei ves at least o ne d ose of t he st u d y dr u g(s) or w h o 
e x perie nces a d ose-li miti n g t o xicit y is c o nsi dere d e val ua ble f or A d verse 
E ve nts. I n a d diti o n, f or t he d ose-escalati o n p orti o n d uri n g C ycle 1, patie nts 
m ust recei ve at least 8 0 % of t he prescri be d d ose per pr ot oc ol g ui deli nes a n d 
m ust ha ve t he a p pr o priate t o xicit y 
m o nit ori n g st u dies perf or me d t o be 
c o nsi dere d e val ua ble f or d ose li miti n g t o xicit y. Patie nts w h o d o n ot ha ve D L T 
a n d are n ot c o nsi dere d e val ua ble f or t o xicit y will be re place d. 
 
 Ma xi m u m T olerate d D ose  
 
T he M T D will be t he ma xi m u m d ose at w hic h fe wer t ha n o ne-t hir d of 
patie nts e x perie nce D L T ( See Secti o n 5. 5 ) d uri n g C ycle 1 of t hera p y.  
 
  
If t w o or m ore of a c o h ort of u p t o si x patie nts e x perie nce D L T at a gi ve n 
d ose le vel, t he n t he M T D has bee n e xcee de d a n d d ose escalati o n will be 
st o p pe d. If re vie w of t he D L Ts s u g gests t hat t he y w o ul d p ote ntiall y be 
acce pta ble (e. g., beca use of ra pi d re versi bilit y, differe nt classes of A d ver se 
Effects) or are p ote ntiall y attri b uta ble t o disease rat her t ha n t hera p y, t he n 
e x pa nsi o n of t he c o h ort t o 1 2 patie nts t o better assess t olera bilit y of t his 
d ose le vel will be c o nsi dere d ass u mi n g t he f oll o wi n g c o n diti o ns are met:   
 
•    
O ne of t he D L Ts d oes n ot a p pear t o be d ose-relate d 
 
•    
T he A d verse Effects are rea dil y re versi ble 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 6 4  
 
•    
T he st u d y c hair, D V L statisticia n, D V L c o m mittee c hair or vice 
c hair, I N D s p o ns or, a n d C T E P all a gree t hat e x pa nsi o n of t he 
c o h ort is acce pta ble 
 
If fe wer t ha n 1/ 3 of patie nts i n t he e x pa n de d c o h ort e x perie nce d ose-li miti n g 
t o xicities, t he d ose escalati o n ca n pr ocee d. 
 
 
T he D L Ts o bser ve d i n t he p har mac o ki netic ( P K) e x pa nsi o n c o h ort will be 
c o u nte d t o war ds t he t otal n u m ber of D L Ts o bser ve d at t he M T D d uri n g t he 
d ose escalati o n p orti o n of t he st u d y. If ≥ 1/ 3 of t he c o h ort of patie nts at t he 
M T D ( d uri n g t he d ose escalati o n pl us t he P K e x pa nsi o n) e x perie nce D L T 
t he n t he M T D will be e xcee de d.  
 
1 1. 3   
D ose Esc al ati o n a n d Deter mi n ati o n of M T D 
 
T he r olli n g si x p hase 1 trial desi g n will be use d f or t he c o n d uct of t his st u d y. 3 5 T w o t o si x 
patie nts ca n be c o nc urre ntl y e nr olle d o nt o a d ose le vel, de pe n de nt u p o n ( 1) t he n u m ber of 
patie nts e nr olle d at t he c urre nt d ose le vel, ( 2) t he n u m b er of patie nts w h o ha ve e x perie nce d 
D L T at t he c urre nt d ose le vel, a n d ( 3) t he n u m ber of patie nts e ntere d b ut wit h t olera bilit y 
data pe n di n g at t he c urre nt d ose le vel. H o we ver, e nr oll me nt will be sta g gere d s o t hat n o 
m ore t ha n 1 patie nt i nitiates e nr oll me nt e ver y 7 da ys f or d ose le vels great er t ha n D L 1. 
Accr ual is s us pe n de d w he n a c o h ort of si x has e nr olle d or w he n t he st u d y e n d p oi nts ha ve 
bee n met.  
 
D ose le vel assi g n me nt is base d o n t he n u m ber of partici pa nts c urre ntl y e nr olle d i n t he 
c o h ort, t he n u m ber of D L Ts o bser ve d, a n d t he n u m ber of partici pa nts at ris k f or de vel o pi n g 
a D L T (i.e., partici pa nts e nr olle d b ut w h o are n ot yet assessa ble f or t o xicit y). F or e xa m ple, 
w he n t hree partici pa nts are e nr olle d o nt o a d ose c o h ort, if t o xicit y data is a vaila ble f or all 
t hree w he n t he f o urt h partici pa nt e ntere d a n d t here are n o D L Ts, t he d ose is escalate d a n d 
t he f o urt h partici pa nt is e nr olle d t o t he s u bse q ue nt d ose le vel. If data is n ot yet a vaila ble 
f or o ne or m ore of t he first t hree partici pa nts a n d n o D L T has bee n o bser ve d, or if o ne D L T 
has bee n o bser ve d, t he ne w partici pa nt is e ntere d at t he sa me d ose le vel. Lastl y, if t w o or 
m ore D L Ts ha ve bee n o bser ve d, t he d ose le vel is de-escalate d. T his pr ocess is re peate d f or 
partici pa nts fi ve a n d si x. I n place of s us pe n di n g accr ual after e ver y t hree partici pa nts, 
accr ual is o nl y s us pe n de d w he n a c o h ort of si x is fille d. W he n partici pa nts are i ne val ua ble 
f or t o xicit y, t he y are re place d wit h t he ne xt a vaila ble partici pa nt if escalati o n or de-
escalati o n r ules ha ve n ot bee n f ulfille d at t he ti me t he ne xt a vaila ble partici pa nt is e nr olle d 
o nt o t he st u d y. 
 
T he f oll o wi n g ta ble pr o vi des t he decisi o n r ules f or e nr olli n g a patie nt at (i) t he c urre nt d ose 
le vel (ii) at a n escalate d d ose le vel, (iii) at a de-escalate d d ose le vel, or w het her t he st u d y 
is s us pe n de d t o accr ual: 
 
 
 
 
 
 
  
# Pts 
E nr olle d  
# Pts wit h 
D L T  
# Pts wit h o ut 
D L T  
# Pts wit h 
D at a Pe n di n g  
Decisi o n  
  
2   
0 or 1   
0, 1 or 2   
0, 1 or 2   
Sa me d ose le vel  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 6 5  
  
2  
2  
0  
0  
De -escalate *  
 
 
 
 
 
 
  
3  
0   
0, 1 or 2   
1, 2 or 3   
Sa me d ose le vel  
  
3  
1   
0, 1 or 2   
0, 1 or 2   
Sa me d ose le vel  
  
3  
0  
3  
0  
Escalate * * 
  
3   
≥ 2   
0 or 1  
0 or 1   
De -escalate * 
 
 
 
 
 
 
  
4  
0   
0, 1, 2 or 3   
1, 2, 3 or 4   
Sa me d ose le vel  
  
4  
1   
0, 1, 2 or 3   
0, 1, 2 or 3   
Sa me d ose le vel  
  
4  
0  
4  
0  
Escalate * * 
  
4   
≥ 2   
0, 1 or 2   
0, 1 or 2   
De -escalate * 
 
 
 
 
 
 
  
5  
0   
0, 1, 2, 3 or 4   
1, 2, 3, 4 or 5   
Sa me d ose le vel  
  
5  
1   
0, 1, 2, 3 or 4   
0, 1, 2, 3 or 4   
Sa me d ose le vel 
  
5  
0  
5  
0  
Escalate * * 
  
5   
≥ 2   
0, 1, 2 or 3   
0, 1, 2 or 3   
De -escalate * 
 
 
 
 
 
 
  
6  
0   
0, 1, 2, 3, or 4   
2, 3, 4, 5 or 6   
S us pe n d  
  
6  
1   
0, 1, 2, 3 or 4   
0, 1, 2, 3 or 4   
S us pe n d  
  
6   
0 or 1   
5 or 6  
0 or 1  
Escalate * * 
  
6   
≥ 2   
0, 1, 2, 3 or 4   
0, 1, 2, 3 or 4   
De -escalate * 
* If si x patie nts alrea d y e ntere d at ne xt l o wer d ose le vel, t he M T D has bee n defi ne d. 
* *If fi nal d ose le vel has bee n reac he d, t he rec o m me n de d d ose has bee n reac he d. 
 
If t w o or m ore of a c o h ort of u p t o si x patie nts e x perie nce D L T at a gi ve n d ose le vel, t he n 
t he M T D has bee n e xcee de d a n d d ose escalati o n will be st o p pe d (see Secti o n 1 1. 2. 2  f or 
e xce pti o n t o r ule). 
 
I n a d diti o n t o deter mi nati o n of t he M T D, a descri pti ve s u m mar y of all t o xicities will be 
re p orte d. 
 
1 1. 4   
I ncl usi o n of C hil dre n, W o me n a n d Mi n orities 
 
 
P L A N N E D E N R O L L M E N T R E P O R T  
R a ci al 
C at e g ori e s  
Et h ni c C at e g ori e s  
T ot al  
N ot Hi s p a ni c or L ati n o  
Hi s p a ni c or L ati n o  
F e m al e   
M al e   
F e m al e   
M al e  
A m eri c a n 
I n di a n/  
Al a s k a 
N ati v e  
0  
0  
0  
0  
0  
A si a n  
0  
1  
0  
0  
1  
N ati v e 
H a w aii a n   
or 
Ot h er   
P a cifi c 
I sl a n d er 
0  
0  
0  
0  
0  
Bl a c k or Afri c a n 
A m eri c a n  
3  
3  
0  
0  
6  
W hit e  
1 4  
2 0  
3  
3  
4 0  
M or e T h a n O n e 
R a c e  
0  
0  
0  
0  
0  
T ot al  
1 7  
2 4  
3  
3  
4 7  
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 6 6  
T he st u d y is o pe n t o all partici pa nts re gar dless of ge n der or et h nicit y.  Re vie w of accr ual 
t o past C O G st u dies of ne w a ge nts de m o nstrates t he accr ual of b ot h ge n ders a n d all NI H-
i de ntifie d et h nicities t o s uc h st u dies.  Eff orts will be ma de t o e xte n d t he accr ual t o a 
re prese ntati ve p o p ulati o n, b ut i n a P hase 1 trial w hic h will accr ue a li mite d n u m ber of 
patie nts, a bala nce m ust be str uc k bet wee n patie nt safet y c o nsi derati o ns a n d li mitati o ns o n 
t he n u m ber of i n di vi d uals e x p ose d t o p ote ntiall y t o xic or i neffecti ve treat me nts o n t he o ne 
ha n d a n d t he nee d t o e x pl ore ge n der, racial, a n d et h nic as pects of cli nical researc h o n t he 
ot her. If differe nces i n o utc o me t hat c orrelate t o ge n der, racial, or et h nic i de ntit y are n ote d, 
accr ual ma y be e x pa n de d or a d diti o nal st u dies ma y be perf or me d t o i n vesti gate t h ose 
differe nces m ore f ull y. 
 
1 1. 5   
P h ar m ac o ki netic a n d C orrel ati ve St u dies a n d Res p o nse A n al ysis 
 
A descri pti ve a nal ysis of p har mac o ki netic ( P K) para meters of fl otet uz u ma b will be 
perf or me d t o defi ne s yste mic e x p os ure, dr u g cleara nce, a n d ot her p har mac o ki netic 
para meters. T he P K para meters will be s u m marize d wit h si m ple s u m mar y statistics, 
i ncl u di n g mea ns, me dia ns, ra n ges, a n d sta n dar d de viati o ns (if n u m bers a n d distri b uti o n 
per mit).   
 
W hile t he pri mar y ai m of t his st u d y is t o e val uate t he t o xicit y of fl otet uz u ma b, patie nts will 
ha ve disease e val uati o ns perf or me d as i n dicate d i n Secti o n 8. 1 .  Disease res p o nse will be 
assesse d acc or di n g t o t he re vise d A M L I nt er nati o nal W or ki n g Gr o u p (I W G) criteria 3 7 a n d 
w ill be re p orte d descri pti vel y. 
 
C D 1 2 3 e x pressi o n will be a nal yze d i n a n e x pl orat or y fas hi o n, b ot h usi n g a bi nar y scale 
a n d usi n g a c o nti n u o us scale t o e val uate w het her t here are c orrelati o ns bet wee n C D 1 2 3 
e x pressi o n a n d a ntit u m or effects. A nti- dr u g a nti b o d y a nal yses will be meas ur e d b y 
Macr o Ge nics. Bi o mar kers, i ncl u di n g t h ose i de ntifie d i n t he sec o n dar y o bjecti ves, will be 
e val uate d f or ass ociati o n wit h c yt o ge netic/ m olec ular feat ures a n d o utc o me.  
 
All t hese a nal yses will be descri pti ve a n d e x pl orat or y a n d h y p ot hesis- ge nerati n g i n nat ure. 
 
 
1 2. 0   
E V A L U A TI O N C RI T E RI A  
 
1 2. 1   
C o m m o n Ter mi n ol o g y Criteri a f or A d verse E ve nts ( C T C A E) 
T he descri pti o ns a n d gra di n g scales f o u n d i n t he re vise d N CI C o m m o n T er mi n ol o g y 
Criteria f or A d verse E ve nts ( C T C A E) versi o n 5. 0 will be utilize d f or A E re p orti n g.  All 
a p pr o priate treat me nt areas s h o ul d ha ve access t o a c o p y of t he C T C A E versi o n 5. 0.  A 
c o p y of t he 
C T C A E versi o n 5. 0 ca n be d o w nl oa de d fr o m t he 
C T E P 
we bsite 
(htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m ). 
 
 
 
1 2. 2   
Res p o nse Criteri a f or P atie nts wit h Le u ke mi a 
Patie nts m ust ha ve recei ve d > 1 c ycle of fl otet uz u ma b, be e val ua ble f or D L T, a n d ha ve ha d 
> 1 b o ne marr o w e val uati o n(s) f oll o wi n g treat me nt. Res p o nse will be defi ne d as best 
res p o nse after u p t o 4 c ycles. T he A M L res p o nse criteria are deri ve d fr o m t he re vise d A M L 
I nter nati o nal W or ki n g Gr o u p (I W G) Criteria. 3 8 It is a ntici pate d t hat patie nts w h o ac hie ve 
m or p h ol o gic re missi o n wit h st u d y treat me nt ma y pr ocee d t o s u bse q ue nt all o ge neic H S C T 
at t he treati n g p h ysicia n’s discreti o n.  
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 6 7  
 C o m plete Re mi ssi o n ( C R) 
Attai n me nt of a n M 1 b o ne marr o w ( < 5 % blasts) wit h n o e vi de nce of circ ulati n g 
blasts or e xtra me d ullar y disease a n d wit h rec o ver y of peri p heral bl o o d c o u nts 
( A N C ≥ 1 0 0 0/m m 3 a n d platelet c o u nt ≥ 1 0 0, 0 0 0/ m m 3). Occasi o nall y, rare 
peri p heral bl o o d blasts ma y be i de ntifie d d uri n g marr o w re ge nerati o n; h o we ver, 
t he marr o w m ust be M 1 stat us b y m or p h ol o g y a n d wit h o ut A uer r o ds t o be 
c o nsi dere d C R. Fl o w c yt o metr y ma y als o be usef ul t o disti n g uis h bet wee n 
le u ke mia a n d a re ge nerati n g b o ne marr o w. T here is n o re q uire me nt f or b o ne 
marr o w cell ularit y. 
 
 C R wit h Partial Rec o ver y of Platelet C o u nt ( C R p)  
Attai n me nt of a n M 1 b o ne marr o w ( < 5 % blasts), n o e vi de nce of circ ulati n g 
blasts or e xtra me d ullar y disease, a n d rec o ver y of A N C ≥ 1 0 0 0/ m m
3 a n d platelet 
tra nsf usi o n i n de pe n de nce ( defi ne d as n o platelet tra nsf usi o ns i n 1 wee k). 
 
 C R wit h i nc o m plete bl o o d c o u nt rec o ver y ( C Ri ) 
Attai n me nt of a n M 1 b o ne marr o w ( < 5 % blasts), n o e vi de nce of circ ulati n g 
blasts or e xtra me d ullar y disease a n d wit h A N C < 1 0 0 0/ m m
3 or platelet c o u nt < 
1 0 0, 0 0 0/ m m 3 wit h o ut platelet tra nsf usi o n i n de pe n de nce ( defi ne d as n o platelet 
tra nsf usi o ns i n 1 wee k). 
 
 Partial Res p o nse ( P R)  
A decrease of at least 5 0 % i n t he perce nta ge of blasts t o 5 % t o 2 5 % i n t he b o ne 
marr o w as pirate. B o ne marr o w m ust ha ve a de q uate cell ularit y (e. g., > 1 5 %) t o 
deter mi ne res p o nse. P R stat us will n ot be i ncl u de d i n calc ulati o n of res p o nse t o 
t he re gi me n. A re peat b o ne marr o w as pirati o n after se veral wee ks ma y be 
re q uire d t o disti n g uis h bet wee n a P R a n d i ncrease d blasts ca use d b y b o ne 
marr o w re ge nerati o n. A val ue of < 5 % blasts ma y als o be c o nsi dere d a P R if 
A uer r o ds are prese nt. 
 
 
 Pr o gressi ve Disease  ( P D) 
I ncrease i n t he a bs ol ute n u m ber of circ ulati n g (i n peri p heral bl o o d) or b o ne 
marr o w blasts of at least 5 0 % fr o m na dir or  de vel o p me nt of e xtra me d ullar y 
disease.  
 
 Sta ble Disease ( S D ) 
Criteria f or C R, C R p, C Ri, C Rc, P R, or pr o gressi ve disease ( P D) n ot met.  
 
 Rela pse  
M or p h ol o gic rela pse after C R/ C R p/ C Ri is defi ne d as a rea p peara nce of 
le u ke mic blasts i n t he peri p heral bl o o d or ≥ 5 % blasts i n t he b o ne marr o w n ot 
attri b uta ble t o a n y ot her ca use (e. g., b o ne 
marr o w re ge nerati o n after 
c o ns oli dati o n t hera p y). I n t he setti n g of rece nt treat me nt, if t here are n o 
circ ulati n g blasts a n d t he b o ne marr o w c o ntai ns 5 % t o 2 0 % blasts, a re peat b o ne 
marr o w perf or me d at least a wee k later is necessar y t o disti n g uis h rela pse fr o m 
b o ne marr o w re ge nerati o n. S h o ul d fl o w c yt o metric a nal yses s u g gest rela pse ( b y 
t he rea p peara nce of a si milar i m m u n o p he n ot y pe t o t he ori gi nal le u ke mia) i n t he 
prese nce of < 5 % blasts, or ≥ 5 % blasts i n a re ge nerati n g marr o w, a re peat b o ne 
marr o w(s) perf or me d at least a wee k later is necessar y t o c o nfir m rela pse b y 
m or p h ol o gic met h o ds. I n s uc h i nsta nces t he date of rec urre nce is defi ne d as t he 
first date t hat 
m ore t h a n 5 % blasts were o bser ve d i n t he 
marr o w. T he 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 6 8  
rea p peara nce or de vel o p me nt of c yt ol o gicall y pr o ve n e xtra me d ullar y disease 
als o i n dicates rela pse. M olec ular a n d/ or ge netic rela pse is c haracterize d b y 
rea p peara nce of a c yt o ge netics or m olec ular a b n or malit y.  
 
 U ne val ua ble  
A plastic or se verel y h y p ocell ular marr o w wit h a n y blast perce nta ge. I n t his 
i nsta nce, 
marr o w e val uati o n s h o ul d be re peate d 
wee kl y u ntil res p o nse 
deter mi nati o n ca n be ma de t hr o u g h at least Da y 4 9. 
 
 B o ne Marr o w Classificati o n:  
M 1 is < 5 % blasts 
M 2 is 5- 2 5 % blasts 
M 3 is > 2 5 % blasts  
 
 
1 2. 3   
C N S Le u ke mi a at Di a g n osis  
 
C N S 1:  I n cere bral s pi nal fl ui d ( C S F), a bse nce of blasts o n c yt os pi n 
pre parati o n, re gar dless of t he n u m ber of W B Cs.  
C N S 2:   I n C S F, prese nce < 5/L W B Cs a n d c yt os pi n p ositi ve f or blasts, or 
≥ 5/ L W B Cs b ut ne gati ve b y Stei n herz/ Ble yer al g orit h m:  
C N S 2a:  < 1 0/ L R B Cs; < 5/ L W B Cs a n d c yt os pi n p ositi ve f or blasts;  
C N S 2 b:  ≥ 1 0/ L R B Cs; < 5/ L W B Cs a n d c yt os pi n p ositi ve f or blasts;  
C N S 2c: 
  
 
≥ 1 0/ L R B Cs; ≥ 5/ L W B Cs a n d c yt os pi n p ositi ve f or blasts , b ut 
ne gati ve b y Stei n herz/ Ble yer al g orit h m  (see bel o w). 
C N S 3:  I n C S F, prese nce of ≥ 5/ µ L W B Cs a n d c yt os pi n p ositi ve f or blasts 
a n d/ or cli nical si g ns of C N S le u ke mia:  
C N S 3a:  < 1 0/ L R B Cs; ≥ 5/ µ L W B Cs a n d c yt os pi n p ositi ve f or blasts;  
C N S 3 b:  ≥ 1 0/ µ L R B Cs, ≥ 5/ µ L 
W B Cs a n d p ositi ve b y Stei n herz/ Ble yer 
al g orit h m (see bel o w); 
C N S 3c: 
  
 
Cli nical si g ns of C N S le u ke mia (s uc h as facial ner ve pals y, brai n/e ye 
i n v ol ve me nt or h y p ot hala mic s y n dr o me). 
 
Met h o d of E val uati n g I nitial Tra u matic L u m bar P u nct ures:  
If t he patie nt has le u ke mic cells i n t he peri p heral bl o o d a n d t he l u m bar p u nct ure is 
tra u matic a n d c o ntai ns  5 W B C/L a n d b lasts, t he f oll o wi n g al g orit h m s h o ul d be use d t o 
disti n g uis h bet wee n C N S 2 a n d C N S 3 disease: 
 
C S F W B C   > 2 X   Bl o o d W B C 
C S F R B C               Bl o o d R B C 
A patie nt wit h C S F W B C  5/ L blasts, w h ose C S F W B C/ R B C is 2 X greater t ha n t he bl o o d 
W B C/ R B C rati o, has C N S disease at dia g n osis. E xa m ple: C S F W B C = 6 0/ L; C S F R B C = 
1 5 0 0/ L; bl o o d W B C = 4 6 0 0 0/ L; bl o o d R B C = 3. 0 X 1 0 6/L:  
  6 0    = 0. 0 4  >  2 X     4 6, 0 0 0      = 0. 0 1 5 
1, 5 0 0                          3. 0 X 1 0 6 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 6 9  
1 3. 0   
A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S 
 
A d verse e ve nt data c ollecti o n a n d re p orti n g w hic h are re q uire d as part of e ver y cli nical trial, are 
d o ne t o e ns ure t he safet y of patie nts e nr olle d i n t he st u dies as well as t h ose w h o will e nr oll i n f ut ure 
st u dies usi n g si milar a ge nts.  A d verse e ve nts are re p orte d i n a r o uti ne ma n ner at sc he d ule d ti mes 
d uri n g a trial.  ( Please f oll o w directi o ns f or r o uti ne re p orti n g pr o vi de d i n t he Case Re p ort F or ms 
f or t his pr ot oc ol).  A d diti o nall y, certai n a d verse e ve nts m ust be re p orte d i n a n e x pe dite d ma n ner t o 
all o w f or o pti mal m o nit ori n g of patie nt safet y a n d care.  T he f oll o wi n g secti o ns pr o vi de i nf or mati o n 
a b o ut e x pe dite d re p orti n g. 
 
 
Re p orti n g re q uire me nts ma y i ncl u de t he f oll o wi n g c o nsi derati o ns: 1) w het her t he patie nt has 
recei ve d a n i n vesti gati o nal or c o m mercial a ge nt; 2) w het her t he a d verse e ve nt is c o nsi dere d seri o us; 
3 ) the gra de (se verit y); a n d 4) w het her or n ot h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n was 
ass ociate d wit h t he e ve nt. 
 
A n i n vesti gati o nal a ge nt is a pr ot oc ol dr u g a d mi nistere d u n der a n I n vesti gati o nal Ne w Dr u g 
A p plicati o n (I N D).  I n s o me i nsta nces, t he i n vesti gati o nal a ge nt ma y be a vaila ble c o m merciall y, 
b ut is act uall y bei n g teste d f or i n dicati o ns n ot i ncl u de d i n t he a p pr o ve d pac ka ge la bel. 
 
C o m mercial a ge nts are t h ose a ge nts n ot pr o vi de d u n der a n I N D b ut o btai ne d i nstea d fr o m a 
c o m mercial s o urce.  T he N CI, rat her t ha n a c o m mercial distri b ut or, ma y o n s o me occasi o ns 
distri b ute c o m mercial a ge nts f or a trial. 
 
1 3. 1   
Ste ps t o Deter mi ne If a n A d verse E ve nt Is T o Be Re p o rte d I n a n E x pe dite d M a n ner 
 
Ste p 1: I de ntif y t he t y pe of a d verse e ve nt usi n g t he N CI C T C A E versi o n 5 . 0.  T he 
descri pti o ns a n d gra di n g scales f o u n d i n t he re vise d C T C A E versi o n 5. 0 will be 
use d f or A E re p orti n g. All a p pr o priate treat me nt areas s h o ul d ha ve access t o a c o p y 
of t he C T C A E versi o n 5. 0.  A c o p y of t he C T C A E versi o n 5. 0 ca n be d o w nl oa de d 
fr o m t he C T E P we bsite (htt p://cte p.ca ncer. g o v ). 
 
Ste p 2:  Gra de t he a d verse e ve nt usi n g t he N CI C T C A E. 
 
Ste p 3:  Re vie w T a ble A i n t his secti o n t o deter mi ne if: 
 
t he a d verse e ve nt is c o nsi dere d seri o us; 
 
t here are a n y pr ot oc ol-s pecific re q uire me nts f or e x pe dite d re p orti n g of s pecific 
a d verse e ve nts t hat re q uire s pecial m o nit ori n g; a n d/ or 
 
t here are a n y pr ot oc ol-s pecific e xce pti o ns t o t he re p orti n g re q uire me nts.  
 
N O T E:  T his i ncl u des all e ve nts t hat occ ur wit hi n 3 0 da ys of t he last d ose of 
pr ot oc ol treat me nt.  A n y e ve nt t hat occ urs m ore t ha n 3 0 da ys after t he 
last d ose of treat me nt a n d is attri b ute d ( p ossi bl y, pr o ba bl y, or defi nitel y) 
t o t he a ge nt(s) m ust als o be re p orte d acc or di n g t o t he i nstr ucti o ns i n t he 
ta ble bel o w. Attri b uti o n cate g ories are as f oll o ws: U nrelate d, U nli kel y, 
P ossi ble, Pr o ba ble, a n d Defi nite. 
 
T a ble A: P h ase 1 a n d E arl y P h ase 2 St u dies:  E x pe dite d Re p orti n g Re q uire me nts f or A d verse E ve nts 
t h at Occ ur o n St u dies u n der a n I N D/I D E wit hi n 3 0 D a ys of t he L ast A d mi nistr ati o n of t he 
I n vesti g ati o n al A ge nt/I nter ve nti o n 1, 2 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 7 0  
F D A R E P O R TI N G R E Q UI R E M E N T S F O R S E RI O U S A D V E R S E E V E N T S ( 2 1 C F R P art 3 1 2)  
N O T E:   I n v e sti g at or s M U S T  i m m e di at el y r e p ort t o t h e s p o n s or A N Y S eri o u s A d v er s e E v e nt s, w h et h er or n ot t h e y 
ar e c o n si d er e d r el at e d t o t h e i n v e sti g ati o n al a g e nt( s)/i nt er v e nti o n ( 2 1 C F R 3 1 2. 6 4)  
A n a d v er s e e v e nt i s c o n si d er e d s eri o u s if it r e s ult s i n A N Y  of t h e f oll o wi n g o ut c o m e s:   
1)  
D e at h  
2)  
A lif e -t hr e at e ni n g a d v er s e e v e nt  
3)  
A n a d v er s e e v e nt t h at r e s ult s i n i n p ati e nt h o s pit ali z ati o n or pr ol o n g ati o n of e xi sti n g h o s pit ali z ati o n f or ≥ 2 4 
h o ur s  
4)  
A p er si st e nt or si g nifi c a nt i n c a p a cit y or s u b st a nti al di sr u pti o n of t h e a bilit y t o c o n d u ct n or m al lif e f u n cti o n s  
5)  
A c o n g e nit al a n o m al y/ birt h d ef e ct.  
6)  
I m p ort a nt M e di c al E v e nt s (I M E) t h at m a y n ot r e s ult i n d e at h, b e lif e t hr e at e ni n g, or r e q uir e h o s pit ali z ati o n m a y 
b e c o n si d er e d s eri o u s w h e n, b a s e d u p o n m e di c al j u d g m e nt, t h e y m a y j e o p ar di z e t h e p ati e nt or s u bj e ct a n d 
m a y r e q uir e m e di c al or s ur gi c al i nt er v e nti o n t o pr e v e nt o n e of t h e o ut c o m e s li st e d i n t hi s d efi niti o n. ( F D A, 2 1 
C F R 3 1 2. 3 2; I C H E 2 A a n d I C H E 6).  
A L L  S E RI O U S  a d v er s e e v e nt s t h at m e et t h e a b o v e crit eri a M U S T b e i m m e di at el y r e p ort e d vi a C T E P -A E R S  wit hi n 
t h e ti m efr a m e s d et ail e d i n t h e t a bl e b el o w. 
H o s pit ali z ati o n  
Gr a d e 1 a n d Gr a d e 2 Ti m efr a m e s  
Gr a d e 3 -5  
Ti m efr a m e s  
R e s ulti n g i n 
H o s pit ali z ati o n       ≥ 
2 4 hr s  
7  C al e n d ar D a y s  
2 4 -H o ur 5 C al e n d ar 
D a y s  
N ot r e s ulti n g i n 
H o s pit ali z ati o n       ≥ 
2 4 hr s  
N ot r e q uir e d  
N O T E:   Pr ot o c ol s p e cifi c e x c e pti o n s t o e x p e dit e d r e p orti n g of s eri o u s a d v er s e e v e nt s ar e f o u n d b el o w u n d er t h e 
s e cti o n e ntitl e d “ A d diti o n al I n str u cti o n s or E x c e pti o n s” . 
E x p e dit e d A E r e p orti n g ti m eli n e s ar e d efi n e d a s:  
o  “ 2 4-H o ur; 5 C al e n d ar D a y s” - T h e A E m u st i niti all y b e r e p ort e d vi a C T E P -A E R S  wit hi n 2 4 h o ur s of 
l e ar ni n g of t h e A E, f oll o w e d b y a c o m pl et e e x p e dit e d r e p ort wit hi n 5 c al e n d ar d a y s of t h e i niti al 2 4-
h o ur r e p ort.  
o   
“ 7 C al e n d ar D a y s” - A c o m pl et e e x p e dit e d r e p or t o n t he A E m u st b e s u b mitt e d wit hi n 7  c al e n d ar d a y s 
of l e ar ni n g of t h e A E.  
1 S eri o u s a d v er s e e v e nt s t h at o c c ur 
m or e t h a n 3 0 d a y s aft er t h e l a st a d mi ni str ati o n of i n v e sti g ati o n al 
a g e nt/i nt er v e nti o n a n d h a v e a n attri b uti o n of p o s si bl e, pr o b a bl e, or d efi nit e r e q uir e r e p orti n g a s f oll o w s:  
E x p e dit e d 2 4 -h o ur n otifi c ati o n f oll o w e d b y c o m pl et e r e p ort wit hi n 5 c al e n d ar d a y s f or:  
 All Gr a d e 3, 4, a n d Gr a d e 5 A E s  
E x p e dit e d 7  c al e n d ar d a y r e p ort s f or:  
 Gr a d e 2 A E s r e s ulti n g i n h o s pit ali z ati o n or pr ol o n g ati o n of h o s pit ali z ati o n  
2  F or st u di e s u si n g P E T or S P E C T I N D a g e nt s, t h e A E r e p orti n g p eri o d i s  li mit e d t o 1 0 r a di o a cti v e h alf-li v e s, 
r o u n d e d U P t o t h e n e ar e st w h ol e d a y, aft er t h e a g e nt/i nt er v e nti o n w a s l a st a d mi ni st er e d.  F o ot n ot e “ 1” a b o v e 
a p pli e s aft er t hi s r e p orti n g p eri o d.  
E ff e cti v e D at e:  M a y 5, 2 0 1 1 
 
 
T he N CI defi nes h os pitalizati o n f or e x pe dite d A E re p orti n g p ur p oses as a n i n patie nt h os pital sta y 
e q ual t o or greater t ha n 2 4 h o urs. H os pitalizati o n is use d as a n i n dicat or  of t he seri o us ness of t he 
A E a n d s h o ul d O N L Y be use d f or sit uati o ns w here t he A E tr ul y fits t his defi niti o n a n d N O T f or 
h os pitalizati o ns ass ociate d wit h less seri o us e ve nts (i.e., a h os pital visit w here a patie nt is a d mitte d 
f or o bser vati o n or mi n or treat me nt s uc h as h y drati o n a n d release d i n less t ha n 2 4 h o urs). 
F urt her m ore, h os pitalizati o n f or p har mac o ki netic sa m pli n g is n ot a n A E a n d t heref ore is n ot t o be 
re p orte d eit her as a r o uti ne A E or i n a n e x pe dite d re p ort.  
 
 
A n y me dical e ve nt e q ui vale nt t o C T C A E gra de 3, 4, or 5 t hat preci pitates h os pitalizati o n ( o r 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 7 1  
pr ol o n gati o n of e xisti n g h os pitalizati o n) m ust be re p orte d re gar dless of attri b uti o n a n d desi g nati o n 
as e x pecte d or u ne x pecte d wit h t he e xce pti o n of a n y e ve nts i de ntifie d as pr ot oc ol-s pecific 
e x pe dite d a d verse e ve nt re p orti n g e xcl usi o ns. 
 
 
A n y e ve nt t hat res ults i n persiste nt or si g nifica nt disa bilities/i nca pacities, c o n ge nital a n o malies, or 
birt h defects m ust be re p orte d via C T E P- A E R S if t he e ve nt occ urs f oll o wi n g treat me nt wit h a n 
a ge nt u n der a C T E P I N D. 
 
 
Use t he N CI pr ot oc ol n u m ber a n d t he pr ot oc ol-s pecific patie nt I D pr o vi de d d uri n g trial re gistrati o n 
o n all re p orts. 
 
A d diti o nal I nstr ucti o ns or E xce pti o ns t o C T E P- A E R S E x pe dite d Re p orti n g Re q uire me nts f or P hase 1 
Trials Utilizi n g a n A ge nt u n der a C T E P-I N D or N o n- C T E P I N D: 
 
 A n y deat h t hat occ urs m ore t ha n 3 0 da ys after t he last d ose of treat me nt wit h a n i n vesti gati o nal 
a ge nt w hic h ca n be attri b ute d ( p ossi bl y, pr o ba bl y, or defi nitel y) t o t he a ge nt a n d is n ot clearl y d ue 
t o pr o gressi ve disease m ust be re p orte d via C T E P- A E R S f or a n a ge nt u n der a C T E P or n o n- C T E P 
I N D a ge nt per t he ti meli nes o utli ne d i n t he ta ble a b o ve. 
 
 M yel os u p pressi o n, ( Gra de 1 t hr o u g h Gra de 4 a d verse e ve nts as defi ne d i n t he ta ble bel o w), d oes 
n ot re q uire e x pe dite d re p orti n g, u nless it is ass ociate d wit h h os pitalizati o n. 
C at e g or y 
A d verse E ve nts  
I N V E S TI G A TI O N S 
Platelet c o u nt decrease d  
I N V E S TI G A TI O N S 
W hite bl o o d cell decrease d  
I N V E S TI G A TI O N S 
N e utr o p hil c o u nt decrease d  
I N V E S TI G A TI O N S 
L y m p h oc yte c o u nt decrease d  
B L O O D/ L Y M P H A TI C S DI S O R D E R S   
A ne mia  
 
 
As refere nce d i n t he C T E P A d verse E ve nts Re p orti n g Re q uire me nts, a n A E t hat res ol ves a n d t he n rec urs 
d uri n g a s u bse q ue nt c ycle d oes n ot re q uire C T E P- A E R S re p orti n g u nless ( 1) t he Gra de i ncreases; or ( 2) 
h os pitalizati o n is ass ociate d wit h t he rec urri n g A E. 
 
1 3. 2   
W he n t o Re p ort a n E ve nt i n a n E x pe dite d M a n ner  
 
 
S o me a d verse e ve nts re q uire n otificati o n wit hi n 2 4 h o urs  (refer t o Ta ble A) t o N CI via 
t he we b at htt p://cte p.ca ncer. g o v  (tele p h o ne C T E P at: 3 0 1- 8 9 7- 7 4 9 7  wit hi n 2 4 h o urs of 
bec o mi n g a ware of t he e ve nt if t he C T E P- A E R S 2 4- H o ur N otificati o n we b- base d 
a p plicati o n is u na vaila ble) a n d b y tele p h o ne call t o t he St u d y C hair. O nce i nter net 
c o n necti vit y is rest ore d, a 2 4- h o ur n otificati o n p h o ne d i n m ust be e ntere d electr o nicall y 
i nt o C T E P- A E R S b y t he ori gi nal s u b mitter at t he site. 
 
 
W he n t he a d verse e ve nt re q uires e x pe dite d re p orti n g, s u b mit t he re p ort wit hi n 5 or 7 
c ale n d ar d a ys  of lear ni n g of t he e ve nt (refer t o T a ble A). 
 
 
E x pe di te d A E re p orti n g f or t his st u d y m ust o nl y use C T E P- A E R S ( A d verse E ve nt 
E x pe dite d Re p orti n g S yste m), accesse d via t he C T E P h o me pa ge htt ps://ea p ps-
cte p. nci. ni h. g o v/cte paers . 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 7 2  
1 3. 3   
E x pe dite d Re p orti n g Met h o ds  
 C T E P -A E R S  Re p orti n g  
T o re p ort a d verse e ve nts i n a n e x pe dite d fas hi o n use t he N CI’s A d verse E ve nt 
E x pe dite d 
Re p orti n g 
S yste m ( C T E P- A E R S) t hat 
ca n 
be f o u n d 
at 
htt p://cte p.ca ncer. g o v . 
A C T E P- A E R S re p ort m ust be s u b mitte d electr o nicall y via t he C T E P- A E R S 
We b - base d a p plicati o n l ocate d at htt ps://ea p ps-cte p. nci. ni h. g o v/cte paers/ .  If 
pr o m pte d 
t o 
e nter 
a 
s p o ns or 
e mail 
a d dress,  
please 
t y pe 
i n: 
P E P C T N A E R S @c hil dre ns o nc ol o g y gr o u p. or g . 
Se n d s u p p orti n g d oc u me ntati o n t o t he C O G P E P- C T N b y fa x (fa x # 3 1 0 - 6 4 0-
9 1 9 3) a n d b y e mail t o t he St u d y Assi g ne d Researc h C o or di nat or.  A L W A Y S 
i ncl u de t he tic ket n u m ber o n all f a xe d a n d e m aile d d oc u me nts. 
 
1 3. 4   
Defi niti o n of O nset a n d Res ol uti o n of A d verse E ve nts 
N ote:  
T hese g ui deli nes bel o w are f or re p orti n g a d verse e ve nts o n t he C O G P E P - C T N 
case re p ort f or ms a n d d o n ot alter t he g ui deli nes f or C T E P- A E R S re p orti n g. 
 If a n a d verse e ve nt occ urs m ore t ha n o nce i n a c o urse (c ycle) of t hera p y o nl y 
t he m ost se vere gra de of t he e ve nt s h o ul d be re p orte d. 
 If a n a d verse e ve nt pr o gresses t hr o u g h se veral gra des d uri n g o ne c o urse of 
t hera p y, o nl y t he m ost se vere gra de s h o ul d be re p orte d. 
 T he d urati o n of t he A E is defi ne d as t he d urati o n of t he hi g hest ( m ost se vere) 
gra de of t he A d verse Effects.  
 T he res ol uti o n date of t he A E is defi ne d as t he date at w hic h t he A E ret ur ns t o 
baseli ne  or less t ha n o r e q ual t o Gra de 1, w hic he ver le vel is hi g her  ( n ote t hat 
the res ol uti o n date ma y t heref ore be differe nt fr o m t he date at w hic h t he gra de 
of t he A E decrea se d fr o m its hi g hest gra de).  If t he A E d oes n ot ret ur n t o 
baseli ne t he res ol uti o n date s h o ul d be rec or de d as " o n g oi n g."   
 A n a d verse e ve nt t hat persists fr o m o ne c o urse t o a n ot her s h o ul d o nl y be 
re p orte d o nce u nless t he gra de bec o mes m ore se vere i n a s u bse q ue nt c o urse. 
A n a d verse e ve nt w hic h res ol ves a n d t he n rec urs d uri n g a differe nt c o urse, 
m ust be re p orte d eac h c o urse it rec urs.  
 
1 3. 5   
Ot her Reci pie nts of A d verse E ve nt Re p orts 
 
 E ve nts t hat d o n ot meet t he criteria f or C T E P -A E R S  re p orti n g (Sec ti o n 1 3. 2) 
s h o ul d be re p orte d at t he e n d of eac h c ycle usi n g t he f or ms pr o vi de d i n t he 
C R F  pac ket ( See Se cti o n 1 4. 1 ). 
 
 C O G will f or war d re p orts a n d s u p p orti n g d oc u me ntati o n t o t he St u d y C hair, 
t o t he F D A ( w he n C O G h ol ds t he I N D) a n d t o t he p har mace utical c o m pa n y 
(f or i n d ustr y s p o ns ore d trials). 
 
 A d verse e ve nts deter mi ne d t o be re p orta ble m ust als o be re p orte d acc or di n g t o 
t he l ocal p olic y a n d pr oce d ures t o t he I nstit uti o nal Re vie w B oar d res p o nsible 
f or o versi g ht of t he patie nt. 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 7 3  
1 3. 6   
Sec o n d ar y M ali g n a nc y:  
 
A sec o n d ary m ali g n a ncy is a ca ncer ca use d b y treat me nt f or a pre vi o us mali g na nc y (e. g., 
treat me nt wit h i n vesti gati o nal a ge nt/i nter ve nti o n, ra diati o n or c he m ot hera p y). A sec o n dar y 
mali g na nc y is n ot c o nsi dere d a metastasis of t he i nitial ne o plas m.  
C T E P re q uires all sec o n dar y mali g na ncies t hat occ ur f oll o wi n g treat me nt wit h a n a ge nt 
u n der a n N CI I N D/I D E b e re p orte d via C T E P- A E R S. T hree o pti o ns are a vaila ble t o 
descri be t he e ve nt:  
1) 
Le u ke mia sec o n dar y t o o nc ol o g y c he m ot hera p y (e. g., ac ute 
m yel oc ytic 
le u ke mia [ A M L])  
2)  
M yel o d ys plastic s y n dr o me ( M D S)  
3) 
Treat me nt-relate d sec o n dar y mali g na nc y.  
 
A n y mali g na nc y p ossi bl y relate d t o ca ncer treat me nt (i ncl u di n g A M L/ M D S) s h o ul d als o 
be re p orte d via t he r o uti ne re p orti n g mec ha nis ms o utli ne d i n eac h pr ot oc ol. 
Sec o n d M ali g n a nc y :  
A sec o n d m ali g n a ncy is o ne u nrelate d t o t he treat me nt of a pri or mali g na nc y (a n d is 
N O T a metastasis fr o m t he i nitial mali g na nc y).  Sec o n d mali g na ncies re q uire O N L Y 
r o uti ne re p orti n g via C D U S u nless ot her wise s pecifie d. 
 
1 3. 7   
Re p orti n g P re g n a nc y, Fet al De at h, a n d De at h Ne o n at al 
W he n s u b mitti n g C T E P- A E R S re p orts f or “ Pre g na nc y”, “ Pre g na nc y l oss”, or “ Ne o natal 
l oss”, t he Pre g na nc y I nf or mati o n F or m s h o ul d be c o m plete d a n d e maile d t o t he St u d y 
Assi g ne d Researc h C o or di nat or al o n g wit h a n y a d diti o nal me dical i nf or mati o n al o n g wit h 
a n y a d diti o nal me dical i nf or mati o n. T he p ote ntial ris k of e x p os ure of t he fet us t o t he 
i n vesti gati o nal a ge nt s h o ul d be d oc u me nte d i n t he “ Descri pti o n of E ve nt” secti o n of t he 
C T E P- A E R S re p ort. 
 
 Pre g na nc y  
 
Patie nts w h o bec o me pre g na nt o n st u d y ris k i ntra uteri ne e x p os ure of t he 
fet us t o a ge nts w hic h ma y be terat o ge nic. F or t his reas o n, pre g na nc y 
occ urri n g o n st u d y or wit hi n 6 m o nt hs f oll o wi n g t he last d ose of st u d y 
t hera p y s h o ul d be re p orte d i n a n e x pe dite d ma n ner via C T E P- A E R S as 
Gr a de 3  “ Pre g n a ncy, p uer peri u m a n d peri n at al c o n diti o ns - Ot her 
( Pre g n a ncy)” u n der t he 
“ Pre g n a ncy, p uer peri u m a n d peri n at al 
c o n diti o ns ”  S yste m Or g a n Cl ass (S O C ). 
 
 
Pre g na nc y s h o ul d be f oll o we d u ntil t he o utc o me is k n o w n. If t he ba b y is 
b or n wit h a birt h defect or a n o mal y, t he n a sec o n d C T E P- A E R S re p ort is 
re q uire d. 
 
 Pre g na nc y L oss ( Fetal Deat h)  
 
Pre g na nc y l oss is defi ne d i n C T C A E as “ Deat h i n uter o.” 
 
 
A n y pre g na nc y l oss s h o ul d be re p orte d e x pe diti o usl y, as 
Gr a de 4  
“ Pre g n a ncy l oss ”  u n der t he “ Pre g n a ncy, p uer peri u m a n d peri n at al 
c o n diti o ns ”  S O C. D o N O T re p ort a pre g na nc y l oss as a Gra de 5 e ve nt 
si nce C T E P- A E R S rec o g nizes a n y Gra de 5 e ve nt as a patie nt deat h. 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 7 4  
 Deat h Ne o natal  
 
Ne o natal deat h, defi ne d i n C T C A E as “ Ne w b or n de at hs occ urri n g d uri n g 
t he first 2 8 d ays after birt h ” t hat is felt b y t he i n vesti gat or t o be at least 
p ossi bl y d ue t o t he i n vesti gati o nal a ge nt/i nter ve nti o n, s h o ul d be re p orte d 
e x pe diti o usl y. 
 
 
A ne o natal deat h s h o ul d be re p orte d e x pe diti o usl y as Gra de 4 ” Deat h 
ne o natal” u n der t he “ Ge neral dis or ders a n d a d mi nistrati o n” S O C w he n 
t he de at h is t he res ult of a p atie nt pre g n a nc y or pre g n a nc y i n p art ners 
of me n o n st u d y  
 
 
D o N O T re p ort a ne o natal deat h res ulti n g fr o m a patie nt pre g na nc y or 
pre g na nc y i n part ners of me n as a Gra de 5 e ve nt si nce C T E P- A E R S 
rec o g nizes a n y Gra de 5 e ve nt as a patie nt deat h.  
 
Pre g na nc y s h o ul d be f oll o we d u p u ntil t he o utc o me of t he pre g na nc y is k n o w n at 
i nter vals dee me d a p pr o priate b y her p h ysicia ns. T he “ Pre g na nc y I nf or mati o n 
F or m” s h o ul d be use d f or all necessar y f oll o w- u ps. T his f or m is a vaila ble at 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ d ocs/ Pre g na
nc y Re p ort F or m. p df .  
 
 
1 4. 0   
R E C O R D S, R E P O R TI N G, A N D D A T A A N D S A F E T Y M O NI T O RI N G P L A N 
 
1 4. 1   
C ate g ories of Rese arc h Rec or ds  
Researc h rec or ds f or t his st u d y ca n be di vi de d i nt o t hree cate g ories: 
 
1.   
N o n-c o m p uterize d I nf or mati o n: T hera p y Deli ver y 
Ma ps, Pat h ol o g y Re p orts, 
S ur gical Re p orts. T hese f or ms are u pl oa de d i nt o R A V E. 
 
2.   
Refere nce La bs, Bi o pat h ol o g y Re vie ws, a n d I ma gi n g Ce nter data: T hese data 
acc o m pa n y s u b missi o ns t o t hese ce nters, w hic h f or war d t heir data electr o nicall y 
t o t he P E P - C T N O perati o ns a n d Data/ Statistics Ce nter. 
 
3.   
C o m p uterize d I nf or mati o n Electr o nicall y S u b mitte d: All ot her data will be e ntere d 
i n R A V E wit h t he ai d of sc he d ules a n d w or ks heets (esse ntiall y pa per c o pies of t he 
O P E N a n d R A V E scree ns) pr o vi de d i n t he case re p ort f or m ( C R F) pac ket. 
 
See se parate C R F  Pac ket, w hic h i ncl u des s u b missi o n sc he d ule. 
 
1 4. 2   
C D U S  
T his st u d y will be m o nit ore d b y t he Cli nical Data U p date S yste m ( C D U S) versi o n 3. 0. 
C u m ulati ve pr ot oc ol- a n d patie nt-s pecific C D U S data will be s u b mitte d electr o nicall y t o 
C T E P o n a q uarterl y basis.  Re p orts are d ue Ja n uar y 3 1, A pril 3 0, J ul y 3 1 a n d Oct o ber 3 1.  
T his is n ot a res p o nsi bilit y of i nstit uti o ns partici pati n g i n t his trial. I nstr ucti o ns f or 
s u b mitti n g data usi n g t he C D U S ca n be f o u n d o n t he C T E P we b site: 
htt p://cte p.ca ncer. g o v/re p orti n g/c d us. ht ml   
 
 
1 4. 3   
D at a a n d S afet y M o nit ori n g Pl a n 
Data a n d safet y is e ns ure d b y se veral i nte grate d c o m p o ne nts i ncl u di n g t he C O G P E P -

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 7 5  
C T N Data a n d Safet y M o nit ori n g C o m mittee. 
 
 Data a n d Safet y M o nit ori n g C o m mittee  
T his st u d y will be m o nit ore d i n acc or da nce wit h t he C O G P E P - C T N p olic y f or 
data a n d safet y m o nit ori n g of P hase 1 a n d 2 st u dies. I n brief, t he r ole of t he 
C O G P E P - C T N Data a n d Safet y 
M o nit ori n g C o m mittee is t o pr otect t he 
i nterests of patie nts a n d t he scie ntific i nte grit y f or all P hase 1 a n d 2 st u dies. T he 
D S M C c o nsists of a c hair; a statisticia n e xter nal t o C O G; o ne e xter nal me m ber; 
o ne c o ns u mer re prese ntati ve; t he lea d statisticia n of t he P E P - C T N scie ntific 
c o m mittee; a n d a me m ber fr o m t he N CI. T he D S M C me ets at least e ver y 6 
m o nt hs t o re vie w c urre nt st u d y res ults, as well as data a vaila ble t o t he D S M C 
fr o m ot her relate d st u dies. A p pr o xi matel y 6 wee ks bef ore eac h meeti n g of t he 
P hase 1 a n d 2 D S M C, st u d y c hairs will be res p o nsi ble f or w or ki n g wit h t he 
st u d y statisticia n t o pre pare st u d y re p orts f or re vie w b y t he D S M C. T he D S M C 
will pr o vi de rec o m me n dati o ns t o t he P E P - C T N C hair a n d t he Gr o u p C hair f or 
eac h st u d y re vie we d t o c ha n ge t he st u d y or t o c o nti n ue t he st u d y u nc ha n ge d. 
Data a n d Safet y C o m mittee re p orts f or i nstit uti o nal re vie w b oar ds ca n be 
pre pare d usi n g t he p u blic data m o nit ori n g re p ort as p oste d o n t he C O G P E P -
C T N We b site.  
 
 M o nit ori n g b y t he St u d y C hair a n d De vel o p me ntal T hera pe utics Lea ders hi p  
T he st u d y c hair will m o nit or t he st u d y re g ularl y a n d e nt er e val uati o ns of 
patie nts’ eli gi bilit y, e val ua bilit y, a n d d ose li miti n g t o xicities i nt o t he st u d y 
data base. I n a d diti o n, st u d y data a n d t he st u d y c hair’s e val uati o ns will be 
re vie we d b y t he P E P - C T N C hair, Vice C hair a n d Statisticia n o n a wee kl y 
c o nfere nce call. 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 7 6  
R E F E R E N C E S 
1.   
R u b nitz J E: H o w I treat pe diatric ac ute m yel oi d le u ke mia. Bl o o d 1 1 9: 5 9 8 0- 5 9 8 8, 2 0 1 2 
2.   
R ossi D L, R ossi E A, Car dill o T M, et al: A ne w class of bis pecific a nti b o dies t o re direct T cells f or 
ca ncer i m m u n ot hera p y. M A bs 6: 3 8 1- 9 1, 2 0 1 4 
3.  
M o ore P A, Z ha n g W, Rai ne y GJ, et al: A p plicati o n of d ual affi nit y retar geti n g m olec ules t o ac hie ve 
o pti mal re directe d T-cell killi n g of B-cell l y m p h o ma. Bl o o d 1 1 7: 4 5 4 2- 5 1, 2 0 1 1 
4.   
Testa U, Pel osi E, Fra n kel A: C D 1 2 3 is a me m bra ne bi o mar k er a n d a t hera pe utic tar get i n 
he mat ol o gic mali g na ncies. Bi o mar k Res 2: 4, 2 0 1 4 
5.   
Ver gez F, Gree n A S, Ta m b uri ni J, et al: Hi g h le vels of C D 3 4 + C D 3 8l o w/- C D 1 2 3 + blasts are 
pre dicti ve of a n a d verse o utc o me i n ac ute m yel oi d le u ke mia: a Gr o u pe O uest- Est des Le uce mies 
Ai g ues et Mala dies d u Sa n g ( G O E L A M S) st u d y. Hae mat ol o gica 9 6: 1 7 9 2- 8, 2 0 1 1 
6.   
A n geli ni D F, Ott o ne T, G uerrera G, et al: A Le u ke mia- Ass ociate d C D 3 4/ C D 1 2 3/ C D 2 5/ C D 9 9 + 
I m m u n o p he n ot y pe I de ntifies F L T 3- M utate d Cl o nes i n Ac ute M yel oi d Le u ke mia. Cli n Ca ncer R es 
2 1: 3 9 7 7- 8 5, 2 0 1 5 
7.   
Graf M, Hec ht K, Reif S, et al: E x pressi o n a n d pr o g n ostic val ue of he m o p oietic c yt o ki ne rece pt ors 
i n ac ute m yel oi d le u ke mia ( A M L): i m plicati o ns f or f ut ure t hera pe utical strate gies. E ur J Hae mat ol 
7 2: 8 9- 1 0 6, 2 0 0 4 
8.   
B o n net D, Dic k J E: H u ma n ac ute m yel oi d le u ke mia is or ga nize d as a hierarc h y t hat ori gi nates fr o m 
a pri miti ve he mat o p oietic cell. Nat Me d 3: 7 3 0- 7, 1 9 9 7 
9.   
J or da n C T, U pc h urc h D, Szil vass y SJ, et al: T he i nterle u ki n- 3 rece pt or al p ha c hai n is a u ni q ue 
mar ker f or h u ma n ac ute m yel o ge n o us le u ke mia ste m cells. Le u ke mia 1 4: 1 7 7 7- 8 4, 2 0 0 0 
1 0.   
Ji n L, Lee E M, Ra ms ha w H S, et al: M o n ocl o nal a nti b o d y- me diate d tar geti n g of C D 1 2 3, I L- 3 
rece pt or al p ha c hai n, eli mi nates h u ma n ac ute m yel oi d le u ke mic ste m cells. Cell Ste m Cell 5: 3 1-
4 2, 2 0 0 9 
1 1.   
K o vt u n Y, J o nes G E, A da ms S, et al: A C D 1 2 3-tar geti n g a nti b o d y- dr u g c o nj u gate, I M G N 6 3 2, 
desi g ne d t o era dicate A M L w hile s pari n g n or mal b o ne marr o w cells. Bl o o d A d v 2: 8 4 8- 8 5 8, 2 0 1 8 
1 2.  
Al - H ussai ni M, Retti g M P, Ritc he y J K, et al: T ar geti n g C D 1 2 3 i n ac ute m yel oi d le u ke mia usi n g a 
T-cell- directe d d ual-affi nit y retar geti n g platf or m. Bl o o d 1 2 7: 1 2 2- 3 1, 2 0 1 6 
1 3.   
B usfiel d SJ, Bi o n d o M, W o n g M, et al: Tar geti n g of ac ute m yel oi d le u ke mia i n vitr o a n d i n vi v o 
wit h a n a nti- C D 1 2 3 m A b e n gi neere d f or o pti mal A D C C. Le u ke mi a 2 8: 2 2 1 3- 2 1, 2 0 1 4 
1 4.   
C hic hili G R, H ua n g L, Li H, et al: A C D 3 x C D 1 2 3 bis pecific D A R T f or re directi n g h ost T cells t o 
m yel o ge n o us le u ke mia: precli nical acti vit y a n d safet y i n n o n h u ma n pri mates. Sci Tra nsl Me d 
7: 2 8 9ra 8 2, 2 0 1 5 
1 5.   
Fra n kel A E, Mc C u bre y J A, Miller M S, et al: Di p ht heria t o xi n f use d t o h u ma n i nterle u ki n- 3 is t o xic 
t o blasts fr o m patie nts wit h m yel oi d le u ke mias. Le u ke mia 1 4: 5 7 6- 8 5, 2 0 0 0 
1 6.   
Mar dir os A, D os Sa nt os C, Mc D o nal d T, et al: T cells e x pressi n g C D 1 2 3-s pecific c hi meric a nti ge n 
rece pt ors e x hi bit s pecific c yt ol ytic effect or f u ncti o ns a n d a ntit u m or effects a gai nst h u ma n ac ute 
m yel oi d le u ke mia. Bl o o d 1 2 2: 3 1 3 8- 4 8, 2 0 1 3 
1 7.   
Gill S, T asia n S K, R uella M, et al: Precli nical tar geti n g of h u ma n ac ute m yel oi d le u ke mia a n d 
m yel oa blati o n usi n g c hi meric a nti ge n rece pt or- m o difie d T cells. Bl o o d 1 2 3: 2 3 4 3- 5 4, 2 0 1 4 
1 8.   
Tasia n S K, Ke n deria n S S, S he n F, et al: O pti mize d de pleti o n of c hi meric a nti ge n rece pt or T cells 
i n m uri ne xe n o graft m o dels of h u ma n ac ute m yel oi d le u ke mia. Bl o o d 1 2 9: 2 3 9 5- 2 4 0 7, 2 0 1 7 
1 9.   
B u d de L SJ, Ki m Y, Bla nc har d S, 
Wa g ner J, Stei n A, et. al: Re missi o ns of Ac ute M yel oi d 
Le u ke mia a n d Blastic Plas mac yt oi d De n dritic Cell Ne o plas m F oll o wi n g Treat me nt wit h C D 1 2 3-
S pecific C A R T Cells: A First- i n- H u ma n Cli nical Trial. Prese nte d at t he A S H, Atla nta, G A, 2 0 1 7 
2 0.   
C u m mi ns K F N, Nels o n A M, Sc h mi dt A, L u ger S, et. al: Treati n g Rela pse d / Refract or y ( R R) 
A M L wit h Bi o de gra da ble A nti- C D 1 2 3 C A R M o difie d T Cells. Prese nte d at t he A S H, Atla nta, G A, 
2 0 1 7 
2 1.   
K u basc h A S, Sc h ulze F, G ötze K S, et al: A nti- C D 1 2 3 T ar gete d T hera p y wit h T alac ot uz u ma b i n 
A d va nce d M D S a n d A M L after Faili n g H y p o met h ylati n g A ge nts - Fi nal Res ults of t he Sa m ba 
Trial. Bl o o d 1 3 2: 4 0 4 5- 4 0 4 5, 2 0 1 8 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 7 7  
2 2.   
T u S, H ua n g R, De n g L, et al: T hera p y of 4s C hi meric A nti ge n Rece pt or T Cells Ac hie ves L o n g-
Ter m Disease- Free S ur vi val wit h N o Se vere C R S or Cres i n Patie nts wit h Rela pse d a n d Refract or y 
Ac ute L y m p h o blastic Le u ke mia. Bl o o d 1 3 2: 2 6 9 6- 2 6 9 6, 2 0 1 8 
2 3.   
Ra va n di F, Bas he y A, F ora n J M, et al: C o m plete Res p o nses i n Rela pse d/ Refract or y Ac ute M yel oi d 
Le u ke mia ( A M L) Patie nts o n a Wee kl y D osi n g Sc he d ule of X m A b 1 4 0 4 5, a C D 1 2 3 x C D 3 T Cell-
E n ga gi n g Bis pecific A nti b o d y: I nitial Res ults of a P hase 1 St u d y. Bl o o d 1 3 2: 7 6 3- 7 6 3, 2 0 1 8 
2 4.   
Da ver N G, Er ba H P, Pa pa da nt o na kis N, et al: A P hase I, First- i n- H u ma n St u d y E val uati n g t he 
Safet y a n d Preli mi nar y A ntile u ke mia Acti vit y of I M G N 6 3 2, a N o vel C D 1 2 3- T ar geti n g A nti b o d y-
Dr u g C o nj u gate, i n Patie nts wit h Rela pse d/ Refract or y Ac ute M yel oi d Le u ke mia a n d Ot her C D 1 2 3-
P ositi ve He mat ol o gic Mali g na ncies. Bl o o d 1 3 2: 2 7- 2 7, 2 0 1 8 
2 5.   
K or pelai ne n EI, Ga m ble J R, Va das M A, et al: I L- 3 rece pt or e x pressi o n, re g ulati o n a n d f u ncti o n i n 
cells of t he vasc ulat ure. I m m u n ol Cell Bi ol 7 4: 1- 7, 1 9 9 6 
2 6.   
Tetta ma nti S, Mari n V, Pizzit ola I, et al: T ar geti n g of ac ute m yel oi d le u kae mia b y c yt o ki ne-i n d uce d 
killer cells re directe d wit h a n o vel C D 1 2 3-s pecific c hi meric a nti ge n rece pt or. Br J Hae mat ol 
1 6 1: 3 8 9- 4 0 1, 2 0 1 3 
2 7.   
Lee D W, Gar d ner R, P orter D L, et al: C urre nt c o nce pts i n t he dia g n osis a n d ma na ge me nt of 
c yt o ki ne release s y n dr o me. Bl o o d 1 2 4: 1 8 8- 9 5, 2 0 1 4 
2 8.   
Teac he y D T, Lace y S F, S ha w P A, et al: I de ntificati o n of Pre dicti ve Bi o mar kers f or C yt o ki ne 
Release S y n dr o me after C hi meric A nti ge n Rece pt or T-cell T hera p y f or Ac ute L y m p h o blastic 
Le u ke mia. Ca ncer Disc o v 6: 6 6 4- 7 9, 2 0 1 6 
2 9.   
Ca m pa g ne O, Del mas A, F o uliar d S, et al: I nte grate d P har mac o ki netic/ P har mac o d y na mic M o del 
of a Bis pecific C D 3 x C D 1 2 3 D A R T M olec ule i n N o n h u ma n Pri mates: E val uati o n of Acti vit y a n d 
I m pact of I m m u n o ge nicit y. Cli n Ca ncer Res 2 4: 2 6 3 1- 2 6 4 1, 2 0 1 8 
3 0.   
N. Ve y J D- M, G. L. U y, M. F oster, D. Rizzieri, J. G o d wi n, M. T o p p, F. Ciceri, M. Carra b ba, G. 
Marti nelli, G. A. H uls, A. We ge ner, M. S ha n n o n, K. Tra n, J. S u n, E. B o n vi ni, B. L ö we n ber g, J. 
Wi g gi nt o n, J. F. Di persi o: I nteri m Res ults fr o m a P hase 1 First- i n- H u ma n st u d y of fl otet uz u ma b, a 
C D 1 2 3 x C D 3 bis pecific D A R T m olec ule, i n A M L/ M D S. E S M O, 2 0 1 7 
3 1.   
U y G L, Retti g M P, Ve y N, et al: P hase 1 C o h ort E x pa nsi o n of Fl otet uz u ma b, a C D 1 2 3 × C D 3 
Bis pecific Dart <s u p > ® </s u p > Pr otei n i n Patie nts wit h Rela pse d/ Refract or y Ac ute 
M yel oi d 
Le u ke mia ( A M L). Bl o o d 1 3 2: 7 6 4- 7 6 4, 2 0 1 8 
3 2.   
Jac o bs K, Vier o C, G o d wi n J, et al: Ma na ge me nt of C yt o ki ne Release S y n dr o me i n A M L Patie nts 
Treate d wit h Fl otet uz u ma b, a C D 1 2 3 x C D 3 Bis pecific Dart <s u p > ® </s u p > M olec ule f or T- Cell 
Re directe d T hera p y. Bl o o d 1 3 2: 2 7 3 8- 2 7 3 8, 2 0 1 8 
3 3.   
Macr o Ge nics I: M G D 0 0 6 I n vesti gat or's Br oc h ure, Versi o n 7. 0, Macr o Ge nics, I nc. , 2 0 1 8 
3 4.   
R utella S, C h urc h S E, Va da ke k olat h u J, et al: A da pti ve I m m u ne Ge ne Si g nat ures C orrelate wit h 
Res p o nse t o Fl otet uz u ma b, a C D 1 2 3 × C D 3 Bis pecific Dart <s u p > ® </s u p > M olec ule, i n Patie nts 
wit h Rela pse d/ Refract or y Ac ute M yel oi d Le u ke mia. Bl o o d 1 3 2: 4 4 4- 4 4 4, 2 0 1 8 
3 5.   
S k ol ni k J M, Barrett J S, J a yara ma n B, et al: S h orte ni n g t he ti meli ne of pe diatric p hase I trials: t he 
r olli n g si x desi g n. J Cli n O nc ol 2 6: 1 9 0- 5, 2 0 0 8 
3 6.   
Lee D W, Sa nt o mass o B D, L oc ke F L, et al: A S B M T C o nse ns us Gra di n g f or C yt o ki ne Release 
S y n dr o me a n d Ne ur ol o gic T o xicit y Ass ociate d wit h I m m u ne Effect or Cells. Bi ol Bl o o d Marr o w 
Tra ns pla nt, 2 0 1 8 
3 7.   
C hes o n B D, Be n nett J M, K o pec k y KJ, et al: Re vise d rec o m me n dati o ns of t he I nter nati o nal 
W or ki n g Gr o u p f or Dia g n osis, Sta n dar dizati o n of Res p o nse Criteria, Treat me nt O utc o mes, a n d 
Re p orti n g Sta n dar ds f or T hera pe utic Trials i n Ac ute M yel oi d Le u ke mia. J Cli n O nc ol 2 1: 4 6 4 2- 9, 
2 0 0 3 
3 8.   
C hes o n B, et al: Re vise d rec o m me n dati o ns of t he I nter nati o nal W or ki n g Gr o u p f or Dia g n osis, 
Sta n dar dizati o n of Res p o nse Criteria, Treat me nt 
O utc o mes, a n d Re p orti n g Sta n dar ds f or 
T hera pe utic Trials i n Ac ute M yel oi d Le u ke mia. J C O 2 1: 4 6 4 2- 4 6 4 9, 2 0 0 3 
  
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 7 8  
A P P E N DI X I: P E R F O R M A N C E S T A T U S S C A L E S/ S C O R E S 
 
 
K ar n ofs k y  
L a ns k y  
Sc ore   
Descri pti o n  
Sc ore  Descri pti o n  
1 0 0   
N or mal, n o c o m plai nts, n o e vi de nce of 
disease  
1 0 0   
F ull y acti ve, n or mal.  
9 0   
A ble t o carr y o n n or mal acti vit y, mi n or 
si g ns or s y m pt o ms of disease. 
9 0   
Mi n or restricti o ns i n p h ysicall y stre n u o us 
acti vit y. 
8 0   
N or mal acti vit y wit h eff ort; s o me si g ns 
or s y m pt o ms of disease.  
8 0   
Acti ve, b ut tires m ore q uic kl y  
7 0   
Cares f or self, u na ble t o carr y o n n or mal 
acti vit y or d o acti ve w or k.  
7 0   
B ot h greater restricti o n of a n d less ti me s pe nt 
i n pla y acti vit y. 
6 0   
Re q uire d occasi o nal assista nce, b ut is 
a ble t o care f or m ost of his/ her nee ds.  
6 0   
U p a n d ar o u n d, b ut mi ni mal acti ve pla y; 
kee ps b us y wit h q uieter acti vities.  
5 0   
Re q uires c o nsi dera ble assista nce a n d 
fre q ue nt me dical care. 
5 0   
Gets dresse d, b ut lies ar o u n d m uc h of t he da y; 
n o acti ve pla y, a ble t o partici pate i n all q uiet 
pla y a n d acti vities.  
4 0   
Disa ble d, re q uires s pecial care a n d 
assista nce. 
4 0   
M ostl y i n be d; partici pates i n q uiet acti vities.  
3 0   
Se verel y disa ble d, h os pitalizati o n 
i n dicate d.  Deat h n ot i m mi ne nt. 
3 0   
I n be d; nee ds assista nce e ve n f or q uiet pla y. 
2 0   
Ver y sic k, h os pitalizati o n i n dicate d.  
Deat h n ot i m mi ne nt.  
2 0   
Ofte n slee pi n g; pla y e ntirel y li mite d t o ver y 
passi ve acti vities.  
1 0   
M ori b u n d, fatal pr ocesses pr o gressi n g 
ra pi dl y. 
1 0   
N o pla y; d oes n ot get o ut of be d.  
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 7 9  
A P P E N DI X II: C O R R E L A TI V E S T U DI E S G UI D E 
 
 
C orrel ati ve St u d y  
A p p x.  
V ol u me per 
S a m ple  
T ot al V ol u me  
P h ar m ac o ki netics  a n al ysis  ( peri p her al 
bl o o d)  
VI   
2 –  3 ml   
2 0  –  5 7  ml  
I m m u n o ge nicit y st u d y ( peri p her al bl o o d) 
VII    
2 –  3 ml   
6  –  9  ml  
B aseli ne C D 1 2 3 site de nsit y 
q u a ntific ati o n ( b o ne m arr o w)  
VIII   
5 ml  
5 ml  
N G S M R D  ( b o ne m arr o w) 
I X 
1 0 –  1 5 m l  
7 0 –  1 0 5 ml  
C D 3 T -l y m p h oc yte q u a ntific ati o n 
( peri p her al bl o o d) 
X   
2 –  3 ml   
2 0 –  3 0  ml  
C yt o ki ne a n al ysis  ( peri p her al bl o o d) 
X I  
2 –  3 ml   
4 –  1 2 ml  
T u m or m icr oe n vir o n me nt p r ofili n g 
( b o ne m arr o w) 
XII   
1 0  –  1 5  ml   
1 0 –  1 5 ml  
T ot al  Bl o o d  + B o ne M arr o w V ol u me  
1 3 5  –  2 3 3  ml  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 8 0  
A P P E N DI X III: T O XI CI T Y- S P E CI FI C G R A DI N G 
 
Bilir u bi n 
 
Gra de 1:   
> U L N - ≤ 1. 5  x U L N  
Gra de 2:   
> 1. 5 x U L N - 3. 0 x U L N  
Gra de 3:   
> 3. 0 x U L N - 1 0. 0 x U L N  
Gra de 4:   
> 1 0. 0 x U L N  
 
A L T : F or t he p ur p ose of t his st u d y, t he U L N f or S G P T is 4 5 U/ L re gar dless of baseli ne.  
 
Gra de 1:   
> 4 5 U/ L - ≤ 1 3 5 U/ L  
Gra de 2:   
1 3 6 U/ L - 2 2 5 U/ L  
Gra de 3:   
2 2 6 U/ L - 9 0 0 U/ L  
Gra de 4:   
> 9 0 0 U/ L  
 
A S T: F or t he p ur p ose of t his st u d y, t he U L N f or S G O T is 5 0 U/ L re gar dless of baseli ne. 
 
Gra de 1:   
> 5 0 U/ L - ≤ 1 5 0 U/ L  
Gra de 2:   
1 5 1 U/ L - 2 5 0 U/ L  
Gra de 3:   
2 5 1 U/ L - 1 0 0 0 U/ L  
Gra de 4:   
> 1 0 0 0 U/ L  
 
G G T: 
 
Gra de 1:   
> U L N - 2. 5 x U L N  
Gra de 2:   
> 2. 5 x U L N - 5. 0 x U L N  
Gra de 3:   
> 5. 0 x U L N - 2 0. 0 x U L N  
Gra de 4:   
> 2 0. 0 x U L N  
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 8 1  
A P P E N DI X I V- A: T H E R A P Y D E LI V E R Y M A P  F O R C Y C L E 1, D O S E L E V E L 1  
 
T hera p y Deli ver y Ma p –  C ycle 1 , D ose Le vel 1 
T his T hera p y Deli ver y Ma p ( T D M) relates t o C ycle 1 . Eac h c ycle lasts  2 9  da ys.  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
P atie nt C O G I D n u m ber  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
D O B  
Criteria t o start eac h c ycle are i n Secti o n 5. 2 . E xte nsi ve treat me nt details are i n Se cti o n 5. 1.  
T his T D M is o n 4 pa ges. Fl otet uz u ma b t hera p y e n ds o n Da y 2 9 gi ve n its c o nti n u o us i nf usi o n a d mi nistrati o n.  
 
D R U G   
R O U T E  
D O S A G E  
D A Y S  
I M P O R T A N T N O T E S 
I T C ytara bi ne 
( A R A C) 
(all patie nts)  
I ntrat hecal (I T)  
A ge -base d d osi n g:  
A ge ( yrs)  D ose  
< 1   
2 0 m g  
1 -1. 9 9   
3 0 m g  
2 -2. 9 9   
5 0 m g  
>  3   
7 0 m g  
 
-6 t o 0   
Patie nts s h o ul d recei ve a si n gle d ose of I T 
cytara bi ne a d mi nistere d pri or t o t he start of 
pr ot oc ol t hera p y.  
Fl otet uz u ma b   
I ntra ve n o us (IV ) 
D a y             D ose  
1                   3 0 na n o gra ms / k g/ da y 
2                   6 0 na n o gra ms / k g/ da y 
3                   1 0 0 na n o gra ms / k g/ da y 
4                   2 0 0 na n o gra ms / k g/ da y 
5                  3 0 0 na n o gra ms / k g/ da y 
6                  4 0 0 na n o gra ms / k g/ da y 
7 -2 8             5 0 0 na n o gra ms / k g/ da y 
1 –  2 8   
See Secti o n 5. 1  f or pre me dicati o ns 
rec o m me n dati o ns.  
 
See Secti o n 6  f or d ose m o dificati o ns f or 
a d verse e ve nts.  
 
 
 
 
 
 
 
 
 
 
 
Pa ge 1 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 8 2  
Ht _ _ _ _ _ _ _ _ _c m   
   
Wt _ _ _ _ _ _ _ _ _ k g   
   
B S A _ _ _ _ _ _ _ _ _ m
2   
   
D ose Le vel _ _ _ _ _ _ _ _ _ n a n o gr a ms/ k g/ d a y 
 
D ate 
D ue  
D ate 
Gi ve n  
D a y  
I T A R A C 
_ _ _ _ _ _ _ _ _ m g  
Fl otet uz u m a b 
3 0 
n a n o gr a ms / k g/
d a y  
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
6 0 
n a n o gr a ms / k g
/ d a y 
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
1 0 0 
n a n o gr a ms / k g
/ d a y  
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
2 0 0 
n a n o gr a ms / k g
/ d a y 
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
3 0 0 
n a n o gr a ms / k g
/ d a y 
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
4 0 0 
n a n o gr a ms / k g
/ d a y 
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
5 0 0 
n a n o gr a ms / k
g/ d a y  
_ _ _ _ _ _ _ _ _ n g  
St u dies  
  
  
 
E nter c alc ul ate d d ose a b ove a n d act u al d ose a d mi nistere d bel o w  
 
  
  
Pre - 
_ _ _ _ _ _ _ _ _ m g  
 
 
 
 
 
 
 
a –  d, f –  
q , u  –  x   
  
  
1   
 
_ _ _ _ _ _ _ _ _ n g  
 
 
 
 
 
 
e, r –  
t  
a, 
b,  
d, 
f, 
g  
  
  
2   
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
 
 
  
 
  
  
3   
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
 
  
e 
  
  
4   
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
e 
  
  
5   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
e 
  
  
6   
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
  
e 
  
  
7   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
  
  
8   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e, r, s 
a, 
b, 
d, 
f, 
g  
  
  
9   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 0   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 1   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 2   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
  
  
1 3   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 4   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 5   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
r, e 
a, 
b, 
d, 
f, 
g  
  
  
1 6   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 7   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 8   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 9   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
  
  
2 0   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
2 1   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
2 2   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e, r 
a, 
b, 
d, 
  
  
2 3   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
2 4   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
Pa ge 2 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 8 3  
  
  
2 5   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
  
f, 
g  
  
  
2 6   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
2 7   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
  
  
2 8   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
2 9   
  
 
 
 
 
 
 
 
e, i, j, q, r, 
v, w , y  
 
 
Re q uire d O bser vati o ns i n C ycle 1 
All b aseli ne st u dies m ust be perf or me d pri or t o st arti n g pr ot oc ol t her a p y u nless ot her wise i n dic ate d bel o w.   
a.    H ist or y. Pri or t o C ycle 1 a n d e ver y wee k d uri n g C ycle 1.  
b.  P h ysical e xa m (i ncl u di n g V S) . Pri or t o C ycle 1 a n d e ver y we e k d uri n g C ycle 1. 
c. 
P erf or ma nce Stat us. Pri or t o C ycle 1.  
d.  C B C/ diff/ platelets.  Pri or t o C ycle 1 a n d t wice wee kl y d uri n g C ycle 1. If patie nts 
ha ve Gra de 4 ne utr o pe nia t he n C B Cs s h o ul d be c hec ke d at least e ver y ot her da y 
u ntil rec o ver y t o Gra de 3 o r u ntil meeti n g t he criteria f or d ose li miti n g t o xicit y.  
e. 
P har mac o ki netics.  S a m ples t o be c ollecte d fr o m all patie nts o n C ycle 1, Da y 1 ( pre -
i nf usi o n), Da ys 3 –  7 ( 3 0 mi n utes pri or t o s yri n g e c ha n ge a n d d ose escalati o n), D a y 
8 ( 2 4 h o urs after Da y 7 s yri n ge c ha n ge a n d fi nal d ose escalati o n), a n d Da ys 1 2, 1 5, 
1 9, 2 2, 2 7, a n d 2 9 (at a n y ti me)  if patie nt f oll o ws t he d osi n g sc he d ule e xactl y as 
o utli ne d i n Secti o n 5. 1 . F or pat ie nts t hat re q uire d ose i nterr u pti o ns d uri n g C ycle 1, 
P K sa m ples s h o ul d be dra w n acc or di n g t o w he n t he patie nt reac hes certai n d ose 
le vels (see A p pe n di x VI -A  f or details). B l o o d sa m ples will als o be c ollecte d 3 0 
mi n utes , 1 h o ur, 2 h o urs, 4 h o urs, 8  h o urs , a n d 2 4 h o urs after t he e n d of i nf usi o n o n 
t he patie nt’s last da y of pr ot oc ol t hera p y. See Secti o n 8. 2  f or details. 
f. 
Electr ol ytes i ncl u di n g Ca + + . Pri or t o C ycle 1 , t wice wee kl y ( e ver y 3 t o 4 da ys) 
d uri n g Wee k 1 of C ycle 1, a n d t he n  wee kl y f or t he d urati o n of C ycle 1.   
g.  Creati ni ne , A L T, bilir u bi n, a n d A S T. Pri or t o C ycle 1 a n d wee kl y d uri n g C ycle 1.  
h.    Al b u mi n. Pri or t o C ycle 1.  
i. 
I ma gi n g ( C T or M RI) of c hl or o ma. O nl y t o be perf or me d if cli nicall y i n dicate d. 
Pri or t o C ycle 1 a n d at t he e n d of C ycle 1 (if prese nt at baseli ne).   
j. 
B o ne marr o w as pirate . Pri or t o C ycle 1 a n d at t he e n d of C ycle  1.   
k.     Uri nal ysis. Pri or t o C ycle 1.   
l.      Pre g na nc y test . Pri or t o C ycle 1 f or w o me n of c hil d beari n g p ote ntial. 
m .    E C H O or gate d ra di o n ucli de st u d y . Pri or t o C ycle 1. 
Pa ge 3 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 8 4  
n .     E K G . Pri or t o C ycle 1.  
o .     Ne ur ol o gic e xa m. Pri or t o C ycle 1.  
p.      Ht/ Wt/ B S A. Pri or t o C ycle 1.   
q.     N G S M R D c o m paris o n wit h f l o w c yt o metr y M R D. I n c o nse nti n g patie nts o nl y at 
t he ti me of b o ne marr o w e val uati o n. See Secti o n 8. 5  f or details.  
r.     C D 3 T -l y m p h oc yte q ua ntificati o n. I n c o nse nti n g patie nts, bl o o d sa m ples will be 
c ollecte d o n C ycle 1 Da ys 1, 8, 1 5 , 2 2, a n d 2 9. See Secti o n 8. 6  f or details.  
s.     C yt o ki ne pr o d ucti o n meas ure me nt. In c o nse nti n g patie nts, bl o o d sa m ples will be 
c ollecte d o n C ycle 1 , Da y 1 ( pri or t o fl otet uz u ma b i nf usi o n), a nd o n C ycle 1, Da y 8.  
A d diti o nall y, if patie nts e x peri e nce I R R/ C R S, bl o o d sa m ples will be c ollecte d fr o m 
c o nse nti n g patie nts at t he ti me of I R R/ C R S a n d at t he ti me of I R R/ C R S res ol uti o n. 
See Secti o n 8. 7  f or details.  
t.     I m m u n o ge nicit y st u d y. O ne s a m ple t o be c ollecte d  fr o m all patie nts o n C ycle 1, Da y 
1 ( pre -i nf usi o n). See Secti o n 8. 3  f or details.  
u.    T u m or micr oe n vir o n me nt pr ofili n g . Pri or t o C ycle 1. See Secti o n 8. 8  f or details. 
v.    Cl ot secti o n/ bi o ps y. Pri or t o C ycle 1 a n d at t he e n d of C ycle 1. T o be perf or me d i n 
c o nj u ncti o n wit h t he b o ne marr o w as pirati o n.  
w.   C D 1 2 3 site de nsit y a nal ysis . I n c o nse nti n g patie nts pri or t o C ycle 1. T o be 
perf or me d o n t he c ollecte d b o ne marr o w as pirate. See Sec ti o n 8. 4 f or details. 
x.    C yt o ge netics a n d FI S H. Pri or t o C ycle 1. T o be perf or me d o n t he c ollecte d b o ne 
marr o w as pirate. It is rec o m me n de d t hat c yt o ge netics/ FI S H be perf or me d b y a 
C O G -a p pr o ve d la b orat or y.  
y.    Fl o w c yt o metr y wit h M R D deter mi nati o n. At t he e n d of C ycle 1 wit h b o ne marr o w 
e val uati o n.  
 
T his listi n g o nl y i ncl u des e v al u ati o ns necess ar y t o a ns wer t he pri m ar y a n d sec o n d ar y ai ms. O B T AI N O T H E R S T U DI E S A S R E Q UI R E D F O R 
G O O D C LI NI C A L C A R E.   
C o m me nts  
(I ncl u de a n y hel d d oses, or d ose m o dificati o ns) 
 
 
Pa ge 4 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 8 5  
A P P E N DI X I V- B: T H E R A P Y D E LI V E R Y M A P F O R C Y C L E 1, D O S E L E V E L - 1  
 
T hera p y Deli ver y Ma p –  C ycle 1, D ose Le vel -1  
T his T hera p y Deli ver y Ma p ( T D M) relates t o C ycle 1 . Eac h c ycle lasts  2 9  da ys.  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
P atie nt C O G I D n u m ber  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
D O B  
Criteria t o start eac h c ycle are i n Secti o n 5. 2 . E xte nsi ve treat me nt details are i n Se cti o n 5. 1.  
T his T D M is o n 4 pa ges. Fl otet uz u ma b t hera p y e n ds o n Da y 2 9 gi ve n c o nti n u o us i nf usi o n a d mi nistrati o n.  
 
D R U G   
R O U T E  
D O S A G E  
D A Y S  
I M P O R T A N T N O T E S 
I T C ytara bi ne 
( A R A C) 
(all patie nts) 
I ntrat hecal (I T)  
A ge -base d d osi n g:  
A ge ( yrs)  D ose  
< 1   
2 0 m g  
1 -1. 9 9   
3 0 m g  
2 -2. 9 9   
5 0 m g  
>  3   
7 0 m g  
 
-6 t o 0   
Patie nts s h o ul d recei ve a si n gle d ose of I T 
cytara bi ne a d mi nistere d pri or t o t he start of 
pr ot oc ol t hera p y.  
Fl otet uz u ma b   
I ntra ve n o us (IV ) 
D a y             D ose  
1                   3 0 na n o gra ms / k g/ da y 
2 -3                6 0 na n o gra ms / k g/ da y 
4 -5                1 0 0 na n o gra ms / k g/ da y 
6 -7                2 0 0 na n o gra ms / k g/ da y 
8 -2 8              3 0 0 na n o gra ms / k g/ da y 
1 –  2 8   
See Secti o n 5. 1  f or pre me dicati o ns 
rec o m me n dati o ns. 
 
See Secti o n 6  f or d ose m o dificati o ns f or 
a d verse e ve nts.  
 
 
Ht _ _ _ _ _ _ _ _ _c m   
   
Wt _ _ _ _ _ _ _ _ _ k g   
   
B S A _ _ _ _ _ _ _ _ _ m
2   
   
D ose Le vel _ _ _ _ _ _ _ _ _ n a n o gr a ms/ k g/ d a y 
 
D ate D ue   
D ate Gi ve n  
D a y  
I T A R A C  
_ _ _ _ _ _ _ _ _ m g  
Fl otet uz u m a b 
3 0 
n a n o gr a ms / k g/
d a y  
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
6 0 
n a n o gr a ms / k g/
d a y  
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 1 0 0 
n a n o gr a ms / k g/ d a y  
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 2 0 0 
n a n o gr a ms / k g/ d a y 
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 3 0 0 
n a n o gr a ms / k g/ d a y 
_ _ _ _ _ _ _ _ _ n g  
St u dies  
 
  
 
E nter c alc ul ate d d ose a b ove a n d act u al d ose a d mi nistere d bel o w  
 
 
  
Pre - 
_ _ _ _ _ _ _ _ _ m g  
 
 
 
 
 
a –  d, f –  q,  
u  –  x  
 
  
1   
 
_ _ _ _ _ _ _ _ _ n g  
 
 
 
  
e, r  
a, b, 
Pa ge 1 of 4  
Pa ge 1 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 8 6  
–  t   
d, f, g  
 
  
2   
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
 
 
 
  
3   
 
  
_ _ _ _ _ _ _ _ _ n g  
 
 
 
 
 
  
4   
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
e 
 
  
5   
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
 
 
  
6   
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
e 
 
  
7   
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
 
  
8   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e, r, 
s 
a, b, d, f, g 
 
  
9   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
 
  
1 0   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 1   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 2   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 3   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
 
  
1 4   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 5   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
r 
a, b, d, f, g  
 
  
1 6   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 7   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
 
  
1 8   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 9   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 0   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 1   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
 
  
2 2   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
r 
a, b, d, f, g 
 
  
2 3   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 4   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 5   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
 
  
2 6   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 7   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 8   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 9   
  
 
 
 
 
  
e, i, j, q, r, v, w, y  
a, b, d, f, g 
 
 
 
 
Pa ge 2 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 8 7  
Re q uire d O bser vati o ns i n C ycle 1 
All b aseli ne st u dies m ust be perf or me d pri or t o st arti n g pr ot oc ol t her a p y u nless ot her wise i n dic ate d bel o w.   
 
a.    H ist or y. Pri or t o C ycle 1 a n d e ver y wee k d uri n g C ycle 1.  
b.  P h ysical e xa m (i ncl u di n g V S) . Pri or t o C ycle 1 a n d e ver y we e k d uri n g C ycle 1. 
c. 
P erf or ma nce Stat us. Pri or t o C ycle 1.  
d.  C B C/ diff/ platelets.  Pri or t o C ycle 1 a n d t wice wee kl y d uri n g C ycle 1. If patie nts 
ha ve Gra de 4 ne utr o pe nia t he n C B Cs s h o ul d be c h ec ke d at least e ver y ot her da y 
u ntil rec o ver y t o Gra de 3 or u ntil meeti n g t he criteria f or d ose li miti n g t o xicit y.  
e. 
P har mac o ki netics.  S a m ples t o be c ollecte d fr o m all patie nts o n C ycle 1, Da y 1 ( pre -
i nf usi o n), Da ys 4, 6, a n d 8 ( 3 0 mi n utes pri or t o s yri n ge c ha n ge a n d d ose escalati o n), 
Da y 9 ( 2 4 h o urs after Da y 8 s yri n ge c ha n ge a n d fi nal d ose escalati o n)  a n d Da ys 1 3 , 
1 7, 2 1 , 25 , a n d 2 9 (at a n y ti me) if patie nt f oll o ws t he d osi n g sc he d ule e xactl y as 
o utli ne d i n Secti o n 5. 1 . F or patie nts t hat re q uire d ose i nterr u pti o ns d uri n g C ycle 1, 
P K sa m ples s h o ul d be dra w n acc or di n g t o w he n t he patie nt reac hes certai n d ose 
le vels (see A p pe n di x VI -B  f or details). B l o o d sa m ples will als o be c ollecte d 3 0 
mi n utes , 1 h o ur, 2 h o urs, 4 h o urs, 8  h o urs , a n d 2 4 h o urs after t he e n d of i nf usi o n o n 
t he patie nt’s last da y of pr ot oc ol t hera p y. See Secti o n 8. 2  f or details. 
f. 
Electr ol ytes i ncl u di n g Ca + + . Pri or t o C ycle 1 , t wice wee kl y ( e ver y 3 t o 4 da ys) 
d uri n g Wee k 1 of C ycle 1, a n d t he n wee kl y  f or t he d urati o n of C ycle 1.   
g.  Creati ni ne, A L T, bilir u bi n, a n d A S T. Pri or t o C ycle 1 a n d wee kl y d uri n g C ycle 1.  
h.    Al b u mi n. Pri or t o C ycle 1.  
i. 
I ma gi n g ( C T or M RI) of c hl or o ma. O nl y t o be perf or me d if cli nicall y i n dicate d. 
Pri or t o C ycle 1 a n d at t he e n d of C ycle 1 (if prese nt at baseli ne).   
j. 
B o ne marr o w a s pirate. Pri or t o C ycle 1 a n d at t he e n d of C ycle 1.   
k.     Uri nal ysis. Pri or t o C ycle 1.   
l.      Pre g na nc y test. Pri or t o C ycle 1 f or w o me n of c hil d beari n g p ote ntial.  
m.    E C H O or gate d ra di o n ucli de st u d y. Pri or t o C ycle 1.  
n .     E K G. Pri or t o C ycle 1.  
o .     Ne ur ol o gic e xa m. Pri or t o C ycle 1.  
p.     Ht/ Wt/ B S A. Pri or t o C ycle 1.   
q.     N G S M R D c o m paris o n wit h fl o w c yt o metr y M R D. I n c o nse nti n g patie nts o nl y at 
t he ti me of b o ne marr o w e val uati o n. See Secti o n 8. 5  f or details.  
r.     C D 3 T-l y m p h oc yte q ua ntificati o n. I n c o nse nti n g patie nts, bl o o d sa m ples will be 
c ollecte d o n C ycle 1 Da ys 1, 8, 1 5 , 2 2, a n d 2 9. See Secti o n 8. 6  f or details.  
Pa ge 3 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 8 8  
s.     C yt o ki ne pro d ucti o n meas ure me nt. I n c o nse nti n g patie nts, bl o o d sa m ples will be 
c ollecte d o n  C ycle 1 , Da y 1 ( pri or t o fl otet uz u ma b i nf usi o n) a n d o n C ycle 1, Da y 8. 
A d diti o nall y, if patie nts e x peri e nce I R R/ C R S, bl o o d sa m ples will be c ollecte d fr o m 
c o nse nti n g patie nts a t t he ti me of I R R/ C R S a n d at t he ti me of I R R/ C R S res ol uti o n. 
See Secti o n 8. 7  f or details.  
t.     I m m u n o ge nicit y st u d y. O ne sa m ple t o be c ollecte d fr o m all patie nts o n C ycle 1, Da y 
1 ( pre -i nf usi o n). See Secti o n 8. 3  f or details.  
u.    T u m or micr oe n vir o n me nt pr ofili n g. Pri or t o C ycle 1.  See Secti o n 8. 8  f or details.  
v.    Cl ot secti o n/ bi o ps y. Pri or t o C ycle 1 a n d at t he e n d of C ycle 1. T o be perf or me d i n 
c o nj u ncti o n wit h t he b o ne marr o w as pirati o n.  
w.   C D 1 2 3 site de nsit y a nal ysis. I n c o nse nti n g patie nts pri or t o C ycle 1. T o be 
perf or me d o n t he c ollecte d b o ne marr o w as pirate. See Secti o n 8. 4  f or details. 
x.    C yt o ge netics a n d FI S H. Pri or t o C ycle 1. T o be perf or me d o n t he c ollecte d b o ne 
marr o w as pirate. It is rec o m me n de d t hat c yt o ge netics/ FI S H be perf or me d b y a 
C O G -a p pr o ve d la b o rat or y. 
y.    Fl o w c yt o metr y wit h M R D deter mi nati o n. At t he e n d of C ycle 1 wit h b o ne marr o w 
e val uati o n.  
 
T his listi n g o nl y i ncl u des e v al u ati o ns necess ar y t o a ns wer t he pri m ar y a n d sec o n d ar y ai ms. O B T AI N O T H E R S T U DI E S A S R E Q UI R E D F O R 
G O O D C LI NI C A L C A R E.   
 
 
 
 
 
 
 
 
C o m me nts  
(I ncl u de a n y hel d d oses, or d ose m o dificati o ns) 
 
 
Pa ge 4 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 8 9  
A P P E N DI X I V- C: T H E R A P Y D E LI V E R Y M A P F O R C Y C L E 1, D O S E L E V E L 2  
 
T hera p y Deli ver y Ma p –  C ycle 1, D ose Le vel 2  
T his T hera p y Deli ver y Ma p ( T D M) relates t o C ycle 1 . Eac h c ycle lasts  2 9  da ys.  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
P atie nt C O G I D n u m ber  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
D O B  
Criteria t o start eac h c ycle are i n Secti o n 5. 2 . E xte nsi ve treat me nt details are i n Se cti o n 5. 1.  
T his T D M is o n 4 pa ges. Fl otet uz u ma b t hera p y e n ds o n Da y 2 9 gi ve n c o nti n u o us i nf usi o n a d mi nistrati o n.  
 
D R U G   
R O U T E  
D O S A G E  
D A Y S  
I M P O R T A N T N O T E S 
I T C ytara bi ne 
( A R A C) 
(all patie nts) 
I ntrat hecal (I T)  
A ge -base d d osi n g:  
A ge ( yrs)  D ose  
< 1   
2 0 m g  
1 -1. 9 9   
3 0 m g  
2 -2. 9 9   
5 0 m g  
>  3   
7 0 m g  
 
-6 t o 0   
Patie nts s h o ul d recei ve a si n gle d ose of I T 
cytara bi ne a d mi nistere d pri or t o t he start of 
pr ot oc ol t hera p y.  
Fl otet uz u ma b   
I ntra ve n o us (IV ) 
D a y             D ose  
1                  3 0 na n o gra ms / k g/ da y 
2                  1 0 0 na n o gra ms / k g/ da y 
3                  2 0 0 na n o gra ms / k g/ da y 
4                  3 0 0 na n o gra ms / k g/ da y 
5                  4 0 0 na n o gra ms / k g/ da y 
6                  5 0 0 na n o gra ms / k g/ da y 
7                  6 0 0 na n o gra ms / k g/ da y 
8 -2 8             7 0 0 na n o gra ms / k g/ da y 
1 –  2 8   
See Secti o n 5. 1  f or pre me dicati o ns 
rec o m me n dati o ns. 
 
See Secti o n 6  f or d ose m o dificati o ns f or 
a d verse e ve nts.  
 
 
 
 
 
 
 
 
 
 
Pa ge 1 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 9 0  
Ht _ _ _ _ _ _ _ _ _c m   
   
Wt _ _ _ _ _ _ _ _ _ k g   
   
B S A _ _ _ _ _ _ _ _ _ m
2   
   
D ose Le vel _ _ _ _ _ _ _ _ _ n a n o gr a ms/ k g/ d a y 
 
D ate 
D ue  
D ate 
Gi ve n  
D a y  
I T A R A C 
_ _ _ _ _ _ _ _ _ m g  
Fl otet uz u m a b 
3 0 
n a n o gr a ms / k g/
d a y  
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
1 0 0 
n a n o gr a ms / k g/
d a y  
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
2 0 0 
n a n o gr a ms / k g/
d a y  
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
3 0 0 
n a n o gr a ms / k g/
d a y  
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
4 0 0 
n a n o gr a ms / k g/
d a y  
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
5 0 0 
n a n o gr a ms / k g/
d a y  
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
6 0 0 
n a n o gr a ms / k g/
d a y  
_ _ _ _ _ _ _ _ _ n g  
Fl otet uz u m a b 
7 0 0 
n a n o gr a ms / k g/
d a y  
_ _ _ _ _ _ _ _ _ n g  
St u dies  
  
  
 
E nter c alc ul ate d d ose a b ove a n d act u al d ose a d mi nistere d bel o w  
 
  
  
Pre - 
_ _ _ _ _ _ _ _ _ m g  
 
 
 
 
 
 
 
 
a –  d, f –  q,  
u  –  x  
  
  
1   
 
_ _ _ _ _ _ _ _ _ n g  
 
 
 
 
 
 
  
r –  t  
a, b, 
d, f, g  
  
  
2   
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
 
 
 
 
 
  
  
3   
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
 
 
 
e 
  
  
4   
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
 
 
e 
  
  
5   
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
 
e 
  
  
6   
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
 
e 
  
  
7   
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
e 
  
  
8   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e, r, s 
a, b, d, 
f, g 
  
  
9   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
  
  
1 0   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 1   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 2   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 3   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
  
  
1 4   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 5   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
r 
a, b, d, 
f, g  
  
  
1 6   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 7   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
  
  
1 8   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
1 9   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
2 0   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
2 1   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
  
  
2 2   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
r 
a, b, d, 
f, g 
  
  
2 3   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
2 4   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
2 5   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
e 
  
  
2 6   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
2 7   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
2 8   
 
 
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ n g  
 
  
  
2 9   
  
 
 
 
 
 
 
 
 
e, i, j, q, r , v, w, y  
 
 
 
Pa ge 2 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 9 1  
Re q uire d O bser vati o ns i n C ycle 1 
All b aseli ne st u dies m ust be perf or me d pri or t o st arti n g pr ot oc ol t her a p y u nless ot her wise i n dic ate d bel o w.   
 
a.    H ist or y. Pri or t o C ycle 1 a n d e ver y wee k d uri n g C ycle 1.  
b.  P h ysical e xa m (i ncl u di n g V S) . Pri or t o C ycle 1 a n d e ver y we e k d uri n g C ycle 1. 
c. 
P erf or ma nce Stat us. Pri or t o C ycle 1.  
d.  C B C/ diff/ platelets.  Pri or t o C ycle 1 a n d t wice wee kl y d uri n g C ycle 1. If patie nts 
ha ve Gra de 4 ne utr o pe nia t he n C B Cs s h o ul d be c hec ke d at least e ver y ot her da y 
u ntil rec o ver y t o Gra de 3 or u ntil meeti n g t he criteri a f or d ose li miti n g t o xicit y.  
e. 
P har mac o ki netics.  S a m ples t o be c ollecte d fr o m all patie nts o n C ycle 1, Da y 1 ( pre -
i nf usi o n), Da ys 3 –  8 ( 3 0 mi n utes pri or t o s yri n ge c ha n ge a n d d ose escalati o n), Da y 
9 ( 2 4 h o urs after Da y 8 s yri n ge c ha n ge a n d fi nal d ose e scalati o n) a n d Da ys 1 3, 1 7, 
2 1, 2 5, a n d 2 9 (at a n y ti me)  if patie nt f oll o ws t he d osi n g sc he d ule e xactl y as o utli ne d 
i n Secti o n 5. 1 . F or patie nts t hat re q uire d ose i nterr u pti o ns d uri n g C ycle 1, P K 
sa m ples s h o ul d be dra w n acc ordi n g t o w he n t he patie nt reac hes certai n d ose le vels 
(see A p pe n di x VI -C  f or details). B l o o d sa m ples will als o be c ollecte d 3 0 mi n utes , 1 
h o ur, 2 h o urs, 4 h o urs, 8  h o urs , a n d 2 4 h o urs after t he e n d of i nf usi o n o n t he 
patie nt’ s last da y of pr ot oc ol t hera p y. See Secti o n 8. 2  f or details. 
f. 
Electr ol ytes i ncl u di n g Ca + + . Pri or t o C y cle 1 , t wice wee kl y ( e ver y 3 t o 4 da ys) 
d uri n g Wee k 1 of C ycle 1, a n d t he n  wee kl y f or t he d urati o n of C ycle 1.   
g.  Creati ni ne, A L T, bilir u bi n, a n d A S T. Pri or t o C ycle 1 a n d wee kl y d uri n g C ycle 1.  
h.    Al b u mi n. Pri or t o C ycle 1.  
i. 
I ma gi n g ( C T or M RI) of c hl or o ma. O nl y t o be perf or me d if cli nicall y i n dicate d. 
Pri or t o C ycle 1 a n d at t he e n d of C ycle 1 (if prese nt at baseli ne).   
j. 
B o ne marr o w as pirate . Pri or t o C ycle 1 a n d at t he e n d of C ycle 1.   
k.     Uri nal ysis. Pri or t o C ycle 1 .   
l.      Pre g na nc y test. Pri or t o C ycle 1 f or w o me n of c hil d beari n g p ote ntial.  
m.    E C H O or gate d ra di o n ucli de st u d y. Pri or t o C ycle 1.  
n .     E K G. Pri or t o C ycle 1.  
o .     Ne ur ol o gic e xa m. Pri or t o C ycle 1.  
p.     Ht/ Wt/ B S A. Pri or t o C ycle 1.   
q.     N G S M R D c o m paris o n wit h fl o w c yt o metr y M R D. I n c o nse nti n g patie nts o nl y at 
t he ti me of b o ne marr o w e val uati o n. See Secti o n 8. 5  f or details.  
r.     C D 3 T-l y m p h oc yte q ua ntificati o n. I n c o nse nti n g patie nts, bl o o d sa mples will be 
c ollecte d o n C ycle 1 Da ys 1, 8, 1 5 , 2 2, a n d 2 9. See Secti o n 8. 6  f or details.  
Pa ge 2 of 4  
Pa ge 3 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 9 2  
s.     C yt o ki ne pr o d ucti o n meas ure me nt. I n c o nse nti n g patie nts, bl o o d sa m ples will be 
c ollecte d o n  C ycle 1 , Da y 1 ( pri or t o fl otet uz u ma b i nf usi o n) a n d o n C ycle 1, Da y 8. 
A d diti o nall y, if patie nts e x peri e nce I R R/ C R S, bl o o d sa m ples will be c ollecte d fr o m 
c o nse nti n g patie nts at t he ti me of I R R/ C R S a n d at t he ti me of I R R/ C R S res ol uti o n. 
See Secti o n 8. 7  f or details.  
t.     I m m u n o ge nicit y st u d y. O ne sa m ple t o be c ollecte d fr o m all patie nts o n C ycle 1, Da y 
1 ( pre -i nf usi o n). See Secti o n 8. 3  f or details.  
u.    T u m or micr oe n vir o n me nt pr ofili n g. Pri or t o C ycle 1.  See Secti o n 8. 8  f or details.  
v.    Cl ot secti o n/ bi o ps y. Pri or t o C ycle 1 a n d at t he e n d of C ycle 1. T o be perf or me d i n 
c o nj u ncti o n wit h t he b o ne marr o w as pirati o n.  
w.   C D 1 2 3 site de nsit y a nal ysis. I n c o nse nti n g patie nts pri or t o C ycle 1. T o be 
perf or me d o n t he c ollecte d b o ne marr o w as pirate. See Secti o n 8. 4  f or details. 
x.    C yt o ge netics a n d FI S H. Pri or t o C ycle 1. T o be perf or me d o n t he c ollecte d b o ne 
marr o w as pirate. It is rec o m me n de d t hat c yt o ge netics/ FI S H be perf or me d b y a 
C O G -a p pr o ve d la b orat or y.  
y.    Fl o w c yt o metr y wit h M R D deter mi nati o n. At t he e n d of C ycle 1 wit h b o ne marr o w 
e val uati o n.  
 
T his listi n g o nl y i ncl u des e v al u ati o ns necess ar y t o a ns wer t he pri m ar y a n d sec o n d ar y ai ms. O B T AI N O T H E R S T U DI E S A S R E Q UI R E D F O R 
G O O D C LI NI C A L C A R E.   
 
 
 
 
 
 
 
C o m me nts  
(I ncl u de a n y hel d d oses, or d ose m o dificati o ns) 
 
 
Pa ge 4 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 9 3  
 
A P P E N DI X V: T H E R A P Y D E LI V E R Y M A P F O R C Y C L E S 2 +  
 
T hera p y Deli ver y Ma p –  C ycles 2 +  
T his T hera p y Deli ver y Ma p ( T D M) relates t o C ycle s 2 +. Eac h c ycle lasts  2 9  da ys.  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
P atie nt C O G I D n u m ber  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
D O B  
Criteria t o start eac h c ycle are i n Secti o n 5. 2 . E xte nsi ve treat me nt details are i n Se cti o n 5. 1.  
T his T D M is o n 4 pa ges. Fl otet uz u ma b t hera p y e n ds o n Da y 2 9 gi ve n c o nti n u o us i nf usi o n a d mi nistrati o n.  
 
D R U G   
R O U T E  
D O S A G E  
D A Y S  
I M P O R T A N T N O T E S 
I T C ytara bi ne 
( A R A C) 
(all patie nts) 
I ntrat hecal (I T)  
A ge -base d d osi n g:  
A ge ( yrs)  D ose  
< 1   
2 0 m g  
1 -1. 9 9   
3 0 m g  
2 -2. 9 9   
5 0 m g  
>  3   
7 0 m g  
 
1   
S u bse q ue nt d oses a n d ti mi n g ma y be 
a d mi nistere d at t he discreti o n of t he 
treati n g p h ysicia n.  
Fl otet uz u ma b   
I ntra ve n o us (IV ) At C ycle 1 tar get d ose  
1 -2 8   
See Secti o n 5. 1  f or pre me dicati o ns 
rec o m me n dati o ns. 
 
See Secti o n 6  f or d ose m o dificati o ns f or 
a d verse e ve nts.  
 
 
 
N O T E:  If a tre at me nt-free i nter v al > 3 d a ys occ urs bet wee n a n y 2 c ycles, t he s u bse q ue nt c ycle will re q uire ste p- u p d osi n g. If a tre at me nt-
free i nter v al > 3 d a ys occ urs bet wee n a n y 2 c ycles, t he St u d y C h air m ust be n otifie d a n d t he s u bse q ue nt c ycle d osi n g sc he d ule m ust be 
disc usse d.   
 
 
 
 
 
 
 
Pa ge 1 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 9 4  
 
Ht _ _ _ _ _ _ _ _ _c m   
   
Wt _ _ _ _ _ _ _ _ _ k g   
   
B S A _ _ _ _ _ _ _ _ _ m
2   
   
D ose Le vel _ _ _ _ _ _ _ _ _ n a n o gr a ms/ k g/ d a y 
 
D ate D ue   
D ate  Gi ve n  
D a y  
I T A R A C 
_ _ _ _ _ _ _ _ _ m g  
Fl otet uz u m a b 
at C ycle 1 
T ar get D ose  
_ _ _ _ _ _ _ _ _ 
n a n o gr a ms / k g/
d a y  
St u dies  
 
  
 
E nter c alc ul ate d d ose a b ove a n d act u al d ose 
a d mi nistere d bel o w  
 
  
Pre - 
 
  
a, b, d –  g, i –  
k, m  
 
  
1  
_ _ _ _ _ _ _ _ _ m g   
_ _ _ _ _ _ _ _ _ n g  
l, o 
c 
 
  
2  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
3  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
4  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
5  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
6  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
7  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
8  
 
  _ _ _ _ _ _ _ _ _ n g  
 
c 
 
  
9  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 0  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 1  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 2  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 3  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 4  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 5  
  
_ _ _ _ _ _ _ _ _ n g  
 
c 
 
  
1 6  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 7  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 8  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
1 9  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 0  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 1  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 2  
  
_ _ _ _ _ _ _ _ _ n g  
 
c 
 
  
2 3  
  
_ _ _ _ _ _ _ _ _ n g  
 
Pa ge 2 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 9 5  
 
  
2 4  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 5  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 6  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 7  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 8  
  
_ _ _ _ _ _ _ _ _ n g  
 
 
  
2 9   
 
 
h, n , p, q, r   
 
 
Re q uire d O bser vati o ns f or C ycles 2 + 
 
a.    H ist or y. Pri or t o  s u bse q ue nt c ycles. 
b.  P h ysical e xa m (i ncl u di n g V S) . Pri or t o s u bse q ue nt c ycles. 
c. 
C B C/ diff/ platelets.  Wee kl y. If patie nts de vel o p Gra de 4 ne utr o pe nia t he n C B Cs 
s h o ul d be c hec ke d at least e ver y 3 t o 4 da ys  u ntil rec o ver y t o Gra de 3 or u ntil 
meeti n g t he criteria f or d ose li miti n g t o xicit y .  
d . Ht/ Wt/ B S A . Pri or t o s u bse q ue nt c ycles.    
e. 
Electr ol ytes i ncl u di n g Ca + + . Pri or t o s u bse q ue nt c ycles .   
f. 
Creati ni ne, A L T, bilir u bi n, a n d A S T. Pri or t o s u bse q ue nt c ycles. 
g .    Al b u mi n. Pri or t o s u bse q ue nt c ycles.  
h . I ma gi n g ( C T or M RI) of c hl or o ma. O nl y t o be perf or me d if cli nicall y i n dicate d. At 
t he e n d of e ver y c ycle (if pres e nt o n pre vi o us st u d y ).   
i.    E C H O or gate d ra di o n ucli de st u d y. Pri or t o s u bse q ue nt c ycles. 
j.     E K G. Pri or t o s u bse q ue nt c ycles.  
k .     Ne ur ol o gic e xa m. Pri o r t o s u bse q ue nt c ycles.  
l.     C D3  T -l y m p h oc yte q ua ntificati o n. I n c o nse nti n g patie nts, sa m ples t o be c ollecte d o n 
Da y 1 of C ycles 2 +. See Secti o n 8. 6  f or details.  
m .   C yt o ki ne pr o d ucti o n meas ure me nt. If patie nts e x perie nce I R R/ C R S, bl o o d sa m ples 
are t o be c ollecte d fr o m c o nse nti n g patie nts at t he ti me of I R R/ C R S a n d at t he ti me 
of I R R/ C R S res ol uti o n (if a p plica ble). See Secti o n 8. 7  f or details.  
n .     B o ne marr o w as pirate . At t he e n d of e ver y c ycle.  
o.     I m m u n o ge nicit y st u d y. S a m ples t o be c ollecte d fr o m all patie nts o n C ycle 3, Da y 1 
( pre-i nf usi o n), a n d o n C ycle 5, Da y 1 ( pre-i nf usi o n). See Se cti o n 8. 3  f or details. 
p.    P har mac o ki netics. B l o o d sa m ples will be c ollecte d 3 0 mi n utes , 1 h o ur, 2 h o urs, 4 
h o urs, 8  h o urs , a n d 2 4 h o urs after t he e n d of i nf usi o n o n t he patie nt’s last da y of 
Pa ge 3 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 9 6  
pr ot oc ol t hera p y . See Secti o n 8. 2  f or details. 
q.    N G S M R D c o m paris o n wit h fl o w c yt o metr y M R D. I n c o nse nti n g patie nts o nl y at 
t he ti me of b o ne marr o w eval uati o n. See Secti o n 8. 5  f or details. 
r.    Fl o w c yt o metr y wit h M R D deter mi nati o n. At t he e n d of eac h c ycle wit h b o ne 
marr o w e val uati o n.  
 
T his listi n g o nl y i ncl u des e v al u ati o ns necess ar y t o a ns wer t he pri m ar y a n d sec o n d ar y ai ms. O B T AI N O T H E R S T U DI E S A S R E Q UI R E D F O R 
G O O D C LI NI C A L C A R E.   
 
 
 
 
 
C o m me nts  
(I ncl u de a n y hel d d oses, or d ose m o dificati o ns) 
 
 
Pa ge 4 of 4  

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 9 7  
A P P E N DI X VI- A: P H A R M A C O KI N E TI C S T U D Y F O R M F O R P A TI E N T S O N D L 1 
C O G Pt I D # _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
   
   
   
C ycle 1, Da y 1 Date: _ _ _ _ _ _ _ _ _ _ _ _ _  
   
Please d o n ot write patie nt na mes o n t his f or m or o n sa m ples. 
 
Patie nt Wei g ht: _ _ _ _ _ _ k g    
   
   
 
 
Fl otet uz u ma b D ose Le vel: _ _ _ _ _ _ na n o gra ms/ k g/ da y    
Fl otet uz u ma b T otal Dail y D ose: _ _ _ _ _ _ na n o gra ms 
 
Bl o o d sa m ples ( 2 – 3 ml ) will be c ollecte d i n S S T t u bes at t he f oll o wi n g ti me p oi nts d uri n g C ycle 1 ( ± 1 0 mi n) f or 
patie nts t hat d o N O T re q uire d ose i nterr u pti o ns: Da y 1 ( pri or t o i nf usi o n), Da ys 3 – 7 ( 3 0 mi n utes pri or t o s yri n ge 
c ha n ge a n d d ose escalati o n), Da y 8 ( 2 4 h o urs after Da y 7 s yri n ge c ha n ge a n d fi nal d ose escalati o n) a n d o n Da ys 
1 2, 1 5, 1 9, 2 2, 2 7, a n d 2 9 (at a n y ti me). F or patie nts t hat re q uire d ose i nterr u pti o ns d uri n g C ycle 1, P K sa m ples 
s h o ul d be dra w n acc or di n g t o w he n t he patie nt reac hes certai n d ose le vels (see c hart bel o w). N O T E: Patie nts <  2 3 
k g s h o ul d o nl y ha ve 2 ml of bl o o d dra w n per sa m ple.  
 
A d diti o nal bl o o d sa m ples will als o be c ollecte d at t he f oll o wi n g ti me p oi nts o n t he patie nt’s last da y of pr ot oc ol 
t hera p y ( ± 1 0 mi n): 3 0 mi n utes, 1 h o ur, 2, h o urs, 4 h o urs, 8 h o urs, a n d 2 4 h o urs after t he e n d of i nf usi o n. 
 
Rec or d t he e xact ti me t he sa m ples are dra w n d uri n g C ycle 1, as well as t he e xact ti me i nf usi o n be gi ns a n d e n ds o n 
Da ys 1 a n d 2 9 (res pecti vel y), a n d t he e xact ti me of s yri n ge c ha n ge o n da ys i n w hic h P K sa m ples are c ollecte d. 
Als o rec or d t he e xact ti me t h e sa m ple is dra w n o n t he patie nt’s last da y of pr ot oc ol t hera p y, t he e xact ti me i nf usi o n 
e n ds o n t he patie nt’s last da y of pr ot oc ol t hera p y, t he patie nt’s last c ycle n u m ber, a n d t he da y i n t he 2 9 da y c ycle 
i n w hic h t he patie nt st o p pe d pr ot oc ol t hera p y.  
 
 
C ycle 1  
 
Bl o o d 
S a m ple 
N o.  
Pl a n ne d 
D a y of 
C ollecti o n *  
Act u al 
D a y of 
C ollecti o n  
Sc he d ule d C ollecti o n Ti me  
Act u al 
D ate 
S a m ple 
C ollecte d  
Act u al Ti me 
S a m ple 
C ollecte d  
( 2 4-hr cl oc k)  
1  
D a y 1   
D a y 1  
Pri or t o fl otet uz u ma b i nf usi o n  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b I nf usi o n o n D a y 1                    D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n St art Ti me: | _ _| _ _| : | _ _| _ _|                            
2   
D a y 3   
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge fr o m 6 0 t o 1 0 0 n g/ k g/ d a y                D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge:  | _ _| _ _| : | _ _| _ _|            
3   
D a y 4   
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge fr o m 1 0 0  t o 20 0 n g/ k g/ d a y             D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge:  | _ _| _ _| : | _ _| _ _|            
4   
D a y 5   
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge fr o m 2 00  t o 30 0 n g/ k g/ d a y             D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge:  | _ _| _ _| : | _ _| _ _|            
5   
D a y 6   
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge fr o m 3 00  t o 40 0 n g/ k g/ d a y             D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge:  | _ _| _ _| : | _ _| _ _|            
6   
D a y 7   
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge fr o m 4 00  t o 50 0 n g/ k g/ d a y             D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge:  | _ _| _ _| : | _ _| _ _|            
7   
D a y 8   
D a y 8  
2 4 hrs after s yri n ge c ha n ge f or fi nal d ose escalati o n  _ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
8   
D a y 1 2   
D a y 1 2  
A n y ti me  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
9   
D a y 1 5   
D a y 1 5  
A n y ti me  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
1 0   
D a y 1 9   
D a y 1 9  
A n y ti me  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
1 1   
D a y 2 2   
D a y 2 2  
A n y ti me  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
1 2   
D a y 2 7   
D a y 2 7  
A n y ti me  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 9 8  
1 3   
D a y 2 9   
D a y 2 9  
A n y ti me  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b I nf usi o n o n D a y 2 9       D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n E n d Ti me: | _ _| _ _| : | _ _| _ _| 
* Ass u mi n g patie nt f oll o ws t he d osi n g sc he d ule i n Secti o n 5. 1  a n d re q uires n o d ose i nterr u pti o ns.  
  
 
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                    Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
(site pers o n nel w h o c ollecte d sa m ples) 
 
 
C ycle #: _ _ _ _ _ _ _  
Bl o o d 
S a m ple 
N o.  
Ti me 
P oi nt  
Sc he d ule d C ollecti o n Ti me  
Act u al D ate 
S a m ple 
C ollecte d  
Act u al Ti me 
S a m ple C ollecte d  
( 2 4-hr cl oc k)  
Fl otet uz u m a b  I nf usi o n o n P atie nt’s L ast D a y of T her a p y        D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n E n d  Ti me:  | _ _| _ _| : | _ _| _ _|         
1 4   
D a y _ _  
3 0 mi ns  after e n d of i nf usi o n   
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 5   
D a y _ _  
1 hr after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 6   
D a y _ _  
2 hrs after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 7   
D a y _ _  
4 hrs after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 8   
D a y _ _  
8 hrs after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 9   
D a y _ _  
2 4 hrs after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
 
 
O ne c o p y of t his P har mac o ki netic St u d y F or m s h o ul d be u pl oa de d i nt o R A V E. A sec o n d c o p y s h o ul d be se nt wit h 
t he sa m ples t o t he a d dress liste d i n Secti o n 8. 2 . 6. See Secti o n 8. 2  f or detaile d g ui deli nes f or pac ka gi n g a n d s hi p pi n g 
P K sa m ples.  
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                    Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
(site pers o n nel w h o c ollecte d sa m ples) 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 9 9  
A P P E N DI X VI- B: P H A R M A C O KI N E TI C S T U D Y F O R M F O R P A TI E N T S O N D L- 1 
C O G Pt I D # _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
   
   
   
C ycle 1, Da y 1 Date: _ _ _ _ _ _ _ _ _ _ _ _ _  
   
Please d o n ot write patie nt na mes o n t his f or m or o n sa m ples. 
 
Patie nt Wei g ht: _ _ _ _ _ _ k g    
   
   
 
 
Fl otet uz u ma b D ose Le vel: _ _ _ _ _ _ na n o gra ms/ k g/ da y    
Fl otet uz u ma b T otal Dail y D ose: _ _ _ _ _ _ na n o gra ms 
 
Bl o o d sa m ples ( 2 – 3 ml) will be c ollecte d i n S S T t u bes at t he f oll o wi n g ti me p oi nts d uri n g C ycle 1 ( ± 1 0 mi n) f or 
patie nts t hat d o N O T re q uire d ose i nterr u pti o ns: Da y 1 ( pri or t o i nf usi o n), Da ys 4, 6, a n d 8 ( 3 0 mi n utes pri or t o 
s yri n ge c ha n ge a n d d ose escalati o n), Da y 9 ( 2 4 h o urs after Da y 8 s yri n ge c ha n ge a n d fi nal d ose escalati o n) a n d o n 
Da ys 1 3, 1 7, 2 1, 2 5, a n d 2 9 (at a n y ti me). F or pate nts t hat re q uire d ose i nterr u pti o ns d uri n g C ycle 1, P K sa m ples 
s h o ul d be dra w n acc or di n g t o w he n t he patie nt rea c hes certai n d ose le vels (see c hart bel o w). N O T E: P atie nts <  
2 3 k g s h o ul d o nl y ha ve 2 ml of bl o o d dra w n per sa m ple.  
 
A d diti o nal bl o o d sa m ples will als o be c ollecte d at t he f oll o wi n g ti me p oi nts o n t he patie nt’s last da y of pr ot oc ol 
t hera p y ( ± 1 0 mi n): 3 0 mi n utes, 1 h o ur, 2, h o urs, 4 h o urs, 8 h o urs, a n d 2 4 h o urs after t he e n d of i nf usi o n. 
 
Rec or d t he e xact ti me t he sa m ple are dra w n d uri n g C ycle 1, as well as t he e xact ti me i nf usi o n be gi ns a n d e n ds o n 
D a ys 1 a n d 2 9 (res pecti vel y), a n d t he e xact ti me of s yri n ge c ha n ge o n da ys i n w hic h P K sa m ples are c ollecte d. 
Als o rec or d t he e xact ti me t h e sa m ple is dra w n o n t he patie nt’s last da y of pr ot oc ol t hera p y, t he e xact ti me i nf usi o n 
e n ds o n t he patie nt’s last da y of pr ot oc ol t hera p y, t he patie nt’s last c ycle n u m ber, a n d t he da y i n t he 2 9 da y c ycle 
i n w hic h t he patie nt st o p pe d pr ot oc ol t hera p y.  
 
C ycle 1  
Bl o o d 
S a m ple 
N o.  
Pl a n ne d 
D a y of 
C ollecti o n *  
Act u al 
D a y of 
C ollecti o n  
Sc he d ule d C ollecti o n Ti me  
Act u al D ate 
S a m ple 
C ollecte d  
Act u al Ti me 
S a m ple C ollecte d  
( 2 4-hr cl oc k)  
1  
D a y 1  
D a y 1  
Pri or t o fl otet uz u ma b i nf usi o n 
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b  I nf usi o n o n D a y 1       D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n St art Ti me:  | _ _| _ _| : | _ _| _ _|                                
2  
D a y 4  
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n   
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge fr o m 6 0 t o 1 0 0 n g/ k g/ d a y               D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge : | _ _| _ _| : | _ _| _ _|   
3  
D a y 6  
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n   
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge fr o m 1 0 0 t o 2 0 0 n g/ k g/ d a y               D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge : | _ _| _ _| : | _ _| _ _|   
4  
D a y 8  
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n   
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge 2 0 0 t o 3 0 0 n g/ k g/ d a y                D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge : | _ _| _ _| : | _ _| _ _|   
5   
D a y 9   
D a y 9  
2 4 hrs after Da y 8 s yri n ge c ha n ge a n d fi nal d ose 
escalati o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
6   
D a y 1 3   
D a y 1 3  
A n y ti me  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
7   
D a y 1 7   
D a y 1 7  
A n y ti me  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
8   
D a y 2 1   
D a y 2 1  
A n y ti me  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
9   
D a y 2 5   
D a y 2 5  
A n y ti me  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 0   
D a y 2 9   
D a y 2 9  
A n y ti me  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b  I nf usi o n o n D a y 2 9       D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n E n d Ti me:  | _ _| _ _| : | _ _| _ _| 
 * Ass u mi n g patie nt f oll o ws t he d osi n g sc he d ule i n Secti o n 5. 1  a n d re q uires n o d ose i nterr u pti o ns.  
 
 
(c o nti n ue d ne xt pa ge) 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 0 0  
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                    Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
(site pers o n nel w h o c ollecte d sa m ples) 
 
 
C ycle #: _ _ _ _ _ _ _  
Bl o o d 
S a m ple 
N o.  
Ti me 
P oi nt  
Sc he d ule d C ollecti o n Ti me  
Act u al D ate 
S a m ple 
C ollecte d  
Act u al Ti me 
S a m ple C ollecte d  
( 2 4-hr cl oc k)  
Fl otet uz u m a b  I nf usi o n o n P atie nt’s L ast D a y of T her a p y        D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n E n d Ti me:  | _ _| _ _| : | _ _| _ _|      
1 1   
D a y _ _  
3 0  mi ns after e n d of i nf usi o n   
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 2   
D a y _ _  
1 hr after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 3   
D a y _ _  
2 hrs after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 4   
D a y _ _  
4 hrs after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 5   
D a y _ _  
8 hrs after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 6   
D a y _ _  
2 4 hrs after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
 
 
O ne c o p y of t his P har mac o ki netic St u d y F or m s h o ul d be u pl oa de d i nt o R A V E. A sec o n d c o p y s h o ul d be se nt wit h 
t he sa m ples t o t he a d dress liste d i n Secti o n 8. 2. 6 . See Secti o n 8. 2  f or detaile d g ui deli nes f or pac ka gi n g a n d s hi p pi n g 
P K sa m ples.  
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                    Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
(site pers o n nel w h o c ollecte d sa m ples) 
 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 0 1  
A P P E N DI X VI- C: P H A R M A C O KI N E TI C S T U D Y F O R M F O R P A TI E N T S O N D L 2 
C O G Pt I D # _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
   
   
   
C ycle 1, Da y 1 Date: _ _ _ _ _ _ _ _ _ _ _ _ _  
   
Please d o n ot write patie nt na mes o n t his f or m or o n sa m ples. 
 
Patie nt Wei g ht: _ _ _ _ _ _ k g    
   
   
 
 
Fl otet uz u ma b D ose Le vel: _ _ _ _ _ _ na n o gra ms/ k g/ da y    
Fl otet uz u ma b T otal Dail y D ose: _ _ _ _ _ _ na n o gra ms 
 
Bl o o d sa m ples ( 2 – 3 ml) will be c ollecte d i n S S T t u bes at t he f oll o wi n g ti me p oi nts d uri n g C ycle 1 ( ± 1 0 mi n) f or 
patie nts t hat d o N O T re q uire d ose i nterr u pti o ns: Da y 1 ( pri or t o i nf usi o n), Da ys 3 – 8 ( 3 0 mi n utes pri or t o s yri n ge 
c ha n ge a n d d ose escalati o n), Da y 9 ( 2 4 h o urs after Da y 7 s yri n ge c ha n ge a n d fi nal d ose escalati o n) a n d o n Da ys 
1 3, 1 7 , 2 1, 2 5, a n d 2 9 (at a n y ti me). F or patie nts t hat re q uire d ose i nterr u pti o ns d uri n g C ycle 1, P K sa m ples s h o ul d 
be dr a w n acc or di n g t o w he n t he patie nt reac hes certai n d ose le vels (see c hart bel o w). N O T E: P atie nts <  2 3 k g 
s h o ul d o nl y ha ve 2 ml of bl o o d dra w n per sa m ple. 
 
A d diti o nal bl o o d sa m ples will als o be c ollecte d at t he f oll o wi n g ti me p oi nts o n t he patie nt’s last da y of pr ot oc ol 
t hera p y ( ± 1 0 mi n): 3 0 mi n utes, 1 h o ur, 2, h o urs, 4 h o urs, 8 h o urs, a n d 2 4 h o urs after t he e n d of i nf usi o n. 
 
R ec or d t he e xact ti me t he sa m ples are dra w n d uri n g C ycle 1, as well as t he e xact ti me i nf usi o n be gi ns a n d e n ds o n 
Da ys 1 a n d 2 9 (res pecti vel y), a n d t he e xact ti me of s yri n ge c ha n ge o n da ys i n w hic h P K sa m ples are c ollecte d. 
Als o rec or d t he e xact ti me t h e sa m ple is dra w n o n t he patie nt’s last da y of pr ot oc ol t hera p y, t he e xact ti me i nf usi o n 
e n ds o n t he patie nt’s last da y of pr ot oc ol t hera p y, t he patie nt’s last c ycle n u m ber, a n d t he da y i n t he 2 9 da y c ycle 
i n w hic h t he patie nt st o p pe d pr ot oc ol t hera p y.  
 
C ycle 1  
Bl o o d 
S a m ple 
N o.  
Pl a n ne d 
D a y of 
C ollecti o n  
Act u al 
D a y of 
C ollecti o n  
Sc he d ule d C ollecti o n Ti me  
Act u al D ate 
S a m ple 
C ollecte d  
Act u al Ti me 
S a m ple C ollecte d  
( 2 4-hr cl oc k)  
1  
D a y 1  
D a y 1  
Pri or t o fl otet uz u ma b i nf usi o n 
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b  I nf usi o n o n D a y 1       D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n St art Ti me:  | _ _| _ _| : | _ _| _ _|                               
2  
D a y 3  
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n   
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge fr o m 1 0 0 t o 2 0 0 n g/ k g/ d a y               D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge : | _ _| _ _| : | _ _| _ _|   
3  
D a y 4  
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n   
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge fr o m 2 0 0 t o 3 0 0 n g/ k g/ d a y               D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge : | _ _| _ _| : | _ _| _ _|   
4  
D a y 5  
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n   
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge  fr o m 3 0 0 t o 4 0 0 n g/ k g/ d a y             D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge : | _ _| _ _| : | _ _| _ _|   
5  
D a y 6  
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n   
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge  fr o m 4 0 0 t o 5 0 0 n g/ k g/ d a y               D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge : | _ _| _ _| : | _ _| _ _|   
6  
D a y 7  
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n   
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge fr o m 6 0 0 t o 6 0 0 n g/ k g/ d a y               D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge : | _ _| _ _| : | _ _| _ _|   
7  
D a y 8  
D a y _ _  
3 0 mi ns pri or t o s yri n ge c ha n ge a n d d ose escalati o n   
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
S yri n ge C h a n ge fr o m 7 0 0 t o 8 0 0 n g/ k g/ d a y              D ate: _ _ _/ _ _ _/ _ _ _          Ti me of S yri n ge C h a n ge : | _ _| _ _| : | _ _| _ _|   
8   
D a y 9   
D a y 9  
2 4 hrs after Da y 8 s yri n ge c ha n ge a n d fi nal d ose 
escalati o n 
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
9   
D a y 1 3   
D a y 1 3  
A n y ti me  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 0   
D a y 1 7   
D a y 1 7  
A n y ti me  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 1   
D a y 2 1   
D a y 2 1  
A n y ti me  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 2   
D a y 2 5   
D a y 2 5  
A n y ti me  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 0 2  
1 3   
D a y 2 9   
D a y 2 9  
A n y ti me  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b  I nf usi o n o n D a y 2 9       D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n E n d Ti me:  | _ _| _ _| : | _ _| _ _| 
* Ass u mi n g patie nt f oll o ws t he d osi n g sc he d ule i n Secti o n 5. 1  a n d re q uires n o d ose i nterr u pti o ns.  
  
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                    Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
(site pers o n nel w h o c ollecte d sa m ples) 
 
 
 
C ycle #: _ _ _ _ _ _ _  
Bl o o d 
S a m ple 
N o.  
Ti me 
P oi nt  
Sc he d ule d C ollecti o n Ti me  
Act u al D ate 
S a m ple 
C ollecte d  
Act u al Ti me 
S a m ple C ollecte d  
( 2 4-hr cl oc k)  
Fl otet uz u m a b  I nf usi o n o n P atie nt’s L ast D a y of T her a p y        D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n E n d Ti me:  | _ _| _ _| : | _ _| _ _|      
1 4   
D a y _ _  
3 0 mi ns after e n d of i nf usi o n   
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 5   
D a y _ _  
1 hr after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 6   
D a y _ _  
2 hrs after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 7   
D a y _ _  
4 hrs after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 8   
D a y _ _  
8 hrs after e n d of  i nf usi o n 
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
1 9   
D a y _ _  
2 4 hrs after e n d of i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
 
O ne c o p y of t his P har mac o ki netic St u d y F or m s h o ul d be u pl oa de d i nt o R A V E. A sec o n d c o p y s h o ul d be se nt wit h 
t he sa m ples t o t he a d dress liste d i n Secti o n 8. 2. 6 . See Secti o n 8. 2  f or detaile d g ui deli nes f or pac ka gi n g a n d s hi p pi n g 
P K sa m ples.  
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                    Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
(site pers o n nel w h o c ollecte d sa m ples) 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 0 3  
A P P E N DI X VII: I M M U N O G E NI CI T Y S T U D Y F O R M 
 
C O G Pt I D # _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
   
   
   
C ycle 1, Da y 1 Date: _ _ _ _ _ _ _ _ _ _ _ _ _  
   
Please d o n ot write patie nt na mes o n t his f or m or o n sa m ples. 
 
Patie nt Wei g ht: _ _ _ _ _ _ k g    
   
 
 
Fl otet uz u ma b D ose Le vel: _ _ _ _ _ _ na n o gra ms/ k g/ da y      
Fl otet uz u ma b T otal Dail y D ose: _ _ _ _ _ _ na n o gra ms 
 
Bl o o d sa m ples ( 2 – 3 m L) will be c ollecte d fr o m all patie nts at t he f oll o wi n g ti me p oi nts: C ycle 1, Da y 1 ( pre-
i nf usi o n), C ycle 3, Da y 1 ( pre-i nf usi o n), a n d C ycle 5, Da y 1 ( pre-i nf usi o n). N O T E: Patie nts < 2 3 k g s h o ul d o nl y 
ha ve 2 m L of bl o o d dra w n per sa m ple. 
 
Rec or d t he e xact ti me t he sa m ple is dra w n al o n g wit h t h e e xact ti me fl otet uz u ma b i nf usi o n be gi ns o n Da y 1 of 
C ycles 1, 3, a n d 5.  
 
Bl o o d 
S a m ple 
N o.  
C ycle 
N u m ber  
Sc he d ule d C ollecti o n Ti me  
Act u al D ate S a m ple 
C ollecte d  
Act u al Ti me S a m ple 
C ollecte d  
( 2 4-hr cl oc k) 
1  
1  
Pri or t o fl otet uz u ma b i nf usi o n 
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b I nf usi o n  o n C ycle 1, D a y 1       D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n St art Ti me:  | _ _| _ _| : | _ _| _ _|                
2  
3  
Pri or t o fl otet uz u ma b i nf usi o n 
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b I nf usi o n  o n  C ycle 3,  D a y 1       D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n St art Ti me:  | _ _| _ _| : | _ _| _ _|             
3  
5  
Pri or t o fl otet uz u ma b i nf usi o n 
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b I nf usi o n  o n  C ycle 5,  D a y 1       D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n St art Ti me:  | _ _| _ _| : | _ _| _ _|             
 
 
 
 
O ne c o p y of t his I m m u n o ge ni cit y St u d y F or m s h o ul d be u pl oa de d i nt o R A V E. A sec o n d c o p y s h o ul d be se nt wit h t he 
sa m ples t o t he a d dress liste d i n Secti o n 8. 3. 5 .  See Secti o n 8. 3  f or detaile d g ui deli nes f or pac ka gi n g a n d s hi p pi n g 
i m m u n o ge nicit y sa m ples. 
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                    Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
(site pers o n nel w h o c ollecte d sa m ples) 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 0 4  
A P P E N DI X VIII: B A S E LI N E C D 1 2 3 SI T E D E N SI T Y Q U A N TI FI C A TI O N S T U D Y F O R M  
C O G Pt I D # _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
   
   
   
C ycle 1, Da y 1 Date: _ _ _ _ _ _ _ _ _ _ _ _ _  
   
Please d o n ot write patie nt na mes o n t his f or m or o n sa m ples. 
 
Patie nt Wei g ht: _ _ _ _ _ _ k g    
   
 
 
Fl otet uz u ma b D ose Le vel: _ _ _ _ _ _ na n o gra ms/ k g/ da y    
Fl otet uz u ma b T otal Dail y D ose: _ _ _ _ _ _ na n o gra ms 
 
B o ne marr o w sa m ples ( 3 – 5 ml ) will be c ollecte d fr o m c o nse nti n g patie nts pri or t o C ycle 1.  
 
R ec ord t he e xact ti me t he b o ne marr o w sa m ple is c ollecte d.  
 
B o ne 
M arr o w 
S a m ple 
N o.  
Sc he d ule d C ollecti o n Ti me  
Act u al D ate 
S a m ple  
C ollecte d  
Act u al Ti me 
S a m ple C ollecte d  
( 2 4-hr cl oc k)  
1  
Pri or t o C ycle 1  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
   
 
 
 
O ne c o p y of t his Baseli ne C D 1 2 3 Site De nsit y Q ua ntificati o n St u d y F or m s h o ul d be u pl oa de d i nt o R A V E. A sec o n d 
c o p y s h o ul d be se nt wit h t he s a m ples t o t he a d dress liste d i n Secti o n 8. 4. 5 .  See Secti o n 8. 4  f or detaile d g ui deli nes f or 
pac ka gi n g a n d s hi p pi n g Baseli ne C D 1 2 3 Site De nsit y Q ua ntificati o n sa m ples.  
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                    Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
(site pers o n nel w h o c ollecte d sa m ples) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 0 5  
A P P E N DI X I X: N G S M R D C O M P A RI S O N WI T H F L O W C Y T O M E T R Y M R D S T U D Y F O R M  
C O G Pt I D # _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
   
   
   
C ycle 1, Da y 1 Date: _ _ _ _ _ _ _ _ _ _ _ _ _  
   
Please d o n ot write patie nt na mes o n t his f or m or o n sa m ples. 
 
Patie nt Wei g ht: _ _ _ _ _ _ k g    
   
 
 
Fl otet uz u ma b D ose Le vel: _ _ _ _ _ _ na n o gra ms/ k g/ da y      
Fl otet uz u ma b T otal Dail y D ose: _ _ _ _ _ _ na n o gra ms 
 
B o ne marr o w sa m ples ( 1 0 – 1 5 ml ) will be c ollecte d fr o m c o nse nti n g patie nts at t he ti me of eac h b o ne marr o w 
e val uati o n.  
 
Rec or d t he e xact ti me t he b o ne marr o w sa m ple is c ollecte d at t he e n d of eac h c ycle.  
 
B o ne 
M arr o w 
S a m ple 
N o.  
Sc he d ule d C ollecti o n Ti me  
Act u al D ate 
S a m ple 
C ollecte d  
Act u al Ti me 
S a m ple C ollecte d  
( 2 4-hr cl oc k)  
1  
Pri or t o C ycle 1  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
2  
At t he e n d of C ycle 1  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
3  
At t he e n d of C ycle 2  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
4  
At t he e n d of C ycle 3  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
5  
At t he e n d of C ycle 4  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
6  
At t he e n d of C ycle 5  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
7  
At t he e n d of C ycle 6  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
 
   
O ne c o p y of t his N G S M R D C o m paris o n wit h Fl o w C yt o metr y M R D St u d y F or m s h o ul d b e u pl oa de d i nt o R A V E. A 
sec o n d c o p y s h o ul d be se nt wit h t he sa m ples t o t he a d dress liste d i n Secti o n 8. 5 . 6. See Secti o n 8. 5  f or detaile d 
g ui deli nes f or pac ka gi n g a n d s hi p pi n g N G S M R D C o m paris o n wit h Fl o w C yt o metr y M R D sa m ples.  
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                    Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
(site pers o n nel w h o c ollecte d sa m ples) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 0 6  
A P P E N DI X X: C D 3 T- L Y M P H O C Y T E Q U A N TI FI C A TI O N S T U D Y F O R M 
C O G Pt I D # _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
   
   
   
C ycle 1, Da y 1 Date: _ _ _ _ _ _ _ _ _ _ _ _ _  
   
Please d o n ot write patie nt na mes o n t his f or m or o n sa m ples. 
 
Patie nt Wei g ht: _ _ _ _ _ _ k g    
   
 
 
Fl otet uz u ma b D ose Le vel: _ _ _ _ _ _ na n o gra ms/ k g/ da y      
Fl otet uz u ma b T otal Dail y D ose: _ _ _ _ _ _ na n o gra ms 
 
Bl o o d sa m ples ( 2 – 3 ml ) will be c ollecte d fr o m c o nse nti n g patie nts at t he f oll o wi n g ti me p oi nts d uri n g C ycle 1: 
pre-i nf usi o n o n Da y 1, a n d o n Da ys 8, 1 5, 2 2, a n d 2 9 ( pri or t o t he e n d of i nf usi o n). F or s u bse q ue nt c ycles, bl o o d 
sa m ples ( 2 – 3 ml) will be c ollecte d o n Da y 1 pri or t o i nf usi o n. N O T E: P atie nts < 2 3 k g s h o ul d o nl y ha ve 2 ml of 
bl o o d dra w n per sa m ple. 
 
Rec or d t he e xact ti me t he sa m ple is dra w n al o n g wit h t h e e xact ti me fl otet uz u ma b i nf usi o n be gi ns o n Da y 1 of 
eac h c ycle. Q ua ntificati o n res ults will be c ollecte d i n R A V E per t he g ui da nce i n t he C R F pac ket.  
 
C ycle 1  
Bl o o d 
S a m ple 
N o.  
Sc he d ule d C ollecti o n Ti me  
Act u al D ate 
S a m ple 
C ollecte d  
Act u al Ti me S a m ple C ollecte d  
( 2 4-hr cl oc k)  
1  
Da y 1 , pre-i nf usi o n 
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b I nf usi o n  o n D a y 1       D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n St art Ti me:  | _ _| _ _| : | _ _| _ _| 
2  
Da y 8  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
3  
Da y 1 5  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
4  
Da y 2 2  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
5  
Da y 2 9  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b I nf usi o n o n D a y 2 9        D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n E n d Ti me:  | _ _| _ _| : | _ _| _ _| 
 
 
C ycl es 2 +  
Bl o o d 
S a m ple 
N o.  
C ycle N u m ber   
Sc he d ule d C ollecti o n Ti me  
Act u al D ate 
S a m ple 
C ollecte d  
Act u al Ti me 
S a m ple C ollecte d  
( 2 4-hr cl oc k)  
1   
C ycle # _ _ _ _ _  
Pri or t o fl otet uz u ma b i nf usi o n  
_ _ _/ _ _ _/ _ _ _   
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b  I nf usi o n o n D a y 1       D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n St art Ti me:  | _ _| _ _| : | _ _| _ _| 
   
O ne c o p y of t his C D 3 T- L y m p h oc yte Q ua ntificati o n St u d y F or m s h o ul d be u pl oa de d i nt o R A V E.  
 
 
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                    Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
(site pers o n nel w h o c ollecte d sa m ples) 
 
 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 0 7  
 
A P P E N DI X XI: C Y T O KI N E A N A L Y SI S  
C O G Pt I D # _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
   
   
   
C ycle 1, Da y 1 Date: _ _ _ _ _ _ _ _ _ _ _ _ _  
   
Please d o n ot write patie nt na mes o n t his f or m or o n sa m ples. 
 
Patie nt Wei g ht: _ _ _ _ _ _ k g    
   
 
 
Fl otet uz u ma b D ose Le vel: _ _ _ _ _ _ na n o gra ms/ k g/ da y      
Fl otet uz u ma b T otal Dail y D ose: _ _ _ _ _ _ na n o gra ms 
 
Bl o o d sa m ples ( 2 – 3 ml ) will be c ollecte d fr o m c o nse nti n g patie nts at t he f oll o wi n g ti me p oi nts: pri or t o C ycle 1, 
C ycle 1 Da y 8, at t he ti me of I R R/ C R S (if a p plica ble), a n d at t he ti me of I R R/ C R S res ol uti o n (if a p plica ble).   
N O T E: P atie nts < 2 3 k g s h o ul d o nl y ha ve 2 ml of bl o o d dra w n per sa m ple.   
 
Rec or d t he e xact ti me t he sa m ple is dra w n al o n g wit h t h e e xact ti me fl otet uz u ma b i nf usi o n be gi ns o n Da y 1 of 
C ycle 1.  
 
Bl o o d 
S a m ple 
N o.  
C ycle 
N u m ber  
Sc he d ule d C ollecti o n Ti me  
Act u al D ate S a m ple 
C ollecte d  
Act u al Ti me S a m ple 
C ollecte d  
( 2 4-hr cl oc k)  
1  
1  
Da y 1, pre -i nf usi o n 
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
Fl otet uz u m a b I nf usi o n  o n D a y 1       D ate: _ _ _/ _ _ _/ _ _ _       I nf usi o n St art Ti me:  | _ _| _ _| : | _ _| _ _|                       
2  
1  
Da y 8  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
3  
C ycle # _ _ _  At t he ti me of I R R/ C R S 1 
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
4  
C ycle # _ _ _  At t he ti me of I R R/ C R S res ol uti o n1  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
  1O nl y a p plica ble f or patie nts w h o e x perie nce I R R/ C R S 
 
O ne c o p y of t his C yt o ki ne Pr o d ucti o n Meas ure me nt St u d y F or m s h o ul d be u pl oa de d i nt o R A V E. A sec o n d c o p y 
s h o ul d be se nt wit h t he sa m ples t o t he a d dress liste d i n Secti o n 8. 7 . 6.  See Secti o n 8. 7  f or detaile d g ui deli nes f or 
pac ka gi n g a n d s hi p pi n g C yt o ki ne Pr o d ucti o n Meas ure me nt sa m ples.  
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                    Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
(site pers o n nel w h o c ollecte d sa m ples) 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 0 8  
A P P E N DI X XII: T U M O R MI C R O E N VI R O N M E N T S T U D Y F O R M  
C O G Pt I D # _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
   
   
   
C ycle 1, Da y 1 Date: _ _ _ _ _ _ _ _ _ _ _ _ _  
   
Please d o n ot write patie nt na mes o n t his f or m or o n sa m ples. 
 
Patie nt Wei g ht: _ _ _ _ _ _ k g    
   
 
 
Fl otet uz u ma b D ose Le vel: _ _ _ _ _ _ na n o gra ms/ k g/ da y      
Fl otet uz u ma b T otal Dail y D ose: _ _ _ _ _ _ na n o gra ms 
 
B o ne marr o w sa m ples ( 1 0 – 1 5 m L ) a n d paraffi n-e m be d de d tiss ue bl oc ks will be c ollecte d fr o m c o nse nti n g 
patie nts at t he f oll o wi n g ti me p oi nt: pri or t o C ycle 1.  
 
Rec or d t he e xact ti me t he b o ne marr o w sa m ple is c ollecte d.  
  
 
Bl o o d 
S a m ple 
N o.  
C ycle 
N u m ber  
Sc he d ule d C ollecti o n Ti me  
Act u al D ate S a m ple 
C ollecte d  
Act u al Ti me S a m ple 
C ollecte d  
( 2 4-hr cl oc k)  
1  
Pre - 
Pri or t o C ycle 1  
_ _ _/ _ _ _/ _ _ _  
| _ _| _ _| : | _ _| _ _| 
 
 
 
 
O ne c o p y of t his T u m or Micr oe n vir o n me nt St u d y F or m s h o ul d be u pl oa de d i nt o R A V E. A sec o n d c o p y s h o ul d be 
se nt wit h t he sa m ples t o t he a d dress liste d i n Secti o n 8. 8 . 6.  See Secti o n 8. 8  f or detaile d g ui deli nes f or pac ka gi n g a n d 
s hi p pi n g T u m or Micr oe n vir o n me nt st u d y sa m ples. 
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                    Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
(site pers o n nel w h o c ollecte d sa m ples) 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 0 9  
A P P E N DI X XIII: C T E P A N D C T S U R E GI S T R A TI O N P R O C E D U R E S  
F o o d a n d Dr u g A d mi nistrati o n ( F D A) re g ulati o ns a n d Nati o nal Ca ncer I nstit ute ( N CI) p olic y re q uire all 
i n di vi d uals c o ntri b uti n g t o N CI-s p o ns ore d trials t o re gister a n d t o re ne w t heir re gistrati o n a n n uall y.  T o 
re gister, all i n di vi d uals m ust o btai n a Ca ncer T her a p y E val uati o n Pr o gra m ( C T E P) I de ntit y a n d Access 
Ma na ge me nt (I A M) acc o u nt ( htt ps:// cte pc ore. nci. ni h. g o v/ia m ).  I n a d diti o n, pers o ns wit h a re gistrati o n t y pe 
of I n vesti gat or (I V R), N o n- P h ysicia n I n vesti gat or ( N PI V R), or Ass ociate Pl us ( A P) (i.e., cli nical site staff 
re q uiri n g write access t o O P E N, R A V E, or T RI A D or acti n g as a pri mar y site c o ntact) m ust c o m plete t heir 
a n n ual re gistrati o n 
usi n g 
C T E P’s  
we b- base d 
Re gistrati o n 
a n d 
Cre de ntial 
Re p osit or y ( R C R) 
( htt ps://cte pc ore. nci. ni h. g o v/rcr).  D oc u me ntati o n re q uire me nts per re gistrati o n t y pe are o utli ne d i n t he ta ble 
bel o w. 
 
D oc u me nt ati o n Re q uire d  
I V R  
N PI V R  
A P   
A  
F D A F or m 1 5 7 2  
  
 
  
 
Fi na ncial Discl os ure F or m  
  
  
 
 
N CI  
Bi os ketc h 
(e d ucati o n, 
trai ni n g, 
e m pl o y me nt, lice nse, a n d certificati o n)  
  
  
 
 
H S P/ G C P trai ni n g  
  
  
 
 
A ge nt S hi p me nt F or m (if a p plica ble)  
 
  
  
 
C V ( o pti o nal)  
  
  
 
 
 
 
A n acti ve C T E P-I A M user acc o u nt a n d a p pr o priate R C R re gistrati o n is re q uire d t o access all C T E P a n d 
C T S U ( Ca ncer Trials S u p p ort U nit) we bsites a n d a p plicati o ns.  I n a d diti o n, I V Rs a n d N PI V Rs m ust list all 
cli nical practice sites a n d I R Bs c o veri n g t heir practice sites o n t he F D A F or m 1 5 7 2 i n R C R t o all o w t he 
f oll o wi n g: 
 
A d de d t o a site r oster 
 
Assi g ne d t he treati n g, cre dit, c o nse nti n g, or dr u g s hi p me nt (I V R o nl y) tas ks i n O P E N 
 
Act as t he site- pr ot oc ol PI o n t he I R B a p pr o val 
 
Assi g ne d t he Cli nical I n vesti gat or ( CI) r ole o n t he Dele gati o n of T as ks L o g ( D T L).     
 
A d diti o nal   
i nf or mati o n   
ca n   
be   
f o u n d   
o n   
t he   
C T E P   
we bsite   
at   
< 
htt ps://cte p.ca ncer. g o v/i n vesti gat or Res o urces/ defa ult. ht m  >.  F or q uesti o ns, please c o ntact t he R C R Hel p 
Des k  b y e mail at < R C R Hel p Des k @ ni h. g o v  >.  
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 1 0  
C T S U Re gistr ati o n Pr oce d ures 
 
T his st u d y is s u p p orte d b y t he N CI Ca ncer Trials S u p p ort U nit ( C T S U). 
 
I R B A p pr o v al:   
Eac h i n vesti gat or or gr o u p of i n vesti gat ors at a cli nical site m ust o btai n I R B a p pr o val f or t his pr ot oc ol a n d 
s u b mit I R B a p pr o val a n d s u p p orti n g d oc u me ntati o n t o t he C T S U Re g ulat or y Office bef ore t he y ca n be 
a p pr o ve d t o e nr oll patie nts.  Assi g n me nt of site re gistrati o n stat us i n t he C T S U Re g ulat or y S u p p ort S yste m 
( R S S) uses e xte nsi ve data t o ma ke a deter mi nati o n of w het her a site has f ulfille d all re g ulat or y criteria 
i ncl u di n g b ut n ot li mite d t o t he f oll o wi n g: 
 
A n acti ve Fe deral Wi de Ass ura nce ( F W A) n u m ber 
 
A n acti ve r oster affiliati o n wit h t he Lea d Net w or k or a partici pati n g or ga nizati o n 
 
A vali d I R B a p pr o val 
 
C o m plia nce wit h all pr ot oc ol s pecific re q uire me nts . 
 
I n a d diti o n, t he site- pr ot oc ol Pri nci pal I n vesti gat or ( PI) m ust meet t he f oll o wi n g criteria: 
 
Acti ve re gistrati o n stat us 
 
T he I R B n u m ber of t he site I R B of rec or d liste d o n t heir F or m F D A 1 5 7 2 
 
A n acti ve stat us o n a partici pati n g r oster at t he re gisteri n g site. 
 
Sites partici pati n g o n t he N CI CI R B i nitiati ve t hat are a p pr o ve d b y t he CI R B f or t his st u d y are n ot re q uire d 
t o s u b mit I R B a p pr o val d oc u me ntati o n t o t he C T S U Re g ulat or y Office. F or sites usi n g t he CI R B, I R B 
a p pr o val i nf or mati o n is recei ve d fr o m t he CI R B a n d a p plie d t o t he R S S i n a n a ut o mate d pr ocess. Si g nat or y 
I nstit uti o ns m ust s u b mit a St u d y S pecific W or ks heet f or L ocal C o nte xt ( S S W) t o t he CI R B via I R B Ma na ger 
t o i n dicate t heir i nte nt t o o pe n t he st u d y l ocall y.  T he CI R B’s a p pr o val of t he S S W is t he n c o m m u nicate d 
t o t he C T S U Re g ulat or y Office.  I n or der f or t he S S W a p pr o val t o be pr ocesse d, t he Si g nat or y I nstit uti o n 
m ust i nf or m t he C T S U w hic h CI R B-a p pr o ve d i nstit uti o ns ali g ne d wit h t he Si g nat or y I nstit uti o n are 
partici pati n g i n t he st u d y. 
 
Re q uire me nts F or P E P N 1 8 1 2  Site Re gistr ati o n:  
 
 
IR B a p pr o val ( F or sites n ot partici pati n g via t he N CI CI R B; l ocal I R B d oc u me ntati o n, a n I R B-si g ne d 
C T S U I R B Certificati o n F or m, Pr ot oc ol of H u ma n S u bjects Ass ura nce I de ntificati o n/I R B 
Certificati o n/ Declarati o n of E xe m pti o n F or m, or c o m bi nati o n is acce pte d ) 
 
F or a p plica ble st u dies wit h a ra diati o n a n d/ or i ma gi n g ( R TI) c o m p o ne nt, t he e nr olli n g site m ust be 
ali g ne d t o a R TI pr o vi der.  T o ma na ge pr o vi der ass ociati o ns access t he Pr o vi der Ass ociati o n ta b o n 
t he C T S U we bsite at htt ps:// w w w.cts u. or g/ R S S/ R T F Pr o vi der Ass ociati o n , t o a d d or re m o ve 
ass ociate d pr o vi ders.  Sites m ust be li n ke d t o at least o ne I R O C cre de ntiale d pr o vi der t o partici pate o n 
trials wit h a n R T c o m p o ne nt. E nr olli n g sites are res p o nsi ble f or e ns uri n g t hat t he a p pr o priate 
a gree me nts are i n place wit h t heir R TI pr o vi der, a n d t hat a p pr o priate I R B a p pr o vals are i n place.   
 
 
 
 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 1 1  
S u b mitti n g Re g ul at or y D oc u me nts:  
S u b mit re q uire d f or ms a n d d oc u me nts  t o t he C T S U Re g ulat or y Office, w here t he y will be e ntere d a n d 
trac ke d i n t he C T S U R S S.  
 
Re g ulat or y S u b missi o n P ortal: w w w.cts u. or g   ( me m bers’ area)  Re g ulat or y Ta b Re g ulat or y 
S u b missi o n  
W he n a p plica ble, ori gi nal d oc u me nts s h o ul d be maile d t o: 
C T S U Re g ulat or y Office 
      1 8 1 8 Mar ket Street, S uite 3 0 0 0 
      P hila del p hia, P A 1 9 1 0 3 
 
I nstit uti o ns wit h patie nts waiti n g t hat are u na ble t o use t he P ortal s h o ul d alert t he C T S U Re g ulat or y Office 
i m me diatel y at 1- 8 6 6- 6 5 1- 2 8 7 8 i n or der t o recei ve f urt her i nstr ucti o n a n d s u p p ort. 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 1 2  
A P P E N DI X XI V: R E Q UI R E M E N T S F O R P O T E N TI A L S A T E L LI T E P H A R M A C Y SI T E S  
 
W he n t he re gisteri n g/treati n g i nstit uti o n is c o nsi deri n g use of a h o me healt h care a ge nc y as a satellite 
p har mac y, t he f oll o wi n g m ust be assesse d b y t he re gisteri n g/treati n g i nstit uti o n i n relati o n t o t he 
s uita bilit y of t he h o me healt h car e a ge nc y:  
 
 
A bilit y t o a p pr o priatel y st ore (te m perat ure a n d sec urit y) t he i ntact a ge nt vials a n d/ or pre pare d 
i nf usi o n ba gs.  
 
 
A bilit y t o pr o vi de d oc u me ntati o n of c o ntr olle d a n d m o nit ore d te m perat ure st ora ge c o n diti o ns w hile 
t he I N D a ge nt is i n t he l ocal i nf usi o n ce nter or h o me healt h care a ge nc y p ossessi o n.  
 
 
A vaila bilit y of a p pr o priatel y trai ne d staff t o pre pare d oses i n c o m plia nce wit h t he pr ot oc ol i n a n I S O 
Class 5 c o ntai n me nt de vice (i deall y i n a n I S O Class 7 r o o m as descri be d i n U S P ), t o la bel i nf usi o n 
ba gs acc or di n g t o t he pr ot oc ol i nstr ucti o ns a n d t o st ore a ge nt d oses u n der a p pr o priate c o ntr olle d 
te m perat ure c o n diti o ns.  
 
 
 F or h o me healt h care a ge nc y ser vices, t he a bilit y t o tra ns p ort eac h pre pare d d ose i n di vi d uall y t o t he 
s u bj ect’s h o me u n der a p pr o priate c o ntr olle d st ora ge c o n diti o ns or t he a bilit y t o assess a n d c o nfir m 
t hat c ol d-c hai n ma na ge me nt of pre pare d i nf usi o n ba gs s hi p pe d t o t he s u bject’s h o me is mai ntai ne d 
pri or t o a d mi nistrati o n.  
 
 
A vaila bilit y of a p pr o priatel y trai ne d staff t o a d mi nister t he pre pare d d oses a n d perf or m t he i nf usi o n 
ba g c ha n ges acc or di n g t o t he pr ot oc ol.  
 
 
Met h o ds f or pr o per dis p osal of t he waste, e m pt y vials, I V ba gs, etc. are i n place.  
 
 
Pla n f or ret ur n of u n use d i ntact vials t o t he re gisteri n g/treati n g i nstit uti o n is i n place.  
 
 
S o urce d oc u me ntati o n t o c o nfir m a ge nt a d mi nistrati o n m ust be mai ntai ne d b y t he l ocal i nf usi o n 
ce nter or h o me healt h care a ge nc y a n d m ust be pr o vi de d t o t he re gisteri n g/treati n g i nstit uti o n f or 
i nc or p orati o n i nt o t he patie nt’s me dical/researc h rec or ds a n d f or a u dit p ur p oses.  
 
 
Pla n f or ha n dli n g misse d d oses is i n place 
 
 
A ge nt acc o u nta bilit y m ust be mai ntai ne d via use of t he N CI Dr u g Acc o u nta bilit y Rec or d F or m 
( D A R F).  T he ori gi nati n g site m ust kee p a C o ntr ol D A R F a n d t he l ocal i nf usi o n ce nter or h o me 
healt h care a ge nc y w o ul d be re q uire d t o mai ntai n a Satellite D A R F if recei vi n g a n d st ori n g s u p plies 
of i ntact vials or recei vi n g a n d st ori n g i nf usi o n ba gs pre pare d b y t he re gisteri n g/treati n g i nstit uti o n. 
Mai nte na nce of a Satellite D A R F is n ot re q uire d b y h o me healt h care a ge nc y staff f or pre pare d 
i nf usi o ns ba gs s hi p pe d t o t he s u bject’s h o me. 
 
 
T he D A R F m ust be pr o vi de d t o t he re gisteri n g/treati n g i nstit uti o n f or rec or d kee pi n g p ur p oses a n d 
a u dits.  
 
 
D oc u me ntati o n of I R B c o vera ge f or t he pr ot oc ol m ust be mai ntai ne d. T he I R B of rec or d f or t he site 
m ust be i nf or me d t hat t he st u d y s u bject ma y recei ve t hera p y a d mi nistere d b y a n o n -researc h site (i.e., 
t he l ocal i nf usi o n ce nter or h o me healt h care a ge nc y). 
 
 

                       
P E P N 1 8 1 2  
 
T H I S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O NL Y , S E E P A G E 1  F O R U S A G E P O LI C Y 
 
Versi o n Date: 0 7/ 0 8/ 2 0 
 
P a ge 1 1 3  
A P P E N DI X X V: P A TI E N T C LI NI C A L T RI A L W A L L E T C A R D  
 
 
 
CLI NI C AL T RI AL W ALL E T C A R D  
S h o w t his c ar d t o all of 
y o ur h e alt hc ar e pr o vi d ers 
a n d k e e p it wit h y o u i n 
c as e y o u g o t o t h e 
e m er g e nc y r o o m.  
P ati e nt N a m e:        
Di a g n osis:        
St u d y D oct or:       
St u d y D oct or P h o n e #:       
N CI Tri al #:        
St u d y Dr u g( S):        
 
 
 
 
F or m or e i nf or m ati o n : 1 -8 0 0 -4 -C A N C E R  
c a nc er. g o v | cli nic altri als. g o v  
 
Versi o n 0 7 / 2 0 1 9