A TWO-PART, PHASE 1A/B, OPEN-LABEL, MULTICENTER TRIAL EVALUATING PHARMACOKINETICS, SAFETY AND EFFICACY OF PF 07284890 (ARRY 461) IN PARTICIPANTS WITH BRAF V600 MUTANT SOLID TUMORS WITH AND WITHOUT BRAIN INVOLVEMENT
Phase: PHASE1
Conditions: Malignant Melanoma, Carcinoma, Non-Small-Cell Lung, Brain Neoplasms, Primary, Brain Neoplasms, Malignant Neoplasms
Sponsor: Pfizer

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1
A T W O -P A R T, P H A S E 1 A/ B , O P E N-L A B E L, M U L TI C E N T E R T RI A L 
E V A L U A TI N G P H A R M A C O KI N E TI C S, S A F E T Y A N D E F FI C A C Y O F 
P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1) I N P A R TI CI P A N T S WI T H B R A F V 6 0 0 -M U T A N T S O LI D 
T U M O R S WI T H A N D WI T H O U T B R AI N I N V O L V E M E N T
St u d y I nter ve nti o n N u m ber :
P F - 0 7 2 8 4 8 9 0 (A R R Y -4 6 1 )
St u d y I nter ve nti o n N a me:
N ot A p plica ble ( N/ A)
U S I N D N u m ber:
1 4 9 8 4 5
Cli nic al Tri als. g o v I D: 
N C T 0 4 5 4 3 1 8 8
E u dr a C T N u m ber:
N/ A
Pr ot oc ol N u m ber:
C 4 4 7 1 0 0 1
P h ase:
1 a/ b
S h ort Title: A First -I n-H u m a n St u dy of P F -0 7 2 8 4 8 9 0 i n P artici p a nts Wit h B R A F V 6 0 0
M ut a nt S oli d T u m ors W it h a n d Wit h o ut Br ai n I nv olve me nt
T his d oc u me nt a n d acc o m pa n yi n g materials c o ntai n c o nfi de ntial i nf or mati o n bel o n gi n g t o Pfizer.  E xce pt as 
ot her wise a gree d t o i n writi n g, b y acce pti n g or re vie wi n g t hese d oc u me nt s, yo u a gree t o h ol d t his 
i nf or mati o n i n c o nfi de nce a n d n ot c o p y or discl ose it t o ot hers (e xce pt w here re q uire d b y a p plica ble la w) or 
use it f or u na ut h orize d p ur p oses.  I n t he e ve nt of a n y act ual or s us pecte d breac h of t his o bli gati o n, Pfizer 
m ust be pr o m ptl y n otifie d.
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2
D oc u me nt Hist or y
D oc u me nt
Versi o n D ate
A me n d me nt 3 
2 0 J ul y  2 0 2 2
A me n d me nt 2
1 4 Ja n uar y  2 0 2 1
A me n d me nt 1
0 3 A u g ust 2 0 2 0
Ori gi nal pr ot oc ol
1 2 J u ne 2 0 2 0
T his a me n d me nt i nc or p orates all re visi o ns t o date, i ncl u di n g a me n d me nts ma de at t he 
re q uest of c o u ntr y healt h a ut h orities a n d I R Bs/ E Cs a n d a n y pr ot oc ol a d mi nistrati ve c ha n ge 
letter(s).
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble 
A m e n d me nt 3 ( 2 0 J ul y 2 0 2 2 )
O ver all R ati o n ale f or t he A me n d me nt: T he pr ot oc ol was a me n de d t o m o dif y  t he re q uire d 
n u m ber of patie nts per e x pa nsi o n c o h ort, t o all o w f or a n o pti o nal f o o d effect s u bst u d y, a n d t o
clarif y as pects of t he pr ot oc ol.
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
1 . 1 S y n o psis
A d diti o n of i ntracra nial 
e xtracra nial res p o nse 
e val uati o n t o e n d p oi nts relate d 
t o o bjecti ve of a nti-t u m or 
efficac y 
E xtracra nial a n d i ntracra nial will 
be e val uate d se paratel y a n d 
c ollecti vel y as o verall res p o nse.
1 . 1 S y n o psis
Re vise d sa m ple size f or P hase 
1 b e x pa nsi o n c o h orts
Re m o val of N S C L C p o p ulati o n 
fr o m c o h orts 1- 4 t o e val uate 
efficac y i n patie nts wit h 
mela n o ma ; sa m ple size was 
re d uce d t o reflect t he re m o val of 
N S C L C wit h n o i m pact t o 
statistical desi g n. A d diti o n of 
patie nts t o c o h ort 5 t o better 
esti mate treat me nt effect i n 
di verse p o p ulati o n i ncl u di n g 
N S C L C.
1 . 1 S y n o psis
E val uati o n of re peate d 
a d mi nistrati o n of P F -0 7 2 8 4 8 9 0 
i n c o m bi nati o n wit h 
bi ni meti ni b o n si n gle d ose P K 
of mi daz ola m ( C o h ort 6 o nl y ) 
T his s u bst u d y  is n o w o pti o nal.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 3
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
m o ve d fr o m sec o n dar y  t o 
tertiar y o bjecti ve
1 . 1 S y n o psis
A d diti o n of o pti o nal 
f o o d-effect s u bst u d y 
If t he effect of f o o d o n 
e x p os ures, base d o n res ults fr o m 
C 4 4 7 1 0 0 2 is p ositi ve a n d lar ge 
( 2-f ol d or m ore), t he t olera bilit y 
of re peat d os i n g wit h f o o d will 
be st u die d i n a s u bst u d y  of 
patie nts.  
1 . 1 S y n o psis
M o dificati o n of D DI s u bst u d y  
t o o pti o nal
A D DI s u bst u d y ma y be 
perf or me d o pti o nall y n o w. 
1 . 1 S y n o psis
A d de d i nf or mati o n re gar di n g 
t he c o m m u nicati o n of res ults 
fr o m t he o n g oi n g f o o d-effect
st u d y, C 4 4 7 1 0 0 2
T o a d dress h o w fasti n g 
re q uire me nts ma y be c ha n ge d.
1. 2 Sc he ma
U p date d wit h s u bst u dies, 
c ha n ges t o eli gi bilit y a n d 
sa m ple sizes.
F or c o nsiste nc y .
1 . 3 Sc he d ule of 
Acti vities
Clarificati o ns a n d a d diti o n of 
testi n g a n d e val uati o n 
T o assess mat urit y  a n d tri g ger 
re q uire me nt f or c o ntrace pti ve 
meas ures .
2. 2. 3 N o ncli nical 
Safeet y 
U p date d ge n ot o xicit y  ris k
D ue t o ne w data fr o m i n vitr o 
m o use l y m p h o ma, c o met assa y , 
a n d i n vi v o micr o n ucle us .
2. 3 Be nefit/ Ris k
A d de d facial paresis t o list of 
ris ks f or B R A F in hi bit or s
F or c o m plete ness a n d 
c o nsiste nc y wit h pac ka ge i nserts 
of ot her a p pr o ve d B R A Fis.
2. 2. 4. 1 P F - 0 7 2 8 4 8 9 0
I nstr ucti o n t o refere nce I B f or 
i nf or mati o n re gar di n g cli nical 
e x perie nce
T o clarif y  t hat t he acc u m ulate d 
cli nical data are s u m marize d 
t here.
3 O bjecti ves a n d 
E n d p oi nts
A d diti o n of i ntracra nial a n d 
e xtracra nial res p o nse 
e val uati o n t o e n d p oi nts relate d 
t o o bjecti ve of a nti-t u m or 
efficac y 
E xtracra nial a n d i ntracra nial will 
be e val uate d se paratel y a n d 
c ollecti vel y as o verall res p o nse.
3 O bjecti ves a n d 
E n d p oi nts
E val uati o n of re peate d 
a d mi nistrati o n of P F -0 7 2 8 4 8 9 0 
i n c o m bi nati o n wit h 
bi ni meti ni b o n si n gle d ose P K 
of mi daz ola m ( C o h ort 6 o nl y ) 
T his s u bst u d y  is n o w o pti o nal.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 4
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
m o ve d fr o m sec o n dar y  t o 
tertiar y o bjecti ve
4. 1 O verall Desi g n
Re vise d sa m ple size f or 
P hase 1 b e x pa nsi o n c o h orts
Re m o val of N S C L C p o p ulati o n 
fr o m c o h orts 1- 4 t o e val uate 
efficac y i n patie nts wit h 
mela n o ma; sa m ple size was 
re d uce d t o reflect t he re m o val of 
N S C L C wit h n o i m pact t o 
statistical desi g n. A d diti o n of 
patie nts t o c o h ort 5 t o better 
esti mate treat me nt effect i n 
di verse p o p ulati o n i ncl u di n g 
N S C L C.
4. 1 O verall Desi g n
A d diti o n of o pti o nal f o o d-
effect s u bst u d y a n d 
m o dificati o n of D DI s u bst u d y  
t o o pti o nal
If t he effect of f o o d o n 
e x p os ures, base d o n res ults fr o m 
C 4 4 7 1 0 0 2 is p ositi ve a n d lar ge 
( 2-f ol d or m ore), t he t olera bilit y 
of re peat d osi n g wit h f o o d will 
be st u die d i n a s u bst u d y  of 
patie nts.  A D DI s u bst u d y  m a y 
be perf or me d o pti o nall y  n o w. 
4. 1 O verall Desi g n
A d de d i nf or mati o n re gar di n g 
t he c o m m u nicati o n of res ults 
fr o m t he o n g oi n g f o o d-effect
st u d y, C 4 4 7 1 0 0 2
T o a d dress h o w fasti n g 
re q uire me nts ma y be c ha n ge d.
4. 2. 6 Rati o nale f or 
F o o d -effect
A d de d Rati o nale f or 
F o o d -effect S u bst u d y
T o clarif y  t he rati onale f or t he 
s u bst u d y.
4. 3. 5 St o p pi n g 
Criteria i n P hase 1 b 
D ose E x pa nsi o n
A d de d St o p pi n g Criteria i n 
P hase 1 b D ose E x pa nsi o n
F or patie nt safet y.
5. 1 I ncl usi o n Criteria
A d diti o n of a d olesce nts a ge d 
1 6 a n d o ver wit h b o d y wei g ht 
4 0 k g a n d o ver a n d a d de d 
clarificati o n o n c o nse nti n g 
a d olesce nt partici pa nts
Base d o n g ui da nce fr o m t he 
re g ulat or y a ut h orities, 
a d olesce nt patie nts ma y be 
c o nsi dere d f or i ncl usi o n i n trials 
i ncl u di n g a d ult patie nts u n der 
certai n circ u msta nces.
A d olesce nts wit h certai n B R A F 
V 6 0 0 -m uta n t ca ncers 
(e g, pri mar y  brai n t u mr os) ha ve 
u n met nee d a n d t heref ore are 
a p pr o priate f or t his st u d y .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 5
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
5. 1 I ncl usi o n Criteria
A d di n g re q uire me nt f or 
meas ura ble disease i n C o h ort 5
T o ai d i n t he assess me nt of 
a nti-t u m or res p o nse.
6. 1. 1. 1 F o o d 
Re q uire me nts
A d de d i nf or mati o n re gar di n g 
t he c o m m u nicati o n of res ults 
fr o m t he o n g oi n g f o o d-effect
st u d y, C 4 4 7 1 0 0 2
T o a d dress h o w fasti n g 
re q uire me nts ma y be c ha n ge d.
6. 4 St u d y  
I nter ve nti o n 
c o m plia nce
Clarif y re q uire me nts f or st u d y  
i nter ve nti o n c o m plia nce
F or clarit y .
6. 6. 3 D ose Dela y s
Re m o val of se parate 
he mat ol o gic re q uire me nts f or 
c ycle start; clarificati o n t o refer 
t o t he D ose M o dificati o n ta ble
a n d clarificati o n o n treat me nt 
res u m pti o n
T o eli mi nate c o ntra dict or y 
g ui da nce .
6. 6. 4 D ose 
Re d ucti o ns
Clarif y  d ose re d ucti o ns f or 
patie nts recei vi n g 
P F - 0 7 2 8 4 8 9 0 BI D
Base d o n o bser ve d data wit hi n 
t he trial, BI D d osi n g was 
i m ple me nte d, a n d d ose 
re d ucti o n g ui da nce has bee n 
clarifie d t heref ore.
7. 2 Partici pa nt 
Disc o nti n uati o n/ Wit h
dra wal fr o m St u d y
Clarificati o n criteria f or 
wit h dra wal fr o m st u d y
F or clarificati o n.
8. 1 Efficac y  
Assess me nts
Clarif y  t u m or res p o nse 
assess me nts f or patie nts wit h 
pri mar y  brai n t u m ors
F or clarit y .
8. 2. 1 P h y sical 
E xa mi nati o ns
A d d Ta n ner Sta ge assess me nt 
t o P h ysical E xa m f or 
a d olesce nts
T o assess mat urit y  a n d tri g ger 
re q uire me nt f or c o ntrace pti ve 
meas ures .
8. 2. 8 Cli nical Safet y  
La b orat or y  
Assess me nts
Re m o ve re q uire me nt f or re peat 
la b orat or y assess me nts at 
C 1 D 1 if c ollecte d i n 7 da ys 
pri or d uri n g scree ni n g
T o re d uce patie nt b ur de n 
wit h o ut i m pact t o st u d y 
o bjecti ves .
8. 2. 1 1 A d diti o nal 
Asssess me nts f or 
A d olesce nt 
Partici pa nts
A d de d assess me nts f or 
a d olesce nt partici pa nts
T o assess mat urit y  a n d tri g ger 
re q uire me nt f or c o ntrace pti ve 
meas ures .
8. 3. 8 A d verse E ve nts 
of S peical I nterest
A d de d clarificat i o n o n A E SI 
re vie w
F or clarit y .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 6
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
8. 5 P har mac o ki netics
C ha n ge t o sa m ple v ol u me of 
C S F sa m ple
T o facilitate t he re q uire d testi n g.
9. 2 Sa m ple Size 
Deter mi nati o n
U p date sa m ple size f or c o h orts 
1 -4, a d diti o n of o pti o nal 
f o o d-effect s u bst u d y a n d 
m o dificati o n of D DI s u bst u d y  
t o o pti o nal 
Re m o val of N S C L C p o p ulati o n 
fr o m c o h orts 1- 4 t o e val uate 
efficac y i n patie nts wit h 
mela n o ma; sa m ple size was 
re d uce d t o reflect t he re m o val of 
N S C L C wit h n o i m pact t o 
statistical desi g n. A d diti o n of 
patie nts t o c o h ort 5 t o better 
esti mate treat me nt effect i n 
di verse p o p ulati o n i n N S C LC.
9. 5 Data M o nit ori n g 
C o m mittee or Ot her 
I n de pe n de nt 
O versi g ht C o m mittee
A d diti o n of safet y re vie w 
c o m mittee f or re vie w of safet y 
d uri n g d ose e x pa nsi o n p hase
T o e ns ure patie nt safet y.
1 0 A p p pe n dices
A d diti o n of list of pr o hi bite d 
c o nc o mita nt me dicati o ns t hat 
ma y  res ult i n D DI; 
clarificati o ns of alter nati ve 
meas ures t o ta ke d uri n g p u blic 
e mer ge ncies
F or patie nt safet y a n d t o all o w 
f or a de q uate m o nit ori n g of 
patie nts d uri n g t he trial.
1 0 A p pe n dices
A d diti o n of asse nt 
re q uire me nts f or a d olesce nts; 
a d diti o n of f o o d-effect
s u bst u d y a p pe n di x; f urt her 
s pecificati o n of res p o nse 
assess me nt b y m R E CI S T 1. 1; 
f urt her s pecificati o n of 
res p o nse assess me nt b y R A N O 
( H G G vs. L G G); 
T o facilitate ot her c ha n ges as 
pre vi o usl y  refere nce d.
0 9
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 7
T A B L E O F C O N T E N T S
LI S T O F T A B L E S ...................................................................................................................1 5
LI S T O F FI G U R E S ................................................................................................................. 1 5
1. P R O T O C O L  S U M M A R Y................................................................................................... 1 6
1. 1. S y n o psis .................................................................................................................. 1 6
1. 2. Sc he ma .................................................................................................................... 2 1
1. 3. Sc he d ule of Acti vities ............................................................................................. 2 4
2. I N T R O D U C TI O N ............................................................................................................... 3 5
2. 1. St u d y  Rati o nale....................................................................................................... 3 5
2. 2. Bac k gr o u n d ............................................................................................................. 3 5
2. 2. 1. N o ncli nical P har mac ol o g y  of P F-0 7 2 8 4 8 9 0 .............................................. 3 7
2. 2. 2. N o ncli nical P har mac o ki netics a n d Meta b olis m of P F -0 7 2 8 4 8 9 0.............. 3 8
2. 2. 3. N o ncli nical Safet y of P F -0 7 2 8 4 8 9 0 ........................................................... 3 9
2. 2. 4. Cli nical O ver vie w ....................................................................................... 4 1
2. 2. 4. 1. P F -0 7 2 8 4 8 9 0............................................................................. 4 1
2. 2. 4. 2. Bi ni meti ni b ................................................................................ 4 1
2. 3. Be nefit/ Ris k Assess me nt ......................................................................................... 4 3
2. 3. 1. Ris k Assess me nt ......................................................................................... 4 5
2. 3. 2. Be nefit Assess me nt ..................................................................................... 4 7
2. 3. 3. O verall Be nefit/ Ris k C o ncl usi o n ................................................................ 4 7
3. O BJ E C TI V E S A N D E N D P OI N T S ..................................................................................... 4 7
4. S T U D Y D E SI G N ................................................................................................................. 4 9
4. 1. O verall Desi g n ......................................................................................................... 4 9
4. 2. Sci e ntific Rati o nale f or St u d y Desi g n..................................................................... 5 1
4. 2. 1. Rati o nale f or D ose Escalati o n A p pr oac h ....................................................5 2
4. 2. 2. Rati o nale f or C o m bi nati o n wit h Bi ni meti ni b ............................................. 5 2
4. 2. 3. Rati o nale f or U n met Me dical Nee d f or Partici pa nts wit h 
S y m pt o matic Brai n I n v ol ve me nt ..................................................................... 5 3
4. 2. 4. Rati o nale f or B R A F V 6 0 0 M utati o n Testi n g Para di g m ............................. 5 4
4. 2. 5. Rati o nale f or 
 Assess me nt...........................................5 4
4. 2. 6. Rati o nale f or F o o d -effect S u b St u d y ...........................................................5 4
4. 2. 7. Rati o nale f or C Y P 3 A 4 Dr u g- Dr u g I nteracti o n S u bst u d y ...........................5 5
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 8
4. 3. J ustificati o n f or D ose ..............................................................................................5 5
4. 3. 1. Starti n g D ose ..............................................................................................5 5
4. 3. 2. Criteria f or D ose Escalati o n ........................................................................ 5 5
4. 3. 2. 1. P F -0 7 2 8 4 8 9 0 M o n ot hera p y  D ose Escalati o n............................ 5 5
4. 3. 2. 2. P F -0 7 2 8 4 8 9 0 D ose Escalati o n i n C o m bi nati o n wit h 
Bi ni meti ni b ........................................................................................ 5 6
4. 3. 2. 3. I ntra patie nt D ose Escalati o n ...................................................... 5 7
4. 3. 3. D ose L i miti n g T o xicit y Defi niti o n............................................................. 5 7
4. 3. 4. Rec o m me n de d D ose F or F urt her St u d y ..................................................... 6 0
4. 3. 5. St o p pi n g Criteria i n P hase 1 b D ose E x pa nsi o n .......................................... 6 0
4. 4. E n d of St u d y  Defi niti o n .......................................................................................... 6 0
5. S T U D Y P O P U L A T I ON ...................................................................................................... 6 0
5. 1. I ncl usi o n Criteria ..................................................................................................... 6 1
5. 2. E xcl usi o n Criteria .................................................................................................... 6 5
5. 3. Li fest yle C o nsi derati o ns.......................................................................................... 6 8
5. 3. 1. P h ot ose nsiti vit y ........................................................................................... 6 8
5. 3. 2. Acti vit y ....................................................................................................... 6 9
5. 3. 3. C o ntrace pti o n ..............................................................................................6 9
5. 4. Scr ee n Fail ures ........................................................................................................ 6 9
6. S T U D Y I N T E R V E N TI O N .................................................................................................. 6 9
6. 1. St u d y  Inter ve nti o n(s) A d mi nistere d ........................................................................ 7 0
6. 1. 1. A d mi nistrati o n ............................................................................................ 7 0
6. 1. 1. 1. F o o d Re q uire me nts f or All C o h orts a n d S u bst u dies 
E xcl u di n g t he F o o d -effect C o h ort/ S u bst u d y ..................................... 7 1
6. 2. Pre parati o n/ Ha n dli n g/ St ora g e/ Acc o u nta bilit y ........................................................ 7 3
6. 2. 1. Pre parati o n a n d Dis pe nsi n g ........................................................................ 7 4
6. 3. Meas ures t o Mi ni mize Bias: Ra n d o mizati o n a n d Bli n di n g .....................................7 4
6. 3. 1. All ocati o n t o St u d y I nter ve nti o n ................................................................7 4
6. 4. St u d y  Inter ve nti o n C o m plia nce ............................................................................... 7 5
6. 5. C o nc o mita nt T hera p y ..............................................................................................7 6
.................................................... 7 6
............................................................................7 6
 
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 9
6. 5. 1. 2. Bi ni meti ni b ................................................................................7 7
6. 5. 2. Ot her A nti -t u m or/ A nti-ca ncer or E x peri me ntal Dr u gs ...............................7 7
6. 5. 3. S u p p orti ve Care ..........................................................................................7 8
6. 5. 4. A nti- e pile ptic Me dicati o ns .........................................................................7 8
6. 5. 5. He mat o p oietic Gr o wt h Fact ors ...................................................................7 8
6. 5. 6. A nti- Diarr heal, A nti -E metic T hera p y......................................................... 7 8
6. 5. 7. A nti- I nfla m mat or y T hera py ........................................................................7 8
6. 5. 8. C ortic oster oi ds............................................................................................ 7 8
6. 5. 9. S ur ger y ........................................................................................................7 9
6. 5. 1 0. Ra diati o n T hera p y .................................................................................... 7 9
6. 6. D ose M o dificati o n ...................................................................................................7 9
6. 6. 1. D osi n g I nterr u pti o ns ...................................................................................8 0
6. 6. 2. Resc ue Me dici ne .........................................................................................8 0
6. 6. 3. D ose Dela y s................................................................................................ 8 0
6. 6. 4. D ose Re d ucti o ns .........................................................................................8 1
6. 7. I nter ve nti o n After t he E n d of t he St u d y ..................................................................8 8
7. DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L ...........................................................................8 8
7. 1. Disc o nti n uati o n of St u d y  Inter ve nti o n ....................................................................8 8
7. 1. 1. Re q uest t o C o nti n ue St u d y  Inter ve nti o n .....................................................8 9
7. 2. Partici pa nt Disc o nti n uati o n/ Wit h dra wal Fr o m t he St u d y .......................................8 9
7. 2. 1. Wit h dra wal of C o nse nt ...............................................................................9 0
7. 3. L ost t o F oll o w - u p....................................................................................................9 1
8. S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S ...............................................................9 1
8. 1. Efficac y  Assess me nts..............................................................................................9 2
8. 1. 1. T u m or Res p o nse Assess me nts ....................................................................9 2
8. 1. 1. 1. N o n - gli o ma Pri mar y T u m ors....................................................9 2
8. 1. 1. 2. Gli o ma .......................................................................................9 3
8. 1. 2. Ma na ge me nt of I nci de ntal Fi n di n gs ...........................................................9 3
8. 2. Safet y Assess me nts .................................................................................................9 3
8. 2. 1. P h y sical E xa mi nati o ns ................................................................................9 4
8. 2. 2. Der mat ol o gical E xa mi nati o ns .................................................................... 9 4
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 0
8. 2. 3. O pt hal mic E xa mi nati o ns ............................................................................ 9 4
8. 2. 3. 1. Testi n g at Scree ni n g a n d D uri n g t he Treat me nt Peri o d............ 9 4
8. 2. 3. 2. A d diti o nal O pt hal mic Testi n g................................ ...................9 5
8. 2. 4. Ne u r ol o gic E xa mi nati o ns ...........................................................................9 5
8. 2. 5. E C O G Perf or ma nce Stat us .........................................................................9 5
8. 2. 6. Vital Si g ns a n d Wei g ht ...............................................................................9 5
8. 2. 7. Electr ocar di o gra ms..................................................................................... 9 6
8. 2. 8. Cli nical Safet y  La b orat or y Assess me nts....................................................9 7
8. 2. 9. Ec h ocar di o gra m ..........................................................................................9 8
8. 2. 1 0. Pre g na nc y  Testi n g ....................................................................................9 8
8. 2. 1 1. A d diti o nal Assess me nts f or A d olesce nt Partici pa nts ...............................9 8
8. 3. A d verse E ve nts a n d Seri o us A d verse E ve nts................................ ..........................9 9
8. 3. 1. Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A E a n d S A E I nf or mati o n.......9 9
8. 3. 1. 1. Re p orti n g S A Es t o Pfizer Safet y .............................................1 0 0
8. 3. 1. 2. Rec or di n g N o nseri o us A Es a n d S A Es o n t he C R F................. 1 0 0
8. 3. 2. Met h o d of Detecti n g A Es a n d S A Es ........................................................1 0 1
8. 3. 3. F oll o w -u p of A Es a n d S A Es .....................................................................1 0 1
8. 3. 4. Re g ulat or y Re p orti n g Re q uire me nts f or S A Es .........................................1 0 1
8. 3. 5. E x p os ure D uri n g Pre g na nc y  or Breastfee di n g, a n d Occ u pati o nal 
E x p os ure ........................................................................................................1 0 2
8. 3. 5. 1. E x p os ure D uri n g P re g na nc y....................................................1 0 2
8. 3. 5. 2. E x p os ure D uri n g Breastfee di n g ..............................................1 0 3
8. 3. 5. 3. Occ u pati o nal E x p os ure ...........................................................1 0 4
8. 3. 6. Car di o vasc ular a n d Deat h E ve nts .............................................................1 0 4
8. 3. 7. Disease -Relate d E ve nts a n d/ or Disease - Relate d O utc o me N ot 
Q ualif yi n g as A Es or S A Es ............................................................................1 0 4
8. 3. 8. A d verse E ve nts of S pecial I nterest........................................................... 1 0 4
8. 3. 8. 1. Lac k of Efficac y ......................................................................1 0 5
8. 3. 9. Me dical De vice Deficie ncies ....................................................................1 0 5
8. 3. 1 0. Me dicati o n Err ors ...................................................................................1 0 5
8. 4. Treat me nt of O ver d ose................................ ..........................................................1 0 6
8. 5. P har mac o ki netics ..................................................................................................1 0 6
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 1
8. 6. P har mac o d y na mics ................................................................................................1 0 8
8. 7. Ge netics .................................................................................................................1 0 8
8. 7. 1. B R A F Testi n g ...........................................................................................1 0 8
8. 7. 2. Arc hi ve d Tiss ue Sa m ple/ Bl o o d Sa m ple f or C D x..................................... 1 0 9
8. 7. 3. S pecifie d Ge netics ....................................................................................1 0 9
8. 7. 4. P har mac o ge netics .....................................................................................1 1 0
8. 7. 5. Ba n ke d Bi os peci me ns f or Ge netics ..........................................................1 1 0
8. 8. Bi o mar kers ............................................................................................................1 1 0
8. 8. 1. O pti o nal De N o v o T u m or Bi o psies ..........................................................1 1 0
8. 8. 2. W h ole Bl o o d, Plas ma Bi o mar kers ............................................................1 1 1
8. 9. I m m u n o ge nicit y Assess me nts ...............................................................................1 1 1
8. 1 0. Healt h Ec o n o mics ...............................................................................................1 1 1
9. S T A TI S TI C A L C O N SI D E R A TI O N S .............................................................................. 1 1 1
9. 1. Statistical H y p ot heses ...........................................................................................1 1 2
9. 2. Sa m ple Size Deter mi nati o n ...................................................................................1 1 2
9. 2. 1. P hase 1a D ose Escalati o n .........................................................................1 1 2
9. 2. 2. P hase 1 b D ose E x pa nsi o n......................................................................... 1 1 2
9. 2. 3. O pti o nal P hase 1 b D DI S u b St u d y ............................................................1 1 4
9. 2. 4. O pti o nal F o o d -effect S u bst u d y .................................................................1 1 4
9. 3. Statistical A nal y ses ...............................................................................................1 1 5
9. 3. 1. Pri mar y  E n d p oi nt(s)..................................................................................1 1 5
9. 3. 1. 1. P hase 1a: Ma xi m u m T olerate d D ose Deter mi nati o n ..............1 1 5
9. 3. 1. 2. P hase 1 b: O verall Res p o nse a n d I ntracra nial Res p o nse.......... 1 1 7
9. 3. 2. Sec o n dar y  E n d p oi nt(s)..............................................................................1 1 7
9. 3. 2. 1. Efficac y  A nalys is ....................................................................1 1 7
9. 3. 2. 2. Si n gle -D ose a n d Stea d y -State P F -0 7 2 8 4 8 9 0 a n d 
Bi ni meti ni b P har mac o ki netic A nal ys is...........................................1 1 7
9. 3. 2. 3. Si n gle -D ose Mi daz ola m P har mac o ki netic A nal y sis ...............1 1 8
9. 3. 2. 4. P har mac o d y na m ic A nalys es ...................................................1 1 9
9. 3. 3. Tertiar y / E x pl orat or y E n d p oi nt(s) .............................................................1 1 9
9. 3. 3. 1. P K -Q Tc Relati o ns hi p ..............................................................1 1 9
9. 3. 3. 2. C S F C o nce ntrati o n ..................................................................1 1 9
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 2
9. 3. 4. Ot her Safet y A nal yses ..............................................................................1 1 9
9. 3. 4. 1. Electr ocar di o gra m A nal y ses....................................................1 2 0
9. 3. 4. 2. A d verse E ve nts ........................................................................1 2 1
9. 3. 4. 3. La b orat or y  Test A b n or malities ...............................................1 2 1
9. 3. 5. Ot her A nal ys e(s) .......................................................................................1 2 1
9. 4. I nteri m A nalys es ...................................................................................................1 2 2
9. 5. Data M o nit ori n g C o m mittee or Ot her I n de pe n de nt O versi g ht C o m mittee ...........1 2 2
1 0. S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S................................ ........................................................................1 2 4
1 0. 1. A p pe n di x 1: Re g ulat or y , Et hical, a n d St u d y O versi g ht C o nsi derati o ns.............1 2 4
1 0. 1. 1. Re g ulat or y a n d Et hical C o nsi derati o ns ..................................................1 2 4
1 0. 1. 1. 1. Re p orti n g of Safet y  Iss ues a n d Seri o us Breac hes of t he 
Pr ot oc ol or I C H G C P .......................................................................1 2 4
1 0. 1. 2. Fi na ncial Discl os ure ...............................................................................1 2 5
1 0. 1. 3. I nf or me d C o nse nt/ Asse nt Pr ocess ..........................................................1 2 5
1 0. 1. 4. Data Pr otecti o n .......................................................................................1 2 7
1 0. 1. 5. Disse mi nati o n of Cli nical St u d y  Data ....................................................1 2 8
1 0. 1. 6. Data Q ualit y Ass ura nce ..........................................................................1 2 9
1 0. 1. 7. S o urce D oc u me nts ..................................................................................1 3 0
1 0 . 1. 8. St u d y a n d Site Start a n d Cl os ure ............................................................1 3 0
1 0. 1. 9. P u blicati o n P olic y................................................................................... 1 3 1
1 0. 1. 1 0. S p o ns or’s Q ualifie d Me dical Pers o n nel ...............................................1 3 2
1 0. 2. A p pe n di x 2: Cli nical La b orat or y  Tests...............................................................1 3 3
1 0. 3. A p pe n di x 3: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g ....................................................................1 3 5
1 0. 3. 1. Defi niti o n of A E .....................................................................................1 3 5
1 0. 3. 2. Defi niti o n of S A E................................................................................... 1 3 6
1 0. 3. 3. Rec or di n g/ Re p orti n g a n d F oll o w- u p of A Es a n d/ or S A Es .....................1 3 8
1 0. 3. 4. Re p orti n g of S A Es ..................................................................................1 4 1
1 0. 4. A p pe n di x 4: C o ntrace pti ve G ui da nce .................................................................1 4 2
1 0. 4. 1. Male Partici pa nt Re pr o d ucti ve I ncl usi o n Criteria.................................. 1 4 2
1 0. 4. 2. Fe male Partici pa nt Re pr o d ucti ve I ncl usi o n Criteria ...............................1 4 2
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 3
1 0. 4. 3. W o ma n of C hil d beari n g P ote ntial ..........................................................1 4 3
1 0. 4. 4. C o ntrace pti o n Met h o ds ...........................................................................1 4 4
1 0. 5. A p pe n di x 5: Ge netics................................ ..........................................................1 4 6
1 0. 6. A p pe n di x 6: L i ver Safet y: S u g geste d Acti o ns a n d F oll o w-u p Assess me nts ......1 4 7
1 0. 7. A p pe n di x 7: E C G Fi n di n gs of P ote ntial Cli nical C o ncer n .................................1 4 9
1 0. 8. A p pe n di x 8 : C o u ntr y-S pecific Re q uire me nts .....................................................1 5 1
1 0. 8. 1. Fra nce C o ntrat U ni q ue............................................................................ 1 5 1
1 0. 9. A p pe n di x 9: Detaile d D ose Escalati o n/ De- Escalati o n Sc he me f or B L R M 
Desi g n ......................................................................................................................1 5 2
1 0. 9. 1. Statistical M o dels ....................................................................................1 5 2
1 0. 9. 2. Pri or S pecificati o ns f or M o n ot hera p y B L R M................................ ........1 5 2
1 0. 9. 3. Pri or S pecificati o ns f or C o m bi nati o n B L R M .........................................1 5 3
1 0. 1 0. A p pe n di x 1 0: A nti -e pile ptic Me dicati o n ...........................................................1 5 6
1 0. 1 1. A p pe n di x 1 1: Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) 
versi o n 1. 1 ................................ ...............................................................................1 5 7
1 0. 1 2. A p pe n di x 1 2: M o difie d Res p o nse E val uati o n Criteria i n S oli d T u m ors 
( m R E CIS T) versi o n 1. 1................................ ...........................................................1 6 2
1 0. 1 3. A p pe n di x 1 3: Res p o nse Assess me nt i n Ne ur o -O nc ol o g y  ( R A N O)..................1 6 9
1 0. 1 4. A p pe n di x 1 4: E C O G Classificati o n of Perf or ma nce Stat us ..............................1 7 3
1 0. 1 5. A p pe n di x 1 5: A Dr u g- Dr u g I nteracti o n S u bst u d y ............................................1 7 4
1 0. 1 5. 1. Rati o nale f or E val uati o n of Mi daz ola m P K I nteracti o n....................... 1 7 4
1 0. 1 5. 2. St u d y  Desi g n.........................................................................................1 7 4
1 0. 1 5. 3. Rati o nale f or t he Desi g n .......................................................................1 7 4
1 0. 1 5. 4. Partici pa nt P o p ulati o n ...........................................................................1 7 4
1 0. 1 5. 5. Treat me nt A d mi nistrati o n .....................................................................1 7 5
1 0. 1 5. 6. A d diti o nal C o nc o mita nt Me dicati o ns Pr o hi bite d T hr o u g h t he E n d 
of C y cle 1................................ .......................................................................1 7 5
1 0. 1 5. 7. A d diti o nal P K A ssess me nt ...................................................................1 7 6
1 0. 1 5. 8. Safet y Assess me nts ...............................................................................1 7 6
1 0. 1 5. 9. Sa m ple Size ..........................................................................................1 7 7
1 0. 1 5. 1 0. P K Data A nal ysis ................................................................................1 7 7
1 0. 1 5. 1 1. Sc he d ule of Acti vities f or t he D DI S u b St u d y .....................................1 7 8
1 0. 1 6. A p pe n di x 1 6: A F o o d -effect S u b St u d y .............................................................1 8 5
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 4
1 0. 1 6. 1. Rati o nal f or E val uati o n of F o o d Effect ................................................1 8 5
1 0. 1 6. 2. St u d y  Desi g n.........................................................................................1 8 5
1 0. 1 6. 3. Partici pa nt P o p ulati o n ...........................................................................1 8 6
1 0. 1 6. 4. A d diti o nal P K Assess me nts.................................................................. 1 8 6
1 0. 1 6. 5. Safet y Assess me nts ...............................................................................1 8 6
1 0. 1 6. 6. A d diti o nal P K Assess me nts.................................................................. 1 8 7
1 0. 1 6. 7. Statistical A nal yses............................................................................... 1 8 7
1 0. 1 6. 8. Tra nsiti o n t o Fe d State A d mi nistrati o n .................................................1 8 7
1 0. 1 7. A p pe n di x 1 7: Pr o hi bite d C o nc o mita nt Me dicati o ns T hat Ma y  Res ult i n 
D DI ..........................................................................................................................1 8 9
1 0. 1 8. A p pe n di x 1 8: Str o n g C Y P 3 A I n hi bit ors a n d I n d ucers ......................................1 9 1
1 0. 1 9. A p pe n di x 1 9: Alter nati ve Meas ures D uri n g P u blic E mer ge ncies .....................1 9 2
1 0. 1 9. 1. Eli gi bilit y ..............................................................................................1 9 2
1 0. 1 9. 2. Tele heat h Visits ....................................................................................1 9 2
1 0. 1 9. 3. Alter nati ve Facilities f or Safet y Assess me nts ......................................1 9 3
1 0. 1 9. 3. 1. La b orat or y  Testi n g..............................................................1 9 3
1 0. 1 9. 3. 2. I ma gi n g ................................................................................1 9 3
1 0. 1 9. 3. 3. Electr ocar di o gra ms................................ ..............................1 9 3
1 0. 1 9. 4. O pt hal mic E xa ms .................................................................................. 1 9 3
1 0. 1 9. 5. St u d y  Inter ve nti o n ................................................................................1 9 3
1 0. 1 9. 6. H o me Healt h Visits ...............................................................................1 9 4
1 0. 1 9. 7. A d verse E ve nts a n d Seri o us A d verse E ve nts....................................... 1 9 5
1 0. 1 9. 8. Efficac y  Assess me nts ...........................................................................1 9 5
1 0. 2 0. A p pe n di x 2 0: Pr ot oc ol A me n d me nt S u m mar y  of C ha n ges Ta ble....................1 9 6
1 0. 2 1. A p pe n di x 2 1: A b bre viati o ns .............................................................................2 0 0
1 0. 2 2. A p pe n di x 2 2: Ta n ner Sta gi n g ................................ ...........................................2 0 7
1 1. R E F E R E N C E S ................................................................................................................2 0 9
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 5
LI S T O F T A B L E S
Ta ble 1.
Pre vale nce of B R A F V 6 0 0 M utati o ns i n Differe nt T u m or T y pes ...........3 6
Ta ble 2.
E xa m ple D ose L e vels f or P F- 0 7 2 8 4 8 9 0................................................... 5 6
Ta ble 3.
A vaila ble D ose Le vels ( P F -0 7 2 8 4 8 9 0 M o n ot hera p y )..............................8 1
Ta ble 4.
A vaila ble D ose Le vels ( P F -0 7 2 8 4 8 9 0 Pl us Bi ni meti ni b 
C o m bi nati o n T hera p y ).............................................................................. 8 2
Ta ble 5.
Rec o m me n de d D ose M o dificati o ns f or P F -0 7 2 8 4 8 9 0 -relate da
A d verse E ve nts .........................................................................................8 3
Ta ble 6. 
Rec o m me n de d D ose M o dificati o ns f or Bi ni meti ni b- relate da
A d verse E ve nts .........................................................................................8 6
Ta ble 7.
Safet y  La b orat or y Tests..........................................................................1 3 3
Ta ble 8.
Mec ha nis m of Eli mi nati o n of A nti- E pile ptic A ge nts a n d P ote ntial 
f or P F-0 7 2 8 4 8 9 0 t o Alter T heir P K a 3 7, 5 0, 5 1 .............................................1 5 6
Ta ble 9. 
Res p o nse E val uati o n Criteria i n S oli d T u m ors ......................................1 6 1
Ta ble 1 0. 
E val uati o n of Brai n Lesi o n Res p o nse................................ .....................1 6 4
Ta ble 1 1.
E val uati o n of E xtracra nial Lesi o n Res p o nse.......................................... 1 6 6
Ta ble 1 2.
E val uati o n of O verall Res p o nse ( m R E CI S T) .........................................1 6 8
Ta ble 1 3.
O verall Res p o nse Criteria ( R A N O H G G) ..............................................1 7 0
Ta ble 1 4.
O verall Res p o nse Criteria ( R A N O L G G) ...............................................1 7 2
Ta ble 1 5.
P har mac o ki netic, E C G a n d Selecte d Bi o mar ker Sa m pli n g f or 
F o o d -effect S u bst u d y ..............................................................................1 8 8
Ta ble 1 6.
Pr o hi bite d C o nc o mita nt Me dicati o ns t hat Ma y  Res ult i n D DI ..............1 8 9
LI S T O F FI G U R E S
Fi g ure 1.
St u d y  Sc he ma f or P hase 1a D ose Escalati o n ( A p pr o xi matel y 
3 5 Partici pa nts) .........................................................................................2 2
Fi g ure 2.
St u d y  Sc he ma f or P hase 1 b D ose E x pa nsi o n wit h O pti o nal F o o d-
Effect a n d D DI S u bst u d y ( A p pr o xi matel y  2 0 Partici pa nts Per 
C o h ort f or C o h orts 1- 4, 4 0 Pa rtici pa nts f or C o h ort 5 a n d 1 0 
Partici pa nts f or O pti o nal C o h ort 6 a n d 6 -8 Partici pa nts f or 
C o h ort 7)................................ ...................................................................2 3
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 6
1. P R O T O C O L S U M M A R Y 
1. 1. S y n o psis 
S h ort Title: A P hase 1 a/ b St u d y  of P F-0 7 2 8 4 8 9 0 i n Partici pa nts Wit h B R A F V 6 0 0 -M uta nt 
S oli d T u m ors Wit h a n d Wit h o ut Brai n I n v ol ve me nt
R ati o n ale : T he p ur p ose of t his first -i n-h u ma n st u d y  is t o assess t he P K, safet y a n d 
preli mi nar y  cli nical acti vit y of P F -0 7 2 8 4 8 9 0 (als o k n o w n as A R R Y- 4 6 1) as a si n gle a ge nt 
a n d i n c o m bi nati o n wit h t he M E K i n hi bit or, M E K T O VI ( bi ni meti ni b), i n partici pa nts wit h 
B R A F V 6 0 0 - m utate d a d va nce d s oli d t u m or mali g na ncies wit h a n d wit h o ut brai n 
i n v ol ve me nt.
O bjecti ves a n d E n d p oi nts
O bjecti ves
E n d p oi nts
P h ase 1 a Pri m ar y: 
P h ase 1 a Pri m ar y:

T o assess t he safet y a n d t olera bilit y of P F -0 7 2 8 4 8 9 0 at 
i ncreasi n g d ose le vels, t o esti mate t he M T D, a n d t o 
select t he rec o m me n de d d ose f or f urt her st u d y, as b ot h
a si n gle a ge nt a n d i n c o m bi nati o n wit h bi ni meti ni b, i n 
partici p a nts wit h B R A F V 6 0 0 - m utate d a d va nce d s oli d 
t u m or mali g na ncies wit h a n d wit h o ut brai n 
i n v ol ve me nt.

I nci de nce of C ycle 1 D L Ts.

M T D/rec o m me n de d d ose f or f urt her st u d y .

A Es as c haracterize d b y t y pe, fre q ue nc y, se verit y (as 
gra de d b y N CI C T C A E versi o n 5. 0), t i mi n g, 
seri o us ness, a n d relati o ns hi p t o st u d y t hera p y.

La b orat or y a b n or malities as c haracterize d b y t y pe, 
fre q ue nc y, se verit y (as gra de d b y N CI C T C A E 
versi o n 5. 0), a n d ti mi n g .

I nci de nce of d ose i nterr u pti o ns, d ose m o dificati o ns 
a n d disc o nti n uati o ns d ue t o A Es .
P h ase 1 a Sec o n d ar y: 
P h ase 1 a Sec o n d ar y:

T o c haracterize t he si n gle- a n d m ulti ple -d ose P K of 
P F - 0 7 2 8 4 8 9 0 as a si n gle a ge nt a n d i n c o m bi nati o n 
wit h bi ni meti ni b a n d of bi ni meti ni b i n c o m bi nati o n 
wit h P F -0 7 2 8 4 8 9 0 .

P K para meters of P F -0 7 2 8 4 8 9 0 a n d bi ni meti ni b: 

Si n gle d ose: C ma x , Tma x , A U Clast, a n d as data per mit, 
t½ , A U Ci nf, C L/ F a n d Vz/ F.

M ulti ple d ose (ass u mi n g stea d y state is ac hie ve d): 
C ss, ma x, Tss, ma x, A U Css,τ, Css, mi n, a n d as data per mit, 
C L ss/ F, Vss/ F, t½ a n d R ac ( A U Css,τ/ AU C s d,τ).

T o e val uate preli mi nar y cli nical acti vit y of 
P F - 0 7 2 8 4 8 9 0 as a si n gle a ge nt a n d i n c o m bi nati o n 
wit h bi ni meti ni b .

E xtracra nial res p o nse b y R E CI S T versi o n 1. 1 .

I ntracra nial res p o nse b y m R E CI S T versi o n 1. 1.

O verall res p o nse (c o m bi ne d e xtracra nial a n d 
i ntracra nial) b y m R E CI S T versi o n 1. 1 .

R A N O f or pri mar y brai n t u m ors .
P h ase 1 a Terti ar y/ E x pl or at or y:
P h ase 1 a Terti ar y/ E x pl or at or y:

T o e x pl ore t he effect of 
 o n 
P F -0 7 2 8 4 8 9 0 e x p os ures i n partici pa nts treate d wit h 
P F - 0 7 2 8 4 8 9 0 as a si n gle a ge nt a n d i n c o m bi nati o n 
wit h bi ni meti ni b .

P F - 0 7 2 8 4 8 9 0 P K para meters (si n gle d ose Cma x a n d 
A U C last; m ulti ple d ose Css, ma x, A U Css,τ) i n 
partici pa nts 
.

T o e x pl ore t he brai n pe netrati o n of P F -0 7 2 8 4 8 9 0 as a 
si n gle a ge nt a n d i n c o m bi nati o n wit h bi ni meti ni b.

C S F c o nce ntrati o ns of P F -0 7 2 8 4 8 9 0 (i n partici pa nts 
i n w h o m C S F is o btai ne d as S O C).

T o e val uate t u m or a n d bl o o d- base d bi o mar kers of 
res p o nse a n d resista nce t o P F- 0 7 2 8 4 8 9 0 as a si n gle 
a ge nt a n d i n c o m bi nati o n wit h bi ni meti ni b .
 
C CI
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 7
O bjecti ves
E n d p oi nts

T o assess t he relati o ns hi p bet wee n P F- 0 7 2 8 4 8 9 0 
c o nce ntrati o ns a n d cha n ges i n Q Tc F .

Ma xi mal c ha n ges i n Q Tc F esti mate d usi n g a li near 
mi xe d effect m o del.
P h ase 1 b Pri m ar y :
P h ase 1 b Pri m ar y:

T o e val uate a nti -t u m or efficac y of P F-0 7 2 8 4 8 9 0 at t he 
rec o m me n de d d ose f or f urt her st u d y i n c o m bi nati o n 
wit h bi ni meti ni b i n partici pa nts wit h B R A F 
V 6 0 0 m utate d a d va nce d s oli d t u m or mali g na ncies wit h 
a n d wit h o ut brai n i n v ol ve me nt .

E xtracra nial res p o nse b y R E CI S T versi o n 1. 1 .

I ntracra nial res p o nse b y m R E CI S T versi o n 1. 1.

O verall res p o nse (c o m bi ne d e xtracra nial a n d 
i ntracra nial) b y m R E CI S T versi o n 1. 1 .

R A N O f or pri mar y brai n t u m ors .
P h ase 1 b Sec o n d ar y:
P h ase 1 b Sec o n d ar y:

T o c o nfir m t he safet y a n d t olera bilit y of P F - 0 7 2 8 4 8 9 0 
at t he rec o m me n de d d ose f or f urt her st u d y i n 
c o m bi nati o n wit h bi ni meti ni b.

A Es as c haracterize d b y t y pe, fre q ue nc y, se verit y (as 
gra de d b y N CI C T C A E versi o n 5. 0), ti mi n g, 
seri o us ness, a n d relati o ns hi p t o st u d y t hera p y.

La b orat or y a b n or malities as c haracterize d b y t y pe, 
fre q ue nc y, se verit y (as gra de d b y N CI C T C A E 
versi o n 5. 0), a n d ti mi n g.

I nci de nce of d ose i nterr u pti o ns, d ose m o dificati o ns 
a n d disc o nti n uati o ns d ue t o A Es.

T o e val uate si n gle - a n d m ulti ple -d ose P K pr ofiles of 
P F - 0 7 2 8 4 8 9 0 at t he rec o m me n de d d ose f or f urt her 
st u d y i n c o m bi nati o n wit h bi ni meti ni b a n d of 
bi ni meti ni b i n c o m bi nati o n wit h P F- 0 7 2 8 4 8 9 0 .
P K para meters of P F -0 7 2 8 4 8 9 0 a n d bi ni meti ni b: 

Si n gle d ose - Cma x , Tma x , A U Clast, a n d as data per mit, 
t½ , A U Ci nf, C L/ F a n d Vz/ F.

M ulti ple d ose (ass u mi n g stea d y state is ac hie ve d) -
C ss, ma x, Tss, ma x, A U Css,τ, Css, mi n, a n d as data per mit, 
C L ss/ F, Vss/ F, t½ a n d R ac ( A U Css,τ/ A U Cs d,τ).

T o assess a d diti o nal meas ures of a nti -t u m or efficac y 
of P F - 0 7 2 8 4 8 9 0 at t he rec o m me n de d d ose f or f urt her 
st u d y i n c o m bi nati o n wit h bi ni meti ni b.

D C R ( o verall a n d i ntracra nial) .

P F S ( o verall a n d i ntracra nial), O S, D o R ( o v erall a n d 
i ntracra nial) a n d T T R ( o verall a n d i ntracra nial).
P h ase 1 b Terti ar y/ E x pl or at or y:
P h ase 1 b Terti ar y/ E x pl or at or y:

T o e x pl ore t he effect of 
 o n 
P F -0 7 2 8 4 8 9 0 e x p os ures i n partici pa nts treate d wit h 
P F - 0 7 2 8 4 8 9 0 i n c o m bi nati o n wit h bi ni meti ni b .

T o e x pl ore t he brai n pe netrati o n of P F - 0 7 2 8 4 8 9 0 i n 
c o m bi nati o n wit h bi ni meti ni b.

C S F c o nce ntrati o ns of P F 0 7 2 8 4 8 9 0 (i n partici pa nts 
i n w h o m C S F is o btai ne d as S O C).

T o e val uate t u m or a n d bl o o d- base d bi o mar kers of 
res p o nse a n d resista nce t o P F- 0 7 2 8 4 8 9 0 i n 
c o m bi nati o n wit h bi ni meti ni b.

T o e val uate t he effect of re peate d a d mi nistrati o n of 
P F -0 7 2 8 4 8 9 0 i n c o m bi nati o n wit h bi ni meti ni b o n 
si n gle d ose P K of mi daz ola m ( C o h ort 6 o nl y).
P K para meters of C Y P 3 A 4 pr o be s u bstrate mi daz ola m: 

C ma x, Tma x , A U Clast, a n d as data per mit, t½ , A U Ci nf, 
C L/ F a n d V z/ F.
O ver all Desi g n
T his is a P hase 1 a/ b, o pe n-la bel, m ultice nter, d ose -fi n di n g st u d y of t he safet y, P K a n d 
preli mi nar y  cli nical acti vit y of P F -0 7 2 8 4 8 9 0 i n a d ult or a d olesce nt partici pa nts wit h selecte d 
B R A F V 6 0 0 -m uta nt a d va nce d or metastatic s oli d t u m or mali g na ncies a n d pri mar y  brai n 
t u m ors.  T he st u d y will be c o n d ucte d i n 2 parts, ie , P hase 1a ( D ose Escalati o n) a n d P hase 1 b
( D ose E x pa nsi o n , a n o pti o nal D DI su b st u d y, a n d o pti o nal f o o d-effect s u bst u d y). 
 
C CI
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 8
Partici pa nts will ha ve e x perie nce d disease pr o gressi o n after pri or treat me nt a n d ha ve n o 
acce pta ble alter nati ve treat me nt o pti o ns. 
Partici pa nts m ust pr o vi de d oc u me nte d e vi de nce of a B R A F V 6 0 0 m utati o n i n t u m or tiss ue or 
bl o o d (ie,  
) as pre vi o usl y  deter mi ne d by P C R or N G S -base d la b orat or y  assa y i n a 
C L I A or si milarl y certifie d la b orat or y at a n y ti me pri or t o Scree ni n g.  L ocal testi n g is 
per mitte d ( see Secti o n 4. 2. 4 ).  Partici pa nts are re q uire d t o s u b mit eit her arc hi val or ne wly 
c ollecte d tiss ue sa m ple (t he latter if a bi o psy is safe t o perf or m ; if n ot, participa nts ma y  be 
eli gi ble as l o n g as t he y meet ot her eli gi bilit y criteria) a n d a bl o o d sa m ple pri or t o e nr oll me nt, 
w hic h ma y  be use d f or retr os pecti ve a nal ysis of B R A F V 6 0 0 m utati o n stat us b ut n ot t o 
deter mi ne eli gi bilit y /e nr oll me nt.
E nr olle d partici pa nts ma y be wit h or wit h o ut brai n i n v ol ve me nt at baseli ne, wit h t he all o we d 
e xte nt of a n d s ym pt o ms fr o m i ntracra nial disease deter mi ne d b y  t he de gree of calc ulate d 
B R A F V 6 0 0 E tar get c o vera ge d uri n g d ose escalati o n, a n d t he s pecific c o h ort d uri n g d ose 
e x pa nsi o n (see Secti o n 5 ).
P hase 1a D ose Escalati o n
A p pr o xi matel y  3 5 partici pa nts will be e nr olle d t o deter mi ne t he M T D a n d/ or rec o m me n de d 
d ose f or f urt her st u d y of P F - 0 7 2 8 4 8 9 0 al o ne a n d i n c o m bi nati o n wit h bi ni meti ni b 4 5 m g 
BI D.
M o n ot hera p y  d ose escalati o n will i nitiate first.
A partici pa nt is classifie d as D L T e val ua ble if he/s he e x perie nces a D L T (S ecti o n 4. 3. 3) or if 
he/s he ot her wise i n t he a bse nce of a D L T recei ves at least 7 5 % of t h e pla n ne d P F -0 7 2 8 4 8 9 0
d oses (a n d at least 7 5 % of t he pla n ne d bi ni meti ni b d oses if t he partici pa nt is recei vi n g 
c o m bi nati o n treat me nt) a n d has recei ve d all sc he d ule d safet y assess me nts d uri n g t he D L T 
o bser vati o n wi n d o w (first c ycle of treat me nt , a 2 1- d a y c y cle).
A B L R M will be use d t o m o del t he D L T relati o ns hi p of P F - 0 7 2 8 4 8 9 0.  T his m o del, al o n g 
wit h t he E W O C, will g ui de t he d ose escalati o n of P F - 0 7 2 8 4 8 9 0 after t he c o m pleti o n of t he 
D L T o bser vati o n peri o d of eac h c o h ort, u ntil a de q uate D L T data has acc u m ula te d t hr o u g h o ut 
t he m o n ot hera py d ose escalati o n t o i nf or m t he n c o m bi nati o n B L R M or u ntil t he 
deter mi nati o n of M T D/rec o m me n de d d ose f or P F -0 7 2 8 4 8 9 0 m o n ot hera p y.  
C o h orts of 2 - 4 e val ua ble partici pa nts will be treate d at eac h d ose le vel of P F -0 7 2 8 4 8 9 0 o n a n 
o ut patie nt basis starti n g fr o m 5 0 m g Q D u ntil t he deter mi nati o n of M T D/rec o m me n de d d ose 
f or f urt her st u d y. A mi ni m u m of 6 partici pa nts are e x pecte d t o be treate d at 
M T D/rec o m me n de d d ose f or f urt her st u d y (ie, 6 partici pa nts eac h f or b ot h m o n ot hera p y a n d 
c om bi nati o n t hera p y) i n or der t o e val uate safety, t olera bilit y , P K as well as preli mi nar y 
acti vit y of P F - 0 7 2 8 4 8 9 0 w he n gi ve n at t he M T D/rec o m me n de d d ose f or f urt her st u d y ( b ot h 
al o ne a n d i n c o m bi nati o n wit h bi ni meti ni b) . T he act ual d ose i ncreases bet wee n d ose le vels 
will be deter mi ne d b y safet y a n d o bser ve d P K as descri be d i n Secti o n 4. 3. 2 . I n a d diti o n, a n 
alter nati ve sc he d ule (e g, B I D, d osi n g h oli da y) ma y be e val uate d de pe n di n g o n safety a n d 
o bser ve d P K.
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 9
B L R M a n d E W O C will be use d t o m o del t he D L T relati o ns hi p of P F -0 7 2 8 4 8 9 0 i n 
c o m bi nati o n wit h bi ni meti ni b at t he a p pr o ve d d ose of 4 5 m g  BI D ( m o n ot hera py d ose 
escalati o n will c o nti n ue s i m ulta ne o usl y). Base d o n preli mi nar y  P K a n d safet y, t he 
c o m bi nati o n d ose escalati o n p hase of P F -0 7 2 8 4 8 9 0 wit h bi ni meti ni b ma y  be starte d pri or t o 
t he deter mi nati o n of t he m o n ot hera py P F -0 7 2 8 4 8 9 0 M T D/rec o m me n de d d ose f or f urt her 
st u d y. T he starti n g d ose le vel f or P F - 0 7 2 8 4 8 9 0 i n t he c o m bi nati o n d ose t hera py escalati o n
will n ot be hi g her t ha n pre vi o usl y  st u die d d oses i n t he m o n ot hera p y escalati o n a n d will 
satisf y E W O C criteria. T he para meters will be deri ve d fr o m t he c o m bi nati o n B L R M b y  
inc or p orati n g D L T data o btai ne d fr o m t he P F -0 7 2 8 4 8 9 0 m o n ot hera p y  escalati o n a n d 
hist orical data f or bi ni meti ni b (see Secti o n 9. 3. 1. 1 ). 
F or b ot h m o n ot hera p y a n d c o m bi nati o n t hera p y d ose escalati o ns, t o xicities will o nl y  be 
c o nsi dere d D L Ts if t he y  occ ur wit hi n t he D L T wi n d o w of t he first c ycle ( 2 1 da ys).
H o we ver , o verall safety, i ncl u di n g later c y cles, a n d P K data will be e val uate d f or t he 
rec o m me n de d d ose f or f urt her st u d y deter mi nati o n.
P hase 1 b D ose E x pa nsi o n , o pti o nal D DI S u b st u d y, a n d o pti o nal F o o d-Effect S u bst u d y
After i de ntificati o n of t he c o m bi nati o n M T D/rec o m me n de d d ose f or f urt her st u d y , 
a p pr o xi matel y 2 0 partici pa nts will be e nr olle d t o eac h of t he C o h orts 1- 4 a n d 4 0 partici pa nts
t o C o h ort 5 of P hase 1 b d ose e x pa nsi o n base d o n t u m or t ype, w het her brai n i n v ol ve me nt is 
as ym pt o matic or s y m pt o matic a n d meas ura ble or n o n -meas ura ble, pri or treat me nt hist or y  
a n d a hist or y of or c urrent le pt o me ni n geal metastases. T he partici pa nts i nte n de d f or eac h 
c o h ort are descri be d i n Secti o n 1. 2 a n d Secti o n 5 .  T he d ose e x pa nsi o n p hase ( C o h orts 1- 5) 
will e val uate efficac y , safet y a n d P K at t he rec o m me n de d d ose f or f urt her st u d y i n 
c o m bi nati o n wit h bi ni meti ni b .
T he effect of f o o d (l o w fat a n d hi g h fat meal vers us faste d state) o n P F -0 7 2 8 4 8 9 0 P K is 
bei n g assesse d i n st u d y C 4 4 7 1 0 0 2 i n healt h y  partici p a nts.  O nce t he res ults of t h is
f o o d-effect st u d y are a vaila ble, it ma y tri g ger t he o pe ni n g of a n o pti o nal C o h ort 7 a n d/ or t he 
i nstr ucti o ns f or a d mi nistrati o n of C 4 4 7 1 0 0 1 ma y  be c ha n ge d as a p pr o priate s o t hat patie nts 
ca n ta ke P F-0 7 2 8 4 8 9 0 wit h o ut re gar d t o f o o d at t he M T D/ R D E , or s h o ul d ta ke P F- 0 7 2 8 4 8 9 0 
i n t he fe d state, wit h a dj ust me nt of d ose base d o n C 4 4 7 1 0 0 2 data (ie, t he d ose e q ui vale nt t o 
t he faste d state M T D/ R D E a dj uste d base d o n t he differe nce i n e x p os ure o bser ve d i n 
C 4 4 7 1 0 0 2 i n t he faste d state c o m pare d t o t he fe d state). H o we ver, i f t he effect of f o o d is 
f o u n d t o be s u bsta ntial, p ositi ve a n d cli nicall y si g nifica nt (ie, ≥2-f ol d i ncrease i n A U C f or 
eit her t he l o w-fat or hi g h-fat meal), a n a d diti o nal c o h ort of patie nts will be e nr olle d i n t he 
c urre nt st u d y bef ore c ha n gi n g a d mi nistrati o n i nstr ucti o ns f or t he c urre nt st u d y. T his c o h ort
( o pti o nal C o h ort 7) of a p pr o xi matel y  6- 8 patie nts will be e nr olle d t o assess t he safety a n d P K 
of a rec o m me n de d d ose f or f urt her st u d y (ie, t he d ose e q ui vale nt t o t he faste d state 
M T D/ R D E a dj uste d base d o bser ve d o n C 4 4 7 1 0 0 2 P K ) t o be gi ve n wit h f o o d.  If t he 
rec o m me n de d d ose i n c o m bi nati o n wit h f o o d is t olerate d, patie nts accr ue d i nt o C o h orts 1 - 6
will recei ve i nstr ucti o n t o a d mi nister dr u g wit h f o o d.  T o miti gate b ur de n t o patie nts, 
c ha n ge(s) i n d ose a n d d osi n g i nstr ucti o ns re gar di n g a d mi nistrati o n wit h f o o d ma y  i nitiall y be 
c o m m u nicate d b y P A C L f oll o we d b y s u bse q ue nt pr ot oc ol a me n d me nt .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 0
I n a d diti o n, a p pr o xi matel y 1 0 partici pa nts m a y be e nr olle d t o a n o pti o nal s u bst u d y ( C o h ort 6) 
t o e val uate t he effect of P F - 0 7 2 8 4 8 9 0 i n c o m bi nati o n wit h bi ni meti ni b o n C Y P 3 A acti vit y
usi n g mi daz ola m as a pr o be C Y P 3 A 4 s u bstrate.  
Treat me nt wit h st u d y  i nter ve nti o n will c o nti n ue u ntil eit her disease pr o gressi o n, partici pa nt 
ref usal, u naccepta ble t o xicit y  occ urs, or u p t o 2 ye ars, w hic he ver occ urs first.   Partici pa nts 
w h o ha ve disease pr o gressi o n b ut are deri vi n g cli nical be nefit m a y  c o nti n ue if criteria are 
met a n d t he partici pa nt c o nse nts /asse nts t o c o nti n ue treat me nt (see Secti o n 7. 1. 1 ).  
Partici pa nts w h o c o m plete 2 ye ars o n st u d y i nter ve nti o n a n d de m o nstrate cli nical be nefit 
wit h ma na gea ble t o xicit y a n d are willi n g t o c o nti n ue recei vi n g t he st u d y  i nter ve nti o n will be 
gi ve n t he o p p ort u nit y  t o c o nti n ue treat me nt u p o n a gree me nt bet wee n i n vesti gat or a n d 
s p o ns or, usi n g t he sa me safet y assess me nts as were bei n g perf or me d m ost rece ntly, b ut wit h 
efficac y m o nit ore d at i nter vals c o nsiste nt wit h cli nical practice.
N u m ber of P artici p a nts
A n ex pecte d n u m ber of a p pr o xi matel y 1 2 0- 1 3 8 partici pa nts will be e nr olle d t o st u d y 
i nter ve nti o n. Refer t o Secti o n 9. 2 f or sa m ple size deter mi nati o n.
N ote: “E nr olle d ” mea ns a partici pa nt ’s, or his or her le gally a ut h orize d re prese ntati ve’s, 
a gree me nt t o partici pate i n a cli nical st u d y  f oll o wi n g c o m pleti o n of t he i nf or me d 
c o nse nt /asse nt pr ocess. P ote ntial partici pa nts w h o are scree ne d f or t he p ur p ose of 
deter mi ni n g eli gi bilit y  f or t he st u d y, b ut d o n ot partici pate i n t he stu d y , are n ot c o nsi dere d 
e nr olle d, u nless ot her wise s pecifie d b y t he pr ot oc ol.
I nter ve nti o n Gr o u ps a n d D ur ati o n
T he t otal d urati o n of t he st u d y  fr o m t he be gi n ni n g of scree ni n g t o t he safet y f oll o w- u p visit is 
a p pr o xi matel y 2 years.
D ose Le vel Re vie w Meeti n g
T his st u d y  will utilize a D L R M f or d ose escalati o n decisi o ns (see Secti o n 9. 5 ).  The me m bers 
of t he D L R M i ncl u des a mi x of i nter nal Pfizer st u d y  tea m me m bers a n d e xter nal 
i n vesti gat ors a n d/ or me dicall y q ualifie d desi g nee .  
St atistic al Met h o ds
A da pti ve B a y esia n a p pr oac h: T he d ose escalati o n i n t he P hase 1a of t he st u d y  will be g ui de d 
b y  a B L R M a nal ysis of t he first 21 d a y s ( Cycle 1) of D L T data f or P F -0 7 2 8 4 8 9 0. T o xicit y  is 
m o delle d usi n g a l o gistic re gressi o n f or t he pr o ba bilit y of a partici pa nt e x perienci n g a D L T at 
t he gi ve n d ose. A si milar a p pr oac h will be use d t o g ui de t he c o m bi nati o n d ose escalati o n f or 
t he P F-0 7 2 8 4 8 9 0 wit h bi ni meti ni b.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 1
Assess me nt of partici pa nt ris k: After eac h c o h ort of partici pa nts, t he p osteri or distri b uti o n f or 
t he ris k of D L T f or ne w partici pa nts at differe nt d oses of i nterest f or P F-0 7 2 8 4 8 9 0 will be 
e val uate d.  T he p osteri or distri b uti o ns will be s u m marize d t o pr o vi de t he p osteri or 
pr o ba bilit y  t hat t he ris k of D L T lies wit hi n t he f oll o wi n g i nter vals:
U n der -d osi n g:
[ 0, 0. 1 6]
Tar get d osi n g:
[ 0. 1 6, 0. 3 3]
O ver d osi n g:
[ 0. 3 3, 1]
T he E W O C pri nci ple: D osi n g decisi o ns are g ui de d b y  t he E W O C pri nci pal. A d ose ma y  
o nl y  be use d f or ne wly e nr olle d partici pa nts if t he ris k of o ver -d osi n g at t hat d ose is less 
t ha n 2 5 %.
Pri or distri b uti o n s: M A P pri or distri b uti o n base d o n cli nical/e x pert o pi ni o n i nf or mati o n will 
be c h ose n f or t he l o gistic para meters.
F or P hase 1 b , t he e x pa nsi o n ar ms will be c o n d ucte d t o assess efficac y as well as safety a n d 
t olera bilit y of P F-0 7 2 8 4 8 9 0 i n c o m bi nati o n t hera p y wit h bi ni meti ni b.
I n P hase 1 b, t he pri mar y e n d p oi nt of o verall res p o nse b y R E CI S T versi o n 1. 1 a n d 
i ntracra nial res p o nse by m R E CI S T versi o n 1. 1 ( R A N O f or pri mar y  brai n t u m ors) will be 
s u m marize d a n d liste d b y e x pa nsi o n c o h ort a n d disease ty pe. T he sec o n d ar y e n d p oi nts of 
D C R ( o verall a n d i ntracra nial), P F S ( o verall a n d i ntrcra nial), O S, D o R ( o verall a n d 
i ntracra nial) a n d T T R ( o verall a n d i ntracra nial) will be s u m marize d ( gra p hicall y w here 
a p pr o priate) a n d liste d b y e x pa nsi o n c o h ort a n d disease ty pe.
A Es wi ll be gra de d by t he i n vesti gat or acc or di n g t o t he N CI  C T C A E versi o n 5. 0 a n d c o de d 
usi n g t he Me d D R A . T he n u m ber a n d perce nta ge of partici pa nts w h o e x perie nce d a n y  A E, 
S A E, treat me nt-relate d A E, a n d treatme nt -relate d S A E will be s u m marize d acc or di n g t o 
w ors t t o xicit y gra des.  T he s u m maries will prese nt Aes b ot h o n t he e ntire st u d y peri o d a n d b y 
c ycle ( Cycl e 1 a n d be y o n d) .
1. 2. Sc he m a
A dia gra m of t he st u d y desi g n is dis pla y e d i n Fi g ure 1 a n d Fi g ure 2 .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 2
Fi g ure 1 .
St u d y Sc he m a f or P h ase 1 a D ose Esc al ati o n ( A p pr o xi m atel y 3 5 P a rtici p a nts)
a.
O nce t he tr o u g h c o nce ntrati o n of P F -0 7 2 8 4 8 9 0 at stea d y state is ≥0. 1 6 8 µ g/ m L (e q ual t o t he f u -a dj uste d 
I C7 0 f or i n hi biti o n of B R A F V 6 0 0 E) i n at least t wo- t hir ds of partici pa nts at t he sa me d ose le vel (a le vel at 
w hic h a nti- t u m or acti vit y i n t he brai n a n d s yste micall y ma y be e x pecte d), s u bse q ue nt partici pa nts e nteri n g 
t he st u d y d uri n g d ose escalati o n ma y ha ve a lesi o n(s) > 4 c m a n d/ or be s y m pt o matic i n t he brai n as defi ne d 
i n Secti o n 5. 1 .
b.
I ntra patie nt d ose escalati o n a n d/ or a d diti o n of bi ni meti ni b ma y be all o we d after 1 2 wee ks of m o n ot hera p y 
or disease pr o gressi o n. See Secti o n 4. 3. 2. 3 .
c.
If n o D L Ts at t he c urre nt a n d all pri or d ose le vels, a n d if t he o bser ve d tr o u g h c o nce ntrati o n at stea d y state 
wit h t he c urre nt d ose is < t he calc ulate d I C5 0 of P F -0 7 2 8 4 8 9 0 i n at least t w o-t hir ds of partici pa nts, t he ne xt 
d ose w ill n ot e xcee d 3 × t he c urre nt d ose le vel.  See Secti o n 4. 3. 2 .
B R A F V 6 0 0 -m ut a nt u nresect a ble/ met ast atic s oli d t u m or pr o gresse d f oll o wi n g pri or 
tre at me nt a n d n o s atisf act or y alter n ati ve tre at me nt o pti o ns ( as y m pt o m atic br ai n 
met ast ases/ pri m ar y br ai n t u m ors al l o we d if ≤4 c m a)
D L 1, … , D L x ( m o n ot her a p y) b

St arti n g d ose P F- 0 7 2 8 4 8 9 0 5 0 m g Q D

B L R M desi g n

Ne xt d ose = u p t o 2 × c urre nt d ose c
D L x a n d hi g her ( m o n ot her a p y )b

B L R M desi g n

Ne xt d ose = u p t o 2 × c urre nt d ose c

M o n ot her a p y M T D a n d/ or 
rec o m me n de d d ose f or f urt her st u d y
D L x (c o m bi n ati o n)

St arti n g d ose P F- 0 7 2 8 4 8 9 0 D L x 
( m o n ot her a p y)

Bi ni meti ni b 4 5 m g BI D

B L R M desi g n

Ne xt d ose = u p t o 2 × c urre nt d ose c

C o m bi n ati o n M T D a n d/ or 
rec o m me n de d d ose f or 
f urt her st u d y
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 3
Fi g ure 2 .
St u d y Sc he m a f or P h ase 1 b D ose E x p a nsi o n wit h O pti o n al F o o d -Effect a n d
D DI S u b st u d y ( A p pr o xi m atel y 2 0 P artici p a nts Per C o h ort f or C o h orts 1 - 4, 
4 0 P artici p a nts f or C o h ort 5 a n d 1 0 P artici p a nts f or O pti o n al C o h ort 6 a n d 
6 - 8 P a rtici p a nts f or C o h ort 7 )
a.
As y m pt o matic i n t he brai n is defi ne d as , wit hi n 1 4 da ys of t he start of st u d y: n o ne ur ol o gical s y m pt o ms d ue 
t o brai n metastases/ pri mar y brai n t u m or; n ot re q uiri n g i nitiati o n of or a n i ncrease i n ster oi d d osi n g t o 
c o ntr ol ne ur ol o gical s y m pt o ms d ue t o brai n metastases/ pri mar y brai n t u m or ; a n d n ot re q uiri n g i nitiati o n of 
or a n i ncrease i n a nti -e pile ptic d osi n g t o c o ntr ol seiz ure acti vit y d ue t o brai n metastases/ pri mar y brai n 
t u m or. S y m pt o matic i n t he brai n is defi ne d as a n y of t he a b o ve wit hi n 1 4 da ys of t he start of st u d y 
treat me nt.
b.
F or C o h orts 1 - 4: a meas ura ble lesi o n m ust be at least 0. 5 c m a n d ≤4 c m i n l o n g a xis a n d e val ua ble b y  
m R E CI S T v 1. 1 ; if all disease i n t he brai n was pre vi o usl y irra diate d, at least 1 lesi o n m ust de m o nstrate 
pr o gressi o n b y R E CI S T v 1. 1 si nce irra diati o n. F or C o h ort 5 , patie nts m ust ha ve at least 1 meas ura ble 
lesi o n ( per R A N O f or pri mar y brai n t u m or, f or n o n -gli o ma, a n d if e xtracra nial per R E CI S T 1. 1, if 
i ntracra nial per m R E CI S T 1. 1).
B R A F V 6 0 0 -m ut a nt u nresect a ble/ met ast atic s oli d t u m or
P F -0 7 2 8 4 8 9 0 at t he rec o m me n de d d ose f or f urt h er st u d y + bi ni meti ni b at 4 5 m g BI D
C o h ort 1 :
mel a n o m a, n o pri or B R A F or M E K 
i n hi bit or i n met ast atic setti n g ( or i n t he 
a dj u v a nt setti n g wit hi n 6 m o nt hs of st u d y 
tre at me nt), as y m pt o m atica i n t he br ai n, 
wit h me as ur a ble dise ase
b i n t he br ai n.
C o h ort 3:
mel a n o m a, pri or B R A F i n hi bit or i n t he 
met ast atic ( or a dj u v a nt setti n g wit hi n 
6 m o nt hs of st u d y tre at me nt) re q uire d, 
as y m pt o m atic a i n t he br ai n, wit h 
me as ur a ble
b dise ase i n t he br ai n.
C o h ort 5: 
a n y s oli d t u m or; hist or y of or c urre nt le pt o me ni n ge al met ast ases is per mitte d; wit h or 
wit h o ut dise ase i n t he br ai n as l o n g as it is me as ur a ble a n d d oes n ot meet criteri a f or 
C o h orts 1 - 4; wit h or wit h o ut pri or B R A F a n d/ or M E K i n hi bit or; as y m pt o m atica or 
s y m pt o m atica i n t he br ai n.
C o h ort 2:
mel a n o m a, n o pri or B R A F or M E K 
i n hi bit or i n met ast atic setti n g ( or i n t he 
a dj u v a nt setti n g wit hi n 6 m o nt hs of st u d y 
tre at me nt), s y m pt o m atica i n t he br ai n, 
wit h me as ur a ble dise ase b i n t he br ai n.
C o h ort 4:
mel a n o m a, pri or B R A F i n hi bit or
i n t he 
met ast atic ( or a dj u v a nt setti n g wit hi n 6 
m o nt hs of st u d y tre at me nt) re q uire d, 
s y m pt o m atica i n t he br ai n, wit h 
me as ur a ble
b dise ase i n t he br ai n. 
O pti o n al C o h ort 6 : 
D DI ( mi d az ol a m) s u bst u d y
O pti o n al C o h ort 7 : 
F o o d- effect s u bst u d y 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 4
1. 3. S c he d ule of Acti v ities
T he S o A ta ble pr o vi des a n o ver vie w of t he pr ot oc ol visits a n d pr oce d ures.  Refer t o t he S T U D Y A S S E S S M E N T S A N D 
P R O C E D U R E S secti o n of t he pr ot oc ol f or detaile d i nf or mati o n o n eac h assess me nt re q uire d f or c o m plia nce wit h t he pr ot oc ol. 
T he i n vesti gat or ma y  sc hed ule visits ( u n pla n ne d visits) i n a d diti o n t o t h ose liste d in t he S o A ta ble, i n or der t o c o n d uct e val uati o ns or 
assess me nts re q uire d t o pr otect t he well -bei n g of t he partici pa nt .
St u d y Tre at me nt (c ycle d ur ati o n = 2 1 d a ys)
N otes/ Pr ot oc o
l Secti o n
C ycle 1
C ycle 2
S u bse q ue nt 
C ycles
Visit I de ntifier a
Scree ni n g 1
D a y 1
D a y 8
D a y 1 5
D a y 1
D a y 1 5
D a y 1
E O T
3 0 -D a y 
F oll o w -U p 2
S ur vi v al 
F oll o w -U p 3
Visit Wi n d o w
D a y -2 8 t o 
D a y - 1
- 3 d a ysb
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 7 d a ys
± 7 d a ys
Q 1 2 W ± 7 d a ys
I nf or me d 
c o nse nt/asse nt 4
X
Secti o n 1 0. 1. 3
I ncl usi o n/e xcl usi o n 
criteria
X  
X
Secti o ns 5. 1
a n d 5. 2 a n d 5. 2
De m o gra p h y a n d 
baseli ne 
c haracteristics
X
D oc u me ntati o n of 
B R A F V 6 0 0 
m utati o n 5
X
Secti o n 8. 7. 1
Arc hi ve d t u m or 
sa m ple6
X
Secti o n 8. 7. 2
Fres h t u m or sa m ple 
( o pti o nal a n d o nl y if 
c o nse nt pr o vi de d, f or 
p har mac o d y na mic 
a nal ysis) 7
X
X
( wi n-
d o w: 
+ 2 8
da ys)
X (as cl ose 
t o date of 
ra di o gra p hi
c disease 
pr o gressi o n 
as p ossi ble 
if feasi ble)
Secti o n 8. 8. 1
W h ole bl o o d 
( matc he d n or mal)8
X
Bl o o d sa m ple f or 
C D x 9
X
Secti o n 8. 7. 2
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 5
St u d y Tre at me nt (c ycle d ur ati o n = 2 1 d a ys)
N otes/ Pr ot oc o
l Secti o n
C ycle 1
C ycle 2
S u bse q ue nt 
C ycles
Visit I de ntifier a
Scree ni n g 1
D a y 1
D a y 8
D a y 1 5
D a y 1
D a y 1 5
D a y 1
E O T
3 0 -D a y 
F oll o w -U p 2
S ur vi v al 
F oll o w -U p 3
Visit Wi n d o w
D a y -2 8 t o 
D a y - 1
- 3 d a ysb
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 7 d a ys
± 7 d a ys
Q 1 2 W ± 7 d a ys
Bl o o d sa m ple f or 
 ( S pecifie d 
Ge netics) 1 0
X  
X
X  
X
X
(e ver y ot her 
c ycle 
starti n g wit h 
C y cle 3)
X
Secti o n 8. 7. 3
H B V a n d H C V 
ser ol o g y testi n g a n d 
HI V w here 
a p plica ble
X
L H, F S H, a n d 
Estra di ol f or fe male 
a d olesce nts or L H, 
F S H, a n d 
Test oster o ne f or 
male a d olesce nts
( Phase 1 b)
X
E ver y 4 
c ycles 
( ± 1 wee k)
X
F or 
partici pa nts 
< 1 8 years of 
a ge a n d Ta n ner 
Sta ge < 4 at t he 
ti me of 
i nf or me d 
c o nse nt/asse nt 
o nl y. See 
Secti o n 8. 2. 1 1 .
O nc ol o g y hist or y
X
Me dical hist or y, 
pri or s yste mic 
ca ncer t hera pies, 
ra diati o n a n d 
s ur geries
X
P h ysical 
e xa mi nati o n 
(I ncl u di n g hei g ht at 
Scree ni n g o nl y) 1 1 ,3 5
X  
X  
X
X  
X  
X
X
Secti o n 8. 2. 1
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 6
St u d y Tre at me nt (c ycle d ur ati o n = 2 1 d a ys)
N otes/ Pr ot oc o
l Secti o n
C ycle 1
C ycle 2
S u bse q ue nt 
C ycles
Visit I de ntifier a
Scree ni n g 1
D a y 1
D a y 8
D a y 1 5
D a y 1
D a y 1 5
D a y 1
E O T
3 0 -D a y 
F oll o w -U p 2
S ur vi v al 
F oll o w -U p 3
Visit Wi n d o w
D a y -2 8 t o 
D a y - 1
- 3 d a ysb
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 7 d a ys
± 7 d a ys
Q 1 2 W ± 7 d a ys
T a n ner Sta ge
(P hase 1 b )
X
E ver y 4 
c ycles 
( ± 1 wee k)
F or 
partici pa nts 
< 1 8 years of 
a ge at t he ti me 
of i nf or me d 
c o nse nt/asse nt 
o nl y. See 
Secti o n 8. 2. 1 1
F ull o p ht hal mic 
e xa mi nati o n 1 2 ,3 5
X 
If cli nicall y i n dicate d ( n ote: vis ual ac uit y s h o ul d be teste d b y t he treati n g p h ysicia n 
o n Da y 1 of e ver y c ycle).
Secti o n 8. 2. 3
Der mat ol o gic 
e xa mi nati o n 1 3 ,3 5
X  
X
X
C 3 D 1 t he n 
e ver y ot her 
c ycle/ Q 6 W 
X
X
Secti o n 8. 2. 2
Ne ur ol o gic 
e xa mi nati o n 1 4
X
X  
X  
X
Da y 1 of 
C y cles 3- 8, 
t he n if 
cli nicall y 
i n dicate d
Secti o n 8. 2. 4
Vital si g ns a n d 
wei g ht 1 5
X  
X  
X  
X  
X  
X  
X
X
X
Secti o n 8. 2. 6
E C O G P S 1 6 ,3 5
X
X
X
X
X
Secti o n 8. 2. 5
C o ntact I W R S
X
X
X
X
X
L a b or at or y
He mat ol o g y 1 7
X
X
X
X
X
X
X
X
A p pe n di x 2
Bl o o d c he mistr y 
(tr o p o ni n 
meas ure d o nl y 
f or partici pa nts 
recei vi n g 
bi ni meti ni b) 1 8
X  
X  
X  
X  
X
X
X
X
A p pe n di x 2
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 7
St u d y Tre at me nt (c ycle d ur ati o n = 2 1 d a ys)
N otes/ Pr ot oc o
l Secti o n
C ycle 1
C ycle 2
S u bse q ue nt 
C ycles
Visit I de ntifier a
Scree ni n g 1
D a y 1
D a y 8
D a y 1 5
D a y 1
D a y 1 5
D a y 1
E O T
3 0 -D a y 
F oll o w -U p 2
S ur vi v al 
F oll o w -U p 3
Visit Wi n d o w
D a y -2 8 t o 
D a y - 1
- 3 d a ysb
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 7 d a ys
± 7 d a ys
Q 1 2 W ± 7 d a ys
C oa g ulati o n 
(a P T T, 
I N R/ P T)1 9
X  
X  
X  
X  
X  
X
Da y 1 of 
C y cles 3- 8, 
t he n if 
cli nicall y 
i n dicate d
A p pe n di x 2
Uri nal ysis 2 0
X
X
If cli nicall y 
i n dicate d
X
A p pe n di x 2
Ser u m F S H 2 1
X
Ser u m pre g na nc y 
test2 2
X
X
Secti o n 8. 2. 1 0
Ser u m or u ri ne 
pre g na nc y test
X
X
Secti o n 8. 2. 1 0
C o ntrace pti o n 
c hec k 2 3
X  
X
X
X
X
Secti o n 5. 3. 3
Si n gle 1 2 -lea d 
E C G 2 4
X
Secti o n 8. 2. 7
Tri plicate 1 2 -lea d 
E C G 2 5
X
X  
X
Da y 1 of 
C y cles 3 -6 
Secti o n 8. 2. 7
E C H O 2 6
X
X
C 6 D 1 t he n 
e ver y 4 
c ycles/ Q 1 2
W 
X
X
Secti o n 8. 2. 9
Tre at me nt 2 7
Secti o n 6
A d mi nister A M d ose 
of P F - 0 7 2 8 4 8 9 0 a n d 
bi ni meti ni b i n t he 
cli nic
X
X  
X
Da y 1 
C y cles 3 -6 
o n P K 
sa m pli n g/ E C
G da ys
Dis pe nse 
P F - 0 7 2 8 4 8 9 0 a n d 
bi ni meti ni b
X
X
X
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 8
St u d y Tre at me nt (c ycle d ur ati o n = 2 1 d a ys)
N otes/ Pr ot oc o
l Secti o n
C ycle 1
C ycle 2
S u bse q ue nt 
C ycles
Visit I de ntifier a
Scree ni n g 1
D a y 1
D a y 8
D a y 1 5
D a y 1
D a y 1 5
D a y 1
E O T
3 0 -D a y 
F oll o w -U p 2
S ur vi v al 
F oll o w -U p 3
Visit Wi n d o w
D a y -2 8 t o 
D a y - 1
- 3 d a ysb
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 7 d a ys
± 7 d a ys
Q 1 2 W ± 7 d a ys
A d mi nister 
P F - 0 7 2 8 4 8 9 0 a n d 
bi ni meti ni b
C o nti n u o usl y i n 2 1 - da y c ycles ( Q D f or P F- 0 7 2 8 4 8 9 0; BI D f or 
bi ni meti ni b)
Re vie w d osi n g diar y 
X
X
X
X
X
X
T u m or 
assess me nts 2 8
C T or M RI 
i ma gi n g 
X
e ver y 6 wee ks ( 2 c ycles) ± 1 wee k f or 1 year (t hr o u g h C ycle 1 7) t he n e ver y 1 2 wee ks ± 1 wee k t hereafter
Secti o n 8. 1. 1
Ot her cli nic al 
assess me nts
Pri or a n d 
c o nc o mita nt 
me dicati o n 2 9
X
 
 
 
 
 


Seri o us a n d 
n o nseri o us A E 
m o nit ori n g 3 0
X
 
 
 
 
 



D oc u me nt 
s u bse q ue nt 
a ntica ncer t hera pies
X
X
Secti o n 7. 1
S ur vi val stat us
X
X
Secti o n 7. 1
P K bl o o d sa m pli n g 3 1
X
X  
X
X
X
Wi n d o ws f or 
P K bl o o d 
sa m ples 
pr o vi de d i n 
ta bles bel o w; 
Secti o n 8. 5
P K a n d ge netic 
bi o mar ker C S F 
sa m pli n g3 2
A n y ti me C S F is sa m ple d as part of S O C
Secti o n 8. 5
P har mac o ge netics 
sa m pli n g3 3
X
Secti o n 8. 7. 4
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 9
St u d y Tre at me nt (c ycle d ur ati o n = 2 1 d a ys)
N otes/ Pr ot oc o
l Secti o n
C ycle 1
C ycle 2
S u bse q ue nt 
C ycles
Visit I de ntifier a
Scree ni n g 1
D a y 1
D a y 8
D a y 1 5
D a y 1
D a y 1 5
D a y 1
E O T
3 0 -D a y 
F oll o w -U p 2
S ur vi v al 
F oll o w -U p 3
Visit Wi n d o w
D a y -2 8 t o 
D a y - 1
- 3 d a ysb
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 3 d a ys
± 7 d a ys
± 7 d a ys
Q 1 2 W ± 7 d a ys
Pf izer Pre p D 1 
Ba n ke d 
Bi os peci me n(s) 3 4
X
Secti o n 8. 7. 5
a.
D a y  relati ve t o start of st u d y i nter ve nti o n ( Da y 1).
b. - 3 da y  wi n d o w is t o all o w assess me nts a n d e xa mi nati o ns t o occ ur u p t o 3 da ys bef ore i nitiati o n of st u d y dr u g ( C 1 D 1) u nless 
ot her wise state d (e g, tri plicate pre-d ose E C G s h o ul d occ ur per P K S O A ).
A b bre viati o ns use d i n t his ta ble are i n A p pe n di x 2 1 .
1.
Scree ni n g: T o be o btai ne d w it hi n 2 8 da ys pri or t o st u d y e ntr y.
2.
3 0 -D a y F oll o w -u p: At least 2 3 cale n dar da ys a n d n o m ore t ha n 3 7 cale n dar da ys after disc o nti n uati o n fr o m st u d y i nter ve nti o n, partici pa nts will ret ur n t o 
u n der g o re vie w of c o nc o mita nt treat me nts, vital si g ns, a n d assess me nt f or res ol uti o n of a n y treat me nt-relate d Aes.  Partici pa nts c o nti n ui n g t o e x perie nce Aes 
at t his p oi nt f oll o wi n g disc o nti n uati o n of treat me nt will c o nti n ue t o be f oll o we d at least e ver y 4 wee ks u ntil res ol uti o n or deter mi nati o n, i n t he cli nical 
j u d g me nt of t he i n vesti gat or, t hat n o f urt her i m pr o ve me nt is e x pecte d.
3.
S ur vi v al F oll o w -U p : T he s ur vi val f oll o w-u p occ urs a p pr o xi matel y Q 1 2 W .
4.
I nf or me d C o nse nt/ asse nt: M ust be o btai ne d pri or t o u n der g oi n g a n y st u d y -s pecific pr oce d ures.  T he d urati o n of o btai ni n g I C D s h o ul d be c ha n ge d if t he 
scree ni n g wi n d o w is re vise d.
5.
D oc u me nt ati o n of B R A F V 6 0 0 M ut ati o n : tiss ue or bl o o d (e g,
) res ults perf or me d d uri n g n or mal c o urse of cli nical care i n C LI A or si milarl y 
certifie d la b orat or y (ie, l ocal testi n g).  Re dacte d m olec ular re p ort(s) m ust be pr o vi de d d uri n g Scree ni n g.
6.
Tiss ue S a m ple : C o nfir mati o n of a vaila bilit y of a de q uate t u m or tiss ue f or s u b missi o n t o t he sp o ns or. If m ulti ple s peci me ns are a vaila ble, t he m ost rece ntl y 
o btai ne d is preferre d .  If partici pa nts d o n ot ha ve sufficie nt arc hi val tiss ue , a fres h bi o ps y s h o ul d be o btai ne d if it ca n be perf or me d safel y i n t he o pi ni o n of 
t he i n vesti gat or. If a de q uate arc hi ve tiss ue is n ot a vaila ble a n d a fres h bi o ps y ca n n ot be perf or me d safel y, partici pa nts ma y still be eli gi ble if all ot her 
eli gi bilit y criteria are met. See Secti o n 8. 7. 2 f or tiss ue re q uire me nts.
7.
Fres h T u m or S a m ple ( O pti o n al): F or partici pa nts w h o pr o vi de i nf or me d c o nse nt /asse nt f or o pti o nal bi o ps y ; ma y be o btai ne d pri or t o starti n g treat me nt,
bet w ee n C 1 D 8 a n d C 2 D 1 5 , a n d at E O T (as cl ose t o t he date of ra di o gra p hic disease pr o gressi o n as p ossi ble if feasi ble ). If feasi ble, o n-treat me nt a n d E O T 
bi o psies s h o ul d be o btai ne d wit hi n 2- 4 h o urs after d osi n g. See Secti o n 8. 8. 1 .
8.
W h ole B l o o d: as c o ntr ol f or t u m or m olec ular a nal ysis . 
9.
Bl o o d S a m ple f or C D x: See Secti o n 8. 7. 2 .
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 3 0
1 0. Bl o o d S a m ple f or 
( S pecifie d Ge neticss): Bl o o d sa m ple ( 
) s h o ul d als o be c ollecte d at ra di o gra p hic pr o gressi o n. See Secti o n 8. 7. 3 .
1 1. P h ysic al E x a mi n ati o n : Hei g ht will be meas ure d at Scree ni n g o nl y. C o m plete p h ysical e xa mi nati o n will be perf or me d at i nitial e xa mi nati o n o nl y. B rief, 
s y m pt o m-directe d p h ysical e xa mi nati o ns will be perf or me d s u bse q ue ntl y.  See Secti o n 8. 2. 1 .
1 2. F ull O p ht h al mic E x a mi n ati o n : Re peat o p ht hal mic e xa mi nati o n will be perf or me d o nl y if cli nicall y i n dicate d.  Vis ual ac uit y s h o ul d be teste d b y t he 
treati n g p h ysicia n o n Da y 1 of e ver y c ycle. See Secti o n 8. 2. 3 .
1 3. Der m at ol o gic E x a mi n ati o n : Perf or me d Q 6 W after C 3 D 1 a n d t he n Q 9 W after E O T u ntil 6 m o nt hs after t he last d ose of P F -0 7 2 8 4 8 9 0 .  See Secti o n 8. 2. 2 .
1 4. Ne ur ol o gic E x a mi n ati o n : Ne ur ol o gic e xa mi nati o n will be perf or me d o n Da y 1 a n d Da y 1 5 of C ycles 1 - 2 a n d o n Da y 1 of C ycles 3- 8.  A d diti o nal 
e xa mi nati o n will be c o n d ucte d if cli nicall y i n dicate d .  See Secti o n 8. 2. 4 .
1 5. Vit al Si g ns: B P a n d p ulse rate t o be rec or de d i n sitti n g p ositi o n. See Secti o n 8. 2. 6 .
1 6. E C O G P S : see A p pe n di x 1 4 f or E C O G classificati o n of perf or m a nce stat us. See Secti o n 8. 2. 5 .
1 7. H e m at ol o g y : N o nee d t o re peat o n C 1 D 1 if Scree ni n g assess me nt perf or me d wit hi n 7 da ys. See A p pe n di x 2 Cli nical La b orat or y Tests .
1 8. Bl o o d C he m istr y: N o nee d t o re peat o n C 1 D 1 if Scree ni n g assess me nt perf or me d wit hi n 7 da ys pri or t o t hat date. See A p pe n di x 2 Cli nical La b orat or y Tests .
1 9. C o a g ul ati o n : N o nee d t o re peat o n C 1 D 1 if Scree ni n g assess me nt perf or me d wit hi n 7 da ys pri or t o t hat date. See A p pe n di x 2 Cli nical La b orat or y Tests .
Partici pa nts o n a ntic oa g ulati o n treat me nt s h o ul d ha ve para meters m o nit ore d t hr o u g h o ut t he st u d y as cli nicall y i n dicate d.
2 0. Uri n al ysis: Di pstic k is acce pta ble at mi ni m u m at S cree ni n g, C 2 D 1 a n d E O T visit. See A p pe n di x 2 Cli nical La b orat or y Tests .
2 1. Ser u m F S H: Hi g h F S H le vel i n t he p ost me n o pa usal ra n ge m ust be use d t o c o nfir m a p ost me n o pa usal state i n w o me n u n der 6 0 years ol d a n d n ot usi n g 
h or m o nal c o ntrace pti o n or H R T. 
2 2. Pre g n a nc y Test : Ser u m pre g na nc y test w ill be perf or me d at Scree ni n g, a n d if m ore t ha n 7 da ys pri or t o C 1 D 1 at Scree ni n g, a gai n at C 1 D 1, a n d at E O T . 
Details are descri be d i n Secti o n 8. 2. 1 0 . 
2 3. C o ntr ace pti o n C hec k: See Secti o n 5. 3. 3 .
2 4. Si n gle 1 2 -Le a d E C G: Si n gle E C G will be perf or me d d uri n g Scree ni n g t o deter mi ne eli gi bilit y.  Ma y be re peate d t w ice ( perf or me d a p pr o xi matel y 2 mi n utes 
a part) if t he i nitial Q Tc F val ue is > 4 7 0 msec ; if 3 E C Gs are perf or me d, t he a vera ge Q Tc F s h o ul d be ≤4 7 0 msec t o be eli gi ble.
2 5. Tri plic ate 1 2 -Le a d E C G : F or eli gi bilit y, t he Q Tc F i nter val at C 1 D 1 pre -d ose m ust be ≤4 7 0 msec.   A d diti o nal E C Gs will be perf or me d as cli nicall y 
i n dicate d. T he ti mi n g of E C G c ollecti o n ma y be a dj uste d base d o n e mer gi n g data. D uri n g P hase 1 b D ose E x pa nsi o n , E C G c ollecti o n ma y be si m plifie d.
Details of E C G g ui da nce, i ncl u di n g o btai ni n g a d diti o nal E C Gs t o c o nfir m s pecific a b n or malities, are pr o vi de d i n Secti o n 8. 2. 7 . Details pr o vi de d i n ta ble 
bel o w w he n E C Gs are o btai ne d at t he sa me ti me as t he P K sa m ple. 
2 6. E C H O : E C H O sca ns will be perf or me d at Scree ni n g, Da y 1 of C ycle 2, t he n Q 1 2 W u ntil E O T, a n d at E O T a n d 3 0 -Da y f oll o w -u p. F or partici pa nts w h o 
ha ve bee n o n treat me nt f or ≥2 4 m o nt hs , E C H O sca ns s h o ul d be e ver y 2 4 wee ks ( or m ore fre q ue ntl y if cli nical i n dicate d) if t he L V E F is wit hi n 1 0 % of 
baseli ne a n d > L L N at a n y ti me w hile o n st u d y. E val uati o n of t he heart val ves s h o ul d be i ncl u de d a n d a n y baseli ne a n d treat me nt-e mer ge nt fi n di n gs s h o ul d 
be clearl y d oc u me nte d a n d e val uate d f or c o nsi derati o n of A E (i ncl u di n g gra de acc or di n g t o N CI C T C A E versi o n 5. 0 a n d relati o n t o st u d y i nter ve nti o ns).  
See Secti o n 8. 2. 9 .
2 7. St u d y I nter ve nti o n: P F -0 7 2 8 4 8 9 0 a n d bi ni meti ni b (f or partici pa nts recei vi n g c o m bi nati o n treat me nt) will be dis pe nse d w it h d osi n g diar y. P F -0 7 2 8 4 8 9 0 
a n d bi ni meti ni b (f or partici pa nts recei vi n g c o m bi nati o n treat me nt) will be a d mi nistere d orall y Q D a n d BI D, res pecti vel y, c o nti n u o usl y i n a 2 1 -d a y  c ycle. 
 
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 3 1
A M d oses of P F -0 7 2 8 4 8 9 0 a n d bi ni meti ni b will be a d mi nistere d i n t he cli nic o n P K sa m pli n g da ys t hr o u g h C y cle 6.  St u d y i nter ve nti o n will be d escri be d i n 
Secti o n 6 . 
2 8. T u m or Assess me nts : T u mor assess me nts will i ncl u de all k n o w n or s us pecte d disease sites. M RI of brai n
a n d c o ntrast e n ha nce d -C T or M RI of c hest, 
a b d o me n a n d pel vis will be perf or me d at Scr ee ni n g, C 3 D 1 , t he n e ver y ot her c ycle/Q 6 W ± 1 w ee k t hr o u g h C ycle 1 7 (ie, f or 1 year), a n d e ver y 
4 c ycles/Q 1 2 W ± 1 w ee k after C ycle 1 7 u ntil pr o gressi ve disease , wi t h dra wal of c o nse nt, i nitiati o n of s u bse q ue nt a ntica ncer t hera p y, partici pa nt is l ost t o 
f oll o w-u p, deat h, or defi ne d e n d of st u d y . M RI of s pi nal c or d will o nl y occ ur at Scree ni n g f or partici pa nts wit h k n o w n s pi nal c or d disease at baseli ne . C R 
or P R c o nfir mati o n assess me nts m ust ta ke place at least 4 wee ks after t he i nitial res p o nse a n d ma y be perf or me d a mi ni m u m of  4 we e ks ( 2 8 da ys) after t he 
i nitial sca n s h o wi n g a C R or P R at t he discreti o n of t he i n vesti gat or, wit h t he ne xt sca n perf or me d acc or di n g t o t he ori gi nal sc he d ule. Sca n at E O T is n ot 
re q uire d if a sca n was d o ne wit hi n 8 we e ks of treat me nt disc o nti n uati o n a n d pr o gressi ve disease has bee n d oc u me nte d. See Secti o n 8. 1. 1 .
2 9. Pri or a n d C o nc o m it a nt Me dic ati o n : all c o nc o mita nt me dicati o ns a n d N o n Dr u g S u p p orti ve I nter ve nti o ns s h o ul d be rec or de d o n t he C R F.
3 0. A E Assess me nts : Aes s h o ul d be d oc u me nte d a n d rec or de d at eac h visit usi n g t he N CI C T C A E versi o n 5. 0 . Assess me nt of A e s s h o ul d i ncl u de q uesti o ns 
pertai ni n g t o t he i nci de nce, se verit y, a n d ti mi n g of vis ual c ha n ges (e g, flas hes or c ol or c ha n ges) , pal piti o ns, a n d br uisi n g or blee di n g. T he ti me peri o d f or 
acti vel y eliciti n g a n d c ollecti n g Aes a n d S A Es (“acti ve c ollecti o n peri o d”) f or eac h partici pa nt be gi ns fr o m t he ti me t he partici pa nt pr o vi des i nf or me d 
c o nse nt t hr o u g h a n d i ncl u di n g a mi ni m u m of 2 8 cale n dar da ys after t he last st u d y i nter ve nti o n a d mi nistrati o n. If t he partici pa nt be gi ns a ne w a ntica ncer 
t hera p y, t he peri o d f or rec or di n g n o n-seri o us A Es o n t he C R F e n ds at t he ti me t he ne w treat me nt is starte d. H o w e ver, a n y S A Es occ urri n g d uri n g t he acti ve 
c ollecti o n peri o d m ust still be re p orte d t o Pfizer Safet y a n d rec or de d o n t he C R F, irres pecti ve of a n y i nter ve ni n g treat m e nt.  See Secti o n 8. 3 .
3 1. P K B l o o d S a m pli n g : Details pr o vi de d i n t he ta ble bel o w. Als o, see Secti o n 8. 5 .
3 2. P K C S F S a m pli n g : Details pr o vi de d i n t he ta ble bel o w . Als o, see Secti o n 8. 5 .
3 3. P h ar m ac o ge n o mics s a m pl i n g: P har mac o ge n o mic sa m ples will be o btai ne d d uri n g Scree ni n g. See Secti o n 8. 7. 4 .
3 4.
Pfizer Pre p D 1 B a n ke d Bi os peci me n(s): S ee Secti o n 8. 7. 5 .
3 5.
Assess me nt d oes n ot nee d t o be re peate d if perf or me d wit hi n 7 2 h o urs pri or t o C ycle 1 Da y 1 (ie, first da y of d osi n g) u nless ot her wise e x plicitl y state d (e g, pre g na nc y test).
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 3 2
P h ar m ac o ki netic S a m pli n g a n d E C Gs Sc he d ule f or P h ase 1 a
St u d y Tre at me nt (c ycle d ur ati o n = 2 1 d a ys)
C ycle 1
C ycle 2 - 6
C y cles 7-1 2
Visit I de ntifier
Scree ni n g
D a y 1
D a y 2
D a y 1 5 
D a y 1 
D a y 1
E O T
D a y -2 8 
t o D a y - 1
N o wi n d o w
N o 
wi n d o w
( ±3 d a ys)
( ±3 d a ys)
( ±3 d a ys)
( ±7 d a ys)
H o urs Bef ore/ After D ose
0 a
1 
2
4  
6 
8 
0 a
0 a
1 
2 
4
6 
8 
0 a
2 
0 a
2
St u d y i nter ve nti o n 
a d mi nistrati o n ( P F-
0 7 2 8 4 8 9 0 or P F - 0 7 2 8 4 8 9 0 
a n d bi ni meti ni b), A M d ose 
i n cli nic
X
X  
X
X
X
P K bl o o d plas ma sa m pli n g1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
P K a n d ge netic bi o mar ker 
C S F sa m pli n g 2
A n y ti me C S F is sa m ple d as part of S O C
Si n glet 1 2 -lea d E C G3
X
Tri plicate 1 2 -lea d E C G3
X
X
X
X
X
X
a.
Pre -d ose sa m ple c ollecti o n.
1.
P K S a m pli n g : Bl o o d w ill be c ollecte d f or deter mi ni n g t he c o nce ntrati o n of P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b f or patie nts recei vi n g t he c o m bi nati o n) o n C 1 D 1 
a n d C 1 D 1 5 at pre -d ose ( wit hi n 3 0 mi n bef ore t he d ose), 1 h o ur ( ± 5 mi n), 2 h o ur ( w it hi n 1 5 mi n utes after t he last of t he tri plicate E C Gs sc he d ule d at t hat 
ti me p oi nt), 4 h o ur ( ± 1 0 mi n), 6 h o ur ( ± 1 5 mi n), a n d 8 h o ur ( ± 2 0 mi n) p ost d ose, a n d f or Q D a d mi nistrati o n o nl y at 2 4 h o urs ( ± 2 h o urs) p ost d ose o n C 1 D 1 
(ie, pre-d ose o n C 1 D 2 wit hi n 3 0 mi n utes pri or t o d ose ; partici pa nts will nee d to ret ur n t o cli nic o n C 1 D 2 f or t he 2 4 -h o ur p ost d ose sa m ple).  O n D a y  1 of C 2-
C 6, P K sa m p les will als o be o btai ne d pre-d ose ( w it hi n 3 0 mi n) a n d at 2 h o urs ( wit hi n 1 5 mi n utes f oll o wi n g t he last of t he tri plicate E C Gs sc he d ule d at t hat 
ti me p oi nt) p ost d ose.  A P K sa m ple will als o be o btai ne d d uri n g t he E O T visit a n d at t he ti me of C S F sa m pli n g ( w he n C S F sa m pli n g is n ot d o ne o n a P K
da y) if p ossi ble.   A d diti o nal P K sa m ples ma y be o btai ne d at ot her ti me p oi nts if cli nicall y i n dicate d.  Detaile d i nstr ucti o n of sa m ple c ollecti o n, pr ocessi n g 
a n d s hi p me nt will be pr o vi de d i n t he La b Ma n ual. See Secti o n 8. 5 .
2.
P K a n d ge netic bi o m ar ker C S F S a m pli n g : P K a n d ge netic bi o mar ker C S F sa m ples will be c ollecte d f or partici pa nts i n w h o m C S F sa m pli n g is bei n g 
perf or me d as part of S O C.  If p ossi ble, sa m ples s h o ul d be c ollecte d d uri n g scree ni n g, o n a n y P K da y, i deall y 2 t o 4 h o urs after d osi n g o n a n y P K da y, w it h 
t he ti me c ollecte d relati ve t o d osi n g clearl y i n dicate d o n t he re q uisiti o n a n d/ or e C R F .  If t he C S F sa m ple is c ollecte d b ut n ot o n a P K da y, a n a d diti o nal P K 
sa m ple s h o ul d be c ollecte d s o o n after if p ossi ble. See Secti o n 8. 5 .
3.
1 2 -Le a d E C G: A si n glet E C G w ill be c ollecte d at Scree ni n g. Tri plicate E C Gs will be c ollecte d at pre -d ose ( wit hi n a p pr o xi matel y 1 5 mi n utes bef ore t he pre -d ose
P K sa m ple ) a n d at 2 h o urs ( ± 1 0 mi n) after d osi n g o n C 1 D 1 a n d C 1 D 1 5 ; w he n P F -0 7 2 8 4 8 9 0 is a d mi nistere d Q D a n d P K sa m pli n g necessitates a pre -d ose 
visit o n C 1 D 2 at 2 4 h o urs after t he C 1 D 1 d ose o n C 1 D 2 (ie, wit hi n 3 0 mi n utes pri or t o t he d ose o n C 1 D 2) t he E C G will be c ollecte d pre -d ose ( w it hi n 
a p pr o xi matel y 1 5 mi n utes bef ore t he pre -d ose P K sa m ple) ; a n d at 2 h o urs ( ± 3 0 mi n) p ost d ose o n Da y 1 of C ycles 2- 6 (i nte n de d t o a p pr o xi mate t he Tma x of 
P F -0 7 2 8 4 8 9 0), wit h 3 c o nsec uti ve 1 2 lea d E C Gs perf or me d a p pr o xi matel y 2 mi n utes a part t o deter mi ne mea n Q Tc F i nter val. W he n E C Gs are o btai ne d at 
t he sa me ti me as a P K sa m ple, t he E C Gs m ust be c o m plete d bef ore t he P K sa m ple is ta ke n. A d diti o nal E C Gs will be perf or me d as cli nicall y i n dicate d.  T he 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 3 3
ti mi n g of E C G c ollecti o n ma y be a dj uste d base d o n e mer gi n g data. Details of E C G g ui da nce, i ncl u di n g o btai ni n g a d diti o nal E C Gs t o c o nfir m s pecific 
a b n or malities, are pr o vi de d i n Secti o n 8. 2. 7 .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 3 4
P h ar m ac o ki netic S a m pli n g a n d E C Gs Sc he d ule f or C o h orts 1 - 5a i n P h ase 1 b
St u d y Tre at me nt (c ycle d ur ati o n = 2 1 d a ys)
C ycle 1
C ycle 2 - 6
Visit I de ntifier
Scree ni n g
D a y 1
D a y 1 5 
D a y 1 
E O T
D a y -2 8 t o 
D a y - 1
N o wi n d o w
( ±3 d a ys)
( ±3 d a ys)
( ±7 d a ys)
H o urs Bef ore/ After D ose
0 b
1 
2
4 
0 b
1 
2 
4
0 b
2
St u d y i nter ve nti o n 
a d mi nistrati o n ( P F- 0 7 2 8 4 8 9 0 
a n d bi ni meti ni b) , A M d ose i n 
cli nic
X
X
X
P K bl o o d plas ma sa m pli n g1
X
X
X
X
X
X
X
X
X
X
X
P K C S F sa m pli n g 2
A n y ti me C S F is sa m ple d as part of S O C
Si n glet 1 2 -lea d E C G3
X
Tri plicate 1 2 -lea d E C G3
X
X
X
X
X
a.
Ta ble f or P K sa m pli n g a n d E C Gs f or C o h ort 6 i n P hase 1 b is f o u n d i n A p pe n di x 1 5 .
b.
Pre d ose sa m ple c ollecti o n.
1.
P K S a m pli n g : Bl o o d w ill be c ollecte d f or deter mi ni n g t he c o nce ntrati o n of P F-0 7 2 8 4 8 9 0 a n d bi ni meti ni b o n C 1 D 1 a n d C 1 D 1 5 at pre -d ose ( w it hi n 3 0 mi n 
bef ore t he d ose), 1 h o ur ( ± 5 mi n), 2 h o ur ( w it hi n 1 5 mi n utes after t he last of t he tri plicate E C Gs sc he d ule d at t hat ti me p oi nt) a n d 4 h o ur ( ± 1 0 mi n) p ost d ose.  
O n Da y 1 of C 2 -C 6, P K sa m ples will als o be o btai ne d pre -d ose ( w it hi n 3 0 mi n) a n d at 2 h o urs ( w it hi n 1 5 mi n utes f ollo wi n g t he last of t he tri plicate E C Gs 
sc he d ule d at t hat ti me p oi nt) p ost d ose.  A P K sa m ple will als o be o btai ne d d uri n g t he E O T visit a n d at t he ti me of C S F sa m pli n g ( w he n C S F sa m pli n g is n ot 
d o ne o n a P K da y) if p ossi ble.  A d diti o nal P K sa m ples ma y be o bt ai ne d at ot her ti me p oi nts if cli nicall y i n dicate d.  Detaile d i nstr ucti o n of sa m ple c ollecti o n, 
pr ocessi n g a n d s hi p me nt will be pr o vi de d i n t he La b Ma n ual. See Secti o n 8. 5 .
2.
P K C S F S a m pli n g : P K C S F sa m ples will be c ollecte d f or partici pa nts i n w h o m C S F sa m pli n g is bei n g perf or me d as part of S O C.  If p ossi ble, sa m ples 
s h o ul d be c ollecte d o n a n y P K da y, i deall y 2 t o 4 h o urs after d osi n g o n a n y P K da y, wit h t he ti me c ollecte d relati ve t o d osi n g clearl y i n dicate d o n t he 
re q uisiti o n a n d/ or e C R F .  If t he C S F sa m ple is c ollecte d b ut n ot o n a P K da y, a n a d diti o nal P K sa m ple s h o ul d be c ollecte d s o o n after if p ossi ble. See 
Secti o n 8. 5 .
3.
1 2 -Le a d E C G: A si n glet E C G w ill be c ollecte d at Scree ni n g. Tri plicate E C Gs will be c ollecte d at pre -d ose ( wit hi n a p pr o xi matel y 1 5 mi n utes bef or e t he pre-d ose 
P K sa m ple ) a n d at 2 h o urs ( ± 1 0 mi n) after d osi n g o n C 1 D 1 a n d C 1 D 1 5, a n d at 2 h o urs ( ± 3 0 mi n) p ost d ose o n Da y 1 of C ycles 2-6 (i nte n de d t o a p pr o xi mate 
t he Tma x of P F -0 7 2 8 4 8 9 0), w it h 3 c o nsec uti ve 1 2 lea d E C Gs perf or me d a p pr o xi matel y 2 mi n utes a part t o deter mi ne mea n Q Tc F i nter val. W he n E C Gs are 
o btai ne d at t he sa me ti me as a P K sa m ple, t he E C Gs m ust be c o m plete d bef ore t he P K sa m ple is ta ke n. A d diti o nal E C Gs w ill be perf or me d as cli nicall y 
i n dicate d.  T he ti mi n g of E C G c ollecti o n ma y be a dj uste d base d o n e mer gi n g data. Details of E C G g ui da nce, i ncl u di n g o btai ni n g a d diti o nal E C Gs t o 
c o nfir m s pecific a b n or malities, are pr o vi de d i n Secti o n 8. 2. 7 .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 3 5
2. I N T R O D U C TI O N
P F - 0 7 2 8 4 8 9 0 (als o k n o w n as A R R Y- 4 6 1) is a p ote nt, selecti ve, hi g hl y brai n - pe netra nt 
s mall -m olec ule i n hi bit or of B R A F V 6 0 0 m utati o ns t hat is bei n g i n vesti gate d i n partici pa nts 
wit h B R A F V 6 0 0 - m uta nt s oli d t u m ors wit h or wit h o ut brai n i n v ol ve me nt. P F - 0 7 2 8 4 8 9 0 is 
bei n g de vel o pe d t o a d dress t he li mite d o verall efficac y  of a p pr o ve d B R A F i n hi bit ors 
res ulti n g fr o m disease pr o gressi o n i n t he brai n.  B y i n hi biti n g B R A F V 6 0 0 -m uta nt e nz yme i n 
t u m or cells b ot h e xtracra niall y  a n d i ntracra niall y, P F - 0 7 2 8 4 8 9 0 has t he p ote ntial t o pr ol o n g 
t he d urati o n of o verall disease c o ntr ol c o m pare d t o a p pr o ve d B R A F i n hi bit ors. 
2. 1. St u d y R ati o n ale 
T he p ur p ose of t he st u d y  is t o assess t he P K, safet y a n d preli mi nar y clinical acti vit y of 
P F -0 7 2 8 4 8 9 0, as m o n ot hera p y a n d i n c o m bi nati o n wit h t he M E K i n hi bit or, M E K T O VI ®
( bi ni meti ni b), i n partici pa nts wit h B R A F V 6 0 0 -m utate d a d va nce d s oli d t u m or mali g na ncies 
wit h a n d wit h o ut brai n metastases. Alt h o u g h a p pr o ve d B R A F i n hi bit ors ha ve tra nsf or me d 
t he treat me nt of patie nts wit h certai n B R A F V 6 0 0-m uta nt ca ncers, t heir l o n g ter m efficac y is 
t h o u g ht t o be li mite d b y p o or brai n pe netrati o n.1 As a res ult, disease pr o gressi o n i n t he brai n 
is a si g nifica nt ca use of m or bi dit y a n d m ortalit y. P F -0 7 2 8 4 8 9 0 is f ull y  brai n pe netra nt, wit h 
t he p ote ntial t o a d dress t his ke y u n met me dical nee d a n d t here b y defi ne a ne w class of
brai n -pe netra nt , p ote nt a n d selecti ve B R A F i n hi bit or.
2. 2. B ac k gr o u n d 
Metastatic s prea d t o t he C N S is a partic ularl y p o or pr o g n ostic fact or f or ma n y s oli d ca ncers, 
wit h a vera ge s ur vi val t y p icall y < 6 m o nt hs. 2 A m o n g s oli d t u m ors, metastatic mela n o ma a n d 
N S C L C ha ve t he hi g hest ris ks of s prea d t o t he C N S, wit h lifeti me pre vale nce’s of 4 0- 6 0 %
a n d 2 0 -4 0 %, res pecti vel y. 3 ,4 ,5
B R A F V 6 0 0 m utati o ns occ ur i n a p pr o xi matel y 5 0 % of mela n o ma a n d P T C , 4 5 % of A T C, 
1 5 % of C R C, 2 % of N S C L C a n d less c o m m o nly i n se veral ot her t u m or ty pes (Ta ble 1 ).  
B R A F m utati o ns dri ve c o nstit uti ve M A P K pat h wa y  acti vati o n a n d i n t ur n pr oliferati o n wit h 
e n ha nce d cell ular s ur vi val. S mall m olec ule B R A F i n hi bit ors bl oc k m uta nt B R A F, M A P K 
si g nali n g, pr oliferati o n a n d s ur vi val i n s o me B R A F V 6 0 0 -m uta nt t u m or cells, effects t hat are 
e n ha nce d b y c o m bi nati o n wit h M E K
i n hi bit ors. T o date, t here are 3 B R A F i n hi bit or/ M E K
i n hi bit or c o m bi nati o ns a p pr o ve d f or select B R A F V 6 0 0 -m uta nt ca ncers: 
da brafe ni b/tra meti ni b ( mela n o ma, N S C LC a n d A T C), ve m urafe ni b/c o bi meti ni b ( mela n o ma)
a n d e nc orafe ni b /bi ni meti ni b ( mela n o ma).  Alt h o u g h B R A F i n hi bit ors ha ve li mite d acti vit y i n
B R A F V 6 0 0 -m uta nt C R C as m o n ot hera p y d ue t o e n d o ge n o us E G F R -me diate d si g nali n g, 
t his ca n be o verc o me by c o nc o mita nt treat me nt wit h E G F R i n hi bit ors; c o nsiste nt wit h t his,
e nc orafe ni b i n c o m bi nati o n wit h t he E G F R a nti b o d y cet u xi ma b was rece ntl y a p pr o ve d f or
B R A F V 6 0 0 -m uta nt C R C .6
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 3 6
T a ble 1 .
Pre v ale nce of B R A F V 6 0 0 M ut ati o ns i n Differe nt T u m or T y pes
T u m or T y pe
Fre q ue nc y
Esti m ate d U S pre v ale nce a
Mela n o ma
0. 5
3 5 0 0
A T C
0. 4 5
5 0 0
P T C
0. 5
1 0 0 0
C R C
0. 1 5
7 5 0 0
Biliar y ca ncer
0. 0 5
3 5 0
N S C L C
0. 0 2
2 0 0 0
L o w gra de gli o ma
0. 6 -0. 8 P X A, 0. 1 -0. 2 P A
N E b
Hi g h gra de gli o ma
0. 0 3
N E b
Ot her c
Varies
N E b
a.
Wit h a d va nce d, sta n dar d treat me nt -refract or y disease; calc ulate d fr o m S E E R database (seer.ca ncer. g o v) 
usi n g o verall m o rtalit y fr o m eac h ca ncer t ype as s urr o gate f or a d va nce d , treat me nt-refract or y ca ncer .
b.
N ot esti mate d; o verall n u m ber is e x pecte d t o be l o w.
c.
Ot her e xa m ples i ncl u de breast ca ncer a n d o varia n ca ncer .
D ue t o p o or brai n pe netrati o n a n d li mite d i ntracra nial acti vit y i n earl y cli nical trials, 
ra n d o mize d st u dies of a p pr o ve d B R A F/ M E K i n hi bit ors i n patie nts wit h mela n o ma a n d 
N S C L C (t he fre q ue nc y  of brai n metastases i n C R C a n d A T C is l o w) e xcl u de d patie nts wit h 
u ntreate d (ie , wit h l ocal brai n t hera p y) , sy m pt o matic (i ncl u di n g a re q uire me nt f or ster oi ds 
a n d a nti -e pile ptic t hera p y t o c o ntr ol s ym pt o ms) a n d/ or pr o gressi n g brai n metastases. 7 ,8 ,9  I n a 
rece nt P hase 2 trial ( C O M BI -M B),
da brafe ni b pl us tra meti ni b treat me nt of B R A F
V 6 0 0 -m uta nt mela n o ma patie nts wit h brai n metastases ac hie ve d o verall a n d i ntracra nial 
t u m or res p o nse rates of 4 1-7 5 % a n d 4 4 -5 9 %, res pecti vel y, de pe n di n g o n w het her brai n 
metastases were as y m pt o matic or s y m pt o matic a n d u ntreate d or pre vi o usl y treate d wit h l ocal 
brai n t hera p y. 7 H o we ver, t he me dia n D o R f or patie nts wit h as y m pt o matic, u ntreate d brai n 
metastases was s h ort er ( 6. 5 m o nt hs o verall) t ha n f or patie n ts wit h o ut brai n metastases treate d 
o n t he C O M BI -d trial ( 1 2 m o nt hs ),1 0 ,1 1 a n d e ve n s h orter ( 4. 5 m o nt hs) f or patie nts wit h 
s ym pt o matic brai n metastases. A si milar tre n d has bee n o bser ve d f or ve m urafe ni b a n d
e nc orafe ni b. 8 ,9 ,1 2 ,1 3 Alt h o u g h ra n d o mize d trials of I CI s als o e xcl u de d patie nts wit h u ntreate d, 
s ym pt o matic a n d/ or pr o gressi ve brai n metastases at baseli ne, i n t he P hase 2 Ke y n ote - 2 0 4 
trial, i pil u mi ma b pl us ni v ol u ma b treat me nt of metastatic mela n o ma patie nts wit h 
as ym pt o matic, u ntreate d brai n metastases ac hie ve d o verall a n d i ntracra nial res p o nse rates of 
5 4 a n d 5 9 % (i ncl u di n g 2 9 % i ntracra nial C R), wit h me dia n i ntracra nial a n d o verall D o R n ot
reac he d ( 1 2 m o nt h la n d mar k gl o bal P F S was 5 6. 6 %) .1 4 H o we ver, treat me nt wit h I CI s is 
t o xic, wit h hi g h rates of se vere A Es ; as a res ult, o nl y a mi n orit y of patie nts recei ve all 
prescri be d d oses. F urt her m ore, t he efficac y  of I CIs i n patie nts wit h sy m pt o matic a n d/ or 
pr o gressi ve brai n metastases is n ot k n o w n.
F or t hese reas o ns, patie nts wit h B R A F V 6 0 0 -m uta nt mela n o ma a n d N S C L C wit h metastases 
t o t he brai n us uall y recei ve l ocal brai n t hera p y (e g, S R S, s ur gical resecti o n, W B R T) at s o me 
p oi nt d uri n g t heir disease c o urse. S R S a n d s ur ger y are ge nerall y  li mite d t o 3 or fe wer lesi o ns 
( S R S) or a si n gle lar ge ( > 3 c m) or p osteri or f ossa lesi o n (s ur ger y ) a n d d o n o t c o ntr ol disease 
at u ntreate d sites.   W B R T
ca uses accelerate d c o g niti ve decli ne a n d was n o better t ha n 
s u p p orti ve care i n N S C L C patie nts. 1 5 A m ultice nter retr os pecti ve re vie w re p orte d t hat 
3 7 % of t he patie nts wit h brai n metastases treate d wit h stere otactic ra di os ur ger y  al o ne 
u n der we nt sal va ge t hera p y  at a me dia n 5. 7 m o nt hs after treat me nt c o m pare d t o 7 % after a 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 3 7
me dia n 8 m o nt hs w he n S R S was f oll o we d b y  W B R T.1 6  T he o pti mal n u m ber of lesi o ns a n d 
fracti o natio n sc he d ules a p pr o priate f or S R S, t he feasi bilit y of re peat S R S a n d t he r ole of 
W B R T
gi v e n ne ur ol o gical t o xicit y re mai n t o pics of i n vesti gati o n. 
B R A F V 6 0 0 m utati o ns occ ur i n se veral ot her ca ncers wit h brai n i n v ol ve me nt, i ncl u di n g 
pri mar y  brai n t u m ors. T heir occ urre nce i n pe diatric gli o mas is pre dicti ve of p o or res p o nse t o 
c o n ve nti o nal ra dia ti o n a n d c he m ot hera py. 1 7 B R A F i n hi bit ors al o ne or i n c o m bi nati o n wit h
M E K
i n hi bit ors ha ve li mite d acti vit y i n patie nts wit h B R A F V 6 0 0 -m uta nt pri mar y  gli o mas, 
es peciall y f or patie nts wit h hi g her gra de t u m ors (ie, gli o blast o ma) .1 8 ,1 9 ,2 0
T heref ore, t here is a n ur ge nt nee d t o i de ntif y  ne w treat me nt a p pr oac hes t hat tar get B R A F
V 6 0 0- m uta nt ca ncers b ot h s y ste mically a n d i n t he brai n.
2. 2. 1. N o ncli nic al P h ar m ac ol o g y of P F - 0 7 2 8 4 8 9 0 
P F - 0 7 2 8 4 8 9 0 is a n A T P-c o m petiti ve i n hi bit or of t he B R A F ki nase fa mil y  t hat de m o nstrates 
distri b uti o n t o t he brai n. Its bi ol o gical acti vit y has bee n e val uate d i n n u mer o us n o n-G L P i n 
vitr o, cell c ult ure, a n d i n vi v o st u dies. I n cell-free s yste ms, P F - 0 7 2 8 4 8 9 0 i n hi bits B R A F a n d 
C R A F wit h 
. A d diti o nall y , P F -0 7 2 8 4 8 9 0 i n hi bits t he cli nicall y rele va nt 
ki nase d o mai n B R A F V 6 0 0 m uta nts ( V 6 0 0 E a n d V 6 0 0 K) at si milar c o nce ntrati o ns. I n 
cell-base d s ys te ms, P F - 0 7 2 8 4 8 9 0
 
I n vi v o, P F - 0 7 2 8 4 8 9 0 has bee n e val uate d f or its a bilit y  t o i n hi bit p h os p h or ylati o n of E R K 
si g nal tra ns d ucti o n pat h wa y pr otei n i n t u m ors a n d t o c o ntr ol B R A F V 6 0 0 E cell li ne a n d 
patie nt -deri ve d xe n o graft t u m or gr o wt h i n n u de mice w he n i m pla n te d eit her s u bc uta ne o usly 
or i ntracra niall y .
 
 I n 
all m o dels, re gar dless of t u m or l ocati o n, ma xi mal efficac y was o bser ve d i n d ose ra n ges of 
. T he a d diti o n of t he M E K i n hi bit or, bi ni meti ni b, i m pr o ve d acti vit y  i n 
s o me m o dels w hic h s u p p orts c o m bi nati o n t hera py of P F - 0 7 2 8 4 8 9 0 a n d bi ni meti ni b. F urt her, 
acti vit y i n i ntracra nial m o dels was s u peri or i n d ura bilit y t o a p pr o ve d B R A F/ M E K i n hi bit ors 
t hat d o n ot effecti vel y partiti o n t o t he brai n, s u p p orti n g t he h yp ot hesis t hat a brai n pe netra nt 
B R A F V 6 0 0 i n hi bit or ma y  pr o vi de a d diti o nal t hera pe utic be nefit i n patie nts wit h B R A F 
V 6 0 0 m uta nt brai n m etastases.   
P F - 0 7 2 8 4 8 9 0 was e val uate d at c o nce ntrati o ns u p 
 
 I n a d diti o n, sec o n dar y p har mac o dy n a mic 
e val uati o ns s h o we d t hat P F -0 7 2 8 4 8 9 0 de m o nstrate d hi g h selecti vit y  f or
 
Base d o n t hese res ults, off -tar get ki nase, rece pt or, a n d 
tra ns p orter acti vit y at rele va nt free-t hera pe utic c o nce ntrati o ns i n vi v o is n ot a ntici pate d. 
 
 
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P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 3 8
2. 2. 2. N o ncli nic al P h ar m ac o ki netics a n d Met a b olis m of P F - 0 7 2 8 4 8 9 0 
Plas ma P K of P F -0 7 2 8 4 8 9 0 has bee n i n vesti gate d f oll o wi n g si n gle oral a n d I V d oses i n 
m o use, rat, d o g a n d m o n ke y . After I V a d mi nistrati o n acr oss precli nical s pecies,
P F - 0 7 2 8 4 8 9 0 P K para meters c o nsiste ntl y  de m o nstrate d l o w t otal sys te mic plas ma cleara nce, 
l o w he patic e xtracti o n ( < 1 0 %), a n d l o w v ol u me of distri b uti o n at stea d y state ( Vss
< 1. 0 L/ k g). T he mea n
 
T he l o w cleara nce a n d l o w v ol u me of distri b uti o n of 
P F -0 7 2 8 4 8 9 0 c orrelate d wit h t he hi g h o bser ve d i n vitr o plas ma pr otei n bi n di n g acr oss 
s pecies ( 9 9. 2 % i n h u ma ns). After oral a d mi nistrati o n, plas ma e x p os ures of P F -0 7 2 8 4 8 9 0 
( A U C a n d Cma x ) i ncrease d wit h d ose i n all s pecies a n d t he a bs ol ute oral bi oa vaila bilit y was 
m o derate t o c o m plete.
G L P T K st u dies i n t he rat ( d oses of 1 0, 3 0 a n d 6 0 m g/ k g) a n d 
m o n ke y  ( d oses of 1 0, 3 0 a n d 1 0 0 m g/ k g) s h o we d less t ha n d ose-pr o p orti o nal e x p os ures, as 
mi g ht be e x pecte d base d o n relati vely l o w a q ue o us s ol u bilit y (ie, i n si m ulate d gastric fl ui d at 
3 7 oC at a p H of 1 . 2, 1 3 1. 6 µ g / m L, a n d i n faste d state si m ulate d i ntesti nal fl ui d at a p H of 6. 5, 
7. 6 µ g/ m L ). 
P F -0 7 2 8 4 8 9 0 was desi g ne d t o distri b ute t o t he brai n b y  g o o d cell ular me m bra ne per mea bilit y 
a n d mi ni mal effl u x t hr o u g h tra ns p orters e x presse d i n t he bl o o d- brai n barrier i ncl u di n g P- g p
a n d B C R P.
As s uc h, i n vitr o e x peri me nts i n dicate d t hat P F - 0 7 2 8 4 8 9 0 ha d hi g h per mea bilit y  
a n d was n ot a s u bstrate f or h u ma n P -g p. Alt h o u g h P F - 0 7 2 8 4 8 9 0 was a s u bstrate f or h u ma n 
B C R P , its c o m bi nati o n of hi g h i ntri nsic per mea bilit y a n d m o dest effl u x rati o of 3. 7 i n a n 
o vere x presse d s ys te m was t h o u g ht t o be acce pta ble as mi ni mal effl u x , w hic h was f urt her 
e x pl ore d i n vi v o . After oral a d mi nistrati o n of P F - 0 7 2 8 4 8 9 0 t o mice a n d rats, P F -0 7 2 8 4 8 9 0
distri b ute d t o brai n w here t he free fracti o n a dj uste d e x p os ure i n brai n was a p pr o xi matel y 
pr o p orti o nal t o t he free fracti o n a dj uste d e x p os ure i n plas ma (ie, t he u n b o u n d c o nce ntrati o n 
i n t he brai n di vi de d b y  t he u n b o u nd c o nce ntrati o n i n t he plas ma a p pr oac he d 1. 0).
T he r o utes of P F -0 7 2 8 4 8 9 0 meta b olis m were ge nerall y c o nser ve d acr oss n o ncli nical s pecies. 
H o we ver, t he efficie nc y  of P F - 0 7 2 8 4 8 9 0 meta b olis m t o s pecific meta b olites varie d acr oss 
s pecies. I n vitr o a n d i n vi v o meta b olite i de ntificati o n s u g geste d t hat P F -0 7 2 8 4 8 9 0 was 
meta b olize d t hr o u g h m ulti ple o xi dati ve a n d/ or gl uc ur o n os yl tra nsferase e nz ymes. 
C o m paris o ns acr oss s pecies s u g geste d t hat direct N- gl uc ur o ni dati o n is pre dicte d t o be t he 
pre d o mi n a nt meta b olic r o ute i n h u ma ns. P F -0 7 2 8 4 8 9 0 gl uc ur o ni dati o n is t he pri mar y  r o ute 
of meta b olis m i n h u ma n he pat oc y tes wit h mi n or c o ntri b uti o n fr o m gl uc ose c o nj u gati o n a n d 
o xi dati o n me diate d b y  C Y P 3 A 4 a n d al de h y de o xi dase .
 
 Re nal cleara nce was a mi n or eli mi nati o n r o ute of 
u nc h a n ge d P F -0 7 2 8 4 8 9 0 i n rats ( < 1 % of a n I V d ose) a n d is pre dicte d t o be a mi n or r o ute 
acr oss all s pecies, i ncl u di n g h u ma ns.
 
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P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 3 9
T he P K D DI p ote ntial of P F - 0 7 2 8 4 8 9 0 f or e nz ymes was assesse d i n vari o us i n vitr o s y ste ms. 
P F - 0 7 2 8 4 8 9 0 i n hi bite d C Y P 2 C 9 ( Ki = 8. 0 µ M ) a n d C Y P 3 A 4 ( Ki = 6. 8 µ M ). T he K i val ues 
f or P F- 0 7 2 8 4 8 9 0 f or all t he ot her C Y Ps e val uate d were greater t ha n 1 0 µM. 
P F -0 7 2 8 4 8 9 0 
was a wea k ti me -de pe n de nt i n hi bit or of C Y P 3 A 4 ( K I = 2 0. 8 μ M a n d k i nact = 0. 1 4 9 mi n - 1) a n d 
a wea k c o nce ntrati o n -de pe n de nt i n d ucer of C Y P 3 A 4. 
 
T he D DI p ote ntial of P F - 0 7 2 8 4 8 9 0 f or tra ns p orters was als o assesse d i n vitr o. As me nti o ne d 
earlier, P F -0 7 2 8 4 8 9 0 was a s u bstrate f or B C R P , w hic h is als o e x presse d i n t he GI tract a n d 
t heref ore prese nts t he p ote ntial f or a D DI i n ter ms of rate of a bs or pti o n. P F - 0 7 2 8 4 8 9 0 was 
a n i n hi bit or of P- g p i n M D R 1 L L C -P K 1 cell m o n ola y ers (I C 5 0 = 2. 9 µ M ). T he i n hi biti o n of 
vari o us tra ns p orters b y P F -0 7 2 8 4 8 9 0 was st u die d i n tra nsfecte d cells or vesicles. T he I C 5 0
f or P F- 0 7 2 8 4 8 9 0 i n hi biti o n of O A T P 1 B 1 a n d O A T P 1 B 3 were 5. 7 a n d 8. 0 µM, res pecti vel y. 
P F -0 7 2 8 4 8 9 0 was n ot a p o te nt i n hi bit or of ot her tra ns p orters teste d ( B C R P, B S E P, M A T E 1, 
M A T E 2 -K, M R P 2, O A T 1 , O A T 3, O A T P 1 B 1, O A T P 1 B 3, O C T 1, O C T 2 a n d P -g p, I C5 0
a p pr o xi matel y 1 0 µ M or hi g her).
T he a bilit y  of bi ni meti ni b t o i m pact P F-0 7 2 8 4 8 9 0 P K or P F -0 7 2 8 4 8 9 0 t o i m pact bi ni meti ni b 
P K a p pears t o be mi ni mal . Bi ni meti ni b is a s u bstrate of P -g p , but n o cli nicall y  i m p orta nt 
dr u g i nteracti o ns ha ve bee n o bser ve d wit h bi ni meti ni b eit her as a victi m or per petrat or of 
i nteracti o ns. 
2. 2. 3. N o ncli nic al S afet y of P F - 0 7 2 8 4 8 9 0
T he ac ute, 2 8 -d a y  st u dies i n S pra g ue Da wle y rats a n d c yn o m ol g us m o n ke ys were c o n d ucte d 
i n acc or da nce wit h i nter nati o nal re g ulat or y g ui deli nes f or n o ncli nical t o xicit y st u dies a n d i n 
a d here nce t o c urre nt G L P re g ulati o ns, a n d were i nte n de d t o s u p p ort a d mi nistrati o n of 
P F - 0 7 2 8 4 8 9 0 i n h u ma ns. T hese st u dies were s u p ple me nte d wit h G L P ge n ot o xicit y  assa ys
( bacterial m uta ge nicity , i n vitr o m o use l ym p h o ma, c o met assa y , a n d i n vi v o micr o n ucle us)
a n d a G L P p h ot ot o xicit y  st u d y, a n d 4 G L P safety p har mac ol o g y  st u dies (i n vitr o h E R G, i n 
vi v o cardi o vasc ular tele metr y i n m o n ke y, a n d Ir wi n F O B a n d G I m otilit y i n rats).
F oll o wi n g 2 8 da y s of Q D oral a d mi nistrati o n of P F - 0 7 2 8 4 8 9 0 ( 
 m g/ k g) t o 
S pra g ue Da wle y  rats, t he t o xic ol o gical res p o nse was c haracterize d pri maril y by cli nical 
o bser vati o ns of hi n d li m b s well i n g re q uiri n g e ut ha nasia of 6 ( o ut of 1 5 0) 
P F - 0 7 2 8 4 8 9 0-treate d rats, mil d cli nical pat h ol o g y  c ha n ges ( decrease d A L P, decrease d re d 
cell para meters, i ncrease d retic ul oc y tes, i ncrease d w hite cell para meters, i ncrease d A P T T 
a n d i ncrease d ur i ne v ol u mes); all of w hic h res ol ve d i n rec o ver y a ni mals. It is im p orta nt t o 
n ote t hat ma n y  P F -0 7 2 8 4 8 9 0 -treate d a ni mals were n ote d t o ha ve blisteri n g, s welli n g or 
sca b bi n g o n t he hi n dli m bs a n d, i n all b ut t he 6 a ni mals t hat were e ut ha nize d, t he fi n di n gs 
res ol ve d or were of re d uce d se verity a n d i nci de nce wit h c o nti n ue d d osi n g.  Or ga n wei g ht 
decreases i n e pi di d y m i des a n d i ncreases i n heart at 
 m g/ k g  
 i n males a n d/ or 
fe males a n d i ncreases i n li ver, o varies, a n d s plee n i n males a n d/ or fe males were n ote d at all 
d ose le vels. M y x o mat o us de ge nerati o n of t he heart val ves at  
 m g/ k g, de ge nerati o n 
of se mi nifer o us t u b ules i n t he testes a n d de bris i n t he l u me n a n d decrease d cell ularit y  of 
 
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P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 4 0
s per m i n t he e pi di d ymi des at 
m g/ k g were c o nsi der e d a d verse hist o pat h ol o g y 
c ha n ges fr o m ter mi nal necr o ps y. Pr o gressi o n of t he heart val ve fi n di n g o ver ti me p ossi bl y  
c o ul d lea d t o i nc o m plete cl os ure of t he val ves. T he effects see n i n male re pr o d ucti ve or ga ns 
w o ul d i m pact fertilit y .  All P F - 0 7 2 8 4 8 9 0-relate d c ha n ges fr o m ter mi nal necr o ps y e x hi bite d 
si g nifica nt rec o ver y, e xce pt f or t h ose i n t he testes a n d e pi di d ymi des at 
m g/ k g. 
Base d o n t he re q uire me nt f or e ut ha nasia d ue t o i m pair me nt of m o bilit y  a n d pai n at t he l o wer 
d ose le vel a n d a d verse pat h o l o g y fi n di n gs at 
m g/ k g, t he N O A E L c o ul d n ot be 
deter mi ne d .  I n li g ht of t he i nte n de d t hera pe utic usa ge of t his c o m p o u n d i n patie nts wit h 
a d va nce d ca ncer, t he I C H S 9 g ui da nce w o ul d a p pl y . T he S T D 1 0 was deter mi ne d fr o m test 
article-relate d let halit y or irre versi ble a n d life-t hreate ni n g fi n di n gs. T h us, t he 
 
m g/ k g base d o n t he earl y  e ut ha nasia of 4 a ni mals at t hat d ose le vel, d ue t o i m paire d 
m o bilit y  a n d cli nical si g ns c o nsiste nt wit h pai n ( 4 o ut of 3 2). T his c orres p o n ds t o 
 
 males a n d 
fe males, res pecti vely. A n d a h u ma n e q ui vale nt d ose of  
 m g/ m 2.
F oll o wi n g 2 8 d a y s of Q D oral a d mi nistrati o n of P F - 0 7 2 8 4 8 9 0 (
m g/ k g) i n 
c yn o m ol g us m o n ke y s, n o a d verse t o xic ol o gical fi n di n gs were see n a n d t he o nl y 
hist o pat h ol o gic fi n di n g was mi ni mal st o mac h ulcerati o n at t he hi g h d ose. Decreases i n t he 
wei g hts of male re pr o d ucti ve or ga ns c o ul d p orte n d effects o n fertilit y  i n l o n ger ter m st u dies 
i n m ore mat ure a ni mals. Gi ve n t he lac k of a d verse fi n di n gs at a n y d ose le vel, t he N O A E L 
a n d H N S T D f or dail y oral d osi n g of P F - 0 7 2 8 4 8 9 0 i n male a n d fe male c yn o m ol g us m o n ke y s 
f or 2 8 d a y s was 
m g/ k g. T his c orres p o n ds t o a n 
T he testic ular a n d e pi di d y mal t o xicit y  o bser ve d i n rats wit h fi n di n gs of atr o p h y, 
de ge nerati o n, e pi di d y mal de bris a n d h y p os per mia were o bser ve d at h u ma n e q ui vale nt d oses 
a p pr o xi matel y 6 ti mes greater t ha n t he pla n ne d i nitial d ose i n h u ma ns. H o we ver, base d o n 
pre dicte d h u ma n P K, t he e x p os ure wi n d o w is pre dicte d t o be t he 
. T hese effects o n 
male re pr o d ucti ve or ga ns are k n o w n , o n-tar get effects of B R A F i n hi biti o n a n d ha ve bee n 
re p orte d f or da brafe ni b2 1 a n d e nc orafe ni b .2 2
Gi ve n t hat P F - 0 7 2 8 4 8 9 0 was desi g ne d t o be brai n -pe netra nt i n or der t o a d dress t he u n met 
nee d i n patie nts wit h B R A F V 6 0 0 E brai n metastases, ne ur ol o gical safet y i s of para m o u nt 
i m p orta nce. T here were n o pat h ol o gical fi n di n gs i n t he brai ns of rats or m o n ke ys recei vi n g 
P F - 0 7 2 8 4 8 9 0 f or 2 8 c o nsec uti ve da ys. M ost i m p orta ntl y , detaile d ne ur ol o gical assess me nts 
perf or me d d uri n g t he c o urse of b ot h re peat -d ose t o xic ol o g y  st u dies re veale d n o effect o n 
m ot or acti vit y , reacti o ns t o e n vir o n mental sti m uli, oc ul o m ot or, p u pillar y  assess me nts or b o d y  
te m perat ure.
I n a d diti o n t o t he n o ncli nical i n vesti gati o ns s u m marize d a b o ve, t he wei g ht of e vi de nce fr o m 
t he ge n ot o xicit y  batter y  of assa ys s h o ws l o w ge n ot o xic ris k a n d n o a d verse effects o n GI 
m uc osa i n t he rat GI irritati o n assa y.
 
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P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 4 1
Safet y  p har mac ol o g y st u dies were c o n d ucte d i n rats a n d m o n ke ys t o assess t he effects of 
P F -0 7 2 8 4 8 9 0 o n ke y  or ga n s yste ms (car di o vasc ular, res pirat or y, ne ur o be ha vi oral a n d 
gastr oi ntesti nal f u ncti o n).  All safet y p har mac ol o g y st u dies were c o n d ucte d i n acc or da nce 
wit h G L P ( 2 1 C F R § 5 8).  Rats recei ve d si n gle oral d oses of
 
of P F - 0 7 2 8 4 8 9 0.  
T here were n o si g nifica nt i n vi v o safet y  p har mac ol o g y fi n di n gs at d oses u p t o 
 
 i n m o n ke ys.
P F - 0 7 2 8 4 8 9 0 was deter mi ne d t o ha ve p h ot o t oxic p ote ntial i n t he i n vitr o ne utral re d assa y . 
T h us, it is rec o m me n de d t hat patie nts recei vi n g P F - 0 7 2 8 4 8 9 0 s h o ul d a v oi d e xcessi ve direct 
s u n e x p os ure a n d ta ke a p pr o priate preca uti o ns (e g, s u nscree n, U V-pr otecti ve cl ot hi n g, etc.) 
T he o verall c o ncl usi o n fr o m t hese st u dies is t hat P F - 0 7 2 8 4 8 9 0 has a n acce pta ble safet y 
pr ofile f or h u ma n a d mi nistrati o n at t he d oses selecte d f or treati n g patie nts wit h B R A F 
V 6 0 0 E -dri ve n mali g na ncies. 
2. 2. 4. Cli nic al O ver vie w
2. 2. 4. 1. P F -0 7 2 8 4 8 9 0 
D uri n g t he c o n d uct of t his st u d y , please refer t o t he P F -0 7 2 8 4 8 9 0 I n vesti gat or Br oc h ure f or 
u p date d i nf or mati o n re gar di n g cli nical e x perie nce.
2. 2. 4. 2. Bi ni meti ni b
Bi ni meti ni b is a p ote nt a n d selecti ve all osteric, A T P- u nc o m petiti ve i n hi bit or of M E K 1/ 2.
Bi ni meti ni b 4 5 m g orall y BI D i n c o m bi nati o n wit h t he p ote nt a n d selecti ve A T P -c o m petiti ve 
i n hi bit or of B R A F V 6 0 0 - m uta nt ki nase e nc orafe ni b 4 5 0 m g orall y  Q D ha ve bee n a p pr o ve d 
b y  t he U S F D A, t he E M A a n d ot her gl o bal healt h a ut h orities f or t he treat me nt of patie nts 
wit h u nresecta ble or metastatic mela n o ma wit h a B R A F V 6 0 0 E or V 6 0 0 K m utati o n . 
Detaile d i nf or mati o n re gar di n g n o ncli nical st u dies a n d cli nical p har mac o ki netics of 
bi ni meti ni b are prese nte d i n t he bi ni meti ni b I nvesti gat or’s Br oc h ure .
Cli nical Safet y  of Bi ni meti ni b as a Si n gle A ge nt
T he ma xi m u m well -t olerate d d ose of bi ni meti ni b w he n gi ve n as a si n gle a ge nt is 
6 0 m g BI D .2 3 A n o bser ve d i nci de nce of re versi ble reti nal e ve nts a n d ras h le d t o t he selecti o n 
of 4 5 m g BI D as t he R P 2 D.
A m o n g 4 4 patie nts recei vi n g bi ni meti ni b at t he R P 2 D i n t he 
P hase 1 trial, t he m ost c o m m o n A Es (≥2 0 %, all gra des) were ras h ( 7 7 %), na usea ( 6 1 %), 
v o miti n g ( 5 2 %), diarr hea ( 3 9 %), peri p heral e de ma ( 4 5 %) a n d fati g ue ( 4 6 %). C o m bi nati o n 
of bi ni meti ni b at t his d ose wit h e nc orafe ni b at 4 5 0 m g Q D res ulte d i n a si g nifica ntl y  l o wer 
fre q ue nc y of ras h wit h si milar fre q ue ncies of gastr oi ntesti nal A Es. 
Detaile d i nf or mati o n re gar di n g cli nical safet y of bi ni meti ni b is prese nte d i n t he bi ni meti ni b 
I n vesti gat or’s Br oc h ure.
 
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 4 2
Cli nical Safet y of Bi ni meti ni b i n C o m bi nati o n W it h a B R A F I n hi bit or
As descri be d a b o ve, b i ni meti ni b i n c o m bi nati o n wit h enc orafe ni b ha ve bee n a p pr o ve d f or t he 
treat me nt of patie nts wit h u nresecta ble or metastatic mela n o ma wit h a B R A F V 6 0 0 E or 
V 6 0 0 K m utati o n .
T h is is c o nsiste nt wit h a b o d y of literat ure t hat s u g gests t he c o m bi nati o n of a M E K i n hi bit or 
a n d a B R A F i n hi bit or res ults i n i m pr o ve d t olera bilit y  c o m pare d wit h eit her a ge nt al o ne, d ue 
t o t he a meli orati o n of para d o xical acti vati o n of wil d-t ype B R A F i n n or mal tiss ues w he n a 
B R A F i n hi bit or is utilize d as m o n ot hera p y. 8 ,1 0 ,2 4 ,2 5 ,2 6
A m o n g patie nts recei vi n g e nc orafe ni b a n d bi ni meti ni b c o m bi nati o n t hera p y i n t he 
ra n d o mize d cli nical trial of e nc orafe ni b a n d bi ni meti ni b (C O L U M B U S trial)9 ,2 7 t he m ost 
c o m m o n a d verse reacti o ns ( ≥2 0 %, all gra des) w ere fati g ue ( 4 3 %), na usea ( 4 1 %), diarr hea 
( 3 6 %), v o miti n g ( 3 0 %), a b d o mi nal pai n ( 2 8 %), art hral gia ( 2 6 %), my o pat h y ( 2 3 %), 
h y per kerat osis ( 2 3 %), ras h ( 2 2 %), hea dac he ( 2 2 %), c o nsti pati o n ( 2 2 %), vis ual i m pair me nt 
( 2 0 %) a n d ser o us reti n o pat h y ( 2 0 %). M ost of t h ese t o xicities were ge nerall y re versi ble a n d 
ma na gea ble b y s u p p orti ve me dical care, d ose m o dificati o ns or treat me nt disc o nti n uati o n. 
Ot her cli nicall y i m p orta nt a d verse reacti o ns occ urri n g i n < 1 0 % of patie nts were facial 
paresis, pa ncreatitis, pa n nic ulitis, dr u g h y perse nsiti vit y  a n d c olitis. The m ost c o m m o n 
la b orat or y a b n or malities (≥2 %, Gra de 3 or 4) were i ncrease d G G T ( 1 1%), i ncrease d A L T 
( 6%), i ncrease d creati ne p h os p h o ki nase ( 5 %), i ncrease d fasti n g gl uc ose ( 5 %), i ncrease d 
creati ni ne (4 %), a ne mia ( 4 %), h y p o natre mia ( 4 %), i ncrease d A S T (3 %) , ne utr o pe nia ( 3 %) 
a n d l ym p h o pe nia ( 2 %).
Detaile d i nf or mati o n re gar di n g cli nical safet y is prese nte d i n t he 
res pecti ve in vesti gat or’s b r oc h ures f or e nc orafe ni b a n d bi ni meti ni b.
I m p orta nt p ote ntial a d verse effects ass ociate d wit h t he a d mi nistrati o n of t he c o m bi nati o n of 
e nc orafe ni b a n d bi ni meti ni b esta blis he d pri maril y  fr o m safety data fr o m t he C O L U M B U S 
st u d y a n d, w here i n dicate d, fr o m ot her st u dies of t he c o m bi nati o n, i ncl u de:

Ne w pri m ar y m ali g n a ncies: Base d o n its mec ha nis m of acti o n, e nc orafe ni b ma y  
pr o m ote mali g na ncies ass ociate d wit h acti vati o n of R A S t hr o u g h m utati o n or ot her 
mec ha nis ms. C uta ne o us a n d n o n -c uta ne o us mali g na ncies occ urre d i n patie nts,
i ncl u di n g c uta ne o us s q ua m o us carci n o ma/ kerat oaca nt h o m a ( 2. 6%) a n d basal cell 
carci n o ma ( 1. 6 %).

Left ve ntric ul ar d ysf u ncti o n: S y m pt o matic or as y m pt o matic decreases i n ejecti o n 
fracti o n occ urre d i n 7 % of patie nts, wit h Gra de 3 left ve ntric ular dys f u ncti o n 
occ urri n g i n 1. 6 % of patie nts. 

He m orr h a ge: He m orr ha ge occ urre d i n 1 9 % of patie nts, wit h e ve nts ≥Gra de 3 
occ urri n g i n 3. 2 % of patie nts. Fatal i ntracra nial he m orr ha ge i n t he setti n g of ne w or 
pr o gressi ve brai n metastases occ urre d i n 1. 6 % of patie nts. T he m ost fre q ue nt 
he m orr ha gic e ve nts were gastr oi ntesti nal, i ncl u di n g rectal he m orr ha ge ( 4. 2 %), 
he mat oc hezia ( 3. 1 %), a n d he m orr h oi dal he m orr ha ge ( 1 %) .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 4 3

Ve n o us t hr o m b oe m b olis m: Occ urre d i n 6 % of patie nts, i ncl u di n g 3. 1 % of patie nts 
w h o de vel o pe d p ul m o nar y e m b olis m.

Oc ul ar t o xicities: Ser o us reti n o pat h y  is a class effect of M E K i n hi bit ors. It is 
ge nerall y as y m pt o matic or mil dl y  sy m pt o matic a n d re versi ble. 2 8 Ser o us reti n o pat h y  
occ urre d i n 2 0 % of pat ie nts. S y m pt o matic ser o us reti n o pat h y  occ urre d i n 8 % of 
patie nts wit h n o cases of bli n d ness. T he me dia n ti me t o o nset of t he first e ve nt of 
ser o us reti n o pat hy (all gra des) was 1. 2 m o nt hs. R V O is a k n o w n class -relate d 
a d verse reacti o n of M E K i n hi bit ors a n d ma y  occ ur i n patie nts treate d wit h 
bi ni meti ni b i n c o m bi nati o n wit h e nc orafe ni b. I n patie nts wit h B R A F
m utati o n - p ositi ve mela n o ma acr oss m ulti ple cli nical trials, 0. 1 % of patie nts 
e x perie nce d R V O.

P ne u m o nitis/I nterstiti al L u n g Dise ase : P ne u m o nitis occ urre d i n 0. 3 % of patie nts 
wit h B R A F m utati o n -p ositi ve mela n o ma acr oss m ulti ple cli nical trials.

He p at ot o xicit y: T he i nci de nce of Gra de 3 or 4 i ncreases i n li ver f u ncti o n la b orat or y  
tests was 6 % f or A L T, 2. 6 % f or A S T, a n d 0. 5 % f or al kali ne p h os p hatase. N o patie nt 
e x perie nce d Gra de 3 or 4 ser u m bilir u bi n ele vati o n.

C K Ele v ati o n/ R h a b d o m y ol ysis : Asy m pt o matic ele vati o ns of la b orat or y  val ues of 
ser u m C K occ urre d i n 5 8 % of patie nts. R ha b d o m y ol y sis was re p orte d i n 0. 1 % of 
patie nts wit h B R A F m utati o n -p ositi ve m ela n o ma acr oss m ulti ple cli nical trials.

Q Tc Pr ol o n g ati o n: Q T pr ol o n gati o n has bee n o bser ve d i n patie nts treate d wit h 
B R A F i n hi bit ors. E nc orafe ni b is ass ociate d wit h d ose- de pe n de nt Q Tc i nter val 
pr ol o n gati o n i n s o me patie nts. I n t he C O L U M B U S st u d y, a n i ncrease i n Q Tc F 
t o > 5 0 0 msec was meas ure d i n 0. 5 % of patie nts.

E m br y o -Fet al T o xicit y: E nc orafe ni b or bi ni meti ni b ca n ca use fetal har m w he n 
a d mi nistere d t o pre g na nt w o me n ( base d o n a ni mal st u dies).
2. 3. Be nefit/ Ris k Assess me nt
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y 
e x pecte d A Es of P F -0 7 2 8 4 8 9 0 ma y be f o u n d i n t he I n vesti gat or’s Br oc h ure, w hic h is t he 
S R S D f or t his st u d y .
T he S R S D f or t he c o m bi nati o n a ge nt bi ni meti ni b is t he bi ni meti ni b 
In vesti gat or’s B r oc h ure.
P ote ntial ris ks of P F-0 7 2 8 4 8 9 0 base d o n n o ncli nical st u dies i ncl u de: GI  irritati o n, s ki n 
t o xicit y (h y per kerat osis), p h ot ot o xicit y , heart val ve ultrastr uct ural c ha n ges, h y per plasia of 
se veral tiss ues i ncl u di n g t he GI tract, i ncrease d uri ne v ol u me, decrease d testitc ular size a n d 
oli g os per mia, mil d decrease i n re d bl o o d cell c o u nt , mil d i ncrease i n w hite bl o o d cell c o u nt , 
i ncrease d heart rate a n d vasc ular i nfla m mati o n. All fi n di n gs are re versi ble e xce pt f or effects 
o n male re pr o d ucti ve or ga ns. Se veral are k n o w n class effects of B R A F i n hi bit ors 
(ie, e nc orafe ni b, da brafe ni b, ve m urafe ni b).
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 4 4
A d diti o nal p ote ntial ris ks of P F - 0 7 2 8 4 8 9 0 al o ne or i n c o m bi nati o n wit h bi ni meti ni b are 
base d o n t he well c haracterize d ris ks of a p pr o ve d B R A F i n hi bit ors a n d bi ni meti ni b fr o m 
pr o d uct la beli n g f or t hese a ge nts . T hese i ncl u de: 

B R A F i n hi bit ors: fati g ue, u veitis, ras h, na usea, v o miti n g, art hral gias, ne w pri mar y 
mali g na ncies, t u m or pr o m oti o n i n B R A F wil d- t ype t u m ors , e m br yo- fetal t o xicit y
( o nl y o bser ve d i n a ni mals t o date), arr h yt h mia, blee di n g i ncl u di n g i n t he GI  tract a n d 
brai n, s ki n reacti o n ( w hic h c o ul d be se vere), he pat ot o xicit y , car di o m yo pat h y , a n d 
facial paresis. 

Bi ni meti ni b : fati g ue, ser o us reti n o pat h y, reti nal vei n occl usi o n, left ve ntric ular 
d y sf u ncti o n, i nterstitial l u n g disease, na usea, v o miti n g, diarr hea, a b d o mi nal pai n, 
ve n o us t hr o m b oe m b olis m, he m orr ha ge, he pat ot o xicit y , C K ele vati o n/r ha b d o m yol ys is 
a n d e m br yo -fetal t o xiciti y ( o nly o bser ve d i n a ni mals t o date).
H o we ver, it is u n k n o w n w het her t hes e e ve nts will be ass ociate d wit h a d mi nistrati o n of 
P F - 0 7 2 8 4 8 9 0. T hese t o xicities are ge nerall y ma na gea ble b y d ose m o dificati o n, te m p orar y  
i nterr u pti o n or disc o nti n uati o n i n c o nj u ncti o n wit h esta blis he d me dical ma na ge me nt.
In vesti gat ors selecte d t o partici pate i n t his st u d y  are e x perie nce d i n ma na gi n g t o xicities 
ass ociate d wit h c o m bi nati o n B R A F a n d M E K i n hi bit or t hera p y. T his, t o get her wit h re g ular 
m o nit ori n g f or t hese p ote ntial t o xicities (see S o A a n d Secti o n 8. 2 ) a n d a p pr o priate patie nt 
c o u nseli n g re gar di n g p ote ntial t o xicities, mi ni mizes t he p ote ntial ris ks ass ocia te d wit h 
treat me nt wit h P F-0 7 2 8 4 8 9 0 al o ne a n d i n c o m bi nati o n wit h bi ni meti ni b. T he le vel of ris k 
c o m pare d t o t he p ote ntial be nefit t o partici pa nts wit h a d va nce d/ metastatic B R A F 
V 6 0 0 -m uta nt s oli d t u m or s is acce pta ble. 
T he st u d y  desi g n, i ncl u di n g i nitial P F-0 7 2 8 4 8 9 0 m o n ot hera p y  d ose escalati o n a n d safety a n d 
P K -g ui de d d ose i ncreases f or b ot h t he m o n ot hera p y  a n d bi ni meti ni b c o m bi nati o n d ose 
escalati o n s will miti gate t hese safet y ris ks. Res ults will i de ntif y  a safe d ose of P F- 0 7 2 8 4 8 9 0 
al o ne a n d i n c o m bi nati o n wit h bi ni meti ni b, a n d ma y  pr o vi de i nitial si g ns of cli nical acti vit y 
f or partici pa nts wit h B R A F V 6 0 0 -m uta nt s oli d t u m ors wit h a n d wit h o ut brai n met astasis. 
T he res ults fr o m t his st u d y will c o ntri b ute t o esta blis hi n g a ne w, p ote ntiall y  effecti ve 
treat me nt alter nati ve f or partici pa nts wit h B R A F V 6 0 0 -m uta nt s oli d t u m ors wit h a n d wit h o ut 
brai n i n v ol ve me nt.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 4 5
2. 3. 1. Ris k Assess me nt
P ote nti al Ris k of Cli nic al Si g nific a nce
S u m m ar y of D at a/ R ati o n ale f or Ris k
Miti g ati o n Str ate g y
St u d y I nter ve nti o n P F -0 7 2 8 4 8 9 0
P ote nti al risks ass oci ate d wit h P F -0 7 2 8 4 8 9 0 i ncl u de 
t he f oll o wi n g: GI irrit ati o n, ski n t oxicity,
p h ot ot oxicity, he art v alve ultr astr uct ur al c h a n ges, 
hy per pl asi a of sever al tiss ues i ncl u di n g t he GI tr act, 
i ncre ase d uri ne v ol u me, decre ase d testic ul ar size 
a n d oli g os per mi a, mil d decre ase i n re d bl o o d cell 
c o u nt, mil d i ncre ase i n w hite bl o o d cell c o u nt , 
incre ase d he art r ate a n d v asc ul ar i nfl a m m ati o n .
T he p ote nti al risks are b ase d o n n o ncli nic al 
t oxic ol o gy st u dies i n t he r at a n d m o nkey. GI 
irrit ati o n ( mi ni m al st o m ac h ulcer ati o ns) occ urre d 
i n t he 2 8-d ay m o nkey st u dy a n d it w as reversi ble. 
Str uct ur al c h a n ge s i n t he he art v alves (res ulti n g 
i n t hicke ni n g of t he v alve le aflets) w as see n i n t he 
2 8 -d ay r at st u dy wit h ne ar c o m plete res ol uti o n 
after a n o n - dos i n g rec overy peri o d. Ski n t oxicity 
(s welli n g, blisters, sc a bs) w as see n i n r at hi n d 
p a ws a n d w as reversi ble. A dverse effects o n m ale 
r at re pr o d uctive or g a ns (testic ul ar 
atr o p hy/ de ge ner ati o n a n d hy p os per mi a) of u p t o 
m arke d severity were see n a n d t hese wer e n ot 
c o m pletely reversi ble after a 2 8 -d ay n o n -d osi n g 
rec overy peri o d. Als o, i n t he r at o nly : mi ni m al t o
mil d decre ases i n R B C, H g b a n d Hc t; mi ni m al 
i ncre ases i n W B C, ne utr o p hils a n d e osi n o p hils 
a n d mil d i ncre ases i n A P T T were o bserve d a n d 
were re versi ble.
Eli gi bility criteri a h ave bee n selecte d t o e ns ure 
t h at o nly a p pr o pri ate p artici p a nts are i ncl u de d i n 
t he st u dy (see Secti o n 5 ).
A dverse eve nts a n d cli nic al l a b or at ory res ults 
will be m o nit ore d o n a n o n g oi n g b asis. 
I nstr ucti o ns f or m a n a gi n g p ote nti al c ases of GI, 
c ar di ac or ski n a b n or m alities or si g nific a nt 
c h a n ges i n cli nic al p at h ol o gy p ar a meters are 
pr ovi de d (see Secti o n 6. 6 ).
St u d y I nter ve nti o ns P F -0 7 2 8 4 8 9 0 + Bi ni m eti ni b 
P ote nti al risks ass oci ate d wit h P F -0 7 2 8 4 8 9 0 
( al o ne or i n c o m bi n ati o n wit h bi ni meti ni b ) m ay 
i ncl u de t he f oll o wi n g: 

B R A F i n hi bit ors: f ati g ue, uveitis, r as h, n a use a, 
v o miti n g, art hr al gi as, ne w pri m ary 
m ali g n a ncies, t u m or pr o m oti o n i n B R A F wil d -
ty pe t u m ors, e m bry o -fet al t oxicity ( o nly 
o bserve d i n a ni m als t o d ate), arr hyt h mi a, 
blee di n g i ncl u di n g i n t he GI tr act a n d br ai n, 
ski n re acti o n ( w hic h c o ul d be severe),
T he p ote nti al risks are b ase d o n pr o d uct l a beli n g 
f or bi ni meti ni b a n d a p pr ove d B R A F i n hi bi t ors.
Eli gi bility criteri a h ave bee n selecte d t o e ns ure 
t h at o nly a p pr o pri ate p artici p a nts are i ncl u de d i n 
t he st u dy (see Secti o n 5 ).
A dverse eve nts a n d cli nic al l a b or at ory res ults will 
be m o nit ore d o n a n o n g oi n g b asis. I nstr ucti o ns 
f or m a n a gi n g t hese p ote nti al risks are pr ovi de d
(see Secti o n 6. 6 a n d A p pe n di x 6 ).
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 4 6
he p at ot oxicity , c ar di o my o p at hy , a n d f aci al 
p aresis .

Bi ni meti ni b: f ati g ue, ser o us reti n o p at hy, 
reti n al vei n occl usi o n, left ve ntric ul ar 
dysf u ncti o n, i nterstiti al l u n g dise ase, n a use a, 
v o miti n g, di a rr he a, a b d o mi n al p ai n, ve n o us 
t hr o m b oe m b olis m, he m orr h a ge, he p at ot oxicity, 
C K elev ati o n/r h a b d o my olysis a n d e m bry o -fet al 
t oxicity ( o nly o bserve d i n a ni m als t o d ate).
St u d y Pr oce d ures 
U p t o 3 o pti o n al t u m or tiss ue bi o psies will be 
perf or me d d uri n g t he st u dy ( bef ore i niti ati n g st u dy 
tre at me nt, o n tre at me nt a n d at E O T/ dise ase 
pr o gressi o n o n/ after tre at me nt). 
T here is a risk of p ai n , blee di n g or i nfecti o n fr o m 
bi o psy .
All bi o psies are o pti o n al , o nly t o be perf or me d if 
t hey c a n be perf or me d s afely ( as assesse d by t he 
i nvesti g at or) a n d i nf or me d c o nse nt / asse nt is 
re q uire d.
Ot her 
B R A F testi n g
P artici p a nts will be eli gi ble f or t he st u dy b ase d o n 
i de ntific ati o n of a B R A F V 6 0 0 m ut ati o n. 
I n acc ur ate B R A F testi n g (ie, f alse p ositive or f alse 
ne g ative) m ay le a d t o i n a p pr o pri ate e nr oll me nt t o 
or excl usi o n fr o m t his st u dy. A p artici p a nt wit h a 
f alse ne g ative res ult m ay be excl u de d fr o m 
receivi n g p ote nti ally be nefici al st u dy i nterve nti o n. 
Alter n atively, a f alse p ositive res ult m ay le a d a 
p artici p a nt t o receive st u dy i nterve nti o n, w hic h 
m ay be i n a p pr o pri ate give n t he t u m or m ut ati o n 
st at us.
P artici p a nts m ust pr ovi de d oc u me nte d evi de nce 
(e g, re d acte d m olec ul ar re p ort(s)) of a B R A F 
V 6 0 0 m ut ati o n i n t u m or tiss ue or bl o o d 
(ie,
) as previ o usly deter mi ne d by P C R or 
N G S -b ase d l oc al l a b or at ory ass ay i n a C LI A or 
si mil arly certifie d l a b or at ory.  T h ere are d at a t o 
s u p p ort t he c o ncl usi o n t h at B R A F V 6 0 0 
m ut ati o n al testi n g is ge ner ally of g o o d q u ality 
wit hi n certifie d l a b or at ories wit hi n t he U nite d 
St ates a n d gl o b ally, wit h hi g h levels ( > 9 7 %) of 
i nterl a b or at ory c o nc or d a nce of res ults.2 9  
Eli gi ble p artici p a nts are re q uire d t o be refr act ory 
t o previ o us tre at me nt a n d h ave n o acce pt a ble 
alter n ative tre at me nt o pti o ns (see Sec ti o n 5. 1
I ncl usi o n Criteri a 6 f or s pecific re q uire me nts 
rel ate d t o pri or tre at me nt wit h a B RA F i n hi bit or).
T heref ore, t he risk of s o me p artici p a nts f ore g oi n g 
or del ayi n g a tre at me nt t h at is k n o w n t o be 
effective is mi ni m al. 
 
T)
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 4 7
2. 3. 2. Be nefit Assess me nt
Partici pa nts wit h B R A F V 6 0 0 -m uta nt s oli d t u m ors wit h or wit h o ut brai n i n v ol ve me nt, 
partic ularl y w he n s y m pt o matic a n d/ or pr o gressi ve i n t he brai n after sta n dar d l ocal a n d 
s yste mic treat me nts, ha ve hi g h u n met cli nical nee d. T reat me nt wit h P F-0 7 2 8 4 8 9 0 (al o ne a n d 
i n c o m bi nati o n wit h bi ni meti ni b) has t he p ote ntial t o alle viate m or bi dit y  a n d m ortalit y fr o m 
i ntracra nial disease i n v ol ve me nt, c o ntr ol disease i n t he brai n a n d e xte n d o verall disease 
c o ntr ol as a res ult.
2. 3. 3. O ver all Be nefit /Ris k C o ncl usi o n
Ta ki n g i nt o acc o u nt t he meas ures ta ke n t o mi ni mize ris k t o partici pa nts partici pati n g i n t his 
st u d y, t he p ote ntial ris ks i de ntifie d i n ass ociati o n wit h P F - 0 7 2 8 4 8 9 0 are j ustifie d b y t he 
a ntici pate d be nefits t hat ma y be aff or de d t o partici pa nts wit h B R A F V 6 0 0 -m uta nt s oli d 
t u m ors.
3. O B J E C TI V E S A N D E N D P O I N T S
T he st u d y  will be c o n d ucte d i n 2 parts ( P hase 1a a n d P hase 1 b ).  T he st u dy o bjecti ves a n d 
e n d p oi nts are prese nte d i n t he ta ble bel o w. 
O bjecti ves
E n d p oi nts
P h ase 1 a Pri m ar y: 
P h ase 1 a Pri m ar y:

T o assess t he safet y a n d t olera bilit y of 
P F 0 7 2 8 4 8 9 0 at i ncreasi n g d ose le vels, t o esti mate 
t he M T D, a n d t o select t he rec o m me n de d d ose 
f or f urt her st u d y, b ot h as a si n gle a ge nt a n d i n 
c o m bi nati o n wit h bi ni meti ni b, i n partici pa nts 
wit h B R A F V 6 0 0 m utate d a d va nce d s oli d t u m or 
mali g na ncies wit h a n d wit h o ut brai n 
i n v ol ve me nt.

I nci de nce of C ycle 1 D L Ts.

M T D/rec o m me n de d d ose f or f urt her st u d y .

A Es as c haracterize d b y t y pe, fre q ue nc y, se verit y (as 
gra de d b y N CI C T C A E versi o n 5. 0), ti mi n g, 
seri o us ness, a n d relati o ns hi p t o st u d y t hera p y.

La b orat or y a b n or malities as c haracterize d b y t y pe, 
fre q ue nc y, se verit y (as gra de d b y N CI C T C A E 
versi o n 5. 0), a n d ti mi n g .

I nci de nce of d ose i nterr u pti o ns, d ose m o dificati o ns 
a n d disc o nti n uati o ns d ue t o A Es .
P h ase 1 a Sec o n d ar y: 
P h ase 1 a Sec o n d ar y:

T o c haracterize t he si n gle- a n d m ulti ple -d ose P K of 
P F 0 7 2 8 4 8 9 0 as a si n gle a ge nt a n d i n c o m bi nati o n wit h 
bi ni meti ni b a n d of bi ni meti ni b i n c o m bi nati o n wit h 
P F 0 7 2 8 4 8 9 0 .

P K para meters of P F -0 7 2 8 4 8 9 0 a n d bi ni meti ni b: 

Si n gle d ose : Cma x , Tma x , A U Clast, a n d as data per mit, 
t½ , A U Ci nf, C L/ F a n d Vz/ F.

M ulti ple d ose (ass u mi n g stea d y state is ac hie ve d):
C ss, ma x, Tss, ma x, A U Css,τ, Css, mi n, a n d as data per mit, 
C L ss/ F, Vss/ F, t½ a n d R ac ( A U Css,τ/ AU C s d,τ).

T o e val uate preli mi nar y cli nical acti vit y of 
P F 0 7 2 8 4 8 9 0 as a si n gle a ge nt a n d i n c o m bi nati o n wit h 
bi ni meti ni b .

E xtracra nial res p o nse b y R E CI S T versi o n 1. 1 .

I ntracra nial res p o nse b y m R E CI S T versi o n 1. 1.

O verall res p o nse (c o m bi ne d e xtracra nial a n d 
i ntracra nial) b y m R E CI S T versi o n 1. 1 .

R A N O f or pri mar y brai n t u m ors .
P h ase 1 a Terti ar y/ E x pl or at or y:
P h ase 1 a Terti ar y/ E x pl or at or y:

T o e x pl ore t he effect of 
 o n 
P F 0 7 2 8 4 8 9 0 e x p os ures i n partici pa nts treate d wit h 

P F - 0 7 2 8 4 8 9 0 P K para meters (si n gle d ose Cma x a n d 
A U C last; m ulti ple d ose Css, ma x, A U Css,τ) i n 
part ici pa nts 
.
 
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 4 8
O bjecti ves
E n d p oi nts
P F 0 7 2 8 4 8 9 0 as a si n gle a ge nt a n d i n c o m bi nati o n wit h 
bi ni meti ni b .

T o e x pl ore t he brai n pe netrati o n of P F 0 7 2 8 4 8 9 0 as a 
si n gle a ge nt a n d i n c o m bi nati o n wit h bi ni meti ni b.

C S F c o nce ntrati o ns of P F 0 7 2 8 4 8 9 0 (i n partici pa nts 
i n w h o m C S F is o btai ne d as S O C).

T o e val uate t u m or a n d bl o o d -base d bi o mar kers of 
res p o nse a n d resista nce t o P F 0 7 2 8 4 8 9 0 as a si n gle 
a ge nt a n d i n c o m bi nati o n wit h bi ni meti ni b .

T o assess t he relati o ns hi p bet wee n P F 0 7 2 8 4 8 9 0 
c o nce ntrati o ns a n d c ha n ges i n Q Tc F.

Ma xi mal c ha n ges i n Q Tc F esti mate d usi n g a li near 
mi xe d effect m o del.
P h ase 1 b Pri m ar y :
P h ase 1 b Pri m ar y:

T o e val uate a nti-t u m or efficac y of P F 0 7 2 8 4 8 9 0 at t he 
rec o m me n de d d ose f or f urt her st u d y i n c o m bi nati o n 
wit h bi ni meti ni b i n partici pa nts wit h B R A F 
V 6 0 0 m utate d a d va nce d s oli d t u m or mali g na ncies wit h 
a n d wit h o ut brai n i n v ol ve me nt .

E xtracra nial res p o nse b y R E CI S T versi o n 1. 1 .

I ntracra nial res p o nse b y m R E CI S T versi o n 1. 1.

O verall res p o nse (c o m bi ne d e xtracra nial a n d 
i ntracra nial) b y m R E CI S T versi o n 1. 1 .

R A N O f or pri mar y brai n t u m ors .
P h ase 1 b Sec o n d ar y:
P h ase 1 b Sec o n d ar y:

T o c o nfir m t he safet y a n d t olera bilit y of P F 0 7 2 8 4 8 9 0 
at t he rec o m me n de d d ose f or f urt her st u d y i n 
c o m bi nati o n wit h bi ni meti ni b.

A Es as c haracterize d b y t y pe, fre q ue nc y, se verit y (as 
gra de d b y N CI C T C A E versi o n 5. 0), ti mi n g, 
seri o us ness, a n d relati o ns hi p t o st u d y t hera p y.

La b orat or y a b n or malities as c haracterize d b y t y pe, 
fre q ue nc y, se verit y (as gra de d b y N CI C T C A E 
versi o n 5. 0), a n d ti mi n g.

I nci de nce of d ose i nterr u pti o ns, d ose m o dificati o ns 
a n d disc o nti n uati o ns d ue t o A Es.

T o e val uate  si n gle - a n d m ulti ple -d ose P K pr ofiles of 
P F 0 7 2 8 4 8 9 0 at t he rec o m me n de d d ose f or f urt her 
st u d y i n c o m bi nati o n wit h bi ni meti ni b a n d of 
bi ni meti ni b i n c o m bi nati o n wit h P F 0 7 2 8 4 8 9 0.
P K para meters of P F -0 7 2 8 4 8 9 0 a n d bi ni meti ni b: 

Si n gle d ose - Cma x , Tma x , A U Clast, a n d as data per mit, 
t½ , A U Ci nf, C L/ F a n d Vz/ F.

M ulti ple d ose (ass u mi n g stea d y state is ac hie ve d) -
C ss, ma x, Tss, ma x, A U Css,τ, Css, mi n, a n d as data per mit, 
C L ss/ F, Vss/ F, t½ a n d R ac ( A U Css,τ / A U Cs d,τ).

T o assess a d diti o nal meas ures of a nti -t u m or efficac y 
of P F 0 7 2 8 4 8 9 0 at t he rec o m me n de d d ose f or f urt her 
st u d y in c o m bi nati o n wit h bi ni meti ni b .

D C R ( o verall a n d i ntracra nial) .

P F S ( o verall a n d i ntracra nial), O S, D o R ( o verall a n d 
i ntracra nial) a n d T T R ( o verall a n d i ntracra nial).
P h ase 1 b Terti ar y/ E x pl or at or y:
P h ase 1 b Terti ar y/ E x pl or at or y:

T o e x pl ore t he effect of 
 o n 
P F 0 7 2 8 4 8 9 0 e x p os ures i n partici pa nts treate d wit h 
P F 0 7 2 8 4 8 9 0 i n c o m bi nati o n wit h bi ni meti ni b.

T o e x pl ore t he brai n pe netrati o n of P F 0 7 2 8 4 8 9 0 i n 
c o m bi nati o n wit h bi ni meti ni b.

C S F c o nce ntrati o ns of P F 0 7 2 8 4 8 9 0 (i n partici pa nts 
i n w h o m C S F is o btai ne d as S O C).

T o e val uate t u m or a n d bl o o d- base d bi o mar kers of 
res p o nse a n d resista nce t o P F 0 7 2 8 4 8 9 0 i n c o m bi nati o n 
wit h bi ni meti ni b .

T o e val uate t he effect of re peate d a d m i nistrati o n of 
P F -0 7 2 8 4 8 9 0 i n c o m bi nati o n wit h bi ni meti ni b o n 
si n gle d ose P K of mi daz ola m ( C o h ort 6 o nl y).
P K para meters of C Y P 3 A 4 pr o be s u bstrate mi daz ola m:

C ma x, Tma x , A U Clast, a n d as data per mit, t½ , A U Ci nf, 
C L/ F a n d V z/ F.
 
C CI
C CI
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 4 9
4. S T U D Y D E SI G N
4. 1. O ver all Desi g n
T his is a P hase 1 a/ b, o pe n-la bel, m ultice nter , d ose -fi n di n g st u d y of t he P K, safety a n d 
preli mi nar y  cli nical acti vit y of P F - 0 7 2 8 4 8 9 0 i n a d ult a n d a d olesce nt partici pa nts wit h 
selecte d B R A F V 6 0 0 -m uta nt a d va nce d or metastatic s oli d t u m or mali g na ncies a n d pri mar y  
brai n t u m ors .  T he st u d y  will be c o n d ucte d i n 2 parts .  Phase 1a will be a D ose Escalati o n
st u d y, w hic h will be di vi de d i nt o m o n ot hera p y ( P F-0 7 2 8 4 8 9 0 al o ne) a n d c o m bi nati o n 
t hera py ( P F -0 7 2 8 4 8 9 0 pl us b i ni meti ni b); P hase 1 b will be a D ose E x pa nsi o n , a n o pti o nal 
f o o d-effect s u bst u d y, a n d an o pti o nal D DI s u bst u d y ( b ot h P F-0 7 2 8 4 8 9 0 pl us b i ni meti ni b).
Partici pa nts will ha ve e x perie nce d disease pr o gress i o n after pri or treat me nt a n d ha ve n o 
acce pta ble alter nati ve treat me nt o pti o ns. S ee Secti o n 5. 1 I ncl usi o n Criteria 6 f or s pecific 
re q uire me nt relate d t o pri or treat me nt wit h a B R A F i n hi bit or.  
P hase 1a D ose Escalati o n
A p pr o xi matel y  3 5 partici pa nts will be e nr olle d t o deter mi ne t he M T D a n d/ or rec o m me n de d 
d ose f or f urt her st u d y of P F - 0 7 2 8 4 8 9 0 al o ne a n d i n c o m bi nati o n wit h bi ni meti ni b 
4 5 m g BI D.
M o n ot hera p y  a n d c o m bi nati o n d ose escalati o n c o h orts m a y  o verla p, wit h 
m o n ot hera p y d ose escalati o n i nitiati n g first.
C o h orts of 2 - 4 e val ua ble partici pa nts will be treate d at eac h d ose le vel of P F - 0 7 2 8 48 9 0 o n a n 
o ut patie nt basis starti n g fr o m 5 0 m g Q D u ntil t he deter mi nati o n of M T D/rec o m me n de d d ose 
f or f urt her st u d y. A mi ni m u m of 6 partici pa nts are e x pecte d t o be treate d at 
M T D/rec o m me n de d d ose f or f urt her st u d y (ie, 6 partici pa nts eac h f or b ot h m o n ot he ra py a n d 
c o m bi nati o n t hera p y) i n or der t o c haracterize safet y, t olera bility, P K as well as preli mi nar y 
acti vit y of P F - 0 7 2 8 4 8 9 0 w he n gi ve n at t he M T D/rec o m me n de d d ose f or f urt her st u d y ( b ot h 
al o ne a n d i n c o m bi nati o n wit h bi ni meti ni b) . T he act ual d ose i ncre ases bet wee n d ose le vels 
will be deter mi ne d b y safet y a n d o bser ve d P K as descri be d bel o w. I n a d diti o n, a n alter nati ve 
sc he d ule (e g, BI D, d osi n g h oli da y) ma y be e val uate d de pe n di n g o n safety a n d o bser ve d P K.
F or t he m o n ot hera p y d ose escalati o n part, a partici pa nt is classifie d as D L T e val ua ble if 
he/s he e x perie nces a D L T ( Secti o n 4. 3. 3 ) or if he/s he ot her wise i n t he a bse nce of a D L T 
recei ves at least 7 5 % of t he pla n ne d P F - 0 7 2 8 4 8 9 0 d oses a n d has recei ve d all sc he d ule d 
safety assess me nts d uri n g t he D L T o bser vati o n wi n d o w (first c ycle of treat me nt , a 2 1 -d a y  
c ycle). F or t he c o m bi nati o n t hera p y  d ose escalati o n part, a partici pa nt is classifie d as D L T 
e val ua ble if he/s he e x perie nces a D L T (Secti o n 4. 3. 3 ) or if he/s he ot her wise i n t he a bse nce of 
a D L T recei ves at least 7 5 % of t he pla n ne d P F -0 7 2 8 4 8 9 0 a n d 7 5 % of t he pla n ne d 
bi ni meti ni b d oses a n d has recei ve d all sc he d ule d safet y assess me nts d uri n g t he D L T 
o bser vati o n wi n d o w (first c ycle of treat me nt , a 2 1- d a y c y cle).
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 5 0
A B L R M will be use d t o m o del t he D L T relati o ns hi p of P F - 0 7 2 8 4 8 9 0.
T his m o del, al o n g 
wit h t he E W O C , will g ui de t he d ose escalati o n of P F - 0 7 2 8 4 8 9 0 after t he c o m pleti o n of t he 
D L T o bser vati o n peri o d of eac h c o h ort, u ntil a de q uate D L T data have acc u m ulate d 
t hr o u g h o ut t he m o n ot hera p y d ose escalati o n t o i nf or m t he c o m bi nati o n B L R M or u ntil t he 
deter mi nati o n of M T D/rec o m me n de d d ose f or P F - 0 7 2 8 4 8 9 0 m o n ot hera p y.  
O nce i nitial d oses of P F - 0 7 2 8 4 8 9 0 m o n ot hera p y are deter mi ne d t o be safe a n d meet t he 
E W O C criteria, B L R M a n d E W O C will be use d t o m o del t he D L T relati o ns hi p of 
P F - 0 7 2 8 4 8 9 0 i n c o m bi nati o n wit h bi ni meti ni b at t he a p pr o ve d d ose of 4 5 m g BI D 
( m o n ot hera py d ose escalati o n will c o nti n ue si m ulta ne o usl y). Base d o n preli mi nar y  P K a n d 
safety, t he c o m bi nati o n d ose escalati o n p hase of P F - 0 7 2 8 4 8 9 0 wit h bi ni meti ni b ma y  be 
starte d pri or t o t he deter mi nati o n of t he m o n ot hera p y P F - 0 7 2 8 4 8 9 0 M T D/rec o m me n de d d ose 
f or f urt her st u d y. T he starti n g d ose le vel f or P F -0 7 2 8 4 8 9 0 i n t he c o m bi nati o n d ose t hera py 
escalati o n will n ot be hi g her t ha n pre vi o usl y  st u die d d oses i n t he m o n ot hera p y  escalati o n a n d 
will satisf y E W O C criteria . T he para meters will be deri ve d f or t he c o m bi nati o n B LR M b y  
i nc or p orati n g D L T da ta o btai ne d fr o m t he P F-0 7 2 8 4 8 9 0 m o n ot hera p y  escalati o n a n d 
hist orical data f or bi ni meti ni b ( see Secti o n 9. 3. 1. 1 ).
F or b ot h m o n ot hera p y a n d c o m bi nati o n t hera py d ose escalati o ns, t o xicities will o nl y  be 
c o nsi dere d D L Ts if t he y  occ ur wit hi n t he D L T wi n d o w of t he first c ycle ( 2 1 da ys); h o we ver, 
o verall safe t y, i ncl u di n g later c ycles, a n d P K data will be e val uate d f or t he rec o m me n de d 
d ose f or f urt her st u d y deter mi nati o n.
P hase 1 b D ose E x pa nsi o n , o pti o nal D DI S u b st u d y, a n d o pti o nal F o o d-effect S u bst u d y
After i de ntificati o n of t he c o m bi nati o n M T D/rec o m me n de d d ose f or f urt her st u d y , 
a p pr o xi matel y 2 0 partici pa nts will be e nr olle d t o eac h of C o h orts 1- 4 a n d 4 0 partici pa nts t o 
C o h ort 5 of P hase 1 b d ose e x pa nsi o n base d o n t u m or t ype, w het her brai n i n v ol ve me nt is 
as ym pt o matic or s y m pt o matic a n d meas ura ble or n o n -meas ura ble, pri or treat me nt hist or y  
a n d a hist or y of or c urre nt le pt o me ni n geal metastases. T he partici pa nts i nte n de d f or eac h 
c o h ort are descri be d i n Secti o n 1. 2 a n d Secti o n 5 .  T he d ose e x pa nsi o n p hase ( C o h orts 1- 5) 
will e val uate efficac y, safet y a n d P K at t he rec o m me n de d d ose f or f urt her st u d y i n 
c o m bi nati o n wit h bi ni meti ni b .
T he effect of f o o d (l o w fat a n d hi g h fat meal vers us faste d state) o n P F -0 7 2 8 4 8 9 0 P K is 
bei n g assesse d i n st u d y C 4 4 7 1 0 0 2 i n healt h y  partici pa nts.  O nce t he res ults of t his 
f o o d-effect st u d y are a vaila ble, it ma y tri g ger t he o pe ni n g of a n o pti o nal C o h ort 7 a n d/ or t he 
i nstr ucti o ns f or a d mi nistrati o n of C 4 4 7 1 0 0 1 ma y be c ha n ge d. See A p pe n di x 1 6 . T o miti gate 
b ur de n t o patie nts, c ha n ge(s) i n d ose a n d d osi n g i nstr ucti o ns re gar di n g a d mi nistrati o n wit h 
f o o d ma y i nitially be c o m m u nicate d b y P A C L f oll o we d b y s u bse q ue nt pr ot oc ol a me n d me nt. 
T he res ults of C 4 4 7 1 0 0 2 a n d/ or C o h ort 7 ma y  n ot be a vaila ble pri or t o i nitiati o n of 
C o h orts 1 - 6. If t he effect of f o o d o n P F -0 7 2 8 4 8 9 0 P K base d o n t he res ults of C 4 4 7 1 0 0 2 is 
f o u n d t o be p ositi ve a n d t he i nstr ucti o ns f or P F -0 7 2 8 4 8 9 0 a d mi nistrati o n are c ha n ge d, t he 
patie nts i n t h ose c o h orts a d mi nistere d P F -0 7 2 8 4 8 9 0 f oll o wi n g t he pre vi o us i nstr ucti o ns ma y  
be re place d wit h partici pa nts fr o m C o h ort 7 or ne wl y  e nr olle d partici pa nts.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 5 1
I n a d diti o n, a p pr o xi matel y 1 0 partici pa nts m a y be e nr olle d t o a s u bst u d y  ( C o h ort 6) t o 
e val uate t he effect of P F - 0 7 2 8 4 8 9 0 i n c o mbi nati o n wit h bi ni meti ni b o n C Y P 3 A acti vit y
usi n g mi daz ola m as a pr o be C Y P 3 A 4 s u bstrate.   A s y n o psis i ncl u di n g S o A f or t he s u bst u d y 
is pr o vi de d i n A p pe n di x 1 5 .
F or b ot h P hase 1a a n d P hase 1 b, t reat me nt wit h st u d y i nter ve nti o n will c o nti n ue u ntil eit her 
disease pr o gressi o n, partici pa nt ref usal, u nacce pta ble t o xicit y  occ urs, or u p t o 2 ye ars,
w hic he ver occ urs first . Partici pa nts w h o ha ve disease pr o gressi o n b ut are deri vi n g cli nical 
be nefit ma y  c o nti n ue if criteria are met a n d t he partici pa nt c o nse nts t o c o nti n ue treat me nt 
(see Secti o n 7. 1. 1 ). Partici pa nt s w h o c o m plete 2 years o n st u d y  i nter ve nti o n a n d de m o nstrate 
cli nical be nefit wit h ma na gea ble t o xicit y  a n d are willi n g t o c o nti n ue recei vi n g t he st u d y 
i nter ve nti o n will be gi ve n t he o p p ort u nit y t o c o nti n ue treat me nt u p o n a gree me nt bet wee n 
i n vesti gat or a n d s p o ns or, usi n g t he s a me s afety assess me nts as were bei n g perf or me d m ost 
rece ntly, b ut wit h effic acy m o nit ore d at i nterv als c o nsiste nt wit h cli nic al pr actice .
Please see S o A f or t he sc he d ule of a d mi nistrati o n.  T he pr o p ose d d oses, sc he d ule(s), a n d P K 
sa m pli n g ti me p oi nts ma y be rec o nsi dere d d uri n g t he st u d y base d o n t he e mer gi n g safety a n d 
P K data. 
O ne of t he ele me nts of t his st u d y  is t he p ossi bilit y t o e val uate p ote ntial m olec ular tar gets t hat 
c o ul d be m o dified i n vi v o b y  t he dr u g P F -0 7 2 8 4 8 9 0 as a si n gle a ge nt or i n c o m bi nati o n wit h 
bi ni meti ni b use d i n t his st u d y .  Pla n ne d b io mar ker st u dies i ncl u de a nal ys is of c ha n ges i n 
 d uri n g treat me nt (all partici pa nts ), a n d a nal ys is of fres h 
t u m or bi o psies f or c ha n ges i n t u m or cell le vels of 
 
 d uri n g treat me nt ( o nly if fres h bi o ps y ca n be perf or me d safely, a n d o nl y 
f or partici pa nts w h o pr o vi de i nf or me d c o nse nt /asse nt f or bi o psy). 
T he bi o mar ker st u dies will be use d t o hel p u n dersta n d t he i n vi v o mec ha nis m of acti o n of t he 
a ge nt(s). T he st u dies ma y  hel p i n t he f ut ure de vel o p me nt of P F - 0 7 2 8 4 8 9 0 as a si n gle a ge nt, 
or i n c o m bi nati o n wit h ot her c o m p o u n ds, a n d ma y pr o vi de i nf or mati o n o n t u m or s u b- t ypes 
t hat ma y res p o n d t o t he st u d y i nter ve nti o n. Details of bi o mar ker st u dies are pr o vi de d i n 
Secti o n 8. 8 .
4. 2. Scie ntific R ati o n ale f or St u d y Desi g n
T he p ur p ose of t he first -i n-h u ma n, o pe n -la bel st u d y is t o deter mi ne t he M T D a n d/ or 
rec o m me n de d d ose f or f urt her st u d y of P F -0 7 2 8 4 8 9 0 as a si n gle a ge nt a n d i n c o m bi nati o n 
wit h bi ni meti ni b a n d e val uate t he P K, safety a n d preli mi nar y cli nical acti vit y o verall a n d i n 
t he brai n.  
T he effect of P F -0 7 2 8 4 8 9 0 o n e m br yo -fetal de vel o p me nt is u n k n o w n. Bi ni meti ni b is k n o w n 
t o ca use ris k f or se vere ma nifestati o ns of de vel o p me ntal t o xicit y i n h u ma ns or s us pecte d o n 
t he basis of t he i nte n de d p har mac ol o g y.
T heref ore, t he use of a hi g hly effecti ve met h o d of 
c o ntrace pti o n is re q uire d, i ncl u di n g at least 1 f or m of n o n - h or m o nal c o ntrace pti o n, gi ve n t he 
p ote ntial f or C Y P 3 A i n d ucti o n b y  P F- 0 7 2 8 4 8 9 0 (see A p pe n di x 4 ).
 
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 5 2
Ba n ke d Bi os peci me ns will be c ollecte d a n d st ore d f or f urt her a nal ys es w hic h ma y, f or 
e xa m ple, pr o vi de greater u n der sta n di n g of t he st u d y i nter ve nti o n.
4. 2. 1. R ati o n ale f or D ose Esc al ati o n A p pr o ac h
P K a n d safet y fr o m pri or d ose le vels will be use d t o g ui de d ose escalati o n (see 
Secti o n 4. 3. 2 ). N o d ose i ncrease will e xcee d a p pr o xi matel y 2-f ol d o ver t he c urre nt d ose 
le vel (“a p pr o xi matel y” t o ta ke i nt o acc o u nt a vaila ble ta blet d ose sizes a n d t o mi ni mize pill 
b ur de n f or partici pa n ts). H o we ver, i f e x p os ures at t he c urre nt d ose le vel are m uc h l o wer t h a n 
e x pecte d, a n d n o D L Ts are o bser ve d at t he c urre nt a n d all pri or d ose le vel s, t he d ose i ncrease 
ma y  be u p t o a p pr o xi matel y 3 -f ol d t he c urre nt d ose le vel. “ L o wer t ha n e x pecte d” is defi ne d 
i n Secti o n 4. 3. 2 as: o bser ve d tr o u g h P F -0 7 2 8 4 8 9 0 c o nce ntrati o n at stea dy- state ( Css, mi n), is 
less t ha n t he calc ulate d f u-a dj uste d I C5 0 f or i n hi biti n g E R K p h os p h or y lati o n i n a B R A F 
V 6 0 0 E cell-base d assa y  i n at least t w o-t hir ds (e g, 2 o ut of 2, 2 o ut of 3 , or 3 o ut of 4) of t he 
partici pa nts treate d at t hat d ose le vel.  After a d ose le vel of 3 0 0 m g, t he ne xt d ose will n ot 
e xcee d 1. 5 ti mes t he c urre nt d ose le vel.
T his a p pr oac h is j ustifie d b y  safety c o nsi derati o ns. T h us, t he le vel of P F -0 7 2 8 4 8 9 0 t hat is 
e q ui vale nt t o t he calc ulate d I C 5 0 f or B R A F V 6 0 0 E is a p pr o xi matel y 3 0- 1 6 0 ti mes l o wer t ha n 
t he le vel ac hie ve d at t he N O A E L i n m o n ke ys a n d S T D1 0 i n rats, res pecti vel y, i n t he G L P 
t o xic ol o g y st u dies. 
I n a d diti o n, t his a p pr oac h is j ustifie d b y et hical c o nsi derati o ns. B y  utilizi n g b ot h o bser ve d 
safety a n d o bser ve d P K t o deter mi ne t he act ual d ose i nter val increase , t he n u m ber of 
partici pa nts e x p ose d t o a p ote ntiall y s u b-efficaci o us d ose of P F - 0 7 2 8 4 8 9 0 ma y  be decrease d, 
w hic h mi ni mizes t he c ha nce t hat a si g nifica nt n u m ber of partici pa nts will n ot be nefit fr o m 
treat me nt.
4. 2. 2. R ati o n ale f or C o m bi n ati o n wit h Bi ni meti ni b
Earl y cli nical trials of B R A F i n hi bit ors i n B R A F V 6 0 0 - m uta nt mela n o ma i n dicate d 
i m pr o ve d efficac y w he n t he B R A F i n hi bit or was c o m bi ne d wit h a M E K i n hi bit or, d ue t o 
m ore r o b ust i n hi biti o n of t he M A P K pat h wa y .2 4 I n a d diti o n, certai n t o xicities (e g, ras h, 
c uta ne o us s q ua m o us cell carci n o ma ), w hic h res ult i n part fr o m para d o xical acti vati o n of t he 
M A P K pat h wa y  t hat occ urs i n t he a bse nce of m uta nt B R A F , c o ul d be a meli orate d b y t he 
a d diti o n of a M E K i n hi bit or.2 7 ,3 0  T hese res ults ha ve bee n vali date d i n m ulti ple cli nical trials; 
t h us, c o m bi ni n g a B R A F i n hi bit or wit h a M E K i n hi bit or is t he sta n dar d tar gete d t hera p y 
treat me nt a p pr oac h f or B R A F V 6 0 0-m uta nt ca ncers.
T he a p pr o ve d d ose of e nc orafe ni b 
w he n c oa d mi nistere d wit h bi ni meti ni b is 4 5 0 m g Q D, b ut w he n a d mi nistere d as a si n gle 
a ge nt is 3 0 0 m g Q D , d ue t o i m pr o ve d t olera bilit y wit h bi nimeti ni b c oa d mi nistrati o n .2 7 ,3 1
T his a p pr oac h has bee n vali date d precli nicall y  wit h P F - 0 7 2 8 4 8 9 0: t he a d diti o n of t he M E K 
i n hi bit or bi ni meti ni b t o P F - 0 7 2 8 4 8 9 0 le d t o m ore ra pi d a n d s ustai ne d t u m or res p o nse i n a n 
i ntracra nial m o use m o del of B R A F V 6 0 0-m uta nt mela n o ma t ha n eit her P F - 0 7 2 8 4 8 9 0
m o n ot hera p y or c o m bi ne d e nc orafe ni b (a p o orl y brai n pe netra nt B R A F 
i n hi bit or)- bi ni meti ni b treat me nt ( data o n file, Pfizer, I nc), wit h t olera bilit y mai ntai ne d.
Fi nall y , bi ni meti ni b has a well-c haracterize d safet y pr ofile a n d e xcelle nt p har mac ol o g y 
(e g, t olerate d e x p os ures c o nsiste nt wit h tar get i n hi biti o n a n d mi ni mal dr u g i nteracti o ns ), 
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 5 3
per mitti n g it t o be c o m bi ne d wit h m ulti ple ot her a ge nts i n cli nical trials, i ncl u di n g s mall 
m olec ule B R A F i n hi bit ors (ie, e nc orafe ni b) a n d t hera pe utic a nti b o dies (ie, cet u xi ma b).   
T heref ore, as descri be d i n Secti o n 4. 3 , d uri n g d ose escalati o n, P F -0 7 2 8 4 8 9 0 will be 
c o m bi ne d wit h bi ni meti ni b at t he a p pr o ve d d ose of 4 5 m g BI D , w hic h is 1 d ose le vel l o wer 
t ha n t he M T D of 6 0 m g  BI D esta blis he d i n t he first -i n-h u ma n cli nical trial .2 3 Si nce 
c o m bi ne d treat me nt wit h a M E K i n hi bit o r ma y  be critical f or ma xi mizi n g efficac y  a n d 
mi ni mizi n g t o xicit y , t he pr ot oc ol is fle xi ble t o t he timi n g of i ntr o d uci n g bi ni meti ni b 
c o-treat me nt d uri n g m o n ot hera py d ose escalati o n of P F - 0 7 2 8 4 8 9 0 (see Secti o n 4. 3. 2 ). 
4. 2. 3. R ati o n ale f or U n met Me dic al Nee d f or P artici p a nts wit h S y m pt o m atic Br ai n 
I n v ol ve me nt
As disc usse d i n Secti o n 2. 2 , ra n d o mize d/re gistrati o nal st u dies of a p pr o ve d B R A F i n hi bit ors 
i n B R A F V 6 0 0-m uta nt mela n o ma a n d N S C L C e xcl u de d patie nts wit h u ntreate d (ie , wit h 
l ocal brai n t hera py), s y m pt o matic (i ncl u di n g a re q uire me nt f or ster o i d or a nti-e pile ptic 
t hera py t o c o ntr ol s y m pt o ms) a n d/ or pr o gressi ve brai n metastases at baseli ne. Rece nt 
si n gle- ar m, n o nc o m parati ve trials i n dicate d t he p ote ntial f or a nti-t u m or acti vit y i n t he brai n 
f or t he B R A F i n hi bit or da brafe ni b (i n c o m bi nati o n wit h tra meti ni b) a n d t he ICI s i pil u mi ma b 
pl us ni v ol u ma b i n patie nts wit h as y m pt o matic brai n metastases n ot re q uiri n g l ocal brai n 
t hera py, ster oi ds or a nti -e pile ptic t hera p y. I n t he f or mer, t he me dia n o verall Do R a n d P F S 
f or patie nts wit h u ntreate d, as ym pt o mat ic brai n metastases was s h orter t ha n f or patie nts 
wit h o ut brai n metastases i n t he re gistrati o nal st u dies, a n d s h orter still f or patie nts wit h 
s ym pt o matic brai n i n v ol ve me nt.  I n t he latter, treat me nt was li mite d t o patie nts wit h 
as ym pt o matic , u ntreate d brai n metastasis a n d was t o xic, a n d o nl y a mi n orit y of patie nts 
recei ve d all pla n ne d treat me nts. L o cal brai n t hera p y wit h S R S or s ur ger y pr o vi des m o dest 
disease c o ntr ol t o treate d lesi o ns b ut ma y  o nly be use d f or a li mite d n u m ber a n d size of 
lesi o ns a n d has n o effect o n u ntreate d lesi o ns . W B R T is ass ociate d wit h l o n g -ter m 
ne ur oc o g niti ve effects a n d is n or mall y  use d o nly o nce.
F or t hese reas o ns, patie nts wit h B R A F V 6 0 0 -m uta nt s oli d t u m ors f or w h o m B R A F i n hi bit ors 
are a p pr o ve d a n d c o nsi dere d sta n dar d s ys te mic treat me nt i n t he a bse nce of acti ve brai n 
metastases (ie , mela n o ma , N S C L C, A T C a n d C R C, t h o u g h t he fre q ue nc y of brai n metastases 
i n A T C a n d C R C is l o w), a n d w h o ha ve s ym pt o matic brai n lesi o ns , ha ve hi g h u n met me dical 
nee d : t he l o n g-ter m efficac y of a vaila ble B R A F i n hi bit ors re mai ns u n pr o ve n i n t his patie nt 
p o p ulati o n . T heref ore, d uri n g m o n ot hera p y d ose escalati o n, o nce t he le vels of P F - 0 7 2 8 4 8 9 0 
ac hie ve d i n partici pa nts are c o nsiste nt wit h si g nifica nt calc ulate d B R A F V 6 0 0 -m uta nt tar get 
c overa ge (ie, stea d y-state c o nce ntrati o n is ≥t he I C7 0 f or i n hi biti o n of B R A F V 6 0 0 E i n t he 
brai n; see Secti o n 5. 1 ), s u bse q ue ntl y e nr olle d partici pa nts (t o b ot h t he m o n ot hera py a n d 
c o m bi nati o n d ose escalati o n) wit h t hese t u m or t ypes w h o are s ufferi n g fr o m s ym pt o matic 
brai n metastases m a y  be eli gi ble wit h o ut pri or treat me nt wit h a B R A F i n hi bit or. T hese 
partici pa nts re q uire pri or treat me nt wit h ot her a vaila ble sta n dar d t hera py pri or t o e nr oll me nt 
(e g, I CI treat me nt f or mela n o ma, plati n u m-base d c he m ot hera p y a n d/ or I CI treat me nt f or 
N S C L C , l ocal brai n t hera p y f or b ot h if c o nsiste nt wit h i nstit uti o nal/c o u ntr y sta n dar d of care)
(see Secti o n 5 f or s pecific I ncl usi o n Criteria). S uc h partici pa nts w h o are wit h o ut brai n 
metastases or wit h as y m pt o matic brai n metastases at baseli ne re q uire pre vi o us treat me nt wit h 
a B R A F i n hi bit or t o be eli gi ble. I n all cases, cl ose f oll o w- u p s ur veilla nce wit h brai n M RI  
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 5 4
e ver y 6 wee ks is re q uire d b y  t he pr ot oc ol, c o nsiste nt wit h c urre nt g ui deli nes f or patie nts wit h 
(acti ve) brai n i n v ol ve me nt treate d wit h s ys te mic t hera p y.3 2
4. 2. 4. R ati o n ale f or B R A F V 6 0 0 M ut ati o n Testi n g P ar a di g m
I n t he c urre nt st u d y, partici pa nts ma y be eli gi ble f or e nr oll me nt base d o n B R A F V 6 0 0 
m utati o n stat us deter mi ne d l ocall y b y  P C R or N G S i n a C LI A ( or si milarl y certifie d) 
la b orat or y (see Secti o n 5. 1 I ncl usi o n Criteria 3 ). T he use of l ocal B R A F V 6 0 0 m utati o n 
testi n g as pla n ne d i n t his st u d y  all o ws efficie nt e nr oll me nt of a n d access f or partici pa nts wit h 
a vali d B R A F V 6 0 0 m utati o n test res ult w h o are s ufferi n g fr o m a d va nce d, 
treat me nt-refract or y ca ncers, a n d has bee n pre vi o usl y de m o nstrate d t o be hi g hly acc urate
w he n perf or me d i n a certifie d la b orat or y .2 9 S pecific q uesti o ns a b o ut w het her a l ocal testi n g 
res ults is eli gi ble s h o ul d be disc usse d wit h t he sp o ns or.
4. 2. 5. R ati o n ale f or 
 Assess me nt
T he pri mar y  mec ha nis m of P F- 0 7 2 8 4 8 9 0 cleara nce is t h o u g ht t o be t hr o u g h 
 (Secti o n 2. 2. 2 ). 
 wit h 
t he p ote ntial f or cli nical rele va nce.3 3 ,3 4 T heref ore, t he relati o ns hi p bet wee n P F- 0 7 2 8 4 8 9 0 
e x p os ures a n d 
 will be assesse d.
4. 2. 6. R ati o n ale f or F o o d -effect S u b St u d y
F o o d ca n ha ve a si g nifica nt i m pact o n dr u g p har mac o ki netics, a n d t heref ore o n dr u g safet y 
a n d efficac y. T he effect of f o o d o n P F -0 7 2 8 4 8 9 0 P K is bei n g assesse d i n cli nical S t u d y 
C 4 4 7 1 0 0 2.  T his o pe n -la bel, ra n d o mize d, si n gle d ose, 2-se q ue nce, 3-peri o d cr oss o ver st u d y  
will e val uate t he effect of a l o w -fat a n d hi g h-fat meal o n t he relati ve bi oa vaila bilit y of 
P F -0 7 2 8 4 8 9 0 i n a p pr o xi matel y 1 2 healt h y partici pa nts. If t he l o w-fat a n d hi g h -fat meal hav e
less t ha n a 2-f ol d i ncrease o n P F- 0 7 2 8 4 8 9 0 e x p os u res, t he res ults of t his st u d y ma y be use d 
t o m o dif y a d mi nistrati o n i nstr ucti o ns f or P F-0 7 2 8 4 8 9 0 i n P hase 1 b of t he c urre nt st u d y , 
i ncl u di n g t he p ote ntial use of t his data t o deter mi ne t he d ose i n t he fe d state t hat is e q ui vale nt 
t o t he faste d state M T D/ R DE. H o we ver , i n t he case of a p ositi ve f o o d effect, as t he effect of 
f o o d o n relati ve bi oa vaila bilit y  of P F-0 7 2 8 4 8 9 0 i ncreases, t he wi dt h of t he c o nfi de nce 
i nter val ar o u n d t he esti mate d effect of f o o d is als o e x pecte d t o i ncrease, a n d t heref ore t he 
precise effect of f o o d is k n o w n wit h less certai nt y.  T heref ore, if f o o d i ncreases t he relati ve 
bi oa vaila bilit y  b y m ore t ha n 2-f ol d f or eit her t he l o w-fat or hi g h-fat meal, m ore data are 
nee de d t o deter mi ne w het her t h e e q ui vale nt d ose f or t he fe d state ac hie ves t he pr o per 
e x p os ure a n d is safe wit h re peat a d mi nistrati o n. F or t his reas o n, t he effect of f o o d o n 
P F - 0 7 2 8 4 8 9 0 P K a n d safet y will be c haracterize d i n a s u bst u d y  (A p pe n di x 1 6 ) if data fr o m 
C 4 4 7 1 0 0 2 i n dica te m ore t ha n a 2-f ol d i ncrease fr o m ta ki n g P F-0 7 2 8 4 8 9 0 wit h f o o d . U ntil 
t he effect of f o o d o n its p har mac o ki netics is u n derst o o d, eit her base d o n C 4 4 7 1 0 0 2 or i n t he 
case of a m ore s u bsta ntial f o o d effect als o base d o n t he f o o d-effect s u bst u d y, P F - 0 7 2 8 4 8 9 0
m ust be ta ke n o n a n e m pt y st o mac h (e xce pt f or f o o d-effect s u bst u d y partici pa nts). 
 
C CI
C CI
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 5 5
4. 2. 7. R ati o n ale f or C Y P 3 A 4 Dr u g - Dr u g I nter acti o n S u bst u d y
P F -0 7 2 8 4 8 9 0 s h o we d c o m petiti ve a n d ti me - de pe n de nt i n hi biti o n as well as i n d ucti o n of 
C Y P 3 A 4 i n vitr o. As a res ult, t here is a p ote ntial t hat P F-0 7 2 8 4 8 9 0 ma y  alter P K i n 
c o nc o mita ntl y a d mi nistere d me dici nes meta b olize d b y C Y P 3 A, p ossi bl y i ncreasi n g or 
decreasi n g t heir e x p os ures. F or t his reas o n, c oa d mi nistrati o n of P F -0 7 2 8 4 8 9 0 wit h C Y P 3 A 
s u bstrates wit h narr o w t hera pe utic i n dices is pr o hi bite d (Secti o n 6. 5. 1. 1 ). F or t his reas o n, 
1 of t he d ose e x pa nsi o n gr o u ps will be i ncl u de d as a s u bst u d y t o e valuate t he effect of 
P F -0 7 2 8 4 8 9 0 i n c o m bi nati o n wit h bi ni meti ni b o n C Y P 3 A pr o be mi daz ola m at t he 
M T D/ rec o m me n de d d ose f or f urt her st u dy a n d sc he d ule ( A p pe n di x 1 5 ). Alt h o u g h 
bi ni meti ni b will be c oa d mi nistere d, it is n ot e x pecte d t o i m pact t he D DI res ults d ue t o its 
li mite d a bilit y t o ca use D DIs.3 5
4. 3. J ustific ati o n f or D ose
D oses prese nte d are pr ojecte d base d o n n o ncli nical data a n d ma y  be m o difie d base d o n 
e mer gi n g safet y, t olera bilit y, a n d P K data.
4. 3. 1. St arti n g D ose
T he starti n g d ose f or P F - 0 7 2 8 4 8 9 0 will be 5 0 m g Q D i n 2 1 -d a y  c ycles. T he starti n g d ose of 
P F - 0 7 2 8 4 8 9 0 is base d o n 
 (t he m ore se nsiti ve of t he 
2 s pecies teste d) fr o m t he 2 8-d a y  G L P n o ncli nical t o xic ol o g y st u dies. T he S T D 1 0 is 
 
( base d o n a 1. 6 2 m 2 h u ma n). B ase d o n a vaila ble ta blet c o nfi g urati o ns
( 1 0, 2 5 a n d 1 0 0 m g) a n d t he rat data, a starti n g d ose of 5 0 m g/ da y  was c h ose n.
T he starti n g d ose of bi ni meti ni b is 4 5 m g BI D, w hic h is t he a p pr o ve d d ose i n c o m bi nati o n 
wit h t he B R A F i n hi bit or e nc orafe ni b, a n d is o ne d ose le vel l o wer t ha n t he M T D i de ntifie d i n 
t he P hase 1 cli nical trial.2 3
4. 3. 2. Criteri a f or D ose Esc al ati o n
D ose Escalati o n will be g ui de d b y  safety a n d o bser ve d P K, wit h o verla p pi n g m o n ot hera p y  
d ose escalati o n a n d c o m bi nati o n d ose escalati o n wit h bi ni meti ni b (see Secti o n 1. 2 Sc he ma ).
B L R M g ui de d b y t he E W O C pri nci ple will be use d i n d ose escalati o n. See Secti o n 9 a n d 
A p pe n di x 9 f or m ore details o n t he m o del.  
4. 3. 2. 1. P F -0 7 2 8 4 8 9 0 M o n ot her a p y D ose Esc al ati o n
D ose escalati o n of P F -0 7 2 8 4 8 9 0 will i nitiate as m o n ot hera p y.  T he D L T e val uati o n peri o d 
will be t he first 2 1 d a y s ( C ycle 1).  T he decisi o n t o e nr oll partici pa nts t o t he ne xt a n d 
s u bse q ue nt d ose le vels will de pe n d o n t he rate of D LTs acc or di n g t o t he B L R M desi g n.  T he 
d ose f or t he ne xt a n d s u bse q ue nt d ose le vels will de pe n d o n t he o bser ve d P K at t he prece di n g 
d ose le vel(s), t he P F -0 7 2 8 4 8 9 0 e x p os ure pre dicte d at t he ne xt d ose le vel a n d t he occ urre nce 
of D L Ts i n t he c urre nt d ose le vel. 
 
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 5 6
D uri n g eac h d ose escalati o n decisi o n, t he ne xt d ose will n or mall y  n ot e xcee d 2 ti mes t he 
c urre nt d ose le vel. H o we ver, i n t he a bse nce of D L Ts at t he c urre nt a n d all pri or d ose le vel s, 
a n d if t he o bser ve d tr o u g h c o nce ntrati o n at stea d y state ( Css, mi n estimate d as t he pre d ose 
plas ma c o nce ntrati o n o n C y cle 1 Da y 1 5) wit h t he c urre nt d ose is < t he calc ulate d IC 5 0
(a dj uste d f or t he u n b o u n d fracti o n, f u, i n plas ma pr otei n a n d i n t he i n vitr o assa y) of 
P F -0 7 2 8 4 8 9 0 f or i n hi biti n g E R K p h os p h or ylati o n i n a B R A F V 6 0 0 E cell -base d assa y i n at 
least t w o-t hir ds of patie nts (e g, 2 o ut of 2, 2 o ut of 3 , or 3 o ut of 4), t he ne xt d ose will n ot 
e xcee d 3 ti mes t he c urre nt d ose le vel.   After a d ose le vel of 3 0 0 m g, t he ne xt d ose will n ot 
e xcee d 1. 5 ti mes t he c urre nt d ose le vel.  T he act ual t otal dail y  d ose ma y be sli g htl y hi g her or 
l o wer t ha n t he calc ulate d d ose base d o n safety, a vaila ble ta blet d ose sizes a n d pill bur de n.
T he c o nce ntrati o n of P F - 0 7 2 8 4 8 9 0 re q uire d t o ac hie ve 
 
 
Stea d y -state le vels of P F - 0 7 2 8 4 8 9 0 i n plas ma are esti mate d t o be ac hie ve d b y pre-d ose o n 
C y cle 1 Da y 1 5 , alt h o u g h t his ti mi n g ma y be a dj uste d base d o n e mer gi n g P K data.
Deter mi nati o n of t he act ual d ose le vels will be ma de b y  t he S R C, w hic h will meet b y 
telec o nfere nce f or eac h d ose escalati o n decisi o n a n d c o nsi der t he P K, t he occ urre nce of 
D L Ts / D L T pr o ba bilit y , a n d t he c u m ulati ve safet y  pr ofile t o date. Base d o n a vaila ble ta blet 
d ose sizes a n d t he para meters i n dicate d a b o ve, p ote ntial d ose le vels f or P F- 0 7 2 8 4 8 9 0 (as 
m o n ot hera p y a n d i n c o m bi nati o n wit h bi ni meti ni b) are o utli ne d i n Ta ble 2:
T a ble 2.
E x a m ple D ose Le vels f or P F -0 7 2 8 4 8 9 0
D ose Le vel
P F -0 7 2 8 4 8 9 0 D ose a
Sce n ari o
D ose le vel -2 
1 0 m g Q D
D L T pr o ba bilit y at D ose le vel -1 e xcee ds 
t hres h ol d b y B L R M.
D ose le vel - 1
2 5 m g Q D
D L T pr o ba bilit y at D ose le vel 1 e xcee ds 
t hres h ol d b y B L R M.
Starti n g D ose le vel 1
5 0 m g Q D 
D ose le vel 2 alter nate 1 b
1 0 0 m g Q D ( 5 0 m g BI D)
N o D L Ts at D ose le vel 1, S R C has n o safet y 
c o ncer ns , calc ulate d C ss, mi n ≥0. 0 7 2 µ g/ m L i n 
2/ 3 partici pa nts .
D ose le vel 2 alter nat e 2 b
1 5 0 m g Q D ( 7 5 m g BI D)
N o D L Ts at D ose le vel 1 , S R C has n o safet y 
c o ncer ns , calc ulate d C ss, mi n < 0. 0 7 2 µ g/ m L i n 
2/ 3 partici pa nt s.
a.
P F -0 7 2 8 4 8 9 0 ta blet d ose sizes are 1 0, 2 5 a n d 1 0 0 m g. Q D d osi n g will be utilize d i nitiall y; d osi n g 
fre q ue nc y ma y be c ha n ge d (e g, BI D) b y S R C base d o n a vaila ble safet y a n d P K data.
b.
D ose le vel 2 , alter nates 1 a n d 2 are ma xi m u m d oses gi ve n t he sce nari os de picte d; t he S R C ma y c h o ose 
a l o wer d ose t ha n s h o w n base d o n a vaila ble P K a n d safet y.
D ose M o dificati o n f or P F- 0 7 2 8 4 8 9 0 is descri be d i n Secti o n 6. 6 .
4. 3. 2. 2. P F -0 7 2 8 4 8 9 0 D ose Esc al ati o n i n C o m bi n ati o n wit h Bi ni meti ni b
T he starti n g d ose of bi ni meti ni b i n c o m bi nati o n wit h P F -0 7 2 8 4 8 9 0 will be t he a p pr o ve d d ose 
of 4 5 m g BI D. D ose escalati o n of P F - 0 7 2 8 4 8 9 0 i n c om bi nati o n wit h bi ni meti ni b at a d ose of 
4 5 m g BI D will f oll o w t he B L R M desi g n, usi n g t he pri or distri b uti o n of t he safet y data 
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 5 7
deter mi ne d i n t he m o n ot hera p y c o h orts t hat ha ve bee n o bser ve d at t hat ti me a n d P K - a n d 
safety- g ui de d d ose escalati o n as i n dicate d f or P F -0 7 2 8 4 8 9 0 m o n ot hera p y.
I nitiati o n of c o m bi nati o n d ose escalati o n will o nl y be gi n at a m o n ot hera py d ose of 
P F - 0 7 2 8 4 8 9 0 pre vi o usl y deter mi ne d t o be safe acc or di n g t o B L R M/ E W O C . T he act ual d ose 
of P F - 0 7 2 8 4 8 9 0 at w hic h c o m bi nati o n d ose escalati o n is i nitiate d will be deter mi ne d b y  t he 
s p o ns or a n d i n vesti gat ors after c o nsi derati o n of P K, safety a n d efficac y data (t he latter if 
a vaila ble) fr o m pre vi o us m o n ot hera py d ose le vels , b ut will n ot be hi g her t ha n t he h i g hest 
m o n ot hera p y d ose deter mi ne d t o be safe base d o n B L R M/ E W O C. 
D ose M o dificati o n f or bi ni meti ni b is descri be d i n Secti o n 6. 6 .
D uri n g P hase 1a , d ose escalati o n will pr ocee d u ntil t he i de ntificati o n of t he 
M T D/rec o m me n de d d ose f or f urt her st u d y f or P F - 0 7 2 8 4 8 9 0 f or eac h of m o n ot hera p y  a n d i n 
c o m bi nati o n wit h bi ni meti ni b ( m o n ot hera p y a n d c o m bi nati o n d ose escalati o n ma y o verla p; 
see Secti o n 4. 3. 2 ).  
D uri n g m o n ot hera p y a n d c o m bi nati o n d ose escalati o n, a c ha n ge t o a differe nt d osi n g 
fre q ue nc y (e g, BI D d osi n g, differe nt n u m ber of da y s of d osi n g per c ycle) of P F - 0 7 2 8 4 8 9 0 
ma y  be e x pl ore d base d o n e mergi n g P K , safet y a n d efficac y data. T he act ual d ose a n d 
fre q ue nc y of P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b) t o be use d f or eac h d ose le vel (a n d t he 
rec o m me n de d d ose f or f urt her st u d y) will be clearl y c o m m u nicate d t o t he st u d y sites b ut will 
n ot re q uire a n i m me diate pr ot oc ol a me n d me nt.
4. 3. 2. 3. I ntr a p atie nt D ose Esc al ati o n
T o mi ni mize t he ris k t hat a n i n di vi d ual partici pa nt ma y  be e x p ose d t o a s u bt hera pe utic d ose, 
i ntra patie nt d ose escalati o n of P F- 0 7 2 8 4 8 9 0 t o a hi g her d ose(s) pre vi o usly deter mi ne d t o be 
safe (base d o n B L R M/ E W O C ) ma y  be all o we d, after a mi ni m u m of 1 2 wee ks of treat me nt at 
t he c urre nt d ose (e g, 4 c ycles i ncl u di n g sc he d ule d disease assess me nts) or disease 
pr o gressi o n , w hic he ver occ urs first . Bi ni meti ni b ma y  als o be a d de d t o patie nts i nitiall y 
recei vi n g P F-0 7 2 8 4 8 9 0 m o n ot hera p y  after t he a b o ve criteria are met (e g, after 1 2 wee ks of 
treat me nt or P D , a n d the c o m bi nati o n d ose was deter mi ne d t o be safe). See Secti o n 7. 1. 1 f or 
re q uest t o c o nti n ue st u dy i nter ve nti o n. 
4. 3. 3. D ose L i miti n g T o xicit y Defi niti o n
A partici pa nt is classifie d as D L T -e val ua ble if he/s he e x perie nces a D L T or if he/s he 
ot her wise i n t he a bse nce of a D L T recei ves at least 7 5 % of t he pla n ne d d oses of t he st u d y 
i nter ve nti o n (ie, ≥1 6/ 2 1 d oses if Q D d osi n g; ≥3 2/ 4 2 d oses if BI D d osi n g ; a partici pa nt treate d 
wit h t he c o m bi nati o n m ust meet t his t hres h ol d f or eac h a ge nt) a n d has recei ve d all sc he d ule d 
safety assess me nts d uri n g t he D L T wi n d o w.  If a partici pa nt fails t o meet t hese criteria, 
he/s he ma y  be re place d. 
F or t he p ur p ose of d ose escalati o n, t he D L T o bser vati o n peri o d will be d uri n g t he first c y cle 
of treat me nt or wit hi n 2 1 da y s after t he start of t he st u d y treat me nt i n eac h partici pa nt.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 5 8
A n y  A E res ulti n g i n a partici pa nt recei vi n g less t ha n 7 5 % of t he pla n ne d d oses of t he st u d y 
i nter ve nti o n d uri n g t he first 2 1 da y s of treat me nt will be e val uate d by t he S R C a n d ma y be 
c o nsi dere d a D L T if it is c o nsi dere d relate d t o st u d y treat me nt (ie, ca n n ot be reas o na bl y 
attrib ute d t o t he partici pa nt ’s u n derlyi n g disease, c o nc o mita nt me dicati o ns or pree xisti n g 
c o n diti o ns ).
Si g nifica nt a d verse e ve nts c o nsi dere d t o be relate d t o t he st u d y i nter ve nti o n or treat me nt 
u n der i n vesti gati o n t hat occ ur afte r t he D L T o bser vati o n peri o d will be re vie we d i n c o nte xt 
of all safet y data a vaila ble.  T hat re vie w ma y res ult i n re -e val uati o n of t he d osi n g le vel or 
re gi me n.
Se verit y  of A Es will be gra de d acc or di n g t o C T C A E versi o n 5. 0. F or t he p ur p ose of d ose 
escalati o n, a n y A E greater t ha n or e q ual t o C T C A E Gra de 3 occ urri n g i n t he first c y cle of 
st u d y treat me nt or wit hi n 2 1 da y s after t he start of st u d y treat me nt is c o nsi dere d a D L T 
u nless it ca n clearl y  be s h o w n t o be u nrelate d t o t he dr u g (e g, d ue t o disease pr o gressi o n ). 
D L T e xce pti o ns a n d clarificati o n are i n dicate d bel o w. 
E xce pti o ns/cl arific ati o ns:
He m at ol o gic al: 

Is olate d Gra de 3 or 4 ne utr o pe nia (e g, wit h o ut ass ociate d i nfecti o n a n d n ot meeti n g 
C T C A E versi o n 5. 0 criteria f or fe brile ne utr o pe nia) lasti n g > 7 d a y s is a D L T;

Gra de 3 or 4 ne utr o pe nia ass ociate d wit h i nfecti o n or meet i n g C T C A E versi o n 5. 0 
criteria f or fe brile ne utr o pe nia is a D L T;

Gra de 3 t hr o m b oc y t o pe nia ass ociate d wit h cli nicall y si g nifica nt (e g, re q uiri n g 
h os pitali zati o n/ pr ol o n gati o n of h os pitalizati o n, disa bli n g, li miti n g self-care A D Ls, or 
i n vasi ve me dical i nter ve nti o n) blee di n g or Gra de 4 t hr o m b oc y t o pe nia is a D LT;

L y m p h oc y te c o u nt decrease d Gra de ≥3 t hat is cli nicall y si g nifica nt (e g, re q uiri n g 
h os pitalizati o n/ pr ol o n gati o n of h os pitalizati o n, disa bli n g, or li miti n g self -care A D Ls)
is a D LT.
N o n -He m at ol o gic: 

Gra de 3 t o xicities t hat are cli nicall y  si g nifica nt (e g, re q uiri n g 
h os pitalizati o n/ pr ol o n gati o n of h os pitalizati o n, disa bli n g, or li miti n g self-care A D Ls), 
e xce pt t h ose t hat ha ve n ot bee n ma xi mall y  treate d (e g, na usea, v o miti n g, diarr hea) or 
ca n be easil y treate d (e g, electr olyt e a b n or malities) a n d a n y Gra de 4 n o n- he mat ol o gic 
a d verse e ve nts are D L Ts;

F or partici pa nts wit h Gra de 2 he p atic tra nsa mi nase or al kali ne p h os p hatase le vels at 
baseli ne as a res ult of li ver metastasis or b o ne metastasis : a he patic tra nsa mi nase or 
al kali ne p h os p hatase le vel > 1 0 × U L N is a D L T;
0 9
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 5 9

C o nfir me d DI LI meeti n g H y’s la w criteria ( A L T/ A S T > 3 × t he U L N wit h bilir u bi n 
> 2 × U L N wit h o ut a n ot her e x pla nati o n [e g, c h olestasis ]) is a D LT;

C K ele vati o n ≥Gra de 3 ass ociate d wit h a n i ncrease i n ser u m creati ni ne ≥1. 5 × t he 
partici pa nt’s scree ni n g ser u m creati ni ne is a D L T ;

Gra de 3 fati g ue persisti n g > 5 da y s is a D L T; 

Gra de 3 diarr hea persisti n g > 4 8 h o urs des pite o pti mal use of a nti diarr heal t hera p y is a 
D L T;

Gra de 3 na usea  persisti n g > 4 8 h o urs des pite o pti mal use of a ntie metic t hera p y  is a 
D L T;

Gra de 3 s ki n t o xicit y  (e g, ras h, der matitis, ha n d f o ot s ki n reacti o n) persisti n g
> 1 4 c o nsec uti ve da ys des pite ma xi mal s ki n t o xicit y treat me nt (as per l ocal practice), 
is a D L T;

Gra de 2 e y e dis or ders assesse d t o be irre versi ble or u nres p o nsi ve t o l ocal t hera p y 
wit hi n 2 1 da y s a n d c o nfir me d b y o p ht hal mic e val uati o n, Gra de ≥3 e y e dis or ders 
c o nfir me d b y o p ht hal mic e val uati o n , or reti nal vasc ular dis or der (i ncl u di n g R V O)
a n d c o nfir me d b y o p ht hal mic e xa mi nati o n, a re D L Ts; 

I n a n asy m pt o matic partici pa nt, Gra de 3 Q Tc F pr ol o n gati o n will first re q uire re peat 
testi n g, ree val uati o n by a q ualifie d pers o n, a n d c orrecti o n of re versi ble ca uses s uc h as 
electr ol yt e a b n or malities or h yp o xia f or c o nfir mati o n.  If, after c orrecti o n of a n y  
re versi ble ca uses, t he Gra de 3 Q Tc F pr ol o n gati o n persists, t he n t he e ve nt is a D L T;

A bs ol ute decrease of L V E F > 1 0 % c o m pa re d t o baseli ne a n d t he L V E F is bel o w t he 
i nstit uti o n’s L L N is a D L T;

Gra de 3 h y p erte nsi o n persisti n g > 1 4 c o nsec uti ve da y s is a D L T;

A n y  deat h n ot clearl y d ue t o t he u n derl yi n g disease or e xtra ne o us ca use is a D L T;

C N S effects (e g, c ha n ges i n s peec h, me m or y, slee p, c o n g niti o n, or visi o n) t hat are 
se vere or cli nically si g nifica nt (e g, re q uiri n g h os pitalizati o n/ pr ol o n gati o n of 
h os pitalizati o n, disa bli n g, or li miti n g self -care A D Ls) are D L Ts.
T he f oll o wi n g A Es will n ot be a dj u dicate d as D L Ts:

Is olate d Gra de 3 or 4 la b orat or y  a b n or malities t hat are n ot ass ociate d wit h cli nical 
se q uelae a n d are c orrecte d wit h s u p ple me ntati o n/a p pr o priate ma na ge me nt wit hi n 
7 2 h o urs of t heir o nset.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 6 0
4. 3. 4. Rec o m me n de d D ose F or F urt her St u d y
T he rec o m me n de d d ose f or f urt her st u d y (R D E ) is t he d ose c h ose n f or f urt her i n vesti gati o n 
base d o n P hase 1 d ose escalati o n st u d y res ults.  If t he M T D pr o ves t o be cli nicall y feasi ble 
f or l o n g-ter m a d mi nistrati o n i n a reas o na ble n u m ber of partici pa nts , t he n t his d ose us uall y 
bec o mes t he rec o m me n de d d ose f or f urt her st u dy .  F urt her e x perie nce wit h t he M T D ma y 
res ult i n a rec o m me n de d d ose f or f urt her st u d y l o wer t ha n t he M T D.  D uri n g escalati o n pri or 
t o a n M T D bei n g reac he d, t he s p o ns or ma y c h o ose t o a d va nce a l o wer d ose i nt o e x pa nsi o n, 
partic ularl y ( b ut n ot e xcl usi vel y ) w he n c o nsi deri n g c o m bi nati o n c o h orts.  T his decisi o n m ust 
be ma de base d o n safet y , P K, P D, a n d/ or efficac y.
4. 3. 5. St o p pi n g Criteri a i n P h ase 1 b D ose E x p a nsi o n
T he criteria f or placi n g t he st u d y  o n te m p orar y h ol d f or safety reas o ns are base d o n B a y esia n 
p osteri or pr o ba bilities usi n g a n o n -i nf or mati ve Beta ( 0. 5, 0. 5) pri or distri b uti o n.
If eit her of t he f oll o wi n g criteria liste d bel o w are met i n a n y of t he c o h orts i n t he P hase 1 b
d ose e x pa nsi o n, f urt her e nr oll me nt i nt o t hat c o h ort will be place d o n h ol d:

T he p osteri or pr o ba bilit y t hat t he tr ue i nci de nce of Gra de 5 treat me nt-relate d A E s
e xcee di n g 1 0 % is ≥0. 9 0 .

T he p osteri or pr o ba bilit y t hat t he tr ue i nci de nce of Gra de 4 - 5 treat me nt-relate d A E s
i n a partic ular c o h ort e xcee di n g 3 0 % is ≥0. 8 0.
If a c o hort is place d o n te m p orar y  h ol d, Pfizer will re vie w all safety i nf or mati o n wit h t he 
S R C a n d s u bse q ue ntl y deci de w het her t he c o h ort will be per ma ne ntly ter mi nate d or res u me 
e nr oll me nt wit h a n y p ote ntial m o dificati o ns.
4. 4. E n d of St u d y Defi niti o n
A partici pa nt is c o nsi dere d t o ha ve c o m plete d t he st u d y if he/s he has c o m plete d all p hases of 
t he st u d y, i ncl u di n g t he last sche d ule d visit/ pr oce d ure s h o w n i n t he S o A .
T he e n d of t he st u d y is defi ne d as 2 y ears after treat me nt i nitiati o n of t he la st partici pa nt 
e nr olle d or t he p oi nt at w hic h all partici pa nts ha ve die d or wit h dra w n c o nse nt /asse nt or ha ve 
bee n l ost t o f oll o w- u p, w hic he ver occ urs first . At t he e n d of t he st u d y, if feasi ble, access t o 
st u d y treat me nt ma y be pr o vi de d i n acc or da nce wit h a p plica ble re g ulati o ns a n d re q uire me nts 
t o all partici pa nts w h o are c o nti n ui n g t o be nefit fr o m st u d y  treat me nt u p o n a gree me nt 
bet wee n i n vesti gat or a n d s p o ns or (s ee Secti o n 6. 7 ).
5. S T U D Y P O P U L A TI O N
T his st u d y  ca n f ulfill its o bjecti ves o nl y if a p pr o priate partici pa nt s are e nr olle d.  T he 
f oll o wi n g eli gi bilit y criteria are desi g ne d t o select partici pa nt s f or w h o m partici pati o n i n t he 
st u d y is c o nsi dere d a p pr o priate.  All rele va nt me dical a n d n o n me dical c o n diti o ns s h o ul d be 
ta ke n i nt o c o nsi derati o n w he n deci di n g w het her a partic ular partici pa nt is s uita ble f or t his 
pr ot oc ol .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 6 1
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria , als o 
k n o w n as pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
Pfizer will re vie w eli gi bilit y  criteria verifie d b y t he i n vesti gat or or q ualifie d desi g nee t o 
c o nfir m t hat partici pa nts meet st u d y  eli gibilit y  criteria bef ore t he y are e nr olle d i nt o t he st u d y.  
T he e nr oll me nt a p pr o val pr ocess will be i nitiate d f or a partici pa nt after a n i nf or me d 
c o nse nt /asse nt d oc u me nt has bee n si g ne d a n d t he i n vesti gat or o r q ualifie d desi g nee has 
assesse d t he partici pa nt as eli g i ble. T he e nr oll me nt a p pr o val will be base d o n re vie w of 
C R F/s y ste m data.
5. 1. I ncl usi o n Criteri a
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g criteria a p pl y.  
U nless ot her wise i n dicate d, criteria a p pl y t o b ot h P hase 1a ( d ose escalati o n ) a n d P hase 1 b
(d ose e x pa nsi o n ).
1.
Fe male a n d/ or male p artici pa nts a ge ≥1 8 ye ars at t he ti me of i nf or me d c o nse nt are 
eli gi ble f or all parts of t he st u d y .
A d olesce nt partici pa nts a ge d 1 6 ye ars a n d ol der (at 
t he ti me of i nf or me d c o nse nt/asse nt) wit h b o d y wei g ht ≥4 0 k g ma y  be e nr olle d i n t he 
P hase 1 b d ose e x p a nsi o n o nl y. A d missi o n of a d olesce nts t o t he st u d y will be as 
a p pr o priate acc or di n g t o i nstit uti o nal a p pr o vals a n d will re q uire t he a d diti o nal 
scrre ni n g/ m o nit ori n g pr oce d ures as descri be d i n Secti o n 8. 2. 1 a n d 8. 2. 1 1 .

Refer t o A p pe n di x 4 f or re pr o d ucti ve criteria f or male (Secti o n 1 0. 4. 1 ) a n d fe male 
(Secti o n 1 0. 4. 2 ) partici pa nts.

Fe male partici pa nts of c hil d beari n g p ote ntial, as descri be d m ust: ( 1) ha ve a 
ne gati ve ser u m β -H C G test res ult o btai ne d wit hi n 2 4 h o urs of C 1 D 1 ; ( 2) use 
pr ot oc ol -a p pr o ve d met h o ds of c o ntrace pti o n (i ncl u di n g at least 1 f or m of 
n o n- h or m o nal c o ntrace pti o n d ue t o p ote ntial C Y P 3 A 4 i n d ucti o n b y  
P F -0 7 2 8 4 8 9 0); a n d ( 3) n ot d o nate o va fr o m Scree ni n g u ntil 2 8 d a y s after t he last 
d ose of st u d y  i nter ve nti o n. 

Male partici pa nts m ust a gree t o: ( 1) use met h o ds of c o ntrace pti o n t hat are hi g hl y 
effecti ve or acce pta ble (i ncl u di n g at least 1 f or m of n o n -h or m o nal c o ntrace pti o n 
d ue t o p ote ntial C Y P 3 A 4 i n d ucti o n b y  P F-0 7 2 8 4 8 9 0) ; a n d ( 2) n ot d o nate s per m 
fr o m Scree ni n g u ntil 2 8 da y s after t he last d ose of st u d y i nter ve nti o n.
2.
Hist ol o gical l y c o nfir me d dia g n osis of a d va nce d/ metastatic s oli d t u m or i ncl u di n g 
pri mar y  brai n t u m or. 
3.
D oc u me nte d e vi de nce of a B R A F V 6 0 0 m utati o n i n t u m or tiss ue or bl o o d 
(e g,
) as pre vi o usl y  deter mi ne d b y eit her P C R or N G S -base d l ocal la b orat or y 
assa y o btai ne d d uri n g t he c o urse of n or mal cli nical care i n a C LI A or si milarl y 
certifie d la b orat or y  at a n y ti me pri or t o Scree ni n g. A m olec ular re p ort clearl y  
d oc u me nti n g t he prese nce of t he B R A F V 6 0 0 m utati o n (a n d ot her m olec ular fi n di n gs 
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 6 2
fr o m sa m ples as perf or me d d uri n g t he n or mal c o urse of cli nical care) m ust be 
pr o vi de d f or c o nfir mati o n t hat tes ti n g meets eli gi bilit y d uri n g Scree ni n g.
4.
C o nfir mati o n of a vaila bilit y  of a de q uate t u m or tiss ue f or s u b missi o n t o t he 
sp o ns or/ce ntral la b orat or y .

N ote: F F P E bl oc k , or a mi ni m u m of 1 5 u nstai ne d sli des m ust be pr o vi de d , i deall y 
wit h ≥2 0 % t u m or n uclei.  Partici pa nts wit h fe wer t ha n 1 5 sli des of a nal yz a ble 
tiss ue ma y be c o nsi dere d eli gi ble if t he sp o ns or deter mi nes t hat t he sli des are 
s ufficie nt f or B R A F V 6 0 0 m utati o n testi n g.  A fres h t u m or tiss ue bi o ps y  ma y be 
pr o vi de d f or partici pa nts u na ble t o pr o vi de arc hi val t u m or tiss ue. If a fres h 
bi o ps y  is ta ke n, t he bi o ps y s h o ul d be ta ke n fr o m a n o ntar get lesi o n w he n p ossi ble.
Partici pa nts w h o d o n ot ha ve s ufficie nt/a de q uate arc hi val tiss ue a n d i n w h o m a 
fres h bi o psy t o o btai n s ufficie nt tiss ue ca n n ot be perf or me d safel y i n t he o pi ni o n 
of t he i n vesti gat or ma y  be eli gi ble if t he y meet all ot her eli gi bilit y criteria.  

N ote : W he ne ver p ossi ble, t he arc hi val sa m ple s h o ul d be fr o m t he sa me t u m or 
bl oc k t hat was use d f or l ocal B R A F V 6 0 0 m utati o n testi n g. If t hat sa m ple is 
differe nt t ha n t he m ost rece nt, pre vi o usl y o btai ne d sa m ple, t he m ost rece nt sa m ple 
s h o ul d als o be pr o vi de d if feasi ble.
5.
Prese nce or a bse nce of brai n i n v ol ve me nt.

Partici pa nts e nteri n g t he st u d y  i n d ose escalati o n:

Brai n i n v ol ve me nt is n ot re q uire d. I nitially d uri n g d ose escalati o n, all brai n 
lesi o ns m ust be ≤4 c m i n l o n gest di me nsi o n, a n d partici pa nts wit h brai n 
i n v ol ve me nt m ust be as y m pt o matic i n t he brai n f or at least 1 4 d a y s pri or t o 
t he start of st u d y treat me nt, defi ne d as: ( 1) be ne ur ol o gicall y  as ym pt o matic 
fr o m brai n metastases/ pri mar y  brai n t u m or; ( 2) n ot re q uir e i nitiati o n of or a n 
i ncrease i n ster oi d d osi n g t o c o ntr ol ne ur ol o gical s ym pt o ms d ue t o brai n 
metastases/ pri mar y  brai n t u m or; a n d ( 3) n ot re q uire i nitiati o n of or a n i ncr ease 
i n a nti-e pile ptic d osi n g t o c o ntr ol seiz ure acti vit y  d ue t o brai n 
metastases/ pri mar y  brai n t u m or. E xce pti o n: a nti -e pile ptic t hera py t o pre ve nt 
ne ur ol o gical s y m pt o ms ca use d b y a pree xisti n g c o n diti o n a n d n ot relate d t o 
brai n i n v ol ve me nt is all o we d pr o vi de d t here are n o c o ncer ni n g dr u g -dr u g 
i nteracti o ns (see Secti o n 6. 5 a n d A p pe n di x 1 0 f or all o we d/ pr o hi bite d 
c o nc o mita nt me dicati o ns, i ncl u di n g a nti -e pile ptic t hera p y).

O nce t he tr o u g h c o nce ntrati o n of P F - 0 7 2 8 4 8 9 0 at stea d y state is 
≥0. 1 6 8 µ g/ m L (e q ual t o t he f u-a dj uste d I C7 0 f or i n hi biti o n of B R A F V 6 0 0 E)
i n at least t w o-t hir ds of partici pa nts at t he sa me d ose le vel , a le vel at w hic h 
a nti-t u m or acti vit y i n t he brai n a n d sys te mically m a y  be e x pecte d, s u bse q ue nt 
partici pa nts e nteri n g t he st u d y d uri n g d ose escalati o n ma y ha ve a lesi o n(s) 
lar ger t ha n 4 c m, a n d/ or be s ym pt o matic i n t he brai n, defi ne d as: a n y of t he 
a b o ve wit hi n 1 4 da y s of t he start of st u d y treat me nt.
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 6 3

Partici pa nts e nteri n g t he st u d y  i n d ose e x pa nsi o n:

C o h orts 1 , 2, 3 a n d 4: mela n o ma, wit h at least 1 pare nc h y m al brai n lesi o n at 
least 0. 5 c m a n d ≤4 c m i n l o n gest dia meter a n d meas ura ble ( by m R E CI S T 
v 1. 1). If all disease i n t he brai n was pre vi o usly irra di ate d, at least 
1 meas ura ble lesi o n m ust de m o nstrate pr o gressi o n si nce irra diati o n or a ne w 
meas ura ble lesi o n(s) m ust be prese nt .

C o h orts 1 , 3: as ym pt o matic i n t he brai n f or at least 1 4 da y s pri or t o t he start of 
st u d y treat me nt as defi ne d a b o ve.

C o h orts 2, 4: s ym pt o matic i n t he brai n wit hi n 1 4 da y s pri or t o t he start of 
st u d y treat me nt as defi ne d a b o ve.

C o h ort 5: a n y s oli d t u m or wit h at least 1 meas ura ble lesi o n (refer t o R E CI S T, 
m R E CI S T , or R A N O criteria) ; hist or y  of or c urre nt le pt o me ni n geal 
metastases is per mitte d; wit h or wit h o ut dise ase i n t he brai n as l o n g as it d oes 
n ot meet re q uire me nts f or C o h orts 1 - 4; wit h or wit h o ut pri or B R A F a n d/ or 
M E K i n hi bit or ; as ym pt o matic or s y m pt o matic i n t he brai n as defi ne d a b o ve.   
F or patie nts wit h pri mar y b rai n t u m ors, R A N O s h o ul d be use d t o deter mi ne 
baseli ne br ain lesi o n stat us a n d res p o nse assess me nt d uri n g t he st u d y.   
Patie nts wit h o ut meas ura ble disease ma y  be all o we d if a c o m pelli n g cli nical 
rati o nale is pr o vi de d by t he i n vesti gat or a n d a p pr o ve d b y  t he s p o ns or.

C o h ort 6 , 7 ( D DI a n d f o o d-effect s u bst u d y): if brai n i n v ol ve me nt is prese nt,
lesi o n(s) m ust be ≤4 c m i n l o n gest dia meter a n d it m ust be as ym pt o matic i n 
t he brai n f or at least 1 4 da ys pri or t o t he start of st u d y treat me nt as defi ne d 
a b o ve.
6.
Disease pr o gress i o n des pite pri or treat me nt a n d n o acce pta ble alter nati ve treat me nt 
o pti o ns a vaila ble. 

N ote: partici pa nts f or w h o m t he ris k: be nefit rati o of a s pecific a vaila ble 
alter nati ve t hera p y is u nfa v ora ble i n t he o pi ni o n of t he i n vesti gat or ma y  be 
eli gi ble if t he reas o n is clearl y d oc u me nte d a n d a p pr o ve d b y t he s p o ns or .

Partici pa nts e nteri n g t he st u d y  i n d ose escalati o n:

O nce t he c o nce ntrati o n of P F - 0 7 2 8 4 8 9 0 at stea d y state is ≥0. 1 6 8 µ g / mL
(e q ual t o t he I C7 0 f or i n hi biti o n of B R A F V 6 0 0 E) i n at least t w o-t hir ds of 
partici pa nts at t he sa me d ose le vel , a le vel at w hic h a nti-t u m or acti vit y i n t he 
brai n a n d s ys te mically m a y be e x pecte d, partici pa nts wit h B R A F 
V 6 0 0 -m uta nt mela n o ma, N S C L C, C R C or A T C d o n ot re q uire pri or treat me nt 
wit h a B R A F i n hi bit or if brai n i n v ol ve me nt is prese nt a n d s y m pt o matic as 
defi ne d a b o ve. T hese partici pa nts still re q uire ot her pri or sta n dar d s ys te mic 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 6 4
t hera py as well as pri or l ocal brai n t hera p y , t he latter if c o nsiste nt wit h 
i nstit uti o nal/c o u ntr y sta n dar d of care. 

Partici pa nts e nteri n g t he st u d y  i n d ose e x pa nsi o n:

C o h orts 1, 2: Pri or B R A F or M E K i n hi bit or i n t he metastatic setti n g (or i n t he 
a dj u va nt setti n g wit hi n 6 m o nt hs of st u d y  treat me nt) is n ot all o we d .

C o h orts 3, 4 : Pri or B R A F i n hi bit or i n t he metastatic setti n g ( or i n t he a dj u va nt 
setti n g wit hi n 6 m o nt hs of st u d y treat me nt) is re q uire d.

C o h ort 5: Pri or B R A F i n hi bit or i n t he metastatic or a dj u va nt setti n g is all o we d 
b ut n ot re q uire d .

C o h ort 6 a n d 7: Pri or B R A F i n hi bit or is all o we d b ut n ot re q uire d.
7.
E C O G P S 0 or 1 .

Partici pa nts e nteri n g t he st u d y i n d ose escalati o n: E C O G P S 2 d ue t o u n derl y i n g 
ca ncer is all o we d o nce t he c o nce ntrati o n of P F- 0 7 2 8 4 8 9 0 at stea dy state is 
≥0. 1 6 8 µ g/ m L (e q ual t o the I C 7 0 f or i n hi biti on o f B R A F V 6 0 0 E) i n at least 
t w o-t hir ds of partici pa nt s at t he sa me d ose le vel , a le vel at w hic h a nti-t u m or 
acti vit y i n t he brai n a n d s yste mically ma y be e x pecte d .

Partici pa nts e nteri n g t he st u d y i n d ose e x pa nsi o n: E C O G P S 2 d ue t o u n d erl yi n g 
ca nc er is all o we d f or C o h orts 1- 5.
8.
A de q uate B o ne Marr o w F u ncti o n, i ncl u di n g:

A N C ≥1, 2 5 0 / m m3 or ≥1. 2 5 × 1 0 9/ L;

Platelets ≥7 5 , 0 0 0/ m m3 or ≥7 5 × 1 0 9/L;

He m o gl o bi n ≥9 g/ d L.   Tra nsf usi o n s u p p ort is per mitte d if c o m plete d 1 4 da y s 
pri or t o t he start of st u d y treat me nt a n d h e m o gl o bi n re mai ns ≥9 g/ d L at t he start 
of st u d y  treat me nt.
9.
A de q uate Re nal F u ncti o n, i ncl u di n g:

Esti mate d creatini ne cle ara nce ≥6 0 m L / mi n (≥5 0 m L / mi n f or d ose e x pa nsi o n) as 
calc ulate d usi n g t he met h o d sta n dar d f or the i nstit ut io n.  I n e q ui v ocal cases, a 
2 4 -h o ur uri ne c ollecti o n test ca n be use d t o esti mate t he creati ni ne cleara nce m ore 
acc uratel y.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 6 5
1 0. A de q uate Li ver F u ncti o n, i ncl u di n g:

T otal s er u m bilir u bi n ≤1. 5 × U L N ; ≤3. 0 × U L N if t he participa nt has d oc u me nte d 
Gil b ert s yn dr o me; ≤2. 5 × U L N f or H C C;

A S T a n d A L T ≤2. 5 × U L N; ≤5. 0 × U L N if t here is li ver i n v ol ve me nt b y  t he 
t u m or; ≤5 × U L N f or H C C ;

Al kali n e p h os p hata se ≤2. 5 × U L N ; ≤5 × U L N i n case of b o ne/li ver metastasis. 
1 1. Res ol ve d ac ute effects of a n y  pri or t hera p y t o baseli ne se verity o r C T C A E Gra de ≤1 
e xce pt for A Es n ot c o nstit uti n g a safet y ris k b y i n vesti gat or j u d g me nt a n d disc ussi o n 
wit h t he s p o ns or.  N ote : Sta ble c hr o nic c o n diti o ns (≤Gra de 2) t hat are n ot e x pecte d t o 
res ol ve (e g, ne ur o pat h y , m yal gia, al o pecia, pri or t hera p y- relate d e n d ocri n o pat hies) 
are als o e xce pti o ns a n d partici pa nts wit h t hese c o n diti o ns ma y  e nr oll.
1 2. Partici pa nts w h o are willi n g a n d a ble t o c o m pl y wit h all sc he d ule d visits, treat me nt 
pla n, la b orat or y  tests, lifest yle c o nsi derati o ns, a n d ot her st u d y pr oce d ures.
1 3. Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt /asse nt as descri be d i n A p pe n di x 1 , w hic h 
i ncl u des c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n t he IC D a n d i n 
t his pr ot oc ol.
1 4. F or a d olesce nt partici pa nts: T he i n vesti gat or, or a pers o n desi g nat e d b y t he 
i n vesti gat or, will o btai n writte n i nf or me d c o nse nt fr o m eac h st u d y partici pa nt’s le gal 
g uar dia n (as defi ne d i n A p pe n di x 1 [a n d t he partici pa nt’s asse nt, w he n a p plica ble,]) 
bef ore a n y st u d y- s pecific acti vit y is perfor me d ( u nless a wai ver of i nf or me d 
c o nse nt/asse nt has bee n gra nte d b y a n I RB/ E C). All le gal g uar dia ns s h o ul d be f ull y  
i nf or me d, a n d partici pa nts s h o ul d be i nf or me d t o t he f ullest e xte nt p ossi ble, a b o ut t he 
st u d y i n la n g ua ge a n d ter ms t he y are a ble t o u n dersta n d. T he i n vesti gat or will retai n 
t he ori gi nal c o p y of eac h partici pa nt's si g ne d c o nse nt/asse nt d oc u me nt.
5. 2. E xcl usi o n Criteri a
Partici pa nts are e xcl u de d fr o m t he st u d y  if a n y of t he f oll o wi n g criteria a p pl y.  
U nless ot her wise i n dicate d, criteria a p pl y t o b ot h P hase 1a ( d ose escalati o n ) a n d P hase 1 b 
(d ose e x pa nsi o n ).
1.
Brai n metastasis/ pri mar y brai n t u m or re q uiri n g i m me diate l ocal i nter ve nti o n (s ur ger y , 
ra di os ur ger y) i n t he o pi ni o n of t he i n vesti gat or.
2.
D uri n g d ose escalati o n (i nitiall y ) a n d d uri n g d ose e x pa nsi o n C o h orts 1 - 4, 6 a n d 7 : 
hist or y  of or c urre nt le pt o me ni n geal metastases. S uc h partici pa nts m a y  be eli gi ble 
d uri n g d ose escalati o n o nce t he c o nce ntrati o n of P F - 0 7 2 8 4 8 9 0 at stea d y state is 
≥0. 1 6 8 µ g/ m L (e q ual t o t he IC 7 0 f or i n hi biti o n of B R A F V 6 0 0 E , a le vel at w hic h 
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 6 6
a nti-t u m or acti vit y i n t he brai n a n d sys te mically m a y be e x pecte d) i n at least 
t w o-t hir ds of partici pa nts at t he sa me d ose le vel .
3.
Partici pa nts wit h a n y  ot her acti ve mali g na nc y wit hi n 2 years pri or t o e nr oll me nt, 
e xce pt for a de q uatel y treate d basal cell or s q ua m o us cell s ki n ca ncer, carci n o ma i n 
sit u of t he cer vi x, B o we n’s disease, pr ostate i ntrae pit helial ne o plas m a n d ≤6 pr ostate 
ca ncer. Partici pa nts wit h a hist or y  of ot her c urati vel y treate d ca ncers m ust be 
re vie we d by t he s p o ns or pri or t o e nteri n g t he st u d y.
4.
Maj or s ur ger y  (e g, i n patie nt pr oce d ure wit h ge neral a nest hesia) wit hi n 2 8 da y s pri or 
t o st u d y e ntr y, wit hi n 1 4 da ys f or cra ni ot o m y.  If cra ni ot o m y perf or me d, ne ur ol o gical 
se q uelae m ust ha ve f ull y res ol ve d. F or mi n o r s ur gical pr oce d ures w it hi n 2 8 da y s
pri or t o start of st u d y  treat me nt, c o ns ult t he s p o ns or.
5.
Ra diati o n t hera p y t o visceral metastases (i ncl u di n g S R S t o t he brai n) wit hi n 1 4 da y s 
pri or t o t he start of st u d y treat me nt or W B R T wit hi n 2 8 da ys pri or t o t he start of st u d y 
treat me nt. If S R S or W B R T perf or me d, ne ur ol o gical se q uelae m ust ha ve f ull y 
res ol ve d a n d ster oi d d osi n g m ust meet I ncl usi o n/ E xcl usi o n Criteria.
6.
S y ste mic a nti-ca nc er t hera p y or s mall- m olec ular t hera pe utic(s) (a p pr o ve d or 
i n vesti gati o nal) wit hi n 1 wee k ( 2 wee ks f or c y t ot o xic c he m ot hera p y, 6 wee ks f or 
mit o m y ci n C or nitr os o ureas) or 5 half -li ves ( w hic he ver is s h orter) of t he a ge nt(s) 
pri or t o t he start of st u d y treat me nt; anti b o d y  base d a ge nt(s) (a p pr o ve d or 
i n vesti gati o nal), wit hi n 4 wee ks of t he start of st u d y treat me nt or 5 half -li ves 
( w hic he ver is s h orter) of t he a ge nt(s) pri or t o t he start of st u d y treat me nt.
A nti h or m o nal t hera py(ies) f or c o nc urre nt breast or pr o state ca ncer, if c o nsiste nt wit h 
i ncl usi o n/e xcl usi o n criteria, c o nc o mita nt t hera py a n d s u p p orti ve care g ui deli nes, (see 
Secti o n s 6. 5. 2 a n d 6. 5. 3 ) ma y be all o we d if a p pr o ve d b y t he s p o ns or.
7.
Partici pa nts wit h acti ve, u nc o ntr olle d bacterial, f u n gal, or viral i nfecti o n , i ncl u di n g 
H B V, H C V, k n o w n HI V or AI D S relate d ill ness.  I n e q ui v ocal cases, partici pa nts 
w h ose viral l oa d is ne gati ve, ma y  be eli gi ble.  HI V ser o p ositi ve partici pa nts w h o are 
healt h y  a n d l o w ris k f or AI D S relate d o utc o mes c o ul d be c o nsi dere d eli gi ble.  
E li gi bilit y criteria f or HI V p ositi ve partici pa nts s h o ul d be e val uate d a n d disc usse d 
wit h s p o ns or ’s me dical m o nit or a n d will be base d o n c urre nt a n d past C D 4 a n d T cell 
c o u nts, hist or y (if a n y) of AI D S defi ni n g c o n diti o ns (e g, o p p ort u nistic i nfecti o ns), 
a n d stat us of HI V treat me nt. T he p ote ntial f or dr u g -dr u g i nteracti o ns will als o be 
ta ke n i nt o c o nsi derati o n.
N ote re g ar di n g C O VI D - 1 9/ S A R S-C o V 2 : t his pr ot oc ol e xcl u des partici pa nts wit h 
acti ve i nfecti o ns, as n ote d a b o ve. W hile S A R S -C o V 2 testi n g is n ot ma n date d f or 
e ntr y i nt o t his pr ot oc ol, testi n g s h o ul d f oll o w l ocal cli nical practice sta n dar ds. If a 
partici pa nt has a p ositi ve test res ult f or S A R S-C o V 2 i nfecti o n, is k n o w n t o ha ve 
as ym pt o matic i nfecti o n or is s us pecte d of ha vi n g S A R S -C o V 2, he/s he is e xc l u de d b ut 
ma y  be rescree ne d acc or di n g t o pr ot oc ol re q uire me nts f or rescree ni n g if t he 
partici pa nt s u bse q ue ntly tests ne gati ve.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 6 7
8.
I m paire d car di o vasc ular f u ncti o n or cli nically si g nifica nt car di o vasc ular disease 
i ncl u di n g, b ut n ot li mite d t o, t he f oll o wi n g:

Baseli ne tri plicate 1 2 -lea d E C G t hat de m o nstrates cli nicall y rele va nt 
a b n or malities t hat ma y affect partici pa nt safety or i nter pretati o n of st u d y res ults . 
E xa m ples i ncl u de: scree ni n g or baseli ne (ie, C 1 D 1 pre -d ose) Q Tc F i nter val 
> 4 7 0 msec , baseli ne Q R S > 1 2 0 msec, c o m plete L B B B, si g ns of a n ac ute or 
i n deter mi nate a ge m yocar dial i nfarcti o n, S T -T i nter val c ha n ges s u g gesti ve of 
acti ve m y ocar dial isc he mia, sec o n d - or t hir d -de gree A V bl oc k, or seri o us 
bra d yarr h yt h mias or tac h y arr h yt h mias. T he Q T i nter val s h o ul d be rate c orrecte d 
usi n g t he Fri dericia met h o d a n d t he res ulti n g Q Tc F s h o ul d be use d f or decisi o n 
ma ki n g a n d re p orti n g.  If Q Tc F e xcee ds 4 7 0 msec or Q R S e xcee ds 1 2 0 msec, t he 
E C G s h o ul d be re peate d 2 m ore ti mes a n d t he a vera ge of t he 3 Q Tc F or Q R S 
val ues s h o ul d be use d t o deter mi ne t he partici pa nt ’s eli gi bilit y (i n a d diti o n, t he 
Q Tc F s h o ul d be < 4 7 0 msec o n at least 2 i n di vi d ual E C Gs).  If m ore t ha n 3 E C Gs 
are perf or me d, t his s h o ul d be re vie we d wit h t he s p o ns or’s me dical m o nit or t o 
c o nfir m el i gi bilit y. C o m p uter i nter prete d E C Gs s h o ul d be o verrea d b y  a 
p h y sicia n e x perie nce d i n rea di n g E C Gs bef ore e xcl u di n g partici pa nts.  S uc h c ases 
m ust be disc usse d i n detail wit h s p o ns or ’s me dical m o nit or t o j u d ge eli gi bilit y. If 
a partici pa nt has a car diac r hyt h m de vice/ pace ma ker place d a n d Q Tc F > 4 7 0 msec
or ca n n ot be acc uratel y deter mi ne d , t he partici pa nt m ust be disc usse d i n detail 
wit h s p o ns or ’s me dical m o nit or t o j u d ge eli gi bilit y. 

A n y  of t he f oll o wi n g i n t he pre vi o us 6 m o nt hs: m yocar dial i nfarcti o n, u n sta ble 
a n gi na, c or o nar y/ peri p heral arter y b ypass graft or c or o nar y  a n gi o plast y/ste nti n g.

O n g oi n g c ar diac d ys rh y t h mias of N CI  C T C A E ≥ Gra de 2 (partici pa nts wit h atrial 
fi brillati o n c o ntr olle d f or > 3 0 da ys pri or t o t he start of st u d y treat me nt are eli gi ble 
p r o vi de d me dicati o ns f or rate c o ntr ol are n ot s u bject t o p ote ntial D DI wit h st u d y  
me dicati o ns ).

Bl o o d press ure t hat ca n n ot be c o ntr olle d by me dicati o ns (e g, > 1 4 0/ 9 0 m m H g) 
des pite o pti mal me dical t hera p y.

C o n gesti ve heart fail ure re q uiri n g treat me nt ( Ne w Y or k Heart Ass ociati o n 
Gra de ≥2) a n d/ or L V E F < 5 0 % as deter mi ne d b y  E C H O.
9.
K n o w n or s us pecte d h y p erse nsiti vit y t o acti ve i n gre die nt/e xci pie nts.
1 0. Acti ve i nfla m mat or y  gastr oi ntesti nal disease, c hr o nic diarr hea, k n o w n di vertic ular 
disease, pre vi o us gastric resec ti o n or la p ba n d s ur ger y or i na bilit y t o s wall o w a n d 
retai n st u d y treat me nt.  Gastr oes o p ha geal refl u x disease u n der treat me nt wit h H 2 
bl oc kers or a ntaci ds is all o we d pr o vi de d d osi n g i nstr ucti o ns i n t he pr ot oc ol are 
f oll o we d. Us e of P PIs are n ot all o we d wi t hi n 7 da ys of st u d y start ( C 1 D 1) a n d d uri n g 
st u d y treat me nt.
1 1. K n o w n hist or y  of ac ute or c hr o nic pa ncreatitis.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 6 8
1 2. C o nc urre nt ne ur o m usc ular dis or der t hat is ass ociate d wit h ele vate d C K (e g, 
i nfla m mat or y my o pat hies, m usc ular d ys tr o p h y, a m yotr o p hic lateral scler o sis, s pi nal 
m usc ular atr o p h y). 
1 3. H ist or y or c urre nt e vi de nce of R V O or c urre nt ris k fact ors f or R V O (e g, u nc o ntr olle d 
gla uc o ma or oc ular h y perte nsi o n, hist or y of h y p er visc osit y or hy perc oa g ula bilit y  
s yn dr o mes); hist or y  of reti nal de ge nerati ve disease. 
1 4. H istor y  of a t hr o m b oe m b olic e ve nt < 1 2 wee ks pri or t o starti n g st u d y treat me nt. 
E xa m ples of t hr o m b oe m b olic e ve nts i ncl u de tra nsie nt isc he mia attac k, 
cere br o vasc ular acci de nt, dee p vei n t hr o m b osis or p ul m o nar y  e m b olis m. 
N ote: Partici pa nts wit h a dee p vei n t hr o m b osis or p ul m o nar y  e m b oli t hat d o n ot res ult 
i n he m o d yna mic i nsta bilit y  are e xce pti o ns a n d ma y partici pate as l o n g as t he y are 
sta ble, asy m pt o matic , a n d o n a sta ble d ose of a ntic oa g ula nts f or at least 4 wee ks pri or 
t o starti n g st u d y treat me nt ( C 1 D 1).
N ote: Cat heter -relate d ve n o us t hr o m b osis is n ot c o nsi dere d a t hr o m b oe m b olic e ve nt 
f or t his trial e ve n if < 1 2 wee ks pri or t o starti n g st u d y  treat me nt.
1 5. C urre nt use or a ntici pate d nee d f or dr u gs t hat are k n o w n 
, 
i ncl u di n g t he a d mi nistrati o n wit hi n 1 0 da y s or 5 half -li ves, w hic he ver is l o n ger, or
, i ncl u di n g t he a d mi nistrati o n wit hi n 5 half -li ves pl us 
1 0 da y s, pri or t o first d ose of P F- 0 7 2 8 4 8 9 0. Refer t o Secti o n 6. 5 f or f urt her details.
1 6. Ser u m or uri ne pre g na nc y  test (f or fe males of c hil d beari n g p ote ntial) p ositi ve at 
S cree ni n g.
1 7. Ot her me dical or ps y c hiatric c o n diti o n i ncl u di n g rece nt ( wit hi n t he past ye ar) or 
acti ve s uici dal i deati o n/be ha vi or or la b orat or y  a b n or malit y t hat ma y i ncrease t he ris k 
of st u d y partici pati o n or, i n t he i n vesti gat or’s j u d g me nt, ma ke t he partici pa nt
i na p pr o priate f or t he st u d y.
1 8. I n vesti gat or site staff or Pfizer e m pl o yees directl y i n v ol ve d i n t he c o n d uct of t he 
st u d y, site staff ot her wise s u per vise d b y t he i n vesti gat or, a n d t heir res pecti ve fa mil y 
me m bers .
1 9. Partici pa nts i n d ose escalati o n: hist or y  of p ne u m o nitis t hat re q uire d ster oi ds or acti ve 
p ne u m o nitis .
5. 3. Lifest yle C o nsi der ati o ns
5. 3. 1. P h ot ose nsiti vit y
Gi ve n t he p ote ntial f or p h ot ot o xicit y  fr o m n o ncli nical t o xic ol o g y st u dies wit h P F- 0 7 2 8 4 8 9 0, 
p artici pa nt s will be a d vise d t o re p ort a n y reacti o n t o s u n e x p ose d s ki n.  In a d diti o n, s pecial 
preca uti o ns will be ta ke n t o li mit a n y  p ote ntial p h ot oirritati o n effect, by mi ni mizi n g t he 
partici pa nt s’ e x p os ure t o li g ht i ncl u di n g s u nli g ht, a n d hi g h i nte nsity U V B li g ht s o urces s uc h 
 
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 6 9
as ta n ni n g be ds, t a n ni n g b o ot hs a n d s u nla m ps.  Partici pa nt s s h o ul d be e nc o ura ge d t o a p ply 
s u nscree n/s u n bl oc k dail y a n d t o wear cl ot hi n g t hat c o vers areas of e x p ose d s ki n w he n 
o ut d o ors d uri n g da y li g ht h o urs.
5. 3. 2. Acti vit y
Stre n u o us p h y sical acti vities, s uc h as c o m petiti ve s p orts, ma y  res ult i n si g nifica nt i ncreases 
i n C K le vels w hile o n bi ni meti ni b treat me nt. Partici pa nts s h o ul d be ca uti o ne d t o a v oi d ne w 
stre n u o us e xercise after first d ose of st u d y treat me nt.
5. 3. 3. C o ntr ace pti o n
T he i n vesti gat or or his or her desi g nee, i n c o ns ultati o n wit h t he partici pa nt , will c o nfir m t hat 
t he partici pa nt has selecte d a n a p pr o priate met h o d of c o ntrace pti o n f or t he i n di vi d ual 
partici pa nt a n d his or her part ner(s) fr o m t he per mitte d list of c o ntrace pti o n met h o ds (see 
A p pe n di x 4 a n d Secti o n 1 0. 4. 4 ) a n d will c o nfir m t hat t he partici pa nt has bee n i nstr ucte d i n 
its c o nsiste nt a n d c orrect use.  At ti me p oi nts i n dicate d i n t he S o A , t he i n vesti gat or or 
desi g nee will i nf or m t he partici pa nt of t he nee d t o use hi g hl y effecti ve c o ntrace pti o n 
c o nsiste ntl y a n d c orrectl y a n d d oc u me nt t he c o n versati o n a n d t he partici pa nt ’s affir mati o n i n 
t he partici pa nt ’s c hart (partici pa nt s nee d t o affir m t heir c o nsiste nt a n d c orrect use of at least 
1 of t he selecte d met h o ds of c o ntrace pti o n).  I n a d diti o n, t he i n vesti gat or or desi g nee will 
i nstr uct t he partici pa nt t o call i m me diatel y if t he selecte d c o ntrace pti o n met h o d is 
disc o nti n ue d or if pre g na nc y is k n o w n or s us pecte d i n t he partici pa nt or part ner.
5. 4. Scree n F ail ures
Scree n fail ures are defi ne d as partici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut 
are n ot s u bse q ue ntl y e nr olle d i n t he st u d y. A mi ni mal set of scree n fail ure i nf or mati o n is 
re q uire d t o e ns ure tra ns pare nt re p ortin g of scree n fail ure partici pa nts t o meet t he C O N S O R T 
p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries fr o m re g ulat or y a ut h orities. Mi ni mal 
i nf or mati o n i ncl u des de m o gra p hy,  scree n fail ure details, eli gi bilit y criteria, a n d a n y S A E.
Tests wit h res ults t ha t fail eli gi bilit y re q uire me nts ma y be re peate d d uri n g Scree ni n g if t he 
in vesti gat or belie ves t he res ult t o be i n err or. A d diti o nall y , a partici pa nt w h o fails Scree ni n g 
ma y  re peat t he Scree ni n g pr ocess 1 time if t he i n vesti gat or belie ves t hat t here has bee n a 
c ha n ge i n eli gi bilit y stat us. 
6. S T U D Y I N T E R V E N TI O N
St u d y  i nter ve nti o n is defi ne d as a n y i n vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s), 
place b o, me dical de vice(s) , or st u d y pr oce d ure(s) i nte n de d t o be a d mi nistere d t o a st u d y 
partici pa nt acc or di n g t o t he st u d y pr ot oc ol.
F or t he p ur p oses of t his pr ot oc ol, st u d y i nter ve nti o ns refer t o P F - 0 7 2 8 4 8 9 0 a n d bi ni meti ni b
(a n d mi daz ola m, f or partici pa nts e nr olle d i nt o P hase 1 b D DI s u bst u d y, C o h ort 6). 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 7 0
6. 1. St u d y I nter ve nti o n(s) A d mi nistere d
I nter ve nti o n N a me
P F -0 7 2 8 4 8 9 0
Bi ni meti ni b
Mi d az ol a m
A R M N a m e
( gr o u p of p artici p a nts 
recei vi n g a s pecific 
tre at me nt 
P hase 1a d ose escalati o n 
( mo n ot hera p y a n d 
c o m bi nati o n)
P hase 1 b d ose e x pa nsi o n 
(c o m bi nati o n)
P hase 1a d ose 
escalati o n 
(c o m bi nati o n)
P hase 1 b d ose 
e x pa nsi o n 
(c o m bi nati o n)
P hase 1 b D DI s u bst u d y
T y pe
Dr u g
Dr u g
Dr u g
D ose F or m ul ati o n
Ta blet
Ta blet
S y r u p
U nit D ose Stre n gt h(s)
1 0 m g, 2 5 m g, 1 0 0 m g
1 5 m g
2 m g/ m L
D os a ge Le vel(s)
Starti n g d ose 5 0 m g Q D; 
see Sc he ma
4 5 m g BI D
2 m g, 3 si n gle d oses
R o ute of 
A d mi nistr ati o n
Oral
Oral
Oral
Use
E x peri me ntal
E x peri me ntal
Pr o be
I M P or NI M P
I M P 
I M P 
I M P
S o urci n g
Pr o vi de d ce ntrall y b y t he 
s p o ns or.
Ple ase see I P M a n u al.
Pr o vi de d ce ntrall y b y 
t he s p o ns or.
Ple ase see I P M a n u al.
Pr o vi de d ce ntrall y b y 
t he s p o ns or.
P ac k a gi n g a n d 
L a beli n g
St u d y i nter ve nti o n will 
be pr o vi de d i n hi g h -
de nsit y p ol yet h yle ne 
b ottles . Eac h b ottle w ill 
be la bele d as re q uire d 
per c o u ntr y re q uire me nt.
Ple ase see I P M a n u al.
St u d y i nter ve nti o n will 
be pr o vi de d i n 
hi g h -de nsit y 
p ol yet h yle ne b ottles .  
Eac h b ottle w ill be 
la bele d as re q uire d per 
c o u ntr y re q uire me nt.
Ple ase see I P M a n u al.
C o m mercial dr u g will 
be pr o vi de d.  Eac h 
b ottle w ill be la bele d as 
re q uire d per c o u ntr y 
re q uireme nt. Ple ase see 
I P M a n u al.
C urre nt/ F or mer 
N a m e(s) or Ali as(es)
P F -0 7 2 8 4 8 9 0
A R R Y -4 6 1
A R 0 0 5 0 4 4 6 1
Bi ni meti ni b
P F -0 6 8 1 1 4 6 2
A R R Y -4 3 8 1 6 2
M E K 1 6 2
O N O -7 7 0 3
M E K T O VI
Mi daz ol a m
P F - 0 7 28 4 8 9 0 will be pr o vi de d as ta blets f or oral a d mi nistrati o n.  T he 1 0 m g, 2 5 m g  a n d 
1 0 0 m g ta blets will be s u p plie d i n se parate b ottles a n d la bele d acc or di n g t o l ocal re g ulat or y  
re q uire me nts.
Bi ni meti ni b will be pr o vi de d as ta blets f or oral a d mi nistrati o n.  T he 1 5 m g ta blets will be 
s u p plie d i n b ottles a n d la bele d acc or di n g t o l ocal re g ulat or y re q uire me nts.
Mi daz ola m will be pr o vi de d as s yr u p f or oral a d mi nistrati o n.
6. 1. 1. A d mi nistr ati o n
Partici pa nt s will s wall o w t he st u d y i nter ve nti o n w h ole, a n d will n ot ma ni p ulate or c he w t he 
st u d y i nter ve nti o n pri or t o s wall o wi n g.   
P F - 0 7 2 8 4 8 9 0 will be a d mi nistere d Q D (i nitiall y ; t he d osi n g fre q ue nc y ma y be c ha n ge d,
e g, BI D) o n a c o nti n u o us basis. 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 7 1
I n partici pa nts a d mi nistere d t he c o m bi nati o n, b i ni meti ni b will be a d mi nistere d BI D o n a 
c o nti n u o us basis.
A c y cle is defi ne d as 2 1 da ys, re gar dless of misse d d oses or d ose dela y s.  
P F -0 7 2 8 4 8 9 0 will be a d mi nistere d orall y  o n a n e m pt y st o mac h wit h o ut a dj ust me nt f or b o d y 
size at e ver y c ycle.
W he n bi ni meti ni b is a d mi nistere d t o get her wit h P F-0 7 2 8 4 8 9 0, it will be a d mi nistere d orall y 
o n a n e m pt y st o mac h wit h o ut a dj ust me nt f or b o d y size at e ver y c ycle.
W he n a d ose of bi ni meti ni b is a d mi nistere d wit h o ut a d ose of P F -0 7 2 8 4 8 9 0 (e g, t he sec o n d 
d ose of bi ni meti ni b, w he n P F- 0 7 2 8 4 8 9 0 d osi n g is Q D a n d bi ni meti ni b d osi n g is B I D), it ma y 
be a d mi nistere d orall y  wit h o ut re gar d t o f o o d a n d wit h o ut a dj ust me nt f or b o d y size at e ver y 
c ycle.
See Secti o n 6. 1. 1. 1 f or a d diti o nal details o n f o o d re q uire me nts a n d ti mi n g of d osi n g.
Partici pa nts s h o ul d be i nstr ucte d t o ta ke t heir me dicati o n at t he sa me ti me eac h da y  a n d t o 
n ot ta ke m ore t ha n t he prescri be d d ose at a n y ti me. 
If a partici pa nt misses a d ose of treat me nt, he/s he m ust be i nstr ucte d n ot t o “ ma ke it u p” b ut 
t o res u me wit h t he s u bse q ue nt d ose as prescri be d. A misse d d ose of treat me nt is defi ne d as 
m ore t ha n 2 h o urs past t he pla n ne d/sc he d ule d d osi n g ti me f or BI D d osi n g, or m ore t ha n 
4 h o urs past t he pla n ne d/sc h e d ule d d osi n g ti me f or Q D d osi n g.
If less t ha n or e q ual t o 2 h o urs (f or BI D d osi n g) or less t ha n or e q ual t o 4 h o urs (f or Q D 
d osi n g) has passe d, t he n t he partici pa nt s h o ul d be i nstr ucte d t o ta ke t he d ose, a n d c o nti n ue
t he n or mal d osi n g sc he d ule.
If m ore t ha n 2 h o urs (f or BI D d osi n g) or m ore t ha n 4 h o urs (f or Q D d osi n g) has passe d, t he n 
t he partici pa nt s h o ul d be i nstr ucte d t o s ki p t he misse d d ose, a n d res u me t he n or mal d osi n g 
sc he d ule d/ti me f or t he ne xt d ose.
If a partici pa nt v o mits a n y ti me after ta ki n g a dose, he/s he m ust be i nstr ucte d n ot t o “ ma ke it 
u p” b ut t o res u me wit h t he s u bse q ue nt d ose as prescri be d. 
If a partici pa nt i na d verte ntl y ta kes 1 e xtra d ose d uri n g a da y, t he partici pa nt s h o ul d n ot ta ke 
t he ne xt pla n ne d d ose .
6. 1. 1. 1. F o o d Re q uire me nts f or A ll C o h or ts a n d S u b st u dies E xcl u di n g t he F o o d -effect
C o h ort/ S u bst u d y
P F - 0 7 2 8 4 8 9 0 will be a d mi nistere d wit h at least 8 -oz ( 2 4 0 m L ) of water o n a n e m pt y st o mac h 
at t he sa me ti me eac h da y.  N o f o o d or li q ui ds ot her t ha n water will be c o ns u me d f or 2 h o urs 
bef ore a n d 1 h o ur f oll o wi n g eac h d ose t hr o u g h o ut t he st u d y .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 7 2

P F - 0 7 2 8 4 8 9 0 a d mi nistere d Q D (m o n ot hera p y or c o m bi nati o n) : P F-0 7 2 8 4 8 9 0 will be 
a d mi nistere d Q D i n t he m or ni n g.  

P F -0 7 2 8 4 8 9 0 a d mi nistere d BI D (m o n ot hera p y or c o m bi nati o n) : P F-0 7 2 8 4 8 9 0 will be 
a d mi nistere d BI D, 1 2 ± 2 h o urs a part , i n t he m or ni n g a n d i n t he e ve ni n g.
B i ni meti ni b will be ta ke n wit h at least 8 -oz ( 2 4 0 m L) of water i n t he m or ni n g a n d i n t he
e ve ni n g at a p pr o xi matel y t he sa me ti me e ver y  da y.  

Bi ni meti ni b i n c o m bi nati o n wit h Q D P F -0 7 2 8 4 8 9 0: T he m or n i n g d ose of bi ni meti ni b 
s h o ul d be ta ke n wit h P F- 0 7 2 8 4 8 9 0 f oll o wi n g t he P F-0 7 2 8 4 8 9 0 f o o d i nstr ucti o ns.
W he n ta ke n wit h o ut P F -0 7 2 8 4 8 9 0 i n t he e ve ni n g, bi ni meti ni b ma y  be ta ke n wit h o ut 
re gar d t o f o o d. T he m or ni n g a n d e ve ni n g d oses of bi ni meti ni b s h o ul d be ta ke n
1 2 ± 2 h o urs a part. 

Bi ni meti ni b i n c o m bi nati o n wit h BI D P F- 0 7 2 8 4 8 9 0: T he m or ni n g a n d e ve ni n g d ose 
of bi ni meti ni b s h o ul d be ta ke n wit h t he m or ni n g a n d e ve ni n g d ose of P F -0 7 2 8 4 8 9 0 
a n d s h o ul d be ta ke n 1 2 ± 2 h o urs a part f oll o wi n g t he P F- 0 7 2 8 4 8 9 0 f o o d i nstr ucti o ns.
N ote : O n P K sa m pli n g da ys, partici pa nts m ust be i n faste d state, ie, n o f o o d wit hi n 2 h o urs 
bef ore or 2 h o urs after d osi n g ( t his re q uire me nt ma y res ult i n n o f o o d u ntil m ore t ha n 2 h o urs 
after d osi n g beca use t he y ca n n ot eat u ntil after t heir 2 -h o ur p ost d ose E C Gs a n d P K sa m ple).  
T he sites s h o ul d rec or d i n t he s o urce d oc u me nts if partici pa nts di d or di d n ot eat wit hi n t his 
ti me fra me.
T hese fasti n g re q uire me nts f or P F- 0 7 2 8 4 8 9 0 m a y  be re m o ve d or m o difie d ( via a P A C L  t o 
t he i n vesti gat ors) if t he data fr o m a se parate f o o d-effect st u d y i n dicate t hat t here is n o effect 
of f o o d or a p ositi ve effect of f o o d o n P F -0 7 2 8 4 8 9 0 P K .  
T he effect of f o o d (l o w fat a n d hi g h fat meal vers us faste d state) o n P F -0 7 2 8 4 8 9 0 P K is 
bei n g ass esse d i n C 4 4 7 1 0 0 2 i n a st u d y of healt h y partici pa nts .  O nce t he res ults of t his 
f o o d-effect st u d y are a vaila ble, t he i nstr ucti o ns f or a d mi nistrati o n of P F -0 7 2 8 4 8 9 0 i n
C 4 4 7 1 0 0 1 ma y  be c ha n ge d as a p pr o priate s o t hat patie nts ca n ta ke P F-0 7 2 8 4 8 9 0 wit h o ut 
re gar d t o f o o d at t he M T D/ R D E, or s h o ul d ta ke P F-0 7 2 8 4 8 9 0 i n t he fe d state, wit h 
a dj ust me nt of d ose base d o n C 4 4 7 1 0 0 2 data (ie, t he d ose e q ui vale nt t o t he faste d state 
M T D/ R D E a dj uste d base d o n t he differe nce i n e x p os ure o bser ve d i n C 4 4 7 1 0 0 2 i n t he faste d 
state c o m pare d t o t he fe d state). H o we ver, if t he effect of f o o d is f o u n d t o be s u bsta ntial, 
p ositi ve a n d cli nicall y  si g nifica nt (ie, ≥2-f ol d i ncrease i n A U C f or eit her t he l o w-fat or hi g h-
fat meal), a n a d diti o nal c o h ort of patie nts will be e nr olle d bef ore c h a n gi n g a d mi nistrati o n 
i nstr ucti o ns i n t he c urre nt st u d y. T his c o h ort of a p pr o xi matel y  6-8 patie nts will be e nr olle d 
t o assess t he safety a n d P K of a rec o m me n de d d ose f or f urt her st u d y (ie, t he d ose e q ui vale nt 
t o t he faste d state M T D/ R D E a dj uste d base d o n o bser ve d C 4 4 7 1 0 0 2 P K) t o be gi ve n wit h 
f o o d.  If t he rec o m me n de d d ose i n c o m bi nati o n wit h f o o d is t olerate d, patie nts accr ue d i nt o 
c o h orts 1-6 will recei ve i nstr ucti o n t o a d mi nister dr u g wit h f o o d.  
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 7 3
6. 2. Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
1.
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve 
bee n mai ntai ne d d uri n g tra nsit f or all st u d y  i nter ve nti o ns recei ve d a n d a ny 
discre pa ncies are re p orte d a n d res ol ve d bef ore use of t he st u d y  i nter ve nti o n. 
2.
O nl y  partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y i nter ve nti o n a n d o nl y 
a ut h orize d site staff ma y  s u p pl y or a d mi nister st u d y i nter ve nti o n. All st u d y 
i nter ve nti o ns m ust be st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d 
( ma n ual or a uto mate d rec or di n g) area i n acc or da nce wit h t he la bele d st ora ge 
c o n diti o ns wit h access li mite d t o t he i n vesti gat or a n d a ut h orize d site staff.  At a 
mi ni m u m, dail y  mi ni m u m a n d ma xi m u m te m perat ures f or all site st ora ge l ocati o ns 
m ust be d oc u me nte d a n d a vaila bl e u p o n re q uest.  Data f or n o n w or ki n g da ys m ust 
i n dicate t he mi ni m u m a n d ma xi m u m te m perat ures si nce pre vi o usly d oc u me nte d f or 
all site st ora ge l ocati o ns u p o n ret ur n t o b usi ness.
3.
A n y  e xc ursi o ns fr o m t he st u d y i nter ve nti o n la bel st ora ge c o n diti o ns s h o ul d be 
re p orte d t o Pfizer u p o n disc o ver y  al o n g wit h a ny acti o ns ta ke n.  T he site s h o ul d 
acti vel y p urs ue o pti o ns f or ret ur ni n g t he st u d y i nter ve nti o n t o t he st ora ge c o n diti o ns 
descri be d i n t he la beli n g, as s o o n as p ossi ble.  O nce a n e xc ursi o n is i de ntifie d, t he 
st ud y  i nter ve nti o n m ust be q uara nti ne d a n d n ot use d u ntil Pfizer pr o vi des per missi o n 
t o use t he st u d y i nter ve nti o n.  S pecific details re gar di n g t he defi niti o n of a n e xc ursi o n 
a n d i nf or mati o n t he site s h o ul d re p ort f or eac h e xc ursi o n will be pr o vi de d t o t he si te 
i n t he IP ma n ual . 
4.
A n y  st ora ge c o n diti o ns state d i n t he S R S D will be s u perse de d b y t he st ora ge 
c o n diti o ns state d o n t he la bel.
5.
St u d y  i nter ve nti o ns s h o ul d be st ore d i n t heir ori gi nal c o ntai ners.
6.
Site staff will i nstr uct partici pa nts o n t he pr o per st ora g e re q uire me nts f or ta ke-h o me 
st u d y i nter ve nti o n.
7.
T he i n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) 
is res p o nsi ble f or st u dy i nter ve nti o n acc o u nta bilit y, rec o nciliati o n, a n d rec or d 
mai nte na nce (ie, recei pt, rec o nciliat i o n, a n d fi nal dis p ositi o n rec or ds), s uc h as t he 
I P A L or s p o ns or-a p pr o ve d e q ui vale nt . All st u d y  i nter ve nti o ns will be acc o u nte d f or 
usi n g a st u d y i nter ve nti o n acc o u nta bilit y f or m/rec or d .
All P F - 0 7 2 8 4 8 9 0 (a n d 
bi ni meti ni b if c o m bi nati o n treat me nt) t hat is ta ke n h o me b y t he partici pa nt, b ot h use d 
a n d u n use d, m ust be ret ur ne d t o t he i n vesti gat or b y t he partici pa nt.  Ret ur ne d st u d y  
i nter ve nti o n m ust n ot be re dis pe nse d t o t he partici pa nts.
8.
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y  
i nter ve nti o ns are pr o vi de d i n t he IP m a n ual. All destr ucti o n m ust be a de q uatel y  
d oc u me nte d.  If destr ucti o n is a ut h orize d t o ta ke place at t he i n vesti gat or site, t he 
i n vesti gat or m ust e ns ure t hat t he materials are destr o ye d i n c o m plia nce wit h 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 7 4
a p plica bl e e n vir o n me ntal re g ulati o ns, i nstit uti o nal p olic y , a n d a n y s pecial i nstr ucti o ns 
pr o vi de d b y Pfizer.
U p o n i de ntificati o n of a pr o d uct c o m plai n t, n otif y t he s p o ns or wit hi n 1 b usi ness da y  of 
disc o ver y  as descri be d i n t he IP Ma n ual.
6. 2. 1. Pre p ar ati o n a n d Dis pe nsi n g
A q ualifie d staff me m ber will dis pe nse P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b if c o m bi nati o n 
treat me nt) i n t he b ottles pr o vi de d, i n q ua ntities a p pr o priate f or t he partici pa nts ’ d osi n g 
c o h ort. T he I R T Ma n ual s h o ul d be refere nce d f or tec h nical i nstr ucti o ns.
A sec o n d staff 
me m ber will verif y  t he dis pe nsi n g.  T he p artici p a nt/c are giver s h o ul d be i nstr ucte d t o 
m ai nt ai n t he pr o d uct i n t he b ottle pr ovi de d t hr o u g h o ut t he c o urse of d osi n g, kee p t he st u dy 
i nterve nti o n a w ay fr o m c hil dre n, a n d ret ur n t he b ottle t o t he site at t he next st u dy visit. 
See t he I P ma n ual f or i nstr ucti o ns o n h o w t o pre pare t he st u d y i nter ve nti o n f or 
a d mi nistrati o n.  St u d y  i nter ve nti o n s h o ul d be pre pare d a n d dis pe nse d by a n a p pr o priatel y 
q ualifie d a n d e x perie nce d me m ber of t he st u d y staff (e g, p h y sicia n, n urse, p h ysicia n’s 
assista nt, n urse practiti o ner, p har mac y  assista nt/tec h nicia n, or p har macist) as all o we d b y 
l ocal, state, a n d i nstit uti o nal g ui da nce.  A sec o n d staff me m ber will verif y  t he dis pe nsi n g.
6. 3.
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g
6. 3. 1. All oc ati o n t o St u d y I nter ve nti o n
Eli gi ble partici pa nts will be e nr olle d t o recei ve P F - 0 7 2 8 4 8 9 0 al o ne or i n c o m bi nati o n wit h 
bi ni meti ni b i n a n o pe n-la bel, u n bli n de d ma n ner. D ose le vel all ocati o n will be perf or me d b y 
t he s p o ns or after partici pa n ts ha ve gi ve n t heir writte n i nf or me d c o nse nt /asse nt a n d ha ve 
c o m plete d t he necessar y baseli ne assess me nts. T he site staff will c o m plete a Re gistrati o n 
F or m a n d ret ur n it t o t he desi g nate d s p o ns or st u dy tea m me m ber or desi g nee .  T he s p o ns or 
will assi g n a partici pa nt i de ntificati o n n u m ber a n d s u p pl y t his n u m ber t o t he site.  T he 
partici pa nt i de ntificati o n n u m ber will be use d o n all st u d y-relate d d oc u me ntati o n at t he site.
N o partici pa nt will recei ve st u d y i nter ve nti o n u ntil t he i n vesti gat or or desi g nee has recei ve d 
t he f oll o wi n g i nf or mati o n i n writi n g fr o m t he s p o ns or:

C o nfir mati o n of t he partici pa nt’s eli gi bilit y;

S pecificati o n of t he d ose le vel f or t hat partici pa nt a n d;

Per missi o n t o pr ocee d wit h d osi n g t he partici pa nt .
St u d y  i nter ve nti o n will be dis pe nse d at t he st u d y visits s u m marize d i n t he S o A .
Ret ur ne d st u d y  i nter ve nti o n m ust n ot be re dis pe nse d t o t he partici pa nt.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 7 5
All ocati o n of partici pa nt s t o treat me nt gr o u ps will pr ocee d t hr o u g h t he use of a n I R T sys te m 
(IW R).  T he site pers o n nel (st u d y  c o or di nat or or s pecifie d desi g nee) will be re q uire d t o ha ve 
a n acti ve or vali d acc o u nt a n d pass w or d wit h t he I R T s yste m, e nter or select i nf or mati o n 
i ncl u di n g b ut n ot li mite d t o t he users I D a n d pass w or d, pr ot o c ol n u m ber, s pecific pr ot oc ol 
e ntra nce criteria i n dicate d i n t he s y ste m a n d t he partici pa nt n u m ber.  T he site pers o n nel will 
t he n be pr o vi de d wit h, at a mi ni m u m, a treat me nt assi g n me nt, ra n d o mizati o n n u m ber, a n d 
D U or c o ntai ner n u m ber w he n st u d y i nter ve ntio n is bei n g s u p plie d via t he I R T s yste m.  T he 
I R T sys te m will pr o vi de a c o nfir mati o n re p ort c o ntai ni n g t he partici pa nt n u m ber, 
ra n d o mizati o n n u m ber, a n d D U or c o ntai ner n u m ber assi g ne d.  T he c o nfir mati o n re p ort m ust 
be st ore d i n t he site’s files.
T he st u d y-s pecific I RT refere nce ma n ual will pr o vi de t he c o ntact i nf or mati o n a n d f urt her 
details o n t he use of t he I R T s yste m. 
6. 4. St u d y I nter ve nti o n C o m pli a nce
W he n partici pa nts are d ose d at t he site, t he y  will recei ve st u d y i nter ve nti o n directl y fr o m t he 
i n vesti gat or or desi g nee, u n der me dical s u per visi o n.  T he date a n d ti me of eac h d ose 
a d mi nistere d i n t he cli nic will be rec or de d i n t he s o urce d oc u me nts a n d rec or de d i n t he C R F.  
T he d ose of st u d y i nter ve nti o n a n d st u d y partici pa nt i de ntificati o n will be c o nfir m e d at t he 
ti me of d osi n g by a me m ber of t he st u d y site staff ot her t ha n t he pers o n a d mi nisteri n g t he 
st u d y i nter ve nti o n. Partici pa nt fasti n g c o m plia nce will be c o nfir me d a n d d oc u me nte d at eac h 
visit . 
W he n p artici pa nt s self-a d mi nister st u d y i nter ve nti o n at h o me, c o m plia nce wit h st u d y 
i nter ve nti o n will be disc usse d at eac h visit t o t he st u d y site.  D uri n g b ot h p hases of t he st u d y , 
c o m plia nce will be assesse d at t he e n d of t he c ycle b y  direct q uesti o ni n g, d iar y re vie w a n d 
c o u nti n g of ret ur ne d ta ble ts.
D uri n g t he p hase 1a, c o m plia nce will be assesse d at eac h visit 
i n C ycle 1 b y direct q uesti o ni n g a n d diar y re vie w.  C o m plia nce will be d oc u me nte d i n t he 
s o urce d oc u me nts a n d C R F.  De viati o n(s) fr o m t he prescri be d d osa ge re gi me n s h o ul d be 
rec or de d i n t he C R F.
A rec or d of t he n u m ber of P F - 0 7 2 8 4 8 9 0 ta blets (a n d bi ni meti ni b, if c o m bi nati o n treat me nt) 
dis pe nse d t o a n d ta ke n b y eac h partici pa nt m ust be mai ntai ne d a n d rec o ncile d wit h st u d y  
i nter ve nti o n a n d c o m plia nce rec or ds.  It is i m p orta nt f or partici pa nts t o be f ull y i nf or me d a n d 
pr o vi de d wit h detaile d i nstr ucti o ns t o a v oi d o ver d osi n g (see Secti o n 8. 4 ). I nter ve nti o n start 
a n d st o p dates, i ncl u di n g dates f or i nter ve nti o n dela y s a n d/ or d ose re d ucti o ns, will als o be 
rec or de d i n t he C R F.
A diar y  will be pr o vi de d t o t he partici pa nts t o ai d i n c o m plia nce wit h t he d osi n g i nstr ucti o ns.  
T he diar y  will be mai ntai ne d b y t he partici pa nt t o i ncl u de misse d or c ha n ge d P F- 0 7 2 8 4 8 9 0
(a n d bi ni meti ni b if c o m bi nati o n treat me nt) d oses.  Partici pa nts will be re q uire d t o ret ur n all 
b ottles of P F - 0 7 2 8 4 8 9 0 (a n d bi ni meti ni b) at e ver y c ycle.  T he n u m ber of P F- 0 7 2 8 4 8 9 0 (a n d 
bi ni meti ni b) ta blets re mai ni n g will be d oc u me nte d a n d rec or de d at eac h c ycle.  T he 
partici pa nt diar y  ma y als o be use d t o s u p p ort t his part of t he P F- 0 7 2 8 4 8 9 0 (a n d bi ni meti ni b) 
acc o u nta bilit y pr oc ess. 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 7 6
6. 5. C o nc o mit a nt T her a p y
C o nc o mita nt treat me nt c o nsi dere d necessar y  f or t he partici pa nt ’s well-bei n g ma y  be gi ve n at 
discreti o n of t he treati n g p h y sicia n.  
All c o nc o mita nt treat me nts, bl o o d pr o d ucts, as well as n o n dr u g i nter ve nti o ns 
(e g, parace ntesis) recei ve d b y partici pa nt s fr o m scree ni n g u ntil t he e n d of treat me nt visit will 
be rec or de d o n t he C R F.
Sites are e nc o ura ge d t o c o ntact t he sp o ns or s h o ul d t here be q uesti o ns as t o w het her a 
me dicati o n is per mitte d or pr o hi bite d.
C Y P 3 A 4/ 5:
C o nc o mita nt use of P F -0 7 2 8 4 8 9 0 a n d a C Y P 3 A 4/ 5 s u bstrate ma y  i ncrease or decrease t he 
e x p os ure of t he C Y P 3 A 4/ 5 s u bstrate.  C oa d mi nistrati o n of P F -0 7 2 8 4 8 9 0 wit h C Y P 3 A 4/ 5 
s u bstrates wit h narr o w t hera pe utic i n dices, s uc h as aste miz ole, terfe na di ne, cisa pri de, 
pi m ozi de, q ui ni di ne, tacr oli m us, c y cl os p ori ne, sir oli m us, alfe nta nil a n d fe nta n y l (e xcl u di n g 
tra ns der mal patc h), or er g ot al kal oi ds (er g ota mi ne, di h ydr o er g ota mi ne) 3 7 ,3 8 is n ot per mitte d.  
C oa d mi nistrati o n wit h ot her C Y P 3 A 4/ 5 s u bstrates is per mitte d b ut ca uti o n is warra nte d.   D ue 
t o p ote ntial C Y P 3 A 4 i n d ucti o n, t he use of at least 1 f or m of n o n- h or m o nal c o ntrace pti o n will 
be nee de d d uri n g partici pati o n i n t his st u d y .
C Y P 2 B 6:
C o nc o mita nt use of P F- 0 7 2 8 4 8 9 0 a n d a C Y P 2 B 6 s u bstrate ma y  decrease t he e x p os ure of t he 
C Y P 2 B 6 s u bstrate.   P F -0 7 2 8 4 8 9 0 c oa d mi nistrati o n wit h C Y P 2 B 6 s u bstrates (e g, a se nsiti ve 
s u bstrate li ke b u pr o pi o n a n d narr o w t hera pe utic i n de x s u bstrates li ke efa vire nz, als o a 
se nsiti ve s u bstrate, a n d c ycl o p h os p ha mi de )3 7 ,3 9 is per mitte d b ut ca uti o n is warra nte d.
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 7 7
C Y P 2 C 9:
C o nc o mita nt use of P F- 0 7 2 8 4 8 9 0 a n d a C Y P 2 C 9 s u bstrate ma y  i ncrease t he e x p os ure of t he 
C Y P 2 C 9 s u bstrate. C Y P 2 C 9 s u bstrates of a narr o w t hera pe utic i n de x, ma y i ncl u de warfari n, 
p he n y t oi n, gli me piri de, gli pizi de, gl yb uri de, i b u pr ofe n, dicl ofe nac, i n d o met hac i n, na pr o xe n, 
r osi glitaz o ne, s ulfa met h o xaz ole, t ol b uta mi de, ca n desarta n, ir besarta n, l osarta n a n d 
valsarta n. 3 7 ,4 0 P F - 0 7 2 8 4 8 9 0 c oa d mi nistrati o n wit h t hese a n d ot her C Y P 2 C 9 s u bstrates is 
per mitte d b ut ca uti o n is warra nte d.
B C R P :
C o nc o mita nt use of P F- 0 7 2 8 4 8 9 0 a n d a B C R P i n hi bit or or i n d ucer ma y  alter t he rate a n d/ or
e xte nt of P F- 0 7 2 8 4 8 9 0 a bs or pti o n , w hic h c o ul d p ote ntiall y  i ncrease (i n hi bit or) or decrease 
(i n d ucer) P F -0 7 2 8 4 8 9 0 e x p os ures . P F - 0 7 2 8 4 8 9 0 c oa d mi nistrati o n wit h B C R P i n hi bit ors or 
i n d ucers is per mitte d b ut ca uti o n is warra nte d.
P- gl yc o pr otei n:
C o nc o mita nt use of P F- 0 7 2 8 4 8 9 0 a n d a P -gl yc o pr otei n s u bstrate ma y i ncrease t he e x p os ure 
of t he P -gl yc o pr otei n s u bstrate. P F - 0 7 2 8 4 8 9 0 c oa d mi nistrati o n wit h P- gl yc o pr otei n
s u bstrates is per mitte d b ut ca uti o n is warra nte d .
Aci d Re d uci n g A ge nts:
C o nc o mita nt use of P F- 0 7 2 8 4 8 9 0 a n d a n aci d re d uci n g a ge nt (e g, P PI s) m a y  ca use re d uce d 
e x p os ures t o P F - 0 7 2 8 4 8 9 0.  P PI s are n ot all o we d wit hi n 7 da y s of st u d y start ( C 1 D 1) a n d 
d uri n g st u d y treat me nt , b ut ot her aci d re d uci n g a ge nts (e g, H 2 bl oc kers, a ntaci ds ) m a y  be 
use d , b ut o nl y bet wee n 2 a n d 3 h o urs after a d mi nistrati o n of eac h d ose of P F - 0 7 2 8 4 8 9 0.
6. 5. 1. 2. Bi ni meti ni b 
U G T 1 A 1:
I n vitr o, bi ni meti ni b has bee n i de ntifie d t o be pri maril y meta b olize d b y gl uc ur o ni dati o n. It is 
a d vise d t hat i n hi bit ors a n d i n d ucers of U G T 1 A 1 s h o ul d be ta ke n wit h ca uti o n w he n 
c o-a d mi nistere d wit h bi ni meti ni b.
P- gl yc o pr otei n:
Bi ni meti ni b has bee n s h o w n t o be a s u bstrate of P- g p a n d B C R P. It is a d vise d t hat i n hi bit ors 
a n d i n d ucers of P -g p a n d B C R P tra ns p orters s h o ul d be ta ke n wit h ca uti o n w he n 
c o-a d mi nistere d wit h bi ni meti ni b. 
6. 5. 2. Ot her A nti -t u m or/ A nti- c a ncer or E x peri me nt al Dr u gs
N o a d diti o nal a nti -t u m or treat me nt will be per mitte d w hile partici pa nt s are recei vi n g st u d y 
treat me nt. A d diti o nall y , t he i nitiati o n of ne w c o nc urre nt vita mi ns or her bal s u p ple me nts is 
n ot per mitte d u nless disc usse d a n d a gree d wit h t he s p o ns or.
P ote ntial e xce pti o n: p artici pa nts c urre ntl y bei n g treate d wit h a nti -h or m o nal t hera p y f or 
c o nc urre nt breast or pr ostate ca ncer m a y  c o nti n ue treat me nt w hile o n cli nical st u d y as l o n g as 
t he treat me nt has bee n well t olerate d f or at least 3 m o nt hs pri or t o st u d y  e ntr y a n d treat me nt, 
is n ot s u bject t o dr u g-dr u g i nteracti o ns a n d c o nti n ue d treat me nt is disc usse d wit h t he 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 7 8
s p o ns or’s me dical m o nit or.  Ta m o xife n a n d e xe mesta ne s h o ul d be u se d wit h ca uti o n d ue t o 
t he c o ncer n of P F -0 7 2 8 4 8 9 0 ca usi n g C Y P 3 A i n d ucti o n.   F or dr u gs s uc h as a nastraz ole, 
letr oz ole, f ul vestra nt, le u pr oli de, a n d g oseleri n, n o i nteracti o n is e x pecte d.
6. 5. 3. S u p p orti ve C are
Palliati ve a n d s u p p orti ve care f or disease relate d s y m pt o ms ma y  be a d mi nistere d at t he 
i n vesti gat or’s discreti o n a n d acc or di n g t o t he s pecific s u p p orti ve care pr o d uct Prescri bi n g 
I nf or mati o n or t he c urre nt A S C O g ui deli nes. 
6. 5. 4. A nti -e pile ptic Me dic ati o ns
Certai n a nti -e pile ptic me dicati o ns ma y be a d mi nistere d if cli nicall y i n dicate d, c o nsiste nt wit h 
I ncl usi o n/ E xcl usi o n Criteria (s ee Secti o n 5 ) a n d n ot s u bject t o dr u g-dr u g i nteracti o ns wit h 
st u d y me dicati o n(s).
G ui da nce f or a nti-e pile ptic me dicati o ns t hat ca n be use d o n st u d y  are 
pr o vi de d i n A p pe n di x 1 0 .
6. 5. 5. He m at o p oietic Gr o wt h F act ors
Pri mar y  pr o p h ylactic use of c ol o n y sti m ulati n g fact ors is n ot per mitte d d uri n g C y cle 1 (t he 
first 2 1 d a y s) f or partici pa nts i n P hase 1a , b ut t he y ma y be use d t o treat treat me nt e mer ge nt 
ne utr o pe nia as i n dicate d b y t he c urre nt A S C O g ui deli nes. 3 7  D uri n g t he scree ni n g wi n d o w 
(ie, 1 4 da y s pri or t o Da y 1), g ra n ul oc yte c ol o n y sti m ulati n g fact ors are n ot per mitte d t o 
q ualif y  a partici pa nt wit h l o w W B C c o u nts. 
Er y t hr o p oieti n ma y be use d at t he i n vesti gat or’s discreti o n f or t he s u p p orti ve treat me nt of 
a ne mia. 
6. 5. 6. A nti -Di arr he al, A nti -E metic T her a p y
Pri mar y  pr o p h yla xis be y o n d t he first c ycle is at t he i n vesti gat or’s discreti o n . T he c h oice of 
t he pr o p hyl actic dr u g as well as t he d urati o n of treat me nt is u p t o t he i n vesti gat or wit h 
s p o ns or a p pr o val ass u mi n g t here is n o k n o w n or e x pecte d dr u g-dr u g i nteracti o n a n d 
ass u mi n g t he dr u g is n ot i ncl u de d i n t he C o nc o mita nt T hera p y secti o n.
6. 5. 7. A nti -I nfl a m m at or y T her a p y
A nti- i nfla m mat or y or narc otic a nal gesic ma y be offere d as nee de d ass u mi n g t here is n o 
k n o w n or e x pe cte d dr u g -dr u g i nteracti o n a n d ass u mi n g t he dr u g is n ot i ncl u de d i n t he 
C o nc o mita nt T hera p y secti o n. 
6. 5. 8. C ortic oster oi ds 
S y ste mic c ortic oster oi d use t o c o ntr ol/treat sy m pt o ms fr o m brai n metastases/ pri mar y  brai n 
t u m or is all o we d, u p t o 8 m g/ da y  dexa met has o ne or e q ui vale nt, pr o vi de d use is c o nsiste nt 
wit h I ncl usi o n/ E xcl usi o n Criteria ( see Secti o n 5 ) a n d n ot s u bject t o dr u g-dr u g i nteracti o ns 
wit h st u d y  me dicati o ns. T he mi ni m u m d ose re q uire d t o c o ntr ol sy m pt o ms s h o ul d be use d if 
feasi ble.  F or ot her palliati ve or s u p p orti ve p ur p oses, chr o nic s ys te mic c ortic oster oi d use 
(e g, pre d nis o ne > 1 0 m g / da y or e q ui vale nts) is n ot per mitte d.   Ster oi d use f or s h ort d urati o n 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 7 9
(e g, 5 m g Q D of pre d nis o ne, f or 2 wee ks) as s y m pt o matic treat me nt o n i n di vi d ual basis a n d 
u p o n disc ussi o n wit h t he s p o ns or is all o we d.  Ac ute e mer ge nc y  a d mi nistrati o n, t o pical 
a p plicati o ns, i n hale d s pra ys, e ye dr o ps, or l ocal i njecti o ns of c ortic oster oi ds are all o we d.
6. 5. 9. S ur ger y 
W hile partici pa nts are o n st u d y treat me nt, palliati ve s ur ger y is per mitte d f or n o n-tar get 
lesi o ns t hat are eit her ne w or prese nt at baseli ne. Ca uti o n is a d vise d o n t he oretical gr o u n ds 
f or a ny s ur gical pr oce d ures d uri n g t he st u d y.  T he a p pr o priate i nter val of ti me bet wee n 
s ur ger y a n d P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b) re q uire d t o mi ni mize t he ris k of i m paire d w o u n d 
heali n g a n d blee di n g has n ot bee n deter mi ne d.  St o p pi n g P F - 0 7 2 8 4 8 9 0 (a n d bi ni meti ni b) is 
rec o m me n de d at least 2 d a y s pri or t o s ur ger y.  P ost o perati vely, t h e decisi o n t o rei nitiate 
P F - 0 7 2 8 4 8 9 0 (a n d bi ni meti ni b) treat me nt s h o ul d be base d o n a cli nical assess me nt of 
satisfact or y w o u n d heali n g a n d rec o ver y fr o m s ur ger y. F or partici pa nts o btai ni n g a t u m or 
bi o ps y , P F-0 7 2 8 4 8 9 0 a d mi nistrati o n ma y  be hel d or c o nti n ue d, at t he discreti o n of t he 
i n vesti gat or, pri or th e pr oce d ure.   T hese p artici pa nts s h o ul d still st o p d osi n g bi ni meti ni b at 
least 2 da ys pri or t o t he pr oce d ure, if a p plica ble. T hese ti me i nter vals ma y be altere d base d 
o n e mer gi n g P K data.
6. 5. 1 0. R a di ati o n T her a p y
W hile partici pa nts are o n st u d y treat me nt, palliati ve ra diati o n t hera p y is per mitte d f or 
n o n -tar get lesi o ns t hat are eit her ne w or prese nt at baseli ne. Ca uti o n is a d vise d o n t he oretical 
gr o u n ds f or a n y ra diati o n d uri n g t he st u dy.  T he a p pr o priate i nter val of ti me bet wee n 
ra diati o n a n d P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b) re q uire d t o mi ni mize t he ris k of i m paire d 
w o u n d heali n g a n d ra diati o n s ki n i nj ur y has n ot bee n deter mi ne d.  St o p pi n g P F - 0 7 2 8 4 8 9 0 
(a n d bi ni meti ni b) is rec o m me n de d at least 2 da ys pri or t o ra diati o n.  P ost o perati vel y, t he 
decisi o n t o rei nitiate P F- 0 7 2 8 4 8 9 0 (a n d bi ni meti ni b) treat me nt s h o ul d be base d o n a cli nical 
assess me nt of satisfact or y w o u n d heali n g a n d rec o ver y fr o m ra diati o n. T hese ti me i nter vals 
ma y  be altere d base d o n e mer gi n g P K data.
6. 6. D ose M o dific ati o n
E ver y  eff ort s h o ul d be ma de t o a d mi nister st u d y i nter ve nti o n o n t he pla n ne d d ose a n d 
sc he d ule.  I n t he e ve nt of si g nifica nt t o xicit y, d osi n g ma y be dela ye d a n d/ or re d uce d as 
descri be d bel o w.  I n t he e ve nt of m ulti ple t o xicities, d ose m o dificati o n s h o ul d be base d o n 
t he w orst t o xicit y o bser ve d (a n d attri b uti o n f or t he c o m bi nati o n treat me nt – use if a 
c o m bi nati o n is t o be teste d).  Partici pa nt s are t o be i nstr ucte d t o n otif y i n vesti gat ors at t he 
first occ urre nce of a ny a d verse s y m pt o m.
D ose m o dificati o ns ma y  occ ur i n 1 of 3 w a y s:

Wit hi n a c y cle: d osi n g i nterr u pti o n u ntil a de q uate rec o ver y a n d d ose re d ucti o n, if 
re q uire d, d uri n g a gi ve n treat me nt c ycle; 

Bet wee n c y cles: ne xt c ycle a d mi nistrati o n ma y be dela ye d d ue t o persisti n g t o xicit y 
w he n a ne w c y cle is d ue t o start;
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 8 0

I n t he ne xt c ycle: d ose re d ucti o n ma y be re q uire d i n a s u bse q ue nt c ycle base d o n 
t o xicit y e x perie nce d i n t he pre vi o us c ycle. 
I n di vi d ual g ui da nce f or d ose m o dificati o ns a n d i nterr u pti o ns are o utli ne d i n Ta ble 5
(P F - 0 7 2 8 4 8 9 0) a n d Ta ble 6 ( bi ni meti ni b).  T h ese ta bles i nc or p orate g ui da nce fr o m t he F D A
la bels f or t he B R A F i n hi bit or e nc orafe ni b (f or P F- 0 7 28 4 8 9 0) a n d bi ni meti ni b, a n d i ncl u de 
g ui da nce base d o n n o ncli nical t o xic ol o g y  fi n di n gs f or P F- 0 7 28 4 8 9 0. I n di vi d ual decisi o ns 
re gar di n g d ose i nterr u pti o ns a n d m o dificati o ns s h o ul d be ma de usi n g a p pr o priate cli nical 
j u d g me nt i n c o ns ultati o n wit h t he sp o ns or m e dical m o nit or, c o nsi deri n g relate d ness of t he 
A E t o t he st u d y  treat me nt a n d t he partici pa nt ’s u n derl yi n g c o n diti o n. A Es t hat ha ve a clear 
alter nati ve e x pla nati o n, or tra nsie nt ( ≤7 2 h o urs) a b n or mal la b orat or y  val ues wit h o ut 
ass ociate d cli nicall y si g nifica nt si g ns or s y m pt o ms ma y  be e xe m pt fr o m d ose-re d ucti o n r ules
as cli nicall y a p pr o priate. D ose i nterr u pti o ns are per mitte d i n t he case of me dical or s ur gical 
e ve nts or l o gis tical reas o ns n ot relate d t o st u d y treat me nt (e g, electi ve s ur ger y, u nrelate d 
me dical e ve nts, partici pa nt vacati o n, h oli da y s). T he reas o n f or i nterr u pti o n will be 
d oc u me nte d i n t he partici pa nt ’s st u d y rec or d. All d ose m o dificati o ns are base d o n t he w orst
prece di n g t o xicit y . 
D uri n g C ycl e 1 of P hase 1a d ose escalati o n, d ose m o dificati o ns (e g , i nterr u pti o ns/ decreases) 
t hat res ult i n treat me nt wit h < 7 5 % of t he prescri be d d ose (s) m a y  be c o nsi dere d D L Ts, 
pr o vi de d t hat t he A E t hat le d t o t he d ose m o dificati o n in t he o pi ni o n of t he i n vesti gat or 
ca nn ot be reas o na bl y attri b ute d t o t he partici pa nt’s u n derl y i n g disease, c o nc o mita nt 
me dicati o ns or pree xisti n g c o n diti o ns.
6. 6. 1. D osi n g I nterr u pti o ns
Wit h res pect t o st u d y i nter ve nti o n, partici pa nt s e x perie nci n g t he f oll o wi n g A Es s h o ul d ha ve 
t heir treat me nt i nterr u pte d: partici pa nts e x perie nci n g G ra de 3 or 4 p ote ntiall y treat me nt 
relate d t o xicit y or i nt olera ble G ra de 2 t o xicit y des pite s u p p orti ve care.  Criteria f or treat me nt 
res u m pti o n a n d t he nee d f or a d ose re d ucti o n are descri be d i n Secti o n 6. 6. 3 a n d 
Secti o n 6. 6. 4 . D oses ma y  be hel d u p t o 4 wee ks u ntil t o xicit y res ol uti o n. I n t he e ve nt of a 
treat me nt i nterr u pti o n f or reas o ns ot her t ha n treat me nt-relate d t o xicit y lasti n g > 4 wee ks, 
treat me nt res u m pti o n will be deci de d i n c on s ultati o n wit h t he s p o ns or.
6. 6. 2. Resc ue Me dici ne 
T here is n o resc ue t hera p y t o re verse t he A Es o bser ve d wi t h P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b);
sta n dar d me dical s u p p orti ve care m ust be pr o vi de d t o ma na ge t he A Es. 
6. 6. 3. D ose Del a ys
Re -treat me nt f oll o wi n g treat me nt i nterr u pti o n f or treat me nt-relate d t o xicit y or at t he start of 
a n y ne w c ycle ma y n ot occ ur u ntil t he para meters o utli ne d f or eac h st u d y  i nter ve nti o n i n 
Ta ble 5 a n d Ta ble 6 ha ve b ee n met.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 8 1
If partici pa nt s re q uire disc o nti n uati o n of treat me nt(s) f or m ore t ha n 4 wee ks at a n y  ti me 
d uri n g t he st u d y, t he n st u d y treat me nt s h o ul d be per ma ne ntl y disc o nti n ue d, u nless t he 
i n vesti gat or’s be nefit/ris k assess me nt s u g gests ot her wise after disc ussi o n wit h t he sp o ns or’s 
me dical m o nit or.  
T he nee d f or a d ose re d ucti o n at t he ti me of treat me nt res u m pti o n s h o ul d be base d o n t he 
criteria defi ne d i n t he D ose Re d ucti o ns secti o n ( Secti o n 6. 5. 1 ), u nless e x pressly a gree d 
ot her wise f oll o wi n g disc ussi o n bet wee n t he i n vesti gat or a n d t he s p o ns or.
I n t he e ve nt of a treat me nt i nterr u pti o n f or reas o ns ot her t ha n treat me nt-relate d t o xicit y 
(e g, electi ve s ur ger y) lasti n g m ore t ha n 4 wee ks, treat me nt res u m pti o n will be decide d i n 
c o ns ultati o n wit h t he s p o ns or.
If a partici pa nt recei vi n g c o m bi nati o n treat me nt per ma ne ntl y disc o nti n ues bi ni meti ni b (ie, n o 
d ose f or m ore t ha n 4 wee ks), t he partici pa nt m a y  c o nti n ue si n gle-a ge nt P F - 0 7 2 8 4 8 9 0 if, i n 
t he o pi ni o n of t he i n vesti gat or, t he partici pa nt is deri vi n g cli nical be nefit.
If a partici pa nt recei vi n g c o m bi nati o n treat me nt per ma ne ntl y disc o nti n ues P F - 0 7 2 8 4 8 9 0, he 
or s he m ust A L S O disc o nti n ue treat me nt wit h bi ni meti ni b.
6. 6. 4. D ose Re d ucti o ns
D ose re d ucti o n of st u d y  treat me nt(s) by 1 a n d, if nee de d, 2 d ose le vels will be all o we d 
de pe n di n g o n t he t y pe a n d se verit y of t o xicit y  e nc o u ntere d. Partici pa nts re q uiri n g m ore t ha n 
2 d ose re d ucti o ns will be disc o nti n ue d fr o m t he treat me nt a n d e nter t he f o ll o w-u p p hase, 
u nless ot her wise a gree d bet wee n t he i n vesti gat or a n d t he s p o ns or. O nce a d ose has bee n 
re d uce d a n d t he partici pa nt has t olerate d treat me nt at t he re d uce d d ose f or a mi ni m u m of 
1 f ull c ycle, i ntrapartici pa nt d ose re -escalati o n b y 1 d ose le ve l at a ti me ma y be all o we d after 
disc ussi o n bet wee n t he i n vesti gat or a n d t he s p o ns or.
T a ble 3.
A v ail a ble D ose Le vels ( P F -0 7 2 8 4 8 9 0 M o n ot her a p y)
D ose 
Le vel
P F -0 7 2 8 4 8 9 0 ( at 
st arti n g d oses n ot 
n ote d t o t he ri g ht)
M o n ot her a p y
St arti n g D oses
C urre nt
C urre nt d ose le vel
Starti n g 
D ose
3 0 0 m g 
BI D
2 0 0 m g 
BI D
2 0 0 m g 
Q D
1 0 0 m g 
Q D
5 0 m g Q D
- 1
1 d ose le vel l o w er 
( BI D)
- 1
2 0 0 m g 
BI D
1 0 0 m g 
BI D
5 0 m g 
BI D
2 5 m g 
BI D
1 0 m g BI D
- 2
2 d ose le vels l o w er a
( BI D)
- 2
1 0 0 m g 
BI D
5 0 m g 
BI D
2 5 m g 
BI D
1 0 m g 
BI D
Disc o nti n ue
a.
P F -0 7 2 8 4 8 9 0 ta blet d ose sizes are 1 0, 2 5 a n d 1 0 0 m g; d ose decrease bel o w  1 0 m g Q D is n ot all o we d.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 8 2
T a ble 4.
A v ail a ble D ose Le vels ( P F -0 7 2 8 4 8 9 0 Pl us Bi ni meti ni b C o m bi n ati o n 
T her a p y)
D ose Le vel
P F -0 7 2 8 4 8 9 0 
( at st arti n g 
d oses n ot n ote d 
t o t he ri g ht)
-
C o m bi n ati o n T her a p y P F -0 7 2 8 4 8 9 0 
St arti n g D oses
Bi ni meti ni b
Starti n g
C urre nt d ose 
le vel
Starti n g 
D ose
2 2 5 m g 
BI D
1 5 0 m g 
BI D
1 0 0 m g 
BI D
1 0 0 m g 
Q D
4 5 m g BI D
- 1
1 d ose le vel 
l o wer
- 1
1 5 0 m g 
BI D
1 0 0 m g 
BI D
5 0 m g 
BI D
2 5 m g 
BI D
3 0 m g BI D
- 2
2 d ose le vels 
l o wer a
- 2
1 0 0 m g 
BI D
5 0 m g 
BI D
2 5 m g 
BI D
1 0 m g 
BI D
1 5 m g BI D b
a.
P F -0 7 2 8 4 8 9 0 ta blet d ose sizes are 1 0, 2 5 a n d 1 0 0 m g; d ose decrease bel o w  1 0 m g BI D is n ot all o we d.
b.
Bi ni meti ni b ta blet d ose size is 1 5 m g; d ose decrease bel o w  1 5 m g BI D is n ot all o we d.
Partici pa nts e x perie nci n g a D L T ma y  res u me d osi n g at t he ne xt l o wer d ose le vel o nce 
a de q uate rec o ver y is ac hie ve d, a n d i n t he o pi ni o n of t he i n vesti gat or a n d t he s p o ns or, t he 
partici pa nt is be nefitti n g fr o m t hera p y. 
F or c o m bi nati o n treat me nt wit h bi ni meti ni b, d ose m o dificati o ns, dela y s or i nterr u pti o ns 
s h o ul d be assi g ne d t o eac h pr o d uct base d o n attri b uti o n t o eac h c o m p o ne nt (ie, w he n 
P F - 0 7 2 8 4 8 9 0 a n d bi ni meti ni b are c o m bi ne d a n d t o xicit y  occ urs a n d is attri b ute d t o 
P F - 0 7 2 8 4 8 9 0, a d ose l o weri n g, dela y, or i nterr u pti o n of P F - 0 7 2 8 4 8 9 0 m a y  be a p plica ble b ut 
n ot necessaril y t o bi ni meti ni b).  
Rec o m me n de d d ose re d ucti o ns f or st u d y i nter ve nti o n are descri be d i n Ta ble 5
(P F - 0 7 2 8 4 8 9 0) a n d Ta ble 6 ( bi ni meti ni b).
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 8 3
T a ble 5 .
Rec o m me n de d D ose M o dific ati o ns f or P F-0 7 2 8 4 8 9 0 -rel ate d a A d verse 
E ve nts
Se verit y of A d verse E ve nt
D ose M o dific ati o ns
Ne w Pri m ary M ali g n a ncies
N o n -c uta ne o us R A S
m utati o n -p ositi ve mali g na ncies
Per m a ne ntl y disc o nti n ue P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b).
Uveitis
Gra de 1 - 3
If Gra de 1 or 2 d oes n ot res p o n d t o s pecific oc ular t hera p y, or f or 
Gra de 3 u veitis, wit h h ol d P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b) f or u p t o 
4 we e ks.

If i m pr o ve d, res u me at sa me or re d uce d d ose.

If n ot i m pr o ve d, per ma ne ntl y disc o nti n ue P F-0 7 2 8 4 8 9 0 
(a n d bi ni meti ni b).
Gra de 4 
P e r ma ne ntl y disc o nti n ue P F-0 7 2 8 4 8 9 0 (a n d bi ni meti ni b).
Ot her Eye Dis or ders (i e, n o n-Uveitis Eve nts)
Gra de 1 – 2
Mai ntai n d ose le vel of P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b) a n d i ncrease 
fre q ue nc y of o p ht hal mic m o nit ori n g t o at least e ver y 1 4 d a y s u ntil 
sta bilizati o n or res ol uti o n.
Gra de 3
I nterr u pt d osi n g of P F-0 7 2 8 4 8 9 0 (a n d bi ni meti ni b ) a n d refer 
partici pa nts t o o p ht hal m ol o gist wit hi n 7 da ys.

If res ol ve d t o Gra de ≤1 i n ≤2 1 da ys, res u me treat me nt at 
1 re d uce d d ose le vel of P F -0 7 2 8 4 8 9 0 ( a n d bi ni meti ni b).

If n ot res ol ve d t o Gra de ≤1 i n ≤2 1 da ys, per ma ne ntl y 
disc o nti n ue P F -0 7 2 8 4 8 9 0 ( a n d bi ni meti ni b) a n d cl ose 
f oll o w-u p wit h o p ht hal mic m o nit ori n g u ntil sta bilizati o n or 
res ol uti o n.
Gra de 4
Per m a ne ntl y disc o nti n ue P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b) a n d 
i m me diate f oll o w-u p wit h o p ht hal mic m o nit ori n g u ntil sta bilizati o n 
or res ol uti o n.
Q Tc Pr ol o n g ati o n
Q Tc F > 5 0 0 ms ec a n d ≤6 0 ms ec
i ncrease fr o m baseli ne
First occ urre nce: 

T e m p oraril y i nterr u pt d osi n g of P F -0 7 2 8 4 8 9 0 treat me nt 
u ntil Q Tc F ≤4 7 0 msec. T he n res u me treat me nt at 
1 re d uce d d ose le vel of P F-0 7 2 8 4 8 9 0.
Sec o n d occ urre nce :

T e m p oraril y i nterr u pt d osi n g of P F -0 7 2 8 4 8 9 0 treat me nt 
u ntil Q Tc F ≤4 7 0 msec. T he n res u me treat me nt at 
1 re d uce d d ose le vel of P F-0 7 2 8 4 8 9 0. 
T hir d occ urre nce: 

Per m a ne ntl y disc o nti n ue P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b).
Q Tc F > 5 0 0 ms ec a n d > 6 0 ms ec
i ncrease fr o m baseli ne
Per m a ne ntl y disc o nti n ue P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b).
He p at ot o xicity
Gra de 2 A S T or A L T i ncrease d  
Mai ntai n P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b) d ose.

If n o i m pr o ve me nt wit hi n 4 wee ks, wit h h ol d P F -0 7 2 8 4 8 9 0 
(a n d bi ni meti ni b) u ntil i m pr o ve d t o Gra de 0- 1 or t o 
pretreat me nt/ baseli ne le vels a n d t he n res u me at t he sa me 
d ose.
Gra de 3 or 4 A S T or A L T i ncrease d
See Ot her A d verse Reacti o ns .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 8 4
Der m at ol o gic ( E xce pt H a n d -f o ot S ki n Re acti o ns)
Gra de 2
If n o i mpr o ve me nt wit hi n 2 wee ks (s u p p orti ve meas ures, s uc h as 
t o pical t hera p y, f or s y m pt o matic relief, are per mitte d) , wit h h ol d 
P F -0 7 2 8 4 8 9 0 u ntil Gra de 0- 1. Res u me at sa me d ose if first 
occ urre nce or re d uce d ose if rec urre nt (s u p p orti ve meas ures ma y 
be c o nti n ue d) .
Gra de 3
Wit h h ol d P F -0 7 2 8 4 8 9 0 u ntil Gra de 0 - 1 (s u p p orti ve meas ures, s uc h 
as t o pical t hera p y, f or s y m pt o matic relief, are per mitte d) . Res u me 
at sa me d ose if first occ urre nce or re d uce d ose if rec urre nt
(s u p p orti ve meas ures ma y be c o nti n ue d).
Gra de 4
Per m a ne ntl y disc o nti n ue P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b).
H a n d -f o ot S ki n Re acti o n ( H F S R)/ P al m ar-pl a nt ar Eryt hr o dysest hesi a Sy n dr o me 
( D ose A dj ust me nt f or P F-0 7 2 8 4 8 9 0 O N L Y )
Gra de 1
Mai ntai n d ose of P F -0 7 2 8 4 8 9 0 . Pr o m ptl y i nstit ute s u p p orti ve 
meas ures, s uc h as t o pical t hera p y, f or s y m pt o matic relief. 
Gi ve 
i nstr ucti o n o n life-st yle m o dificati o ns.
Gra de 2
First occ urre nce: 

Mai ntai n d ose of P F -0 7 2 8 4 8 9 0 a n d H F S R s h o ul d be 
cl osel y m o nit ore d. Pr o m ptl y i nstit ute s u p p orti ve 
meas ures, s uc h as t o pical t hera p y, f or s y m pt o matic relief. 
Gi ve i nstr ucti o n o n life -st yle m o dificati o ns.

If n o i m pr o ve me nt ≤1 4 da ys, i nterr u pt d osi n g of 
P F -0 7 2 8 4 8 9 0 u ntil res ol ve d t o Gra de ≤1. Res u me 
treat me nt wit h P F-0 7 2 8 4 8 9 0 at c urre nt d ose le vel. 
C o nti n ue s u p p orti ve meas ures, s uc h as t o pical t hera p y, f or 
s y m pt o matic relief. Gi ve i nstr ucti o n o n life -st yle 
m o dificati o ns.
A d diti o nal occ urre nce: 

Treat me nt wit h P F -0 7 2 8 4 8 9 0 ma y be mai ntai ne d or 
i nterr u pte d base d u p o n t he in ve sti gat or’s discreti o n. 
C o nti n ue s u p p orti ve meas ures, s uc h as t o pical t hera p y, f or 
s y m pt o matic relief. Gi ve i nstr ucti o n o n life -st yle 
m o dificati o ns.
If i nterr u pte d d osi n g of P F -0 7 2 8 4 8 9 0 per in vesti gat or’s j u d g me nt, 
i nterr u pt u ntil res ol ve d t o Gra de ≤1. Res u me treat me nt wit h 
P F -0 7 2 8 4 8 9 0 at t he sa me d ose le vel or 1 re d uce d d ose le vel base d 
u p o n t he in vesti gat or’s discreti o n.
Gra de 3
First or sec o n d occ urre nce: 

I nterr u pt d osi n g of P F -0 7 2 8 4 8 9 0 u ntil res ol ve d t o 
Gra de ≤1. Pr o m ptl y i nitiate s u p p orti ve meas ures, s uc h as 
t o pical t hera p y, f or s y m pt o matic relief. Gi ve i nstr ucti o n 
o n life -st yle m o dificati o ns. Reassess t he partici pa nt
wee kl y. T he n res u me treat me nt at 1 re d uce d d ose le vel of 
P F -0 7 2 8 4 8 9 0.

C o nsi der referral t o der mat ol o gist a n d ma na ge H F S R per 
der mat ol o gist’s rec o m me n dati o n.
T hir d occ urre nce:

I nterr u pt d osi n g of P F -0 7 2 8 4 8 9 0 u ntil res ol ve d t o 
Gra de ≤1, decisi o n t o res u me treat me nt wit h P F -0 7 2 8 4 8 9 0 
at 1 re d uce d d ose le vel or per ma ne ntl y disc o nti n ue 
P F -0 7 2 8 4 8 9 0 ( a n d bi ni meti ni b) s h o ul d be base d u p o n t he 
in vesti gat or’s discreti o n.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 8 5
N a use a/ V o miti n g
Gra de 1 - 2
Mai ntai n d ose le vel of P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b ). Pr o m ptl y 
i nstit ute a ntie metic meas ure.
Gra de 3
I nterr u pt d osi n g of P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b ) u ntil res ol ve d 
t o Gra de ≤1. T he n res u me treat me nt at 1 re d uce d d ose le vel of 
P F -0 7 2 8 4 8 9 0 . Res u me treat me nt wit h bi ni meti ni b at t he c urre nt 
d ose if, i n t he j u d g me nt of t he in vesti gat or, t he t o xicit y is 
c o nsi dere d t o be u nrelate d t o bi ni meti ni b, or at 1 r e d uce d d ose 
le vel.
N ote: I nterr u pt d osi n g of P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b ) f or 
Gra de 3 v o miti n g or Gra de 3 na usea o nl y if t he v o miti n g or na usea 
ca n n ot be c o ntr olle d wit h o pti mal a ntie metics (as per l ocal 
practice).
Gra de 4
Per m a ne ntl y disc o nti n ue P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b ).
C N S effects (e g, c h a n ges i n s peec h, me m ory, slee p, c o g niti o n or visi o n)
Gra de 1
Mai ntai n d ose le vel of P F -0 7 2 8 4 8 9 0 or w it h h ol d d ose u ntil 
rec o ver y t o baseli ne a n d t he n c o nti n ue at t he sa me d ose.
Gra de 2
Mai ntai n d ose le vel of P F -0 7 2 8 4 8 9 0 or w it h h ol d d ose u ntil 
rec o very t o Gra de ≤1. C o nsi der d ose re d ucti o n or res u me at sa me 
d ose.
Gra de 3
I nterr u pt d osi n g of P F-0 7 2 8 4 8 9 0 u ntil res ol ve d t o Gra de ≤1. T he n 
res u me treat me nt at 1 re d uce d d ose le vel of P F -0 7 2 8 4 8 9 0.
Gra de 4
Per m a ne ntl y disc o nti n ue P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b).
Ot her A dverse Re acti o ns (i ncl u di n g he m orr h a ge) 
Rec urre nt Gra de 2 or 
First occ urre nce of a n y Gra de 3
Wit h h ol d P F -0 7 2 8 4 8 9 0 f or u p t o 4 w ee ks.

If i m pr o ves t o Gra de 0-1 or t o pretreat me nt/ baseli ne 
le vels, res u me at re d uce d d ose of P F-0 7 2 8 4 8 9 0.

If n o i m pr o ve me nt, per ma ne ntl y disc o nti n ue P F 0 7 2 8 4 8 9 0 
(a n d bi ni meti ni b).
First occ urre nce of a n y Gra de 4
Per m a ne ntl y disc o nti n ue P F -0 7 2 8 4 8 9 0 or w it h h ol d f or u p t o 
4 we e ks.

If i m pr o ves t o Gra de 0-1 or t o pretreat me nt/ baseli ne 
le vels, t he n res u me at a re d uce d d ose of P F-0 7 2 8 4 8 9 0.

If n o i m pr o ve me nt, per ma ne ntl y disc o nti n ue P F 0 7 2 8 4 8 9 0 
(a n d bi ni meti ni b).
Rec urre nt Gra de 3
C o nsi der per ma ne ntl y disc o nti n ui n g P F -0 7 2 8 4 8 9 0 (a n d 
bi ni meti ni b) .
Rec urre nt Gra de 4
Per ma ne ntl y disc o nti n ue P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b).
a. 
F or A Es t hat ma y be relate d t o b ot h P F -0 7 2 8 4 8 9 0 a n d bi ni meti ni b, g ui da nce is pr o vi de d f or t he ot her 
a ge nt als o, f or partici pa nts recei vi n g t he c o m bi nati o n.  If P F -0 7 2 8 4 8 9 0 is per ma ne ntl y disc o nti n ue d, 
bi ni meti ni b m ust be disc o nti n ue d as well. 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 8 6
T a ble 6 .
Rec o m me n de d D ose M o dific ati o ns f or Bi ni meti ni b -rel ate d a A d verse 
E ve nts
Se verit y of A d verse E ve nt
D ose M o dific ati o ns
C ar di o my o p at hy
As y m pt o matic, a bs ol ute decrease i n 
L V E F of > 1 0 % fr o m baseli ne t hat is 
als o bel o w t he L L N
Wit h h ol d bi ni meti ni b f or u p t o 4 w ee ks, e val uate L V E F e ver y 
2 we e ks.
Res u me bi ni meti ni b at a re d uce d d ose if t he f oll o wi n g are prese nt:

L V E F is at or a b o ve t he L L N ; a nd

A bs ol ute decrease fr o m baseli ne is 1 0 % or less ; a n d

T he partici pa nt is as y m pt o matic.
If L V E F d oes n ot rec o ver wit hi n 4 wee ks per ma ne ntl y disc o nti n ue 
bi ni meti ni b.
Gra de 3 -4 ( S y m pt o matic c o n gesti ve 
heart fail ure or a bs ol ute decrease i n 
L V E F of > 2 0 % fr o m baseli ne t hat is 
als o bel o w L L N)
Per m a ne ntl y disc o nti n ue bi ni meti ni b. Cl osel y m o nit or L V E F u ntil 
res ol uti o n or u p t o 1 6 we e ks.
Ve n o us T hr o m b oe m b olis m
U nc o m plicate d D V T or P E
Wit h h ol d bi ni meti ni b.

If i m pr o ves t o Gra de 0-1, res u me at a re d uce d d ose.

If n o i mpr o ve me nt, per ma ne ntl y disc o nti n ue bi ni meti ni b.
Life t hreate ni n g P E
Per m a ne ntl y disc o nti n ue bi ni meti ni b.
Ser o us Reti n o p at hy
S y m pt o matic ser o us 
reti n o pat h y/ Reti nal pi g me nt 
e pit helial detac h me nts
Wit h h ol d bi ni meti ni b f or u p t o 1 0 da ys.

If i m pr o ves a n d bec o m es as y m pt o matic, res u me at t he 
sa me d ose.

If n ot i m pr o ve d, res u me at a l o wer d ose le vel or 
per ma ne ntl y disc o nti n ue bi ni meti ni b.
R V O
A n y Gra de
Per m a ne ntl y disc o nti n ue bi ni meti ni b.
Uveitis
Gra de 1 - 3
If Gra de 1 or 2 d oes n ot res p o n d t o s pecific oc ular t hera p y, or f or 
Gra de 3 u veitis, wit h h ol d bi ni meti ni b a n d P F -0 7 2 8 4 8 9 0 f or u p t o 
4 we e ks.

If i m pr o ve d, res u me at sa me or re d uce d d ose.

If n ot i m pr o ve d, per ma ne ntl y disc o nti n ue bi ni meti ni b a n d 
P F -0 7 2 8 4 8 9 0 .
Gra de 4 
Per m a ne ntl y disc o nti n ue bi ni meti ni b a n d P F -0 7 2 8 4 8 9 0 .
Ot her Eye Dis or ders (ie, N o n -reti n al Eve nts, n o n-Uveitis Eve nts)
Gra de 1 - 2
Mai ntai n d ose le vel of bi ni meti ni b a n d P F -0 7 2 8 4 8 9 0 a n d i ncrease 
fre q ue nc y of o p ht hal mic m o nit ori n g t o at least e ver y 1 4 d a y s u ntil 
sta bilizati o n or res ol uti o n.
Gra de 3
I nterr u pt d osi n g of bi ni meti ni b a n d P F -0 7 2 8 4 8 9 0 a n d refer 
partici pa nts t o o p ht hal m ol o gist wit hi n 7 da ys.

If res ol ve d t o Gra de ≤1 i n ≤2 1 da ys, res u me treat me nt at 
1 re d uce d d ose le vel of bi ni meti ni b a n d P F -0 7 2 8 4 8 9 0 .

If n ot res ol ve d t o Gra de ≤1 i n ≤2 1 da ys, per ma ne ntl y 
disc o nti n ue bi ni meti ni b a n d P F -0 7 2 8 4 8 9 0 a n d cl ose 
f oll o w-u p wit h o p ht hal mic m o nit ori n g u ntil sta bilizati o n 
or res ol uti o n. 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 8 7
Gra de 4
Per m a ne ntl y disc o nti n ue bi ni meti ni b a n d P F -0 7 2 8 4 8 9 0 a n d 
i mme diate f oll o w -u p wit h o p ht hal mic m o nit ori n g u ntil 
sta bilizati o n or res ol uti o n.
I nterstiti al L u n g Dise ase
Gra de 2
Wit h h ol d bi ni meti ni b f or u p t o 4 w ee ks.

If i m pr o ve d t o Gra de 0-1, res u me at a re d uce d d ose.

If n ot res ol ve d wit hi n 4 wee ks, per ma ne ntl y disc o nti n ue.
Gra de 3 or Gra de 4
Per m a ne ntl y disc o nti n ue bi ni meti ni b.
He p at ot o xicity
Gra de 2 A S T or A L T i ncrease d
Mai ntai n bi ni meti ni b a n d P F -0 7 2 8 4 8 9 0 d ose.

If n o i m pr o ve me nt wit hi n 2 wee ks, wit h h ol d bi ni meti ni b 
a n d P F-0 7 2 8 4 8 9 0 u ntil i m pr o ve d t o Gra de 0- 1 or t o 
pretreat me nt/ baseli ne le vels a n d t he n res u me at t he sa me 
d ose.
Gra de 3 or 4 A S T or A L T i ncrease d
See Ot her A d verse Reacti o ns .
R h a b d o my olysis or C P K elev ati o ns
Gra de 4 as y m pt o matic C P K 
ele vati o n or an y Gra de C P K 
ele vati o n wit h s y m pt o ms or wit h 
re nal i m pair me nt
Wit h h ol d bi ni meti ni b d ose f or u p t o 4 w ee ks.

If i m pr o ve d t o Gra de 0-1 res u me at a re d uce d d ose.

If n ot res ol ve d wit hi n 4 wee ks, per ma ne ntl y disc o nti n ue 
bi ni meti ni b .
Der m at ol o gic
Gra de 2
If n o i m pr o ve me nt wit hi n 2 wee ks, wit h h ol d bi ni meti ni b u ntil 
Gra de 0 -1. Res u me at sa me d ose if first occ urre nce or re d uce d ose 
if rec urre nt.
Gra de 3
Wit h h ol d bi ni meti ni b u ntil Gra de 0 -1. Res u me at sa me d ose if first 
occ urre nce or re d uce d ose if rec urre nt.
Gra de 4
Per m a ne ntl y disc o nti n ue bi ni meti ni b.
N a use a/ V o miti n g
Gra de 1 - 2
Mai ntai n d ose le vel of bi ni meti ni b a n d P F -0 7 2 8 4 8 9 0 . Pr o m ptl y 
i nstit ute a ntie metic meas ure.
Gra de 3
I nterr u pt d osi n g of bi ni meti ni b a n d P F -0 7 2 8 4 8 9 0 u ntil res ol ve d t o 
Gra de ≤1. T he n res u me treat me nt at 1 re d uce d d ose le vel of 
P F -0 7 2 8 4 8 9 0. Res u me treat me nt wit h bi ni meti ni b at t he c urre nt 
d ose if, i n t he j u d g me nt of t he in vesti gat or, t he t o xicit y is 
c o nsi dere d t o be u nrelate d t o bi ni meti ni b, or at 1 re d uce d d ose 
le vel.
N ote: I nterr u pt d osi n g of bi ni meti ni b a n d P F -0 7 2 8 4 8 9 0 f or 
≥Gra de 3 v o miti n g or Gra de 3 na usea o nl y if t he v o miti n g or 
na usea ca n n ot be c o ntr olle d wit h o pti mal a ntie metics (as per l ocal 
practice).
Gra de 4
Per m a ne ntl y disc o nti n ue bi ni me ti ni b.
Ot her A dverse Re acti o ns (i ncl u di n g he m orr h a ge)
Rec urre nt Gra de 2 or F irst 
occ urre nce of a n y Gra de 3
Wit h h ol d bi ni meti ni b f or u p t o 4 w ee ks.

If i m pr o ves t o Gra de 0-1 or t o pretreat me nt/ baseli ne 
le vels, res u me at re d uce d d ose.

If n o i m pr o ve me nt, p er m a ne ntl y disc o nti n ue.
First occ urre nce of a n y Gra de 4
Per m a ne ntl y disc o nti n ue bi ni meti ni b or w it h h ol d f or u p t o 
4 we e ks.

If i m pr o ves t o Gra de 0-1 or t o pretreat me nt/ baseli ne 
le vels, t he n res u me at a re d uce d d ose. 

If n o i m pr o ve me nt, per ma ne ntl y disc o nti n ue bi ni meti ni b.
Rec urre nt Gra de 3
C o nsi der per ma ne ntl y disc o nti n ui n g bi ni meti ni b.
Rec urre nt Gra de 4
Per m a ne ntl y disc o nti n ue bi ni meti ni b.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 8 8
b.
F or A Es t hat ma y be relate d t o b ot h bi ni meti ni b a n d P F-0 7 2 8 4 8 9 0 , gui da nce is pr o vi de d f or t he ot her 
a ge nt als o. If bi ni meti ni b is per ma ne ntl y disc o nti n ue d, P F-0 7 2 8 4 8 9 0 ma y be c o nti n ue d u nless 
ot her wise i n dicate d i n Ta ble 5 a b o ve.
6. 7. I nter ve nti o n A fter t he E n d of t he St u d y
As t his is a first- i n-h u ma n cli nical trial, n o p ost -trial st u d y i nter ve nti o n is c urre ntly pla n ne d 
t o be pr o vi de d t o st u d y  partici pa nts at t he e n d of t he st u d y. De pe n di n g o n t he o verall 
de vel o p me nt pat h, t he sp o ns or will ma ke a n eff ort t o pr o vi de p ost -trial st u d y i nter ve nti o n t o 
a p pr o priate partici pa nts w h o are t olerati n g treat me nt a n d c o nti n ui n g t o e x perie nce cli nical 
be nefit.
7. DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L
7. 1. Disc o nti n u ati o n of St u d y I nter ve nti o n
I n rare i nsta nces, it ma y be necessar y f or a partici pa nt t o per ma ne ntly disc o nti n ue st u d y 
i nter ve nti o n ( defi niti ve disc o nti n uati o n). Reas o ns f or defi niti ve disc o nti n uati o n of st u d y  
i nter ve nti o n ma y i ncl u de t he f oll o wi n g:

O bjecti ve disease pr o gressi o n ( partici pa nts c o nti n ui n g t o deri ve cli nical be nefit ma y 
be per mitte d t o c o nti n ue treat me nt, see Secti o n 7. 1. 1 f or re q uire me nts);

Gl o bal de teri orati o n of healt h stat us re q uiri n g disc o nti n uati o n;

U nacce pta ble t o xicit y ;

Pre g na nc y ;

Si g nifica nt pr ot oc ol vi olati o n ;

L ost t o f oll o w u p ;

Partici pa nt ref use d f urt her treat me nt ;

St u d y  ter mi nate d b y s p o ns or;

Deat h .
N ote t hat disc o nti n uati o n of st u d y  i nter ve nti o n d oes n ot re prese nt wit h dra wal fr o m t he st u d y.  
If st u d y i nter ve nti o n is defi niti vel y disc o nti n ue d, t he partici pa nt will re mai n i n t he st u d y t o 
be e val uate d f or safety, disease assess me nts, s u bse q ue nt a ntica ncer t hera pies, a n d s ur vi val .  
See t h e S o A f or data t o be c ollecte d at t he ti me of disc o nti n uati o n of st u d y i nter ve nti o n a n d 
f oll o w-u p f or a n y f urt her e val uati o ns t hat nee d t o be c o m plete d.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 8 9
I n t he e ve nt of disc o nti n uati o n of st u d y i nter ve nti o n, it m ust be d oc u me nte d o n t he 
a p pr o priate C R F/i n t he me dical rec or ds w het her t he partici pa nt is disc o nti n ui n g f urt her 
recei pt of st u dy i nter ve nti o n or als o fr o m st u d y  pr oce d ures, p osttreat me nt st u d y f oll o w- u p, 
a n d/ or f ut ure c ollecti o n of a d diti o nal i nf or mati o n.
After partici pa nts h a ve disc o nti n ue d treat me nt f or a n y  reas o n, t he y will be c o ntacte d 
a p pr o xi matel y e ver y 3 m o nt hs u ntil wit h dra wal of c o nse nt, t he partici pa nt is l ost t o f oll o w- u p
(Secti o n 7. 3 ), deat h or defi ne d E n d of St u d y (Secti o n 4. 3. 5 ). If partici pa nts wit h dra w 
c o nse nt f or st u d y i nter ve nti o n t he y will c o nti n ue t o be c o ntacte d f or s ur vi val stat us u nless 
t he y s pecificall y re q uest t hat t he y n ot be c o ntacte d. If t he partici pa nt ref uses t o be c o ntacte d,
atte m pts t o deter mi ne s ur vi val stat us s h o ul d be ma de via access t o p u blic rec or ds w here 
per mitte d b y  l ocal la ws (Secti o n 7. 2. 1 ). 
E xa m ples of A Es re q uiri n g d ose m o dificati o n/st u d y  i nter ve nti o n disc o nti n uati o n are 
pr o vi de d i n Ta ble 5 a n d Ta ble 6 .
7. 1. 1. Re q uest t o C o nti n ue St u d y I nter ve nti o n
If t he i n vesti gat or feels t he partici pa nt is still deri vi n g be nefit fr o m st u d y i nter ve nti o n, t he n 
disc uss wit h t he s p o ns or t o elect treat me nt f or t he partici pa nt at t he sa me d ose or 1 d ose
l o wer u ntil s uc h be nefit n o l o n ger e xists. F or a patie nt t o c o nti n ue treat me nt past disease 
pr o gressi o n all of t he f o ll o wi n g criteria m ust be met:

A bse nce of u nacce pta ble t o xicit y ;

A bse nce of cli nical s y m pt o ms or si g ns i n dicati n g cli nicall y  si g nifica nt disease 
pr o gressi o n;

N o decli ne i n perf or ma nce stat us;

A bse nce of ra pi d disease pr o gressi o n or t hreat t o vital or ga ns or critical a nat o mical 
sites (e g, C N S metastasis, respirat or y  fail ure d ue t o t u m or c o m pressi o n, s pi nal c or d 
c o m pressi o n) re q uiri n g ur ge nt alter nati ve me dical i nter ve nti o n; a n d

Patie nt pr o vi des i nf or me d c o nse nt t o c o nti n ue t hera p y .
7. 2. P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al F r o m t he St u d y
A partici pa nt ma y  wit h dra w fr o m t he st u d y at a ny ti me at his/ her o w n re q uest.  Reas o ns f or 
disc o nti n uati o n fr o m t he st u d y  ma y i ncl u de:

C o m plete d st u d y  f oll o w u p;

St u d y  ter mi nate d b y s p o ns or;

L ost t o f oll o w u p ;
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 9 0

Ref us e d f urt her f oll o w-u p ;

Wit h dra wal of c o nse nt b y  pare nt/le gal g uar dia n or asse nt b y  a n a d olesce nt w h o has 
pr o vi de d asse nt d uri n g a n y  p hase of t he st u d y.

Deat h .
At t he ti me of disc o nti n ui n g fr o m t he st u d y, if p ossi ble, a n earl y disc o nti n uati o n visit s h o ul d 
be c o n d ucte d. See t he S o A f or assess me nts t o be c ollecte d at t he ti me of st u d y 
disc o nti n uati o n a n d f oll o w- u p a n d f or a n y f urt her e val uati o ns t hat nee d t o be c o m plete d.  
T he earl y  disc o nti n uati o n visit a p plies o nl y  t o partici pa nts w h o are e nr olle d a n d t he n are 
pre mat urel y wit h dra w n fr o m t he st u d y.   Partici pa nts s h o ul d be q uesti o ne d re gar di n g t heir 
reas o n f or wit h dra wal.  
T he partici pa nt will be per ma ne ntl y disc o nti n ue d b ot h fr o m t he st u d y i nter ve nti o n a n d fr o m 
t he st u d y at t hat ti me.
If a partici pa nt wit h dra ws fr o m t he st u d y, he/s he ma y re q uest destr ucti o n of a n y re mai ni n g 
sa m ples ta ke n a n d n ot teste d, a n d the i n vesti gat or m ust d oc u me nt a n y  s uc h re q uests i n t he 
site st u d y rec or ds a n d n otif y t he s p o ns or acc or di n gl y.
If t he partici pa nt wit h dra ws fr o m t he st u d y a n d als o wit h dra ws c o nse nt/asse nt (see 
Secti o n 7. 2. 1 ) f or discl os ure of f ut ure i nf or mati o n, n o f urt her e val uati o ns s h o ul d be 
perf or me d a n d n o a d diti o nal data s h o ul d be c ollecte d.  T he s p o ns or ma y  retai n a n d c o nti n ue 
t o use a ny data c ollecte d bef ore s uc h wit h dra wal of c o nse nt.
Lac k of c o m pleti o n of all or a n y of t he wit h dra wal/earl y ter mi nati o n pr oce d ures will n ot be 
vie we d as pr ot oc ol de viati o ns s o l o n g as t he partici pa nt ’s safety was preser ve d.
7. 2. 1. Wit h dr a w al of C o nse nt 
Partici pa nt s w h o re q uest t o disc o nti n ue recei pt of st u d y i nter ve nti o n will re mai n i n t he st u d y 
a n d m ust c o nti n ue t o be f oll o we d f or pr ot oc ol -s pecifie d f oll o w- u p pr oce d ures.  T he o nly 
e xce pti o n t o t his is w he n a partici pa nt s pecifically wit h dra ws c o nse nt f or a n y f urt her c o ntact 
wit h hi m or her or pers o ns pre vi o usl y  a ut h orize d b y t he partici pa nt t o pr o vi de t his 
i nf or mati o n.  Partici pa nt s s h o ul d n otif y t he i n vesti gat or i n writi n g of t he decisi o n t o 
wit h dra w c o nse nt fr o m f ut ure f oll o w- u p, w he ne ver p ossi ble.  T he wit h dra wal of c o nse nt 
s h o ul d be e x plai ne d i n detail i n t he me dical rec or ds b y t he i n vesti gat or, as t o w het her t he 
wit h dra wal is o nl y  fr o m f urt her recei pt of st u d y i nter ve nti o n or als o fr o m st u d y  pr oce d ures 
a n d/ or p osttreat me nt st u d y f oll o w-u p, a n d e ntere d o n t he a p pr o priate C R F pa ge.  I n t he e ve nt 
t hat vital stat us ( w het her t he partici pa nt is ali ve or dea d) is bei n g meas ure d, p u blicl y 
a vaila ble i nf or mati o n s h o ul d be use d t o deter mi ne vital stat us o nl y  as a p pr o priatel y directe d 
i n acc or da nce wit h l ocal la w.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 9 1
7. 3. L ost t o F ol l o w- up 
A partici pa nt will be c o nsi dere d l ost t o f oll o w- u p if he or s he re pe ate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d by t he st u d y  site.
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa nt fails t o atte n d a re q uire d st u d y visit:

T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he mi sse d visit as 
s o o n as p ossi ble a n d c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he 
assi g ne d visit sc he d ule a n d ascertai n w het her or n ot t he partici pa nt wis hes t o a n d/ or 
s h o ul d c o nti n ue i n t he st u d y.

Bef ore a parti ci pa nt is dee me d l ost t o f oll o w- u p, t he i n vesti gat or or desi g nee m ust 
ma ke e ver y  eff ort t o re gai n c o ntact wit h t he partici pa nt ( w here p ossi ble, 3 tele p h o ne 
calls a n d, if necessar y, a certifie d letter t o t he partici pa nt’s last k n o w n maili n g 
a d dress or l ocal e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d 
i n t he partici pa nt’s me dical rec or d.

S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve 
wit h dra w n fr o m t he st u d y. 
8. S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S
T he i n vesti gat or ( or a n a p pr o priate d ele gate at t he i n vesti gat or site) m ust o btai n a si g ne d a n d 
date d I C D bef ore perf or mi n g a n y  st u d y-s pecific pr oce d ures.  
St u d y  pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A . Pr ot oc ol wai vers or 
e xe m pti o ns are n ot all o we d.
S afet y iss ues s h o ul d be disc usse d wit h t he s p o ns or i m me diatel y u p o n occ urre nce or 
a ware ness t o deter mi ne w het her t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y 
i nter ve nti o n.
A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A , is esse ntial 
a n d re q uire d f or st u d y c o n d uct.
All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y  criteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g t o 
rec ord details of all partici pa nts scree ne d a n d t o c o nfir m eli gi bilit y  or rec or d reas o ns f or 
scree ni n g fail ure, as a p plica ble.
Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne cli nical ma na ge me nt (e g, bl o o d 
c o u nt) a n d o btai ne d bef ore si g ni n g of t he I C D ma y  be utilize d f or scree ni n g or baseli ne 
p ur p oses pr o vi de d t he pr oce d ures met t he pr ot oc ol -s pecifie d criteria a n d were perf or me d 
wit hi n t he ti me fra me defi ne d i n t he S o A .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 9 2
E ver y  eff ort s h o ul d be ma de t o e ns ure t hat pr ot oc ol-re q uire d tests a n d pr oce d ures are 
c o m plete d as descri be d.  H o we ver, it is a ntici pate d t hat fr o m ti me t o ti me t here ma y  be 
circ u msta nces o utsi de t he c o ntr ol of t he i n vesti gat or t hat ma y  ma ke it u nfeasi ble t o perf or m 
t he test.  In t hese cases, t he i n vesti gat or m ust ta ke all ste ps necessar y t o e ns ure t he safety a n d 
well -bei n g of t he partici pa nt .  W he n a pr ot oc ol-re q uire d test ca n n ot be perf or me d, t he 
i n vesti gat or will d oc u me nt t he reas o n f or t he misse d test a n d a ny c orrecti ve a n d pre ve nti ve 
acti o ns t hat he or s he has ta ke n t o e ns ure t hat re q uire d pr ocesses are a d here d t o as s o o n as 
p ossi ble.  T he st u d y  tea m m ust be i nf or me d of t hese i nci de nts i n a ti mel y ma n ner.
F or sa m ples bei n g c ollecte d a n d s hi p pe d, detaile d c ollecti o n, pr ocessi n g, st ora ge, a n d 
s hi p me nt i nstr ucti o ns a n d c o ntact i nf or mati o n will be pr o vi de d t o t he i n vesti gat or site pri or 
t o i nitiati o n of t he st u d y.
8. 1. Effic ac y Assess me nts
8. 1. 1. T u m or Res p o nse Assess me nts 
8. 1. 1. 1. N o n -gli o m a Pri m ar y T u m ors
T u m or assess me nts will i ncl u de all k n o w n or s us pecte d disease sites .  I ma gi n g will i ncl u de 
c o ntrast -e n ha nce d c hest, a b d o me n a n d pel vis C T or M RI  sca ns; brai n M RI sca n f or 
partici pa nts wit h k n o w n or s us pecte d brai n metastases; b o ne sca n a n d/ or b o ne x -ra ys f or 
partici pa nts wit h k n o w n or s us pecte d b o ne metastases.  F or partici pa nts wit h k n o w n C T
c o ntrast aller g y, a n o n c o ntrast C T of t he c hest wit h c o ntrast e n ha nce d a b d o mi nal a n d pel vic 
M RI  ca n be use d.  T he sa me i ma gi n g tec h ni q ue use d t o c haracterize eac h i de ntifie d a n d 
re p orte d lesi o n at baseli ne will be e m pl o ye d i n t he f oll o wi n g t u m o r assess me nts.
A nti- t u m or acti vit y will be assesse d t hr o u g h ra di ol o gical t u m or assess me nts c o n d ucte d at 
Scree ni n g, C 3 D 1, t he n e ver y  ot her c ycle/ Q 6 W ±1 wee k t hr o u g h C ycle 1 7 (ie, f or 1 ye ar), 
a n d e ver y 4 c ycles/ Q 1 2 W ± 1 wee k after C ycl e 1 7 u ntil pr o gressi ve disease, wit h dra wal of 
c o nse nt, i nitiati o n of s u bse q ue nt a ntica ncer t hera p y, partici pa nt is l ost t o f oll o w -u p, deat h, or 
defi ne d e n d of st u d y .  A nti-t u m or acti vit y will als o be assesse d w he ne ver disease pr o gressi o n 
is s us pecte d (e g, s ym pt o matic deteri orati o n), a n d at t he ti me of wit h dra wal fr o m treat me nt 
(if n ot d o ne i n t he pre vi o us 8 wee ks).  M RI of s pi nal c or d will o nl y  occ ur at Scree ni n g f or 
partici pa nts wit h k n o w n or s us pecte d disease at baseli ne.  F or patie nts wit h o ut brai n 
i n v ol ve me nt, assess me nt of o verall res p o nse will be ma de usi n g R E CIS T versi o n 1. 1 (see
A p pe n di x 1 1 ).4 2  F or patie nts wit h i ntracra nial disease, assess me nt of o verall, e xtracra nial, 
a n d i ntracra nial res p o nse will ma de usi n g m R E CI S T versi o n 1. 1 (see A p pe n di x 1 2 ).
All partici pa nts’ files a n d ra di ol o gic i ma ges m ust be a vaila ble f or s o urce verificati o n a n d f or 
p ote ntial peer re vie w , i ncl u di n g b y i n de pe n de nt ce ntral re vie w.
If si m ulta ne o us C T-P E T sca ns are use d, it m ust be a s piral-C T sca n of t he sa me dia g n ostic 
q ualit y as de dicate d C T sca ns (ie, wit h o ut P E T) . P E T data will n ot be use d f or pri mar y
t u m or res p o nse assess me nts.
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 9 3
8. 1. 1. 2. Gli o m a
I ma gi n g will c o nf or m wit h re q uire me nts f or R A N O a n d assess me nt of disease at baseli ne 
a n d o n st u d y will i ncl u de re vie w of brai n M RI sca ns perf or me d per i nstit uti o nal i ma gi n g 
pr ot oc ol se q ue nce.  M RI of s pi nal c or d will o nl y  occ ur at Scree ni n g f or partici pa nts wit h 
k n o w n or s us pecte d disease at baseli ne.  T he sa me i ma gi n g tec h ni q ue use d t o c haracterize 
eac h i de ntifie d a n d re p orte d lesi o n at baseli ne will be e m pl o y e d i n t he f oll o wi n g t u m or 
assess me nts.
A nti- t u m or acti vit y will be assesse d t hr o u g h M RI
assess me nts c o n d ucte d at Scree ni n g, 
C 3 D 1, t he n e ver y  ot her c ycle/ Q 6 W ± 1 wee k t hr o u g h C ycle 1 7 (ie, f or 1 ye ar), a n d e ver y 
4 c ycles/ Q 1 2 W ± 1 wee k after C ycle 1 7 u ntil pr o gressi ve disease, wit h dra wa l of c o nse nt, 
i nitiati o n of s u bse q ue nt a ntica ncer t hera py, partici pa nt is l ost t o f oll o w -u p, deat h, or defi ne d 
e n d of st u d y.  A nti-t u m or acti vit y will als o be assesse d base d o n c ortic oster oi d usa ge a n d 
w he ne ver disease pr o gressi o n is s us pecte d (e g, deteri o rati o n of cli nical stat us), a n d at t he 
ti me of wit h dra wal fr o m treat me nt (if n ot d o ne i n t he pre vi o us 8 wee ks).  Assess me nt of 
o verall res p o nse will be ma de usi n g R A N O 4 3 ,4 4 f or H G G or L GG , as a p plica ble [see 
A p pe n di x 1 3 ]). 
All p artici pa nts’ files a n d ra di ol o gic i ma ges m ust be a vaila ble f or s o urce verificati o n a n d f or 
p ote ntial peer re vie w, i ncl u di n g b y i n de pe n de nt ce ntral re vie w.  
8. 1. 2. M a n a ge me nt of I nci de nt al Fi n di n gs
A n i nci de ntal fi n di n g is o ne u n k n o w n t o t he partici pa nt t hat has p ote ntial healt h or 
re pr o d ucti ve i m p orta nce, w hic h is disc o vere d u ne x pecte dl y i n t he c o urse of a researc h st u d y, 
b ut is u nrelate d t o t he p ur p ose a n d be y o n d t he ai ms of t he st u d y .
I ma ges ma y be re vie we d b y a ce ntral re vie w facilit y.  If d o ne, t he p ur p ose of t his re vie w is t o 
e val uate i ma ges f or i n de pe n de nt assess me nt of efficac y . Ce ntral i ma ge re vie w is n ot a 
c o m plete me dical re vie w of t he partici pa nt; t heref ore, n o i nci de ntal fi n di n gs will be s hare d 
wit h t he PI , site staff, or t he partici pa nt.  All safety re vie ws will be t he s ole res p o nsi bilit y of 
site staff.
8. 2. S afet y Assess me nts
Pla n ne d ti me p oi nts f or all safet y  assess me nts are pr o vi de d i n t he S o A .  U nsc he d ule d cli nical 
la b orat or y meas ure me nts ma y be o btai ne d at a n y ti me d uri n g t he st u dy t o assess a n y 
percei ve d safet y  iss ues.
Safet y  assess me nts will i ncl u de c ollecti o n of A Es, S A Es, vital si g ns a n d p h ysical 
e xa mi nati o ns, E C G ( 1 2 -lea d), E C H O sca ns, o pht hal mic e xa mi nati o ns, der mat ol o gic 
e xa mi nati o ns, ne ur ol o gic e xa mi nati o ns, a n d la b orat or y  assess me nts, i ncl u di n g pre g na nc y 
tests a n d verificati o n of c o nc o mita nt treat me nts.  
Assess me nt of A Es will i ncl u de t he t y pe, i nci de nce, se verit y ( as gra de d b y N CI  C TC A E 
versi o n 5. 0 ), ti mi n g, seri o us ness, a n d relate d ness.
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 9 4
8. 2. 1. P h ysic al E x a mi n ati o ns
Partici pa nt s will ha ve a p h ysical e xa mi nati o n t o i ncl u de wei g ht, assess me nt of E C O G stat us 
a n d hei g ht; hei g ht will be meas ure d at Scree ni n g o nl y . All p h y sical e xa mi nati o ns occ urri n g 
o n d osi n g da y s m ust be perf or me d pri or t o st u d y dr u g a d mi nistrati o n.
A c o m plete p h ys ical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he ge neral 
a p peara nce, s ki n, nec k (i ncl u di n g t h yr oi d), e y es, ears, n ose, t hr oat, l u n gs, heart, a b d o me n, 
bac k, l y m p h n o des, e xtre mities, vasc ular a n d ne ur ol o gical. If i n dicate d base d o n me dical 
hist or y  a n d/ or sy m pt o ms, rectal, e xter nal ge nitalia, breast a n d p el vic e xa mi nati o ns will be 
perf or me d.
A brief p h ys ical e xa mi nati o n s h o ul d be tar gete d as cli nicall y i n dicate d a n d i ncl u de at a 
mi ni m u m l u n gs, car di o vasc ular s ys te m, a n d a b d o me n (li ver a n d s plee n).
A c o m plete p h ys ical e xa mi nati o n will be perf or me d at Scree ni n g. S u bse q ue nt brief p h y sical 
e xa mi nati o n ma y be perf or me d as directe d b y s ym pt o ms . 
I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses.  Fi n di n gs of all p h y sical e xa mi nati o ns s h o ul d be rec or de d i n t he s o urce d oc u me nts, 
a n d a n y c ha n ge fr o m baseli ne c o nsi dere d b y t he i n vesti gat or t o be cli nicall y si g nifica nt 
s h o ul d be rec or de d as a n A E i n t he C R F.
Ta n ner Sta ge s h o ul d be assesse d i n a d olesce nt partici pa nts at Scree ni n g a n d at t he ti me 
p oi nts s pecifie d i n t he S o A . O nce a partici pa nt reac hes Ta n ner Sta ge 5, assess me nt is n o 
l o n ger necessar y. See 1 0. 2 2 f or Ta n ner Sta ge Defi niti o n.
8. 2. 2. Der m at ol o gic al E x a mi n ati o ns
Der mat ol o gical e val uati o ns will be perf or me d at t he site b y  t he in vesti gat or t o m o nit or f or 
t he p ossi ble de vel o p me nt of kerat oaca nt h o ma a n d/ or s q ua m o us cell carci n o ma, as t hese ha ve 
bee n re p orte d t o occ ur wit h selecti ve B R A F i n hi bit or treat me nt .4 5 A f ull der mat ol o gic
e xa mi nati o n will be perf or me d at Scree ni n g.  T h e o n treat me nt assess me nt ma y be perf or me d 
pre -d ose or p ost d ose at t he ti me p oi nt s s pecifie d i n t he S o A . I n a d diti o n, der mat ol o gic 
scree ni n g f or s ki n mali g na ncies will be perf or me d e ver y 6 wee ks u ntil E O T a n d t he n e ver y  
9 wee ks fr o m E O T u ntil 6 m o nt h s after t he last d ose of P F - 0 7 2 8 4 8 9 0.
I n case of t he occ urre nce of kerat oaca nt h o ma or s q ua m o us cell carci n o ma, partici pa nt s will 
u n der g o c o m plete s ur gical e xcisi o n of t he s ki n lesi o n f oll o wi n g i nst ituti o nal sta n dar ds. 
Der mat ol o gic eval ua ti o ns will be perf or me d by a der mat ol o gist as cli nicall y i n dicate d.
8. 2. 3. O pt h al mic E x a mi n ati o ns
8. 2. 3. 1. Testi n g at Scree ni n g a n d D uri n g t he Tre at me nt Peri o d
F ull o p ht hal mic e xa mi nati o n will be perf or me d b y a n o p ht hal m ol o gist at Scree ni n g (S o A )
i ncl u di n g best c orrecte d vis ual ac uit y, slit la m p e xa mi nati o n, i ntra oc ular press ure, dilate d
f u n d osc o py a n d O C T . E xa mi nati o n of t he reti na is re q uire d (es peciall y  t o i de ntif y fi n di n gs 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 9 5
ass ociate d wit h R P E D, ser o us detac h me nt of t he reti na a n d R V O). T he o p ht hal mic 
e val uati o n s h o ul d be re peate d at a n y p oi nt d uri n g t he treat me nt peri o d as cli nicall y i n dicate d. 
D uri n g t he treat me nt peri o d, vis ual ac uit y  testi n g will be perf or me d o n Da y 1 of eac h c ycle. 
8. 2. 3. 2. A d diti o n al O pt h al mic Testi n g
Partici pa nts wit h cli nical s us pici o n of reti nal a b n or malities of a n y  gra de (e g, R P E D, ser o us
detac h me nt of t he reti na, R V O, p h ot o psia, meta m or p h o psia, i m pair me nt of vis ual ac uit y ) 
m ust c o m plete at least 1 of t he f oll o wi n g a d diti o nal asses s me nts:

F or n o n -vasc ular a b n or malities: O C T (s pectral d o mai n O C T rec o m me n de d);

F or vasc ular a b n or malities: fl u orescei n a n gi o gra p h y  of t he ce ntral 3 0 de grees.
I ma ges/res ults of t he o p ht hal mic e xa mi nati o ns (at a mi ni m u m, o ptical c o here nce t o m o gra p hy
a n d/ or fl u orescei n a n gi o gra p h y) m ust be se nt t o t he i n vesti gati o nal site a n d be mai ntai ne d i n 
t he partici pa nt ’s s o urce d oc u me nt file. T hese i ma ges/res ults m ust be ma de a vaila ble u p o n 
sp o ns or re q uest.
8. 2. 4. Ne ur ol o gic E x a mi n ati o ns
Ne ur ol o gic e xa mi nati o ns will be perf or me d as i n dicate d i n t he S o A a n d will i ncl u de me ntal 
stat us, cra nial ner ves, gait (e g, rise fr o m c hair wit h o ut ha n ds, wal k o n t oes a n d heels, ta n de m 
hee l t o t oe), refle xes (e g, at trice ps, bice ps, brachi ora dialis, patellar, a n kle a n d pla ntar, 
Ba bi ns ki ), m ot or (e g, m uscle stre n gt h i n all 4 e xtre mities, prese nce of e xtra ne o us 
m o ve me nts), se nsati o n (e g, t o li g ht t o uc h i n all 4 e xtre mities, vi brati o n a n d pi n pric k at great 
t oes) a n d bala nce/ c o or di nati o n (e g, R o m ber g, fi n ger -t o-n ose).   Ne ur ol o gical s y m pt o ms t o 
i n q uire a b o ut m a y  i ncl u de ( b ut are n ot li mite d t o) c ha n ges i n s peec h, me m or y, slee p, 
c o g niti o n, a n d/ or visi o n .
8. 2. 5. E C O G Perf or m a nce S t at us
C riteria are pr o vi de d i n A p pe n di x 1 4 .  
8. 2. 6. Vit al Si g ns a n d Wei g ht
Vital si g ns (t o be ta ke n c o nsiste ntl y bef ore or at least 3 0 mi n utes after bl o o d c ollecti o n f or 
la b orat or y tests) a n d wei g ht will be meas ure d per i nstit uti o nal sta n dar ds . Vital si g ns will 
i ncl u de te m perat ure, sys t olic a n d diast olic bl o o d press ure, p ulse rate a n d res pirat or y  rate. All 
vital si g n meas ure me nts o n d osi n g da y s m ust be perf or me d pri or t o st u d y dr u g 
a d mi nistrati o n.
Bl o o d press ure a n d p ulse rate meas ure me nts will be assesse d sitti n g wit h a c o m pletel y  
a ut o mated de vice. Ma n ual tec h ni q ues will be use d o nl y  if a n a ut o mate d de vice is n ot 
a vaila ble. Bl o o d press ure a n d p ulse rate meas ure me nts s h o ul d be prece de d b y at least 
5 mi n utes of rest f or t he partici pa nt i n a q uiet setti n g wit h o ut distracti o ns (e g, tele visi o n , 
cell p h o nes).
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 9 6
Wei g ht s h o ul d be meas ure d i n a c o nsiste nt fas hi o n (e g, wit h t he sa me scale if feasi ble), a n d 
wit h o uter wear a n d s h oes re m o ve d.
8. 2. 7. Electr oc ar di o gr a ms
Sta n dar d 1 2 -lea d E C Gs utilizi n g li m b lea ds ( wit h a 1 0-sec o n d r h yt h m stri p) s h o ul d be 
c ollecte d at ti mes s pecifie d i n t he P har mac o ki netic Sa m pli n g a n d E C Gs Sc he d ule ta bles 
usi n g a n E C G mac hi ne t hat a ut o maticall y calc ulates t he heart rate a n d meas ures P R, Q T, a n d 
Q Tc F i nter vals a n d Q R S c o m ple x.  Alter nati ve lea d pla ce me nt met h o d ol o g y usi n g t ors o 
lea ds (e g, Mas o n -Li kar) is n ot rec o m me n de d gi ve n t he p ote ntial ris k of discre pa ncies wit h 
E C Gs ac q uire d usi n g sta n dar d li m b lea d place me nt. All sc he d ule d E C Gs s h o ul d be 
perf or me d after t he partici pa nt has reste d q uietl y  f or a p pr o xi matel y 1 0 mi n utes i n a s u pi ne 
p ositi o n , a n d t he patie nt s h o ul d re mai n i n t his p ositi o n w hile t he E C Gs are c o n d ucte d. W he n 
a n E C G is t o be perf or me d at t he sa me ti me p oi nt as a bl o o d c ollecti o n, t he E C G is t o be 
perf or me d first. T he E C G meas ure me nt at a n y ti me p oi nt will be use d f or A E gra di n g a n d 
rec o m me n de d d ose m o dificati o ns.
A si n gle E C G s h o ul d be perf or me d d uri n g Scree ni n g a n d ma y  be re peate d t wice m ore
( perf or me d a p pr o xi matel y 2 mi n utes a part) if t he i nitial Q Tc F val ue is > 4 7 0 msec.  If m ore 
tha n 3 E C Gs are perf or me d d uri n g Scree ni n g, t his s h o ul d be re vie we d wit h t he s p o ns or’s 
me dical m o nit or t o c o nfir m eli gi bilit y . F or eli gi bilit y, t he Q Tc F i nter val at Scree ni n g a n d at 
C 1 D 1 pre -d ose m ust be ≤4 7 0 msec (f or tri plicate E C Gs, t he a vera ge Q Tc F m ust be 
≤4 7 0 msec).  T he pre - d ose E C Gs o n C 1 D 1 will be c o nsi dere d baseli ne.  
T hree c o nsec uti ve E C Gs perf or me d a p pr o xi matel y 2 mi n ute s a part t o deter mi ne t he mea n 
Q Tc F i nter val will be perf or me d at pre -d ose (wit hi n a p pr o xi matel y1 5 mi n bef ore t he
pre -d ose P K sa m ple) a n d at 2 h o urs ( ±1 0 mi n) after d ose o n C 1 D 1 a n d C 1 D 1 5 a n d, d uri n g 
P hase 1a of t he st u d y w he n P F- 0 72 8 4 8 9 0 is a d mi nistere d Q D a n d P K sa m pli n g necessitates a 
pre -d ose visit o n C 1 D 2 , at 2 4 h o urs after t he C 1 D 1 d ose o n C 1 D 2 ( ie, wit hi n 3 0 mi n utes 
pri or t o t he d ose o n C 1 D 2) t he E C G will be c ollecte d pre-d ose ( wit hi n a p pr o xi matel y  
1 5 mi n utes bef ore t he pre -d ose P K sa m ple) . Tri plicate E C G s will als o be perf or me d at
2 h o urs ( ± 3 0 mi n utes) after d osi n g o n Da y 1 of C y cles 2- 6 as s pecifie d i n t he S o A secti o n of 
t his pr ot oc ol.
Pre -d ose E C Gs s h o ul d be perf or me d wit hi n a p pr o xi matel y  1 5 mi n utes bef ore t he pre -d ose 
P K sa m ple . T he 2 h o ur ti me p oi nt is i nte n de d t o a p pr o xi mate t he T ma x of P F -0 7 2 8 4 8 9 0, b ut 
base d o n i nitial P K data t he ti me of t he tri plica te E C Gs ma y be a dj uste d t o better matc h t he 
T ma x via a P A C L  t o t he i n vestig at ors.
T o e ns ure safet y of t he partici pa nts, a q ualifie d i n di vi d ual at t he i n vesti gat or site will ma ke 
c o m paris o ns t o baseli ne meas ure me nts.   A d diti o nal E C G m o nit ori n g will occ ur if a) t he 
mea n val ue fr o m t he tri plicate meas ure me nts or t he val ue fr o m a n y  si n gle meas ure me nt f or 
a n y p ost d ose Q TcF i nter val is i ncrease d by ≥6 0 msec fr o m t he baseli ne a n d is > 4 5 0 msec; or 
b) a n a bs ol ute Q Tc F val ue is > 5 0 0 msec f or a n y sc he d ule d E C G. If eit her of t hese c o n diti o ns 
occ urs, t he n a si n gle E C G meas ure me nt m ust be re peate d at least h o url y u ntil Q Tc F val ues 
fr o m 2 s uccessi ve E C Gs fall bel o w t he t hres h ol d val ue t hat tri g gere d t he re peat 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 9 7
meas ure me nt . I n a d diti o n, if verifie d Q TcF val ues c o nti n u e t o e xcee d t he criteria a b o ve, 
i m me diate c orrecti o n f or re versi ble ca uses i ncl u di n g electr olyt e a b n or malities, h yp o xia a n d 
c o nc o mita nt me dicati o ns f or dr u gs wit h t he p ote ntial t o pr ol o n g t he Q Tc F i nter val s h o ul d be 
perf or me d.
If t he Q TcF i nter val re verts t o ≤4 7 0 msec , a n d i n t he j u d g me nt of t he i n vesti gat or(s) a n d 
s p o ns or, it is deter mi ne d t hat t he ca use(s) of Q Tc F pr ol o n gati o n is s o met hi n g ot her t ha n 
st u d y i nter ve nti o n, treat me nt ma y be c o nti n ue d wit h re g ular E C G m o nit ori n g.  If i n t hat ti me
fra me t he Q TcF i nter vals rise a b o ve t he t hres h ol d val ues, t he st u d y i nter ve nti o n will be hel d 
u ntil t he Q Tc F i nter val decreases t o bel o w t he t hres h ol d val ues.  Partici pa nts will t he n restart 
t he st u d y i nter ve nti o n at t he ne xt l o west d ose le vel.  If t he Q Tc i nter val has still n ot 
decrease d t o t he baseli ne val ue o n C ycle 1 Da y 1 pre-d ose after 2 wee ks, or if at a n y  ti me a 
partici pa nt has a Q Tc F i nter val > 50 0 msec or bec o mes s y m pt o matic, t he partici pa nt will be 
re m o ve d fr o m t he st u dy.  A d diti o nal tri plicate E C Gs ma y be perf or me d as cli nicall y  
i n dicate d.
E C G data will be s u b mitte d t o a ce ntral la b orat or y f or meas ure me nt.  T he fi nal E C G re p ort 
fr o m t he ce ntral la b orat or y s h o ul d be mai ntai ne d i n t he partici pa nt’s s o urce d oc u me ntati o n 
a n d be t he fi nal i nter pretati o n of t he E C G rec or di n g.  A n y cli nicall y si g nifica nt c ha n ges fr o m 
t he baseli ne/C y cle 1 D a y 1 pre -d ose E C G ma y  p ote ntiall y be A Es (A p pe n di x 7 ) a n d s h o ul d 
be e val uate d f urt her, as cli nicall y  warra nte d.  
I n s o me cases, it ma y be a p pr o priate t o re peat a b n or mal E C Gs t o r ule o ut i m pr o per lea d 
place me nt as c o ntri b uti n g t o t he E C G a b n or malit y .  It is i m p orta nt t hat lea ds be place d i n t he 
sa me p ositi o ns eac h ti me i n or der t o ac hie ve precise E C G rec or di n gs.  If a mac hi ne-rea d 
Q Tc F val ue is pr ol o n ge d, as defi ne d a b o ve, re peat meas ure me nts ma y  n ot be necessar y if a 
q ualifie d me dica l pr o vi der’s i nter pretati o n deter mi nes t hat t he Q Tc F val ues are i n t he 
acce pta ble ra n ge.
If a partici pa nt e x perie nces a car diac or ne ur ol o gic A E (s pecificall y s y nc o pe, dizzi ness, 
seiz ures, or str o ke), a n E C G (tri plicate) s h o ul d be o btai ne d at t he ti me of the e ve nt. 
E C G val ues of p ote ntial cli nical c o ncer n are liste d i n A p pe n di x 7 .
8. 2. 8. Cli nic al S afet y L a b or at or y Assess me nts
See A p pe n di x 2 f or t he list of cli nical safety la b orat or y tests t o be perf or me d a n d t he S o A f or 
t he ti mi n g a n d fre q ue nc y. All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n 
A p pe n di x 2 , m ust be c o n d ucte d i n acc or da nce wit h t he la b orat or y ma nual a n d t he S o A .  
U nsc he d ule d cli nical la b orat or y  meas ure me nts ma y be o btai ne d at a n y ti me d uri n g t he st u d y 
t o assess a ny percei ve d safet y iss ues.  
T he i n vesti gat or m ust re vie w t he la b orat or y  re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y i n t he A E secti o n of t he C R F. 
Cli nicall y  si g nifica nt a b n or mal la b orat or y fi n di n gs are t h ose w hic h are n ot ass ociate d wit h 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 9 8
t he u n derlyi n g disease, u nless j u d ge d b y  t he i n vesti gat or t o be m ore se vere t ha n e x pecte d f or 
t he partici pa nt’s c o n diti o n.
All la b orat or y  tests wit h val ues c o nsi dere d cli nicall y si g nifica ntly a b n or mal d uri n g 
partici pati o n i n t he st u d y  or wit hi n 3 0 da y s after t he last d ose of st u d y i nter ve nti o n s h o ul d be 
re peate d u ntil t he val ues ret ur n t o n or mal or baseli ne or are n o l o n ger c o nsi dere d cli nicall y  
si g nifica nt by t he i n vesti gat or or me dical m o nit or.
If s uc h val ues d o n ot ret ur n t o n or mal/ baseli ne wit hi n a peri o d of ti me j u d ge d reas o na ble b y 
t he i n vesti gat or, t he eti ol o g y s h o ul d be i de ntifie d a n d t he s p o ns or n otifie d.
See A p pe n di x 6 f or s u g geste d acti o ns a n d f oll o w- u p assess me nts i n t he e ve nt of p ote ntial 
dr u g -i n d uce d li ver i nj ur y.
If C ycle 1 Da y 1 re q uires assess me nt of cli nical la b orat or y val ues a n d t h ose were perf or me d 
f or Scree ni n g i n t he pri or 7 da ys, t h ose la b orat or y assess me nt s are n ot re q uire d t o be 
re peate d.
8. 2. 9. E c h oc ar di o gr a m
Car diac ejecti o n fracti o n a n d car diac val ve m or p h ol o g y  will be assesse d b y tra nst h oracic 
E C H O at t he ti me p oi nts specifie d i n t he S o A . T he sa me met h o d s h o ul d be use d t hr o u g h o ut 
t he st u d y. Partici pa nts w h o de vel o p si g ns/s y m pt o ms of C H F at a n y  p oi nt d uri n g t he st u dy
are re q uire d t o ha ve a n e val uati o n of L V E F meas ure me nts b y  E C H O a n d s h o ul d be 
m o nit ore d per i nstit uti o nal g ui deli nes.
8. 2. 1 0. Pre g n a nc y Testi n g 
Pre g na nc y  tests ma y be uri ne or ser u m tests as s pecifie d i n t he S o A , b ut m ust ha ve a 
se nsiti vit y of at least 2 5 mI U/ m L.  Pre g na nc y  tests will be perf or me d i n W O C B P at t he ti mes 
liste d i n t he S o A .  F oll o wi n g a ne gati ve pre g na nc y test res ult at S cree ni n g, a p pr o priate 
c o ntrace pti o n m ust be c o m me nce d a n d a s ec o n d ne gati ve pre g na nc y  test res ult will be 
re q uire d at t he baseli ne visit pri or t o t he partici pa nt’s recei vi n g t he st u dy treat me nt.  
Pre g na nc y  tests will als o be d o ne w he ne ver 1 me nstr ual c y cle is misse d d uri n g t he acti ve 
treat me nt peri o d ( or w he n p ote ntial pre g na nc y is ot her wise s us pecte d) a n d at t he e n d of t he 
st u d y.  Pre g na nc y tests ma y als o be re peate d if re q ueste d b y IR Bs/ E C s or if re q uire d by l ocal 
re g ulati o ns.  If a uri ne test ca n n ot be c o nfir me d as ne gati ve (e g, a n a m bi g u o us res ult), a 
ser u m pre g na n c y test is re q uire d.  I n s uc h cases, t he partici pa nt m ust be e xcl u de d if t he 
ser u m pre g na nc y res ult is p ositi ve.
8. 2. 1 1. A d diti o n al Assess me nts f or A d olesce nt P a rtici p a nts
T a n ner St a ge :
See Secti o n 8. 2. 1 a n d 1 0. 2 2 A p pe n di x 2 2 : Ta n ner Sta gi n g.
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 9 9
Me as ure me nts of L H, F S H, a n d E str a di ol (fe m ale) or Test oster o ne ( m ale) : 
F or fe male partici pa nts w h o are less t ha n Ta n ner Sta ge 4 ( i e, Ta n ner Sta ge 1 -3), ser u m f or 
meas ure me nt of L H, F S H, a n d estra di ol le vels s h o ul d be perf or me d at S cree ni n g, e ver y 
4 c ycles t hereafter, a n d at t he E n d of Treat me nt visit. F or male partici pa nts w h o are less t ha n 
Ta n ner Sta ge 4 ( ie, Ta n ner Sta ge 1- 3), ser u m f or meas ure me nt of L H, F S H, a n d test oster o ne 
le vels s h o ul d be perf or me d at S cree ni n g, e ver y 4 c ycles t hereafter, a n d at t he E n d of 
Treat me nt visit.
S uici d al I de ati o n a n d Be h avi or Risk M o nit ori n g: 
N o a d diti o nal scree ni n g or detecti o n met h o ds are rec o m me n de d . Fa milies a n d care gi vers of 
partici pa nts m ust be i nstr ucte d t o m o nit or partici pa nts f or t he e me r ge nce of s uici dal i deati o n 
a n d be ha vi or, a n d t o re p ort s uc h s y m pt o ms i m me diatel y  t o t he i n vesti gat or.
8. 3. A d verse E ve nts a n d Seri o us A d verse E ve nts
T he defi niti o ns of a n A E a n d a n S A E ca n be f o u n d i n A p pe n di x 3 .
A E s will be re p orte d b y t he partici pa nt ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or 
t he partici pa nt’s le gall y a ut h orize d re prese ntati ve).
T he i n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble t o p urs ue 
a n d o btai n a de q uate i nf or mati o n b ot h t o deter mi ne t he o utc o me a n d t o assess w het her t he 
e ve nt meets t he criteria f or classificati o n as a n S A E or ca use d t he partici pa nt t o disc o nti n ue 
t he st u d y i nter ve nti o n (see Secti o n 7. 1 ). 
Eac h partici pa nt will be q uesti o ne d a b o ut t he occ urre nce of A Es i n a n o nle a di n g ma n ner.   I n 
a d diti o n, t he i n vesti gat or ma y be re q ueste d b y Pfizer Safety t o o btai n s pecific f oll o w - u p 
i nf or mati o n i n a n e x pe dite d fas hi o n.
8. 3. 1. Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d S A E I nf or m ati o n
T he ti me peri o d f or acti vel y  eliciti n g a n d c ollecti n g A Es a n d S A Es (“acti ve c ollecti o n 
peri o d”) f or eac h partici pa nt be gi ns fr o m t he ti me t he partici pa nt pr o vi des i nf or me d 
c o nse nt /asse nt, w hic h is o btai ne d bef ore t he partici pa nt ’s partici pati o n i n t he st u dy (ie, bef ore 
u n der g oi n g a n y st u d y- relate d pr oce d ure a n d/ or recei vi n g st u d y i nter ve nti o n), t hr o u g h a n d 
i ncl u di n g a mi ni m u m of 3 0 cale n dar da ys, e xce pt as i n dicate d bel o w, after t he last 
a d mi nistrati o n of t he st u d y i nter ve nti o n.
D uri n g t he s ur vi val f oll o w-u p peri o d i n t his st u d y, o nl y  S A Es will be acti vel y elicite d a n d 
c ollecte d after c o m pleti o n of t he acti ve c ollecti o n peri o d descri be d a b o ve. T he S A Es 
i de ntifie d d uri n g s ur vi val f oll o w-u p will be re p orte d t o Pfizer Safet y  o n t he C T S A E Re p ort 
F or m o nl y if c o nsi dere d reas o na bl y relate d t o t he st u d y  i nter ve nti o n.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 0 0
F oll o w -u p b y  t he i n vesti gat or c o nti n ues t hr o u g h o ut a n d after t he acti ve c ollecti o n peri o d a n d 
u ntil t he A E or S A E or its se q uelae res ol ve or sta bilize at a le vel acce pta ble t o t he 
i n vesti gat or a n d Pfizer c o nc urs wit h t hat assess me nt.
F or partici pa nts w h o are scree n fail ures, t he acti ve c ollecti o n peri o d e n ds w he n scree n fail ure 
stat us is deter mi ne d.
If t he partici pa nt wit h dra ws fr o m t he st u d y a n d als o wit h dra ws c o nse nt/asse nt f or t he 
c ollecti o n of f ut ure i nf or mati o n, t he acti ve c ollecti o n peri o d e n ds w he n c o nse nt /asse nt is 
wit h dra w n.
If a partici pa nt defi niti vel y disc o nti n ues or te m p oraril y disc o nti n ues st u d y i nter ve nti o n 
beca use of a n A E or S A E, t he A E or S A E m ust be rec or de d o n t he C R F a n d t he S A E 
re p orte d usi n g t he C T S A E Re p ort F or m.
I n vesti gat ors are n ot o bli gate d t o acti vely see k A E s or S A E s after t he partici pa nt has 
c o ncl u de d st u d y partici pati o n. H o we ver, if t h e i n vesti gat or lear ns of a n y S A E, i ncl u di n g a 
deat h, at a n y ti me after a partici pa nt has c o m plete d t he st u d y, a n d he/s he c o nsi ders t he e ve nt 
t o be reas o na bl y relate d t o t he st u d y i nter ve nti o n, t he i n vesti gat or m ust pr o m ptl y re p ort t he 
S A E t o Pfizer usi n g t he C T S A E Re p ort F or m .
8. 3. 1. 1. Re p orti n g S A Es t o Pfizer S afet y
All S A Es occ urri n g i n a partici pa nt d uri n g t he acti ve c ollecti o n peri o d as descri be d i n 
Secti o n 8. 3. 1 are re p orte d t o Pfizer Safet y o n t he C T S A E Re p ort F or m im me diatel y  u p o n 
a ware ness a n d u n der n o circ u msta nce s h o ul d t his e xcee d 2 4 h o urs, as i n dicate d i n 
A p pe n di x 3 . T he i n vesti gat or will s u b mit a n y  u p date d S A E data t o t he s p o ns or wit hi n 
2 4 h o urs of it bei n g a vaila ble.
If a partici pa nt be gi ns a ne w a ntica ncer t hera p y, S A Es occ urri n g d uri n g t he a b o ve- i n dicate d 
acti ve c ollecti o n peri o d m ust still be re p orte d t o Pfizer Safet y irres pecti ve of a ny i nter ve ni n g 
treat me nt.  N ote t hat a s witc h t o a c o m merciall y  a vaila ble versi o n of t he st u d y i nter ve nti o n is 
c o nsi dere d as a ne w a ntica ncer t hera p y f or p ur p oses of S A E re p orti n g.
8. 3. 1. 2. Rec or di n g N o nseri o us A Es a n d S A E s o n t he C R F
All n o nseri o us A Es a n d S A Es occ urri n g i n a partici pa nt d uri n g t he acti ve c ollecti o n peri o d, 
w hic h be gi ns after o btai ni n g i nf or me d c o nse nt /asse nt as descri be d i n Secti o n 8. 3. 1 , will be 
rec or de d o n t he A E secti o n of t he C R F.  
T he i n vesti gat or is t o rec or d o n t he C R F all directl y  o bser ve d a n d all s p o nta ne o usl y re p orte d 
A Es a n d S A Es re p orte d b y  t he partici pa nt.
If a partici pa nt be gi ns a ne w a ntica ncer t hera p y, t he rec or di n g peri o d f or n o nseri o us A Es 
e n ds at t he ti me t he ne w treat me nt is starte d; h o we ver, S A Es m ust c o nti n ue t o be rec or de d o n 
t he C R F d uri n g t he a b o ve-i n dicate d acti ve c ollecti o n peri o d.  N ote t hat a s wit c h t o a 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 0 1
c o m merciall y a vaila ble versi o n of t he st u d y i nter ve nti o n is c o nsi dere d as a ne w a ntica ncer 
t hera py f or t he p ur p oses of S A E re p orti n g .
8. 3. 2. Met h o d of Detecti n g A Es a n d S A Es
T he met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y  of A Es a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n A p pe n di x 3 .
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A Es a n d/ or S A Es.
O pe n -e n de d a n d 
n o nlea di n g ver bal q uesti o ni n g of t he par tici pa nt is t he preferre d met h o d t o i n q uire a b o ut 
A E occ urre nces.
8. 3. 3. F oll o w - u p of A Es a n d S A Es
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h 
partici pa nt at s u bse q ue nt visits/c o ntacts. F or eac h e ve nt, t he i n vesti gat o r m ust p urs ue a n d 
o btai n a de q uate i nf or mati o n u ntil res ol uti o n, sta bilizati o n, t he e ve nt is ot her wise e x plai ne d, 
or t he partici pa nt is l ost t o f oll o w- u p (as defi ne d i n Secti o n 7. 3 ).
I n ge neral, f oll o w- u p i nf or mati o n will i ncl u de a descri pti o n of t he e ve nt i n s ufficie nt detail t o 
all o w f or a c o m plete me dical assess me nt of t he case a n d i n de pe n de nt deter mi nati o n of 
p oss i ble ca usalit y.  A ny i nf or mati o n rele va nt t o t he e ve nt, s uc h as c o nc o mita nt me dicati o ns 
a n d ill nesses, m ust be pr o vi de d.  I n t he case of a partici pa nt deat h, a s u m mar y of a vaila ble 
a ut o ps y fi n di n gs m ust be s u b mitte d as s o o n as p ossi ble t o Pfizer Safet y. 
F urt her i nf or mati o n o n f oll o w -u p pr oce d ures is gi ve n i n A p pe n di x 3 .
8. 3. 4. Re g ul at or y Re p orti n g Re q uire me nts f or S A Es
Pr o m pt n otificati o n b y  t he i n vesti gat or t o t he s p o ns or of an S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of partici pa nts a n d t he safet y of a 
st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met.
T he s p o ns or has a le gal res p o nsi bilit y  t o n otif y b ot h t he l ocal re g ulator y  a ut h orit y a n d ot her 
re g ulat or y a ge ncies a b o ut t he safety of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n. T he 
s p o ns or will c o m pl y wit h c o u ntr y-s pecific re g ulat or y re q uire me nts relati n g t o safety 
re p orti n g t o t he re g ulat or y a ut h ority, I RBs / ECs , a nd i n vesti gat ors.
I n vesti gat or safet y re p orts m ust be pre pare d f or S U S A Rs acc or di n g t o l ocal re g ulat or y 
re q uire me nts a n d s p o ns or p olic y a n d f or war de d t o i n vesti gat ors as necessar y.
A n i n vesti gat or w h o recei ves S U S A Rs or ot her s pecific safet y i nf or mati o n (e g , s u m mar y or 
listi n g of S A Es) fr o m t he s p o ns or will re vie w a n d t he n file it al o n g wit h t he S R S D(s) f or t he 
st u d y a n d will n otif y t he I R B/ E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 0 2
8. 3. 5. E x p os ure D uri n g Pre g n a nc y or Bre astfee di n g, a n d Occ u p ati o n al E x p os u re
E x p os ure t o t he st u d y i nter ve nti o n u n der st u d y d uri n g pre g na nc y  or breastfee di n g a n d 
occ u pati o nal e x p os ure are re p orta ble t o Pfizer Safet y  wit hi n 2 4 h o urs of i n vesti gat or 
a ware ness.
8. 3. 5. 1. E x p os ure D uri n g Pre g n a nc y
A n E D P occ urs if: 

A fe male partici pa nt is f o u n d t o be pre g na nt w hile recei vi n g or after disc o nti n ui n g 
st u d y i nter ve nti o n.

A male partici pa nt w h o is recei vi n g or has disc o nti n ue d st u d y  i nter ve nti o n e x p oses a 
fe male part ner pri or t o or ar o u n d t he ti me of c o nce pti o n.

A fe male is f o u n d t o be pre g na nt w hile bei n g e x p ose d or ha vi n g bee n e x p ose d t o 
st u d y i nter ve nti o n d ue t o e n vir o n me ntal e x p os ure. Bel o w are e xa m ples of 
e n vir o n me ntal e x p os ure d uri n g pre g na nc y :  

A fe male fa mil y  me m ber or healt hcare pr o vi der re p orts t hat s he is pre g na nt after 
ha vi n g bee n e x p ose d t o t he st u d y  i nter ve nti o n b y i ng esti o n, i n halati o n or s ki n 
c o ntact .

A male fa mil y me m ber or healt hcare pr o vi der w h o has bee n e x p ose d t o t he st u d y  
i nter ve nti o n b y i n gesti o n, i n halati o n or s ki n c o ntact t he n e x p oses his fe male 
part ner pri or t o or ar o u n d t he ti me of c o nce pti o n .
T he i n vesti gat or m ust re p ort E D P t o Pfizer Safet y wit hi n 2 4 h o urs of t he i n vesti gat or’s 
a ware ness, irres pecti ve of w het her a n S A E has occ urre d. T he i nitial i nf or mati o n s u b mitte d 
s h o ul d i ncl u de t he a ntici pate d date of deli ver y (see bel o w f or i nf or mati o n relate d t o 
ter mi nati o n of pre g na nc y). 

If E D P occ urs i n a partici pa nt or a partici pa nt’s part ner, t he i n vesti gat or m ust re p ort 
t his i nf or mati o n t o Pfizer Safet y o n t he C T S A E Re p ort F or m a n d a n E D P 
S u p ple me ntal F or m, re gar dless of w het her a n S A E has occ urre d. Details of t he 
pre g na nc y  will be c ollecte d after t he start of st u d y i nter ve nti o n a n d u ntil a ti me peri o d 
t hat is at least 5 ter mi nal halfli ves after t he last d ose ( u ntil t he half-life is deter mine d 
fr o m cli nical data, t his s h o ul d be at least u ntil t he ti me of last f oll o w- u p).

If E D P occ urs i n t he setti n g of e n vir o n me ntal e x p os ure, t he i n vesti gat or m ust re p ort 
i nf or mati o n t o Pfizer Safet y usi n g t he C T S A E Re p ort F or m a n d E D P S u p ple me ntal 
F or m. Si nce t he e x p os ure i nf or mati o n d oes n ot pertai n t o t he partici pa nt e nr olle d i n 
t he st u d y, t he i nf or mati o n is n ot rec or de d o n a C R F; h o we ver, a c o p y of t he 
c o m plete d C T S A E Re p ort F or m is mai ntai ne d i n t he i n vesti gat or site file.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 0 3
F oll o w -u p is c o n d ucte d t o o bt ai n ge neral i nf or mati o n o n t he pre g na nc y  a n d its o utc o me f or 
all E D P re p orts wit h a n u n k n o w n o utc o me. T he i n vesti gat or will f oll o w t he pre g na nc y  u ntil 
c o m pleti o n ( or u ntil pre g na nc y  ter mi nati o n) a n d n otif y Pfizer Safety of t he o utc o me as a 
f oll o w-u p t o t h e i nitial E D P S u p ple me ntal F or m. I n t he case of a li ve birt h, t he str uct ural 
i nte grity of t he ne o nate ca n be assesse d at t he ti me of birt h. I n t he e ve nt of a ter mi nati o n, t he 
reas o n(s) f or ter mi nati o n s h o ul d be s pecifie d a n d, if cli nicall y p ossi ble, t he str uct ural 
i nte grity of t he ter mi nate d fet us s h o ul d be assesse d b y gr oss vis ual i ns pecti o n ( u nless 
pre pr oce d ural test fi n di n gs are c o ncl usi ve f or a c o n ge nital a n o maly a n d t he fi n di n gs are 
re p orte d).
A b n or mal pre g na nc y  o utc o mes are c o nsi dere d S A Es. If t he o utc o me of t he pre g na nc y meets 
t he criteria f or a n S A E (ie, ect o pic pre g na nc y, s p o nta ne o us a b orti o n, i ntra uteri ne fetal 
de mise, ne o natal deat h , or c o n ge nital a n o maly i n a li ve -b or n ba b y, a ter mi nate d fet us, a n 
i ntra uteri ne fetal de mise, or a ne o natal deat h), t he i n vesti gat or s h o ul d f oll o w t he pr oce d ures 
f or re p orti n g S A Es. A d diti o nal i nf or mati o n a b o ut pre g na nc y  o utc o mes t hat are re p orte d t o 
Pfi zer Safet y as S A Es f oll o ws: 

S p o nta ne o us a b orti o n i ncl u d i n g miscarria ge a n d misse d a b orti o n;

Ne o natal deat hs t hat occ ur wit hi n 1 m o nt h of birt h s h o ul d be re p orte d, wit h o ut re gar d 
t o ca usalit y, as S A Es. I n a d diti o n, i nfa nt deat hs after 1 m o nt h s h o ul d be re p orte d as 
S A Es w he n t he i n vesti gat or assesses t he i nfa nt deat h as relate d or p ossi bl y  relate d t o 
e x p os ure t o t he st u d y i nter ve nti o n. 
A d diti o nal i nf or mati o n re gar di n g t he E D P ma y  be re q ueste d b y t he s p o ns or. F urt her 
f oll o w- u p of birt h o utc o mes will be ha ndle d o n a case -b y -case basis (e g, f oll o w- u p o n 
preter m i nfa nts t o i de ntif y de vel o p me ntal dela y s). I n t he case of pater nal e x p os ure, t he 
i n vesti gat or will pr o vi de t he partici pa nt wit h t he Pre g na nt Part ner Release of I nf or mati o n 
F or m t o deli ver t o his part n er.  T he i n vesti gat or m ust d oc u me nt i n t he s o urce d oc u me nts t hat 
t he partici pa nt was gi ve n t he Pre g na nt Part ner Release of I nf or mati o n F or m t o pr o vi de t o his 
part ner.
8. 3. 5. 2. E x p os ure D uri n g Bre astfee di n g
A n e x p os ure d uri n g breastfee di n g occ urs if: 

A fe male parti ci pa nt is f o u n d t o be breastfee di n g w hile recei vi n g or after 
disc o nti n ui n g st u d y  i nter ve nti o n.

A fe male is f o u n d t o be breastfee di n g w hile bei n g e x p ose d or ha vi n g bee n e x p ose d t o 
st u d y i nter ve nti o n (ie, e n vir o n me ntal e x p os ure). A n e xa m ple of e n vir o n me ntal
e x p os ure d uri n g breastfee di n g is a fe male fa mil y  me m ber or healt hcare pr o vi der w h o 
re p orts t hat s he is breastfee di n g after ha vi n g bee n e x p ose d t o t he st u d y i nter ve nti o n 
b y  i n halati o n or s ki n c o ntact.  
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 0 4
T he i n vesti gat or m ust re p ort e x p os ure d uri n g breastfe e di n g t o Pfizer Safet y wit hi n 2 4 h o urs 
of t he i n vesti gat or’s a ware ness, irres pecti ve of w het her a n S A E has occ urre d. T he 
i nf or mati o n m ust be re p orte d usi n g t he C T S A E Re p ort F or m. W he n e x p os ure d uri n g 
breastfee di n g occ urs i n t he setti n g of e n vir o n me ntal e x p os ure, t he e x p os ure i nf or mati o n d oes 
n ot pertai n t o t he partici pa nt e nr olle d i n t he st u d y, s o t he i nf or mati o n is n ot rec or de d o n a 
C R F. H o we ver, a c o p y of t he c o m plete d C T S A E Re p ort F or m is mai ntai ne d i n t he 
i n vesti gat or site file.
A n e x p os ure d uri n g breastfee di n g re p ort is n ot create d w he n a Pfizer dr u g s pecificall y 
a p pr o ve d f or use i n breastfee di n g w o me n (e g, vita mi ns) is a d mi nistere d i n acc or d wit h 
a ut h orize d use. H o we ver, if t he i nfa nt e x perie nces a n S A E ass ociate d wit h s uc h a dr u g, t he 
S A E is re p orte d t o get her wit h t he e x p os ure d uri n g breastfee di n g.
8. 3. 5. 3. Occ u p ati o n al E x p os ure
A n occ u pati o nal e x p os ure occ urs w he n a pers o n recei ves u n pla n ne d direct c o ntact wit h t he 
st u d y i nter ve nti o n, w hic h ma y or ma y n ot lea d t o t he occ urre nce of a n A E.  S uc h pers o ns 
ma y i ncl u de healt hcare pr o vi ders , fa mily me m bers, a n d ot her r oles t hat are i n v ol ve d i n t he 
trial partici pa nt’s care.
T he i n vesti gat or m ust re p ort occ u pati o nal e x p os ure t o Pfizer Safety wit hi n 2 4 h o urs of t he 
i n vesti gat or’s a ware ness re gar dless of w het her t here is a n ass ociate d S A E.  T he i nf or mati o n 
m ust be re p orte d usi n g t he C T S A E Re p ort F or m.  Si nce t he i nf or mati o n d oes n ot pertai n t o a 
partici pa nt e nr olle d i n t he st u d y, t he i nf or mati o n is n ot rec or de d o n a C R F; h o we ver, a c o p y 
of t he c o m plete d C T S A E Re p ort F or m is mai ntai ne d i n t he i n vesti gat or site file .
8. 3. 6. C ar di o v asc ul ar a n d De at h E ve nts
N ot a p plica ble t o t his st u d y .
8. 3. 7. Dise ase -Rel ate d E ve nts a n d/ or Dise ase -Rel ate d O utc o me N ot Q u alif yi n g as A Es 
or S A Es
N ot a p plica ble t o t his st u d y .
8. 3. 8. A d verse E ve nts of S peci al I nterest
P F - 0 7 2 8 4 8 9 0: t here are n o A Es of S pecial I nterest at t his ti me (as n o patie nts ha ve bee n 
d ose d at t he ti me of t he writi n g of t his pr ot oc ol versi o n); t his secti o n will be u p date d as data 
e mer ges fr o m t he o n g oi n g st u d y.
Bi ni meti ni b A Es of S pecial I nterest, liste d as --Cate g or y  ( A E SI)--acc or di n g t o Me d D R A 
Versi o n 2 1. 0 : car diac e ve nts ( bra d ycar dia, left ve ntric ular d ys f u ncti o n), der mat ol o gic e ve nts 
(ac neif or m der matitis, nail dis or ders, ras h, se vere c uta ne o us a d verse reacti o ns, s ki n 
i nfecti o ns), e de ma e ve nts ( peri p heral e de ma), he m orr ha ge ( he m orr ha ge), h yperte nsi o n 
( h yperte nsi o n), li ver e ve nts ( he patic fail ure, lifer f u ncti o n test a b n or malities), o p ht hal mic 
e ve nts (reti nal vei n occl usi o n, reti n o pat h y  e xcl u di n g R V O), p ne u m o nitis e ve nts 
( p ne u m o nitis), ve n o us t hr o m b oe m b olis m ( ve n o us t hr o m b oe m b olis m).
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 0 5
A d verse e ve nts of s pecial i nterest ( A E SIs) are e xa mi ne d as part of r o uti ne safet y data re vie w 
pr oce d ures t hr o u g h o ut t he cli nical trial a n d as part of si g nal detecti o n pr ocesses.
All A E SI s m ust be re p orte d as a n A E or S A E f oll o wi n g t he pr oce d ures descri be d i n 
Secti o n s 8. 3. 1 t hr o u g h 8. 3. 4 .  A n A E SI  is t o be rec or de d as a n A E or S A E o n t he CR F.  I n 
a d diti o n, a n A E SI t hat is als o a n S A E m ust be re p orte d usi n g t he C T S A E Re p ort F or m.
8. 3. 8. 1. L ac k of Effic ac y
N ot a p plica ble t o t his st u d y .
8. 3. 9.
Me dic al De vice Deficie ncies
N ot a p plica ble t o t his st u d y .
8. 3. 1 0. Me dic ati o n Err ors
Me dicati o n err ors ma y  res ult fr o m t he a dmi nistrati o n or c o ns u m pti o n of t he st u d y 
i nter ve nti o n b y  t he wr o n g partici pa nt , or at t he wr o n g ti me, or at t he wr o n g d osa ge stre n gt h.
S afet y E ve nt
Rec or de d o n t he C R F
Re p orte d o n t he C T S A E Re p ort 
F or m t o Pfizer S afet y Wit hi n 
2 4 H o urs of A w are ness
Me dicati o n err ors 
All (re gar dless of w het her 
ass ociate d wit h a n A E)
O nl y  if ass ociate d wit h a n S A E
Me dicati o n err ors i ncl u de:

Me dicati o n err ors i n v ol vi n g partici pa nt e x p os ure t o t he st u d y i nter ve nti o n;

P ote ntial me dicati o n err ors or uses o utsi de of w hat is f oresee n i n t he pr ot oc ol t hat d o 
or d o n ot i n v ol ve t he st u d y partici pa nt .
S uc h me dicati o n err ors occ urri n g t o a st u d y partici pa nt are t o be ca pt ure d o n t he me dicati o n 
err or pa ge of t he C R F, w hic h is a s pecific versi o n of t he A E pa ge.
I n t he e ve nt of a me dicati o n d osi n g err or, t he s p o ns or s h o ul d be n otifie d wit hi n 2 4 h o urs .
W het her or n ot t he me dicati o n err or is acc o m pa nie d b y  a n A E, as deter mi ne d b y t he 
i n vesti gat or, t he me dicati o n err or is rec or de d o n t he me dicati o n err or pa ge of t he C R F a n d, if 
a p plicable, a n y ass ociate d A E(s), seri o us a n d n o nseri o us, are rec or de d o n t he A E pa ge of t he 
C R F.
Me dicati o n err ors s h o ul d be re p orte d t o Pfizer Safet y wit hi n 2 4
h o urs o n a C T S A E Re p ort 
F or m o nl y w he n ass oci ate d wit h a n S A E.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 0 6
Ot her e xa m ples i ncl u de, b ut are n ot li mite d t o:

T he a d mi nistrati o n of e x pire d st u d y i nter ve nti o n;

T he a d mi nistrati o n of a n i nc orrect st u d y i nter ve nti o n;

T he a d mi nistrati o n of a n i nc orrect d osa ge;

T he a d mi nistrati o n of st u d y i nter ve nti o n t hat has u n der g o ne te m perat ure e xc ursi o n 
fr o m t he s pecifie d st ora ge ra n ge, u nless it is deter mi ne d b y t he s p o ns or t hat t he st u d y 
i nter ve nti o n u n der q uesti o n is acce pta ble f or use.
8. 4. Tre at me nt of O ver d ose
F or t his st u d y , a n y d ose of P F - 0 7 2 8 4 8 9 0 or bi ni meti ni b greater t ha n t he prescri be d re gi me n 
f or t he partici pa nt wit hi n a 2 4 -h o ur ti me peri o d ± 6 h o urs will be c o nsi dere d a n o ver d ose.
S p o ns or d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose.
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or/treati n g p hys icia n s h o ul d:
1.
C o ntact t he m e dical m o nit or wit hi n 2 4 h o urs .
2.
Cl osel y  m o nit or t he partici pa nt f or a ny A E s/ S A Es a n d la b orat or y a b n or malities f or at 
least 5 half -li ves or 2 8 cale n dar da ys after t he o ver d ose of P F - 0 7 2 8 4 8 9 0 a n d/ or 
bi ni meti ni b ( w hic he ver is l o n ger).
3.
D oc u me nt t he q ua ntit y of t he e xcess d ose as well as t he d urati o n of t he o ver d ose i n 
t he C R F.
4.
O ver d ose is re p orta ble t o Safet y  o nl y w he n ass oci ate d wit h a n S A E.
5.
O btai n a bl o o d sa m ple f or P K a nal ys is wit hi n 7 da ys fr o m t he date of t he last d ose of 
st u d y i nter ve nti o n if re q ueste d b y t he me dical m o nit or ( deter mi ne d o n a case-b y -case 
basis).   
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y  t he i n vesti gat or i n 
c o ns ultati o n wit h t he m e dical m o nit or base d o n t he cli nical e val uati o n of t he partici pa nt.
8. 5. P h ar m ac o ki netics 
F or partici pa nts recei vi n g o nly P F - 0 7 2 8 4 8 9 0, bl o o d sa m ples of a p pr o xi matel y 3 m L , t o 
pr o vi de a mi ni m u m of 1 . 2 m L plas ma , will be c ollecte d. F or partici pa nts recei vi n g 
P F - 0 7 2 8 4 8 9 0 a n d bi ni meti ni b , bl o o d sa m ples of a p pr o xi matel y 5 m L , t o pr o vi de a mi ni m u m 
of 2 m L  plas ma, will be c ollecte d. T he sa m ples will be c ollecte d as s pecifie d i n t he 
P har mac o ki netic Sa m pli n g a n d E C Gs Sc he d ule ta bles. Instr ucti o ns f or t he c ollecti o n a n d 
ha n dli n g of bi ol o gical sa m ples will be pr o vi de d i n t he la b orat or y ma n ual or b y  t he s p o ns or. 
T he act ual date a n d ti me ( 2 4- h o ur cl oc k ti me) of eac h sa m ple will be rec or de d.
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 0 7
T he act ual ti mes of P K sa m ples ma y  c ha n ge, b ut t he n u m ber of sa m ples will re mai n t he 
sa me.  All eff orts will be ma de t o o btai n t he sa m ples at t he e xact n o mi nal ti me relati ve t o 
d osi n g.  C ollecti o n of sa m ples wit hi n t he sa m pli n g ti me wi n d o w s pecifie d i n t he 
P har mac o ki netic Sa m pli n g a n d E C Gs Sc he d ule ta bles will n ot be ca pt ure d as a pr ot oc ol 
de viati o n, as l o n g as t he e xact ti me of t he c ollecti o n is n ote d o n t he s o urce d oc u me nt a n d t he
C R F / D C T.  If a sc he d ule d bl o o d sa m ple c ollecti o n ca n n ot be c o m plete d f o r a ny reas o n, t he 
misse d sa m ple ti me ma y  be re-sc he d ule d wit h a gree me nt of t he cli nical i n vesti gat or, 
partici pa nt , a n d s p o ns or.
Plas ma P K sa m ples will be use d t o e val uate t he P K of P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b i n 
partici pa nts recei vi n g t he c o m bi nati o n). F or partici pa nts recei vi n g o nly P F - 0 7 2 8 4 8 9 0, t he
plas ma P K sa m ple will be use d as 1 ali q u ot a p pr o xi matel y 1 m L i n v ol u me ( 1 sa m ple f or 
meas uri n g P F - 0 7 2 8 4 8 9 0). F or partici pa nts recei vi n g P F - 0 7 2 8 4 8 9 0 a n d bi ni meti ni b, eac h 
plas ma P K sa m ple will be di vi de d i nt o 2 ali q u ot s a p pr o xi matel y 1 m L i n v ol u me eac h 
( 1 sa m ple f or meas uri n g P F - 0 7 2 8 4 8 9 0 a n d 1 sa m ple f or meas uri n g bi ni meti ni b ). Sa m ples 
c ollecte d f or a nal ys es of plas ma c o nce ntrati o n ma y als o be use d t o e val uate safety or efficac y 
aspects relate d t o c o ncer ns arisi n g d uri n g or after t he st u d y , f or meta b olite i de ntificati o n 
a n d/ or e val uati o n of t he bi oa nal y tical met h o d, or f or ot her i nter nal e x pl orat or y p ur p oses.
Ge netic a nal ys es will n ot be perf or me d o n t hese plas ma sa m ples u nless c o ns e nt f or t his 
a nal ys is w as o btai ne d . Partici pa nt c o nfi de ntialit y  will be mai ntai ne d.
A n o pti o nal C S F sa m ple of 5 m L  is t o be c ollecte d a n y ti me C S F is sa m ple d as part of S O C. 
If feasi ble C S F sa m ples are t o be c ollecte d o n P K da y s ( C 1 D 1 a n d C 1 D 1 5), i deall y 2 t o 
4 h o urs p ost -d ose. If C S F sa m ples are o btai ne d o n da ys t hat are n ot P K da ys, if p ossi ble a n 
a d diti o nal P K sa m ple will be c ollecte d at a p pr o xi matel y  t he sa me ti me. T he e xact ti mes of 
t he a d mi nistrati o n of t he d ose bef ore t he C S F sa m ple c ollecti o n, of t he C S F sa m ple
c ollecti o n itself, a n d if a p pr o priate of t he u nsc he d ule d P K sa m ple c ollecti o n s h o ul d be
rec or de d. C S F sa m ples , o btai ne d o nl y w he n perf or me d as part of S O C, will be use d t o 
e val uate t he C S F le vels of P F - 0 7 2 8 4 8 9 0, a n d m a y  be use d f or  
 a nal ysis , if t he a m o u nt 
c ollecte d is s ufficie nt . Eac h C S F sa m ple will be di vi de d i nt o 2 ali q u ots, 1 sa m ple
a p pr o xi matel y 1 m L  i n v ol u me f or meas uri n g P F - 0 7 2 8 4 8 9 0 a n d 1 sa m ple at least 4 m L f or 
a nal yz i n g 
. T he sa m ple c ollecte d f or a nal ysis of P F - 0 7 2 8 4 8 9 0 c o nce ntrati o n ma y als o 
be use d t o deter mi ne t he bi ni meti ni b c o nce ntrati o n. Ger mli ne g e netic a nal yses will n ot be 
perf or me d o n t h ese C S F sa m ples u nless c o nse nt f or t his was i ncl u de d i n t he i nf or me d 
c o nse nt /asse nt. Partici pa nt c o nfi de ntialit y  will be mai ntai ne d.
Sa m ples c ollecte d f or meas ure me nt of plas ma c o nce ntrati o ns of P F - 0 7 2 8 48 9 0 (a n d 
bi ni meti ni b i n partici pa nt s recei vi n g t he c o m bi nati o n) a n d of C S F c o nce ntrati o ns of
P F -0 7 2 8 4 8 9 0 will be a nal y ze d usi n g vali date d a nal ytical met h o ds i n c o m plia nce wit h 
a p plica ble S O Ps.   P ote ntial meta b olites i n plas ma sa m ples ma y  be a nal yze d wit h eit her 
vali date d or e x pl orat or y  met h o ds.
T he P K sa m ples m ust be pr ocesse d a n d s hi p pe d as i n dicate d i n t he i nstr ucti o ns pr o vi de d t o 
t he i n vesti gat or site t o mai ntai n sa m ple i nte grit y.  A n y  de viati o ns fr o m t he P K sa m ple 
ha n dli n g pr oce d ure (e g, sa m ple c ollecti o n a n d pr ocessi n g ste ps, i nteri m st ora ge or s hi p pi n g 
 
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 0 8
c o n diti o ns), i ncl u di n g a n y acti o ns ta ke n, m ust be d oc u me nte d a n d re p orte d t o t he s p o ns or.  
O n a case -b y -case basis, t he s p o ns or ma y  ma ke a deter mi nati o n as t o w het her sa m ple 
inte grit y has bee n c o m pr o mise d.
A n y  c ha n ges i n t he ti mi n g or a d diti o n or re m o val of ti me p oi nts f or a n y pla n ne d st u d y P K 
assess me nts m ust be d oc u me nte d a n d a p pr o ve d b y  t he rele va nt st u dy tea m me m ber a n d t he n 
arc hi ve d i n t he s p o ns or a n d site st u d y  files, b ut will n ot c o nstit ute a pr ot oc ol a me n d me nt. 
T he I R B/ E C will be i nf or me d of a n y  safety iss ues t hat re q uire alterati o n of t he safet y 
m o nit ori n g sc he me or a me n d me nt of t he I C D.
8. 6. P h ar m ac o d y n a mics
P D para meters will be e val uate d i n t his st u d y.  See Secti o n 8. 8 Bi o mar kers.
Bl o o d sa m ples of a p pr o xi matel y  2 0 m L , t o pr o vi de a mi ni m u m of a p pr o xi matel y 8 m L  
plas ma v ol u me , will be c ollecte d f or meas ure me nt of 
(t otal a m o u nt) a n d B R A F V 6 0 0 
m utati o n acc or di n g t o t he S o A .
As part of u n dersta n di n g t he P D of t he st u d y  i nter ve nti o n, sa m ples ma y be use d f or 
e val uati o n of t he bi oa nal ytical met h o d, as well as f or ot her i nter nal e x pl orat or y  p ur p oses.  
Sa m ples will be a nal y ze d usi n g a vali date d a nal yt ical met h o d i n c o m plia nce wit h a p plicab le 
S O Ps. 
T he P D sa m ples m ust be pr ocesse d a n d s hi p pe d as i n dicate d i n t he i nstr ucti o ns pr o vi de d t o 
t he i n vesti gat or site t o mai ntai n sa m ple i nte grit y.  A n y de viati o ns fr o m t he P D sa m ple 
ha n dli n g pr oce d ure (e g, sa m ple c ollecti o n a n d pr ocessi n g ste ps, i nteri m st ora ge, or s hi p pi n g 
c o n diti o ns), i ncl u di n g a n y acti o ns ta ke n, m ust be d oc u me nte d a n d re p orte d t o t he s p o ns or.  
O n a case -b y -case basis, t he s p o ns or ma y  ma ke a determi nati o n as t o w het her sa m ple 
i nte grity has bee n c o m pr o mise d.
Details o n P D sa m ples a n d a nal ys is ca n be f o u n d i n t he La b orat or y Ma n ual.
8. 7. Ge netics
8. 7. 1. B R A F Testi n g
Partici pa nt s will be eli gi ble f or t he st u dy base d o n d oc u me nte d e vi de nce of a B R A F V 6 0 0 
m utati o n in t u m or tiss ue or bl o o d (e g,  
) o btai ne d d uri n g t he c o urse of n or mal cli nical 
care i n a C LI A or si milarl y  certifie d la b orat or y at a n y ti me pri or t o Scree ni n g . O nl y P C R 
a n d N G S -base d l ocal assa y s res ults will be acce pta ble.  A m olec ular re p ort clearl y 
d oc u me nti n g t he prese nce of t he B R A F V 6 0 0 m utati o n (a n d a n y ot her m olec ular fi n di n gs 
fr o m sa m ples as perf or me d d uri n g t he n or mal c o urse of cli nical care) m ust be pr o vi de d f or 
c o nfir mati o n t hat testi n g meets eli gi bilit y. B R A F V 6 0 0 m utati o n c o nfir mati o n (e g, b y  
ce ntral testi n g) is n ot re q uire d f or st u d y eli gi bilit y, b ut ma y be perf or me d retr os pecti vel y 
usi n g s u b mitte d t u m or tiss ue a n d/ or baseli ne bl o o d sa m ple (ie, “ bl o o d sa m ple f or B R A F 
C D x ”; see S o A a n d Secti o n 8. 7. 2 ) at a Pfizer desi g nate d ce ntral la b orat or y.  
 
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 0 9
8. 7. 2. Arc hi ve d Tiss ue S a m ple/ Bl o o d S a m ple f or C D x
C o nfir mati o n of t he a vaila bil it y of ade q uate t u m or tiss ue ( pri mar y  or metastatic, arc hi val), if 
p ossi ble fr o m t he sa me sa m ple t hat was use d t o perf or m l ocal B R A F m utati o n testi n g, m ust 
be pr o vi de d f or all partici pa nts e nr olle d i n t he st u d y a n d s u b mitte d t o t he s p o ns or. A de q uate 
is defi ne d as: F F P E t u m or tiss ue bl oc k , ne wl y c ollecte d fi xe d bi o ps y sa m ple, or a mi ni m u m 
of 1 5 u nstai ne d sli des i deall y wit h at least 2 0 % t u m or n uclei c o nte nt.
T his sa m ple ma y  be utilize d f or C D x de vel o p me nt , b ut will n ot be use d f or deter mi ni n g
eli gi bilit y.
If a n arc hi val t u m or sa m ple is n ot a vaila ble, a fres h t u m or bi o ps y s h o ul d be o btai ne d if 
bi o ps y  ca n be perf or me d safely ( i n t he o pi ni o n of t he i n vesti gat or); if bi o ps y ca n n ot be 
perf or me d safel y, t he partici pa nt ma y  be eli gi ble if ot her I ncl usi o ns/ E xcl usi o n Criteria are 
met).  If a fres h bi o psy is ta ke n, t he bi o ps y s h o ul d be fr o m a n o ntar get lesi o n w he n p ossi ble.
Sli de secti o ns s h o ul d be fres hl y c ut (ie, i deall y n o m ore t ha n 3 0 da y s pri or t o s hi p me nt t o t he 
ce ntral la b orat or y), 4- 5 µ m t hic k a n d m o u nte d o n p ositi vel y-c har ge d micr osc o pe sli des 
( S u per Fr ost Pl us glass sli des are rec o m me n de d). 
Disc uss wit h t he sp o ns or if less t he n t his n u m ber of or q ualit y  of t hese sli des is a vaila ble. 
A peri p hera l bl o o d sa m ple ( 2 0 m L) will als o be c ollecte d d uri n g Scree ni n g ( Bl o o d Sa m ple 
f or C D x, see S o A ).
Sa m ples c ollecte d fr o m t his st u d y  m a y be use d as part of t he de vel o p me nt of a n i n vitr o 
dia g n ostic assa y  i n acc or da nce wit h F D A’s Q ualit y S yste m Re g ulati o ns a n d Desi g n C o ntr ol 
re q uire me nts. A n y t u m or sa m ples re mai ni n g after testi n g f or B R A F V 6 0 0 a n d/ or a bl o o d 
sa m ple c ollecte d d uri n g Scree ni n g m a y  be use d f or c o m pa ni o n dia g n ostic de vel o p me nt a n d 
Healt h A ut h orit y  re gistrati o n, a n d t o assess t he c o nc or da nce bet wee n t he res ults f or B R A F
V 6 0 0 stat us o btai ne d usi n g t he ce ntral la b orat or y  assa y a n d t he c o m pa ni o n dia g n ostic assa y 
w hic h will be s u b mitte d f or pre mar ket a p pr o val. 
Alt h o u g h it is a ntici pate d t hat m ost sa m ples will be c o ns u me d b y  pla n ne d a nal yses d uri n g t he 
c o urse of t he st u d y, a n y u n use d sa m ples m a y  be st ore d at a facilit y selecte d b y t he s p o ns or 
f or a ma xi m u m of 1 0 years ( or acc or di n g t o l ocal re g ulati o ns) f oll o wi n g t he last partici pa nt’s 
last visit f or t he st u d y u nless pr o hi bite d b y  l ocal re g ulati o ns or et hics c o m mittee decisi o n.
A d diti o nal i nf or mati o n re gar di n g tiss ue s peci me n re q uire me nts, sa m ple ha n dli n g a n d 
s hi p me nt will be pr o vi de d i n t he la b orat or y ma n ual.
8. 7. 3. S pecifie d Ge netics
A 2 0- m L  bl o o d sa m ple f or D N A is olati o n will be c ollecte d at t he ti me p oi nts f or  
 
bl o o d c ollecti o n are pr o vi de d i n t he S o A , a n d at disease pr o gressi o n . D N A sa m ples will be 
a nal yz e d f or t he p ur p ose of q ua ntif y i n g cfD N A, B R A F V 6 0 0 m utati o ns a n d ot her m utati o ns 
c orrelate d wit h res p o nse a n d resista nce t o treat me nt.
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 1 0
I n t he e ve nt of D N A e xtracti o n fail ure, a re place me nt ge netic bl o o d sa m ple ma y be re q ueste d 
fr o m t he partici pa nt.
Ge netic testi n g ma y  als o be perf or me d o n C S F sa m ples c ollecte d a n d re mai ni n g plas ma 
sa m ples f or C D x ( Bl o o d Sa m ple f or C D x, see S o A ) f or t he p ur p ose of q ua ntif y i n g cf D N A, 
B R A F V 6 0 0 m utati o ns a n d ot her m utati o ns c orrelate d wit h res p o nse a n d resista nce. 
See A p pe n di x 5 f or inf or mati o n re gar di n g ge netic researc h.  Details o n pr ocesses f or 
c ollecti o n a n d s hi p me nt of t hese sa m ples ca n be f o u n d i n t he la b orat or y ma n ual.
8. 7. 4. P h ar m ac o ge netics
A 6 - m L bl o o d sa m ple pri or t o t he first d ose of st u d y  dr u g will be o btai ne d f or 
p har mac o ge netics a nal ys is. Ge netic varia nt a nal ysis of t he 
 will be perf or me d 
t o i n vesti gate t he c orrelati o n bet wee n vari o us ge n ot y pes o n P F -0 7 2 8 4 8 9 0 e x p os ure. Ot her 
ge ne tic a nal yses o n ge nes t hat are relate d t o t he disease or P F-0 7 2 8 4 8 9 0 meta b olis m a n d 
acti o n ma y als o be perf or me d usi n g t hese sa m ples. T his sa m ple c ollecti o n is re q uire d i n t his 
st u d y. It is i ncl u de d i n t he mai n c o nse nt a n d is n ot o pti o nal u nless ot her wis e i n dicate d b y 
l ocal IR B/ E C or Healt h A ut h orit y  re q uire me nts.
8. 7. 5. B a n ke d Bi os peci me ns f or Ge netics
A 4 m L  bl o o d sa m ple o pti mize d f or D N A is olati o n Pre p D 1 will be c ollecte d as l ocal 
re g ulati o ns a n d I R Bs/ E Cs all o w.  
Ba n ke d Bi os peci me ns ma y  be use d f or researc h relate d t o t he st u d y i nter ve nti o n(s) a n d 
ca ncer.  Ge nes a n d ot her a nalyt es (e g, pr otei ns , R N A, n o n dr u g meta b olites) ma y  be st u die d 
usi n g t he ba n ke d sa m ples. 
See A p pe n di x 5 f or inf or mati o n re gar di n g ge netic resear c h. Details o n pr ocesses f or 
c ollecti o n a n d s hi p me nt of t hese sa m ples ca n be f o u n d i n t he la b orat or y ma n ual.
8. 8. Bi o m ar kers
Bi os peci me ns c ollecte d f or p har mac o d y na mic a n d ot her bi o mar ker assess me nts ma y i ncl u de 
peri p heral bl o o d a n d t u m or tiss ues, a n d ma y be use d t o a nalyz e D N A, R N A, or pr otei ns, f or 
ac hie vi n g pla n ne d bi o mar ker o bjecti ves. Refer t o t he S o A f or sa m ple c ollecti o n ti me p oi nts 
a n d St u d y/ La b orat or y Ma n ual f or sa m ple pr ocessi n g a n d s hi p pi n g. T he f oll o wi n g 
bi os peci me n t y pes are pla n ne d t o be c ollecte d i n s u p p ort of st u d y  o bjecti ves. A d diti o nal 
bi os peci me ns c ollecte d o ver t he c o urse of partici pa nt disease ma na ge me nt ma y  be s u b mitte d 
f or bi o mar ker a nalys es. 
8. 8. 1. O pti o n al De N o v o T u m or Bi o psies
T u m or bi os peci me ns fr o m de n o v o bi o psies will be use d t o a nal yz e ca n di date n ucleic aci d 
a n d pr otei n bi o mar kers f or t heir a bilit y  t o i de ntif y t h ose partici pa nts w h o are m ost li kel y t o 
be nefit fr o m treat me nt wit h t he st u d y  dr u gs. O pti o nal t u m or bi o psies ( o btai ned pri or t o 
C 1 D 1, bet wee n C 1 D 8 a n d C 2 D 1 5 , a n d at disease pr o gressi o n ) will be use d t o meas ure 
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 1 1
c ha n ges fr o m baseli ne i n 
.  I nhi biti o n of B R A F ki nase acti vit y is 
e x pecte d t o bl oc k d o w nstrea m si g nali n g lea di n g t o a decrease of 
 as meas ure d 
b y  i m m u n o hist oc he mistr y of tiss ue sa m ples.  A d diti o nal pr otei n mar kers of cell c ycle 
pr otei ns a n d a p o pt osis ma y be meas ure d as m olec ular c ha n ges i n cell pr oliferati o n. Bi o p sy 
sa mp les ma y  als o be use d t o i de ntif y  ac q uire d c ha n ges i n t u m or D N A t hat c o ul d i de ntif y  
mec ha nis ms of resista nce t o st u d y  dr u gs.
A d diti o nal bi o mar kers ma y  i ncl u de, b ut are n ot li mite d t o tar get e x pressi o n, n ucleic aci d 
a nal ys es, as well as cell t ypes a n d c o nstit ue nts of t he T M E. 
T hese bi o psies will o nl y  be o btai ne d in partici pa nt s i n w h o m bi o ps y is safe t o perf orm i n t he 
o pi ni o n of t he i n vesti gat or , a n d o nly wit h t he partici pa nt’s i nf or me d c o nse nt/asse nt. If a 
partici pa nt re q uires a resecti o n of t u m or tiss ue (e g, i n t he brai n) as part of sta n dar d of care of 
t heir disease ( n ot a st u d y pr oce d ure) w hile o n st u d y  treat me nt, t he partici pa nt ma y pr o vi de 
o pti o nal c o nse nt t o s u b mit t his tiss ue or a p orti o n of t his tiss ue t o t he st u d y  f or a nalys is. 
A d diti o nall y , t he partici pa nt ma y c o nse nt t o c ollecti o n of a n o pti o nal ti me-matc he d P K 
sa m ple c ollecte d near t he ti me of t he t u m or tiss ue c ollecti o n. 
A d diti o nal i nf or mati o n o n tiss ue c ollecti o n pr oce d ures ca n be f o u n d i n t he La b orat or y / St u d y 
Ma n ual.
8. 8. 2. W h ole
Bl o o d , Pl as m a Bi o m ar kers
Peri p heral bl o o d a n d deri vati ves ma y  be use d t o c haracterize cell p he n oty p es, meas ure 
s ol u ble pr otei ns a n d a nal yze n ucleic aci ds t o s u p p ort st u d y o bjecti ves. E xa m ples ma y  
i ncl u de cell-free D N A, a n d c yt o ki nes. T otal cf D N A i n plas ma sa m ples will be q ua ntifie d 
a n d B R A F V 6 0 0 m uta nt allele fracti o n will be meas ure d b y P C R or N G S fr o m t he 
cf D N A/ plas ma sa m ple.  M uta nt allele fracti o ns ma y be re p orte d as n u m ber of m uta nt c o pies 
or t he perce nta ge of m uta nt c o pies fr o m t otal rea ds.  Re d ucti o n i n t u m or v ol u me is e x pecte d 
t o res ult i n a decrease i n s he d D N A fr om t u m ors as meas ure d b y  cf D N A a n d t he s pecific 
B R A F V 6 0 0 m uta nt cl o nes as meas ure d b y B R A F V 6 0 0 m uta nt  
.
A d diti o nal 
a nal ys es, i ncl u di n g a d diti o nal n ucleic aci d a nalys es, ma y  be warra nte d base d o n e mer gi n g 
data. Plas ma sa m ples at E O T/ disease pr o gress i o n will be use d t o i de ntif y ac q uire d c ha n ges 
i n 
 t hat c o ul d i de ntif y mec ha nis ms of resista nce t o st u d y dr u gs.
8. 9. I m m u n o ge nicit y Assess me nts
I m m u n o ge nicity assess me nts are n ot i ncl u de d i n t his st u d y .
8. 1 0. He alt h Ec o n o mics
Healt h ec o n o mics/m e dical res o urce u tilizati o n a n d h ealt h ec o n o mics para meters are n ot 
e val uate d i n t his st u d y.
9. S T A TI S TI C A L C O N SI D E R A TI O N S
Detaile d met h o d ol o g y  f or s u m mar y a n d statistical a nalys es of t he data c ollecte d i n t his st u d y  
is o utli ne d here a n d f urt her detaile d i n an S A P, w hic h will be mai ntai ne d b y t he s p o ns or.  
C CI
C CI
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 1 2
T he data will be s u m marize d wit h res pect t o de m o gra p hic a n d baseli ne c haracteristics, 
efficac y o bser vati o ns a n d meas ure me nts, safety o bser vati o ns a n d meas ure me nts, 
p har mac o ki netic a n d bi o mar ker meas ure me nts.
9. 1. St atistic al H y p ot heses
T here will be n o f or mal h y p ot hesis testi n g i n t his st u d y .
9. 2. S a m ple Size Deter mi n ati o n
T otal n u m ber of partici pa nts f or Phase 1a a n d P hase 1 b c o m bi ne d, is esti mate d t o be 
a p pr o xi matel y 1 2 0 - 1 3 8. 
9. 2. 1. P h ase 1 a D ose Esc al ati o n
Acc or di n g t o criteria t o declare t he M T D, a p pr o xi matel y 3 5 partici pa nts will be e nr olle d. 
H o we ver, t he t otal n u m ber of partici pa nts will de pe n d o n t he n u m ber of d ose le vels nee de d 
t o deter mi ne t he M T D/rec o m me n de d d ose f or f urt her st u d y a n d n u m ber of partici pa nts 
e val ua ble f or D L T at eac h d ose le vel, f or b ot h t he m o n o t hera py a n d t he c o m bi nati o n t hera p y 
d ose escalati o ns .
9. 2. 2. P h ase 1 b D ose E x p a nsi o n
A p pr o xi matel y  2 0 partici pa nts will be e nr olle d t o eac h of C o h ort s 1- 4. F or C o h ort 5, 
4 0 partici pa nts , f or C o h ort 6, 1 0 partici pa nts m a y be e nr olle d . O pti o nal C o h ort 7, if nee de d, 
ma y  e nr oll 6- 8 partici pa nts .

C o h ort 1 will i ncl u de partici pa nts wit h as y m pt o matic brai n metastases a n d n o pri or 
B R A F i n hi bit or t hera p y.  T his c o h ort will i ncl u de mela n o ma partici pa nts. F or t his 
c o h ort, t he ta bl e bel o w s h o ws t he pr o ba bilities t hat t he tr ue O R R is wit hi n a s pecific 
i nter val, gi ve n a n o bser ve d res p o nse. F or e xa m ple, ass u mi n g t he o bser ve d O R R is at 
4 0 % ( 8 / 2 0), ass u mi n g a n o n-i nf or mati ve pri or (ie, Jeffre y’s pri or), a sa m ple size of 
2 0 e val ua ble partici pa nt s will yiel d 6 5 % % Ba y esia n p osteri or pr o ba bilit y t hat t he 
‘ Tr ue O R R’ is bet wee n 3 0 % a n d 5 0 %.
O bser ve d O R R
P( O R R) 0 - 3 0 %
P( O R R) 3 0 -5 0 %
P( O R R) 5 0 -1 0 0 %
2 /2 0 ( 1 0 %)
0. 9 8 2
0. 0 1 8
0
4 /2 0 ( 2 0 %)
0. 8 3 5
0. 1 6 2
0. 0 0 3
6 /2 0 ( 3 0 %)
0. 4 8 7
0. 4 7 8
0. 0 3 5
8 /2 0 ( 4 0 %)
0. 1 6 4
0. 6 5 0
0. 1 8 6
1 0 /2 0 ( 5 0 %)
0. 0 2 9
0. 4 7 1
0. 5
1 2 /2 0 ( 6 0 %)
0. 0 0 3
0. 1 8 3
0. 8 1 4

C o h ort 2 will i ncl u de partici pa nts wit h s y m pt o matic brai n metastases a n d n o pri or 
B R A F i n hi bit or t hera p y. T his c o h ort will i ncl u de mela n o ma partici pa nts. Si nce t hese 
partici pa nts are m ore a d va nce d relati ve t o t heir brai n metastases, we e x pect m ore 
varia bilit y  i n t heir cli nical o utc o me, i ncl u di n g varia bilit y relati ve t o t u m or t ype. 
T heref ore, wit h t he a p pr o xi matel y  2 0 partici pa nts a ntici pate d, t he ta ble bel o w s h o ws 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 1 3
t he pr o ba bilities t hat t he tr ue O R R is wit hi n a s pecific i nter val, gi ve n a n o bser ve d 
res p o nse. F or e xa m ple, ass u mi n g t he o bser ve d O R R is at 4 0 % ( 8/ 2 0), ass u mi n g a 
n o n -i nf or mati ve pri or (ie, Jeffre y’s pri or), a sa m ple size of 2 0 e val ua ble partici pa nts
will y iel d 6 5 % Ba yesia n p osteri or pr o ba bilit y  t hat t he ‘ Tr ue O R R’ is bet wee n 
3 0 % a n d 5 0 %.
O bser ve d O R R
P( O R R) 0 - 3 0 %
P( O R R) 3 0 -5 0 %
P( O R R) 5 0 -1 0 0 %
2/ 2 0 ( 1 0 %)
0. 9 8 2
0. 0 1 8
0
4/ 2 0 ( 2 0 %)
0. 8 3 5
0. 1 6 2
0. 0 0 3
6/ 2 0 ( 3 0 %)
0. 4 8 7
0. 4 7 8
0. 0 3 5
8/ 2 0 ( 4 0 %)
0. 1 6 4
0. 6 5
0. 1 8 6
1 0/ 2 0 ( 5 0 %)
0. 0 2 9
0. 4 7 1
0. 5
1 2/ 2 0 ( 6 0 %)
0. 0 0 3
0. 1 8 3
0. 8 1 4

C o h orts 3 a n d 4 will i ncl u de partici pa nts ( C o h ort 3 wit h as ym pt o matic brai n 
metastases, C o h ort 4 wit h s y m pt o matic brai n metastases) wit h pri or B R A F i n hi bit or 
t hera py. T hese 2 c o h orts will i ncl u de mela n o ma partici pa nts. Si nce t hese 
partici pa nts ha ve recei ve d pri or B R A F i n hi bit ors, i n a d diti o n t o ot her pri or t hera pies, 
we e x pect varia bilit y i n t heir cli nical o utc o me. F or b ot h C o h ort 3 a n d 4, t he pla n is t o 
e nr oll a p pr o xi matel y 2 0 partici pa n ts i n eac h c o h ort wit h mela n o ma. T he ta ble bel o w 
s h o ws t he pr o ba bilit y t hat t he tr ue O R R is wit hi n a s pecific i nter val, gi ve n a n 
o bser ve d res p o nse. F or e xa m ple, ass u mi n g t he o bser ve d O R R is at 4 0 % ( 8/ 2 0), 
ass u mi n g a n o n -i nf or mati ve pri or (ie, Jeffre y’s pri or), a sa m ple size of 2 0 e val ua ble 
partici pa nts will y iel d 6 5 % Ba ye sia n p osteri or pr o ba bilit y t hat ‘ Tr ue O R R’ is 
bet wee n 3 0 % a n d 5 0 %.
O bser ve d O R R
P( O R R) 0 - 3 0 %
P( O R R) 3 0 -5 0 %
P( O R R) 5 0 -1 0 0 %
2/ 2 0 ( 1 0 %)
0. 9 8 2
0. 0 1 8
0
4/ 2 0 ( 2 0 %)
0. 8 3 5
0. 1 6 2
0. 0 0 3
6/ 2 0 ( 3 0 %)
0. 4 8 7
0. 4 7 8
0. 0 3 5
8/ 2 0 ( 4 0 %)
0. 1 6 4
0. 6 5
0. 1 8 6
1 0/ 2 0 ( 5 0 %)
0. 0 2 9
0. 4 7 1
0. 5
1 2/ 2 0 ( 6 0 %)
0. 0 0 3
0. 1 8 3
0. 8 1 4

C o h ort 5 will i ncl u de a mi xt ure of t u m or t y pes, a n y  brai n disease ( ie n o b rai n disease, 
s ym pt o matic or as y m pt o matic brai n metastases) a n d wit h or wit h o ut pri or B R A F 
i n hi bit or t hera p y. Partici pa nts wit h t he f oll o wi n g t u m or t y pes are li kel y t o e nr oll t o 
t his c o h ort: N S C L C, gli o mas (l o w a n d hi g h gra de), c h ola n gi ocarci n o ma, a na plas tic 
t h yr oi d ca ncer, a n d pa pillar y t h yr oi d ca ncer. We pla n t o e nr oll a p pr o xi matel y  
4 0 partici pa nts i nt o t his c o h ort. T heref ore, we a ntici pate t hat f or a gi ve n t u m or t y pe 
t he sa m ple size will be at m ost n = 1 0. T he ta ble bel o w s h o ws t he p r o ba bilit y t hat t he
tr ue O R R is wit hi n a s pecific i nter val, gi ve n a n o bser ve d res p o nse. F or e xa m ple, 
ass u mi n g t he o bser ve d O R R is at 3 0 % ( 3/ 1 0) f or a gi ve n t u m or t y pe, ass u mi n g a 
n o n -i nf or mati ve pri or (ie, Jeffre y’s pri or), a sa m ple size of 1 0 e val ua ble partici pa nts
will y iel d 4 1. 7 % Ba yesia n p osteri or pr o ba bilit y  t o de m o nstrate t hat ‘ Tr ue O R R’ is 
bet wee n 3 0 % a n d 5 0 %. If we o bser ve a relati vely hi g h res p o nse rate of 6 0 % ( 6/ 1 0) 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 1 4
i n a n y gi ve n gr o u p, ass u mi n g a n o n -i nf or mati ve pri or (ie, Jeffre y’s pri or), a sa m ple 
size of 1 0 e val ua ble partici pa nts will y iel d 7 3. 5 % Ba yesia n p osteri or pr o ba bilit y t hat 
‘ Tr ue O R R’ is bet wee n 6 0 % a n d 1 0 0 %.
O bser ve d O R R
P( O R R) 0 - 3 0 %
P( O R R) 3 0 -5 0 %
P( O R R) 5 0 -1 0 0 %
1/ 1 0 ( 1 0 %)
0. 9 2 6
0. 0 7
0. 0 0 4
2/ 1 0 ( 2 0 %)
0. 7 4 5
0. 2 2 9
0. 0 2 6
3/ 1 0 ( 3 0 %)
0. 4 8 1
0. 4 1 7
0. 1 0 2
4/ 1 0 ( 4 0 %)
0. 2 3 8
0. 4 9 7
0. 2 6 5
5/ 1 0 ( 5 0 %)
0. 0 8 8
0. 4 1 2
0. 5
6/ 1 0 ( 6 0 %)
0. 0 2 3
0. 2 4 1
0. 7 3 5
9. 2. 3. O pti o n al P h ase 1 b D DI S u b S t u dy
Ass u mi n g t he i ntra -partici pa nt A U C varia bilit y  is a p pr o xi matel y 3 0 % f or mi daz ola m , base d 
o n a 2-si de d si g nifica nce le vel of 0. 0 5, a sa m ple size of at least 8 partici pa nts i n t he D DI  
St u d y E x pa nsi o n C o h ort will pr o vi de 9 0 % p o wer t o detect a p pr o xi matel y 1. 5 -f ol d or greater 
c ha n ge i n mi daz ola m A U C w he n mi daz ola m is c oa d mi nistere d wit h P F -0 7 2 8 4 8 9 0 (test 
c o n diti o n) as c o m pare d t o mi daz o la m a d mi nistere d al o ne bef ore t he first P F - 0 7 2 8 4 8 9 0 d ose 
(refere nce c o n diti o n). A p pr o xi matel y  1 0 partici pa nts will be e nr olle d. See A p pe n di x 1 5 .
9. 2. 4. O pti o n al F o o d -effect S u bst u d y
T he f o o d-effect s u bst u d y is desi g ne d t o q ualitati vel y  assess safety of a d mi nistrati o n of 
P F - 0 7 2 8 4 8 9 0 wit h f o o d at a rec o m me n de d d ose f or f urt her st u d y . A p pr o xi matel y 
6 - 8 partici pa nts will be e nr olle d.  See A p pe n di x 1 6 : A F o o d-effect S u b St u d y.
1.
F ull a nal ys is set.
T he f ull a nal ys is set i ncl u des all e nr olle d partici pa nts .
“E nr olle d ” mea ns a partici pa nt ’s, or t heir le gall y a ut h orize d re prese ntati ve’s, 
a gree me nt t o partici pate i n a cli nical st u d y  f oll o wi n g c o m pleti o n of t he i nf or me d 
c o nse nt /asse nt pr ocess. P ote ntial partici pa nts w h o are scree ne d f or t he p ur p ose of 
deter mi ni n g eli gi bilit y  f or t he st u d y, b ut d o n ot partici pate i n t he stu d y , are n ot 
c o nsi dere d e nr olle d, u nless ot her wise s pecifie d b y t he pr ot oc ol.
2.
Safet y  a nalys is set.
T he safet y a nal ys is set i ncl u des all e nr olle d partici pa nts w h o recei ve at least 1 d ose of 
st u d y i nter ve nti o n.  U nless ot her wise s pecifie d t he safety a nal ys is set will be t he 
defa ult a nal ys is set use d f or all a nalys es.
3.
Per pr ot oc ol a nal ys is set (e val ua ble f or M T D).
T he per pr ot oc ol a nal ys is set i ncl u des all e nr olle d partici pa nts w h o ha d at least 1 d ose 
of st u d y  treat me nt a n d eit her e x perie nce d D L T or d o n ot ha ve maj or treat me nt 
de viati o ns d uri n g t he D L T o bser vati o n peri o d .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 1 5
4.
mI T T P o p ulati o n .  
T he mI T T is t he a nal ys is p o p ulati o n t hat will f oll o w t he I T T pri nci ple a n d i ncl u de 
partici pa nts recei vi n g at least 1 d ose of st u d y i nter ve nti o n wit h baseli ne assess me nt 
a n d at least 1 p ost baseli ne assess me nt, disease pr o gressi o n, or deat h bef ore t he first 
t u m or assess me nt.  T he mIT T p o p ulati o n ma y  be use d f or i nteri m a nal ysis a n d 
c o nfere nce prese ntati o ns w he n t he st u d y is still o n g oi n g.
5.
P K a nal y sis sets.
T he P K para meter a nal ys is p o p ulati o n is defi ne d as all e nr olle d partici pa nts treate d 
w h o d o n ot ha ve pr ot oc ol de viati o ns i nfl ue nci n g P K assess me nt, a n d ha ve s ufficie nt 
i nf or mati o n t o esti mate at least 1 of t he P K para meters of i nterest.
T he P K c o nce ntrati o n p o p ulati o n is defi ne d as all e nr olle d p artici pa nts w h o are 
treate d a n d ha ve at least 1 a nalyt e c o nce ntrati o n.
6.
Res p o nse E val ua ble Set.
T he res p o nse e val ua ble p o p ulati o n will i ncl u de all partici pa nts w h o recei ve d at least 
1 d ose of st u d y  treat me nt a n d ha d baseli ne disease assess me nt a n d at least 1 p ost 
baseli ne disease assess me nt .
7.
P D/ Bi o mar ker a nal ys is set(s).
T he P D/ Bi o mar ker a nal ysis p o p ulati o n is defi ne d as all e nr olle d p artici pa nts wit h at 
least 1 of t he P D/ Bi o mar kers e val uate d at pre a n d/ or p ost d ose.
9. 3. St atistic al A n al yses
T he S A P will be de vel o pe d a n d fi nalize d bef ore a n y a nalys es are p erf or me d a n d will 
descri be t he a nal ys es a n d pr oce d ures f or acc o u nti n g f or missi n g, u n use d, a n d s p uri o us data. 
T his secti o n is a s u m mar y of t he pla n ne d statistical a nal y ses of t he pri mar y  a n d sec o n dar y 
e n d p oi nts.
9. 3. 1. Pri m ar y E n d p oi nt(s)
9. 3. 1. 1. P h ase 1 a : M a xi m u m T oler ate d D ose Deter mi n ati o n
Deter mi nati o n of M T D will be perf or me d usi n g Per- pr ot oc ol a nal y sis set (e val ua ble f or 
M T D) .  
T he d ose escalati o n i n t he P hase 1a of t he st u d y  will be g ui de d b y a Ba ye sia n a nalys is of 
D L T. T o xicit y  i n m o n ot hera p y is m o dele d usi n g a 2 para meter l o gistic re gressi o n f or t he 
pr o ba bilit y  of a partici pa nt e x perie nci n g a D L T at t he gi ve n d ose.  T o xicit y i n t he 
c o m bi nati o n -t hera py d ose escalati o n is m o dele d usi n g a 5 para meter l o gistic re gressi o n 
( w hic h i ncl u des a n i nteracti o n para meter) f or t he pr o ba bilit y of a partici pa nt e x perie nci n g a 
D L T at t he gi ve n c o m bi nati o n d ose. A mi xt ure of wea kl y i nf or mati ve pri or distri b uti o n 
base d o n n o ncli nical/e x pert o pi ni o n i nf or m ati o n a n d a n M A P pri or base d o n e nc orafe ni b
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 1 6
hist orical data will be use d t o defi ne t he pri or distri b uti o n f or t he P F ‑0 7 2 8 4 8 9 0 m o n ot hera p y 
d ose escalati o n . T he M A P pri or f or t he l o gistic m o del para meters f or t his st u d y  is t he 
c o n diti o nal distri b uti o n of t he para meters gi ve n t he hist orical data.
T he P F -0 7 2 8 4 8 9 0 t o xicit y  data c ollecte d i n t he m o n ot hera p y d ose escalati o n will be use d b y 
t he B L R M c o m bi nati o n t o g ui de t he P F - 0 7 2 8 4 8 9 0+ bi ni meti ni b d ose escalati o n.
After eac h c o h ort of partici pa nts, t he p osteri or distri b uti o n f or t he ris k of D L T f or ne w 
partici pa nts at differe nt d oses of i nterest f or P F ‑0 7 2 8 4 8 9 0 will be e val uate d, i n t he 
m o n o - a n d c o m bi nati o n t hera p y d ose escalati o ns se paratel y. T he p osteri or distri b uti o ns will 
be s u m marize d t o pr o vi de t he p oster i or pr o ba bilit y t hat t he ris k of D L T lies wit hi n t he 
f oll o wi n g i nter vals:
U n der -d osi n g:
[ 0, 0. 1 6]
Tar get d osi n g:
[ 0. 1 6, 0. 3 3]
O ver d osi n g:
[ 0. 3 3, 1]
D osi n g decisi o ns are g ui de d b y  t he E W O C pri nci pal. A d ose ma y  o nly be use d f or ne wl y 
e nr olle d partici pa nts if t he ris k of o ver d osi n g at t hat d ose is less t ha n 2 5 %.
Pri or distri b uti o ns:
M A P
pri or distri b uti o n base d o n hist orical e nc orafe ni b D L T i nf or mati o n will be c h ose n f or 
t he l o gistic para meters f or t he m o n ot hera py d ose escalati o n of P F ‑0 7 2 8 4 8 9 0 a n d the 
P F - 0 7 2 8 4 8 9 0 t o xicit y data c ollecte d i n t he m o n ot hera p y d ose escalati o n will be use d b y t he 
B L R M c o m bi nati o n t o g ui de t he P F - 0 7 2 8 4 8 9 0+ bi ni meti ni b d ose escalati o n , see 
S ecti o n 1 0. 9 , A p pe n di x 9 .
Starti n g d ose:
T he starti n g d ose f or t he m o n ot hera p y P F ‑0 7 2 8 4 8 9 0 is 5 0 m g Q D.  T his d ose satisfies t he 
E W O C criteri o n.  A f ull assess me nt of t he pri or ris k t o partici pa nts is gi ve n i n Secti o n 1 0. 9 ,
A p pe n di x 9 .
Criteria t o declare M T D : 
T he sp o ns or esti mates t hat t he ma xi m u m n u m ber of partici pa nts i n t he P hase 1a d ose 
escalati o n p orti o n of t he trial (f or m o n ot hera py a n d c o m bi nati o n wit h bi ni meti ni b) is 
3 5 partici pa nts. H o we ver, t he act ual n u m ber ma y  be m ore or less base d o n o bser ve d P K a n d 
safety. T he P hase 1a part of t he trial ca n declare a n M T D w he n t he f oll o wi n g criteria are 
met:

At least 6 partici pa nts ha ve bee n treate d at t he rec o m me n de d M T D/ rec o m me n de d 
d ose f or f urt her st u d y f or b ot h t he m o n o- a n d t he c o m bi nati o n t hera p y escalati o ns.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 1 7

T he d ose d f or P F ‑0 7 2 8 4 8 9 0 satisfies 1 of t he f oll o wi n g c o n diti o ns f or eac h t he 
m o n o - a n d t he c o m bi nati o n t hera p y escalati o n part :

T he pr o ba bilit y  of tar get t o xicit y at d ose d e xcee ds 5 0 %, 
ie, Pr( 0. 1 6 ≤п d < 0. 3 3) ≥5 0 %, or

A mi ni m u m of 1 5 partici pa nts ha ve bee n treate d i n P hase 1a.
9. 3. 1. 2. P h ase 1 b : O ver all Res p o nse a n d I ntr acr a ni al Res p o nse
T he Res p o nse E val ua ble Set will be use d f or all res p o nse relate d a nalys es. T he pri mar y  
e n d p oi nt of o verall res p o nse b y  R E CI S T versi o n 1. 1 a n d i ntracra nial res p o nse b y m R E CI S T 
versi o n 1. 1 ( R A N O f or H G G or L G G ) will be s u m marize d a n d liste d b y  e x pa nsi o n c o h ort 
a n d disease t y pe . 
9. 3. 2. Sec o n d ar y E n d p oi nt(s)
9. 3. 2. 1. Effic ac y A n al ysis
Res p o nse E va l ua ble Set will be use d f or all res p o nse relate d a nalys es i ncl u di n g o verall a n d 
i ntracra nial t u m or res p o nse, D oR, P F S, D F S (i ntracra nial) a n d T T R. T u m or res p o nse will be 
prese nte d i n t he f or m of partici pa nt data listi n gs t hat i ncl u de, b ut are n ot li mite d t o t u m or 
t ype, d ose o n Da y  1, t u m or res p o nse at eac h visit, a n d best o verall res p o nse. O S will be 
re p orte d o n t he F ull A nal ysis Set as well as o n t he mIT T.
F or P hase 1 a , t he f oll o wi n g sec o n dar y e n d p oi nts will be re p orte d f or efficac y: o verall 
res p o nse by R E CI S T versi o n 1. 1 a n d i ntracra nial res p o nse b y  mR E CI S T versi o n 1. 1 ( R A N O 
f or H G G or L G G ).
F or P hase 1 b , t he sec o n dar y efficac y e n d p oi nts of Disease C o ntr ol Rate ( o verall a n d 
i ntracra nial), P F S ( o verall a n d i ntracra nial), O S, D o R ( o vera ll a n d i ntracra nial) a n d T T R 
( o verall a n d i ntracra nial) will be s u m marize d (als o gra p hically w here a p pr o priate) a n d liste d 
b y  e x pa nsi o n c o h ort a n d disease ty pe. 
9. 3. 2. 2. Si n gle -D ose a n d Ste a d y -St ate P F - 0 7 2 8 4 8 9 0 a n d Bi ni meti ni b P h ar m ac o ki netic 
A n al ysis
Plas ma c o nce ntrati o ns of P F - 0 7 2 8 4 8 9 0 will be s u m marize d descri pti vel y  ( n, mea n, sta n dar d 
de viati o n, c oefficie nt of variati o n, me dia n, mi ni m u m, ma xi m u m, ge o metric mea n a n d its 
ass ociate d c oefficie nt of variati o n) b y d ose, c ycle, da y a n d n o mi nal ti me. T his 
s u m marizati on will als o be re p orte d f or P F-0 7 2 8 4 8 9 0 a d mi nistere d al o ne a n d c oa d mi nistere d 
wit h bi ni meti ni b . Plas ma c o nce ntrati o ns of bi ni meti ni b will be s u m marize d descri pti vel y 
( n, mea n, sta n dar d de viati o n, c oefficie nt of variati o n, me dia n, mi ni m u m, ma xi m u m, 
ge o metr ic mea n a n d its ass ociate d c oefficie nt of variati o n) b y d ose of P F-0 7 2 8 4 8 9 0, c y cle, 
da y  a n d n o mi nal ti me, a n d a gai n b y c ycle, da y a n d n o mi nal ti me. 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 1 8
I n di vi d ual partici pa nt plas ma c o nce ntrati o n-ti me data wit hi n a d ose i nter val after C ycle 1 
D a y 1 a n d C ycle 1 Da y  1 5 will be a nal yz e d usi n g n o nc o m part me ntal met h o ds t o deter mi ne 
si n gle- a n d m ulti ple- d ose P K para meters f or P F -0 7 2 8 4 8 9 0 (a n d bi ni meti ni b w he n 
c oa d mi nistere d) .  F or P hase 1a a n d P hase 1 b C o h ort 6 partici pa nts, s i n gle-d ose P K 
para meters t o be esti mat e d will i ncl u de t he plas ma C ma x , Tma x , a n d A U Clast, a n d if data 
per mit, A U C i nf, t½ , C L/ F, a n d Vz/ F. M ulti ple -d ose P K para meters t o be esti mate d will 
i ncl u de C ss,ma x , Tss,ma x , A U Css,, plas ma Css,mi n , C Lss/ F, a n d if data per mit, Vss/ F, t1/ 2, a n d Rac.
F or P hase 1 b C o h ort 1- 5 partici pa nts, s i n gle-d ose P K para meters t o be esti mate d will i ncl u de 
t he plas ma Cma x a n d T ma x . M ulti ple - d ose P K para meters t o be esti mate d will i ncl u de Css, ma x, 
T ma x , plas ma Css, mi n, a n d Rac. F or P F - 0 7 2 8 4 8 9 0, t he si n gle d ose a n d stea dy- state P K 
para meters will be s u m marize d descri pti vel y ( n, mea n, sta n dar d de viati o n, c oefficie nt of 
variati o n, me dia n, mi ni m u m, ma xi m u m, ge o metric mea n a n d its ass ociate d c oefficie nt of 
variati o n ) by d ose le vel, c ycle a n d da y. T his su m marizati o n will als o be re p orte d f or 
P F - 0 7 2 8 4 8 9 0 a d mi nistere d al o n e a n d c oa d mi nistere d wit h bi ni meti ni b . F or bi ni meti ni b t he 
si n gle d ose a n d stea dy- state P K para meters will be s u m marize d descri pti vel y ( n, mea n, 
sta n dar d de viati o n, c oefficie nt of variati o n, me dia n, mi ni m u m, ma xi m u m, ge o metric mea n 
a n d its ass ociate d c oefficie nt of variati o n) b y d ose of P F - 0 7 2 8 4 8 9 0, c ycle a n d da y, a n d a gai n 
b y  c ycle a n d da y.
F or P hase 1 a , P F -0 7 2 8 4 8 9 0 d ose n or malize d A U C i nf ( A UC at stea d y state), A U Clast a n d 
C ma x will be pl otte d a gai nst d ose ( usi n g a l o garit h mic scale) b y c ycle a n d da y.  T hese pl ots 
will i ncl u de i n di vi d ual p artici pa nt val ues a n d t he ge o metric mea ns f or eac h d ose. T he pl ots 
will als o be d o ne se paratel y  f or si n gle a ge nt P F -0 7 2 8 4 8 9 0 a n d P F -0 7 2 8 4 8 9 0 c oa d mi nistere d 
wit h bi ni meti ni b.
Uri ne dr u g c o nce ntrati o ns of P F - 0 7 2 8 4 8 9 0 (uri ne P K will be a nal y ze d d uri n g D DI s u bst u d y, 
see A p pe n di x 1 5 ) as well as uri ne v ol u me, a m o u nt i n t he uri ne, a n d re nal cleara nce will be 
s u m marize d b y descri pti ve statistics ( n, mea n, sta n dar d de viati o n, c oefficie nt of variati o n , 
me dia n, mi ni m u m, ma xi m u m, ge o metric mea n a n d its ass ociate d c oefficie nt of variati o n ).
9. 3. 2. 3. Si n gle -D ose Mi d az ol a m P h ar m ac o ki netic A n al ysis
F or P hase 1 b C o h ort 6, p las ma c o nce ntrati o ns of mi daz ola m will be s u m marize d 
descri pti vel y ( n, mea n, sta n dar d de viati o n, c oefficie nt of variati o n, me dia n, mi ni m u m, 
ma xi m u m, ge o metric mea n a n d its ass ociate d c oefficie nt of variati o n) b y  da y a n d n o mi nal 
ti me.
I n di vi d ual partici pa nt plas ma c o nce ntrati o n-ti me data f or mi daz ola m o n Da y - 7, C y cle 1 
D a y 1 a n d C ycle 1 Da y  1 5 will be a nal yz e d usi n g n o nc o m part me ntal met h o ds t o deter mi ne 
si n gle-d ose P K para meters. P K para meters t o be esti mate d will i ncl u de t he plas ma C ma x , 
T ma x , a n d A U Clast, a n d if data per mit, A U Ci nf, t½ , C L/ F, a n d Vz/ F. Mi daz ola m
P K para meters 
will be s u m marize d descri pti vel y  ( n, mea n, sta n dar d de viati o n, c oefficie nt of variati o n, 
me dia n, mi ni m u m, ma xi m u m, ge o metric mea n a n d its ass ociate d c oeffici e nt of variati o n ) by 
da y .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 1 9
If a p pr o priate, a mi xe d effects m o del will t he n be use d t o a nalyz e nat ural l o g-tra nsf or me d 
mi daz ola m A U C last.  T his m o del will ha ve a fi xe d effect ter m f or treat me nt, wit h partici pa nts
c o nsi dere d ra n d o m.  C o m p o u n d s y m metr y  will be ass u me d a n d esti mati o n will use R E M L.  
T he differe nce i n treat me nt mea ns will be deter mi ne d al o n g wit h t heir ass ociate d 9 0 % CI.  If 
a p pr o priate, mi daz ola m C ma x a n d A U C last will als o be a nal yz e d usi n g a mi xe d e ffects m o del 
wit h a fi xe d effect of treat me nt a n d partici pa nt as ra n d o m. T here will be n o s uc h statistical 
a nal ys es of ot her para meters (e g, T ma x , C L/ F, a n d t½ ).
9. 3. 2. 4. P h ar m ac o d y n a mic A n al yses 
P D a nal y sis descri be d i n Secti o n 8. 6 (ie,
 
 i n o pti o nal paire d t u m or bi o psies) will be s u m marize d b y  
descri pti ve statistics.
9. 3. 3. Terti ar y/ E x pl or at or y E n d p oi nt(s)
9. 3. 3. 1. P K -Q Tc R el ati o ns hi p 
Matc he d P K a n d E C G data fr o m P hase 1a m a y  be use d t o i n vesti gate a n y p ossi ble 
relati o ns hi p bet wee n P F -0 7 2 8 4 8 9 0 e x p os ure (as meas ure d b y P K assess me nts of 
P F - 0 7 2 8 4 8 9 0 plas ma c o nce ntrati o n) a n d Q T pr ol o n g ati o n. T o i n vesti gate t he p ossi ble 
relati o ns hi p bet wee n P F - 0 7 2 8 4 8 9 0 c o nce ntrati o n a n d c ha n ge fr o m baseli ne i n Q Tc F, 
hereafter de n ote d Δ Q Tc F, a li near mi xe d effect m o del will be use d t o q ua ntif y  t he 
relati o ns hi p bet wee n Δ Q Tc F a n d ti me- matc he d plas ma c o nce ntrati o ns of P F - 0 7 2 8 4 8 9 0. 
Ti me -matc he d P K a n d tri plicate E C G data will be use d i n t he a nal ys is. T he m o del will be of 
t he f or m:
Δ Q Tc F =a + b × Baseli ne Q Tc F + c × C p
w here C p is t he l o garit h m of ti me -matc he d plas ma c o nce ntrati o n of P F -0 7 2 8 4 8 9 0 , a is t he 
i nterce pt, b a n d c are t he sl o pe f or Baseli ne Q Tc F a n d C p, res pecti vel y. 9 0 % CI ar o u n d b 
a n d c will be deter mi ne d. C oa d mi nistrati o n of bi ni meti ni b will be teste d as a c o variate.
A d diti o nal m o del str uct ures ma y  be teste d as a p pr o priate. T he Δ Q Tc F at C ma x of t he R D E 
will be calc ulate d.
9. 3. 3. 2. C S F C o nce ntr ati o n
T he c o nce ntrati o n of P F - 0 7 2 8 4 8 9 0 i n C S F, as well as ti me-matc he d P K sa m ples, will be 
liste d f or i n di vi d ual s u bjects. As C S F sa m ples are o nl y  o btai ne d w he n t he y are nee de d as 
part of sta n dar d of care, t hese data ma y  o nly be o btai ne d f or a s mall n u m ber of patie nts. 
A d diti o nall y , t he ti me of t he C S F sa m ples relati ve t o dr u g a d mi nistrati o n will be 
i nc o nsiste nt. Gi ve n t he c halle n ges, t hese data will n ot be s u m marize d.
9. 3. 4. Ot her S afet y A n al yses
All safet y a nal ys es will be perf or me d o n t he safet y p o p ulati o n. S u m maries a n d a nal ys es of 
safety para meters will i ncl u de all partici pa nts i n t he safet y a nal ys is set.
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 2 0
A Es , E C Gs, B P, H R, E C H O a n d safet y la b orat or y data will be re vie we d a n d s u m marize d o n 
a n o n g oi n g basis d uri n g t he st u d y  t o e val uate t he safety of partici pa nts. A n y  cli nical 
la b orat or y, E C G, B P, a n d H R a b n or malities of p ote ntial cli nical c o ncer n will be descri be d. 
Safet y  data will be prese nte d i n ta b ular a n d/ or gra p hical f or mat a n d s u m marize d 
descri pti vel y, w here a p pr o priate.
Me dical hist or y  a n d p h ysical e xa mi nati o n a n d ne ur ol o gical e xa mi nati o n i nf or mati o n, as 
a p plica ble, c ollecte d d uri n g t he c o urse of t he st u d y  will be c o nsidere d s o urce data a n d will 
n ot be re q uire d t o be re p orte d, u nless ot her wise n ote d.  H o we ver, a n y u nt o war d fi n di n gs 
i de ntifie d o n p h ysical a n d/ or ne ur ol o gical e xa mi nati o n s c o n d ucte d d uri n g t he acti ve 
c ollecti o n peri o d will be ca pt ure d as A Es , if t h ose fi n din gs meet t he defi niti o n of a n A E . 
Data c ollecte d at scree ni n g t hat are use d f or i ncl usi o n/e xcl usi o n criteria, s uc h as la b orat or y  
data, E C Gs , a n d vital si g ns , will be c o nsi dere d s o urce data, a n d will n ot be re q uire d t o be 
re p orte d, u nless ot her wise n ote d.  De m o gra p hic data c ollecte d at scree ni n g will be re p orte d.
9. 3. 4. 1. Electr oc ar di o gr a m A n al yses
C ha n ges fr o m baseli ne f or t he E C G para meters Q T i nter val, heart rate, Q Tc i nter val, P R 
i nter val, a n d Q R S c o m ple x will be s u m marize d b y treat me n t a n d ti me.
T he n u m ber ( %) of partici pa nt s wit h ma xi m u m p ost d ose Q TcF val ues a n d m F a xi m u m 
i ncreases fr o m baseli ne i n t he f oll o wi n g cate g ories will be ta b ulate d b y treat me nt: 
S afet y Q Tc F Assess me nt
De gree of Pr ol o n g ati o n
Mil d
( msec)
M o der ate
( msec)
Se vere ( m sec)
A bs ol ute val ue
> 4 5 0 -4 8 0
> 4 8 0 -5 0 0
> 5 0 0
I ncrease fr o m b aseli ne
3 0 -6 0
> 6 0
T he mea n of t he re plicate meas ure me nts will be use d t o re prese nt a si n gle o bser vati o n at t hat 
ti me p oi nt.  If a ny of t he 3 i n di vi d ual E C G traci n gs has a Q Tc val ue > 5 0 0 ms ec, b ut t he mea n 
of t he tri plicates is n ot > 5 0 0 ms ec, t he data fr o m t he partici pa nt ’s i n di vi d ual traci n g will be 
descri be d i n a safet y secti o n of t he C S R i n or der t o place t he > 5 0 0- ms ec val ue i n a p pr o priate 
cli nical c o nte xt.  H o we ver, val ues fr o m i n d i vi d ual traci n gs wit hi n tri plicate meas ure me nts 
t hat are > 5 0 0 ms ec will n ot be i ncl u de d i n t he cate g orical a nal ys is u nless t he a vera ge fr o m 
t he tri plicate meas ure me nts is als o > 5 0 0 ms ec.  C ha n ges fr o m baseli ne will be defi ne d as t he 
c ha n ge bet wee n t he p ost d ose Q Tc val ue a n d t he a vera ge of t he ti me- matc he d baseli ne 
tri plicate val ues o n Da y -1, or t he a vera ge of t he pre d ose tri plicate val ues o n Da y 1.  
T he a nal ys is of E C G res ults will be base d o n partici pa nts i n t he safety a nal ysis set wit h 
baseli ne (ie, pre -d ose o n C y cle 1 Da y 1) a n d o n-treat me nt E C G data.
E C G meas ure me nts (a n a vera ge of t he tri plicate meas ure me nts) will be use d f or t he 
statistical a nal ysis a n d all data prese ntati o ns.  A n y data o btai ne d fr o m E C Gs re peate d f or 
safety reas o ns after t he n o mi nal ti me -p oi nts will n ot be a vera ge d al o n g wit h t he prece di n g 
tri plicates.  I nter val meas ure me nts fr o m re peate d E C Gs will be i ncl u de d i n t he o utlier 
a nal ys is (cate g orical a nal ysis) as i n di vi d ual val ues o btai ne d at u nsc he d ule d ti me p oi nts.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 2 1
Q T i nter vals will be c orrecte d f or H R ( Q Tc) usi n g sta n dar d c orrecti o n fact ors (ie, Fri dericia’s 
( defa ult c orrecti o n), Bazett’s, a n d p ossi bl y a st u d y-s pecific fact or, as a p pr o priate).  Data will 
be s u m marize d a n d liste d f or Q T, H R, R R, P R, Q R S, Q Tc F (a n d ot her c orrecti o n fact ors, 
e g, Q Tc B as a p pr o priate), a n d b y  st u d y treat me nt (ie, m o n ot hera p y vers us c o m bi nati o n 
t hera py) a n d d ose.  I n di vi d ual Q T (all e val uate d c orrecti o ns) i nter vals will be liste d b y  st u d y 
treat me nt, ti me a n d d ose.  T he m ost a p pr o priate c orrecti o n fact or will be selecte d a n d use d 
f or t he f oll o wi n g a nalys es of ce ntral te n de nc y a n d o utliers a n d use d f or t he st u d y 
c o ncl usi o ns.  Descri pti ve statistics ( n, mea n, me dia n, sta n dar d de viati o n, mi ni m u m, a n d 
ma xi m u m) will be use d t o s u m marize t he a bs ol ute c orrecte d Q T i nter val a n d c ha n ges fr o m 
baseli ne i n c orrecte d Q T after treat me nt b y st u d y treat me nt, d ose a n d ti me p oi nt.  Details of 
a d diti o nal a nal ys is (if a n y) will be s pecifie d i n S A P.  
9. 3. 4. 2. A d verse E ve nts
A Es will be gra de d b y t he i n vesti gat or acc or di n g t o t he C T C A E versi o n 5. 0 a n d c o de d usi n g 
Me d D R A.  A d verse
e ve nt data will be re p orte d i n ta bles a n d listi n gs.  S u m maries of A E b y  
ma p pe d ter ms, a p pr o priate t hesa ur us le vel, t o xicit y  gra de, a n d seri o us ness a n d relati o ns hi p t o 
st u d y treat me nt will be prese nte d, as well as s u m maries of A E s lea di n g t o deat h a n d 
pre mat ure wit h dra wal fr o m st u d y  treat me nt. T he n u m ber a n d perce nta ge of p artici pa nts w h o 
e x perie nce d a n y A E, S A E, treat me nt relate d A E, a n d treat me nt relate d S A E will be 
s u m marize d acc or di n g t o w orst t o xicit y gra des.  T he s u m maries will prese nt A Es b ot h o n t he 
e ntire st u d y peri o d a n d b y c ycle ( C ycl e 1 a n d C yc les be yo n d 1). Li sti n gs of D L Ts a n d 
deat hs will be pr o vi de d.
9. 3. 4. 3. L a b or at or y Test A b n or m alities
T he n u m ber a n d perce nta ge of p artici pa nts w h o e x perie nce d la b orat or y  test a b n or malities 
will be s u m marize d acc or di n g t o w orst t o xicit y  gra de o bser ve d f or eac h la b orat or y assa y.  
T he a nal ys es will s u m marize la b orat or y tests b ot h o n t he e ntire st u d y peri o d a n d b y c ycle 
( C ycle 1 a n d C ycles b e y o n d 1).   F or la b orat or y  tests wit h o ut C T C A E gra de defi niti o ns, 
res ults will be cate g orize d as n or mal, a b n or mal, or n ot d o ne. 
9. 3. 5. Ot her A n al yse (s)
P ha r mac o ge n o mic or bi o mar ker data fr o m Ba n ke d Bi os peci me ns ma y be c ollecte d d uri n g or 
after t he trial a n d retai ne d f or f ut ure a nal ys es; t he res ults of s uc h a nal y ses are n ot pla n ne d t o 
be i ncl u de d i n t he C S R.
A n al ysis of Bi o m ar ker E n d p oi nts
F or
 a n d bi o ps y sa m ples, s u m mar y statistics (e g, t he mea n a n d sta n dar d de viati o n, 
me dia n, a n d mi ni m u m/ ma xi m u m le vels of c o nti n u o us, a n d fre q ue ncies a n d perce nta ges of 
cate g orical bi o mar ker meas ures) will be deter mi ne d at baseli ne a n d p ost -treat me nt.  F urt her 
a nal ys is will be s pecifie d i n S A P. 
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 2 2
Cli nicall y  rele va nt a n d i nter preta ble bi o mar ker assess me nts ge nerate d f or Pri mar y a n d 
Sec o n dar y  o bjecti ves will be s u m marize d i n t he C S R. Ot her bi o mar ker data mi g ht be 
s u m marize d i n a se parate tec h nical d oc u me nt.
P o p ul ati o n P h ar m ac o ki netic A n al ysis or P K/ P D M o deli n g 
P K a n d P D data fr o m t his st u d y  ma y be a nalyz e d usi n g c o m part me ntal m o deli n g a p pr oac hes 
a n d ma y als o be p o ole d wit h data fr o m ot her st u dies t o i n vesti gate a n y ass ociati o n bet wee n 
P F - 0 7 2 8 4 89 0 e x p os ure a n d bi o mar kers or si g nifica nt safet y a n d/ or efficac y e n d p oi nts.  T he 
res ults of t hese a nal yses, if perf or me d, ma y be re p orte d se parately.
9. 4. I nteri m A n al yses
N o f or mal i nteri m a nal ys is will be c o n d ucte d f or t his st u d y.
As t his is a n o pe n-la bel st u d y,
t he s p o ns or ma y c o n d uct u n bli n de d re vie ws of t he data d uri n g t he c o urse of t he st u d y f or t he 
p ur p ose of safet y assess me nt, facilitati n g d ose -escalati o n decisi o ns, facili tati n g P K/ P D 
m o deli n g, a n d/ or s u p p orti n g cli nical de vel o p me nt.
9. 5. D at a M o nit ori n g C o m mittee or Ot her I n de pe n de nt O versi g ht C o m mittee
T his st u d y  will n ot use a D M C.
P h ase 1 a:
I n t he p hase 1a d ose escalati o n, me m bers will c o n ve ne a D L R M f or d ose escalati o n 
decisi o ns.  T he act ual d ose selecte d at eac h d ose decisi o n ma y be at or bel o w t he B L R M 
rec o m me n de d d ose as deter mi ne d b y t he me m bers of t he D L R M after c o nsi deri n g all
a vaila ble safet y, P K a n d P D i nf or mati o n.  T he me m bers hi p of t he D L R M w ill be c o m p ose d, 
at a mi ni m u m, of all st u d y i n vesti gat or(s) or me dicall y  q ualifie d desi g nee wit h patie nts 
partici pati n g i n t he d ose le vel u n der re vie w a n d Pfizer Gl o bal Cli nical Lea d, Pfizer St u d y 
Cli nicia n, a n d Pfizer St u d y  Ma na ger. If a re prese ntati ve of a n i n di vi d ual site(s) d oes n ot 
partici pate i n t he D L R M, t heir i n p ut ma y  be o btai ne d i n writi n g after war d. T he me m bers hi p 
m ust reac h c o nse ns us (eit her at t he meeti n g or t hr o u g h writte n c o m m u nicati o n) o n t he d ose 
escalati o n decisi o n. A d diti o nal me m bers ma y  be a d de d as nee de d (e g, Cli nical 
P har mac ol o gist Lea d, Tra nslati o nal O nc ol o g y , Safet y Ris k Lea d or desi g nee a n d Pfizer 
Bi ostatistic re prese ntati ve).
All a vaila ble st u d y  data i ncl u di n g de m o gra p hics, me dical hist or y, c o nc o mita nt me dicati o ns, 
A Es, E C Gs, vital si g ns, la b orat or y  res ults, a n d e mer gi n g P K or P D data will be re vie we d.  
Data t o be re vie we d m a y n ot be verifie d .
P h ase 1 b:
I n t he P hase 1 b d ose e x pa nsi o n, t he st u d y  will use a safet y re vie w c o m mittee ( S R C) 
c o m prise d of i nter nal a n d e xter nal me m bers t o assess safet y as well as efficac y  of d ose 
e x pa nsi o n c o h orts.  T he S R C will be res p o nsi ble f or o n g oi n g m o nit ori n g of t he safet y of 
partici pa nts a n d will meet re g ularl y t o assess t he t otalit y  of t he safety i nf or mati o n i n t he 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 2 3
de vel o p me nt pr o gra m. T he S R C will als o be res p o nsi ble f or pres pecifie d a n d a d h oc 
assess me nts of safet y a n d f utilit y of eac h c o h ort, a nalys is of i nc o mi n g e x pe dite d safety 
re p orts, de vel o p me nt of c u m ulati ve s u m maries of all a d verse e ve nts, a n d ma ki n g 
rec o m me n dati o ns t o t he s p o ns or re gar di n g pr ot oc ol m o dificati o ns.  T he rec o m me n dati o ns 
ma de b y t he S R C t o alter t he c o n d uct of t he st u d y will be f or war de d t o t he a p pr o priate Pfizer 
pers o n nel f or fi nal decisi o n.  Pfizer will f or war d s uc h decisi o ns, w hic h ma y i ncl u de 
s u m maries of a g gre gate a nalys es of safet y data, t o re g ulat or y a ut h orities, as a p pr o priate .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 2 4
1 0. S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L C O N SI D E R A TI O N S
1 0. 1. A p pe n di x 1: Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns
1 0. 1. 1. Re g ul at or y a n d Et hic al C o nsi der ati o ns
T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g:

C o nse ns us et h ical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d CI O M S I nter nati o nal Et hical G ui deli nes ;

A p plica ble I C H G C P g ui deli nes ;

A p plica ble la ws a n d re g ulati o ns , i ncl u di n g a p plica ble pri vac y la ws.
T he pr ot oc ol, pr ot oc o l a me n d me nts, IC D, S R S D(s) , a n d ot her rele va nt d oc u me nts 
(e g, a d vertise me nts) m ust be re vie we d a n d a p pr o ve d b y  t he s p o ns or a n d s u b mitte d t o a n 
I RB/ E C b y  t he i n vesti gat or a n d re vie we d a n d a p pr o ve d b y t he I R B/ E C bef ore t he st u d y is 
i nitiate d.
A n y  a me n d me nts t o t he pr ot oc ol will re q uire I R B/ E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n ges necessar y  t o eli mi nate a n i m me diate 
hazar d t o st u d y  partici pa nts.
T he i n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:

Pr o vi di n g w ritte n s u m maries of t he stat us of t he st u d y t o t he I R B/ E C a n n uall y or 
m ore fre q ue ntl y  i n acc or da nce wit h t he re q uire me nts, p olicies, a n d pr oce d ures 
esta blis he d b y t he I R B/ E C.

N otif y i n g t he I R B/ E C of S A Es or ot her si g nifica nt safety fi n di n gs as re q uire d b y 
I RB/ E C pr oce d ures .

Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at t he site a n d a d here nce t o 
re q uire me nts of 2 1 C F R, I C H g ui deli nes, t he I RB/ E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 
f or cli nical st u dies (if a p plica ble), a n d all ot her a p plica ble l ocal re g ulati o ns.
1 0. 1. 1. 1. Re p orti n g of S afet y Iss ues a n d Seri o us Bre ac hes of t he Pr ot oc ol or I C H G C P

I n t he e ve nt of a ny pr o hi biti o n or restricti o n i m p ose d (ie, cli nical h ol d) b y a n 
a p plica ble re g ulat or y a ut h orit y i n a ny area of t he w orl d, or if t he i n vesti gat or is a ware 
of a n y ne w i nf or mati o n t hat mi g ht i nfl ue nce t he e val uati o n of t he be nefits a n d ris ks of 
t he st u d y i nter ve nti o n, Pfizer s h o ul d be i nf or me d i m me diatel y.  

I n a d diti o n, t he i n vesti gat or will i nf or m Pfizer i m me diatel y of a n y ur ge nt safety 
meas ures ta ke n b y t he i n vesti gat or t o pr otect t he st u d y  partici pa nt s a gai nst a n y 
i m me diate hazar d, a n d of a n y seri o us breac hes of t his pr ot oc ol or of I C H G C P t hat 
t he i n vesti gat or bec o mes a ware of.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 2 5
1 0. 1. 2. Fi n a nci al Discl os ure
I n vesti gat ors a n d s u bi n vesti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mati o n as re q ueste d t o all o w t he s p o ns or to s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y  a ut h orities. I nvesti gat ors 
are res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y 
a n d f or 1 ye ar after co m pleti o n of t he st u d y .
1 0. 1. 3. I nf or me d C o nse nt/ Asse nt Pr ocess
T he i n vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t he 
partici pa nt or his/ her le gall y  a ut h orize d re prese ntati ve a n d a ns wer all q uesti o ns re gar di n g t he 
st u d y.  T he parti ci pa nt or his/ her le gall y a ut h orize d re prese ntati ve s h o ul d be gi ve n s ufficie nt 
ti me a n d o p p ort u nit y t o as k q uesti o ns a n d t o deci de w het her or n ot t o partici pate i n t he trial.
Partici pa nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y . Partici pa nts or t heir 
le gall y a ut h orize d re prese ntati ve will be re q uire d t o si g n a state me nt of i nf or me d 
c o nse nt /asse nt t hat meets t he re q uire me nts of 2 1 C F R 5 0, l ocal re g ulati o ns, I C H g ui deli nes, 
HI P A A re q uire me nts, w here a p plica ble, a n d t he I R B/ E C or stu d y  ce nter.
T he i n vesti gat or m ust e ns ure t hat eac h st u d y  partici pa nt or his or her le gall y  a ut h orize d
re prese ntati ve is f ull y i nf or me d a b o ut t he nat ure a n d o bjecti ves of t he st u d y, t he s hari n g of 
data relate d t o t he st u d y , a n d p ossi ble ris ks ass ociate d wit h partici pati o n, i ncl u di n g t he ris ks 
ass ociate d wit h t he pr ocessi n g of t he partici pa nt ’s pers o nal data. 
T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d data will be use d b y t he 
s p o ns or i n acc or da nce wit h l ocal data pr otecti o n la w. T h e le vel of discl os ure m ust als o be 
e x plai ne d t o t he partici pa nt or his or her le gall y a ut h orize d re prese ntati ve .
T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y  be e xa mi ne d b y Cli nical 
Q ualit y  Ass ura nce a u dit ors or ot her a ut h orize d pers o nnel a p p oi nte d b y  t he s p o ns or, b y 
a p pr o priate I RB/ E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities.
T he i n vesti gat or f urt her m ust e ns ure t hat eac h st u d y  partici pa nt or his or her le gall y 
a ut h orize d re prese ntati ve is f ull y i nf or me d a b o ut his or her ri g ht t o access a n d c orrect his or 
her pers o nal data a n d t o wit h dra w c o nse nt f or t he pr ocessi n g of his or her pers o nal data.
T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt /asse nt was 
o btai ne d bef ore t he partici pa nt was e nr olle d i n t he st u d y  a n d t he date t he writte n 
c o nse nt /asse nt was o btai ne d. T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust 
als o si g n t he I C D.
Partici pa nts m ust be rec o nse nte d t o t he m ost c urre nt versi o n of t he I C D (s) d uri n g t heir 
partici pati o n i n t he st u d y .
A c o p y of t he I C D(s) m ust be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gall y 
a ut h orize d re prese ntati ve.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 2 6
A partici pa nt w h o is rescree ne d is n ot re q uire d t o si g n a n ot her I C D if t he rescree ni n g occ urs 
wit hi n 2 8 da y s fr o m t he pre vi o us IC D si g nat ure date.
U nless pr o hi bite d b y  l ocal re q uire me nts or I R B/ E C decisi o n, the I C D will c o ntai n a se parate 
secti o n t hat a d dresses t he use of sa m ples f or o pti o nal a d diti o nal researc h.  T he o pti o nal 
a d diti o nal researc h d oes n ot re q uire t he c ollecti o n of a n y f urt her sa m ples.   T he i n vesti gat or 
or a ut h orize d desi g nee will e x plai n t o eac h partici pa nt t he o bjecti ves of t he a d diti o nal 
researc h. Partici pa nts will be t ol d t hat t he y  are free t o ref use t o partici pate a n d ma y 
wit h dra w t heir c o nse nt at a n y  ti me a n d f or a n y reas o n d uri n g t he st ora ge peri o d. A se parate 
si g nat ure will be re q uire d t o d oc u me nt a partici pa nt’s a gree me nt t o all o w s peci me ns t o be 
use d f or a d diti o nal researc h.  Partici pa nts w h o decli ne t o partici pate i n t his o pti o nal 
a d diti o nal researc h w ill not p r o vi de t his se parate si g nat ure.
A d olesce nt P artici p a nts:
T he i n vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t he 
partici pa nt a n d his/ her pare nt (s)/le gal g uar dia n a n d a ns wer all q uesti o ns re gar di n g t he st u d y. 
T he partici pa nt a n d his/ her pare nt(s)/le gal g uar dia n s h o ul d be gi ve n s ufficie nt ti me a n d 
o p p ort u nit y  t o as k q uesti o ns a n d t o deci de w het her or n ot t o partici pate i n t he trial. 
W he n c o nse nt is o btai ne d fr o m a partici pa nt’s pare nt(s)/le gal g uar dia n, t he par tici pa nt’s 
asse nt (affir mati ve a gree me nt) m ust be s u bse q ue ntl y  o btai ne d w he n t he partici pa nt has t he 
ca pacit y t o pr o vi de asse nt, as deter mi ne d b y t he I R B/ E C. If t he i n vesti gat or deter mi nes t hat 
a partici pa nt’s decisi o nal ca pacit y  is s o li mite d he/s he ca n not reas o na bl y be c o ns ulte d, t he n, 
as per mitte d b y t he I R B/ E C a n d c o nsiste nt wit h l ocal re g ulat or y a n d le gal re q uire me nts, t he 
partici pa nt’s asse nt ma y  be wai ve d wit h s o urce d oc u me ntati o n of t he reas o n asse nt was n ot 
o btai ne d. If t he st u dy partici pa nt d oes n ot pr o vi de his or her o w n asse nt, t he s o urce 
d oc u me nts m ust rec or d w h y  t he partici pa nt di d n ot pr o vi de asse nt (f or e xa m ple, mi n or c hil d), 
h o w t he i n vesti gat or deter mi ne d t hat t he pers o n si g ni n g t he c o nse nt was t he partici pa nt’s 
pare nt(s)/le gal g uar dia n, t he c o nse nt si g ner’s relati o ns hi p t o t he st u d y partici pa nt, a n d t hat 
t he partici pa nt’s asse nt was o btai ne d or wai ve d. If asse nt is o btai ne d ver ball y, it m ust be 
d oc u me nte d i n t he s o urce d oc u me nts. 
If st u d y partici pa nts are mi n ors w h o reac h t he a ge of majorit y d uri n g t he st u d y, as rec o g nize d 
u n der l ocal la w, t he y  m ust be rec o nse nte d as a d ults t o re mai n i n t he st u d y. If t he e nr oll me nt 
of e ma nci pate d mi n ors is per mitte d b y  t he I RB/ E C a n d l ocal la w, t he y  m ust pr o vi de 
d oc u me ntati o n of le gal stat us t o gi ve c o n se nt wit h o ut t he per missi o n of a le gally a ut h orize d 
re prese ntati ve. 
Partici pa nts a n d t heir pare nt(s)/le gal g uar dia n m ust be i nf or me d t hat t heir partici pati o n is 
v ol u ntar y . Partici pa nt’s pare nt(s)/le gal g uar dia n will be re q uire d t o si g n a state me nt of 
i nfor me d c o nse nt t hat meets t he re q uire me nts of 2 1 C F R 5 0, l ocal re g ulati o ns, I C H 
g ui deli nes, HI P A A re q uire me nts, w here a p plica ble, a n d t he I R B/ E C or st u d y  ce nter. 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 2 7
T he i n vesti gat or m ust e ns ure t hat eac h st u d y partici pa nt’s pare nt(s)/le gal g uar dia n a n d t he 
stu d y  partici pa nt as a p plica ble is f ully i nf or me d a b o ut t he nat ure a n d o bjecti ves of t he st u d y, 
t he s hari n g of data relate d t o t he st u d y, a n d p ossi ble ris ks ass ociate d wit h partici pati o n, 
i ncl u di n g t he ris ks ass ociate d wit h t he pr ocessi n g of t he partici pa nt’s pers o nal data.  
T he partici pa nt’s pare nt(s)/le gal g uar dia n m ust be i nf or me d t hat t he partici pa nt’s pers o nal 
st u d y-relate d data will be use d b y t he s p o ns or i n acc or da nce wit h l ocal data pr otecti o n la w. 
T he le vel of discl os ure m ust als o be e x plai ne d t o t he partici pa nt’s pare nt(s)/le gal g uar dia n. 
T he partici pa nt’s pare nt(s)/ le gal g uar dia n m ust be i nf or me d t hat t he partici pa nt’s me dical 
rec or ds ma y be e xa mi ne d b y Cli nical Q uality Ass ura nce a u dit ors or ot her a ut h orize d 
pers o n nel a p p oi nte d b y t he s p o ns or, b y a p pr o priate I R B/ E C me m bers, a n d b y  i ns pect ors 
fr o m re g ulat or y a ut h orities. 
T he i n vesti gat or f urt her m ust e ns ure t hat eac h st u d y  partici pa nt’s pare nt(s)/le gal g uar dia n is 
f ull y i nf or me d a b o ut his or her ri g ht t o access a n d c orrect his or her c hil d’s pers o nal data a n d 
t o wit h dra w c o nse nt f or t he pr ocessi n g of his or her c hil d’s pers o nal data kee pi n g i n mi n d t he 
pri vac y  ri g hts t hat ma y restrict access of ol der a d olesce nts me dical rec or ds b y t heir 
pare nt(s)/le gal g uar dia n i n certai n re gi o ns. 
T he s o urce d oc u me ntati o n m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt a n d as 
a p plica ble, asse nt, was o btai ne d bef ore t he partici pa nt was e nr olle d i n t he st u d y  a n d t he date 
t he writte n c o nse nt/asse nt was o btai ne d. T he a ut h orize d pers o n o btai ni n g t he i nf or me d 
c o nse nt m ust als o si g n t he IC D. 
Pare nt(s)/le gal g uar dia n a n d t he partici pa nt m u st be rec o nse nte d t o t he m ost c urre nt versi o n 
of t he I C D(s)/asse nt d uri n g t heir partici pati o n i n t he st u d y . 
A c o p y of t he I C D(s) a n d asse nt, if writte n, m ust be pr o vi de d t o t he pare nt(s)/le gal g uar dia n 
a n d t he partici pa nt.
1 0. 1. 4. D at a Pr otecti o n
All parties will c o m pl y wit h all a p plica ble la ws, i ncl u di n g la ws re gar di n g t he i m ple me ntati o n 
of or ga nizati o nal a n d tec h nical meas ures t o e ns ure pr otecti o n of partici pa nt data.
Partici pa nts’ pers o nal data will be st ore d at t he st u d y  site i n e ncr ypte d electr o nic a n d/ or pa p er 
f or m a n d will be pass w or d pr otecte d or sec ure d i n a l oc ke d r o o m t o e ns ure t hat o nl y 
a ut h orize d st u d y staff ha ve access.  T he st u d y site will i m ple me nt a p pr o priate tec h nical a n d 
or ga nizati o nal meas ures t o e ns ure t hat t he pers o nal data ca n be rec o vere d i n t he e ve nt of 
disaster.  I n t he e ve nt of a p ote ntial pers o nal data breac h, t he st u d y  site will be res p o nsi ble 
f or deter mi ni n g w het her a pers o nal data breac h has i n fact occ urre d a n d, if s o, pr o vi di n g 
breac h n otificati o ns as re q uire d b y  la w.
T o pr otect t he ri g hts a n d free d o ms of partici pa nts wit h re gar d t o t he pr ocessi n g of pers o nal 
data, partici pa nts will be assi g ne d a si n gle, partici pa nt -s pecific n u merical c o de. A n y 
partici pa nt rec or ds or data sets t hat are tra nsferre d t o t he s p o ns or will c o ntai n t he n u merical 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 2 8
c o de; partici pa nt na mes will n ot be tra nsferre d. All ot her i de ntifia ble data tra nsferre d t o t he 
s p o ns or will be i de ntifie d b y t his si n gle, partici pa nt -s pecific c o de. T he st u d y  site will 
mai ntai n a c o nfi de ntial list of partici pa nt s w h o partici pate d i n t he st u d y, li n ki n g eac h 
partici pa nt ’s n u merical c o de t o his or her act ual i de ntit y a n d me dical rec or d i de ntificati o n . I n 
case of data tra nsfer, t he s p o ns or will pr otect t he c o nfi de ntialit y  of partici pa nt s’ pers o nal data 
c o nsiste nt wit h t he cli nical st u d y agree me nt a n d a p plica ble pri vac y  la ws.
1 0. 1. 5. Disse mi n ati o n of Cli nic al St u d y D at a
Pfizer f ulfills its c o m mit me nt t o p u blicl y  discl ose cli nical st u d y res ults t hr o u g h p osti n g t he 
res ults of st u dies o n w w w.cli nicaltrials. g o v ( Cli nical Trials. g o v), t he E u dra C T, a n d/ or 
w w w. pfizer .c o m, a n d ot her p u blic re gistries i n acc or da nce wit h a p plica ble l ocal 
la ws/re g ulati o ns.  I n a d diti o n, Pfizer re p orts st u d y res ults o utsi de of t he re q uire me nts of l ocal 
la ws/re g ulati o ns p urs ua nt t o its S O Ps.
I n all cases, st u dy res ults are re p orte d by Pfizer i n a n o bjecti ve, acc urate, bala nce d, a n d 
c o m plete ma n ner a n d are re p orte d re gar dless of t he o utc o me of t he st u d y or t he c o u ntr y i n 
w hic h t he st u d y  was c o n d ucte d.
w w w.cli nicaltrials . g o v
Pfizer p osts cli nical trial res ults o n w w w.cli nicalt rials. g o v f or Pfizer-s p o ns ore d i nter ve nti o nal 
st u dies (c o n d ucte d i n partici pa nt s) t hat e val uate t he safety a n d/ or efficac y of a pr o d uct, 
re gar dless of t he ge o gra p hical l ocati o n i n w hic h t he st u d y is c o n d ucte d.  T hese r es ults are 
s u b mitte d f or p osti n g i n acc or da nce wit h t he f or mat a n d ti meli nes set f ort h b y  U S la w.
E u dra C T
Pfizer p osts cli nical trial res ults o n E u dra C T f or Pfizer -s p o ns ore d i nter ve nti o nal st u dies i n 
acc or da nce wit h t he f or mat a n d ti meli nes set f ort h b y  E U re q uire me nts.  
w w w. pfizer .c o m
Pfizer p osts p u blic discl os ure s y n o pses ( C S R s y n o pses i n w hic h a n y data t hat c o ul d be use d 
t o i de ntif y i n di vi d ual partici pa nt s ha ve bee n re m o ve d) o n w w w. pfizer .c o m f or 
Pfizer -s p o ns ore d i nter ve nti o nal st u dies at t he sa me ti me t he c orres p o n di n g st u d y res ults are
p oste d t o w w w.cli nicaltrials . g o v.
D oc u me nts wit hi n mar keti n g a ut h orizati o n pac ka ges/s u b missi o ns
Pfizer c o m plies wit h t he E ur o pea n U ni o n P olic y  0 0 7 0, t he pr oacti ve p u blicati o n of cli nical 
data t o t he E M A we bsite.  Cli nical data, u n der P hase 1 of t his p olic y , i ncl u des cli nical 
o ver vie ws, cli nical s u m maries, C S Rs, a n d a p pe n dices c o ntai ni n g t he pr ot oc ol a n d pr ot oc ol 
a me n d me nts, sa m ple C R Fs, a n d statistical met h o ds.  Cli nical data, u n der P hase 2 of t his 
p olic y , i ncl u des t he p u blis hi n g of i n di vi d ual partici pa nt data.  P olic y 0 0 7 0 a p plies t o ne w 
mar keti n g a ut h orizati o n a p plicati o ns s u b mitte d via t he ce ntralize d pr oce d ure si nce 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 2 9
0 1 Ja n uar y 2 0 1 5 a n d a p plicati o ns f or li ne e xte nsi o ns a n d f or ne w i n dicati o ns s u b mitte d via 
t he ce ntralize d pr oce d ure si nce 0 1 J ul y 2 0 1 5.
Data S hari n g
Pfizer pr o vi des researc hers sec ure access t o patie nt- le vel data or f ull C S Rs f or t he p ur p oses 
of “ b o na -fi de scie ntific researc h” t hat c o ntri b utes t o t he scie ntific u n dersta n di n g of t he 
disease, tar get, or c o m p o u n d class.  Pfizer will ma ke a vaila ble data fr o m t hese trials 
2 4 m o nt hs after st u d y  c o m pleti o n.  Patie nt-le vel data will be a n o ny m ize d i n acc or da nce wit h 
a p plica ble pri vac y la ws a n d re g ulati ons.  C S Rs will ha ve pers o nall y i de ntifia ble i nf or mati o n 
re dacte d.
Data re q uests are c o nsi dere d fr o m q ualifie d researc hers wit h t he a p pr o priate c o m pete ncies t o 
perf or m t he pr o p ose d a nal yses.  Researc h tea ms m ust i ncl u de a bi ostatisticia n.  Data will n ot 
be pr o vi de d t o a p plica nts wit h si g nifica nt c o nflicts of i nterest, i ncl u di n g i n di vi d uals 
re q uesti n g access f or c o m mercial/c o m petiti ve or le gal p ur p oses.
1 0. 1. 6. D at a Q u alit y Ass ur a nce
All partici pa nt data relati n g t o t he st u d y will be rec or de d o n pri nte d or electr o nic C R F u nless 
tra ns mitte d t o t he s p o ns or or desi g nee electr o nicall y (e g, la b orat or y data). T he i n vesti gat or is 
res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y p h ysicall y or 
electr o nicall y si g ni n g t he C R F.
T he i n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t he C R F.
T he i n vesti gat or m ust e ns ure t hat t he C R Fs are sec urel y st ore d at t he st u d y site i n e ncr y pte d 
electr o nic a n d/ or pa per f or m a n d are pass w or d pr otecte d or sec ure d i n a l oc ke d r o o m t o 
pre ve nt access b y u na ut h orize d t hir d parties.
T he i n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/ E C re vie w, a n d 
re g ulat or y a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts.  T his 
verificati o n ma y  als o occ ur after st u d y c o m pleti o n.  It is i m p orta nt t hat t he i n vesti gat or(s) 
a n d t heir rele va nt pers o n nel are a vaila ble d uri n g t he m o nit ori n g visits a n d p ossi ble a u dits or 
i ns pecti o ns a n d t hat s ufficie nt ti me is de v ote d t o t he pr ocess.
M o nit ori n g details descri bi n g strate g y  (e g, ris k-base d i nitiati ves i n o perati o ns a n d q ualit y  
s uc h as ris k m a na ge me nt a n d m iti gati o n strate gies a n d anal yt ical ris k- base d m o nit ori n g), 
met h o ds, res p o nsi bilities , a n d re q uire me nts, i ncl u di n g ha n dli n g of n o n c o m plia nce iss ues a n d 
m o nit ori n g tec h ni q ues (ce ntral, re m ote, or o n -site m o nit ori n g), are pr o vi de d i n t he Cli nical 
M o nit ori n g Pla n .
T he s p o ns or or desi g nee is res p o nsi ble f or t he data ma na ge me nt of t his st u d y , i ncl u di n g 
q ualit y  c hec ki n g of t he data.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 3 0
St u d y  m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d 
i nt o t he C R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m s o urce 
d oc u me nts; t hat t he safet y a n d ri g hts of partici pa nts are bei n g pr otecte d; a n d t hat t he st u d y is 
bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntl y  a p pr o ve d pr ot oc ol a n d a n y ot her st u d y 
a gree me nts, IC H G C P, a n d all a p plica ble re g ulat or y  re q uire me nts.
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C D s, pertai ni n g t o t he c o n d uct of t his st u d y m ust 
be retai ne d b y t he i n vesti gat or f or 1 5 ye ars after st u d y c o m pleti o n u nless l ocal re g ulati o ns or 
i nstit uti o nal p olicies re q uire a l o n ger rete nti o n peri o d. N o rec or ds ma y  be destr o ye d d uri n g 
t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of t he s p o ns or. N o rec or ds ma y  be 
tra nsferre d t o a n ot her l ocati o n or part y wit h o ut writte n n otificati o n t o t he s p o ns or. T he 
i n vesti gat or m ust e ns ure t hat t he rec or ds c o nti n ue t o be st ore d sec urely f or as l o n g as t he y are 
mai ntai ne d.
W he n partici pa nt data are t o be delete d, t he i n vesti gat or will e ns ure t hat all c o pies of s uc h 
data are pr o m ptl y  a n d irre v oca bly delete d fr o m all s yste ms.
T he i n vesti gat or(s) will n otif y  t he s p o ns or or its a ge nts i m me diatel y of a n y re g ulat or y 
i ns pecti o n n otificati o n i n relati o n t o t he st u d y.  F urt her m ore, t he i n vesti gat or will c o o perate 
wit h t he s p o ns or or its a ge nts t o pre pare t he i n vesti gat or site f or t he i ns pecti o n a n d will all o w 
t he s p o ns or or its a ge nt, w he ne ver feasi ble, t o be prese nt d uri n g t he i ns pecti o n.  T he 
i n vesti gat or site a n d i n vesti gat or will pr o m ptl y res ol ve a n y discre pa ncies t hat are i de ntifie d 
bet wee n t he st u d y data a n d t he partici pa nt ’s me dical rec or ds.  T he i n vesti gat or will pr o m ptl y 
pr o vi de c o pies of t he i ns pecti o n fi n di n gs t o t he s p o ns or or its a ge nt.  Bef ore res p o nse 
s u b missi o n t o t he re g ulat or y a ut h orities, t he i n vesti gat or will pr o vi de t he s p o ns or or its 
a ge nts wit h a n o p p ort u nit y t o re vie w a n d c o m me nt o n res p o nses t o a n y s uc h fi n di n gs.
1 0. 1. 7. S o urce D oc u me nts
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grity of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or site.
Data re p orte d o n t he C R F or e ntere d i n t he e C R F t hat are fr o m s o urce d oc u me nts m ust be 
c o nsiste nt wit h t he s o urce d oc u me nts o r t he discre pa ncies m ust be e x plai ne d. T he 
i n vesti gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g o n 
t he st u d y. Als o, c urre nt me dical rec or ds m ust be a vaila ble.
Defi niti o n of w hat c o nstit utes s o urce data ca n be f o u n d i n t he Cli nical M o nit ori n g Pla n.
Descri pti o n of t he use of c o m p uterize d s yste m is d oc u me nte d i n the Data Ma na ge me nt Pla n .
1 0. 1. 8. St u d y a n d Site St art a n d Cl os ure
T he st u d y  start date is t he date o n w hic h t he cli nical st u d y will be o pe n f or recr uit me nt of 
partici pa nts.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 3 1
T he first act of recr uit me nt is t he date of t he first partici pa nt’s first visit a n d will be t he st u d y  
start date.
T he s p o ns or desi g nee reser ves t he ri g ht t o cl ose t he st u d y  site or ter mi nate t he st u d y at a n y 
ti me f or a ny reas o n at t he s ole di screti o n of t he s p o ns or. St u d y  sites will be cl ose d u p o n 
st u d y c o m pleti o n. A st u d y  site is c o nsi dere d cl ose d w he n all re q uire d d oc u me nts a n d st u d y 
s u p plies ha ve bee n c ollecte d a n d a st u dy- site cl os ure visit has bee n perf or me d.
T he i n vesti gat or ma y  i nitiate st u d y-site cl os ure at a n y ti me u p o n n otificati o n t o t he s p o ns or 
or desi g nee/ C R O if re q ueste d t o d o s o b y  t he res p o nsi ble IR B/ E C or if s uc h ter mi nati o n is 
re q uire d t o pr otect t he healt h of st u d y partici pa nts.
Reas o ns f or t he earl y cl os ure of a st u d y site b y  t he s p o ns or ma y i ncl u de b ut are n ot li mite d 
t o:

Fail ure of t he i n vesti gat or t o c o m pl y  wit h t he pr ot oc ol, t he re q uire me nts of t he 
I RB/ E C or l ocal healt h a ut h orities, t he s p o ns or ’s pr oce d ures, or G C P g ui deli nes;

I na de q uate recr uit me nt of partici pa nts b y  t he i n vesti gat or;

Disc o nti n uati o n of f urt her st u d y  i nter ve nti o n de vel o p me nt.
If t he st u dy is pre mat urel y ter mi nate d or s us pe n de d, t he s p o ns or s hall pr o m ptl y i nf or m t he 
in vesti gat ors, t he E Cs /IR Bs, t he re g ulat or y  a ut h orities, a n d a n y C R O (s) use d i n t he st u dy of 
t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y t he a p plica ble re g ulat or y 
re q uire me nts. T he in vesti gat or s hall pr o m ptl y  i nf or m t he partici pa nt a n d s h o ul d ass ure 
a p pr o priate partici pa nt t hera p y a n d/ or f oll o w- u p.
St u d y  ter mi nati o n is als o pr o vi de d f or i n t he cli nical st u d y  a gree me nt.  If t here is a n y c o nflict 
bet wee n t he c o ntract a n d t his pr ot oc ol, t he c o ntract will c o ntr ol as t o ter mi nati o n ri g hts.
1 0. 1. 9. P u blic ati o n P olic y
T he res ults of t his st u d y  ma y be p u blis he d or prese nte d at scie ntific meeti n gs by t he 
i n vesti gat or after p u blicati o n of t he o verall st u d y res ults or 1 ye ar after t he e n d of t he st u d y 
( or st u d y ter mi nati o n), w hic he ver c o mes first.  
T he i n vesti gat or a grees t o refer t o t he pri mar y  p u blicati o n i n a n y s u bse q ue nt p u blicati o ns 
s uc h as sec o n dar y ma n uscri pts, a n d s u b mit s all ma n uscri pts or a bstracts t o t he s p o ns or 
3 0 da y s bef ore s u b missi o n. T his all o ws t he s p o ns or t o pr otect pr o prietar y  i nf or mati o n a n d t o 
pr o vi de c o m me nts a n d t he i n vesti gat or will, o n re q uest, re m o ve a n y pre vi o usl y  u n discl ose d 
c o nfi de ntial i nf or mati o n bef ore discl os ure, e xce pt f or a n y st u d y- or Pfizer 
i nter ve nti o n-relate d i nf or mati o n necessar y f or t he a p pr o priate scie ntific prese ntati o n or 
u n dersta n di n g of t he st u d y  res ults.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 3 2
F or all p u blicati o ns relati n g t o t he st u d y, t he i n vesti gat or will c o m pl y wit h rec o g nize d et hical 
sta n dar ds c o ncer ni n g p u blicati o ns a n d a ut h ors hi p, i ncl u di n g t h ose esta blis he d b y t he 
I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors.
T he s p o ns or will c o m pl y  wit h t he re q uire me nts f or p u blicati o n of t he o ver all st u d y res ults 
c o veri n g all i n vesti gat or sites. I n acc or da nce wit h sta n dar d e dit orial a n d et hical practice, t he 
s p o ns or will s u p p ort p u blicati o n of m ultice nter st u dies o nl y i n t heir e ntiret y a n d n ot as 
i n di vi d ual site data. In t his case, a c o or di nati n g i n vesti gat or will be desi g nate d b y m ut ual 
a gree me nt.
A ut h ors hi p of p u blicati o ns f or t he o verall st u d y  res ults will be deter mi ne d b y m ut ual 
a gree me nt a n d i n li ne wit h Inter nati o nal C o m mittee of Me dical J o ur nal E dit ors a ut h ors hi p 
re q uire me nts.  
If p ublicati o n is a d dresse d i n t he cli nical st u d y  a gree me nt, t he p u blicati o n p olic y set o ut i n 
t his secti o n will n ot a p pl y.
1 0. 1. 1 0. S p o ns or’s Q u alifie d Me dic al Pers o n nel
T he c o ntact i nf or mati o n f or t he s p o ns or ’s a p pr o priatel y q ualifie d me dical pers o n nel f or t he 
st u d y is d oc u me nte d i n t he st u d y c o ntact list l ocate d i n t he s u p p orti n g st u d y 
d oc u me ntati o n/st u d y  p ortal or ot her electr o nic s ys te m.  
T o facilitate access t o a p pr o priatel y q ualifie d me dical pers o n nel o n st u d y- relate d me dical 
q uesti o ns or pr o ble ms, partici pa nt s are pr o vi de d wit h a c o ntact car d at t he ti me of i nf or me d 
c o nse nt /asse nt.  T he c o ntact car d c o ntai ns, at a mi ni m u m, pr ot oc ol a n d st u d y i nter ve nti o n
i de ntifiers, partici pa nt n u m bers, c o ntact i nf or mati o n f or t he i n vesti gat or site, a n d c o ntact 
details f or a c o ntact ce nter i n t he e ve nt t hat t he i n vesti gat or site staff ca n n ot be reac he d t o 
pr o vi de a d vice o n a me dical q uesti o n or pr o ble m ori gi nati n g fr o m a n ot her healt hcare 
pr ofessi o nal n ot i n v ol ve d i n t he partici pa nt ’s partici pati o n i n t he st u d y.  T he c o ntact n u m ber 
ca n als o be use d b y i n vesti gat or staff if t he y are see ki n g a d vice o n me dical q uesti o ns or 
pr o ble ms; h o we ver, it s h o ul d be use d o nl y i n t he e ve nt t hat t he esta blis he d c o m m u nicati o n 
pat h wa y s bet wee n t he i n vesti gat or site a n d t he st u d y tea m are n ot a vaila ble.  It is t heref ore 
i nte n de d t o a u g me nt, b ut n ot re place, t he esta blis he d c o m m u nicati o n pat h wa ys bet wee n t he 
i n vesti gat or site a n d t he st u d y tea m f or a d vice o n me dical q uesti o ns or pr o ble ms t hat ma y 
arise d uri n g t he st u d y.  T he c o ntact n u m ber is n ot i nte n de d f or use b y t he partici pa nt directl y, 
a n d if a partici pa nt calls t hat n u m ber, he or s he will be directe d bac k t o t he i n vesti gat or site.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 3 3
1 0. 2. A p pe n di x 2: Cli nic al L a b or at or y Tests
T he f oll o wi n g safet y la b orat or y  tests will be perf or me d at ti mes defi ne d i n t he S o A secti o n of 
t his pr ot oc ol.  A d diti o nal la b orat or y res ults ma y be re p orte d o n t hese sa m ples as a res ult of 
t he met h o d of a nalys is or t he t ype of a nal yz er use d b y t he cli nical la b orat or y, or as deri ve d 
fr o m calc ulate d val ues.  T hese a d diti o nal tests w o ul d n ot re q uire a d diti o nal c ollecti o n of 
bl o o d.  U nsc he d ule d cli nical la b orat or y  meas ure me nts ma y be o btai ne d at a n y ti me d uri n g 
t he st u d y t o assess a n y percei ve d safet y iss ues.
T a ble 7 .
S afet y L a b or at or y Tests
H e m at ol o g y
C he mistr y
Ser ol o g y
( at 
scree ni n g 
o nl y)
C o a g ul ati o n
Uri n al ysis
Pre g n a nc y 
Test
A d h oc 
Ce ntr al 
L a b 
C yt o ki ne 
A n al ysis
H e m o gl o bi n
A L T
H B V 
P T /I N R
p H
Gl uc ose 
( q ual)
Pr otei n 
( q ual)
Bl o o d ( q ual)
Ket o nes
Nitrites
Le u k oc yte 
esterase
Ur o bili n o ge n
Uri ne 
bilir u bi n
Micr osc o p y a
F or fe male 
partici pa nts 
of 
c hil d beari n g 
p ote ntial
I L-6, 
I L-1 0, 
I L- 2, 
sI L 2 R, 
I L-1 2, 
I L-4, 
I L-5, 
I L-1 0, 
I L-1 3, 
I L-1 7, 
I L-1 b, 
I L-8, 
I F Nγ, a n d 
T N F -α
H e m at ocrit
A S T
H C V
P T T
T otal R B C c o u nt
bicar b o nate
HI V (if 
a p plica ble)
Platelets
C R P
W B C
Al k P h os
A bs ol ute 
Ne utr o p hils
S o di u m
A bs ol ute 
L y m p h oc ytes
P otassi u m
A bs ol ute M o n oc ytes
Ma g nesi u m
O pti o n al 
A d h oc 
L oc al 
L a b 
C yt o ki ne 
A n al ysis
A bs ol ute 
E osi n o p hils
C hl ori de
A bs ol ute Bas o p hils
T otal 
calci u m
I L- 6
Tr o p o ni n (f or 
partici pa nts recei vi n g 
bi ni meti ni b)
T otal 
bilir u bi n * * *
I L- 1
T otal 
Pr otei n
I L-1 0
B U N
T N F 
Creati ni ne
Uric Aci d
Gl uc ose 
( n o nfaste d)
L D H
Al b u mi n
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 3 4
T a ble 7 .
S afet y L a b or at or y Tests
H e m at ol o g y
C he mistr y
Ser ol o g y
( at 
scree ni n g 
o nl y)
C o a g ul ati o n
Uri n al ysis
Pre g n a nc y 
Test
A d h oc 
Ce ntr al 
L a b 
C yt o ki ne 
A n al ysis
P h os p h or us 
or P h os p hate
Creati n e 
Ki nase ( C K)
a. O nl y if uri ne di pstic k is p ositi ve f or bl o o d, pr otei n, nitrites, or le u k oc yte esterase.
* * * F or p ote ntial H y ’s La w cases, i n a d diti o n t o re peati n g A S T a n d A L T, la b orat or y tests s h o ul d i ncl u de 
al b u mi n, creati ne ki nase, t otal bilir u bi n, direct a n d i n direct bilir u bi n, ga m ma -gl uta m yl tra nsferase, P T/I N R, 
al kali ne p h os p hatase, t otal bile aci ds a n d aceta mi n o p he n dr u g a n d/ or pr otei n a d d uct le vels. 
T he i n vesti gat or m ust re vie w t he la b orat or y  re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y i n t he A E secti o n of t he C R F.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 3 5
1 0. 3. A p pe n di x 3: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g
1 0. 3. 1. Defi niti o n of A E
A E Defi niti o n

A n A E is a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical st u d y  
partici pa nt, te m p orall y ass ociate d wit h t he use of st u d y i nter ve nti o n, w het her or n ot 
c o nsi dere d relate d t o t he st u d y  i nter ve nti o n.

N O T E: A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), sy m pt o m, or dis ease ( ne w or e xacer bate d) 
te m p orall y ass ociate d wit h t he use of st u d y i nter ve nti o n.
E ve nts Meeti n g
t he A E Defi niti o n

A n y  a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) 
or ot her safet y assess me nts (e g, E C G, ra di ol o gical sca ns, vital si g n meas ure me nts), 
i ncl u di n g t h ose t hat w orse n fr o m baseli ne, c o nsi dere d cli nically si g nifica nt i n t he 
me dical a n d scie ntific j u d g me nt of t he i n vesti gat or.   A n y a b n or mal la b orat or y test 
res ults t hat meet a ny of t he c o n diti o ns bel o w m ust be re c or de d as a n A E:

Is ass ociate d wit h acc o m pa n yi n g sy m pt o ms ;

Re q uires a d diti o nal dia g n ostic testi n g or me dical/s ur gical i nter ve nti o n ;

Lea ds t o a c ha n ge i n st u d y  d osi n g ( o utsi de of a n y pr ot oc ol-s pecifie d d ose 
a dj ust me nts) or disc o nti n uati o n fr o m t he st u d y , si g nifica nt a d diti o nal 
c o nc o mita nt dr u g treat me nt, or ot her t hera p y.

E xacer bati o n of a c hr o nic or i nter mitte nt pree xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncrease i n fre q ue 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 detecte d or dia g n ose d after st u d y  i nter ve nti o n a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve bee n prese nt bef ore t he start of t he st u d y.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -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 st u d y  
i nter ve nti o n or a c o nc o mita nt me dicati o n. O ver d ose per se will n ot be re p orte d as 
a n A E/ S A E u nless it is a n i nte nti o nal o ver d ose ta ke n wit h p ossi ble 
s uici dal/self- har mi n g i nte nt. S uc h o ver d oses s h o ul d be re p orte d re gar dless of 
se q uelae.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 3 6
E ve nts N O T Meeti n g t he A E Defi niti o n

A n y  cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs or ot her a b n or mal safety 
assess me nts w hic h are ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he 
i n vesti gat or t o be m ore se vere t ha n e x pecte d f or t he partici pa nt’s c o n diti o n.

T he disease/ dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o ms of 
t he disease/ dis or der bei n g st u die d, u nless m ore se vere t ha n e x pecte d f or t he 
parti ci pa nt’s c o n diti o n.

Me dical or s ur gical pr oce d ure (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 t he A E.

Sit uati o ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).

A nti ci pate d da y-t o-d a y  fl uct uati o ns of pree xisti n g disease(s) or c o n diti o n(s) prese nt 
or detecte d at t he start of t he st u d y t hat d o n ot w orse n.

W orse ni n g of si g ns a n d s y m pt o ms of t he mali g na nc y  u n der st u d y s h o ul d be 
rec or de d as A Es i n t he a p pr o priate secti o n of t he C R F.  Disease pr o gressi o n 
assesse d b y meas ure me nt of mali g na nt lesi o ns o n ra di o gra p hs or ot her met h o ds 
s h o ul d n ot be re p orte d as A Es.
1 0. 3. 2. Defi niti o n of S A E
If a n e ve nt is n ot a n A E per defi niti o n a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us 
c o n diti o ns are met (e g, h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n der st u d y , deat h 
d ue t o pr o gressi o n of disease).
A n S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:
a.
Res ults i n deat h
b.
Is life-t hreate ni n g
T he ter m “life-t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h t he 
partici pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt t hat
h y p ot heticall y  mi g ht ha ve ca use d deat h if it were m ore se vere.
c.
Re q uires i n patie nt h o s pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n
I n ge neral, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n detai ne d ( us uall y 
i n v ol vi n g at least a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or o bser vati o n 
a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h ys icia n’s office or 
o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are A Es. If a 
c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, t he e ve nt is 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 3 7
seri o us. W he n i n d o u b t as t o w het her “ h os pitalizati o n” occ urre d or was necessar y, t he A E 
s h o ul d be c o nsi dere d seri o us.
H os pitalizati o n f or electi ve treat me nt of a pree xisti n g c o n diti o n t hat di d n ot w orse n fr o m 
baseli ne is n ot c o nsi dere d a n A E.
d.
Res ults i n persiste nt disa bilit y /i nca pacity

T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y  t o c o n d uct 
n or mal life f u ncti o ns.

T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, na usea, vo miti n g, diarr hea, 
i nfl ue nza, a n d acci de ntal tra u ma (e g, s prai ne d a n kle) w hic h ma y i nterfere wit h or 
pre ve nt e ver y d a y  life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n.
e.
Is a c o n ge nital a n o maly/ birt h defect
f.
Ot her sit uati o ns:

Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E 
re p orti n g is a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat 
ma y  n ot be i m me diately l ife-t hreate 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 partici pa nt or ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt o ne of t he ot her o utc o mes liste d i n t he a b o ve defi niti o n. T hese e ve nts 
s h o ul d us uall y be c o nsi dere d seri o us.

E xa m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt 
i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g 
de pe n de nc y  or dr u g a b use.

Pr o gressi o n of t he mali g na nc y  u n der st u dy (i ncl u di n g si g ns a n d sy m pt o ms of 
pr o gressi o n) s h o ul d n ot be re p orte d as a n S A E u nless t he o utc o me is fatal wit hi n 
t he acti ve c ollecti o n peri o d.  H os pitalizati o n d ue t o si g ns a n d sy m pt o ms of disease 
pr o gressi o n s h o ul d n ot be re p orte d as a n S A E.  If t he mali g na nc y has a fatal 
o utc o me d uri n g t he st u d y or wit hi n t he acti ve c ollecti o n peri o d, t he n t he e ve nt 
lea di n g t o deat h m ust be rec or de d as a n A E o n t he C R F, a n d as a n S A E wit h 
C T C A E Gra de 5 (see t he Assess me nt of I nte nsit y secti o n).

S us pecte d tra ns mis si o n via a Pfizer pr o d uct of a n i nfecti o us a ge nt, pat h o ge nic or 
n o n -pat h o ge nic, is c o nsi dere d seri o us.  T he e ve nt ma y  be s us pecte d fr o m cli nical 
s ym pt o ms or la b orat or y  fi n di n gs i n dicati n g a n i nfecti o n i n a patie nt e x p ose d t o a 
Pfizer pr o d uct.  T he ter ms “s us pecte d tra ns missi o n” a n d “tra ns missi o n” are 
c o nsi dere d s y n o n y m o us.  T hese cases are c o nsi dere d u ne x pecte d a n d ha n dle d as 
seri o us e x pe dite d cases b y p har mac o vi gila nce pers o n nel.  S uc h cases are als o 
c o nsi dere d f or re p orti n g as pr o d uct defects, if a p pr o pri ate.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 3 8
1 0. 3. 3. Rec or di n g / Re p orti n g a n d F oll o w - up of A E s a n d/ or S A E s
A E a n d S A E Rec or di n g / Re p orti n g
T he ta ble bel o w s u m marizes t he re q uire me nts f or rec or di n g a d verse e ve nts o n t he C R F 
a n d f or re p orti n g seri o us a d verse e ve nts o n t he C T S A E Re p ort F or m t o Pfizer Safet y.  
T hese re q uire me nts are deli neate d f or 3 t y pes of e ve nts: ( 1) S A Es; ( 2) n o nseri o us a d verse 
e ve nts ( A Es); a n d ( 3) e x p os ure t o t he st u d y i nter ve nti o n u n der st u d y  d uri n g pre g na nc y or 
breastfee di n g, a n d occ u pati o nal e x p os ure.  
It s h o ul d be n ote d t hat t he C T S A E Re p ort F or m f or re p orti n g of S A E i nf or mati o n is n ot 
t he sa me as t he A E pa ge of t he C R F.  W he n t he sa me data are c ollecte d, t he f or ms m ust be 
c o m plete d i n a c o nsiste nt ma n ner.  A Es s h o ul d be rec or de d usi n g c o ncise me dical 
ter mi n ol o g y a n d t he sa me A E ter m s h o ul d be use d o n b ot h t he C R F a n d t he C T S A E 
Re p ort F or m f or re p orti n g of S A E i nf or mati o n.
S afet y E ve nt
Rec or de d o n t he C R F
Re p orte d o n t he C T S A E 
Re p ort F or m t o Pfizer 
S afet y Wit hi n 2 4 H o urs of 
A w are ness
S A E
All
All
N o nseri o us A E
All
N o ne
E x p os ure t o t he st u d y 
i nter ve nti o n u n der st u d y 
d uri n g pre g na nc y  or 
breastfee di n g, a n d 
occ u pati o nal e x p os ure
All A Es/ S A Es ass ociate d 
wit h e x p os ure d uri n g 
pre g na nc y  or breastfee di n g
Occ u pati o nal e x p os ure is 
n ot rec or de d.
All ( an d E D P s u p ple me ntal 
f or m f or ED P)  
N ote: I ncl u de all S A Es 
ass ociate d wit h e x p os ure 
d uri n g pre g na nc y  or 
breastfee di n g. I ncl u de all 
A Es/ S A Es ass ociate d wit h 
occ u pati o nal e x p os ure.

W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y  of t he i n vesti gat or t o re vie w all 
d oc u me ntati o n (e g, h os pital pr o gress n otes, la b orat or y  re p orts, a n d dia g n ostic 
re p orts) relate d t o t he e ve nt.

T he i n vesti gat or will t he n rec or d all rele va nt A E/ S A E i nf or mati o n i n t he C R F.

It is n ot acce pta ble f or t he i n vesti gat or t o se n d p h ot oc o pies of t he partici pa nt’s 
me di cal rec or ds t o Pfizer Safet y  i n lie u of c o m pleti o n of t he C T S A E Re p ort 
F or m / A E/ S A E C R F pa ge.

T here ma y  be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are 
re q ueste d by Pfizer Safet y . I n t his case, all partici pa nt i de ntifiers, wit h t he 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 3 9
e xce pti o n of t he partici pa nt n u m ber, will be re dacte d o n t he c o pies of t he me dical 
rec or ds bef ore s u b missi o n t o Pfizer Safet y .

T he i n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s ym pt o ms, a n d/ or ot her cli nical i nf or mati o n. W he n e ver p ossi ble, t he dia g n osis 
( n ot t he i n di vi d ual si g ns/s ym pt o ms) will be d oc u me nte d as t he A E/ S A E.
Assess me nt of I nte nsit y
G R A D E
Cli nical Descri pti o n of Se verit y
1
MI L D a d verse e ve nt
2
M O D E R A T E a d verse e ve nt
3
S E V E R E a d verse e ve nt
4
LI F E -T H R E A T E NI N G c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d
5
D E A T H R E L A T E D T O a d verse e ve nt
Assess me nt of C a us alit y

T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n 
a n d eac h occ urre nce of eac h A E/ S A E.

A “reas o na ble p ossi bilit y” of a relati o ns hi p c o n ve y s t hat t here are facts, e vi de nce, 
a n d/ or ar g u me nts t o s u g gest a ca usal relati o ns hi p, rat her t ha n a relati o ns hi p ca n n ot 
be r ule d o ut.

T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.

Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her 
ris k fact ors, as well as t he te m p oral relati o ns hi p of t he e ve nt t o st u d y i nter ve nti o n 
a d mi nistrati o n , will be c o nsi dere d a n d i n vesti gate d.

T he i n vesti gat or will als o c o ns ult t he I B a n d/ or p r o d uct i nf or mati o n, f or mar kete d 
pr o d ucts, i n his/ her assess me nt.

F or eac h A E/ S A E, t he i n vesti gat or m ust d oc u me nt i n t he me dical n otes t hat he/s he 
has re vie we d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y .

T here ma y  be sit uati o ns i n w hic h a n S A E has occ urre d a n d t he i n vesti gat or has 
mi ni mal i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o t he s p o ns or. H o we ver, it is 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 4 0
ver y i m p ort a nt t h at t he i n vesti g at or al w a ys m a ke a n assess me nt of c a us alit y 
f or e ver y e ve nt bef ore t he i niti al tr a ns missi o n of t he S A E d at a t o t he s p o ns or.

T he i n vesti gat or ma y  c ha n ge his/ her o pi ni o n of ca usalit y i n li g ht of f oll o w- u p 
i nf or mati o n a n d se n d a n S A E f oll o w -u p re p ort wit h t he u p date d ca usalit y  
assess me nt.

T he ca usalit y  assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y 
re p orti n g re q uire me nts.

If t he i n vesti gat or d oes n ot k n o w w het her or n ot t he st u d y i nter ve nti o n ca use d t he 
e ve nt, t he n t he e ve nt will be ha n dle d as “relate d t o st u d y i nter ve nti o n” f or re p orti n g 
p ur p oses, as defi ne d b y t he s p o ns or .  I n a d diti o n, if t he i n vesti gat or deter mi nes t hat 
a n S A E is ass ociate d wit h st u d y  pr oce d ures, t he i n vesti gat or m ust rec or d t his 
ca usal relati o ns hi p i n t he s o urce d oc u me nts a n d C R F, a n d re p ort s uc h a n 
assess me nt i n t he de dicate d secti o n of t he C T S A E Re p ort F or m a n d i n acc or da nce 
wit h t he S A E re p orti n g re q uire me nts.
F oll o w - u p of A Es a n d S A Es

T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as me dicall y  i n dicate d or as re q ueste d b y t he 
s p o ns or t o el uci date t he nat ure a n d/ or ca usality of t he A E or S A E as f ull y as 
p ossi ble. T his ma y  i ncl u de a d diti o nal la b orat or y tests or i n vesti gati o ns, 
hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n wit h ot her healt hcare pr o vi ders .

If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d 
f oll o w- u p peri o d, t he i n vesti gat or will pr o vi de Pfizer Safet y wit h a c o p y of a n y 
p ost m orte m fi n di n gs i ncl u di n g hist o pat h ol o g y , if re q ueste d.

Ne w or u p date d i nf or mati o n will be rec or de d i n t he ori gi nall y  c o m plete d C R F.

T he i n vesti gat or will s u b mit a n y  u p date d S A E data t o t he s p o ns or wit hi n 2 4 h o urs 
of recei pt of t he i nf or mati o n.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 4 1
1 0. 3. 4. Re p orti n g of S A Es
S A E Re p orti n g t o Pfizer S afet y vi a a n Electr o nic D at a C ollecti o n T o ol

T he pri mar y  mec ha nis m f or re p orti n g a n S A E t o Pfizer Safet y will be t he 
electr o nic data c ollecti o n t o ol.

If t he electr o nic s yste m is u na vaila ble, t he n t he site will use t he pa per S A E data 
c ollecti o n t o ol (see ne xt secti o n) i n or der t o re p ort t he e ve nt wit hi n 2 4 h o urs.

T he site will e nter t he S A E data i nt o t he electr o nic s y ste m as s o o n as t he data 
bec o me a vaila ble.

After t he st u d y  is c o m plete d at a gi ve n site, t he electr o nic data c ollecti o n t o ol will 
be ta ke n offli ne t o pre ve nt t he e ntr y  of ne w data or c ha n ges t o e xisti n g data.

If a site recei ves a re p ort of a ne w S A E fr o m a st u d y partici pa nt or recei ves u p date d 
data o n a pre vi o usl y  re p orte d S A E after t he electr o nic data c ollecti o n t o ol has bee n 
ta ke n offli ne, t he n t he site ca n re p ort t his i nf or mati o n o n a pa per S A E f or m (see 
ne xt secti o n) or t o Pfizer Safet y  b y tele p h o ne.
S A E Re p orti n g t o Pfizer S afet y vi a C T S A E Re p ort F or m

Facsi mile tra ns missi o n of t he C T S A E Re p ort F or m is t he preferre d met h o d t o 
tra ns mit t his i nf or mati o n t o Pfizer Safet y.

I n circ u msta nces w he n t he facsi mile is n ot w or ki n g, n otificati o n by tele p h o ne is 
acce pta ble wit h a c o p y of t he C T S A E Re p ort F or m se nt b y o ver ni g ht mail or 
c o urier ser vice.

I nitial n otificati o n via tele p h o ne d oes n ot re place t he nee d f or t he i n vesti gat or t o 
c o m plete a n d si g n t he C T S A E Re p ort F or m pa ges wit hi n t he desi g nate d re p orti n g 
ti me fra mes.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 4 2
1 0. 4. A p pe n di x 4: C o ntr ace pti ve G ui d a nce 
1 0. 4. 1. M ale P artici p a nt Re pr o d ucti ve I ncl usi o n Criteri a
Male partici pa nts are eli gi ble t o partici pate if t he y  a gree t o t he f oll o wi n g re q uire me nts d uri n g 
t he i nter ve nti o n peri o d a n d f or at least 2 8 da y s after t he last d ose of st u d y i nter ve nti o n, w hic h 
c orres p o n ds t o t he ti me nee de d t o eli mi n ate re pr o d ucti ve safety ris k of t he st u dy 
i nterve nti o n(s): 

Refrai n fr o m d o nati n g s per m.
P L U S eit her :

Be a bsti ne nt fr o m heter ose x ual i nterc o urse wit h a fe male of c hil d beari n g p ote ntial as 
t heir preferre d a n d us ual lifest yle (a bsti ne nt o n a l o n gter m a n d persiste nt basis) a n d 
a gree t o re mai n a bsti ne nt. 
O R

M ust a gree t o use a male c o n d o m w he n e n ga gi n g i n a n y  acti vit y t hat all o ws f or 
passa ge of ejac ulate t o a n ot her pers o n.

I n a d diti o n t o male c o n d o m use, a hi g hl y effecti ve met h o d of c o ntrace pti o n ma y  be 
c o nsi dere d i n W O C B P of male partici pa nts (refer t o t he list of hi g hl y  effecti ve 
met h o ds bel o w i n Secti o n 1 0. 4. 4 ).
1 0. 4. 2. Fe m ale P artici p a nt Re pr o d ucti ve I ncl usi o n Criteri a
A fe male partici pa nt is eli gi ble t o partici pate if s he is n ot pre g na nt or breastfee di n g, a n d at 
least 1 of t he f oll o wi n g c o n diti o ns a p plies :

Is n ot a W O C B P (see defi niti o ns bel o w i n Secti o n 1 0. 4. 3 ).
O R

Is a W O C B P a n d usi n g a c o ntrace pti ve met h o d t hat is hi g hl y effecti ve ( wit h a fail ure 
rate of < 1 % per year), prefera bl y wit h l o w user de pe n de nc y , as descri be d bel o w
d uri n g t he i nter ve nti o n peri o d a n d f or at least 2 8 d a y s after t he last d ose of st u d y  
i nter ve nti o n, w hic h c orres p o n d s t o t he ti me nee de d t o eli mi nate a n y re pr o d ucti ve 
safety ris k of t he st u d y i nter ve nti o n(s). T he i nvesti g at or s h o ul d ev al u ate t he 
effective ness of t he c o ntr ace ptive met h o d i n rel ati o ns hi p t o t he first d ose of st u dy 
i nterve nti o n.

Is a W O C B P a n d usi n g a c o ntrace pti ve met h o d t hat is hi g hl y effecti ve ( wit h a fail ure 
rate of < 1 % per year), wit h hi g h user de pe n de nc y , as descri be d bel o w d uri n g t he 
i nter ve nti o n peri o d a n d f or at least 2 8 d a y s after t he last d ose of st u d y i nter ve nti o n,
w hic h c orres p o n ds t o t he ti me nee de d t o eli mi nate a n y  re pr o d ucti ve safety ris k of t he 
st u d y i nter ve nti o n(s). I n a d diti o n, a sec o n d effecti ve met h o d of c o ntrace pti o n, as 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 4 3
descri be d bel o w, m ust be use d. T he i n vesti gat or s h o ul d e vl uate t he effecti ve ness of 
t he c o ntrace pti ve met h o d i n relati o ns hi p t o t he first d ose of st u d y i nter ve nti o n.

A W O C B P a grees n ot t o d o nate e g gs ( o va, o oc ytes) f or t he p ur p ose of re pr o d ucti o n 
d uri n g t his peri o d. T he i n vesti gat or s h o ul d e val uate t he effecti ve ness of t he 
c o ntrace pti ve met h o d i n relati o ns hi p t o t he first d ose of st u d y i nter ve nti o n.
T he i n vesti gat or is res p o nsi ble f or re vie w of me dical hist or y , me nstr ual hist or y, a n d rece nt 
se x ual acti vit y t o decrease t he ris k f or i ncl usi o n of a w o ma n wit h a n early u n detecte d 
pre g na nc y . 
1 0. 4. 3. W o m a n of C hil d be ari n g P ote nti al
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal 
u nless per ma ne ntl y sterile (see bel o w).
If fertilit y is u nclear (e g, a me n orr hea i n a d olesce nts or at hletes) a n d a me nstr ual c ycle ca n n ot 
be c o nfir me d bef ore t he first d ose of st u d y i nter ve nti o n, a d diti o nal e val uati o n s h o ul d be 
c o nsi dere d.
W o me n i n t he f oll o wi n g cate g ories are n ot c o nsi dere d W O C B P:
1.
Pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:

D oc u me nte d h ys terect o m y;

D oc u me nte d bilateral sal pi n gect o m y ;

D oc u me nte d bilateral o o p h orect o m y.
F or i n di vi d uals wit h per ma ne nt i nfertilit y  d ue t o a n alter nate me dical ca use ot her t ha n 
t he a b o ve, (e g, m ulleria n a ge nesis, a n dr o ge n i nse nsiti vit y), i n vesti gat or discreti o n 
s h o ul d be a pplie d t o deter mi ni n g st u d y  e ntr y.
N ote: D oc u me ntati o n f or a n y  of t he a b o ve cate g ories ca n c o me fr o m t he site 
pers o n nel’s re vie w of t he partici pa nt’s me dical rec or ds, me dical e xa mi nati o n, or 
me dical hist or y  i nter vie w.  T he met h o d of d oc u me ntati o n s h o ul d be rec or de d i n t he 
partici pa nt’s me dical rec or d f or t he st u d y.
2.
P ost me n o pa usal fe male .

A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n 
alter nati ve me dical ca use. I n a d diti o n, a

Hi g h F S H le vel i n t he p ost me n o pa usal ra n ge m ust be use d t o c o nfir m a 
p ost me n o pa usal state i n w o me n u n der 6 0 ye ars ol d a n d n ot usi n g h or m o nal 
c o ntrace pti o n or H R T. 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 4 4

Fe male o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o 
use o ne of t he n o nestr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds 
if t he y wis h t o c o nti n ue t heir H R T d uri n g t he st u d y. Ot her wise, t he y  m ust 
disc o nti n ue H R T t o all o w c o nfir mati o n of p ost me n o pa usal stat us bef ore st u d y  
e nr oll me nt.
1 0. 4. 4. C o ntr ace pti o n Met h o ds
C o ntrace pti ve use b y me n or w o me n s h o ul d be c o nsiste nt wit h l ocal a vaila bilit y/re g ulati o ns 
re gar di n g t he use of c o ntrace pti ve met h o ds f or t h ose partici pati n g i n cli nical trials.
Hi g hl y Effecti ve Met h o ds T h at H a ve L o w User De pe n de n c y
1.
I m pla nta ble pr o gest o ge n-o nl y  h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n .
2.
I ntra uteri ne de vice.
3.
I ntra uteri ne h or m o ne-releasi n g sys te m.
4.
Bilateral t u bal occl usi o n .
5.
Vasect o mize d part ner .

Vasect o mize d part ner is a hi g hl y effecti ve c o ntrace pti ve met h o d pr o vi de d t hat t he 
part ner is t he s ole se x ual part ner of t he W O C B P a n d t he a bse nce of s per m has 
bee n c o nfir me d. If n ot, a n a d diti o nal hi g hly effecti ve met h o d of c o ntrace pti o n 
s h o ul d be use d. T he s per mat o ge nesis c y cle is a p pr o xi matel y 9 0 d a y s.
Hi g hl y Effecti ve Met h o ds T h at Are User De pe n de nt 
1.
C o m bi ne d (estr o ge n - a n d pr o gest o ge n -c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n .

O ral;

I ntra va gi nal;

T ra ns der mal;

Injecta ble .
2.
Pr o gest o ge n - o nly h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n .

O ral;

Injecta ble .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 4 5
3.
Se x ual a bsti ne nce .

Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y  if defi ne d as 
refrai ni n g fr o m heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d 
wit h t he st u d y  i nter ve nti o n. T he relia bilit y of se x ual a bsti ne nce nee ds t o be 
e val uate d i n relati o n t o t he d urati o n of t he st u dy a n d t he preferre d a n d us ual 
lifest yle of t he partici pa nt.
O ne of t he f oll o wi n g effecti ve barrier met h o ds m ust be use d i n a d diti o n t o t he hi g hl y 
effecti ve met h o ds liste d a b o ve t hat are user de pe n de nt:

Male or fe male c o n d o m wit h or wit h o ut s per mici de;

Cer vical ca p, dia p hra g m, or s p o n ge wit h s per mici de;

A c o m bi nati o n of male c o n d o m wit h eit her cer vical ca p, dia p hra g m, or s p o n ge wit h 
s per mici de ( d o u ble-barrier met h o ds).
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 4 6
1 0. 5. A p pe n di x 5: Ge netics
Use/ A n al ysis of D N A

Ge netic variati o n ma y  i m pact a partici pa nt’s res p o nse t o st u d y i nter ve nti o n, 
s usce pti bilit y t o, a n d se verit y a n d pr o gressi o n of disease. T heref ore, w here l ocal 
re g ulati o ns a n d I R Bs/E Cs all o w, a bl o o d sa m ple will be c ollecte d f or D N A a nal ys is.

T he sc o pe of t he ge netic researc h ma y be narr o w (e g, 1 or m ore ca n di date ge nes ) or
br oa d (e g , t he e ntire ge n o me), as a p pr o priate t o t he scie ntific q uesti o n u n der 
i n vesti gati o n.

T he sa m ples ma y  be a nal yze d as part of a m ultist u d y assess me nt of ge netic fact ors 
i n v ol ve d i n t he res p o nse t o st u d y i nter ve nti o n or st u d y i nter ve nti o ns of t his class t o 
u n dersta n d treat me nts f or t he disease(s) u n der st u d y  or t he disease(s) t he msel ves.

T he res ults of ge netic a nal y ses ma y be re p orte d i n t he C S R or i n a se parate st u d y 
su m mar y , or ma y be use d f or i nter nal decisi o n ma ki n g wit h o ut bei n g i ncl u de d i n a 
st u d y re p ort.

T he s p o ns or will st ore t he D N A sa m ples i n a sec ure st ora ge s pace wit h a de q uate 
meas ures t o pr otect c o nfi de ntialit y . 

T he sa m ples will be retai ne d as i n dicate d:

Sa m ples f or s pecifie d ge netic a nal ys is (see Secti o n 8. 7. 3 ) will be st ore d f or u p t o 
1 5 ye ars or ot her peri o d as per l ocal re q uire me nts.

Sa m ples f or ba n ki n g will be st ore d i n defi nitel y or f or a not her peri o d as per l ocal 
re q uire me nts. 

Partici pa nt s ma y wit h dra w t heir c o nse nt f or t he st ora ge a n d/ or use of t heir Ba n ke d 
B i os peci me ns at a n y ti me b y ma ki n g a re q uest t o t he i n vesti gat or; i n t his case, a n y 
re mai ni n g material will be destr oye d.  Data alrea d y ge nerate d fr o m t he sa m ples will 
be retai ne d t o pr otect t he i nte grit y of e xisti n g a nal yses.

Ba n ke d B i os peci me ns will be la bele d wit h a c o de.  T he ke y bet wee n t he c o de a n d t he 
partici pa nt ’s pers o nall y i de ntif yi n g i nf or mati o n (e g, na me, a d dress) will be hel d at t he 
st u d y site a n d will n ot be pr o vi de d t o t he sa m ple ba n k.  
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 4 7
1 0. 6. A p pe n di x 6: Li ver S afet y: S u g geste d Acti o ns a n d F oll o w -u p Assess m e nts 
P ote nti al C ases of Dr u g -I n d uce d Li ver I nj ur y
H u ma ns e x p ose d t o a dr u g w h o s h o w n o si g n of li ver i nj ur y  (as deter mi ne d b y ele vati o ns i n 
tra nsa mi nases) are ter me d “t olerat ors,” w hile t h ose w h o s h o w tra nsie nt li ver i nj ur y, b ut a da pt 
are ter me d “a da pt ors .”  I n s o me partici pa nt s, tra nsa mi nase ele vati o ns are a har bi n ger of a 
m ore seri o us p ote ntial o utc o me.  T hese partici pa nt s fail t o a da pt a n d t heref ore are 
“s usce pti ble” t o pr o gressi ve a n d seri o us li ver i nj ur y, c o m m o nly referre d t o as DI LI.  
Partici pa nts w h o e x perie nce a tra nsa mi nase ele vati o n a b o ve 3 × U L N s h o ul d be m o nit ore d 
m ore fre q ue ntl y  t o deter mi ne if t he y are a n “a da pt or” or are “s usce pti ble.”
I n t he maj orit y of DI LI cases, ele vati o ns i n A S T a n d/ or A L T prece de T Bili ele vati o ns
( > 2 × U L N) b y s e veral da ys or wee ks.  T he i ncrease i n TB ili t ypicall y  occ urs w hile 
A S T/ A L T is/are still ele vate d a b o ve 3 × U L N (ie, A S T/ A L T a n d T B ili val ues will be 
ele vate d wit hi n t he sa me la b orat or y sa m ple).  I n rare i nsta nces, b y t he ti me T Bili ele vati o ns 
are detecte d, A S T/ A L T val ues mi g ht ha ve decrease d.  T his occ urre nce is still re gar de d as a 
p ote ntial DI LI.  T heref ore, a b n or mal ele vati o ns i n eit her A S T O R A L T i n a d diti o n t o T Bili
t hat meet t he criteria o utli ne d bel o w are c o nsi dere d p ote ntial DI LI (assesse d per H y’s la w 
criteria) cases a n d s h o ul d al wa ys be c o nsi dere d i m p orta nt me dical e ve nts, e ve n bef ore all 
ot her p ossi ble ca uses of li ver i nj ur y  ha ve bee n e xcl u de d.
T he t hres h ol d of la b orat or y  a b n or malities f or a p ote ntial DI LI case de pe n ds o n t he 
partici pa nt ’s i n di vi d ual baseli ne val ues a n d u n derl yi n g c o n diti o ns.  Partici pa nt s w h o prese nt 
wit h t he f oll o wi n g la b orat or y  a b n or malities s h o ul d be e val uate d f urt her as p ote ntial DI LI 
( Hy’s la w) cases t o defi niti vel y  deter mi ne t he eti ol o g y of t he a b n or mal la b orat or y val ues:

Partici pa nt s wit h A S T/ A L T a n d T Bili baseli ne val ues wit hi n t he n or mal ra n ge w h o 
s u bse q ue ntl y prese nt wit h A S T O R A LT val ues > 3 × U L N A N D a T Bili val ue 
> 2 × U L N wit h n o e vi de nce of he m ol ys is a n d a n al kali ne p h os p hatase val ue 
< 2 × U L N or n ot a vaila bl e.

F or partici pa nt s wit h baseli ne A S T O R A L T O R T Bili val ues a b o ve t he U L N, t he 
f oll o wi n g t hres h ol d val ues are use d i n t he defi niti o n me nti o ne d a b o ve, as nee de d, 
de pe n di n g o n w hic h val ues are a b o ve t he U L N at baseli ne:

Pree xisti n g A S T or A L T baseli ne val ues a b o ve t he n or mal ra n ge: A S T or A L T 
val ues > 2 ti mes t he baseli ne val ues A N D > 3 × U L N; or > 8 × U L N ( w hic he ver is 
s maller).

Pree xisti n g val ues of T Bili a b o ve t he n or mal ra n ge: T Bili le vel i ncrease d fr o m 
baseli ne val ue b y a n a m o u nt of at least 1 × U L N o r if t he val ue reac hes 
> 3 × U L N ( w hic he ver is s maller).
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 4 8
Rises i n A S T/ A L T a n d T Bili se parate d by m ore t ha n a fe w wee ks s h o ul d be assesse d 
i n di vi d uall y base d o n cli nical j u d g me nt; a n y case w here u ncertai nt y re mai ns as t o w het her it 
re prese nts a p ote ntial H y’s la w case s h o ul d be re vie we d wit h t he s p o ns or.  
T he partici pa nt s h o ul d ret ur n t o t he i n vesti gat or site a n d be e val uate d as s o o n as p ossi ble, 
prefera bl y wit hi n 4 8 h o urs fr o m a ware ness of t he a b n or mal res ults.  T his e val uati o n s h o ul d 
i ncl u de la b orat or y tests, detaile d hist or y, a n d p h ysical assess me nt.  
I n a d diti o n t o re peati n g meas ure me nts of A S T a n d A LT a n d T Bili f or s us pecte d cases of 
H y ’s la w, a d diti o nal la b orat or y tests s h o ul d i ncl u de al b u mi n, C K, direct a n d i n direct 
bilir u bi n, G G T, P T/I N R, t otal bile aci ds, a n d al kali ne p h os p hatase.  C o nsi derati o n s h o ul d 
als o be gi ve n t o dra wi n g a se parate t u be of cl otte d bl o o d a n d a n a ntic oa g ulate d t u be of bl o o d 
f or f urt her testi n g, as nee de d, f or f urt her c o nte m p ora ne o us a nalys es at t he ti me of t he 
rec o g nize d i nitial a b n or malities t o deter mi ne eti ol o g y.  A detaile d hist or y, i ncl u di n g rele va nt 
i nf or mati o n, s uc h as re vie w of et ha n ol, aceta mi n o p he n/ paraceta m ol (eit her b y itself or as a 
c of or m ulate d pr o d uct i n prescri pti o n or o ver -t he-c o u nter me dicati o ns), recreati o nal dr u g, 
s u p ple ment ( her bal) use a n d c o ns u m pti o n, fa mil y  hist or y, se x ual hist or y, tra vel hist or y, 
hist or y  of c o ntact wit h a ja u n dice d pers o n, s ur ger y, bl o o d tra nsf usi o n, hist or y of li ver or 
aller gic disease, a n d p ote ntial occ u pati o nal e x p os ure t o c he micals, s h o ul d be c olle cte d.  
F urt her testi n g f or ac ute he patitis A, B, C, D, a n d E i nfecti o n a n d li ver i ma gi n g (e g, biliar y  
tract) a n d c ollecti o n of ser u m sa m ple s f or aceta mi n o p he n/ paraceta m ol dr u g a n d/ or pr otei n 
a d d uct le vels m a y  be warra nte d. 
All cases de m o nstrate d o n re peat testi n g as meeti n g t he la b orat or y criteria of A S T/ A LT a n d 
T Bili ele vati o n defi ne d a b o ve s h o ul d be c o nsi dere d p ote ntial DI LI ( H y ’s la w) cases if n o 
ot her reas o n f or t he L F T a b n or malities has yet bee n f o u n d.  S uc h p ote nti al DI LI ( H y’s l a w) 
c ases are t o be re p orte d as S A Es, irres pecti ve of a v ail a bilit y of all t he res ults of t he 
i n vesti g ati o ns perf or me d t o deter mi ne eti ol o g y of t he L F T a b n or m alities.
A p ote ntial DI LI ( H y ’s la w) case bec o mes a c o nfir me d case o nly after all res ults of 
reas o na ble i n vesti gati o ns ha ve bee n recei ve d a n d ha ve e xcl u de d a n alter nati ve eti ol o g y .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 4 9
1 0. 7. A p pe n di x 7: E C G Fi n di n gs of P ote nti al Cli nic al C o ncer n
E C G Fi n di n gs T h at M a y Q u alif y as A d verse E ve nts

Mar ke d si n us b ra dyc ar dia (rate < 4 0 b p m) lasti n g mi n utes .

Ne w P R i nter val pr ol o n gati o n > 2 8 0 ms ec.

Ne w pr ol o n gati o n of Q Tc F t o > 4 8 0 ms ec (a bs ol ute) or by ≥6 0 ms ec fr o m baseli ne.

Ne w - onset atrial fl utter or fi brillati o n, wit h c o ntr olle d ve ntric ular res p o nse rate: 
ie, rate < 1 2 0 b p m .

Ne w - onset ty pe I sec o n d - de gree ( We nc ke bac h) A V b l oc k of > 3 0 sec o n ds’
d urati o n .

Fre q ue nt P V Cs, tri plets, or s h ort i nter vals ( < 3 0 sec o n ds) of c o nsec uti ve ve ntric ular 
c o m ple xes .
E C G Fi n di n gs T h at M a y Q u alif y as Seri o us A d verse E ve nts

Q Tc F pr ol o n gati o n > 5 0 0 ms ec.

Ne w S T -T c ha n ges s u g gesti ve of m y ocar dial isc he mia .

Ne w - onset left b u n dle b ra nc h b l oc k ( Q R S > 1 2 0 ms ec).

Ne w - onset ri g ht b u n dle b ra nc h b l oc k ( Q R S > 1 2 0 ms ec).

S y m pt o matic b ra dyc ar dia.

As y st ole:

I n a wa ke, sy m pt o m -free partici pa nt s i n si n us r h yt h m, wit h d oc u me nte d peri o ds 
of as ys t ole ≥3. 0 sec o n ds or a n y esca pe rate < 4 0 b p m, or wit h a n esca pe r h yt h m 
t hat is bel o w t he A V n o de. 

I n a wa ke, sy m pt o m -free partici pa nt s wit h atrial fi brillati o n a n d bra d yc ar dia 
wit h 1 or m ore pa uses of at least 5 sec o n ds or l o n ger. 

Atrial fl utter or fi brillati o n, wit h ra pi d ve ntric ular res p o nse rate:
ra pi d = rate 
> 1 2 0 b p m.

S ustai ne d su pra ve ntric ular tac h yc ar dia (rate > 1 2 0 b p m) ( “s ustai ne d” = s h ort 
d urati o n wit h rele va nt s y m pt o ms or lasti n g > 1 mi n ute) .
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 5 0

Ve ntric ular r h y t h ms > 3 0 sec o n ds’ d urati o n, i ncl u di n g i di o ve ntric ular r h yt h m ( heart 
rate < 4 0 b p m), accelerate d i di o ve ntric ular r h y t h m (H R > 4 0 b p m t o < 1 0 0 b p m ), a n d 
m o n o m or p hic/ p ol y m or p hic ve ntric ular tac h ycar dia ( H R > 1 0 0 b p m (s uc h as
torsa des de p oi ntes) ).

T y pe II sec o n d - de gree ( M o bitz II) A V b l oc k.

C o m plete (t hir d- de gree) h eart b l oc k.
E C G Fi n di n gs T h at Q u alif y as Seri o us A d verse E ve nts

C ha n ge i n patter n s u g gesti ve of ne w m y ocar dial i nfarcti o n.

S ustai ne d v e ntric ular ta c h yarr h yt h mias ( > 3 0 sec o n ds’ d urati o n) .

Sec o n d - or t hir d -de gree A V bl oc k re q uiri n g pace ma ker place me nt.

As y st olic pa uses re q uiri n g pace ma ker place me nt.

Atrial fl utter or fi brillati o n wit h ra pi d ve ntric ular res p o nse re q uiri n g car di o versi o n .

Ve ntric ular fi brillati o n/fl utter.

At t he discreti o n of t he i n vesti gat or, a n y arr h yt h mia classifie d as a n a d verse 
e x perie nce .
T he e n u merate d list of maj or e ve nts of p ote ntial cli nical c o ncer n are rec o m me n de d as “alerts” or 
n otificati o ns fr o m t he c ore E C G la b orat or y t o t he i n vesti gat or a n d Pfizer st u d y tea m, a n d n ot t o be 
c o nsi dere d as all i ncl usi ve of w hat t o be re p orte d as A Es/ S A Es.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 5 1
1 0. 8. A p pe n di x 8 : C o u ntr y - Specific Re q uire me nts
1 0. 8. 1. Fr a nce C o ntr at U ni q ue
1.
G C P Trai ni n g 
Bef ore e nr olli n g a n y partici pa nt s, t he i n vesti gat or a n d a ny s u bi n vesti gat ors will 
c o m plete t he Pfizer -pr o vi de d G o o d Cli nical Practice trai ni n g c o urse (“ Pfizer G C P 
Trai ni n g”) or trai ni n g dee me d e q ui vale nt b y Pfizer.  A n y i n vesti gat ors w h o later j oi n 
t he st u d y will d o t he sa me bef ore perf or mi n g st u d y-relate d d uties.  F or st u dies of 
a p plica ble d urati o n, t he i n vesti gat or a n d s u bi n vesti gat ors will c o m plete Pfizer G C P 
Trai ni n g or e q ui vale nt e ver y  3 years d uri n g t he ter m of t he st u d y, or m ore ofte n if 
t here are si g nifica nt c ha n ges t o t he I CH G C P g ui deli nes or c o urse materials. 
2.
St u d y  Inter ve nti o n
N o partici pa nt s or t hir d-part y  p a yers will be c har ge d f or st u d y i nter ve nti o n.
3.
Ur ge nt Safet y M eas ures
I n a d diti o n, t he i n vesti gat or will i nf or m Pfizer i m me diatel y of a n y ur ge nt safety 
meas ures ta ke n b y t he i n vesti ga t or t o pr otect t he st u d y partici pa nt s a gai nst a n y 
i m me diate hazar d, a n d of a n y seri o us breac hes of t his pr ot oc ol or of I C H G C P t hat 
t he i n vesti gat or bec o mes a ware of.
4.
Ter mi nati o n R i g hts 
Pfizer retai ns t he ri g ht t o disc o nti n ue de vel o p me nt of P F - 0 7 2 8 4 8 9 0 at a n y t i me.
T he i n vesti gat or a grees t o a bi de b y t he et hical pri nci ples set f ort h i n t he W orl d Healt h 
Or ga nizati o n’s G ui di n g Pri nci ples f or H u m a n Cell, Tiss ue a n d Or g a n Tr a ns pl a nt ati o n 
( W H A 6 3. 2 2) (htt p:// w w w . w h o.i nt/tra ns pla ntati o n/e n/) wit h re gar d t o t he s t u d y.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 5 2
1 0. 9. A p pe n di x 9 : Det aile d D ose Esc al ati o n/ De -Esc al ati o n Sc he me f or B L R M Desi g n
Ba yesia n desi g n usi n g E W O C will g ui de t he d ose escalati o n f or P F - 0 72 8 4 8 9 0 m o n ot hera p y 
as well as f or its c o m bi nati o ns wit h bi ni meti ni b . T he use of Ba y esia n res p o nse a da pti ve 
desi g ns f or P hase 1 st u dies has bee n a d v ocate d f or a n d is o ne of t he ke y  ele me nts of t he 
F D A’s Critical Pat h I nitiati ve. 4 7 ,4 8
T he B L R M will be set -u p se paratel y f or t he d ose-t o xicit y relati o ns hi p of P F - 0 7 2 8 4 8 9 0 w he n 
a d mi nistere d as m o n ot hera p y  a n d i n c o m bi nati o n wit h bi ni meti ni b. T his Ba yesia n a nal ysis 
will be base d o n t he d ose li miti n g t o xicit y  data (a bse nce or prese nce of D L T) d uri n g t he first
c ycle ( DL T o bser vati o n peri o d) acc u m ulate d t hr o u g h o ut t he d ose escalati o n.   T his a p pe n di x 
pr o vi des t he details of t he statistical m o del, t he descri pti o n of pri or distri b uti o n. T he res ults 
of t he Ba y esia n a nal ys es a n d res pecti ve d osi n g decisi o ns f or s o me h y p ot hetical data 
sce nari os, a n d a si m ulati o n st u d y of t he o perati n g c haracteristics of t he m o del c o ul d be f o u n d 
i n t he se parate Tec h nical s u p ple me nt t o t his a p pe n di x.
1 0. 9. 1. St atistic al M o dels
D uri n g P hase 1 a d ose escalati o n, B L R M wit h E W O C will be use d t o descri be t he D L T 
relati on s hi p of P F-0 7 2 8 4 8 9 0 m o n ot hera p y , t o descri be t he D L T relati o ns hi p of P F- 0 7 2 8 4 8 9 0 
+ bi ni meti ni b , a n d t o g ui de t he decisi o n t o escalate t he d ose of P F -0 7 2 8 4 8 9 0 . 
1 0. 9. 2. Pri or S pecific ati o ns f or M o n ot her a p y B L R M
I n t he m o n ot hera py d ose escalati o n p orti o n of P hase 1 a, t he D L T relati o ns hi p of 
P F - 0 7 2 8 4 8 9 0 gi ve n as a si n gle a ge nt will be descri be d b y  a 2-para meter B L R M f or m ulate d 
as f oll o ws:
l o git π( ) = l o g( ) + β l o g  ∗W here, π( d) is t he pr o ba bilit y  t hat a patie nt has a D LT d uri n g t he first c y cle ( 2 1 da ys) w he n 
P F -0 7 2 8 4 8 9 0 is gi ve n as si n gle a ge nt. T he para meter d * is t he refere nce d ose i n t he m o del 
a n d is use d t o scale t he d oses of P F - 0 7 2 8 4 8 9 0.  T he α, β > 0 are t he para meters of t he m o del 
s uc h t hat  ( > 0) is t he P F - 0 7 2 8 4 8 9 0 o d ds of a D L T at  ∗; a n d  ( > 0) is t he i ncrease i n t he 
l o g- o d ds of a D L T b y  a u nit i ncrease i n l o g-d ose.
T he Ba y esia n a p pr oac h re q uires t he s pecificati o n of pri or distri b uti o ns f or t he m o del 
para meters l o g ( ) a n d l o g( ).  A vaila ble precli nical t o xic ol o g y ma kes it diffic ult t o pre dict 
t o xicit y pr ofile of P F-0 7 2 8 4 8 9 0 si n gle a ge nt i n h u ma ns.  A vaila ble t o xicit y data fr o m a 
si milar c o m p o u n d (e nc orafe ni b) will be use d a n d c o m bi ne d wit h a wea kl y i nf or mati ve pri or 
all o wi n g f or c o nsi dera ble u ncertai nt y, s o t hat t he a -pri ori ra n ge f or t he para meters c o vers a 
wi de ra n ge of pla usi ble val ues.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 5 3
1 0. 9. 3. Pri or S pecific ati o ns f or C o m bi n ati o n B L R M
I n t he c o m bi nati o n-t hera p y d ose escalati o n p orti o n of Phase 1a , t he D L T relati o ns hi p of 
P F -0 7 2 8 4 8 9 0 a n d bi ni meti ni b gi ve n as a c o m bi nati o n -t hera py will be descri be d b y  a 
5 - para meter B L R M f or m ulate d as f oll o ws:

P F - 0 7 2 8 4 8 9 0 si n gle a ge nt t o xicit y, re prese nte d b y para meters α1, a n d β1:
l o git π  (d  ) = l o g(α  ) + β  l o g d d ∗
T he si n gle a ge nt t o xicit y  of t he c o m bi nati o n part ner, bi ni meti ni b, re prese nte d b y 
para meters α 2, a n d β2:
l o git π  (d  ) = l o g(α  ) + β  l o g d d ∗w here π 1( d1) a n d π2( d2) are t he pr o ba bilit y t hat a patie nt has a D L T d uri n g t he first c ycle of 
c o m bi nati o n treat me nt wit h P F - 0 7 2 8 4 8 9 0 a n d t he c o m bi nati o n part ner, bi ni meti ni b at d ose d 1
a n d d 2 res pecti vely a n d w here d ∗a n d d ∗are t he P F -0 7 2 8 4 8 9 0 a n d c o m bi nati o n part ner 
refere nce d oses.
T he n, t he d ose - D L T relati o ns hi p of t he c o m bi nati o n is defi ne d as:
        (  ,  ) =
   (  ,  )
1 −   (  ,  ) = e x p ( η   ∗
  ∗)   (  ) +   (  ) −  (  )  (  )
( 1 − (  ))( 1 −  (  ))
w here η is t he i nteracti o n para meter bet wee n P F - 0 7 2 8 4 8 9 0 a n d its c o m bi nati o n part ner. T he 
dr u g c o m bi nati o n ma y  pr o d uce a t o xic effect w h ose ma g nit u de is less t ha n ( pr otecti ve, η < 0), 
e q ual t o ( n o i nteracti o n, η = 0), or greater t ha n (s y ner gistic, η > 0) t hat o btai ne d b y  t he 
treat me nts acti n g i n de pe n de ntl y.
T he Ba y esia n a p pr oac h re q uires t he s pecificati o n of pri or distri b uti o ns f or t he m o del 
para meters l o g(  ), l o g(  ), l o g(  ), l o g(  ) a n d t he i nteracti o n para meter η.
T he pri or f or l o g(  ), l o g(  ) will be base d o n e mer gi n g D L T dat a fr o m P F - 0 7 2 8 4 8 9 0 i n t he 
m o n ot hera p y p orti o n of P hase 1a . T he pri or f or l o g(  ), l o g(  ) will be base d o n safet y  
data a vaila ble i n t he literat ure f or bi ni meti ni b f or t he c o m bi nati o n part of P hase 1a . A 
wea kl y i nf or mati ve pri or f or t he i nteracti o n para mete r η will be use d reflecti n g t he c urre nt 
u ncertai nt y a b o ut t he i nteracti o n.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 5 4
Met a - An al ytic -Pre dicti ve Pri ors A p pr o ac h 
A M A P pri or ma y  be use d t o defi ne t he pri or f or a n y or all of t he d ose c o h orts i n t he d ose 
escalati o n i n or der t o acc o u nt f or heter o ge neit y bet wee n t he a vaila ble D L T data a n d t he 
act ual st u d y pr ot oc ol p o p ulati o n a n d treat me nt re gi me n/sc he d ule. A M A P pri or ma y be use d 
i nstea d of, or i n a d diti o n t o a wea kly i nf or mati ve pri or t o f or m a wei g hte d mi xt ure pri or a n d 
acc o u nt f or u ncertai nt y. A mi xt ure pri or ca n ta ke t he f or m :
 ×      +
(1 − ) ×       T he wei g hts of t he mi xt ure pri or are dri ve n b y cli nical j u d ge me nt. T he ai m of t he M A P pri or 
a p pr oac h f or treat me nt  is t o deri ve a pri or distri b uti o n f or t he l o gistic para meters 
(l o g( ∗),l o g( ∗) ) usi n g pri or D L T data, a vaila ble fr o m pre vi o usl y  c o n d ucte d trial, or fr o m 
t he sa me st u d y b ut wit h a n ot her re gi me n. 
Let  a n d   be t he n u m ber of partici pa nts wit h a D L T, a n d t he t otal n u m ber of partici pa nts 
at d ose   i n t he D L T data a vaila ble fr o m t he hist orical trial. T he c orres p o n di n g pr o ba bilit y  
of a D L T is   .  T he m o del s pecificati o ns are as f oll o ws:
 |   ~ Bi n (  , )
l o git(  ) = l o g( ) +   l o g( /  ∗)
   ( ),  (  )  ,  ~ B V N ( , )
   ( ∗),  ( ∗)  ,  ~ B V N ( , )
T he para meter   = (   ,  ) is t he mea n f or t he l o gistic para meters, a n d   is t he 
bet wee n -re gi me n/st u dy c o varia nce matri x.  C o varia nce matri x   is defi ne d by t he sta n dar d 
de viati o ns ( ,  ), a n d c orrelati o n .  
T he f oll o wi n g pri ors will be use d f or t hese para meters: 
n or mal pri ors f or    a n d   ; 
l o g-n or mal pri ors f or   a n d  , a n d 
a u nif or m pri or f or .
T o f urt her s pecif y  t he details of t hese distri b uti o ns t he pri nci ples descri be d i n 
Ne ue nsc h wa n der et.al., 2 0 1 4 4 9 will be f oll o we d. T he M A P pri or f or m o del para meters of 
P F - 0 7 2 8 4 8 9 0,    ( ∗),  ( ∗) , is t he pre dicti ve distri b uti o n. 
   ( ∗),  ( ∗)  (, )
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 5 5
Si nce t he pre dicti ve distr i b uti o n is n ot a vaila ble a nal yticall y, t he M C M C met h o d is use d t o 
si m ulate val ues fr o m t his distri b uti o n. T his is i m ple me nte d usi n g J A G S versi o n 4. 1 0 .
Se nsiti vit y a n al ysis
Des pite bei n g pres pecifie d i n t he pr ot oc ol, s o me A Es t hat fall i nt o t he cate g or y  of D L Ts ma y  
nee d t o be c o nsi dere d differe ntl y. C o n versel y , s o me A Es t hat are n ot defi ne d as a D L T per 
pr ot oc ol s h o ul d be c o nsi dere d b y t he d ose escalati o n al g orit h m. Acc or di n gl y, t he ne w 
c o nce pt of a n “e q ui v ocal” D L T or A E is i ntr o d uce d: m ost A E/ D L Ts are c o nsi dere d 
“ u ne q ui v ocal,” b ut certai n t ypes of A Es/ D L Ts are c o nsi dere d t o be “e q ui v ocal.” T o miti gate 
t he ris k of dic h ot o mizi n g a n d misclassif yi n g D L Ts, t he se nsiti vit y a nalys is t hat uses t h ose 
wei g hte d e q ui v ocal D L T/ A E data i nt o t he B L R M m o del esti mati o n will als o be perf or me d.
T he B L R M m o del uses all t he e q ui v ocal a n d u ne q ui v ocal A E/ D L T data, b ut t he varia bilit y 
ass ociate d wit h e q ui v ocal A Es/ D L Ts (less i nter preta ble) is i ncrease d. S o, t he m o del 
rec o m me n dati o ns are m ore hea vily wei g hte d t o war ds u ne q ui v oc al data. See bel o w f or t he 
p osteri or distri b uti o n of t he B L R M m o del para meters base d o n t he t he or y  of p o wer pri or.
S u p p ose n partici pa nts treate d at d ose  wit h u ne q ui v ocal D L Ts a n d r e q ui v ocal 
D L Ts/ A Es, a n d t he wei g ht w f or t he e q ui v ocal data, t he n base d o n t he p o wer pri or,
       ( ,  | , , , )
∝ (  | , , , )
×  (  | , , , ) ×
    ( , )
∝ ( , , )  × [1 − ( , , )]      ×  ( , , )   ×
    ( , ),
w here L is t he li keli h o o d of t he o bser ve d D L T data, a n d  ( , , ) is t he pr o ba bilit y of D L T 
at d ose  t hat is m o dele d b y l o gistic re gressi o n i n B L R M. T o ac hie ve t he e q ualit y si g n,
a p pr o priate n or malizi n g c o nsta nt is re q uire d. T he c o ntri b uti o n of e q ui v ocal A Es/ D L Ts t o t he 
data (li keli h o o d) a n d t he Ba yesia n p osteri or esti mati o n of t he M T D are wei g hte d; t he wei g ht 
para meter c o ntr ols t he i nfl ue nce a n d ca n be i nter prete d as a precisi o n para meter f or t he 
e q ui v ocal A E/ D L T data, si milar t o t he scale para meter i n t he p o wer pri or f or t he Ba y esia n 
hist orical b orr o wi n g. T he wei g ht f or a n e q ui v ocal D L T is decrease d (e g, 1 decrease d t o 0. 5) 
a n d t he wei g ht f or a n e q ui v ocal A E ( n o n -D L T b y pr ot oc ol) is i ncrease d (e g, 0 i ncrease d t o 
0. 5). T o mai ntai n t he i nte grit y of a trial, t he wei g ht is pre-s pecifie d as 0. 5 i n t he a nalys is. If 
all t he i n vesti gat ors a n d t he s p o ns or a gree o n t he e q ui v ocal D L T/ A E data, t he D L T 
wei g h ti n g a p pr oac h c o ul d be t he pri mar y d ose escalati o n met h o d. T his D L T wei g hti n g 
a p pr oac h pr o vi des a fle xi ble a n d p o werf ul t o ol t hat ma y  i nc or p orate t he cli nicia n’s val ua ble 
e x perie nce wit h s o me s pecific D L Ts/ A Es a n d i m pr o ve M T D esti mati o n i n d ose -escalati o n
trials.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 5 6
1 0. 1 0. A p pe n di x 1 0 : A nti -e pile ptic Me dic ati o n
T a ble 8 .
Mec h a nis m of E li mi n ati o n of A nti - Epile ptic A ge nts a n d P ote nti al f or 
P F -0 7 2 8 4 8 9 0 t o A lter T heir P K a 3 7 ,5 0 ,5 1
A nt i-e pile ptic dr u g
Mec h a nis m  of eli mi n ati o n
P ote nti al D DI wit h 
P F -0 7 2 8 4 8 9 0
G ui d a nce
Ol der
Car ba maze pi ne b
C Y P 3 A 4
P ossi ble i nteracti o n
Use wit h ca uti o n
Et h os u xi mi de
C Y P 3 A 4
P ossi ble i nteracti o n
Use wit h ca uti o n
P he n yt oi n b
C Y P 2 C 9/ C Y P 2 C 1 9
P ossi ble i nteracti o n 
( C Y P 2 C 9)
Use wit h ca uti o n
P he n o bar bital b
C Y P 2 C 9
P ossi ble i nteracti o n
Use wit h ca uti o n
Pri mi d o ne b
C Y P 2 C 9
P ossi ble i nteracti o n
Use wit h ca uti o n
S o di u m val pr oate b
Se veral U G Ts
N o a p pare nt mec ha nis m
M a y  be use d
Ne wer
La m otri gi ne
U G Ts
N o a p pare nt mec ha nis m
M a y  be use d
O xcar baze pi ne b
C y t os olic e nz y mes i n t he 
li ver
P ossi ble i m pact o n 
meta b olites t hr o u g h P -g p, 
b ut n o a p pare nt cli nical 
rele va nce
M a y  be use d
Ga ba pe nti n
Re nal (eli mi nati o n 
pr o p orti o nal t o C Lcr)
N o a p pare nt mec ha nis m
M a y  be use d
T o pira mate b
Re nal ( n ot P -g p s u bstrate 
i n vitr o)
N o a p pare nt mec ha nis m
M a y  be use d
Le vetiraceta m
Re nal (c orrelate d t o C Lcr)
N o a p pare nt mec ha nis m
M a y  be use d
Z o nisa mi de
C Y P 3 A 4
P ossi ble i nteracti o n
Use wit h ca uti o n
Vi ga batri n
Re nal ( n ot P -g p s u bstrate 
i n vitr o)
N o a p pare nt mec ha nis m
M a y  be use d
Pre ga bali n
Re nal (eli mi nati o n 
pr o p orti o nal t o C Lcr)
N o a p pare nt mec ha nis m
M a y  be use d
Tia ga bi ne
C Y P 3 A 4
P ossi ble i nteracti o n
Use wit h ca uti o n
Lac osa mi de
C Y P 2 C 1 9
N o a p pare nt mec ha nis m
M a y  be use d
Eslicar baze pi ne b
U G Ts
N o a p pare nt mec ha nis m
M a y  be use d
Pera m pa nel b
C Y P 3 A 4
P ossi ble i nteracti o n
Use wit h ca uti o n
Reti ga bi ne
Ar yla mi ne N -acet yl 
tra nsferase-2
N o a p pare nt mec ha nis m
M a y  be use d
R ufi na mi de b
Car b o x ylesterases
N o a p pare nt mec ha nis m
M a y  be use d
a.
Base d o n i n vitr o data of P F -0 7 2 8 4 8 9 0 as a per petrat or of D DIs .
b.
T hese dr u gs ca n n ot be use d i n t he P hase 1 b C o h ort 6 D DI s u bst u d y wit h mi daz ola m u ntil after C ycle 1 
d ue t o i n d ucti o n a n d/ or i n hi biti o n of C Y P 3 A, w hic h c o ul d alter mi daz ola m P K.
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 5 7
1 0. 1 1. A p pe n di x 1 1 : Res p o nse E v al u ati o n Criteri a i n S oli d T u m ors (R E CI S T )
versi o n 1. 1
At baseli ne, i n di vi d ual t u m or lesi o ns will be cate g orize d b y  t he i n vesti gat or as eit her 
meas ura ble or n ot, acc or di n g t o t he criteria s u m marize d bel o w:
1.
Meas ura ble Lesi o ns.
Lesi o ns t hat ca n be acc uratel y  meas ure d i n at least 1 di me nsi o n (l o n gest dia meter i n t he 
pla ne of meas ure me nt is t o be rec or de d) wit h a mi ni m u m size of: 

1 0 m m f or lesi o ns ot her t ha n l y m p h n o des a n d assesse d b y  C T sca n ( C T sca n slice 
t hic k ness n o greater tha n 5 m m).

1 0 m m f or lesi o ns assesse d cli nicall y b y cali per meas ure me nt (lesi o ns w hic h ca n n ot 
be acc uratel y meas ure d wit h cali pers s h o ul d be rec or de d as n o n -meas ura ble).

2 0 m m f or lesi o ns assesse d b y  c hest X-ra y.

1 5 m m i n s h ort a xis f or l y m p h n o des w he n as sesse d b y C T sca n ( C T sca n slice 
t hic k ness rec o m me n de d t o be n o greater t ha n 5 m m).
2.
N o n - meas ura ble Lesi o ns .
N o n -meas ura ble lesi o ns i ncl u de s mall lesi o ns (l o n gest dia meter < 1 0 m m or pat h ol o gical 
l ym p h n o des wit h a ≥1 0 b ut < 1 5 m m s h ort a xis) a s well as tr ul y n o n- meas ura ble lesi o ns.  
Tr ul y  n o n- meas ura ble lesi o ns i ncl u de: le pt o me ni n geal disease, ascites, ple ural or pericar dial 
eff usi o n, i nfla m mat or y breast disease, l ym p ha n gitic i n v ol ve me nt of s ki n or l u n g, a b d o mi nal 
masses i de ntifie d b y p h ysical e xa mi nati o n a n d n ot meas ura ble b y re pr o d uci ble i ma gi n g 
tec h ni q ues.
N o des t hat ha ve a s h ort a xis < 1 0 m m are c o nsi dere d n o n -pat h ol o gical a n d s h o ul d n ot be 
rec or de d or f oll o we d. 
3.
S pecial C o nsi derati o ns Re gar di n g S pecific Lesi o ns.
B o ne lesi o ns:

B o ne sca n, P E T sca n or p lai n fil ms are n ot c o nsi dere d a de q uate i ma gi n g tec h ni q ues 
t o meas ure b o ne lesi o ns.  H o we ver, t hese tec h ni q ues ca n be use d t o c o nfir m t he 
prese nce or disa p peara nce of b o ne lesi o ns.

L yt ic b o ne lesi o ns or mi xe d l ytic-blastic lesi o ns, wit h i de ntifia ble s oft ti ss ue 
c o m p o ne nts, t hat ca n be e val uate d b y cr oss secti o nal i ma gi n g tec h ni q ues s uc h as C T 
or M RI  ca n be c o nsi dere d as meas ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt meets 
t he defi niti o n of meas ura bilit y descri be d a b o ve.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 5 8

Blastic b o ne lesi o ns are n o n- meas ura b le. 
C y stic lesi o ns:

Lesi o ns t hat meet t he criteria f or ra di o gra p hicall y defi ne d si m ple c y sts s h o ul d n ot be 
c o nsi dere d as mali g na nt lesi o ns ( neit her meas ura ble n or n o n -meas ura ble) si nce t he y  
are, b y defi niti o n, si m ple c y sts.

‘ C ystic lesi o ns’ t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d as 
meas ura ble lesi o ns, if t he y meet t he defi niti o n of meas ura bilit y  descri be d a b o ve.  
H o we ver, if n o nc y stic lesi o ns are prese nt i n t he sa me partici pa nt, t hese are preferre d 
f or selecti o n as tar get lesi o ns.
Lesi o ns wit h pri or l ocal treat me nt:

T u m or lesi o ns sit uate d i n a pre vi o usl y irra diate d area, or i n a n area s u bjecte d t o ot her 
l oc o-re gi o nal t hera py, are us uall y n ot c o nsi dere d meas ura ble u nless t here has bee n 
de m o nstrate d pr o gressi o n i n t he lesi o n.
S olitar y  lesi o ns:

If a meas ura ble disease is restricte d t o a s olitar y lesi o n, its ne o plastic nat ure s h o ul d be 
c o nfir me d b y c yt ol o g y / hist ol o g y. 
Rec or di n g T u m or Me as ure me nts
All meas ura ble lesi o ns u p t o a ma xi m u m of 2 lesi o ns per or ga n a n d u p t o 5 i n t otal a n d 
re prese ntati ve of all i n v ol ve d orga ns s h o ul d be i de ntifie d as tar get lesi o ns a n d meas ure d a n d 
rec or de d at baseli ne a n d at t he sti p ulate d i nter vals d uri n g treat me nt.  Tar get lesi o ns s h o ul d be 
selecte d o n t he basis of t heir size (lesi o ns wit h t he l o n gest dia meters) a n d t heir s uita bilit y f or 
acc urate re petiti ve meas ure me nts (eit her b y i ma gi n g tec h ni q ues or cli nicall y). 
T he l o n gest dia meter will be rec or de d f or eac h tar get lesi o n.  T he s u m of t he l o n gest 
dia meter of all tar get lesi o ns will be calc ulate d a n d rec or de d as t he baseli ne s u m dia meter t o 
be use d as refere nce t o f urt her c haracterize t he o bjecti ve t u m or res p o nse of t he meas ura ble 
di me nsi o n of t he disease d uri n g treat me nt. 
O ne ( 1) e xce pti o n t o t he a b o ve descri be d a p pr oac h is relate d t o pat h ol o gical l y m p h n o des.  
Pat h ol o gical l y m p h n o des are defi ne d as meas ura ble lesi o ns a n d ma y  be i de ntifie d as tar get 
lesi o ns if t he criteri o n of a s h ort a xis of ≥1 5 m m b y C T sca n is met.  O nl y t he s h ort a xis of 
t hese n o des will c o ntri b ute t o t he baseli ne s u m.  N o dal size is n or mall y  re p orte d as t w o 
di me nsi o ns i n t he pla ne i n w hic h t he i ma ge is o btai ne d (f or C T sca n t his is al m ost al wa ys t he 
a xial pla ne; f or M RI t he pla ne of ac q uisiti o n ma y be a xial, sa gittal or c or o nal).  T he s maller 
of t hese meas ures is t he s h ort a xis. 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 5 9
A s u m of t he dia meters (l o n gest f or n o n -n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or all 
tar get lesi o ns will be calc ulate d a n d re p orte d as t he baseli ne s u m dia meters.  T he baseli ne 
s u m dia meters will be use d as refere nce t o f urt her c haracterize a ny o bjecti ve t u m or 
re gressi o n i n t he meas ura ble di me nsi o n of t he disease.
All ot her lesi o ns ( or sites of disease) s h o ul d be i de ntifie d as n o n -tar get lesi o ns a n d s h o ul d 
als o be rec or d e d at baseli ne.  Meas ure me nts are n ot re q uire d a n d t hese lesi o ns s h o ul d be 
f oll o we d as ‘ prese nt’, ‘a bse nt’, or i n rare cases ‘ u ne q ui v ocal pr o gressi o n’.  I n a d diti o n, it is 
p ossi ble t o rec or d m ulti ple n o n -tar get lesi o ns i n v ol vi n g t he sa me or ga n as a si n gle ite m o n 
t he case rec or d f or m (e g, ‘ m ulti ple e nlar ge d pel vic l ym p h n o des’ or ‘ m ulti ple li ver 
metastases’).
Defi niti o n of T u m or Res p o nse 
T ar get Lesi o ns
Res p o nse i n tar get lesi o ns is defi ne d as f oll o ws:

C o m plete Res p o nse ( C R): disa p peara nce of all tar get les i o ns. 

Partial Res p o nse ( P R): at least a 3 0 % decrease i n t he s u m of dia meters of tar get 
lesi o ns, ta ki n g as refere nce t he baseli ne s u m dia meters.

Pr o gressi ve Disease ( P D): at least a 2 0 % i ncrease i n t he s u m of dia meters of tar get 
lesi o ns, ta ki n g as refere nce t he s mallest s u m o n st u d y (t his i ncl u des t he baseli ne s u m 
if t hat is t he s mallest o n st u d y).  I n a d diti o n t o t he relati ve i ncrease of 2 0 %, t he s u m 
m ust als o de m o nstrate a n a bs ol ute i ncrease of at least 5 m m.  T he a p peara nce of o ne 
or m ore ne w lesi o ns is als o c o nsi dere d a si g n of pr o gressi o n.

Sta ble Disease ( S D): neit her s ufficie nt s hri n ka ge t o q ualif y  f or P R n or s ufficie nt 
i ncrease t o q ualif y f or P D, ta ki n g as refere nce t he s mallest s u m dia meters w hile o n 
st u d y.
W he n n o dal disease is i ncl u de d i n t he s u m of tar get lesi o ns a n d t he n o des decrease t o 
‘ n or mal’ size ( < 1 0 m m), t he y  ma y still ha ve a meas ure me nt re p orte d o n sca ns.  T his 
meas ure me nt s h o ul d be rec or de d e ve n t h o u g h t he n o des are n or mal i n or der n ot t o o verstate 
pr o gressi o n s h o ul d it be base d o n i ncrea se i n size of t he n o des.  As n ote d earlier, t his mea ns 
t hat partici pa nts wit h C R ma y n ot ha ve a t otal s u m of ‘zer o’ o n t he C R F.
N o n -T ar get Lesi o ns
W hile s o me n o n -tar get lesi o ns ma y act uall y be meas ura ble, t he y nee d n ot be meas ure d a n d 
i nstea d s h o ul d be assesse d o nl y q ualitati vely at t he ti me p oi nts s pecifie d i n t he pr ot oc ol. 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 6 0
Res p o nse i n n o n- tar get lesi o ns is defi ne d as f oll o ws:

C o m plete Res p o nse ( C R): Disa p peara nce of all n o n- tar get lesi o ns a n d n or malizati o n 
of t u m or mar ker le vel.  All l y m p h n o des m ust be n o n -pat h ol o gical i n size ( < 1 0 m m 
s h ort a xis).

N o n -C R/ N o n -P D: Persiste nce of 1 or m ore n o n -tar get lesi o n(s) a n d/ or mai nte na nce of 
t u m or mar ker le vel a b o ve t he n or mal li mits. 

Pr o gressi ve Disease ( P D): U ne q ui v ocal pr o gressi o n of e xisti n g n o n -tar get lesi o ns.  
( N ote: t he a p peara nce of 1 or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n).
C yt ol o g y, hist ol o g y 
T hese tec h ni q ues ca n be use d t o differe ntiate bet wee n P R a n d C R i n rare cases if re q uire d b y  
pr ot oc ol (f or e xa m ple, resi d ual lesi o ns i n ger m cell t u m ors). W he n eff usi o ns are k n o w n t o 
be a p ote ntial a d verse effect of treat me nt (e g, ta xa ne c o m p o u n ds or a n gi o ge nesis i n hi bit ors), 
t he c yt ol o gical c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n t hat a p pears or w orse ns 
d uri n g treat me nt ca n be c o nsi dere d if t he meas ura ble t u m or has met criteria f or res p o nse or 
sta ble disease i n or der t o differe ntiate bet wee n res p o nse or sta ble disease a n d pr o gressi ve 
disease.
F or partici pa nts ha vi n g eff usi o ns or ascites, o nl y cases ha vi n g c yt ol o gical pr o of of 
mali g na nc y  s h o ul d be rec or de d o n t he C R F.  Eff usi o ns t hat ha ve n ot bee n e val uate d usi n g 
c yt ol o g y or were f o u n d t o be n o n- mali g na nt s h o ul d n ot be rec or de d o n t he C R F. 
Ne w Lesi o ns 
T he a p peara nce of ne w mali g na nt lesi o ns i n dicates P D.  Ne w lesi o n s h o ul d be u ne q ui v ocal 
(e g, n ot attri b uta ble t o differe nces i n i ma gi n g tec h ni q ue, or c ha n ge i n i ma gi n g m o dalit y or 
fi n di n gs n ot attri b uta ble t o t u m or).  If a ne w lesi o n is e q ui v ocal, f or e xa m ple d ue t o its s mall 
size, c o nti n ue d t hera py a n d f oll o w -u p assess me nt will clarif y  t he eti ol og y  of t he disease.  If 
re peat sca ns c o nfir m t here is defi nitel y a ne w lesi o n, t he n pr o gressi o n s h o ul d be declare d 
usi n g t he date of t he i nitial sca n. 
C o nfir m ati o n of T u m or Res p o nse 
C o nfir mati o n of res p o nse is re q uire d f or n o n -ra n d o mize d trials wit h pri mar y e n d p oi nt of 
res p o nse b ut is n ot re q uire d i n ra n d o mize d st u dies si nce t he c o ntr ol ar m ser ves as a p pr o priate 
mea ns of i nter pretati o n of data.
Deter mi n ati o n of O ver all Res p o nse b y t he R E CI S T versi o n 1. 1 Criteri a
W he n b ot h tar get a n d n o n -tar get lesi o ns are prese nt, i n di vi d ual assess me nts will be rec or de d 
se paratel y.  T he o verall assess me nt of res p o nse will i n v ol ve all para meters as de picte d i n 
T a ble 9 .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 6 1
T a ble 9 .
Res p o nse E v al u ati o n Criteri a i n S oli d T u m ors
T ar get lesi o ns
N o n -t ar get lesi o ns
Ne w Lesi o ns
O ver all res p o nse
C R
C R
N o
C R
C R
N o n -C R/ n o n -P D
N o
P R
C R
N ot e val uate d
N o
P R
P R
N o n -P D or n ot all e val uate d
N o
P R
S D
N o n -P D or n ot all e val uate d
N o
S D
N ot all e val uate d
N o n -P D
N o
N E
P D
A n y
Yes or N o
P D
A n y
P D
Yes or N o
P D
A n y
A n y
Yes
P D
A b bre viati o ns: C R = c o m plete res p o nse; N E = n ot e val ua ble; S D = sta ble disease; P D = pr o gressi ve 
disease; P R = partial res p o nse.
Best o ver all res p o nse
T he best o verall res p o nse is deter mi ne d o nce all t he data f or t he partici pa nt is k n o w n.  Best 
res p o nse i n trials i n w hic h c o nfir mati o n of c o m plete or partial res p o nse is n ot re q uire d 
(ie, ra n d o mize d trails) is defi ne d as t he best res p o nse acr oss all ti me p oi nts (f or e xa m ple, a 
partici pa nt w h o has S D at first assess me nt, P R at sec o n d assess me nt, a n d P D o n last 
assess me nt has a best o verall res p o nse of P R).  W he n S D is belie ve d t o be t he best res p o nse, 
it m ust als o meet t he pr ot oc ol s pecifie d mi ni m u m ti me fr o m baseli ne.  If t he mi ni m u m ti me 
is n ot met w he n S D is ot her wise t he best ti me p oi nt res p o nse, t he partici pa nt’s best res p o nse 
de pe n ds o n t he s u bse q ue nt assess me nts.  F or e xa m ple, a partici pa nt w h o has S D at first 
assess me n t, P D at sec o n d a n d d oes n ot meet mi ni m u m d urati o n f or S D, will ha ve a best 
res p o nse of P D.  T he sa me partici pa nt l ost t o f oll o w-u p after t he first S D assess me nt w o ul d 
be c o nsi dere d n ot e val ua ble. 
W he n c o nfir mati o n of C R a n d P R is re q uire d (ie, n o n- ra n d o mize d trials wit h pri mar y 
e n d p oi nt of res p o nse), t he best o verall res p o nse is defi ne d acc or di n g t o t he t u m or res p o nse 
al o n g t he st u d y.  C o m plete or partial res p o nses ma y be clai me d o nl y if t he criteria f or eac h 
are met at a f oll o wi n g ti me p oi nt as s pecifie d i n t he pr ot oc ol ( ge nerally 4 wee ks later).
Partici pa nts wit h a gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n of treat me nt 
wit h o ut o bjecti ve e vi de nce of disease pr o gressi o n at t hat ti me s h o ul d be re p orte d as 
‘s ym pt o matic deteri orati o n’.  E ver y  eff ort s h o ul d be ma de t o d oc u me nt o bjecti ve pr o gressi o n 
e ve n after disc o nti n uati o n of treat me nt.  S y m pt o matic deteri orati o n is n ot a descri pt or of a n 
o bjecti ve res p o nse: it is a reas o n f or st o p pi n g st u d y  t hera p y.  T he o bjecti ve res p o nse stat us of 
s uch partici pa nts is t o be deter mi ne d b y e val uati o n of tar get a n d n o n -tar get lesi o ns.
I n s o me circ u msta nces it ma y be diffic ult t o disti n g uis h resi d ual disease fr o m n or mal tiss ue.  
W he n t he e val uati o n of C R de pe n ds u p o n t his deter mi nati o n, it is rec o m me n de d t hat t he 
resi d ual lesi o n be i n vesti gate d (fi ne nee dle as pirate/ bi o ps y) bef ore assi g ni n g a stat us of 
c o m plete res p o nse.  
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 6 2
1 0. 1 2. A p pe n di x 1 2 : M o difie d Res p o nse E v al u ati o n Criteri a i n S oli d T u m ors 
( mR E CI S T ) versi o n 1. 1 
1.
M o dificati o ns t o R E CI S T v 1. 1 f or Assess me nt of Brai n Lesi o ns
T he m o dificati o ns t o R E CI S T v 1. 1 i m pact t he n u m ber a n d t he mi ni mal size of t he tar get 
brai n lesi o ns selecte d at baseli ne. U p t o 5 a d diti o nal lesi o ns wit hi n t he brai n ma y  be selecte d 
as tar get lesi o ns ; all brai n lesi o ns be yo n d t hese 5 tar get lesi o ns will be re gar de d as n o ntar get 
lesi o ns. Patie nts wit h i ntracra nial disease will ha ve u p t o 1 0 t otal tar get lesi o ns 
( 5 e xtracra nial, 5 i ntracra nial) f or e val uati o n.  Meas ura ble lesi o ns are defi ne d as t h ose t hat 
ca n be acc uratel y meas ure d i n at leas t 1 di me nsi o n wit h t he l o n gest dia meter ≥5 m m w he n 
e val uate d wit h ga d oli ni u m -e n ha nce d M RI.
G a d oli ni u m -e n h a nce d M RI is t he o nl y i m a gi n g m o d alit y acce pte d f or t he assess me nt of 
br ai n lesi o ns.

T he tec h nical s pecificati o n of t he M RI  sca n ni n g se q ue nce will be opti mize d f or t he 
e val uati o n of brai n lesi o ns , w hic h m ust be meas ure d i n t he sa me a nat o mic pla ne 
usi n g t he sa me i ma gi n g e xa mi nati o ns. W he ne ver p ossi ble t he sa me sca n ner s h o ul d 
be use d. 4 2

As a m o dificati o n t o R E CI S T v 1. 1, tar get lesi o ns as s mall as 5 m m ma y  be selecte d, 
h o we ver t he sca n ni n g s h o ul d f oll o w R E CI S T v 1. 1: c o nti g u o us slices of ma xi m u m 
t hic k ness c orres p o n di n g t o half t he size of t he lesi o n. A ll meas ure me nts m ust be 
ta ke n a n d rec or de d i n milli meters ( m m) usi n g a r uler or cali pers.

I ma ge Ac q uisiti o n g ui deli nes pr o vi de t he slice t hic k ness re q uire me nts t hat s h o ul d be 
use d f oll o wi n g R E CI S T v 1. 1 criteria.
2.
E val uati o n of Tar get Brai n Lesi o ns
Defi niti o ns f or assess me nt of tar get brai n lesi o n(s) are as f oll o ws:
C o m plete Res p o nse ( C R) : Disa p peara nce of all tar get lesi o ns. 
P arti al Res p o nse ( P R) : At least a 3 0 % decrease i n t he s u m of dia meters of tar get lesi o ns, 
ta ki n g as refere nce t he baseli ne s um dia meters (e g, perce nt c ha n ge fr o m baseli ne).
St a ble Dise ase ( S D): Neit her s ufficie nt s hri n ka ge t o q ualif y  f or P R n or s ufficie nt i ncrease t o 
q ualif y  f or P D.
Pr o gressi ve Dise ase ( P D) : At least a 2 0 % i ncrease i n t he s u m of dia meters of tar get lesi o ns, 
ta kin g as refere nce t he s m allest s u m of di a meters rec or de d si nce t he treat me nt starte d 
(e g, perce nt c ha n ge fr o m na dir, w here na dir is defi ne d as t he s mallest s u m of dia meters 
rec or de d si nce treat me nt start). I n a d diti o n, t he s u m m ust ha ve a n a bs ol ute i ncrease of at 
least 5 m m. 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 6 3
N ot E v al u a ble ( N E): Ca n n ot be classifie d b y 1 of t he 4 prece di n g defi niti o ns.

S pecial N otes o n t he Assess me nt of Tar get Brai n Lesi o ns :
If a tar get brai n lesi o n disa p pears a n d rea p pears at a s u bse q ue nt ti me p oi nt it s h o ul d c o nti n ue 
t o be meas ure d. T he res p o nse at t he ti me w he n t he lesi o n rea p pears will de pe n d u p o n t he 
stat us of ot her lesi o ns. F or e xa m ple, if t he disease ha d reac he d a C R stat us t he n P D w o ul d be 
d oc u me nte d at t he ti me of rea p peara nce. H o we ver, if t he res p o nse stat us were P R or S D, t he 
dia meter of t he rea p peari n g lesi o n s h o ul d be a d de d t o t he re mai ni n g dia meters a n d res p o nse 
deter mi ne d base d o n perce nt c ha n ge fr o m baseli ne a n d perce nt c ha n ge fr o m na dir.
3.
E val uati o n of N o n -tar get Brai n Lesi o n s
Defi niti o ns f or assess me nt of n o n- tar get brai n lesi o n(s) are as f oll o ws:
C o m plete Res p o nse ( C R) : Disa p peara nce of all n o n -tar get lesi o ns. 
N o n -C R/ N o n -P D: T he persiste nce of 1 or m ore n o n -tar get lesi o n(s) i de ntifie d as a site of 
disease.
P r o gressi ve Dise ase ( PD) : U ne q ui v ocal pr o gressi o n of e xisti n g n o n -tar get lesi o ns.
N ot A p plic a ble ( N/ A): N o n o n -tar get brai n lesi o ns at baseli ne.
N ot E v al u a ble ( N E): Ca n n ot be classifie d b y 1 of t he 4 prece di n g defi niti o ns.

S pecial N otes o n t he Assess me nt of N o n -tar get Brai n Lesi o ns :
N o n -tar get brai n lesi o ns t hat are n ot assesse d at a partic ular ti me p oi nt base d o n t he S o A
s h o ul d be e xcl u de d fr o m t he res p o nse deter mi nati o n (e g, n o n-tar get res p o nse d oes n ot ha ve 
t o be “ N ot E val ua ble”).
4.
Ne w Lesi o n s
Ne w brai n mali g na ncies de n oti n g disease pr o gressi o n m ust be u ne q ui v ocal. Lesi o ns 
i de ntifie d i n f oll o w u p i n a n a nat o mical l ocati o n n ot sca n ne d at baseli ne are c o nsi dere d ne w 
lesi o ns.
A n y  e q ui v ocal ne w lesi o n s h o ul d c o nti n ue t o be f oll o we d. Treat me nt ca n c o nti n ue at t he 
discreti o n of t he in vesti gat or u ntil t he ne xt sc he d ule d assess me nt. If at t he ne xt assess me nt 
t he ne w lesi o n is c o nsi dere d t o be u ne q ui v ocal, pr o gressi o n s h o ul d be d oc u me nte d.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 6 4

Ti me P oi nt Res p o nse f or Brai n Lesi o ns
Ta ble 1 0 prese nts t he i ntracra nial res p o nse at a n i n di vi d ual ti me p oi nt f or all p ossi ble 
c o m bi nati o ns of t u m or res p o nse i n tar get a n d n o n -tar get brai n lesi o ns, wit h or wit h o ut t he 
a p peara nc e of ne w brai n lesi o ns f or partici pa nts wit h meas ura ble i ntracra nial disease at 
baseli ne.
Partici pa nts wit h a gl o bal deteri orati o n of healt h stat us t hat re q uiri n g disc o nti n uati o n of 
treat me nt wit h o ut o bjecti ve e vi de nce of disease pr o gressi o n at t hat ti me sh o ul d be classifie d 
as ha vi n g “s y m pt o matic deteri orati o n.” O bjecti ve res p o nse stat us is deter mi ne d b y 
e val uati o ns of disease b ur de n. E ver y  eff ort s h o ul d be ma de t o d oc u me nt t he o bjecti ve 
pr o gressi o n e ve n after disc o nti n uati o n of treat me nt.
I n s o me circ u msta nces, it ma y be diffic ult t o disti n g uis h resi d ual disease fr o m n or mal tiss ue. 
W he n t he e val uati o n of C R de pe n ds o n t his deter mi nati o n, it is rec o m me n de d t hat t he 
resi d ual lesi o n be i n vesti gate d (e g, fi ne nee dle as pirate or bi o psy) t o c o nfir m t he C R.
T a ble 1 0 .
E v al u ati o n of Br ai n Lesi o n Res p o nse
T ar get Lesi o ns
N o n -t ar get Lesi o ns
Ne w Lesi o ns
Res p o nse
C R
C R 
N o
C R
C R
N o n -C R/ N o n -P D or N E
N o
P R
P R
N o n -P D or N E
N o
P R
S D
N o n -P D or N E
N o
S D
N E
N o n -P D 
N o
N E
P D
A n y
Yes or N o
P D
A n y
P D
Yes or N o
P D
A n y
A n y
Yes
P D

Best O veral l Brai n Metastasis Res p o nse: All Ti me P oi nts f or Brai n Lesi o ns
T he best o verall brai n metastasis res p o nse is defi ne d as t he best res p o nse rec or de d fr o m t he 
start of treat me nt u ntil pr o gressi o n of brai n metastasis a n d will be deter mi ne d 
pr o gra m maticall y b y t he sp o ns or base d o n t he i n vesti gat or’s assess me nt of brai n metastasis 
res p o nse at eac h ti me p oi nt. O nl y  t u m or assess me nts perf or me d bef ore t he start of a n y 
s u bse q ue nt a ntica ncer t hera pies a n d n ot later t ha n 3 0 da y s after last d ose of st u d y  dr u g will 
be c o nsi dere d i n t he assess me nt of best o verall brai n metastasis res p o nse . Cli nical 
deteri orati o n or cli nical pr o gressi o n n ote d o n t he c o m pleti o n e C R F will n ot be c o nsi dere d as 
d oc u me nte d disease pr o gressi o n. 
T o be assi g ne d a stat us of brai n metastasis S D, f oll o w -u p disease assess me nt m ust meet t he 
S D criteria at least o nce after t he first d ose of st u d y  treat me nt f or a mi ni m u m of 6 wee ks.
If t he mi ni m u m ti me f or S D is n ot met, t he best res p o nse will de pe n d o n s u bse q ue nt 
assess me nts. F or e xa m ple, if a n assess me nt of P D f oll o ws t he assess me nt of S D a n d S D 
d oes n ot meet t he mi ni m u m ti me re q uire me nt, t he best res p o nse will be P D. Alter nati vel y, 
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 6 5
partici pa nts l ost t o f oll o w- u p after a n S D assess me nt w h o d o n ot meet t he mi ni m u m ti me 
criteri o n will be c o nsi dere d N E.

E xtracra nial Tar get, N o n -tar get, Ne w Lesi o n Assess me nt a n d Res p o nse
R E CI S T 1. 1 g ui deli nes will be use d f or assess me nt of tar get, n o n-tar get, a n d ne w lesi o ns f or 
extracra nial res p o nse 
Defi niti o ns f or assess me nt of res p o nse f or e xtracra nial tar get lesi o n(s) are as f oll o ws:  

C o m plete Res p o nse ( C R): Disa p peara nce of all tar get lesi o ns.

Partial Res p o nse ( P R): At least a 3 0 % decrease i n t he s u m of t he dia meters of tar get
lesi o ns, ta ki n g as a refere nce, t he baseli ne s u m of t he dia meters (e g, perce nt c ha n ge 
fr o m baseli ne).

Sta ble Disease ( S D): Neit her s ufficie nt s hri n ka ge t o q ualif y  f or P R n or s ufficie nt 
i ncrease t o q ualif y f or pr ogressi ve disease.

Pr o gressi ve Disease ( P D): At least a 2 0 % i ncrease i n t he s u m of t he dia meters of 
tar get lesi o ns, ta ki n g as a refere nce, t he s mallest s u m of dia meters rec or de d si nce t he 
treat me nt starte d (e g, perce nt c ha n ge fr o m na dir, w here na dir is defi ne d as t he 
s mallest s u m of dia meters rec or de d si nce treat me nt start). I n a d diti o n, t he s u m m ust 
ha ve a n a bs ol ute i ncrease fr o m na dir of 5 m m.

N ot E val ua ble ( N E): Ca n n ot be classifie d b y o ne of t he f o ur prece di n g defi niti o ns.

If a n e xtracra nial tar get lesi on disa p pears a n d rea p pears at a s u bse q ue nt ti me p oi nt it 
s h o ul d c o nti n ue t o be meas ure d. T he res p o nse at t he ti me w he n t he lesi o n rea p pears 
will de pe n d u p o n t he stat us of t he ot her lesi o ns. F or e xa m ple, if t he disease ha d 
reac he d a C R stat us t he n P D w o uld be d oc u me nte d at t he ti me of rea p peara nce. 
H o we ver, if t he res p o nse stat us was P R or S D, t he dia meter of t he rea p peari n g lesi o n 
s h o ul d be a d de d t o t he re mai ni n g dia meters a n d res p o nse deter mi ne d base d o n 
perce nt c ha n ge fr o m baseli ne a n d perce nt c ha n ge f r o m na dir.
Defi niti o ns f or assess me nt of res p o nse f or e xtracra nial n o n -tar get lesi o ns are as f oll o ws:

C o m plete Res p o nse ( C R): T he disa p peara nce of all n o n- tar get lesi o ns.

N o n -C R/ N o n -P D: T he persiste nce of 1 or m ore n o n -tar get lesi o n(s) i de ntifie d as a 
site of disease.

Pr o gressi ve Disease ( P D): U ne q ui v ocal pr o gressi o n of e xisti n g n o n -tar get lesi o ns.

N ot A p plica ble ( N A): N o e xtracra nial n o n -tar get lesi o ns at baseli ne.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 6 6

N ot E val ua ble ( N E): Ca n n ot be classifie d b y o ne of t he f o ur prece di n g defi niti o ns.
N ote:
E xt racra nial n o n-tar get lesi o ns w hic h are n ot assesse d at a partic ular ti me p oi nt base d o n t he 
assess me nt sc he d ule s h o ul d be e xcl u de d fr o m t he res p o nse deter mi nati o n (t hat is, t he 
n o n -tar get res p o nse d oes n ot ha ve t o be " N ot E val ua ble" if t he n o n-tar get lesi ons were n ot 
sc he d ule d f or assess me nt at a partic ular ti me p oi nt).   
T a ble 1 1 .
E v al u ati o n of E xtr acr a ni al Lesi o n Res p o nse
T ar get Lesi o ns
N o n -t ar get Lesi o ns
Ne w Lesi o ns
E xtr acr a ni al Res p o nse
C R
C R 
N o
C R
C R
N o n -C R/ N o n -P D or N E
N o
P R
P R
N o n -P D or N E
N o
P R
S D
N o n -P D or N E
N o
S D
N E
N o n -P D 
N o
N E
P D
A n y
Yes or N o
P D
A n y
P D
Yes or N o
P D
A n y
A n y
Yes
P D

O verall Tar get, N o n -tar get, a n d Ne w Lesi o n Assess me nt a n d Res p o nse
O verall tar get lesi o n res p o nse is base d o n all (t hat is, i ntracra nial a n d e xtracra nial) tar get 
lesi o ns, u p t o 1 0 t otal as a m o dificati o n t o R E CIS T 1. 1 . T he s u m of l o n gest dia meters of all 
tar get lesi o ns will be use d t o deter mi ne o verall res p o nse. 
Defi niti o ns f or assess me nt of res p o nse f or tar get lesi o n(s) base d o n m o difie d R E CI S T 1. 1 are 
as f oll o ws:

C o m plete Res p o nse ( C R): Disa p peara nce of all tar get lesi o ns. A n y pat h ol o gical 
l ym p h n o des m ust be < 1 0 m m i n t he s h ort a xis.

Partial Res p o nse ( P R): At least a 3 0 % decrease i n t he s u m of t he dia meters of tar get 
lesi o ns, ta ki n g as a refere nce, t he baseli ne s u m of t he dia meters (e g, perce nt c ha n ge 
fr o m baseli ne).

Sta ble Disease ( S D): Neit her s ufficie nt s hri n ka ge t o q ualif y  f or P R n or s ufficie nt 
i ncrease t o q ualif y f or pr o gressi ve disease.

Pr o gressi ve Disease ( P D): At least a 2 0 % i ncrease i n t he s u m of t he dia meters of 
tar get lesi o ns, ta ki n g as a refere nce, t he s mallest s u m of dia meters rec or de d si nce t he 
treat me nt starte d (e g, perce nt c ha n ge fr o m na dir, w here na dir is defi ne d as t he
s mallest s u m of dia meters rec or ded si nce treat me nt start). I n a d diti o n, t he s u m m ust
ha ve a n a bs ol ute i ncrease fr o m na dir of 5 m m.

N ot A p plica ble ( N A): N o e xtracra nial tar get lesi o ns at baseli ne.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 6 7

N ot E val ua ble ( N E): Ca n n ot be classifie d b y o ne of t he 5 prece di n g defi niti o ns.
N ote:

If l ym p h n o des are d oc u me nte d as tar get lesi o ns t he s h ort a xis is a d de d i nt o t he s u m
of t he dia meters ( e g, s u m of dia meters is t he s u m of t he l o n gest dia meters f or 
n o n - no dal lesi o ns a n d t he s h ort a xis f or n o dal lesi o ns). W he n l y m p h n o des decrease 
t o n o n - pat h ol o gical size (s h ort a xis < 1 0 m m) t he y  s h o ul d still ha ve a meas ure me nt
re p orte d i n or der n ot t o o verstate pr o gressi o n.

If at a gi ve n assess me nt ti me p oi nt all tar get lesi o ns i de ntifie d at baseli ne are n ot
assesse d, s u m of t he dia meters ca n n ot be calc ulate d f or p ur p oses of assessi n g C R, P R, 
or S D, or f or use as t he na dir f or f ut ure assess me nts. H o we ver, t he s u m of t he
dia meters of t he assesse d lesi o ns a n d t he perce nt c ha n ge fr o m na dir s h o ul d be
calc ulate d t o e ns ure t hat pr o gressi o n has n ot bee n d oc u me nte d. If a n assess me nt of
P D ca n n ot be ma de, t he res p o nse assess me nt s h o ul d be N E.

All tar get lesi o ns ( n o dal a n d n o n- n o dal) s h o ul d ha ve t heir meas ure me nts rec or de d
e ve n w he n ver y s mall (e g, 2 m m). If lesi o ns are prese nt b ut t o o s mall t o meas ure, 
5 m m s h o ul d be rec or de d a n d s h o ul d c o ntri b ute t o t he s u m of t he dia meters, u nless it 
is li kel y t hat t he lesi o n has disa p peare d i n w hic h case 0 m m s h o ul d be re p orte d.

If a tar get lesi o n disa p pears a n d rea p pears at a s u bse q ue nt ti me p oi nt it s h o ul d
c o nti n ue t o be meas ure d. T he res p o nse at t he ti me w he n t he lesi o n rea p pears will
de pe n d u p o n t he stat us of t he ot her lesi o ns. F or e xa m ple, if t he disease ha d reac he d a 
C R stat us t he n P D w o ul d be d oc u me nte d at t he ti me of rea p peara nce. H o we ver, if
t he res p o nse stat us was P R or S D, t he dia meter of t he rea p peari n g lesi o n s h o ul d be
a d de d t o t he re mai ni n g dia meters a n d res p o nse deter mi ne d base d o n perce nt c ha n ge
fr o m baseli ne a n d perce nt c ha n ge fr o m na dir.
O verall n o n -tar get lesi o n res p o nse is base d o n all (t hat is, i ntracra nial a n d e xtracra nial)
n o n -tar get lesi o ns. 
Defi niti o ns f or assess me nt of res p o nse f or n o n -tar get lesi o ns are as f oll o ws:

C o m plete Res p o nse ( C R): T he disa p peara nce of all n o n- tar get lesi o ns. All l y m p h 
n o des i de ntifie d as a site of disease at baseli ne m ust be n o n- pat h ol o gical ( e g, < 1 0 m m 
s h ort a xis).

N o n -C R/ N o n -P D: T he persiste nce of 1 or m ore n o n -tar get lesi o n(s) or l ym p h n o des 
i de ntifie d as a site of disease at baseli ne ≥1 0 m m s h ort a xis.

Pr o gressi ve Disease ( P D): U ne q ui v ocal pr o gressi o n of e xisti n g n o n -tar get lesi ons. 

N ot A p plica ble ( N A): N o i ntracra nial or e xtracra nial n o n -tar get lesi o ns at baseli ne.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 6 8

N ot E val ua ble ( N E): Ca n n ot be classifie d b y o ne of t he fi ve prece di n g defi niti o ns.
N ote:

I n t he prese nce of meas ura ble disease, pr o gressi o n o n t he basis of s olel y n o n-tar get 
disease re q uires s u bsta ntial w orse ni n g s uc h t hat e ve n i n t he prese nce of S D or P R i n 
tar get disease, t he o verall t u m or b ur de n has i ncrease d s ufficie ntly t o merit 
disc o nti n uati o n of t hera p y .

I n t he prese nce of n o n-meas ura ble o nl y  disease c o nsi deratio ns s h o ul d be gi ve n t o 
w het her or n ot t he i ncrease i n o verall disease b ur de n is c o m para ble i n ma g nit u de t o 
t he i ncrease t hat w o ul d be re q uire d t o declare P D f or meas ura ble disease.

Sites of n o n -tar get lesi o ns w hic h are n ot assesse d at a partic ular ti me p oi nt base d o n 
t he assess me nt sc he d ule s h o ul d be e xcl u de d fr o m t he res p o nse deter mi nati o n 
(ie, n o n-tar get res p o nse d oes n ot ha ve t o be " N ot E val ua ble").
Ne w i ntracra nial or e xtracra nial mali g na ncies de n oti n g disease pr o gressi o n m ust be
u ne q ui v ocal. Lesi o ns i de ntifie d i n f oll o w -u p i n a n a nat o mical l ocati o n n ot sca n ne d at
baseli ne are c o nsi dere d ne w lesi o ns.
A n y  e q ui v ocal ne w lesi o ns s h o ul d c o nti n ue t o be f oll o we d. Treat me nt ca n c o nti n ue at t he 
discreti o n of t he i n vesti gat or u ntil t he ne xt sc he d ule d assess me nt. If at t he ne xt assess me nt 
t he ne w lesi o n is c o nsi dere d t o be u ne q ui v ocal, pr o gressi o n s h o ul d be d oc u me nte d.
T a ble 1 2 .
E v al u ati o n of O ver all Res p o nse ( m R E CI S T)
T ar get Lesi o ns
N o n -t ar get Lesi o ns
Ne w Lesi o ns
O ver all Res p o nse
C R
C R
N o
C R
C R
N o n -C R/ N o n -P D or N E
N o
P R
P R
N o n -P D or N E
N o
P R
S D
N o n -P D or N E
N o
S D
N E
N o n -P D or N E
N o
N E
P D
A n y
Yes or N o
P D
A n y
P D
Yes or N o
P D
A n y
A n y
Yes
P D
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 6 9
1 0. 1 3. A p pe n di x 1 3: Res p o nse A ssess men t i n N e ur o- Onc ol o g y ( R A N O)
R A N O f or H G G 4 3
Efficac y  e val uati o ns usi n g t he Mac d o nal d criteria i n v ol ve p ost-c o ntrast M RI fi n di n gs, n o n 
c o ntrast T 1 a n d T 2 fl ui d atte n uate d i n versi o n rec o ver y (F L AI R) i ma ges , use of c ortic oster oi d 
d ose, a n d ne ur ol o gical e xa mi nati o n as defi ne d bel o w:
C o m plete Res p o nse ( C R) – A L L of t he f oll o wi n g:

C o m plete disa p peara nce of all e n ha nci n g meas ura ble a n d n o n - meas ura ble disease 
s ustai ne d f or ≥4 wee ks.

N o ne w lesi o ns.

Sta ble or i m pr o ve d n o n -e n ha nci n g ( T 2/ F L AI R) lesi o ns.

Offster oi ds.

Ne ur ol o gical c o n diti o n sta ble or i m pr o ve d.
P arti al Res p o nse ( P R) – A L L of t he f oll o wi n g:

Greater t ha n or e q ual t o 5 0 % decrease c o m pare d t o baseli ne i n t he s u m of t he 
per pe n dic ular dia meters of all meas ura ble e n ha nci n g lesi o ns s ustai ne d f or at least 
4 wee ks.

N o pr o gressi o n of n o n - meas ura ble disease.

N o ne w lesi o ns.

Sta ble or i m pr o ve d n o ne n ha nci n g ( T 2/ F L AI R) lesi o ns o n t he sa me or l o wer d ose of 
c ortic oster oi ds c o m pare d wit h baseli ne sca n.

T he c ortic oster oi d d ose at t he ti me of t he sca n e val uati o n s h o ul d be n o greater t ha n 
t he d ose at t he ti me of t he baseli ne sca n.

Ne ur ol o gical c o n diti o n sta ble or i m pr o ve d.
Pr o gressi ve Dise ase ( P D) – A N Y of t he f oll o wi n g:

Greater t ha n or e q ual t o 2 5 % i ncrease i n t he s u m of t he pr o d ucts of per pe n dic ular 
dia meters of e n ha nci n g lesi o ns c o m pare d t o t he s mallest t u m or meas ure me nt o btai ne d 
eit her at baseli ne (if n o decrease) or best res p o nse, o n sta ble or i ncreasi n g d ose of 
c ortic oster oi ds .*
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 7 0

Si g nifica nt i ncrease i n T 2/ F L AI R n o ne n ha nci n g lesi o n o n sta ble or i ncreasi n g d ose of 
c ortic oster oi ds c o m pare d wit h baseli ne sca n or best res p o nse f oll o wi n g i nitiati o n of 
t hera py, * n ot d ue t o c o -m or bi d e ve nts (e g, ra d iati o n t hera p y, de myeli nati o n, isc he mic 
i nj ur y, i nfecti o n, seiz ures, p ost- o perati ve c ha n ges, or ot her treat me nt effects).

A n y  ne w lesi o n.

Cli nical deteri orati o n n ot attri b uta ble t o ot her ca uses a part fr o m t he t u m or 
(e g, seiz ures, me dicati o n si de effects, co m plicati o ns of t hera p y , cere br o vasc ular 
e ve nts, i nfecti o n, etc.) or c ha n ges i n c ortic oster oi d d ose.

Fail ure t o ret ur n f or e val uati o n d ue t o deat h or deteri orati n g c o n diti o n.

Clear pr o gressi o n of n o n -meas ura ble disease .
* Sta ble d oses of c ortic oster oi ds i ncl u des patie nts n ot o n c ortic oster oi ds.
St a ble Dise ase ( S D):

D oes n ot q ualif y  f or C R, P R, or P D.

Sta ble n o ne n ha nci n g ( T 2/ F L AI R) lesi o ns o n sa me or l o wer d ose of c ortic oster oi ds 
c o m pare d wit h baseli ne sca n.  I n t he e ve nt t hat t he c ortic oster oi d d ose has bee n
i ncrease d, t he last sca n c o nsi dere d t o s h o w S D will be t he sca n o btai ne d w he n t he 
c ortic oster oi d d ose was e q ui vale nt t o t he baseli ne d ose.

Sta ble cli nicall y .
T a ble 1 3 .
O ver all Res p o nse Criteri a ( R A N O H G G)
C R
P R
S D
P D a
T 1 -G d
N o ne
≥5 0 % 
< 2 5 % - < 5 0 % 
≥2 5 % *
T 2/ F L AI R
Sta ble or 
Sta ble or 
Sta ble or  
*
N e w  Lesi o n
N o ne
N o ne
N o ne
Prese nt *
C ortic oster oi ds
N o ne
Sta ble or 
Sta ble or 
N A
Cli nical Stat us
Sta ble or 
Sta ble or 
Sta ble or  
*
Re q uire me nt of 
res p o nse
All
All
All
A n y *
: decrease; : i ncrease
a.
Pr o gressi o n occ urs w he n a n y of t he criteria wit h * are prese nt; N A: i ncrease i n c ortic oster oi d d ose 
al o ne will n ot be ta ke n i nt o acc o u nt i n deter mi ni n g pr o gressi o n i n t he a bse nce of persiste nt cli nical 
deteri orati o n .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 7 1
R A N O f or L G G 4 4
Diff use l o w gra de gli o ma ( L G G) are defi ne d b y W H O as diff use i nfiltrati ve gra de II gli o ma 
(e g, astr oc yt o ma, oli g o de n dr o gli o ma, mi xe d oli g oastr ocyt o ma) a n d are pre d o mi na ntl y  
ra di o gra p hicall y n o n-c o ntrast e n ha nci n g t u m ors t hat are best vis ualize d o n fl ui d atte n uate d 
i n versi o n rec o ver y ( F L AI R) a n d T 2-wei g hte d i ma ges. 
Basic M RI pr ot oc ol s h o ul d i ncl u de:

A xial F L AI R (ca nt h o meatal ali g n me nt) .

A xial T 2 .

C or o nal T 1 .

P ost -ga d oli ni u m c helate (c o ntrast per l ocal cli nical practice) .
Efficac y  e val uati o ns are as defi ne d bel o w:
C o m plete Res p o nse ( C R) – A L L of t he f oll o wi n g:

C o m plete disa p peara nce of t he lesi o n o n T 2 or F L AIR i ma gi n g (if e n ha nce me nt ha d 
bee n prese nt, it m ust ha ve res ol ve d c o m pletel y) .

N o ne w lesi o ns , n o ne w T 2 or F L AIR a b n or malities a part fr o m t h ose c o nsiste nt wit h 
ra diati o n effects, a n d n o ne w or i ncrease d e n ha nce me nt.

Off c ortic oster oi ds or o nl y  p h ysi ol o gical re place me nt d oses.

M ust be sta ble or i m pr o ve d cli nicall y.
P arti al Res p o nse ( P R) – A L L of t he f oll o wi n g:

Greater t ha n or e q ual t o 5 0 % decrease c o m pare d t o baseli ne i n t he s u m of t he 
per pe n dic ular dia meters of t he lesi o n o n T 2 or F L AIR i ma gi n g s ustai ne d f or at least 
4 wee ks.

N o ne w lesi o ns , n o ne w T 2 or F L AIR a b n or malities a part fr o m t h ose c o nsiste nt wit h 
ra diati o n effects, n o ne w or i ncrease d e n ha nce me nt.

T he c ortic oster oi d d ose s h o ul d be n o greater t ha n t he d o se at t he ti me of t he baseli ne 
sca n a n d s h o ul d be sta ble or i m pr o ve d cli nicall y.
Mi n or Res p o nse – A L L of t he f oll o wi n g:

Decrease of t he area of n o n -e n ha nci n g lesi o n o n T 2 or F L AIR M R i ma gi n g bet wee n 
2 5 % a n d 5 0 % c o m pare d t o baseli ne .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 7 2

N o ne w lesi o ns, n o ne w T 2 or F L AI R a b n or malities a part fr o m t h ose c o nsiste nt wit h 
ra diati o n effect, a n d n o ne w or i ncrease d e n ha nce me nt.

T he c ortic oster oi d d ose s h o ul d n ot be greater t ha n t he d ose at ti me of baseli ne sca n 
a n d s h o ul d be sta ble or i m pr o ve d cli nicall y.
St a ble dise a se – A L L of t he f oll o wi n g:

D oes n ot q ualif y  f or C R, P R, mi n or res p o nse, or P D.

Sta ble area of n o n -e n ha nci n g a b n or malities o n T 2 or F L AIR M R i ma gi n g .

N o ne w lesi o ns, n o ne w T 2 or F L AI R a b n or malities a part fr o m t h ose c o nsiste nt wit h 
ra diati o n effect, a n d n o ne w or i ncrease d e n ha nce me nt .

T he c ortic oster oi d d ose s h o ul d n ot be greater t ha n t he d ose at ti me of baseli ne sca n 
a n d s h o ul d be sta ble or i m pr o ve d cli nicall y.
Pr o gressi ve Dise ase ( P D) – A N Y of t he f oll o wi n g :

Ne w lesi o ns or i ncrease of e n ha nce me nt (ra di ol o gical e vi de nce of mali g na nt 
tra nsf or mati o n).

Greater t ha n or e q ual t o 2 5 % i ncrease of t he T 2 or F L AI R n o n -e n ha nci n g lesi o n o n 
sta ble or i ncreasi n g d oses of c ortic oster oi ds c o m pare d t o baseli ne sca n or best 
res p o nse after i nitiati o n of t hera py, n ot attri b u ta ble t o ra diati o n effect or t o c o m or bi d 
e ve nts.

Defi nite cli nical deteri orati o n n ot attri b uta ble t o ot her ca uses a part fr o m t he t u m or, or 
decrease i n c ortic oster oi d d ose .

Fail ure t o ret ur n f or e val uati o n beca use of deat h or deteri orati n g c o n diti o n u nless 
ca use d b y d oc u me nte d n o n -relate d dis or ders.
T a ble 1 4.
O ver all Res p o nse Criteri a ( R A N O L G G)
C R
P R
M R
S D
P D
T 2/ F L AI R
N o ne
≥5 0 % 
2 5 % - < 5 0 % 
< 2 5 % - < 2 5 % 
≥2 5 % *
N e w  Lesi o n
N o ne
N o ne
N o ne
N o ne
Prese nt *
C ortic oster oi ds
N o ne
Sta ble or 
Sta ble or 
Sta ble or 
N A * *
Cli nical Stat us
Sta ble or 
Sta ble or 
Sta ble or 
Sta ble or  
*
Re q uire me nt of 
res p o nse
All  
All
All
All
A n y *
: decrease; : i ncrease; C R: c o m plete res p o nse; P R: partial res p o nse; M R: mi n or res p o nse; S D: sta ble 
disease; P D: pr o gressi ve disease; N A: n ot a p plica ble 
* Pr o gressi o n occ urs w he n a n y of t he criteria wit h * are prese nt
* * N A: i ncrease i n c ortic oster oi d d ose al o ne will n ot be ta ke n i nt o acc o u nt i n deter mi ni n g pr o gressi o n i n t he 
a bse nce of persiste nt cli nical deteri orati o n .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 7 3
1 0. 1 4. A p pe n di x 1 4 : E C O G Cl assific ati o n of Perf or m a nce St at us 
E C O G P S 
Gr a de
Defi niti o n
0
F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut restricti o n.
1
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a 
li g ht or se de ntar y nat ure, e g, li g ht h o use w or k or office w or k.
2
A m b ulat or y a n d ca pa ble of all self -care b ut u na ble t o carr y o ut a n y w or k acti vities .  U p 
a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs.
3
Ca pa ble of o nl y li mite d self -care, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of w a ki n g 
h o urs.
4
C o m pletel y disa ble d.  Ca n n ot carr y o n a n y self -care.  T otall y c o nfi ne d t o be d or c hair.
5
Dea d .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 7 4
1 0. 1 5. A p pe n di x 1 5 : A Dr u g -Dr u g I nter acti o n S u bst u d y
T he o bjecti ve of t his D DI s u bst u d y is t o e val uate t he effect of si n gle a n d re peate d 
a d mi nistrati o n of P F -0 7 2 8 4 8 9 0 i n c o m bi nati o n wit h bi ni meti ni b o n C Y P 3 A acti vit y usi n g 
orall y  a d mi nistere d mi daz ola m as a pr o be C Y P 3 A s u bstrate.
1 0. 1 5. 1. R ati o n ale f or E v al u ati o n of Mi d az ol a m P K I nter acti o n
P F -0 7 2 8 4 8 9 0 s h o we d c o m petiti ve a n d ti me - de pe n de nt i n hi biti o n as well as i n d ucti o n of 
C Y P 3 A i n vitr o.  As a res ult, t here is a p ote ntial t hat P F- 0 7 2 8 4 8 9 0 ma y  alter P K i n 
c o nc o mita ntl y a d mi nistere d me dici nes meta b olize d b y  C Y P 3 A 4, p ossi bl y i ncreasi n g or 
decreasi n g t heir e x p os ures. T o e val uate t he effect of si n gle a n d re peat e d a d mi nistrati o n of 
P F -0 7 2 8 4 8 9 0 o n C Y P 3 A acti vit y , t he si n gle d ose P K of oral mi daz ola m will be e val uate d 
bef ore C ycl e 1 Da y 1, a n d d uri n g re peat a d mi nistrati o n ( C y cle 1 Da y 1 5) of P F-0 7 2 8 4 8 9 0 i n 
c o m bi nati o n wit h bi ni meti ni b at rec o m me n de d d ose a n d sc he d ule f or f urt her st u d y.  
Alt h o u g h bi ni meti ni b will be c oa d mi nistere d, it is n ot e x pecte d t o i m pact t he D DI res ults ,
si nce bi ni metini b has bee n de m o nstrate d n ot t o alter t he e x p os ure of mi daz ola m .
Mi daz ola m is a be nz o diaze pi ne use d cli nicall y  f or c o nsci o us se dati o n.  It is s pecifically 
meta b olize d b y  C Y P 3 A a n d is wi del y use d as a n i n vi v o pr o be f or C Y P 3 A acti vit y .  A n oral 
f or m ulati o n of mi daz ola m is use d t o e val uate t he effects o n C Y P 3 A acti vit y i n t he GI tract 
a n d t he li ver. T he res ulti n g i nf or mati o n will be use d t o deter mi ne w het her a n y restricti o ns or 
d ose m o dificati o ns of c o nc o mita nt me dicati o ns are a p pr o priate i n f ut ure st u dies.
1 0. 1 5. 2. St u d y Desi g n
T his is a n o pe n -la bel fi xe d-se q ue nce st u dy. A p pr o xi matel y  1 0 partici pa nts will be e nr olle d. 
Partici pa nts will recei ve a si n gle , 2 m g oral d ose of mi daz ola m o n Da y -7. P F - 0 7 2 8 4 8 9 0 at 
t he rec o m me n de d d ose f or c o m bi nati o n wit h bi ni meti ni b ( 4 5 m g BI D) (see Secti o n 4. 3. 4 ), 
will be i nitiate d o n C 1 D 1. Partici pa nts will t he n recei ve a si n gle oral d ose of mi daz ola m o n 
C 1 D 1 a n d C 1 D 1 5 . Bl o o d P K sa m pli n g will be c o n d ucte d fr o m 0 t o 8 h o urs o n Da y  - 7, 
C 1 D 1 a n d C 1 D 1 5 .
Uri ne P K sa m pli n g will be c o n d ucte d o n C 1 D 1 5.
1 0. 1 5. 3. R ati o n ale f or t he Desi g n
P K sa m pli n g will be c o n d ucte d o n Da y  - 7, C 1 D 1 a n d C 1 D 1 5 s o t hat t he effect of 
P F - 0 7 2 8 4 8 9 0 i n c o m bi nati o n wit h bi ni meti ni b ca n be assesse d f or b ot h si n gle a n d re peat 
d osi n g, d ue t o P F -0 7 2 8 4 8 9 0 i n hi biti o n, ti me- de pe n de nt i n hi biti o n, a n d i n d ucti o n of C Y P 3 A 
p ote ntiall y  ca usi n g a differe nt i nteracti o n o n Da y 1 c o m pare d t o stea d y state. 
1 0. 1 5. 4. P artici p a nt P o p ul ati o n
I n a d diti o n t o all of t he i ncl usi o n criteria o utli ne d i n Secti o n 5. 1 , t his a d diti o nal i ncl usi o n 
criteria a p pl y:

B rai n i n v ol ve me nt if prese nt m ust be: ( 1) ne ur ol o gicall y as ym pt o matic fr o m brai n 
lesi o ns f or at least 1 4 da ys pri or t o t he start of st u d y treat me nt; ( 2) if re q uiri n g 
ster oi ds t o c o ntr ol ne ur ol o gical s ym pt o ms, o n a sta ble t o decreasi n g d ose of ster oi ds 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 7 5
f or 1 4 da ys pri or t o t he start of st u d y treat me nt; a n d ( 3) n o pr o p hyl actic or 
pre ve ntati ve a nti -e pile ptic t hera p y t o pre ve nt ne ur ol o gical s y m pt o ms ca use d b y  brai n 
lesi o ns. E xce pti o n: a nti -e pile ptic t hera p y t o pre ve nt ne ur ol o gical s y m pt o ms ca use d 
b y  a pree xisti n g c o n diti o n a n d n ot relate d t o brai n i n v ol ve me nt is all o we d (see 
Secti o n 6. 5 f or all o we d/ pr o hi bite d c o nc o mita nt me dicati o ns, i ncl u di n g a nti-e pile ptic 
t hera py).
I n a d diti o n t o all of t he e xcl usi o n criteria o utli ne d i n Secti o n 5. 2 , t his ad diti o nal e xcl usi o n 
criteria a p pl y:

C urre nt use or a ntici pate d nee d i n C ycle 1 f or dr u gs t hat are k n o w n C Y P 3 A
i n hi bit ors, i ncl u di n g t he a d mi nistrati o n wit hi n 1 0 da y s or 5 half -li ves, w hic he ver is 
l o n ger, or C Y P 3 A i n d ucers, i ncl u di n g t he a d mi nistratio n wit hi n 5 half -li ves pl us 
1 0 da y s, pri or t o first d ose of mi daz ola m . Refer t o Secti o n 6. 5 f or f urt her details. See 
A p pe n di x 1 8 for e xa m ple str o n g C Y P 3 A i n hi bit ors a n d i n d ucers.
1 0. 1 5. 5. Tre at me nt A d mi nistr ati o n
Oral mi daz ola m s yr u p will be s u p plie d t o sites. Mi daz ola m will be a d mi nistere d i n a n oral 
s yri n ge after a d mi nistrati o n of st u d y a ge nts. Refer t o t he P har mac y  Ma n ual f or a d diti o nal 
i nf or mati o n.
Refer t o Secti o n 6. 1 f or a d mi nistrati o n directi o ns f or t he ot her st u d y dr u g(s).
1 0. 1 5. 6. A d diti o n al C o nc o mit a nt Me dic ati o ns Pr o hi bite d T hr o u g h t he E n d of C ycle 1
Partici pa nts o n t his s u bst u d y m ust f oll o w t he g ui da nce i n t he pr ot oc ol Secti o n 6. 5 . 
A d diti o nall y , t he y m ust f oll o w t he f oll o w restricti o ns t hr o u g h t he e n d of C ycle 1 t o all o w a 
r o b ust assess me nt of P F - 0 7 2 8 4 8 9 0 o n mi daz ola m P K.
Beca use i n hi biti o n of C Y P 3 A 4/ 5 is oe nz y mes ma y  i ncrease mi daz ola m e x p os ure, t he use of 
C Y P 3 A 4/ 5 i n hi bit ors is pr o hi bite d t hr o u g h t he e n d of C y cle 1. Str o n g C Y P 3 A 4/ 5 i n hi bit ors 
ma y  i ncl u de gra pefr uit j uice or gra pefr uit/ gra pefr uit relate d citr us fr uits (e g, Se ville ora n ges, 
p o mel os), ket oc o naz ole, mic o naz ole, itrac o naz ole, v oric o naz ole , p osac o naz ole, 
clarit hr o m yci n, telit hr o m yci n, i n di na vir, sa q ui na vir, rit o na vir, nelfi na vir, a m pre na vir, 
f osa m pre na vir, nefaz o d o ne, l o pi na vir, tr olea n d o m yci n, mi befra dil, a n d co ni va pta n.  
M o derate C Y P 3 A 4 i n hi bit ors
ma y  i ncl u de er yt hr o m y ci n, vera pa mil, ataza na vir, fl uc o naz ole, 
dar u na vir, diltiaze m, dela vir di ne, a pre pita nt, i mati ni b, t ofis o pa m, ci pr ofl o xaci n, a n d 
ci meti di ne. 3 7 See A p pe n di x 1 8 f or e xa m ple str o n g C Y P 3 A i n hi bit ors.
Beca use i n d ucti o n of C Y P 3 A 4/ 5 is oe nz y mes ma y  decrease mi daz ola m e x p os ure, t he use 
C Y P 3 A 4/ 5 i n d ucers is pr o hi bite d t hr o u g h t he e n d of C y cle 1. Str o n g C Y P 3 A 4/ 5 i n d ucers 
ma y  i ncl u de p he n o bar bital, rifa m pi n, p he n yt oi n, car ba maze pi ne, rifa b uti n, rifa pe nti ne,
cle vi di pi ne, a n d St. J o h n’s W ort.3 7  M o derate C Y P 3 A 4/ 5 i n d ucers ma y i ncl u de b ose nta n, 
efa vire nz, etra viri ne, m o dafi nil, a n d nafcilli n. See A p pe n di x 1 8 f or e xa m ple str o n g C Y P 3 A 
i n d ucers.
 
T)

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 7 6
C o ns u m pti o n of gra pefr uit, p o me gra nates, star fr uits, Se ville ora n ges or pr o d ucts c o ntai ni n g 
t he j uice of eac h starti n g fr o m Da y -1 4 t hr o u g h t he D DI p hase ( Da y  2 8) is pr o hi bite d, d ue t o 
p ote ntial C Y P 3 A 4 i nteracti o n wit h t he st u d y  dr u gs. Ora n ge j uice is all o we d. 
Certai n a nti -e pile ptic me dicati o ns ma y be a d mi nistere d if cli nically i n dicate d, c o nsiste nt wit h 
I ncl usi o n/ E xcl usi o n Criteria a n d n ot s u bject t o dr u g -dr u g i nteracti o ns wit h st u d y  
me dicati o ns.  G ui da nce f or a nti- e pile ptic me dicati o ns t hat ca n be use d o n st u d y  is pr o vi de d 
i n A p pe n di x 1 0 .  Beca use certai n a nti-e pile ptic me dicati o ns i n d uce or i n hi bit C Y P 3 A 4, t he y  
ca n n ot be use d u ntil after C y cle 1.
D uri n g t he D DI p hase of t he st u d y , dri n ks a n d f o o d c o ntai ni n g caffei ne m ust be e xcl u de d 
4 8 h o urs bef ore P K assess me nts a n d t he da y  of P K assess me nts (ie, Da ys -9 t o - 7, -2 t o 
C 1 D 1, C 1 D 1 3 t o C 1 D 1 5).
1 0. 1 5. 7. A d diti o n al P K A ssess me nt
P K assess me nts (f or plas ma a n d C S F) will be c o n d ucte d as descri be d i n Secti o n 8. 5 , e xce pt 
f or t he f oll o wi n g differe nces. B l o o d sa m ples of a p pr o xi matel y 8 m L , t o pr o vi de a mi ni m u m 
of 3 . 2 m L  plas ma, will be c ollecte d. T he sa m ples will be c ollecte d as s pecifie d i n t he 
P har mac o ki netic Sa m pli n g a n d E C G s Sc he d ule ta ble. Plas ma P K sa m ples will be use d t o 
e val uate t he P K of mi daz ola m, P F -0 7 2 8 4 8 9 0 a n d bi ni meti ni b .  E ac h plas ma P K sa m ple will
be di vi de d i nt o 3 ali q u ot s a p pr o xi matel y 1 m L i n v ol u me eac h (1 sa m ple f or meas uri n g 
mi daz ola m, 1 sa m ple f or meas uri n g P F - 0 7 2 8 4 8 9 0 a n d 1 sa m ple f or meas uri n g bi ni meti ni b).  
Sa m ples c ollecte d f or a nal y ses of plas ma c o nce ntrati o n ma y als o be use d t o e val uate safety 
or efficac y  as pects relate d t o c o ncer ns arisi n g d uri n g or after t he st u d y, f or meta b olite 
i de ntificati o n a n d/ or e val uati o n of t he bi oa nalyt ical met h o d, or f or ot her i nter nal e x pl orat or y 
p ur p oses.
A d diti o nal l y, a pre-d ose uri ne sa m ple a n d a p ost -d ose 8 -h o ur uri ne c ollecti o n will be 
o btai ne d o n C y cle 1 Da y 1 5 as s pecifie d i n t he P har mac o ki netic Sa m pli n g a n d E C G s
Sc he d ule ta ble.  T he a m o u nt of uri ne c ollecte d o ver 8 h o urs will be rec or de d i n t he C R F. 
Fr o m eac h of t he pre -d ose uri ne sa m ple a n d t he p ost -d ose 8 -h o ur c ollecti o n, 1 ali q u ot of 
a p pr o xi matel y 8 m L will be tra nsferre d t o a 1 0 m L sa m ple t u be f or deter mi nati o n of 
P F - 0 7 2 8 4 8 9 0 c o nce ntrati o n. T he uri ne sa m ples ma y be use d f or a d diti o nal e x pl orat or y  
a nal ys es (e g, c o nce ntrati o n of a meta b olite of P F- 0 7 2 8 4 8 9 0 i n uri ne). A d diti o nal details will 
be f o u n d i n t he La b orat or y  Ma n ual.
Sa m ples c ollecte d f or meas ure me nt of uri ne c o nce ntrati o ns of P F - 0 7 2 8 48 9 0 will be a nal yz e d
usi n g a vali date d a nal yt ical met h o d i n c o m plia nce wit h a p plica ble S O Ps. P ote ntial 
meta b olites i n uri ne sa m ples ma y be a nalyz e d wit h eit her vali date d or e x pl orat or y met h o ds.
1 0. 1 5. 8. S afet y Assess me nts
Safet y  assess me nts will i ncl u de c ollecti o n of A Es, S A Es, vital si g ns a n d p h ysical 
e xa mi nati o ns, E C G ( 1 2-lea d), E C H O sca ns, o p ht hal mic e xa mi nati o ns, der mat ol o gic 
e xa mi nati o ns, ne ur ol o gic e xa mi nati o ns, a n d la b orat or y assess me nts, i ncl u di n g pre g na nc y 
tests a n d verificati o n of c o nc o mita nt treat me nts.  
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 7 7
Safet y  assess me nts are s u m marize d i n t he D DI S o A (see Secti o n 1 0. 1 5. 1 1 ).
1 0. 1 5. 9. S a m ple Size
Ass u mi n g t he i ntra -partici pa nt A U C varia bilit y  is a p pr o xi matel y 3 0 % f or mi daz ola m, base d 
o n a 2-si de d si g nifica nce le vel of 0. 0 5, a sa m ple size of at least 8 partici pa nts i n t he D DI  
St u d y E x pa nsi o n C o h ort will pr o vi de 9 0 % p o wer t o detect a p pr o xi matel y 1. 5 -f ol d or greater 
c han ge i n mi daz ola m A U C w he n mi daz ola m is c oa d mi nistere d wit h P F -0 7 2 8 4 8 9 0 (test 
c o n diti o n) as c o m pare d t o mi daz ola m a d mi nistere d al o ne bef ore t he first P F - 0 7 2 8 4 8 9 0 d ose 
(refere nce c o n diti o n). A p pr o xi matel y  1 0 partici pa nts will be e nr olle d.
1 0. 1 5. 1 0. P K D at a A n al ysis
T he P F - 0 7 2 8 4 8 9 0 a n d bi ni meti ni b P K a nal ysis will be c o n d ucte d as descri be d i n 
Secti o n 9. 3. 2. 2 . A d diti o nal details o f t he mi daz ola m P K a nal ys is are f o u n d i n 
Secti o n 9. 3. 2. 3 . Plas ma c o nce ntrati o ns of mi daz ola m will be s u m marize d descri pti vel y 
( n, mea n, sta n dar d de viati o n, c oefficie nt of variati o n, me dia n, mi ni m u m, ma xi m u m, 
ge o metric mea n a n d its ass ociate d c oefficie nt of variati o n) b y da y a n d n o mi nal ti me. Plas ma 
co nce ntrati o n -ti me data of mi daz ola m after eac h d ose will be a nalyz e d usi n g 
n o n -c o m part me ntal met h o ds t o esti mate t he f oll o wi n g P K para meters i n i n di vi d ual 
partici pa nt s: Cma x , T ma x , A U C last, a n d, if data per mit, t½ , A U Ci nf, C L/ F a n d V z/ F. P K 
para meters will be s u m marize d descri pti vel y ( n, mea n, sta n dar d de viati o n, c oefficie nt of 
variati o n, me dia n, mi ni m u m, ma xi m u m, ge o metric mea n a n d its ass ociate d c oefficie nt of 
variati o n ) by da y.
If a p pr o priate, a mi xe d effects m o del will t he n be use d t o a nalyz e nat ural l o g-tra nsf or me d 
mi daz ola m A U C last.  Als o if a p pr o priate, mi daz ola m Cma x a n d A U C last will als o be a nal yz e d 
usi n g a mi xe d effects m o del wit h a fi xe d effect of treat me nt a n d partici pa nt as ra n d o m.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 7 8
1 0. 1 5. 1 1. Sc he d ule of Acti vit ies f or t he D DI S u b St u d y
T h e So A ta ble pr o vi des a n o ver vie w of t he pr ot oc ol visits a n d pr oce d ures.  Refer t o t he S T U D Y A S S E S S M E N T S A N D 
P R O C E D U R E S secti o n of t he pr ot oc ol f or detaile d i nf or mati o n o n eac h assess me nt re q uire d f or c o m plia nce wit h t he pr ot oc ol. 
O nce a partici pa nt c o m pletes C 2 D 1, refer t o Secti o n 1. 3 f or s u bse q ue nt visit acti vities.
T he i n vesti gat or ma y sc he d ule visits ( u n pla n ne d visits) i n a d diti o n t o t h ose liste d i n t he So A ta ble, i n or der t o c o n d uct e val uati o ns or 
assess me nts re q uire d t o pr otect t he well -bei n g of t he partici pa nt.
C ycle d ur ati o n = 2 1 d a ys
C ycle 1
C ycle 2 - x
Visit I de ntifiera
Scree ni n g 1
Le a d -i n
D a y 1
D a y 1 5
D a y 1 b
Visit Wi n d o w
D a y -3 5 t o D a y - 8
D a y - 7
- 3 d a ysc
N o wi n d o w
± 3 d a ys
I nf or me d c o nse nt/asse nt2
X
I ncl usi o n/e xcl usi o n criteria
X
X
De m o gra p h y a n d baseli ne c haracteristics
X
D oc u me ntati o n of B R A F V 6 0 0 m utati o n 3
X
Arc hi ve d t u m or sa m ple4
X
Fres h t u m or sa m ple ( o pti o nal a n d o nl y if 
c o nse nt pr o vi de d , f or p har mac o d y na mic 
a nal ysis)5
X
C 1 D 8 ( wi n d o w: ± 2 8 da ys)
W h ole bl o o d ( matc he d n or mal)
6
X
Bl o o d sa m ple f or C D x 7
X
Bl o o d sa m ple f or 
( S pecifie d 
Ge netics )8
X
X
X
X
H B V a n d H C V ser ol o g y testi n g a n d HI V 
w here a p plica ble
X
L H, F S H, a n d Estra di ol f or fe male 
a d olesce nts or L H, F S H, a n d Test oster o ne 
f or male a d olesce nts (P hase 1 b )
X
E ver y 4 c ycles ( ± 1 wee k)
O nc ol o g y hist or y
X
Me dical hist or y, pri or s yste mic ca ncer 
t hera pies, ra diati o n a n d s ur geries
X
P h ysical e xa mi nati o n (I ncl u di n g hei g ht at 
scree ni n g o nl y)9 ,3 4
X
X
X
X
T a n ner Sta ge ( p hase 1 b)
X
E ver y 4 c ycles ( ± 1 wee k)
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 7 9
C ycle d ur ati o n = 2 1 d a ys
C ycle 1
C ycle 2 - x
Visit I de ntifiera
Scree ni n g 1
Le a d -i n
D a y 1
D a y 1 5
D a y 1 b
Visit Wi n d o w
D a y -3 5 t o D a y - 8
D a y - 7
-3 d a ys c
N o wi n d o w
± 3 d a ys
F ull o p ht hal mic e xa mi nati o n 1 0 ,3 4
X
If cli nicall y i n dicate d ( n ote: vis ual ac uit y s h o ul d be teste d b y t he treati n g 
p h ysicia n o n Da y 1 of e ver y c ycle)
Der mat ol o gic e xa mi nati o n 1 1 ,3 4
X
X
X
X 
( C 2 D 1, C 3 D 1, t he n e ver y 
ot her c ycle/ Q 6 W)
Ne ur ol o gic e xa mi nati o n 1 2
X
X
X
X
( C 2 D 1, C 2 D 1 5, Da y 1 of 
C 3 -C 8, t he n if cli nicall y 
i n dicate d)
Vital si g ns a n d wei g ht 1 3
X
X
X
X
X
E C O G P S 1 4 ,3 4
X
X
X
C o ntact I W R S
X
X
X
X
L a b or at or y
He mat ol o g y 1 5
X
X
X
X
X
Bl o o d c he mistr y (tr o p o ni n meas ure d 
o nl y f or partici pa nts recei vi n g 
bi ni meti ni b) 1 6
X
X
X
X
X
C oa g ulati o n (a P T T, I N R/ P T) 1 7
X
X
X
X
X
( C 2 D 1, C 2 D 1 5, Da y 1 of 
C 3 -C 8, t he n i f cli nicall y 
i n dicate d)
Uri nal ysis 1 8
X
X
( Starti n g C 3 D 1 if cli nicall y 
i n dicate d)
Ser u m F S H 1 9
X
Ser u m pre g na nc y test2 0
X
Uri ne pre g na nc y test 3 4
X
X
C o ntrace pti o n c hec k 2 1
X
X
X
Si n gle 1 2 -lea d E C G2 2
X
Tri plicate 1 2 -lea d E C G2 3
X
X
X
X
( Da y 1 of C ycles 2-6)
E C H O 2 4
X
X
( C 2 D 1, C 6 D 1, t he n e ver y 
4 c ycles/ Q 1 2 W)
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 8 0
C ycle d ur ati o n = 2 1 d a ys
C ycle 1
C ycle 2 - x
Visit I de ntifiera
Scree ni n g 1
Le a d -i n
D a y 1
D a y 1 5
D a y 1 b
Visit Wi n d o w
D a y -3 5 t o D a y - 8
D a y - 7
- 3 d a ysc
N o wi n d o w
± 3 d a ys
Tre at me nt 2 5
A d mi nister mi daz ola m ( A M d ose i n 
cli nic)
X
X
X
A d mi nister P F - 0 7 2 8 4 8 9 0 a n d 
bi ni meti ni b ( A M d ose i n cli nic)
X
X
X
( Da y 1 of C y cles 2 -6 o n P K 
sa m pli n g/ E C G da ys)
Dis pe nse P F -0 7 2 8 4 8 9 0 a n d bi ni meti ni b
X
X
A d mi nister P F - 0 7 2 8 4 8 9 0 a n d 
bi ni meti ni b
C o nti n u o usl y i n 2 1 -da y c ycles (rec o m me n de d d ose f or f urt her st u d y a n d 
re gi me n f or P F-0 7 2 8 4 8 9 0; 4 5 m g BI D f or bi ni meti ni b)
Re vie w d osi n g diar y a n d assess dr u g 
c o m plia nce
X
X
T u m or assess me nts
C T or M RI i ma gi n g 2 6
X
e ver y 6 wee ks ( 2 c ycles) ± 1 wee k f or 1 year (t hr o u g h C ycle 1 7) t he n e ver y 
1 2 wee ks ± 1 wee k t hereafter
Ot her cli nic al assess me nts
Pri or a n d c o nc o mita nt me dicati o n 2 7
X




Seri o us a n d n o nseri o us A E m o nit ori n g 2 8
X




P K bl o o d sa m pli n g 2 9
X
X
X
X
P K uri ne sa m pli n g 3 0
X
P K C S F sa m pli n g 3 1
A n y ti me C S F is sa m ple d as part of S O C
P har mac o ge netics sa m pli n g3 2
X
Pf izer Pre p D 1 Ba n ke d Bi os peci me n(s)3 3
X
a.
D a y  relati ve t o start of st u d y i nter ve nti o n ( Da y 1).
b.
F or acti vities/assess me nts after C 2 D 1, please refer t o Secti o n 1. 3 . C 2 D 1 visit is t he e n d of t he D DI s u bst u d y assess me nt .
c.
-3 d a y  wi n d o w is t o all o w assess me nts a n d e xa mi nati o ns t o occ ur u p t o 3 da ys bef ore i nitiati o n of st u d y dr u g(s) ( C 1 D 1) u nless ot her wise state d (e g, 
tri plicate pre-d ose E C G s h o ul d occ ur per P K S O A) . F oll o w t he P K sa m pli n g sc he d ule i n r elati o n t o t he d osi n g of t he st u d y dr u gs, w hic h s h o ul d occ ur 
7 da ys after t he first d ose of mi daz ola m .
A b bre viati o ns use d i n t his ta ble ma y be f o u n d i n A p pe n di x 2 1 .
1.
Scree ni n g: T o be o btai ne d w it hi n 2 8 da ys pri or t o st u d y e ntr y.
2.
I nf or me d C o nse nt/ Asse nt: M ust be o btai ne d pri or t o u n der g oi n g a n y st u d y s pecific pr oce d ures.  T he d urati o n of o btai ni n g I C D s h o ul d be c ha n ge d if t he 
scree ni n g wi n d o w is re vise d.  
3.
D oc u me nt ati o n of B R A F V 6 0 0 M ut ati o n : tiss ue or bl o o d (e g, 
) res ults perf or me d d uri n g n or mal c o urse of cli nical care i n C LI A or si milarl y 
certifie d la b orat or y (ie , l ocal testi n g).  Re dacte d m olec ular re p ort(s) m ust be pr o vi de d d uri n g Scree ni n g. 
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 8 1
4.
Tiss ue S a m ple: C o nfir mati o n of a vaila bilit y of a de q uate t u m or tiss ue f or s u b missi o n t o t he sp o ns or. If m ulti ple s peci me ns are a vaila ble, t he m ost rece ntl y 
o btai ne d is preferre d.  If partici pa nts d o n ot ha ve s ufficie nt arc hi val tiss ue, a fres h bi o ps y s h o ul d be o btai ne d if it ca n b e perf or me d safel y i n t he o pi ni o n of 
t he i n vesti gat or.  If a de q uate arc hi ve tiss ue is n ot a vaila ble a n d a fres h bi o ps y ca n n ot be perf or me d safel y, partici pa nts ma y still be eli gi ble if all ot her 
eli gi bilit y criteria are met. S e e Secti o n 8. 7. 1 f or tiss ue re q uire me nts.
5.
Fres h T u m or S a m ple ( O pti o n al): F or partici pa nts w h o pr o vi de i nf or me d c o nse nt /asse nt f or o pti o nal bi o ps y; ma y be o btai ne d pri or t o starti n g treat me nt, 
bet w ee n C 1 D 8 a n d C 2 D 1 5 , a n d at E O T (as cl ose t o t he date of ra di o gra p hic disease pr o gressi o n as p ossi ble if feasi ble ). If feasi ble, o n-treat me nt a n d E O T 
bi o psies s h o ul d be o btai ne d wit hi n 2 - 4 h o urs after d osi n g. See Secti o n 8. 8. 1 .
6.
W h ole Bl o o d:
as c o ntr ol f or t u m or m olec ular a nal ysis. 
7.
Bl o o d S a m ple f or C D x: See Secti o n 8. 7. 2 .
8.
Bl o o d S a m ple f or  
 ( S pecifie d Ge neticss): Bl o o d sa m ple ( 
) s h o ul d als o be c ollecte d at ra di o gra p hic pr o gressi o n.  See Secti o n 8. 7. 3 .
9.
P h ysic al E x a mi n ati o n : Hei g ht will be meas ure d at Scree ni n g o nl y.  C o m plete p h ysical e xa mi nati o n will be perf or me d at i nitial e xa mi nati o n o nl y.  Brief, 
s y m pt o m-directe d p h ysical e xa mi n ati o ns will be perf or me d s u bse q ue ntl y.  See Secti o n 8. 2. 1 .
1 0. F ull O p ht h al mic E x a mi n ati o n : Re peat o p ht hal mic e xa mi nati o n will be perf or me d o nl y if cli nicall y i n dicate d.  Vis ual ac uit y s h o ul d be teste d b y t he 
treati n g p h ysicia n o n Da y 1 of e ver y c ycle. See Secti o n 8. 2. 3 . 
1 1. Der m at ol o gic E x a mi n ati o n : See Secti o n 8. 2. 2 .
1 2. Ne ur ol o gic E x a mi n ati o n : Ne ur ol o gic e xa mi nati o n will be perf or me d o n Da y 1 a n d Da y 1 5 of C ycles 1- 2.  A d diti o nal e xa mi nati o n will be c o n d ucte d if 
cli nicall y i n dicate d.  See Secti o n 8. 2. 4 .
1 3. Vit al Si g ns: B P a n d p ulse rate t o be rec or de d i n sitti n g p ositi o n.  See Secti o n 8. 2. 6 .
1 4. E C O G P S : S ee A p pe n di x 1 4 f or E C O G classificati o n of perf or ma nce stat us.  See Secti o n 8. 2. 5 .
1 5. H e m at ol o g y : N o nee d t o re peat o n C 1 D 1 if Scree ni n g assess me nt perf or me d wit hi n 7 da ys.  See A p pe n di x 2 Cli nical La b orat or y Tests.
1 6. Bl o o d C he m istr y: N o nee d t o re peat o n C 1 D 1 if Scree ni n g assess me nt perf or me d w it hi n 7 da ys pri or t o t hat date.  See A p pe n di x 2 Cli nical La b orat or y Tests .
1 7. C o a g ul ati o n : N o nee d t o re peat o n C 1 D 1 if Scree ni n g assess me nt perf or me d wit hi n 7 da ys pri or t o t hat date.  See A p pe n di x 2 Cli nical La b orat or y Tests.  
Partici pa nts o n a ntic oa g ulati o n treat me nt s h o ul d ha ve para meters m o nit ore d t hr o u g h o ut t he st u d y as cli nicall y i n dicate d.
1 8. Uri n al ysis: Di pstic k is acce pta ble at mi ni m u m at Scree ni n g, C 2 D 1 a n d E O T visit.  See A p pe n di x 2 Cli nical La b orat or y Tests .
1 9. Ser u m F S H: Hi g h F S H le vel i n t he p ost me n o pa usal ra n ge m ust be use d t o c o nfir m a p ost me n o pa usal state i n w o me n u n der 6 0 years ol d a n d n ot usi n g 
h or m o nal c o ntrace pti o n or H R T.
2 0. Pre g n a nc y Test : Ser u m pre g na nc y test will be perf or me d wit hi n 2 4 h o urs pri or t o C 1 D 1 .  Details are descri be d i n Secti o n 8. 2. 1 0 . 
2 1. C o ntr ace pti o n C hec k : See Secti o n 5. 3. 3 .
2 2. Si n gle 1 2 -Le a d E C G: Si n gle E C G will be perf or me d d uri n g Scree ni n g t o deter mi ne eli gi bilit y.  Ma y be re peate d u p t o t wice m ore ( perf or me d 
a p pr o xi matel y 2 mi n utes a part) if t he i nitial Q Tc F val ue is > 4 7 0 msec ; if 3 E C Gs are perf or me d, t he a vera ge Q Tc F s h o ul d be ≤4 7 0 msec t o be eli gi ble. 
2 3. Tri plic ate 1 2 -Le a d E C G : F or eli gi bilit y, t he Q Tc F i nter val at Scree ni n g a n d C 1 D 1 pre -d ose m ust be ≤4 7 0 msec. A d diti o nal E C Gs ma y be perf or me d as 
cli nicall y i n dicate d. T he ti mi n g of E C G c ollecti o n ma y be a dj uste d base d o n e mer gi n g da ta.  Details of E C G g ui da nce , i ncl u di n g o btai ni n g a d diti o nal E C Gs 
t o c o nfir m s pecific a b n or malities, is pr o vi de d i n Secti o n 8. 2. 7 . De tails pr o vi de d i n ta ble bel o w whe n E C Ds are o btai ne d at t he sa me ti me as t he P K sa m ple.
 
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 8 2
2 4. E C H O : E C H O sca ns will be perf or me d at Scree ni n g, Da y 1 of C ycle 2 . E val uati o n of t he heart val ves s h o ul d be i ncl u de d a n d a n y baseli ne a n d 
treat me nt-e mer ge nt fi n di n gs s h o ul d be clearl y d oc u me nte d a n d e val uate d f or c o nsi derati o n of A E (i ncl u di n g gra de acc or di n g t o N CI C T C A E versi o n 5. 0 
a n d relati o n t o st u d y i nter ve nti o ns).  See Secti o n 8. 2. 9 .
2 5. St u d y I nter ve nti o n : P F-0 7 2 8 4 8 9 0 a n d bi ni meti ni b will be dis pe nse d wit h d osi n g diar y. Partici pa nts will recei ve a si n gle, 2 m g oral d ose of mi daz ola m o n 
D a y -7. P F -0 7 2 8 4 8 9 0 at t he rec o m me n de d d ose a n d re gi me n f or c o m bi nati o n wit h bi ni meti ni b ( 4 5 m g BI D), will be i nitiate d o n Da y 1, c o nti n u o usl y i n a 
2 1 -da y c ycle. Partici pa nts will t he n recei ve a si n gle oral d ose of mi daz ola m o n Da y 1 a n d Da y 1 5.  St u d y i nter ve nti o n will be descri be d i n Secti o n 6 a n d 
Secti o n 1 0. 1 5. 5 .
2 6. T u m or Assess me nts : T u mor assess me nts will i ncl u de all k n o w n or s us pecte d disease sites. M RI of brai n, c o ntrast -e n ha nce d C T or M RI of c hest, a b d o me n 
a n d pel vis will be perf or me d at Scree ni n g, C 3 D 1, t he n e ver y ot her c ycle/Q 6 W ± 1 w ee k. C R or P R c o nfir mati o n assess me nts m ust ta ke place at least 
4 we e ks after t he i nitial res p o nse a n d ma y be perf or me d a mi ni m u m of 4 wee ks ( 2 8 da ys) after t he i nitial sca n s h o wi n g a C R or P R at t he discreti o n of t he 
i n vesti gat or, wit h t he ne xt sca n perf or me d acc or di n g t o t he ori gi nal sc he d ule.  See Secti o n 8. 1. 1 .
2 7. Pri or a n d C o nc o m it a nt Me dic ati o n : all c o nc o mita nt me dicati o ns a n d N o n Dr u g S u p p orti ve I nter ve nti o ns s h o ul d be rec or de d o n t he C R F.
2 8. A E Assess me nts : A Es s h o ul d be d oc u me nte d a n d rec or de d at eac h visit usin g t he N CI C T C A E versi o n 5. 0 .  Assess me nt of A Es s h o ul d i ncl u de q uesti o ns 
pertai ni n g t o t he i nci de nce, se verit y, a n d ti mi n g of vis ual c ha n ges (e g, flas hes or c ol or c ha n ges), pal piti o ns, a n d br uisi n g or blee di n g. T he ti me peri o d f or 
acti vel y eliciti n g a n d c ollecti n g A Es a n d S A Es (“acti ve c ollecti o n peri o d”) f or eac h partici pa nt be gi ns fr o m t he ti me t he partici pa nt pr o vi des i nf or me d 
c o nse nt/asse nt t hr o u g h a n d i ncl u di n g a mi ni m u m of 2 8 cale n dar da ys after t he last st u d y i nter ve nti o n a d mi nistrati o n. If t he partici pa nt be gi ns a ne w 
a ntica ncer t hera p y, t he peri o d f or rec or di n g n o n -seri o us A Es o n t he C R F e n ds at t he ti me t he ne w treat me nt is starte d. H o w e ver, a n y S A Es occ urri n g d uri n g 
t he acti ve c ollecti o n peri o d m ust still be re p orte d t o Pfizer Safet y a n d rec orde d o n t he C R F, irres pecti ve of a n y i nter ve ni n g treat me nt.   See Secti o n 8. 3 .
2 9. P K Bl o o d S a m pli n g: Details pr o vi de d i n t he ta ble bel o w.  Als o, see Secti o n 8. 5 .
3 0. P K Uri ne S a m pli n g : Uri ne P K sa m pli n g will be c o n d ucte d o n C 1 D 1 5.
3 1. P K C S F S a m pli n g : Details pr o vi de d i n t he ta ble bel o w . Als o, s ee Secti o n 8. 5 .
3 2. P h ar m ac o ge n o mics s a m pli n g : P har mac o ge n o mic sa m ples will be o btai ne d d uri n g Scree ni n g.  See Secti o n 8. 7. 4 .
3 3.
Pfizer Pre p D 1 B a n ke d Bi os peci me n(s): See Secti o n 8. 7. 5 .
3 4.
Assess me nt d oes n ot nee d t o be re peate d if perf or me d wit hi n 7 2 h o urs pri or t o C ycle 1 Da y 1 (ie, first da y of d osi n g).
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 8 3
P h ar m ac o ki netic S a m pli n g a n d E C Gs f or C o h ort 6 i n P h ase 1 b
St u d y T re at me nt (c ycle d ur ati o n = 2 1 d a ys)
C ycle 1
C ycle 2 - 6
Visit I de ntifier
Scree ni n g
Le a d -i n
D a y 1
D a y 1 5 
D a y 1 a
D a y -3 5 t o 
D a y - 8
D a y - 7
N o wi n d o w
( ±3 d a ys)
( ±3 d a ys)
H o urs Bef ore/ After D ose
0 b
0. 5
1 
2 
4 
8 
0 b
0. 5
1 
2 
4 
8 
0 b
0. 5
1 
2 
4 
8 
0 b
2
St u d y i nter ve nti o n 
a d mi nistrati o n ( P F- 0 7 2 8 4 8 9 0 
a n d bi ni meti ni b) 1
X
X
X
St u d y i nter ve nti o n
a d mi nistrati o n , C Y P 3 A pr o be 
mi daz ola m 1
X
X
X
P K bl o o d plas ma sa m pli n g2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Uri ne f or P K 3
X
X
X
X
X
X
P K C S F sa m pli n g 4
A n y ti me C S F is sa m ple d as part of S O C
Si n glet 1 2 -lea d E C G
X
Tri plicate 1 2 -lea d E C G5
X
X
X
X
X
X
X
a.
C 2 D 1 visit is t he e n d of t he D DI p hase safet y assess me nt.  F or acti vities/assess me nts after C 2 D 1, please refer t o Secti o n 1. 3 .
b.
Pre d ose sa m ple c ollecti o n.
1.
St u d y dr u g/ Mi dz ol a m  A d m i nistr ati o n: O n P K da ys, m or ni n g d ose of t he st u d y a ge nts will be a d mi nistere d i n t he cli nic. Mi daz ola m will be a d mi nistere d 
after a d mi nistrati o n of st u d y a ge nts. 
2.
P K S a m pli n g : Bl o o d w ill be c ollecte d f or deter mi ni n g t he c o nce ntrati o n of mi daz ola m o n Lea d -i n Da y -7, a n d mi daz ola m, P F -0 7 2 8 4 8 9 0 a n d bi ni meti ni b 
C 1 D 1 a n d C 1 D 1 5 at pre -d ose ( w it hi n 3 0 mi n bef ore t he d ose), 3 0 mi n (± 2 m i n), 1 h o ur ( ± 5 mi n), 2 h o ur ( wit hi n 1 5 mi n utes after t he last of t he tri plicate 
E C Gs sc he d ule d at t hat ti me p oi nt), 4 h o ur ( ± 1 0 mi n), a n d 8 h o ur ( ± 2 0 mi n) p ost d ose.  O n Da y 1 of C 2 -C 6, P K sa m ples will als o be o btai ne d pre -d ose 
( wit hi n 3 0 mi n) a n d at 2 h o urs ( w it hi n 1 5 mi n utes f oll o wi n g t he last of t he tri plicate E C Gs sc he d ule d at t hat ti me p oi nt) p ost d ose. A P K sa m ple will als o be 
o btai ne d d uri n g t he E O T visit a n d at t he ti me of C S F sa m pli n g ( w he n C S F sa m pli n g is n ot d o ne o n a P K da y) if p ossi ble. A d diti o nal P K sa m ples ma y be 
o btai ne d at ot her ti me p oi nts if cli nicall y i n dicate d.  Detaile d i nstr ucti o n of sa m ple c ollecti o n, pr ocessi n g a n d s hi p me nt will be pr o vi de d i n t he La b Ma n ual. 
See Secti o n 8. 5 .
3.
Uri ne f or P K S a m pli n g: T he pre d ose uri ne sa m ple will be se parate fr o m t he s u bse q ue nt c ollecti o n. All uri ne c ollecte d o ver t he 0 t o 8 h o ur peri o d w ill be 
p o ole d.
4.
P K C S F S a m pli n g : P K C S F sa m ples will be c ollecte d f or partici pa nts i n w h o m C S F sa m pli n g is bei n g perf or me d as part of S O C.  If feasi ble sa m ples 
s h o ul d be c ollecte d o n a n y P K da y, i deall y 2 t o 4 h o urs after d osi n g o n a n y P K da y, wit h t he ti me c ollecte d relati ve t o d osi n g clearl y i n dicate d o n t he 
re q uisiti o n.  If t he C S F sa m ple is c ollecte d b ut n ot o n a P K da y, a n a d diti o nal P K sa m ple s h o ul d be c ollecte d s o o n after if possi ble. See Secti o n 8. 5 .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 8 4
5.
1 2 Le a d E C G: A si n glet E C G w ill be c ollecte d at Scree ni n g. Tri plicate E C Gs will be c ollecte d at pre-d ose ( wit hi n a p pr o xi matel y 1 5 mi n utes bef ore t he pre -d ose 
P K sa m ple ) a n d at 2 h o urs ( ± 1 0 mi n) after d osi n g o n C 1 D1 a n d C 1 D 1 5, a n d at 2 h o urs ( ± 3 0 mi n) p ost d ose o n Da y 1 of C ycles 2 -6 (i nte n de d t o a p pr o xi mate 
t he Tma x of P F -0 7 2 8 4 8 9 0), w it h 3 c o nsec uti ve 1 2 lea d E C Gs perf or me d a p pr o xi matel y 2 mi n utes a part t o deter mi ne mea n Q Tc F i nter val.  W he n E C Gs are 
o btai ne d at t he sa me ti me as a P K sa m ple, t he E C Gs m ust be c o m plete d bef ore t he P K sa m ple is ta ke n.  A d diti o nal E C Gs w ill be perf or me d as cli nicall y 
i n dicate d.  T he ti mi n g of E C G c ollecti o n ma y be a dj uste d base d o n e mer gi n g data. Details of E C G g ui da nce, i ncl u di n g o btai ni n g a d diti o nal E C Gs t o c o nfir m 
s pecific a b n or malities, are pr o vi de d i n Secti o n 8. 2. 7 .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 8 5
1 0. 1 6. A p pe n di x 1 6: A F o o d -effect S u b St u d y
1 0. 1 6. 1. R ati o n al f or E v al u ati o n of F o o d Effect
F o o d ca n ha ve a si g nifica nt i m pact o n dr u g p har mac o ki netics, a n d t heref ore o n dr u g safet y 
a n d efficac y. T he effect of f o o d o n P F -0 7 2 8 4 8 9 0 P K is bei n g assesse d i n healt h y 
partici pa nts i n S t u d y C 4 4 7 1 0 0 2 ( m ore details pr o vi de d i n 4. 2. 6 ).  If t he f o o d effect s h o ws a n 
i ncrease i n e x p os ures, t he data fr o m t his st u d y will be use d t o deter mi ne t he d ose i n t he fe d 
state t hat is e q ui vale nt t o t he faste d state M T D/ R D E. If t he o bser ve d f o o d effect is 
s u bsta ntial a n d cli nicall y si g nifica nt, ie, i ncreases t he relati ve bi oa vaila bilit y b y m ore t ha n 
2 -f ol d, m ore data m a y  be nee de d t o deter mi ne w het her t he e q ui vale nt d ose f or t he fe d state 
ac hie ves t he pr o per e x p os ure a n d is safe wit h re peat a d mi nistrati o n. F or t his reas o n, t he 
effect of f o o d o n P F -0 7 2 8 4 8 9 0 P K a n d safet y will be c harac terize d i n t his s u bst u dy if f o o d 
ca uses m ore t ha n a 2 -f ol d i ncrease i n A U C i n C 4 4 7 1 0 0 2.
1 0. 1 6. 2. St u d y Desi g n
T his s u bst u d y will be c o n d ucte d wit hi n C 4 4 7 1 0 0 1 i n C o h ort 7 partici pa nts t o assess t he 
safety a n d P K of a d mi nistrati o n of a rec o m me n d d ose f or f urt her st u d y w he n a d mi nistere d 
wit h f o o d.  A p pr o xi matel y  6- 8 partici pa nts ( P K e val ua ble) are re q uire d f or t he f o o d-effect 
assess me nt, a n d partici pa nts w h o are i ne val ua ble f or t his P K s u bst u d y  ma y be re place d b y 
t he S p o ns or. 
T he P F - 0 7 2 8 4 8 9 0 d ose i n t he fe d state e q ui vale nt t o t he M T D/ R D E d ose i n t he faste d state 
f or a p ositi ve f o o d effect will be deter mi ne d fr o m C 4 4 7 1 0 0 2 P K data ( l o w-fat meal vers us 
faste d) base d o n t he rati o of L S M of t he A U C val ues. If t he rati o, e x presse d as perce nt of 
refere nce, c o m pari n g t he l o w-fat meal (test) t o t he faste d state (refere nce) is < 1 2 5 %, t he d ose 
i n t he fe d state will be t he sa me as t he d ose i n t he faste d state . H o we ver, if t he rati o is 
≥1 2 5 %, t he d ose i n t he fe d state will be a dj uste d base d o n e x p os ures matc hi n g, ass u mi n g 
li near P K, a n d ta ki n g i nt o c o nsi derati o n ta blet stre n gt hs. F or e xa m ple, if A U C f or t he fe d 
state (l o w fat meal) is 2 0 0 % t hat of t he faste d state, t he n a 5 0 % decrease i n d ose will be 
dee me d a p pr o priate. 
Wit hi n C o h ort 7, a ll partici pa nts will be a d mi nistere d P F - 0 7 2 8 4 8 9 0 i n a fe d state. P K 
sa m pli n g ti mes, w hic h i ncl u de a d diti o nal P K sa m pli n g are descri be d bel o w .  I n vesti gati o nal 
pr o d uct will be a d mi nistere d wit h a p pr o xi matel y  8 o u nces ( 2 4 0 ml) of water wit hi n 
a p pr o xi matel y 3 0 mi n utes after t he start of t he meal/s nac k. T he patie nt s h o ul d be i nstr ucte d 
t o rec or d c o m plia nce wit h t he re q uire me nts t o a d mi nister dr u g wit h f o o d i n t he d osi n g diar y.  
St u d y  staff s h o ul d m o nit or c o m plia nce at eac h visit a n d rec or d t his i n t he C R F .  T he effect s
of c o ntr olle d meals were e xa mi ne d i n S t u d y C 4 4 7 1 0 0 2 (ie, sta n dar d l o w-fat a n d hi g h-fat 
meals as descri be d i n F D A g ui da nce). T he g oal of t his s u bst u d y  is t o deter mi ne e x p os ures 
f or a ty pical meal , a n d patie nts s h o ul d eat s o met hi n g ty pical f or t he m . E xa m p les of 
meals /s nac ks t hat a patie nt c o ul d c o ns u me at a mi ni m u m pri or t o t heir P K sa m ples i ncl u de:

O ne b oile d e g g, o ne pac ket of fla v ore d i nsta nt oat meal ma de wit h water, a n d 8 oz of 
mil k ( 1 perce nt fat) – F D A l o w -fat meal.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 8 6

C heese, drie d fr uit , crac kers a n d c o ke.
Patie nts are n ot precl u de d fr o m eati n g a lar ger , hi g h-cal orie meal.  T he a b o ve are o nl y 
e xa m ples of s nac ks/ meals t hat w o ul d be acce pta ble.  T he sc he d ule of acti vities will be as 
descri be d i n Secti o n 1. 3 , b ut t he P har mac o ki netic Sa m pli n g a n d E C Gs Sc he d ule n ote d t here
will be re place d b y  Ta ble 1 5 Sc he d ule of Acti vities f or F o o d -effect S u bst u d y  as n ote d bel o w.
Base d o n t hese data, t he effect of f o o d will be e val uate d t o deter mi ne safet y a n d t olera bilit y 
of t he e q ui vale nt d ose at t he M T D/ R D E w he n a d mi nistere d wit h f o o d. T he S R C will be 
c o n ve ne d after 6 t o 8 patie nts ha ve bee n treate d f or at least 2 1 da y s t o assess safety a n d 
t olera bilit y a n d a vaila ble P K data. If well t olerate d , a P A C L ma y be use d to re place t he 
fasti n g re q uire me nt wit h a n i nstr ucti o n f or a d mi nistrati o n of P F- 0 7 2 8 4 8 9 0 wit h f o o d . If 
e x p os ures are n ot as e x pecte d, t he e q ui vale nt d ose ma y  be f urt her a dj uste d base d o n the data 
fr o m t his s u bst u d y c o h ort.
1 0. 1 6. 3. P artici p a nt P o p ul ati o n
I n a d diti o n t o all of t he i ncl usi o n criteria o utli ne d i n Secti o n 5. 1 , t hese a d diti o nal i ncl usi o n 
criteria a p pl y:

B rai n i n v ol ve me nt if prese nt m ust be: ( 1) ne ur ol o gicall y as ym pt o matic fr o m brai n 
lesi o ns f or at least 1 4 da ys pri or t o t he start of st u d y treat me nt; ( 2) if re q uiri n g 
ster oi ds t o c o ntr ol ne ur ol o gical s ym pt o ms, o n a sta ble t o decreasi n g d ose of ster oi ds 
f or 14 da y s pri or t o t he start of st u d y treat me nt; a n d ( 3) n o pr o p hyl actic or 
pre ve ntati ve a nti -e pile ptic t hera p y t o pre ve nt ne ur ol o gical s y m pt o ms ca use d b y  brai n 
lesi o ns. E xce pti o n: a nti -e pile ptic t hera p y t o pre ve nt ne ur ol o gical s y m pt o ms ca use d 
b y  a pree xistin g c o n diti o n a n d n ot relate d t o brai n i n v ol ve me nt is all o we d ( see 
Secti o n 6. 5 f or all o we d/ pr o hi bite d c o nc o mita nt me dicati o ns, i ncl udi n g a nti- e pile ptic 
t hera py).
I n a d diti o n t o all of t he e xcl usi o n criteria o utli ne d i n Secti o n 5. 2 , t his a d diti o nal e xcl usi o n 
criteri o n a p plies:

C urre nt use or a ntici pate d nee d i n C ycle 1 f or dr u gs t hat are k n o w n C Y P 3 A
i n hi bit ors, i ncl u di n g t he a d mi nistrati o n wit hi n 1 0 da y s or 5 half -li ves, w hic he ver is 
l o n ger, or C Y P 3 A i n d ucers, i ncl u di n g t he a d mi nistrati o n wit hi n 5 half -li ves pl us 
1 0 da y s, pri or t o first d ose of mi daz ola m .  Refer t o Secti o n 6. 5 f or f urt her details. See 
A p pe n di x 1 8 f or e xa m ples of str o n g C Y P 3 A i n hi bit ors a n d i n d ucers.
1 0. 1 6. 4. A d diti o n al P K Assess me nts
Alt h o u g h t he s u bst u d y will be c o n d ucte d i n P hase 1 b, C o h ort 7, a d diti o nal P K sa m pli n g will 
be d o ne, c o nsiste nt wit h P K sa m pli n g i n P hase 1a d ose escalati o n as s h o w n i n Ta ble 1 5 .
1 0. 1 6. 5. S afet y Assess me nts
Safet y  assess me nts are descri be d i n Secti o n 8. 2 .
0 9
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 8 7
1 0. 1 6. 6. A d diti o n al P K Assess me nts
T he a nal ys is of P K -0 7 2 8 4 8 9 0 P K data will be c o n d ucte d as descri be d i n Secti o n 9. 3. 2. 2 .
1 0. 1 6. 7. St atistic al A n al yses
P F -0 7 2 8 4 8 9 0 P K para meters ( A U C 8 a n d C ma x ) will be c o m pare d t o data fr o m P hase 1a i n t he 
faste d state at all d ose le vels b ut f oc usi n g o n t he M T D/ R D E d ose le vel t o deter mi ne w het her 
t he P K at t he e q ui vale nt d ose i n t his fe d state s u bst u d y are as e x pecte d. 
1 0. 1 6. 8. Tr a nsiti o n t o Fe d St ate A d mi nistr ati o n
P K a n d safet y will be assesse d f or t his c o h ort as per t he c urre nt pr ot oc ol/ S o A . T he d ose i n 
t he fe d state deter mi ne d e q ui vale nt t o t he faste d state M T D/ R D E will be a dj uste d if e x p os ure 
a n d/ or t olera bilit y data i n dicate s uc h a n a dj ust me nt is nee de d.
If t he P K data fr o m t his f o o d-effect s u bst u d y i n dicate wit h f o o d P K f or P F-0 7 2 8 4 8 9 0 has a 
p ote ntial be nefit f or patie nts (e g , if e x p os ures are m ore c o nsiste nt i n t he fe d state or if C tr o u g h
val ues are hi g her f or si milar e x p os ures a n d t olera bilit y ) a n d is well t olerate d , t he i nstr ucti o ns 
f or a d mi nisteri n g P F-0 7 2 8 4 8 9 0 i n t he fe d state at t he a p pr o priate e q ui vale nt d ose t o t he 
M T D/ R D E will be i ntr o d uce d i nt o P hase 1 b u n der t he c urre nt a me n d me nt . T he fe d state 
e q ui vale nt d ose will be c o m m u nicate d t o t he st u d y i n vesti gat ors. P artici pa nts w h o starte d 
ta kin g P F -0 7 2 8 4 8 9 0 i n t he faste d state m a y  tra nsiti o n t o t he fe d state at a n e q ui vale nt d ose 
after t he fe d state e q ui vale nt d ose has bee n deter mi ne d a n d t olera bilit y has bee n verifie d i n 
t he f o o d-effect s u bst u d y c o h ort.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 8 8
T a ble 1 5 . P h ar m ac o ki netic, E C G a n d Selecte d Bi o m ar ker S a m pli n g f or F o o d -effect S u bst u d y 
St u d y Tre at me nt (c ycle d ur ati o n = 2 1 d a ys)
1 st C ycle C o m bi n ati o n T her a p y
C ycles 2- 6
S u bse q ue nt C ycles
Visit I de ntifier
Scree ni n g
D a y 1
D a y 1 5 
D a y 1 
D a y 1
E O T
D a y -2 8 
t o D a y - 1
N o wi n d o w
( ±3 d a ys)
( ±3 d a ys)
( ±3 d a ys)
( ±7 d a ys)
H o urs Bef ore/ After D ose
0 a
1 
2
4  
6 
8 
0 a
1 
2 
4
6 
8 
0 a
2
0 a
A d mi nistrati o n of st u d y 
i nter ve nti o n (P F -0 7 2 8 4 8 9 0 , 
or P F - 0 7 2 8 4 8 9 0 a n d 
bi ni meti ni b ), A M d ose i n 
cli nic
X
X
X
X
P K bl o o d plas ma sa m pli n g1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
P K a n d ge netic bi o mar ker 
C S F sa m pli n g 2
A n y ti me C S F is sa m ple d as part of S O C
Si n glet 1 2 -lea d E C G3
X
Tri plicate 1 2 -lea d E C G3
X
X
X
X
X
1.
P K Sa m pli n g f or Partici pa nts partici pati n g i n t he f o o d-effect s u bst u d y: Bl o o d will be c ollecte d f or deter mi ni n g t he c o nce ntrati o n of P F-0 7 2 8 4 8 9 0 (a n d f or 
bi ni meti ni b i n patie nts recei vi n g t he c o m bi nati o n) o n C 1 D 1 a n d o n C 1 D 1 5 at pre -d ose ( w it hi n 3 0 mi n bef ore t he d ose), 1 h o ur ( ± 5 mi n), 2 h o ur ( w it hi n 
1 5 mi n utes after t he last of t he tri plicate E C Gs sc he d ule d at t hat ti me p oi nt), 4 h o ur ( ± 3 0 mi n), 6 h o ur ( ± 4 0 mi n), a n d 8 h o ur ( ± 6 0 mi n) p ost d ose. O n 
D a y 1 of C 2- C 6, P K sa m ples will als o be o btai ne d pre -d o se ( wit hi n 3 0 mi n pri or t o d ose) a n d at 2 h o urs ( wit hi n 1 5 mi n utes f oll o wi n g t he last of t he 
tri plicate E C Gs sc he d ule d at t hat ti me p oi nt) p ost d ose.  O n Da y 1 of s u bse q ue nt c ycles, P K sa m ples will als o be o btai ne d pre-d ose ( w it hi n 3 0 mi n pri or t o 
d ose) . A P K sa m ple will als o be o btai ne d d uri n g t he E O T visit. A d diti o nal P K sa m ples ma y be o btai ne d at ot her ti me p oi nts if cli nicall y i n dicate d.
2.
P K C S F Sa m pli n g: P K C S F sa m ples will be c ollecte d f or partici pa nts i n w h o m C S F sa m pli n g is bei n g perf or me d as part of S O C.  If p ossi ble, sa m ples 
s h o ul d be c ollecte d o n a n y P K da y, i deall y 2 t o 4 h o urs after d osi n g o n a n y P K da y, wit h t he ti me c ollecte d relati ve t o d osi ng clearl y i n dicate d o n t he 
re q uisiti o n a n d/ or e C R F. If t he C S F sa m ple is c ollecte d b ut n ot o n a P K da y, a n a d diti o nal P K sa m ple s h o ul d be c ollecte d s o o n after if p ossi ble. See 
Secti o n 8. 4 .
3.
1 2 - Lea d E C G: A si n glet E C G will be c ollecte d at Scree ni n g.  Tri plicate E C Gs will be c ollecte d at pre-d ose ( wit hi n a p pr o xi matel y 1 5 mi n utes bef ore t he pre -d ose P K 
sa m ple) a n d at 2 h o urs ( ± 1 0 mi n) after d osi n g o n C 1 D 1 a n d C 1 D 1 5; a n d at 2 h o urs ( ± 3 0 mi n) p ost d ose o n Da y 1 of C ycles 2 -6 (i nte n de d t o a p p r o xi mate t he Tma x of 
P F -0 7 2 8 4 8 9 0 ), wit h 3 c o nsec uti ve 1 2 lea d E C Gs perf or me d a p pr o xi matel y 2 mi n utes a part t o deter mi ne mea n Q Tc F i nter val.  W he n E C Gs are o btai ne d at t he sa me ti me as 
a P K sa m ple, t he E C Gs m ust be c o m plete d bef ore t he P K sa m ple is ta ke n.  A d diti o nal E C Gs will be perf or me d as cli nicall y i n dicate d. T he ti mi n g of E C G c ollecti o n ma y 
be a dj uste d base d o n e mer gi n g data. Details of E C G g ui da nce, i ncl u di n g o btai ni n g a d diti o nal E C Gs t o c o nfir m s pecific a b n or mal ities, are pr o vi de d i n Secti o n 8. 2. 6 . W h e n
E C Gs are o btai ne d at t he sa me ti me as a P K sa m ple, t he E C Gs m ust be c o m plete d bef ore t he P K sa m ple is ta ke n.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 8 9
1 0. 1 7. A p pe n di x 1 7 : Pr o hi bite d C o nc o mit a nt Me dic ati o ns T h at M a y Res ult i n D DI 
T he pr o hi bite d c o nc o mita nt me dicati o ns liste d bel o w s h o ul d n ot be ta ke n wit h P F -0 7 2 8 4 8 9 0 
t hr o u g h o ut t he c o n d uct of t he st u d y, a n d s o me ha ve a re q uire d was h o ut peri o d as liste d i n t he 
ta ble.
T he Pfizer st u d y  tea m is t o be n otifie d of a n y pr o hi bite d me dicati o ns ta ke n d uri n g t he st u d y. 
After c o ns ulti n g wit h t he s p o ns or, t he i n vesti gat or will ma ke a j u d g me nt o n t he o n g oi n g 
partici pati o n of a n y partici pa nt wit h pr o hi bite d me dicati o n use d uri n g t he st u d y.
T his li st of dr u gs pr o hi bite d f or p ote ntial D DI c o ncer ns wit h t he I M P ma y be re vise d d uri n g 
t he c o urse of t he st u d y wit h writte n n otificati o n fr o m t he s p o ns or, t o i ncl u de or e xcl u de 
s pecific dr u gs or dr u g cate g ories f or vari o us reas o ns (e g, e mer gi n g D DI res ults f or t he I M P, 
a vaila bilit y of ne w i nf or mati o n i n literat ure o n t he D DI p ote ntial of ot her dr u gs).
T his is n ot a n all -i ncl usi ve list. Site staff s h o ul d c o ns ult wit h t he s p o ns or or desi g nee wit h 
a n y q uesti o ns re gar di n g p ote ntial D DI.
I n vesti gat ors s h o ul d c ons ult t he pr o d uct la bel f or a n y  ot her me dicati o n use d d uri n g t he st u d y 
f or i nf or mati o n re gar di n g me dicati o n t hat is pr o hi bite d f or c o nc o mita nt use.
I n vesti gat ors s h o ul d c o ns ult t he S R S D f or bi ni meti ni b f or i nf or mati o n re gar di n g me dicati o n 
t hat is pr o hi bite d f or c o nc o mita nt use.
T a ble 1 6.
Pr o hi bite d C o nc o mit a nt Me dic ati o ns t h at M a y Res ult i n D DI
Dr u g C ate g or y
Dr u gs
G ui d a nce
Re q uire d W as h o ut 
Peri o d Pri or t o t he First 
D ose of P F - 0 7 2 8 4 8 9 0
P F - 0 72 8 4 8 9 0 as V icti m of D DI
Pr ot o n p u m p 
i n hi bit ors
de xla ns o praz ole
es o me praz ole
ila praz ole a
la ns o praz ole
o me praz ole
pa nt o praz ole
ra be praz ole
Pr o hi bite d
7 da y s
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 9 0
P F - 0 72 8 4 8 9 0 as Per petr at or of D DI
C Y P 3 A s u bstr ates 
t h at h a ve a 
n arr o w 
t her a pe utic i n de x 
( N TI)
alfe nta nil
a mi o dar o ne
ar gatr o ba n
aste miz ole
a
car ba maze pi ne
cisa pri de
a
c ycl os p ori ne
di h y dr oer g ota mi ne
er g ota mi ne
fe nta nyl  (e xcl u di n g 
tra ns der mal patc h)
pi m ozi de
q ui ni di ne
sir oli m us
tacr oli m us
terfe na di ne
Pr o hi bite d
N/ A
a.
N ot a p pr o ve d i n t he U S as of Oct o ber 2 0 2 0, b ut ma y be a vaila ble i n ot her c o u ntries i ncl u di n g K orea, 
C hi na a n d Me xic o.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 9 1
1 0. 1 8. A p pe n di x 1 8: Str o n g C Y P 3 A I n hi bit ors a n d I n d ucers
T his list is n ot c o nsi dere d t o be e x ha usti ve. Alt h o u g h it c o ntai ns o nl y str o n g i n hi bit ors a n d 
i n d ucers, all C Y P 3 A i n hi bit ors a n d i n d ucers are pr o hi bite d t hr o u g h t he e n d of C y cle 1 f or 
partici pa nts i n t he D DI s u bst u d y P hase 1 b C o h ort 6.  A n y  q uesti o ns re gar di n g use of C Y P 3 A 
i n hi bit ors a n d i n d ucers s h o ul d be directe d t o t he S p o ns or st u d y tea m.
C Y P 3 A I n hi bit ors
C Y P 3 A I n d ucers
HI V a nti vir als
HI V a nti vir als
I n di na vir
Ne vira pi ne
Nelfi na vir
Miscell a ne o us
Rit o na vir
Bar bit urates
Sa q ui na vir
Car ba maze pi ne
B oce pre vir
Gl uc oc ortic oi ds (s yste mic)
L o pi na vir/rit o na vir
O xcar baze pi ne
A m pre na vir
P he n o bar bital
Ataza na vir
P he n yt oi n
Tela pre vir
Rifa b uti n
Dar u na vir/rit o na vir
Rifa m pi n
F osa m pre na vir
St. J o h n’s w o rt1
Ti pri na vir/rit o na vir
Tr o glitaz o ne
A nti bi otics
Nafcilli n
Clarit hr o m yci n
A vasi mi be 2
Tr olea n d o m yci n
E nzal uta mi de
Telit hr o m yci n
Rifa pe nti ne
Mit ota ne
Cle vi di pi ne
A nti -i nfecti ve
Itrac o naz ole
Ket oc o naz ole
P osac o naz ole
V oric o naz ole
Mic o n az ole
Miscell a ne o us
Nefaz o d o ne
Gra pefr uit j uice 3
C o ni va pta n
Mi befra dil
4
I delalisi b
1.
T he effect of St. J o h n’s w o rt varies wi del y a n d is pre parati o n -de pe n de nt .
2.
N ot a mar kete d dr u g .
3.
T he effect of gra pefr uit j uice varies wi del y a mo n g bra n ds a n d is c o nce ntrati o n-, d ose -, a n d pre parati o n -
de pe n de nt. St u dies ha ve s h o w n t hat it c a n be classifie d as a “str o n g C Y P 3 A i n hi bit or” w he n a certai n 
pre parati o n wa s use d (e g, hi g h d ose, d o u ble stre n gt h) or as a “ m o derate C Y P 3 A i n hi bit or” w he n a n ot her
pre parati o n wa s use d (e g, l o w d ose, si n gle stre n gt h).
4.
Wit h dra w n
fr o m t he U nite d States mar ket.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 9 2
1 0. 1 9. A p pe n di x 1 9 : Alter n ati ve Me as ures D uri n g P u blic E mer ge ncies
T he alter nati ve st u d y meas ures descri be d i n t his secti o n are t o be f oll o we d d uri n g p u blic 
e mer ge ncies, i ncl u di n g t he p C O VI D -1 9 pa n de mic. T his a p pe n di x a p plies f or t he d urati o n of 
t he C O VI D-1 9 pa n de mic gl o ball y a n d will bec o me effecti ve f or ot her p u blic e mer ge ncies 
o nl y  u p o n writte n n otificati o n fr o m Pfizer. 
Use of t hese alter nati ve st u d y  meas ures are e x pecte d t o cease u p o n t he ret ur n of b usi ness as 
us ual circ u msta nces (i ncl u di n g t he lifti n g of a ny q uara nti nes a n d tra vel ba ns/a d vis ories). 
1 0. 1 9. 1. Eli gi bilit y 
W hile S A R S -C o V 2 testi n g is n ot ma n date d f or t his st u d y , l ocal cli nical practice sta n dar ds f or 
testi n g s h o ul d be f oll o we d. A patie nt s h o ul d be e xcl u de d if he/s he has a p ositi ve test res ult 
f or S A R S-C o V 2 i nfecti o n, is k n o w n t o ha ve as y m pt o matic i nfecti o n, or is s us pecte d of 
ha vi n g S A R S -C o V 2. Patie nts wit h acti ve i nfecti o ns are e xcl u de d fr o m st u d y  partici pati o n as 
per E xcl usi o n Criteri o n 7 . W he n t he i nfecti o n res ol ves, t he patie nt ma y  be c o nsi dere d f or 
re-scree ni n g. 
1 0. 1 9. 2. Tele he at h Visits
I n t he e ve nt t hat i n-cli nic st u d y visits ca n n ot be c o n d ucte d, e ver y  eff ort s h o ul d be ma de t o 
f oll o w u p o n t he safet y of st u d y partici pa nts at sc he d ule d visits per t he Sc he d ule of Acti vities
or u nsc he d ule d visits. Tele healt h visits ma y  be use d t o c o nti n ue t o assess partici pa nt safet y 
a n d c ollect data p oi nts. Tele healt h i ncl u des t he e xc ha n ge of healt hcare i nf or mati o n a n d 
ser vices via telec o m m u nicati o n tec h n ol o gies (e g, a u di o, vi de o, vi de o-c o nfere nci n g s oft ware) 
re m otel y, all o wi n g t he partici pa nt a n d t he i n vesti gat or t o c o m m u nicate o n as pects of cli nical 
care, i ncl u di n g me dical a d vice, re mi n ders, e d ucati o n, a n d safety m o nit ori n g. T he f oll o wi n g 
assess me nts m ust be perf or me d d uri n g a tele healt h visit:

Re vie w a n d rec or d st u d y i nter ve nti o n(s), i ncl u di n g c o m plia nce a n d misse d d oses.

Re vie w a n d rec or d a n y   A Es a n d S A Es si nce t he last c o ntact.  Refer t o Secti o n 8. 3 .

Re vie w a n d rec or d a n y ne w c o nc o mita nt me dicati o ns or c ha n ges i n c o nc o mita nt 
me dicati o ns si nce t he last c o ntact.

Re vie w a n d rec or d c o ntrace pti ve met h o d a n d res ults of pre g na nc y testi n g. C o nfir m 
t hat t he partici pa nt is a d heri n g t o t he c o ntrace pti o n met h o d(s) re q uire d i n t he 
pr ot oc ol. Refer t o A p pe n di x 4 a n d Secti o n 1 0. 1 9. 3. 1 of t his a p pe n di x re gar di n g 
pre g na nc y  tests.
St u d y  partici pa nts m ust be re mi n de d t o pr o m ptl y n otif y site staff a b o ut a n y c ha n ge i n t heir 
healt h stat us.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 9 3
1 0. 1 9. 3. Alter n ati ve F acilities f or S afet y Asses s me nts
1 0. 1 9. 3. 1. L a b or at or y Testi n g
If a st u dy partici pa nt is u na ble t o visit t he site f or pr ot oc ol -s pecifie d safet y la b orat or y 
e val uati o ns, testi n g m a y  be c o n d ucte d at a l ocal la b orat or y  if per mitte d b y l ocal re g ulati o ns.  
T he l ocal la b orat or y  ma y be a sta n dal o ne i nstit uti o n or wit hi n a h os pital. 
If a l ocal la b orat or y is use d, q ualifie d st u d y site pers o n nel m ust or der, recei ve, a n d re vie w 
res ults. Site staff m ust c ollect t he l ocal la b orat or y refere nce ra n ges a n d 
certificat i o ns/accre ditati o ns f or fili n g at t he site.  La b orat or y  test res ults are t o be pr o vi de d t o 
t he site staff as s o o n as p ossi ble.  T he l ocal la b orat or y  re p orts s h o ul d be file d i n t he 
partici pa nt’s s o urce d oc u me nts/ me dical rec or ds. Rele va nt data fr o m t he l oca l la b orat or y 
re p ort s h o ul d be rec or de d o n t he C R F.
If a partici pa nt re q uiri n g pre g na nc y testi n g ca n n ot visit a l ocal la b orat or y f or pre g na nc y 
testi n g, a h o me uri ne pre g na nc y testi n g kit wit h a se nsiti vit y of at least 2 5 mIU/ m L ma y  be 
use d b y  t he partici pa nt t o perf or m t he test at h o me, if c o m plia nt wit h l ocal re g ulat or y 
re q uire me nts. T he pre g na nc y  test o utc o me s h o ul d be d oc u me nte d i n t he partici pa nt’s s o urce 
d oc u me nts/ me dical rec or ds a n d rele va nt data rec or de d o n t he C R F. C o nfir m t hat t he 
partici pa nt is a d heri n g t o t he c o ntrace pti o n met h o d(s) re q uire d i n t he pr ot oc ol.
1 0. 1 9. 3. 2. I m a gi n g
If t he partici pa nt is u na ble t o visit t he st u d y site f or safety i ma gi n g assess me nt(s), t he 
partici pa nt ma y  visit a n alter nati ve facilit y t o ha ve t he safety i ma gi n g assess me nt(s) 
perf o r me d. Q ualifie d st u d y  site pers o n nel m ust or der, recei ve, a n d re vie w res ults.
1 0. 1 9. 3. 3. Electr oc ar di o gr a ms
If t he partici pa nt is u na ble t o visit t he st u d y site f or E C Gs, t he partici pa nt ma y visit a n 
alter nati ve facilit y t o ha ve t he E C Gs perf or me d. Q ualifie d st u d y site pers o n nel m ust or der, 
recei ve, a n d re vie w res ults. 
1 0. 1 9. 4. O pt h al mic E x a ms
If t he partici pa nt is u na ble t o visit t he st u d y site f or o p ht hal mic e xa ms, t he partici pa nt ma y 
visit a n alter nati ve facilit y  t o ha ve t he o p ht hal mic e xa ms perf or me d. A c o nsiste nt rea der
s h o ul d be use d acr oss t he st u d y w he ne ver p ossi ble. Q ualifie d st u d y  site pers o n nel m ust 
or der, r ecei ve, a n d re vie w res ults.
1 0. 1 9. 5. St u d y I nter ve nti o n
If t he safety of a trial partici pa nt is at ris k beca use t he y ca n n ot c o m plete re q uire d e val uati o ns 
or a d here t o critical miti gati o n ste ps, t he n disc o nti n ui n g t hat partici pa nt fr o m st u d y  
i nter ve nti o n m ust be c o nsi dere d.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 9 4
P F -0 7 2 8 4 8 9 0 a n d/ or bi ni meti ni b ma y be s hi p pe d b y  c o urier t o st u d y partici pa nts if per mitte d 
b y  l ocal re g ulati o ns a n d i n acc or da nce wit h st ora ge a n d tra ns p ortati o n re q uire me nts f or t he 
st u d y i nter ve nti on .  Pfizer d oes n ot per mit t he s hi p me nt of st ud y  i nter ve nti on b y  mail. T he 
trac ki n g rec or d of s hi p me nts a n d t he c hai n of c ust o d y of st u d y i nter ve nti o n m ust be ke pt i n 
t he partici pa nt’s s o urce d oc u me nts/ me dical rec or ds.
I n t he e ve nt t hat t he o n g oi n g C O VI D-1 9 pa n de mic precl u des t he partici pa nt visiti n g t he 
cli nical site i n pers o n, st u d y me dicati o n ma y be s hi p pe d directly t o t he partici pa nt u n der t he 
f oll o wi n g c o n diti o ns:

T he partici pa nt has c o m plete d at least 2 c y cles of t heir c urre nt st u d y re gi me n (ie, if 
recei vi n g m o n ot hera py, has recei ve d at least 2 c ycles of m o n ot hera p y;  if c o m bi nati o n 
t hera py, t he partici pa nt nee ds t o ha ve recei ve d at least 2 c y cles of c o m bi nati o n 
t hera py);

Base d o n t he o pi ni o n of t he i n vesti gat or, t here are n o o n g oi n g safet y iss ues t hat 
w o ul d p ut t he partici pa nt at ris k; a n d 

L oca l i nstit uti o nal sta n dar ds all o w t he s hi p me nt of st u d y me dicati o n t o t he 
partici pa nt.
T he f oll o wi n g is rec o m me n de d f or t he a d mi nistrati o n of t he st u d y i nter ve nti o n f or 
partici pa nts w h o ha ve acti ve c o nfir me d ( p ositi ve b y re g ulat or y  a ut h ority- a p pr o ve d test) o r 
pres u me d (test pe n di n g/cli nical s us pici o n) S A R S- C o V 2 i nfecti o n:

F or s y m pt o matic partici pa nts wit h acti ve S A R S -C o V 2 i nfecti o n, t he st u d y 
i nter ve nti o n s h o ul d be dela ye d f or at least 1 4 da ys fr o m t he start of sy m pt o ms. T his 
dela y  is i nte n de d t o all o w t he res ol uti o n of sy m pt o ms of S A R S -C o V 2 i nfecti o n.

Pri or t o restarti n g treat me nt, t he partici pa nt s h o ul d be afe brile f or 7 2 h o urs, a n d 
S A R S -C o V 2 -relate d sy m pt o ms s h o ul d ha ve rec o vere d t o ≤Gra de 1 f or a mi ni m u m of 
7 2 h o urs. N otif y  t he st u d y tea m w he n treat me nt is restarte d.

C o nti n ue t o c o nsi der p ote ntial dr u g -dr u g i nteracti o ns as descri be d i n Secti o n 6. 5 ,
A p pe n di x 1 7 : Pr o hi bite d C o nc o mita nt Me dicati o ns T hat Ma y Res ult i n D DI, a n d 
A p pe n di x 1 8 : Str o n g C Y P 3 A In hi bit ors a n d I n d ucers f or a n y c o nc o mita nt me dicati o n 
a d mi nistere d f or treat me nt of S A R S -C o V 2 i nfecti o n . 
1 0. 1 9. 6. H o me He alt h Visits
A h o me healt h care ser vice ma y be utilize d t o facilitate sc he d ule d visits per t he Sc he d ule of 
Acti vities.   H o me healt h visits i ncl u de a healt hcare pr o vi der c o n d ucti n g a n i n -pers o n st u d y  
visit at t he partici pa nt’s l ocati o n, rat her t ha n a n i n -pers o n st u d y visit at t he site. T he 
f oll o wi n g ma y be perf or me d d uri n g a h o me healt h visit:

Re vie w a n d rec or d st u d y i nter ve nti o n;
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 9 5

Re vie w a n d rec or d a n y ne w c o nc o mita nt me dicati o ns or c ha n ges i n c o nc o mita nt 
me dicati o ns si nce t he last c o ntact ;

C o nfir m t hat t he partici pa nt is a d heri n g t o t he c o ntrace pti o n met h o d(s) re q uire d i n t he 
pr ot oc ol. Refer t o A p pe n di x 4 a n d Secti o n 1 0. 1 9. 3. 1 of t his a p pe n di x re gar di n g
pre g na nc y  tests;

E C G ;

Vital si g ns ;

P h y sical assess me nt; a n d/ or

La b orat or y  sa m ple, P K/ P D sa m ple, a n d bi o mar ker sa m ple c ollecti o n.
1 0. 1 9. 7. A d verse E ve nts a n d Seri o us A d verse E ve nts
If a partici pa nt has C O VI D-1 9 d uri n g t he st u d y , t his s h o ul d be re p orte d as a n a d verse e ve nt 
( A E) or seri o us a d verse e ve nts ( S A E) a n d a p pr o priate me dical i nter ve nti o n pr o vi de d. 
Te m p orar y  disc o nti n uati o n of t he st u d y i nter ve nti o n ma y be me dically a p pr o priate u ntil t he 
partici pa nt has rec o vere d fr o m C O VI D - 1 9. 
It is rec o m me n de d t hat t he i n vesti gat or disc uss te m p orar y or per ma ne nt disc o nti n uati o n of 
st u d y i nter ve nti o n wit h t he st u d y  me dical m o nit or. 
1 0. 1 9. 8. Effic ac y Assess me nts
If t he partici pa nt is u na ble t o visit t he st u d y site f or i ma gi n g assess me nts (e g, C T, M RI), t he 
partici pa nt ma y  visit a n alter nati ve facilit y t o ha ve t he i ma gi n g assess me nts perf or me d, 
prefera bl y wit h c o nsiste nt i ma gi n g m o dalit y use d t hr o u g h o ut t he st u d y. Q ualifie d st u d y  site 
pers o n nel m ust or der, recei ve, a n d re vie w res ults .
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 9 6
1 0. 2 0. A p pe n di x 2 0 : Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble
T he Pr ot oc ol A me n d me nt S u m mar y  of C ha n ges Ta ble f or t he c urre nt a me n d me nt is l ocate d 
directl y  bef ore t he ta ble of c o nte nts ( T O C).  T he pr ot oc ol a me n d me nt s u m mar y of c ha n ges 
ta bles f or past a me n d me nt(s) ca n be f o u n d bel o w
D oc u me nt Hist or y
D oc u me nt  
Versi o n D ate
S u m m ar y a n d R ati o n ale f or C h a n ges
A me n d me nt 2
1 4 Ja n uar y  2 0 2 1
Secti o n 1. 2 Sc he ma, Fi g ure 2: A dj uste d 
sc he ma t o m ore ali g n wit h pla n ne d st u d y 
desi g n.
Secti o n 1. 3 Sc he d ule of Acti vities: A d de d 
C y cle 1, Da y 8 safety assess me nts t o e ns ure 
a de q uate safet y m o nit ori n g d uri n g t he first 
c ycle of treat me nt. A dj uste d 
 
sa m ple ti me p oi nts t o ali g n wit h c ycle 
fre q ue nc y i nstea d of t u m or assess me nt 
fre q ue nc y i n or der t o i ncrease site a n d 
partici pa nt c o n ve nie nce. Clarifie d ser u m 
a n d uri ne pre g na nc y testi n g g ui da nce a n d 
re q uire me nts. 
Secti o n 5. 1 I ncl usi o n Criteria: Clarifie d 
criteri o n 5.
Secti o n 5. 2 E xcl usi o n Criteria: U p date d 
criteri o n 1 4 wit h a d diti o nal i nf or mati o n t o 
s h orte n t he wi n d o w pri or t o st u d y start f or 
partici pa nts wit h a P E or D V T w h o are 
sta ble, asy m pt o matic a n d sta ble o n 
a ntic oa g ula nt treat me nt si nce t he p ote nt ial 
ris k of a d diti o nal c oa g ulati o n ris k is l o wer 
i n t his p o p ulati o n. 
Secti o n 6. 1. 1 A d mi nistrati o n: A d de d 
defi niti o n of a misse d d ose f or clarificati o n.
Secti o n 6. 5. 9 S ur ger y : Clarifie d g ui da nce 
f or partici pa nts u n der g oi n g a t u m or bi o psy 
a n d c oa d mi nistratio n of t he st u d y  dr u g(s).
Secti o n 8. 8. 1 O pti o nal De N o v o T u m or 
Bi o psies: A d de d o pti o n f or partici pa nt t o 
s u b mit resecte d t u m or tiss ue o btai ne d as 
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 9 7
D oc u me nt Hist or y
D oc u me nt  
Versi o n D ate
S u m m ar y a n d R ati o n ale f or C h a n ges
part of sta n dar d of care al o n g wit h a 
ti me-matc he d P K sa m ple. All o wi n g t his 
o pti o n pr o vi des t he st u d y wit h m or e 
o p p ort u nities t o o btai n tiss ue sa m ples w hile 
n ot i ncreasi n g t he n u m ber of pr oce d ures a 
partici pa nt m ust e n d ure.
Secti o n 9. 6 Data M o nit ori n g C o m mittee or 
Ot her I n de pe n de nt O versi g ht C o m mittee: 
Gi ve n t he cli nical data a vaila ble f or ot her 
B R A F a n d M E K i n hi b it or c o m bi nati o ns 
a n d t he precli nical data f or P F - 0 7 2 8 4 8 9 0, 
a n i n de pe n de nt S R C wit h a c harter is n ot 
warra nte d. T he st u d y will utilize a D ose 
Le vel Re vie w Meeti n g c o nsisti n g of 
partici pati n g i n vesti gat ors a n d me m bers of 
t he s p o ns or st u d y tea m t o deter mi ne d ose 
escalati o n decisi o ns. 
Ot her mi n or t y p o gra p hical c ha n ges a n d 
clarificati o ns ha ve bee n ma de t hr o u g h o ut
a n d Secti o n 1. 1 S yn o psis has bee n u p date d 
f or c o nsiste nc y wit h t he b o d y of t he 
pr ot oc ol .
A me n d me nt 1
0 3 A u g ust 2 0 2 0
Secti o n 1. 1 ( S y n o psis), Secti o n 1. 2 
( Sc he ma), a n d Secti o n 1. 3 ( Sc he d ule of 
Acti vities): E dits ma de t o ma ke te xt 
c o nsiste nt wit h c ha n ges ma de t hr o u g h o ut 
t he b o d y of t he pr ot oc ol.
Secti o n 1. 3 ( Sc he d ule of Acti vities) a n d 
Secti o n 1 0. 1 5. 1 1 ( S o A D DI S u b St u d y ): 
U p date d mai n S o A f o ot n ote # 3 0 a n d 
S o A D DI S u bst u d y  f o ot n ote # 2 8 t o 
e x plicitl y o utli ne a d diti o nal q uesti o ns t hat 
s h o ul d be part of t he A E assess me nt.
Secti o n 2. 3 ( Be nefit/ Ris k Assess me nt): 
A d de d p ote ntial ris ks ass ociate d wit h 
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 9 8
D oc u me nt Hist or y
D oc u me nt  
Versi o n D ate
S u m m ar y a n d R ati o n ale f or C h a n ges
P F - 0 7 2 8 4 8 9 0 a n d ris ks ass ociate d wit h 
a p pr o ve d B R A F i n hi bit or s.
Secti o n 3 ( O bjecti ves a n d E n d p oi nts): 
C orrecte d t y p o gra p hical err or i n P hase 1a 
Sec o n dar y  O bjecti ve.
Secti o n 4. 1 ( O verall Desi g n): U p date d t o 
clarif y t he para meters re q uire d t o i de ntif y 
t he starti n g d ose of P F-0 7 2 8 4 8 9 0 i n t he 
c o m bi nati o n d ose escalati o n a n d t o a d d 
state me nt relate d t o c o nti n ue d treat me nt 
past disease pr o gressi o n.
Secti o n 4. 1 ( O verall Desi g n) a n d 
Secti o n 7. 1 ( Disc o nti n uati o n of St u d y  
I nter ve nti o n a n d Partici pa nt 
Disc o nti n uati o n/ Wit h dra wl): I ncl u de d 
a d diti o nal criteria t o be met f or partici pa nts 
t o c o nti n ue o n st u d y treat me nt past disease 
pr o gressi o n a n d a d de d la n g ua ge relate d t o 
s ur vi val f oll o w-u p acti vities.
Secti o n 4. 2. 1 ( Rati o nale f or D ose 
Escalati o n A p pr oac h) a n d Secti o n 4. 3. 2. 1 
( M o n ot hera py D ose Escalati o n): Clarifie d 
criteria f or 3 -fol d d ose escalati o n of 
P F - 0 7 2 8 4 8 9 0 a n d ma xi mal i ncrease 
all o we d after reac hi n g 3 0 0 m g d ose.
Secti o n 4. 3. 2. 3 (I ntra patie nt D ose 
Escalati o n): Clarifie d t hat bi ni meti ni b ma y  
be a d de d t o patie nts recei vi n g P F - 0 7 2 8 4 8 9 0 
m o n ot hera p y if t he d ose c o m bi nati o n has 
pr e vi o usl y met B L R M/ E W O C criteria i n 
t he c o m bi nati o n d ose escalati o n p orti o n of 
t he st u d y.
Secti o n 4. 3. 3 ( D L T Defi niti o n): I ncl u de d 
a d diti o nal D LT defi niti o ns a n d clarifie d 
e xisti n g D LTs.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 1 9 9
D oc u me nt Hist or y
D oc u me nt  
Versi o n D ate
S u m m ar y a n d R ati o n ale f or C h a n ges
Secti o n 5. 1 (I ncl usi o n Criteria): M o difie d 
Criteria 5, 6, a n d 1 0.
Secti o n 5. 2 ( E xcl usi o n Criteria): A d de d 
Criteri o n 1 9 t o e xcl u de partici pa nts i n d ose 
escalati o n wit h a hist or y of p ne u m o nitis 
t hat re q uire d ster oi ds or acti ve p ne u m o nitis. 
M o difie d Criteria 6 , 8 a n d 1 0.
Secti o n 6. 5. 8 ( C ortic oster oi ds): Re d uce d 
ma xi mal all o wa ble ster oi d d osi n g t o 
c o ntr ol/treat s y m pt o ms fr o m brai n 
metastases/ pri mar y  brai n t u m or t o mai ntai n 
a n acce pta ble ris k: be nefit pr ofile a n d ma ke 
c o nsiste nt wit h practice g ui deli nes.
Secti o n 6. 6. 4 ( D ose Re d ucti o ns): G ui da nce 
was a d de d t o Ta ble 5 t o a d dr ess p ote ntial 
C N S effects.
Secti o n 8. 1. 1 ( T u m or Res p o nse 
Assess me nts): Clarifie d ti mi n g of t u m or 
assess me nts.
Secti o n 8. 2. 4 ( Ne ur ol o gic E xa mi nati o ns): 
A d de d ne ur ol o gical s y m pt o ms t hat s h o ul d 
be assesse d f or d uri n g t he ne ur ol o gic 
e xa ms. S y m pt o ms a d de d are c o nsiste nt 
wit h C N S effects i n D L T criteria.
Secti o n 1 0. 1 7 ( A p pe n di x 1 7 
A b bre viati o ns): U p date d t o i ncl u de 
acr o n y m s a d de d wit h a me n d me nt.
Ot her mi n or t y p o gra p hical c ha n ges a n d 
clarificati o ns ha ve bee n ma de t hr o u g h o ut. 
Ori gi nal pr ot oc ol
1 2 J u ne 2 0 2 0
N/ A
T his a me n d me nt i nc or p orates all re visi o ns t o date, i ncl u di n g a me n d me nts ma de at t he 
re q uest of c o u ntr y healt h a ut h orities a n d I R Bs/ E Cs a n d a n y pr ot oc ol a d mi nistrati ve 
clarificati o n letter.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 0 0
1 0. 2 1. A p pe n di x 2 1 : A b bre vi ati o ns
T he f oll o wi n g is a list of a b bre viati o ns t hat ma y be use d i n t he pr ot oc ol.
A b bre vi ati o n
Ter m
Δ Q Tc F
C ha n ge i n c orrecte d Q T ( Fri dericia met h o d)
A D L
acti vities of dail y li vi n g
A E
a d verse e ve nt
A E SI
A d verse e ve nt of s pecial i nterest
AI D S
ac q uire d i m m u n o deficie nc y sy n dr o me
Al k P h os
al kali ne p h os p hatase
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase
A N C
a bs ol ute ne utr o p hil c o u nt
a P T T/ A P T T
acti vate d Partial T hr o m b o plasti n Ti me
A R A F
A -Raf Pr ot o -O nc o ge ne
A S C O
A merica n S ociet y of Cli nical O nc ol o g y
A S T
as partate a mi n otra nsferase
A T C
a na plastic t h yr oi d ca ncer
A T P
a de n osi ne tri p h os p hate
A U C
area u n der t he c ur ve 
A U C 0- 2 4
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me 0
e xtra p olate d t o 2 4 h o urs
A U C 0- 1 2
area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0
e xtra p olate d t o 1 2 h o urs
A U C 8
area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m 0 t o 8 h o urs 
p ost -d ose
A U C i nf
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me 0
e xtra p olate d t o i nfi nit y
A U C last
area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o t he 
last ti me p oi nt of q ua ntifia ble c o nce ntrati o n
A U Css,τ
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve o ver t he d osi n g 
i nter val at stea dy state
A U Cs d,τ
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve o ver t he d osi n g 
i nter val fr o m a si n gle d ose
A V
atri o ve ntric ular
B C R P
breast ca ncer resista nce pr otei n
BI D
t wice daily
B L R M
Ba yesia n l o gistic re gressi o n m o del
B P
bl o o d press ure
b p m
beats per mi n ute
β -H C G
beta h u ma n c h ori o nic g o na d otr o pi n
B R A F
B -t ype Raf pr ot o -o nc o ge ne
B R A Fi
B R A F i n hi bit or
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 0 1
A b bre vi ati o n
Ter m
B S E P
Bile Salt E x p ort P u m p
B U N
bl o o d urea nitr o ge n
C 1 D 1
C ycle 1 D a y 1
C 1 D 2
C y cle 1 Da y 2
C 1 D 8
C y cle 1 Da y 8
C 1 D 1 3
C y cle 1 Da y 1 3
C 1 D 1 5
C y cle 1 Da y 1 5
C 2 -C 6
C y cle 2 t hr o u g h C ycl e 6
C 2 D 1
C y cle 2 Da y 1
C 2 D 1 5
C y cle 2 Da y 1 5
C 3 D 1
C y cle 3 Da y 1
C 6 D 1
C y cle 6 Da y 1
C A P
C olle ge of A merica n Pat h ol o gists
C D 4
cl uster of differe ntiati o n 4
C D x
c o m pa ni o n dia g o n ostic
cf D N A
cell-free D N A
C F R
C o de of Fe deral Re g ulati o ns
C H F
c o n gesti ve heart fail ure
CI
c o nfi de nce i nter val
CI O M S
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces
C K
creati ne ki nase
C L
cleara nce
C L / F
a p pare nt oral cleara nce
C L cr
creati ni ne cleara nce
C L I A
Cli nical L a b orat or y Im pr o ve me nt A me n d me nts 
C L ss/ F
a p pare nt oral cleara nce at stea d y state
C ma x
ma xi m u m o bser ve d c o nce ntrati o n
C tr o u g h
o bser ve d c o nce ntrati o n at tr o u g h
C N S
ce ntral ner v o us s ys te m
C O N S O R T
C o ns oli date d Sta n dar ds of Re p orti n g Trials
C O VI D -1 9
c or o na vir us disease 2 0 1 9
C p
plas ma c o nce ntrati o n
C P K
creati ne p h os p h o ki nase
C R
c o m plete res p o nse
C R A F
Raf -1 pr ot o -o nc o ge ne
C R C
c ol orectal ca ncer
C R F
case re p ort f or m
C R O
c o ntract researc h or ga nizati o n
C R P
c-reacti ve pr otei n
C R S
c yt o ki ne release sy n dr o me
C S F
cere br os pi nal fl ui d
C S R
cli nical st u d y re p ort
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 0 2
A b bre vi ati o n
Ter m
C ss, ma x 
pea k plas ma c o nce ntrati o n at stea d y state
C ss, mi n
tr o u g h plas ma c o nce ntrati o n at stea d y state
C T
cli nical trial
C T
c o m p uterize d t o m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C Y P
c yt oc hr o mes P 4 5 0
D C R
disease c o ntr ol rate
D C T
data c ollecti o n t o ol
D DI
dr u g -dr u g i nteracti o n
D F S
disease -free s ur vi val
DI LI
dr u g -i n d uce d li ver i nj ur y
D L
d ose le vel
D L R M
D ose Le vel Re vie w Meeti n g
D L T
d ose -li miti n g t o xicit y
D M C
data m o nit ori n g c o m mittee
D N A
de o x yri b o n ucleic aci d
D o R
d urati o n of res p o nse
D U
dis pe nsa ble u nit
D V T
dee p ve n o us t hr o m b osis 
E C
et hics c o m mittee
E C G
electr ocar di o gra m
E C H O
ec h ocar di o gra m
E C O G
Easter n C o o perati ve O nc ol o g y  Gr o u p
e C R F
electr o nic case re p ort f or m
E D P
e x p os ure d uri n g pre g na nc y
E G F R
e pi der mal gr o wt h fact or rece pt or
E M A
E ur o pea n Me dici nes A ge nc y
E O T
e n d of treat me nt
E R K
e xtracell ular si g nal-re g ulate d ki nase
E U
E ur o pea n U ni o n
E u dra C T
E ur o pea n Cli nical Trials Data base
E W O C
escalati o n wit h o ver d ose c o ntr ol
F D A
F o o d a n d Dr u g A d mi nistrati o n ( U nite d States)
F F P E
f or mali n-fi xe d paraffi n-e m be d de d   
F L AI R
fl ui d atte n uate d i n versi o n rec o ver y 
F O B
f u ncti o nal o bser vati o nal batter y
F S H
f ollicle-sti m ulati n g h or m o ne
G B M
gli o blast o ma
G C P
G o o d Cli nical Practice
G d
ga d oli ni u m
G G T
ga m ma -gl uta m y l tra nsferase
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 0 3
A b bre vi ati o n
Ter m
GI
gastr oi ntesti nal
G L P
G o o d La b orat or y  Practices
H B V
he patitis B vir us
H C C
h e pat ocell ular carci n o ma
Hct
he mat ocrit
H C V
he patitis C vir us
h E R G
h u ma n et her -a-g o -g o relate d ge ne 
H F S R
ha n d -f o ot s ki n reacti o n
H g b
he m o gl o bi n
H G G
hi g h -gra de gli o mas
HI P A A
Healt h I ns ura nce P orta bilit y  a n d Acc o u nta bilit y Act
HI V
h u ma n i m m u n o deficie nc y vir us
H N S T D
hi g hest n o n -se verel y t o xic d ose
H R
heart rate
H R T
h or m o ne re place me nt t hera p y
I B
I n vesti gat or’s Br oc h ure
I C5 0
5 0 % i n hi bit or y  c o nce ntrati o n
I C7 0
7 0 % i n hi bit or y  c o nce ntrati o n
I C9 0
9 0 % i n hi bit or y  c o nce ntrati o n
I C D
i nf or me d c o nse nt d oc u me nt
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I CI
i m m u ne c hec k p oi nt i n hi bit or
I D
i de ntificati o n
I F N
i nterfer o n-ga m ma
I L
i nterle u ki n
I M P
i n vesti gati o nal me dici nal pr o d uct
I ND
i n vesti gati o nal ne w dr u g
I N R
i nter nati o nal n or malize d rati o
I P ma n ual
i n vesti gati o nal pr o d uct ma n ual
I P A L
I n vesti gati o nal Pr o d uct Acc o u nta bilit y L o g
I RB
I nstit uti o nal Re vie w B oar d
I R T
i nteracti ve res p o nse tec h n ol o g y
I T T
i nte nt t o treat
I V
i ntra ve n o us
I W R
i nteracti ve We b-base d res p o nse
I W R S
i nteracti ve We b-base d res p o nse s y ste m
K i
i n hi bit or y c o nsta nt
k i nact
ma xi m u m rate of e nz y me i nacti vati o n
K I
c o nce ntrati o n of i n hi bit or w hic h gi ves half t he ma xi mal rate of 
i nacti vati o n
L B B B
left b u n dle bra nc h bl oc k
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 0 4
A b bre vi ati o n
Ter m
L D H
lactate de hy d r o ge nase
L F T
li ver f u ncti o n test
L G G
l o w-gra de gli o ma
L H
l utei nizi n g h or m o ne
L L C -P K 1
Lill y  La b orat ories cell p orci ne ki d ne y  1
L L N
l o wer li mit of n or mal
L S M
Li mite d Sa m pli n g M o del
L V
left ve ntric ular
L V E F
left ve ntric ular ejecti o n fracti o n
M A P
meta -a nal yt ic-pre dicti ve
M A P K
Mit o ge n -Acti vate d Pr otei n Ki nase
M A T E
m ulti dr u g a n d t o xi n e xtr usi o n
M D R 1
m ulti dr u g resista nce ge ne 1
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
M E K
mit o ge n -acti vate d a n d e xtracell ular si g nal -re g ulate d ki nase
mI T T
m o difie d i nte nt t o treat
m R E CI S T
m o difie d Res p o nse E val uati o n Criteria i n S oli d T u m ors
M R
Mi n or res p o nse
M RI
ma g netic res o na nce i ma gi n g
M R P 2
m ulti dr u g resista nce -ass ociate d pr otei n 2
M T D
ma xi m u m t olerate d d ose
n
n u m ber
N/ A
n ot a p plica ble
N CI
Nati o nal Ca ncer I nstit ute
N E
n ot e v al uate d
N G S
ne xt -ge nerati o n se q ue nci n g
NI M P
n o n -i n vesti gati o nal me dici nal pr o d uct
N O A E L
n o -o bser ve d -a d verse-effect le vel
N S C L C
n o n -s mall cell l u n g ca ncer
N S R
n o n -si g nifica nt ris k
N TI
Narr o w T hera pe utic I n de x
O A T
o r ga nic ani o n tra ns p orter
O A T P
o r ga nic a ni o n tra ns p orti n g p oly pe pti de
O C T
o ptical c o here nce t o m o gra p h y ; or ga nic cati o n tra ns p orter
O R R
o verall res p o nse rate
O S
o verall s ur vi val
P( O R R)
pr o ba bilit y  of O R R
P A
pil oc y tic astr oc yt o ma
P A C L
pr ot oc ol a d mi nistrati ve c ha n ge letter
P C R
p ol y merase c hai n reacti o n
P D
p har mac o d y n a mics(s); disease pr o gressi o n
P E
p ul m o nar y  e m b olis m, p h ysical e xa mi nati o n
0
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 0 5
A b bre vi ati o n
Ter m
P E T
p ositr o n e missi o n t o m o gra p h y
P F S
pr o gressi o n -free s ur vi val
P -g p
P -gl yc o pr otei n
PI
pri mar y  i n vesti gat or
P K
p har mac o ki netic(s)
P PI
pr ot o n p u m p i n hi bit or
P R
partial res p o nse
P R 2 D
Rec o m me n de d P hase 2 D ose
P S
perf or ma nce stat us
P T
pr ot hr o m bi n ti me
P T C
pa pillar y  t h yr oi d ca ncer
P T T
partial t hr o m b o plasti n ti me
P V C
pre mat ure ve ntric ular c o ntracti o n/c o m ple x
P X A
plei o m or p hic xa nt h oast roc y t o ma
Q 6 W
o nce e ver y  6 wee ks
Q 9 W
o nce e ver y  9 wee ks
Q 1 2 W
o nce e ver y  1 2 wee ks
Q D
o nce dail y
Q Tc
c orrecte d Q T
Q Tc B
c orrecte d Q T ( Bazett met h o d)
Q Tc F
c orrecte d Q T ( Fri dericia met h o d)
Q ual
q ualitati ve
R ac
acc u m ulati o n rati o
R A F
ra pi dl y accelerate d fi br osarc o ma
R A N O
Res p o nse A ssess me nt i n N e ur o-O nc ol o g y
R B C
re d bl o o d cell
R D E
rec o m me n de d d ose f or e x pa nsi o n
R E CI S T
Res p o nse E val uati o n Criteria i n S oli d T u m ors
R E M L
Restricte d Ma xi m u m L i keli h o o d Esti mati o n
R P 2 D
rec o m me n de d p hase 2 d ose
R P E D
reti nal pi g me nt e pit helial detac h me nt
R V O
reti nal vei n occl usi o n
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S A R S -C o V 2
se vere ac ute res pirat or y s yn dr o me c or o na vir us 2
S D
sta ble disease
S E E R
S ur veilla nce, E pi de mi ol o g y , a n d E n d Res ults pr o gra m
sIL -2 R
s ol u ble i nterle u ki n 2 rece pt or
S o A
sc he d ule of acti vities
S O C
sta n dar d-of -care
 
C CI
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 0 6
A b bre vi ati o n
Ter m
S O P
sta n dar d o perati n g pr oce d ure
S R C
Safet y  Re vie w C o m mittee
S R S
ster otactic ra di os ur ger y
S R S D
si n gle refere nce safety d oc u me nt
S T D
se verely t o xic d ose
S T D 1 0
se verely t o xic d ose i n 1 0 % of t he a ni mals
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
t½
ter mi nal eli mi nati o n half-life
T Bili
t otal bilir u bi n
T K
to xic o ki netics 
T N F
t u m or necr osis fact or
T ma x
ti me t o ma xi m u m plas ma c o nce ntrati o n
T ss, ma x
ti me t o ma xi m u m plas ma c o nce ntrati o n at stea dy s tate
T M E
t u m or micr oe n vir o n me nt
T T R
ti me t o res p o nse
U G T
U D P -gl uc ur o n os yl tra nsferase
U L N
u p per li mit of n or mal
U S
U nite d States
U V
ultra vi olet
U V B
ultra vi olet B
V ss
v ol u me of distri b uti o n at stea d y  state
Vss/ F
a p pare nt v ol u me of distri b uti o n at stea d y  state
V z/ F
a p pare nt v ol u me of distri b uti o n
W B C
w hite bl o o d cell
W B R T
w h ole brai n irra diati o n
W H O
W orl d Healt h Or ga nizati o n
W O C B P
w o ma n of c hil d beari n g p ote ntial
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 0 7
1 0. 2 2. A p pe n di x 2 2 : T a n ner St a gi n g
P u bic H air: M ale a n d Fe m ale

P u bic Hair Sta ge 1: Pre p u bertal. T he vell us o ver t he p u bis is si milar t o t hat o n t he 
a b d o me n. T his hair has n ot y et de vel o pe d t he c haracteristics of p u bic hair.

P u bic Hair Sta ge 2: T here is s parse gr o wt h of l o n g, sli g htl y  pi g me nte d d o w n y hair, 
strai g ht or o nly sli g htl y c urle d, mai nl y  at t he base of t he pe nis (i n males).

P u bic Hair Sta ge 3: T he hair is c o nsi dera bl y dar ker, c oarser, a n d m ore c urle d. I t is 
s prea d s parsely o ver t he p u bis.

P u bic Hair Sta ge 4: T he hair is a d ult i n t y pe, b ut t he area o ver w hic h it is prese nt is 
s maller t ha n i n m ost ad ults. It has n ot y et s prea d t o t he me dial t hi g hs or al o n g t he 
li nea al ba (i n males).

P u bic Hair Sta ge 5: T he hair is a d ult i n q ualit y  a n d q ua ntit y a n d has t he classical 
tria n g ular distri b uti o n i n fe males. It ma y s prea d t o t he me dial s urface of t he t hi g hs.
Bre asts: Fe m ales

Breast Sta ge 1: T here is n o de vel o p me nt. O nl y t he ni p ple is ele vate d.

Breast Sta ge 2: T he “ breast b u d” sta ge, t he are ola wi de ns, sli g htl y  dar ke ns, a n d 
ele vates fr o m t he rest of t he breast. A b u d of gla n d ular tiss ue is pal pa ble bel o w t he
ni p ple.

Breast Sta ge 3: T he breast a n d are ola f urt her e nlar ge, prese nti n g a r o u n de d c o nt o ur. 
T here is n o c ha n ge of c o nt o ur bet wee n t he ni p ple a n d are ola a n d t he rest of t he breast. 
T he dia meter of breast tiss ue is still s maller t ha n i n a mat ure breast.

Breast Sta ge 4: T he breast c o nti n ues t o gr o w.
T he pa pilla a n d are ola pr oject t o f or m 
a sec o n dar y m o u n d a b o ve t he rest of t he breast.

Breast Sta ge 5: T he mat ure a d ult sta ge.
T he sec o n dar y  m o u n d disa p pears. S o me 
fe males ne ver pr o gress t o Sta ge 5.
Ge nit als: M ales

Ge nital Sta ge 1: Pre p u bertal. Pe nis, testes, a n d scr ot u m are a b o ut t he sa me size a n d 
pr o p orti o ns as i n earl y c hil d h o o d. It is i m p orta nt t o ta ke i nt o acc o u nt w het her t he 
pe nis is u ncirc u mcise d w he n assessi n g pe nile gr o wt h, as t he u ncirc u mc ise d pe nis ma y  
a p pear lar ger t ha n it reall y is.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 0 8

Ge nital Sta ge 2: O nl y  t he testes a n d scr ot u m ha ve be g u n t o e nlar ge fr o m t he early 
c hil d h o o d size. T he pe nis is still pre p u bertal i n a p peara nce. T he te xt ure of t he 
scr otal s ki n is be gi n ni n g t o bec o me t hi n ner a n d t he s ki n a p pears re d der d ue t o 
i ncrease d vasc ularizati o n.

Ge nital Sta ge 3: T here is f urt her gr o wt h of t he testes a n d scr ot u m. T he pe nis is als o 
be gi n ni n g t o gr o w, mai nl y i n le n gt h wit h s o me i ncrease i n brea dt h. It ca n be diffic ult 
t o disti n g uis h betwee n Sta ges 2 a n d 3.

Ge nital Sta ge 4: T he pe nis e nlar ges f urt her i n le n gt h a n d brea dt h a n d t he gla ns 
bec o mes m ore pr o mi ne nt. T he testes a n d scr ot u m are lar ger. T here is f urt her 
dar ke ni n g of t he scr otal s ki n.

Ge nital Sta ge 5: T he pe nis, testes, a n d scr ot u m are a d ult i n size a n d s ha pe.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 0 9
1 1. R E F E R E N C E S
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2.
Stelzer KJ. E pi de mi ol o g y a n d pr o g n osis of brai n metastases. S u r g Ne ur ol I nt 2 0 1 3; 
4( S u p pl 4): S 1 9 2 - 2 0 2.
3. 
C o he n J V, Ta w bi H, Mar g oli n K A, et al. Mela n o ma ce ntral ner v o us s ys te m metastases: 
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2 9( 6): 6 2 7 - 4 2.
4.
Bar n h oltz - Sl oa n J S, Sl oa n A E, Da vis F G, et al. I nci de nce pr o p orti o ns of brai n 
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S ur veilla nce S yste m. J Cli n O nc ol 2 0 0 4; 2 2( 1 4): 2 8 6 5 - 7 2.
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ra n d o mise d, d o u ble-bli n d, p hase 3 trial. La ncet O nc ol 2 0 1 6; 1 7( 9): 1 2 4 8 -6 0.
9.  
D u m mer R, Asciert o P A, G o gas HJ, et al. O verall s ur vi val i n patie nts wit h 
B R A F - m uta nt mela n o ma recei vi n g e nc orafe ni b pl us bi ni meti ni b vers us ve m urafe ni b or 
e nc orafe ni b ( C O L U M B U S): a m ultice ntre, o pe n -la bel, ra n d o mise d, p hase 3 trial. 
La ncet O nc ol 2 0 1 8; 1 9( 1 0): 1 3 1 5 - 2 7.
1 0.
L o n g G V, Str o y a k o vs ki y D, G o gas H, et al. C o m bi ne d B R A F a n d M E K i n hi biti o n 
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L o n g G V, Fla hert y K T, Str o ya k o vs ki y D, et al. Da brafe ni b pl us tra meti ni b vers us 
da brafe ni b m o n ot hera p y i n patie nts wit h metastatic B R A F V 6 0 0 E/ K-m uta nt mela n o ma: 
l o n g-ter m s ur vi val a n d safet y a nalys is of a p hase 3 st u d y. A n n O nc ol 2 0 1 7; 
2 8( 7): 1 6 3 1 - 9.
1 2.
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wit h brai n met astases: a n o pe n -la bel, si n gle-ar m, p hase 2, m ultice ntre st u d y. A n n O nc ol 
2 0 1 7; 2 8( 3): 6 3 4 - 4 1.
 
T)

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 1 0
1 3.
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Ca ncer 2 0 2 0; 1 2 6( 3): 5 2 3 - 3 0.
1 4.
Me nter T, Tza n k o v A. Ge netic alterati o ns of 9 p 2 4 i n l y m p h o mas a n d t heir i m pact f or 
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M ul ve n na P, Na n ki vell M, Bart o n R, et al. De xa met has o ne a n d s u p p orti ve care wit h or 
wit h o ut w h ole brai n ra di ot hera p y i n treati n g patie nts wit h n o n -s mall cell l u n g ca ncer 
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res ults fr o m a p hase 3, n o n-i nferi orit y, ra n d o mise d trial. La ncet 2 0 1 6; 
3 8 8( 1 0 0 5 5 ): 2 0 0 4- 1 4.
1 6.
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vs. ra di os ur ger y  wit h w h ole brai n ra di ot hera p y as t he i nitial ma na ge me nt of brai n 
metastases. I nt J Ra diat O nc ol Bi ol P h y s 2 0 0 2; 5 3( 3): 5 1 9- 2 6.
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Lassaletta A, Za p ot oc k y M, Mistr y  M, et al. T hera pe utic a n d pr o g n ostic i m plicati o ns of 
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Re vise d A pr 2 0 2 0. Accesse d Ma y  2 0 2 0. 
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2 3.
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Ca ncer 2 0 1 7; 1 1 6( 5): 5 7 5 - 8 3.
 

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 1 1
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Re vise d Ja n 2 0 1 9. Accesse d Ma y  2 0 2 0.
 
C CI

P F -0 7 2 8 4 8 9 0 ( A R R Y -4 6 1)
Pr ot oc ol C 4 4 7 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 3, 2 0 J ul y 2 0 2 2
P FI Z E R C O N FI D E N TI A L
C T 0 2 -G S O P Cli nical Pr ot oc ol Te m plate O nc ol o g y P hase 1 ( 0 5 Dece m ber 2 0 1 9)
Pa ge 2 1 2
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3 7.
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3 8.
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