Conditions: Neutropenia Breast Cancer
Keywords: Neutropenia Breast Cancer Long-acting Granulocyte Colony Stimulating Factor Early Stage Breast Cancer Docetaxel + Cyclophosphamide (TC) chemotherapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 237
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the efficacy of SPI-2012 versus pegfilgrastim in participants with early-stage breast cancer receiving docetaxel and cyclophosphamide (TC) as measured by the duration of severe neutropenia (DSN).

Detailed description:
This is a Phase 3, randomized, open-label, active-controlled, multicenter study to compare the efficacy and safety of SPI-2012 versus pegfilgrastim in participants with early-stage breast cancer treated with TC chemotherapy as measured by the duration of severe neutropenia (DSN).

Each cycle was 21 days. Four cycles were evaluated for this study. On Day 1 of each cycle, participants received TC chemotherapy. On Day 2 of each cycle, participants received study drug (SPI-2012 or pegfilgrastim).

After cycle 1, as applicable, participants who received at least one dose of study drug will be followed for safety for 12 months after the last dose of study treatment.

Arms:
arm 1: At each cycle for 4 cycles, participants received SPI-2012 at a fixed dose of 13.2 milligrams (mg)/0.6 milliliter (mL), \[3.6 mg granulocyte colony-stimulating factor {G-CSF}\] subcutaneously (SC) approximately 24-26 hours after receiving intravenous (IV) infusion of docetaxel 75 mg/m\^2 and cyclophosphamide 600 mg/m\^2 IV infusion per institute's standard of care. All participants were followed for 35 (±5) days after last study treatment or patient discontinuation and long-term safety follow-up continued for 12 months after last dose of study treatment. arm 2: At each cycle for 4 cycles, participants received pegfilgrastim 6 mg (6 mg/0.6 mL GCSF) SC approximately 24-26 hours after receiving IV infusion of docetaxel 75 mg/m\^2 and cyclophosphamide 600 mg/m\^2 IV infusion per institute's standard of care. All participants were followed for 35 (±5) days after last study treatment or patient discontinuation and long-term safety follow-up continued for 12 months after last dose of study treatment.

Interventions: intervention 1: SPI-2012 intervention 2: Pegfilgrastim intervention 3: Docetaxel intervention 4: Cyclophosphamide
Intervention descriptions: intervention 1: Supplied in prefilled single-use syringes for subcutaneous injection, administered on Day 2 of each cycle intervention 2: Subcutaneous injection administered on Day 2 of each cycle. intervention 3: 75mg/m\^2 IV infusion administered on Day 1 of each cycle intervention 4: 600mg/m\^2 IV infusion administered on Day 1 of each cycle

Protocol document:
Prot_000.pdf: 
Offici al Titl e:  
R a n d o miz e d, O p E n -L a b el, Acti v e-C o ntr Ol Tri al of S PI -2 0 1 2 ( Efl a p e gr asti m) 
V ers us P e gfil gr asti m i n t h e M a n a g e m e nt of C h e m ot h er a p y -I n d uc e d 
N e utr o p e ni a i n E arl y -St a g e B R e ast C a nc er P ati e nts R ec ei vi n g D oc et a x el a n d 
C ycl o p h os p h a mi d e ( T C) ( R E C O V E R)  
N C T 0 2 9 5 3 3 4 0  
N C T  Nu m b er: 
D oc u m e nt  D at e : 
A m e n d m e nt 1 : 2 8 J ul 2 0 1 7 










S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
1  
C O N FI D E N TI A L  
C LI NI C A L S T U D Y P R O T O C O L  
Title P a ge  
St u d y Title: 
St u d y N u m ber:  
St u d y P h ase:  
St u d y Dr u g:  
I N D N u m ber: 
S p o ns or:  
R a n d o mize d, O p E n- L a bel, Acti ve- C o nt r O l Tri al of S PI- 2 0 1 2 
( Efl a pe gr asti m) V ers us Pe gfil gr asti m i n t he M an a ge me nt of 
C he m ot her a p y- I n d uced Ne utr o pe ni a i n E arl y- S t a ge B R e ast C a ncer 
P ati e nts Recei vi n g D ocet a xel a n d C yc l o p h os p h a mi de ( T C) 
(R E C O V E R ) 
S PI- G C F- 3 0 2
P h ase 3  
S PI- 2 0 1 2 (efl a pe gr asti m)  
1 0 3, 4 6 1  
S pectr u m P h ar m ace uti c als, I nc. 
1 5 7 Tec h n ol o g y Dri ve 
Ir vi ne, C A, U S A 
Pr ot oc ol V ersi o n/ D ate:  
A me n d me nt 1 /2 8  J U L 2 0 1 7 
T his st u d y is t o be c o n d u cte d acc or di n g t o U S a n d i nter nati o nal sta n dar ds of G o o d Cli nical 
Practice ( F D A Title 2 1 part 3 1 2 a n d I nter nati o nal C o nfere nce o n Har m o nizati o n g ui deli nes), 
a p plica ble g o ver n me nt re g ulati o ns a n d I nstit uti o nal researc h p olicies a n d pr oce d ures.  
C o nfi de nti alit y St ate me nt  
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt, partic ularl y u n p u blis he d d ata, is t he pr o per t y or 
u n der c o ntr ol of S pe ctr u m P har mace uticals, I n c. a n d is pr o vi de d t o y o u i n c o nfi de nce as a n 
I n v esti gat or, p ote ntial I n vesti gat or, or c o ns ulta nt, f or re vie w b y y o u, y o ur staff, a n d a n a p plica ble 
I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee. T he i nf or mati o n is o nl y t o b e use d b y y o u i n 
c o n necti o n wit h a ut h orize d cli nical st u dies of t he i n vesti gati o nal dr u g d escri be d i n t he pr ot oc ol. 
Y o u will n ot discl ose a n y of t he i nf or mati o n t o ot hers wit h o ut writte n a ut h orizati o n fr o m 
S pectr u m P har mace uticals , I nc. e x ce pt t o t he e xte nt necessar y t o o btai n Inf or me d C o nse nt fr o m 
t h ose pers o ns t o w h o m t he dr u g ma y be a d mi nistere d. 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
2  
I N V E S TI G A T O R SI G N A T U R E  
 
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
R a n d o mize d, O p E n -L a bel, Acti ve -C o nt r O l Tri al of S PI-2 0 1 2 ( Efl a pe gr asti m) V ers us 
Pe gfil gr asti m i n t he M a n a ge me nt of C he m ot her a p y -I n d uce d Ne utr o pe ni a i n E arl y -St a ge 
B R e ast C a ncer P ati e nts Recei vi n g D ocet a xel a n d C ycl o p h os p h a mi de ( T C) ( R E C O V E R ) 
I h a ve rea d t his pr ot oc ol a n d a gree t hat it c o ntai ns all t he necess ar y details f or perf or mi n g t he 
st u d y i n acc or da n ce wit h t he Declarati o n of Helsi n ki a n d t he I nter n ati o nal C o nfere n ce o n 
Har m o ni z ati o n (I C H) f or G o o d Cli nical Practice ( G C P).  
I will pr o vi de c o pies of t he pr ot oc ol a n d of t h e cli nical a n d precli nical i nf or mati o n o n t he 
i n vesti gati o nal pr o d uct, w hic h was f ur nis he d t o me b y t he S p o ns or  ( S pectr u m P har mace uticals, 
I n c.), t o all me m bers of t he st u d y te a m res p o nsi bl e t o me w h o partici pat e i n t he st u d y. I will 
disc uss t his material wit h t he m t o ass ure t hat t he y are f ull y i nf or m e d re gar di n g t he  st u d y dr u g 
a n d t he c o n d uct of t h e st u d y.  
I will perf or m t he st u d y acc or di n g t o s pecifi cati o ns o utli ne d i n t he pr ot oc ol a n d a gree t o 
i m ple me nt pr ot oc ol re q uire me nts o nl y after t he pr ot oc ol a n d patie nt i nf or m ati o n/Inf or me d 
C o nse nt f or m ha ve bee n a p pr o ve d b y  t he I nstit uti o nal Re vie w B o ar d/ Et hics C o m mittee 
(I R B/ E C). I will s u b mit a n y pr ot oc ol m o dificati o ns (a me n d me nts) a n d/ or a n y Inf or me d C o nse nt 
f or m m o dificati o ns t o t he I R B/ E C, a n d a p pr o val will be o btai ne d bef ore a n y m o dificati o ns are 
i m ple me nte d. 
I u n d ersta n d t hat t he i nf or mati o n prese nte d i n t his st u d y pr ot oc ol is c o nfi d e ntial, a n d I h ere b y 
ass ure t hat n o i nf or mati o n base d o n t he c o n d u ct of t he st u d y will be releas e d wit h o ut pri or 
c o nse nt fr o m S pectr u m P har mace uticals, I nc.,  u nl ess t his re q uire me nt is s u pe rse de d b y a 
re g ulat or y a ut h orit y (e g, F D A ). 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
I n vesti g at or N a me ( P L E A S E P RI N T):  
 
Si g n at ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ D ate _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
3  
S Y N O P SI S  
Title of St u d y: R a n d o mize d, O p E n -L a bel, Acti ve -C o ntr O l Tri al of S PI-2 0 1 2 ( Efl a pe gr asti m) V ers us 
Pe gfil gr asti m i n t he M a n a ge me nt of C he m ot her a p y -I n d u ce d Ne utr o pe ni a i n E arl y -St a ge B R e ast C a ncer 
P atie nts Recei vi n g D ocet a xel a n d C ycl o p h os p h a mi de ( T C) ( R E C O V E R ) 
N a me of S p o ns or:  S pectr u m P har mace uticals, I nc.  
N a me of I n vesti g ati o n al Pr o d uct: S PI -2 0 1 2   
Pl a n ne d N u m ber of P atie nts:  A p pr o xi matel y 2 1 8  patie nts  
St u d y Ce nters:  A p pr o xi matel y 8 0  st u d y ce nters 
D ur ati o n of St u d y : A p pr o xi matel y 2 8  m o nt hs  wit h 1 6  m o nt hs f or 
e nr oll me nt a n d treat me nt  a n d 1 2 m o nt hs f or safet y f oll o w -u p.   
Cli nic al P h ase:  3  
O bjecti ves:  
Pri m ar y O bjecti ve : 
T o c o m pare t he efficac y of  a si n gle d ose of  S PI -2 0 1 2  wit h p e gfil grasti m i n patie nts wit h e arl y-sta ge breast 
ca ncer recei vi n g d oceta xel a n d c ycl o p h os p ha mi de ( T C), as meas ure d b y t he D ur ati o n of S e vere N e utr o pe ni a  
(D S N ) i n C ycle 1  
Ke y Sec o n d ar y O bjecti ves:  
•  
T o c o m pare S PI -2 0 1 2  wit h pe gfil grasti m i n:  
1.  Ti me t o A bs ol ute Ne utr o p hil C o u nt  ( A N C) Rec o ver y i n C ycle 1  
2.  De pt h of A N C N a dir , defi ne d as t he patie nt’s l o west A N C i n C ycle 1  
3.  I nci de nce of Fe brile Ne utr o p e ni a  (F N ) i n patie nts d uri n g C ycle 1  
A d diti o n al Sec o n d ar y O bjecti ve s: 
•  
T o c o m pare S PI -2 0 1 2  wit h pe gfil grasti m  i n: 
1.  D ur ati o n of Se vere Ne utr o pe ni a  i n C ycles 2 , 3 , a n d 4  
2.  I nci de nce of Ne utr o pe nic C o m plicati o ns, i ncl u di n g a nti -i nfecti ve use a n d h os pitalizati o ns i n patie nts 
d uri n g C ycle 1   
3.  I nci de nce of F N  i n C ycles 2 , 3 , a n d 4  
4.  Rel ati ve D ose I nte nsit y  (R DI ) of T C i n C ycles 1  t o 4  
5.  Safet y  
St u d y Desi g n  a n d Tre at me nt Pl a n : 
T his is a P hase 3, ra n d o mize d, o pe n -la bel, acti ve-c o ntr olle d, m ultice nter  st u d y t o c o m pare t he efficac y a n d 
safet y of S PI -2 0 1 2  wit h pe gfil grasti m  i n breast ca ncer patie nts treate d wit h T C c he m ot hera p y.  
A p pr o xi matel y 2 1 8  patie nts will be e nr olle d a n d ra n d o mize d i n a 1: 1 rati o t o 2 treat me nt ar ms:  
•  
Tre at me nt Ar m 1  ( n = a p pr o xi matel y 1 0 9 ): S PI -2 0 1 2  (1 3. 2 m g/ 0. 6 m L fi xe d d ose S PI -2 0 1 2  e q ui vale nt 
t o 3. 6  m g  G -C S F ) 
•  
Tre at me nt Ar m 2  ( n = a p pr o xi matel y 1 0 9 ): P e gfil grasti m ( 6 m g/ 0. 6 mL )  
Pri or t o T C c he m ot hera p y a d mi nistrati o n, patie nts ma y  rec ei ve pre me dicati o n acc or di n g t o i nstit uti o nal sta n dar d 
of care . I ntra ve n o us (I V) a d mi nistrati o n of T C o n Da y 1 of e ac h c ycle will be as f oll o ws:  
•  
D oceta xel 7 5 m g/ m 2 I V i nf usi o n per i nstit ute ’s sta n dar d of care 
•  
C ycl o p h os p ha mi de 6 0 0 m g/ m 2 I V i nf usi o n per i nstit ute ’s sta n dar d of care  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
4  
Eac h c ycle will be 2 1 da ys. O nl y 4 c ycles will be e val uate d f or t his st u d y After C ycle 1 , patie nts m ust ha ve 
A N C  ≥1. 5 × 1 0 9/ L a n d platelet c o u nt ≥1 0 0 × 1 0 9/ L t o be gi n ea ch of t he ne xt c ycles of c he m ot hera p y .  
T he st u d y dr u g ( S PI -2 0 1 2  or pe gfil grasti m ) will be a d mi nistere d o n D a y 2  of eac h c ycle, a p pr o xi matel y 2 4 t o 
2 6  h o urs after t he last d ose of T C c he m ot hera p y is gi ve n.  St u d y dr u g ( S PI -2 0 1 2  or pe gfil grasti m) d ose 
m o dificati o ns are n ot all o we d.  
O n D a y 1  of eac h c ycle, patie nts will recei ve T C c he m ot her a p y , a n d safet y a n d efficac y assess me nts will be 
perf or me d as o utli ne d i n t he pr ot oc ol. O n D a y 2  of eac h c ycle, patie nts will recei ve st u d y dr u g ( S PI -2 0 1 2  or 
pe gfil grasti m) , a n d  t he s pecifi e d assess me nts will be perf or me d .  
A bs ol ute ne utr o p hil c o u nt will be m o nit ore d  o n D a y 1  a n d D a ys 4  t o 1 5  i n C ycle 1 . I n C ycles 2  t o 4 , all patie nts 
m ust ha ve bl o o d sa m ples dra w n o n D a y 1  ( pri or t o c he m ot hera p y a d mi nistrati o n), o n D a ys 4 , 7 , 1 0 , a n d 1 5  
( ± 1 da y f or eac h c ollecti o n), a n d at t he E n d -of -Tre at me nt Visit . If t he partici pati n g site is n otifie d t hat t he  A N C 
is ≤1. 0 × 1 09/ L at a n y ti me d uri n g C ycles 2  t o 4 , t he n dail y C B Cs will be req uire d u ntil t he A N C is ≥1. 5 × 1 0 9/ L, 
after reac hi n g na dir, b ut bl o o d sa m ples m ust still be dra w n o n D a ys 4 , 7 , 1 0 , a n d 1 5 .  
A fter C ycle 1 , as a p plica ble, patie nts w h o ha ve recei ve d at l east o ne d ose of st u d y dr u g will  be  f oll o we d f or 
1 2  m o nt h s after t he last d ose of st u d y treat me nt f or safet y f oll o w-u p .  
D ur ati o n of St u d y:  A p pr o xi matel y 2 8  m o nt hs wit h 1 6  m o nt hs f or e nr oll me nt a n d treat me nt a n d 1 2 m o nt hs f or 
safet y f oll o w-u p.  
T he d urati o n of t he st u d y f or eac h patie nt i n S PI -G C F -3 0 2  will be a p pr o xi matel y 1 6  m o nt hs i ncl u di n g:  
•  
Scree ni n g Peri o d : 3 0  da ys  
•  
Tre at me nt Peri o d : 4 c ycles, 2 1 da ys per c ycle  
•  
E n d -of -Tre at me nt Visit:  3 5( ± 5) da ys  after last d ose of st u d y treat me nt 
•  
S afet y F oll o w -u p  Peri o d : 1 2 m o nt hs  after t he  last d ose of st u d y treat me nt 
•  
E n d -of -St u d y Visit:  At t he 1 2 M o nt h Visit  or 3 5 ( ± 5)  da ys after t he date of earl y disc o nti n uati o n   
P atie nt Re pl ace me nt Str ate g y:  P atie nts w h o disc o nti n ue fr o m t he st u d y pri or t o ra n d o mi zati o n will be 
re place d. 
I ncl usi o n & E xcl usi o n Crite ri a:  
I ncl usi o n Criteri a: 
1.  P atie nt or le gall y a ut h orize d re prese ntati ve m ust be willi n g a n d ca pa ble of gi vi n g writte n I nf or me d 
C o nse nt a n d m ust b e a ble t o a d here t o d osi n g a n d visit sc he d ules a s well as meet all st u d y re q uire me nts.   
2.  P atie nt m ust ha ve  ne w l y dia g n os e d , hist ol o gicall y c o nfir me d earl y-sta ge breast ca ncer ( E S B C) defi ne d 
as o pera ble S ta ge I t o S ta ge III A breast ca ncer.  
3.  P atie nt m ust  be a ca n di date t o recei ve a dj u va nt or ne oa dj u va nt  T C c he m ot hera p y.  
4.  P atie nt ( male or fe male) m ust be at least 1 8 years of a ge.  
5.  P atie nt m ust ha ve  a d e q uate he mat ol o gical, re nal a n d he patic f u ncti o n as defi ne d b y : 
•  
A N C ≥1. 5 × 1 0 9/ L 
•  
Platelet c o u nt ≥1 0 0 × 1 0 9/ L 
•  
He m o gl o bi n > 9 g/ d L  
•  
Calc ulate d creati ni ne cleara nc e > 5 0 m L/ mi n  
•  
T otal bilir u bi n ≤1. 5 m g/ d L  
•  
As partate a mi n otra nsferase ( A S T)/ser u m gl uta mic -o xal oacetic tra nsa mi nase ( S G O T) a n d ala ni ne 
a mi n otra nsferase (A L T )/ser u m gl uta mic-p yr u vic tra nsa mi nase ( S G P T) ≤2. 5 × U L N, a n d al kali ne 
p h os p hatase ≤2. 0 × U L N  
6.  P atie nt m ust ha ve  a n Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us ≤2.  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
5  
7.  P atie nt m ust b e  willi n g t o practice t w o f or ms of c o ntrace pti o n, o ne of w hic h m ust be a barrier met h o d, 
fr o m st u d y e ntr y t hr o u g h 3 0 da ys after t he last d ose of st u d y dr u g a d mi nistrati o n or 3 0 da ys after date of 
patie nt earl y  disc o nti n uati o n.  
8.  Fe males of c hil d beari n g p ote ntial m ust ha ve a ne gati ve uri ne  pre g na nc y test wit hi n 3 0 da ys  pri or t o 
ra n d o mizati o n. Fe males w h o are p ost me n o pa usal f or at least 1 year ( defi ne d as m ore t ha n 1 2 m o nt hs 
si nce last me nses) or are s ur gi call y sterilize d d o n ot re q uire t his test. 
E xcl usi o n Criteri a:  
1.  P atie nt wit h a n acti ve c o nc urre nt mali g na nc y (e xce pt n o n mela n o ma s ki n ca ncer or carci n o ma i n sit u of 
t he cer vi x) or life-t hreate ni n g disease. If t here is a hist or y of pri or mali g na ncies or c o ntralatera l breast 
ca ncer, t he patie nt m ust b e dis ease free f or at least 5 years. 
2.  P atie nt wit h k n o w n se nsiti vit y or pre vi o us reacti o n t o Esc heric hi a c oli  (E. c oli ) deri ve d pr o d ucts (e g, 
fil grasti m, rec o m bi na nt i ns uli n [ H u m uli n ®], L-as para gi nas e, s o matr o pi n [ H u matr o p ®] gr o wt h h or m o ne, 
rec o m bi na nt i nterfer o n alfa-2 b [I ntr o n ® A]), or a n y of t he pr o d ucts t o be a d mi nistere d d uri n g st u d y 
partici pati o n.  
3.  P atie nt wit h c o nc urre nt a dj u va nt ca ncer t hera p y (c he m ot hera p y, ra diati o n t hera p y, i m m u n ot hera p y, 
bi ol o gic t hera p y ot her t ha n t he trial -s pecifie d t hera pies).  
4.  P atie nt has l ocall y rec urre nt/metastatic breast ca ncer . 
5.  P atie nt wit h pre vi o us e x p os ur e t o fil grasti m, pe gfil grasti m, or ot her G -C S F pr o d ucts i n cli nical 
de vel o p me nt wit hi n 1 2 m o nt hs pri or t o t he a d mi nistrati o n of st u d y dr u g ( S PI -2 0 1 2  or pe gfil grasti m) .  
6.  P atie nt wit h a n acti ve i nfecti o n  or recei vi n g a nti -i nfecti ves, a n u n derl yi n g me dical c o n diti o n, or a not her 
seri o us ill ness t hat w o ul d i m p air t he a bilit y of t he patie nt t o recei ve pr ot oc ol -s pecifie d treat me nt. 
7.  P atie nt has use d a n y i n vesti gati o nal dr u gs, bi ol o gics, or de vices wit hi n 3 0  da ys pri or t o st u d y treat me nt 
or pla ns t o use a n y of t hese d uri n g t he c o urse of t he st u d y.  
8.  P atie nt has ha d pri or b o ne marr o w or he mat o p oietic ste m cell tra ns pla nt. 
9.  P atie nt has ha d pri or ra diat i o n t hera p y wit hi n 3 0 da ys  pri or t o  e nr oll me nt . 
1 0.  P atie nt has ha d maj or s ur ger y wit hi n 3 0 da ys pri or t o e nr oll me nt. P atie nts w h o ha ve breast s ur ger y 
relate d t o t he breast ca ncer dia g n osis or ha ve ha d a p ort-a-cat h place me nt ma y be e nr olle d pri or t o 
3 0  da ys o nce t he y ha ve f ull y rec o vere d fr o m t he pr oce d ure.  
1 1.  P atie nt is pre g na nt or breast -fe e di n g. 
I n vesti g ati o n al Pr o d uct, D ose, a n d R o ute of A d mi nistr ati o n:  
S PI -2 0 1 2  ( 0. 6 m L) is s u p plie d i n a prefille d , si n gle-use s yri n ge f or s u bc uta ne o us i nj ecti o n. Eac h prefille d  
s yri n ge of S PI -2 0 1 2  c o ntai ns 1 3. 2 m g S PI -2 0 1 2 , w hic h is e q ui vale nt t o a  d ose of 3. 6 m g of G -C S F.  
T he d ose of S PI -2 0 1 2  is t o be a d mi nistere d s u bc uta ne o usl y o n Da y 2, a p pr o xi matel y 2 4 t o 2 6 h o urs  after T C 
a d mi nistrati o n. 
Refere nce T her a p y, D ose, a n d R o ute of A d mi nistr ati o n:  
O nl y pe gfil grasti m ( Ne ulasta), ma n ufact ure d b y A m ge n i n t he U nite d States ( N D C 5 5 5 1 3 -1 9 0 -0 1) will be use d 
i n t his st u d y; n o ot her G -C S Fs, i ncl u di n g bi osi mil ars, are t o be use d i n t his st u d y.  
P e gfil grasti m will b e s u p plie d b y S p ectr u m t o all sites ( U S a n d e x-U S) i n 6 m g/ 0. 6 m L prefille d  si n gle-use 
s yri n ges f or s u bc uta ne o us i nj ecti o n. Eac h s yri n ge c o ntai ns 6 m g G -C S F  i n a sterile s ol uti o n. 
P e gfil grasti m s h o ul d be a d mi nistere d s u bc uta ne o usl y o nce per c he m ot hera p y c ycle o n D a y 2 , a p pr o xi matel y 2 4 
t o 2 6 h o urs after T C a d mi nistrati o n , acc or di n g t o t he ma n ufa ct urer’s prescri bi n g i nf or mati o n. 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
6  
Effic ac y Assess me nts:  
Pri m ar y E n d p oi nt:  
•  
C o m paris o n of t he D ur ati o n of S e vere N e utr o pe ni a  (D S N ) i n C ycle 1  bet wee n t he S PI -2 0 1 2 
Tre at me nt Ar m  a n d  t he Pe gfil gr asti m Tre at me nt Ar m .  
D S N  is defi ne d as t he n u m ber of da ys of se vere ne utr o pe nia ( A N C < 0. 5 × 1 0 9/ L) fr o m t he first occ urre nce of a n 
A N C bel o w t he t hres h ol d . T he assess me nt of A N C will be perf or me d o n D a y 1  a n d D a ys 4  t o 1 5  i n C ycle 1 . 
T he e n d p oi nt will b e meas ure d i n all patie nts  i n an  Inte nt -t o-T re at P o p ul ati o n  (I T T P o p ul ati o n). F or patie nts 
w h o d o n ot meet se vere ne utr o pe nia criteria , t he e n d p oi nt meas ureme nt  will be defi ne d as D S N = 0.  
Ke y Sec o n d ar y E n d p oi nts:  
•  
T o c o m pare S PI -2 0 1 2  wit h pe gf il grasti m i n: 
1.  Ti me t o A N C Rec o ver y  i n C ycle 1   
2.  De pt h of A N C N a dir , defi ne d as t he patie nt’s l o west A N C i n C ycle 1  
3.  I nci de nce of F N  i n patie nts d uri n g C ycle 1  
T he a nal yses of t he Ke y Sec o n dar y E n d p oi nts will e m pl o y a hierarc hical , cl ose d testi n g pr oce d ure . 
A d diti o n al Sec o n d ar y E n d p oi nts:  
•  
T o c o m pare S PI -2 0 1 2  wit h pe gfil grasti m i n:  
1.  D ur ati o n of Se vere Ne utr o pe ni a  i n C ycles 2 , 3 , a n d 4  
2.  I nci de nce of Ne utr o pe nic Co m plicati o ns, i ncl u di n g use of a nti -i nfecti ves a n d h os pitalizati o ns, i n 
patie nts d uri n g C ycle 1  
3.  I nci dences of F N  i n C ycles 2 , 3 , a n d 4  
4.  R DI  of T C i n C ycles 1  t o 4  
5.  Safet y  
P h ar m ac o ki netic Assess me nts:  
All patie nts i n t he S PI -2 0 1 2  treat me nt ar m will ha ve bl o o d sa m ples dra w n f or s parse P K sa m pli n g at 6 ti me 
p oi nts d uri n g t he st u d y peri o d f or P K a nal ysis. T he sa m pli n g ti me p oi nts will be: 
•  
C ycle 1 :  
•  
D a y 2  ( 1 t o 4 h o urs after S PI -2 0 1 2  a d mi nistrati o n)  
•  
D a y 4  (at t he sa me ti me as C B C bl o o d dra w) 
•  
D a y 5  (at t he sa me ti me as C B C bl o o d dra w) 
•  
C ycle 3 : 
•  
D a y 2  ( 1 t o 4 h o urs p ost-d ose)  
•  
D a y 4  (± 1 da y, at t he sa me ti me as C B C bl o o d dra w ) 
•  
D a y 7  (± 1 da y, at t he sa me ti me as C B C bl o o d dra w)  
S afet y Assess me nts:  
Safet y (sec o n dar y e n d p oi nt) will be assesse d b y re p orte d/elicite d  a d verse e ve nts  (A Es ), la b orat or y assess me nts, 
a n d p h ysical e xa mi nati o ns.  I n a d diti o n, as a p plica ble, patie nts w h o recei ve at least o ne d ose of st u d y dr u g will 
be f oll o we d f or 1 2 m o nt hs aft er t he  last d ose of st u d y treat me nt t o assess l o n g-ter m safet y; patie nts w h o recei ve 
S PI -2 0 1 2  will b e teste d f or a nti b o dies t o S PI -2 0 1 2 , t he Fc re gi o n of t he S PI -2 0 1 2  m o lec ule, t he P E G m oiet y, 
a n d G-C S F . P atie nts  w h o recei ve pe gfil grasti m will be teste d f or a nti b o dies t o S PI -2 0 1 2 , P E G a n d G -C S F. All 
sera sa m ples p ositi ve f or G-C S F -bi n di n g a nti b o dies will be f urt her teste d f or G -C S F ne utr alizi n g a nti b o dies.   
A d verse E ve nt a n d Seri o us A d verse E ve nt Re p orti n g:  
All A Es t hat occ ur fr o m t he first d ose of st u d y treat me nt t hr o u g h at least 3 5( ± 5) da ys after t he date of last st u d y 
treat me nt or date of patie nt earl y disc o nti n uati o n  are t o be rec or de d o n t he A E C R F . A d diti o nall y, as ap plica ble  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
7  
patie nts w h o recei ve at least o ne d ose of st u d y dr u g ( S PI -2 0 1 2  or pe gfil grasti m ) will be f oll o we d f or 1 2 m o nt hs  
after t he  last d ose of st u d y treat me nt t o e val uate t he l o n g-ter m safet y a n d i m m u n o ge nicit y of S PI -2 0 1 2 . All A Es 
d uri n g t his ti me peri o d will be rec or de d. Fr o m t he ti me t he st u d y I nf or me d C o nse nt is si g ne d t hr o u g h t he first 
d ose of st u d y dr u g a d mi nistrati o n, o nl y S A Es t hat are relate d t o st u d y pr oce d ures are t o be rec or de d.  
St atistic al M et h o ds:  
F or  t he pri mar y efficac y a nal ysis, t he mea n D S N  i n C ycle 1  will be c o m pare d bet wee n t he S PI -2 0 1 2  a n d 
Pe gfil gr asti m Tre at me nt Ar m s usi n g a b o otstra p resa m pli n g met h o d wit h n o n -i nferi orit y h y p ot hesis. A 
2 -si de d 9 5 % co nfi de nce inter val  ( CI) of t he differe nce bet we e n  t he mea n D S N  of t he S PI -2 0 1 2  Tre at me nt A r m 
a n d t he mea n D S N  of t he Pe gfil gr asti m Tre at me nt Ar m  will be calc ulate d usi n g b o otstra p resa m pli n g  wit h 
treat me nt as t he o nl y stratificati o n fact or. T he st u d y will use a n o n -i nferi orit y mar gi n of 0. 6 2  da y f or t he a b o ve 
c o m paris o n.  
T he n o n -i nferi orit y of S PI -2 0 1 2  t o pe gfil grasti m will be declare d if t he u p per b o u n d of 9 5 % CI of t he differe nce 
i n mea n D S N  bet wee n t he treat me nt ar ms is < 0. 6 2 da y s. Pri mar y a nal ysis f or t he  n o n -i nferi orit y h y p ot hesis will 
be base d o n  t he I T T Po p ul ati o n . An a nal ysis base d o n t he P er P r ot oc ol P o p ul ati o n  will be perf or me d as  a 
se nsiti vit y a nal ysis.  
F or t he sec o n dar y efficac y a nal yses, t he res ults will eac h be s u m marize d b y T reat me nt Ar m a n d C ycle . The t w o -
si de d 9 5 % CI f or t he differe nc e bet wee n t he treat me nt ar ms will be calc ulate d.  
F or safet y a nal ysis, t he n u m ber a n d perce nta ge of patie nts wit h a n y treat me nt-e mer ge nt A Es ( T E A Es ), a n y 
seri o us A Es (S A Es ), T E A Es relate d t o st u d y dr u gs, a n d T E A Es ca usi n g treat me nt disc o nti n uati o n  will be 
s u m marize d. A d verse E ve nts of S pecial I nterest ( A E SI) ( m usc ul os keletal pai n, i nj ecti o n site reacti o ns, a n d 
h y perse nsiti vit y reacti o ns ) will b e assesse d a n d s u m marize d b y Preferre d T er m.  A n e x p os ure -res p o nse a nal ysis 
will b e perf or me d base d o n s p ar se P K sa m pli n g. 
Sa m ple size esti mates are base d o n a n o n -i nferi orit y desi g n. T he mar gi n of n o n-i nferi orit y is 0. 6 2 da ys. T he tr ue 
differe nce bet wee n t he mea ns is ass u me d t o be 0. 0 da ys. Sa m ple sizes of 1 0 9  per treat me nt ar m will pr o vi de 
9 0 %, 8 6 %, a n d 8 1 % p o wer t o detect n o n -i nferi orit y usi n g a o ne-si de d, t w o-sa m ple t-test at 2. 5 % le vel of 
si g nifica nce, w he n t he p o ole d sta n dar d de viati o n ( S D) of t he D S N  is 1.4 , 1.5 , or 1.6  da ys, res pecti vel y. T he 
p o ole d S D will be m o nit ore d i n t he o n g oi n g sister st u d y S PI -G C F -3 0 1 . If t he p o ole d S D i n t he sister st u d y is 
esti mate d t o be greater t ha n 1. 4  da ys, t he sa m ple size ma y b e i ncrease d t o reflect t he p ote ntial e xtra varia bilit y 
f or t he c urre nt st u d y. Si nce t he i nf or mati o n t hat ma y be use d is i n de p e n de nt of t he c urre nt stu d y res ults, t he 
n o mi nal t y pe I err or is preser ve d f or t he c urre nt st u d y.   
T he st u d y will e nr oll a n d ra n d o mize a p pr o xi matel y 1 0 9  patie nts per ar m f or a t otal of a p pr o xi matel y 
2 1 8  patie nts.  
Versi o n/ D ate : 2 8  J ul 2 0 1 7  
 
 








S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
1 1  
T A B L E O F C O N T E N T S  
I N V E S TI G A T O R SI GN A T U R E  ..................................................................................................2  
T A B L E O F C O N T E N T S  ............................................................................................................1 1  
List of T a bles  ..........................................................................................................................1 4  
List of Fi g ures  .........................................................................................................................1 4  
LI S T O F A B B R E VI A TI O N S  .....................................................................................................1 5  
1  
I N T R O D U C TI O N ................................................................................................................1 7  
1. 1  
B ac k gr o u n d  ................................................................................................................1 7  
1. 1. 1  
Bre ast C a ncer a n d R ole of Gr a n ul oc yte C ol o n y Sti m ul ati n g F a ct or  ...........1 7  
1. 1. 2  
S PI -2 0 1 2 ( Efl a pe gr asti m [ R ol o nti s ™]) ............................................................1 9  
1. 1. 2. 1  
N o ncli nic al St u dies  ........................................................................................1 9  
1. 1. 2. 2  
Cli nic al E x perie nce  .......................................................................................2 0  
1. 1. 2. 3  
P h ase 1 St u dies  ..............................................................................................2 0  
1. 2  
R ati o n ale f or t he C urre nt St u d y  ...............................................................................2 4  
2  
S T U D Y O B J E C TI V E S  ........................................................................................................2 5  
2. 1  
Pri m ar y O bjecti ve  ......................................................................................................2 5  
2. 2  
Ke y Sec o n d ar y O bjecti ves  .........................................................................................2 5  
2. 3  
A d diti o n al Sec o n d ar y O bjecti ves  .............................................................................2 5  
3  
I N V E S TI G A TI O N A L P L A N ..............................................................................................2 6  
3. 1  
St u d y Desi g n a n d Tre at me nt Pl a n ............................................................................2 6  
3. 2  
St u d y a n d Tre at me nt D ur ati o n  ................................................................................2 8  
4  
P A TI E N T P O P U L A TI O N  ...................................................................................................2 9  
4. 1  
I ncl usi o n Criteri a .......................................................................................................2 9  
4. 2  
E xcl usi o n Criteri a  ......................................................................................................2 9  
4. 3  
P a ti e nt Disc o nti n u ati o n/ Wit h dr a w al Criteri a .........................................................3 0  
5  
S T U D Y P R O C E D U R E S  ......................................................................................................3 1  
5. 1  
Scree ni n g  .....................................................................................................................3 1  
5. 2  
P ati e nt Assi g n me nt  ....................................................................................................3 1  
5. 3  
Ti mi n g of Assess me nts a n d Pr oce d ures  ...................................................................3 1  
5. 3. 1  
Scree ni n g ( D a ys -3 0 t o -1)  .................................................................................3 1  
5. 3. 2  
Tre at me nt Peri o d –  C ycle 1, D a y 1 ( B aseli ne)  ................................................3 2  
5. 3. 3  
Tre at me nt Peri o d –  C ycle 1, D a y 2  ..................................................................3 2  
5. 3. 4  
Tre at me nt Peri o d –  C ycle 1, D a ys 4 t o 2 1  .......................................................3 3  
5. 3. 5  
Tre at me nt Peri o d –  C ycles 2 t o 4, D a y 1  .........................................................3 3  
5. 3. 6  
Tre at me nt Peri o d –  C ycles 2 t o 4, D a y 2  .........................................................3 3  
5. 3. 7  
Tre at me nt Peri o d –  C ycles 2 t o 4, D a ys 3 t o 2 1  ..............................................3 3  
5. 3. 8  
E n d -of -Tre at me nt Visit ( At t he e n d o f C ycle 4 or A p pr o xi m atel y 3 5 ( ± 5) 
d a ys After D ate of E arl y Disc o nti n u ati o n) ....................................................3 4  
5. 3. 9  
1 2 M o nt h S afet y F oll o w -u p  ...............................................................................3 4  
5. 3. 9. 1  
Tele p h o ne C o nt act  .........................................................................................3 4  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
1 2  
5. 3. 9. 2  
Cli nic Visit  .....................................................................................................3 4  
5. 3. 1 0  
E n d of St u d y Visit ( M o nt h 1 2 Visit or 3 5 ( ± 5) d a ys after e arl y 
disc o nti n u ati o n)  ...............................................................................................3 5  
5. 4  
Descri pti o n of St u d y Assess me nts a n d Pr o ce d ures .................................................3 5  
5. 4. 1  
E x pl a n ati o n of St u d y a n d O bt ai ni n g Writte n I nf or me d C o nse nt  ................3 5  
5. 4. 2  
Me dic al Hist or y  .................................................................................................3 5  
5. 4. 3  
Re vie w I ncl usi o n/ E xcl usi o n Criteri a  ...............................................................3 5  
5. 4. 4  
R a n d o miz ati o n  ...................................................................................................3 5  
5. 4. 5  
P h ysic al E x a mi n ati o n  ........................................................................................3 5  
5. 4. 6  
E C O G Perf or m a nce St at us  ..............................................................................3 6  
5. 4. 7  
Vit al Si g n Assess me nts  ......................................................................................3 6  
5. 4. 8  
B o d y Te m per at ure  .............................................................................................3 6  
5. 4. 9  
C o m plete Bl o o d C o u nt  ......................................................................................3 6  
5. 4. 1 0  
C he mistr y  ...........................................................................................................3 7  
5. 4. 1 1  
P h ar m a c o ki netic Assess me nts  ..........................................................................3 7  
5. 4. 1 2  
A nti -I nfecti ve Use ..............................................................................................3 7  
5. 4. 1 3  
I m m u n o ge nicit y Testi n g ...................................................................................3 7  
5. 4. 1 4  
A d verse E ve nt  ....................................................................................................3 8  
5. 4. 1 5  
C o nc o mit a nt Me dic ati o ns  .................................................................................3 8  
6  
S T U D Y D R U G A N D P H A R M A C E U TI C A L I N F O R M A TI O N  .....................................3 8  
6. 1  
S PI -2 0 1 2  ......................................................................................................................3 8  
6. 1. 1  
S PI -2 0 1 2 C o m p ositi o n  .......................................................................................3 8  
6. 1. 2  
S PI -2 0 1 2 St or a g e a n d H a n dli n g  .......................................................................3 8  
6. 1. 3  
S PI -2 0 1 2 A d mi nistr ati o n  ..................................................................................3 8  
6. 2  
Pe gfil gr asti m  ...............................................................................................................3 9  
6. 2. 1  
Pe gf il gr asti m C o m p ositi o n ...............................................................................3 9  
6. 2. 2  
Pe gfil gr asti m S u p pl y  .........................................................................................3 9  
6. 2. 3  
Pe gfil gr asti m St or a g e a n d H a n dli n g  ................................................................3 9  
6. 2. 4  
Pe gfil gr asti m A d mi nist r ati o n  ...........................................................................3 9  
6. 3  
Bli n di n g of St u d y Tre at me nts  ...................................................................................3 9  
6. 4  
R a n d o miz ati o n of St u d y Tre at me nts  .......................................................................3 9  
6. 5  
N o n -st u d y Tre at me nts ...............................................................................................3 9  
6. 5. 1  
Pri o r a n d C o nc o mit a nt Me dic ati o ns  ...............................................................3 9  
6. 5. 2  
Pr o hi bite d T her a pies or Me dic ati o ns  ..............................................................4 0  
7  
S A F E T Y A S S E S S M E N T  .....................................................................................................4 0  
7. 1  
S afet y Me as ures  .........................................................................................................4 0  
7. 2  
A d verse E ve nts  ...........................................................................................................4 0  
7. 3  
G ui del i nes f or Rec or di n g a n d Attri b uti o n Sc ori n g of A d verse E ve nts ................4 1  
7. 3. 1  
Rec or di n g of A d verse E ve nts  ...........................................................................4 1  
7. 3. 2  
Gr a di n g of A d verse E ve nts  ...............................................................................4 2  
7. 4  
F oll o w -u p of A d verse E ve nts  ....................................................................................4 2  
7. 5  
Rel ati o ns hi p  ................................................................................................................4 2  
7. 6  
E x pecte d ness  ...............................................................................................................4 3  
7. 7  
Seri o us A d verse E ve nts  .............................................................................................4 3  
7. 7. 1  
Seri o us A d verse E ve nt Re p orti n g  ....................................................................4 4  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
1 3  
7. 7. 2  
E xcl usi o ns t o Seri o us A d verse E ve nt Re p orti n g Re q uire me nts  ....................4 5  
7. 8  
Re pr o d ucti ve Ris ks  ....................................................................................................4 5  
8  
S T A T I S TI C A L P L A N..........................................................................................................4 5  
8. 1  
S a m ple Size  .................................................................................................................4 5  
8. 2  
Met h o d of Tre at me nt Assi g n me nt, R a n d o miz ati o n, a n d/ or Str atific ati o n  ..........4 6  
8. 3  
A n al ysis P o p ul ati o ns  ..................................................................................................4 6  
8. 4  
Ge ner al St atistic al Met h o ds  ......................................................................................4 6  
8. 5  
Effic ac y A n al yses  .......................................................................................................4 6  
8. 5. 1  
Pri m ar y E n d p oi nt  ..............................................................................................4 6  
8. 5. 2  
Ke y Sec o n d ar y E n d p oi nts  .................................................................................4 8  
8. 5. 3  
A d diti o n al Sec o n d ar y E n d p oi nts  .....................................................................4 8  
8. 6  
A n al ysis of S afet y  .......................................................................................................4 8  
8. 7  
Cli nic al L a b or at or y a n d Vit al Si g ns E v al u ati o ns  ...................................................4 9  
9  
A D MI NI S T R A TI V E P R O C E D U R E S A N D S T U D Y M A N A G E M E N T  ........................4 9  
9. 1  
I n vesti g at or Res p o nsi bilities .....................................................................................4 9  
9. 1. 1  
G o o d Cli nic al Pr a ctice  ......................................................................................4 9  
9. 1. 2  
I nstit uti o n al Re vie w B o ar d/ Et hics C o m mittee A p pr o v al ..............................5 0  
9. 1. 3  
I nf or me d C o nse nt ..............................................................................................5 0  
9. 1. 4  
St u d y Files a n d Rete nti o n of Rec or ds  ..............................................................5 0  
9. 2  
Rec or di n g a n d C ollecti n g of D at a  ............................................................................5 0  
9. 2. 1  
C ase Re p ort F or ms  ............................................................................................5 0  
9. 2. 2  
Dr u g Acc o u nt a bilit y  ..........................................................................................5 0  
9. 3  
Pr ot oc ol C o m pli a nce  ..................................................................................................5 1  
9. 4  
S p o ns or Res p o nsi bilities  ............................................................................................5 1  
9. 4. 1  
St u d y M o nit ori n g  ...............................................................................................5 1  
9. 4. 2  
S afet y M o nit ori n g  ..............................................................................................5 1  
9. 5  
J oi nt I n vesti g at or/ S p o ns or Res p o nsi bilities  ............................................................5 1  
9. 5. 1  
Access t o I nf or m ati o n f or M o nit ori n g a n d A u diti n g  .....................................5 1  
9. 5. 2  
Ter mi n ati o n of t he St u d y  ..................................................................................5 1  
9. 5. 3  
P u blic ati o n P olic y  ..............................................................................................5 2  
9. 6  
C o nfi de nti alit y  ............................................................................................................5 2  
1 0  R E F E R E N C E S  .....................................................................................................................5 3  
A P P E N DI X 1  
S C H E D U L E O F A S S E S S M E N T S A N D P R O C E D U R E S - C Y C L E 1  ......5 6  
A P P E N DI X 2  
S C H E D U L E O F A S S E S S M E N T S A N D P R O C E D U R E S - C Y C L E S 2 T O 
4  
5 7  
 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
1 4  
List of T a bles  
T a ble 1  
Re p orte d I nci de nce of Fe brile Ne utr o pe ni a Ass oci ate d wit h T C as A dj u v a nt 
T her a p y wit h a n d wit h o ut G -C S F Pr o p h yl a xis i n P atie nts wit h E arl y -St a ge 
Bre ast C a ncer  ............................................................................................................1 8  
T a ble 2  
S u m m ar y of Tre at me nt -Rel ate d Tre at me nt -E mer ge nt A d verse E ve nts ( ≥5 %) 
b y Preferre d Ter m -P h ase 2 St u d y S PI -G C F -1 2 -2 0 1  .............................................2 3  
T a ble 3  
S u m m ar y of Seri o us Tre at me nt -E mer g e nt A d v erse E ve nts b y Preferre d Ter m -
P h ase 2 St u d y - S PI -G C F -1 2 -2 0 1  .............................................................................2 4  
T a ble 4  
E aster n C o o per ati ve O nc ol o g y Gr o u p St at us  ........................................................3 6  
T a ble 5  
I n vesti g at or Assess me nt of A d verse E ve nt C a us alit y ............................................4 2  
 
List of Fi g ures  
Fi g ure 1  
Me di a n A bs ol ute Ne utr o p hil C o u nt O ver Ti me - C ycle 1 - S PI -G C F -1 2 -2 0 1  .....2 2  
Fi g ure 2  
St u d y Des i g n Di a gr a m ..............................................................................................2 7  
 
 
 






S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
1 7  
1  I N T R O D U C TI O N 
1. 1  B ac k gr o u n d  
1. 1. 1  Bre ast C a ncer  a n d R ole of Gr a n ul oc yte C ol o n y Sti m ul ati n g F a ct or  
Acc or di n g t o t he A merica n Ca ncer S ociet y ( A C S), breast c a ncer is o ne of t he m ost c o m m o n 
f or ms of ca n cer a n d t he s ec o n d hi g hest ca us e of ca ncer deat hs i n w o me n [1 ]. I n 2 0 1 4 i n t he 
U nite d States ( U S) , a n esti mate d 2 3 2,6 7 0 ne w cas es of i n vasi ve breast ca n cer a n d 6 2, 5 7 0  
a d diti o nal cases of i n sit u breast c a ncer occ urre d, a n d a p pr o xi matel y 4 0, 4 3 0  U S w o me n were 
e x pecte d t o die fr o m breast c a ncer. I n a d diti o n, breast ca ncer is als o see n i n males, wit h  a n 
esti mate d 2 3 6 0  me n bei n g dia g n os e d wit h breast c a ncer a n d 4 1 0 d yi n g  fr o m t he disease i n 2 0 1 3. 
Data s h o w t hat m ortalit y rates fr o m breast c a ncer i ncreas e wit h a ge, reac hi n g a p ea k w he n 
patie nts are i n t heir 7 0s  [1 ].  
T he Nati o na l C o m pre he nsi ve Ca ncer Net w or k ( N C C N) cli nical g ui deli nes rec o m me n d t hat m ost 
patie nts wit h earl y -sta ge breast c a ncer ( E S B C) recei ve a dj u va nt c h e m ot hera p y after t he y ha v e 
u n der g o ne c o m plet e s ur gical e x cisi o n of t he pri mar y t u m or b y l u m pect o m y a n d a xillar y 
dissecti o n or m o difie d ra dical mastect o m y  [2 ]. C urre nt N C C N g ui deli nes f or a dj u va nt 
c he m ot hera p y re gi me ns t o treat E S B C  i ncl u de d o ceta xel, d o x or u bici n, a n d c ycl o p h os p ha mi de 
( T A C); d ose de nse d o x or u bici n pl us c ycl o p h os p h a mi de ( A C), wit h or wit h o ut s u bse q ue nt 
wee kl y or se mi w ee kl y paclita x el; a n d d oceta xel pl us c ycl o p h os p ha mi de ( T C).  
T he use of a dj u v a nt c he m ot hera p y t o i m pr o ve s ur vi val i n patie nts wit h E S B C has bee n wi del y 
a d o pte d [3 ]. T h e T C re gi me n is a n attracti ve t hera pe utic o pti o n beca use it h as de m o nstrate d 
effic ac y [4 ] a n d re d uce d ris k o f car di ot o xicit y c o m pare d wit h ot her t hera pies t hat c o ntai n 
a nt hrac ycli n es  [5 ]. U S O 9 7 3 5  was a pi v otal P hase 3 trial t hat c o m pared  T C vs. A C a m o n g 
patie nts wit h o pera ble E S B C  [6 ]. Trial res ults s h o we d t hat after 7 years of f oll o w -u p, 4 c ycles of 
T C were ass o ciate d wit h si g nifica ntl y i m pr o ve d Disease Free S ur vi v al (D F S ) a n d O verall 
S ur vi val ( O S ) c o m pare d wit h 4 c ycl es of A C. S pecificall y, t he  D F S  was 8 1 % a n d 7 5 % f or T C 
a n d A C, res pecti vel y, a n d t he O S  was 8 7 % a n d 8 2 %, res pecti vel y. Alt h o u g h t he T C re gi me n has 
n ot bee n ass ociat e d wit h car di ot o xicit y  [4 , 6 , 7 ], it has bee n ass o ciate d wit h ot her a d verse e v e nts, 
partic ularl y he mat ol o gic t o xicities  [4 , 6 ].  
I n U S O 9 7 3 5 , the re p orte d rates  of F e brile N e utr o pe ni a  (F N ) were 4 % i n w o me n y o u n ger t ha n 
6 5  years a n d 8 % i n t h ose 6 5 years or ol d er , alt h o u g h F N  was n ot a pre -pla n ne d e val ua bl e 
e n d p oi nt i n t he trial [4 ]. N o d ose re d u cti o ns were per mitte d, a n d patie nts w ere ta ke n off 
treat me nt if a n y st u d y dr u g a d mi nistrati o n was d ela ye d b y m ore t ha n 2 wee ks beca us e of dr u g-
relate d t o xicities. Pr o p h ylactic use of q ui n olo ne a nti bi otics was rec o m me n de d at t he discreti o n of 
t he treati n g p h ysicia n. Pr o p h yla ctic gra n ul oc yt e c ol o n y-sti m ulati n g fact or (G -C S F ) was n ot 
all o we d, a n d reacti ve G -C S F  s u p p ort f or c he m ot h era p y-i n d u ce d ne utr o p e nic c o m plicati o ns was 
n ot s pecifie d  [4 ]. 
S u bse q ue nt re p orts ha v e s u g geste d t h at T C is ass ociate d wit h  hi g h er rates of  F N  t ha n t h ose 
re p orte d i n U S O 9 7 3 5 , ra n gi n g fr o m 2 5 % t o 5 0 % i n t he a bse nce of G -C S F  s u p p ort a n d 
decreasi n g t o 0 % t o 6. 3 % wit h pri mar y G -C S F pr o p h yla xis (T a ble 1 ) [8 -1 2 ]. 




S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
1 9  
De vel o p me nt of F N  i n creases dia g n ostic a n d treat me nt c osts, a n d ofte n lea ds t o pr ol o n ge d 
h os pitaliz ati o ns. I n a d diti o n, c ha n ges i n ne utr o p hil c o u nts ha ve bee n c o rrelate d wit h q ualit y of 
life, as meas ur e d b y p h ysical f u ncti o ni n g, vitalit y, a n d me ntal healt h  [1 8 ].  
Fil grasti m, t b o -fil grasti m, a n d pe gfil grasti m are G -C S Fs c urre ntl y a p pr o ve d b y t he U S F o o d a n d 
Dr u g A d mi nistrati o n ( F D A) f or t he pre ve nti o n of c he m ot hera p y -i n d uce d n e utr o pe nia [1 5 ]. W hile 
t he E ur o pea n g ui d eli nes als o i ncl u de le n o grasti m as a rec o m me n de d G -C S F i n s oli d t u m ors a n d 
n o n -m yel oi d mali g na n cies, it is n ot a p pr o ve d f or use i n t he U S.  
St u dies ha ve de m o nstrate d t hat t he use of G -C S F ca n re d uce t he ris k, se v erit y, a n d d urati o n of 
F N  [1 5 ]. G ui deli nes fr o m t he A merica n S ociet y of Cli nical O nc ol o g y ( A S C O), t he E ur o pea n 
Or ga niz ati o n f or Researc h a n d Treat me nt of Ca ncer ( E O R T C) G ui d eli nes , as well as  N C C N 
rec o m me n d t he us e of G-C S F as pri mar y pr o p h yla xis w he n t he a ntici pate d ris k of F N  f or a 
patie nt i nitiati n g c he m ot hera p y is hi g h  [1 5 , 1 9 , 2 0 ].  
1. 1. 2  S PI -2 0 1 2  (Efl a pe gr asti m [R ol o ntis ™]) 
S pectr u m P har mace uticals, I nc. ( S pectr u m) is de v el o pi n g a n o v el, l o n g -acti n g f or m of G -C S F, 
S PI -2 0 1 2  (als o k n o w n as H M 1 0 4 6 0 A, L o n g Acti n g Pr otei n/ Pe pti de Disc o v er y Platf or m 
Tec h n ol o g y -G -C S F  [ L A P S-G -C S F ]), a c he micall y c o nj u gate d f or m  of a m o difie d G -C S F , f or 
t he i n dicati o n of t he re d u cti o n i n t he D ur ati o n of Se vere Ne utr o pe ni a  (D S N ) a n d i nci de nce of 
i nfecti o n, as ma nifest e d b y F N  i n p atie nts wit h s oli d t u m ors a n d n o n-m yel oi d mali g na nci es 
recei vi n g m yel os u p pressi ve a nti-ca n cer t hera p y. S PI -2 0 1 2  is a n o v el bi ol o gic a n d n ot a 
bi osi milar t o eit her fil grasti m or pe gfil grasti m.  
S PI -2 0 1 2  is pr o d uce d b y c o nj u gati n g a n o vel, m o difie d rec o m bi na nt h u ma n G -C S F ( wit h n o 
a d diti o nal N-ter mi nal Met, referre d t o as H M 1 0 4 1 1), a n d t he h u ma n i m m u n o gl o b uli n G 4 Fc 
fra g me nt (referre d t o as H M C 0 0 1) vi a a 3. 4 k Da p ol yet h yle ne gl yc ol ( P E G) li n ker t o pr o d uce  a 
ne w, l o n g -acti n g G -C S F . 
H M 1 0 4 1 1 a n d H M C 0 0 1 are eac h ma n ufact ure d usi n g rec o m bi na nt -D N A tec h n ol o g y i n E.  c oli. 
S pecificall y, H M 1 0 4 1 1 is pr o d uce d b y fer me ntati o n of tra nsf or m e d E. c oli i n t he peri plas mic 
s pace f oll o w e d b y har vesti n g a n d p urifi cati o n. W hereas H M C 0 0 1 is pr o d uce d b y fer m e ntati o n of 
tra nsf or me d E. c oli as a n i ncl usi o n b o d y f oll o we d b y har vesti n g, ref ol di n g, a n d p urificati o n.  
T he h u ma n i m m u n o gl o b uli n G 4 F c fra g me nt ( H M C 0 0 1) was s pecificall y c h ose n as t he 
c o nj u gati o n part ner f or t his n o vel G-C S F  beca use it has a l o n g i n viv o h alf -life of se veral wee ks. 
Details of t he pr o d uct’s c haract eristics ca n b e f o u n d i n t he In v esti gat or’s  B r oc h ure (I B).  
1. 1. 2. 1  N o ncli nic al St u dies  
T he  bi ol o gical  res p o nse t o r h-G -C S F  is n ot  s pecies s pecific, a n d t heref ore t he bi ol o gical  
res p o nse of r h-G -C S F h as bee n e x a m i ne d i n m ice, rats, d o gs, a n d m o n ke ys i n si n gle - a n d re peat -
d ose st u die s.  M o use  b o n e  marr o w  cells, c hem ot hera p y -i n d uce d ne utr o pe nic  m o use  a n d rat 
m o dels, n or m al a n d n e p hrect o m ize d rats, a n d c y n om ol g us  m o n ke ys  ha ve  all bee n  use d  t o 
st u d y t he e ffects of S PI -2 0 1 2 . All t o xic ol o g y stu dies w ere pe rf orm e d u n der G o o d La b orat or y 
Practice ( G L P)  c o n diti o ns.  
T he ki netics of ne utr o p hil pr oliferati o n i n ne utr o p e nic mice a n d rats sti m ulate d wit h S PI -2 0 1 2 , 
pe gfil grasti m, a n d f il grasti m were als o c o m pare d. S PI -2 0 1 2  was s h o w n t o ha ve a n 
a p pr o xi matel y 2 -f ol d hi g her Area U n d er t he Ti me -C o nce ntrati o n c ur ve ( A U C)  f or A bs ol ute 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
2 0  
Ne utr o p hil C o u nt ( A N C) w he n c o m pare d t o pe gfil grasti m at si milar d oses (ie, w he n c o m pari n g 
e q ui vale nt G -C S F c o n ce ntrati o ns of t he c o m p o u n ds). Bas e d o n t hese res ults, S PI -2 0 1 2  was 
esti mate d t o ha ve t wice t he i n viv o p ote nc y as pe gfil grasti m. T he p ote ntial c li nical be nefit of t he 
i ncreas e d p ote nc y of S PI -2 0 1 2  was a n al yze d b y c o m pari n g t he D S N  i n ne utr o pe nic rats t o t he 
D S N  res p o nse t o pe gfil grasti m a n d fil grasti m i n t his sa me m o del. S PI -2 0 1 2  was f o u n d t o be 
m ore p ote nt i n s h orte ni n g t he D S N  wit h a l o wer G -C S F  e q ui vale nt d ose w he n c o m pare d t o 
eit her pe gfil grasti m or fil grasti m. T he D S N  was 0. 2 da ys w he n S PI -2 0 1 2  was c o -a d mi nistere d or 
se q ue ntiall y a d mi nistere d as a si n gl e d ose at 8 8 µ g/ k g (as G-C S F e q ui val e nt) wit h c he m ot hera p y 
dr u gs i n r ats. I n c o ntr ast, t he D S N  was 3. 0 4 da ys wit h fil grasti m a d mi nistere d at d ose of 
2 0  µ g/ k g f or 5 da ys a n d was 2. 8 da ys wit h pe gfil grasti m a d mi nistere d as a si n gle d ose of 
1 0 0  µ g/ k g.  
I n c y n o m ol g us m o n ke ys, ne utr o p hil c o u nts i ncrease d as S PI -2 0 1 2  d ose le vels i ncreas e d ( 1 6 1. 4 8 
t o 3 2 2. 9 6 μ g/ k g S PI -2 0 1 2 ,) b ut were n ot d os e -pr o p orti o nal. Ma xi m u m ne utr o p hil le vels pea ke d 
o n D a y 1  p ost -d ose, decrease d b y D a y 7  f oll o wi n g I V a d mi nistrati o n, pea k e d o n D a y 3  p ost -
d ose, a n d t he n decrease d b y D a y 1 6  f oll o wi n g S C a d mi nistrati o n of S PI -2 0 1 2 . S PI -2 0 1 2  als o 
s h o we d a n a p pr o xi matel y 3-f ol d hi g h er A U C f or A N C c o m pare d t o p e gfil grasti m at t he sa me 
G -C S F e q ui vale nt d osi n g le vel.  
1. 1. 2. 2  Cli nic al E x perie nce  
1. 1. 2. 3  P h ase 1 St u dies  
T w o P hase 1  st u dies of S PI -2 0 1 2  (0 8 -H M 1 0 4 6 0 -1 0 1 , N = 6 0; 0 9 -H M 1 0 4 6 0 -1 0 1 , N = 3 0) were 
c o n d ucte d i n he alt hy  v ol u nteers t o e val u ate t he safet y a n d t he p har mac o ki n etic ( P K) a n d 
p har mac o d y n a mic pr o perties of S PI -2 0 1 2 . M ost a d verse e v e nts ( A Es) re p orte d i n t hese st u dies 
were mil d a n d c o m p ara bl e t o t h ose re p orte d i n ot h er cli nical trials wit h pe gfil grasti m. C o m m o n 
treat me nt-relate d A Es i n cl u de d b o ne pai n, b ac k p ai n, a n d hea d ac h e. N o cli nicall y si g nifica nt 
c ha n ges w ere f o u n d i n el ectr ocar di o gra m ( E C G), vit al si g ns, or s ple nic e v al uati o n.  Is olate d cases 
of tac h ycar dia , p al pitati o n , a n d tra nsie nt ele vati o ns of li ver e nz y mes were s ee n i n s o me patie nts . 
O verall i n t he P hase 1 st u dies i n healt h y v ol u nteers, d oses of  S PI -2 0 1 2  bet wee n  1. 1 µ g/ k g a n d 
3 5 0 µ g/ k g were ge n erall y w ell -t olerate d a n d i ncrease d w hite bl o o d cell ( W B C) a n d ne utr o p hil  
c o u nts  i n a pro n o u nce d a n d d ose -de pe n d e nt ma n n er.  
1. 1. 2. 3. 1  P h ase 2 St u d y - S PI -G C F -1 2 -2 0 1  
A P hase 2, o pe n -la b el, d ose-ra n gi n g, st u d y (S PI -G C F -1 2 -2 0 1 , N = 1 4 8) has als o bee n c o m plete d. 
T his st u d y c o m pare d t hree wei g ht -bas e d d oses of S PI -2 0 1 2  ( 4 5, 1 3 5, a n d 2 7 0 µ g/ k g) vers us 
pe gfil gr asti m ( 6 m g) f or t he ma na ge m e nt of ne utr o pe nia i n breast ca ncer patie nts recei vi n g T C 
c he m ot hera p y, a n d pr o vi des safet y a n d effi cac y d ata s u p p orti n g a d va n ce m e nt t o P hase 3 a n d t he 
basis f or t he fi x e d d ose rec o m me n dati o n. Brief res ults are prese nte d bel o w a n d a d diti o nal res ults 
are prese nte d i n t he I n vesti gat or’s Br oc h ure (I B).  
1. 1. 2. 3. 1. 1  St u d y Desi g n  
S PI -G C F -1 2 -2 0 1  wa s a P hase 2, o pe n-la bel st u d y t o assess t he effect of test d oses of S PI -2 0 1 2  
o n t he D S N  d uri n g C ycle 1  i n patie nts wit h breast ca ncer w h o were ca n di dates f or a dj u va nt or  
ne oa dj u va nt c h e m ot hera p y wit h t he d oceta xel a n d c ycl o p h os p ha mi de ( T C).  
T he st u d y i ncl u d e d 4 si n gle -d os e treat me nt ar ms:  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
2 1  
•  Ar m 1 : S PI -2 0 1 2  ( 4 5 μ g/ k g) 
•  Ar m 2 : S PI -2 0 1 2  ( 1 3 5 μ g/ k g) 
•  Ar m 3 : S PI -2 0 1 2  ( 2 7 0 μ g/ k g) 
•  Ar m 4 : Pe gfil grasti m ( 6 m g) 
A d mi nistrati o n of T C o n D a y 1  of eac h c ycl e I V was:  
•  D oceta x el at 7 5 m g/ m 2 I V i nf usi o n o ver 1 h o ur 
•  C ycl o p h os p ha mi de 6 0 0 m g/ m 2 I V i nf usi o n o ver 3 0 t o 6 0 mi n utes 
Eac h treat me nt c ycle was 2 1 da ys wit h u p t o a ma xi m u m of 4 c ycl es of c h e m ot hera p y. T o be gi n 
f ull-d ose c he m ot hera p y o n D a y 1  of t he ne xt c ycl e ( D a y 2 2  of t he pre vi o us c ycle), p atie nts m ust 
ha ve rec o vere d t o a n A N C greater t ha n 2. 0 × 1 0 9/ L a n d a platelet c o u nt ≥1 0 0 × 1 0 9/ L. 
S PI -2 0 1 2  w as a d mi nistere d o n D a y 2  of eac h c ycl e, a p pr o xi matel y 2 4 t o 2 6 h o urs  after T C 
c he m ot hera p y. T he d ose of S PI -2 0 1 2  a d mi nistere d de pe n de d o n t he tr eat m e nt ar m t o w hic h eac h 
patie nt was assi g ne d. Pe gfil grasti m was t o be a d mi nistere d acc o r di n g t o t he ma n ufact ur er’s 
Prescri bi n g I nf or m ati o n ( 6 m g s u bc uta ne o usl y o n ce per c h e m ot hera p y c ycl e).  
1. 1. 2. 3. 1. 2  Dis p ositi o n a n d De m o g r a p hics  
I n S PI -G C F -1 2 -2 0 1 , 1 4 8 patie nts were ra n d o mize d i nt o t he 4 treat me nt ar ms. M ost patie nts 
( 1 4 7 patie nts [ 9 9 %]) c o m plete d at least 1 c ycl e of treat me nt. Te n  p atie nts ( 7 %) disc o nti n ue d 
fr o m t he st u d y. T hree p atie nts ( 2 %) wit h dre w c o nse nt, t w o patie nts ( 1 %) disc o nti n ue d d ue t o 
a d verse e ve nts, a n d fi ve patie nts disc o nti n ue d f or ot her reas o ns. F o ur patie nts ( 2 patie nts eac h i n 
t he 13 5 μ g/ k g  S PI -2 0 1 2  gr o u p [ o ne patie nt wit h dre w c o nse nt a n d o ne patie nt i nitiate d a n o n -
pr ot oc ol t hera p y]  a n d 2 7 0 μ g/ k g S PI -2 0 1 2  d os e gr o u p  [ b ot h patie nts wit h dre w c o ns e nt]) 
disc o nti n ue d pri or t o be gi n ni n g C ycle 2  a n d 1 3 8 p atie nts ( 9 3 %) were tr eate d f or all 4 c ycl es.  
T he mea n a ge of all patie nts i n S PI -G C F -1 2 -2 0 1  was 5 8. 2 years a n d ra n ge d fr o m 3 2 years t o 
7 7  years acr oss all gr o u ps. M ost patie nts were less t ha n 6 5 years of a ge ( n = 1 0 0 [ 6 8 %]), fe male 
(n = 1 4 4 [ 9 8 %]), a n d W hite ( n = 1 3 9 [ 9 5 %]). T here were 3 mal e patie nts i n t he st u d y, t w o i n t he 
2 7 0 µ g/ k g S PI -2 0 1 2  gr o u p a n d o ne i n t he 1 3 5  µ g/ k g S PI -2 0 1 2  gr o u p.  
D uri n g C ycle 1 , m ost patie nts ( ≥6 4 %) i n all t hree S PI -2 0 1 2  d ose gr o u ps a n d t he pe gfil grasti m 
gr o u p di d n ot de v el o p ne utr o pe nia ; at S PI -2 0 1 2  d oses ≥1 3 5 µ g/ k g, t he pr o p orti o n of patie nts n ot 
e x perie nci n g n e utr o pe ni a was c o m para ble or hi g h er t o t he i nci de nce wit h p e gfil grasti m.  
1. 1. 2. 3. 1. 3  D ur ati o n of Se vere Ne utr o pe ni a  
I n t he 2 7 0 µ g/ k g S PI -2 0 1 2  gr o u p, n e utr o pe nia was re p orte d i n o nl y o ne pati e nt ( 3 %), w hic h 
laste d o nl y 1 da y. I n t he 1 3 5 µ g/ k g S PI -2 0 1 2  gr o u p, se ve n patie nts ( 1 9 %) e x perie nce d 
ne utr o pe nia, w hic h l aste d f or 1  da y i n t hree patie nts ( 8 %), 2 da ys i n t hree patie nts ( 8 %), a n d 
7  da ys i n o n e patie nt ( 3 %). A p pr o xi matel y o ne -t hir d of patients i n t he 4 5 µ g/ k g S PI -2 0 1 2  gr o u p 
e x perie nce d ne utr o pe nia t hat laste d bet wee n 1 t o 5 da ys. I n t he pe gfil grasti m gr o u p, fi v e patie nts 
( 1 4 %) e x perie n ce d ne utr o pe nia, w hic h laste d f or 1 da y i n o n e patie nt ( 3 %), 2 da ys i n t w o 
patie nts ( 6 %), a n d 3 d a ys i n t w o patie nts ( 6 %). T h e ma g nit u de of D S N  a n d t he mea n val ues i n 
t he vari o us treat me nt ar ms ma y be m uc h l o wer i n t his st u d y as c o m pare d t o t hat i n t he literat ure 








S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
2 5  
cli nical be nefits of t he pr o p h yla ctic use of G -C S F  f or patie nt safet y, t o ma xi mize treat me nt 
i nte nsit y a n d o utc o mes, a n d c ost -effi cie nc y.  
P har mac ol o gical a n al ysis  of S PI -2 0 1 2  i n vi v o re v eale d a 2- t o 3-f ol d i ncrease i n t he A U C of t he 
A N C at G -C S F -e q ui v ale nt d oses si milar t o pe gfil grasti m. Cli nical e x perie nce fr o m t he P has e 2 
trial (S PI -G C F -1 2 -2 0 1) i n breast c a ncer patie nts h as s h o w n t hat S PI -2 0 1 2  is n o n-i nferi or t o 
pe gfil grasti m an d has a si milar safet y pr ofile. All d oses of S PI -2 0 1 2  a d mi nistere d i n 
S PI -G C F --1 2 -2 0 1  w ere well t olerate d. N o si g nifi ca nt d ose -relate d t o xicities were o bser ve d. T he 
D S N  i n t he 1 3 5 µ g/ k g S PI -2 0 1 2  ar m was n o n -i nf eri or t o pe gfil grasti m i n C ycle 1  a n d t he D S N  
i n t he 2 7 0 µ g/ k g S PI -2 0 1 2  Treat me nt A r m was s u peri or t o t he Pe gfil gr asti m Tre at me nt Ar m . 
N o n -i nferi orit y i n D S N  was als o o bser ve d i n C ycles 2  t o 4  i n b ot h t he 1 3 5 µ g/ k g a n d 2 7 0 µ g/ k g 
treat me nt ar ms w h e n c o m pare d t o pe gfil grasti m. 
T he c urre nt P hase  3 st u d y  is desi g ne d t o e x pa n d o n t he i nf or mati o n o btai ne d i n t he P hase 2 trial 
a n d e val uat e t he efficac y, a n d safet y of S PI -2 0 1 2 , as c o m pare d wit h pe gfil grasti m (Ne ulasta 
[ N D C 5 5 5 1 3-1 9 0 -0 1 ] ma n ufact ur e d b y A m ge n i n t he U nite d States), i n breast ca ncer patie nts 
recei vi n g T C.  
T he d ose of S PI -2 0 1 2  t o be st u die d i n t his trial is 1 3. 2 m g S PI -2 0 1 2  e q ui v ale nt t o 3 . 6 m g 
G -C S F, a p pr o xi matel y h alf of t he G -C S F e q ui val e nt d ose i n 6 m g pe gfil grasti m. T his d ose was 
selecte d o n t he b asis of t he p har mac ol o gi cal a n d p har mac o d yn a mic data fr o m t he P hase  2 trial 
(S PI -G C F -1 2 -2 0 1 ).  
As a p plica ble, p atie nts w h o ha ve recei ve d at least o ne d ose of st u d y dr u g ( S PI -2 0 1 2  or 
pe gfil grasti m) will be f oll o we d f or 1 2 m o nt hs after t he last d ose of st u d y tr eat me nt f or safet y 
f oll o w-u p. P atie nts will visit t he cli nic at a p pr o xi matel y 6 m o nt hs a n d 1 2 m o nt hs f or a bl o o d 
dra w f or e val uati o n of i m m u n o ge nicit y a n d f or e v al uati o n of A Es, s u bse q ue nt a nti -ca n cer 
t hera p y, use of ot her m yel oi d  gr o wt h f act ors, a n d partici pati o n i n a n y ot her s u bse q ue nt cli nical 
trials. I n a d diti o n, patie nts  will als o be c o ntacte d b y tele p h o n e at a p pr o xi matel y 3  m o nt hs a n d 
9  m o nt hs f or e val uati o n of A Es, s u bse q ue nt a nti-ca ncer t hera p y, use of ot her m yel oi d gr o wt h 
fact ors, a n d p artici pati o n i n a n y ot her s u bse q ue nt cli nical trials.  
2  S T U D Y O B J E C TI V E S   
2. 1  Pri m ar y O bjecti ve  
•  T o c o m pare t h e efficac y of S PI -2 0 1 2  wit h pe gfil grasti m  i n patie nts wit h earl y-sta ge 
breast c a ncer recei vi n g d oceta xel a n d c ycl o p h os p ha mi de ( T C), as me a s ure d b y t he D S N  
i n C ycle 1  
2. 2  Ke y Sec o n d ar y O bjecti ves  
•  T o c o m pare S PI -2 0 1 2  wit h pe gfil grasti m i n:  
•  
Ti me t o A N C Rec o ver y i n C ycle 1  
•  
De pt h of A N C N a dir , defi ne d as t he p atie nt’s l o west A N C i n C ycle 1  
•  
I n ci de nce of F N  i n patie nts d uri n g C ycl e 1   
2. 3  A d diti o n al Sec o n d ar y O bjecti ves  
•  T o c o m pare S PI -2 0 1 2  wit h pe gfil grasti m i n:  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
2 6  
•  
D S N  i n C ycles 2 , 3 , a n d 4  
•  
I nci de nce of Ne utr o pe nic C o m plic ati o ns, i ncl u di n g a nti-i nf ecti ve use a n d 
h os pitaliz ati o ns i n patie nts d uri n g C ycl e 1   
•  
I n ci de nce of F N  i n C y cle s 2 , 3 , a n d 4  
•  
Rel ati ve D ose I nte nsit y  (R DI ) of T C i n C ycl es 1  t o 4  
•  
Safet y  
3  I N V E S TI G A TI O N A L P L A N 
3. 1  St u d y Desi g n  a n d Tre at me nt Pl a n  
T his is a P hase 3, ra n d o mize d, o pe n -la bel, acti ve -c o ntr olle d, m ultice nter  st u d y t o c o m pare t he 
effic ac y a n d s afet y of S PI -2 0 1 2  wit h pe gfil grasti m i n breast ca n cer patie nts treate d wit h T C 
c he m ot hera p y.  
A p pr o xi matel y 2 1 8  p atie nts will be e nr olle d a n d ra n d o mize d i n a 1: 1 rati o t o 2 treat me nt ar ms 
(Fi g ure 2 ):  
•  Tre at me nt Ar m 1  ( n = a p pr o xi matel y 1 0 9 ): S PI -2 0 1 2  (1 3. 2 m g/ 0. 6 m L fi x e d d ose 
S PI -2 0 1 2  e q ui v ale nt t o 3. 6  m g  G -C S F ) 
•  Tre at me nt Ar m 2  ( n =a p pr o xi matel y 1 0 9 ): Pe gfil grasti m ( 6 m g G -C S F / 0. 6 m L)  




S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
2 8  
Pri or t o T C c he m ot hera p y a d mi nistrati o n, patie nts ma y recei ve pre -me dicati o n s acc or di n g t o 
i nstit uti o nal sta n dar d of care. I ntr a ve n o us (I V) a d mi nistrati o n of T C o n D a y 1  of eac h c ycle will 
be as f oll o ws:  
•  D oceta x el 7 5 m g/ m 2 I V i nf usi o n per i nstit ute ’s sta n dar d of care 
•  C ycl o p h os p ha mi de 6 0 0 m g/ m 2 I V i nf usi o n per i nstit ute ’s sta n dar d of care 
Eac h c ycl e will be 2 1 da ys. O nl y 4 c ycles will be e val uate d f or t his st u d y. After C y cle 1, patie nts 
m ust ha ve A N C ≥1. 5  ×  1 0 9/ L a n d platelet c o u nt ≥1 0 0  ×  1 0 9/ L t o be gi n t he eac h of n e xt c ycl e s of 
c he m ot hera p y.  
T he st u d y dr u g ( S PI -2 0 1 2  or pe gfil grasti m) will be a d mi nistere d o n D a y 2 of eac h c ycle, 
a p pr o xi matel y 2 4 t o 2 6 h o urs  after t h e last d ose of T C c he m ot hera p y is gi v e n.  St u d y dr u g 
(S PI -2 0 1 2  or pe gfil grasti m) d ose m o dificati o ns are n ot all o we d.  
O n D a y 1  of eac h c ycle, patie nts will recei ve T C c he m ot hera p y, a n d safet y a n d effi cac y 
assess me nts will be perf or me d as o utli ne d i n  Secti o n 5. 3 . O n D a y 2  of eac h c ycle, patie nts will 
recei v e st u d y dr u g (S PI -2 0 1 2  o r pe gfil grasti m), a n d t he s pecifie d assess me nts will be perf or m e d. 
Patie nts will be m o nit ore d o n D a y 1 a n d D a ys 4 t o 1 5 i n C ycle 1 . If t he p artici pati n g site is 
n otifie d t hat t he  A N C is ≤1. 0  ×  1 0 9/ L at a n y ti me d uri n g C ycle 1 , t he n dail y C B Cs will be 
re q uire d u ntil A N C is ≥1. 5  ×  1 0 9/ L, after reac hi n g na dir. I n C ycl es 2 t o 4 , all patie nts m ust ha ve 
bl o o d sa m ples dra w n o n D a y 1  ( pri or t o c h e m ot hera p y a d mi nistrati o n), o n D a ys 4 , 7 , 1 0 , a n d 1 5  
( ± 1 da y f or eac h c ollecti o n ), a n d at t he E n d -of -Tre at me nt Visit . If t h e partici pati n g site is 
n otifie d t hat t he  A N C is ≤1. 0  ×  1 0 9/ L at a n y ti me d uri n g C ycles 2  t o 4 , t he n dail y C B Cs will be 
re q uire d u ntil t he A N C is ≥1. 5  ×  1 0 9/ L, after reac hi n g na dir, b ut bl o o d sa m ples m ust still be 
dra w n o n D a ys 4 , 7 , 1 0 , a n d 1 5 . A s a p plica ble, p atie nts w h o ha ve recei ve d at least o ne d ose of 
st u d y dr u g will be f oll o w e d f or a p pr o xi matel y 1 2  m o nt hs after t he last d ose of st u d y tr eat me nt 
f or safet y f oll o w-u p .  
3. 2  S t u d y a n d Tre at me nt D ur ati o n  
T he d urati o n of t he S PI -G C F -3 0 2  st u d y is a p pr o xi matel y 2 8  m o nt hs ( 1 6  m o nt hs f or e nr oll me nt 
a n d 1 2 m o nt hs of treat me nt/f oll o w -u p). T he t otal d urati o n of t he st u d y f or eac h patie nt i n 
S PI -G C F -3 0 2  will be f or a p pr o xi matel y 1 6 m o nt hs i ncl u di n g:  
•  Scree ni n g Peri o d : 3 0 da ys  
•  Tre at me nt Peri o d : 4 c ycles, 2 1 da ys per c ycle 
•  E n d -of -Tre at me nt Visit : 3 5  ( ± 5) d a ys after last d ose of st u d y tr eat me nt 
•  S afet y F oll o w -u p : 1 2 m o nt hs after t he last d ose of st u d y tr eat me nt  
•  E n d -of -St u d y Visit : At t he 1 2 M o nt h Visit  or 3 5  ( ± 5) da ys after earl y disc o nti n uati o n  
A s a p plica ble, patie nts w h o recei v e at least o ne d ose of st u d y dr u g will be f oll o we d f or safet y f or 
1 2 m o nt hs  after t he last d ose of st u d y tr eat ment f or safet y f oll o w-u p . 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
2 9  
4  P A TI E N T P O P U L A TI O N  
4. 1  I ncl usi o n Criteri a  
1.  Patie nt or le gall y a ut h orize d re prese nt ati ve m ust be willi n g a n d ca pa bl e of gi vi n g writte n 
I nf or me d C o nse nt a n d m ust be a ble t o a d here t o d osi n g a n d visit sc he d ules as well as 
meet all st u d y re q uire me nts.  
2.  Patie nt m ust ha ve a ne w l y dia g n os e d, hist ol o gicall y c o nfir me d earl y -sta ge breast c a ncer 
( E S B C), defi n e d as o pera ble Sta ge I t o Sta ge III A breast c a ncer.  
3.  Patie nt m ust be a ca n di date t o recei v e a dj u va nt or ne oa dj u va nt T C c he m ot h era p y.  
4.  Patie n t ( male or fe m ale) m ust be at least 1 8 years of a ge.  
5.  Patie nt m ust ha ve a de q uate he mat ol o gi cal, re n al a n d he patic f u ncti o n as d efi ne d b y : 
•  
A N C ≥1. 5  ×  1 0 9/ L 
•  
Platelet c o u nt ≥1 0 0  ×  1 0 9/ L 
•  
He m o gl o bi n > 9 g/ d L  
•  
Calc ulate d creati ni ne cle ara nce > 5 0 m L/ mi n  
•  
T otal bil ir u bi n ≤1. 5 m g/ d L  
•  
As partate a mi n otra nsferase ( A S T)/ser u m gl uta mic -o x al oacetic tra nsa mi nas e ( S G O T) 
a n d ala ni ne a mi n otra nsferase A L T/ser u m gl uta mic -p yr u vic tr a nsa mi nase ( S G P T) 
≤2. 5  ×  U L N, a n d al kali ne p h os p hatase ≤2. 0  ×  U L N  
6.  Patie nt m ust ha ve a n Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce 
stat us ≤2.  
7.  Patie nt m ust be willi n g t o practice t w o f or ms of c o ntrace pti o n, o ne of w hic h m ust be a 
barrier m et h o d, fr o m st u d y e ntr y t hr o u g h 3 0 da ys after t he l ast d ose of st u d y dr u g 
a d mi nistrati o n or 3 0 da ys aft er d ate of patie nt earl y disc o nti n uati o n.  
8.  Fe males of c hil d beari n g p ote ntial m ust ha ve a ne gati ve uri ne pre g na nc y t est wit hi n 
3 0  da ys pri or t o ra n d o mi zati o n. Fe males w h o are p ost me n o pa usal f or at least 1 year 
( defi ne d as m ore t ha n 1 2 m o nt hs si nce last me nses) or are s ur gicall y sterilize d d o n ot 
re q uire t his test.  
4. 2  E xcl usi o n Criteri a   
1.  Patie nt wit h a n acti ve c o nc urre nt mali g na n c y (e x ce pt n o n mela n o ma s ki n ca ncer or 
carci n o ma i n sit u of t he cer vi x) or life -t hreate ni n g disease. If t h ere is a hist or y of pri or 
mal i g na n cies or c o ntr alat eral br east ca n cer , t he patie nt m ust be disease free f or at least 
5  years.  
2.  Patie nt wit h k n o w n se nsiti vit y or pre vi o us reacti o n t o Esc heric hi a c oli  (E. c oli ) deri ve d 
pr o d ucts (e g, fil grasti m, rec o m bi na nt i ns uli n [ H u m uli n ®], L -as para gi n ase, s o matr o pi n 
[ H u matr o p ®] gr o wt h h or m o ne, rec o m bi na nt i nterfer o n alf a-2 b [I ntr o n ® A]), or a n y of 
t he pr o d ucts t o be a d mi nistere d d uri n g st u d y partici pati o n.  
3.  Patie nt wit h c o nc urre nt a dj u va nt ca ncer t hera p y (c he m ot hera p y, ra diati o n t hera p y, 
i m m u n ot hera p y, bi ol o gic t hera p y ot her t h a n t he tri al s pecifie d t hera pies).  
4.  Patie nt has l ocall y rec urre nt/metastatic breast ca n cer.  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
3 0  
5.  Patie nt wit h pre vi o us e x p os ure t o fil grasti m, pe gfil grasti m, or ot her G -C S F pr o d ucts i n 
cli nical de vel o p me nt wit hi n 1 2 m o nt hs pri or t o t he  a d mi nistrati o n of st u d y dr u g ( S PI-
2 0 1 2  or pe gfil grasti m) .  
6.  Patie nt wit h a n acti ve i nf ecti o n  or o n a nti -i nfecti ves, a n u n derl yi n g me dical c o n diti o n or 
a not her seri o us ill ness t h at w o ul d i m pair t he a bilit y of t he p atie nt t o recei ve pr ot oc ol -
s pecifie d treat me nt.  
7.  Patie nt has use d a n y i n vesti gati o nal dr u gs, bi ol o gi cs, or de vices wit hi n 3 0 da ys pri or t o 
st u d y treat me nt or pla ns t o use a n y of t hes e d uri n g t he c o urse of t h e st u d y.  
8.  Patie nt has ha d pri or b o n e marr o w or he mat o p oietic ste m cell tra ns pla nt.  
9.  Patie nt has  ha d pri or ra diati o n t hera p y wit hi n 3 0 da ys pri or t o e nr oll me nt.  
1 0.  Patie nt has ha d maj or s ur ger y wit hi n 3 0 da ys pri or t o e nr oll me nt. Patie nts w h o ha ve 
breast s ur ger y rel ate d t o t he breast ca ncer dia g n osis or ha ve ha d a p ort -a-cat h place me nt 
ma y b e e nr olle d pri or t o 3 0 da ys o n ce t he y h a ve f ull y rec o vere d fr o m t he pr oce d ure.  
1 1.   Patie nt is pre g n a nt or breast -fee di n g. 
4. 3  P ati e nt  Disc o nti n u ati o n/ Wit h dr a w al Criteri a   
P atie nts ca n wit h dra w fr o m partici pati o n i n t his st u d y at a n y ti me, f or a n y reas o n, s pecifi e d or 
u ns pecifie d, a n d wit h o ut prej u dice.  
•  Patie nts m ust  be wit h dra w n fr o m st u d y dr u g treat me nt f or a n y of t he f oll o wi n g reas o ns, 
b ut will c o nti n ue i n t he 1 2 -M o nt h S afet y F oll o w -u p :  
•  
De vel o p me nt of a n a d verse e ve nt ( A E) t hat i nterferes wit h t he patie nt’s partici pati o n  
•  
Disc o nti n uati o n of T C  
•  
Disc o nti n uati o n of S PI -2 0 1 2  or pe gfil grasti m  
•  
Dela y of T C a d mi nistrati o n f or > 4 2 da ys si nce last st u d y dr u g a d mi nistrati o n  
•  
I n v esti gat or decisio n  
•  
S p o ns or decisi o n  
•  
Pre g n a nc y  
•  Patie nts m ust be wit h dra w n fr o m t he st u d y, treat me nt p hase or 1 2 -M o nt h Safet y  F oll o w -
u p f or a n y of t h e f oll o wi n g reas o ns:  
•  
I nitiati o n of n o n-pr ot oc ol s yste mic c h e m ot hera p y or bi ol o gical t hera p y f or t he 
treat me nt of breast ca n cer 
•  
Patie nt w it h dra wal of i nf or me d c o nse nt  
•  
Treat me nt wit h a d diti o nal m yel oi d gr o wt h f act ors d uri n g f oll o w -u p  
•  
L ost t o f oll o w -u p  
•  
Deat h  
T he reas o n f or a p atie nt’s disc o nti n uati o n of st u d y treat me nt or disc o nti n uati o n fr o m t he st u d y is 
t o be rec or de d o n t he  ele ctr o nic  cas e re p ort  f or m (C R F ). A s a p plica ble, p atie nts w h o recei ve at 
least o ne d ose of st u d y dr u g (S PI -2 0 1 2  or pe gfil grasti m ) will be f oll o we d f or 1 2 m o nt hs  after t he 
last d ose of st u d y tr eat me nt f or safet y. All A Es d uri n g t his ti me peri o d will be rec or de d.   


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
3 1  
5  S T U D Y P R O C E D U R E S   
T he st u d y d esi g n dia gra m is prese nte d i n Fi g ure 2  a n d t he Sc he d ule s of St u d y Assess me nts a n d 
Pr oce d ures is pr ese nte d i n A p pe n di x 1  a n d A p pe n di x 2 . 
5. 1  Scree ni n g  
I nf or me d c o ns e nt is t o be o btai ne d pri or t o t he start of a n y pr ot oc ol-s pecifie d assess me nts or 
pr oce d ures. T he pr oce d ures a n d e v al uati o ns re q uire d f or e nr oll me nt i nt o t he st u d y are 
s u m marize d bel o w. All p ote ntial st u d y patie nts will be scree n e d a n d eli gi bi lit y d eter mi ne d pri or 
t o e nr oll me nt. Scree ni n g assess me nts perf or me d pri or t o t he si g ni n g of i nf or me d c o nse nt as p art 
of t he site’s r o uti ne sta n d ar d of practice will be all o we d at t he discreti o n of S pectr u m. T his 
i nf or mati o n s h o ul d be disc usse d wit h t he Medical M o nit or.  
5. 2  P ati e nt Assi g n me nt  
C o nfir mati o n of eli gi bilit y is t o be recei v e d b y t he i n vesti gati o nal site fr o m S pectr u m pri or t o 
e nr ollme nt of  a patie nt. After a p atie nt has si g ne d t he I C F, t he I n v esti gat or or site staff s h o ul d 
l o g i nt o I W R S a n d o btai n a Patie nt I D. T he Patie nt I D will i ncl u de t w o parts: t he site n u m ber 
c o m prise d of 5 di gits wit h a 2 -di git al p h a betic c o u ntr y c o d e [ Refere nce I S O 3 1 6 6] f oll o we d b y a 
3 -di git site s pecifi c n u meri c c o de a n d a 3-di git patie nt se q ue ntial n u m ber, u ni q ue t o a site, 
se parat e d b y a h y p he n (ie, 
). O nce t h e I n vesti gat or or site staff h a ve c o m plete d t he 
re q uire d C R F s, a n d a p pr o val f or ra n d o mizati o n has bee n recei ve d fr o m S p ectr u m,  t he site will 
ra nd o mize t he patie nt usi n g a pre -s p ecifie d ra n d o mizati o n sc he me. Please refer t o t he st u d y 
bi n der f or det aile d i nstr ucti o ns re gar di n g e nr oll me nt.  
5. 3  Ti mi n g of Assess me nts  a n d Pr oce d ures  
5. 3. 1  Scree ni n g ( D a ys -3 0  t o -1)  
T he f oll o wi n g s cree ni n g assess me nts a n d pr oce d u res are t o be perf or me d wit hi n 3 0 da ys of t he 
first da y of st u d y dr u g a d mi nistrati o n. Scree ni n g assess me nts perf or me d pri or t o t he si g ni n g of 
t he I C F as p art of t he site’s r o uti ne sta n dar d of practice (i ncl u di n g, b ut n ot li mite d t o i ma gi n g 
pr oce d ures, pat h ol o g y bi o ps y res ults) will be all o we d at t he discreti o n of t he S p o ns or. T his 
i nf or mati o n s h o ul d be disc usse d wit h t he Me dical M o nit or. 
•  Inf or me d C o nse nt  
•  C o m plete me dical hist or y  
•  De m o gra p hic d ata  
•  C o m plete p h ysical e x a mi nati o n   
•  Hei g ht a n d wei g ht  
•  Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us  
•  Vital si g ns  
•  C o m plete bl o o d c o u nt ( C B C) wit h 5 -part differe ntial  ( Ma y be o btai ne d wit hi n  3 da ys 
pri or t o C ycle 1 , D a y  1  wit h o ut re peati n g o n C ycle 1, D a y 1 ) 
•  C he mistr y  ( Ma y b e o btai ne d wit hi n  3 da ys pri or t o C ycle 1 , D a y  1  wit h o ut re peati n g o n 
C ycle 1, D a y 1 ) 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
3 2  
•  Pre g n a nc y test ( uri ne bet a h u ma n c h ori o nic g o n a d otr o pi n [ β -h C G]) i n w o me n of 
c hil d beari n g p ote ntial )  
•  A d verse e ve nts usi n g N CI C T C A E Versi o n 4. 0 3 , rec or d Seri o us A d verse E ve nts ( S A Es ) 
relate d t o a st u d y pr oce d ure o nl y 
•  H or m o ne rece pt or stat us, i ncl u di n g estr o ge n rece pt or ( E R), pr o gester o ne rece pt or ( P R) 
a n d h u ma n e pi der m al gr o wt h fact or 2 ( H E R 2 ), n u m ber of n o des , a n d sta ge. 
•  Ra n d o mizati o n (t he patie nt ca n be ra n d o mize d at a n y ti me bet wee n t h e ti me t he patie nt is 
a p pr o ve d f or st u d y p artici pati o n a n d C ycle 1 , D a y 1 ) 
5. 3. 2  Tre at me nt Peri o d  –  C y cle 1, D a y 1  ( B aseli ne) 
T he f oll o wi n g pr oce d ures a n d Bas eli ne assess me nts are t o be perf or me d b ef ore t he 
a d mi nistrati o n of T C c he m ot hera p y:  
•  Eli gi bilit y c o nfir m ati o n  
•  Patie nt I D assi g n me nt  
•  P h ysical e x a mi nati o n ( Ma y b e perf or me d wit hi n  3 da ys pri or t o C ycle 1 , D a y  1  wit h o ut 
re peati n g o n C y cle 1, D a y 1 ) 
•  Wei g ht  
•  E C O G perf or ma nce stat us  
•  Vital si g ns  
•  B o d y te m perat ure 
•  C o m plete bl o o d c o u nt  ( C B C) wit h 5 -part differe ntial  (Ma y be o btai ne d wit hi n  3 da ys 
pri or t o C ycle 1 , D a y  1  wit h o ut re peati n g o n C ycle 1, D a y 1 )  
•  C he mistr y  (o nce wit hi n 3 da ys pri or t o C ycle 1 , D a y 1  wit h o ut re peati n g o n C ycle 1, 
D a y  1 )  
•  Bl o o d dra w f or i m m u n o ge nicit y testi n g (all patie nts) 
•  C o nc o mita nt me dicati o ns   
•  A d verse e ve nts usi n g N CI C T C A E Versi o n 4. 0 3  
D oceta x el a n d c ycl o p h os p ha mi de  are t o b e a d mi nistere d as des cri be d i n  Secti o n 3. 1 . 
•  D oceta x el 7 5 m g/ m 2 I V i nf usi o n per i nstit ute ’s sta n dar d of care  
•  C ycl o p h os p ha mi de 6 0 0 m g/ m 2 I V i nf usi o n per i nstit ute ’s sta n dar d of care  
5. 3. 3  Tre at me nt Peri o d –  C y cle 1, D a y 2  
•  Vital si g ns (rec or de d pri or t o treat me nt, as w ell as a p pr o xi matel y 3 0 a n d 6 0 mi n utes after 
dr u g (S PI -2 0 1 2  or pe gfil grasti m ) a d mi nistrati o n  
•  B o d y te m perat ure  
•  C o nc o mita nt me dicati o ns  
•  A d vers e e ve nts  
•  St u d y dr u g ( S PI -2 0 1 2  or pe gfil grasti m ) a d mi nistrati o n  acc or di n g t o ra n d o mizati o n  
assi g n me nt  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
3 3  
•  Bl o o d sa m ple f or P K a nal ysis ( S PI -2 0 1 2 Tre at me nt A r m o nl y)  
5. 3. 4  Tre at me nt Peri o d –  C y cle 1, D a y s 4  t o 2 1  
•  T wice d ail y b o d y te m perat ure  
•  C o m plete bl o o d c o u nt wit h 5 -part differe ntial  o n D a ys 4  t o 1 5  o nl y . If t h e partici pati n g 
site is n otifie d t hat t he A N C is ≤1. 0 × 1 09/ L o n D a y 1 5 , t he n dail y C B Cs will be re q uire d 
u ntil t heir A N C is ≥1. 5 × 1 0 9/ L p ost-n a dir.  
•  Bl o o d sa m ple f or P K  a nal ysis (S PI -2 0 1 2 Tre at me nt A r m o nl y) ( D a ys 4  a n d 5  o nl y , at 
t he sa me ti me as C B C bl o o d dra w) 
5. 3. 5  Tre at me nt Peri o d –  C y cle s 2  t o 4, D a y 1  
T he f oll o wi n g pr oce d ures are t o be p erf or m e d bef ore t he a d mi nistrati o n of T C c he m ot hera p y:  
•  P h ysical e x a mi nati o n ( Ma y b e perf or me d wit hi n  3 da ys pri or t o D a y 1  of a n y treat me nt 
c ycle)  
•  Wei g ht  
•  E C O G perf or ma nce stat us  
•  Vital si g ns  
•  B o d y te m perat ure 
•  C o m plete bl o o d c o u nt wit h 5 -part differe ntial  ( Ma y be o bt ai ne d wit hi n 3 da ys pri or t o 
D a y  1  of a n y treat me nt c ycl e)  
•  C he mist r y ( Ma y b e o btai ne d wit hi n 3 da ys pri or t o D a y 1  of a n y treat me nt c ycle)  
•  A d verse e ve nts  
•  Bl o o d dra w f or i m m u n o ge nicit y testi n g (all patie nts) 
•  C o nc o mita nt me dicati o ns  
D oceta x el a n d c ycl o p h os p ha mi de are t o b e a d mi nistere d as des cri be d i n  Secti o n 3. 1 . 
5. 3. 6  Tre at me nt Peri o d –  C y cles 2 t o 4, D a y 2  
•  Vital si g ns rec or de d pri or t o treat me nt, as w ell as a p pr o xi matel y 3 0 a n d 6 0 mi n utes after 
st u d y dr u g (S PI -2 0 1 2  or pe gfil grasti m ) a d mi nistrati o n  
•  T wice dail y b o d y  te m perat ure 
•  C o nc o mita nt me dicati o ns  
•  A d verse e ve nts  
•  St u d y dr u g ( S PI -2 0 1 2  or pe gfil grasti m ) a d mi nistrati o n  
•  Bl o o d sa m ple f or P K a nal ysis ( S PI -2 0 1 2 Tre at me nt A r m o nl y) ( D a y 2  of C ycle 3  o nl y)  
5. 3. 7  Tre at me nt Peri o d –  C y cles 2 t o 4, D a ys 3 t o 2 1   
•  T wice dail y b o d y t e m perat ure  
•  C o m plete bl o o d c o u nt wit h 5 -part differe ntial  o nl y o n D a ys 4 , 7 , 1 0 , a n d 1 5  ( ±1  da y  f or 
eac h c ollecti o n ) or u ntil patie nts’ A N C is ≥1. 5 × 1 0 9/ L p ost-n a dir, w hic h e v er occ urs first.  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
3 4  
If t he partici p ati n g site is n otifie d t hat t he A N C is ≤1. 0 × 1 09/ L at a n y ti me, t he n dail y 
C B Cs will be re q uire d u ntil A N C is ≥1. 5 × 1 0 9/ L p ost -na dir . 
•  Bl o o d sa m ple f or P K a nal ysis ( S PI -2 0 1 2 Tre at me nt A r m o nl y) ( D a ys 4  a n d 7  of 
C ycle  3  o nl y , ± 1 da y, at t he sa me ti me as C B C bl o o d dra w ) 
5. 3. 8  E n d -of -Tre at me nt Visit ( At t he e n d of C ycle 4  or  A p pr o xi m atel y 3 5  ( ± 5) d a ys After  
D ate of E arl y D isc o nti n u ati o n) 
•  P h ysical e x a mi nati o n  
•  Wei g ht  
•  E C O G perf or ma nce stat us  
•  Vital si g ns  
•  B o d y te m perat ure  
•  C B C wit h 5 -part differe ntial  
•  C he mistr y  
•  Bl o o d dra w f or i m m u n o ge nicit y testi n g  (all patie nts) 
•  C o nc o mita nt me dicati o ns  
•  A d verse e ve nts usi n g N CI C T C A E Versi o n 4. 0 3  
5. 3. 9  1 2 M o nt h  S afet y F oll o w -u p  
All ra n d o mize d patie nts w h o ha ve recei v e d at least o ne d ose of st u d y dr u g ( S PI -2 0 1 2  or 
pe gfil grasti m ) will c o nti n ue t o be f oll o we d f or 1 2  m o nt h s after t he last d ose of st u d y tr eat me nt 
f or e val u ati o n of l o n g-ter m safet y, i ncl u di n g i m m u n o ge ni cit y.  
5. 3. 9. 1  Tele p h o ne C o nt act  
At a p pr o xi matel y 3 m o nt hs ( ± 2 wee ks ) a n d 9 m o nt hs ( ±2 wee ks ) after t he l ast d ose of st u d y dr u g 
(S PI -2 0 1 2  or pe gfil grasti m) i n S PI -G C F -3 0 2  (t hr o u g h t he e n d of C ycle 4  or earl y 
disc o nti n uati o n), patie nts will be c o ntacte d b y tele p h o ne f or:  
•  M yel oi d gr o wt h fact or us e (i ncl u di n g t h e t y p e of G -C S F, t he sc he d ul e of a d mi nistrati o n 
a n d reas o n f or use)  
•  S u bse q ue nt t y pes of a nti -ca ncer t hera p y, i ncl u di n g d oses a n d n u m ber of c ycles recei ve d   
•  A d verse e ve nts usi n g N CI C T C A E Versi o n 4. 0 3  
•  Partici pati o n i n a n y ot her s u bse q ue nt cli nical trial, w here i n vesti gati o nal pr o d uct is 
a d mi nistere d  
5. 3. 9. 2  Cli nic Visit  
At a p pr oxi matel y 6 m o nt hs ( ± 2 wee ks ) a n d 1 2 m o nt hs ( ±2 wee ks ) after t he last d ose of st u d y 
dr u g ( S PI -2 0 1 2  or pe gfil grasti m) i n S PI -G C F -3 0 2  (t hr o u g h t h e e n d of C ycle 4  or earl y 
disc o nti n uati o n), patie nts will visit t he cli nic f or:  
•  Bl o o d dra w f or i m m u n o ge nicit y tes ti n g ( patie nts w h o ha ve use d a d diti o nal G-C S F 
pr o d ucts d uri n g t he f oll o w -u p will be e x cl u de d)  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
3 5  
•  M yel oi d gr o wt h fact or us e (i ncl u di n g t h e t y p e of G -C S F, t he sc he d ul e of a d mi nistrati o n 
a n d reas o n f or use)  
•  S u bse q ue nt t y pes of a nti -ca ncer t hera p y, i ncl u di n g d ose s a n d n u m ber of c ycles recei ve d   
•  A d verse e ve nts usi n g N CI C T C A E Versi o n 4. 0 3  
•  Partici pati o n i n a n y ot her s u bse q ue nt cli nical trial, w here i n vesti gati o nal pr o d uct is 
a d mi nistere d  
5. 3. 1 0  E n d of St u d y Visit ( M o nt h 1 2 Visit or 3 5  ( ± 5) d a ys after e arl y disc o nti n u ati o n)  
•  Bl o o d dra w f or i m m u n o ge nicit y testi n g if disc o nti n ue d pri or t o M o nt h 1 2  
•  C o nc o mita nt me dicati o ns li mite d t o G -C S F a n d ot her a nti -ca ncer t hera p y 
•  A d verse e ve nts usi n g N CI C T C A E Versi o n 4. 0 3  
5. 4  Descri pti o n of St u d y Assess me nts a n d Pr o ce d ures   
5. 4. 1  E x pl a n ati o n of  St u d y a n d O bt ai n i n g Writte n I nf or me d C o nse nt  
I nf or me d C o nse nt is t o be o btai ne d pri or t o t he start of a n y pr ot oc ol -s p ecifi e d assess me nts or 
pr oce d ures (i ncl u di n g re q uire d was h o ut of a n y pr o hi bite d me dicati o ns). T he Pri nci pal 
I n v esti gat or or desi g nee is t o disc uss t he st u d y f ull y wit h t he patie nt a n d o btai n writte n I nf or m e d 
C o nse nt. T he writte n I C F is t o be si g ne d b y t he patie nt a n d t he Pri nci pal I n v esti gat or or 
desi g nee. A c o p y of t he si g ne d I C F is t o be gi ve n t o t he patie nt. 
5. 4. 2  Me dic al Hist or y  
Me dical hist or y i n cl u des t he hist or y of t he n e o plastic disease, its pre vi o us t hera p y a n d 
i n vesti gati o ns as well as si g nifica nt p ast a n d all c o-e xisti n g diseases a n d c urre nt me dicati o ns f or 
t he pre vi o us 5 years. 
5. 4. 3  Re vie w I ncl usi o n/ E xcl usi o n Criteri a  
At Scree ni n g  a n d pri or t o e nr oll me nt, t he i ncl usi o n a n d e x cl usi o n criteria will be re vie we d b y 
t he Pri nci pal I n vesti gat or or ot her q ualifie d h ealt h care pr ofessi o nal t o e ns ure t hat t he patie nt 
q ualifies f or t he st u d y.  
5. 4. 4  R a n d o miz ati o n  
O nce it has bee n c o nfir m e d t hat a patie nt is e li gi ble f or e nr oll me nt, as assesse d b y S pectr u m, t he 
patie nt will be ra n d o mize d a n d recei ve a ra n d o mizati o n n u m ber acc or di n g t o t he i nf or mati o n i n 
Secti o n 8. 2 . 
5. 4. 5  P h ysic al E x a mi n ati o n  
A c o m plete p h ysical e x a mi nati o n, i ncl u di n g a des cri pti o n of e xter nal si g ns of t he ne o plastic 
disease a n d c o -m or bi dities is perf or me d at  t he Scree ni n g  Visit , D a y 1  of eac h c ycl e, a n d at t he 
E n d -of -Tre at me nt  Visit . Brief p h ysi cal e xa mi nati o ns are c o n d u cte d at all ot her visits. P h ysic al 
e x a m i nati o ns are t o be c o m plete d b y a p h ysi cia n or ot her healt h pr ofessi o nal lice nse d t o perf or m 
s uc h e x a mi nati o ns. Fi n di n gs will be d oc u me nt e d i n t he patie nt’s me dical r ec or d a n d o n t he 
a p pr o priate C R F . A n y a b n or malities are t o be rec or de d o n t he A E C R F .  




S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
3 7  
≤1. 0 × 1 0 9/ L at a n y ti me d uri n g C y cles 2  t o 4 , t he n dail y C B Cs will be re q uire d u ntil t he A N C is 
≥1. 5 × 1 0 9/ L, after reac hi n g na dir, b ut bl o o d sa m ples m ust still be dra wn o n D a ys 4 , 7 , 1 0 , a n d 1 5 .  
If t he patie nt c o nti n ues t o be ne utr o pe nic , t h e In vesti gat or will c o ns ult wit h S pectr u m  t o 
deter mi ne w het h er st u d y treat me nt s h o ul d be disc o nti n ue d. A h o me healt h care a ge n c y will be 
ma de a vaila ble f or t he c o n ve nie nce of patie nt s w h o d o n ot wis h t o ma ke m ulti ple tri ps t o t he 
st u d y site. 
5. 4. 1 0  C he mistr y  
Bl o o d c he mistr y a n al ysis will be perf or me d b y t h e ce ntral la b orat or y. Bl o o d sa m ples will be 
dra w n f or ser u m c h e mistr y p a nel, i ncl u di n g cal ci u m, s o di u m, p otassi u m, creati ni ne, t otal 
bilir u bi n, A S T, A L T, al k ali ne p h os p hatase, will b e dra w n at Scree ni n g , D a y 1  of eac h treat me nt 
c ycle a n d at t he E n d -of -Tre at me nt Visit . A uri n e b eta-h C G pre g na n c y test nee ds t o be 
perf or me d at S cree ni n g f or patie nts of c hil d beari n g p ote ntial.  
5. 4. 1 1  P h ar m a c o ki netic Assess me nts  
P har mac o ki netic sa m ples will be a nal yze d  b y a ce ntral la b orat or y. All patie nts i n t he S PI -2 0 1 2 
T re at me nt A r m will ha ve bl o o d sa m p les dra w n f or s parse P K sa m pli n g at 6 ti me p oi nts d uri n g 
t he st u d y peri o d f or p o p ulati o n P K a nal ysis. T he s a m pli n g ti me p oi nts will be: 
•  C ycle 1 :  
•  
D a y 2  ( 1 t o 4 h o urs after S PI -2 0 1 2  a d mi nistrati o n)  
•  
D a y 4  (at t he sa me ti me as C B C bl o o d dra w ) 
•  
D a y 5  (at t he same ti me as C B C bl o o d dra w ) 
•  C ycle 3 : 
•  
D a y 2  ( 1 t o 4 h o urs p ost-d ose)  
•  
D a y 4  (± 1 da y, at t he sa me ti me as C B C bl o o d dra w ) 
•  
D a y 7  (± 1 da y, at t he sa me ti me as C B C bl o o d dra w ) 
A h o me healt hcare a ge nc y will be ma d e a vaila ble f or t he c o n v e nie nce of patie nts w h o d o n ot 
wis h t o ma ke m ulti ple tri ps t o t he st u d y site.  
5. 4. 1 2  A nti -Infecti ve Use  
All a nti -i nfecti ves prescri be d b y  t h e In vesti gat or or patie nts’ ot her h ealt h care pr o vi ders d uri n g 
t he st u d y peri o d will be rec or de d o n t h e C R F .  
5. 4. 1 3  I m m u n o ge nicit y Testi n g  
I m m u n o ge nicit y sa m ples will be a nal yze d b y a ce ntral la b orat or y. T o assess i m m u n o ge nicit y, 
bl o o d sa m ples will be c ollecte d o n D a y 1  of C ycles 1  t o 4 , bef ore t he a d mi nistrati o n of 
c ortic oster oi ds, at t he E n d -of -Tre at me nt Visit , a n d als o at a p pr o xi matel y 6  m o nt hs a n d 1 2 
m o nt hs after C ycle 4 , D a y 2  or after t h e date of earl y disc o nti n uati o n . Patie nts w h o recei v e d 
S PI -2 0 1 2  will be teste d f or a nti b o dies t o S PI -2 0 1 2 , t he Fc re gi o n of t he S PI -2 0 1 2  m olec ule, t he 
P E G m oiet y, a n d G -C S F , a n d t h ose patie nts w h o recei ve d pe gfil grasti m will be teste d f or 
a nti b o dies t o S PI -2 0 1 2 , P E G a n d G -C S F. All sera sa m ples p ositi ve f or G -C S F -bi n di n g 
a nti b o dies will be f urt her teste d f or G -C S F n e utralizi n g a nti b o dies.   


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
3 8  
Details of bl o o d sa m ple c ollecti o n, pr ocessi n g, a n d s hi p p i n g i nstr ucti o ns are descri be d i n t he 
st u d y bi n der/la b orat or y ma n ual.  
5. 4. 1 4  A d verse E ve nt  
At e ver y visit, t he I n vesti gat or or desi g nee will i n q uire a b o ut a d verse e v e nts a n d i nterc urre nt 
ill nesses si nce t he last visit, w hic h will be gra de d  acc or di n g t o t he Nati o nal Ca ncer I nstit ute 
( N CI) C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) Scale Versi o n 4. 0 3 f or A E 
gra di n g, a n d will rec or d t he perti ne nt i nf or mati o n o n t he C R F . 
At a p pr o xi matel y 3 m o nt hs a n d 9 m o nt hs, t he I n v esti gat or or desi g nee will c o ntact t h e patie nt b y 
tele p h o ne a n d i n q uire a b o ut a d verse e ve nts a n d i nterc urre nt ill nesses si nce t he last visit, w hic h 
will be gra de d acc or di n g t o t he Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n T er mi n ol o g y Criteri a 
f or A d verse E ve nts ( C T C A E) Scale Versi o n 4. 0 3 f or A E gra di n g, a n d will rec or d t h e perti ne nt 
i nf or mati o n o n t he C R F . At a p pr o xi matel y 6 m o nt hs a n d 1 2 m o nt hs A Es will be assesse d at t he 
st u d y site. 
5. 4. 1 5  C o nc o mit a nt Me dic ati o ns  
All me dicati o ns a d mi nistere d fr o m t he ti me t he I C F is si g ne d t hr o u g h 3 5 ( ± 5)  da ys after t he last 
d ose of st u d y dr u g a d mi nistrati o n will be rec or de d o n t he C R F . Start a n d st o p dates a n d reas o ns 
f or me dicati o n use will als o be n ote d.  A n y h os pitalizati o ns will als o be rec or de d o n t he C R F. 
After 3 5 ( ± 5)  da ys , a n d d uri n g t he 1 2 -m o nt h f oll o w -u p peri o d, o nl y a d diti o nal treat me nt wit h 
m yel oi d gr o wt h f act ors, i ncl u di n g fil grasti m, pe gfil grasti m or bi osi milars, a n d a d diti o nal ca ncer 
t hera p y will be rec or de d .  
6  S T U D Y D R U G A N D P H A R M A C E U TI C A L I N F O R M A TI O N  
6. 1  S PI -2 0 1 2  
S PI -2 0 1 2  will be s u p plie d b y S pectr u m .  
6. 1. 1  S PI -2 0 1 2  C o m p ositi o n  
S PI -2 0 1 2  ( 0. 6 m L) is s u p plie d i n prefille d  si n gle-use s yri n ges f or s u b c uta ne o us i njecti o n. Eac h 
prefille d  s yri n ge of S PI -2 0 1 2  c o ntai ns 1 3. 2 m g S PI -2 0 1 2,  e q ui vale nt t o 3. 6 m g G -C S F.  
6. 1. 2  S PI -2 0 1 2 St or a g e a n d H a n dli n g  
S PI -2 0 1 2  s h o ul d be st ore d u n der refri gerati o n wit h te m perat ur e c o ntr olle d bet wee n  2 º C a n d 8º C 
( 3 6º F t o 4 6º F) a n d pr ot ecte d fr o m li g ht . D o n ot s h a ke prefille d s yri n ges. If S PI -2 0 1 2  is 
acci de nt all y fr oze n, d o n ot use. S PI -2 0 1 2  prefille d  s yri n ges ca n b e left at r o o m te m perat ure f or 
u p t o 7 2 h o urs.  
6. 1. 3  S PI -2 0 1 2 A d mi nistr ati o n  
T he d ose of S PI -2 0 1 2  t o be a d mi nistere d is 1 3. 2 m g/ 0. 6 m L fi x e d d ose S PI -2 0 1 2  e q ui vale nt t o 
3. 6  m g  G -C S F  p er c ycle. S PI -2 0 1 2  s h o ul d be a d mi nistere d s u bc uta ne o usl y o n D a y 2 , 
a p pr o xi matel y 2 4 t o 2 6 h o urs  after T C a d mi nistrati o n.  T he e ntire c o nt e nt of t he prefille d s yri n ge 
s h o ul d be a d mi nistere d. N o d ose m o dificati o ns are all o we d. 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
3 9  
6. 2  Pe gfil gr asti m  
6. 2. 1  Pe gfil gr asti m  C o m p ositi o n  
Pe gfil grasti m will be s u p plie d b y S pectr u m  i n 0. 6 m L prefille d  si n gl e-use s yri n ges f or 
s u bc uta ne o us i njecti o n. Eac h s yri n ge c o ntai ns 6 m g pe gfil grasti m i n a sterile s ol uti o n.  
6. 2. 2  Pe gfil gr asti m  S u p pl y  
O n l y pe gfil grasti m ( Ne ul asta  [ N D C 5 5 5 1 3-1 9 0 -0 1]  ma n ufact ure d b y A m ge n i n t he U nite d 
States ) a n d s u p plie d b y S pectr u m  will be use d ; n o o t her G-C S Fs , i ncl u di n g bi osi mil ars , are  t o 
be use d i n t his st u d y .  
6. 2. 3  Pe gfil gr asti m St or a g e a n d H a n dli n g  
Pe gfil grasti m s h o ul d be st ore d a n d h a n dle d i n acc or da nce wit h t he Ne ulast a U nite d States 
Pac ka ge I ns ert ( U S PI ).  
6. 2. 4  Pe gfil gr asti m A d mi nist r ati o n  
Pe gfil grasti m 6  m g s h o ul d be a d mi nistere d s u bc ut a ne o usl y o nc e p er c h e m ot hera p y c ycl e o n 
D a y  2 , a p pr o xi matel y 2 4 t o 2 6 h o urs  after T C a d mi nistrati o n, acc or di n g t o t he ma n ufact urer’s 
prescri bi n g i nf or mati o n.  
T he e ntire c o nte nt of t he prefille d  s yri n ge s h o ul d be a d mi nistere d. N o d ose m o dificati o ns are 
all o we d.  
6. 3  Bli n di n g of St u d y Tre at me nts  
T his is a n o pe n -la bel st u d y. N o bli n di n g will be a p plie d.  
6. 4  R a n d o miz ati o n of St u d y Tre at me nts  
Patie nts w h o meet all eli gi bilit y criteria will be c o nsi dere d f or ra n d o mizati o n. Eli gi bilit y of all 
patie nts will be re vie we d a n d a p pr o ve d f or ra n d o mizati o n b y t he S p o ns or’s Me dical M o nit or, or 
desi g nee. Patie nts a p pr o v e d f or ra n d o mizati o n will be ra n d o mize d 1: 1 t o recei ve eit her S PI -2 0 1 2  
or pe gfil grast i m. T he det ail of t he ra n d o mizati o n sc he me is pr o vi de d i n Secti o n 8. 2 . 
6. 5  N o n -st u d y Tre at me nts 
6. 5. 1  Pri o r a n d C o nc o mit a nt Me dic ati o ns  
A c o nc o mita nt me dicati o n is a n y me dicati o n a patie nt e nteri n g t he trial is usi n g fr o m D a y 1  of 
C ycle 1  t o t he E n d -of -Tre at me nt  Visit . T he st u d y dr u gs are n ot c o nsi dere d c o nc o mita nt 
me dicati o ns.  
All c o nc o mita nt me dicati o ns rec or de d at trial e ntr y m ust ha ve a rel ate d, o n g oi n g c o n c o mita nt 
ill ness liste d u n der t he me dical hist or y at t he ti me of patie nt e ntr y i nt o t he trial u nless t he 
me dicati o n is use d f or pr o p h yla xis. Patie nts ma y c o nti n ue t o use a n y o n g oi n g me dicati o ns n ot 
pr o hi bite d b y t he pr ot oc ol.  
All prescri pti o n a n d o ver -t he-c o u nter me dicati o ns at trial e ntr y as w ell as a n y ne w me dicati o ns 
starte d d uri n g t he trial m ust be d oc u me nte d o n t he C R F  a n d i n t he s o urce d oc u me nts. T he 
d oc u me ntati o n s h o ul d c o nti n ue t hr o u g h t he e n d of t he 1 2 -M o nt h S afet y F oll o w -u p Peri o d  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
4 0  
(a p pr o xi matel y 1 2 m o nt hs  after t he last d ose of st u d y treat me nt) or 3 5  ( ± 5) da ys after t h e date of 
patie nt earl y disc o nti n uati o n.  D uri n g t he st u d y treat me nt peri o d a n d t he s u bse q ue nt 1 2 -m o nt h 
f oll o w-u p peri o d, a d diti o nal c o nc o mita nt treat me nt wit h m yel oi d gr o wt h fact ors, i ncl u di n g 
fil grasti m, pe gfil grasti m or its bi osi milars, a n d ot her  a nti-ca ncer t hera pies are pr o hi bite d wit h t he 
e x ce pti o n of h or m o nal t hera p y a n d H E R -2 tar gete d t hera p y f or t h e patie nts w h o nee d s uc h a 
tar gete d t hera p y.  
Pre me dicati o ns (s uc h as a ntie metics) use d f or s u p p orti ve care are all o we d as per i nstit uti o nal 
sta n dar ds or g ui deli nes.  
C ortic oster oi ds as pre me dicati o n f or d oceta xel are all o we d d uri n g st u d y tr eat me nt. Ot her use of 
s yste mic ster oi ds m ust b e a p pr o ve d b y t h e Me dical M o nit or.  
6. 5. 2  Pr o hi bite d T her a pies or Me dic ati o ns  
N o ot her a nti -ca ncer t hera p y i n cl u di n g c he m o t hera p y, ra diati o n t hera p y, i m m u n ot hera p y, or 
e x peri me ntal me dicati o ns are per mitte d d uri n g t h e st u d y, e x ce pt t hat r a diati o n t hera p y is all o we d 
d uri n g t he 1 2 -M o nt h Safet y F oll o w -u p Peri o d . A n y diseas e pr o gressi o n t hat re q uires a nti-t u m or 
t hera p y, ot her t h an T C, will be ca use f or disc o nti n uati o n fr o m t he trial.  
N o m yel oi d gr o wt h fact ors ot her t ha n st u d y dr u gs  (S PI -2 0 1 2  or pe gfil grasti m)  are t o be 
a d mi nistere d t o patie nts at a n y ti me d uri n g t h e treat me nt p hase or f oll o w -u p.  
N o w hite bl o o d cell  or w h ole bl o o d tra nsf usi o ns are all o we d. 
7  S A F E T Y A S S E S S M E N T  
7. 1  S afet y Me as ures  
It is t he res p o nsi bilit y of t he Pri nci pal I n vesti gat or t o o versee t he s afet y of t he patie nt s at t heir 
site a n d t o re p ort all A Es/ S A Es t hat are o bser ve d or re p orte d d uri n g t he st u d y, re gar dl ess of 
relati o ns hi p t o st u d y dr u g or cli nical si g nifi ca nce.  
Safet y d ata will  als o be re vie we d o n a re g ular basis b y S pectr u m’s  st u d y m o nit ori n g tea m, w hic h 
incl u des a Cli nical Researc h Ass ociate ( C R A ), Me dical M o nit or, a n d ot her pers o n nel fr o m t he 
c o m pa n y or its desi g n ee .  
A d verse e ve nts will be c haract erize d b y i nte nsit y (se verit y), ca usalit y, a n d seri o us ness b y t he 
I n v esti gat or base d o n t h e re g ulat or y defi ni ti o ns i ncl u de d bel o w. 
T his st u d y will utilize t he Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts ( C T C A E) Scale Versi o n 4 .0 3  f or A E gra di n g. 
7. 2  A d verse E ve nts  
A n A E is defi ne d as a n y u nt o war d  me dical o cc urre nce i n a patie nt or c li nical i n vesti gati o n 
patie nt, te m p orall y ass ociate d wit h t he use of a m e dici nal pr o d uct  or st u d y pr oce d ure , w het h er or 
n ot c o nsi dere d relate d t o t he me dici nal pr o d uct . T heref ore, a n A E ca n be a n y u nfa v ora bl e a n d 
u ni nte n de d si g n (i n cl u di n g a n a b n or mal la b o rat or y fi n di n g), s y m pt o m, or disease ( ne w or 
e x acer bate d) te m p orall y ass ociate d wit h t he use of a me dici nal pr o d u ct.  A treat me nt -e mer ge nt 
A E ( T E A E) is a n y A E t h at occ urs fr o m t he first d ose of st u d y tr eat me nt t hr o u g h 1 2 m o nt hs after 
t he last d ose of st u d y tr eat me nt or 3 5 ( ± 5)  da ys after t he date of patie nt earl y disc o nti n uati o n. 
A d diti o nall y, as a p plica ble, patie nts w h o recei ve at least o ne d ose of st u d y dr u g ( S PI -2 0 1 2  or 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
4 1  
pe gfil grasti m) will be f oll o we d f or safet y f or 1 2 m o nt hs after t he last d ose of st u d y tr eat me nt or 
date of patie nt e arl y disc o nti n uati o n . All A Es d uri n g t his ti me peri o d will be rec or de d. 
T he st u d y will rec or d all A Es acc or di n g t o t he i nf or mati o n i n  Secti o n 7. 3 . 
E x a m ples of A E s i ncl u de: 
•  E x acer bat i o n of a c hr o ni c or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncreas e i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n. 
•  Ne w c o n diti o ns detect e d or dia g n os e d after i n vesti gati o nal pr o d u ct a d mi nistrati o n . 
•  Si g ns, s y m pt o ms, or t he cli nical se q uela e of a s us pecte d dr u g i nteracti o n.  
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her 
i n vesti gati o nal pr o d u ct or a c o nc urre nt me di cati o n. 
•  A Es ma y i n cl u de pre -treat me nt or p ost-treat me nt e ve nts t hat occ ur as a res ult of pr ot oc ol-
ma n date d pr oce d ures , ie, i n vasi ve pr oce d ures. 
A b n or mal la b orat or y res ults are t o be rec or de d as A Es, if a n y of t he f oll o wi n g c o n diti o ns are 
met:  
•  T he a b n or mal la b orat or y val ue lea ds t o a t hera p e utic i nter ve nti o n.  
•  T he a b n or mal la b orat or y val ue is c o nsi dere d t o b e cli nicall y si g nifica nt b y t he 
I n v esti gat or. 
•  T he a b n or mal la b orat or y val ue is pre defi ne d as a n A E i n t he pr ot oc ol or i n a n ot her 
d oc u me nt c o m m u nicate d t o t he I n v esti gat or b y S pectr u m  or desi g nee.  
•  T he a b n or mal  la b orat or y val ue is ≥Gra de 3 b ase d o n C T C A E V ersi o n 4. 0 3 . 
E x a m ples of e ve nts t hat  d o n ot c o nstit ute A Es i ncl u de : 
•  Me dical or s ur gic al pr oce d ure s (e g, e n d osc o p y, a p pe n dect o m y); t he c o n diti o n t hat lea ds 
t o t he pr oce d ure is a n A E. 
•  Sit uati o ns w here a n u nt o war d  me dical occ urre n ce d oes n ot occ ur ( e g, s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).  
•  A ntici pate d da y -t o-d a y fl uct uati o ns of pre -e xisti n g disease(s) or c o n diti o n(s) prese nt or 
detecte d at t he start of t h e st u d y t hat d o n ot w ors e n.   
•  Pla n ne d a n d pres c h e d ule d h os pitalizati o ns a n d pr oce d ures.  
•  Pr o gressi ve disease . 
7. 3  G ui deli nes f or Rec or di n g a n d Attri b uti o n Sc ori n g of A d verse E ve nts  
Ti mel y a n d c o m plete re p orti n g of all A Es is re q uire d f or all patie nts. M o nit ori n g a n d 
d oc u me ntati o n of all A Es all o ws f or i de nt ificati o n of p ote ntial st u d y-dr u g or d ose -relate d A Es, 
a n d f or a d h ere n ce t o r e g ulat or y re q uire m e nts . Please refer t o t he C R F  C o m pleti o n G ui deli nes 
l ocate d i n t he st u d y bi n d er f or detaile d i nstr ucti o ns f or A E re p orti n g . 
7. 3. 1  Rec or di n g of A d verse E ve nts  
All A Es t hat occ ur fr o m t he first d ose of st u d y treat me nt t hr o u g h 3 5 ( ± 5)  d a ys after last d ose of 
st u d y treat me nt (S PI -2 0 1 2  or pe gfil grasti m) or 3 5 ( ± 5)  da ys after t he date of patie nt earl y 






S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
4 4  
•  I n cl u des i m p orta nt me dic al e ve nts t hat ma y n ot be i m me diatel y life-t hreat e ni n g or res ult 
i n deat h or h os pitalizati o n, b ut ma y je o par dize t he patie nt or ma y re q uir e i nter ve nti o n t o 
pre ve nt o ne  of t he o utc o mes liste d i n t his defi niti o n.  
A d verse e ve nts t hat d o n ot meet a n y of t he a b o v e criteria f or seri o us will b e re gar de d as n ot 
seri o us. 
7. 7. 1  Seri o us A d verse E ve nt Re p orti n g  
All S A Es t hat occ ur fr o m t he ti me t he st u d y I nf or me d C o nse nt  is o btai ne d a n d t hr o u g h 3 5 ( ± 5)  
da ys after l ast d ose of st u dy dr u g a d mi nistrati o n or 3 5 ( ± 5)  da ys after t he date of patie nt earl y 
disc o nti n uati o n  are t o be re p orte d t o S pectr u m  wit hi n 2 4 h o urs of k n o wle d ge of t he e v e nt. Fr o m 
t he ti me t he st u d y I C F is si g ne d t hr o u g h t he first d ose of st u d y dr u g a d mi nistrati o n, o nl y S A Es 
t hat are relate d t o st u d y pr oce d ures are t o be rec or de d. A d diti o nall y, all patie nts w h o recei ve at 
least o ne d ose of st u d y dr u g will ha ve all A Es rec or de d t hr o u g h t he e n d of t he 1 2  M o nt h S afet y 
F oll o w -u p Peri o d . 
S A Es (re gar dless of t heir relati o ns hi p t o st u d y treat me nt) are t o be re p ort e d a n d t he Seri o us 
A d verse E v e nt Re p ort (S A E R ) fa x e d or e -m aile d wit hi n 2 4 h o urs of k n o wle d ge of t he e ve nt t o:  
S pectr u m P h ar m ace uti c als, I nc . 
Pri m ar y C o nt a ct: P h ar m a c o vi gil a nce De p art me nt  
F a x: 
 
E -m ail: 
 
S pectr u m  ma y re q u est a d diti o nal i nf or mati o n fr o m t he I n v esti gat or t o e ns ure t he ti mel y 
c o m pleti o n of acc urate s afet y re p orts . Safet y dat a t hat are critical t o t he re p orta bilit y of a n S A E, 
s uc h as ca us alit y ass ess me nt a n d seri o usness  criteria, s h o ul d be i ncl u de d i n t he i nitial fa xe d or 
e-maile d S A E R . If o mitte d, a ti mel y res p o nse t o dr u g s afet y dat a q ueri es recei ve d fr o m S pectr u m  
or desi g n ee is e x pecte d.  
T he I n vesti gat or is t o ta k e all a p pr o pri ate t hera pe utic meas ures necessar y f or res ol uti o n of S A Es. 
A n y me di cati o ns necessar y f or treat me nt of t he S A E are t o b e rec or de d i n t he c o nc o mita nt 
me dicati o n secti o n of t he patie nt’s C R F . 
S A Es t hat are st u d y treat me nt -relate d will be f oll o we d u ntil res ol uti o n or u ntil t he y ha ve ret ur n e d 
t o Gra de 1, w hi c he ver is l o n ger, or u ntil it is deter mi ne d t hat t he o utc o me will n ot c ha n ge wit h 
f urt her f oll o w-u p.  
A d diti o nall y, t he S A E is t o be e ntere d i n t he A E C R F . F oll o w-u p S A E Rs n ee d t o be s u b mitte d t o 
S pectr u m wit hi n 2 4 h o urs o nce a d diti o nal i nf or mati o n re g ar di n g t he e v e nt bec o mes a v aila ble 
(e g, fi nal dia g n osis is ma de, la b orat or y or test res ults, e ve nt c o urse, o utc o m e, etc).  
S pectr u m  or desi g nee will be res p o nsi ble f or re p orti n g S A Es t o t he re g ulat or y a ut h orities i n 
acc or da nce wit h a p plica ble e x pe dite d re p orti n g re g ulat or y g ui deli nes. T he I n v esti gat or is 
res p o nsi ble f or s u b mitti n g S A Es t o his/ her l ocal I nstit uti o nal Re vie w B oar d (I R B)/ Et hics 
C o m mittee ( E C). C o pies of eac h S A E R , a n d d oc u me ntati o n of I R B/ E C n otificati o n a n d 
ac k n o wle d ge me nt of recei pt, will be ke pt i n t he Site’s Re g ulat or y Bi n der.  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
4 5  
7. 7. 2  E xcl usi o ns t o Seri o us A d verse E ve nt Re p orti n g Re q uire me nts  
T he f oll o wi n g are n ot c o nsi dere d S A Es : 
•  Sit uati o ns w here a n u nt o war d me dical occ urre n ce di d n ot occ ur (e g, s o cial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital , h os pitalizati o n f or dia g n ostic tests s uc h as C T 
sca ns). 
•  A ntici pate d da y -t o-d a y fl uct uati o ns of pre -e xisti n g disease(s) or c o n diti o n(s) p rese nt or 
detecte d pri or t o first st u d y treat me nt a d mi nistrati o n t hat d o n ot w orse n.  
•  Pla n ne d a n d p res c he d ule d h os pitalizati o ns a n d pr oce d ures.  
•  Pr o gressi ve disease . 
7. 8  Re pr o d ucti ve Ris ks  
N o a de q uat e a n d w ell -c o ntr olle d st u dies of S PI -2 0 1 2  ha ve bee n c o n d uct e d i n pre g n a nt w o me n. 
T he effect s of S PI -2 0 1 2  o n  fertilit y a n d fetal de v el o p me nt ha ve n ot bee n st u die d i n pre g na nt 
w o me n. S PI -2 0 1 2  is n ot rec o m me n de d f or use d uri n g pre g na n c y. 
Pre g n a ncies i n v ol vi n g a st u d y patie nt or a patie nt’s part ner, t hat occ ur fr o m t he first d ose of 
st u d y treat me nt t hr o u g h 3 5  ( ± 5) da ys after last d ose of st u d y dr u g a d mi nistrati o n or 3 5 ( ± 5)  da ys 
after t he d ate of p atie nt e arl y dis c o nti n uati o n, will  be re p ort e d wit hi n 2 4 h o urs after t h e 
I n v esti gat or has gai n e d k n o wle d ge of t he e ve nt vi a f a x or e-mail (see c o ntact i nf or mati o n i n  
Secti o n 7. 7. 1 ). Pre g na n cies s h o ul d be f oll o we d u p u ntil o utc o me a n d f oll o w -u p i nf or mati o n 
re gar di n g t he o ut c o me of t he pre g na n c y s h o ul d be fa x e d or e -maile d t o S pectr u m ’s 
P h ar mac o vi gila nce De part me nt.  
All patie nts w h o bec o me pre g na nt d uri n g partici pati o n i n t his st u d y are t o be wit h dra w n fr o m t he 
st u d y. 
8  S T A TI S TI C A L P L A N  
T his secti o n c o ntai ns a brief o ver vie w of t he statistical a nal yses  pla n ne d f or t his st u d y.  A f or mal 
statistical a nal ysis pla n ( S A P) will be fi nalize d pri or t o first patie nt e nr olle d .  
8. 1  S a m ple Size  
A p pr o xi matel y 2 1 8  p atie nts will be e nr olle d i n t his st u d y. T he pri mar y e n d p oi nt a nal ysis is base d 
o n t he test of n o n-i nferi orit y of S PI -2 0 1 2  as c o m p are d t o pe gfil grasti m.  
F or t he test of n o n -i nferi orit y h y p ot hesis, t he mar gi n of n o n-i nferi orit y t o be use d i n t he st u d y is 
0. 6 2 da y. T he tr ue differe nce bet w ee n t he mea ns is ass u me d t o be 0. 0 da ys. Sa m ple siz es of 
1 0 9  per treat me nt ar m will pr o vi de 9 0 %, 8 6 % , a n d 8 1 % p o wer t o det ect n o n -i nferi orit y usi n g a 
o ne -si de d, t w o-sa m ple t-t est at 2. 5 % le vel of si g nifica nce, w he n t he p o ole d sta n dar d de viati o n 
( S D) of t he D S N  is 1.4 , 1.5 , or 1.6  da ys, res p ecti vel y. T he p o ole d S D will be m o nit ore d i n t he 
o n g oi n g sister s t u d y S PI -G C F -3 0 1 . If t he p o ole d S D i n t he sister st u d y is esti mate d t o be greater 
t ha n 1.4  da ys, t he sa m ple siz e ma y be i ncreas e d t o reflect t he p ote ntial e xtra varia bilit y f or t he 
c urre nt st u d y. Si nce t he i nf or mati o n t hat ma y be use d is i n de pe n de nt of t he c urre nt st u d y res ults, 
t he n o mi nal t y pe I err or is preser ve d f or t he c urre nt st u d y. T he stu d y will e nr oll a n d ra n d o mize 
1 0 9  patie nts per ar m f or a t otal of a p pr o xi matel y 2 1 8  patie nts.  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
4 6  
T he n o n -i nferi orit y of S PI -2 0 1 2  t o pe gfil grasti m will be declare d if t he u p per b o u n d of 9 5 % CI 
of t he differe nce i n mea n D S N  bet wee n t he treat m e nt ar ms is < 0. 6 2 da ys.   
8. 2  Met h o d of Tre at me nt Assi g n me nt, R a n d o miz ati o n, a n d/ or Str atific ati o n  
T he patie nts e nr olle d i n t his st u d y will be ra n d o mi ze d at a 1: 1 rati o t o  t he S PI -2 0 1 2  a n d 
Pe gfil gr asti m Tre at me nt Ar m s a n d stratifie d b y st u d y site. A ra n d o mizati o n sc he me usi n g a 
per m ute d bl oc k desi g n will be de vel o pe d. A n i nteracti ve we b res p o nse s yst e m will be use d t o 
assi g n a ra n d o mizati o n i de ntificati o n (I D) o nce p atie nts meet eli gi bilit y criteria a n d are rea d y t o 
be ra n d o mize d. T he ra n d o mizati o n I D will be differe nt t ha n t he Patie nt I D, a n d a ma p pi n g of 
ra n d o mizati o n I D t o Pati e nt I D will be ke pt i n a s ec ure d d ata bas e.  
8. 3  A n al ysis P o p ul ati o ns  
•  I nte nt-t o-Tre at P o p ul ati o n  (I T T): will c o nsist of all patie nts w h o are ra n d o mize d . 
Patie nts will be a nal yze d as ra n d o mize d  if t he act u al treat me nt assi g n me nts de viate fr o m 
t he ra n d o mizati o n sc he me.  
•  Per Pr ot oc ol ( P P) P o p ul ati o n:  will  i ncl u de all patie nts i n t he I T T p o p ul ati o n wit h n o 
maj or pr ot oc ol de viati o n  i n C ycle 1 . Patie nts will be a nal yz e d as tr eate d if t he act ual 
treat me nt assi g n me nts de viate fr o m t he ra n d o mizati o n sc he me.  
•  S afet y A n al ysis P o p ul ati o n  (S A F ): will c o nsist of all patie nts w h o recei ve at least o ne 
d ose of a n y pr ot o c ol -s pecifie d dr u g ( T C or S PI -2 0 1 2  o r pe gfil grasti m) 
Patie nts w h o disc o nti n ue fr o m t he st u d y pri or t o ra n d o mizati o n will be re place d  as t he y are n ot 
c o nsi dere d t o be t h e I T T patie nts .  
8. 4  Ge ner al St atistic al Met h o ds  
S pectr u m’s Bi ostatistics a n d Data Ma n a ge me nt ( B D M) gr o u p  ( or a c o ntracte d data ma na ge me nt 
ve n d or) will be res p o nsi ble f or data m a na ge me nt a n d statistical a nal ysis of t his st u d y. All 
statistical a nal ys es will be perf or me d usi n g S A S f or Wi n d o ws ( versi o n 9. 3  or hi g her). Patie nt 
data listi n gs a n d ta b ular prese ntati o ns of res ults will be pr o vi de d. F urt her details of t he criteri a 
a n d c o n d uct of t he st atistical a nal yses will be i ncl u de d i n t he Statistical A nal ysis Pla n f or t his 
st u d y t o be fi naliz e d pri or t o first patie nt e nr olle d. 
8. 5  Effic ac y A n al yses  
8. 5. 1  Pri m ar y E n d p oi nt  
T he pri mar y a n al ysis of t he c o m paris o n of t he D S N  i n C ycle 1  bet w ee n t he S PI -2 0 1 2 
Tre at me nt Ar m a n d t he Pe gfil gr asti m Tre at me nt Ar m will be c o n d ucte d usi n g t he I T T 
P o p ul ati o n . 
D S N  i n C ycle 1  is defi ne d  as t he n u m ber of d a ys of se vere ne utr o p e nia ( A N C < 0. 5 × 1 0 9/ L) fr o m 
t he first occ urre nce of a n A N C bel o w t he t hres h ol d. T he assess me nt of A N C will be perf or me d 
o n D a y 1  a n d D a ys 4 -1 5  i n C ycle  1 . T he e n d p oi nt will be meas ure d i n all p atie nts i n t he I T T 
P o p ul a ti o n. F or patie nts w h o d o n ot meet se vere ne utr o pe nia criteria, t he e n d p oi nt meas ure me nt 
will be defi ne d as  D S N = 0.  
F or t he pri mar y efficac y a nal ysis, t he m ea n D S N  i n C ycle 1  will be c o m pare d bet wee n t he 
S PI -2 0 1 2 Tre at me nt Ar m  a n d t he P e gfil gr asti m T re at me nt A r m usi n g a b o otstra p resa m pli n g 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
4 7  
met h o d wit h n o n -i nferi orit y h y p ot hesis. A 2-si de d 9 5 % c o nfi de n ce i nter val ( CI) of t he differe nce 
bet wee n t he m ea n D S N  of t he S PI -2 0 1 2 T re at me nt A r m a n d t he m ea n D S N  of t he 
P e gfil gr asti m Tre at me nt A r m will be calc ul at e d usi n g b o otstra p resa m pli n g  wit h treat me nt as 
t he o nl y stratificati o n fact or. T he st u d y will use n o n i nferi orit y m ar gi n of 0. 6 2 da y s f or t he a b o ve 
c o m paris o n. T he n o n -i nf eri orit y of S PI -2 0 1 2  t o pe gfil grasti m will be declare d if t he u p per b o u n d 
of 9 5 % C I of t he differe n ce i n mea n D S N  b et wee n t he treat me nt ar ms is < 0. 6 2  da y s.  
Pri mar y a nal ysis f or t he n o n -i nferi orit y h y p ot hesis will be base d o n  t he I T T p o p ulati o n. A n 
anal ysis b ase d o n t he P P  P o p ul ati o n  will be perf or me d as a se nsiti vit y a nal ysis .  
I n a d diti o n t o b o otstra p resa m pli n g met h o d t o calc ulate 9 5 % CI of t h e differe nce i n mea n D S N  
bet wee n tr eat me nt ar ms, t he test of t he differe nce i n mea n D S N  bet wee n tr eat me nt ar ms will be 
c o n d ucte d usi n g P oiss o n distri b uti o n  as a n ot her se nsiti vit y a n al ysis. If t he data is o ver dis perse d, 
a ne gati ve bi n o mial distri b uti o n will be i nc or p orat e d f or t he test. F or t he P oiss o n a n d ne gati ve 
bi n o mial re gressi o n, t he i de ntical li n k will be use d a n d treat me nt will be t he o nl y c o v ariate i n t he 
m o del. T he differe nce i n me a n D S N  bet wee n S PI -2 0 1 2  a n d p e gfil grasti m will be calc ulate d 
al o n g wit h 2 -si de d 9 5 % CI, bas e d o n P oiss o n or ne gati ve bi n o mial re gressi o n. Base d o n t h e 
i nitial re vie w of t he effici e nc y of t he esti mates of b o otstra p, P oiss o n a n d ne gati ve bi n o mial 
distri b uti o ns, 9 5 % CI cal c ulate d usi n g b o otstr a p resa m pli n g met h o d a p p ear t o be r o b ust a n d 
t heref ore is pr o p ose d t o b e t he pri mar y a nal ysis  met h o d f or t he pri mar y e n d p oi nt.  D etaile d 
si m ulati o n res ults will be pr o vi de d al o n g wit h S A P.  
A d diti o nal se nsiti vit y a n al yses will als o be use d t o e x a mi ne  t he: 
•  T reat me nt effect, a dj usti n g f or t he vari o us st u d y sites. T his a nal ysis will be carri e d o ut 
usi n g t he sa me m et h o d ol o g y as t h e pri mar y a n al ysis ( b o otstra p resa m pli n g met h o d) , a n d 
st u d y site will be use d as a n a d diti o nal stratificati o n fact or i n t he resa m pli n g.  
•  T reat me nt effect, a dj usti n g f or disease st at us at ra n d o mizati o n (a dj u va nt or ne oa dj u va nt). 
T his a nal ysis will be t he sa me as t he pri mar y a nal ysis ( b o otstra p resa m pli n g met h o d) a n d 
disease stat us will be use d as a d diti o nal stratificati o n fact or i n t he resa m pli n g.  
•  I m pa ct of missi n g d ata, usi n g a w orst case s ce n ari o. W he n A N C data are missi n g o n or 
after D a y 5 , a n d bef ore p atie nts’ A N C i ncrease t o ≥1. 5 × 1 0 9/ L after t he e x pecte d na dir i n 
C ycle 1 , missi n g A N C val ues will be i m p ute d as < 0. 5 × 1 0 9/ L f or S PI -2 0 1 2  a n d ≥0. 5 ×
1 0 9/ L f or pe gfil grasti m, f or t he p ur p ose of D S N  calc ulati o n. T he met h o d of a nal ysis of 
i m p ute d D S N  data usi n g w orst case s ce nari o will be t he sa me as t h e pri mar y a n al ysis 
( b o otstra p res a m pli n g met h od).  
I n a d diti o n, t he f oll o wi n g s u b gr o u ps will be e x a mi ne d f or D S N  i n C ycl e 1 :  
•  A ge : < 6 5 y ears, ≥6 5 y ea rs 
•  Ge n der ( Male, Fe male)  
•  Race  
•  Disease Stat us ( A dj u va nt, Ne oa dj u va nt) at ra n d o mizati o n  
•  Ge o gra p hic R e gi o n  
•  Wei g ht : < 6 5 k g, 6 5 t o 7 5 k g, or > 7 5 k g  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
4 8  
8. 5. 2  Ke y Sec o n d ar y E n d p oi nts  
•  T o c o m pare S PI -2 0 1 2  wit h pe gfil grasti m i n:  
 Ti me t o A N C Rec o v er y i n  C ycle 1 , defi ne d as t h e ti me fr o m c he m ot hera p y 
a d mi nistrati o n u ntil t he patie nt ’s A N C i ncreases t o ≥1. 5 × 1 0 9/ L after t he e x pecte d 
na dir. F or patie nts wit h A N C val ue ≥1. 5 × 1 0 9/ L at all ti mes, T i me t o A N C R ec o ver y 
will be assi g ne d t o a val u e of 0 . 
 De pt h of A N C N a dir , defi ne d as t he p atie nt’s l o west A N C i n C ycle 1  
 I nci de nce of F N i n patie nts d uri n g C ycl e 1 , i n w hic h F N  is d efi ne d as a n oral 
te m perat ur e > 3 8. 3° C ( 1 0 1. 0° F) or t w o c o nsec uti v e rea di n gs of > 3 8. 0° C ( 1 0 0. 4° F) f or 
2 h o urs a n d A N C < 1. 0 × 1 0 9/ L 
8. 5. 3  A d diti o n al Sec o n d ar y E n d p oi nts  
•  T o c o m pare S PI -2 0 1 2  wit h pe gfil grasti m i n:  
 D S N  i n C ycles 2 , 3 , a n d 4  
 I nci de nce of Ne utr o pe nic C o m plic ati o ns, i ncl u di n g use of a nti-i nfecti ves a n d 
h os pitaliz ati o ns, i n patie nts d uri n g C ycl e 1  
 I n ci de nce of F N  i n C y cles 2 , 3 , a n d 4  
 R DI  of T C i n C ycles 1  t o 4  
 Safet y  
T he a nal yses of Ke y Sec o n dar y E n d p oi nts will e m pl o y a hierarc hical cl os e d testi n g pr oce d ure 
[2 9 ], w here e n d p oi nts are ra n ke d wit h t he pri mar y e n d p oi nt first a n d t he n t he Ke y Sec o n d ar y 
E n d p oi nts i n t he or der liste d a b o ve. S pecifi call y, t he or der of testi n g is:  
1.  D S N  i n C ycle 1  
2.  Ti me t o A N C Rec o v er y  i n C ycle 1  
3.  De pt h of A N C Na dir i n C ycle 1  
4.  I n ci de nce of F N  i n C y cle 1  
F or t he sec o n dar y efficac y a n al ys es, t he res ults will eac h be s u m marize d b y Treat me nt Ar m a n d 
C ycle a n d will use t he I T T p o p ulati o n. T w o -si de d 9 5 % CI f or t he differe nce bet wee n t he 
treat me nt ar ms will be calc ulate d. 
N o a dj ust me nt t o al p ha will be necessar y o nce t h e prece di n g e n d p oi nt c o m paris o n is si g nifica nt 
f or t he s u bse q ue nt e n d p oi nts i n t he a b o ve or der of e n d p oi nts, with eac h test at t he sa me 
si g nifica n ce le v el of α = 0. 0 5. 
8. 6  A n al ysis of S afet y  
T he o verall i nci de nce of treat me nt -e mer ge nt A Es ( T E A E) (i e, A Es occ urri n g fr o m t he ti me t he 
first d ose of t he st u d y dr u g t hr o u g h 1 2 m o nt hs  aft er t he last d ose of st u d y dr u g a d mi nistrati o n or 
3 5 ( ± 5)  da ys after t he d ate of patie nt earl y disc o nti n uati o n) a n d t he pr o p orti o n of patie nts w h o 
disc o nti n ue beca us e of a T E A E are t he pri mar y s afet y o ut c o me meas ures.  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
4 9  
T he n u m ber a n d p erce nt of patie nts wit h ne w -o ns et T E A Es will be s u m marize d b y t he Me d D R A 
S yste m -Or ga n -Class ( S O C) le vel a n d P referre d T er m ( P T) f or all treate d patie nts. T he s u m mar y 
of T E A Es will be pres e nte d i n t he f oll o wi n g cate g ories:  
•  N u m ber a n d p erce nta ge of patie nts wit h a n y T E A Es b y S O C  a n d P T . 
•  N u m ber a n d p erce nta ge of patie nt s wit h a n y S A Es b y S O C  a n d P T . 
•  N u m ber a n d p erce nta ge of patie nts wit h relate d T E A Es b y S O C  a n d P T . 
•  
Relate d t o T C  
•  
Relate d t o S PI -2 0 1 2  
•  
Relate d t o pe gfil grasti m   
•  N u m ber a n d p erce nta ge of patie nts wit h T E A Es ca usi n g disc o nti n uati o n of t he st u d y b y 
S O C  a n d P T . 
•  N u m ber a n d p erce nta ge of patie nts wit h A Es of S pecial I nterest  b y P T  
•  
M usc ul os keletal p ai n  
•  
I nje cti o n site reacti o ns 
•  
H y p erse nsiti vit y reacti o ns   
I n a d diti o n, t he n u m ber a n d perce nt of patie nts wit h T E A Es b y gra d e will be s u m marize d. 
A d verse e ve nts re p orte d pri or t o treat me nt b ut aft er I nf or me d C o nse nt will be pr o vi de d i n a 
listi n g. A n e x p os ure -res p o nse a nal ysis will be perf or me d base d o n s p arse P K sa m pli n g. 
8. 7  Cli nic al L a b or at or y  a n d  Vit al Si g ns  E v al u ati o ns  
Ke y la b orat or y para meters  a n d vital si g ns  will be s u m m arize d usi n g s hift ta bles, w hic h will 
dis pla y a cr oss -ta b ulati o n of t he B aseli ne  gra de v ers us t he hi g h est o n -st u d y gra de f or eac h 
la b orat or y para meter.  
All a b n or malities will be classifie d acc or di n g t o N CI C T C A E Versi o n 4. 0 3  a n d s u m marize d b y 
w orst gra de s e verit y per patie nt b y c ycle a n d b y tr eat me nt wit hi n c ycle.  
9  A D MI NI S T R A TI V E P R O C E D U R E S A N D S T U D Y M A N A G E M E N T   
9. 1  I n vesti g at or Res p o nsi bilities  
9. 1. 1  G o o d Cli nic al Pr a ctice  
It is t he res p o nsi bilit y of t he Pri nci pal I n vesti gat or t o o versee t he s afet y of t he patie nts at t heir 
site. T he I n vesti gat or will e ns ure t hat t his st u d y is c o n d ucte d i n f ull c o m plia nce wit h t he 
pri nci ples of t he “ D eclarati o n of Helsi n ki” (as a me n de d i n T o k y o, Ve nice, H o n g K o n g, a n d 
S o ut h Africa), I C H g ui d eli nes, or wit h t he la ws a n d re g ulati o ns of t he c o u ntr y i n w hi c h t he 
researc h is c o n d u cte d. B y si g ni n g t he U S F or m F D A 1 5 7 2, “ State me nt of I n v esti gat or,” t he 
I n v esti gat or c o m mits t o a d here t o a p plica ble secti o ns of t he U S C F R parts 5 0 “ Pr otecti o n of 
H u ma n Patie nts ,” 5 4 “ Fi na ncial Discl os ure b y Cli nical I n vesti gat ors ,” 5 6 "I nstit uti o nal Re vie w 
B oar ds ,” a n d 3 1 2 s u b part D “ Res p o nsi bilities of S p o ns ors a n d I n vesti gat ors .” All I n v esti gat ors 
will e ns ure a d here nce t o I C H g ui deli nes f or G C P a n d Cli nical Safet y Data Ma na ge me nt . 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
5 0  
9. 1. 2  I nstit uti o n al Re vie w B o ar d/ Et hics C o m mittee A p pr o v al 
T he I n vesti gat or s hall ass ure t hat t he I R B/ E C will pr o vi de i nitial a n d c o nti n ui n g re vi e w of t he 
st u d y. Pri or t o scree ni n g a n d e nr oll me nt of st u d y patie nts, d oc u me nte d I R B/ E C a p pr o val of t h e 
pr ot oc ol, I C F a n d a n y patie nt materials m ust be o btai ne d a n d pr o vi de d t o S pectr u m or its 
desi g nee.  
9. 1. 3  I nf or me d C o nse nt  
T he i n vesti gat or will e ns ure t hat t he met h o d of o btai ni n g a n d d o c u me nti n g t he Inf or me d C o nse nt 
c o m plies wit h I C H -G C P a n d all a p plica ble re g ulat or y re q uire m e nt(s). I nf or me d C o nse nt m ust be 
o btai ne d bef ore st u d y pr oce d ures are p erf or me d, u nless perf or m e d as sta n dar d of care. T he 
s u bject’s s o urce d oc u me nts s hall d oc u me nt t he i nf or me d c o nse nt pr ocess a n d t hat I nf or me d 
C o nse nt was o btai ne d pri or t o st u d y par tici pati o n. A c o p y of eac h si g ne d I C F m ust be pr o vi de d 
t o t he patie nt or t he patie nt’s le gall y a ut h orize d re prese ntati ve. All si g ne d IC F s m ust re mai n i n 
eac h p atie nt’s st u d y file a n d m ust be a vaila ble f or verificati o n at a n y ti me.  
9. 1. 4  St u d y Files a n d Rete nti o n  of Rec or ds  
T he I n vesti gat or will ret ai n all st u d y rec or ds u ntil at least 2 years after t he l ast a p pr o val of a 
mar keti n g a p plicati o n or at least 2 years ha ve ela pse d si nce t he f or mal disc o nti n uati o n of cli nical 
de vel o p me nt of t he i n vesti gati o nal pr o d uct. T h ese d oc u me nts will be retai n e d f or a l o n ger 
peri o d, h o we v er, if re q uire d b y t he a p plica ble re g ulat or y re q uire m e nts or b y a n a gree me nt wit h 
S pectr u m. If t he I n v esti gat or rel oc ates, or f or a n y reas o n desir es t o dis p ose of t he rec or ds, t he 
st u d y rec or ds ma y b e tra nsferre d t o a n ot her i nstit uti o n, a n ot her i n vesti gat or, or t o S pectr u m u p o n 
writte n a gree me nt bet w ee n t he I n vesti gat or a n d S pectr u m.  
9. 2  Rec or di n g a n d C ollecti n g of D at a  
I n acc or da n ce wit h I C H a n d G C P g ui deli nes, t he I n v esti gat or will mai ntai n c o m plete, acc urat e, 
le gi ble, a n d easil y retrie v a ble data, a n d will all o w pers o n nel a ut h orize d b y S pectr u m access t o all 
st u d y data at a n y ti me. S uc h data s hall als o be s ec ure d i n or der t o pre ve nt l oss of data.  
9. 2. 1  C ase Re p ort F or ms  
At sc he d ule d m o nit ori n g visits, C R F s will be verifie d a gai nst s o urce d o c u m e ntati o n a n d 
s u b mitte d as fi nal data. A n y s u bse q u e nt c ha n ges t o t he C R F s are t o be perf or me d i n acc or da n ce 
wit h S pectr u m’s sta n dar d o perati n g pr oce d ures f or e diti n g a n d clarif yi n g C R F s. Data e ntr y will 
be perf or me d b y  t he sites usi n g a n electr o nic d ata ca pt ure ( E D C) s yste m.  
9. 2. 2  Dr u g Acc o u nt a bilit y  
I n acc or da n ce wit h all a p plica ble re g ulat or y re q uir e me nts, t he I n vesti gat or or desi g n ate d site 
staff is t o mai ntai n st u d y treat me nt acc o u nta bilit y rec or ds t hr o u g h o ut t he c o urse of t he st u d y. 
T his pers o n(s) will d oc u me nt t he a m o u nt of t he st u d y dr u g ( S PI -2 0 1 2  or pe gfil grasti m  
a d mi nistere d t o patie nts. T he C R A will re vie w i n v e nt or y a n d acc o u nta bilit y d oc u me ntati o n 
d uri n g m o nit ori n g visits.  
T he I n vesti gat or will n ot s u p pl y i n vesti ga ti o nal st u d y dr u gs t o ot her i n vesti gat ors n ot liste d o n 
t he U S F or m F D A 1 5 7 2 or e q ui vale nt. I n v esti gati o nal st u d y dr u g us e, ot her t ha n as directe d b y 
t his pr ot oc ol, is n ot all o we d. 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
5 1  
All u n use d s yri n ges of S PI -2 0 1 2  are t o b e acc o u nte d f or at t he site a n d m ai ntai ne d i n a sec ure d, 
l oc ke d st ora ge area wit h access li mite d t o a ut h orize d st u d y p ers o n nel o nl y. Use d S PI -2 0 1 2  
s yri n ges will be destr o ye d per i nstit uti o n, l ocal, a n d all a p plica ble p olicies a n d pr oce d ures. After 
st u d y c o n cl usi o n, all u n use d s yri n ges of S PI -2 0 1 2  ma y b e destr o ye d at t he site, f oll o wi n g 
verificati o n of acc o u nt a bilit y b y a S pectr u m re prese ntati ve.  
9. 3  Pr ot oc ol C o m pli a nce  
T he Pri nci pal I n vesti gat or is res p o nsi ble f or e ns uri n g t he st u d y is c o n d uct e d i n acc or da nce wit h 
t he pr oce d ures a n d e val u ati o ns descri be d i n t his pr ot oc ol. 
9. 4  S p o ns or Res p o nsi bilities  
9. 4. 1  St u d y M o nit ori n g  
T he st u d y will be m o nit ore d b y e m pl o yees or re prese ntati ves of S pectr u m. C R As will m o nit or 
eac h site o n a p eri o dic b asis a n d perf or m v erificati o n of s o urce d o c u me ntati o n f or eac h patie nt as 
well as ot her r o uti ne c o m plia nce re vi e ws. S pectr u m’s Me dical M o nit or a n d P har mac o vi gila nce 
De part me nt will re vi e w s afet y data a n d be res p o nsi ble f or e ns uri n g ti mel y re p orti n g of e x pe dite d 
S A E Rs t o re g ulat or y a ge ncies a n d I n v esti gat ors.  
9. 4. 2  S afet y M o nit or i n g 
T he cli nical dr u g safet y of st u d y tr eat me nt will be c o nti n u o usl y e val u ate d b y t he st u d y Me dical 
M o nit or or desi g n ee o n a n o n g oi n g basis d uri n g t h e c o urse of t his cli nical st u d y. All S A Es 
relate d t o st u d y treat me nt i n t his st u d y a n d all ot her o n g oi n g cli nical st u dies wit h st u d y treat me nt 
will be pr ocesse d i n c o m plia nce wit h c urre nt re g ulat or y g ui deli nes b y S pectr u m’s 
P har mac o vi gila nce De part me nt. T his pr ocessi n g will i ncl u de a f or mal ass ess me nt of eac h S A E 
b y dr u g s afet y. I n a d diti o n, a c u m ulati ve re vi e w  of all S A Es fr o m all s o urces will be assesse d 
peri o dicall y  
9. 5  J oi nt I n vesti g at or/ S p o ns or Res p o nsi bilities  
9. 5. 1  Access t o I nf or m ati o n f or M o nit ori n g a n d A u diti n g  
I n acc or da n ce wit h I C H G C P g ui deli nes a n d 2 1 C F R 3 1 2, t he C R A/a u dit or is t o ha ve direct 
access t o t he  patie nt’s s o urce d oc u m e ntati o n i n or der t o verif y t he data rec or de d i n t he C R F s. 
T he C R A is res p o nsi ble f or r o uti ne re vie w of t he C R F s at re g ular i nter vals t hr o u g h o ut t he st u d y 
a n d t o verif y a d h ere n ce t o t he pr ot oc ol, as well as t he c o m plete ness, c o nsist e nc y, a n d acc urac y of 
t he data bei n g rec or de d. T he C R A/a u dit or is t o ha ve access t o a n y patie nt r ec or ds nee de d t o 
verif y t he e ntri es o n t he C R F s, as well as access t o all ot her st u d y-relat e d d oc u me ntati o n a n d 
materials. T he I n v esti gat or a grees t o pr o vi de t h e m o nit or wit h s ufficie nt ti me a n d facilities t o 
c o n d uct m o nit ori n g.  
9. 5. 2  Ter mi n ati o n of t he St u d y  
F or reas o na bl e ca us e, eit her t he I n v esti gat or or S pectr u m ma y ter mi nate t h e I n vesti gat or’s 
partici pati o n i n t his st u d y. I n a d diti o n, S pectr u m P har mace uticals I nc.  m a y ter mi nate t he st u d y at 
a n y ti me u p o n i m me diate n otice f or a n y reas o n, i n cl u di n g b ut n ot li mite d t o, S pectr u m’s belief 
t hat ter mi nati o n is necess ar y f or t he s afet y of patie nts. 


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
5 2  
9. 5. 3  P u blic ati o n P olic y  
T o c o or di nate t he disse mi nati o n of data fr o m t his st u d y,  S pectr u m e n c o ura ges t he f or mati o n of a 
p u blicati o n c o m mittee c o nsisti n g of t he Pri nci pal I n vesti gat or a n d a p pr o priate S pectr u m staff. 
T he c o m mittee is e x pecte d t o s olicit i n p ut a n d assista nce fr o m ot her In vesti gat ors a n d S p o ns or 
staff as a p pr o priate. M e m bers hi p o n t he c o m mittee ( b ot h f or In vesti gat ors a n d S taff) d o es n ot 
g uara nte e a ut h ors hi p - t he criteria d escri be d b el o w s h o ul d be met f or e ver y p u blicati o n. 
A ut h ors hi p of a n y p u blicati o ns res ulti n g fr o m t his st u d y will be deter mi ne d o n t he basis of t he 
U nif or m Re q uire me nts f or Ma n uscri pt S u b mitte d t o Bi o me dical J o ur nals (I nter nati o nal 
C o m mittee of Me dical J o ur nal E dit ors, 2 0 0 5), w hi c h states:  
•  A ut h ors hi p cre dit s h o ul d be base d o n t he f oll o wi n g; a ut h ors s h o ul d meet all t hree 
c o n diti o ns:  
1.  S u bsta ntial c o ntri b uti o ns t o c o nce pti o n a n d desi g n, ac q uisiti o n of data, or a n al ysis 
a n d i nter pret ati o n of data;  
2.  Drafti n g t he article or re visi n g it criticall y f or i m p orta nt i ntellect ual c o nte nt; a n d  
3.  Fi nal a p pr o val of t he versi o n t o be p u blis he d.  
•  W he n a lar ge, m ultice nter gr o u p has c o n d u cte d t h e w or k, t he gr o u p s h o ul d i de ntif y t he 
i n di vi d uals w h o acce pt direct res p o nsi bilit y f or t h e ma n uscri pt. T hes e i n di vi d uals s h o ul d 
f ull y meet t he criteri a f or a ut h ors hi p defi ne d a b o v e.  
•  Ac q uisiti o n of f u n di n g, c ollecti o n of data, or ge neral s u per visi o n of t he res earc h gr o u p 
al o ne d oes n ot c o nstit ute a ut h ors hi p.  
•  All pers o ns desi g n ate d as a ut h ors s h o ul d q ualif y f or a ut h ors hi p, a n d all t h ose w h o q ualif y 
s h o ul d be liste d. 
•  Eac h a ut h or s h o ul d ha v e partici pate d s ufficie ntl y i n t he w or k t o ta ke p u blic res p o nsi bilit y 
f or a p pr o priate p orti o ns of t he c o nte nt. 
All p u blicati o ns (e g, m a n uscri pts, a bstracts, or al/sli de prese ntati o ns, b o o ks c ha pters) base d o n 
t his st u d y m ust be s u b mitte d t o S pectr u m wit hi n 3 0 da ys ( b ut n o less t ha n 1 0 da ys) pri or t o 
s u b missi o n or p u blicati o n f or c or p orate re vie w.  
9. 6  C o nfi de nti alit y  
All i nf or mati o n pr o vi de d t o t he I n v esti gat or b y S pectr u m, i ncl u di n g n o n cli nical data, pr ot oc ols, 
C R F s, a n d ver bal a n d writte n i nf or mati o n, will be ke pt strictl y c o nfi de ntial a n d c o nfi ne d t o t he 
cli nical pers o n nel i n v ol v e d i n c o n d ucti n g t his st u d y, a n d n o dis cl os ure s hall be ma de e x ce pt i n 
acc or da nce wit h a n y ri g ht of p u blicati o n gra nte d t o t he I n v esti gat or. All pers o n nel will ha n dle 
patie nt data i n a c o nfi de ntial ma n ner i n  acc or da n ce wit h a p plica ble re g ulati o ns g o ver ni n g cli nical 
researc h. U p o n re q uest b y a re g ulat or y a ut h orit y s uc h as t he U S F D A a n d ot her re g ulat or y 
a ut h orities w orl d wi de, t h e I n vesti gat or/i nstit uti o n is t o ma ke a vaila ble f or direct access all 
re q ueste d st ud y -relate d rec or ds or re p orts ge n erate d as a res ult of a patie nt’s partici pati o n i n t his 
st u d y. T his i nf or mati o n ma y b e relat e d i n c o nfi de nce t o t he I R B/ E C or ot h er c o m mittee 
f u ncti o ni n g i n a si milar ca pacit y. I n a d diti o n, n o r e p orts or i nf or mati o n a b o ut the st u d y or its 
pr o gress will be pr o vi de d t o a n y o n e n ot i n v ol ve d i n t he st u d y ot her t h a n t o S pectr u m, or i n 
c o nfi de nce t o t he I R B/ E C or si milar c o m mittee, e x ce pt if re q uire d b y la w.  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
5 3  
1 0  R E F E R E N C E S  
1.  
A merica n Ca n cer S oci et y - Ca n cer Facts a n d  Fi g ures 2 0 1 4.  
2.  
Nati o nal C o m pre he nsi ve Ca ncer Net w or k. Breast Ca ncer ( Versi o n 3, 2 0 1 4) [ Se pte m ber 
2, 2 0 1 4]. A vaila ble fr o m: w w w. ncc n. or g/ pr ofessi o nals/ p h ysicia n _ gls/ p df/ breast. p df.  
3.  
Harla n L C, A bra ms J, Warre n J L, Cle g g L, Ste ve ns J, Ballar d -Bar bas h R.  A dj u va nt 
T hera p y f or Breast Ca ncer: Practice Patter ns of C o m m u nit y P h ysicia ns. J Cli n O nc ol. 
2 0 0 2; 2 0( 7): 1 8 0 9 -1 7.  
4.  
J o nes S, H ol mes F A, O' S ha u g h n ess y J, Bl u m J L, V u kelja SJ, McI nt yre KJ, et al. 
D oceta x el wit h C ycl o p h os p ha mi de Is Ass ociate d wit h a n O verall  S ur vi val Be nefit 
C o m pare d wit h D o x or u bici n a n d C ycl o p h os p h a mi de: 7 -Year F oll o w -u p of Us O nc ol o g y 
Researc h Trial 9 7 3 5. J Cli n O nc ol. 2 0 0 9; 2 7( 8): 1 1 7 7 -8 3.  
5.  
C ortes -F u nes H, C or o na d o C. R ole of A nt hrac ycli nes i n t he Era of Tar get e d T hera p y. 
Car di o vasc T o xic o l. 2 0 0 7; 7( 2): 5 6-6 0.  
6.  
J o nes S E, Sa vi n M A, H ol mes F A, O' S ha u g h ness y J A, Bl u m J L, V u kelja S, et al. P hase 
Iii Trial C o m pari n g D o x or u bici n Pl us C ycl o p h os p ha mi de wit h D oceta xel Pl us 
C ycl o p h os p ha mi de as A dj u va nt T hera p y f or O pera ble Breast Ca ncer. J Cli n O nc ol. 
2 0 0 6; 2 4( 3 4): 5 3 8 1 -7.  
7.  
Tre nt J C, Valer o V, B o os er DJ, Es parza -G uerra L T, I bra hi m N, Ra h ma n Z, et al. A P hase 
I St u d y of D o ceta x el Pl us C ycl o p h os p ha mi de i n S oli d T u m ors F oll o we d b y a P hase Ii 
St u d y as First -Li n e T hera p y i n M etastatic Breast Ca ncer. Cli n C a ncer Res. 
2 0 0 3; 9( 7): 2 4 2 6 -3 4.  
8.  
B or d o ni R, Haisli p S, Gil m ore J, S har pe J, A bella E, C h oi M. P 5 -2 0 -0 7: Esti mati o n of 
Fe brile Ne utr o pe ni a  i n W o me n Recei vi n g D ocet a x el Pl us C ycl o p h os p ha mi de as 
A dj u va nt T hera p y f or Earl y Sta ge Breast Ca ncer: A Retr os pecti ve A nal ysis. Ca ncer 
Researc h. 2 0 1 1; 7 1( 2 4 S u p ple me nt 3).  
9.  
C ha n A, F u W H, S hi h V, C o y uc o J C, Ta n S H, N g R. I m pact of C ol o n y -Sti m ulati n g 
Fact ors t o Re d u ce Fe bril e Ne utr o pe ni c E ve nts i n Breast Ca ncer Patie nts Recei vi n g 
D oceta x el Pl us C ycl o p h os p ha mi de C he m ot hera p y. S u p p ort Care Ca ncer. 
2 0 1 1; 1 9( 4): 4 9 7 -5 0 4.  
1 0.  
M yers R, Hi g gi ns B, M yers J, Le u n g M, Raja g o p al S, J o nes G, et al. C he m ot hera p y 
I n d u ce d Fe brile Ne utr o pe ni a  of D oceta xel wit h C ycl o p h os p ha mi de ( Tc) f or A dj u va nt 
T hera p y of Breast Ca ncer i n t he C o m m u nit y: Rea lit y C hec k. Ca n cer Res earc h. 
2 0 0 9; 6 9( 2 4 S u p pl): A bstract nr 2 0 9 2.  
1 1.  
S o o n g D, Haj R, Le u n g M G, M yers R, Hi g gi ns B, M yers J, et al. Hi g h Rat e of Fe brile 
Ne utr o pe ni a  i n Patie nts wit h O pera ble Breast Ca ncer Recei vi n g D oceta xel a n d 
C ycl o p h os p ha mi de. J Cli n O nc ol. 2 0 0 9; 2 7( 2 6):e 1 0 1 -2.  
1 2.  
Va n de n ber g T, Y o u n us J, Al -K ha y yat S. Fe brile Ne utr o pe ni a  Rates wit h A dj u va nt 
D oceta x el a n d C ycl o p h os p ha mi de C he m ot hera p y i n Earl y Breast Ca ncer: Discre pa n c y 
bet wee n P u blis he d Re p orts a n d C o m m u nit y Practice -a R etr os pecti ve A nal y sis. C urr 
O nc ol. 2 0 1 0; 1 7( 2): 2 -3.  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
5 4  
1 3.  
K u derer N M, Dal e D C, Cra wf or d J, L y ma n G H. I m pact of Pri mar y Pr o p h yl a xis wit h 
Gra n ul oc yte C ol o n y -Sti m ulati n g Fact or o n Fe brile Ne utr o pe ni a  a n d M ortalit y i n A d ult 
Ca ncer Patie nts Recei vi n g C he m ot hera p y: A S yst e matic Re vi e w. J Cli n O nc ol. 
2 0 0 7; 2 5( 2 1): 3 1 5 8 -6 7.  
1 4.  
L y m a n G H, Mic hels S L, Re y n ol ds M W, Barr o n R, T o mic K S, Y u J. Ris k of M ortalit y i n 
Patie nts wit h Ca ncer W h o E x perie nce Fe brile Ne utr o pe ni a . Ca ncer. 2 0 1 0; 1 1 6( 2 3): 5 5 5 5-
6 3.  
1 5.  
Nati o nal C o m pre he nsi ve Ca ncer Net w or k. M yel oi d Gr o wt h Fact ors ( Versi o n 2, 2 0 1 4). 
A vaila ble fr o m: w w w. ncc n. or g/ pr ofessi o n als/ p h ysicia n _ gls/ p df/ m yel oi d _ gr o wt h. p df.  
1 6.  
Dale D C, Mc Cart er G C, Cra wf or d J, L y ma n G H. M yel ot o xicit y a n d D os e I nte nsit y of 
C he m ot hera p y: Re p orti n g Practices fr o m Ra n d o mize d  Cli nical Trials. J Natl C o m pr Ca nc 
Net w. 2 0 0 3; 1( 3): 4 4 0 -5 4.  
1 7.  
L y m a n G H, K u derer N M, Cra wf or d J, W olff D A, C ula k o va E, P o nie wiers ki M S, et al. 
Pre dicti n g I n di vi d ual Ris k of Ne utr o pe ni c C o m plicati o ns i n Patie nts Recei vi n g Ca ncer 
C he m ot hera p y. Ca ncer. 2 0 1 1; 1 1 7( 9): 1 9 1 7 -2 7.  
1 8.  
F ort ner B V, Sc h wartz ber g L, T a uer K, H o uts A C, Hac kett J, St ols he k B S. I m pact of 
C he m ot hera p y -I n d u ce d Ne utr o pe nia o n Q ualit y of Lif e: A Pr os pecti ve Pil ot 
I n v esti gati o n. S u p p ort Care Ca n cer. 2 0 0 5; 1 3( 7): 5 2 2-8.  
1 9.  
Aa pr o M S, B o hli us J, Ca m er o n D A, Dal La g o L, D o n nell y J P, Kear ne y N, et al. 2 0 1 0 
U p date of E ort c G ui deli n es f or t he Us e of Gra n ul o c yt e -C ol o n y Sti m ulati n g Fact or t o 
Re d uce t he I n ci de nce of C he m ot hera p y -I n d u ce d Fe brile Ne utr o pe ni a  i n A d ult Patie nts 
wit h L y m p h o pr oliferati v e Dis or der s a n d S oli d T u m o urs. E ur J Ca ncer. 2 0 1 1; 4 7( 1): 8-3 2.  
2 0.  
S mit h TJ, K hatc heressia n J, L y ma n G H, Ozer H, Ar mita ge J O, Bal d ucci L, et al. 2 0 0 6 
U p date of Rec o m me n dati o ns f or t he Use of W hite Bl o o d Cell Gr o wt h Fact ors: A n 
E vi de nce -Bas e d Cli nical Practice G ui deli ne. J Cli n O nc ol. 2 0 0 6; 2 4( 1 9): 3 1 8 7 -2 0 5.  
2 1.  
Cra wf or d J, Ozer H, St oller R, J o h ns o n D, L y m a n G, Ta b bara I, et al. Re d u cti o n b y 
Gra n ul oc yte C ol o n y -Sti m ulati n g Fact or of Fe v er a n d Ne utr o pe nia I n d uce d b y 
C he m ot hera p y i n Patie nts wit h S mall -Cell L u n g Ca ncer. N E n gl J Me d. 
1 9 9 1; 3 2 5( 3): 1 6 4 -7 0.  
2 2.  
Ga bril o ve J L, J a k u b o ws ki A, Sc her H, Ster n ber g C, W o n g G, Gr o us J, et al. Effect of 
Gra n ul oc yte C ol o n y -Sti m ulati n g Fact or o n Ne utr o pe nia a n d Ass oci ate d M or bi dit y D ue t o 
C he m ot hera p y f or Tra nsiti o nal -Cell Carci n o ma of t he  Ur ot heli u m. N E n gl J Me d. 
1 9 8 8; 3 1 8( 2 2): 1 4 1 4 -2 2.  
2 3.  
M orst y n G, Ca m p bell L, S o uza L M, Alt o n N K, Keec h J, Gree n M, et al. Effect of 
Gra n ul oc yte C ol o n y Sti m ulati n g Fact or o n Ne utr o pe nia I n d uce d b y C yt ot o xic 
C he m ot hera p y. La n cet. 1 9 8 8; 1( 8 5 8 7): 6 6 7 -7 2.  
2 4.  
Tril let-Le n oir V, Gree n J, Ma ne g ol d C, V o n Pa wel J, Gatze meier U, Le b ea u B, et al. 
Rec o m bi na nt Gra n ul oc yt e C ol o n y Sti m ulati n g Fact or Re d uces t he I nfecti o us 
C o m plicati o ns of C yt ot o xic C he m ot hera p y. E ur J Ca ncer. 1 9 9 3; 2 9a( 3): 3 1 9 -2 4.  


S pectr u m P h ar m ace utic als, I nc . 
Cli nic al  St u d y Pr ot oc ol  
Efl a pe gr asti m  
Pr ot oc ol N u m ber: S PI -G C F -3 0 2  
Pr ot oc ol  A me n d me nt 1: 2 8  J ul 2 0 1 7  
C o nfi de nti al  
5 5  
2 5.  
Meza L A, Gree n M D, Hac ket t J R, Ne u ma n n T A, H ol mes F A. Fil grasti m-Me diate d 
Ne utr o p hil Rec o ver y i n Patie nts wit h Breast Ca n cer Treate d wit h D oceta xel a n d 
D o x or u bici n. P har mac ot hera p y. 2 0 0 3; 2 3( 1 1): 1 4 2 4 -3 1.  
2 6.  
Meza L, Bas el ga J, H ol mes F, Lia n g B, Bre d d y J. I n ci de nce of Fe brile Ne utr o pe ni a  
(F N ) Is Dir ectl y Relate d t o D ur ati o n of Se vere Ne utr o pe ni a  (D S N ) aft er 
M yel os u p pressi ve C he m ot hera p y Pr oc A m S oc Cli n O nc ol. 2 0 0 2; 2 1: 2 8 4 0.  
2 7.  
O ke n M M, Creec h R H, T or me y D C, H ort o n J, Da vis T E, Mc Fa d de n E T, et al. T o xicit y 
a n d Res p o nse Criteria of t he Easter n C o o perati ve O nc ol o g y Gr o u p. A m J Cli n O nc ol. 
1 9 8 2; 5( 6): 6 4 9 -5 5.  
2 8.  
G necc o C. N e ulasta Statistical Re vie w. I n: Researc h Ce nter f or Dr u g E v al uati o n a n d 
Researc h a n d Ce nter f or Bi ol o gics E val uati o n a n d Researc h. 2 0 0 2.  
htt p:// w w w.access dat a.f da. g o v/ dr u gs atf da _ d o cs/ n da/ 2 0 0 2/ 1 2 5 0 3 1 _ 0 0 0 _ Ne ulasta _statr. p d
f 
2 9.  
L u bse n J, Kir wa n B -A. C o m bi ne d E n d p oi nts: Ca n We Use T he m? Statistics i n Me dici ne. 
2 0 0 2; 2 1( 1 9): 2 9 5 9 -7 0.  
 
 
 
 





SAP_001.pdf: 
 
Offici al Titl e:  
 
R a n d o miz e d, O p E n -L a b el, Acti v e-C o ntr Ol Tri al of S PI -2 0 1 2 ( Efl a p e gr asti m) 
V ers us P e gfil gr asti m i n t h e M a n a g e m e nt of C h e m ot h er a p y -I n d uc e d 
N e utr o p e ni a i n E arl y -St a g e B R e ast C a nc er P ati e nts R ec ei vi n g D oc et a x el a n d 
C ycl o p h os p h a mi d e ( T C) ( R E C O V E R)  
 
N C T N u m b er:  
N C T 0 2 9 5 3 3 4 0  
 
D oc u m e nt D at e:  
 
S A P  V ersi o n 1 . 1: 0 6 A u g  2 0 1 8 
 
 
 
 
 
 
 
 
 
 
 




S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
2  
1. 1  
S A P A me n d me nt: S u m m a r y of C h a n ges  
T he p ur p ose of A me n d m e nt Versi o n 1. 1  is t o i nc or p orate t he f oll o wi n g maj or c ha n ges t o t he 
c urre nt S A P:  
•  Re or der t he c o nte nts of S A P t o reflect t he u p d ates of S O P of S pectr u m P har mace uticals, 
I n c. 
•  T o re vise secti o n 6 . 1. 2 f or clarificati o n of missi n g data ha n dli n g. 
•  T o re vise secti o n 6 . 3. 1. 3 u p dati n g t he met h o d of s e nsiti vit y a nal ysis usin g w orst case 
sce nari o. 
See A p pe n di x A - S A P A me n d me nt: List of C ha n ges, f or a n ite mize d list of all c ha n ges m a de t o 
t he S A P u n der t his a me n d me nt. 
 
 


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
3  
 
T A B L E O F C O N T E N T S  
1  
TI T L E P A G E  ..........................................................................................................1  
1. 1  
S A P A me n d me nt: S u m m a r y of C h a n ges  ............................................................ 2  
T A B L E O F C O N T E N T S  ..............................................................................................................3  
LI S T O F A B B R E VI A TI O N S  .......................................................................................................5  
2  
I N T R O D U C TI O N..................................................................................................6  
3  
O B J E C TI V E S  ........................................................................................................6  
3. 1  
Pri m ar y O bjecti ve:  ............................................................................................... 6  
3. 2  
Ke y Sec o n d ar y O bjecti ves:  .................................................................................. 6  
3. 3  
A d diti o n al Sec o n d ar y O bjecti ves:  ....................................................................... 6  
4  
S T U D Y O V E R VI E W  ............................................................................................7  
4. 1  
S a m ple Size C o nsi der ati o ns  ................................................................................. 8  
4. 2  
R a n d o miz ati o n  ...................................................................................................... 8  
5  
A N A L Y SI S P O P U L A TI O N S  ...............................................................................9  
6  
S T A TI S T IC A L M E T H O D S O F A N A L Y SI S  ...................................................1 1  
6. 1  
Ge ner al Pri nci ples  ............................................................................................... 1 1  
6. 1. 1  
Defi niti o n of B aseli ne V a l ues ..............................................................................1 1  
6. 1. 2  
H a n dli n g of Missi n g D at a  ....................................................................................1 2  
6. 1. 3  
P o oli n g of Ce nters  ................................................................................................1 4  
6. 1. 4  
I nteri m A n al ysis ...................................................................................................1 4  
6. 1. 5  
Testi n g/ V ali d ati o n Pl a n  .......................................................................................1 4  
6. 2  
B ac k gr o u n d C h ar acteristics  .............................................................................. 1 4  
6. 2. 1  
P ati e nt Dis p ositi o n  ...............................................................................................1 4  
6. 2. 2  
De m o gr a p hic a n d B aseli ne C h ar acteristics  .......................................................1 5  
6. 2. 3  
D r u g E x p os ure a n d C o m pli a nce .........................................................................1 5  
6. 2. 4  
Me dic al Hist or y  ....................................................................................................1 6  
6. 2. 5  
C o nc o mit a nt Me dic ati o n  .....................................................................................1 6  
6. 2. 6  
Pr ot oc ol D e vi ati o ns  ..............................................................................................1 6  
6. 3  
Effic ac y A n al yses  ................................................................................................ 1 7  
6. 3. 1  
Pri m ar y Effic ac y E n d p oi nt  .................................................................................1 7  
6. 3. 1. 1  
S A S C o de f or Pri mar y A nal ysis  ............................................................................1 8  
6. 3. 1. 2  
J ustificati o n of B o otstra p Resa m pli n g Met h o d as Pri mar y A nal ysis  ....................1 9  
6. 3. 1. 3  
A d diti o nal Se nsiti vit y A nal ysis  .............................................................................2 0  
6. 3. 1. 4  
S u b gr o u p A n al ysis  .................................................................................................2 1  
6. 3. 2  
Ke y Sec o n d ar y Effic ac y E n d p oi nts  ....................................................................2 2  
6. 3. 2. 1  
Ti me t o A N C Rec o ver y i n C ycle 1  ........................................................................2 2  
6. 3. 2. 2  
De pt h of A N C Na dir i n C ycle 1  ............................................................................2 2  
6. 3. 2. 3  
I n ci de nce of Fe brile N e utr o pe nia i n C ycl e 1  .........................................................2 2  
6. 3. 3  
Testi n g Pr o ce d ure f or Pri m ar y a n d Ke y Sec o n d ar y Effic ac y E n d p oi nts  .......2 3  
6. 3. 4  
A d diti o n al Sec o n d ar y Effic ac y E n d p oi nts  .........................................................2 3  
6. 3. 4. 1  
D S N i n C ycles 2, 3, a n d 4  ......................................................................................2 3  


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
4  
6. 3. 4. 2  
I n ci de nce of Ne utr o pe nic C o m plicati o ns i n C ycle 1 .............................................2 4  
6. 3. 4. 3  
I n ci de nce of Fe brile N e utr o pe nia i n C ycl es 2, 3, a n d 4 .........................................2 4  
6. 3. 4. 4  
Relati ve D ose I nte nsit y ( R DI)  ...............................................................................2 4  
6. 3. 5  
Ot her Effic ac y A n al yses  ......................................................................................2 4  
6. 3. 5. 1  
Ti me t o A N C Rec o ver y i n C ycles 2, 3, a n d 4  .......................................................2 4  
6. 3. 5. 2  
De pt h of A N C Na dir i n C ycles 2, 3, a n d 4  ............................................................2 4  
6. 3. 5. 3  
I n ci de nce of Ne utr o pe nic C o m plicati o ns i n C ycles 2, 3, a n d 4 .............................2 5  
6. 4  
S afet y A n al yses  .................................................................................................... 2 5  
6. 4. 1  
A d verse E ve nts  .....................................................................................................2 5  
6. 4. 1. 1  
Ge neral  ...................................................................................................................2 5  
6. 4. 1. 2  
I n ci de nce of Treat me nt E mer ge nt A d verse E ve nts ...............................................2 5  
6. 4. 1. 3  
I n ci de nce of T E A Es of S pecial I nterest .................................................................2 6  
6. 4. 1. 4  
I n ci de nce of Treat me nt Relate d A d verse E ve nts ...................................................2 6  
6. 4. 1. 5  
T E A E Cate g orize d b y Se verit y  ..............................................................................2 6  
6. 4. 1. 6  
Seri o us A d verse E v e nts a n d A d verse E ve nts Lea di n g t o St u d y Dr u g 
M o dificati o ns  .........................................................................................................2 7  
6. 4. 2  
L a b or at or y P ar a meters  .......................................................................................2 7  
6. 4. 3  
Vit al Si g n D at a  .....................................................................................................2 7  
6. 4. 4  
E C O G Perf or m a nce St at us  .................................................................................2 7  
7  
R E F E R E N C E S  .....................................................................................................2 8  
8  
A P P E N DI X - A. S A P A M E N D M E N T: LI S T O F C H A N G E S  ........................2 9  
 
List of T a bles  
 
T a ble 1  
S u m m ar y of B aseli ne f or E ac h E n d p oi nt/ D at a  ......................................................1 1  
T a ble 2  
Si m ul ati o n Res ults  ....................................................................................................1 9  
 
 
 
 
 




S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
6  
2  
I N T R O D U C TI O N 
T he p ur p ose of t his statistical a nal ysis pla n  ( S A P) is t o pr o vi de details of t he statistical a nal yses 
t hat ha ve bee n o utli ne d withi n t he ori gi nal pr ot oc ol f or S t u d y S PI -G C F -3 0 2 , date d 2 7 Se p  2 0 1 6 . 
T he sc o pe of t his pla n i n cl u des all effi cac y a n d safet y a nal yses of S PI -2 0 1 2  or p e gfil grasti m i n 
t he m a na ge me nt of che m ot hera p y in d uce d n e utr o p e nia i n earl y-st a ge b reast ca ncer p atie nts 
recei vi n g d oceta x el a n d c ycl o p h os p h a mi de ( T C) .  
3  
O B J E C TI V E S  
3. 1  
Pri m ar y O bjecti ve :  
•  T o c o m pare t h e efficac y of a si n gl e d ose of S PI -2 0 1 2  wit h pe gfil grasti m i n patie nts wit h 
earl y-sta ge breast ca n cer recei vi n g d oceta xel a n d c ycl o p h os p h a mi de ( T C), as meas ure d 
b y t h e D urati o n of Se vere Ne utr o pe ni a ( D S N ) i n C ycle 1  
3. 2  
Ke y Sec o n d ar y O bjecti ves :  
•  T o c o m pare S PI -2 0 1 2  wit h pe gfil grasti m  i n: 
 Ti me t o A bs ol ute Ne utr o p hil C o u nt ( A N C) Rec o ver y  i n C ycle 1  
 De pt h of A N C N a dir , defi ne d as t he p atie nt’s l o west A N C i n C ycle 1  
 I n ci de nce of Fe brile Ne utr o pe ni a  (F N ) i n patie nts d uri n g C ycl e 1  
3. 3  
A d diti o n al Sec o n d ar y O bjecti ves :  
•  T o c o m pare S PI -2 0 1 2  wit h pe gfil grasti m i n:  
1.  D ur ati o n of Se vere Ne utr o pe ni a  i n C ycles 2 , 3 , a n d 4  
2.  I n ci de nce of ne utr o p e nic c o m plicati o ns, i ncl u di n g a nti-i nfecti ve use an d 
h os pitaliz ati o ns i n patie nts d uri n g C ycl e 1   
3.  I n ci de nce of F N  i n C y cles 2 , 3 , a n d 4  
4.  Rel ati ve D ose I nte nsit y  (R DI ) of T C i n C ycl es 1  t o 4  
5.  Safet y  


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
7  
4  
S T U D Y O V E R VI E W  
T his is a P hase 3, ra n d o mize d, o pe n -la bel, acti ve-c o ntr olle d, m ultice nter st u d y t o c o m pare t he 
effic ac y a n d s afet y of S PI -2 0 1 2  wit h pe gfil grasti m  i n breast ca n cer patie nts treate d wit h T C 
c he m ot hera p y.  
A p pr o xi matel y 2 1 8  p atie nts will be e nr olle d a n d ra n d o mize d i n a 1: 1 rati o t o 2 treat me nt ar ms:  
•  Tre at me nt Ar m 1  ( n =1 0 9 ): S PI -2 0 1 2  (1 3. 2 m g/ 0. 6 m L fi x e d d ose S PI -2 0 1 2  e q ui vale nt 
t o 3. 6 m g G-C S F ) 
•  Tre at me nt Ar m 2  ( n =1 0 9 ): Pe gfil grasti m ( 6 m g/ 0. 6  m L)  
Pri or t o T C c he m ot hera p y a d mi nistrati o n, patie nts ma y rec ei ve pre me dicati o n acc or di n g t o 
i nstit uti o nal sta n dar d of care. I ntr a ve n o us (I V) a d mi nistrati o n of TC o n D a y 1  of eac h c ycle will 
be as f oll o ws:  
•  D oceta x el 7 5 m g/ m 2 I V i nf usi o n per i nstit utes sta n dar d of care  
•  C ycl o p h os p ha mi de 6 0 0 m g/ m 2 I V i nf usi o n per i nstit utes sta n dar d of care  
Eac h c ycl e will be 2 1 da ys. O nl y 4 c ycles will be e val uate d f or t his st u d y. After C ycle 1 , patie nts 
m ust ha ve  a n A N C ≥1. 5  ×  1 0 9/ L a n d platel et c o u nt ≥1 0 0 ×  1 0 9/ L t o be gi n t he ne xt c ycl e of 
c he m ot hera p y.  
T he st u d y dr u g ( S PI -2 0 1 2  or pe gfil grasti m) will be a d mi nistere d o n D a y 2  of eac h c ycle, 
a p pr o xi matel y 2 4 t o 2 6  h o urs  after t h e last d ose of T C c he m ot hera p y is gi v e n . St u d y dr u g ( S PI -
2 0 1 2  or pe gfil grasti m) d ose m o dificati o ns are n ot all o we d.  
O n D a y 1  of eac h c ycle, patie nts will recei ve T C c he m ot hera p y, a n d safet y a n d effi cac y 
assess me nts will be perf or me d as o utli ne d i n t he pr ot oc ol. O n D a y 2  of eac h c ycle, patie nts will 
recei v e st u d y dr u g (S PI -2 0 1 2  or pe gfil grasti m), a n d t he s pecifie d assess me nts will be perf or m e d.  
A bs ol ute ne utr o p hil c o u nt will be m o nit ore d o n D a y 1  a n d D a ys 4 t o 1 5  i n C ycle 1 .  
I n C ycles 2 t o 4 , all patie nts m ust ha ve bl o o d sa m ples dra w n o n D a y 1  ( pri or t o c he m ot hera p y 
a d mi nistrati o n), o n D a ys 4, 7, 1 0, a n d 1 5  ( ± 1 da y f or eac h ti me p oi nt), a n d at t he E n d -of -
Tre at me nt Visit . If t he p artici pati n g site is n otifie d t hat t he A N C is ≤1. 0  ×  1 0 9/ L at a n y ti me 


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
8  
d uri n g C y cles 2 t o 4 , t he n dail y C B Cs will be req uire d u ntil t he A N C is ≥1. 5  ×  1 0 9/ L, after 
reac hi n g n a dir, b ut bl o o d sa m ples m ust still be dra w n o n D a ys 4, 7, 1 0, a n d  1 5 .  
After C y cle 1 , as a p plica ble,  patie nts w h o ha ve recei ve d at least o ne d ose of st u d y dr u g will be 
f oll o we d f or 1 2 m o nt hs after t he l ast d ose of st u d y treat me nt f or s afet y f oll o w-u p . 
4. 1  
S a m ple Size C o nsi der ati o ns  
A p pr o xi matel y 2 1 8  p atie nts will be e nr olle d i n t his st u d y. T he pri mar y e n d p oi nt a nal ysis is base d 
o n t he test of n o n -i nferi orit y of S PI -2 0 1 2  as c o m p are d t o pe gfil grasti m.  
F or t he test of n o n-i nferi orit y h y p ot hesis, t he mar gi n of n o n-i nferi orit y t o be use d i n t he st u d y is 
0. 6 2 da y. T he tr ue differe nce bet w ee n t he mea ns is ass u me d t o be 0. 0 da ys. Sa m ple siz es of 
1 0 9  per treat me nt ar m will pr o vi de 9 0 %, 8 6 %, a n d 8 1 % p o wer t o det ect n o n -i nferi orit y usi n g a 
o ne -si de d, t w o-sa m ple t-t est at 2. 5 % le vel of si g nifica nce, w he n t he p o ole d sta n dar d de viati o n 
( S D) of t he D S N  is 1.4 , 1.5 , or 1.6  da ys, res p ecti vel y. T he p o ole d S D will be m o nit ore d i n t he 
o n g oi n g sister st u d y S PI -G C F -3 0 1 . If t he p o ole d S D i n t he sister st u d y is esti mate d t o be greater 
t ha n 1.4  da ys, t he sa m ple siz e ma y be i ncreas e d t o reflect t he p ote ntial e xtra varia bilit y f or t he 
c urre nt st u d y. Si nce t he i nf or mati o n t hat ma y be use d is i n de pe n de nt of t he c urre nt st u d y res ults, 
t he no mi nal t y pe I err or is preser ve d f or t he c urre nt st u d y. T he st u d y will e nr oll a n d ra n d o mize 
1 0 9  patie nts per ar m f or a t otal of a p pr o xi matel y 2 1 8  patie nts.  
T he n o n -i nferi orit y of S PI -2 0 1 2  t o pe gfil grasti m will be declare d if t he u p per b o u n d of 9 5 % CI 
of t he differe nce i n mea n D S N  bet wee n t he treat m e nt ar ms is < 0. 6 2 da ys.    
4. 2  
R a n d o miz ati o n  
T his is a n o pe n -la bel st u d y. T he r a n d o mizati o n sc he d ule will be ge nerate d a n d a p pr o ve d b y 
S pectr u m ’s Bi ostatistics De part me nt. T h e list will be se nt t o D S G - I W R S ve n d or for 
i m ple me ntati o n. T he ra n d o mizati o n list will be sec urel y l ocat e d a n d onl y li mite d st u d y t ea m 
me m bers  will ha ve access t o it. T hese will i ncl u de:  
•  Lea d Bi ostatisticia n, S pectr u m P har mace uticals  
•  Hea d of Bi ostatistics , S pectr u m P har mace uticals  
•  O verall St u d y Pr oject Ma na ger, D S G  
•  I W R S Pr oject Ma na ger, D S G  


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
9  
•  Ass ociate  I W R S Pr oject Ma na ger, D S G  
T he detaile d ra n d o mizati o n s pecificati o n  is as f oll o ws: 
T ot al n u m ber of r a n d o miz ati o n s ge ner ate d : 2 0 0 patie nts f or eac h c o u ntr y wit h 2 0 c o u ntries. 
T otal per st u d y  =  4 , 0 0 0 r an d o mizati o n  n u m bers .  
Tre at me nt  Ar m : A =S PI -2 0 1 2 ; B = p e gfil grasti m . 
Bl oc k size : 4 ( A: B =  1: 1)  
Str atific ati o n f act or : C o u ntr y ( 1 t o 2 0 ) 
5  
A N A L Y SI S P O P U L A TI O N S  
I nte nt-t o-Tre at (I T T) P o p ul ati o n  
T he I T T P o p ul ati o n  will c o nsist of all patie nts w h o are ra n d o mize d . P atie nts will be a nal yze d i n 
t he treat me nt ar m as ra n d o mize d  if t he act ual treat me nt assi g n me nts de viat e fr o m t he 
ra n d o mizati o n sc he ma. T his p o p ulati o n will be use d f or t he s u m mar y of de m o gra p hi cs a n d 
baseli ne c haracteristics as well as effi cac y a nal ysis.  T he pri mar y a n al ysis will be base d o n t he 
I T T P o p ul ati o n .  
Per Pr ot oc ol ( P P) P o p ul ati o n  
T he  P P P o p ul ati o n  will i ncl u de all patie nts i n t he I T T P o p ul ati o n  wit h n o i m p orta nt pr ot oc ol 
de viati o n s (I P Ds) t hat affect t he a n al ysis of t he pri mar y effi cac y e n d p oi nt . T he f oll o wi n g will be 
c o nsi dere d I P Ds : 
•  Fail ure t o meet i ncl usi o n/e x cl usi o n criteria  
•  A n y d os e m o dificati o n s of t he st u d y dr u g (S PI -2 0 1 2  or pe gfil grasti m)  i n C ycle 1  
•  R DI  of T C c he m ot hera p y  < 8 0 % or > 1 2 0 % i n C ycle 1  
•  A n y a d diti o nal m yel oi d gr o wt h fact ors ot h er  t ha n t he pr ot oc ol s pecifie d st u d y dr u g (S PI -
2 0 1 2  or pe gfil grasti m)  i n C ycle 1  
•  St u d y dr u g ( S PI -2 0 1 2  or pe gfil grasti m ) a d mi nistere d less t ha n 1 2 h o urs or m ore t ha n 4 8 
h o urs after t h e e n d of T C c he m ot hera p y a d mi nistrati o n  i n C ycle 1  


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
1 0  
A d diti o nal I P Ds ma y be a d de d aft er ma n u al data re vie w d uri n g t he c o urse of t he st u d y, if t he y 
will  affect t he pri mar y efficac y a nal ysis . T hese a d diti o nal I P Ds will be d oc u me nte d bef ore 
data base l oc k.  
P atie nts will be a nal yze d as treate d if t h e act u al treat me nt assi g n me nts de vi at e fr o m t he 
ra n d o mizati o n sc he ma. T his p o p ulati o n will be use d as se nsiti vit y a n al ysis f or assessi n g n o n -
i nferi orit y h y p ot h esis f or t he pri mar y efficac y e n d p oi nt  (D S N  i n C ycle 1 ).  
S afet y  ( S A F) P o p ul ati o n  
T he S A F  P o p ul ati o n  will c o nsist of all patie nts w h o r ecei v e at least o ne d ose of a n y pr ot o c ol -
s pecifie d dr u g (T C , S PI -2 0 1 2  or pe gfil grasti m) . Patie nts will be a nal yze d i n t he treat me nt ar m as 
treate d. Patie nts w h o i na d verte ntl y recei ve b ot h st u d y dr u gs (S PI -2 0 1 2  a n d pe gfil grasti m) d uri n g 
t he st u d y will be di sc o nti n ue d fr o m t he trial. H o we ver, f or t he p ur p os es of t he safet y a n al ysis, 
t hese patie nts will be assi g ne d t o t he tr eat me nt ar m f or w hic h t he y recei v e d m ore d oses  (e. g., 
patie nts w h o recei ve d 3 d oses of S PI -2 0 1 2  a n d 1 d ose of pe gfil grasti m  will be assi g n e d t o S PI -
2 0 1 2  ar m). T his p o p ulati o n will be use d f or safet y a nal ysis i ncl u di n g d ose e x p os ure, a d verse 
e ve nts, c o nc o mita nt me dicati o ns, vital si g ns, la b orat or y res ults a n d a n y ot her safet y d ata   
I n or der t o pr o p erl y assi g n patie nts t o a treat me nt ar m i n t he S A F p o p ulati o n, t he f oll o wi n g 
criteria will be use d:  
•  Patie nts will be assi g ne d as treate d if t h e sa me dr u g is use d f or all 4 c ycl es  
•  If a patie nt h as s witc he d all ocati o n of st u d y dr u g (eit her S PI-2 0 1 2 or pe gfil grasti m) 
a m o n g 4 c ycles, t he assi g n me nt of tr eat me nt i n S A F p o p ulati o n is as f oll o ws:  
o  Patie nt will be assi g ne d t o a treat me nt ar m i n w hic h m ore n u m ber of d oses/c ycl es 
of t hat st u d y dr u g was a d mi nistere d  
o  If a patie nt h as recei ve d e q ual n u m ber of d os es of b ot h st u d y dr u gs (e. g. 2 c ycles 
of S PI -2 0 1 2 a n d 2 c ycl es of pe gfil grasti m), t he patie nt will be assi g ne d t o t he 
treat me nt ar m of t h e C ycle 1 
o  If a patie nt h as j ust recei ve d T C b ut n ot a n y d ose of t he st u d y dr u g, t he patie nt 
will be assi g ne d t o a n ar m as ra n d o mize d a n d will still be i ncl u de d i n t he S A F 
p o p ulati o n.  




S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
1 2  
6. 1. 2  
H a n dli n g of M issi n g D at a  
Assess me nt of A N C will be perf or me d dail y fr o m Da ys 4 t o 1 5 i n C ycle 1. D uri n g t his ti me 
wi n d o w, patie nts are e x pecte d t o ha v e se vere ne utr o pe nia, a n d missi n g A N C val ues c o ul d affect 
t he calc ulati o n of t he pri mar y effi cac y e n d p oi nt. Missi n g A N C data are li kel y d u e t o missi n g 
bl o o d sa m pli n g i n a dail y bl o o d sa m pli n g sc he d ule fr o m Da ys 4 t o 1 5 i n C ycle 1.  S pectr u m’s 
Cli nical O perati o ns tea m will w or k cl osel y wit h st u d y sites t o mi ni mize missi n g data d uri n g t he 
st u d y c o n d u ct. S pectr u m has e n ga ge d a h o me healt h care v e n d or,  
, t o facilitate bl o o d 
sa m pli n g at patie nts’ c o n ve nie nce at h o me or i n t h e office. O n a p eri o dic basis d uri n g t he st u d y 
c o n d uct, t he Cli nical O perati o ns tea m trac ks t h e bl o o d sa m p li n g stat us of all e nr olle d patie nts t o 
i de ntif y iss ues a n d i m ple me nts miti gati o n pla ns w here ver p ossi ble.   
It is e x pecte d t hat t he e xte nt of missi n g A N C data will be si milar bet wee n tr eat me nt ar ms i n t his 
ra n d o mize d st u d y, as t he reas o n f or missi n g is m ostl y l o gistical a n d relat e d t o c o n ve nie nce rat h er 
t ha n i nf or me d missi n g of t he effic ac y e n d p oi nt. T he perce nta ge of patie nts wit h missi n g A N C 
val ues fr o m Da ys 4 t o 1 5 i n C ycle 1 will be prese nte d b y tr eat me nt ar m.  
I n ge neral, missi n g data will n ot be i m p ute d. H o we ver, it will be acc o u nt e d f or i n a c o nser vati ve 
ma n ner t o cal c ulate t he pri mar y efficac y e n d p oi nt ( D S N i n C ycle 1) as f oll o ws.  
F or all da ys i n C ycle 1, if a patie nt has a missi n g A N C val ue(s) a n d t he t w o a djace nt A N C val ues 
(ie, t he last a vaila ble v al ue bef ore t he missi n g v al ue a n d t he first a vaila ble val ue after t he missi n g 
val ue) are b ot h ≥0. 5 × 1 0 9/ L, t he missi n g A N C val u e(s) will be c o nsi dere d as ≥ 0. 5 × 1 09/ L a n d 
t he da y(s) wit h missi n g v al ue(s) will n ot be c o u nte d t o calc ulate D S N.  
If eit her of t he t w o a dja ce nt A N C val ues are < 0. 5 × 1 0 9/ L, t he missi n g A N C val ue(s) will be 
c o nsi dere d as < 0. 5 × 1 0 9/ L a n d t h e da y(s) wit h missi n g val ue(s) will be c o u nte d t o calc ulate D S N.  
If a n A N C v al ue is missi n g i n C ycle 1 b ut t he c orres p o n di n g W B C val ue is prese nt a n d is 
≤0. 5 x 1 0 9// L, t he A N C val ue will be i m p ute d as W B C val ue f or t hat ti me p oi nt. 
I n p u blis he d st u dies of l o n g-acti n g m yel oi d gr o wt h fact ors, w he n patie nts r ecei ve c he m ot hera p y 
o n Da y 1 a n d a g ra n ul oc yt e c ol o n y-sti m ulati n g fact or o n Da y 2 of eac h c ycle, t he A N C na dir 
te n ds t o occ ur d uri n g a 3-da y peri o d b et wee n Da ys 6 t o 8 i n m ost patie nts a n d t he mea n D S N has 
bee n re p orte d i n t he ra n ge of 0. 3 t o 2 da ys. Acc or di n g t o t he pr ot oc ol, pati e nts ma y disc o nti n ue 
t he st u d y f or a n u m ber of reas o ns as s p ecifie d i n t he pr otoc ol. If a patie nt i n eit her treat me nt ar m 


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
1 3  
has n o bl o o d dra ws ( missi n g A N C val u es) beca use of disc o nti n uati o n fr o m Da ys 4 t o 1 5 or f or 
a n y p art of t his d urati o n, t he D S N will be i m p ute d as 3 da ys f or t hat p atie nt.   
T he missi n g A N C val ues i n C ycles 2 t o 4 will be ha n dle d differe ntl y fr o m t hat i n C ycle 1 as 
bl o o d sa m ples are o nl y t o be e val uat e d o n n o mi nal da ys 4, 7, 1 0, a n d 1 5 i n C ycle 2 t o 4. T h e 
missi n g data will be ha n dle d as bel o w:  
•  If t here are m ulti ple A N C val ues o n a n o mi nal visit da y, use t he l atest o ne.  
•  If a patie nt h as a missi n g A N C val ue a n d t he t w o a djace nt A N C val ues (ie, t he last 
a vaila ble val ue b ef ore t h e missi n g val ue a n d t he first a vaila ble val ue after t he missi n g 
val ue)  are b ot h ≥0. 5 × 1 0 9/ L, t he missi n g A N C val u e(s) will be c o nsi dere d as ≥ 0. 5 × 1 09/ L 
a n d t he da y(s) wit h missi n g val u e(s) will n ot be c o u nte d t o calc ulate D S N.  
•  If t he t w o a dja ce nt A N C val ues are b ot h < 0. 5 × 1 09/ L, t he missi n g A N C val ues will be 
c o nsi dere d as < 0. 5 t o cal c ulate D S N.  
•  If eit her of t he t w o a dja ce nt A N C val ues is < 0. 5 × 1 09/ L, o nl y t he ti me p oi nt wit h A N C 
val ues < 0. 5 × 1 0 9/ L will be use d f or t he calc ul ate D S N 
•  If a patie nt i n eit her treat me nt ar m has n o bl o o d dra ws ( missi n g A N C val u es) beca use of 
t he disc onti n uati o n fr o m Da ys 4 t o 1 5 or f or a n y p art of t his d urati o n, t he D S N will be 
i m p ute d as 3 da ys f or t hat patie nt. 
A se nsiti vit y a nal ysis usi n g w orst case s ce nari o will be perf or me d t o e xa mi ne t he i m pact of 
missi n g data i n C ycl e 1. As detaile d i n Secti o n 6 . 3. 1. 3, w he n A N C data are missi n g o n or after 
Da y 5, a n d bef ore p atie nts’ A N C i ncrease t o ≥ 1. 5 × 1 0 9/ L after t he e x pecte d na dir i n C ycl e 1, 
missi n g A N C val ues will be i m p ute d as < 0. 5 × 1 0 9/ L f or S PI-2 0 1 2 a n d ≥0. 5 × 1 0 9/ L f or 
pe gfil grasti m, f or t he p ur p ose of D S N cal c ulati o n i n t his se nsiti vit y a nal ysis.  
Patie nt disc o nti n uati o n or missi n g bl o o d sa m pli n g f or t he e ntire d urati o n of Da ys 4 t o 1 5 will 
als o be ha n dle d differe ntiall y f or D S N cal c ulati o n bet wee n tr eat me nt ar ms i n t he w orst -cas e 
sce nari o. If a p atie nt has n o bl o o d dra ws ( missi n g A N C val ues) beca use of disc o nti n uati o n fr o m 
Da ys 4 t o 1 5 or f or a n y p art of t his d urati o n, t he D S N will be i m p ute d as 3 da ys f or t hat patie nt 
f or S PI-2 0 1 2 a n d 0 f or pe gfil grasti m. T he reas o n f or i m p uti n g D S N = 3 d a ys f or S PI -2 0 1 2 i s 
descri be d a b o ve.  
.  


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
1 4  
6. 1. 3  
P o oli n g of C e nters  
Data fr o m differe nt ce nters will be c o m bi ne d f or t he p ur p ose of t h e a nal ysis. T he n u m ber of 
patie nts ra n d o mize d will be prese nt e d b y st u d y sit e  a n d c o u ntr y. A s u m mar y of t he pri mar y 
effic ac y a n al ysis will be pr o vi d e d b y g e o gra p hic  re gi o n t o deter mi ne if t here is a n y re gi o nal 
differe n ce.  
6. 1. 4  
I nteri m A n al ysis 
T here will be n o f or mal i nteri m a nal ysis s pecifie d or c o n d ucte d i n t his st u d y. T he d ata will be 
peri o dicall y re vie we d f or q ualit y a n d c o m pleti o n.  Si nce t his is a n o pe n-la bel st u d y, t he data 
re vie w will use a dr y r u n of s u m mar y ta bles a n d listi n gs usi n g t he act ual tr eat me nt ar ms a n d t he 
data k n o wle d ge will be restricte d t o t he St u d y T ea m . N o i nfere ntial statistics will be calc ulate d 
a n d n o decisi o ns will be ma de.  
6. 1. 5  
Testi n g/ V ali d ati o n Pl a n  
S A S ®  Versi o n 9. 3  o n t he Wi n d o ws s yste m will be use d f or  creati o n of  T a bl es, Listi n gs, a n d 
Fi g ure s. All ta bles, listi n gs, a n d fi g ures will be vali date d a n d re vie we d bef ore bei n g fi nalize d. 
I n d e pe n de nt pr o gra m mi n g will be c o n d u cte d t o verif y t a bles a n d listi n gs as a p pr o priate. Ta bles 
will be re vie we d f or acc urac y, c o nsiste n c y wit h t his pla n, c o nsiste nc y wit hi n ta bles, a n d 
c o nsiste nc y wit h c orres p o n di n g o ut p ut s. 
6. 2  
B ac k gr o u n d C h ar acteristics  
6. 2. 1  
P ati e nt  Dis p ositi o n  
Dis p ositi o n of patie n ts will be s u m marize d b y treat me nt ar m a n d o verall. T he s u m mar y data will 
i ncl u de n u m ber ( %) of p atie nt s ra n d o mize d a n d d ose d,  n u m ber ( %) of pati e nts t hat c o m plete d 4 
c ycles of treat me nt s a n d n u m ber ( %) of patie nt s w h o disc o nti n ue d treat me nt. T he reas o ns f or 
treat me nt disc o nti n uati o n will als o be s u m marize d. 
T he a nal ysis p o p ulati o ns will be s u m marize d b y tr eat me nt ar m a n d o v erall . T he I T T P o p ul ati o n  
will als o be prese nte d b y c o u ntr y a n d st u d y site .  
T he perce nta ge of patie nts wit h missi n g A N C val ues fr o m  D a ys 4 t o 1 5  i n C ycle 1  i n t he I T T 
P o p ul ati o n  will be prese nte d b y tr eat me nt ar m.  


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
1 5  
6. 2. 2  
De m o gr a p hic a n d B aseli ne C h ar acteristics  
D em o gra p hics (a ge, ge n der, et h nicit y, race, a ge gr o u p < 6 5, 6 5 t o 7 5, a n d > 7 5) a n d ot her 
baseli ne disease c hara cteristics will b e su m marize d usi n g  des cript i ve statistics. T he s u m mar y 
will i ncl u de , b ut  will  n ot  be  li mite d t o, hei g ht, wei g ht,  b o d y s urface area,  E C O G perf or m a nce 
stat us, sta gi n g, h or m o ne rece pt or stat us , a n d baseli ne A N C . T hese d ata will be s u m marize d b y 
treat me nt ar m a n d o verall.  
6. 2. 3  
Dr u g E x p os ure  a n d  C o m pli a nce  
T he e xte nt of e x p os ure t o T C  (d oceta x el  a n d c ycl o p h os p ha mi de ) a n d st u d y dr u g (S PI -2 0 1 2  or 
pe gfil grasti m ) will be s u m marize d b y t he f oll o wi n g para meters : 
•  N u m ber of c ycles a d mi nistere d  
•  T he n u m ber of c ycles a d mi nistere d will be prese nt e d f or b ot h T C a n d st u d y dr u g .  
•  T otal c u m ulati ve d ose recei ve d  
•  F or eac h patie nt, t he t otal d ose recei ve d d uri n g t he st u d y will be cal c ulate d b y a d di n g t he 
t otal d oses recei v e d o ver all c ycles. T his para meter will be prese nte d f or T C . 
•  Relati ve d ose inte nsit y ( R DI)  
•  Relati ve d ose i nte nsit y is defi ned  as t he p erce nta ge of t he pla n ne d d os e t hat eac h patie nt 
act uall y recei ve d d uri n g t he st u d y, e x presse d as t h e t otal d ose recei ve d, di vi de d b y t otal 
d ose pla n ne d ti mes 1 0 0.  
 
T he pla n ne d d ose is defi ne d as t he d ose  t hat w o ul d be gi v e n if n o d oses w ere misse d 
a n d/ or n o d ose re d ucti o ns were ma de f or t h e n u m ber of c ycles starte d. T he t otal 
pla n ne d d ose is t he s u m of pla n ne d d oses o v er all c ycles.  R DI  will be calc ulate d f or 
C ycles 1  t o 4 a n d o verall . T his para meter will be prese nte d f or T C .  
•  D ose R e d uced , D isc o nti n ue d, D ela ye d or  Interr u pt e d  
R DI =
Tot al D os e Pl a n n e d
Tot al D os e R ec eiv e d × 1 0 0


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
1 6  
•  T he n u m ber a n d p erce nta ge of patie nts w h o e x peri e nce d ose c o m plia nce o utsi de 8 0 %  t o 
1 2 0 % , or d oses re d uce d, disc o nti n ue d, dela ye d , or  i nterr u pte d will be s u m marize d b y 
eac h c ycle a n d  o verall . T hese will be pres e nte d f or T C.  
St u d y dr u g ( S PI -2 0 1 2  or pe gfil grasti m) d ose m o dificati o ns are n ot all o we d  d uri n g t he st u d y . 
A n y m o dificati o n t o  t he st u d y dr u g will be re p orte d.  
6. 2. 4  
Me dic al Hist or y  
Me dical hist or y i nf or mati o n will o nl y b e pr o vi de d  in patie nt data listi n gs . 
6. 2. 5  
C o nc o mit a nt Me dic ati o n  
A c o nc o mita nt me dicati o n will be defi ne d as a n y me dicati o n t hat was ta ke n eit her o n t he da y of 
or after t h e a d mi nistrati o n of t he first d ose of T C c he m ot hera p y  t hr o u g h t he e n d of t he st u d y. 
T his i ncl u des me di cati o ns t hat starte d pri or t o t he i nitiati o n of t he first d ose of T C c he m ot hera p y  
if t he patie nt c o nti n ues usi n g it.  
F or all c o n c o mita nt me dicati o ns, c o u nts a n d perce nta ges of patie nts will be prese nte d b y 
me dicati o n class a n d preferre d n a me c o d e d b y t he W orl d Healt h Or ga nizati o n Dr u g ( W H O 
Dr u g) dicti o nar y. Patie nts wit h m ore t ha n o ne me dicati o n of t he sa me me dicati o n class or 
preferre d n a me will be c o u nte d o nl y o nce. Patie nt data listi n gs will be pr o vi de d.   
6. 2. 6  
Pr ot oc ol D e vi ati o ns  
I m p ort a nt pr ot oc ol de viati o n s (I P Ds) will be defi n e d as f oll o wi n g:  
•  Fail ure t o meet i ncl usi o n/e x cl usi o n criteria  
•  A n y  d os e  m o dificati o n s of t he st u d y dr u g (S PI -2 0 1 2  or pe gfil grasti m)  i n C ycle 1 
•  R DI  of T C c he m ot hera p y < 8 0 % or > 1 2 0 %  i n C ycle 1 
•  A n y a d diti o nal m yel oi d gr o wt h fact ors ot h er t ha n t he pr ot oc ol s pecifie d st u d y dr u g (S PI -
2 0 1 2  or pe gfil grasti m)  i n C ycle 1 
•  St u d y dr u g ( S PI -2 0 1 2  or pe gfil grasti m ) a d mi nistere d less t ha n 1 2 h o urs or m ore t ha n 4 8 
h o urs after t h e e n d of T C  c he m ot hera p y a d mi nistrati o n  i n C ycle 1 
I P Ds will be liste d a n d s um marize d. A d diti o nal I P Ds ma y be a d de d after ma n ual data re vie w 
d uri n g t he st u d y, a n d will be d oc u me nte d bef ore d ata base l oc k.  


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
1 7  
D uri n g m o nit ori n g of st u d y sites, a d diti o nal mi n or pr ot oc ol de viati o ns ma y be c ollecte d b y t h e 
st u d y m o nit ors. T hese de viati o ns w ill be ca pt ure d i n a Pr ot oc ol De viati o n L o g a n d will be 
cate g orize d usi n g a pre -d efi ne d de viati o n t y pe . T h e br oa d mi n or de vi ati o n t y p es are t h e 
f oll o wi n g: 
•  0 1 –  I nf or me d C o nse nt Pr oce d ures 
•  0 2 –  I n cl usi o n/ E x cl usi o n C riteria 
•  0 3 –  St u d y M e dicati o n/ D osi n g  
•  0 4 –  La b orat or y/ Pr oce d ures  
•  0 5 –  Visit Sc he d ules/ I nter vals 
 
•  0 6 –  Safet y  
 
•  0 7 –  Ra n d o mizati o n   
•  0 8 –  Pr o hi bite d/ C o nc o mita nt Me dicati o ns  
•  0 9  –  Ot her s 
 
6. 3  
Effic ac y  A n al yses  
6. 3. 1  
Pri m ar y Effic ac y E n d p oi nt  
T he pri mar y effic ac y e n d p oi nt of t he st u d y is D S N  i n C ycle 1 , defi ne d as t h e n u m ber of da ys i n 
w hic h t he patie nt has a n A N C <  0. 5 × 1 0 9/ L i n C ycle 1 , after a d mi nistrati o n of st u d y dr u g ( S PI  
2 0 1 2  or pe gfil grasti m) . D S N  will be calc ulate d f or all patie nts i n  t he I T T P o p ul ati o n . Patie nts 
w h o d o n ot prese nt wit h se vere n e utr o pe nia w ill be gi v e n a D S N  val u e of 0 . If a patie nt h as 
m ulti ple A N C val ues wit hi n t he sa me da y, t he last A N C val ue rec or de d will be use d f or t hat da y.  
F or t he pri mar y efficac y a nal ysis, t he m ea n D S N  i n C ycle 1  w ill be c o m pare d bet wee n t he 
S PI -2 0 1 2 a n d P e gfil gr as ti m T re at me nt A r ms usi n g a b o otstra p resa m pli n g met h o d wit h n o n -
i nferi orit y h y p ot h esis. A 2-si de d 9 5 % c o nfi d e nce i nter val ( CI) of t he differe nce bet w ee n t he 
mea n D S N  of t he S PI -2 0 1 2  Tre at me nt Ar m  a n d t he mea n D S N  of t he Pe gfil gr asti m 
Tre at me nt Ar m  (ie, S PI -2 0 1 2  mi n us Pe gfil grasti m)  will be calc ulate d b as e d u p o n 1 0, 0 0 0 
b o otstra p sa m ples  wit h treat me nt as t he o nl y stratificati o n fact or.   
F or eac h sa m ple, t h e differe nce bet w ee n tr eat me nt ar ms w ill be calc ul ate d . T he p erce ntile 
c o nfi de nce i nter val will be o btai ne d fr o m t he resa m pli n g. T he n o n -i nf eri orit y of S PI -2 0 1 2  t o 


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
1 8  
pe gfil grasti m will be declare d if t he u p p er b o u n d of 9 5 % CI of t he differe n ce i n mea n D S N  
bet wee n t he treat me nt ar ms (i.e., S PI -2 0 1 2  mi n us Pe gfil grasti m)  is < 0. 6 2 da y . T h e n o n -
i nferi orit y i nfere ntial statistics f or pri mar y e n d p oi nt i nfere nce will be base d o n t he esti mate d 
9 5 % CI  as descri be d a b o ve .  
Pri mar y a nal ysis f or t he n o n -i nferi orit y h y p ot hes is will be base d o n  t he I T T P o p ul ati o n . 
A nal ysis bas e d o n t he P P  P o p ul ati o n  will be perf or me d as se ns iti vit y a n al ys is. 
6. 3. 1. 1  
S A S C o de f or P ri m ar y A n al ysis  
T he f oll o wi n g are t h e S A S c o de use d t o ge nerate 9 5 % CI b ase d o n b o otstra p resa m pli n g m et h o d .  
/ * B e g i n n i n g  o f  p r o g r a m * /  
/ * G e t  D S N  D a t a * /  
p r o c  s o r t  d a t a = a d a m . a d e f  o u t = f i n a l ;   
      w h e r e  I T T F L = ' Y '  a n d  p a r a m c d = ' D S N '  a n d  A V I S I T = ' C y c l e  1 ' ;  
 
b y  t r t 0 1 p n ;  
r u n ;  
 
/ * G e t  1 0 0 0 0  B o o t s t r a p  S a m p l e s * /  
p r o c  s u r v e y s e l e c t  d a t a = f i n a l  m e t h o d = u r s  s a m p r a t e  =  1  r e p s = 1 0 0 0 0  o u t h i t s  
s e e d = 2 0 1 7 0 2  o u t = S a m p l e S t r a t a ;  
s t r a t a  t r t 0 1 p n ;  
r u n ;  
 
p r o c  m e a n s  n o p r i n t  d a t a = S a m p l e S t r a t a ;  w h e r e  t r t 0 1 p n = 1 ;  
c l a s s  R e p l i c a t e ;  o u t p u t  o u t = t 1  m e a n ( a v a l ) = d s n 1 ;  r u n ;  
D a t a  t 1 ;  s e t  t 1 ;  i f  
T Y P E
= 1 ;  k e e p  R e p l i c a t e  d s n 1 ;  r u n ;  
p r o c  m e a n s  n o p r i n t  d a t a = S a m p l e S t r a t a ;  w h e r e  t r t 0 1 p n = 2 ;  
c l a s s  R e p l i c a t e ;  o u t p u t  o u t = t 2  m e a n ( a v a l ) = d s n 2 ;  r u n ;  
D a t a  t 2 ;  s e t  t 2 ;  i f  _ T Y P E _ = 1 ;  k e e p  R e p l i c a t e  d s n 2 ;  r u n ;  
 
D a t a  o u t ;  m e r g e  t 1  t 2 ;  b y  R e p l i c a t e ;  
d 1 = d s n 1 - d s n 2 ;         / * m e a n  d i f f e r e n c e  ( S P I - 2 0 1 2  m i n u s  N e u l a s t a )  i n  e a c h  
s a m p l e * /  
r u n ;   
 
/ * O b t a i n  9 5 %  C I  f o r  M e a n  D i f f e r e n c e * /  
p r o c  u n i v a r i a t e  d a t a  =  o u t  a l p h a  =  . 0 5  n o p r i n t ;   v a r  d 1 ;    
o u t p u t  o u t = c 1  m e a n = m e a n  p c t l p t s   =  2 . 5  9 7 . 5  p c t l p r e   =  n  p c t l n a m e  =  p c t 2 5  
p c t 9 7 5 ;  r u n ;  
D a t a  C I 9 5 ;  s e t  c 1 ;   
m e a n = r o u n d ( m e a n , . 0 0 1 ) ;   n p c t 2 5 = r o u n d ( n p c t 2 5 , . 0 0 1 ) ;   
n p c t 9 7 5 = r o u n d ( n p c t 9 7 5 , . 0 0 1 ) ;   
r u n ;  
/ * E n d  o f  p r o g r a m * /  






S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
2 1  
A d diti o nal se nsiti vit y a n al ysis will be use d t o e xa mi ne treat me nt effect a dj usti n g f or dise ase 
stat us at ra n d o mizati o n (a dj u va nt or ne oa dj u v a nt). T his a nal ysis will be t he sa me as t he pri mar y 
a nal ysis ( b o otstra p res a m pli n g met h o d) a n d diseas e stat us will be use d as a d diti o nal stratificati o n 
fact or i n t he resa m pli n g. 
S u m mar y statistics will be pr o vi de d b y treat me nt ar m a n d s u b gr o u p al o n g wit h n o mi nal p -val ues 
at 5 % le vel of si g nifica nce f or t he differe nce b et w ee n treat me nt ar ms f or all s u b gr o u ps i ncl u de d 
i n Secti o n6. 3. 1. 4 .  
A d diti o nal se nsiti vit y a n al ysis usi n g w orst c ase sce nari o will be use d t o e xa mi ne t he i m pact of 
missi n g data a n d t he d etails are i ncl u de d i n Sect i o n 6. 1. 2 . W he n A N C data are missi n g o n or 
after Da y 5, a n d b ef ore p atie nts’ A N C i ncrease t o ≥ 1. 5 × 1 0 9/ L after t he e x pecte d na dir i n C ycl e 
1, missi n g A N C val ues will be i m p ute d as < 0. 5 × 1 0 9/ L f or S PI-2 0 1 2 a n d ≥ 0. 5 × 1 0 9/ L f or 
pe gfil grasti m, f or t he p ur p ose of D S N cal c ulati o n.  
T he w orst -case sce nari o a nal ysis of D S N will use t he sa me b o otstra p resa m pli n g met h o d as i n 
t he pri mar y a n al ysis. 
T hese a d diti o nal se nsiti vit y a nal yses will be perf or me d base d o n t he I T T P o p ulati o n.  
6. 3. 1. 4  
S u b gr o u p A n al ysis   
T he f oll o wi n g s u b gr o u ps will be e x a mi ne d f or D S N  i n C ycle 1 :  
•  A ge  ( <6 5  y ears, ≥6 5 y ears) 
•  A ge ( < 6 5 years, 6 5 t o < 7 5, ≥7 5 years)  
•  Ge n der ( Male, Fe male)  
•  Race  
•  Disease Stat us ( A dj u va nt, Ne oa dj u va nt) at ra n d o mizati o n 
•  G e o gra p hic re gi o n   
•  W ei g ht ( < 6 5 k g, 6 5 t o 7 5 k g, or > 7 5 k g)  
T he s u b gr o u p a n al ys es will be perf or me d b ase d o n t he I T T P o p ul at i o n.  


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
2 2  
6. 3. 2  
Ke y Sec o n d ar y  Effic ac y E n d p oi nt s 
T he ke y sec o n dar y effic ac y e n d p oi nts f or t he st u d y are t o c o m pare S PI -2 0 1 2  wit h pe gfil grasti m 
i n:  
1.  Ti me t o A N C Rec o v er y  i n C ycle 1  
2.  De pt h of A N C N a dir  i n C ycle 1  
3.  I n ci de nce of F N  i n patie nts d uri n g C ycl e 1  
6. 3. 2. 1  
Ti me t o A N C R ec o v er y i n C ycle 1  
Ti me t o A N C R ec o v er y  is defi ne d as t he ti me fr o m c he m ot hera p y a d mi nistrati o n u ntil t he 
patie nt’s A N C i ncreases t o ≥1 . 5 × 1 09/ L after t h e e x pecte d na dir. F or patie nts wit h A N C val ue 
≥1. 5 × 1 0 9/ L at all ti mes , T i me t o A N C R ec o v er y  will  be assi g ne d t o a val u e of 0 .  
T he me an T i me t o A N C R ec o ver y  i n C ycle 1  wit h t w o -si de d 9 5 % CI  will be esti m ate d f or eac h 
treat me nt ar m usi n g ne gati ve bi n o mial re gressi o n . I d e ntical li n k will be use d a n d treat me nt will 
be t he o nl y c o vari ate i n t he m o del . T he differe n ce i n t he mea n T ime t o A N C Rec o v er y  i n C ycl e 
1  bet wee n S PI -2 0 1 2  a n d Pe gfil grasti m will be calc ulate d base d o n n e gati v e bi n o mial re g ressi o n, 
al o n g wit h 2 -si de d 9 5 % CI. T he a nal ysis will be perf or me d b ase d o n t he I T T P o p ul ati o n . A 
se nsiti vit y a nal ysis will be perf or me d bas e d o n t he P P  P o p ul ati o n . 
6. 3. 2. 2  
De pt h of A N C N a dir  i n C ycle 1 
De pt h of A N C N a dir  is defi ne d as t he l o w est A N C val ue after a d mi nistrati o n of st u d y dr u g 
(S PI -2 0 1 2 or pe gfil grasti m)  f or eac h c ycl e . Mea n a n d me dia n D e pt h of A N C N a dir  i n C ycle 1  
will be s u m mariz e d b y tr eat me nt ar m.  T o ass ess  tr eat me nt differe nces, l o g 1 0 tra nsf or mati o n will 
be use d o n t he na dirs t o s atisf y t he n or ma lit y ass u m pti o n, d ue t o t he s ke w ness of t he data. T h e 
A N C na dir rati o bet w ee n t he treat me nt ar ms, ass ociate d 2 -si de d 9 5 % CI, ass u mi n g as y m pt otic 
n or malit y o n t he l o g tra nsf or me d data , will be pr o vi de d.  T he a nal ysis will be perf or me d bas e d o n 
t he I T T P o p ul a ti o n. A se nsiti vit y a nal ysis base d o n t he P P  P o p ul ati o n  will be perf or me d.  
6. 3. 2. 3  
I nci de nce of Fe brile Ne utr o pe ni a  i n C ycle 1 
Fe brile n e utr o pe nia (F N ) is defi ne d as a n oral te m perat ur e > 3 8. 3° C ( 1 0 1. 0° F) or t w o c o nsec uti ve 
rea di n gs of > 3 8. 0° C ( 1 0 0. 4° F) f or 2 h o urs a n d A N C < 1. 0 × 1 0 9/ L.  


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
2 3  
I n ci de nce of F N  after a d mi nistrati o n of st u d y dr u g (S PI -2 0 1 2  or pe gfil grasti m)  i n C ycle 1  will 
be s u m mariz e d b y tr eat m e nt ar m. Patie nts w h o e x perie nce m ore t ha n o ne e ve nt will be c o u nte d  
o nl y o nce  i n eac h c ycl e. A n e x act 2 -si de d 9 5 % CI will be pr o vi de d. T he a n al ysis will be 
perf or me d b ase d o n t he I T T P o p ul ati o n . A se nsiti vit y a nal ysis base d o n t h e P P  P o p ul ati o n  will 
be perf or me d.  
6. 3. 3  
Testi n g Pr o ce d ure f or Pri m ar y a n d Ke y Sec o n d ar y  Effic ac y E n d p oi nt s 
A  hierarc hical cl ose d testi n g pr oce d ure  [5 ] will be use d t o test pri mar y a n d ke y s ec o n dar y 
effic ac y e n d p oi nts. T he t esti n g will be bas e d o n t he f oll o wi n g or der:  
1.  D S N  i n C ycle 1  
2.  T i me t o A N C R ec o v er y  i n C yc le 1 
3.  D e pt h of A N C N a dir  i n C ycle 1  
4.  I n ci de nces of F N  i n C y cle 1  
N o a dj ust me nt t o al p ha will be necessar y o nce t h e prece di n g e n d p oi nt c o m paris o n is si g nifica nt 
f or t he s u bse q ue nt e n d p oi nts i n t he a b o ve or der of e n d p oi nts, wit h eac h test at t he sa me 
si g nifican ce le v el of α = 0. 0 5.  
6. 3. 4  
A d diti o n al Sec o n d ar y  Effic ac y E n d p oi nt s 
T he a d diti o nal sec o n d ar y effic ac y e n d p oi nts are:  
1.  D S N  i n C ycles 2 , 3 , a n d 4  
2.  I n ci de nce of ne utr o p e nic c o m plicati o ns i n C ycle 1  
3.  I n ci de nce of F N  i n C y cles 2 , 3 , a n d 4  
4.  Rel ati ve D ose I nte nsit y  (R DI ) of T C  i n C ycl es 1  t o 4  
6. 3. 4. 1  
D S N  i n C ycles 2, 3, a n d 4 
T hese e n d p oi nts will be defi ne d a n d a nal yz e d si milarl y t o D S N  i n C ycle 1 . T w o -si de d 9 5 % CI 
c o m pari n g S PI -2 0 1 2  t o pe gfil grasti m base d o n b o otstra p resa m pli n g met h o d will be pr o vi de d. 
T he a nal yses will be perf o r me d base d o n t he I T T P o p ul ati o n .  


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
2 4  
6. 3. 4. 2  
I nci de nce of N e utr o pe nic C o m plic ati o ns  i n C ycle 1 
Ne utr o pe nic c o m plicati o n s refer t o h os pitalizati o n s d ue t o ne utr o pe nic e ve nts a n d / or use of a nti -
i nfecti ves d ue t o ne utr o p e nia.   
I n ci de nce of ne utr o p e nic c o m plicati o ns  after a d mi nistrati o n of st u d y dr u g (S PI -2 0 1 2  or 
pe gfil grasti m)  i n C ycle 1  will be s u m marize d b y treat me nt ar m. Patie nts w h o e x perie nce m or e 
t ha n o ne e ve nt will be c o u nte d o nl y o nce  f or eac h c ycle. A n e x act 2 -si de d 9 5 % CI will be 
pr o vi de d. T he a n al ysis will be  perf or me d b ase d o n t he I T T P o p ul ati o n .  
6. 3. 4. 3  
I nci de nce of Fe brile Ne utr o pe ni a  i n C ycle s 2, 3, a n d 4 
T hese e n d p oi nts will be defi ne d a n d a nal yz e d si milarl y t o i nci de nce of F N  i n C ycle 1 . A n e x act 
2 -si de d 9 5 % CI c o m pari n g S PI -2 0 1 2  t o pe gfil grasti m will be pr o vi d e d. T he a nal yses will be 
perf or me d b ase d o n t he I T T P o p ul ati o n .  
6. 3. 4. 4  
Rel ati ve D os e Inte nsit y ( R DI)  
T he a nal yses of t hese e n d p oi nts are descri be d i n Secti o n 6 . 2. 3 (Dr u g E x p os ure  a n d C o m plia nce ). 
6. 3. 5  
Ot her Effic ac y A n al yses  
I n ad diti o n t o t he e n d p oi nts s pecifie d i n t he pr ot o c ol a n d descri be d i n t he pre vi o us secti o ns, t his 
secti o n prese nts s o me a d diti o nal efficac y e n d p oi nts:  
1.  Ti me t o A N C Rec o v er y  i n C ycles 2 , 3 , a n d 4  
2.  De pt h of A N C N a dir  i n C ycles 2 , 3 , a n d 4  
3.  I n ci de nce of ne utr o p e nic c o m plicati o ns i n C ycles 2 , 3 , a n d 4  
6. 3. 5. 1  
Ti me t o A N C Rec o v er y i n C ycles 2, 3, a n d 4  
T hese e n d p oi nts will be defi ne d a n d a nal yz e d si milarl y t o T i me t o A N C R ec o ver y  i n C ycle 1 . 
T w o -si de d 9 5 % CI c o m p ari n g S PI -2 0 1 2  t o p e gfil grasti m base d o n ne gati v e bi n o mial re g ressi o n 
will be pr o vi de d.  I de ntical li n k will be use d a n d tr eat me nt will be t he o nl y c o variate i n t he 
m o del . T he a nal yses will be perf or me d bas e d o n t he I T T P o p ul ati o n .  
6. 3. 5. 2  
De pt h of A N C N a dir i n C ycles 2, 3, a n d 4  
T hese e n d p oi nts will be defi ne d a n d a nal yz e d si milarl y t o D e pt h of A N C N a dir  i n C ycle 1 . 
L o g 1 0 tr a nsf or mati o n will be use d o n t he na dirs t o satisf y t he n or malit y ass u m pti o n. T he A N C 


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
2 5  
na dir rati o bet w ee n t he treat me nt ar ms, ass o ciate d 2 -si de d 9 5 % CI ass u mi n g as y m pt otic 
n or malit y o n t he l o g tra nsf or me d data, will be pr o vi de d. T he a nal ys es will be perf or me d bas e d 
o n t he I T T P o p ul ati o n .  
6. 3. 5. 3  
I nci de nce of Ne utr o pe nic C o m plic ati o ns i n C ycles 2, 3, a n d 4 
T hese e n d p oi nts will be defi ne d a n d a nal yz e d si milarl y t o i nci de nce of ne utr o pe nic 
c o m plicati o ns i n C ycle 1 . A n e x act 2 -si de d 9 5 % CI c o m p ari n g S PI -2 0 1 2  t o pe gfil grasti m will be 
pr o vi de d. T he a n al ys es will be perf or me d b ase d o n t he I T T P o p ul ati o n .  
6. 4  
S afet y A n al yses  
6. 4. 1  
A d verse E ve nts  
6. 4. 1. 1  
Ge ner al  
A treat me nt -e mer ge nt a d verse e v e nt ( T E A E) is a n y a d v erse e ve nt ( A E ) t hat occ urs fr o m t he first 
d ose of T C c he m ot hera p y  t hr o u g h 1 2 m o nt hs  after t he last d ose of st u d y tr eat me nt or 3 0 da ys  
after t he d ate of p atie nt e arl y dis c o nti n uati o n.   
A E se verit y will be gra de d b y t he I n vesti gat or acc or di n g t o t he defi niti o ns set f ort h b y t he 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E versi o n 4. 0 3).  A Es will be c o de d 
usi n g t he Me dic al Dicti o nar y of Re g ulat or y Acti vities ( Me d D R A) a n d will be classifie d b y 
Me d D R A s yste m or ga n class ( S O C) a n d preferre d ter m ( P T).  O nl y treat me nt e mer ge nt a d ve rse 
e ve nts ( T E A Es) will be i ncl u de d i n s u m mar y ta bl es. If it ca n n ot be deter mi ne d w het her a n 
a d verse e ve nt is treat me nt -e mer ge nt ( b ase d o n start date or, if t he start d ate is missi n g  t he n base d 
o n  t he st o p date), t he n t h e a d vers e e v e nt will be c o nsi dere d treat me nt-e mer ge nt.  
6. 4. 1. 2  
I nci de nce of Tre at me nt E mer ge nt A d verse E ve nts 
I n ci de nces of T E A E s will be s u m marize d b y Me d D R A S O C a n d P T. Patie nts w h o e x perie nce 
m ore t ha n o ne t y pe of a d verse e v e nt will be c o u nt e d u n der eac h of t he c orres p o n di n g preferre d 
ter ms. Pati e nts w h o e x perie nce differe nt e pis o des of t he sa me a d v erse e ve nt will be c o u nte d o nl y 
o nce u n der t h e c orres p o n di n g preferre d ter m. Si milarl y, f or deter mi nati o n of Me d D R A S O C 
i nci de nces, patie nts w h o e x perie nce m ulti ple a d verse e ve nts u n d er t he sa m e S O C will be c o u nte d 
o nl y o nce f or t hat S O C.  


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
2 6  
6. 4. 1. 3  
I nci de nce of T E A Es of S peci al I nterest  
Preferre d Ter ms  will be gr o u pe d t o get her t o assess t he f oll o wi n g three  cate g ories of A Es of 
s pecial i nterest.  
•  M usc ul os keletal pai n: i ncl u des S O C of m usc ul os keletal a n d c o n n ecti ve tiss ue dis or ders. 
•  I nje cti o n site reacti o ns: i ncl u des H L T of i njecti o n site reacti o ns .  
•  H y p erse nsiti vit y reacti o ns: i ncl u des h y perse nsiti vit y S M Q N a n d a na p h ylactic reacti o n 
S M Q N.  
T he i nci de nce of A Es of s pecial i nterest will be s u m marize d b y s pecial i nteres t cate g or y a n d 
preferre d t er m wit hi n t he s pecial i nterest. Patie nts w h o e x perie nce m ulti ple a d verse e ve nts u n der 
t he sa me s peci al i nterest will be c o u nte d o nl y o n ce f or t hat s pecial i nterest. 
6. 4. 1. 4  
I nci de nce of Tre at me nt Rel ate d Ad vers e E ve nt s 
A ssess me nt of relat e d ness t o T C or  st u d y dr u g (S PI -2 0 1 2  or pe gfil grasti m) f or all ad v erse e ve nts 
will be  classifie d b y i n vesti gat ors  a n d re p orte d. T he i nci de nces of treat me nt relate d a n d u nrelate d 
A E s will be prese nte d b y Me d D R A S O C a n d P T  f or eac h T C c o m p o ne nt a n d st u d y dru g . F or 
t his a nal ysis, an a d v erse e ve nt will be assi g ne d as  treat me nt relat e d if t he relati o ns hi p t o st u d y 
dr u g is missi n g.  
6. 4. 1. 5  
T E A E C ate g orize d b y Se verit y  
I n ci de nces of T E A E s will als o be s u m marize d b y  Me d D R A S O C, preferre d ter m, a n d  ma xi m u m 
C T C A E se verit y g ra de. A d verse e ve nts wit h a missi n g se verit y gra de will n ot be i ncl u de d i n 
t hese a nal yses. Patie nts w h o e x perie nce t he s a me e ve nt at m ore t ha n o ne s e verit y le vel will be 
c o u nte d o nl y o n ce u n d er t he ma xi m u m se verit y le vel. T he o verall a d verse e ve nt i nci de nc es will 
als o be prese nt e d i n t hese ta bles as a refere nce.  
T he sa me a n al ys es b y  ma xi m u m C T C A E se verit y gra de will be prese nte d f or treat me nt r elate d 
a d verse e ve nts o nl y.  
T he i nci de nce of T E A Es a n d treat me nt r elate d A Es wit h se verit y G ra d e ≥3  will be s u m mari ze d 
b y Me d D R A S O C a n d P T . 


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
2 7  
6. 4. 1. 6  
Seri o us A d verse E ve nts a n d A d verse E ve nts Le a di n g t o St u d y Dr u g 
M o dific ati o ns  
I n ci de nces of seri o us a d v erse e v e nts  a n d a d v erse e ve nts lea di n g t o d os e re d ucti o ns, d ose dela ys, 
d ose i nterr u pti o ns,  a n d st u d y dr u g disc o nti n uati o n  will  be s u m marize d o verall a n d b y 
relati o ns hi p t o st u d y dr u g. Listi n gs of patie nt deat hs, disc o nti n uati o ns d ue t o a d verse e ve nts, a n d 
seri o us a d vers e e v e nts will als o be prese nte d.  
6. 4. 2  
L a b or at or y P ar a meters  
Cli nical la b orat or y sa m ples will be c ollecte d at scree ni n g a n d t hr o u g h o ut t h e st u d y. T h e cli nical 
la b orat or y val u es will be classifie d acc or di n g t o t h e N CI C T C A E versi o n 4. 0 3. Ta bles of s hifts 
i n se verit y fr o m baseli ne t o w orst p ost-baseli ne o n st u d y , f or l a b orat or y p ara meters, will  be 
pr o vi de d  o verall a n d b y C y cle 1 a n d C ycles 2  t o 4  se parat el y.  
La b orat or y v al ues a n d c h a n ge fr o m b aseli ne will be s u m marize d usi n g I nter nati o nal S yste m 
U nits b y pa n el, la b orat or y test, a n d ti me p oi nt. Se parate s u m mar y t a bles a n d listi n gs will be 
pr o d uce d f or la b orat or y a b n or malitie s. 
S u p p orti n g la b orat or y d ata i ncl u di n g n or mal ra n ges a n d a b n or m al la b orat or y fla gs will be 
pr o vi de d i n data listi n gs.  
6. 4. 3  
Vit al Si g n D at a  
A s u m mar y of ra w val ues a n d c ha n ge s fr o m bas eli ne val ues will be pr o vi d e d b y tr eat me nt ar m at 
eac h sc h e d ule d ti me p oi nt f or t he f oll o wi n g m eas ure me nts : b o d y t e m perat ure, s yst olic a n d 
diast olic bl o o d press ure, a n d heart rate . A listi n g of all val ues will als o be i ncl u de d.  
6. 4. 4  
E C O G Perf or m a nce St at us  
Descri pti ve statistics will be prese nt e d f or E C O G sc ores bas eli ne. T he n u m ber a n d  perce nta ge of 
patie nts wit h s hifts fr o m baseli ne E C O G sc ore ( 0, 1, or 2) t o t he  w orst  p ost -baseli ne E C O G sc ore 
( 0, 1, 2, 3, or 4) will be s u m marize d o verall a n d b y C ycle 1  a n d C ycles 2  t o 4  se parat el y.  
 


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
2 8  
7  
R E F E R E N C E S  
1.  
Efr o n B, Ti bs hira ni RJ. A n I ntr o d ucti o n t o t he B o otstra p. C ha p ma n a n d Hall: L o n d o n, 
1 9 9 3.  
2.  
Gree n M D, K oel bl H, Basel ga J, Gali d A, G uille m V, Gasc o n P, et al. A ra n d o mize d 
d o u ble -bli n d m ultice nter p hase III st u d y of fi x e d -d ose si n gle -a d mi nistrati o n pe gfil grasti m 
vers us d ail y fil grasti m i n patie nts recei vi n g m yel os u p pressi ve c h e m ot hera p y. A n n O nc ol. 
2 0 0 3; 1 4( 1): 2 9 -3 5.  
3.  
H ol mes F A, J o nes S E, O' S ha u g h ness y J, V u kelja S, Ge or ge T, Sa vi n M, et al. 
C o m para ble efficac y a n d safet y pr ofiles of o nce -p er -c ycle pe gfil grasti m a n d dail y 
i njecti o n fil grasti m i n c he m ot hera p y-i n d u ce d ne utr o pe nia: a m ultice nter d ose-fi n di n g 
st u d y i n w o me n wit h breast ca ncer. A n n O nc ol. 2 0 0 2; 1 3( 6): 9 0 3-9.  
4.  
R o berts o n N, Hai g h A, A da ms G E, Stratf or d IJ. Fact ors affecti n g se nsiti vit y t o E O 9 i n 
r o de nt a n d h u ma n t u m o ur cells i n vitr o: D T-dia p h orase acti vit y a n d h y p o xia. E ur J 
Ca ncer. 1 9 9 4; 3 0a( 7): 1 0 1 3 -9.  
5.  
L u bse n J, Kir wa n B A. C o m bi ne d e n d p oi nts: ca n we use t he m? Stat Me d. 
2 0 0 2; 2 1( 1 9): 2 9 5 9 -7 0.  
 
 
 


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
2 9  
8  
A P P E N DI X - A. S A P A M E N D M E N T: LI S T O F C H A N G E S  
C h a n ges f r o m t he ori g i n al S A P t o Versi o n 1. 1: 
T he pri mar y p ur p os e of t he S A P a me n d me nt is t o pr o vi de m ore cl arit y a n d details of t he 
ha n dli n g of missi n g data f or A N C a n d efficac y a n al ysis. N o c h a n ges w ere ma de t o t he tests of 
c o m paris o n of efficac y e n d p oi nts a n d statistical me t h o ds of a nal ysis. 
Secti o n 6. 1. 2 H a n dli n g of Missi n g D at a  
P ar a g r a p h delete d:  
A N C assess me nt will be c ollecte d dail y fr o m Da ys 4 t o 1 5 i n C ycle 1. D uri n g t his ti me wi n d o w, 
patie nts are e x pecte d t o ha ve se vere n e utr o pe nia, a n d missi n g A N C val ues c o ul d affect  t he 
calc ulati o n of pri mar y efficac y e n d p oi nt. S pectr u m’s Cli nical O perati o ns tea m will w or k cl osel y 
wit h st u d y sites t o mi ni miz e missi n g data d uri n g t he st u d y c o n d uct. T he p erce nta ge of patie nts 
wit h missi n g A N C val ues fr o m Da ys 4 t o 1 5 i n C ycl e 1 will be pres e nte d b y treat me nt ar m.  
P ar a g r a p hs a d de d:  
A ssess me nt of A N C will be perf or me d dail y fr o m Da ys 4 t o 1 5 i n C ycle 1. D uri n g t his ti me 
wi n d o w, patie nts are e x pecte d t o ha v e se vere ne utr o pe nia, a n d missi n g A N C val ues c o ul d affect 
t he calc ulati o n of t he pri mar y effi cac y e n d p oi nt. Missi n g A N C data are li kel y d u e t o missi n g 
bl o o d sa m pli n g i n a dail y bl o o d sa m pli n g sc he d ule fr o m Da ys 4 t o 1 5 i n C ycle 1. S pectr u m’s 
Cli nical O perati o ns tea m will w or k cl osel y wit h st u d y sites t o mi ni mize missi n g data d uri n g t he 
st u d y c o n d u ct. S pectr u m has e n ga ge d a h o me healt h care v e n d or,  
, t o facilitate bl o o d 
sa m pli n g at patie nts’ c o n ve nie nce at h o me or i n t h e office. O n a p eri o dic basis d uri n g t he st u d y 
c o n d uct, t he Cli nical O perati o ns tea m trac ks t h e bl o o d sa m pli n g stat us of all e nr olle d patie nts t o 
i de ntif y iss ues a n d i m ple me nts miti gati o n pla ns w here ver p ossi ble. 
It is e x pecte d t hat t he e xte nt of missi n g A N C data will be si milar bet wee n tr eat me nt ar ms i n t his 
ra n d o mize d st u d y, as t he reas o n f or missi n g is m ostl y l o gistical a n d relat e d t o c o n ve nie nce rat h er 
t ha n i nf or med missi n g of t he effic ac y e n d p oi nt. T he perce nta ge of patie nts wit h missi n g A N C 
val ues fr o m Da ys 4 t o 1 5 i n C ycle 1 will be prese nte d b y tr eat me nt ar m.  
P ar a g r a p h a d de d:  
I n p u blis he d st u dies of l o n g-acti n g m yel oi d gr o wt h fact ors, w he n patie nts r ecei ve c he m o t hera p y 
o n Da y 1 a n d a gra n ul oc yt e c ol o n y -sti m ulati n g fact or o n Da y 2 of eac h c ycle, t he A N C na dir 
te n ds t o occ ur d uri n g a 3-da y peri o d b et wee n Da ys 6 t o 8 i n m ost patie nts a n d t he mea n D S N has 
bee n re p orte d i n t he ra n ge of 0. 3 t o 2 da ys. Acc or di n g t o t he pr ot oc ol, pati e nts ma y disc o nti n ue 
t he st u d y f or a n u m ber of reas o ns as s p ecifie d i n t he pr ot oc ol. If a patie nt i n eit her treat me nt ar m 
has n o bl o o d dra ws ( missi n g A N C val u es) beca use of disc o nti n uati o n fr o m Da ys 4 t o 1 5 or f or 
a n y p art of t his d urati o n, t he D S N will be i m p ute d as 3 da ys f or t hat p atie nt.  
P ar a g r a p h delete d:  
T he missi n g A N C val ues will be ha n dle d t he sa me wa y t o calc ul ate D S N i n C ycles 2 t o 4.  
P ar a g r a p hs a d de d:  


S PI -2 0 1 2 ( R ol o ntis ™, efl a pe gr asti m, H M 1 0 4 6 0 A, L A P S -G -C S F)  
S t atistic al A n al ysis Pl a n 
I N D 1 0 3, 4 6 1 –  Versi o n 1. 3 –  3 1 J ul 2 0 1 8  
C o nfi de nti al  
3 0  
T he missi n g A N C val ues i n C ycles 2 t o 4 will be ha n dle d differe ntl y fr o m t hat i n C ycle 1 as 
bl o o d sa m ples are o nl y t o be e val uat e d o n n o mi nal da ys 4, 7, 1 0, a n d 1 5 i n C ycle 2 t o 4. T h e 
missi n g data will be ha n dle d as bel o w:  
•  If t here are m ulti ple A N C val ues o n a n o mi nal visit da y, use t he l atest o ne. 
•  If a patie nt h as a missi n g A N C val ue a n d t he t w o a djace nt A N C val ues (ie, t he last 
a vaila ble val ue b ef ore t h e missi n g val ue a n d t he first a vaila ble val ue after t he missi n g 
val ue) are b ot h ≥0. 5 × 1 0 9/ L, t he missi n g A N C val u e(s) will be c o nsi dere d as ≥ 0. 5 × 1 0 9/ L 
a n d t he da y(s) wit h missi n g val u e(s) will n ot be c o u nte d t o calc ulate D S N.  
•  If t he t w o a dja ce nt A N C val ues are b ot h < 0. 5 × 1 09/ L, t he missi n g A N C val ues will be 
c o nsi dere d as < 0. 5 t o cal c ulate D S N.  
•  If eit her of t he t w o a dja ce nt A N C val ues is < 0. 5 × 1 09/ L, o nl y t he ti me p oi nt wit h A N C 
val ues < 0. 5 × 1 0 9/ L will be use d f or t he calc ul ate D S N 
•  If a patie nt i n eit her treat me nt ar m has n o bl o o d dra ws ( missi n g A N C val u es) beca use of 
t he disc o nti n uati o n fr o m Da ys 4 t o 1 5 or f or a n y p art of t his d urati o n, t he D S N will be 
i m p ute d as 3 da ys f or t hat patie nt. 
P ar a g r a p h a d de d:  
Patie nt disc o nti n uati o n or missi n g bl o o d sa m pli n g f or t he e ntire d urati o n of Da ys 4 t o 1 5 will 
als o be ha n dle d differe ntiall y f or D S N cal c ulati o n bet wee n tr eat me nt ar ms i n t he w orst -cas e 
sce nari o. If a p atie nt has n o bl o o d dra ws ( missi n g A N C val ues) beca use of disc o nti n uati o n fr o m 
Da ys 4 t o 1 5 or f or a n y p art of t his d urati o n, t he D S N will be i m p ute d as 3 da ys f or t hat patie nt 
f or S PI-2 0 1 2 a n d 0 f or pe gfil grasti m. T he reas o n f or i m p uti n g D S N = 3 d a ys f or S PI -2 0 1 2 is 
descri be d a b o ve.  
Secti o n 6 . 3. 1. 3 A d diti o n al Se nsiti vit y A n al ysis 
P ar a g r a p h a d de d:  
S u m mar y statistics will be pr o vi de d b y treat me nt ar m a n d s u b gr o u p al o n g wit h n o mi nal p -val ues 
at 5 % le vel of si g nifica nce f or t he differe nce b et w ee n treat me nt ar ms f or all s u b gr o u ps i ncl u de d 
i n Sectio n 6 . 3. 1. 4. 
Te xt delete d:  
W he n A N C data are missi n g o n or after Da y 5, a n d bef ore p atie nts’ A N C i ncreas e t o ≥1. 5 × 1 0
9/ L 
after t he e x pecte d na dir i n C ycle 1, missi n g A N C val ues will be i m p ute d as < 0. 5 × 1 0 9/ L f or S PI-
2 0 1 2 a n d ≥ 0. 5 × 1 0 9/ L f or pe gfil grasti m, f or t he p ur p ose of D S N calc ulati o n.