Conditions: Gastrointestinal Tumors Colorectal Adenocarcinomas Gastric Adenocarcinomas Esophageal Adenocarcinomas
Keywords: Gastric cancer Esophageal cancer Colorectal cancer Advanced esophageal cancer Metastatic esophageal cancer Advanced colorectal cancer Metastatic gastric cancer Advanced gastric cancer Metastatic colorectal cancer GUCY2c Anti-PD1 Anti-VEGF Measurable disease PF-07062119 PF-06801591 Bevacizumab
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 79
Healthy volunteers: no

Brief summary:
A phase 1, open-label, dose escalation and expansion study of PF-07062119 in patients with selected advanced or metastatic gastrointestinal tumors

Detailed description:
This is a Phase 1, open-label, multi-center, non-randomized, multiple dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study of PF-07062119 administered as a single agent in sequential dose levels and then in combination with anti-programmed cell death -1 protein (anti-PD-1) and in combination with an anti-vascular endothelial growth factor (anti-VEGF). In Part 1A, successive cohorts of patients will receive escalating doses of PF-007062119 and then in dose finding (Part 1B) with PF-07062119 in combination with anti-PD-1 and in combination with anti-VEGF. This study contains 2 parts, dose escalation with single agent (Part 1A) and then dose finding with PF-007062119 in combination with ant-PD-1 and in combination with anti-VEGF (Part 1B) followed by dose expansion arms as a single agent and PF-07062119 in combination with anti-PD 1 and in combination with anti-VEGF (Part 2).

Arms:
arm 1: Single Agent Dose Escalation arm 2: Part 1B PF-07062119 plus anti-PD-1 arm 3: Part 1B PF-07062119 plus anti-VEGF arm 4: PF-07062119 as a Single Agent in CRC arm 5: PF-07062119 in Combination with anti-PD-1 in CRC arm 6: PF-07062119 in Combination with anti-VEGF in CRC arm 7: PF-07062119 in Combination with either anti-PD-1 or anti-VEGF in various Tumor Types

Interventions: intervention 1: PF-07062119 intervention 2: Anti-PD1 intervention 3: Anti-VEGF
Intervention descriptions: intervention 1: PF-07062119 intervention 2: Anti-PD1 PF-06801591 intervention 3: Anti-VEGF IV (bevacizumab)

Protocol document:
Prot_000.pdf: 
P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
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A P H A S E 1 D O S E E S C A L A TI O N A N D E X P A N SI O N S T U D Y E V A L U A TI N G T H E
S A F E T Y, T O L E R A BI LI T Y , P H A R M A C O KI N E TI C S, P H A R M A C O D Y N A MI C S 
A N D A N TI T U M O R A C TI V I T Y O F P F-0 7 0 6 2 1 1 9 I N P A TI E N T S WI T H A D V A N C E D 
G A S T R OI N T E S TI N A L T U M O R S
I n vesti g ati o n al Pr o d uct N u m ber:
P F -0 7 0 6 2 1 1 9
I n vesti g ati o n al Pr o d uct N a me:
N ot A p plica ble ( N/ A)
U nite d St ates ( U S) I n vesti g ati o n al Ne w 
Dr u g (I N D) N u m ber:
1 4 3 4 1 6
E ur o pe a n Cli nic al Tri als D at a b ase 
( E u dr a C T) N u m ber:
N ot A p plica ble ( N/ A)
Pr ot oc ol N u m ber:
C 3 8 6 1 0 0 1
P h ase:
1
S h ort Title: A P hase 1, o pe n -la bel, d ose escalati o n a n d e x pa nsi o n st u d y of 
P F -0 7 0 6 2 1 1 9 i n pati ents wit h selecte d a d va nce d or metastatic gastr oi ntesti nal t u m ors.
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 nts, y o 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 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


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D oc u me nt Hist or y
D oc u me nt
Versi o n D ate
A me n d me nt 7
1 9 N o ve m ber 2 0 2 1
A me n d me nt 6
0 8 Oct o ber 2 0 2 1
A me n d me nt 5
1 6 Marc h 2 0 2 1
A me n d me nt 4
0 5 Oct o ber 2 0 2 0
A me n d me nt 3
1 7 A u g ust 2 0 2 0
A me n d me nt 2
1 0 Oct o ber 2 0 1 9
A me n d me nt 1
0 8 Oct o ber 2 0 1 9
Ori gi nal pr ot oc ol
2 0 A u g ust 2 0 1 9
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.
Pr ot oc ol A me n d me nts S u m m ar y of C h a n ges T a bl e
A m e n d me nt 7 ( 1 9 N o ve m ber 2 0 2 1)
O ver all R ati o n ale f or t he A me n d me nt: T he pri mar y  p ur p ose of t he a me n d me nt is t o 
i nc or p orate fee d bac k recei ve d fr o m t he U nite d States ( U S) F o o d a n d Dr u g A d mi nistrati o n 
( F D A). I n a d diti o n, clarificati o ns, a d mi nistrati ve a n d t yp o gra p hical m o dificati o ns were 
ma de.
Secti o n # a n d 
N a me
Descri pti o n of C h a n ge
Brief R ati o n al e
Secti o n 5. 1 
I ncl usi o n Criteria
I ncl usi o n criteri o n # 1 2 was 
a da pte d t o re m o ve t he f oll o wi n g 
la n g ua ge, “< U L N if t here is 
li ver i n v ol ve me nt sec o n dar y t o 
t u m or”
T o re q uire all partici pa nts 
(i ncl u di n g t h ose wit h li ver 
metastases) t o ha ve A S T a n d A L T 
≤ 2. 5 x U L N at st u d y e ntr y.
Secti o n 6. 7. 3 
Ta ble 1 2
D ose m o dificati o n g ui deli nes f or 
s pecific i m m u ne relate d t o xicit y 
attri b ute d t o i n vesti gati o nal 
pr o d uct were u p date d t o pr o vi de 
a d diti o nal detail ar o u n d Li ver 
( He patitis) a n d C R S e ve nts. 
T o pr o vi de s pecific d ose 
i nterr u pti o n a n d m o dificati o n 
g ui deli nes base d o n gra des f or 
patie nts w h o e x perie nce li ver a n d 
C R S e ve nts.
Secti o n 1 0. 1 1
A p pe n di x 1 1
C R S ma na ge me nt g ui deli nes 
were a d de d t o acc o m pa n y t he 
C R S ma na ge me nt al g orit h m
T o pr o vi de s u g geste d ma na ge me nt 
g ui deli nes f or C R S
Secti o n 1 0. 1 3
A p pe n di x 1 3
D osi n g m o dificati o ns a n d d ose 
i nterr u pti o ns f or Gra de 2 
he patitis a d verse e ve nts t hat last 
T o pr o vi de m ore detaile d f oll o w 
u p i nstr ucti o ns f or He patitis 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


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Secti o n # a n d 
N a me
Descri pti o n of C h a n ge
Brief R ati o n al e
l o n ger t ha n 7 da ys ha ve bee n 
pr o vi de d i n Ta ble 1 2, 
ma na ge me nt g ui deli nes ha ve 
bee n ali g ne d i n Ta ble 2 0 a n d 
t hr o u g h o ut the pr ot oc ol .
(ir A Es) ma na ge me nt of Gra de 2 
e ve nts.  
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
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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 1
LI S T O F FI G U R E S .................................................................................................................1 2
1. S C H E D U L E O F A C TI V I TI E S ( S O A)................................................................................1 3
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 6
2. 2. 1. A d va nce d Ga str oi ntesti nal A de n ocarci n o mas ............................................3 6
2. 2. 2. G U C Y 2c E x pressi o n i n H u ma n Ca ncers ....................................................3 7
2. 2. 3. Bis pecific Re directe d T -cell E n ga gi n g T hera pies...................................... 3 7
2. 2. 4. P F - 0 7 0 6 2 1 1 9...............................................................................................3 7
2. 2. 5. N o ncli n ical P har mac ol o g y..........................................................................3 8
2. 2. 5. 1. I n Vitr o P har mac o d y na mics ......................................................3 8
2. 2. 6. N o ncli nical P har mac o ki netics a n d Meta b olis m ......................................... 4 2
2. 2. 7. N o ncli nical Safet y ...................................................................................... 4 3
2. 2. 8. S u m mar y  of C urre nt Cli nical Data fr o m St u d y C 3 8 6 1 0 0 1........................4 4
2. 2. 8. 1. Safet y Data U p date ....................................................................4 4
2. 2. 8. 2. P har mac o ki netics ................................ ......................................4 4
2. 3. A nti- Pr o gra m me d Cell Deat h Pr otei n -1 ( A nti -P D - 1)............................................. 4 5
2. 3. 1. P F -0 6 8 0 1 5 9 1, a n A nti -P D -1 A nti b o d y : Cli nical E x perie nce i n 
St u d y B 8 0 1 1 0 0 1 ( N C T 0 2 5 7 3 2 5 9)................................................................... 4 5
2. 4. O ver vie w of Be vaciz u ma b- Pfizer ( Zira be v ™)................................ .......................4 6
2. 5. Be nefit/ Ris k Assess me nt................................ .........................................................4 6
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 .................................................................................................................5 0
4. 1. O verall Desi g n................................ .........................................................................5 0
4. 1. 1. Part 1 A........................................................................................................ 5 2
4. 1. 1. 1. P F -0 7 0 6 2 1 1 9 Treat me nt Wit h o ut a Pri mi n g D ose ....................5 2
4. 1. 1. 2. P F -0 7 0 6 2 1 1 9 Treat me nt Wit h a Pri mi n g D ose .........................5 2
4. 1. 2. Part 1 B ( C o m bi nati o n C o h orts) ..................................................................5 3
4. 1. 3. Part 2........................................................................................................... 5 4
4. 2. Scie ntific Rati o nale f or St u d y  Desi g n.....................................................................5 5
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P F -0 7 0 6 2 1 1 9
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4. 3. J ustificati o n f or D ose ..............................................................................................5 5
4. 3. 1. Starti n g D ose f or M o n ot hera p y D ose Escalati o n Wit h o ut a Pri mi n g 
D ose ( Part 1 A) .................................................................................................5 5
4. 3. 2. Starti n g D ose f or M o n ot hera p y D ose Escalati o n Wit h a Pri mi n g 
D ose ( Part 1 A) .................................................................................................5 6
4. 3. 3. S u bc uta ne o us R o ute.................................................................................... 5 7
4. 3. 4. Fi xe d D osi n g A p pr oac h ..............................................................................5 7
4. 3. 5. D osi n g I nter val ( Q 2 W) ...............................................................................5 7
4. 3. 6. Starti n g D ose f or C o m bi nati o n D ose Fi n di n g ( Part 1 B) ............................5 7
4. 3. 7. Criteria f or D o se Escalati o n........................................................................5 8
4. 3. 8. D ose L i miti n g T o xicit y Defi niti o n.............................................................5 9
4. 3. 9. L ate O nset T o xicit y ....................................................................................6 1
4. 3. 1 0 . Ma xi m u m T olerate d D ose Defi niti o n.......................................................6 1
4. 3. 1 1. Rec o m me n de d P hase 2 D ose Defi niti o n ..................................................6 1
4. 3. 1 2. Part 2 Res pecti ve Starti n g D oses f or P F- 0 7 0 6 2 1 1 9 as a Si n gle 
A ge nt a n d C o m bi nati o n D ose E x pa nsi o n C o h orts ..........................................6 1
4. 3. 1 3. Part 2 P F -0 7 0 6 2 1 1 9 as a Si n gle A ge nt i n A d va nce d or Metastatic 
C ol orectal A de n ocarci n o ma................................ .............................................6 2
4. 3. 1 4. Part 2 P F -0 7 0 6 2 1 1 9 i n C o m bi nati o n wit h P F -0 6 8 0 1 5 9 1 i n 
A d va nce d or Metastatic C ol orectal A de n ocarci n o ma................................ .....6 2
4. 3. 1 5. Part 2 P F -0 7 0 6 2 1 1 9 i n C o m bi nati o n wit h Be vaciz u ma b -Pfizer i n 
A d va nce d or Metastatic C ol orectal A de n ocarci n o ma................................ .....6 2
4. 4. E n d of St u d y  Defi niti o n ..........................................................................................6 2
5. S T U D Y P O P U L A T I ON................................ ......................................................................6 2
5. 1. I ncl usi o n Criteria .....................................................................................................6 3
5. 2. E xcl usi o n Criteria ....................................................................................................6 4
5. 3. L ifest yle C o nsi derati o ns..........................................................................................6 7
5. 3. 1. C o ntrace pti o n ..............................................................................................6 7
5. 4. Scree n Fail ures ........................................................................................................6 8
6. S T U D Y I N T E R V E N TI O N ..................................................................................................6 8
6. 1. St u d y  Inter ve nti o n(s) A d mi nistere d ........................................................................6 8
6. 1. 1. A d mi nistrati o n ............................................................................................6 9
6. 1. 1. 1. P F - 0 7 0 6 2 1 1 9.............................................................................6 9
6. 1. 1. 2. P F - 0 6 8 0 1 5 9 1.............................................................................7 0
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
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6. 1. 1. 3. Be vaciz u ma b -Pfizer ..................................................................7 0
6. 2. Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ........................................................7 1
6. 3. Pre parati o n a n d Dis pe nsi n g .....................................................................................7 2
6. 4. Meas ures t o Mi ni mize Bias: Ra n d o mizati o n a n d Bli n di n g .....................................7 2
6. 4. 1. All ocati o n t o I n vesti gati o nal Pr o d uct/ St u d y  Inter ve nti o n ..........................7 2
6. 5. St u d y I nter ve nti o n C o m plia nce...............................................................................7 3
6. 6. C o nc o mita nt T hera p y ..............................................................................................7 3
6. 6. 1. Ot her A nti -t u m or/ A nti-ca ncer Treat me nt ...................................................7 4
6. 6. 2. S u p p orti ve Care ..........................................................................................7 4
6. 6. 2. 1. S u p p orti ve Care f or C y t o ki ne Release Sy n dr o me .....................7 4
6. 6. 2. 2. S u p p orti ve Care f or I nf usi o n -Relate d Reacti o ns ......................7 5
6. 6. 2. 3. S u p p orti ve Care f or H y perse nsiti vit y  Reacti o ns T ypes 1 
a n d 3 ..................................................................................................7 5
6. 6. 2. 4. S u p p orti ve Care f or I m m u ne - Relate d A d verse E ve nts............. 7 5
6. 6. 3. He mat o p oietic Gr o wt h Fact ors ...................................................................7 5
6. 6. 4. A nti- Diarr heal, A nti -E metic T hera p y......................................................... 7 6
6. 6. 5. A nti- I nfla m mat or y T hera p y................................ ........................................ 7 6
6. 6. 6. C ortic oster oi ds............................................................................................ 7 6
6. 6. 7. S ur ger y ........................................................................................................7 7
6. 6. 8. Resc ue Me dici ne .........................................................................................7 7
6. 7. D ose M o dificati o n ...................................................................................................7 7
6. 7. 1. D osi n g I nterr u pti o ns ...................................................................................7 7
6. 7. 1. 1. D ose I nterr u pti o n of Partici pa nts wit h Pres u me d or Acti ve 
C O VI D -1 9/ S A R S -C o V 2 I nfecti o n ....................................................7 8
6. 7. 2. D ose Dela y s................................................................................................ 7 9
6. 7. 3. D ose Re d uct i o ns.........................................................................................7 9
6. 8. I nter ve nti o n After t he E n d of t he St u d y ..................................................................8 6
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 6
7. 1. Disc o nti n uati o n of St u d y  Inter ve nti o n ....................................................................8 6
7. 1. 1. Re q uest t o C o nti n ue Treat me nt ..................................................................8 6
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 7
7. 3. L ost t o F oll o w - u p....................................................................................................8 8
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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 ...............................................................8 9
8. 1. Safet y Assess me nts .................................................................................................9 0
8. 1. 1. P h y sical E xa mi nati o ns ................................................................................9 0
8. 1. 2. C O VI D ‑ 1 9: Use of Alter nati ve Met h o ds f or I n-Pers o n Visits ...................9 0
8. 1. 3. Vital Si g ns ..................................................................................................9 0
8. 1. 4. Electr ocar di o gra ms..................................................................................... 9 0
8. 1. 5. Cli nical Safet y  La b orat or y Assess me nts....................................................9 1
8. 1. 6. Pre g na nc y  Testi n g ......................................................................................9 2
8. 1. 7. I njecti o n Site T olera bilit y  Assess me nt.......................................................9 2
8. 2. A d verse E ve nts a n d Seri o us A d verse E ve nts................................ ..........................9 2
8. 2. 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 3
8. 2. 1. 1. Re p orti n g S A Es t o Pfizer Safet y ...............................................9 3
8. 2. 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................... 9 4
8. 2. 2. Met h o d of Detecti n g A Es a n d S A Es ..........................................................9 4
8. 2. 3. F oll o w -u p of A Es a n d S A Es .......................................................................9 4
8. 2. 4. Re g ulat or y Re p orti n g Re q uire me nts f or S A Es ...........................................9 4
8. 2. 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 ..........................................................................................................9 5
8. 2. 5. 1. E x p os ure D uri n g Pre g na nc y ......................................................9 5
8. 2. 5. 2. E x p os ure D uri n g Breastfee di n g ................................................9 5
8. 2. 5. 3. Occ u pati o nal E x p os ure .............................................................9 5
8. 2. 6. Me dicati o n Err ors .......................................................................................9 6
8. 3. Tre at me nt of O ver d ose ............................................................................................9 6
8. 4. P har mac o ki netics a n d I m m u n o ge nicit y.................................................................. 9 7
8. 4. 1. P har mac o ki netic Assess me nts.................................................................... 9 7
8. 4. 2. A nal y sis of A nti-Dr u g A nti b o dies a n d Ne utralizi n g A nti -A nti b o dies 
( P F-0 7 0 6 2 1 1 9, P F -0 6 8 0 1 5 9 1, or be vaciz u ma b -Pfizer) ...................................9 8
8. 5. P har mac o d y na mics ..................................................................................................9 8
8. 6. Bi o mar ker a n d P har mac o d y na mic Assess me nts .....................................................9 9
8. 7. Ge netics ...................................................................................................................9 9
8. 7. 1. S pecifie d Ge netics ......................................................................................9 9
8. 7. 2. Ba n ke d Bi os peci me ns f or Ge netics ............................................................9 9
8. 8. Bi o mar kers ............................................................................................................1 0 0
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P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
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8. 8. 1. Arc hi val Pre -treat me nt a n d O pti o nal De N o v o Pre- a n d O n -
Treat me nt T u m or Bi o psies f or Part 1 A a n d Pa rt 1 B......................................1 0 0
8. 8. 2. Ma n dat or y  De N o v o Pre- a n d O n -Treat me nt T u m or Bi o psies at 
R P 2 D i n Part 1 A, Part 1 B, a n d Part 2 ............................................................1 0 1
8. 8. 3. Peri p heral Bl o o d Sa m ple Assess me nts .....................................................1 0 2
8. 8. 4. C y t o ki ne Assess me nts ..............................................................................1 0 2
8. 8. 5. T Cell I m m u n o p he n ot y pi n g ......................................................................1 0 2
8. 9. T u m or Res p o nse Assess me nts ..............................................................................1 0 3
8. 1 0. Healt h Ec o n o mics ...............................................................................................1 0 3
9. S T A TI S T I C A L C O N SID E R A TI O N S ................................ ..............................................1 0 3
9. 1. Statistical H y p ot heses ...........................................................................................1 0 3
9. 2. Sa m ple Size Deter mi nati o n ...................................................................................1 0 3
9. 2. 1. Part 1 D ose Escalati o n ..............................................................................1 0 3
9. 2. 2. Part 2 D ose E x pa nsi o n ..............................................................................1 0 4
9. 3. P o p ulati o ns f or A nal ysis .......................................................................................1 0 4
9. 4. Statistical A nal y ses ...............................................................................................1 0 5
9. 4. 1. Ma xi m u m T olerate d D ose Deter mi nati o n ................................................1 0 5
9. 4. 2. Efficac y  A nalys es .....................................................................................1 0 7
9. 4. 3. Safet y A nal ys es ........................................................................................1 0 7
9. 4. 3. 1. Electr ocar di o gra m A nal y ses....................................................1 0 8
9. 4. 3. 2. A d verse E ve nts ........................................................................1 0 9
9. 4. 3. 3. La b orat or y  Test A b n or malities ...............................................1 0 9
9. 4. 4. Ot her A nal ys es ..........................................................................................1 0 9
9. 4. 4. 1. P har mac o ki netic A nal y ses ......................................................1 0 9
9. 4. 4. 2. P har mac o d y na m ic A nalys es ...................................................1 1 0
9. 5. I nteri m A nalys es ...................................................................................................1 1 1
9. 5. 1. Dat a M o nit ori n g C o m mittee .....................................................................1 1 1
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 1 2
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 1 2
1 0. 1. 1. Re g ulat or y a n d Et hical C o nsi derati o ns ..................................................1 1 2
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 1 2
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9
1 0. 1. 2. Fi na ncial Discl os ure ...............................................................................1 1 3
1 0. 1. 3. I nf or me d C o nse nt Pr ocess ......................................................................1 1 3
1 0. 1. 4. Data Pr otecti o n .......................................................................................1 1 4
1 0. 1. 5. Disse mi nati o n of Cli nical St u d y  Data ....................................................1 1 4
1 0. 1. 6. Data Q ualit y Ass ura nce ..........................................................................1 1 5
1 0. 1. 7. S o urce D oc u me nts ..................................................................................1 1 7
1 0. 1. 8. St u d y  a n d Site Cl os ure............................................................................1 1 7
1 0. 1. 9. P u blicati o n P olic y................................................................................... 1 1 7
1 0. 1. 1 0. S p o ns or’s Q ualifie d Me dical Pers o n nel ...............................................1 1 8
1 0. 2. A p pe n di x 2: Cli nical La b orat or y  Tests...............................................................1 1 9
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 2 1
1 0. 3. 1. Defi niti o n of A E .....................................................................................1 2 1
1 0. 3. 2. Defi niti o n of S A E................................................................................... 1 2 2
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 2 4
1 0. 3. 4. Re p orti n g of S A Es.................................................................................. 1 2 7
1 0. 4. A p pe n di x 4: C o ntrace pti ve G ui da nce a n d C ollecti o n of Pre g na nc y 
I nf or mati o n ..............................................................................................................1 2 8
1 0. 4. 1. Male Partici pa nt Re pr o d ucti ve I ncl usi o n Criter ia..................................1 2 8
1 0. 4. 2. Fe male Partici pa nt Re pr o d ucti ve I ncl usi o n Criteria ...............................1 2 8
1 0. 4. 3. W o ma n of C hil d beari n g P ote ntial ( W O C B P) ........................................1 2 9
1 0. 4. 4. C o ntrace pti o n Met h o ds ...........................................................................1 3 0
1 0 . 5. A p pe n di x 5: Ge netics..........................................................................................1 3 3
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 3 4
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 3 6
1 0. 8. A p pe n di x 8: C o u ntr y -S pecific Re q uire me nts .....................................................1 3 8
1 0. 9. A p pe n di x 9: Preli mi nar y  Cli nical S u m mar y f or St u d y B 8 0 1 1 0 0 1 P hase 1 
FI H ( P F - 0 6 8 0 1 5 9 1).................................................................................................1 3 9
1 0. 1 0. A p pe n di x 1 0: Detaile d D ose Escalati o n/ Fi n di n g Sc he me f or B L R M ..............1 4 1
1 0. 1 0. 1. Statistical M o del ...................................................................................1 4 1
1 0. 1 0. 2. Pri or S pecificati o ns f or M o n ot hera p y Wit h o ut Pri mi n g ...................... 1 4 1
1 0. 1 0. 3. Pri or S pecificati o ns f or M o n ot hera p y wit h Pri mi n g ............................1 4 2
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0
1 0. 1 1. A p pe n di x 1 1: S u g geste d C yt o ki ne R elease S yn dr o me Ma na ge me nt 
Al g orit h m a n d Re vise d C R S Gra di n g S y ste m ........................................................1 4 4
1 0. 1 2. A p pe n di x 1 2: E C O G Perf or ma nce Stat us .........................................................1 4 6
1 0. 1 3. A p pe n di x 1 3: S u p p orti ve Care f or I m m u ne- Relate d A d verse E ve nts 
(ir A Es) .....................................................................................................................1 4 7
1 0. 1 4. A p pe n di x 1 4: R E CI S T ( Res p o nse E val uati o n Criteria i n S oli d T u m ors) 
Versi o n 1. 1 G ui deli nes ............................................................................................1 5 1
1 0. 1 5. A p pe n di x 1 5: I m m u ne -Relate d Res p o nse Criteria Deri ve d fr o m R E CI S T 
1. 1 (ir R E CI S T) ........................................................................................................1 5 6
1 0. 1 6. A p pe n di x 1 6: A b bre viati o ns .............................................................................1 5 8
1 0. 1 7. A p pe n di x 1 7: Ja pa n S pecific Matters................................ ................................1 6 4
1 0. 1 8. A p pe n di x 1 8: Alter nati ve Meas ures D uri n g P u blic E mer ge ncies .....................1 6 5
1 0. 1 9. P E T I ma gi n g S u bst u d y  wit h 8 9Zr -Df -I AB 2 2 M 2 C ............................................1 7 0
1 0. 1 9. 1. O verall desi g n a n d Scie ntific Rati o nal f or S u bst u d y ............................1 7 0
1 0. 1 9. 2. Be nefit/ Ris k Assess me nt...................................................................... 1 7 1
1 0. 1 9. 3. P E T I ma gi n g S u bst u d y  O bjecti ves.......................................................1 7 2
1 0. 1 9. 4. P E T I ma gi n g S u bst u d y  Desi g n.............................................................1 7 2
1 0. 1 9. 5. C D 8 P E T Tracer I ma gi n g Pr oce d ures: .................................................1 7 4
1 0. 2 0. S u bc uta ne o us I njecti o n Site L ocati o ns .............................................................1 7 9
1 0. 2 1. Pr ot oc ol A me n d me nt S u m mar y of C ha n ges Ta ble T hr o u g h A me n d me nt 6 ....1 8 0
1 1. R E F E R E N C E S ................................................................................................................2 0 2
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1
LI S T O F T A B L E S
Ta ble 1.
Sc he d ule of Acti vities f or Part 1 A, Part 1 B, a n d Part 2 Wit h o ut 
Pri mi n g D ose ............................................................................................1 3
Ta ble 2.
Sc he d ule of Acti vities f or Part 1 A, Part 1 B, a n d Part 2 Wit h 
Pri mi n g D ose ............................................................................................1 9
Ta ble 3.
Sc he d ule of P har mac o ki netic, P har mac o d y na mic, a n d 
I m m u n o ge nicity Assess me nts f or Part 1 A a n d Part 1 B Wit h o ut 
Pri mi n g D ose ............................................................................................2 4
Ta ble 4.
Sc he d ule of P har mac o ki netic, P har mac o d y n a mic, a n d 
I m m u n o ge nicity Assess me nts f or Part 1 A a n d Part 1 B Wit h 
Pri mi n g D ose ............................................................................................2 7
Ta ble 5.
Sc he d ule of P har mac o ki netic, P har mac o d y na mic, a n d 
I m m u n o ge nicity Assess me nts f or Part 2 Wit h o ut Pri mi n g D ose .............3 0
Ta ble 6.
Sc he d ule of P har mac o ki n etic, P har mac o d y n a mic, a n d 
I m m u n o ge nicity Assess me nts f or Part 2 Wit h Pri mi n g D ose ..................3 2
Ta ble 7.
Mea n ( % C V) P K Para meters F oll o wi n g S i n gle S C D oses of 
P F - 0 7 0 6 2 1 1 9 i n Partici pa nts wit h A d va nce d GI T u m ors 
( St u d y C 3 8 6 1 0 0 1) .....................................................................................4 5
Ta ble 8.
Mi ni m u m I n patie nt O bser vati o n Sta ys .....................................................5 1
Ta ble 9.
S C D ose Escalati o n Le vels f or A d mi nistrati o n Wit h o ut Pri mi n g 
D ose ..........................................................................................................5 9
Ta ble 1 0.
A d mi nistere d St u d y  Inter ve nti o ns ............................................................6 8
Ta ble 1 1.
D ose M o dificati o ns f or T o xicit y  Attri b ute d t o I n vesti gati o nal 
Pr o d uct or I n vesti gati o nal C o m bi nati o n T hera p y  f or N o n-I m m u ne-
Relate d A Es c .............................................................................................8 1
Ta ble 1 2.
D ose M o dificati o ns f or S pecific I m m u ne Relate d T o xicit y  
Attri b ute d t o I n vesti gati o nal Pr o d uct or C o m bi nati o n 
I n vesti gati o nal T hera py............................................................................ 8 3
Ta ble 1 3.  
D osa ge M o dificati o ns f or A d verse Reacti o ns ..........................................8 5
Ta ble 1 4.
Bi o mar ker C ollecti o ns a n d A nal y ses........................................................9 9
Ta ble 1 5.
Safet y  La b orat or y Tests..........................................................................1 1 9
Ta ble 1 6.
Pri or Distri b uti o n f or t he M o del Para meters ..........................................1 4 2
Ta ble 1 7.
S u m mar y  of Pri or Distri b uti o n of D ose Li miti n g T o xicit y Rates f or 
P F - 0 7 0 6 2 1 1 9...........................................................................................1 4 2
Ta ble 1 8.
Pri or Distri b uti o n f or t he M o del Para meters ( Wit h Pri mi n g)................. 1 4 3
Ta ble 1 9.
S u m mar y  of Pri or Distri b uti o n of D ose Li miti n g T o xicit y Rates f or 
P F - 0 7 0 6 2 1 1 9 ( Wit h Pri mi n g D ose of 4 0 0 µ g).......................................1 4 3
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2
Ta ble 2 0.
Ma na ge me nt of I mm u ne Relate d A d verse E ve nts (ir A Es) ....................1 4 7
Ta ble 2 1.
O bjecti ve Res p o nse Stat us at Eac h E val uati o n ...................................... 1 5 4
Ta ble 2 2.
O bjecti ve Res p o nse Stat us at Eac h E val uati o n f or Patie nts wit h N o n 
Tar get Disease O nl y ............................................................................... 1 5 5
Ta ble 2 3.
O verall Res p o nse Deri ve d fr o m C ha n ges i n I n de x, N o n i n de x a n d 
Ne w Lesi o ns ...........................................................................................1 5 7
Ta ble 2 4.
O ver vie w of P E T I ma gi n g S u bst u d y  Visits............................................1 7 4
Ta ble 2 5.
Sc he d ule of Assess me nts f or 8 9Zr -Df -I AB 2 2 M 2 C I m m u n o -P E T 
C D 8 Mi ni -b o d y  Ima gi n g S u bst u d y ........................................................1 7 8
LI S T O F FI G U R E S
Fi g ure 1.
Si n gle A ge nt P F -0 7 0 6 2 1 1 9 Efficac y  i n Esta blis he d T u m or M o dels 
wit h A d o pti ve H u ma n T Cell Tra nsfer .....................................................4 0
Fi g ure 2.
A nti- t u m or Efficac y f oll o wi n g P F-0 7 0 6 2 1 1 9 i n C o m bi nati o n wit h 
A nti P D - 1, A nti-P D -L 1 , or A nti-V E G F -A i n C ol orectal T u m or 
M o dels ......................................................................................................4 2
Fi g ure 3.
C 3 8 6 1 0 0 1 St u d y  Sc he ma..........................................................................5 0
Fi g ure 4.
S u m mar y  of D L T Rates f or P F- 0 7 0 6 2 1 1 9 ............................................. 1 4 2
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3
1. S C H E D U L E O F A C TI VI TI E S ( S O A)  
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 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 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 wel l-bei n g of t he partici pa nt.
A p pe n di x 1 8 prese nts alter nati ve meas ures t hat ma y be use d d uri n g t he c o urse of t he st u d y i n li g ht of t he C O VI D -1 9 pa n de mic.
T a ble 1 . 
Sc he d ule of Acti vities f or P art 1 A, P art 1 B, a n d P art 2 Wit h o ut Pri mi n g D ose
Pr ot oc ol Acti vit y
Scree ni n g 1
Acti ve Tre at me nt P h ase - O ne C ycle = 2 8 d a ys
E n d of 
Tre at me nt/ 
Wit h dr a w al
1 9
P ost -Tre at me nt 
F oll o w -U p 2 0
C ycle 1
C ycles ≥2 
St u d y D a y
Wit hi n 2 8 d a ys 
pri or t o 
re gistr ati o n
D a y 
1
D a y 2
D a y 
3
D a y 
5 2 3
D a y
8
D a y
1 5
D a y
2 2
D a y 
1
D a y 
2
D a y 
5
D a y 
8
D a y
1 5
Visit Wi n d o w
± 1 
d a y
± 1
d a y
± 2 
d a ys
± 2
d a ys
± 2
d a ys
± 1 
d a y
± 1 
d a y 
± 2
d a ys
± 7
d a ys
I nf or me d C o nse nt2
X
Me dical/ O nc ol o gical Hist or y
X
Baseli ne Si g ns/ S y m pt o ms 3
X
P h ysical E xa mi nati o n 3
X
( X)
X
Brief P h ysical E xa mi nati o n 3
X
X  
X  
X  
X
X
X
Vital Si g ns 4
X  
X
X  
X  
X  
X
X  
X
X
E C O G Perf or ma nce Stat us 5
X  
X
X
X
C o ntrace pti o n C hec k
X  
X
X
X
X
1 2 -Lea d E C G 6
X  
X  
X
X 6
X
X
X 6
X ( C 4 
o nl y)
X ( C 4 
o nl y)
X ( C 4 
o nl y)
X ( C 4 
o nl y)
X
L a b or at ory St u dies
Viral disease scree ni n g 7
X
He mat ol o g y 8
X  
X
X  
X  
X  
X
X ( C 2 
& C 3 
o nl y)
X
( X)
Bl o o d C he mistr y 9
X  
X
X  
X  
X  
X
X ( C 2 
& C 3 
o nl y)
X
( X)
C oa g ulati o n 1 0
X  
X
X
( X)
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4
T a ble 1 . 
Sc he d ule of Acti vities f or P art 1 A, P art 1 B, a n d P art 2 Wit h o ut Pri mi n g D ose
Pr ot oc ol Acti vit y
Scree ni n g 1
Acti ve Tre at me nt P h ase - O ne C ycle = 2 8 d a ys
E n d of 
Tre at me nt/ 
Wit h dr a w al
1 9
P ost -Tre at me nt 
F oll o w -U p 2 0
C ycle 1
C ycles ≥2 
St u d y D a y
Wit hi n 2 8 d a ys 
pri or t o 
re gistr ati o n
D a y 
1
D a y 2
D a y 
3
D a y 
5 2 3
D a y
8
D a y
1 5
D a y
2 2
D a y 
1
D a y 
2
D a y 
5
D a y 
8
D a y
1 5
Visit Wi n d o w
± 1 
d a y
± 1
d a y
± 2 
d a ys
± 2
d a ys
± 2
d a ys
± 1 
d a y
± 1 
d a y 
± 2
d a ys
± 7
d a ys
Uri nal ysis 1 1
X
X 1 1
X 1 1
X 1 1
X 1 1
X
( X)
Pre g na nc y test 1 2
X  
X
X 1 2
X
X 1 2
C y t o ki ne e val uati o n (l ocal la b) 
C y t o ki nes s h o ul d be assesse d wit h la b orat or y st u dies i n t he e ve nt of C R S.
P K, P D, a n d I m m u n o ge nicit y 
Assess me nts
Refer t o Ta ble 3 a n d Ta ble 5
St u dy Tre at me nt
Re gistrati o n 1 3
X
Pre me dicati o n 2 4
X
P F -0 7 0 6 2 1 1 9 a d mi nistrati o n 1 4
X
X
X
X
P F -0 6 8 0 1 5 9 1 a d mi nistrati o n 1 4
X
X
Be vaciz u ma b - Pf izer a d mi nistrati o n 1 4
X
X
X
X
I njecti o n Site T olera bilit y 
Assess me nt 1 5
X  
X ( C 1 
o nl y)
X
A s cli nic ally i n dic ate d
I n patie nt M o nit ori n g1 6
◄--►
◄--►
X
X
Ot her Cli nic al Assess me nts
A d verse E ve nt Re p orti n g 1 7
◄----------------------------------------------------------------------------------------------------------------------------- ----------------------------------►
C o nc o mita nt Me dicati o ns/ Treat me nts 1 8
◄------------------------------------------------------------------------------------------------------------------------------ ►
Dise ase Assess me nts 2 1
C T/ M RI Sca ns of C hest, A b d o me n, 
Pel vis, a n y cli nicall y i n dicate d sites of 
disease, a n d of b o ne lesi o ns; Cli nical 
e val uati o n of s u perficial disease 
X
Perf or me d e ver y 8 wee ks fr o m C 1 D 1 ( ± 7 da ys) f or t he first 6 m o nt hs, e ver y 1 2 wee ks 
( ± 7 da ys) f or t he ne xt 1 8 m o nt hs, a n d e ver y 4 m o nt hs t hereafter.
X
Carci n oe m br y o nic A nti ge n ( C E A) 
Assess me nt 2 2
X  
X
X
X
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5
T a ble 1 . 
Sc he d ule of Acti vities f or P art 1 A, P art 1 B, a n d P art 2 Wit h o ut Pri mi n g D ose
Pr ot oc ol Acti vit y
Scree ni n g 1
Acti ve Tre at me nt P h ase - O ne C ycle = 2 8 d a ys
E n d of 
Tre at me nt/ 
Wit h dr a w al
1 9
P ost -Tre at me nt 
F oll o w -U p 2 0
C ycle 1
C ycles ≥2 
St u d y D a y
Wit hi n 2 8 d a ys 
pri or t o 
re gistr ati o n
D a y 
1
D a y 2
D a y 
3
D a y 
5 2 3
D a y
8
D a y
1 5
D a y
2 2
D a y 
1
D a y 
2
D a y 
5
D a y 
8
D a y
1 5
Visit Wi n d o w
± 1 
d a y
± 1
d a y
± 2 
d a ys
± 2
d a ys
± 2
d a ys
± 1 
d a y
± 1 
d a y 
± 2
d a ys
± 7
d a ys
N otes: Visit wi n d o ws are calc ulate d fr o m t he first da y of eac h c ycle. Assess me nts t hat a p pear as ( X) are o pti o nal.
1 Scree ni n g : t o be o btai ne d wit hi n 2 8 da ys pri or t o re gistrati o n.
2 I nf or me d C o nse 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. Ma y be o btai ne d m ore t ha n 2 8 da ys pri or t o re gistrati o n. I n Ja pa n, after c o m pleti o n of 
C y cle 1, partici pa nts will be as ke d t o si g n a n a d diti o nal c o nse nt d oc u me nt i n at least Part 1 A f or c o nfir mati o n of t he partici pa nt’ s willi n g ness t o c o nti n ue partici pati o n i n t his st u d y 
bef ore starti n g C ycle 2.
3 C o m plete P h ysic al E x a m i n 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 is perf or me d wit hi n 3 da ys of d osi n g, i ncl u di n g assess me nt of wei g ht . Brief P h ysic al 
E x a m i n ati o n i ncl u di n g Baseli ne Si g ns a n d S y m pt o ms: A s y m pt o m directe d e xa m a n d assess me nt f or e mer ge nt t o xicities or c ha n ges fr o m pri or vis its ( See Secti o n 8. 1. 1 ), d oes n ot 
nee d t o be re peate d if d o ne wit hi n 2 4 h o urs of C 1 D 1.
4 Vit al Si g ns: I ncl u des te m perat ure ( oral, t y m pa nic, te m p oral or a xillar y), b o d y wei g ht, bl o o d press ure ( B P), a n d p ulse rate t o be rec or de d i n a se mis u pi ne or seate d p ositi o n. O n 
eac h d osi n g da y, vitals s h o ul d be meas ure d pri or t o t he P F -0 7 0 6 2 1 1 9 i njecti o n or i nf usi o n. I n a d diti o n, p ulse o xi metr y is t o be rec or de d o n d osi n g da ys pri or t o t he P F -0 7 0 6 2 1 1 9 
i njecti o n or i nf usi o n as part of t he vital si g n e val uati o n.
5 Perf or m a nce St at us: Use Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G).
6 Tri plic ate 1 2 -Le a d E C G: Tri plicate E C Gs t o be c ollecte d i n C ycle 1 o n Da y 1, 2, 3 ( partici pa nts i n Part 1 A a n d 1 B o nl y), 5, a n d 1 5 a n d o n Da y 1 of C y cles 2, 3, 4 a n d 5.
A d diti o nall y, i n C ycle 4 o nl y, E C Gs will be c ollecte d o n Da y 2, 5, 8, a n d 1 5, c oi nci di n g wit h t he P K sa m ple c ollecti o n . F oll o wi n g C ycle 5, E C Gs will be ta ke n o n Da y 1 of e ver y 
3r d c ycle o nl y (ie, C ycle 5 Da y 1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc). A d diti o nal E C Gs s h o ul d be c ollecte d as cli nicall y i n dicate d, at t he discreti o n of t he i n vesti gat or. At eac h 
ti me p oi nt 3 c o nsec uti ve 1 2 -lea d E C Gs will be 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 ( Q T usi n g Fri dericia's f or m ula). W he n c oi nci di n g wit h bl o o d 
sa m ple c ollecti o ns f or p har mac o ki netics ( P K), E C G assess me nt s h o ul d be perf or me d pri or t o bl o o d sa m ple c ollecti o n, s uc h t hat t he bl o o d sa m ple is c ollecte d at t he n o mi nal ti me. 
If t he mea n Q Tc F is pr ol o n ge d ( > 5 0 0 msec), t he E C Gs s h o ul d be re -e val uate d b y a q ualifie d pers o n at t he i nstit uti o n f or c o nfir mati o n.
7 U ni q ue Scree ni n g/ Vir al Dise ase L a b or at or y Tests: He patitis B s urface a nti ge n, he patitis B c ore a nti b o d y, he patitis C a nti b o d y a n d HI V or AI D S as well as f ollicle sti m ulati n g 
h or m o ne ( F S H) f or p ost me n o pa usal w o me n w h o are a me n orr h oeic f or at least 1 2 c o nsec uti ve m o nt hs o nl y. Sa m ples will be a nal yze d l ocall y.
8 He m at ol o g y: N o nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 7 da ys of d osi n g. Assess me nts perf or me d at all s u bse q ue nt d osi n g visits s h o ul d be o btai ne d 
wit hi n 4 8 h o urs pri or t o d osi n g. He mat ol o g y assess me nt f oll o wi n g c ycle 1 (e g, C 1 D 2 9 or C 1 D 3 0) s h o u l d be c ollecte d a n d re vie we d pri or t o d osi n g o n C 2 D 1. Sa m ples will be 
a nal yze d l ocall y. A c o m plete list of he mat ol o g y la bs ca n be f o u n d i n A p pe n di x 2 .
9 Bl o o d C he mistr y: A c o m plete list of bl o o d c he mistr y la bs ca n b e f o u n d i n A p pe n di x 2 . Meas ure me nt of C -reacti ve pr otei n ( C R P) n ot re q uire d after C 2 D 1 if wit hi n n or mal 
ra n ge or si milar t o baseli ne le vels; h o we ver, C R P s h o ul d be meas ure d a n yti me c yt o ki ne release s y n dr o me is s us pecte d a n d n ot alrea d y sc he d ule d t o be meas ure d (e g, C ycle 2). N o 
nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 7 da ys pri or t o d osi n g. Assess me nts perf or me d at all s u bse q ue nt d osi n g visits s h o ul d be o btai ne d wit hi n 4 8 h o urs 
pri or t o d osi n g. Bl o o d c he mistr y assess me nt f oll o wi n g C ycle 1 (e g, C 1 D 2 9 or C 1 D 3 0) s h o ul d be c ollecte d a n d re vie we d pri or t o d osi n g o n C 2 D 1. Sa m ples will be a nal yze d 
l ocall y.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6
T a ble 1 . 
Sc he d ule of Acti vities f or P art 1 A, P art 1 B, a n d P art 2 Wit h o ut Pri mi n g D ose
Pr ot oc ol Acti vit y
Scree ni n g 1
Acti ve Tre at me nt P h ase - O ne C ycle = 2 8 d a ys
E n d of 
Tre at me nt/ 
Wit h dr a w al
1 9
P ost -Tre at me nt 
F oll o w -U p 2 0
C ycle 1
C ycles ≥2 
St u d y D a y
Wit hi n 2 8 d a ys 
pri or t o 
re gistr ati o n
D a y 
1
D a y 2
D a y 
3
D a y 
5 2 3
D a y
8
D a y
1 5
D a y
2 2
D a y 
1
D a y 
2
D a y 
5
D a y 
8
D a y
1 5
Visit Wi n d o w
± 1 
d a y
± 1
d a y
± 2 
d a ys
± 2
d a ys
± 2
d a ys
± 1 
d a y
± 1 
d a y 
± 2
d a ys
± 7
d a ys
1 0 C o a g ul ati o n: A c o m plete list of c oa g ulati o n la bs ca n be f o u n d i n A p pe n di x 2 . N o nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 7 da ys of d osi n g. Sa m ples 
will be a nal yze d l ocall y.
1 1 Uri n al ysis: Di pstic k is acce pta ble. Micr osc o pic a nal yses if di pstic k a b n or mal. N o nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 7 da ys of d osi n g, wit h t he 
e xce pti o n of partici pa nts w h o are recei vi n g be vaciz u ma b -Pf izer w h o will re q uire uri nal ysis ( di pstic k is acce pta ble) pri or t o e ver y d ose of be vaciz u ma b-Pf izer. Sa m ples will be 
a nal yze d l ocall y. Ur i nal ysis ( di pstic k is acce pta ble) assess me nt is re q uire d pri or t o e ver y be vaciz u ma b-Pf izer d ose t hr o u g h o ut t he c o urse of t he st u d y. If uri nal ysis de m o nstrates 
pr otei n greater t ha n or e q ual t o 2 +, t he n a 2 4 -h o ur ur i ne pr otei n c ollecti o n s h o ul d f oll o w. I n pa rtici pa nts wit h pr otei n uria greater t ha n or e q ual t o 2 gra ms per 2 4 h o urs, 
be vaciz u ma b -Pf izer s h o ul d be hel d u ntil rec o ver y (less t ha n 2 gra ms per 2 4 h o urs). Disc o nti n ue be vaciz u ma b-Pf izer i n partici pa nts t hat de vel o p ne p hr otic s y n dr o me.
1 2 Pre g n a nc y Test: F or fe male partici pa nts of c hil d beari n g p ote ntial, a ser u m or uri ne pre g na nc y test, wit h se nsiti vit y of at least 2 5 mI U/ m L will be perf or me d o n 2 occasi o ns 
pri or t o starti n g st u d y treat me nt – o nce at t he start of scree ni n g a n d o nce o n C 1 D 1 i m me diatel y bef ore a d mi nistrati o n of st u d y i nter ve nti o n ( wit hi n 2 4 h o urs pri or t o C 1 D 1 d osi n g). 
Pre g na nc y tests will als o be r o uti nel y re peate d at e ver y ot her c ycle d uri n g t he acti ve treat me nt peri o d f oll o wi n g C 1 D 1 a n d C 2 D 1, at t he e n d of st u d y treat me nt a n d a d diti o nal 
w he ne ver o ne me nstr ual c ycle is misse d or w he n p ote ntial pre g na nc y is ot her wise s us pecte d. D uri n g f oll o w -u p, a pre g na nc y test is o nl y re q uire d 3 0, 9 0, a n d 1 8 0  da ys after E O T 
f or partici pa nts w h o recei ve P F- 0 6 8 0 1 5 9 1. A d diti o nal pre g na nc y tests ma y als o be u n derta ke n if re q ueste d b y I R B or if re q uire d b y l ocal re g ulati o ns.
1 3 Re gistr ati o n: Partici pa nt e nr oll me nt n u m ber a n d d ose le vel all ocati o n pr o vi de d b y Pfizer I nc. Re gistrati o n s h o ul d occ ur bef ore a n y ot her Da y 1 acti vities are perf or me d.
1 4 St u d y Tre at me nt: P F -0 7 0 6 2 1 1 9 will be a d mi nistere d o nce e ver y 1 4 da ys as a n S C i njecti o n. P F -0 6 8 0 1 5 9 1 will be a d mi nistere d o nce e ver y 2 8 -d a y  c ycle as a n S C i njecti o n 
be gi n ni n g o n C 1 D 1 of Part 1 B. Be vaciz u ma b -Pf izer or t he bi osi milar versi o n of A vasti n® , ma n ufact ure d b y Pfizer a n d hereafter referre d t o as be vaciz u ma b -Pf izer will be use d f or 
t his st u d y a n d a d mi nistere d o nce e ver y 1 4 da ys as I V i nf usi o n be gi n ni n g o n C 1 D 1 of Part 1 B. See Secti o n 6. 1. 1 of t he pr ot oc ol f or a d mi nistrati o n i nf or mati o n. Partici pa nts pla n ne d 
t o recei ve P F-0 7 0 6 2 1 1 9 i n c o m bi nati o n wit h be vaciz u ma b -Pf izer s h o ul d be wei g he d wit hi n 7 2 h o urs pri or t o d osi n g f or e ver y c ycle t o e ns ure t he y di d n ot e x perie nce eit her a 
wei g ht l oss or gai n > 1 0 % fr o m t he pri or wei g ht use d t o calc ulate t he a m o u nt of be vaciz u ma b -Pf izer re q uire d f or d ose pre parati o n. Decisi o n t o recalc ulate be vaciz u ma b-Pf izer d ose 
base d o n t he wei g ht o bta i ne d at eac h c ycle ca n be i n acc or da nce wit h i nstit uti o nal practice, h o we ver if t he partici pa nt e x perie nce d eit her a wei g ht loss or gai n > 1 0 % c o m pare d t o 
t he wei g ht use d t o calc ulate eit her t he i nitial or pre vi o us d ose, t he a m o u nt of be vaciz u ma b-Pf izer re quire d f or pre parati o n a n d a d mi nistrati o n f or t he c urre nt c ycle m ust be 
recalc ulate d usi n g t his m ost rece nt wei g ht o btai ne d. Partici pa nts i n Part 2 will be o bser ve d f or at least 2 4 h o urs after t he first S C d ose. Partici pa nts ma y o nl y be release d after t he 
in vesti gat or has c o nfir me d t he partici pa nt has n ot e x hi bite d si g ns of c yt o ki ne release s y n dr o me.
1 5 I njecti o n Site T oler a bilit y Assess me nt: Assess me nt of eac h i njecti o n s h o ul d be c o n d ucte d f or at least 1 h o ur f oll o wi n g eac h treat me nt a d mi nistrati o n i n C ycle 1. I n a d diti o n, 
a n assess me nt s h o ul d be perf or me d 2 4 h o urs ( ± 1 h o ur) after t he C 1 D 1 d ose. I njecti o n site t olera bilit y assess me nts s h o ul d c o nt i n ue after eac h d osi n g visit i n C ycle 2 a n d be y o n d, 
o nl y if i njecti o n site pai n or I S R c haracteristics c o nti n ue t o persist. T he assess me nts s h o ul d c o nti n ue at re g ularl y sc he d ule d visits u ntil t he s y m pt o ms res ol ve. All fi n di n gs s h o ul d 
be rec or de d o n t he i njecti o n site reacti o n C R F. See Secti o n 8. 1. 7 f or m ore details.
1 6 I n p atie nt M o nit ori n g: Partici pa nts recei vi n g P F -0 7 0 6 2 1 1 9 S C will be a d mitte d f or i n patie nt m o nit ori n g f or at least 4 8 h o urs f oll o wi n g t he first a d mi nistrati o n of st u d y 
treat me nt ( C 1 D 1) a n d f or at least 8 h o urs f oll o wi n g t he sec o n d a d mi nistrati o n of st u d y treat me nt ( C 1 D 1 5). Partici pa nts s h o ul d re mai n i n h o use f or o bser vati o n f or at least 1-h o ur 
p ost d ose f or all visits after C 1 f or Parts 1 A a n d 1 B; i n patie nt m o nit ori n g after C 1 f or Part 2 is at t he i n vesti gat or’s discreti o n. Partici pa nts ma y be release d o nl y after t he 
i n vesti gator has c o nfir me d t he partici pa nt has n ot e x hi bite d si g ns of a c yt o ki ne reacti o n. Partici pa nts s h o ul d c o m plete t he re q uire d st u d y s pecific la b orat or y assess me nts as detaile d 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7
T a ble 1 . 
Sc he d ule of Acti vities f or P art 1 A, P art 1 B, a n d P art 2 Wit h o ut Pri mi n g D ose
Pr ot oc ol Acti vit y
Scree ni n g 1
Acti ve Tre at me nt P h ase - O ne C ycle = 2 8 d a ys
E n d of 
Tre at me nt/ 
Wit h dr a w al
1 9
P ost -Tre at me nt 
F oll o w -U p 2 0
C ycle 1
C ycles ≥2 
St u d y D a y
Wit hi n 2 8 d a ys 
pri or t o 
re gistr ati o n
D a y 
1
D a y 2
D a y 
3
D a y 
5 2 3
D a y
8
D a y
1 5
D a y
2 2
D a y 
1
D a y 
2
D a y 
5
D a y 
8
D a y
1 5
Visit Wi n d o w
± 1 
d a y
± 1
d a y
± 2 
d a ys
± 2
d a ys
± 2
d a ys
± 1 
d a y
± 1 
d a y 
± 2
d a ys
± 7
d a ys
i n t he Sc he d ule of P har mac o ki netic, P har mac o d y na mic, a n d I m m u n o ge nicit y Assess me nts f or Parts 1 A a n d 1 B w here P F- 0 7 0 6 2 1 1 9 will be a d mi nistere d S C a n d s h o ul d be 
m o nit ore d per l ocal sta n dar d practice f or i n patie nt m o nit ori n g.
1 7 A d verse E ve nt ( 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 usi n g t he Nati o nal Ca ncer I n stit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts ( N CI C T C A E) versi o n 5. 0. Partici pa nts m ust be f oll o we d f or A Es f or 2 8 da ys after t he last st u d y treat me nt a d mi nistrati o n or u ntil all dr u g -relate d t o xicities ha ve res ol ve d, 
w hic he ver is later; or earli er t ha n 2 8 da ys s h o ul d t he partici pa nt c o m me nce a n ot her a ntica ncer t hera p y i n t he mea nti me. F or seri o us a d verse e ve nts ( S A Es) , t he acti ve re p orti n g 
peri o d t o Pfizer or its desi g nate d re prese ntati ve be gi ns fr o m t he ti me t hat t he partici pa nt pr o vi des i nf or me d c o nse nt, w hic h is o btai ne d pri or t o t he partici pa nt’s partici pati o n i n t he 
st u d y, ie, pri or t o 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 2 8 cale n dar da ys after t he last st u d y treat me nt a d mi nistrati on. 
S A Es occ urri n g t o a partici pa nt after t he acti ve re p orti n g peri o d has e n de d s h o ul d be re p orte d t o t he s p o ns or if t he i n vesti g at or bec o mes a ware of t he m; at a mi ni m u m, all S A Es 
t hat t he i n vesti gat or belie ves ha ve at least a reas o na ble p ossi bilit y of bei ng relate d t o st u d y i nter ve nti o n are t o be re p orte d t o t he s p o ns or.
1 8 C o nc o mit a nt Tre at me nts: Al l c o nc o mita nt me dicati o ns s h o ul d be rec or de d i n t he case re p ort f or m ( C R F) i ncl u di n g s u p p orti ve care dr u gs (e g, a nti-e metic treat me nt a n d 
pr o p h yla xis), a n d t he dr u gs use d t o treat a d verse e ve nts or c hr o nic diseases, a n d n o n- dr u g s u p p orti ve i nter ve nti o ns (e g, tra nsf usi o ns).
1 9 E n d of Tre at me nt Visit/ Wit h dr a w al ( E O T): O btai n t hese assess me nts if n ot c o m plete d i n t he last wee k (last 6 wee ks f or t u m or assess me nts).
2 0 F oll o w -U p: At least 2 8 da ys, a n d n o m ore t ha n 3 5 da ys, after disc o nti n uati o n of treat me nt, all partici pa nts will ret ur n t o o btai n t hese assess me nts as well as a n e val uate t he
res ol uti o n of a n y treat me nt-relate d t o xicit y. Partici pa nts w h o recei ve P F- 0 6 8 0 15 9 1 will als o ret ur n f or f oll o w -u p assess me nts 3 0, 9 0, a n d 1 8 0 da ys after treat me nt disc o nti n uati o n. 
Partici pa nts c o nti n ui n g t o e x perie nce t o xicit y 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 nt il 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. Partici pa nts wit h a n u n res ol ve d A E p ossi bl y relate d t o a nti-dr u g a nti b o dies 
( A D A) will be as ke d t o ret ur n t o t he cli nic f or A D A/ ne utralizi n g a nti b o dies ( NA b) a n d dr u g c o nce ntrati o n assess me nts at a p pr o xi matel y 3- m o nt h i nter vals u ntil t he 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 s p o ns or u p t o a ma xi m u m of 9 m o nt hs. S u bse q ue nt t o t he F oll o w- U p visi t, partici pa nts s h o ul d be c o ntacte d 
b y tele p h o ne e ver y 8 wee ks ( ± 7 d a y s) t o o btai n i nf or mati o n o n s u bse q ue nt a nti-ca ncer treat me nt a n d o verall s ur vi val f or u p t o t w o years fr o m t he date of ra n d o mizati o n.
2 1 T u m or Assess me nts: 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 ma y i ncl u de c hest, a b d o me n a n d pel vis C T or M RI sca ns or e q ui vale nt. 
T he sa me m o dalit y s h o ul d be c o m plete d, if p ossi ble t hr o u g h o ut t he st u d y. B o ne sca ns will be perf or me d at baseli ne if disease is s us pecte d a nd o n st u d y as a p pr o priate t o f oll o w 
disease. Baseli ne ce ntral ner v o us s yste m ( C N S) i ma gi n g is n ot re q uire d wit h t he e xce pti o n of s y m pt o matic partici pa nts t o r ule o ut C N S metastases; partici pa nt i neli gi ble if p ositi ve 
f or ne w C N S metastases, pre vi o usl y treate d C N S metastases are all o we d as o utli ne d e xcl usi o n criteria. C T or M RI sca ns t o be d o ne as o utli ne d i n t he Sc he d ule of Acti vities ( S O A ) 
u ntil disease pr o gressi o n b y ir R E CI S T or deat h, or u ntil per ma ne nt disc o nti n uati o n of st u d y treat me nt. Res p o nse (c o m plete res p o nse ( C R)/ partial res p o nse ( P R)) a n d disease 
pr o gressi o n will be c o nfir me d wit h 2 c o nsec uti ve ti me p oi nts at least 4 wee ks a part (i n t he a bse nce of ra pi d cli nical deter i orati o n f or pr o gressi o n). T u m or assess me nts s h o ul d be 
fi xe d acc or di n g t o t he cale n dar, re gar dless of treat me nt dela ys. T u m or assess me nts s h o ul d be re peate d at t he E n d of Treat me nt visit if m ore t ha n 6 wee ks ha ve passe d si nce t he last 
e val uati o n.
2 2 C E A As sess me nts: Perf or me d o n Da y 1 of eac h C ycle f or u p t o 1 year. After 1 year, perf or m e ver y 4 m o nt hs t hereafter.
2 3 T he Da y 5 visit wi n d o w is e x pa n de d ( ± 1 da y) f or partici pa nts i n Part 2 o nl y.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8
T a ble 1 . 
Sc he d ule of Acti vities f or P art 1 A, P art 1 B, a n d P art 2 Wit h o ut Pri mi n g D ose
Pr ot oc ol Acti vit y
Scree ni n g 1
Acti ve Tre at me nt P h ase - O ne C ycle = 2 8 d a ys
E n d of 
Tre at me nt/ 
Wit h dr a w al
1 9
P ost -Tre at me nt 
F oll o w -U p 2 0
C ycle 1
C ycles ≥2 
St u d y D a y
Wit hi n 2 8 d a ys 
pri or t o 
re gistr ati o n
D a y 
1
D a y 2
D a y 
3
D a y 
5 2 3
D a y
8
D a y
1 5
D a y
2 2
D a y 
1
D a y 
2
D a y 
5
D a y 
8
D a y
1 5
Visit Wi n d o w
± 1 
d a y
± 1
d a y
± 2 
d a ys
± 2
d a ys
± 2
d a ys
± 1 
d a y
± 1 
d a y 
± 2
d a ys
± 7
d a ys
2 4 Pre m e dic ati o n: A p pr o xi matel y 1 h o ur pri or t o P F -0 7 0 6 2 1 1 9 d osi n g o n C 1 D 1 o nl y, a d mi nister pre me dicati o n as f oll o ws: aceta mi n o p he n 6 5 0 m g ( or e q ui vale nt), oral; 
di p he n h y dra mi ne 2 5 m g, oral or I V; de xa met has o ne 1 2 m g ( or e q ui vale nt), oral or I V. I n a d diti o n, pre me dicati o n be y o n d t he 1st f ull d ose a n d m o dificati o ns t o t he pre me dicati o n 
re gi me n (e g, fre q ue nc y of pre me dicati o n, d oses of i n di vi d ual a ge nts, re m o val or a d diti o n of a ge nts) ma y be i m ple me nte d b y t he s p o ns or base d o n e mer gi n g data. A n y e xce pti o ns 
t o pre me dicati o n re q uire disc ussi o n a n d a gree me nt bet wee n t he s p o nsor a n d i n vesti gat or.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9
T a ble 2 . 
Sc he d ule of Acti vities f or P art 1 A, P art 1 B, a n d P art 2 Wit h Pri mi n g D ose
Pr ot oc ol Acti vit y
Scree ni n g 1
Acti ve Tre at me nt P h ase ( 1 C ycle = 2 8 d a ys)
C ycle 1
C ycles ≥2
E n d of 
Tre at me nt/ 
Wit h dr a w al
1 9
P ost -Tre at me nt 
F oll o w -U p 2 0
St u d y D a y
Wit hi n 2 8 d a ys 
pri or t o 
re gistr ati o n
D a y 
1
D a y 2
D a y 
8
D a y 
1 5
D a y
1 6
D a y
1 9
D a y
2 2
D a y 
1
D a y 
2
D a y 
5
D a y 
8
D a y
1 5
Visit Wi n d o w
± 1 
d a y
± 2 
d a ys
± 1 
d a ys
± 2
d a ys
± 2 
d a ys
± 1 
d a y
± 1 
d a y 
± 2
d a ys
± 7
d a ys
I nf or me d C o nse nt2
X
Me dical/ O nc ol o gical Hist or y
X
Baseli ne Si g ns/ S y m pt o ms 3
X
P h ysical E xa mi nati o n 3
X
( X)
X
X
Brief P h ysical E xa mi nati o n 3
X  
X
X  
X
X
X
Vital Si g ns 4
X  
X  
X  
X
X  
X
X  
X
X
E C O G Perf or ma nce Stat us 5
X  
X
X
X
C o ntrace pti o n C hec k
X  
X
X
X
X
1 2 -Lea d E C G 6
X  
X  
X
X 6
X
X 6
X ( C 4 
o nl y)
X ( C 4 
o nl y)
X ( C 4 
o nl y)
X ( C 4 
o nl y)
X
L a b or at ory St u dies
Viral disease scree ni n g 7
X
He mat ol o g y 8
X  
X  
X  
X
X  
X
X ( C 2 
& C 3 
o nl y)
X
( X)
Bl o o d C he mistr y 9
X  
X  
X  
X
X  
X
X ( C 2
& C 3 
o nl y)
X
( X)
C oa g ulati o n 1 0
X  
X
X
( X)
Uri nal ysis 1 1
X
X 1 1
X 1 1
X 1 1
X 1 1
X
( X)
Pre g na nc y test 1 2
X  
X
X 1 2
X
X 1 2
C y t o ki ne e val uati o n (l ocal la b) 
C y t o ki nes s h o ul d be assesse d wit h la b orat or y st u dies i n t he e ve nt of C R S.
P K, P D, a n d I m m u n o ge nicit y 
Assess me nts
See Ta ble 4 a n d Ta ble 6
St u dy Tre at me nt
Re gistrati o n 1 3
X
Pre me dicati o n 2 3
X
X
P F -0 7 0 6 2 1 1 9 a d mi nistrati o n 1 4
X
X
X
X
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0
T a ble 2 . 
Sc he d ule of Acti vities f or P art 1 A, P art 1 B, a n d P art 2 Wit h Pri mi n g D ose
Pr ot oc ol Acti vit y
Scree ni n g 1
Acti ve Tre at me nt P h ase ( 1 C ycle = 2 8 d a ys)
C ycle 1
C ycles ≥2
E n d of 
Tre at me nt/ 
Wit h dr a w al
1 9
P ost -Tre at me nt 
F oll o w -U p 2 0
St u d y D a y
Wit hi n 2 8 d a ys 
pri or t o 
re gistr ati o n
D a y 
1
D a y 2
D a y 
8
D a y 
1 5
D a y
1 6
D a y
1 9
D a y
2 2
D a y 
1
D a y 
2
D a y 
5
D a y 
8
D a y
1 5
Visit Wi n d o w
± 1 
d a y
± 2 
d a ys
± 1 
d a ys
± 2
d a ys
± 2 
d a ys
± 1 
d a y
± 1 
d a y 
± 2
d a ys
± 7
d a ys
P F -0 6 8 0 1 5 9 1 a d mi nistrati o n 1 4
X
X
Be vaciz u ma b - Pf izer a d mi nistrati o n1 4
X
X
X
I njecti o n Site T olera bilit y 
Assess me nt 1 5
X  
X ( C 1 
o nl y)
X
A s cli nic ally i n dic ate d
I n patie nt M o nit ori n g1 6
◄--► 
◄--►
X
X
Ot her Cli nic al Assess me nts
A d verse E ve nt Re p orti n g 1 7
◄---------------------------------------------------------------------------------------------------------------------------------------------------------------►
C o nc o mita nt Me dicati o ns/ Treat me nts 1 8
◄----------------------------------------------------------------------------------------------- -------------------------------►
Dise ase Assess me nts 2 1
C T/ M RI Sca ns of C hest, A b d o me n, 
Pel vis, a n y cli nicall y i n dicate d sites of 
disease, a n d of b o ne lesi o ns; Cli nical 
e val uati o n of s u perficial disease 
X
Perf or me d e ver y 8 wee ks fr o m C 1 D 1 ( ± 7 da ys) f or t he first 6 m o nt hs, e ver y 1 2 wee ks 
( ± 7 da ys) f or t he ne xt 1 8 m o nt hs, a n d e ver y 4 m o nt hs t hereafter.
X
C E A Assess me nt 2 2
X  
X
X
X
N otes: Visit wi n d o ws are calc ulate d fr o m t he first da y of  eac h c ycle. Assess me nts t hat a p pear as ( X) are o pti o nal.
1 Scree ni n g : t o be o btai ne d wit hi n 2 8 da ys pri or t o re gistrati o n.
2 I nf or me d C o nse 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. Ma y be o btai ne d m ore t ha n 2 8 da ys pri or t o re gistrati o n.
3 C o m plete P h ysic al E x a m i n 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 is perf or me d wit hi n 3 da ys of d osi n g, i ncl u di n g assess me nt of wei g ht . Brief P h ysic al 
E x a m i n ati o n i ncl u di n g Baseli ne Si g ns a n d S y m pt o ms: A s y m pt o m directe d e xa m a n d assess me nt f or e mer ge nt t o xicities or c ha n ges fr o m pri or visits ( See Secti o n 8. 1. 1 ), d oes n ot 
nee d t o be re peate d if d o ne wit hi n 2 4 h o urs of C 1 D 1.
4 Vit al Si g ns: I ncl u des te m perat ure ( oral, t y m pa nic, te m p oral or a xillar y), b o d y wei g ht, B P, a n d p ulse rate to be rec or de d i n a se mis u pi ne or seate d p ositi o n. O n eac h d osi n g da y, 
vitals s h o ul d be meas ure d pri or t o t he P F - 0 7 0 6 2 1 1 9 i njecti o n or i nf usi o n. I n a d diti o n, p ulse o xi metr y is t o be rec or de d o n d osi n g da ys pri or t o t he P F-0 7 0 6 2 1 1 9 i njecti o n or 
i nf usi o n as p art of t he vital si g n e val uati o n.
5 Perf or m a nce St at us: Use E C O G.
6 Tri plic ate 1 2 -Le a d E C G: Tri plicate E C Gs t o be c ollecte d i n C ycle 1 o n Da y 1, 2 ( partici pa nts i n Part 1 A a n d 1 B o nl y), 8, a n d 1 5 a n d o n Da y 1 of C ycle s 2, 3, 4 a n d 5.
A d diti o nall y, i n C ycle 4 o nl y, E C Gs will be c ollecte d o n Da y 2, 5, 8, a n d 1 5, c oi nci di n g wit h t he P K sa m ple c ollecti o n. F oll o wi n g C ycle 5, E C Gs will be ta ke n o n Da y 1 of e ver y 
3r d c ycle o nl y (ie, C ycle 5 Da y 1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc). A d diti o nal E C Gs s h o ul d be c ollecte d as cli nicall y i n dicate d, at t he discreti o n of t he i n vesti gat or. At eac h 
ti me p oi nt 3 c o nsec uti ve 1 2 -lea d E C Gs will be 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. W he n c oi nci di n g wit h bl o o d sa m ple c ollecti o ns f or P K, E C G 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1
T a ble 2 . 
Sc he d ule of Acti vities f or P art 1 A, P art 1 B, a n d P art 2 Wit h Pri mi n g D ose
Pr ot oc ol Acti vit y
Scree ni n g 1
Acti ve Tre at me nt P h ase ( 1 C ycle = 2 8 d a ys)
C ycle 1
C ycles ≥2
E n d of 
Tre at me nt/ 
Wit h dr a w al
1 9
P ost -Tre at me nt 
F oll o w -U p 2 0
St u d y D a y
Wit hi n 2 8 d a ys 
pri or t o 
re gistr ati o n
D a y 
1
D a y 2
D a y 
8
D a y 
1 5
D a y
1 6
D a y
1 9
D a y
2 2
D a y 
1
D a y 
2
D a y 
5
D a y 
8
D a y
1 5
Visit Wi n d o w
± 1 
d a y
± 2 
d a ys
± 1 
d a ys
± 2
d a ys
± 2 
d a ys
± 1 
d a y
± 1 
d a y 
± 2
d a ys
± 7
d a ys
assess me nt s h o ul d be perf or me d pri or t o bl o o d sa m ple c ollecti o n, s uc h t hat t he bl o o d sa m ple is c ollecte d at t he n o mi nal ti me. If t he mea n Q Tc F is pr ol o n ge d ( > 5 0 0 msec), t he 
E C Gs s h o ul d be re -e val uate d b y a q ualifie d pers o n at t he i nstit uti o n f o r c o nfir mati o n.
7 U ni q ue Scree ni n g/ Vir al Dise ase L a b or at or y Tests: He patitis B s urface a nti ge n, he patitis B c ore a nti b o d y, he patitis C a nti b o d y a n d HI V or AI D S as well as F S H f or 
p ost me n o pa usal w o me n w h o are a me n orr h oeic f or at least 1 2 c o nsec uti ve m o nt hs o nl y. Sa m ples will be a nal yze d l ocall y.
8 He m at ol o g y: N o nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 7 da ys of d osi n g. Assess me nts perf or me d at all s u bse q ue nt d osi n g visits s h o ul d be o btai ne d 
wit hi n 4 8 h o urs pri or t o d osi n g. He mat ol o g y assess me nt f oll o wi n g c ycle 1 (e g, C 1 D 2 9 or C 1 D 3 0) s h o ul d be c ollecte d a n d re vie we d pri or t o d osi n g o n C 2 D 1. Sa m ples will be 
a nal yze d l ocall y. A c o m plete list of he mat ol o g y la bs ca n be f o u n d i n A p pe n di x 2 .
9 Bl o o d C he mistr y:
A c o m plete list of bl o o d c he mistr y la bs ca n be f o u n d i n A p pe n di x 2 . Meas ure me nt of C R P n ot re q uire d after C 2 D 1 if wit hi n n or mal ra n ge or si milar t o 
baseli ne le vels; h o we ver, C R P s h o ul d be meas ure d a n yti me c yt o ki ne release s y n dr o me is s us pecte d a n d n ot alrea d y sc he d ule d t o be meas ure d (e g, C ycle 2). N o nee d t o re peat o n 
C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 7 da ys pri or t o d osi n g. Assess me nts perf or me d at all s u bse q ue nt d osi n g visits s h o ul d be o btai ne d wit hi n 4 8 h o urs pri or t o d osi n g. 
Bl o o d c he mistr y assess me nt f oll o wi n g C ycle 1 (e g, C 1 D 2 9 or C 1 D 3 0) s h o ul d be c ollecte d a n d re vie we d pri or t o d osi n g o n C 2 D 1. Sa m ples will be a nal yze d l ocall y.
1 0 C o a g ul ati o n: A c o m plete list of c oa g ulati o n la bs ca n be f o u n d i n A p pe n di x 2 . N o nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 7 da ys of d osi n g. Sa m ples 
will be a nal yze d l ocall y.
1 1 Uri n al ysis: Di pstic k is acce pta ble. Micr osc o pic a nal yses if di pstic k a b n or mal. N o nee d t o re peat o n C 1 D 1 if baseli ne assess me nt perf or me d wit hi n 7 da ys of d osi n g, wit h t he 
e xce pti o n of partici pa nts w h o are recei vi n g be vaciz u ma b -Pf izer w h o will re q uire uri nal ysis ( di pstic k is acce pta ble) pri or t o e ver y d ose of be vaciz u ma b-Pf izer. Sa m p les will be 
a nal yze d l ocall y. Uri nal ysis ( di pstic k is acce pta ble) assess me nt is re q uire d pri or t o e ver y be vaciz u ma b-Pf izer d ose t hr o u g h o ut t he c o urse of t he st u d y. If uri nal ysis de m o nstrates 
pr otei n greater t ha n or e q ual t o 2 +, t he n a 2 4 -h o ur ur i ne pr otei n c ollecti o n s h o ul d f oll o w. I n partici pa nts wit h pr otei n uria greater t ha n or e q ual t o 2 gra ms per 2 4 h o urs, 
be vaciz u ma b -Pf izer s h o ul d be hel d u ntil rec o ver y (less t ha n 2 gra ms per 2 4 h o urs). Disc o nti n ue be vaciz u ma b-Pf izer i n partici pa nts t hat de vel o p ne p hr otic s y n dr o me.
1 2 Pre g n a nc y Test: F or fe male partici pa nts of c hil d beari n g p ote ntial, a ser u m or uri ne pre g na nc y test, wit h se nsiti vit y of at least 2 5 mI U/ m L will be perf or me d o n 2 occasi o ns 
pri or t o starti n g st u d y treat me nt – o nce at t he start of scree ni n g a n d o nce o n C 1 D 1 i m me diatel y bef ore a d mi nistrati o n of st u d y i nter ve nti o n ( wit hi n 2 4 h o urs pri or t o C 1 D 1 d osi n g). 
Pre g na nc y tests will als o be r o uti nel y re peate d at e ver y ot her c ycle d uri n g t he acti ve treat me nt peri o d f oll o wi n g C 1 D 1 a n d C 2 D 1, at t he e n d of st u d y treat me nt a n d a d diti o nal 
w he ne ver o ne me nstr ual c ycle is misse d or w he n p ote ntial pre g na nc y is ot her wise s us pecte d. D uri n g f oll o w -u p, a pre g na nc y test is o nl y re q uire d 3 0, 9 0 a n d 1 8 0 da ys after E O T f or 
partici pa nts w h o recei ve P F -0 6 8 0 1 5 9 1. A d diti o nal pre g na nc y tests ma y als o be u n derta ke n if re q ueste d b y I R B or if re q uire d b y l ocal re g ulati o ns.
1 3 Re gistr ati o n: Partici pa nt e nr oll me nt n u m ber a n d d ose le vel all ocati o n pr o vi de d b y Pfizer I nc. Re gistrati o n s h o ul d occ ur bef ore a n y ot her Da y 1 acti vities ar e perf or me d.
1 4 St u d y Tre at me nt: P F -0 7 0 6 2 1 1 9 will be a d mi nistere d o nce e ver y 1 4 da ys as a n S C i njecti o n. A pri mi n g d ose will be a d mi nistere d o n C 1 D 1 f oll o we d b y a f ull d ose o n C 1 D 1 5 
a n d Q 2 W t hereafter.  See Secti o n 4. 1. 1. 2 f or p ote ntial c ha n ges t o t he pri mi n g d ose re gi me n (e g, ste p-u p d osi n g strate g y).  P F - 0 6 8 0 1 5 9 1 will be a d mi nistere d o nce e ver y 2 8-da y 
c ycle as a n S C i njecti o n be gi n ni n g o n C 1 D 1 5 of Part 1 B. Be vaciz u m a b -Pf izer or t he bi osi milar versi o n of A vasti n® , ma n ufact ure d b y Pfizer a n d hereafter referre d t o as 
be vaciz u ma b -Pf izer will be use d f or t his st u d y a n d a d mi nistere d o nce e ver y 1 4 da ys as I V i nf usi o n be gi n ni n g o n C 1 D 1 5 of Part 1 B. See Secti o n 6. 1. 1 of t he pr ot oc ol f or 
a d mi nistrati o n i nf or mati o n. Partici pa nts pla n ne d t o recei ve P F -0 7 0 6 2 1 1 9 i n c o m bi nat i o n wit h be vaciz u ma b-Pf izer s h o ul d be wei g he d wit hi n 7 2 h o urs pri or t o d osi n g f or e ver y 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2
T a ble 2 . 
Sc he d ule of Acti vities f or P art 1 A, P art 1 B, a n d P art 2 Wit h Pri mi n g D ose
Pr ot oc ol Acti vit y
Scree ni n g 1
Acti ve Tre at me nt P h ase ( 1 C ycle = 2 8 d a ys)
C ycle 1
C ycles ≥2
E n d of 
Tre at me nt/ 
Wit h dr a w al
1 9
P ost -Tre at me nt 
F oll o w -U p 2 0
St u d y D a y
Wit hi n 2 8 d a ys 
pri or t o 
re gistr ati o n
D a y 
1
D a y 2
D a y 
8
D a y 
1 5
D a y
1 6
D a y
1 9
D a y
2 2
D a y 
1
D a y 
2
D a y 
5
D a y 
8
D a y
1 5
Visit Wi n d o w
± 1 
d a y
± 2 
d a ys
± 1 
d a ys
± 2
d a ys
± 2 
d a ys
± 1 
d a y
± 1 
d a y 
± 2
d a ys
± 7
d a ys
c ycle t o e ns ure t he y di d n ot e x perie nce eit her a wei g ht l oss or gai n > 1 0 % fr o m t he pri or wei g ht use d t o calc ulate t he a m o u nt of be vaciz u ma b -Pf izer re q uire d f or d ose preparati o n. 
Decisi o n t o recalc ulate be vaciz u ma b -Pf izer d ose base d o n t he wei g ht o btai ne d at eac h c ycle ca n be i n acc or da nce wit h i nstit uti o nal practice, h o we ver if t he partici pa nt e x perie nce d 
eit her a wei g ht l oss or gai n > 1 0 % c o m pare d t o t he wei g ht use d t o c alc ulate eit her t he i nitial or pre vi o us d ose, t he a m o u nt of be vaciz u ma b -Pf izer re q uire d f or pre parati o n a n d 
a d mi nistrati o n f or t he c urre nt c ycle m ust be recalc ulate d usi n g t his m ost rece nt wei g ht o btai ne d. Partici pa nts i n Part 2 will be o bser ve d f or at lea st 2 4 h o urs after t he first S C d ose. 
Partici pa nts ma y o nl y be release d after t he i n vesti gat or has c o nfir me d t he partici pa nt has n ot e x hi bite d si g ns of c yt o ki ne re lease s y n dr o me.
1 5 I njecti o n Site T oler a bilit y Assess me nt: Assess me nt of eac h i njecti o n s h o ul d be c o n d ucte d f or at least 1 h o ur f oll o wi n g eac h treat me nt a d mi nistrati o n i n C ycle 1. I n a d diti o n, 
a n assess me nt s h o ul d be perf or me d 2 4 h o urs ( ± 1 h o ur) after t he C 1 D 1 d ose. I njecti o n site t olera bilit y assess me nts s h o ul d c o nt i n ue after eac h d osi n g visit i n C ycle 2 a n d be y o n d, 
o nl y if i njecti o n site pai n or I S R c haracteristics c o nti n ue t o persist. T he assess me nts s h o ul d c o nti n ue at re g ularl y sc he d ule d visits u ntil t he s y m pt o ms res ol ve. All fi n di n gs s h o ul d 
be rec or de d o n t he i njecti o n site reacti o n C R F. See Se cti o n 8. 1. 7 f or m ore details.
1 6 I n p atie nt M o nit ori n g: Partici pa nts recei vi n g P F -0 7 0 6 2 1 1 9 S C will be a d mitte d f or i n patie nt m o nit ori n g f or at least 2 4 h o urs f oll o wi n g t he first a d mi nistrati o n of st u d y 
treat me nt ( C 1 D 1) a n d f or at least 2 4 h o urs f oll o wi n g t he sec o n d a d mi nistrati o n of st u d y treat me nt ( C 1 D 1 5). Partici pa nts s h o uld re mai n i n h o use f or o bser vati o n f or at least 1- h o ur 
p ost d ose f or all visits after C 1 D 1 f or Pa rts 1 A a n d 1 B; i n patie nt m o nit ori n g after C 1 f or Part 2 is at t he i n vesti gat or’s discreti o n. Partici pa nts ma y be release d o nly after t he 
i n vesti gat or has c o nfir me d t he partici pa nt has n ot e x hi bite d si g ns of a c yt o ki ne reacti o n. Partici pa nts s h o ul d c o m plete t he re q uire d st u d y s pecific la b orat or y assess me nts as detaile d 
i n t he Sc he d ule of P har mac o ki netic, P har mac o d y na mic, a n d I m m u n o ge nicit y Assess me nts f or Parts 1 A a n d 1 B w here P F- 0 7 0 6 2 1 1 9 will be a d mi nistere d S C a n d s h o ul d be 
m o nit ore d per l ocal sta n dar d pra ctice f or i n patie nt  m o nit ori n g.
1 7 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 usi n g t he N CI C T C A E versi o n 5. 0. Partici pa nts m ust be f oll o we d f or A Es f o r 2 8 da ys after t he last 
st u d y treat me nt a d mi nistrati o n or u ntil all dr u g-relate d t o xicities ha ve res ol ve d, w hic he ver is later; or earlier t ha n 2 8 da ys s h o ul d t he partici pa nt c o m me nce a n ot her a ntica ncer 
t hera p y i n t he mea nti me. F or S A Es, t he acti ve re p orti n g peri o d t o Pfizer or its desi g nate d re prese ntati ve be gi ns fr o m t he ti me t hat t he partici pa nt pr o vi des i nf or me d c o nse nt, w hic h 
is o btai ne d pri or t o t he partici pa nt’s partici pati o n i n t he st u d y, ie, pri or t o 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 2 8 
cale n dar da ys after t he last st u d y treat me nt a d mi nistrati o n. S A Es occ urri n g t o a partici pa nt after t he acti ve re p orti n g peri o d has e n de d s h o ul d be re p orte d t o t he s p o ns or if t he 
i n vesti gat or bec o mes a ware of t he m; at a mi ni m u m, all S A Es t hat t he i n vesti gat or belie ves ha ve at least a reas o na ble p ossi bilit y of bei n g relate d t o st u d y i nter ve nti o n are t o be 
re p orte d t o t he s p o ns or.
1 8 C o nc o mit a nt Tre at me nts: All c o nc o mita nt me dicati o ns s h o ul d be rec or de d i n t he C R F i ncl u di n g s u p p orti ve care dr u gs (e g, a nti -e metic treat me nt a n d pr o ph yla xis), a n d t he 
dr u gs use d t o treat a d verse e ve nts or c hr o nic diseases, a n d n o n- dr u g s u p p orti ve i nter ve nti o ns (e g, tra nsf usi o ns).
1 9 E O T / Wit h dr a w al: O btai n t hese assess me nts if n ot c o m plete d i n t he last wee k (last 6 wee ks f or t u m or assess me nts).
2 0 F oll o w -U p: At least 2 8 da ys, a n d n o m ore t ha n 3 5 da ys, after disc o nti n uati o n of treat me nt, all partici pa nts will ret ur n t o o btai n t hese assess me nts as well as a n e val uate t he
res ol uti o n of a n y treat me nt-relate d t o xicit y. Partici pa nts w h o recei ve P F-0 6 8 0 1 5 9 1 wi ll als o ret ur n f or f oll o w-u p assess me nts 3 0, 9 0 a n d 1 8 0 da ys after treat me nt disc o nti n uati o n. 
Partici pa nts c o nti n ui n g t o e x perie nce t o xicit y 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 o l 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. Partici pa nts wit h a n u n res ol ve d A E p ossi bl y relate d t o A D A will be as ke d t o 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3
T a ble 2 . 
Sc he d ule of Acti vities f or P art 1 A, P art 1 B, a n d P art 2 Wit h Pri mi n g D ose
Pr ot oc ol Acti vit y
Scree ni n g 1
Acti ve Tre at me nt P h ase ( 1 C ycle = 2 8 d a ys)
C ycle 1
C ycles ≥2
E n d of 
Tre at me nt/ 
Wit h dr a w al
1 9
P ost -Tre at me nt 
F oll o w -U p 2 0
St u d y D a y
Wit hi n 2 8 d a ys 
pri or t o 
re gistr ati o n
D a y 
1
D a y 2
D a y 
8
D a y 
1 5
D a y
1 6
D a y
1 9
D a y
2 2
D a y 
1
D a y 
2
D a y 
5
D a y 
8
D a y
1 5
Visit Wi n d o w
± 1 
d a y
± 2 
d a ys
± 1 
d a ys
± 2
d a ys
± 2 
d a ys
± 1 
d a y
± 1 
d a y 
± 2
d a ys
± 7
d a ys
ret ur n t o t he cli nic f or A D A/ NA b a n d dr u g c o nce ntrati o n assess me nts at a p pr o xi matel y 3 - m o nt h i nter vals u ntil t he 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 s p o ns or u p t o a ma xi m u m of 9 m o nt hs. S u bse q ue nt t o t he F oll o w-U p visit, partici pa nts s h o ul d be c o ntacte d b y tele p h o ne e ver y 8 wee ks ( ± 7 d a y s) t o o btai n 
i nf or mati o n o n s u bse q ue nt a nti-ca ncer treat me nt a n d o verall s ur vi val f or u p t o t w o years fr o m t he date of ra n d o mizati o n.
2 1 T u m or Assess me nts: 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 ma y i ncl u de c hest, a b d o me n a n d pel vis C T or M RI sca ns or e q ui vale nt. 
T he sa me m o dalit y s h o ul d be c o m plete d, if p ossi ble t hr o u g h o ut t he st u d y. B o ne sca ns will be perf or me d at baseli ne if disease is s us pecte d a n d o n st u d y as a p pr o priate t o f oll o w 
disease. Baseli ne C N S i ma gi n g is n ot re q uire d wit h t he e xce pti o n of s y m pt o matic partici pa nts t o r ule o ut C N S metastases; partici pa nt i neli gi ble if p ositi ve f or ne w C N S 
metastases, pre vi o usl y treate d C N S metastases are all o we d as o utli ne d e xcl usi o n criteria. C T or M RI sca ns t o be d o ne as o utli ne d i n t he Sc he d ule of Acti vities ( S O A ) u ntil disease 
pr o gressi o n b y ir R E CI S T or deat h, or u ntil per ma ne nt disc o nti n uati o n of st u d y treat me nt. Res p o nse ( C R , P R) a n d disease pr o gressi o n will be c o nfir me d wit h 2 c o nse c uti ve 
ti me p oi nts at least 4 wee ks a part (i n t he a bse nce of ra pi d cli nical deteri orati o n f or pr o gressi o n). T u m or assess me nts s h o ul d be fi xe d acc or di n g t o t he cale n dar, re gar dless of 
treat me nt dela ys. T u m or assess me nts s h o ul d be re peate d at t he E n d of Treatme nt visit if m ore t ha n 6 wee ks ha ve passe d si nce t he last e val uati o n.
2 2 C E A Assess me nts : Perf or me d o n Da y 1 of eac h C ycle f or u p t o 1 year. After 1 year, perf or m e ver y 4 m o nt hs t hereafter.
2 3 Pre m e dic ati o n: A p pr o xi matel y 1 h o ur pri or t o P F-0 7 0 6 2 1 1 9 d osi n g d uri n g C ycle 1 o nl y, a d mi nister pre me dicati o n as f oll o ws: aceta mi n o p he n 6 5 0 m g ( or e q ui vale nt), oral; 
di p he n h y dra mi ne 2 5 m g, oral or I V; de xa met has o ne 1 2 m g ( or e q ui vale nt), oral or I V. I n a d diti o n, pre me dicati o n be y o n d t he 1st f ull d ose a n d m o dificati o ns t o t he pre me dicati o n 
re gi me n (e g, fre q ue nc y of pre me dicati o n, d oses of i n di vi d ual a ge nts, re m o val or a d diti o n of a ge nts) ma y be i m ple me nte d b y t he s p o ns or base d o n e mer gi n g data. A n y e xce pti o ns 
t o pre me dicati o n re q uire disc ussi o n a n d a gree me nt bet wee n t he s p o ns or a n d i n vesti gat or. 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 4
T a ble 3 .
Sc he d ule of P h ar m ac o ki netic, P h ar m ac o d y n a mic, a n d I m m u n o ge nicit y Assess me nts f or P art 1 A a n d P art 1 B 
Wit h o ut Pri mi n g D ose
Visit I de ntifier 
Scree ni n g
C ycle 1
C ycle ≥2
St u d y D a y
Wit hi n 
2 8 d a ys 
pri or t o 
re gistr ati o n
1
2
3
5
8
1 5
2 2
1
2
5
8
1 5
E n d of 
Tre at me nt/
Wit h dr a w al
H o urs Pre -/ P ost-D ose 1
0 2
4
8
2 4
4 8
9 6
1 6 8
0
8 
( P art 
1 B 
o nl y)
1 6 8
0
2 4
9 6
1 6 8
0
Visit wi n d o w 
± 0. 5 hr ± 1 hr
± 3 hrs
± 6 hrs
± 2 4 hrs ± 2 4 hrs
± 1 hr ± 4 8 hrs
± 3 hrs
± 2 4 
hrs
± 2 4 hrs
P har mac o ki netic sa m ples
Bl o o d sa m ples f or 
P F - 0 7 0 6 2 1 1 9 
c o nce ntrati o ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
( C 4 o nl y)
X 1
( C 4 
o nl y)
X
( C 4 
o nl y)
X
X
Bl o o d sa m ples f or 
A D A/ N A b a gai nst 
P F -0 7 0 6 2 1 1 9 3
X
X
X 3
X
Bl o o d sa m ples f or 
P K/ A D A/ N A b a gai nst 
P F -0 6 8 0 1 5 9 1 3
X
X
X 3
X
Bl o o d sa m ples f or 
P K/ A D A/ N A b a gai nst 
be vaciz u ma b -Pf izer3
X
X
X 3
X
P har mac o d y na mic sa m ples
Pf izer Pre p D 1 ba n ke d 
sa m ple4
X
Arc hi val T u m or 
Sa m ple 5
X
O pti o nal or Ma n dat or y 
De N o v o Pre -treat me nt 
bi o ps y 5 ,6
X
O pti o nal or Ma n dat or y 
O n -Treat me nt T u m or 
Bi o ps y 6
X 
C 3 o nl y
( ± 7 
da ys)
X                
( or 2n d o n 
treat me nt)
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 5
T a ble 3 .
Sc he d ule of P h ar m ac o ki netic, P h ar m ac o d y n a mic, a n d I m m u n o ge nicit y Assess me nts f or P art 1 A a n d P art 1 B 
Wit h o ut Pri mi n g D ose
Visit I de ntifier 
Scree ni n g
C ycle 1
C ycle ≥2
St u d y D a y
Wit hi n 
2 8 d a ys 
pri or t o 
re gistr ati o n
1
2
3
5
8
1 5
2 2
1
2
5
8
1 5
E n d of 
Tre at me nt/
Wit h dr a w al
H o urs Pre -/ P ost-D ose 1
0 2
4
8
2 4
4 8
9 6
1 6 8
0
8 
( P art 
1 B 
o nl y)
1 6 8
0
2 4
9 6
1 6 8
0
Visit wi n d o w 
± 0. 5 hr ± 1 hr
± 3 hrs
± 6 hrs
± 2 4 hrs ± 2 4 hrs
± 1 hr ± 4 8 hrs
± 3 hrs
± 2 4 
hrs
± 2 4 hrs
Bl o o d sa m ple f or T cell 
I m m u n o p he n ot y pi n g7
X
X  
X  
X  
X  
X  
X  
X 7
X ( C 2 a n d C 3 
o nl y)
Bl o o d (ser u m) sa m ple 
f or C yt o ki nes & 
Circ ulati n g Mar kers 8
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 7
X ( C 2 a n d C 3 
o nl y)
1 Sa m pli n g ti mes i n dicate d are relate d t o t he e n d of t he S C i njecti o n. All eff orts s h o ul d be ma de t o o btai n t he P K sa m ples at t he e xact n o mi nal ti me relati ve t o d osi n g. H o we ver, 
sa m ples o btai ne d wit hi n t he wi n d o w s pecifie d will be c o nsi dere d acce pta ble. Starti n g C ycle 5, pre d ose P K sa m ples will be c ollecte d o nl y o n Da y 1 of e ver y 3 r d c ycle ( C ycle 5 
Da y 1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc.). A d di ti o n al P K/ P D s a m ples s h o ul d als o be t a ke n if C R S is s us pecte d, a n d P K/ P D s a m ples are n ot alre a d y sc he d ule d t o be 
t a ke n. 
2 T he 0 -h o ur P K a n d A D A/ N A b sa m ples s h o ul d be ta ke n wit hi n 6 h o urs pri or t o P F - 0 7 0 6 2 1 1 9 a d mi nistrati o n.
3 Bl o o d s a m ples f or P F -0 7 0 6 2 1 1 9 , P F-0 6 8 0 1 5 9 1, a n d be v aciz u m a b -Pfizer i m m u n o ge nicit y testi n g a n d P F -0 6 8 0 1 5 9 1, a n d be v aciz u m a b -Pfizer P K: Bl o o d sa m ples f or 
P F -0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer will o nl y be c ollecte d i n partici pa nts recei vi n g c o m bi nati o n t hera p y (ie, P art 1 B): Refer t o Secti o n 8. 4 f or details. A bl o o d sa m ple f or 
P F -0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer P K a nal yses s h o ul d be dra w n wit h eac h i m m u n o ge nicit y sa m ple f or P F-0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer, res pecti vel y. All sa m ples s h o ul d 
be c ollecte d o n Da y 1 of a c ycle ( als o o n D a y 1 5, i n C ycle 1 o nl y ) a n d will be dra w n pre d ose - wit hi n 6 h o urs pri or t o a n y of t he dr u gs bei n g a d mi nistere d. Starti n g at C ycle 5, 
bl o o d sa m ples f or P K a n d A D A/ N A b a gai nst P F -0 7 0 6 2 1 1 9 (a n d P F -0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer i n Part 1 B) will be c ollecte d e ver y 3r d c ycle pre d ose (ie, C ycle 5 Da y 1, 
C y cle 8 Da y 1, C ycle 1 1 Da y 1, etc.). Partici pa nts wit h a n u nres ol ve d A E p ossi bl y relate d t o A D A will be as ke d t o r et ur n t o t he cli nic f or A D A a n d dr u g c o nce ntrati o n 
assess me nts at a p pr o xi matel y 3 - m o nt h i nter vals u ntil t he 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 s p o ns or u p t o a ma xi m u m of 9 m o nt hs.
4 Pfizer Pre p D 1 B a n ke d S a m ple: If n ot c ollecte d o n t he desi g nate d c ollecti o n da y, c ollect at t he ne xt a vaila ble ti me p oi nt w he n bi os peci me ns are bei n g c ollecte d i n c o nj u ncti o n 
wit h a partici pa nt visit.
5 T u m or Tiss ue S a m ples: Partici pa nts e nr olle d i n Part 1 A, a n d Part 1 B of t his st u d y will pr o vi de eit her a n arc hi val f or mali n-fi xe d paraffi n e m be d de d material c o ntai ni n g t u m or 
t hat is of dia g n ostic q ualit y a n d re prese ntati ve of t heir dia g n ose d mali g na nc y or prefera bl y a de n o v o pre-treat me nt bi o ps y. If t he arc hi val t u m or is n ot a vaila ble, partici pa nts m ust 
pr o vi de a de n o v o  pre -treat me nt bi o ps y f or e val uati o n of baseli ne tiss ue bi o mar kers ( prefera bl y c ollecte d wit hi n 2 8 da ys of st u d y start). O n-treat me nt bi o ps y sa m ples c ollecte d 
prefera bl y after t he t hir d d ose a n d wit hi n 7 da ys of C 3 D 1 are o pti o nal f or partici pa nts e nr olle d i n eac h c o h ort i n Part 1 A a n d Part 1 B f or e val uati o n of tiss ue bi o mar ker 
m o d ulati o ns d uri n g treat me nt . If o n tre at me nt t u m or c ollecti o n t a kes pl ace gre ater t h a n ± 3 d a ys fr o m C 3 D 1, a d diti o n al u nsc he d ule d bl o o d s a m ple f or c yt o ki ne a n d 
circ ul ati n g m ar kers a n d a n u nsc he d ule d bl o o d s a m ple f or T cell i m m u n o p he n ot y pi n g s a m ple s h o ul d be c ollecte d t o m atc h t he d a y of bi o ps y c ollecti o n. S pecific tiss ue 
re q uire me nts a n d i nstr ucti o ns are liste d i n Bi o mar ker Secti o n 8. 8 .
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 6
T a ble 3 .
Sc he d ule of P h ar m ac o ki netic, P h ar m ac o d y n a mic, a n d I m m u n o ge nicit y Assess me nts f or P art 1 A a n d P art 1 B 
Wit h o ut Pri mi n g D ose
Visit I de ntifier 
Scree ni n g
C ycle 1
C ycle ≥2
St u d y D a y
Wit hi n 
2 8 d a ys 
pri or t o 
re gistr ati o n
1
2
3
5
8
1 5
2 2
1
2
5
8
1 5
E n d of 
Tre at me nt/
Wit h dr a w al
H o urs Pre -/ P ost-D ose 1
0 2
4
8
2 4
4 8
9 6
1 6 8
0
8 
( P art 
1 B 
o nl y)
1 6 8
0
2 4
9 6
1 6 8
0
Visit wi n d o w 
± 0. 5 hr ± 1 hr
± 3 hrs
± 6 hrs
± 2 4 hrs ± 2 4 hrs
± 1 hr ± 4 8 hrs
± 3 hrs
± 2 4 
hrs
± 2 4 hrs
6 P aire d T u m or S a m ples : As t he R P 2 D/ M T D is a p pr oac he d or t he R P 2 D/ M T D of P F-0 7 0 6 2 1 1 9 has bee n deter mi ne d, a n o pti o nal s u bset of partici pa nts ma y be e nr olle d 
(a p pr o xi matel y 6-1 2 partici pa nts) wit h t he re q uire me nt of pr o vi di n g ma n dat or y paire d de n o v o pretreat me nt a n d o n treat me nt bi o ps y sa m ples i n P arts 1 A a n d 1 B t o e na ble 
e val uati o n of tiss ue bi o mar ker P D acti vit y. T he o pti o n t o e nr oll t he s u bset of partici pa nts f or ma n dat or y paire d t u m or sa m ples will be base d o n e val uati o n of e mer gi n g cli nical 
data (i ncl u di n g a vaila ble safet y/t olera bilit y, P K, a n d P D fi n di n gs) b y t he s p o ns or. De n o v o pre -treat me nt a n d o n-treat me nt bi o psies s h o ul d be ta ke n fr o m t he sa me lesi o n, n ot 
pre vi o usl y irra diate d, if p ossi ble. De n o v o pre -treat me nt bi o psies s h o ul d be prefera bl y c ollecte d wit hi n 2 8 da ys of st u d y start after all eli gi bilit y criteria ha ve bee n verifie d. 
O n -treat me nt bi o ps y sa m ples are t o be collecte d prefera bl y after t he 3r d d ose a n d wit hi n 7 da ys of C 3 D 1. If o n tre at me nt t u m or c ollecti o n t a kes pl ace gre ater t h a n ± 3 d a ys 
fr o m C 3 D 1, a d diti o n al u nsc he d ule d bl o o d s a m ple f or c yt o ki ne a n d circ ul ati n g m ar kers a n d a n u nsc he d ule d bl o o d s a m ple f or T cell i m m u n o p he n ot y pi n g s h o ul d be 
c ollecte d t o m atc h t he d a y of bi o ps y c ollecti o n. A d diti o nal u nsc he d ule d o n -treat me nt bi o psies, after C 4 D 1 5 ( > 6 wee ks after i nitial o n treat me nt bi o ps y) ma y be c ollecte d, if 
i n dicate d t o e val uate p ote ntial res p o nses t o treat ment or s us pecte d ac q uire d resista nce t o t hera p y a n d a gree d u p o n b y t he s p o ns or a n d i n vesti gat or a n d a gree d t o b y t he partici pa nt. 
If t he partici pa nt disc o nti n ues t he st u d y bef ore t he sc he d ule d o n-treat me nt bi o ps y ( C 3 D 1), t he partici pa nt will be as ke d t o pr o vi de a bi o ps y at t he E n d of Treat me nt visit. S pecific 
tiss ue re q uire me nts a n d i nstr ucti o ns are liste d i n Bi o mar ker Secti o n 8. 8 .
7 Bl o o d s a m ple f or T cell I m m u n o p he n ot y pi n g : O ne 5 m L bl o o d sa m ple will be c ollecte d f or i m m u n o p he n ot y pe circ ulati n g l y m p h oc ytes at baseli ne ( pre d ose C ycle 1 Da y 1), 
a n d d uri n g treat me nt as descri be d a b o ve t o e val uate c ha n ges fr o m baseli ne. If Gra de ≥1 c yt o ki ne release s y n dr o me is s us pecte d, a d diti o nal u nsc he d ule d sa m ples s h o ul d be 
c ollecte d. If Gra de ≥2 diarr hea is o bser ve d or s us pecte d a n d P D sa m ples are n ot alrea d y sc he d ule d f or meas ure me nt t his sa m ple s h o ul d be c ollecte d. Starti n g wit h C ycle 5, bl o o d 
will be c ollecte d e ver y 3 r d c ycle pre d ose ( ie., C ycle 5 Da y 1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc.) (Secti o n 8. 8. 5 ).
8 Bl o o d S a m ple f or C yt o ki nes a n d Circ ul ati n g M ar kers (ce ntr al l a b): F or ce ntral la b orat or y testi n g, o ne 5 m L bl o o d sa m ple will be c ollecte d t o is olate ser u m f or c yt o ki ne a n d 
circ ulati n g mar ker meas ure me nt. Baseli ne c ollecti o n is re q uire d pre d ose o n C ycle 1 Da y 1. O n -treat me nt sa m ples f or c yt o ki ne a n d circ ulati n g mar ker meas ure me nt will be 
c ollecte d as descri be d a b o ve. T hese sa m ples will be use d t o e val uate c ha n ges fr o m baseli ne. If Gra de ≥1 c yt o ki ne release s y n d r o me is s us pecte d, a d diti o nal u nsc he d ule d sa m ples 
s h o ul d be c ollecte d t o matc h cli nicall y i n dicate d safet y c yt o ki ne sa m ples. If Gra de ≥2 diarr hea is o bser ve d or s us pecte d a n d P D sa m ples are n ot alrea d y sc he d ule d f or 
meas ure me nt t his sa m ple s h o ul d be c ollecte d. Starti n g wit h C ycle 5, bl o o d sa m ples f or c yt o ki ne a n d circ ulati n g mar kers will be c ollecte d e ver y 3 r d c ycle pre d ose (ie., C ycle 5 
Da y 1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc.) ( Secti o n 8. 8. 4 ).
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 7
T a ble 4 .
Sc he d ule of P h ar m ac o ki netic, P h ar m ac o d y n a mic, a n d I m m u n o ge nicit y Assess me nts f or P art 1 A a n d P art 1 B Wit h 
Pri mi n g D ose
Visit I de ntifier
Scree ni n g
C ycle 1
C ycle ≥2
St u d y D a y
Wit hi n 
2 8 d a ys 
pri or t o 
re gistr ati o n
1
2
8
1 5
1 6
1 9
2 2
1
2
5
8
1 5
E O T/
Wit h dr a w al
H o urs Pre -/ P ost-D ose 1
0 2
8
2 4
1 6 8
0
4
8 
2 4
9 6
1 6 8
0
2 4
9 6
1 6 8
0
Visit wi n d o w 
± 1 hr
± 3 hrs
± 2 4 hrs
± 0. 5 hr ± 1 hr ± 3 hrs ± 2 4 hrs ± 4 8 hrs
± 3 hrs
± 2 4 hrs ± 2 4 hrs
P har mac o ki netic sa m ples
Bl o o d sa m ples f or 
P F - 0 7 0 6 2 1 1 9 
c o nce ntrati o ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
( C 4 
o nl y)
X 1
( C 4 
o nl y)
X
(C 4 
o nl y)
X  
X
Bl o o d sa m ples f or 
A D A/ N A b a gai nst 
P F -0 7 0 6 2 1 1 9 3
X
X
X 3
X
Bl o o d sa m ples f or 
P K/ A D A/ N A b a gai nst 
P F -0 6 8 0 1 5 9 1 3
X
X 3
X
Bl o o d sa m ples f or 
P K/ A D A/ N A b a gai nst 
be vaciz u ma b -Pf izer3
X
X 3
X
P har mac o d y na mic sa m ples
Pf izer Pre p D 1 ba n ke d 
sa m ple4
X
Arc hi val T u m or Sa m ple 5
X
O pti o nal or Ma n dat or y De 
N o v o Pre -treat me nt 
bi o ps y 5 ,6
X
O pti o nal or Ma n dat or y 
O n -Treat me nt T u m or 
Bi o ps y 6
X C 3 
o nl y
( ± 7 da ys)
X ( or 2 n d o n 
treat me nt)
Bl o o d sa m ple f or T cell 
I m m u n o p he n ot y pi n g7
X
X  
X  
X
X  
X  
X  
X 7
X ( C 2 a n d 
C 3 o nl y)
Bl o o d (ser u m) sa m ple f or 
C y t o ki nes & Circ ulati n g 
Mar kers
8
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 7
X ( C 2 a n d 
C 3 o nl y)
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 8
T a ble 4 .
Sc he d ule of P h ar m ac o ki netic, P h ar m ac o d y n a mic, a n d I m m u n o ge nicit y Assess me nts f or P art 1 A a n d P art 1 B Wit h 
Pri mi n g D ose
Visit I de ntifier
Scree ni n g
C ycle 1
C ycle ≥2
St u d y D a y
Wit hi n 
2 8 d a ys 
pri or t o 
re gistr ati o n
1
2
8
1 5
1 6
1 9
2 2
1
2
5
8
1 5
E O T/
Wit h dr a w al
H o urs Pre -/ P ost-D ose 1
0 2
8
2 4
1 6 8
0
4
8 
2 4
9 6
1 6 8
0
2 4
9 6
1 6 8
0
Visit wi n d o w 
± 1 hr
± 3 hrs
± 2 4 hrs
± 0. 5 hr ± 1 hr ± 3 hrs ± 2 4 hrs ± 4 8 hrs
± 3 hrs
± 2 4 hrs ± 2 4 hrs
1 Sa m pli n g ti mes i n dicate d are relate d t o t he e n d of t he S C i njecti o n. All eff orts s h o ul d be ma de t o o btai n t he P K sa m ples at t he e xact n o mi nal ti me relati ve t o d osi n g. H o we ver, 
sa m ples o btai ne d wit hi n t he wi n d o w s pecifie d will be c o nsi dere d acce pta ble. Starti n g C ycle 5, pre d ose P K sa m ples will be c ollecte d o nl y o n Da y 1 of e ver y 3 r d c ycle ( C ycle 5 Da y 
1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc.). A d diti o n al P K/ P D s a m ples s h o ul d als o be t a ke n if C R S is s us pec te d, a n d P K/ P D s a m ples are n ot alre a d y sc he d ule d t o be t a ke n. 
2 T he 0 -h o ur P K a n d A D A/ N A b sa m ples s h o ul d be ta ke n wit hi n 6 h o urs pri or t o P F - 0 7 0 6 2 1 1 9 a d mi nistrati o n.
3 Bl o o d s a m ples f or P F -0 7 0 6 2 1 1 9, P F -0 6 8 0 1 5 9 1, a n d be v aciz u m a b -Pfizer i m m u n o ge nicit y testi n g a n d P F -0 6 8 0 1 5 9 1, a n d be v aciz u m a b -Pfizer P K: Bl o o d sa m ples f or P F -
0 7 0 6 2 1 1 9 will be c ollecte d i n partici pa nts recei vi n g m o n ot hera p y ( ie, P art 1 A D ose Pri mi n g). Bl o o d sa m ples f or P F -0 7 0 6 2 1 1 9, P F -0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer will be 
c ollecte d i n partici pants recei vi n g c o m bi nati o n t hera p y ( ie, P art 1 B D ose Pri mi n g): Refer t o Secti o n 8. 4 f or details. A bl o o d sa m ple f or P F-0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer P K  
a nal yses s h o ul d be dra w n wit h eac h i m m u n o ge nicit y sa m ple f or P F -0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer, res pecti vel y. All sa m ples f or be vaciz u ma b-Pf izer s h o ul d be c ollecte d o n 
Da y 1 of a c ycle ( e xce pt o n Da y 1 5, i n C ycle 1 o nl y) a n d f or P F-0 6 8 0 1 5 9 1 o n Da y 1 5 of eac h c ycle. Sa m ples will be dra w n pre d ose - wit hi n 6 h o urs pri or t o a n y of t he dr u gs bei n g 
a d mi nistere d. Starti n g at C ycle 5, bl o o d sa m ples f or P K a n d A D A/ N A b a gai nst P F -0 7 0 6 2 1 1 9 (a n d P F -0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer i n Part 1 B) will be c ollecte d e ver y 3r d c ycle 
pre d ose (ie, C ycle 5 Da y 1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc. f or P F-0 7 0 6 2 1 1 9/ be vaciz u ma b -Pf izer a n d C ycle 5 Da y 1 5, C ycle 8 Da y 1 5, C ycle 1 1 Da y 1 5 f or P F- 0 6 8 0 1 5 9 1 ). 
Partici pa nts wit h a n u nres ol ve d A E p ossi bl y relate d t o A D A will be as ke d t o re t ur n t o t he cli nic f or A D A a n d dr u g c o nce ntrati o n assess me nts at a p pr o xi matel y 3-m o nt h i nter vals 
u ntil t he 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 s p o ns or u p t o a ma xi m u m of 9 m o nt hs.
4 Pfizer Pre p D 1 B a n ke d S a m ple: If n ot c ollecte d o n t he desi g nate d c ollecti o n da y, c ollect at t he ne xt a vaila ble ti me p oi nt w he n bi os peci me ns are bei n g c ollecte d i n c o nj u ncti o n 
wit h a partici pa nt visit.
5 T u m or Tiss ue S a m ples: Partici pa nts e nr olle d i n Part 1 A, a n d Part 1 B of t his s t u d y will pr o vi de eit her a n arc hi val f or mali n-fi xe d paraffi n e m be d de d material c o ntai ni n g t u m or 
t hat is of dia g n ostic q ualit y a n d re prese ntati ve of t heir dia g n ose d mali g na nc y or prefera bl y a de n o v o pre-treat me nt bi o ps y. If t he arc hi val t u m or is n ot a vailable, partici pa nts m ust 
pr o vi de a de n o v o  pre -treat me nt bi o ps y f or e val uati o n of baseli ne tiss ue bi o mar kers ( prefera bl y c ollecte d wit hi n 2 8 da ys of st u d y start). O n-treat me nt bi o ps y sa m ples c ollecte d 
prefera bl y after t he t hir d d ose a n d wit hi n 7 da ys of C 3 D 1 are o pti o nal f or partici pa nts e nr olle d i n eac h c o h ort i n Part 1 A a n d Part 1 B f or e val uati o n of tiss ue bi o mar ker m o d ulati o ns
d uri n g treat me nt . If o n tre atme nt t u m or c ollecti o n t a kes pl ace gre ater t h a n ± 3 d a ys fr o m C 3 D 1, a d diti o n al u nsc he d ule d bl o o d s a m ple f or c yt o ki ne a n d circ ul ati n g m ar kers 
a n d a n u nsc he d ule d bl o o d s a m ple f or T cell i m m u n o p he n ot y pi n g s a m ple s h o ul d be c ollecte d t o m atc h t he d a y of bi o ps y c ollecti o n. S pecific tiss ue re q uire me nts a n d 
i nstr ucti o ns are liste d i n Bi o mar ker Secti o n 8. 8 .
6 P aire d T u m or S a m ples : As t he R P 2 D/ M T D is a p pr oac he d or t he R P 2 D/ M T D of P F- 0 7 0 6 2 1 1 9 has bee n deter mi ne d, a n o pti o nal s u bset of partici pa nts ma y be e nr olle d 
(a p pr o xi matel y 6-1 2 partici pa nts) wit h t he re q uire me nt of pr o vi di n g ma n dat or y paire d de n o v o pretreat me nt a n d o n treat me nt bi o ps y sa m ples i n P arts 1 A a n d 1 B t o e na ble 
e val uati o n of tiss ue bi o mar ker P D acti vit y. T he o pti o n t o e nr oll t he s u bset of partici pa nts f or ma n dat or y paire d t u m or sa m ples will be base d o n e val uati o n of e mer gi n g cli nical data 
(i ncl u di n g a vaila ble safet y/t olera bilit y, P K, a n d P D fi n di n gs) b y t he s p o ns or. De n o v o pre-treat me nt a n d o n-treat me nt bi o psies s h o ul d be ta ke n fr o m t he sa me lesi o n, n ot pre vi o usl y 
irra diate d, if p ossi ble. De n o v o pre-treat me nt bi o psies s h o ul d be prefera bl y c ollecte d wit hi n 2 8 da ys of st u d y start after all eli gi bilit y criteria ha ve bee n verifie d. O n-treat me nt bi o ps y 
sa m ples are t o be c ollecte d prefera bl y after t he 3r d d ose a n d wit hi n 7 da ys of C 3 D 1. If o n tre atme nt t u m or c ollecti o n t a kes pl ace gre ater t h a n ± 3 d a ys fr o m C 3 D 1, a d diti o n al 
u nsc he d ule d bl o o d s a m ple f or c yt o ki ne a n d circ ul ati n g m ar kers a n d a n u nsc he d ule d bl o o d s a m ple f or T cell i m m u n o p he n ot y pi n g s h o ul d be c ollecte d t o m atc h t he d a y of 
bi o ps y c ollecti o n. A d diti o nal u nsc he d ule d o n -treat me nt bi o psies, after C 4 D 1 5 ( > 6 wee ks after i nitial o n treat me nt bi o ps y) ma y be c ollecte d, if i n dicate d t o e val uate p ote ntial 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 9
T a ble 4 .
Sc he d ule of P h ar m ac o ki netic, P h ar m ac o d y n a mic, a n d I m m u n o ge nicit y Assess me nts f or P art 1 A a n d P art 1 B Wit h 
Pri mi n g D ose
Visit I de ntifier
Scree ni n g
C ycle 1
C ycle ≥2
St u d y D a y
Wit hi n 
2 8 d a ys 
pri or t o 
re gistr ati o n
1
2
8
1 5
1 6
1 9
2 2
1
2
5
8
1 5
E O T/
Wit h dr a w al
H o urs Pre -/ P ost-D ose 1
0 2
8
2 4
1 6 8
0
4
8 
2 4
9 6
1 6 8
0
2 4
9 6
1 6 8
0
Visit wi n d o w 
± 1 hr
± 3 hrs
± 2 4 hrs
± 0. 5 hr ± 1 hr ± 3 hrs ± 2 4 hrs ± 4 8 hrs
± 3 hrs
± 2 4 hrs ± 2 4 hrs
res p o nses t o treat me nt or s us pecte d ac q uire d resista nce t o t hera p y a n d a gree d u p o n b y t he s p o ns or a n d i n vesti gat or a n d a gree d t o b y t he partici pa nt. If t he partici pa nt disc o nti n ues 
t he st u d y bef ore t he sc he d ule d o n-treat me nt bi o ps y ( C 3 D 1), t he partici pa nt will be as ke d t o pr o vi de a bi o ps y at t he E n d of Treat me nt visit. S pecific tiss ue re quire me nts a n d 
i nstr ucti o ns are liste d i n Bi o mar ker Secti o n 8. 8 .
7 Bl o o d s a m ple f or T cell I m m u n o p he n ot y pi n g: O ne 5 m L bl o o d sa m ple will be c ollecte d f or i m m u n o p he n ot y pe circ ulati n g l y m p h oc ytes at baseli ne ( pre d ose C ycle 1 Da y 1), 
a n d d uri n g treat me nt as descri be d a b o ve t o e val uate c ha n ges fr o m baseli ne. If Gra de ≥1 c yt o ki ne release s y n dr o me is s us pecte d, a d diti o nal u nsc he d ule d sa m ples s h o ul d be c ollecte d. 
If Gra de ≥2 diarr hea is o bser ve d or s us pecte d a n d P D sa m ples are n ot alrea d y sc he d ule d f or meas ure me nt t his sa m ple s h o ul d be c ollecte d. Starti n g wit h C ycle 5, bl o o d will be 
c ollecte d e ver y 3 r d c ycle pre d ose ( ie., C ycle 5 Da y 1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc.) (Secti o n 8. 8. 5 ).
8 Bl o o d S a m ple f or C yt o ki nes a n d Circ ul ati n g M ar kers (ce ntr al l a b): F or ce ntral la b orat or y testi n g, o ne 5 m L bl o o d sa m ple will be c ollecte d t o is olate ser u m f or c yt o ki ne a n d 
circ ulati n g mar ker meas ure me nt. Baseli ne c ollecti o n is re q uire d pre d ose o n C ycle 1 Da y 1. O n -treat me nt sa m ples f or c yt o ki ne a n d circ ulati n g mar ker meas ure me nt will be c ollecte d 
as descri be d a b o ve. T hese sa m ples will be use d t o e val uate c ha n ges fr o m baseli ne. If Gra de ≥1 c yt o ki ne release s y n dr o me is s us pecte d, a d diti o nal u nsc he d ule d sa m ples s h o ul d be 
c ollecte d t o matc h cli nicall y i n dicate d safet y c yt o ki ne sa m ples. If Gra de ≥2 diarr hea is o bser ve d or s us pecte d a n d P D sa m ples are n ot alrea d y sc he d ule d f or meas ure me nt t his 
sa mple s h o ul d be c ollecte d. Starti n g wit h C ycle 5, bl o o d sa m ples f or c yt o ki ne a n d circ ulati n g mar kers will be c ollecte d e ver y 3 r d c ycle pre d ose (ie., C ycle 5 Da y 1, C ycle 8 Da y 1, 
C y cle 1 1 Da y 1, etc.) ( Secti o n 8. 8. 4 ).
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 0
T a ble 5 .
Sc he d ule of P h ar m ac o ki netic, P h ar m ac o d y n a mic, a n d I m m u n o ge nicit y Assess me nts f or P art 2 Wit h o ut Pri mi n g 
D ose
Visit I de ntifier 
Scree ni n g
C ycle 1
C ycle ≥2
St u d y D a y
Wit hi n 
2 8 d a ys 
pri or t o 
re gistr ati o n
1
5
8
1 5
2 2
1
2
5
8
1 5
E O T/
wit h dr a w al
P ost 
tre atme nt 
f oll o w u p
H o urs Pre -/ P ost-D ose 1
0 2
8
9 6
1 6 8
0
1 6 8
0
2 4
9 6
1 6 8
0
Visit wi n d o w 
± 1 hr ± 2 4 hrs
± 2 4 hrs
± 4 8 hrs
± 3 hrs
± 2 4 hrs
± 2 4 hrs
± 7 d a ys
P har mac o ki netic sa m ples
Bl o o d sa m ples f or P F - 0 7 0 6 2 1 1 9 
c o nce ntrati o ns
X  
X  
X  
X  
X  
X  
X
X 
( C 4 o nl y)
X 1
( C 4 o nl y)
X 
( C 4 o nl y)
X  
X  
X
Bl o o d sa m ples f or A D A/ N A b a gai nst 
P F -0 7 0 6 2 1 1 9 3
X
X
X 3
X  
X
Bl o o d sa m ples f or P K/ A D A/ N A b a gai nst 
P F -0 6 8 0 1 5 9 1 3
X
X
X 3
X
Bl o o d sa m ples f or P K/ A D A/ N A b a gai nst 
be vaciz u ma b -Pf izer3
X
X
X 3
X
P har mac o d y na mic sa m ples
Pf izer Pre p D 1 ba n ke d sa m ple4
X
Arc hi val T u m or sa m ple 5
X
De N o v o Pre -treat me nt T u m or Bi o ps y5 ,6
X
O pti o nal or Ma n dat or y O n -Treat me nt 
T u m or Bi o ps y 6
X 
C 2 o nl y 
( ± 7 da ys)
X
( or 2n d o n 
treat me nt)
Bl o o d sa m ple f or C yt o ki nes a n d 
Circ ulati n g Mar kers 7
X  
X  
X  
X  
X  
X  
X 7
X 
( C 2 o nl y)
Bl o o d sa m ple f or T cell 
I m m u n o p he n ot y pi n g8
X
X  
X  
X  
X 7
X 
( C 2 o nl y)
1 Sa m pli n g ti mes i n dicate d are relate d t o t he e n d of t he S C i njecti o n. All eff orts s h o ul d be ma de t o o btai n t he P K sa m ples at t he e xact n o mi nal ti me relati ve t o d osi n g. H o we ver, 
sa m ples o btai ne d wit hi n t he wi n d o w s pecifie d will be c o nsi dere d acce pta ble. Starti n g C ycle 5, pre d ose P K sa m ples will be c ollecte d o nl y o n Da y 1 of e ver y 3 r d c ycle ( C ycle 5 Da y 
1, C ycle 8 Da y 1 , C ycle 1 1 Da y 1, etc.). A d diti o nal P K/ P D sa m ples s h o ul d als o be ta ke n if C R S is s us pecte d, a n d P K/ P D sa m ples are n ot alrea d y sc he d ul e d t o be ta ke n.
2 T he 0 -h o ur P K a n d A D A/ N A b sa m ples s h o ul d be ta ke n wit hi n 6 h o urs pri or t o P F - 0 7 0 6 2 1 1 9 a d mi nistrati o n.
3 B l o o d s a m ples f or P F-0 7 0 6 2 1 1 9, P F -0 6 8 0 1 5 9 1, a n d be v aciz u m a b -Pfizer i m m u n o ge nicit y testi n g a n d P F -0 6 8 0 1 5 9 1, a n d be v aciz u m a b - Pfizer P K: Bl o o d sa m ples f or P F -
0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer will o nl y be c ollecte d i n partici pa nts recei vi n g c o m bi nati o n t hera p y : Refer t o Secti o n 8. 4 f or details. A bl o od sa m ple f or P F -0 6 8 0 1 5 9 1 or 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 1
T a ble 5 .
Sc he d ule of P h ar m ac o ki netic, P h ar m ac o d y n a mic, a n d I m m u n o ge nicit y Assess me nts f or P art 2 Wit h o ut Pri mi n g 
D ose
Visit I de ntifier 
Scree ni n g
C ycle 1
C ycle ≥2
St u d y D a y
Wit hi n 
2 8 d a ys 
pri or t o 
re gistr ati o n
1
5
8
1 5
2 2
1
2
5
8
1 5
E O T/
wit h dr a w al
P ost 
tre atme nt 
f oll o w u p
H o urs Pre -/ P ost-D ose 1
0 2
8
9 6
1 6 8
0
1 6 8
0
2 4
9 6
1 6 8
0
Visit wi n d o w 
± 1 hr ± 2 4 hrs
± 2 4 hrs
± 4 8 hrs
± 3 hrs
± 2 4 hrs
± 2 4 hrs
± 7 d a ys
be vaciz u ma b -Pf izer P K a nal yses s h o ul d be dra w n wit h eac h i m m u n o ge nicit y sa m ple f or P F-0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer, res pecti vel y. All sa m ples s h o ul d be c ollecte d o n 
Da y 1 of a c ycle (als o o n Da y 1 5, i n C ycle 1 o nl y) a n d will b e dra w n pre d ose wit hi n 6 h o urs pri or t o a n y of t he dr u gs bei n g a d mi nistere d. Starti n g C ycle 5, bl o o d sa m ples f or P K 
a n d A D A/ N A b a gai nst P F -0 7 0 6 2 1 1 9 (a n d P F -0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer i n c o m bi nati o n) will be c ollecte d e ver y 3r d c ycle pre d ose (ie, C ycle 5 Da y 1, C ycle 8 Da y 1, 
C y cle 1 1 Da y 1, etc.). Partici pa nts wit h a n u nres ol ve d A E p ossi bl y relate d t o A D A will be as ke d t o ret ur n t o t he cli nic f or A D A a n d dr u g c o nce ntrati o n assess me nts at 
a p pr o xi matel y 3 -m o nt h i nter vals u ntil t he 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 s p o ns or u p t o a ma xi m u m of 9 m o nt hs.
4 Pfizer Pre p D 1 B a n ke d S a m ple: If n ot c ollecte d o n t he desi g nate d c ollecti o n da y, c ollect at t he ne xt a vaila ble ti me p oi nt w he n bi os peci me ns are bei n g c ollecte d i n c o nj u ncti o n 
wit h a partici pa nt visit.
5 Pretre at me nt T u m or Tiss ue S a m ples: Partici pa nts s h o ul d pr o vi de a de n o v o pre -treat me nt bi o ps y f or e val uati o n of baseli ne tiss ue bi o mar kers, u nless n ot me dicall y feasi ble, 
f or e val uati o n of baseli ne tiss ue bi omar kers. De n o v o pretreat me nt bi o psies are prefera bl y c ollecte d wit hi n 2 8 da ys of st u d y start after all eli gi bilit y criteria ha ve bee n verifie d. I n 
a d diti o n, s u b missi o n of arc hi val sa m ples if a vaila ble is als o e nc o ura ge d, b ut n ot ma n dat or y, t o c o m pare p oss i ble c ha n ges i n baseli ne tiss ue bi o mar kers d ue t o pri or t hera pies. 
S pecific tiss ue re q uire me nts, i nstr ucti o ns, a n d c o n diti o ns f or s u b mitti n g arc hi val sa m ples w he n c ollecti o n of de n o v o sa m ples is n ot me dicall y feasi ble are liste d i n Bi o mar ker 
Secti o n 8. 8 .
6 P aire d T u m or S a m ples : Paire d de n o v o pretreat me nt a n d o n-treat me nt bi o ps y sa m ples will be ma n dat or y f or a p pr o xi matel y 1 0 partici pa nts i n eac h of t he d ose e x pa nsi o n ar ms 
a n d o pti o nal b ut e nc o ura ge d f or all ot her partici pa nts t o e na ble e val uati o n of tiss ue bi o mar ker P D acti vit y. O n -treat me nt bi o psies s h o ul d be ta ke n fr o m t he sa me lesi o n, n ot 
pre vi o usl y irra dia te d, if p ossi ble. O n-treat me nt bi o ps y sa m ples are t o be c ollecte d prefera bl y after t he 3r d d ose a n d wit hi n 7 da ys of C 2 D 1 5. If o n tre atme nt t u m or c ollecti o n 
t a kes pl ace gre ater t h a n ± 3 d a y s fr o m C 2 D 1 5, a d diti o n al u nsc he d ule d bl o o d s a m ple f or c yt o ki ne a n d circ ul ati n g m ar kers a n d a n u nsc he d ule d bl o o d s a m ple f or T cell 
i m m u n o p he n ot y pi n g s a m ple s h o ul d be c ollecte d t o m atc h t he d a y of bi o ps y c ollecti o n. A d diti o nal u nsc he d ule d o n -treat me nt bi o psies, after C 4 D 1 5 ( > 6 wee ks after i nitial o n 
treat me nt bi o ps y) ma y be c ollecte d, if i n dicate d t o e val uate p ote ntial res p o nses t o treat me nt or s us pecte d ac q uire d resista nce t o t hera p y a n d a gree d u p o n b y t he s p o ns or a n d 
i n vesti gat or a n d a gree d t o b y t he partici pa nt. If t he partici pa nt disc o nti n ues t he st u d y bef ore t he sc he d uled o n -treat me nt bi o ps y ( C 2 D 1 5), t he partici pa nt will be as ke d t o pr o vi de a 
bi o ps y at t he E n d of Treat me nt visit. S pecific tiss ue re q uire me nts a n d i nstr ucti o ns are liste d i n Bi o mar ker Secti o n 8. 8 .
7 Bl o o d S a m ple f or C yt o ki nes a n d Circ ul ati n g M ar kers (ce ntr al l a b) : F or ce ntral la b orat or y testi n g, o ne 5 m L bl o o d sa m ple will be c ollecte d t o is olate ser u m f or c yt o ki ne a n d 
circ ulati n g mar ker meas ure me nt. Baseli ne c ollecti o n is re q uire d pre d ose o n C ycle 1 Da y 1. O n -treat me nt sa m ples f or c yt o ki ne a n d circ ulati n g mar kers meas ure me nt will be 
c ollecte d as descr i be d a b o ve. T hese sa m ples will be use d t o e val uate c ha n ges fr o m baseli ne. If Gra de ≥1 c yt o ki ne release s y n dr o me is s us pecte d, a d diti o nal u nsc he d ule d sa m ples 
s h o ul d be c ollecte d t o matc h cli nicall y i n dicate d safet y c yt o ki ne sa m ples. If Gra de ≥2 diarr hea is o bser ve d or s us pecte d a n d P D sa m ples are n ot alrea d y sc he d ule d f or 
meas ure me nt t his sa m ple s h o ul d be c ollecte d. Starti n g wit h C ycle 5, bl o o d sa m ples f or c yt o ki ne a n d circ ulati n g mar kers will b e c ollecte d e ver y 3 r d c ycle pre d ose (i.e., C ycle 5 Da y 
1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc.).
8 Bl o o d s a m ple f or T cell I m m u n o p he n ot y pi n g: O ne 5 m L bl o o d sa m ple will be c ollecte d t o i m m u n o p he n ot y pe circ ulati n g l y m p h oc ytes at baseli ne, pre d ose C ycle 1 Da y 1, a n d 
d uri n g treat me nt as descri be d a b o ve t o e val uate c ha n ges fr o m baseli ne. If Gra de ≥1 c yt o ki ne release s y n dr o me is s us pecte d, a d diti o nal u nsc he d ule d sa m ples s h o ul d be c ollecte d. If 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 2
T a ble 5 .
Sc he d ule of P h ar m ac o ki netic, P h ar m ac o d y n a mic, a n d I m m u n o ge nicit y Assess me nts f or P art 2 Wit h o ut Pri mi n g 
D ose
Visit I de ntifier 
Scree ni n g
C ycle 1
C ycle ≥2
St u d y D a y
Wit hi n 
2 8 d a ys 
pri or t o 
re gistr ati o n
1
5
8
1 5
2 2
1
2
5
8
1 5
E O T/
wit h dr a w al
P ost 
tre atme nt 
f oll o w u p
H o urs Pre -/ P ost-D ose 1
0 2
8
9 6
1 6 8
0
1 6 8
0
2 4
9 6
1 6 8
0
Visit wi n d o w 
± 1 hr ± 2 4 hrs
± 2 4 hrs
± 4 8 hrs
± 3 hrs
± 2 4 hrs
± 2 4 hrs
± 7 d a ys
Gra de ≥2 diarr hea is o bser ve d or s us pecte d a n d P D sa m ples are n ot alrea d y sc he d ule d f or meas ure me nt t his sa m ple s h o ul d be c ollecte d. S tarti n g wit h C ycle 5, bl o o d sa m ples f or 
c yt o ki ne a n d circ ulati n g mar kers a n d bl o o d sa m ple will be c ollecte d e ver y 3r d c ycle pre d ose (i.e., C ycle 5 Da y 1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc).
T a ble 6 .
Sc he d ule of P h ar m ac o ki netic, P h ar m ac o d y n a mic, a n d I m m u n o ge nicit y Assess me nts f or P art 2 Wit h Pri mi n g D ose
Visit I de ntifier 
Scree ni n g
C ycle 1
C ycle ≥2
St u d y D a y
Wit hi n 
2 8 d a ys pri or 
t o 
re gistr ati o n
1
8
1 5
1 9
2 2
1
2
5
8
1 5
E O T/
Wit h dr a w al
P ost tre at me nt 
f oll o w u p
H o urs Pre -/ P ost-D ose 1
0 2
8
1 6 8
0
8
9 6
1 6 8
0
2 4
9 6
1 6 8
0
Visit wi n d o w 
± 1 hr
± 2 4 hrs
± 1 hr
± 2 4 hrs ± 4 8 hrs
± 3 hrs
± 2 4 hrs
± 2 4 hrs
± 7 d a ys
P har mac o ki netic sa m ples
Bl o o d sa m ples f or 
P F - 0 7 0 6 2 1 1 9 
c o nce ntrati o ns
X  
X  
X  
X  
X  
X  
X  
X  
X
( C 4 
o nl y)
X 1
( C 4 o nl y)
X
( C 4 o nl y)
X  
X
X
Bl o o d sa m ples f or 
A D A/ N A b a gai nst 
P F -0 7 0 6 2 1 1 9 3
X
X
X 3
X
X
Bl o o d sa m ples f or 
P K/ A D A/ N A b a gai nst 
P F -0 6 8 0 1 5 9 1 3
X
X 3
X
Bl o o d sa m ples f or 
P K/ A D A/ N A b a gai nst 
be vaciz u ma b -Pf izer3
X
X 3
X
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 3
T a ble 6 .
Sc he d ule of P h ar m ac o ki netic, P h ar m ac o d y n a mic, a n d I m m u n o ge nicit y Assess me nts f or P art 2 Wit h Pri mi n g D ose
Visit I de ntifier 
Scree ni n g
C ycle 1
C ycle ≥2
St u d y D a y
Wit hi n 
2 8 d a ys pri or 
t o 
re gistr ati o n
1
8
1 5
1 9
2 2
1
2
5
8
1 5
E O T/
Wit h dr a w al
P ost tre at me nt 
f oll o w u p
H o urs Pre -/ P ost-D ose 1
0 2
8
1 6 8
0
8
9 6
1 6 8
0
2 4
9 6
1 6 8
0
Visit wi n d o w 
± 1 hr
± 2 4 hrs
± 1 hr
± 2 4 hrs ± 4 8 hrs
± 3 hrs
± 2 4 hrs
± 2 4 hrs
± 7 d a ys
P har mac o d y na mic 
sa m ples
Pf izer Pre p D 1 ba n ke d 
sa m ple4
X
Arc hi val T u m or sa m ple 5
X
De N o v o Pre -treat me nt 
T u m or Bi o ps y 5 ,6
X
O pti o nal or Ma n dat or y 
O n -Treat me nt T u m or 
Bi o ps y 6
X 
C 2 o nl y 
( ± 7 da ys)
X
( or 2n d o n 
treat me nt)
Bl o o d sa m ple f or 
C y t o ki nes a n d 
Circ ulati n g Mar kers 7
X  
X  
X  
X  
X  
X  
X  
X 7
X 
( C 2 o nl y)
Bl o o d sa m ple f or T cell 
I m m u n o p he n ot y pi n g8
X
X  
X
X  
X  
X 7
X 
( C 2 o nl y)
1 Sa m pli n g ti mes i n dicate d are relate d t o t he e n d of t he S C i njecti o n. All eff orts s h o ul d be ma de t o o btai n t he P K sa m ples at t he e xact n o mi nal ti me relati ve t o d osi n g. H o we ver, 
sa m ples o btai ne d wit hi n t he wi n d o w s pecifie d will be c o nsi dere d acce pta ble. Starti n g C ycle 5, pre d ose P K sa m ples will be c ollecte d o nl y o n Da y 1 of e ver y 3 r d c ycle ( C ycle 5 
Da y 1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc.). A d diti o nal P K/ P D sa m ples s h o ul d als o be ta ke n if C R S is s us pecte d, a n d P K/ P D sa m ples are n ot alrea d y sc he d ule d t o be ta ke n.
2 T he 0 -h o ur P K a n d A D A/ N A b sa m ples s h o ul d be ta ke n wit hi n 6 h o urs pri or t o P F - 0 7 0 6 2 1 1 9 a d mi nistrati o n.
3 Bl o o d s a m ples f or P F -0 7 0 6 2 1 1 9, P F -0 6 8 0 1 5 9 1, a n d be v aciz u m a b -Pfizer i m m u n o ge nicit y testi n g a n d P F -0 6 8 0 1 5 9 1, a n d be v aciz u m a b - Pfizer P K: Bl o o d sa m ples f or P F -
0 7 0 6 2 1 1 9 will be c ollecte d i n partici pa nts recei vi n g m o n ot hera p y. Bl o o d sa m ples f or P F -0 7 0 6 2 1 1 9, P F -0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer will be c ollecte d i n partici pa nts 
recei vi n g c o m bi nati o n t hera py : Refer t o Secti o n 8. 4 f or details. A bl o o d sa m ple f or P F-0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer P K a nal yses s h o ul d be dra w n wit h eac h i m m u n o ge nicit y 
sa m ple f or P F-0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer, res pecti vel y. All sa m ples f or be vaciz u ma b-Pf izer s h o ul d be c ollecte d o n Da y 1 of a c ycle (e xce pt o n Da y 1 5, i n C ycle 1 o nl y) 
a n d f or P F-0 6 8 0 1 5 9 1 o n Da y 1 5 of a c ycle. Sa m ples will be dra w n pre d ose wit hi n 6 h o urs pri or t o a n y of t he dr u gs bei n g a d mi nistere d. Starti n g C ycle 5, bl o o d sa m ples f or P K 
a n d A D A/ N A b a gai nst P F -0 7 0 6 2 1 1 9 (a n d P F -0 6 8 0 1 5 9 1 or be vaciz u ma b -Pf izer i n c o m bi nati o n) will be c ollecte d e ver y 3r d c ycle pre d ose (ie, C ycle 5 Da y 1, C ycle 8 Da y 1, 
C y cle 1 1 Da y 1, etc. f or P F-0 7 0 6 2 1 1 9/ be vaciz u ma b -Pf izer a n d C ycle 5 Da y 1 5, C ycle 8 Da y 1 5, C ycle 1 1 Da y 1 5 f or P F- 0 6 8 0 1 5 9 1 ). Partici pa nts wit h a n u nres ol ve d A E p ossi bl y 
relate d t o A D A will be as ke d t o ret ur n t o t he cli nic f or A D A a n d dr u g c o nce ntrati o n assess me nts at a p pr o xi matel y 3-m o nt h i nter vals u ntil t he A E or its se q uelae r es ol ve or 
sta bilize at a le vel acce pta ble t o t he i n vesti gat or a n d s p o ns or u p t o a ma xi m u m of 9 m o nt hs.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 4
T a ble 6 .
Sc he d ule of P h ar m ac o ki netic, P h ar m ac o d y n a mic, a n d I m m u n o ge nicit y Assess me nts f or P art 2 Wit h Pri mi n g D ose
Visit I de ntifier 
Scree ni n g
C ycle 1
C ycle ≥2
St u d y D a y
Wit hi n 
2 8 d a ys pri or 
t o 
re gistr ati o n
1
8
1 5
1 9
2 2
1
2
5
8
1 5
E O T/
Wit h dr a w al
P ost tre at me nt 
f oll o w u p
H o urs Pre -/ P ost-D ose 1
0 2
8
1 6 8
0
8
9 6
1 6 8
0
2 4
9 6
1 6 8
0
Visit wi n d o w 
± 1 hr
± 2 4 hrs
± 1 hr
± 2 4 hrs ± 4 8 hrs
± 3 hrs
± 2 4 hrs
± 2 4 hrs
± 7 d a ys
4 Pfizer Pre p D 1 B a n ke d S a m ple: If n ot c ollecte d o n t he desi g nate d c ollecti o n da y, c ollect at t he ne xt a vaila ble ti me p oi nt w he n bi os peci me ns are bei n g collecte d i n c o nj u ncti o n 
wit h a partici pa nt visit.
5 Pretre at me nt T u m or Tiss ue S a m ples: Partici pa nts s h o ul d pr o vi de a de n o v o pre -treat me nt bi o ps y f or e val uati o n of baseli ne tiss ue bi o mar kers, u nless n ot me dicall y feasi ble, 
f or e val uati o n of baseli ne tiss ue bi o mar kers. De n o v o pretreat me nt bi o psies are prefera bl y c ollecte d wit hi n 2 8 da ys of st u d y start after all eli gi bilit y criteria ha ve bee n verifie d. I n 
a d diti o n, s u b missi o n of arc hi val sa m ples if a vaila ble is als o e nc o ura ge d, b ut n ot ma n dat or y, t o c o m pare p ossi ble c ha n ges i n b aseli ne tiss ue bi o mar kers d ue t o pri or t hera pies. 
S pecific tiss ue re q uire me nts, i nstr ucti o ns, a n d c o n diti o ns f or s u b mitti n g arc hi val sa m ples w he n c ollecti o n of de n o v o sa m ples is n ot me dicall y feasi ble are liste d i n Bi o mar ker 
Secti o n 8. 8 .
6 P aire d T u m or S a m ples : Paire d de n o v o pretreat me nt a n d o n-treat me nt bi o ps y sa m ples will be ma n dat or y f or a p pr o xi matel y 1 0 partici pa nts i n eac h of t he d ose e x pa nsi o n ar ms 
a n d o pti o nal b ut e nc o ura ge d f or all ot her partici pa nts t o e na ble e val uati o n of tiss ue bi o mar ker P D acti vit y. O n -treat me nt bi o psies s h o ul d be ta ke n fr o m t he sa me lesi o n, n ot 
pre vi o usl y irra diate d, if p ossi ble. O n- treat me nt bi o ps y sa m ples are t o be c ollecte d prefera bl y after t he 3r d d os e a n d wit hi n 7 da ys of C 2 D 1 5. If o n tre atme nt t u m or c ollecti o n 
t a kes pl ace gre ater t h a n ± 3 d a y s fr o m C 2 D 1 5, a d diti o n al u nsc he d ule d bl o o d s a m ple f or c yt o ki ne a n d circ ul ati n g m ar kers a n d a n u nsc he d ule d bl o o d s a m ple f or T cell 
i m m u n o p he n ot y pi n g s a m ple s h o ul d be c ollecte d t o m atc h t he d a y of bi o ps y c ollecti o n. A d diti o nal u nsc he d ule d o n -treat me nt bi o psies, after C 4 D 1 5 ( > 6 wee ks after i nitial o n 
treat me nt bi o ps y) ma y be c ollecte d, if i n dicate d t o e val uate p ote ntial res p o nses t o treat me nt or s us pecte d ac q uire d resista nce t o t hera p y a n d a gree d u p o n b y t he s p o ns or a n d 
i n vesti gat or a n d a gree d t o b y t he partici pa nt. If t he partici pa nt disc o nti n ues t he st u d y bef ore t he sc he d ule d o n-treat me nt bi o ps y ( C 2 D 1 5), t he partici pa nt will be as ke d t o pr o vi de a 
bi o ps y at t he E n d of Treat me nt visit. S pecific tiss ue re q uire me nts a n d i nstr ucti o ns are liste d i n Bi o mar ker Secti o n 8. 8 .
7 Bl o o d S a m ple f or C yt o ki nes a n d Circ ul ati n g M ar k ers (ce ntr al l a b) : F or ce ntral la b orat or y testi n g, o ne 5 m L bl o o d sa m ple will be c ollecte d t o is olate ser u m f or c yt o ki ne 
a n d circ ulati n g mar ker meas ure me nt. Baseli ne c ollecti o n is re q uire d pre d ose o n C ycle 1 Da y 1. O n -treat ment sa m ples f or c yt o ki ne a n d circ ulati n g mar kers meas ure me nt will be 
c ollecte d as descri be d a b o ve. T hese sa m ples will be use d t o e val uate c ha n ges fr o m baseli ne. If Gra de ≥1 c yt o ki ne release s y n dr o me is s us pecte d, a d diti o nal u nsc he d ule d sa m ples 
s h o ul d be c ollecte d t o matc h cli nicall y i n dicate d safet y c yt o ki ne sa m ples. If Gra de ≥2 diarr hea is o bser ve d or s us pecte d a n d P D sa m ples are n ot alrea d y sc he d ule d f or 
meas ure me nt t his sa m ple s h o ul d be c ollecte d. Starti n g wit h C ycle 5, bl o o d sa m ples f or c yt o ki ne a n d circ ulati n g mar kers will b e c o llecte d e ver y 3r d c ycle pre d ose (ie, C ycle 5 
Da y 1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc.).
8 Bl o o d s a m ple f or T -cell I m m u n o p he n ot y pi n g : O ne 5 m L bl o o d sa m ple will be c ollecte d t o i m m u n o p he n ot y pe circ ulati n g l y m p h oc ytes at baseli ne, pre d ose C ycle 1 Da y 1, 
a n d d uri n g treat me nt as descri be d a b o ve t o e val uate c ha n ges fr o m baseli ne. If Gra de ≥1 c yt o ki ne release s y n dr o me is s us pecte d, a d diti o nal u nsc he d ule d sa m ples s h o ul d be 
c ollecte d. If Gra de ≥2 diarr hea is o bser ve d or s us pecte d a n d P D sa m ples are n ot alrea d y sc he d ule d f or meas ure me nt t his sa m ple s h o ul d be c ollecte d. Starti n g wit h C ycle 5, bl o o d 
sa m ples f or c yt o ki ne a n d circ ulati n g mar kers a n d bl o o d sa m ple will be c ollecte d e ver y 3r d c ycle pre d ose (ie, C ycle 5 Da y 1, C ycle 8 Da y 1, C ycle 1 1 Da y 1, etc).
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 5
2. I N T R O D U C TI O N
P F -0 7 0 6 2 1 1 9 is a n a nti -G ua n yl yl  Cyclase 2 C ( G U C Y 2c)/a nti-C D 3 bis pecific Fc dia b o d y 
tar geti n g C D 3 o n T cells wit h o ne bi n di n g d o mai n a n d G U C Y 2c wit h t he ot her bi n di n g 
d o mai n. P F - 0 7 0 6 2 1 1 9 acts as a T cell re directi n g bis pecific f or t he treat me nt of 
gastr oi ntesti nal t u m ors i ncl u di n g c ol orectal, gastr ic a n d es o p ha geal a de n ocarci n o mas.
2. 1. St u d y R ati o n ale
I n t he d ose-escalati o n/fi n di n g p hase ( Part 1), P F -0 7 0 6 2 1 1 9 will be e val uate d wit h or wit h o ut 
a pri mi n g d ose f or t he treat me nt of a d ult partici pa nts wit h a d va nce d gastr oi ntesti nal 
a de n ocarci n o mas (c ol orecta l, gastric, a n d es o p ha geal) k n o w n t o e x press G U C Y 2c a n d f or 
w h o m n o sta n dar d t hera p y  is a vaila ble. T he pri mi n g d ose has bee n i m ple me nte d t o miti gate 
c yt o ki ne release sy n dr o me ( C R S) wit h t he i nitial f ull d ose. Base d o n a vaila ble data fr o m 
partici pa nts e nr ol le d acr oss d ose escalati o n wit h o ut pri mi n g, c yt o ki ne pr o d ucti o n a n d C R S 
occ ur pri maril y wit h t he i nitial d ose of P F -0 7 0 6 2 1 1 9, s u p p orti n g t he h y p ot hesis t hat 
i n d ucti o n of i m m u ne acti vati o n wit h a l o wer pri mi n g d ose ma y atte n uate C R S ass ociate d 
wit h t he i nit ial f ull d ose. T he use of a pri mi n g a p pr oac h t o miti gate C R S is als o s u p p orte d by 
data fr o m cli nical st u dies wit h ot her T- cell e n ga gi n g a ge nts a n d will be e val uate d i n t his 
cli nical st u d y. 
I n t he d ose-e x pa nsi o n p hase ( Part 2), P F -0 7 0 6 2 1 1 9 will be e val uate d wit h or wit h o ut a 
pri mi n g d ose i n se parate d ose- e x pa nsi o n ar ms as m o n ot hera p y a n d i n c o m bi nati o n wit h 
a n ot her a ge nt (e g, i m m u ne c hec k p oi nt i n hi bit or a n d a nti- V E G F, se paratel y ) i n c ol orectal 
ca ncer ( C R C) a n d t he n p ossi bl y be e val uate d i n ot her gastr oi ntesti nal a de n ocarci n o mas, C R C 
s u bt ypes, or c o m bi nati o n o pti o ns, as i n dicate d.
A n u m ber of cli nical trials ha ve s h o w n a c orrelati o n bet wee n certai n t u m or m utati o ns 
(e g, K R A S or B R A F) a n d t he lac k of res p o nse t o tar gete d t hera p y , s uc h as a nti-E G F R 
a nti b o dies i n partici pa nts wit h t u m ors t hat are K R A S p ositi ve ( Alle gra et al, 2 0 0 9; Di 
Nic ola nt o ni o et al, 2 0 0 8; Pratilas et al, 2 0 0 8; S olit et al, 2 0 0 6). 2 ,1 4 ,3 5 ,4 2  Pfizer’s i n vi v o 
p har mac ol o g y  st u dies de m o nstrate d a nti-t u m or efficac y wit h P F-0 7 0 6 2 1 1 9 i n cell li ne 
xe n o graft ( C L X) a n d partici pa nt- deri ve d xe n o graft ( P D X) m o dels of c ol orectal ca ncer, m ost 
of w hic h are m uta nt f or K R A S or B R A F o nc o ge nes. A d diti o nall y , P F-0 7 0 6 2 1 1 9 has t he 
p ote ntial t o be use d i n t he setti n gs of eit her micr osatellite sta ble ( M S S) or hi g h micr osatellite 
i nsta bilit y ( M SI- H) disease gastr oi ntesti nal a de n ocarci n o mas as G U C Y 2 C is e x presse d 
acr oss b ot h s u bt ypes ( Bas hir et al, 2 0 1 9). 5
A d diti o nall y , i m m u ne c hec k p oi nt i n hi biti o n mec ha nis ms ( Sal ma ni neja d, 2 0 1 9),3 9 s uc h as 
u pre g ulati o n of P D -L 1 ( Pr o gra m me d deat h li ga n d 1) i n res p o nse t o treat me nt c o ul d lea d t o 
resista nce t o P F-0 7 0 6 2 1 1 9 acti vit y , w hic h is de pe n de nt o n T-cell acti vati o n. T o a d dress t his 
iss ue, P F-0 7 0 6 2 1 1 9 c o m bi nati o ns wit h i m m u ne c hec k p oi nt i n hi bit ors were e val uate d a n d 
s h o we d e n ha nce d efficac y c o m pare d t o si n gle a ge nts. F urt her m ore, c o m bi nati o ns of 
P F -0 7 0 6 2 1 1 9 were e val uate d wit h a nti -a n gi o ge nesis a ge nts, w hic h ha ve bee n re p orte d t o 
e n ha nc e T-cell i nfiltrati o n i nt o t u m ors ( Alle n et al 2 0 1 7). 3 Acc or di n gl y, c o m bi nati o ns of 
P F - 0 7 0 6 2 1 1 9 wit h eit her a n a nti-V E G F -A a nti b o d y , or a xiti ni b, a small m olec ule 
a nti-a n gi o ge nic a ge nt, s h o we d c o m plete t u m or re gressi o ns c o m pare d t o si n gle a ge nts, w hic h 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 6
ha d mi ni mal t o m o derate efficac y  i n t he c ol orectal t u m or m o del teste d. T hese st u dies 
c ollecti vel y s u g gest t hat si n gle a ge nt efficac y  o bser ve d wit h P F- 0 70 6 2 1 1 9 ca n be e n ha nce d 
wit h i m m u ne c hec k p oi nt bl oc ka de a ge nts, w hic h pre ve nt T -cell e x ha usti o n, as well as wit h 
a nti-a n gi o ge nesis a ge nts w hic h c o ul d i ncrease t u m or i nfiltrati n g l y m p h oc y tes ( TI Ls).
2. 2. B ac k gr o u n d
2. 2. 1. A d v a nce d G astr oi ntesti n al A de n oc arci n o m as
Certai n gastr oi ntesti nal t u m ors, i ncl u di n g c ol orectal ca ncer ( C R C), gastric ca ncer, a n d 
gastr oes o p ha geal ca ncer, c o nti n ue t o be a n area of u n met me dical nee d des pite a d va nces i n 
c yt ot o xic c he m ot hera pies a n d ne wer tar gete d a ge nts.
C R C gl o ball y  ra n ks t hir d i n ter ms of i nci de nce wit h o ver 1. 8 milli o n ne w C R C cases a n d 
8 8 1, 0 0 0 deat hs are esti mate d t o occ ur ( Bra y  et al, 2 0 1 8).1 0 I n t he U S, nearl y 1 5 0, 0 0 0 ne w 
cases of C R C are dia g n ose d eac h year, res ulti n g i n t he deat hs of nearl y 5 0, 0 0 0 pe o ple 
a n n uall y ( A h me di n et al, 2 0 0 9).1  C urre ntl y , treat me nt o pti o ns i nclu de c o m bi nati o ns of a 
fl u or o p yri mi di ne wit h eit her o xali plati n or iri n oteca n as a bac k b o ne. Tar gete d a ge nts ha ve 
s h o w n a d de d be nefit w he n a d de d t o t hese re gi me ns, i ncl u di n g m o n ocl o nal a nti b o dies 
directe d a gai nst t he E pi der mal Gr o wt h Fact or Rece pt or ( E G F R; cet u xi ma b a n d 
pa nit u m u ma b) a n d vasc ular e n d ot helial gr o wt h fact or ( V E G F; be vaciz u ma b, afli berce pt) 
( H ur witz HI et al, 2 0 0 9; Saltz L B et al, 2 0 0 8, C ha u I a n d C u n ni n g ha m D, 2 0 0 9). 2 0 ,3 8 ,1 2 Als o , 
t h o u g h t he cli nical be nefit is ver y li mite d, treat me nt f or a d va nce d refract or y C R C has bee n 
de vel o pe d, i ncl u di n g re g orafe ni b, a n oral m ulti ki nase i n hi bit or, a n d trifl uri di ne/ti piracil 
( Lo ns urf ® ), a D N A s y nt hesis m o d ulat or t hat i n hi bits cell pr oliferati o n ( Gr ot he y A et al, 2 0 1 3, 
L o ns urf ® U S PI ).1 7  H o we ver, des pite a d va nces i n t he treat me nt of C R C, pr o gressi o n of 
disease will occ ur i n a si g nifica nt pr o p orti o n of partici pa nts lea di n g t o m or bi dit y  a n d 
m ortalit y .
Gastric ca ncer is als o pre vale nt wit h a n esti mate d 2 0 0, 0 0 0 ne w cases i n t he U S, E U 5, a n d 
Ja pa n a n d is t he fift h m ost fre q ue ntly dia g n ose d ca ncer w orl d wi de ( Bra y  F et al, 2 0 1 8).1 0 T he 
dia g n osis of gastric ca ncer occ urs w he n alrea d y i n a d va nce d sta ge disease a n d ma y prese nt i n 
differe nt areas of t he st o mac h i ncl u di n g t he gastr oes o p ha geal j u ncti o n. S yste mic 
c he m ot hera p y is t he m ost c o m m o n treat me nt a p pr oac h f or rec urre nt/ metastatic disease t hat 
ma y  i ncl u de t he use of F O L F O X a n d e pir u bici n-base d plati n u m c o m bi nati o n c he m ot hera p y 
al o n g wit h trast uz u ma b a d diti o n t o t h ose o vere x pressi n g H E R 2 as c o m m o n fr o ntli ne 
re gi me ns. Ra m ucir u ma b ( C yra mza® ) wit h or wit h o ut paclita xel or paclita xel wit h iri n oteca n 
a n d ge mcita bi ne or ot her m o n o a n d c o m b o c he m ot hera pies are use d i n m ore a d va nce d li nes 
( Na gaic h N a n d S har ma R, 2 0 1 8).3 3  Als o, i m m u n o -o nc ol o g y  c o m p o u n ds, s uc h as 
pe m br oliz u ma b, ha ve de m o nstrate d li mite d cli nical be nefit a n d ma y  be c o nsi dere d 
( Ki yoz u mi Y et al, 2 0 1 8). 2 3
Eac h ye ar, o ver 5 0 0, 0 0 0 ne w cases of es o p ha geal ca ncer are dia g n ose d w orl d wi de wit h o ver 
1 7, 0 0 0 cases dia g n ose d i n t he U S, of w hic h a de n ocarci n o ma c o m prises a n est i mate d 2 0 % of 
cases ( Bra y et al, 2 0 1 8).1 0 Treat me nt o pti o ns f or es o p ha geal a de n ocarci n o ma are ge nerall y 
si milar t o t h ose use d i n gastric a de n ocarci n o ma. C he m ot hera p y, p ossi bl y al o n g wit h tar gete d 
dr u g t hera p y has bee n use d. Si milar t o C R C patie nts, o utc o mes f or patie nts wit h rec urre nt 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 7
metastatic gastric a n d es o p ha geal ca ncer disease are p o or. T h us, effecti ve t hera pies t o 
a d dress c ol o n, gastric a n d es o p h a geal a de n ocarci n o mas are nee de d.
2. 2. 2. G U C Y 2c E x pressi o n i n H u m a n C a ncers 
G U C Y 2c is a ca n di date tar get f or bis pecific a nti b o d y -base d i m m u n ot hera p y  d ue t o its hi g h 
e x pressi o n acr oss gastr oi ntesti nal t u m ors i ncl u di n g c ol o n ca ncer (e x presse d i n > 9 0 % of cases 
acr oss all sta ges), a n d gastric or gastr oes o p ha geal j u ncti o n ca ncer (e x presse d i n > 5 0 % of 
a de n ocarci n o ma cases of t he es o p ha g us a n d st o mac h) ( Bir be et al, 2 0 0 5; Da naee et al, 
2 0 1 7). 9 ,1 3  Tar get e x pressi o n i n n or mal tiss ues is lar gel y restricte d t o t he a pical si de of 
i ntesti nal e pit helial ti g ht j u ncti ons, w hic h c o ul d all o w f or prefere ntial u pta ke of G U C Y 2 C 
tar gete d bi ol o gics b y t u m ors t hat ha ve disr u pte d ti g ht j u ncti o n arc hitect ure ma ki n g it a n 
a p pr o priate a nti ge n t o tar gete d t hera p y a p pr oac hes. T hese c o nsi derati o ns hi g hli g ht t he 
p ote ntial of P F - 0 7 0 6 2 1 19 as a treat me nt o pti o n f or c ol o n, gastric a n d es o p ha geal 
a de n ocarci n o mas.
2. 2. 3. Bis pecific Re directe d T -cell E n g a gi n g T her a pies
T he p ote ntial of re directe d T -cell t hera pe utics i n ca ncer treat me nt has bee n de m o nstrate d b y 
t he U nite d States F o o d a n d Dr u g A d mi nistrati o n’s a p pr o val of t he bis pecific T-cell e n ga ger, 
bli nat u m o ma b f or t he treat me nt of rela pse d or refract or y  B-cell prec urs or ac ute 
l ym p h o blastic le u ke mia. 4 2 Bis pecifics wit h a re directe d T -cell e n ga gi n g m o dalit y ha ve als o 
s h o w n pr o mise f or t he treat me nt of s oli d t u m ors, i ncl u di n g C R C, wit h se veral bis pecific 
a ge nts i n earl y cli nical st u dies ( Ta ber ner o et al, 2 0 1 7; M o ore P A et al, 2 0 1 8). 4 5 ,2 7
C y t ot o xic T l ym p h oc y tes ( C T Ls) c o n ve nti o nally rec o g nize cell pr otei n a nti ge ns prese nte d i n 
c o m ple x wit h Maj or Hist oc o m pati bilit y C o m ple x ( M H C) Class I m olec ules o n t he cell 
s urface via t heir T- cell rece pt ors ( T C Rs). 3 8 C D 3 bis pecifics circ u m ve nt t he nee d f or T C R 
e n ga ge me nt t hr o u g h M H C Class I  i n c o m ple x wit h a nti ge nic pe pti de, a n d i nstea d recr uit 
T cells t o tar get cells e x pressi n g cell s urface tar get pr otei n (a nti ge n). O ne ar m of t he 
bis pecific bi n ds t o a t u m or ass ociate d cell s urface a nti ge n, a n d t he ot her ar m bi n ds t o t he 
C D 3ε pr otei n, w hic h is a part of t he T C R c o m ple x o n T cells. C o-e n ga ge me nt of C D 3ε o n 
T cells a n d tar get a nti ge n o n t u m or cells via a bis pecific m olec ule lea ds t o a c y t ot o xic 
res p o nse. Cyt ot o xicit y  is me diate d b y release a n d tra nsfer of gra nz yme B a n d perf ori n fr o m 
t he T cell t o t he tar get cell. Usi n g t his C D 3 -bis pecific mec ha nis m of acti o n, P F - 0 7 0 6 2 1 1 9 
re directs T cells t o tar get G U C Y 2c e x pressi n g t u m or cells t hr o u g h c o-e n ga ge me nt of C D 3ε
o n t he T cell, a n d G U C Y 2c o n t he t u m or cell s urface, t here b y br oa de ni n g t he re pert oire of 
T cells t hat ca n rec o g nize t u m ors a n d act as effect or cells.
2. 2. 4. P F -0 7 0 6 2 1 1 9
P F -0 7 0 6 2 1 1 9 is a f ull y h u ma nize d a n d o pti mize d a nti - G U C Y 2c bis pecific t hera pe utic dr u g 
ca n di date t hat is a heter o di meric dia b o d y Fc f usi o n pr otei n c o m prise d of t w o rec o m bi na nt 
sc F v d o mai ns, o ne f ull y h u ma n d o mai n directe d a gai nst G U C Y 2c a n d t he ot her a gai nst t he 
C D 3ε c hai n ( h u ma nize d), f use d t o t he h u ma n Fc d o mai n of i m m u n o gl o b uli n 1 (I g G 1). 
P F - 0 7 0 6 2 1 1 9 bi n di n g of C D 3ε o n T cells a n d G U C Y 2c o n t u m or cells re directs T cells t o 
tar get G U C Y 2c-e x pressi n g t u m or cells w hic h i nitiates killi n g of t he G U C Y 2c e x pressi n g 
t u m or cell. P F-0 7 0 6 2 1 1 9 all o ws t he T -cell t o circ u m ve nt t he nee d f or t he i nteracti o n of t he 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 8
T C R a n d M H C class I  i n c o m ple x wit h a nti ge n, a n d i nstea d re directs T-cells t o tar get cells 
t hr o u g h direct c o-e n ga ge me nt of C D 3ε e x presse d o n T -cells.
2. 2. 5. N o ncli nic al P h ar m ac ol o g y
F urt her details of t he n o ncli nical p har mac ol o g y  of P F-0 7 0 6 2 1 1 9 are pr o vi de d i n t he I B.
2. 2. 5. 1. I n Vitr o P h ar m ac o d y n a mics
P F -0 7 0 6 2 1 1 9 de m o nstrate d l o w -n M bi n di n g t o h u ma n G U C Y 2c ( K D = 7. 4 7 n M) a n d h u ma n 
C D 3 ( K D = 2 3. 9 7 n M) b y  s urface plas m o n res o na nce ( S P R, 2 5° C), a n d l o w-n M bi n di n g t o 
b ot h tar gets si m ulta ne o usl y  ( E C5 0 = 8. 7 8 n M) b y  rec o m bi na nt pr otei n e nzy me li n ke d 
i m m u n os or be nt assa y ( E LI S A). P F-0 7 0 6 2 1 1 9 bi n di n g t o c y n o m ol g us m o n ke y  G U C Y 2c a n d 
m o use G U C Y 2c de m o nstrate d K D val ues of 3. 0 1 n M a n d 1 7. 2 7 n M, res pecti vel y .
2. 2. 5. 1. 1. Cell S urf ace Bi n di n g a n d C yt ot o xicit y of P F- 0 7 0 6 2 1 1 9 i n G U C Y 2c E x pressi n g 
T u m or Cell Li nes
P F -0 7 0 6 2 1 1 9 s h o we d d ose de pe n de nt bi n di n g b y fl o w c yt o metr y t o cell li ne 
3 0 0. 1 9 e n gi neere d t o e x press h u ma n G U C Y 2c, w h ile n o bi n di n g was o bser ve d i n pare ntal 
n o n -G U C Y 2c e x pressi n g 3 0 0. 1 9 cells, t here b y de m o nstrati n g s pecificit y  of P F-0 7 0 6 2 1 1 9 t o 
G U C Y 2c. G U C Y 2c cell s urface e x pressi o n was q ua ntifie d o ver a pa nel of ca ncer cell li nes 
usi n g a fl o w c y t o metr y-base d assa y  wit h a n a nti-h u ma n G U C Y 2c m o n ocl o nal a nti b o d y  
( m A b). H C T 1 1 6 cells were verifie d as ne gati ve f or G U C Y 2c e x pressi o n a n d were use d as 
t he ne gati ve c o ntr ol cell li ne i n s u bse q ue nt C T L assa ys.
P F - 0 7 0 6 2 1 1 9- me diate d cell killi n g was assesse d i n t hese cell li nes i n a 4 8- h o ur C T L  assa y 
at a 5: 1 or 1: 1 effect or ( T cell) t o tar get (t u m or cell) rati o. T he o bser ve d c y t ot o xicit y was 
T cell de pe n de nt si nce n o acti vit y  was o bser ve d wit h P F-0 7 0 6 2 1 1 9 i n t he a bse nce of T cells. 
P F - 0 7 0 6 2 1 1 9 de m o nstrate d cell killi n g i n all G U C Y 2c e x pressi n g cell li nes b ut n ot i n 
G U C Y 2c ne gati ve H C T 1 1 6 cells. C y t o ki ne release was als o assesse d i n t hese i n vitr o C T L 
assa ys as a s urr o gate meas ure of P F-0 7 0 6 2 1 1 9 a bilit y  t o acti vate h u ma n T cells. F oll o wi n g 
t he a d diti o n of P F-0 7 0 6 2 1 1 9 a n d T cells, c y t o ki nes were detecte d i n t he s u per nata nts of all 
G U C Y 2c -e x pressi n g ca ncer cell li nes, b ut n ot i n G U C Y 2c -ne gati ve H C T 1 1 6 cells.
A d diti o nall y , P F-0 7 0 6 2 1 1 9 was assesse d f or its p ote ntial t o a g o nize G U C Y 2c pat h wa y  
acti vit y b y meas uri n g t he pr o d ucti o n of t he d o w nstrea m effect or c yclic g ua n osi ne 
m o n o p h os p hate (c G M P) i n G U C Y 2c e x pressi n g T 8 4 t u m or cells. W hile t he G U C Y 2c 
pat h wa y  a g o nist, bacterial e nter ot o xi n S T p, i ncrease d c G M P i n a d ose- de pe n de nt ma n ner, 
c G M P pr o d ucti o n was n ot e n ha nce d b y t he a d diti o n of i ncreasi n g c o nce ntrati o ns of 
P F -0 7 0 6 2 1 1 9. A d diti o nall y , P F-0 7 0 6 2 1 1 9 di d n ot affect c G M P pr o d ucti o n i n d uce d b y S T p, 
i n dicati n g t hat P F-0 7 0 6 2 1 1 9 is neit her a G U C Y 2c pat h wa y  a g o nist, n or d oes it ne utralize 
G U C Y 2c pat h wa y  f u ncti o n i n t he prese nce of li ga n d.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 3 9
2. 2. 5. 1. 2. I n Vi v o P h ar m ac o d y n a mics
Si n gle A ge nt P F -0 7 0 6 2 1 1 9 St u dies: A nti -t u m or Effic ac y of P F-0 7 0 6 2 1 1 9 i n C ol orect al 
T u m or M o dels wit h V ar yi n g G U C Y 2c E x pressi o n
I n vi v o st u dies wit h P F-0 7 0 6 2 1 1 9 were c o n d ucte d i n C L X a n d P D X m o dels of c ol orectal 
ca ncer wit h var yi n g le vels of G U C Y 2c e x pressi o n. Fi g ure 1 hi g hli g hts d ose -de pe n de nt si n gle 
a ge nt a nti -t u m or acti vit y o bser ve d i n t he L S 1 0 3 4 C LX m o del a n d t he P D X -C R X - 1 1 2 0 1 
P D X m o del, b ot h of w hic h ha d relati vel y  hi g h e x pressi o n of G U C Y 2c a n d were m uta nt f or 
B R A F a n d K R A S.
Fe male N O D -sci d I L- 2 Rn ull ( N S G) mice were i m pla nte d s u bc uta ne o usl y wit h t he 
L S 1 0 3 4 cell li ne or fra g me nts of P D X -C R X -1 1 2 0 1, usi n g a d o pti ve h u ma n T -cell tra nsfer. I n 
t he LS 1 0 3 4 m o del, P F -0 7 0 6 2 1 1 9 treat me nt res ulte d i n si g nifica nt ef ficac y ( p 0. 0 0 0 1 vers us 
ve hicle) wit h c o m plete t u m or re gressi o ns i n 1 0/ 1 0 mice d ose d as l o w as 0. 1 m g/ k g 
(Fi g ure 1 - A). T he a nti-t u m or acti vit y was d ose-de pe n de nt, si nce l o wer efficac y  was o bser ve d 
at 0. 0 3 m g/ k g of P F -0 7 0 6 2 1 1 9. P D X -C R X - 1 1 2 0 1 t u m or beari n g mice treate d wit h 
P F -0 7 0 6 2 1 1 9 als o s h o we d si g nifica nt efficac y  ( p 0. 0 0 0 1 vers us ve hicle) wit h 9/ 1 0 c o m plete 
t u m or re gressi o ns at 0. 1 5 m g/ k g ( Fi g ure 1 - B). A l o wer d ose of 0. 0 5 m g/ k g res ulte d i n 
re d uce d efficac y ( p 0. 0 5 vers us ve hicle), w hereas 0. 0 1 m g/ k g di d n ot s h o w a n y t u m or 
i n hi biti o n. Neit her t he P BS ve hicle c o ntr ol, n or t he ne gati ve c o ntr ol bis pecific, P F - 0 7 0 6 9 6 9 9, 
i n hi bite d t u m or gr o wt h i n a n y m o del. All treat me nts were well t olerate d wit h n o o verall 
effect o n b o d y wei g ht.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 0
Fi g ure 1.
Si n gle A ge nt P F -0 7 0 6 2 1 1 9 Effic ac y i n Est a bl is he d T u m or M o dels wit h 
A d o pti ve H u m a n T Cell Tr a nsfer
N S G mice beari n g A. L S 1 0 3 4, B. P D X -C R X -1 1 2 0 1 t u m ors were d ose d I V w it h P F-0 7 0 6 2 1 1 9, P F -0 7 0 6 9 6 9 9 or 
P B S w it h wee kl y I V d oses ( 3 d oses f or L S 1 0 3 4 a n d 4 d oses f or P D X-C R X -1 1 2 0 1), a n d h u ma n T cells were 
a d mi nistere d o ne da y after t he first d ose. T u m ors were meas ure d t w ice wee kl y. Data are re p orte d as mea n 
t u m or v ol u me ± S E M.
I V =i ntra ve n o us; N S G = N O D-sci d I L-2 Rγ n ull; P F-0 7 0 6 2 1 1 9 = G U C Y 2c -C D 3 bis pecific; P F -0 7 0 6 9 6 9 9 = ne gati ve 
c o ntr ol C D 3 bis pecific; S E M =sta n dar d err or of t he mea n.
2. 2. 5. 1. 2. 1. E v al u ati o n of I ntr a ve n o us vers us S u bc ut a ne o us D osi n g F oll o wi n g Si n gle 
A ge nt P F -0 7 0 6 2 1 1 9 i n a C ol orect al T u m or M o del
T he r o ute of a d mi nistrati o n of d osi n g P F -0 7 0 6 2 1 1 9 was c o m pare d i n efficac y  st u dies usi n g 
t he hi g h G U C Y 2c-e x pressi n g LS 1 0 3 4 S C C L X m o del, w here t he bis pecific was d ose d 
Q 7 D x 3 I V or S C 0. 1 m g/ k g, 0. 0 6 m g/ k g a n d 0. 0 3 m g/ k g. T here was n o statisticall y  
si g nifica nt differe nce i n t he efficac y o bser ve d wit h I V or S C a d mi nistrati o n of P F-0 7 0 6 2 1 1 9 
at eac h d ose le vel teste d ( p -val ues 0. 0 5).
2. 2. 5. 1. 2. 2. C o m bi n ati o n St u dies wit h P F -0 7 0 6 2 1 1 9 a n d A nti -P D -L 1, A nti -P D -1, or 
A nti -V E G F - A
T he L S 1 0 3 4 C L X m o del de m o nstrate d P F -0 7 0 6 2 1 1 9 treat me nt de pe n de nt i ncrease i n TI Ls 
wit h e x pressi o n of gra nz y me B t hat was p olarize d t o war ds t u m or cells, s u g g esti n g t hat t hese 
TI Ls were p oise d t o f or m i m m u ne s y na pses a n d kill t u m or cells. A d diti o nall y , t u m ors treate d 
wit h P F -0 7 0 6 2 1 1 9 als o s h o we d u pre g ulati o n of P D -L 1 (a vel u ma b m o use re verse c hi meric 
a nti b o d y) at b ot h 1 m g/ k g a n d 0. 0 3 m g/ k g d oses, i n dicati n g t hat c hec k p oi nt mec ha nis ms t hat 
c o ul d da m pe n C T L acti vit y were bei n g i n d uce d wit h treat me nt. T heref ore, P F-0 7 0 6 2 1 1 9 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 1
c o m bi nati o ns wit h P D - 1 ( pe m br oliz u ma b a nti b o d y wit h h u ma n I g G 2 Fc effect or f u ncti o n 
m uta nt bac k b o ne [ D 2 6 5 A hl g G 2 d A Fc effect or f u ncti o n m uta nt] )/ P D-L 1  c hec k p oi nt 
i n hi bit ors were e val uate d i n t his m o del. T u m or-beari n g mice were treate d wit h a mi ni mall y  
efficaci o us d ose of 0. 0 3 m g/ k g of P F -0 7 0 6 2 1 1 9 as a si n gle a ge nt, i n c o m bi nati o n wit h eit her 
1 0 m g/ k g a nti -P D -L 1 or 5 m g/ k g a nti -P D -1. I n b ot h a nti -P D -L 1  a n d a nti-P D -1 c o m bi nati o ns 
wit h P F -0 7 0 6 2 1 1 9, a si g nifica nt c o m bi nati o n be nefit was o bser ve d ( p -val ues of < 0. 0 0 0 1 a n d 
0. 0 0 0 4 res pecti vel y), w hereas mi ni mal t o n o efficac y  was o bser ve d wit h si n gle a ge nts 
(Fi g ure 2 ).
I n a d diti o n, a nti-V E G F bl oc ka de, a mec ha nis m k n o w n t o i ncrease T -cell i nfiltrati o n i n 
t u m ors was c o m bi ne d wit h P F-0 7 0 6 2 1 1 9. T he P D X -C R X -1 1 2 0 1 m o del, w hic h is partiall y  
res p o nsi ve t o a nti- VE G F - A m A b treat me nt, was use d t o e val uate t he be nefit of c o m bi ni n g 
P F - 0 7 0 6 2 1 1 9 wit h a nti-V E G F -A t hera p y. T he c o m bi nati o n of t he a nti -V E G F -A treat me nt 
wit h a mi ni mall y  efficaci o us si n gle a ge nt d ose of P F-0 7 0 6 2 1 1 9 at 0. 0 5 m g / k g le d t o 
c o m plete t u m or re gressi o ns i n 1 0/ 1 0 mice. I n all c o m bi nati o n st u dies, all treat me nts were 
well t olerate d a n d t here was n o o verall effect o n b o d y  wei g ht.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 2
Fi g ure 2.
A nti -t u m or Effic ac y f oll o wi n g P F-0 7 0 6 2 1 1 9 i n C o m bi n ati o n wit h A nti P D -1, 
A nti -P D -L 1, or A nt i-V E G F -A i n C ol orect al T u m or M o dels
A . N S G mice beari n g S C L S 1 0 3 4 t u m ors were d ose d I V wit h P F-0 7 0 6 2 1 1 9 (as si n gle a ge nt or i n c o m bi nati o n 
wit h a nti -P D -L 1/ a nti -P D -1 m A bs), P F -0 7 0 6 9 6 9 9 or P B S o n Da ys -1, 6 a n d 1 3 ( Q 7 D x 3) I V. A nti -P D -L 1 m A b 
wa s a d mi nistere d I V o n da ys -1, 2, 5, 8, 1 1 a n d 1 4 ( Q 3 D x 6) eit her as a si n gle a ge nt or c o m bi nati o n wit h 
P F -0 7 0 6 2 1 1 9. A nti -P D - 1 m A b w as d ose d I V o n da ys -1, 6 a n d 1 3 ( Q 7 D x 1 3) eit her as si n gle a ge nt or i n 
c o m bi nati o n wit h P F-0 7 0 6 2 1 1 9. All mice were d ose d I V wit h T cells o n Da y 0 t o e val uate c o m bi nati o n be nefits 
of a d mi nisteri n g P F -0 7 0 6 2 1 1 9 w it h a nti-P D -L 1/a nti -P D -1 vs si n gle a ge nt treat me nt. 
B. N S G mice beari n g S C P D X -C R X -1 1 2 0 1 t u m ors were d ose d I V w it h P F-0 7 0 6 2 1 1 9 (as si n gle a ge nt or i n 
c o m bi nati o n wit h a nti -V E G F -A m A b), P F -0 7 0 6 9 6 9 9 or P B S o n Da ys 0, 7 a n d 1 4 ( Q 7 D x 3) I V. A nti -V E G F -A 
m A b was a d mi nistere d I V o n da ys 0, 3, 6, 9 ( Q 3 D x 4) eit her as a si n gle a ge nt or c o m bi nati o n wit h 
P F -0 7 0 6 2 1 1 9. All mice were d ose d I V w it h T cells o n Da y 1 t o e val uate c o m bi nati o n be nefit of a d mi nisteri n g 
P F -0 7 0 6 2 1 1 9 wit h V E G F bl oc ka de. T u m or were meas ure d t w ice wee kl y. Data are re p orte d as mea n t u m or 
v ol u me ± S E M.
I V =i ntra ve n o us; N S G = N O D-sci d I L-2 R n ull; P F-0 7 0 6 2 1 1 9 = G U C Y 2c -C D 3 bis pecific; P F -0 7 0 6 9 6 9 9 = ne gati ve 
c o ntr ol C D 3 bis pecific; m A b = m o n ocl o nal a nti b o d y; Q 7 D x 3 = d osi n g e ver y 7 d a y s f or a t otal of 3 d oses; 
Q 3 D x 6 = d osi n g e ver y 3 da ys f or a t otal of 6 d oses; Q 3 D x 4 = d osi n g e ver y 3 da ys f or a t otal of 4 d oses; 
S E M =sta n dar d err or of t he mea n.
F or a d diti o nal details of t he i n vitr o a n d i n vi v o acti vit y  of P F -0 7 0 6 2 1 1 9 refer t o t he I B.
2. 2. 6. N o ncli nic al P h ar m ac o ki netics a n d Met a b olis m
P K of P F -0 7 0 6 2 1 1 9 was e val uate d i n c y n o m ol g us m o n ke y s f oll o wi n g I V i njecti o ns of P F-
0 7 0 6 2 1 1 9 at d oses fr o m 1 µ g/ k g t o 1 8 0 µ g / k g a n d S C a d mi nistrati o n at 3 µ g/ k g t o 6 0 µ g/ k g. 
P F -0 7 0 6 2 1 1 9 mea n s ys te mic e x p os ure i ncrease d wit h d ose i n a ge nerall y d ose-pr o p orti o nal 
ma n ner s u g gesti n g n o e vi de nce of tar get -me diate d dr u g dis p ositi o n ( T M D D) acr oss t he 
teste d d ose ra n ge. Base d o n p o p ulati o n P K a nal ysis, t he mea n dr u g cleara nce fr o m t he ce ntral 
c o m part me nt ( C L) i n c yn o m ol g us m o n ke y s was 0. 2 2 m L / h/ k g, t he mea n stea d y state v ol u me 
of distri b uti o n ( V ss) was 7 3 m L / k g, a n d t he mea n ter mi nal eli mi nati o n half-life (t½ ) was 1 0 
da y s. F oll o wi n g s u bc uta ne o us ( S C) a d mi nistrati o n, bi oa vaila bilit y was m o derate ( ~ 6 0 %) [as 
assesse d b y area u n der t he c ur ve wit hi n t he first d osi n g i nter val ( A U Cta u)]. T he mea n P F-
0 7 0 6 2 1 1 9 ma xi m u m o bser ve d c o nce ntrati o n ( Cma x ) after t he first d ose a d mi nistrati o n of 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 3
6 0 µ g/ k g S C was ~ 7 0 % l o wer c o m pare d t o 6 0 µ g / k g I V a d mi nistrati o n. T he i nci de nce of 
A D A i n d ucti o n i n t he pi v otal t o xicit y  st u d y was a p pr o xi matel y 1/ 2 7 ( 3. 7 %), t h us n o f or mal 
assess me nt of t he i m pact o n A D A o n P F- 0 7 0 6 2 1 1 9 e x p os ure was c o n d ucte d. N o a p pare nt 
i m pact of ge n der o n t he s yste mic e x p os ure of P F-0 7 0 6 2 1 1 9 was o bse r ve d. Base d o n t he P K 
o bser ve d i n c y n o m ol g us m o n ke y s, t he P K of P F- 0 7 0 6 2 1 1 9 i n h u ma ns is e x pecte d t o be 
li near acr oss t he d ose ra n ge t o be teste d wit h a t½ of a p pr o xi matel y  2 1 da ys.
2. 2. 7. N o ncli nic al S afet y
I n n o ncli nical I V or S C st u dies wit h P F-0 7 0 6 2 1 1 9 i n c y n o m ol g us m o n ke y s of u p t o 1-m o nt h 
i n d urati o n, se verely t o xic fi n di n gs were o bser ve d at t he hi g h n o n -t olerate d d ose of 6 0 µ g/ k g 
( o nce wee kly I V or S C) i n t he 1-m o nt h G L P t o xicit y  st u d y. T his d ose was n ot t olerate d d ue 
t o decli ni n g c o n diti o n relate d t o e xte nsi ve a n d persiste nt cli nical o bser vati o ns of 
gastr oi ntesti nal distress (i ncl u di n g diarr hea, de h y d rati o n, h yp oacti vit y , re d uce d a p petite, etc.) 
a n d b o d y wei g ht l oss t hat res ulte d i n u nsc he d ule d e ut ha nasia of 4 a ni mals ( 2 a ni mals i n t he 
I V gr o u p a n d 2 a ni mals i n t he S C gr o u p) a n d disc o nti n uati o n of dr u g treat me nt f or 
3 a d diti o nal a ni mals at t he hi g h d ose ( 1 a n d 2 a ni mals i n t he I V a n d S C gr o u ps, res pecti vel y). 
Cli nical si g ns of gastr oi ntesti nal distress, partic ularl y  diarr hea a n d de hy d rati o n, were als o 
o bser v e d at a l o wer d ose of 3 0 µ g/ k g I V d uri n g 1 0 -d a y  n o n-G L P t o xic ol o g y  st u dies b ut were 
t olerate d wit h s u p p orti ve care ( oral a n d S C fl ui ds). T he d ose of 3 µ g / k g S C was t olerate d i n 
t he 1-m o nt h G L P t o xicit y  st u d y wit h o nl y mi n or occasi o nal cli nical o bser vati o ns of e mesis 
or l o ose st o ol. A d diti o nall y , cli nical o bser vati o ns of c yt o ki ne release sy n dr o me (i ncl u di n g 
e mesis, h yp oacti vit y , c ha n ges i n b o d y te m perat ure, h u nc he d p ost ure, etc) were o bser ve d after 
t he first d ose of P F-0 7 0 6 2 1 1 9 a n d were ass ociate d wit h ele va te d ser u m c yt o ki nes a n d 
mar kers of T -cell acti vati o n. T hese o bser vati o ns were li mite d t o 1/ 1 0 a ni mals wit h tra nsie nt 
e mesis o n Da y 1 at 3 µ g / k g S C. T he i nci de nce of cli nical o bser vati o ns relate d t o c yt o ki ne 
release as well as t he ma g nit u de of ser u m c yt o ki ne ele vati o ns were si g nifica ntl y  l o wer a n d 
was ass ociate d wit h a decrease d C ma x of a p pr o xi matel y 7 0 % i n a ni mals d ose d via t he S C 
r o ute c o m pare d wit h t he I V r o ute.
Test article -relate d, b ut n o na d verse, tar get or ga ns i de ntifie d i ncl u de d t he gastr oi ntesti nal tract 
(cry pt cell h y per plasia, vill o us atr o p h y , mi xe d cell i nfla m mati o n, gastric gla n d h ypertr o p h y ), 
he mat ol y m p h o p oietic s yste m ( decrease d cell ularit y of b o ne marr o w, s plee n a n d t h y m us), 
pa ncreas ( m o n o n uclear cell i nfiltrates of islet cells), testis (se mi nifer o us t u b ular de ge nerati o n 
a n d re d uce d s per m), e pi di d y mis (cell ular de bris a n d e pit helial vac u olati o n), a n d ki d ne y  
(t u b ular dilatati o n of pr o xi mal a n d distal t u b ules a n d c ollecti n g d uct) a n d all fin di n gs 
c o m pletel y rec o vere d or were o nly see n i n a ni mals e ut ha nize d earl y ( ki d ne y, testis, 
e pi di d ymis).
T he N o A d verse Effect Le vel ( N O A E L)/ Hi g hest N o n- Se verel y  T o xic D ose ( H N S T D) i n t he 
pi v otal 1 -m o nt h g o o d la b orat or y  practice ( G LP) st u d y  was 3 µ g/ k g S C. T he mea n C ma x a n d 
A U C 1 6 8 after a d mi nistrati o n of o ne d ose of 3 µ g / k g S C were 2 4. 7 n g/ m L  a n d 3 7 1 0 n g· h/ m L, 
res pecti vely. T he mea n C ma x a n d A U C 1 6 8 after a d mi nistrati o n of 5 wee kl y d oses of 3 µ g/ k g 
S C were 8 9. 7 n g/ m L  a n d 1 3, 6 0 0 n g· h/ m L, res pecti vel y . 
T he sta rti n g d ose of 4 5 µ g Q 2 W is pre dicte d t o ha ve a h u ma n Cma x of 4. 2 n g/ m L a n d 
A U C 1 6 8 of 5 6 6 n g• hr/ m L. T he mar gi n of safet y base d o n C ma x a n d A U C 1 6 8 was calc ulate d as 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 4
a p pr o xi matel y 2 1 × a n d 2 4 ×, res pecti vely base d o n t he c o m paris o n of H N S T D e x p os ure i n 
t he 1-m o nt h re peat -d ose G L P t o xicit y  st u d y i n m o n ke ys t o t he pre dicte d h u ma n e x p os ure at 
t he rec o m me n de d starti n g d ose.
F urt her details of t he n o ncli nical safet y pr o gra m are pr o vi de d i n t he c urre nt I B.
2. 2. 8. S u m m ar y of C urre nt Cli nic al D at a fr o m St u d y C 3 8 6 1 0 0 1
T he c urre nt s u m mar y  of cli nical data is base d o n Part 1 A, d ose escalati o n of t he 
P F -0 7 0 6 2 1 1 9 m o n ot hera p y  wit h o ut pri mi n g d ose, of St u d y C 3 8 6 1 0 0 1. As of 
2 8 Dece m ber 2 0 2 0, 2 2 partici pa nts ha ve bee n d ose d acr oss 5 d ose le vels ( 4 5 µ g, 1 3 5 µ g, 
4 0 0 µ g, 8 0 0 µ g, a n d 1 6 0 0 µ g) of P F -0 7 0 6 2 1 1 9 a d mi nistere d S C Q 2 W. 
2. 2. 8. 1. S afet y D at a U p d ate
T he m ost c o m m o n treat me nt -e mer ge nt a d verse e ve nts occ urri n g i n ≥1 0 % of partici pa nts a n d 
p ossi bl y  relate d t o P F-0 7 0 6 2 1 1 9 i ncl u de d fe ver, diarr hea, v o miti n g, C R S, na usea, pr urit us, 
fati g ue, i njecti o n site reacti o n, decrease d a p petite, h yp ote nsi o n, li pase i ncrease, ala ni ne 
a mi n otra nsferase i ncrease d, a m yl ase i ncrease d, as partate a mi n otra nsferase i ncrease d, c hills, 
c o nsti pati o n, hea dac he, a n d h y p o kale mia. A D L T of Gra de 3 diarr hea (lasti n g > 3 da ys)
occ u rre d i n b ot h partici pa nts treate d at t he hi g hest d ose le vel ( 1 6 0 0 µ g) wit h o ut pri mi n g, a n d 
D L T of Gra de 3 diarr hea (lasti n g > 3 da y s) a n d Gra de 3 C R S occ urre d res pecti vel y i n 2 of 9 
partici pa nts treate d at t he d ose le vel ( 8 0 0 µ g) esta blis he d as t he si n gle -age nt ma xi m u m 
t olerate d d ose ( M T D) wit h o ut pri mi n g.
2. 2. 8. 2. P h ar m ac o ki netics
Preli mi nar y  P K para meters f or partici pa nts esti mate d usi n g n o mi nal c ollecti o n ti mes a n d 
q ualit y -c o ntr olle d, n ot q ualit y-ass ure d bi oa nal ytical data are prese nte d i n Ta ble 7 . Data are 
s u m marize d f or all c o h orts ( 4 5 µ g, 1 3 5 µ g, 4 0 0 µ g, 8 0 0 µ g, a n d 1 6 0 0 µ g) treate d wit h a 
si n gle S C d ose of P F-0 7 0 6 2 1 1 9. 
F oll o wi n g S C a d mi nistrati o n, P F -0 7 0 6 2 1 1 9 was a bs or be d sl o wl y wit h a me dia n T ma x f or 
m ost c o h orts ra n gi n g fr o m 4 t o 7 da y s p ost si n gle- d ose a d mi nistrati o n. O verall, e x p os ures 
i ncrease d i n a n a p pr o xi matel y d ose-pr o p orti o nal ma n ner wit h i ncreasi n g d oses. 
F oll o wi n g re peate d d osi n g Q 2 W, t he pre d ose c o nce ntrati o ns i ncrease d wit h eac h s uccessi ve 
d ose i n dicati n g p ote ntial acc u m ulati o n of t he dr u g. Li mite d data are a vaila ble f or m ulti ple 
d ose P K i n C y cle 4, d ue t o m ost partici pa nts c o mi n g off st u d y  pri or t o t he assess me nt.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 5
T a ble 7 .  
Me a n ( % C V) P K P ar a meters F oll o wi n g Si n gle S C D oses of P F-0 7 0 6 2 1 1 9 
i n P artici p a nts wit h A d v a nce d GI T u m ors ( St u d y C 3 8 6 1 0 0 1)
D ose ( µ g) S C/ # of 
p artici p a nts
St u d y D a y
T m a x 2
( hr)
C m a x 1
( n g/ m L)
A U C 1 6 8 1, 3
( n g * hr/ m L)
A U C 3 3 6 1, 3 ( n g * hr/ m L)
4 5 ( n = 2)
C 1 D 1
8- 3 3 6 
2. 9 7 
3 3 9 
8 0 3 
1 3 5 ( n = 3)
C 1 D 1
1 6 8 
( 9 6-1 6 8)
9. 0 3 ( 9. 8)
1 2 0 5 ( 4. 4)
2 6 0 0 ( 8. 0)
4 0 0 ( n = 6)
C 1 D 1
9 6 
( 9 6-3 3 6)
4 3. 7 ( 4 0)
5 5 8 2 ( 5 4)
1 2 0 6 8 ( 4 2)
8 0 0 ( n = 9)
C 1 D 1
9 6
( 2 4-1 6 8)
6 6. 8 ( 3 9)
9 0 4 1 ( 3 9)
1 8 9 4 3 ( 3 5)
1 6 0 0 ( n = 2) 4
C 1 D 1
2 4 
1 1 5 
1 6 4 5 1
--
1 C ma x , A U C 1 6 8 a n d A U C 3 3 6: mea n ( % C V). O nl y mea n prese nte d f or N = 2. O nl y i n di vi d ual val ue prese nte d if 
N = 1.
2 T ma x : Me dia n ( Ra n ge). O nl y ra n ge prese nte d f or N = 2. O nl y i n di vi d ual val ue prese nte d if N = 1.
3 8 0 0 µ g: n = 8 f or A U C1 6 8 a n d A U C 3 3 6
4 1 6 0 0 µ g: n = 1 f or T ma x , Cma x a n d A U C 1 6 8. O ne of t he 2 partici pa nts at t his d ose le vel pr o vi de d P K o nl y u p t o 
4 8 h o urs.
2. 3. A nti - Pr o gr a m me d Cell De at h Pr otei n-1 ( A nti -P D -1)  
Bi n di n g of t he pr o gra m me d cell deat h pr otei n -1 li ga n ds, P D -L 1 a n d P D -L 2 , t o t he P D- 1 
rece pt or f o u n d o n T cells i n hi bits T -cell pr oliferati o n, c yt o ki ne pr o d ucti o n, a n d its c yt ot o xic 
f u ncti o ns. U pre g ulati o n of P D-1 li ga n ds occ ur i n certai n t u m or t y pes a n d si g nali n g t hr o u g h 
t his pat h wa y ca n c o ntri b ute t o t he i n hi biti o n of acti ve T-cell i m m u ne s ur veilla nce of t u m ors. 
I n sy n ge neic m o use t u m or m o dels, bl oc ki n g P D -1 acti vit y  res ulte d i n decrease d t u m or 
gr o wt h. A p pr o val of ni v ol u ma b/ O p di v o ® (a f ully h u ma n i m m u n o gl o b uli n G 4 [I g G 4] 
a nti-P D -1 a nti b o d y  [ A b]), pe m br oliz u ma b/ Ke ytr u da® (a h u ma nize d I g G 4 a nti-P D -1 A b), 
Atez oliz u ma b/ Tece ntri q ® (a h u ma nize d I g G 1 a nti-P D -L 1  A b), d ur val u ma b/I mfizi®
(a h u ma nize I g G 1 a nti -P D - 1 A b), a n d a vel u ma b/ Ba ve nci o® (a f ully h u ma n I g G 1 a nti -P D -L 1 
A b) f or t he treat me nt of m ulti ple t u m or i n dicati o ns pr o vi de c o m pelli n g e vi de n ce t hat 
bl oc ka ge of t he P D -1 pat h wa y  is a vali date d i m m u n ot hera pe utic a p pr oac h ( O p di v o® U nite d 
States Pac ka ge I nsert ( U S PI ), 2 0 1 9; Tece ntri q® U S PI , 2 0 1 9; Ke ytr u da® U S PI , 2 0 1 9; 
I mfi nzi™U S PI , 2 0 1 8; Ba ve nci o® U S PI, 2 0 1 9).
2. 3. 1. P F -0 6 8 0 1 5 9 1, a n A nti -P D -1 A nti b o d y: Cli nic al E x perie nce i n St u d y B 8 0 1 1 0 0 1 
( N C T 0 2 5 7 3 2 5 9)
B 8 0 1 1 0 0 1 is a n o n g oi n g P hase 1, o pe n -la bel, m ulti-ce nter, m ulti ple-d ose, d ose escalati o n 
a n d e x pa nsi o n, safet y, P K, a n d P D st u d y of P F -0 6 8 0 1 5 9 1. T he pri mar y  p ur p ose of t his st u d y 
is t o e val uate safet y a n d earl y si g ns of efficac y . T his cli nical st u d y was di vi de d i nt o a d ose 
escalati o n ( Part 1) p hase a n d a d ose e x pa nsi o n ( Part 2) p hase. As of 1 0 Fe br uar y  2 0 2 1, 
e nr oll me nt has bee n c o m plete d i n t his st u d y  a n d 1 4 6 partici pa nts ha ve bee n d ose d o n t he 
st u d y ra n gin g fr o m 0. 5 m g/ k g I V u p t o 3 0 0 m g S C. Refere nce Secti o n 1 0. 9 f or Preli mi nar y 
Cli nical S u m mar y . M ore detaile d i nf or matio 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 bly e x pecte d A Es of P F -0 6 8 0 1 5 9 1 ma y  be f o u n d i n t he res pecti ve I B, w hic h 
is t he si n gle refere nce safet y d oc u me nt ( S R S D).
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 6
2. 4. O ver vie w of Be v aciz u m a b -Pfizer ( Zir a be v ™)
Be vaciz u ma b is a vasc ular e n d ot heli n gr o wt h fact or ( V E G F) i n hi bit or a n d a p pr o ve d f or 
treat me nt of metastatic c ol orectal ca ncer, i n c o m bi nati o n wit h i ntra ve n o us fl u or o uracil-base d 
c he m ot hera p y f or first- or sec o n d-li ne treat me nt a n d als o i n c o m bi nati o n wit h 
fl u or o p yri mi di ne-, iri n oteca n- or fl u or o p y ri mi di ne-o xali plati n base d c he m ot hera p y  f or 
sec o n d-li ne treat me nt i n partici pa nts w h o ha ve pr o gresse d o n a first-li ne be vaciz u ma b 
pr o d uct -c o ntai ni n g re gi me n. Cli nicall y si g nifica nt a d verse reacti o ns i ncl u de gastr oi ntesti nal 
perf orati o ns a n d fis t ulae, s ur ger y a n d w o u n d heali n g c o m plicati o ns, he m orr ha ge, arterial a n d 
ve n o us t hr o m b oe m b olic e ve nts, h y perte nsi o n, p osteri or re versi ble e nce p hal o pat h y s y n dr o me, 
re nal i nj ur y a n d pr otei n uria, i nf usi o n-relate d reacti o ns, o varia n fail ure, a n d c o n gesti ve heart 
fail ure ( Pfizer, U nite d States Pac ka ge I nsert ( U S PI), 2 0 1 9). T he bi osi milar versi o n of 
A vasti n ® will be use d i n t his st u d y , ma n ufact ure d b y Pfizer a n d hereafter referre d t o as 
be vaciz u ma b -Pfizer. Be vaciz u ma b -Pfizer is c o m merciall y a vaila ble a n d will be use d i n 
acc or da nce wit h its l ocal la bel. T he S R S D f or be vaciz u ma b- Pfizer is its c ore data s heet 
( C D S).
2. 5. Be nefit/ Ris k Assess me nt
T here c o nti n ues t o be si g nifica nt u n met me dical nee d f or m ore effecti ve t hera pies f or 
a d va nce d or metastatic gastr oi ntesti nal a de n ocarci n o mas t hat ha ve rela pse d or are refract or y  
t o c urre nt t hera pies. C urre ntl y a vaila ble t hera pies f or a d va nce d or metastatic c ol orectal a n d 
gastric a de n ocarci n o mas ha ve ver y  li mite d cli nical be nefit b ot h i n ter ms of res p o nse a n d 
d urati o n of res p o nse. A lt h o u g h t here is li mite d cli nical e x perie nce wit h P F-0 7 0 6 2 1 1 9, w hic h 
is a n a nti-G U C Y 2c/a nti -C D 3 -bis pecific bei n g de vel o pe d f or a d va nce d gastr oi ntesti nal 
mali g na ncies i ncl u di n g c ol orectal a n d gastric a de n ocarci n o mas, si g nifica nt t u m or re d ucti o n 
was o bser ve d i n precli nical p har mac ol o g y st u dies wit h P F- 0 7 0 6 2 1 1 9 i n a n u m ber of m o dels 
wit h c ol orectal a de n ocarci n o mas, i ncl u di n g t h ose t hat are es peciall y resista nt s uc h as t h ose 
wit h K R A S a n d B R A F p ositi vit y . A d diti o nall y, P F-0 7 0 6 2 1 1 9 has t he p ote ntial t o be use d i n 
t he setti n gs of eit her micr osatellite sta ble ( M S S) or hi g h micr osatellite i nsta bilit y hi g h 
( M SI-H) disease gastr oi ntesti nal a de n ocarci n o mas si nce G U C Y 2c is e x presse d acr oss b ot h 
s u bt ypes ( Bas hir et al, 2 0 1 9). 5
T he safet y pr ofile of P F -0 7 0 6 2 1 1 9 has bee n c haracterize d i n e x pl orat or y  a n d pi v otal 
t o xic ol o g y st u dies a n d is descri be d i n Secti o n 2. 2. 8 . T he pri mar y t o xicities ass ociate d wit h 
P F -0 7 0 6 2 1 1 9 i n n o n -h u ma n pri mates i ncl u de diarr hea a n d C R S at d oses c o nsi dere d t o n ot be 
t olera ble. H o we ver, t hese t o xicities were of li mite d fre q ue nc y a n d gra de a n d t heref ore 
c o nsi dere d n o n -a d verse at t olera ble d oses. C R S a n d diarr hea ha ve bee n o bser ve d i n t he 
cli nical st u d y. Cl ose me dical m o nit ori n g, i ncl u di n g i n patie nt o bser vati o n f or at least 4 8 h o urs 
f oll o wi n g t he i nitial P F-0 7 0 6 2 1 1 9 S C d ose a n d f or at least 8 h o urs f oll o wi n g t he sec o n d P F-
0 7 0 6 2 1 1 9 S C d ose i n t he c o h ort wit h o ut a pri mi n g d ose a n d at least 2 4 h o urs after t he first 
( pri mi n g) S C d ose a n d 2 4 h o urs after t he sec o n d (f ull) S C d ose i n t he c o h ort wit h a pri mi n g 
d ose, al o n g wit h safet y assess m e nts will occ ur t hr o u g h o ut t he st u d y. S u p p orti ve care 
meas ures as descri be d i n Secti o n 6. 6. 2 are a vaila ble t hat ma y be c o nsi dere d i n t he 
ma na ge me nt o f b ot h C R S a n d diarr hea ( Lee et al, 2 0 1 4; Lee et al, 2 0 1 9; Be ns o n et al, 
2 0 0 4). 2 4 ,2 5 ,7
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 7
At t his sta ge of de vel o p me nt, t he be nefit -ris k f or P F-0 7 0 6 2 1 1 9 is c o nsi dere d acce pta ble i n 
partici pa nts wi t h a d va nce d gastr oi ntesti nal a de n ocarci n o mas.
F or t his st u d y , t he st u d y i nter ve nti o n is P F-0 7 0 6 2 1 1 9. P F - 0 6 8 0 1 5 9 1 a n d be vaciz u ma b-Pfizer 
will be use d as c o m bi nati o n a ge nts wit h P F -0 7 0 6 2 1 1 9. 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 0 6 2 1 1 9 a n d 
P F -0 6 8 0 1 5 9 1 ma y  be f o u n d i n t heir res pecti ve I Bs, w hic h are t heir S R S Ds f or t his st u d y. F or 
t he P E T i ma gi n g st u d y 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 bly e x pecte d A Es of t he P E T tracer bei n g use d ma y  be f o u n d i n t he 
I ma gi n A B I B w hic h is t he res pecti ve S R S D f or t his st u d y. Be vaciz u ma b -Pfizer is a p pr o ve d 
a n d will be c o m merciall y a vaila ble i n certai n re gi o ns a n d will be use d i n acc or da nce wit h its 
l ocal la bel. T he S R S D f or be vaciz u ma b-Pfizer is its C D S.
3. O B J E C TI V E S A N D E N D P O I N T S
D ose Esc al ati o n ( P art 1):
O bjecti ves
E n d p oi nts
Pri m ar y: 
Pri m ar y: 

T o assess safet y a n d t olera bilit y of i ncreasi n g d ose 
le vels of P F-0 7 0 6 2 1 1 9 wit h a n d wit h o ut pri mi n g d ose 
a d mi nistere d i n partici pa nts wit h a d va nce d 
gastr oi ntesti nal  t u m ors, i ncl u di n g c ol o n, gastric, a n d 
es o p ha geal a de n ocarci n o mas, f or w h o m n o sta n dar d 
t hera p y is a vaila ble i n or der t o esti mate t he Ma xi m u m 
T olerate d D ose ( M T D) a n d select t he Rec o m me n de d 
P hase 2 D ose ( R P 2 D) as a m o n ot hera p y i n Part 1 A 
a n d i n c o m bi nati o n t hera p y i n Part 1 B wit h select 
t u m or(s).

First c ycle D ose Li miti n g T o xicities ( D L Ts);

A d ve rse E ve nts as c haracterize d b y t y pe, fre q ue nc y, 
se verit y (as gra de d b y Nati o nal Ca ncer I nstit ute 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 
[N CI C T C A E ] versi o n 5) , 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 har acterize 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 [ versi o n 5. 0]), a n d ti mi n g.
Sec o n d ar y: 
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 0 6 2 1 1 9;

T o e val uate t he i m m u n o ge nicit y of P F -0 7 0 6 2 1 1 9;

T o e val uate t he i m m u n o ge nicit y of P F- 0 6 8 0 1 5 9 1 a n d 
be vaciz u ma b -Pf izer gi ve n i n c o m bi nati o n wit h 
P F -0 7 0 6 2 1 1 9 ( Part 1 B);

T o e val uate i m m u ne cells i n arc hi val t u m or bi o psies 
a n d/ or pre a n d p ost treat me nt t u m or bi o psies (if 
a vaila ble);

T o e val uate preli mi nar y a nti- t u m or acti vit y.
P K para meters of P F - 0 7 0 6 2 1 1 9:

C y cle 1 a n d C ycle 4 P K para meters ma xi m u m 
c o nce ntrati o n ( C ma x), ti me t o ac hie ve Cma x ( Tma x ), 
area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m 
ti me zer o t o t he last q ua ntifia ble c o nce ntrati o n 
( A U Clast). If data per mits, ot her P K para meters will 
be deri ve d s uc h as a p pare nt cleara nce ( C L/ F), 
ter mi nal half-life (t1/ 2), a n d t he area u n der t he plas ma 
c o nce ntrati o n -ti me pr ofile fr o m ti me zer o 
e xtra p olate d t o i nfi nite ti me ( A U C i nf);

Pre d ose tr o u g h c o nce ntrati o ns after m ulti ple d oses of 
P F -0 7 0 6 2 1 1 9; 

I nci de nce a n d titers of A D A a n d NA b P F -0 7 0 6 2 1 1 9;

I nci de nce a n d titers of A D A a n d NA b a gai nst 
P F -0 6 8 0 1 5 9 1 a n d be vaciz u ma b -Pf izer gi ve n i n 
c o m bi nati o n wit h P F -0 7 0 6 2 1 1 9 ( Part 1 B); 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 8
O bjecti ves
E n d p oi nts

Assess me nt of le vels of i ntra- t u m or T cells (e g, C D 8 
I H C);

O bjecti ve res p o nse, as assesse d usi n g R E CI S T 
versi o n 1. 1.
Terti ar y/ E x pl or at or y: 
Terti ar y/ E x pl or at or y:

T o e x pl ore preli mi nar y a nti- t u m or acti vit y b y sta n dar d 
a n d i m m u ne-relate d res p o nse criteria a n d ti me t o e ve nt 
e n d p oi nts;

T o e x pl ore t he relati o ns hi p bet wee n tar get e x pressi o n 
a n d bi o mar kers i n arc hi val t u m or bi o psies a n d/ or pre 
a n d p ost treat me nt t u m or bi o psies (if a vaila ble), w h ole 
bl o o d, a n d ser u m sa m ples i n or der t o el uci date 
mec ha nis m of acti o n a n d res p o nse t o t hera p y;

T o e x pl ore a d diti o nal bi o mar kers relate d t o cli nical 
res p o nse, i n or der t o el uci date t he mec ha nis m of 
acti o n of P F -0 7 0 6 2 1 1 9, pre dict res p o nse t o t hera p y, 
a n d t o u n dersta n d resista nce mec ha nis ms t hat ma y 
pre dict esca pe fr o m t hera p y;

T o e val uate T, B, a n d Nat ural Killer ( N K) s u bt y pes f or 
i m m u n o p he n ot y pi n g i n a d diti o n t o T cell pr oliferati o n, 
acti vati o n, a n d e x ha usti o n mar kers i n w h ole bl o o d; 

T o e x pl ore c yt o ki nes a n d c he m o ki nes as 
p har mac o d y na mic ( P D) mar kers i n pre a n d o n 
treat me nt ser u m sa m ples;

T o e x pl ore t he t u m or bi o mar ker carci n oe m br y o nic 
a nti ge n ( C E A) le vels;

T o e na ble e x pl orat or y researc h t hr o u g h c ollecti o n of 
ba n ke d bi os peci me ns, 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.

T o e val uate t he tr o u g h le vels of P F- 0 6 8 0 1 5 9 1 a n d 
be vaci z u ma b -Pf izer gi ve n i n c o m bi nati o n wit h 
P F -0 7 0 6 2 1 1 9 ( Part 1 B;

Pr o gressi o n free s ur vi val ( P F S) a n d d urati o n of 
res p o nse ( D O R) b y R E CI S T versi o n 1. 1;

O verall t u m or assess me nt b y t he I m m u ne Relate d 
Res p o nse Criteria i n S oli d T u m or (ir R E CI S T) 
(criteria a n d i m m un e -relate d pr o gressi o n free 
s ur vi val (ir P F S);

G U C Y 2c e x pressi o n le vels i n arc hi val a n d/ or pre a n d 
o n/ p ost treat me nt t u m or bi o psies;

I m m u n o p he n ot y pi n g of bl o o d I m m u ne cell s u bt y pes 
fre q ue nc y a n d acti vati o n;

I ntra-t u m or i m m u ne pat h wa y m o d ulati o n, ge ne 
e x pressi o n pr ofiles, D N A m utati o ns a n d i m m u ne cell 
bi o mar kers i n pre - a n d p ost - d ose t u m or bi o psies;

C y t o ki ne a n d c he m o ki ne P D mar kers i n pre a n d o n 
treat me nt ser u m sa m ples;

C E A le vels i n ser u m;

C ha n ges i n C D 8 P E T tracer u pta ke pre a n d p ost 
treat me nt f or p artici pa nts i n v ol ve d i n C D 8 P E T 
tracer s u bst u d y (Secti o n 1 0. 1 9. 3 )

P ote ntial res ults fr o m e x pl orat or y a nal ysis of ba n ke d 
bi os peci me ns (t hese res ults ma y or ma y n ot be 
ge nerate d i n t he c o nte xt of t he prese nt st u d y).

Tr o u g h le vels of P F - 0 6 8 0 1 5 9 1 a n d 
be vaciz u ma b -Pf izer
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 4 9
D ose E x p a nsi o n ( P art 2):
O bjecti ves
E n d p oi nts
Pri m ar y: 
Pri m ar y: 

T o c o nfir m safet y a n d t olera bilit y a n d e val uate 
preli mi nar y e vi de nce of a nti -t u m or acti vit y of 
P F - 0 7 0 6 2 1 1 9 at t he R P 2 D i n partici pa nts wit h 
a d va nce d c ol orectal a de n ocarci n o mas (as a 
m o n ot hera p y a n d i n c o m bi nati o n t hera p 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 Nati o nal Ca ncer I nstit ute C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( N CI 
C T C A E versi o n [ 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 v 
5. 0]), a n d t i mi n g;

O R R as deter mi ne d b y t he R E CI S T versi o n 1. 1 
criteria.
Sec o n d ar y: 
Sec o n d ar y: 

T o e val uate t he P K of P F -0 7 0 6 2 1 1 9 at t he R P 2 D;

T o e val uate t he i m m u n o ge nicit y of P F -0 7 0 6 2 1 1 9;

T o e val uate t he i m m u n o ge nicit y of P F - 0 6 8 0 1 5 9 1 
a n d be vaciz u ma b -Pf izer gi ve n i n c o m bi nati o n wit h 
P F - 0 7 0 6 2 1 1 9;

T o e val uate i m m u ne P D effects of P F - 0 7 0 6 2 1 1 9 
bet wee n pre -treat me nt a n d p ost treat me nt t u m or 
bi o psies;

T o e val uate preli mi nar y a nti-t u m or acti vit y t hr o u g h 
ti me t o e ve nt e n d p oi nts.

P K c o nce ntrati o ns of P F -0 7 0 6 2 1 1 9; 

Pre d ose t r o u g h c o nce ntrati o ns after m ulti ple d oses of 
P F - 0 7 0 6 2 1 1 9;

I nci de nce a n d titers of A D A a n d NA b P F -0 7 0 6 2 1 1 9;

I nci de nce a n d titers of A D A a n d NA b a gai nst 
P F -0 6 8 0 1 5 9 1 a n d be vaciz u ma b -Pf izer gi ve n i n 
c o m bi nati o n wit h P F - 0 7 0 6 2 1 1 9;

Assess me nt of i ncrease d i ntra -tu m or T cells f oll o wi n g 
P F -0 7 0 6 2 1 1 9 treat me nt (e g, C D 8 I H C);

P F S a n d D O R b y R E CI S T versi o n 1. 1.
Terti ar y/ E x pl or at or y: 
Terti ar y/ E x pl or at or y:

T o d oc u me nt a n y a nti -t u m or acti vit y as assesse d b y 
i m m u ne relate d res p o nse criteria;

T o e x pl ore t he relati o ns hi p bet wee n tar get 
e x pressi o n a n d bi o mar kers i n arc hi val t u m or 
bi o psies a n d/ or pre - a n d p ost -treat me nt t u m or 
bi o psies, w h ole bl o o d, a n d ser u m sa m ples i n or der 
t o el uci date mec ha nis m of acti o n a n d res p o nse t o 
t hera p y;

T o e x pl ore a d di ti o nal bi o mar kers relate d t o cli nical 
res p o nse, i n or der t o el uci date t he mec ha nis m of 
acti o n of P F -0 7 0 6 2 1 1 9, pre dict res p o nse t o t hera p y, 
a n d t o u n dersta n d resista nce mec ha nis ms t hat ma y 
pre dict esca pe fr o m t hera p y;

T o e val uate T, B, a n d N K s u bt y pes f or 
im m u n o p he n ot y pi n g i n a d diti o n t o T cell 
pr oliferati o n, acti vati o n, a n d e x ha usti o n mar kers i n 
w h ole bl o o d; 

ir R E CI S T a n d ir P F S;

G U C Y 2c e x pressi o n le vels i n arc hi val a n d/ or pre - a n d 
o n/ p ost -treat me nt t u m or bi o psies;

I m m u n o p he n ot y pi n g of bl o o d I m m u ne cell s u bt y pes 
fre q ue nc y a n d acti vati o n;  

I ntra-t u m or i m m u ne pat h wa y m o d ulati o n, ge ne 
e x pressi o n pr ofiles, D N A m utati o ns a n d i m m u ne cell 
bi o mar kers i n pre - a n d p ost - d ose t u m or bi o psies;

C y t o ki ne a n d c he m o ki ne P D mar kers i n pre- a n d 
o n -treat me nt ser u m sa m ples;

C E A le vels i n ser u m;
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 0
O bjecti ves
E n d p oi nts

T o e x pl ore c yt o ki ne a n d c he m o ki ne P D mar kers i n 
pre a n d o n treat me nt ser u m sa m ples;

T o e x pl ore t he t u m or bi o mar ker C E A le vels;

T o e na ble e x pl orat or y r esearc h t hr o u g h c ollecti o n 
of ba n ke d bi os peci me ns, 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. 

T o e val uate t he tr o u g h le vels of P F -0 6 8 0 1 5 9 1 a n d 
be vaciz u ma b -Pf izer gi ve n i n c o m bi nati o n wit h 
P F -0 7 0 6 2 1 1 9;

C ha n ges i n C D 8 P E T tracer u pta ke pre a n d p ost 
treat me nt f or partici pa nts i n v ol ve d i n C D 8 P E T tracer 
s u bst u d y (Secti o n 1 0. 1 9. 3 )

P ote ntial res ults fr o m e x pl orat or y a nal ysis of ba n ke d 
bi os peci me ns (t hese res ults ma y or ma y n ot be 
ge nerate d i n t he c o nte xt of t he prese nt st u d y).

Tr o u g h le vels of P F -0 6 8 0 1 5 9 1 a n d be vaciz u ma b -
Pf izer
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, o pe n -la bel, m ulti-ce nter, m ulti ple-d ose, safet y, P K a n d P D st u d y  of 
P F -0 7 0 6 2 1 1 9 i n partici pa nts wit h selecte d a d va nce d or m etastatic gastr oi ntesti nal t u m ors. 
T his st u d y  c o ntai ns 2 parts: Part 1 d ose escalati o n of P F -0 7 0 6 2 1 1 9, wit h a n d wit h o ut a 
pri mi n g d ose, as a m o n ot hera p y ( Part 1 A) a n d i n c o m bi nati o n wit h a n a nti -P D - 1 or 
a nti-V E G F a ge nt ( Part 1 B) a n d Part 2 d ose e x pa nsi o n ( Fi g ure 3 ). T he P F-0 7 0 6 2 1 1 9 
a d mi nistrati o n re gi me n f or Parts 1 A, 1 B, a n d 2 ma y  be g ui de d b y S C d ose pri mi n g escalati o n 
c o h orts a n d all a vaila ble data will be use d t o ma ke a decisi o n o n f ut ure d ose re gi me ns.
Fi g ure 3.
C 3 8 6 1 0 0 1 St u d y Sc he m a
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 1
As t he R P 2 D/ M T D of P F - 0 7 0 6 2 1 1 9 is a p pr oac he d or has bee n deter mi ne d i n Parts 1 A a n d 
1 B, a n o pti o nal s u bset of partici pa nts ma y  be e nr olle d (a p pr o xi matel y 6 t o 1 2 partici pa nts) 
wit h t he re q uire me nt of pr o vi di n g ma n dat or y  paire d de n o v o pre-treat me nt a n d o n-treat me nt 
bi o ps y  sa m ples t o e na ble e val uati o n of tiss ue bi o mar ker P D acti vit y. T he o pti o n t o e nr oll t he 
s u bset of partici pa nts f or ma n dat or y paire d t u m or sa m ples will be base d o n e val uati o n of 
e mer gi n g cli nical data i ncl u di n g a vaila ble safet y/ t olera bilit y, P K, a n d P D fi n di n gs b y t he 
s p o ns or.
I n t he o verall FI P st u d y, a p pr o xi matel y 1 3 0 partici pa nts are e x pecte d t o be e nr olle d. Part 1 is 
esti mate d t o e nr oll a p pr o xi m atel y 7 0 partici pa nts ( 3 5 partici pa nts i n Part 1 A a n d 
3 5 partici pa nts i n Part 1 B). I n Part 2, a p pr o xi matel y 2 0 partici pa nts eac h will be e nr olle d i n 
t he m o n ot hera py a n d b ot h c o m bi nati o n c o h orts f or a t otal of a p pr o xi matel y 6 0 partici pa nts. If 
1 5 partici pa n ts ha ve bee n e nr olle d i n a c o h ort a n d < 5 paire d pre- a n d o n-treat me nt bi o psies 
ha ve bee n c ollecte d, c ollecti o ns ma y  be ma de ma n dat or y f or t he re mai ni n g partici pa nts 
a n d/ or t he c o h ort ma y be e x pa n de d b y u p t o 5 partici pa nts t o o btai n s ufficie nt n u m bers of 
p aire d pre- a n d o n -treat me nt bi o psies.
A s u bset of partici pa nts e nr olle d i n P art 1 a n d P art 2 will als o be eli gi ble f or e nr oll me nt i n 
t he P E T i ma gi n g s u bst u d y wit h t he C D 8 T-cell s pecific 8 9Zr -defer o xa mi ne ( Df )-I AB 2 2 M 2 C 
P E T tracer ( C D 8 P E T Tracer). T he C D 8 P E T tracer s u bst u d y is i ncl u de d t o facilitate
meas ure me nt of C D 8 T- cell distri b uti o n acr oss b ot h t u m or a n d n or mal tiss ues bef ore a n d 
after t hera p y wit h P F - 0 7 0 6 2 1 1 9. T he C D 8 P E T tracer s u bst u d y will be o pe ne d i nitiall y at a 
s u bset of U S sites t hat ha ve bee n q ualifie d f or use wit h 8 9Zr -Df -I AB 2 2 M 2 C .  A d diti o nal 
details are pr o vi de d i n Secti o n 1 0. 1 9 .
Partici pa nts i n c o h orts wit h o ut a pri mi n g d ose will be o bser ve d i n patie nt f or at least 4 8 h o urs 
after t he first S C d ose o n C 1 D 1 a n d f or at least 8 h o urs after t he sec o n d S C d ose o n C 1 D 1 5 
a n d f or at least 1 h o ur p ost d ose f or all s u bse q ue nt visits. Partici p a nts i n c o h orts wit h a 
pri mi n g d ose will be o bser ve d i n patie nt f or at least 2 4 h o urs after t he first ( pri mi n g) S C d ose 
o n C 1 D 1 a n d 2 4 h o urs after t he sec o n d (f ull) S C d ose o n C 1 D 1 5, a n d 1 h o ur p ost d ose f or all 
s u bse q ue nt visits. Partici pa nts s h o ul d be o bser ve d f or at least 1 h o ur p ost d ose f or all visits 
starti n g wit h C2 D 1 1 i n b ot h c o h orts , u ntil t he i n vesti gat or has c o nfir me d t he partici pa nt has 
n ot e x hi bite d si g ns of c y t o ki ne reacti o n. 
I n Part 2, all partici pa nts will be o bser ve d i n patie nt f or at least 2 4 h o urs after t he first S C 
d ose, a n d if a pri mi n g d ose a p pr oac h is use d, partici pa nts will be o bser ve d f or  u p t o 2 4 h o urs 
after t he sec o n d (f ull) S C d ose o n C 1 D 1 5. Partici pa nts ma y  o nly be release d after t he 
i n vesti gat or has c o nfir me d t he partici pa nt has not e x hi bite d si g ns of C R S.
T a ble 8 .  
Mi ni m u m I n p atie nt O bser v ati o n St a ys
P art
C o h ort
C 1 D 1
C 1 D 1 5
All Ot her Visits
1
Wit h o ut Pri mi n g
4 8 h o urs
8 h o urs
1 h o ur
Wit h Pri mi n g
2 4 h o urs
2 4 h o urs
1 h o ur
2
2 4 h o urs
2 4 h o urs if pri mi n g 
is use d
At i n vesti gat or’s 
discreti o n
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 2
All i n patie nt o bser vati o n sta y s ma y be e xte n de d at t he discreti o n of t he i n vesti gat or a n d/ or 
e v ol vi n g cli nical data. 
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, or u nacce pta ble t o xicit y  occ urs, w hic he ver is earliest, u nless t he i n vesti gat or a n d 
me dical m o nit or a gree t o treat me nt be y o n d disease pr o gressi o n base d o n i n di vi d ual 
be nefit/ris k assess me nts.
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) u n der st u d y, as well as p ote ntial mec ha nis ms of resista nce. 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 0 6 2 1 1 9 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.
4. 1. 1. P art 1 A
Part 1 A will esti mate t he M T D a n d/ or R P 2 D of P F -0 7 0 6 2 1 1 9 as a m o n ot hera p y  wit h a n d 
wit h o ut a pri mi n g d ose. I n Part 1 A, se q ue ntial c o h orts of partici pa nts wit h a d va nce d 
gastr oi ntesti nal t u m ors, i ncl u di n g c ol orectal, gastric a n d es o p ha geal a de n ocarci n o mas, w h o 
are n ot ca n di dates f or re gi me ns k n o w n t o pr o vi de cli nical be nefit, will recei ve escalati n g 
d oses of P F - 07 0 6 2 1 1 9 a d mi nistere d as a n S C i njecti o n as g ui de d b y  t he Ba yesia n L o gistic 
Re gressi o n M o del ( B L R M). 
4. 1. 1. 1. P F -0 7 0 6 2 1 1 9 Tre at me nt Wit h o ut a Pri mi n g D ose
Wit h t he deter mi nati o n t hat a d ose le vel is safe f oll o wi n g a D L T o bser vati o n peri o d of 
2 8 da y s f or t he c o h ort wit h o ut a pri mi n g d ose a n d base d o n t he disc ussi o n b y  t he safety 
re vie w tea m, d ose escalati o n will pr ocee d t o t he ne xt d ose le vel. T he S C r o ute has t he 
p ote ntial t o re d uce t he C ma x w hic h is belie ve d t o be ass ociate d wit h C R S a n d i nfla m mat or y  
res p o nses, a co m m o n A E f or bis pecific a nti b o dies. T he starti n g S C d ose is 4 5 µ g Q 2 W. 
Ma xi m u m d ose i ncreases fr o m t he pre vi o us d ose le vels will be u p t o 2 0 0 %, w hic h is a 
c o nsiste nt a p pr oac h wit h bi ol o gic c o m p o u n ds i ncl u di n g a n a nti- C D 3 bis pecific ( Sa ber et al, 
2 0 1 7), 3 7 b ut will be a dj uste d t o n o m ore t ha n 1 0 0 % f oll o wi n g t he o bser vati o n of a D L T or if 
t here are t w o Gra de 2 or hi g her cli nically si g nifica nt treat me nt re late d A Es. C o h ort size will 
be a p pr o xi matel y  3 partici pa nts. T he first c o h ort of 4 5 µ g Q 2 W i n Part 1 A will ha ve at least 
1 D L T- e val ua ble partici pa nt. All ot her c o h orts i n Part 1 A will ha ve at least 2 D L T e val ua ble 
partici pa nts. Part 1 A is esti mate d t o e nr o ll a p pr o xi matel y 3 5 partici pa nts, b ut t he act ual 
n u m ber of partici pa nts e nr olle d will de pe n d o n t he t olera bilit y  of P F-0 7 0 6 2 1 1 9 a n d t he 
n u m ber of d ose le vels re q uire d t o i de ntif y  t he M T D, b ut will i ncl u de at least 6 partici pa nts 
treate d at t he rec o m me n de d R P 2 D/ M T D (see Secti o n 9. 4. 1 ).
4. 1. 1. 2. P F -0 7 0 6 2 1 1 9 Tre at me nt Wit h a Pri mi n g D ose
A n a d diti o nal d ose escalati o n c o h ort i n Part 1 A, w hic h i nc or p orates a l o wer pri mi n g d ose o n 
C 1 D 1 f oll o we d b y  a f ull d ose o n C 1 D 1 5 f or all d ose le vels, will be i nitiate d. A p pr o xi matel y 
2 0 partici pa nts will be e nr olle d i n t he Part 1 A c o h ort wit h a pri mi n g d o se, wit h 
a p pr o xi matel y 3 partici pa nts ( mi ni m u m of 2 D L T e val ua ble partici pa nts) per d ose le vel; 
a d diti o nal partici pa nts will be treate d at t he R P 2 D/ M T D f or a t otal of 6 t o 1 2 partici pa nts at 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 3
t hat d ose le vel. T he act ual n u m ber of partici pa nts e nr olle d will de pe n d o n t he t olera bilit y  of 
t he pri mi n g strate g y f or P F-0 7 0 6 2 1 1 9 a n d t he n u m ber of f ull d ose le vels re q uire d t o i de ntif y  
t he M T D (see Secti o n 9. 4. 1 ). 
T w o wee ks after t he pri mi n g d ose, partici pa nts will recei ve escalati n g f ull d oses of 
P F -0 7 0 6 2 1 1 9 a d mi nistere d Q 2 W as a n S C i njecti o n as g ui de d b y  t he B L R M. Wit h t he 
deter mi nati o n t hat a d ose le vel is safe f oll o wi n g a D L T o bser vati o n peri o d of 4 2 d a y s 
(i ncl u di n g b ot h pri mi n g a n d 2 f ull d oses) a n d base d o n t he disc ussi o n b y t he safety re vie w 
tea m, d ose escalati o n will pr ocee d t o t he ne xt d ose le vel. T he pri mi n g d ose will be 4 0 0 µ g. 
T he starti n g f ull d ose will be 8 0 0 µ g, w hi c h re prese nts t he M T D of t he Part 1 A c o h ort 
wit h o ut a pri mi n g d ose. T he i nitial P F - 0 7 0 6 2 1 1 9 re gi me n wit h a pri mi n g d ose satisfies 
E W O C criteria (see Secti o n 9. 4. 1 a n d A p pe n di x 1 0 , Secti o n 1 0. 1 0 ). T he ma xi m u m all o wa ble 
i ncrease i n t he f ull d ose, t o be gi ve n after t he pri mi n g d ose, will be 1 0 0 %. T he pri mi n g d ose 
ma y  be m o difie d base d o n e mer gi n g cli nical data t o a ma xi m u m of t he hi ghest d ose 
pre vi o usl y  deter mi ne d t o be safe. A n alter nate pri mi n g sc he d ule (e g, usi n g a ste p-u p d osi n g 
strate g y, wit h serially i ncreasi n g d oses t o reac h t he f ull d ose le vel), ma y be e x pl ore d if 
e v ol vi n g cli nical data s u p p ort t he nee d a n d t he D L T o bser vati o n peri o d will be a dj uste d 
acc or di n gl y (e g, t o i ncl u de t he a d mi nistrati o ns of 2 f ull d oses). If ste p-u p d osi n g is 
i n vesti gate d, partici pa nts will recei ve f ull d oses of P F - 0 7 0 6 2 1 1 9 2 wee ks after t he m ost 
rece nt pri mi n g d ose.
4. 1. 2. P art 1 B ( C o m bi n ati o n C o h orts)
U p o n deter mi ni n g t he si n gle -a ge nt P F -0 7 0 6 2 1 1 9 R P 2 D/ M T D, Part 1 B will be i nitiate d t o 
e x pl ore t he safet y, t olera bilit y , a n d preli mi nar y a nti-t u m or acti vit y of P F-0 7 0 6 2 1 1 9 i n 
c o m bi nati o n wit h P F -0 6 8 0 1 5 9 1 (a nti -P D -1) a n d be vaciz u ma b -Pfizer (a nti -V E G F) i n 
partici p a nts wit h c ol orectal, gastric a n d es o p ha geal a de n ocarci n o mas. 
T he D L T peri o d will be 2 8 da y s. B L R M will be use d t o g ui de t he d ose 
escalati o n/ de -escalati o n pr ocess f or eac h c o m bi nati o n ( P F -0 7 0 6 2 1 1 9/ P F -0 6 8 0 1 5 9 1 a n d 
P F -0 7 0 6 2 1 1 9/ be vaciz u ma b -Pfizer) se paratel y. T he deter mi nati o n of safet y f or a gi ve n d ose 
le vel f or eac h c o m bi nati o n will be base d o n t he disc ussi o n b y t he safety re vie w tea m.
I n eac h c o m bi nati o n treat me nt, t here ma y be c o h orts wit h o ut a P F-0 7 0 6 2 1 1 9 pri mi n g d ose 
a n d  c o h orts wit h a P F -0 7 0 6 2 1 1 9 pri m i n g d ose; t he decisi o n t o use a pri mi n g d ose ( o n C 1 D 1 
f oll o we d by a f ull d ose o n C 1 D 1 5) will be ma de f oll o wi n g a re vie w of all a vaila ble cli nical 
data fr o m Part 1 A a n d i n c o ns ultati o n wit h t he St u d y C 3 8 6 1 0 0 1 Safet y Re vie w Tea m. I n t he 
e ve nt t hat t he P F- 0 7 06 2 1 1 9 d ose pri mi n g strate g y  is e m pl o ye d wit h eit her c o m bi nati o n 
t hera py, t he D L T peri o d will be i ncrease d t o 4 2 da y s t o e ns ure a f ull 2 8 da y c ycle f oll o wi n g 
t he i nitiati o n of t he f ull d ose. A d diti o nall y , a n alter nati ve P F- 0 7 0 6 2 1 1 9 d osi n g re gi me n (e g, 
Q 4 W) or a sta g gere d d osi n g a p pr oac h (e g, P F -0 7 0 6 2 1 1 9 t o be i nitiate d al o ne o n C 1 D 1 
f oll o we d by t he c o m bi nati o n t hera p y 1 or 2 wee ks later) ma y be i nitiate d as g ui de d b y t he 
cli nical data. T he starti n g d ose of ne w re gi me n will satisf y  E W O C criteria.
F or t he P F - 0 7 0 6 2 1 1 9/P F - 0 6 8 0 1 5 9 1 c o m bi nati o n, t he starti n g first d ose of P F-0 7 0 6 2 1 1 9 i n 
c o m bi nati o n wit h P F -0 6 8 0 1 5 9 1 will be o ne d ose le vel l o wer t ha n t he P F -0 7 0 6 2 1 1 9 
m o n ot hera p y M T D t o acc o u nt f or a n y p ote ntial i ncrease i n C R S t hat mi g ht be ass ociate d 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 4
wit h t he P F - 0 7 0 62 1 1 9/ P F -0 6 8 0 1 5 9 1 c o m bi nati o n. If t he P F -0 7 0 6 2 1 1 9 R P 2 D fr o m Part 1 A is 
l o wer t ha n t he M T D, t he R P 2 D will be use d i n c o m bi nati o n wit h P F-0 6 8 0 1 5 9 1. Ma xi m u m 
i ncreases of P F-0 7 0 6 2 1 1 9 fr o m t he pre vi o us le vel will be 1 0 0 %. H o we ver, P F -0 7 0 6 2 1 1 9 i n 
c o m bi nati o n will n ot be d ose -escalate d be yo n d t he c orres p o n di n g si n gle -a ge nt M T D/ R P 2 D 
as deter mi ne d wit h or wit h o ut pri mi n g f or P F -0 7 0 6 2 1 1 9 i n Part 1 A. T he d ose of 
P F -0 6 8 0 1 5 9 1 will be 3 0 0 m g Q 4 W S C ( Ta ble 1 0 ). St u d y partici pa nts will be e val uate d f or 
safety a n d t olera bilit y of t he c o m bi nati o n a n d t he P F -0 7 0 6 2 1 1 9 d ose use d i n t he ne xt c o h ort 
ma y  re mai n t he sa me, escalate d, or de-escalate d as g ui de d b y  e mer gi n g cli nical data a n d t he 
B L R M desi g n (see Secti o n 4. 3. 6 ). 
F or t he P F - 0 7 0 6 2 1 1 9/be vaciz u ma b - Pfizer c o m bi nati o n, t he starti n g d ose of P F- 0 7 0 6 2 1 1 9 
will be t he M T D or t he R P 2 D deter mi ne d i n Part 1 A wit h or wit h o ut pri mi n g. St u d y  
partici pa nts will be e val uate d f or safet y a n d t olera bilit y  of t he c o m bi nati o n a n d t he 
P F -0 7 0 6 2 1 1 9 d ose use d i n t he ne xt c o h ort ma y  re mai n t he sa me or de-escalate d as g ui de d b y 
e mer gi n g cli nical data a n d B L R M ( See Secti o n 4. 3. 6 ). H o we ver, P F-0 7 0 6 2 1 1 9 i n 
co m bi nati o n will n ot be d ose -escalate d be yo n d t he c orres p o n di n g si n gle -a ge nt M T D/ R P 2 D 
as deter mi ne d wit h or wit h o ut pri mi n g f or P F -0 7 0 6 2 1 1 9 i n Part 1 A. T he d ose of 
be vaciz u ma b -Pfizer will be 5 m g/ k g Q 2 W I V i nf usi o n ( Ta ble 1 0 ). 
T he c o h ort size at eac h d ose le vel of Part 1 B f or t he P F- 0 7 0 6 2 1 1 9/ P F -0 6 8 0 1 5 9 1 a n d 
P F -0 7 0 6 2 1 1 9/ be vaciz u ma b -Pfizer c o m bi nati o n will eac h be a p pr o xi matel y  3 partici pa nts; all 
c o h orts in Part 1 B will eac h ha ve at least 3 D L T e val ua ble partici pa nts. Part 1 B is esti mate d 
t o e nr oll a p pr o xi matel y 3 5 partici pa nts (a p pr o xi matel y 1 5 t o 2 0 partici pa nts f or eac h 
c o m bi nati o n), b ut t he act ual n u m ber of partici pa nts e nr olle d will de pe n d o n t he t oler a bilit y of 
P F -0 7 0 6 2 1 1 9 i n c o m bi nati o n wit h P F -0 6 8 0 1 5 9 1 a n d wit h be vaciz u ma b -Pfizer a n d t he 
n u m ber of d ose le vels re q uire d t o i de ntif y  t he c orres p o n di n g P F-0 7 0 6 2 1 1 9 M T Ds i n t he 
c o m bi nati o n setti n g wit h or wit h o ut d ose pri mi n g, b ut will i ncl u de at least 6 pa rtici pa nts 
treate d at t he c orres p o n di n g rec o m me n de d R P 2 D/ M T Ds (see Secti o n 9. 4. 1 ). 
Alter nate pri mi n g strate gies (e. g. ste p u p pri mi n g strate g y  or pr o p hyl actic treat me nt) ma y be 
e x pl ore d if e v ol vi n g cli nical data s u p p orts t he nee d i n Part 1 B d ose pri mi n g. 
4. 1. 3. P art 2
I n Part 2, t he d ose e x pa nsi o n p hase will e val uate t he R P 2 D (as deter mi ne d eit her wit h or 
wit h o ut a pri mi n g d ose) of P F -0 7 0 6 2 1 1 9 as m o n ot hera p y  a n d wit h a c o m bi nati o n a ge nt (a nti-
P D -1 [ P F - 0 6 8 0 1 5 9 1] a n d a nti- V E G F [ be vaciz u ma b-Pfizer]) i n partici pa nts wit h c ol orect al 
a de n ocarci n o ma. A p pr o xi matel y  6 0 partici pa nts will be e nr olle d; 2 0 partici pa nts i n eac h 
m o n ot hera p y a n d c o m bi nati o n c o h orts. . Res p o nses i n t hese i nitial d ose e x pa nsi o n ar ms ma y  
lea d t o f urt her e val uati o n of P F-0 7 0 6 2 1 1 9 i n a d diti o nal t u m or i n dicati o ns a n d c o m bi nati o n 
t hera pies.
I n Part 2, de n o v o pre-treat me nt bi o psies will be re q uire d fr o m all partici pa nts, u nless n ot 
me dicall y  feasi ble, i n or der t o esta blis h relati o ns hi p bet wee n tar get e x pressi o n a n d efficac y 
o bser vati o ns. If a de n o v o pre- treat me nt bi ops y  is n ot me dicall y feasi ble, t he s p o ns or s h o ul d 
be c o ntacte d f or a p pr o val bef ore i nitiati n g scree ni n g acti vities. F or a s u bset of partici pa nts i n 
all c o h orts (a p pr o xi matel y 1 0 partici pa nts), ma n dat or y o n -treat me nt bi o psy sa m ples will als o 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 5
be c ollecte d i n or der t o c o nfir m t he mec ha nis m of acti o n a n d e val uate p ote ntial resista nce 
mec ha nis m d uri n g treat me nt. F or all ot her partici pa nts, o n-treat me nt bi o psies are o pti o nal b ut 
e nc o ura ge d.
4. 2. Scie ntific R ati o n ale f or St u d y Desi g n
I n t his cli nical st u dy, P F - 0 7 0 6 2 1 1 9 wit h a n d wit h o ut a pri mi n g d ose will be e val uate d f or t he 
treat me nt of a d ult partici pa nts wit h t u m or t ypes k n o w n t o e x press G U C Y 2c, s uc h as 
a d va nce d c ol orectal, gastric, a n d es o p ha geal a de n ocarci n o mas, f or w hic h n o sta n dar d t hera p y 
is a vaila ble ( Part 1). I n t he d ose e x pa nsi o n p hase ( Part 2), P F-0 7 0 6 2 1 1 9 wit h a n d wit h o ut a 
pri mi n g d ose will be e val uate d i n se parate d ose e x pa nsi o n ar ms as m o n ot hera p y  a n d i n 
c o m bi nati o n wit h a n ot her a ge nt (e g, i m m u ne c hec k p oi nt i n hi bit or, a nti -V E G F) i n a d va nce d 
C R C a n d t he n p ossi bl y  be e val uate d i n ot her gastr oi ntesti nal a de n ocarci n o mas, c ol orectal 
ca ncer s u bt y pes, or c o m bi nati o n o pti o ns, as i n dicate d. Ke y sta n dar d assess me nts i n t he st u d y 
will i ncl u de safet y/ t olera bilit y, P K, P D a n d preli mi nar y a nti-t u m or acti vity e n d p oi nts.
As part of t he P D e val uati o n, t he o bjecti ve of t he bi o mar ker assess me nts is t o pr o vi de i nsi g ht 
i nt o t he p har mac ol o gical effects of P F-0 7 0 6 2 1 1 9 al o ne a n d p ote ntiall y i n c o m bi nati o n wit h 
a nti-P D -1 ( P F -0 6 8 0 1 5 9 1) a n d i n c o m bi nati o n wit h a nti - V E G F ( be vaciz u ma b-Pfizer) b y 
c haracterizi n g t he cell ular a n d m olec ular pr ofile of t he partici pa nt pri or t o treat me nt, d uri n g 
treat me nt, a n d u p o n pr o gressi o n. T he bi o mar ker assess me nts, i ncl u di n g t he P E T i ma gi n g 
s u bst u d y, m a y  c o ntri b ute t o c o nfir mi n g tar get e n ga ge me nt, T cell acti vati o n, deter mi ni n g 
p har mac o d y n a mic effects of P F -0 7 0 6 2 1 1 9 al o ne a n d p ote ntiall y  i n c o m bi nati o n wit h ot her 
a ge nts, i de ntif yi n g 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, a n d 
i de ntif y p ote ntial resista nce mec ha nis ms t o P F- 0 7 0 6 2 11 9 al o ne a n d i n c o m bi nati o n wit h 
ot her a ge nts. T he c ollecti o n of arc hi val a n d/ or de n o v o pre- treat me nt a n d o n-treat me nt 
bi o psies will be use d t o e val uate t he ass ociati o n bet wee n tar get e x pressi o n a n d res p o nse 
para meters t o P F- 0 7 0 6 2 1 1 9 as descri be d i n t he Sc he d ule of Acti vities ) a n d t he 
St u d y / La b orat or y Ma n ual.
Ba n ke d bi os peci me ns will be c ollecte d f or e x pl orat or y / p har mac o ge n o mic/ ge n o mic/ 
bi o mar ker a nal ys es a n d retai ne d i n t he Bi os peci me n Ba n ki n g S ys te m ( B B S), w hic h ma kes it 
p ossi ble t o better u n dersta n d t he mec ha nis m of acti o n of t he st u d y  i nter ve nti o n t o see k 
e x pla nati o ns f or differe nces i n, f or e xa m ple, e x p os ure, t olera bilit y , safety, a n d/ or efficac y n ot 
a ntici pate d pri or t o t he be gi n ni n g of t he st u d y.
4. 3. J ustific ati o n f or D ose
4. 3. 1. St arti n g D ose f or M o n ot her a p y D ose Esc al ati o n Wit h o ut a Pri mi n g D ose 
( P art 1 A)
T he i nitial cli nical starti n g d ose f or P F -0 7 0 6 2 1 1 9 f or t his first-i n-partici pa nt ( FI P) st u d y is 
4 5 µ g a d mi nistere d as a S C i njecti o n o nce e ver y  2 wee ks ( Q 2 W). T he selecti o n of t he 
starti n g d ose f or t his st u d y was base d o n t he mi ni m u m a ntici pate d bi ol o gical effect le vel
( M A B E L) i n acc or da nce wit h t he Inter nati o nal C o nfere nce o n Har m o nizati o n (I C H) S 9 
G ui da nce, gi ve n t hat P F- 0 7 0 6 2 1 1 9 is a bis pecific T cell -e n ga gi ng a ge nt wit h i m m u ne 
a g o nistic pr o perties. T he 4 5 µ g Q 2 W S C starti n g d ose is pre dicte d t o res ult i n mi ni mal 
bi ol o gical effect c o nsi deri n g a) i n vitr o c y t o ki ne release a n d c yt ot o xicit y e x peri me nts, b) 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 6
rece pt or occ u pa nc y calc ulate d base d o n i n vitr o bi n di n g affi nities, a n d c) m o use P K/ P D 
st u dies.
T he i n vitr o bi ol o gical acti vities f or P F -0 7 0 6 2 1 1 9 were deter mi ne d via c y t o ki ne release a n d 
c yt ot o xicit y e x peri me nts a n d t he m ost se nsiti ve P F-0 7 0 6 2 1 1 9 c o nce ntrati o n t o ac hie ve 
5 0 % ma xi mal effect ( E C 5 0) acr oss all i n vitr o assa y s was esti mate d as 1 3. 6 n g/ m L. Wit h 
4 5 μ g Q 2 W as a starti n g d ose, t he pre dicte d P F- 0 7 0 6 2 1 1 9 C ma x at stea d y-state ass u mi n g 
5 0 % bi oa vaila bilit y  fr o m t he S C r o ute is 8. 9 n g/ m L, w hic h is ~ 3 4 % l o wer t ha n t he E C 5 0 of 
t he m ost se nsiti ve i n vitr o assa y.
T he rece pt or occ u pa nc y  ( R O) calc ulate d base d o n i n vitr o bi n di n g affi nities at a starti n g d ose 
of 4 5 μ g Q 2 W S C was ≤0. 3 % f or b ot h G U C Y 2c a n d C D 3.
T he pre dicte d tr o u g h c o nce ntrati o n ( C tr o u g h) after f o ur d oses ac hie ve d wit h 4 5 µ g Q 2 W 
starti n g d ose is 4. 5 n g/ m L w hic h is less t ha n t he pre dicte d cli nical efficaci o us c o nce ntrati o n 
( Ceff) esti mate d fr o m m o use P K/ P D st u dies.
Fi nall y , P F-0 7 0 6 2 1 1 9 e x p os ure at t he rec o m me n de d starti n g d ose is e x pecte d t o be l o wer 
(e g, 2 1-f ol d l o wer Cma x a n d 2 4-f ol d l o wer A U C1 6 8) c o m pare d t o t he H N S T D deter mi ne d i n 
t he G LP o ne -m o nt h t o xic ol o g y  st u d y ( 3 µ g/ k g S C).
T heref ore, as state d a b o ve, t he rec o m me n de d M A B E L starti n g d ose of 4 5 µ g Q 2 W via t he 
S C r o ute is e x pecte d t o res ult i n mi ni mal bi ol o gical effect a n d t o pr o vi de a n a de q uate safety 
mar gi n . If t he 4 5 µ g  Q 2 W d ose is  n ot t olerate d, t he n a l o wer d ose of 3 0 µ g  Q 2 W via S C 
r o ute will be e val uate d.
4. 3. 2. St arti n g D ose f or M o n ot her a p y D ose Esc al ati o n Wit h a Pri mi n g D ose ( P art 1 A)
A vaila ble data fr o m partici pa nts e nr olle d i n Part 1 A wit h o ut pri mi n g s h o ws t hat c y t o ki ne 
pr o d ucti o n a n d cli nical C R S occ ur pri maril y wit h t he i nitial d ose of P F -0 7 0 6 2 1 1 9,  
s u p p orti n g t he hy p ot hesis t hat i n d ucti o n of i m m u ne acti vati o n wit h a pri mi n g d ose atte n uates 
s u bse q ue nt occ urre nce of C R S. T he use of a pri mi ng a p pr oac h t o miti gate c yt o ki ne -me diate d 
A Es is als o s u p p orte d b y  data fr o m cli nical st u dies of t he bis pecific T-cell e n ga ger, 
bli nat u m o ma b, w hic h ha ve de m o nstrate d t hat use of a pri mi n g d ose (ie, usi n g a l o wer first 
d ose) ca n be effecti ve i n da m pe ni n g c y to ki ne release -me diate d A Es f oll o wi n g a d mi nistrati o n 
of s u bse q ue nt hi g her mai nte na nce d oses ( T o p p et al, 2 0 1 4a; T o p p et al, 2 0 1 4 b). 
T he first d ose le vel f or P F -0 7 0 6 2 1 1 9 i n t he Part 1 A c o h ort wit h a pri mi n g d ose will be a 
starti n g pri mi n g d ose of 4 0 0 μ g gi v e n as a S C i njecti o n o n C 1 D 1 f oll o we d b y  a f ull d ose of 
8 0 0 µ g, w hic h c orres p o n ds t o t he si n gle a ge nt M T D wit h o ut pri mi n g a d mi nistere d as a S C 
i njecti o n, o n C 1 D 1 5 a n d Q 2 W t hereafter.
T he starti n g pri mi n g d ose of 4 0 0 µ g P F- 0 7 0 6 2 1 1 9 was selecte d base d o n t he f oll o wi n g 
c o nsi derati o ns fr o m t he a vaila ble cli nical data fr o m t he c o h ort wit h o ut a pri mi n g d ose: 
( 1) P F -0 7 0 6 2 1 1 9 was o bser ve d t o be safe a n d t olera ble, wit h n o D L Ts after t he first or 
sec o n d d ose a n d n o C R S e ve nts Gra de ≥2 re p orte d; ( 2) it was t he l o west d ose t hat 
de m o nstrate d mea ni n gf ul i m m u ne acti vati o n t hat is necessar y  t o acc o m plis h a pri mi n g effect, 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 7
as e vi de nce d b y i ncrease d meas ura ble c yt o ki ne mar kers of T -cell acti vati o n a n d 
i nfla m mati o n; a n d ( 3) 4/ 6 partici pa nts at t his d ose le vel als o de m o nstrate d re d ucti o ns i n 
C E A, a t u m or mar ker. 
T he starti n g f ull d ose of P F -0 7 0 6 2 1 1 9 will be 8 0 0 µ g Q 2 W. T his d ose c orres p o n ds t o t he 
si n gle a ge nt M T D wit h o ut pri mi n g a n d t here is alrea dy a vaila ble cli nical data f or 
9 partici pa nts at t his d ose le vel. T his d ose w o ul d all o w f or o bjecti ve assess me nt of t he 
pri mi n g strate g y  base d o n c o m paris o n bet wee n t he pri mi n g a n d n o n-pri mi n g setti n gs at t he 
sa me f ull d ose ( 8 0 0 µ g) of P F-0 7 0 6 2 1 1 9, i n t he c o nte xt of  safet y  e ve nts a n d le vel of 
c yt o ki ne acti vati o n. A d diti o nall y, t he pri mi n g/f ull d ose of 4 0 0 µ g/ 8 0 0 µ g Q 2 W satisfies 
E W O C criteria (see Secti o n 9. 4. 1 a n d A p pe n di x 1 0 , Secti o n 1 0. 1 0 ).
4. 3. 3. S u bc ut a ne o us R o ute 
T he S C r o ute will be e m pl o y e d i n t his st u d y gi ve n t he p ote ntial t o re d uce t he Cma x, w hic h is 
belie ve d t o be ass ociate d wit h C R S a n d i nfla m mat or y res p o nses. De pe n di n g o n t he a vaila ble 
e mer gi n g cli nical data (i ncl u di n g safet y/ t olera bilit y, P K, P D) fr o m t he d ose escalati o n 
c o h orts wit h S C a d mi nistrati o n, I V a d mi nistrati o n, i ncl u di n g t he use of a n I V pri mi n g d ose 
ma y  be e val uate d a n d w o ul d be acc o m pa nie d wit h a pr ot oc ol a me n d me nt. 
I n case of c ha n ge of t he d osi n g re gi me n, D L T data acc u m ulate d d uri n g t he d ose escalati o n 
wit h t he pre vi o usl y  e x pl ore d re gi me n mi g ht be use d t o f or m a pri or ass u m pti o n f or f urt her 
B L R M a nal ys is. 
4. 3. 4. Fi xe d D osi n g A p pr o ac h 
A fi xe d -d ose a p pr oac h will be a p plie d f or t he FI P st u d y  of P F-0 7 0 6 2 1 1 9 gi ve n t hat fi xe d 
d osi n g a p pr oac h was s h o w n t o pr o vi de si milar P K varia bilit y  c o m pare d t o a b o d y-wei g ht 
a dj uste d d osi n g f or m o n ocl o nal a nti b o dies, t hera pe utic pe pti des, a n d pr otei ns ( Wa n g D et al; 
Z ha n g S et al). 4 9 ,5 1  I n a d diti o n, fi xe d d osi n g offers ease of pre parati o n a n d less c ha nce of 
d osi n g err ors. Alter nati vel y , base d o n e mer gi n g P K data, b o d y wei g ht, or b o d y s urface area 
base d d osi n g ma y  be c o nsi dere d.
4. 3. 5. D osi n g I nter v al ( Q 2 W)
T he Q 2 W d osi n g fre q ue nc y  of P F- 0 7 0 6 21 1 9 i n t his st u d y  was selecte d base d o n ( 1) t he 
pr ojecte d t1/ 2 of 2 1 da y s i n h u ma ns a n d ( 2) t he c o m bi nati o n a ge nts f or P F- 0 7 0 6 2 1 1 9 
( P F-0 6 8 0 1 5 9 1 a n d be vaciz u ma b -Pfizer) i n t his st u d y  will be a d mi nistere d Q 2 W or Q 4 W. A 
Q 2 W re gi me n was selecte d f or t his FI P s t u d y t o re d uce Cma x , w hic h is belie ve d t o be 
ass ociate d wit h C R S, c o m pare d t o Q 4 W a d mi nistrati o n (c o m pari n g d oses ac hie vi n g 
matc hi n g o verall e x p os ure bet wee n Q 2 W a n d Q 4 W re gi me ns). Base d o n e mer gi n g P K, P D, 
a n d safet y data, re gi me ns wit h alter nati ve d osi n g fre q ue ncies (e g, wee kly a d mi nistrati o n or 
Q 4 W) ma y  als o be c o nsi dere d.
4. 3. 6. St arti n g D ose f or C o m bi n ati o n D ose Fi n di n g ( P art 1 B)
T he d ose -fi n di n g e val uati o n of P F-0 7 0 6 2 1 1 9 i n c o m bi nati o n wit h P F -0 6 8 0 1 5 9 1 or 
be vaciz u ma b -Pfizer will be i nitiate d after deter mi nat i o n of t he M T D a n d/ or R P 2 D f or 
P F -0 7 0 6 2 1 1 9 as m o n ot hera p y wit h or wit h o ut pri mi n g ( Part 1 A) a n d s u p p orte d b y  e mer gi n g 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 8
cli nical data i ncl u di n g a n y a vaila ble safet y/ t olera bilit y, P K, P D, or preli mi nar y e vi de nce of 
efficac y.
F or t he P F - 0 7 0 6 2 1 1 9/P F -0 6 8 0 1 5 9 1 c o m bi nati o n, t he starti n g d ose of P F-0 7 0 6 2 1 1 9 will be 
o ne d ose le vel l o wer t ha n t he P F -0 7 0 6 2 1 1 9 m o n ot hera p y M T D or t he R P 2 D  ( or t he hi g hest 
d ose le vel pre vi o usl y deter mi ne d t o be safe if t he M T D or R P 2 D has n ot yet bee n i de ntifie d) 
t o acc o u nt f or a ny p ote nt ial o verla p pi n g t o xicities t hat mi g ht be ass ociate d wit h t he 
P F -0 7 0 6 2 1 1 9/ P F -0 6 8 0 1 5 9 1 c o m bi nati o n.  T he starti n g d ose f or P F -0 7 0 6 2 1 1 9/ P F - 0 6 8 0 1 5 9 1 
c o m bi nati o n ( Part 1 B wit h o ut pri mi n g) will be 4 0 0 µ g. T he d ose of P F -0 6 8 0 1 5 9 1 will be 
3 0 0 m g Q 4 W S C.
F or t he P F -0 7 0 6 2 1 1 9 c o m bi nati o n wit h be vaciz u ma b -Pfizer, t he starti n g d ose of 
P F - 0 7 0 6 2 1 1 9 will be t he M T D or R P 2 D deter mi ne d wit h o ut pri mi n g i n Part 1 A, a n d t he d ose 
of be vaciz u ma b -Pfizer will be 5 m g/ k g Q 2 W I V i nf usi o n ( Ta ble 1 0 ).
T he starti n g d ose of a n y ne w re gi me n, i ncl u di n g c o m bi nati o n wit h pri mi n g will satisf y  
E W O C criteria (see Tec h nical S u p ple me nt t o A p pe n di x 1 0 ).
F or t he P F -0 7 0 6 2 1 1 9 c o m bi nati o ns wit h P F -0 6 8 0 1 5 9 1 or be vaciz u ma b -Pfizer wit h pri mi n g, 
P F - 0 7 0 6 2 1 1 9 will be a d mi nistere d o n C 1 D 1 al o ne a n d will be a d mi nistere d o n C 1 D 1 5 i n 
c o m bi nati o n wit h eit her P F- 0 6 8 0 1 5 9 1 or be vaciz u ma b - Pfizer. F or a d diti o nal details, refer t o 
Secti o n 4. 1 .
4. 3. 7. Criteri a f or D ose Esc al ati o n
A 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 i n Part 1 A a n d 
d ose fi n di n g i n Part 1 B. See Secti o n 9. 4 a n d A p pe n di x 1 0 f or m ore details o n t he m o del. 
Usi n g D L T data at all teste d d ose le vels a n d pres pecifie d pri or distri b uti o n of m o del 
para meters, p osteri or pr o ba bilities of t he pr o ba bilit y  of ha vi n g a D L T falli n g i nt o 3 d osi n g 
i nter vals ( u n der d osi n g, tar get d osi n g, a n d o ver d osi n g) will be calc ulate d f or all d ose le vels. 
A d ose ma y  o nly be use d f or ne wl y e nr olle d partici pa nts if it satisfies E W O C pri nci ple 
(ie, t he ris k of o ver-d osi n g at t his d ose is pre dicte d t o be less t ha n 2 5 %). 
T y picall y , partici pa nts will be e nr olle d i n d ose le vel c o h orts of a p pr o xi matel y 3 partici pa nts 
wit h at least 1 D L T e val ua ble partici pa nt i n t he first d ose le vel i n Part 1 A wit h o ut a pri mi n g 
d ose a n d 2 D L T e val ua ble partici pa nts at all ot her d ose le vels i n Part 1 A wit h a n d wit h o ut a 
pri mi n g d ose. All d ose le vels i n Part 1 B wit h or wit h o ut a pri mi n g d ose will ha ve at least 
3 D L T e val ua ble partici pa nts.
T he ma xi m u m d ose i ncreases fr o m t he pre vi o us d ose le vels f or re gi me n will be u p t o 2 0 0 % 
f or c o h orts wit h o ut a pri mi n g d ose b ut will be a dj uste d t o n o m ore t ha n 1 0 0 % f oll o win g t he 
o bser vati o n of a D L T or if t here are t w o Gra de ≥2 cli nicall y  si g nifica nt treat me nt-relate d 
A Es. T he ma xi m u m all o wa ble d ose i ncre me nt f or d ose escalati o n will be 1 0 0 % f or c o h orts 
wit h a pri mi n g d ose.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 5 9
T a ble 9 . S C D ose Esc al ati o n Le vels f or A d mi nistr ati o n Wit h o ut Pri mi n g D ose
D ose Le vel *
D ose ( µ g)
D L 1 ( Starti n g D ose * *)
4 5
D L 2
1 3 5
D L 3 a n d hi g her
Escalati o n t o c o nti n ue t o M T D or desire d p har mac ol o gic acti vit y
* I nter me diate d oses ma y be e val uate d base d o n cli nical fi n di n gs; D L = D ose Le vel; M T D = Ma xi m u m 
T olerate d D ose; S C = S u bc uta ne o us.
* * If t he 4 5 μ g S C Q 2 W d ose is n ot t olerate d, t he n a l o wer d ose of 3 0 μ g Q 2 W via S C r o ute w ill be 
e val uate d.
D ose escalati o n will st o p w he n st o p pi n g criteria are met (see Secti o n 4. 3. 8 a n d 
A p pe n di x 1 0 ). Acc or di n g t o t he st o p pi n g criteria, at least 6 partici pa nts will be e val uate d at 
t he M T D.
I ntra partici pa nt d ose escalati o n t o t he ne xt d ose le vel ma y be c o nsi dere d i n c o ns ultati o n wit h 
t he s p o ns or f or partici pa nts(s) w h o ha ve c o m plete d t he D L T peri o d i n t he d ose escalati o n 
p hase if t he ne xt hi g her d ose le vel has bee n cleare d.
4. 3. 8. D ose Li 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 (irres pecti ve of 
w het her t he y  recei ve d all of t he pla n ne d d oses of eac h st u d y i nter ve nti o n a n d sc he d ule d 
safety assess me nts d uri n g t he D L T wi n d o w) or if he/s he ot h er wise i n t he a bse nce of a D L T 
recei ves all of t he pla n ne d d oses of eac h st u d y i nter ve nti o n a n d has recei ve d 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. 
D L Ts will be assesse d t hr o u g h C ycl e 1 ( 2 8-d a y  c ycle wit h Da y 2 9 [e g, C 2 D 1]) f or c o h orts 
wit h o ut pri mi n g a n d will be assesse d t hr o u g h C 2 D 1 5 ( 4 2 -d a y c y cle wit h Da y 4 3 
[e g, C 2 D 1 5]) f or c o h orts wit h pri mi n g. 
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 f or Q 2 W S C re gi me n will be 
2 8 da y s f or c o h orts wit h o ut a pri mi n g d ose a n d 4 2 da ys  f or c o h orts wit h a pri mi n g d ose after 
t he start of st u d y treat me nt i n eac h partici pa nt.
Si g nifica nt A Es 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 after 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 
safety 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 v 5. 0. 
F or t he p ur p ose of d ose escalati o n, a n y  of t he f oll o wi n g A Es wit h t he ass ociate d para meters 
t hat occ ur d uri n g t he D L T o bser vati o n peri o d t hat are attri b uta ble t o o ne, t he ot her, or b ot h 
a ge nts i n t he c o m bi nati o n will be classifie d as D L Ts:
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 0
He m at ol o gic al D L Ts:

Gra de 3 ne utr o pe nia lasti n g > 5 da y s is a D L T.

Fe brile ne utr o pe nia is a D L T defi ne d as a n a bs ol ute ne utr o p hil c o u nt ( A N C) 
< 1. 0 x 1 0 9/ L  wit h a si n gle te m perat ure of > 3 8. 3° C, or 1 0 1° F, or a s ustai ne d 
te m perat ure of 3 8 C , or 1 0 0.4 F , f or m ore t ha n o ne h o ur is a D L T.

Gra de 3 ne utr o pe nia wit h i nfecti o n is a D L T.

Gra de 3 t hr o m b oc y t o pe nia wit h Gra de 2 (cli nicall y  si g nifica nt) blee di n g is a D L T.

A n y  Gra de 4 t hr o m b oc yt o pe nia is a D L T.

A ne mia or t hr o m b oc y t o pe nia re q uiri n g tra nsf usi o n is a D L T.
N o n -He m at ol o gic al D L Ts:

Gra de ≥3 f ati g ue lasti n g ≥7 da y s is a D L T.

F or partici pa nts wit h li ver, b o ne, or l u n g metastasis, a n A S T or A L T i ncrease 
> 8 x U L N or al kali ne p h os p hatase > 1 0 x U L N is a D L T.

C o nfir me d dr u g i n d uce d li ver i nj ur y  ( DI LI) meeti n g H y’s la w criteria is a D LT.

Gra de 3 v o mit i n g or diarr hea lasti n g ≥3 d a y s des pite a de q uate treat me nt 
(e g, a ntie metic or a nti diarr heal me dicati o ns, res pecti vel y ) a n d ot her s u p p orti ve care is 
a D L T.

Gra de 4 v o miti n g or diarr hea is a D L T.

Gra de ≥3 C R S re gar dless of d urati o n is a D L T.

Gra de ≥3 Q Tc F pr ol o n gati o n irres pecti ve of d urati o n is a D L T.

A n y  deat h n ot clearly d ue t o t he u n derl yi n g disease or e xtra ne o us ca uses is a D L T.
Cli nicall y  i m p orta nt or persiste nt t o xicities (e g, t o xicities res p o nsi ble f or si g nifica nt d ose 
dela y ) t hat are n ot i ncl u de d i n t he a b o ve criteria ma y als o be c o nsi dere d a D LT f oll o wi n g 
re vie w by t he i n vesti gat ors a n d t he S p o ns or. All D L Ts nee d t o re prese nt a cli nicall y  
si g nifica nt s hift fr o m baseli ne.
Ot her wise, A Es of C T C A E Gra de greater t ha n or e q ual t o 3 will be c o nsi dere d t o b e D L Ts, 
wit h t he e xce pti o n of t he A Es liste d bel o w.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 1
T he f oll o wi n g A Es will n ot be a dj u dic ate d as D L Ts:

Is olate d Gra de 3 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.

Gra de 3 a m y lase or li pase ele vati o n n ot ass ociate d wit h cli nical s ym pt o ms or cli nical 
ma nifestati o ns of pa ncreatitis.
4. 3. 9. L ate O nset T o xicit y
Si g nifica nt A Es c o nsi dere d t o be relate d t o P F- 0 7 0 6 2 1 1 9 as m o n ot hera p y  or i n c o m bi nati o n
treat me nt u n der i n vesti gati o n t hat occ ur after t he D LT o bser vati o n peri o d will be re vie we d i n 
t he c o nte xt of all safety data a vaila ble. T his 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.
Pfizer will sc he d ule a safet y  re vie w meeti n g wit h t he i n vesti gat ors t o re vie w t he details of t he 
p ote ntial late o nset t o xicit y  a n d deter mi ne if e nr oll me nt s h o ul d be hel d, c o nti n ue d or if d ose 
re d ucti o n s h o ul d be i m ple me nte d f or o n g oi n g partici pa nts. Late o nset t o xicities t hat meet t he 
defi niti o n of D L T will be c o nsi dere d i n t he e val uati o n of t he M T D.
4. 3. 1 0. M a xi m u m T oler ate d D ose Defi niti o n
M T D is defi ne d as a d ose wit h tr ue D L T rate fr o m t he tar get t o xicit y  i nter val. T he tar get 
i nter val f or t he D L T rate is defi ne d as ( 0. 1 6, 0. 3 3).
4. 3. 1 1. Rec o m me n de d P h ase 2 D ose Defi niti o n 
T he R P 2 D f or P F -0 7 0 6 2 1 1 9 will be retr os pecti vel y  deter mi ne d as a m o n ot hera p y wit h a n d 
wit h o ut pri mi n g, a n d i n c o m bi nati o n wit h P F - 0 6 8 0 1 5 9 1 or i n c o m bi nati o n wit h 
be vaciz u ma b -Pfizer f or f urt her st u d y  base d o n P hase 1 st u d y res ults. If t he M T D pro 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 
M T D wit h or wit h o ut a pri mi n g d ose c o ul d be selecte d as t he R P 2 D. F urt her e x perie nce wit h 
t he M T D ma y res ult i n a R P 2 D d ose l o wer t ha n t he M T D. Alter nati vel y, if data all o ws, t he 
R P 2 D c o ul d be selecte d as t he safe d ose t hat de m o nstrates t he desire d p har mac ol o gical 
acti vit y ( o pti mal bi ol o gical d ose). P K data as well p ote ntial e x p os ure-res p o nse relati o ns hi ps 
(safety a n d efficac y, as data per mits) will be c o nsi dere d i n i de ntif y i n g t he R P 2 D. D uri n g 
escalati o n a n d 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 data.
4. 3. 1 2. P art 2 Res pecti ve St arti n g D oses f or P F -0 7 0 6 2 1 1 9 as a Si n gle A ge nt a n d 
C o m bi n ati o n D ose E x p a nsi o n C o h orts
Part 2 d ose e x pa nsi o n is a n o pe n -la bel, m ulti-ce nter, n o n-ra n d o mize d st u d y t o assess t he 
preli mi nar y  a nti-t u mor acti vit y  al o n g wit h safet y/t olera bilit y, P K, a n d P D of P F- 0 7 0 6 2 1 1 9. 
P F - 0 7 0 6 2 1 1 9 will be e val uate d at t he R P 2 D i n 2 8-da y  c ycles i n d ose e x pa nsi o n ar ms as a 
si n gle a ge nt, i n c o m bi nati o n wit h P F-0 6 8 0 1 5 9 1, a n d i n c o m bi nati o n wit h 
be vaciz u ma b -Pfizer. F oll o wi n g a re vie w of all a vaila ble data i n Part 1 a n d i n c o ns ultati o n 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 2
wit h t he St u d y C 3 8 6 1 0 0 1 Safet y  Re vie w Tea m, a pri mi n g strate g y f or P F-0 7 0 6 2 1 1 9 ma y  be 
i nitiate d i n Part 2.
T he si n gle -a ge nt P F -0 7 0 6 2 1 1 9 R P 2 D fr o m Part 1 A will be use d t o i nitiate t he Part 2 
sin gle -a ge nt d ose -e x pa nsi o n ar m, w hic h ma y be de-escalate d base d o n e mer gi n g cli nical 
data. A d diti o nall y , t he P F-0 7 0 6 2 1 1 9 R P 2 D i n c o m bi nati o n wit h P F -0 6 8 0 1 5 9 1 a n d 
P F -0 7 0 6 2 1 1 9 R P 2 D i n c o m bi nati o n wit h be vaciz u ma b - Pfizer fr o m Part 1 B will be use d t o 
i nitiate the Part 2 res pecti ve c o m bi nati o n d ose e x pa nsi o n ar m st u dies, w hic h ma y  be 
de-escalate d, if i n dicate d fr o m e mer gi n g cli nical data.
4. 3. 1 3. P art 2 P F - 0 7 0 6 2 1 1 9 as a Si n gle A ge nt i n A d v a nce d or Met ast atic C ol orect al 
A de n oc arci n o m a
P F -0 7 0 6 2 1 1 9 will be e val uate d as a si n gle a ge nt at t he R P 2 D i n a d va nce d or metastatic 
c ol orectal a de n ocarci n o ma t hat is resista nt t o sta n dar d t hera p y or f or w hic h n o sta n dar d 
t hera py is a vaila ble. T his e x pa nsi o n c o h ort will e nr oll a p pr o xi matel y 2 0 partici pa nts.
4. 3. 1 4. P art 2 P F -0 7 0 6 2 1 1 9 i n C o m bi n ati o n wit h P F -0 6 8 0 1 5 9 1 i n A d v a nce d or 
Met ast atic C ol orect al A de n oc arci n o m a
P F -0 7 0 6 2 1 1 9 will be e val uate d i n c o m bi nati o n wit h P F -0 6 8 0 1 5 9 1 at t he R P 2 D i n a d va nce d 
or metastatic c ol orectal a de n ocarci n o ma t hat is resista nt t o sta n dar d t hera p y or f or w hic h n o 
sta ndar d t hera p y is a vaila ble. T his e x pa nsi o n c o h ort will e nr oll a p pr o xi matel y 
2 0 partici pa nts.
4. 3. 1 5. P art 2 P F - 0 7 0 6 2 1 1 9 i n C o m bi n ati o n wit h Be v aciz u m a b- Pfizer i n A d v a nce d or 
Met ast atic C ol orect al A de n oc arci n o m a
P F - 0 7 0 6 2 1 1 9 will be e val uate d i n c o m bi nati o n wit h be vaciz u ma b -Pfizer at t he R P 2 D i n 
a d va nce d or metastatic c ol orectal a de n ocarci n o ma t hat is resista nt t o sta n dar d t hera p y  or f or 
w hic h n o sta n dar d t hera p y is a vaila ble. T his e x pa nsi o n c o h ort will e nr oll a p pr o xi matel y  
2 0 partici pa nts.
4. 4. E n d of St u d y Defi niti o n
A p artici 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 e n d of treat me nt visit.
T he e n d of t he st u d y is defi ne d as t he date of t he last visit of t he last partici pa nt i n t he st u d y.
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 nts 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 nts 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 co 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 3
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.
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:  
1.
Fe male a n d/ or male partici pa nts a ge ≥1 8 y ears a n d/ or ≥2 0 years i n Ja pa n.
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. 
2.
F or d ose escalati o n/fi n di n g c o h ort(s) ( Part 1 A a n d 1 B): Hist ol o gical or c y t ol o gical 
dia g n osis of a d va nce d/ metastatic c ol orectal, gastric, or es o p ha geal a de n ocarci n o ma 
t hat is resista nt t o sta n dar d t hera py or f or w hic h n o l ocal re g ulat or y a p pr o ve d 
sta n dar d t hera py is a vaila ble t hat w o ul d c o nfer si g nifica nt cli nical be nefit i n t he 
me di cal j u d ge me nt of t he i n vesti gat or.
3.
F or d ose escalati o n/fi n di n g c o h ort(s) ( Part 1 A a n d 1 B): M ust ha ve t u m or tiss ue 
a vaila ble f or s u b missi o n t o t he s p o ns or. Partici pa nts e nr olle d i n Part 1 s h o ul d ha ve 
access t o t heir arc hi val f or mali n-fi xe d paraffi n e m be d de d material c o ntai ni n g t u m or 
t hat is of dia g n ostic q ualit y a n d re prese ntati ve of t heir dia g n ose d mali g na nc y or 
c o nse nt t o u n der g o a bi o ps y  d uri n g scree ni n g.
4.
F or d ose e x pa nsi o n ( Part 2): Hist ol o gical or c y t ol o gical dia g n osis of pre vi o usl y 
treate d c ol orectal ade n ocarci n o ma t hat is resista nt t o sta n dar d t hera p y or f or w hic h n o 
l ocal re g ulat or y a p pr o ve d sta n dar d t hera p y is a vaila ble t hat w o ul d c o nfer cli nical 
be nefit i n t he me dical j u d ge me nt of t he i n vesti gat or.
5.
F or d ose e x pa nsi o n ( Part 2): M ust ha ve t u m or tiss ue a vaila ble f or s u b missi o n t o t he 
s p o ns or. Partici pa nts e nr olle d i n Part 2 s h o ul d eit her ha ve access t o t heir arc hi val 
F F P E material c o ntai ni n g t u m or t hat is of dia g n ostic q ualit y  a n d re prese ntati ve of 
t heir dia g n ose d mali g na nc y or c o nse nt t o u n der g o a bi o ps y d uri n g scree ni n g.
6.
Partici pa nts e nteri n g t he st u d y  i n t he e x pa nsi o n c o h ort(s) ( Part 2) ha ve at least 
1 meas ura ble lesi o n as defi ne d b y Res p o nse E val uati o n Criteria i n S oli d T u m ors 
( R E CIS T) versi o n 1. 1 t hat has n ot bee n pre vi o usl y  irra diate d.
7.
Partici pa nts e nteri n g t he st u d y i n t he s u b gr o u p(s) re q uiri n g ma n dat or y pre- a n d 
o n -treat me nt t u m or bi o psies i n t he d ose escalati o n/fi n di n g c o h ort(s) ( Part 1 A a n d 1 B) 
a n d d ose e x pa nsi o n i n Part 2 m ust ha ve a t u m or a me na ble t o bi o ps y  a n d c o nse nt t o 
t hese pla n ne d bi o psy pr oce d ures.
8.
B o d y wei g ht of > 7 0 k g f or D ose Le vel 1 o nl y.
9.
Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce Stat us ( P S) m ust be 
0 or 1.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 4
1 0. A de q uate b o ne marr o w f u ncti o n, i ncl u di n g:

A bs ol ute Ne utr o p hil C o u nt ( A N C) 1, 5 0 0/ m m 3 or 1. 5 x 1 0 9/ L;

Platelets 1 0 0, 0 0 0/ m m 3 or ≥1 0 0 x 1 0 9/ L;

He m o gl o bi n 9 g/ d L.
1 1. A de q uate re nal f u ncti o n, i ncl u di n g:

Esti mate d creati ni ne cleara nce 6 0 m L/ mi n f or Part 1 a n d 5 0 m L / mi n f or Part 2 
as calc ulate d usi n g t he met h o d sta n dar d f or t he i nstit uti o n. I n e q ui v ocal cases, a 
2 4 h o ur ur i 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.
1 2. A de q uate li ver f u ncti o n, i ncl u di n g:

T otal ser u m bilir u bi n 1. 5 x U L N u nless t he partici pa nt has d oc u me nte d Gil bert 
s yn dr o me;

As partate a n d ala ni ne tra nsa mi nase ( A S T a n d A L T) 2. 5 x U L N; 

Al kali ne p h os p hatase 2. 5 x U L N; ( 5 x U L N i n case of b o ne, li ver, or l u n g 
metastasis).
1 3. Res ol ve d ac ute effects of a n y  pri or t hera p y t o baseli ne se verity or C T C A E Gra de ≤1 
e xce pt f or a d verse e ve nts ( 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.
1 4. T h y r oi d sti m ulati n g h or m o ne ( T S H) wit hi n n or mal li mits ( W N L) f or i nstit uti o n; 
s u p ple me ntati o n is acce pta ble t o ac hie ve a T S H W N L; i n partici pa nts wit h a b n or mal 
T S H if Free T 4 a n d Free T h y r o xi ne are n or mal, a n d partici pa nt is cli nicall y 
e ut h yr oi d, partici pa nt is eli gi ble.
1 5. 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 6. Ca pa ble of gi vi n g si g ne d i nf or me d c o nse 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 i nf or me d 
c o nse nt d oc u me nt (I C D) a n d i n t his pr ot oc ol.
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:
1.
Partici pa nts wit h k n o w n s y m pt o matic brai n metastases re q uiri n g c ortic oster oi ds. 
Partici pa nts wit h pre vi o usl y  dia g n ose d brai n metastases are eli gi ble if t he y ha ve 
c o m plete d t heir treat me nt a n d ha ve rec o vere d fr o m t he ac ute effects of ra diati o n 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 5
t hera py or s ur ger y pri or t o st u d y e ntr y, ha ve disc o nti n ue d c ortic oster oi d treat me nt f or 
t hese metastases f or at least 4 wee ks a n d are ne ur ol o gically sta ble f or 3 m o nt hs 
(re q uires ma g netic res o na nce i ma gi n g [ M RI] c o nfir mati o n). 
2.
Partici pa nts wit h a n y  ot her acti ve mali g na nc y wit hi n 3 ye ars pri or t o e nr oll me nt, 
e xce pt f or a de q uatel y treate d basal cell or s q ua m o us cell s ki n ca ncer, or carci n o ma i n 
sit u.
3.
Maj or s ur ger y  wit hi n 3 wee ks pri or t o st u d y  e ntr y (e xce pt i n partici pa nts recei vi n g 
be vaciz u ma b -Pfizer i n w hic h maj or s ur ger y  wit hi n 4 wee ks pri or t o st u d y e ntr y 
w o ul d be e xcl usi o nar y ).
4.
Ra diati o n t hera p y wit hi n 3 wee ks pri or t o st u d y e ntr y. Palliati ve ra di ot hera p y t o a 
li mite d fiel d ma y be all o wed after c o ns ultati o n wit h t he s p o ns or’s me dical m o nit or 
u nless it is clearl y  i n dicati ve of disease pr o gressi o n.
5.
S y ste mic a nti-ca ncer t hera p y wit hi n 4 wee ks pri or t o st u d y e ntr 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 recei vi n g t he st u d y  i nter ve nti o n/st u d y treat me nt is re q uire d.
6.
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 
he patitis B vir us ( H B V), he patitis C vir us ( H C V), k n o w n h u ma n i m m u n o deficie nc y 
vir us ( HI V) or ac q uire d i m m u n o deficie nc y  s y n dr o me ( 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 hy 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 der e d eli gi ble. Eli 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 n fecti o ns), a n d stat us of HI V treat me nt. Als o, t he p ote ntial f or 
dr u g - dr u g i nteracti o ns will be ta ke n i nt o c o nsi derati o n.
7.
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 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, he/s he will be e xcl ude d.
8.
Baseli ne 1 2 -lea d electr ocar di o gra m ( 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 g, baseli ne c orrecte d Q T [ Q Tc F ] i nter val > 4 7 0 msec, c o m plete left b u n dle bra nc h 
bl oc k [ LB B B], si g ns of a n ac ute or i n deter mi nate a ge m y ocar dial i nfarcti o n, S T 
se g me nt or T wa ve i nter val c ha n ges s u g gesti ve of acti ve my ocar dial isc he mia, sec o n d 
or t hir d de gree atri o ve ntric ular [ A V] bl oc k, or seri o us bra d yarr h yt h mias or 
tac hyarr h yt h mias). If t he baseli ne u nc orrecte d Q T i nter val is > 4 7 0 msec, t his 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 or 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 6
Q R S val ues s h o ul d be use d t o deter mi ne t he partici pa nts eli gi bilit y . C o m p uter 
i nter prete d E C Gs s h o ul d be o verrea d by a p h ys icia 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. Cases 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 .
9.
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, l o n g Q T 
s yn dr o me, T orsa de de P oi ntes, arr h y t h mias (i ncl u di n g s ustai ne d ve ntric ular 
tac hyarr h yt h mia a n d ve ntric ular fi brillati o n), seri o us c o n d ucti o n s y ste m a b n or malities 
(e g, left a nteri or he mi bl oc k, left b u n dle bra nc h bl oc k), u nsta ble a n gi na, 
c or o nar y/ peri p heral arter y b ypass graft, s y m pt o matic c o n gesti ve heart fail ure ( C H F, 
Ne w Y or k Heart Ass ociati o n class III o r I V), cere br o vasc ular acci de nt, tra nsie nt 
isc he mic attac k, sy m pt o matic p ul m o nar y  e m b olis m, a n d/ or ot her cli nical si g nifica nt 
e pis o de of t hr o m b o-e m b olic disease, o n g oi n g car diac d ysr h yt h mias of Nati o nal 
Ca ncer I nstit ute ( N CI) C T C A E > Gra de 2, atrial fi bril lati o n of a n y gra de ( > Gra de 2 
i n t he case of asy m pt o matic l o ne atrial fi brillati o n). If a partici pa nt has a car diac 
r h yt h m de vice/ pace ma ker place d a n d Q Tc F > 4 7 0 msec, t he partici pa nt ca n be 
c o nsi dere d eli gi ble. Partici pa nts wit h car diac r h yt h m de vice/ pace ma ker 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 .
1 0. A ntic oa g ulati o n wit h vita mi n K a nta g o nists or fact or Xa i n hi bit ors is n ot all o we d. 
A ntic oa g ulati o n wit h S C he pari n is all o we d.
1 1. H y perte nsi o n t hat ca n n ot be c o ntr olle d b y  me dicati o ns (e g, > 1 5 0/ 9 0 m m H g) des pite 
o pti mal me dical t hera p y.
1 2. Partici pati o n i n ot her st u dies i n v ol vi n g i n vesti gati o nal dr u g(s) wit hi n 2 wee ks of 
st u d y e ntr y e xce pt f or partici pati o n i n me dical i ma gi n g st u dies, w hic h is all o we d.
1 3. K n o w n or s us pecte d h y p ersensiti vit y  t o P F-0 7 0 6 2 1 1 9, P F -0 6 8 0 1 5 9 1, or 
be vaciz u ma b - Pfizer, or e xci pie nts ass ociate d wit h t he prece di n g c o m p o u n ds f or t he 
res pecti ve pla n ne d i n vesti gati o nal st u dy treat me nts. Hist or y of Gra de 3 i m m u ne 
me d iate d or relate d A E (i ncl u di n g A S T/ A L T ele vati o ns t hat were c o nsi dere d dr u g 
relate d a n d c yt o ki ne release sy n dr o me) t hat was c o nsi dere d relate d t o pri or i m m u ne 
m o d ulat or y  t hera p y (e g, i m m u ne c hec k p oi nt i n hi bit ors, c o-sti m ulat or y a ge nts, etc) 
a n d re q uire d i m m u n os u p pressi ve t hera p y. A n e xce pti o n w o ul d be a partici pa nt wit h a 
hist or y  of vitili g o or t hyr oi d d y sf u ncti o n w h o has bee n off i m m u n os u p pressi ve 
t hera py f or at least 6 m o nt hs.
1 4. Acti ve or hist or y  of cli nicall y si g nifica nt a ut oi m m u ne disease t hat re q uire d s yste mic 
i m m u n os u p pressi ve t hera p y or a n ot her me dical c o n diti o n t hat re q uire d 
i m m u n os u p pressi o n wit hi n 2 years of treat me nt.
1 5. Re q uire me nt f or s ys te mic i m m u ne s u p pressi ve me dicati o n [e g, ≥1 0 m g  of pre d nis o ne 
or e q ui vale nt ( ≥1. 5 m g  of de xa met has o ne)]. I n hale d, i ntra nasal, i ntra oc ular, 
i ntraartic ular, a n d t o pical c ortic oster oi ds are all o we d.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 7
1 6. Acti ve blee di n g dis or der, i ncl u di n g gastr oi ntesti nal blee di n g, as e vi de nce d b y  
he mate mesis, si g nifica nt he m o pt y sis or mele na i n t he past 6 m o nt hs.
1 7. Partici pa nts wit h t he prese nce of a n y o pe n, acti ve w o u n d.
1 8. 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 
scree ni n g or breast fee di n g fe male partici pa nts (i ncl u di n g partici pa nts w h o i nte n d t o 
i nterr u pt breastfee di n g).
1 9. Hist or y  of or acti ve cli nicall y si g nifica nt gastr oi ntesti nal disease (i ncl u di n g b ut n ot 
li mite d t o i nfla m mat or y gastr oi ntesti nal disease [e g, ulcerati ve c olitis, Cr o h n’s 
disease], pe ptic ulcer disease, gastr oes o p ha geal refl u x disease, gastr oi ntesti nal 
blee di n g, c hr o nic diarr hea) a n d ot her c o n diti o ns t hat are u nres ol ve d a n d/ or ma y  
i ncrease t he ris k ass ociate d wit h st u d y partici pati o n or st u d y i nter ve nti o n/st u d y 
treat me nt a d mi nistrati o n or ma y i nterfere wit h t he i nter pretati o n of st u d y res ults a n d, 
i n t he j u d g me nt of t he i n vesti gat or, w o ul d ma ke t he partici pa nt i na p pr o priate f or 
e ntr y i nt o t his st u d y .
2 0. Ot her se vere ac ute or c hr o nic me dical or ps yc hi atric c o n diti o n, i ncl u di n g rece nt 
( wit hi n t he past year) or acti ve s uici dal i deati o n or 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 ass ociate d wit h st u d y partici pati o n or st u d y 
i nter ve nti o n/st u d y treat me nt a d mi nistrati o n or ma y i nterfere wit h t he i nter pretati o n of 
st u d y res ults a n d, i n t he j u d g me nt of t he i n vesti gat or, w o ul d ma ke t he partici pa nt 
i na p pr o priate f or e ntr y i nt o t his st u d y.
2 1. I n vesti gat or site staff me m bers directl y i n v ol ve d i n t he c o n d uct of t he st u d y a n d t heir 
fa mil y me m bers, site staff me m bers ot her wise s u per vise d b y t he i n vesti gat or, or 
Pfizer e m pl o y ees, i ncl u di n g t heir fa mil y me m bers, directl y i n v ol ve d i n t he c o n d uct of 
t he st u d y.
Secti o n 1 0. 1 9. 4 lists a d diti o nal i ncl usi o n/e xcl usi o n criteria f or t he P E T tracer s u bst u d y.
5. 3. Lifest yle C o nsi der ati o ns
5. 3. 1. C o ntr ace pti o n
T he i n vesti gat or or his or her de si 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 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 nts 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 se lecte 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 8
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 ntere d i n t he st u d y. Scree n fail ure data are c ollecte d as s o urce a n d are 
re p orte d t o t he cli nical data base.
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his trial (scree n fail ure) beca use 
of a s pecific m o difia ble fact or (e g, la b a b n or malit y) ma y  be rescree ne d. Rescree ne d 
partici pa nts s h o ul d be assi g ne d t he sa me partici pa nt n u m ber as f or t he i nitial scree ni n g.
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, or me dical de vice(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, t h e ter m st u d y i nter ve nti o n ma y be use d s yn o n y m o usl y 
wit h st u d y  dr u g.
6. 1. St u d y I nter ve nti o n(s) A d mi nistere d
See Ta ble 1 0 f or st u d y i nter ve nti o ns a d mi nistere d.
T a ble 1 0 . A d mi nistere d St u d y I nter ve nti o ns
I nter ve nti o n N a me
P F -0 7 0 6 2 1 1 9
P F -0 6 8 0 1 5 9 1
Be vaciz u ma b -Pfizer
T y pe
Bi ol o gic
Bi ol o gic
Bi ol o gic
D ose F or m ul ati o n
L y o p hilize d p o w der f or 
s ol uti o n f or i njecti o n
a n d
dil ue nt s ol uti o n 
( histi di ne, s ucr ose, P S 8 0, 
E D T A) f or i njecti o n
S ol uti o n f or i njecti o n 
S ol uti o n f or i njecti o n
U nit D ose Stre n gt h(s)
1. 3 m L ( 5 m g/ m L) 
P F -0 7 0 6 2 1 1 9 s ol uti o n i n 
vial f oll o wi n g 
rec o nstit uti o n wit h water 
f or i njecti o n
a n d
dil ue nt wit h 9. 8 m L 
s ol uti o n i n 2 0 m L vial f or 
dil uti o n of rec o nstit ute d 
P F -0 7 0 6 2 1 1 9 
5 0 m g/ m L ( 2 m L vial)  
1 0 0 m g/ 4 m L 
( 2 5 m g / m L) or 
4 0 0 m g/ 1 6 m L 
( 2 5 m g / m L) i n a si n gle 
d ose vial
D os a ge Le vel(s)
D ose a m o u nt a n d 
fre q ue nc y – see t he st u d y 
sc he ma a n d 
acc o m pa n yi n g te xt i n 
Secti o n 4. 1
3 0 0 m g Q 4 W
5 m g/ k g Q 2 W 
R o ute of 
A d m i nistr ati o n
S C after rec o nstit uti o n 
wit h water f or i njecti o n
S C
I V
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 6 9
T a ble 1 0 . A d mi nistere d St u d y I nter ve nti o ns
I n vesti g ati o n al 
Me dici n al Pr o d uct 
(I M P) a n d N o n 
I n vesti g ati o n al 
Me dici n al Pr o d uct 
( NI M P)
I M P 
a n d
NI M P - dil ue nt
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
Pr o vi de d ce ntrall y b y t he 
s p o ns or
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 o pe n la bel 
si n gle use vials 
Eac h vial a n d dil ue nt will 
be la bele d as re q uire d per 
c o u ntr y re q uire me nt
St u d y i nter ve nti o n will be 
pr o vi de d as 5 0 m g/ m L ( 2 
m L vial) i n vials
Eac h vial will be la bele d 
as re q uire d per c o u ntr y 
re q uire me nt
St u d y i nter ve nti o n will 
be pr o vi de d as si n gle use 
vial as 1 0 0 m g/ 4 m L 
( 2 5 m g / m L) or 
4 0 0 m g/ 1 6 m L 
( 2 5 m g / m L).
Eac h vial will be la bele d 
as re q uire d per c o u ntr y 
re q uire me nt
6. 1. 1. A d mi nistr ati o n
6. 1. 1. 1. P F -0 7 0 6 2 1 1 9 
P F -0 7 0 6 2 1 1 9 will be a d mi nistere d via S C i njecti o n wit h o ut a dj ust me nt f or b o d y  size at e ver y 
c ycle. 
Partici pa nts s h o ul d ha ve S C i njecti o ns i n t he a b d o me n. F or partici pa nts recei vi n g 2 or m ore 
S C i njecti o ns, st u d y dr u g s h o ul d be a d mi nistere d i n 2 or m ore differe nt q ua dra nts of t he 
a b d o me n ( wit h prefere nce gi ve n t o t he l o wer q ua dra nt w he n p ossi ble); 1 or 2 i njecti o ns per 
q ua dra nt. T he i njecti o n ca n be r otate d wit h eac h a d mi nistrati o n f or partici pa nt c o mf ort. 
A d diti o nal g ui da nce o n s u bc uta ne o us i njecti o n site l ocati o ns is pr o vi de d i n Secti o n 1 0. 2 0 . 
Details f or P F - 0 7 0 6 2 1 1 9 pre parati o n i nstr ucti o ns are pr o vi de d i n t he c urre nt P F - 0 7 0 6 2 1 1 9 I P 
Ma n ual. 
Pre me dicati o n wit h b ot h t he pri mi n g d ose(s) a n d i nitial f ull d ose of P F -0 7 0 6 2 1 1 9 f or all 
partici pa nts has bee n i m ple me nte d i nt o t his st u d y  t o f urt her i m pr o ve t olera bilit y a n d 
partici pa nt e x perie nce. 
T he f oll o wi n g pre me dicati o n s h o ul d be a d mi nistere d a p pr o xi matel y 1 h o ur pri or t o 
P F - 0 7 0 6 2 1 1 9:

Aceta mi n o p he n 6 5 0 m g ( or e q ui vale nt), oral

Di p he n h y dra mi ne 2 5 m g, oral or I V

De xa met has o ne 1 2 m g ( or e q ui vale nt), oral or I V
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 0
Pre me dicati o n s h o ul d be a d mi nistere d i n C y cle 1 o nl y o n C 1 D 1 i n c o h orts wit h o ut a pri mi n g 
d ose a n d s h o ul d be a d mi nistere d o n b ot h C 1 D 1 a n d C 1 D 1 5 i n c o h orts wit h a pri mi n g d ose. 
P re me dicati o n re gi me n b e y o n d t he first f ull d ose a n d m o dificati o ns t o t he pre me dicati o n 
re gi me n (e g, fre q ue nc y of pre me dicati o n, d oses of i n di vi d ual a ge nts, re m o val or a d diti o n of 
a ge nts) ma y be i m ple me nte d b y t he s p o ns or base d o n e mer gi n g data. A ny e xce pti o ns t o 
pre me dicati o n re q uire disc ussi o n a n d a gree me nt bet wee n t he s p o ns or a n d i n vesti gat or. 
Partici pa nts will be re q uire d t o re mai n i n t he cli nic t o o bser ve d f or s pecific peri o ds of ti me 
d uri n g t he first c y cle (see Secti o n 4. 1 f or details).
G ui da nce is pr o vi de d bel o w ( Secti o n 8 ) f or ma na ge me nt of treat me nt relate d a d verse e ve nts. 
G ui da nce f or e val uati o n of I njecti o n Site T olera bilit y  is pr o vi de d i n Secti o n Injecti o n Site 
T olera bilit y  Assess me nt ( S C O nl y) (Secti o n 8. 1. 7 ). Treat me nt-relate d A Es are all c o nsi dere d 
t o xicities e xce pt t h ose t hat are clearl y n ot relate d t o P F- 0 7 0 6 2 1 1 9 (e g, disease pr o gressi o n, 
e n vir o n me ntal, u nrelate d tra u ma, etc). Treat me nt relate d t o xicities i ncl u de a n y  e ve nt 
c o nsi dere d relate d, pr o ba bl y  relate d, or p ossi bly relate d t o P F - 0 7 0 6 2 1 1 9.
6. 1. 1. 2. P F -0 6 8 0 1 5 9 1
I n t he i n vesti gati o nal c o m bi nati o n t hera p y wit h P F-0 7 0 6 2 1 1 9, P F -0 6 8 0 1 5 9 1 3 0 0 m g
( 5 0 m g/ m L ), will be a d mi nistere d S C Q 4 W t o t he a b d o me n. P F -0 6 8 0 1 5 9 1 s h o ul d be 
a d mi nistere d t o 2 or m ore differ e nt q ua dra nts of t he a b d o me n ( wit h prefere nce gi ve n t o t he 
l o wer q ua dra nts w he n p ossi ble); 1 or 2 i njecti o ns per q ua dra nt. 
I njecti o ns t o t he a b d o me n are preferre d. If S C i njecti o ns i n t he a b d o mi nal l ocati o n are n ot 
p ossi ble, S C i njecti o ns ca n be a d mi niste re d i n a distri b ute d ma n ner i n t he t hi g hs after 
disc ussi o n a n d a gree me nt bet wee n i n vesti gat or a n d t he S p o ns or. S C i njecti o ns i n t he u p per 
e xtre mities (e g, delt oi d, u p per a n d l o wer ar m) are n ot per mitte d.
P F -0 6 8 0 1 5 9 1 S C i njecti o n will be a d mi nistere d at lea st 3 0 mi n utes after a d mi nistrati o n of 
P F - 0 7 0 6 2 1 1 9. A d diti o nal g ui da nce o n s u bc uta ne o us i njecti o n site l ocati o ns is pr o vi de d i n
Secti o n 1 0. 2 0 . F or s pecific i nstr ucti o ns o n t he ha n dli n g a n d pre parati o n i nstr ucti o ns of st u d y  
dr u g, refer t o t he Pr o d uct S pecific I n vesti gati o nal Pr o d uct (I P) Ma n ual.
6. 1. 1. 3. Be v aciz u m a b -Pfizer
F or partici pa nts treate d wit h t he i n vesti gati o nal t hera p y  wit h P F-0 7 0 6 2 1 1 9,
be vaciz u ma b - Pfizer will be s u p plie d as 1 0 0 m g/ 4 m L  ( 2 5 m g / m L) or 4 0 0 m g/ 1 6 m L  
( 2 5 m g/ m L) i n a si n gle d ose vial. T he necessar y  a m o u nt of be vaciz u ma b- Pfizer s h o ul d be 
wit h dra w n, base d o n 5 m g / k g of b o dy wei g ht, a n d dil ute d i n a t otal v ol u me of 1 0 0 m L  of 
0. 9 % s o di u m c hl ori de s ol uti o n. T he first i nf usi o n of t he dil ute d s ol uti o n s h o ul d be 
a d mi nistere d wit h a n i nf usi o n p u m p o ver 9 0 mi n utes. T he sec o n d i nf usi o n s h o ul d be 
a d mi nistere d o ver 6 0 mi n utes if t he first i nf usi o n is well t olerate d. All s u bse q ue nt i nf usi o n s 
s h o ul d be a d mi nistere d o ver 3 0 mi n utes if t he sec o n d i nf usi o n a d mi nistere d o ver 6 0 mi n utes 
is well t olerate d. Be vaciz u ma b-Pfizer I V i nf usi o n will be a d mi nistere d at least 3 0 mi n utes 
after a d mi nistrati o n of P F - 0 7 0 6 2 1 1 9. F or s pecific i nstr ucti o ns o n t he ha n dli n g a n d 
pre parati o n i nstr ucti o ns of st u d y  dr u g, refer t o t he Pr o d uct S pecific I P Ma n ual. Partici pa nts 
pla n ne d t o recei ve P F -0 7 0 6 2 1 1 9 i n c o m bi nati o n wit h be vaciz u ma b -Pfizer s h o ul d be wei g he d 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 1
wit hi n 7 2 h o urs pri or t o d osi n g f or e ver y  c ycle t o e ns ure t he y di d n ot e x perie nce eit her a 
wei g ht l oss or gai n > 1 0 % fr o m t he pri or wei g ht use d t o calc ulate t he a m o u nt of 
be vaciz u ma b - Pfizer re q uire d f or d ose pre parati o n. Decisi o n t o recalc ulate 
be vaciz u ma b -Pfizer d ose base d o n t he wei g ht o btai ne d at eac h c y cle ca n be i n acc or da nce 
wit h i nstit uti o nal practice, h o we ver if t he partici pa nt e x perie nce d eit her a wei g ht l oss or gai n 
> 1 0 % c o m pare d t o t he wei g ht use d t o calc ulate eit her t he i nitial or pre vi o us d ose, t he a m o u nt 
of be vaciz u ma b -Pfizer re q uire d f or pre parati o n a n d a d mi nistrati o n f or t he c urre nt c y cle m ust 
be recalc ulate d usi n g t his m ost rece nt wei g ht o btai ne d.
All partici pa nts recei vi n g be vaciz u ma b -Pfizer will re q uire a pr otei n uria assess me nt ( di pstic k 
is acce pta ble) pri or t o eac h d ose of be vaciz u ma b-Pfizer f or t he d urati o n of t he st u d y . If 
uri nal y sis de m o nstrates pr otei n greater t ha n or e q ual t o 2 +, t he n a 2 4-h o ur uri ne pr otei n 
c ollecti o n s h o ul d f oll o w. I n partici pa nts wit h pr otei n uria greater t ha n or e q ual t o 2 gra ms per 
2 4 h o urs, be vaciz u ma b -Pfizer s h o ul d be hel d u ntil rec o ver y  (less t ha n 2 gra ms per 2 4 h o urs). 
Disc o nti n ue be vaciz u ma b -Pfizer i n partici pa nts t hat de vel o p ne p hr otic s y n dr o me.
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
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 be e 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 n y 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, as a p plica ble f or 
te m perat ure-m o nit ore d s hi p me nts.
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 ut o 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 ble 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 ure 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.
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 b ilit y, rec o nciliati o n, a n d rec or d mai nte na nce 
(ie, recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds). 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. 
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 I P ma n ual.
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 pr o d uct la bel.
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 a n d i n acc or da nce wit h t he 
la bels. 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 2
See t he I P Ma n ual, or e q ui vale nt f or st ora ge c o n diti o ns of t he st u d y i nter ve nti o n o nce 
rec o nstit ute d a n d/ or dil ute d.
De viati o ns fr o m t he st ora ge re q uire me nts, 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 Pfizer u p o n disc o ver y. 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 o m 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 u d 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. It will n ot be c o nsi dere d a 
pr ot oc ol de viati o n if Pfizer a p pr o ves t he use of t he st u d y  i nter ve nti o n after t he te m perat ure 
e xc ursi o n. Use of t he st u d y i nter ve nti o n pri or t o Pfizer a p pr o val will be c o nsi dere d a pr ot oc ol 
de viati 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 site i n t he IP ma n ual.
T he s p o ns or or desi g nee will pr o vi de g ui da nce o n t he destr ucti o n of u n use d st u d y  
i nter ve nti o n (e g, at t he site). 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 a p plica ble 
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, a n d all destr ucti o n m ust be a de q uatel y d oc u me nte d.
6. 3. Pre p ar ati o n a n d Dis pe nsi n g
Detaile d i nstr ucti o ns f or P F -0 7 0 6 2 1 1 9  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 are pr o vide d i n t he c urre nt I P Ma n ual. I n vesti gati o nal pr o d uct s h o ul d be 
pre pare d a n d dis pe nse d b y  a n a p pr o priately 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 hys icia 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.
See t he I P ma n ual f or i nstr ucti o ns o n h o w t o pre pare P F -0 6 8 0 1 5 9 1 a n d be vaciz u ma b -Pfizer 
f or a d mi nistrati o n. P F-0 6 8 0 1 5 9 1 a n d be vaciz u ma b -Pfizer s h o ul d be pre pare d a n d dis pe nse d 
b y  a n a p pr o priately 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 ys icia n, 
n urse, p h ys icia 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.
All acti ve a n d dil ue nt vi als are f or si n gle use o nl y .
6. 4. 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. 4. 1. All oc ati o n t o I n vesti g ati o n al Pr o d uct/ St u d y I nter ve nti o n
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 nts ha ve gi ve n t heir 
writte n i nf or me d c o nse 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 fa x/e mail a c o m plete Re gistrati o n F or m t o t he desi g nate d s p o ns or st u d y 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 3
N o partici pa nt s hall recei ve st u d y  i nter ve nti o n/st u d y treat me nt 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 e nr oll me nt;

S pecificati o n of t he d ose le vel f or t hat pa rtici 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.
F or P art 2 of t he st u dy:
All ocati o n of partici pa nts t o treat me nt gr o u ps ma y pr ocee d t hr o u g h t he use of a n i nteracti ve 
res p o nse tec h n ol o g y (IR T) s y ste m (i nteracti ve We b-base d res p o nse [I W 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 ys te 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 pr ot oc ol n u m ber, s pecific pr ot oc ol e ntra nce criteria i n dicate d i n t he s yste m a n d 
t he scree ni n g 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 dis pe nsa ble u nit ( D U) or c o ntai ner n u m ber 
w he n st u d y  i nter ve nti o n/st u d y treat me nt is bein g s u p plie d via t he I R T s ys te m. T he IR T 
s yste 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. I n vesti gati o nal pr o duct/st u d y  treat me nt will be dis pe nse d at t he st u d y visits as 
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/st u d y treat me nt m ust n ot be re-
dis pe nse d t o t he partici pa nts.
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. 5. St u d y I nter ve nti o n C o m pli a nce
All d oses of st u d y  i nter ve nti o n/st u d y treat me nt will be a d mi nistere d b y t he a p pr o priately 
desi g nate d st u d y  staff at t he i n vesti gat or site. 
T he site will c o m plete re q uire d d osa ge Pre parati o n Rec or d l ocate d i n t he I P ma n ual. T he use 
of t he Pre parati o n Rec or d is preferre d b ut it d oes n ot precl u de t he use of a n e xisti n g 
a p pr o priate cli nical site d oc u me ntati o n s y ste m. T he e xisti n g cli nical sites d oc u me ntati o n 
s yste m s h o ul d ca pt ure all perti ne nt/re q uire d i nf or mati o n o n t he pre parati o n a n d 
a d mi nistrati o n of t he d ose. T his ma y be use d i n place of t he Pre parati o n Rec or d after 
a p pr o val fr o m t he s p o ns or a n d/ or desi g nee.
6. 6. 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 nts fr o m scree ni n g u ntil t he e n d of st ud y  visit will be 
rec or de d o n t he C R F as o utli ne d i n t he data e ntr y g ui deli nes.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 4
All c o nc o mita nt treat me nts m ust be a p pr o ve d b y t he s p o ns or at st u d y e ntr y.
A ut h orize d or a p pr o ve d C O VI D -1 9 vacci nes are c o nsi dere d all o we d c o nc o mita nt 
me dicati o ns a n d sta n dar d A E c ollecti o n a n d re p orti n g pr ocesses s h o ul d be f oll o we d. T he 
ti mi n g of vacci ne d osi n g relati ve t o t he d osi n g of st u d y dr u g(s) is at t he discreti o n of t he 
i n vesti gat or, alt h o u g h it ma y best t o a v oi d t he 7 da ys pri or t o C 1 D 1 a n d t he D L T o bser vati o n 
peri o d, t o c o nsi der t he p ote ntial f or vacci ne -relate d a d verse e ve nts, a n d t o a d mi nister t he 
vacci ne d uri n g sc he d ule d d osi n g h oli da y s, if a p plica ble. Disc ussi o ns bet wee n t he i n vesti gat or 
a n d t he s p o ns or re gar di n g i n di vi d ual cases ma y  occ ur if f urt her clarificati o n is re q uire d.
P F -0 7 0 6 2 1 1 9 has bee n de m o nstrate d t o tra nsie ntl y  i ncrease c yt o ki ne le vels (e g, I L-6) i n vi v o 
i n m o n ke ys (als o de m o nstrate d via i n vitr o assa ys) w hic h is e x pecte d wit h C D 3-tar gete d 
bis pecifics. C y t o ki nes ha ve bee n s h o w n t o res ult i n m o dest i n hi biti o n of s o me 
c yt oc hr o me P 4 5 0 e nz y mes. T heref ore, treat me nt wit h P F- 0 7 0 6 2 1 1 9 has t he p ote ntial t o 
m o dest l y i ncrease t he e x p os ure of c o nc o mita nt me dicati o ns t hat are s u bstrates f or t hese 
e nz ymes. Ca uti o n s h o ul d be use d u p o n c o nc o mita nt use of se nsiti ve s u bstrates of c yt oc hr o me 
P 4 5 0 e nz ymes wit h narr o w t hera pe utic i n de x (e g, C Y P 3 A 4: alfe nta nil, c y cl os p ori ne, 
di h y dr oer g ota mi ne, er g ota mi ne, fe nta n yl , pi m ozi de, q ui ni di ne, sir oli m us a n d tacr oli m us; 
C Y P 2 C 9: p he n y t oi n, warfari n) es pecially d uri n g t he i nitial treat me nt c ycle.
6. 6. 1. Ot her A nti -t u m or/ A nti-c a ncer Tre at me nt 
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 nts are recei vi n g st u dy 
treat me nt. 
Palliati ve ra di ot hera p y o n st u d y  is per mitte d f or t he treat me nt of pai nf ul b o n y lesi o ns 
pr o vi de d t hat t he lesi o ns were k n o w n at t he ti me of st u d y  e ntr y a n d t he i n vesti gat or clearly 
i n dicates t hat t he nee d f or palliati ve ra di ot hera py i s n ot i n dicati ve of disease pr o gressi o n. I n 
vie w of t he c urre nt lac k of data a b o ut t he i nteracti o n of P F - 0 7 0 6 2 1 1 9 wit h ra di ot hera py, 
P F - 0 7 0 6 2 1 1 9 treat me nt s h o ul d be i nterr u pte d d uri n g palliati ve ra di ot hera p y, st o p pi n g 7 d a y s 
bef ore a n d res u mi n g treat me nt after rec o ver y  t o baseli ne.
6. 6. 2. 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 b e 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 merica n S ociety of Cli nical O nc ol o g y  ( A S C O) g ui deli nes.
6. 6. 2. 1. S u p p orti ve C are f or C yt o ki ne Rele ase S y n dr o me
S y m pt o ms ass ociate d wit h c y t o ki ne release sy n dr o me ( C R S) var y  greatl y a n d ma y be 
diffic ult t o disti n g uis h fr o m ot her c o n diti o ns. T he m ore c o m m o n s y m pt o ms i ncl u de fe ver, 
na usea, hea dac he, tac h yc ar dia, h y p ote nsi o n, ras h a n d s h ort ness of breat h. T he se verit y of 
s ym pt o ms ca n be mil d t o life t hreate ni n g a n d t h us t here s h o ul d be a hi g h s us pici o n f or C R S 
if t hese sy m pt o ms occ ur. T he gra di n g of C R S a n d cli nical ma na ge me nt c o nsi derati o ns are 
descri be d b y t he A S T C T c o nse ns us w or ki n g gr o u p a n d n ote d i n A p pe n di x 1 1 ( Lee et al 
2 0 1 9). 2 5  H o we ver, if l ocal sta n dar d of care f or C R S ma na ge me nt i n v ol ves a differe nt 
re gi me n t he n t hese g ui delines s h o ul d be c o nsi dere d a n d p ote ntiall y  utilize d.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 5
T he decisi o n t o i nc or p orate a n d/ or c ha n ge t he pre me dicati o n strate g y  (see Secti o n 6. 1. 1 ) f or 
C R S pr o p h y la xis i n all partici pa nts will be ma de f oll o wi n g disc ussi o ns bet wee n t he s p o ns or 
a n d t he i n vesti gat ors. 
6. 6. 2. 2. S u p p orti ve C are f or I nf usi o n -Rel ate d Re acti o ns
A n I R R is c haracterize d b y  fe ver a n d c hills, a n d less c o m m o nl y h yp ote nsi o n, eit her 
e x perie nce d b y a partic ular part ici pa nt or if see n i n ot her partici pa nts, pretreat me nt 
me dicati o n s h o ul d be a d mi nistere d t o re d uce t he i nci de nce a n d se verit y . In t he e ve nt of 
i nf usi o n relate d reacti o ns, In vesti gat ors s h o ul d i nstit ute treat me nt meas ures acc or di n g t o best 
me dical a n d n ursi n g practice. A l ocal sta n dar d of care f or t he ma na ge me nt of I R R s h o ul d be 
utilize d.
6. 6. 2. 3. S u p p orti ve C are f or H y perse nsiti vit y Re acti o ns T y pes 1 a n d 3
T y pe 1 h y perse nsiti vit y  or aller gic (e g, s h ort ness of breat h, urticaria, a na p h yla xis, 
a n gi oe de ma) reacti o ns are t he oreticall y  p ossi ble i n res p o nse t o a n y i njecte d pr otei n. Im m u ne 
c o m ple x me diate d T ype 3 h y perse nsiti vit y  reacti o ns are si milar t o t he A Es of T yp e 1 
reacti o ns b ut are li kely t o be d ela ye d fr o m t he ti me of i nf usi o n a n d ma y  i ncl u de s ym pt o ms 
s uc h as ras h, urticaria, p ol yart hritis, m yal gia, p ol ys y n o vitis, fe ver, a n d, if se vere, 
gl o mer ul o ne p hritis.
All partici pa nts s h o ul d be cl osel y o bser ve d w hile recei vi n g st u d y i nter ve nti o n/st u d y  
treat me nt i nf usi o ns a n d m o nit ori n g f or cli nical si g ns of a s ys te mic reacti o n will c o nti n ue 
t hereafter f or cli nical si g ns of aller gic reacti o ns/ h yperse nsiti vit y .
I n t he case of a hy p erse nsiti vit y reacti o n, t he partici pa nt will be treate d sy m pt o maticall y  wit h 
s u p p orti ve care, f urt her m o nit ori n g, a n d treat me nt wit h a nti-hista mi nes a n d/ or 
c ortic oster oi ds. St u d y i nf usi o ns ma y be st o p pe d, a n d t he partici pa nt will be f oll o we d u ntil t he 
e n d of t he st u d y.
6. 6. 2. 4. S u p p orti ve C are f or I m m u ne -Rel ate d A d verse E ve nts
F or i m m u n ot hera pe utic a ge nts, treat me nt of i m m u ne- relate d a d verse e ve nts (ir A Es) is mai nl y 
de pe n de nt u p o n se verit y ( N CI C T C A E gra de v 5. 0). I n ge neral, Gra de 1 or 2 ir A Es are treate d 
s ym pt o maticall y a n d persiste nt Gra de 2, 3, or 4 ir A Es are treate d wit h m o derate t o hi g h
d oses of c ortic oster oi ds.
Treat me nt of ir A Es s h o ul d f oll o w g ui deli nes as s u m marize d i n A p pe n di x 1 3 .
6. 6. 3. He m at o p oietic Gr o wt h F act ors
Pri mar y  pr o p h ylactic use of gra n ul oc yte-c ol o n y sti m ulati n g fact ors is n ot per mitte d d uri n g 
t he first 2 8 d a y s of Cycle 1 f or c o h orts wit h o ut a pri mi n g d ose a n d t he first 4 2 da y s ( C 2 D 1 5) 
f or c o h orts wit h a pri mi n g d ose, 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 merica n S ociet y of Cli nical O nc ol o g y ( A S C O) 
g ui deli nes or l ocal re gi o nal g ui deli nes. D uri n g scree ni n g wi n d o w ( 2 8 da y s pri or t o Da y 1), 
G C S F is 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 6
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 ( N ote: er yt hr o p oieti n is n ot a p pr o ve d f or a ne mia ca use d b y c he m ot hera p y i n all l ocal 
re gi o ns, n or is it c urre ntl y a p pr o ve d i n Ja pa n).
6. 6. 4. 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 rec o m me n de d pre me dicati o n f or t he first c ycle (see 
Secti o n 6. 1. 1 ) 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 the dr u g is n ot pr o hi bite d i n t he 
C o nc o mita nt T hera p y secti o n.
Dia rr hea has bee n o bser ve d i n partici pa nts recei vi n g P F -0 7 0 6 2 1 1 9. (see Secti o n 2. 2. 8. 1 ). 
Earl y i de ntificati o n a n d i nter ve nti o n is critical f or t he o pti mal ma na ge me nt of diarr hea. A t 
t he first si g n of l o ose st o ols, partici pa nts s h o ul d be i nstr ucte d t o start a nti-diarr heal t hera p y
(e g, l o pera mi de 4 m g i nitial d ose f oll o we d b y  2 m g after e ver y s u bse q ue nt l o ose st o ol wit h 
n o m ore t ha n 1 6 m g dail y ), i ncrease oral fl ui ds, a n d n otif y t he pri nci pal i n vesti gat or f or 
f urt her i nstr ucti o ns a n d a p pr o priate f oll o w u p. Partici pa nts s h o ul d be e nc o ura ge d t o i ncrease 
oral fl ui ds. 
I n ge neral, ma na ge me nt of ca ncer treat me nt-i n d uce d diarr hea has bee n descri be d ( Be ns o n et 
al, 2 0 0 4). 7 I nitial ma na ge me nt f or mil d t o m o derate diarr hea ma y i ncl u de dietar y 
m o dificati o ns (eli mi nati n g lact ose a n d ot her hi g h -os m olar dietar y  s u p ple me nts), l o pera mi de 
or di p he n o x yl ate/atr o pi ne, al o n g wit h oral a nti bi otics if persiste nt wit h c o ncer n f or i nfecti o n. 
Ma na ge me nt of hi g her se verit y  or m ore c o m plicate d diarr hea ma y als o i ncl u de c o nsi derati o n 
of i ntra ve n o us fl ui ds f or h y drati o n, electr ol yt e re place me nt, octre oti de, st o ol w or k u p al o n g 
wit h h os pitalizati o n f or o bser vati o n a n d treat me nt if i n dicate d i n t he i n vesti gat or’s me dical 
j u d ge me nt. 
I n a d diti o n, ma na ge me nt of diarr hea as descri be d i n s u p p orti ve care f or i m m u ne-relate d 
a d verse e ve nts f or diarr hea ( A p pe n di x 1 3 ) ma y als o be c o nsi dere d if t he cli nical i m pressi o n 
of t he eti ol o g y  of diarr hea is ass ociate d wit h i m m u ne d ysf u ncti o n.
6. 6. 5. 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 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 
Secti o n 6. 6 .
6. 6. 6. C ortic oster oi ds 
C hr o nic s y ste mic c ortic oster oi d use (pre d nis o ne > 1 0 m g/ da y  or e q ui vale nts) f or palliati ve or 
s u p p orti ve p ur p oses is n ot per mitte d. H o we ver, s yste mic c ortic oster oi d use at a lo w d ose f or 
a s h ort d urati o n (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. 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 7
6. 6. 7. S ur ger y 
Ca uti o n is a d vise d o n t he oretical gr o u n ds f or a n y 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 0 6 2 1 1 9 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 0 6 2 1 1 9 
a n d/ or P F-0 6 8 0 1 5 9 1 is rec o m me n de d at least 7 da y s pri or t o s ur ger y. P ost o perati vely, t he 
decisi o n t o rei nitiate P F- 0 7 0 6 2 1 1 9 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.
I n t he setti n g of be vaciz u ma b-Pfizer use as part of i n vesti gati o nal c o m bi nati o n t hera p y , 
be vaciz u ma b -Pfizer s h o ul d be disc o nti n ue d f or at least 2 8 da y s pri or t o electi ve s ur ger y. 
Als o, d o n ot a d mi nister be vaciz u ma b -Pfizer f or at least 2 8 da ys f oll o wi n g s ur ger y a n d u ntil 
t he w o u n d is f ull y heale d.
6. 6. 8. 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 wit h P F- 0 7 0 6 2 1 1 9 ; 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. 7. 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/st u d y treat me nt 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, w hic h ma y i ncl u de a D L T, d osi n g ma y 
be dela y e d, re d uce d a n d/ or disc o nti n ue d as descri be d bel o w a n d i n Secti o ns 6. 7. 1 , 6. 7. 2 a n d 
6. 7. 3 . 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 level (if 
a p plica ble) 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 
s p o ns or, t he partici pa nt is be nefiti n g fr o m t hera p y. In 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 (an d attri b uti o n f or t he 
c o m bi nati o n treat me nt i n Part 1 B a n d Part 2). Partici pa nts 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 ym pt o m.
D ose m o dificati o ns ma y  occ ur i n o ne of t hree wa ys:

Wit hi n a c y cle: d osi n g i nterr upti 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;

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.
6. 7. 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 or i n vesti gati o nal c o m bi nati o n t hera p y, partici pa nts 
e x perie nci n g Gra de 3 or 4 p ote ntiall y  treat me nt relate d t o xicity or i nt olera ble Gra de 2 
t o xicit y des pite s u p p orti ve care s h o ul d ha ve t heir treat me nt i nterr u pte d.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 8
C o m bi nati o n t hera p y  wit h i m m u ne o nc ol o g y c o m p o u n ds ma y a u g me nt ir A Es, p ne u m o nitis, 
c olitis, creati ni ne, a n d li ver f u ncti o n test ( L F T) ele vati o n s h o ul d be m o n it ore d caref ully wit h 
t his class of a ge nts. T o facilitate t he early rec o g niti o n a n d pr o m pt i nter ve nti o n of cli nicall y 
rele va nt A Es relate d t o st u d y treat me nt, ma na ge me nt al g orit h ms ha ve bee n de vel o pe d f or 
s us pecte d p ul m o nar y, gastr oi ntesti nal, li ver, e n d ocri ne, s ki n, car diac, re nal, or ot her 
i m m u ne-relate d t o xicities (see A p pe n di x 1 3 ).
All partici pa nts recei vi n g be vaciz u ma b -Pfizer will re q uire a pr otei n uria assess me nt ( di pstic k 
is acce pta ble) pri or t o eac h d ose of be vaciz u ma b -Pfizer f or t he d urati o n of t he st u d y . If 
uri nal y sis de m o nstrates pr otei n greater t ha n or e q ual t o 2 +, t he n a 2 4-h o ur uri ne pr otei n 
c ollecti o n s h o ul d f oll o w. I n partici pa nts wit h pr otei n uria greater t ha n or e q ual t o 2 gra ms per 
2 4 h o urs, be vaci z u ma b-Pfizer s h o ul d be hel d u ntil rec o ver y  (less t ha n 2 gra ms per 2 4 h o urs). 
Disc o nti n ue be vaciz u ma b -Pfizer i n partici pa nts t hat de vel o p ne p hr otic s y n dr o me.
A p pr o priate f oll o w- u p assess me nts s h o ul d be d o ne u ntil a de q uate rec o ver y occ urs as 
assesse d b y t he i n vesti gat or. Criteria re q uire d bef ore treat me nt ca n res u me are descri be d i n 
t he D ose Dela y s secti o n.
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. De pe n di n g o n w he n t he a d verse 
e ve nt res ol ve d, a treat me nt i nterr u pti o n ma y  lea d t o t he partici pa nt missi n g all s u bse q ue nt 
pla n ne d d oses wit hi n t hat sa me c y cle or e ve n t o dela y t he i nitiati o n of t he s u bse q ue nt c ycle.
If t he a d verse e ve nt t hat le d t o t he treat me nt i nterr u pti o n rec o vers wit hi n t he sa me c ycle, t he n 
re-d osi n g i n t hat c y cle is all o we d. D oses o mitte d f or t o xicit y are n ot re place d wit hi n t he sa me 
c ycle. 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 os e Re d ucti o ns secti o n, u nless e x pressl y 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 > 4 wee ks, treat me nt res u m pti o n will be deci de d i n c o ns ultati o n 
wit h t he s p o ns or.
6. 7. 1. 1. D ose I nterr u pti o n of P artici p a nts wit h Pres u me d or Acti v e 
C O VI D -1 9/ S A R S -C o V 2 I nfecti o n
O n g oi n g 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 orit y-a p pr o ve d 
test] or 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, s h o ul d f oll o w t he 
treat me nt g ui deli nes bel o w:

F or s y m pt o mati c partici pa nts wit h acti ve S A R S- C o V 2 i nfecti o n, i n vesti gati o nal 
treat me nt s h o ul d be dela ye d f or at least 1 4 da ys fr o m start of s ym pt o ms. T his dela y  is 
i nte n de d t o all o w res ol uti o n of s ym 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 parti ci 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. T he s p o ns or s h o ul d be i nf or me d w he n restarti n g treat me nt.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 7 9

C o nti n ue t o c o nsi der p ote ntial dr u g -dr u g i nteracti o ns f or a n y  c o nco 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.
M ore i nf or mati o n o n C O VI D- 1 9 is pr o vi de d i n A p pe n di x 1 8 .
6. 7. 2. 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 all of t he f oll o wi n g para meters ha ve bee n met:

A N C 1, 0 0 0/ m m 3.

Platelets c o u nt 5 0, 0 0 0/ m m 3.

N o n he mat ol o gic t o xicities ha ve ret ur ne d t o baseli ne or Gra de 1 se verit y  ( or, at t he 
i n vesti gat or’s discreti o n, Gra de 2 if n ot c o nsi dere d a safet y ris k f or t he partici pa nt).
If a treat me nt dela y  res ults fr o m w orse ni n g of he mat ol o gic or bi oc he mical para meters, t he 
fre q ue nc y of rele va nt bl o o d tests s h o ul d be i ncrease d as cli nically i n dicate d.
If t hese c o n diti o ns are met wit hi n 4 wee ks of treat me nt i nterr u pti o n, P F -0 7 0 6 2 1 1 9 ma y  be 
res u me d. Refer t o t he D os e Re d ucti o ns secti o n f or a d verse e ve nts re q uiri n g d ose re d ucti o n at 
t he ti me of treat me nt res u m pti o n.
If partici pa nts re q uire disc o nti n uati o n of P F -0 7 0 6 2 1 1 9 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 S p o ns or’s 
me dical m o nit or. 
If a treat me nt i nterr u pti o n c o nti n ues be yo n d Da y  2 8 of t he c urre nt c y cle, t he n t he da y w he n 
treat me nt is restarte d will be c o u nte d as Da y 1 of t he ne xt c ycle.
6. 7. 3. D os e Re d ucti o ns
F oll o wi n g d osi n g i nterr u pti o n or c y cle dela y d ue t o t o xicit y, t he P F-0 7 0 6 2 1 1 9 d ose ma y  nee d 
t o be re d uce d w he n treat me nt is res u me d.
N o s pecific d ose a dj ust me nts are rec o m me n de d f or Gra de 1/ 2 treat me nt -relate d t o xicit y. 
H o we ver, i n vesti gat ors s h o ul d al wa ys ma na ge t heir partici pa nts acc or di n g t o t heir me dical 
j u d g me nt base d o n t he partic ular cli nical circ u msta nces.
F or n o n -i m m u ne-relate d t o xicities, t o xicities n ot ot her wise s pecifie d i n Ta ble 1 1 , a n d 
i m m u ne-relate d t o xicities, d ose re d ucti o n of P F -0 7 0 6 2 1 1 9 b y  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 a n d base d o n t he 
dis creti o n of t he i n vesti gat or a n d i n c o m m u nicati o n wit h t he s p o ns or. 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 ntere d i nt o t he 
f oll 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 . 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 0
F or i n vesti gati o nal c o m bi nati o n t hera p y, 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 c o m p o u n d 
A a n d 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 c o m p o u n d A, a d ose l o weri n g, 
dela y , or i nterr u pti o n of c o m p o u n d A ma y be a p plica ble b ut n ot necessaril y t o c o m p o u n d B). 
If i n t he i n vesti gat or’s me dical j u d ge me nt, a t o xicit y lea di n g t o d ose i nterr u pti o n or dela y is 
attri b ute d t o t he c o m bi nati o n a ge nt ( eit her P F-0 6 8 0 1 5 9 1 or be vaciz u ma b -Pfizer), a n d 
treat me nt wit h P F- 0 7 0 6 2 1 1 9 al o ne is e x pecte d t o deri ve cli nical be nefit, t he n t he treat me nt 
wit h P F -0 7 0 6 2 1 1 9 ma y  be res u me d at t he sa me or re d uce d d ose le vel (acc or di n g t he ta bles 
bel o w) wit h disc o nti n uati o n of t he c o m b i nati o n a ge nt f oll o wi n g disc ussi o n a n d a gree me nt 
wit h t he S p o ns or.
F or n o n -i m m u ne-relate d t o xicities s pecifie d i n Ta ble 1 1 : In t he setti n g of i n vesti gati o nal 
c o m bi nati o n t hera p y wit h P F -0 7 0 6 2 1 1 9 a n d c o m bi nati o n a ge nt (eit her P F -0 6 8 0 1 5 9 1 or 
be vaciz u ma b -Pfizer), disc o nti n uati o n, b ut n o d ose re d ucti o n f or t he c o m bi na ti o n a ge nt 
(eit her P F-0 6 8 0 1 5 9 1 or be vaciz u ma b -Pfizer), is all o we d. All d ose 
disc o nti n uati o ns/ m o dificati o ns/a dj ust me nts m ust be clearl y  d oc u me nte d i n t he partici pa nt’s 
s o urce n otes a n d C R F.
F or i m m u ne -relate d t o xicities s pecifie d i n Ta ble 1 2 : In t he setti n g of i n vesti gati o nal 
c o m bi nati o n t hera p y wit h P F -0 7 0 6 2 1 1 9 a n d c o m bi nati o n a ge nt (eit her P F -0 6 8 0 1 5 9 1 or 
be vaciz u ma b -Pfizer), disc o nti n uati o n, b ut n o d ose r e d ucti o n f or t he c o m bi nati o n a ge nt 
(eit her P F-0 6 8 0 1 5 9 1 or be vaciz u ma b -Pfizer), is all o we d de pe n di n g o n t he t o xicit y  a n d 
se verity. All d ose disc o nti n uati o ns/ m o dificati o ns/a dj ust me nts m ust be clearl y d oc u me nte d i n 
t he partici pa nt’s s o urce n otes a n d C R F.
O nce a d ose has bee n re d uce d f or a gi ve n partici pa nt, all s u bse q ue nt c y cles s h o ul d be 
a d mi nistere d at t hat d ose le vel, u nless f urt her d ose re d ucti o n is re q uire d. I ntra partici pa nt d ose 
re-escalati o n 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 (if 
a p plica ble) 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 
s p o ns or, t he partici pa nt is be nefiti n g fr o m t hera py. 
I n s o me cases, partici pa nts e x perie nci n g rec urre nt a n d i nt olera ble Gra de 2 t o xicit y ma y 
res u me d osi n g at t he ne xt l o wer d ose le vel o nce rec o ver y t o Gra de ≤1 or baseli ne is 
ac hie ve d. 
St u d y  treat me nt f or partici pa nts s h o ul d i ncl u de P F -0 7 0 6 2 1 1 9 a n d n ot be li mite d t o a 
c o m bi nati o n a ge nt ( P F-0 6 8 0 1 5 9 1 or be vaciz u ma b -Pfizer) o nl y .
Rec o m me n de d d ose re d ucti o ns f or n o n-i m m u ne relate d t o xicities a n d t o xicities n ot ot her wise 
s pecifie d i n Ta ble 1 2 t hat are attri b ute d t o st u d y i nter ve nti o n or i n vesti gati o nal c o m bi nati o n 
t hera py are descri be d i n Ta ble 1 1 . D ose M o dificati o ns f or A d verse Reacti o ns relate d t o 
Be vaciz u ma b -Pfizer ca n be f o u n d bel o w i n Ta ble 1 4 .
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 1
T a ble 1 1 .
D ose M o dific ati o ns f or T o xicit y Attri b ute d t o I n vesti g ati o n al Pr o d uct or 
I n vesti g ati o n al C o m bi n ati o n T her a p y f or N o n-I m m u ne-Rel ate d A Es c
T o xicit y
Gr a de 1  
Gr a de 2
Gr a de 3
Gr a de 4
N o n he mat ol o gic 
C o nti n ue at 
t he sa me d ose 
le vel
C o nti n ue at t he 
sa me d ose le vel 

Wit h h ol d d ose u ntil 
t o xicit y is Gra de 1, 
or has ret ur ne d t o 
baseli ne, t he n res u me 
treat me nt at t he sa me 
d ose le vel or re d uce 
t he P F-0 7 0 6 2 1 1 9 
d ose b y 1 le vel a n d 
s u bse q ue ntl y a n 
a d diti o nal 1 le vel at 
t he discreti o n of t he 
in vesti gat or. a,b d

A d diti o nall y, i n 
c o m bi nati o n t hera p y 
( wit h P F-0 6 8 0 1 5 9 1), 
P F -0 6 8 0 1 5 9 1 ma y 
res u me treat me nt at 
t he sa me d ose le vel 
or disc o nti n ue at t he 
discreti o n of t he 
in vesti gat or. a, b

A d diti o nall y, i n 
c o m bi nati o n t hera p y 
( wit h 
be vaciz u ma b -Pfizer), 
be vaciz u ma b -Pfizer 
ma y res u me 
treat me nt at t he sa me 
d ose le vel or 
disc o nti n ue at t he 
discreti o n of t he 
i n vesti gat or.a, b

Wit h h ol d d ose u ntil 
t o xicit y is Gra de 1, 
or has ret ur ne d t o 
baseli ne, t he n re d uce 
t he P F-0 7 0 6 2 1 1 9 d ose 
b y 1 le vel a n d 
s u bse q ue ntl y a n 
a d diti o nal 1 le vel or 
disc o nti n ue at t he 
discreti o n of t he 
i n vesti gat or.a, b d

A d diti o nall y, i n 
c o m bi nati o n t hera p y 
( wit h P F-0 6 8 0 1 5 9 1), 
disc o nti n ue 
P F -0 6 8 0 1 5 9 1. a, b

A d diti o nall y, i n 
c o m bi nati o n t hera p y 
( wit h be vaciz u ma b-
Pfizer), disc o nti n ue 
t he be vaciz u ma b-
Pfizer d ose. a, b
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 2
T a ble 1 1 .
D ose M o dific ati o ns f or T o xicit y Attri b ute d t o I n vesti g ati o n al Pr o d uct or 
I n vesti g ati o n al C o m bi n ati o n T her a p y f or N o n-I m m u ne-Rel ate d A Es c
T o xicit y
Gr a de 1  
Gr a de 2
Gr a de 3
Gr a de 4
H e m at ol o gic
C o nti n ue at 
t he sa me d ose 
le vel
C o nti n ue at t he 
sa me d ose le vel

Wit h h ol d d ose u ntil 
t o xicit y is Gra de ≤2, 
or has ret ur ne d t o 
baseli ne, t he n res u me 
treat me nt at t he sa me 
d ose le vel at t he 
discreti o n of t he 
i n vesti gat or.a, b, d

A d diti o nall y, i n 
c o m bi nati o n t hera p y 
( wit h P F-0 6 8 0 1 5 9 1), 
P F -0 6 8 0 1 5 9 1 ma y 
res u me treat me nt at 
the sa me d ose le vel 
or disc o nti n ue at t he 
discreti o n of t he 
i n vesti gat or.a, b

A d diti o nall y, i n 
c o m bi nati o n t hera p y 
( wit h be vaciz u ma b-
Pfizer), be vaciz u ma b -
Pfizer ma y res u me 
treat me nt at t he sa me 
d ose le vel or 
disc o nti n ue at t he 
discreti o n of t he 
i n vesti gat or.a, b

Wit h h ol d d ose u ntil 
t o xicit y is Gra de ≤2, 
or has ret ur ne d t o 
baseli ne, t he n re d uce 
t he P F-0 7 0 6 2 1 1 9 d ose 
b y 1 le vel a n d 
s u bse q ue ntl y a n 
a d diti o nal 1 le vel at 
a n d res u me treat me nt 
at t he discreti o n of t he 
i n vesti gat or.a, b, d

A d diti o nall y, i n 
c o m bi natio n t hera p y 
( wit h P F-0 6 8 0 1 5 9 1), 
disc o nti n ue t he 
P F -0 6 8 0 1 5 9 1 d ose. a, b

A d diti o nall y, i n 
c o m bi nati o n t hera p y 
( wit h be vaciz u ma b-
Pfizer), disc o nti n ue 
t he be vaciz u ma b-
Pfizer d ose .a, b
a Na usea, v o miti n g, or diarr hea m ust persist at Gra de 3 or 4 des pite ma xi mal me dical t hera p y t o re q uire d ose 
m o dificati o n.
b C y cle will n ot be e xte n de d t o c o ver f or t he missi n g d oses.
c If t o xicit y is c o nsi dere d i m m u ne relate d t he n s h o ul d f oll o w T a ble 1 2 – D ose M o dificati o ns f or S pecific 
I m m u ne Relate d T o xicit y Attri b ute d t o I n vesti gati o nal Pr o d uct or C o m bi nati o n I n vesti gati o nal T hera p y 
(T a ble 1 2 ).
d D ose re d ucti o n of P F -0 7 0 6 2 1 1 9 ma y be re d uce d t o t he ne xt l o w er d ose le vel(s) t hat was pre vi o usl y 
deter mi ne d t o be safe/t olera ble d uri n g t he d ose escalati o n p h ase of t he st u d y.
Rec o m me n de d d ose re d ucti o ns f or i m m u ne relate d t o xicities t hat are attri b ute d t o st u d y  
i nter ve nti o n or i n vesti gati o nal c o m bi nati o n t hera p y are descri be d i n Ta ble 1 2 .
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 3
T a ble 1 2 .
D ose M o dific ati o ns f or S pecific I m m u ne Rel ate d T o xicit y Attri b ute d t o 
I n vesti g ati o n al Pr o d uct or C o m bi n ati o n I n vesti g ati o n al T her a p y
Or g a n S yste m
Gr a de 1  
Gr a de 2
Gr a de 3
Gr a de 4
GI 
( diarr hea)
C o nti n ue 
i n vesti gati o nal 
treat me nt.
Wit h h ol d 
i n vesti gati o nal 
treat me nt.
If d iarr hea 
i mpr o ves t o 
Gra de ≤1, 
res u me 
treat me nt at t he 
sa me d ose le vel.
Wit h h ol d i n vesti gati o nal 
treat me nt.
If diarr hea i mpr o ves t o 
Gra de ≤1, res u me treat me nt at 
t he sa me d ose le vel or re d uce 
P F -0 7 0 6 2 1 1 9 d ose b y 1 le vel
at t he discreti o n of t he 
i n vesti gat or.
A d diti o nall y, i n c o m bi nati o n 
t hera p y ( wit h P F-0 6 8 0 1 5 9 1), 
P F -0 6 8 0 1 5 9 1 ma y res u me 
treat me nt at t he sa me d ose 
le vel or disc o nti n ue at t he 
discreti o n of t he 
i n vesti gat or.*
A d diti o nall y, i n c o m bi nati o n 
t hera p y ( wit h be vaciz u ma b-
Pfizer), be vaciz u ma b -Pfizer 
ma y res u me treat me nt at t he 
sa me d ose le vel or 
disc o nti n ue at t he discreti o n 
of t he i n vesti gat or.*
Disc o nti n ue 
i n vesti gati o nal 
treat me nt.
S ki n
( Der matitis)
C o nti n ue 
i n vesti gati o nal 
treat me nt.
If persists > 1-2 
wee ks, wit h h ol d. 
If i m pr o ves after 
treat me nt wit h 
c ortic oster oi ds, 
t he n res u me 
i n vesti gati o nal 
treat me nt.
C o nti n ue 
i n vesti gati o nal 
treat me nt.
If persists > 1-2 
wee ks, 
wit h h ol d. If 
i mpr o ves after 
treat me nt wit h 
c ortic oster oi ds, 
t he n res u me 
i n vesti gati o nal 
treat me nt.
Wit h h ol d or disc o nti n ue 
i n vesti gati o nal treat me nt.
If i m pr o ves t o Gra de ≤1 , 
res u me i n vesti gati o nal 
t hera p y at t he discreti o n of 
t he i n vesti gat or.
Wit h h ol d or 
disc o nti n ue 
i n vesti gati o nal 
treat me nt.
If i m pr o ves t o 
Gra de 1 after 
treat me nt, 
res u me 
i n vesti gati o nal 
t hera p y at t he 
discreti o n of 
t he 
i n vesti gat or.
L u n g
( p ne u m o nitis)
C o nsi der dela y of 
i n vesti gati o nal 
treat me nt
M o nit or
Wit h h ol d 
i n vesti gati o nal 
treat me nt; re-
i ma ge.
If s y m pt o ms 
ret ur n t o 
baseli ne t he n 
res u me 
Disc o nti n ue
Disc o nti n ue
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 4
T a ble 1 2 .
D ose M o dific ati o ns f or S pecific I m m u ne Rel ate d T o xicit y Attri b ute d t o 
I n vesti g ati o n al Pr o d uct or C o m bi n ati o n I n vesti g ati o n al T her a p y
Or g a n S yste m
Gr a de 1  
Gr a de 2
Gr a de 3
Gr a de 4
i n vesti gati o nal 
treat me nt.
Li ver
( he patitis)
C o nti n ue 
i n vesti gati o nal 
treat me nt
Wit h h ol d 
i n vesti gati o nal 
treat me nt a n d 
i ncrease 
m o nit ori n g of 
tra nsa mi nases.
If tra nsa mi nases 
i mpr o ve wit h i n 
≤7 da ys t o 
Gra de ≤1 , 
res u me 
treat me nt at 
sa me d ose le vel.
If tra nsa mi nases 
d o n ot i m pr o ve 
wit hi n ≤7 da ys 
t o Gra de ≤1 , 
treat wit h 
c ortic oster oi ds
a n d re d uce d ose 
of P F -0 7 0 6 2 1 1 9
b y 1 le vel w he n 
tra nsa mi nases 
i mpr o ve t o 
Gra de ≤1.
Disc o nti n ue
Disc o nti n ue
C yt o ki ne 
Release 
S y n dr o me
H ol d 
i n vesti gati o nal 
treat me nt; after 
res ol uti o n, 
c o nti n ue 
i n vesti gati o nal 
treat me nt,
after res ol ves, 
c o nti n ue 
i n vesti gati o nal 
treat me nt
H ol d
i n vesti gati o nal 
treat me nt; after 
res ol uti o n, 
c o nti n ue 
i n vesti gati o nal 
treat me nt,
after res ol ves, 
c o nti n ue 
i n vesti gati o nal 
treat me nt
H ol d i n vesti gati o nal 
treat me nt; after res ol uti o n, 
c o nti n ue i n vesti gati o nal 
treat me nt, after res ol ves, 
re d uce d ose of P F -0 7 0 6 2 1 1 9
b y 1 le vel
Disc o nti n ue
E n d ocri ne:
T S H 
a b n or malit y
C o nti n ue i n vesti gati o nal treat me nt
S y m pt o matic 
e n d ocri n o pat h y
If s y m pt o matic, a b n or mal la bs, a b n or mal pit uitar y sca n- wit h h ol d i n vesti gati o nal 
treat me nt. After treat me nt, a n d wit h n or mal la bs a n d M RI, res u me i n vesti gati o nal 
treat me nt.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 5
T a ble 1 2 .
D ose M o dific ati o ns f or S pecific I m m u ne Rel ate d T o xicit y Attri b ute d t o 
I n vesti g ati o n al Pr o d uct or C o m bi n ati o n I n vesti g ati o n al T her a p y
Or g a n S yste m
Gr a de 1  
Gr a de 2
Gr a de 3
Gr a de 4
S us pici o n of 
a dre nal crisis
Wit h h ol d or disc o nti n ue i n vesti gati o nal treat me nt. If a dre nal crisis r ule d o ut, treat as f or 
s y m pt o matic e n d ocri n o pat h y.
* D ose re d ucti o n of P F -0 7 0 6 2 1 1 9 ma y be re d uce d t o t he ne xt l o w er d ose le vel(s) t hat was pre vi o usl y 
deter mi ne d t o be safe/t olera ble d uri n g t he d ose escalati o n p hase of t he st u d y.
T a ble 1 3 . D os a ge M o dific ati o ns f or A d verse Re acti o ns 
Se verit y 
D os a ge M o dific ati o n 
Gastr oi ntesti nal Perf orati o ns 
a n d Fist ulae

Gastr oi ntesti nal perf orati o n, a n y gra de 

Trac he oes o p ha geal fist ula, a n y gra de 

Fist ula, Gra de 4 

Fist ula f or mati o n i n v ol vi n g a n y 
i nter nal or ga n 
Disc o nti n ue 
B E V A CI Z U M A B -P FI Z E R  
W o u n d Heali n g 
C o m plicati o ns 

W o u n d heali n g c o mplicati o ns 
re q uiri n g me dical i nter ve nti o n

Necr otizi n g fasciitis 
Disc o nti n ue 
B E V A CI Z U M A B -P FI Z E R  
H e m orr ha ge 

Gra de 3 or 4 
Disc o nti n ue 
B E V A CI Z U M A B -P FI Z E R  

Rece nt hist or y of he m o pt ysis of ½ 
teas p o o n ( 2. 5 m L) or m ore 
Wit h h ol d B E V A CI Z U M A B -
P FI Z E R  
T hr o m b oe m b olic E ve nts 

Arterial t hr o m b oe m b olis m, se vere 
Disc o nti n ue 
B E V A CI Z U M A B -P FI Z E R  

Ve n o us t hr o m b oe m b olis m, Gra de 4 
Disc o nti n ue 
B E V A CI Z U M A B -P FI Z E R  
H y perte nsi o n 

H y perte nsi ve crisis H y perte nsi ve 
e nce p hal o pat h y 
Disc o nti n ue 
B E V A CI Z U M A B -P FI Z E R  

H y perte nsi o n, se vere 
Wit h h ol d B E V A CI Z U M A B -
P FI Z E R  if n ot c o ntr olle d wit h 
me dical ma na ge me nt; res u me 
o nce c o ntr olle d 
P osteri or Re versi ble 
E nce p hal o pat h y S y n dr o me 
( P R E S) 

A n y 
Disc o nti n ue 
B E V A CI Z U M A B -P FI Z E R  
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 6
T a ble 1 3 . D os a ge M o dific ati o ns f or A d verse Re acti o ns 
Se verit y 
D os a ge M o dific ati o n 
Re nal I nj ur y a n d Pr otei n uria 

Ne p hr otic s y n dr o me 
Disc o nti n ue 
B E V A CI Z U M A B -P FI Z E R  

Pr otei n uria greater t ha n or e q ual t o 2 
gra ms per 2 4 h o urs i n a bse nce of 
ne p hr otic s y n dr o me
Wit h h ol d B E V A CI Z U M A B -
P FI Z E R  u ntil pr otei n uria less 
t ha n 2 gra ms per 2 4 h o urs
I nf usi o n-Relate d Reacti o ns 

Se vere
Disc o nti n ue 
B E V A CI Z U M A B -P FI Z E R 

Cli nicall y si g nifica nt
I nterr u pt i nf usi o n; res u me at a 
decrease d rate of i nf usi o n 
after s y m pt o ms res ol ve

Mil d, cli nicall y i nsi g nifica nt 
Decrease i nf usi o n rate
C o n gesti ve Heart Fail ure 

A n y
Disc o nti n ue 
B E V A CI Z U M A B -P FI Z E R 
6. 8. I nter ve nti o n After t he E n d of t he St u d y
N o i nter ve nti o n will 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 .
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
See t he S o A f or data t o be c ollecte d at t he ti me of i nter ve nti o n 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.
7. 1. 1. Re q uest t o C o nti n ue Tre at me nt
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 treat me nt, f oll o wi n g 
disc ussi o n wit h t he s p o ns or t he partici pa nt ma y ha ve a n o pti o n t o c o nti n ue d osi n g at t he 
sa me d ose or o ne d ose l o wer, as l o n g as t he criteria bel o w are met, u ntil s uc h be nefit n o 
l o n ger e xists.
Criteria t hat m ust be met t o e ns ure t hat partici pa nts are n ot e x p ose d t o u nreas o na ble ris ks b y 
c o nti n ue d use of t he i n vesti gati o nal a ge nt i n s pite of pr o gressi o n of disease. S uc h criteria 
ma y  i ncl u de t he f oll o wi n g:

A bse nce of s y m pt o ms a n d si g ns i n dicati n g cli nicall y  si g nifica nt pr o gressi o n of 
disease.

N o decli ne i n E C O G perf or ma nce stat us.

A bse nce of s y m pt o matic ra pi d disease pr o gressi o n re q uiri n g ur ge nt me dical 
i nter ve nti o n (e g, sy m pt o matic ple ural eff usi o n, s pi nal c or d c o m pressi o n).
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 7
At t he ti me of ra di o gra p hic pr o gressi o n of disease, o btai n t he re -c o nse nt of partici pa nts usi n g 
a writte n i nf or me d c o nse nt d oc u me nt t hat details all F D A -a p pr o ve d t hera p y, a n d p ote ntial 
cli nical be nefit, t hat t he partici pa nt ma y  be f ore g oi n g i n or der t o c o nti n ue recei vi n g t he st u d y 
i nter ve nti o n.
7. 2. P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al Fr 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 or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he i n vesti gat or f or safet y, be ha vi oral, c o m plia nce , 
or a d mi nistrati ve reas o ns.
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 ra n d o mize 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, b ut data alrea dy ge nerate d fr o m t he sa m ples will c o nti n ue t o be a vaila ble a n d ma y  
be use d t o pr otect t he i nte grit y  of e xisti n g a nalys es. T he 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.
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 (see bel o w) 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 n y data 
c ollecte d bef ore s uc h wit h dra wal of c o nse nt.
W he n a partici pa nt wit h dra ws fr o m t he st u d y beca use of a n S A E, t he S A E m ust be rec or de d 
o n t he C R F a n d re p orte d o n t he Cli nical Trial S A E Re p ort.
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.
Reas o ns f or wit h dra wal of st u d y  treat me nt ma y i ncl u de:

O bjecti ve disease pr o gressi o n; 

Gl o bal deteri 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;
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 8

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.
Wit h dr a w al of C o nse nt: 
Partici pa nts w h o re q uest t o disc o nti n ue recei pt of st u d y  treat me nt 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 pecificall y 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 nts 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 furt 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 priately directe d i n 
acc or da nce wit h l ocal la w.
7. 3. L ost t o F oll o w -u p 
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 peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u nable t o be c o ntacte d b y t he st u d y  site.
Reas o ns f or wit h dra wal fr o m st u d y  f oll o w-u p 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;

Ref use d f urt her f oll o w -u p;

Deat h.
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa n t fails t o ret ur n t o t he cli nic f or 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 misse 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 as certai 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 8 9

Bef ore a partici 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.
Disc o nti n uati o n of s pecific sites or of t he st u d y  as a w h ole is ha n dle d as part of A p pe n di x 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
T he i n vesti gat or ( or a n a p pr o priate dele 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 a ll o we d.
I m me diate safet y c o ncer ns 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 if 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 e li 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 or d 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.
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 t a 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 an 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 0
8. 1. 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  c o ncer ns.
Safet y  assess me nts will i ncl u de c ollecti o n of A Es, seri o us a d verse e ve nts ( S A Es), vital si g ns 
a n d p h ysical e xa mi nati o n, electr ocar di o gra m ( E C G [ 1 2-lea 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. 
8. 1. 1. P h ysic al E x a mi n ati o ns
Partici pa nts will ha ve a p h y sical e xa mi nati o n t o i ncl u de wei g ht, vital si g ns, assess me nt of 
E C O G perf or ma nce stat us a n d hei g ht; hei g ht will be meas ure d at baseli ne o nl y.
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 
car di o vasc ular, res pirat or y, gastr oi ntesti nal, a n d ne ur ol o gical s ys te ms.
A brief 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 s ki n, 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).
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.
8. 1. 2. C O VI D ‑ 1 9: Use of Alter n ati ve Met h o ds f or I n-Pers o n Visits
I n li g ht of t he C O VI D- 1 9 pa n de mic, alternati ve met h o ds f or c o n d ucti n g safet y  assess me nts 
m ust be c o nsi dere d, w he n feasi ble a n d w he n safet y  ca n be ass ure d. T hese ma y i ncl u de:

C o n d ucti n g tele healt h visits (e g, p h o ne/ vi de o [ usi n g HI P A A ‑c o m plia nt vi de o‑c o nfere nce 
t o ols or as per mitte d b y l ocal re g ulati o ns]) 

M o vi n g partici pa nts t o less cr o w de d fa mil y  healt h ce nters a n d l ocal la b orat ories f or bl o o d 
dra ws, a n d i ma gi n g/ra di o gra p hs.

Refer t o A p pe n di x 1 8 f or a m ore c o m pre he nsi ve list of acce pta ble alter nati ve meas ures 
d uri n g t he C O VI D -1 9 p u blic e mer ge nc y .
8. 1. 3. Vit al Si g ns
Vital si g ns will be meas ure d wit h t he partici pa nt i n a se mi -s u pi ne p ositi o n or seate d p ositi o n 
after 5 mi n utes of rest a n d will i ncl u de te m perat ure, s y st olic a n d diast olic bl o o d press ure, 
p ulse rate , p ulse o xi metr y a n d wei g ht. 
8. 1. 4. 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 i n tri plicate at ti mes s pecifie d i n t he S o A secti o n of t his pr ot oc ol 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 i nter vals 
a n d Q R S c o m ple x. Alter nati ve lea d place me nt met h o d ol o g y  usi n g t ors o lea ds 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 1
(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 at least 1 0 mi n utes i n a s u pi ne p ositi o n.
At eac h ti me p oi nt (S o A ), 3 c o nsec uti ve E C Gs will be perf or me d at a p pr o xi matel y  ( 1 t o 4) 
mi n utes a part t o deter mi ne t he mea n Q Tc F i nter val. 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 o cc ur if a) t he mea n val ue fr o m t he tri plicate meas ure me nts 
f or a ny p ost d ose Q Tc F i nter val is i ncrease d b y 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 s c 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 meas ure me nt. I n a d diti o n, if verifie d Q Tc F val ues c o nti n ue 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 ol yt e a b n or malities, 
h y p 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.
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 dical 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 pecifically 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 t he 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. 1. 5. 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.
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 
t he u n derlyi n g disease, u nless j u d ge d b y  t he i nvesti 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 8 4 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 2
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 L a b orat or y M a n ual a n d t he S o A .
If la b orat or y val ues fr o m n o n-pr ot oc ol -s pecifie d la b orat or y assess me nts perf or me d at t he 
i nstit uti o n’s l ocal la b orat or y re q uire a c ha n ge i n partici pa nt ma na ge me nt or are c o nsi dere d 
cli nicall y si g nifica nt by t he i n vesti gat or (e g, S A E or A E or d ose m o dificati o n), t he n t he 
res ults m ust be rec or de d i n t he C R F.
8. 1. 6. 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 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 me n of c hil d beari n g p ote ntial 
( 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 
scree 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 sec 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 prior t o t he partici pa nt’s recei vi n g t he 
P F -0 7 0 6 2 1 1 9. 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 m a y als o be re peate d if re q ueste d b y IR Bs/ E Cs 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 nc 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. 1. 7. I njecti o n Site T oler a bilit y Assess me nt 
Assess me nts of t he i njecti o n sites i n t he a b d o mi nal fat f ol d t o m o nit or l ocal t olera bilit y  t o 
P F - 0 7 0 6 2 1 1 9 a n d P F-0 6 8 0 1 5 9 1 S C i njecti o ns will be perf or me d f or at least 1 h o ur f oll o wi n g 
st u dy dr u g a d mi nistrati o n i n C y cle 1, as per t he S o A . A n assess me nt s h o ul d als o be 
perf or me d 2 4 h o urs ( ± 1 h o ur) after t he C 1 D 1 d ose. I njecti o n site t olera bilit y  assess me nts f or 
at least 1 h o ur p ost t he P F-0 7 0 6 2 1 1 9 i nje cti o n s h o ul d c o nti n ue after eac h d osi n g da y visit i n 
C y cle 2 a n d be y o n d, o nl y  if i njecti o n site pai n or I S R c haracteristics c o nti n ue t o persist. T he 
assess me nts s h o ul d c o nti n ue at re g ularl y sc he d ule d visits u ntil t he s ym pt o ms res ol ve. T he 
i njecti o n sites will be assesse d f or er yt he ma, i n d urati o n, ecc hy m osis, i njecti o n site pai n, 
i njecti o n site pr urit us, or ot her o bser ve d c haracteristics after P F-0 7 0 6 2 1 1 9 a n d P F - 0 6 8 0 1 5 9 1 
a d mi nistrati o n. T he dia meter of t he affecte d area will be meas ure d, a n d t he c o n diti o n of t he 
i njecti o n site will be rec or de d o n t he i njecti o n site reacti o n C R F. A ny o bser ve d a b n or malit y 
at t he i njecti o n site will be j u d ge d b y t he i n vesti gat or t o deter mi ne if t he e ve nt s h o ul d als o be 
re p orte d as a n A E. I SRs s h o ul d be i m me diatel y  p h ot o gra p he d in c ol or, wit h scale d r uler 
place d b y t he reacti o n, a n d t hese p h ot o gra p hs s h o ul d be i ncl u de d i n t he partici pa nt’s s o urce 
d oc u me ntati o n. W he n a p pr o priate, at t he discreti o n of t he i n vesti gat or, a partici pa nt wit h a n 
I S R ma y be referre d f or a der mat ol o gical co ns ultati o n a n d s ki n bi o ps y  ma y be o btai ne d f or 
f ut ure e xa mi nati o n of t he IS R. 
8. 2. 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 Es 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).
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 3
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 it 
meets t he criteria f or classificati o n as a n S A E or t hat ca use d t he partici pa nt t o disc o nti n ue t he 
st u d y (Secti o n 7. 1 ).
I n a d diti o n, t he i n vesti gat or ma y be re q ueste d b y Pfizer Safet y 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. 2. 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, 
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 d y  (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 n i m u m of 2 8 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.
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 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 is wit h dra w n.
Me dical occ urre nces t hat be gi n bef ore t he start of st u d y  i nter ve nti o n b ut after o btai ni n g 
i nf or me d c o nse nt will be rec or de d o n t he Me dical Hist or y/ C urre nt Me dical C o n diti o ns 
secti o n of t he case re p ort f or m ( C R F), n ot t he A E secti o n.
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.
I n vesti gat ors are n ot o bli gate d t o acti vely see k A Es or S A Es 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 he 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 or st u d y partici pati 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. 2. 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 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 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 py, 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 n y i nter ve ni n g 
treat me nt.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 4
S A Es occ urri n g i n a partici pa nt after t he acti ve c ollecti o n peri o d has e n de d are re p orte d t o 
Pfizer Safet y  if t he i n vesti gat or bec o mes a ware of t he m; at a mi ni m u m, all S A Es t hat t he 
i n vesti gat or belie ves ha ve at least a reas o na ble p ossi bilit y of bei n g relate d t o st u d y 
i nter ve nti o n m ust be re p orte d t o Pfizer Safety.
8. 2. 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
D uri n g t he acti ve c ollecti o n per i o d, b ot h n o nseri o us A Es a n d S A Es are rec or de d o n t he C R F.
If a partici pa nt be gi ns a ne w a ntica ncer t hera py, 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.
8. 2. 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 partici 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. 2. 3. F oll o w - u p of A Es a n d S A Es
Af ter 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 vely 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 or 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 h er 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. 2. 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 a n 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 ulat or y a ut h orit y a n d ot her 
re g ulat or y a ge ncies a b out 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. 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/ E Cs , a n d i n vesti gat ors.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 5
I n vesti gat or safet y re p orts m ust be pre pare d f or s us pecte d u ne x pecte d seri o us a d verse 
reacti o ns ( 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 a n i n vesti gat or safet y re p ort descri bi n g a n S A E or ot her 
s pecific safety 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 i n vesti gat or’s br oc h ure 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.
8. 2. 5. E x p os ure D uri n g Pre g n a n c y or Bre astfee di n g, a n d Occ u p ati o n al E x p os ure
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. 2. 5. 1. E x p os ure D uri n g Pre g n a nc y
D etails of all pre g na ncies i n fe male partici pa nts a n d, if i n dicate d, fe male part ners of male 
partici pa nts 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 1 0 5 da y s after t he 
last d ose.
If a pre g na nc y is re p orte d, t he i n vesti gat or s h o ul d i nfor m t he s p o ns or wit hi n 2 4 h o urs of 
lear ni n g of t he pre g na nc y a n d s h o ul d f oll o w t he pr oce d ures o utli ne d i n A p pe n di x 4 .
A b n or mal pre g na nc y  o utc o mes (e g, s p o nta ne o us a b orti o n, fetal deat h, still birt h, c o n ge nital
a n o malies, ect o pic pre g na nc y ) are c o nsi dere d S A Es.
8. 2. 5. 2. E x p os ure D uri n g Bre astfee di n g
Sce nari os of e x p os ure d uri n g breastfee di n g m ust be re p orte d, irres pecti ve of t he prese nce of 
a n ass ociate d S A E, t o Pfizer Safet y wit hi n 2 4 h o urs of t he i n vesti gat or’s a ware ne ss, usi n g t he 
C T S A E Re p ort F or m. 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 nce s a n S A E ass ociate d wit h s uc h 
a dr u g’s a d mi nistrati o n, 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. 2. 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, d uri n g t he perf or ma nce of j o b d uties, a pers o n 
( w het her a healt hcare pr ofessi o nal or ot her wise) gets i n u n pla n ne d direct c o ntact wit h t he 
pr o d uct, w hic h ma y  or ma y n ot lea d t o t he occ urre nce of a n A E.
A n occ u pati o nal e x p os ure is re p orte d 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, usi n g t he C T S A E Re p ort F or m, re gar dless of w het her t here is a n ass ociate d 
S A E. 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 6
8. 2. 6. Me dic ati o n Err ors
Me dicati o n err ors ma y  res ult fr o m t he a d mi 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/st u d y treat me nt 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 i m me diatel y ( 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 plica ble, 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 a n 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.
8. 3. 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 0 6 2 1 1 9 as a m o n ot hera p y or wit h a c o m bi nati o n a ge nt 
gr eater t ha n t he i nte n de d d ose wit hi n a 2 4- h o ur ti me peri o d will be c o nsi dere d a n o ver d ose, 
u nless t his d ose le vel has bee n declare d as safe i n t he d ose escalati o n p hase. A d diti o nall y  a ny 
d ose of P F -0 6 8 0 1 5 9 1 or be vaciz u ma b - Pfizer greater t ha n t he i nte n de d d ose wit hi n a 2 4-h o ur 
ti me peri o d 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 me dical m o nit or wit hi n 2 4 h o urs.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 7
2.
Cl osel y m o nit or t he partici pa nt f or a n y A Es/ 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 st u d y i nter ve nti o n 
( w hic he ver is l o n ger).
3.
O btai n a bl o o d sa m ple f or P K a nal ys is wit hi n t w o wee ks fr o m t he date of t he last 
d ose of t he 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).
4.
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.
5.
O ver d ose is re p orta ble t o Safet y  o nl y w he n ass oci ate d w it h a n S A E.
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 me 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. 4. P h ar m ac o ki netics a n d I m m u n o ge nicit y 
8. 4. 1. P h ar m ac o ki netic Assess me nts
Bl o o d sa m ples of a p pr o xi matel y  4 m L , t o pr o vi de a mi ni m u m of 2 m L ser u m, will be 
c ollecte d f or meas ure me nt of ser u m c o nce ntrati o ns of P F -0 7 0 6 2 1 1 9, P F -0 6 8 0 1 5 9 1 or 
be vaciz u ma b - Pfizer as s pecifie d i n t he S o A . I nstr 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 L a b orat or y M a 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.
T he act ual c ollecti o n ti mes ma y c ha n ge, b ut t he n u m ber of pla n ne d 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 t hat are o btai ne d wit hi n t he s pecifie d ti me wi n d o w 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 data c ollecti o n t o ol (e g, C R F).
Sa m ples will be use d t o e val uate t he P K of P F -0 7 0 6 2 1 1 9, P F -0 6 8 0 1 5 9 1 or 
be vaciz u ma b - Pfizer. Sa m ples c ollecte d f or a nalyses of ser u m dr u g c o nce ntrati o ns ma y als o 
be use d t o e val uate safet y 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 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.
Ge netic a nal ys es will n ot be perf or me d o n t hese ser u m sa m p les 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. 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 ser u m c o nce ntrati o ns of P F- 0 7 0 6 2 1 1 9, P F - 0 6 8 0 1 5 9 1 
or be vaciz u ma b -Pfizer as i n dicate d 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 sta n dar d o perati n g pr oce d ures ( S O Ps).
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 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 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 
i nte grity 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 of ti me p oi nts f or a n y pla n ne d st u dy 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 d y 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 IR B/ E C will 
be i nf or me d of a n y safet y 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. 4. 2. A n al ysis of A nti - Dr u g A nti b o dies a n d Ne utr alizi n g A nti-A nti b o dies 
( PF- 0 7 0 6 2 1 1 9, P F - 0 6 8 0 1 5 9 1, or be v aciz u m a b-Pfizer)
Bl o o d sa m ples of a p pr o xi matel y  4 m L , t o pr o vi de a mi ni m u m of ser u m 2 m L, will be 
c ollecte d f or deter mi nati o n of A D A a n d N A b a gai nst P F -0 7 0 6 2 1 1 9, P F -0 6 8 0 1 5 9 1 or 
be vaciz u ma b -Pfizer, as i n dicate d as s pecifie d i n t he S o A . I nstr 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 L a b orat or y M a 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.
Sa m ples c ollecte d f or deter mi nati o n of A D A a n d N A b ma y  als o be use d f or a d diti o nal 
c haracterizati o n of t he i m m u ne res p o nse a n d/ or e val uati o n of t he bi oa nal ytical met h o d, or f or 
ot her i nter nal e x pl orat or y p ur p oses. T hese data will be use d f or 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 ser u m 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. Partici pa nt c o nfi de ntialit y will be mai ntai ne d.
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 plica ble 
S O Ps. Sa m ples deter mi ne d t o be p ositi ve f or A D A ma y  be f urt her c haracterize d f or N A b.
T he i m m u n o ge nicit y 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 ny de viati o ns fr o m t he 
i m m u n o ge nicity 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 deter mi nati o n 
as t o w het her sa m ple i nte 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 of ti me p oi nts f or a n y pla n ne d st u dy 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 d y tea m me m ber a n d t he n arc hi ve d in 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 IR B/ E C will 
be i nf or me d of a n y safet y 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. 5. P h ar m ac o d y n a mics
P har mac o d y na mic ( P D) para met ers will be e val uate d i n t his st u d y. See Secti o n 8. 8
Bi o mar kers.
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P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 9 9
8. 6. Bi o m ar ker a n d P h ar m ac o d y n a mic Assess me nts
A ke y  ele ment of t his st u d y  is t he e val uati o n of p ote ntial cell ular a n d m olec ular si g nat ures 
t hat e xist bef ore treat me nt a n d c o ul d be m o difie d i n vi v o b y P F-0 7 0 6 2 1 1 9 use d i n t his st u d y  
t o tar get G U C Y 2 C a n d acti vate T cells. 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 P F -0 7 0 6 2 1 1 9, t o e val uate t he m o n ot hera p y 
P F -0 7 0 6 2 1 1 9, a n d p ote ntial c o m bi nat orial effects of P F - 0 7 0 6 2 1 1 9 wit h ot her a ge nts, as well 
as e val uate p ote ntial mec ha nis ms of resista nce. Bi o mar ker st u dies ma y  hel p i n t he f ut ure 
de vel o p me nt of t his dr u g 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.
Ta ble 1 4 bel o w s u m marizes t he bi o mar ker assa y s t hat i ncl u de, b ut are n ot li mite d t o, t h ose 
w hic h will be use d a n d t he s o urce of t he sa m ples. 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. Refer t o 
t he S o A f or details pertai ni n g t o s pecific da ys of sa m ple c ollecti o n a n d t o t he st u d y ma n ual 
f or details of sa m ple pre parati o n.
T a ble 1 4 . Bi o m ar ker C ollecti o ns a n d A n al yses
Ass a y
S a m ple T y pe
Meas ure me nt of G U C Y 2 C E x pressi o n Le vels
Arc hi val a n d de n o v o pre -treat me nt t u m or bi o psies
I m m u n o p he n ot y pi n g of bl o o d i m m u ne cell s u bt y pes 
fre q ue nc y a n d acti vati o n m o d ulati o n
W h ole bl o o d
Meas ure me nt
of peri p heral c yt o ki nes a n d ot her 
circ ulati n g mar kers
W h ole bl o o d
M o d ulati o n of i ntra -t u m oral tar get pat h wa y m o d ulati o n 
(ie, ge ne e x pressi o n si g nat ure, cell ular a n d pr otei n 
c ha n ges)
De n o v o pre -, o n-, p ost-treat me nt t u m or bi o psies
P har mac o d y na mic 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.
8. 7. Ge netics
8. 7. 1. S pecifie d Ge netics
Ge netics (s pecifie d a nal yses) are n ot e val uate d i n t his st u d y .
8. 7. 2. B a n ke d Bi os peci me ns f or Ge netics
A 4 m L  w h ole bl o o d sa m ple o pti mize d f or D N A is olati o n ( Pre p D 1/ Pre p D 1. 5) will be 
c ollecte d as l ocal re g ulati o ns a n d IR Bs/ E Cs all o w (refer t o t he S o A f or c ollecti o n 
ti me p oi nts). 
Ba n ke d bi os peci me ns ma y be use d f or researc h relate d t o dr u g res p o nse a n d disease u n der 
st u d y. Ge nes a n d ot her a nal ytes (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. 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 0
U nless pr o hi bite d b y  l ocal re g ulati o ns or I R B/ E C decisi o n, partici pa nts will be as ke d t o 
i n dicate o n t he c o nse nt d oc u me nt w het her t he y will all o w t heir ba n ke d bi os peci me ns t o als o 
be use d t o desi g n a n d c o n d uct researc h i n or der t o gai n a f urt her u n dersta n di n g of ot her 
diseases a n d t o a d va nce scie nce, i ncl u di n g de vel o p me nt of ot her me dici nes f or partici pa nts. 
T his c o m p o ne nt of t he sa m pli n g ba n ki n g is o pti o nal f or partici pa nts; t he y  ma y still 
partici pate i n t he st u d y e ve n if t he y d o n ot a gree t o t he a d diti o nal researc h o n t heir ba n ke d 
bi os peci me ns. 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.
See A p pe n di x 5 f or i nf 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 b e f o u n d i n t he st u d y ma n ual.
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 L a 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, 
b ut are n ot li mite d t o peri p heral bl o o d, t u m or tiss ues a n d ma y  be use d t o a nal yze D N A, 
R N A, pr otei ns, or meta b olic bi o mar kers, 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 nal ys es.
T u m or bi os pec i me ns fr o m arc hi val a n d/ de n o v o bi o psies will be use d t o a nal yze ca n di date 
n ucleic aci d a n d pr otei n a n d cell ular bi o mar kers f or t heir a bilit y  t o i nf or m 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. Bi o mar kers ma y i n cl 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 u m or micr oe n vir o n me nt ( T M E). O pti o nal, a n d/ or de n o v o t u m or bi o psies 
o btai ne d d uri n g t hera p y a n d u p o n disease pr o gressi o n ma y  be use d t o hel p c o nfir m 
p har mac o d y n a mic effects of treat me nt a n d i n vesti gate p ote ntial ac q uire d mec ha nis ms of 
resista nce (ie, prese nce of b ut n ot li mite d t o re g ulat or y T-cells or m yel oi d -deri ve d s u p press or 
cells a n d ot her i m m u ne s u p pressi ve cells or pr otei ns). 
8. 8. 1. Arc hi v al Pre -tre at me nt a n d O pti o n al De N o v o Pre- a n d O n -Tre at me nt T u m or 
Bi o psies f or P art 1 A a n d P art 1 B
All partici pa nts i n Part 1 A a n d Part 1 B m ust pr o vi de a n arc hi ve d F F P E t u m or tiss ue sa m ple 
( bl oc k preferre d). Sa m ples pr o vi de d s h o ul d be ta ke n fr o m t he m ost rece ntl y c o n d ucte d 
a vaila ble bi o ps y, prefera bl y  wit hi n 6 m o nt hs of start of st u d y  treat me nt. Tiss ue bl oc ks are 
prefera ble, b ut fres hl y c ut paraffi n secti o ns are acce pta ble. Sites s h o ul d c o ntact s p o ns or f or 
a p pr o val t o s u b mit sli des a n d refer t o La b orat or y /St u d y  ma n ual f or i nstr ucti o ns o n s u b mitti n g 
sli des. C yt ol o gical or fi ne- nee dle as pirati o n sa m ples are n ot acce pta ble. 
If t he arc hi ve d sa m ple is ol der t ha n 6 m o nt hs, t he i n vesti gat or m ust c o ntact t he s p o ns or’s 
Me dical M o nit or t o disc uss eli gi bilit y  pri or to e nr oll me nt.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 1
If a n a p pr o priate arc hi val F F P E t u m or sa m ple is n ot a vaila ble, a de n o v o fres h F F P E t u m or 
sa m ple s h o ul d be c ollecte d. Eac h de n o v o c ollecti o ns ( pre-treat me nt a n d o n-treat me nt) 
s h o ul d atte m pt t o o btai n 6 c ore bi o psies, wit h a mi ni m u m of prefera bl y 3 c ores. Sa m ples 
s h o ul d be o btai ne d i n acc or da nce wit h l ocal i nstit uti o nal practice f or t u m or bi o psies.
I n Part 1 A a n d Part 1 B, o pti o nal de n o v o pre - a n d o n-treat me nt t u m or bi o psies are 
e nc o ura ge d f or all partici pa nts o n t he trial w he n partici pa nts ha ve accessi ble lesi o ns. 
O pti o nal o n -treat me nt t u m or bi o psies are prefere ntiall y c ollecte d after t he t hir d d ose, wit hi n 
7 da y s of C 3 D 1 ( C 3 D 1 ± 7 da y s). If o n treat me nt t u m or c ollecti o n ta kes places greater t ha n 
± 3 da y s fr o m C 3 D 1, a d diti o nal u nsc he d ule d bl o od sa m ple f or c y t o ki ne a n d circ ulati n g 
mar kers a n d a n u nsc he d ule d bl o o d sa m ple f or T- cell i m m u n o p he n ot ypi n g sa m ple s h o ul d be 
c ollecte d t o matc h t he da y of bi o ps y 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 o r y/ St u d y 
Ma n ual.
8. 8. 2. M a n d at or y De N o v o
Pre - a n d O n -Tre at me nt T u m or Bi o psies at R P 2 D i n P art 1 A, 
P art 1 B, a n d P art 2
As t he R P 2 D/ M T D is a p pr oac he d or t he R P 2 D/ M T D of P F- 0 7 0 6 2 1 1 9 has bee n deter mi ne d, 
a n o pti o nal s u bset of partici pa nts ma y  be e nr olle d (a p pr o xi matel y 6 t o 1 2 partici pa nts) base d 
o n e mer gi n g cli nical data wit h t he re q uire me nt of pr o vi di n g ma n dat or y  paire d de n o v o 
pretreat me nt a n d o n -treat me nt bi o ps y sa m ples i n Parts 1 A a n d P art 1 B wit hi n 7 da y s of 
C 3 D 1 ( ± 7 d a y s) t o e na ble e val uati o n of tiss ue bi o mar ker P D acti vit y. T he o pti o n t o e nr oll t he 
s u bset of partici pa nts f or ma n dat or y paire d t u m or sa m ples will be base d o n e val uati o n of 
e mer gi n g cli nical data i ncl u di n g a vaila ble safet y/ t olera bilit y, P K, a n d P D fi n di n gs b y t he 
s p o ns or.
I n Part 2, de n o v o pre-treat me nt bi o psies will be re q uire d fr o m all partici pa nts, u nless n ot 
me dicall y  feasi ble, i n or der t o esta blis h relati o ns hi p bet wee n tar get e x pressi o n a n d efficac y 
o bser vati o ns. If a de n o v o pre- treat me nt bi o ps y is n ot me dicall y feasi ble, t he s p o ns or s h o ul d 
b e c o ntacte d f or a p pr o val bef ore i nitiati n g scree ni n g acti vities. F or a s u bset of partici pa nts i n 
all c o h orts (a p pr o xi matel y 1 0 partici pa nts), ma n dat or y o n -treat me nt bi o psy sa m ples will als o 
be c ollecte d i n or der t o c o nfir m t he mec ha nis m of acti o n a n d e val u ate p ote ntial resista nce 
mec ha nis m d uri n g treat me nt. F or all ot her partici pa nts, o n-treat me nt bi o psies are o pti o nal b ut 
e nc o ura ge d. I n Part 2, a p pr o xi matel y 2 0 partici pa nts eac h will be e nr olle d i n t he 
m o n ot hera p y a n d b ot h c o m bi nati o n c o h orts. If 1 5 partic i pa nts ha ve bee n e nr olle d i n a c o h ort 
a n d < 5 paire d pre - a n d o n-treat me nt bi o psies ha ve bee n c ollecte d, c ollecti o ns ma y be ma de 
ma n dat or y  f or t he re mai ni n g partici pa nts a n d t he c o h ort ma y be e x pa n de d b y u p t o 
5 partici pa nts t o o btai n s ufficie nt n u m bers of paire d pre - a n d o n-treat me nt bi o psies.
Fr o m t hese partici pa nts wit h paire d pre - a n d o n-treat me nt bi o psies, a n o pti o nal sec o n d o n 
treat me nt- bi o ps y is als o e nc o ura ge d after C 4 D 1 5 or at disease pr o gressi o n t o e val uate 
p ote ntial res p o nses t o treat me nt or s us p ecte d ac q uire d resista nce t o t hera p y.
Ma n dat or y  de n o v o t u m or c ollecti o ns ( pre-treat me nt a n d o n-treat me nt) s h o ul d atte m pt t o 
o btai n 6 c ore bi o psies, wit h a mi ni m u m of prefera bl y 3 c ores. Sa m ples s h o ul d be o btai ne d i n 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 2
acc or da nce wit h l ocal i nstit uti o nal pra ctice f or t u m or bi o psies. 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.
Ma n dat or y  pre-treat me nt de n o v o t u m or bi o psies are t o be c ollecte d wit hi n 2 8 da ys of first 
st u d y treat me nt d ose. O n-treat me nt t u m or bi o psies are prefera bly c ollecte d after t he t hir d 
d ose, wit hi n 7 da y s of C 2 D 1 5 ( C 2 D 1 5 ± 7 d a y s). 
If o n-treat me nt t u m or c ollecti o n ta kes place greater t ha n ± 3 d a y s fr o m C 2 D 1 5, u nsc he d ule d 
bl o o d sa m ples f or c y t o ki ne a n d circ ulati n g mar kers a n d T-cell i m m u n o p he n ot y pi n g sa m ple 
s h o ul d be c ollecte d t o matc h t he da y of bi o psy c ollecti o n.
O pti o nal bi o psies are e nc o ura ge d at disease pr o gressi o n a n d/ or e n d of treat me nt (ass u mi n g 
a vaila ble t u m or t o bi o ps y) a n d as cli nicall y i n dicate d t hr o u g h o ut treat me nt f or all 
par tici pa nts. If bi o psy is t o be c o m plete d t he sa me da y as C T sca n, it m ust be c o m plete d after 
t he C T sca n.
8. 8. 3. Peri p her al Bl o o d S a m ple Assess me nts
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 
b ut are n ot li mite d t o t u m or e x os o mes, cell free D N A, circ ulati n g t u m or cells ( C T C), 
c yt o ki nes. A d diti o nal a nal yses ma y be warra nte d base d o n e mer gi n g data. I nstr ucti o ns f or 
sa m ple c ollecti o n, pr ocessi n g, st ora ge a n d s hi p me nt will be pr o vi de d i n t he La b orat or y/ St u d y
ma n ual.
8. 8. 4. C yt o ki ne Assess me nts
Sa m ples will be c ollecte d f or ce ntral e val uati o n of c y t o ki nes at t he ti me p oi nts s pecifie d i n t he 
S o A . T he c yt o ki nes t o be meas ure d ma y i ncl u de, b ut n ot li mite d t o I F N-, T N F-, I L- 1, 
I L-2, I L -4, I L -5, I L -6, I L -8, I L -1 0, I L 1 2 -p 7 0 a n d s ol u ble I L -2 R (s C D 2 5). A d diti o nal 
e x pl orat or y circ ulati n g meas ures will als o be e val uate d t o meas ure c ha n ges i n i m m u ne 
acti vati o n after t hera p y. I nstr ucti o ns f or sa m ple c ollecti o n, pr ocessi n g, st ora ge a n d s hi p me nt 
will be pr o vi de d i n t he La b orat or y / St u d y ma n ual.
8. 8. 5. T Cell I m m u n o p he n ot y pi n g 
W h ole bl o o d sa m ples f or e val uati o n of T -cell, B -cell, a n d N K i m m u n o p he n ot ypi n g as well 
as c har acterizati o n of T cells f or mar kers s uc h as b ut n ot li mite d t o KI 6 7, P D -1, H L A -D R 
a n d ot her pr oliferati o n, acti vati o n, a n d e x ha usti o n mar kers t o meas ure c ha n ges i n i m m u ne 
acti vati o n after t hera p y. Sa m ples will be c ollecte d at t he ti mes s pecifie d i n t he S o A . 
I nstr ucti o ns f or sa m ple c ollecti o n, pr ocessi n g, st ora ge a n d s hi p me nt will be pr o vi de d i n t he 
La b orat or y / St u d y ma n ual.
Sa m ples ma y  be use d f or fl o w c yt o metr y assa y de vel o p me nt. Sa m ples use d f or t his p ur p ose 
will be retai ne d i n acc or da nce wit h l ocal re g ulati o ns a n d if n ot use d wit hi n t his ti mefra me, 
will be destr o y e d.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 3
8. 9. T u m or Res p o nse Assess me nts 
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 C T or 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 or 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 
baseli ne, d uri n g treat me nt as s pecifie d i n t he S o A , w he ne ver disease pr o gressi o n is s us pecte d 
(e g, sy m 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 4 wee ks). Assess me nt of res p o nse will be ma de usi n g R E CI S T versi o n 1. 1 
(A p pe n di x 1 4 ).
All partici pa nts’ files a n d ra di ol o gic i ma ges a n d pat h ol o g y  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. 
Disease res p o nse assess me nts will be base d u p o n disease- s pecific res p o nse criteria 
(A p pe n di x 1 4 ).
8. 1 0. He alt h Ec o n o mics
Healt h ec o n o mics/ me dical res o urce utilizati o n a n d healt 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 a statistical a nalys is pla n ( S A P), w hic h will be 
mai ntai ne d b y t he s p o ns or. 
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 is esti mate d t o be a p pr o xi matel y 1 3 0 partici pa nts.
9. 2. 1. P art 1 D ose Esc al ati o n
A p pr o xi matel y  3 5 partici pa nts eac h will be e nr olle d i n t he Part 1 A ( m o n ot hera p y) a n d 
Part 1 B (c o m bi nati o n) d ose escalati o n p orti o ns of t he st u d y . H o we ver, t he t otal n u m ber of 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 4
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 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.
9. 2. 2. P art 2 D ose E x p a nsi o n
Eac h of e x pa nsi o n c o h orts will e nr oll a p pr o xi matel y  2 0 t o 3 0 partici pa nts. Partici pa nts fr o m 
Part 1 A a n d Part 1 B w h o were treate d at t he d ose le vel selecte d f or Part 2 a n d f ulfilli n g 
Part 2 i ncl usi o n/e xcl usi o n cri teria ma y be c o u nte d t o war ds t he sa m ple size of Part 2 at t he 
c orres p o n di n g re gi me n ( m o n ot hera p y a n d c o m bi nati o ns).
Ass u mi n g a n o n -i nf or mati ve pri or (ie, Jeffre y’s pri or) if 6 o ut of 2 0 partici pa nts ha ve t u m or 
res p o nse, t his w o ul d pre dict a p osteri or pr o ba bilit y ( Beta Bi n o mial) e q ual t o 0. 7 1 t hat t he 
tr ue res p o nse is n ot i nferi or t o tar get res p o nse rate of 2 5 % a n d a p osteri or pr o ba bilit y cl ose t o 
0 (e q ual t o 4e -0 7) t hat t he tr ue res p o nse is i nferi or t o be nc h mar k rate of 2 %.
9. 3. P o p ul ati o ns f or A n al ysis

F ull a na l ysis set.

T he f ull a nal ys is set i ncl u des all e nr olle d partici pa nts.

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 o ne d ose 
of st u d y  treat me nt. U nless ot her wise s pecifie d t he safety a nal ysis set will be t he defa ult 
a nal ys is set use d f or all a nal yses.

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 o ne 
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.

M o difie d I nte nt t o Treat ( 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 me dicati 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 mI T T p o p ulati o n ma y  be use d f or i nteri m a nalys is 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.

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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 5

T he P K c o nce ntrati o n p o p ul ati o n is defi ne d as all e nr olle d partici 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.

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 
o ne d ose of st u d y treat me nt a n d ha d basel i ne disease a n d at least o ne p ost baseli ne 
disease assess me nt.

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 partici 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.

I m m u n o ge nicity a nal ys is set.

T he i m m u n o ge nicit y a nal y sis set i ncl u des all e nr olle d partici pa nts w h o recei ve at 
least o ne d ose of st u dy treat me nt a n d ha ve at least o ne sa m ple teste d f or A D A.
9. 4. 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 data base l oc k a n d will descri be t he 
partici pa nt p o p ulati o ns t o be i ncl u de d i n t he a nal y ses, 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 ys es of t he pri mar y a n d sec o n dar y e n d p oi nts.
9. 4. 1. 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).
B ayesi a n a d a ptive a p pr o ac h:
T he d ose escalati o n i n t he Part 1 A a n d Part 1 B ( wit h a n d wit h o ut pri mi n g se paratel y ) of t he 
st u d y will be g ui de d b y a Ba yesia n a nal ys is of D L T data f or P F-0 7 0 6 2 1 1 9. T o xicit y  is 
m o delle d usi n g t w o - para meter l o gistic re gressi o n f or t he pr o ba bility of a partici pa nt 
e x perie nci n g a D L T at t he gi ve n d ose f or t he m o n ot hera p y a n d usi n g B L R M m o del 
s pecifically de vel o pe d f or c o m bi nati o ns se paratel y  f or re gi me ns wit h a n d wit h o ut pri mi n g. 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 6
Assess me nt of p artici p a nt risk (t he t hree d osi n g i nterv als b o u n d aries c a n be m o difie d): 
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 
part ici pa nts at differe nt d oses of i nterest f or P F-0 7 0 6 2 1 1 9 will be e val uate d se paratel y  f or 
c o h orts wit h a n d wit h o ut pri mi n g, ta ki n g i nt o acc o u nt t he differe nt D L T o bser vati o n peri o ds 
( 2 8 da ys f or t he re gi me n wit h o ut pri mi n g a n d 4 2 da ys f or t he re gi me n wit h pri mi n g). 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 gete d 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 escalati o n wit h o ver d ose c o ntr ol pri nci pal. 3 1  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 e xcessi ve t o xicit y  at t hat d ose is 
less t ha n 2 5 %.
Pri or distri b uti o ns:
Wea kl y  i nf or mati ve pri or distri b uti o ns base d o n pre-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 pri or distri b uti o n i n Part 1 A, see A p pe n di x 1 0 .
A meta -a nal ytic-pre dicti ve ( M A P) a p pr oac h will be use d t o deri ve t he pri or distri b uti o n f or 
m o del para meters use d i n Part 1 B base d o n t he data c ollecte d i n Part 1 A. 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 dy 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. 4 0 ,2 7 ,3 1  M A P pri ors are deri ve d fr o m
hierarc hical m o dels, w hic h 
ta ke i nt o acc o u nt p ossi ble differe nces bet wee n t he st u dies. A f ull descri pti o n of t he 
a p plicati o n of t he M A P a p pr oac h t o deri ve t he pri or distri b uti o ns of t he m o del para meters is 
pr o vi de d i n A p p e n di x 1 0 .
St arti n g d ose: 
T he starti n g d ose of Part 1 A wit h o ut pri mi n g is 4 5 µ g. F or t his d ose t he pri or ris k of 
o ver d osi n g is 9. 7 %, w hic h 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 A p pe n di x 1 0 .
T he starti n g d ose of Part 1 A wit h pri mi n g is 4 0 0 µ g f or t he pri mi n g d ose a n d 8 0 0 µ g f or t he 
f ull d ose. F or t his d ose t he pri or ris k of o ver d osi n g is 1 2. 8 %, w hic h 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 A p pe n di x 1 0 .
T he ma xi m u m n u m ber of partici pa nts i n d ose escalati o n part of t he st u d y  was set t o 5 0. T he 
trial will be st o p pe 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/ R P 2 D.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 7

T he d ose  satisfies o ne of t he f oll o wi n g c o n diti o ns:
T he pr o ba bilit y  of tar get t o xicit y at d ose  e xcee ds 5 0 %, ie, Pr( 0. 1 6 ≤  < 0. 3 3) ≥5 0 %.

A mi ni m u m of 1 5 partici pa nts ha ve bee n treate d i n t he trial.
9. 4. 2. Effic ac y A n al yses
Res p o nse E val ua ble Set will be use d f or all res p o nse relate d a nal ys es i ncl u di n g O R R, D O R, 
a n d P F S.
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 y pe, 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.
Part 1 A a n d Part 1 B: pr o gressi o n date, deat h date, date of first res p o nse a n d last t u m or 
assess me nt date a n d date of last c o ntact will be liste d.
Part 2: T he Ka pla n -Meier met h o ds will be use d t o a nal yz e all ti me t o e ve nt e n d p oi n ts. 
Me dia n P F S (if reac he d). Details of t hese e n d p oi nt a nal ys es met h o ds will be i ncl u de d i n t he 
S A P.
P F S is defi ne d t he ti me fr o m start date t o date of first d oc u me ntati o n of pr o gressi o n, or deat h 
d ue t o a n y ca use. Pr o gressi o n is defi ne d as t he a p peara nce of l ocal, re gi o nal or dista nt 
disease of t he sa me t y pe after c o m plete res p o nse or pr o gressi o n of pre -e xisti n g lesi o ns. It 
d oes n ot i ncl u de sec o n d pri mar y  mali g na ncies of u nrelate d ty pes.
T he defi niti o n of eac h res p o nse cate g or y  is pr o vi de d i n A p pe n di x 1 4 ( R E CI S T v 1. 1) a n d 
A p pe n di x 1 5 (ir R E CIS T).
9. 4. 3. 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 safet y para meters wil l i ncl u de all partici pa nts i n t he safety 
a nal ys is set.
A Es, E C Gs, B P, P R, c o nti n u o us car diac m o nit ori n g, 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 dy t o e val uate t he safet y of 
partici pa nts. A n y cli nical la b orat or y , E C G, B P, a n d p ulse rate 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 vely, 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 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. 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 ns 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 di n gs meet t he defi niti o n of a n A E. 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 8
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. 4. 3. 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 ra te, 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 nt a n d ti me.
T he n u m ber ( %) of partici pa nts wit h ma xi m u m p ost d ose Q Tc val ues a n d ma 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 by treat me nt: 
S afet y Q Tc 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 baseli ne
3 0 -6 0
> 6 0
I n a d diti o n, t he n u m ber of partici pa nts wit h u nc orrecte d Q T val ues > 5 0 0 msec will be 
s u m marize d.
If m ore t ha n 1 E C G is c ollecte d at a n o mi nal ti me after d ose a d mi nistrati o n (f or e xa m ple, 
tri plicate E C Gs), 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. I f a n y 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 msec, b ut t he mea n of t he tri plicates is n ot > 5 0 0 msec, 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 safety secti o n of t he cli nical st u d y  re p ort ( C S R) i n 
or der t o place t he > 5 0 0 - msec 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 di vi d ual traci n gs wit hi n tri plicate meas ure me nts t hat are > 5 0 0 msec will n ot be i ncl u de d i n 
t he cate g orical a nal ysis u nless t he a vera ge fr o m t he tri plicate meas ure me nts is als o 
> 5 0 0 msec. C ha n ges fr o m baseli ne will be d efi 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. 
I n a d diti o n, a n atte m pt will be ma de t o e x pl ore a n d c haracterize t he relati o ns hi p bet wee n 
plas ma c o nce ntrati o n a n d Q T i nter val le n gt h usi n g a P K/ P D m o deli n g a p pr oac h. If a P K/ P D 
relati o ns hi p is f o u n d, t he i m pact of partici pa nt fact ors (c o variates) o n t he relati o ns hi p will be 
e xa mi ne d.
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 safet y a nal ysis set wit h 
baseli ne a n d o n -treat me nt E C G data. Baseli ne is defi ne d as a C 1 D 1 pre d ose.
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. An 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 divi d ual val ues o btai ne d at u nsc he d ule d ti me p oi nts.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 9
Q T i nter vals will be c orrecte d f or heart rate ( H R) ( Q Tc) usi n g sta n dar d c orrecti o n fact ors 
(ie, Fri dericia’s ( Q Tc F; defa ult c orrecti o n), Bazett’s ( Q Tc B), 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, res p o nse rate ( R R), 
partial res p o nse ( 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) b y  
st u d y ar m a n d prese nte d b y  ti me 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, 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 nal ys 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 d ose a n d ti me p oi nt. Details of a d diti o nal a nal ys is 
(if a ny) will be s pecif ie d i n S A P. 
9. 4. 3. 2. A d verse E ve nts
A Es will 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 t he 
Me dical Dicti o nar y  f or Re g ulat or y Acti vities ( 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 d verse eve nt 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 d verse e ve nts 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 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 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 ycles b e yo n d 1). Listi n gs of D L Ts a n d deat hs will be pr o vi de d.
9. 4. 3. 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 partici 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. 4. 4. Ot her A n al ys es 
9. 4. 4. 1. P h ar m ac o ki netic A n al yses
Si n gle - D ose a n d M ulti ple-D ose P F -0 7 0 6 2 1 1 9 P K A n al ysis
T he c o nce ntrati o ns of P F -0 7 0 6 2 1 1 9 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, a n d ge o metric
mea n) b y d osi n g c o h ort, c ycle, a n d n o mi nal ti me. Me dia n pr ofiles of t he c o nce ntrati o n -ti me 
pr ofiles after t he C 1 D 1 d ose, C 1 D 1 5 d ose ( pri mi n g a p pr oac h), a n d d ose will be pl otte d 
se paratel y b y d osi n g c o h ort a n d c ycle usi n g n o mi nal ti mes. Me dia n pr ofiles wil l be prese nte d 
o n b ot h li near -li near a n d l o g-li near scales.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 0
T he i n di vi d ual c o nce ntrati o n -ti me data of P F-0 7 0 6 2 1 1 9 f oll o wi n g t he C 1 D 1 d ose, C 1 D 1 5 
d ose ( pri mi n g a p pr oac h), a n d C 4 D 1 d ose will be a nal y ze d se paratel y usi n g 
n o n -c o m part me ntal a nal ysis t o esti mate t he P K para meters. T he P K para meters esti mate d 
will i ncl u de C ma x , ti me t o ma xi m u m c o nce ntrati o n ( Tma x ), a n d c o nce ntrati o n vers us ti me 
c ur ve ( A U Clast). If data per mit or if c o nsi dere d a p pr o priate, ot her P K para meters i ncl u di n g 
ter mi nal eli mi nati o n half-life (t1/ 2), cleara nce ( C L/ F), A U Ci nf, a n d vol u me of distri b uti o n at 
stea d y state (V ss/ F) ma y be deter mi ne d. N o n-c o m part me ntal P K para meters will be 
s u m marize d descri pti vel y by d ose a n d c ycle. Act ual sa m ple c ollecti o n ti mes will be use d f or 
t he para meter calc ulati o ns.
T he c o nce ntrati o ns of P F -0 6 8 0 1 5 9 1 or be vaciz u ma b -Pfizer fr o m Part 1 B a n d Part 2 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, a n d ge o metric mea n) b y d osi n g c o h ort, c ycle, a n d n o mi nal 
ti me. 
P o p ul ati o n P h ar m ac o ki netic A n al ysis or P h ar m ac o ki netic/ P h ar m ac o d y n a mic ( P K/ P D) 
M o deli n g 
P F -0 7 0 6 2 1 1 9 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 p o p ulati o n 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 f ut ure st u dies t o i n vesti gate a n y 
ass ociati o n bet wee n P F- 0 7 0 6 2 1 1 9 e x p os ure a n d bi o mar kers or selecte d safet y  a n d/ or efficac y 
e n d p oi nts. T he res ults of t hese a nal ys es, if perf or me d, ma y be re p orte d se parately fr o m t he 
cli nical st u d y re p ort.
9. 4. 4. 2. P h ar m ac o d y n a mic A n al yses 
A n al ysis of Bi o m ar ker E n d p oi nts
F or 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 a t baseli ne a n d p ost-treat me nt. F urt her a nalys is will 
be s pecifie d i n S A P.
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.
I m m u n o ge nicit y A n al ysis  
F or t he i m m u n o ge nicit y data, t he perce nta ge of partici pa nts wit h p ositi ve A D A will be 
s u m marize d. Listi n gs a n d s u m mar y ta b ulati o ns of t he A D A data at baseli ne a n d 
p ost -ra n d o mizati o n will be ge nerate d. Sa m ples ma y als o be a nal yze d f or t he prese nce of 
N A b, a n d a n y data will be si milarl y s u m marize d. F or partici pa nts wit h p ositi ve A D A or 
N A b, t he ma g nit u de (titer), ti me of o nset, a n d d urati o n of A D A or N A b res p o nse will als o be 
descri be d, if data per mit. T he p ote ntial i m pact of i m m u n o ge nicit y o n P K a n d cli nical 
res p o nse i ncl u di n g p har mac o dy na mic mar kers, safet y/ t olera bilit y a n d efficac y will be 
e x pl ore d, if warra nte d b y t he data.
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9. 5. 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 dy, 
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, facilitati 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. 1. D at a M o nit ori n g C o m mittee 
T his st u d y  will n ot use a data m o nit ori n g c o m mittee ( D M C). F or t he p ur p ose of t his pr ot oc ol, 
Pfizer pr oce d ures f or peri o dic safet y re vie w b y a safet y re vie w tea m, c o m prise d of t he 
i n vesti gat ors a n d t he s p o ns or, will be a p plie d i n or der t o re vie w i n di vi d ual a n d s u m mar y data 
c ollecte d i n t he safet y a n d cli nical data bases. T hese i n di vi d ual a n d s u m mar y data w o ul d als o 
i ncl u de partici pa nts w h o are deter mi ne d t o be n ot e val ua ble f or D L T assess me nt.
Disc ussi o ns bet wee n t he i n v esti gat ors a n d t he s p o ns or re gar di n g safet y will occ ur i n a n 
o n -g oi n g ma n ner at re g ular telec o nfere nces a n d/ or meeti n gs t o deter mi ne t he safet y pr ofile 
a n d ris k/ be nefit rati o a n d deter mi ne if f urt her partici pa nt e nr oll me nt is a p pr o priate.
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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 hical 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 C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces ( CI O M S) I nter nati o nal Et hical G ui deli nes;

A p plica ble I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u ma n Use (IC H) G o o d Cli nical Practice ( 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 ol a me n d me nts, I C D, i n vesti gat or’s br oc h ure (I B), 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 IR B/ 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 by 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 writte n s u m maries of t he stat us of t he st u d y  t o t he I RB/ 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 u ct 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 o de of Fe deral Re g ulati o ns ( C F R), I C H g ui deli nes, t he I R B/ 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 ority i n a n y 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/st u d y treat me nt, 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 by t he i n vesti gat or t o pr otect t he st u d y partici pa nts a gai nst a n y i m me diate hazar d, a n d 
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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.
1 0. 1. 2. Fi n a nci al Discl os ure
I n vesti gat ors a n d s u b-i 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 t o 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 n vesti 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 c o m pleti o n of t he st u d y.
1 0. 1. 3. I nf or me d C o nse 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  acce pta ble 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.
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 acce pta ble 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 t hat 
meets t he re q u ire me nts of 2 1 C F R 5 0, l ocal re g ulati o ns, IC H g ui deli nes, Healt h I ns ura nce 
P orta bilit y  a n d Acc o u nta bilit y Act ( 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.
T he i n vesti gat or m ust e ns ure t hat eac h st u d y  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 he le vel of discl os ure m ust als o be 
e x plai ne d t o t he partici pa nt.
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 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 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 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 was o btai ne d 
bef ore t he partici pa nt was e nr ol le d i n t he st u d y a n d t he date t he writte n c o nse 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 .
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A c o p y of t he I C Ds 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 acce pta ble 
re prese ntati ve.
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 me as 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 per 
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 have 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 s hall 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 nat ural pers o ns 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 
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 nts 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. 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 nts’ pers o nal data c o nsiste nt wit h t he cli nical st u d y 
a gree 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 ur o pea n Cli nical Trials 
Data base ( 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 sta n dar d o perati n g pr oce d ures ( S O Ps).
I n all cases, st u dy res ults are re p orte d b y 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 dy 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 U S Basic Res ults o n w w w.cli nicaltrials. 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 nts) 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. U S Basic 
Res ults are ge nerall y s u b mitte d f or p osti n g wit hi n 1 ye ar of t he pri mar y c o m pleti o n date 
( P C D) f or st u dies i n ad ult p o p ulati o ns or wit hi n 6 m o nt hs of t he P C D f or st u dies i n pe diatric 
p o p ulati o ns.
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P FI Z E R C O N FI D E N TI A L
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P C D is defi ne d as t he date t hat t he fi nal partici pa nt was e xa mi ne d or recei ve d a n i nter ve nti o n 
f or t he p ur p oses of fi nal c ollecti o n of data f or t he pri mar y o utc o me, w het her t he cli nical 
st u d y c o ncl u de d acc or di n g t o t he pres pecifie d pr ot oc ol or was ter mi nate d.
E u dra C T
Pfizer p osts E ur o pea n U ni o n ( E U) Basic Res ults o n E u dra C T f or all Pfizer -s p o ns ore d 
i nter ve nti o nal st u dies t hat are i n sc o pe of E U re q uire me nts. E U Basic Res ults are s u b mitte d 
f or p osti n g wit hi n 1 year of t he P C D f or st u dies i n a d ult p o p ulati o ns or wit hi n 6 m o nt hs of 
t he P C D f or st u dies i n pe diatric p o p ulati o ns.
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 nts 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 U S Basic Res ults d oc u me nt is 
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 k a 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 ur o pea n Me dici nes A ge nc y ( 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, CS 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 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 partici pa 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 ute 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 o ns. 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 a lit 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 
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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 h e st u d y site i n e ncr ypte 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 udits 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 ma na ge me nt a n d miti gati o n strate gies a n d a nalyt ical ris k-base d m o nit ori n g), 
me t 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 nc 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 
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.
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 Ds, 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 party 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 
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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 m e 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 electr o nic C R F (e C R F) t hat are tra nscri be d 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 or 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 st u d y  ma n ual.
1 0. 1. 8. St u d y a n d Site Cl os ure
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 discreti 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 ny ti me u p o n n otificati o n t o t he c o ntract 
researc h or ga nizati o n ( C R O) if re q ueste d t o d o s o b y t he res p o nsi ble I R 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 o r 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 gator;

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.
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 bl ic 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 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 mits all ma n uscri pts or a bstracts t o t he s p o ns or 
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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.
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 verall 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 wi t 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 u blicati 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 n f 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 tea m S hare P oi nt site. 
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 nts are pr o vi de d wit h a c o ntact car d. 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 co 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 ys 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 y s 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.
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P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 9
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 values. 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 ny percei ve d safet y c o ncer ns.
T a ble 1 5 . S afet y L a b or at or y Tests
He m at ol o g y
C he mi str y
Ser ol o g y
C o a g ul ati o n
Uri n al ysis
Pre g n a nc y Test
A d h oc L oc al 
L a b C yt o ki ne 
A n al ysis †
He m o gl o bi n
A L T
H B V 
P T
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
2 4 h o ur uri ne 
( pr otei n 
c ollecti o n) b
F or fe male 
partici pa nts of 
c hil d beari n g 
p ote ntial, ser u m.
I L-6, I L - 1, 
I L-1 0, I F N , 
T N F -, ot her 
c yt o ki nes
Platelets
A S T
H C V
P T T or A P T T
W B C
Bicar b o nate
A bs ol ute 
Ne utr o p hils
C R P
A bs ol ute 
L y m p h oc ytes
Al k P h os
A bs ol ute 
M o n oc ytes
S o di u m
A bs ol ute 
E osi n o p hils
P otassi u m
A bs ol ute 
Bas o p hils
Ma g nesi u m
Retic ul oc ytes
C hl ori de
T otal calci u m
T otal 
bilir u bi n * * *
T otal Pr otei n
B U N or Urea
Creati ni ne
Uric Aci d
Gl uc ose 
( n o nfaste d)
L D H
Al b u mi n
P h os p h or us or 
P h os p hate
A m ylase
Li pase
T h yr oi d Pa nel §
A b bre viati o ns: Al k P h os = a l kali ne p h os p hatase; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; 
B U N = bl o o d urea nitr o ge n; C R P = C -reacti ve pr otei n; H B V = he patitis B; H C V = he patitis C; I F N = 
i nterfer o n-ga m ma; I L = i nterle u ki n; I N R = I nter nati o nal N or malize d; L D H = lactate de h y dr o ge nase; P T T = partial 
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P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 0
T a ble 1 5 . S afet y L a b or at or y Tests
He m at ol o g y
C he mi str y
Ser ol o g y
C o a g ul ati o n
Uri n al ysis
Pre g n a nc y Test
A d h oc L oc al 
L a b C yt o ki ne 
A n al ysis †
t hr o m b o plasti n ti me; T N F= T u m or necr osis fact or - al p ha; T S H = T h yr oi d -sti m ulati n g h or m o ne; W B C = w hite bl o o d 
cells.
* * * 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, 
pr ot hr o m bi n ti me ( 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 h yr oi d pa nel s h o ul d be o btai ne d at scree ni n g o nl y ( T S H, free t h yr o xi ne [ T 4], free trii o d ot h yr o ni ne [t otal 
or free T 3]). 
† C yt o ki nes f or l ocal la b e val uati o n will be c ollecte d if C R S is s us pecte d. L ocal la b e val uati o n of c yt o ki ne is 
o nl y re q uire d if t he site re q uire t his i nf or mati o n f or partici pa nt ma na ge me nt.
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.
b. If uri nal ysis ( di pstic k acce pta ble) de m o nstrates pr otei n greater t ha n or e q ual t o 2 +, t he n a 2 4- h o ur ur i ne pr otei n 
c ollecti o n s h o ul d f oll o w. I n partici pa nts wit h pr otei n uria greater t ha n or e q ual t o 2 gra ms per 2 4 h o urs, be vaciz u ma b -
Pf izer s h o ul d be hel d u ntil rec o ver y (less t ha n 2 gra ms per 2 4 h o urs). Disc o nti n ue be vaciz u ma b- Pf izer i n partici pa nts 
t hat de vel o p ne p hr otic s y n dr o me.
I n vesti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safety re p ort, i ncl u di n g 
deter mi nati o n of cli nical si g nifica nce.
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1 0. 3. A p pe n di x 3: A d verse E ve nts: Defi ni ti 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 partici pa 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 disease ( 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 inter 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 y sis) 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 nicall y  
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 (ie, n ot 
relate d t o pr o gressi o n of u n derl yi n g disease).

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/selfhar 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.
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C 3 8 6 1 0 0 1
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Pa ge 1 2 2
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 
partici 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 pita l).

A ntici pate d da y  t o da 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 on 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. I t 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 os 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 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 3
seri o us. W he n i n d o u bt 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, v o 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 ifet 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 y scrasias 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 
p r 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 o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E) Gra de 5 (see 
t he A ssess me nt of I nte nsit y secti o n).

S us pecte d tra ns missi 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 partici pa 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 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 4
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 nsidere d f or re p orti n g as pr o d uct defects, if a p pr o priate.
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
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 Cli nical Trial ( C T) Seri o us A d verse 
E ve nt ( 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 ypes 
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 dy 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 dy 
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 oci ate d 
wit h e x p os ure d uri n g 
pre g na nc y ( E D P) or 
bre astfee di n g
Occ u pati o nal e x p os ure is 
n ot rec or de d.
All i nsta nces of E D P a n d 
e x p os ure d uri n g 
breastfee di n g ( w het her or 
n ot t here is a n ass ociate d 
S A E ).
All S A Es ass ociate d wit h 
occ u pati o nal e x p os ure. 
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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 5

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 dical 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 uested b y  Pfizer Safet y. In t his case, all partici pa nt i de ntifiers, wit h t he 
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 ne 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
T he i n vesti gat or will ma ke a n assess me nt of i nte nsit y  for eac h A E a n d S A E re p orte d 
d uri n g t he st u d y a n d assi g n it t o 1 of t he f oll o wi n g cate g ories: 
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 ys 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 6

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 dis ease(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 n vesti gat or’s br oc h ure (I B) a n d/ or pr 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 
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 dat 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 gulat 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 the 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 orda 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 by 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 ofessi o nals.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 7

If a partici pa nt dies d uri n g partici patio 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 Safety 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, w he n a vaila ble.

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 RF.

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.
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 sys te 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 yste 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 S afet 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 b y 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 8
1 0. 4. A p pe n di x 4: C o ntr ace pti ve G ui d a nce a n d C ollecti o n of Pre g n a nc y I nf or m ati o n
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 1 0 5 d a y s after t he last d ose of st u d y i nter ve nti o n of 
P F -0 7 0 6 2 1 1 9 a n d f or at least 6 m o nt hs after t he last d ose of P F -0 6 8 0 1 5 9 1 (sasa nli ma b) a n d 
be vaciz u ma b -Pfizer, w hic h c orres p o n ds t o t he ti me nee de d t o eli mi nate st u d y  i nter ve 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 hly 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 part ners 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), 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 1 0 5 d a y s after t he last d ose of P F -0 7 0 6 2 1 1 9 i nter ve nti o n a n d at least 6 m o nt hs 
after t he last d ose of P F - 0 6 8 0 1 5 9 1 (sasa nli ma b) a n d be vaciz u ma b-Pfizer, 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 st u d y  i nter ve nti o n(s). 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 earl y u n detecte d 
pre g na nc y . 
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1 0. 4. 3. W o m a n of C hil d be ari n g P ote nti al ( W O C B P)
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 
di screti o n s h o ul d be a p plie d t o deter mi ni n g st u dy 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 ume 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 dy.
2.
P ost me n o pa usal fe male.

A p ost me n o pa usal state is defi ne d as a ge 6 0 ye ars or ol der or 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.

A hi g h f ollicle -sti m ulati n g h or m o ne ( F S H) le vel i n t he p ost me n o pa usal ra n ge 
ma y  be use d t o c o nfir m a p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal 
c o ntrace pti o n or h or m o ne re place me nt t hera p y ( H R T). W he n t here is a hi g h F S H 
le vel, it s h o ul d be c o nfir me d t hat t here is n o ot her me dical ca use.

Fe males 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.
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1 0. 4. 4. C o ntr ace pti o n Met h o ds
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 (I U D).
3.
I ntra uteri ne h or m o ne-releasi n g sys te m (I U S).
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 ma n of c hil d beari n g p ote ntial 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 hl y 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.
6.
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.

Oral;

I ntra va gi nal ( n ot a p pr o ve d i n Ja pa n);

Tra ns der mal ( n ot a p pr o ve d i n Ja pa n);

I njecta ble ( n ot a p pr o ve d i n Ja pa n).
7.
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.

Oral ( n ot a p pr o ve d i n Ja pa n);

I njecta ble ( n ot a p pr o ve d i n Ja pa n).
8.
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 d y a n d t he preferre d a n d us ual 
lifest yle of t he partici pa nt.
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C ollecti o n of Pre g n a nc y I nf or m ati o n
F or b ot h u na p pr o ve d/ u nlice nse d pr o d ucts a n d f or mar kete d pr o d ucts, a n e x p os ure d uri n g 
pre g na nc y  ( E D P) occ urs if:

A fe mal e bec o mes, or is f o u n d t o be, pre g na nt eit her w hile recei vi n g or ha vi n g bee n 
e x p ose d (e g, beca use of treat me nt or e n vir o n me ntal e x p os ure) t o t he st u d y  
i nter ve nti o n; or t he fe male bec o mes or is f o u n d t o be pre g na nt after disc o nti n ui n g 
a n d/ or bei n g e x p ose d t o t he st u d y  i nter ve nti o n;

A n e xa m ple of e n vir o n me ntal e x p os ure w o ul d be a case i n v ol vi n g direct c o ntact 
wit h a Pfizer pr o d uct i n a pre g na nt w o ma n (e g, a n urse re p orts t hat s he is pre g na nt 
a n d has bee n e x p ose d t o c he m ot hera pe utic pr o d ucts).

A male has bee n e x p ose d (e g, beca use of treat me nt or e n vir o n me ntal e x p os ure) t o t he 
st u d y i nter ve nti o n pri or t o or ar o u n d t he ti me of c o nce pti o n a n d/ or is e x p ose d d uri n g 
his part ner’s pre g na nc y .
If a partici pa nt or partici pa nt’s part ner bec o mes or is f o u n d t o be pre g na nt d uri n g t he 
partici pa nt’s treat me nt wit h t he st u d y i nter ve nti o n, 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. I n a d diti o n, t he i n vesti gat or m ust s u b mit 
i nf or mati o n re gar di n g e n vir o n me ntal e x p os ure t o a Pfizer pr o d uct i n a pre g na nt w o ma n (e g, a 
partici pa nt re p orts t hat s he is pre g na nt a n d has bee n e x p ose d t o a c yt ot o xi c pr o d uct b y 
i n halati o n or s pilla ge) t o Pfizer Safet y usi n g t he E D P s u p ple me ntal f or m. T his m ust be d o ne 
irres pecti ve of w het her a n A E has occ urre d a n d wit hi n 2 4 h o urs of a ware ness of t he 
e x p os ure. T he 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 d ate 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 ).
F oll o w -u p is c o n d ucte d t o o btai 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  until 
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 he 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 ure test fi n di n gs are c o ncl usi ve f or a c o n ge nital a n o mal y a n d t he fi n di n gs are 
re p orte d).
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 mal y [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.
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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 Pfizer Safety as S A Es 
f oll o ws: 

S p o nta ne o us a b orti o n i ncl u d es 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 d eat 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 n dle d o n a case b y case basis (e g, f oll o w - u p o n 
preter m i nfa n ts t o i de ntif y de vel o p me ntal dela ys). In 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 ner. 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 h at 
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.
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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 nalys is.

Ge netic researc h ma y  c o nsist of t he a nal ysis of 1 or m ore ca n di date ge nes or t he 
a nal ys is of ge netic mar kers t hr o u g h o ut the ge n o me or a nal ys is of t he e ntire ge n o me 
(as a p pr o priate).

T he sa m ples ma y  be a nal yze d as part of a m ulti-st 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 treat me nts of t his class t o 
u n dersta n d treat me nts f or t h e 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 cli nical st u d y re p ort ( C S R) or 
i n a se parate st u d y s u 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 ba n ki n g (see Secti o n 8. 7. 2 ) will be st ore d i n defi nitely or ot her peri o d as per 
l ocal re q uire me nts.

Partici pa nts 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 
bi 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 bi os peci me ns will be la bele d wit h a c o de. T he k e 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. 
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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 me 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 nts, 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 nts 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 dr u g -i n d uce d 
li ver i nj ur y ( 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 ti mes t he 
u p per li mit of n or mal ( × 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 as partate a mi n otra nsferase ( A S T) a n d/ or ala ni ne 
a mi n otra nsferase ( A L T) prece de t otal bilir u bi n ( T bili) ele vati o ns ( > 2 × U L N) b y  se veral da ys 
or wee ks. T he i ncrease i n T bili t y picall y  occ urs w hile A S T/ A LT 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 bili 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, by 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 nts 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 nts 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 ble.

F or partici pa nts 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 or if t he val ue reac hes > 3 × U L N ( w hic he ver is s maller).
Rises i n A S T/ A L T a n d T bili se parate d b y 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. 
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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 wi t 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 lab orat or y  tests s h o ul d i ncl u de al b u mi n, creati ne ki nase ( C K), direct a n d 
i n direct bilir u bi n, ga m ma-gl uta m yl  tra nsferase ( G G T), pr ot hr o m bi n ti me ( P T)/i nter nati o nal 
n or malize d rati o (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 (eit her b y itself or as a c o -f 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 me nt ( 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 ollecte 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 
f or aceta mi n o p he n dr u g a n d/ or pr otei n a d d uct le vels ma 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 d efi 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 li ver f u ncti o n test ( L F T) a b n or malities has y et 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 h e 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 6
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 ( A Es)

Mar ke d si n us bra d y car 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 msec.

Ne w pr ol o n gati o n of Q Tc F t o > 4 8 0 msec (a bs ol ute) or b y ≥6 0 msec fr o m 
baseli ne.

Ne w o nset - 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 -o nset t y pe I sec o n d de gree- ( We nc ke bac h) A V bl oc k of > 3 0 sec o n ds’ 
d urati o n.

Fre q ue nt pre mat ure ve ntric ular c o m ple xes ( 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 ( S A Es)

Q Tc F pr ol o n gati o n > 5 0 0 msec.

Ne w S T -T c ha n ges s u g gesti ve of m y o car dial isc he mia.

Ne w o nset left b u n dle bra nc h bl oc k ( Q R S > 1 2 0 msec).

Ne w o nset ri g ht b u n dle bra nc h bl oc k ( Q R S > 1 2 0 msec).

S y m pt o matic bra d y car dia.

As y st ole:
I n a wa ke, sy m pt o m free partici pa nts i n si n us r h y t h m, wit h d oc u me nte d peri o ds of 
as yst 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 nts wit h atrial fi brillati o n a n d bra d y car 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 s u 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).

Ve ntric ular r h yt 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 hyt h m (rate 
< 4 0 b p m), accelerate d i di o ve ntric ular r h yt h m ( 4 0 < x < 1 0 0), a n d 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 7
m o n o m or p hic/ p ol y m or p hic ve ntric ular tac h y car dia > 1 0 0 b p m (s uc h as t orsa des de 
p oi ntes).

T y pe II sec o n d- de gree ( M o bitz II) A V bl oc k.

C o m plete (t hir d- de gree) heart bl 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 ve ntric ular tac h y arr 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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 8
1 0. 8. A p pe n di x 8: C o u ntr y -S pecific Re q uire me nts
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 st u d y.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 9
1 0. 9. A p pe n di x 9: Preli mi n ar y Cli nic al S u m m ar y f or St u d y B 8 0 1 1 0 0 1 P h ase 1 FI H 
( P F-0 6 8 0 1 5 9 1) 
Data C ut off Date: 2 9 A u g ust 2 0 1 9
St u d y Desi g n: 
B 8 0 1 1 0 0 1 is a n o n g oi n g P hase 1, o pe n- la bel, d ose escalati o n a n d e x pa nsi o n st u d y of 
P F -0 6 8 0 1 5 9 1 i n partici pa nts wit h l ocall y  a d va nce d or metastatic mela n o ma, S C C H N, 
o varia n ca ncer, sarc o ma, N S C L C, ur ot helial carci n o ma or ot her s oli d t u m ors. T he pri mar y  
p ur p ose of t his st u d y  is t o e val uate safety a n d earl y si g ns of efficac y of P F-0 6 8 0 1 5 9 1. T his 
cli nical st u d y was di vi de d i nt o a d ose escalati o n ( Part 1) p hase, a n d a d ose e x pa nsi o n ( Part 2) 
p hase.
P art 1 D ose Esc al ati o n
Part 1 d ose escalati o n e val uate d 4 pre -s pecifie d I V d ose le vels ( 0. 5, 1, 3, a n d 1 0 m g/ k g 
a dmi nistere d e ver y  3 wee ks [ Q 3 W]), a n d 1 s u bc uta ne o us ( S C) d ose le vel ( 3 0 0 m g 
a d mi nistere d e ver y 4 wee ks [ Q 4 W]) i n a d ult partici pa nts wit h l ocall y a d va nce d or metastatic 
mela n o ma, s q ua m o us cell ca ncer of hea d a n d nec k ( S C C H N), o varia n ca ncer, sarc o ma, s mall 
cell l u n g ca ncer ( S C LC), a de n ocarci n o ma of sali var y  gla n d, e n d o metrial a de n ocarci n o ma, 
mali g na nt perit o neal ne o plas m, es o p ha geal a de n ocarci n o ma or re nal cell carci n o ma. Pat ie nts 
ha d pr o gressi ve disease o n ≥1 pri or li ne of t hera p y f or l ocall y a d va nce d or me tastatic disease 
or ref use d sta n dar d of care t hera p y;  were n ot pre vi o usl y treate d wit h a n a nti -P D -1/ P D -L 1  
a ge nt; a n d ha d a de q uate re nal, b o ne marr o w, li ver, a n d car diac f u ncti o n, wit h Easter n 
C o o perati ve O nc ol o g y  Gr o u p ( E C O G)  perf or ma nce stat us 0 or 1. F o rty partici pa nts were 
e nr olle d i nt o Part 1 wit h 2 5 partici pa nts t otal e nr olle d i nt o t he I V d ose c o h orts a n d 1 5 
partici pa nts e nr olle d i nt o t he S C d ose c o h ort. 
P art 2 D ose Ex p a nsi o n
T he 3 0 0 m g S C d ose was e val uate d i n a n e x pa n de d p o p ulati o n of 1 0 6 partici pa nts. T his 
i ncl u de d 6 8 partici pa nts wit h l ocall y  a d va nce d or metastatic n o n-s mall cell l u n g ca ncer 
( N S C LC) a n d 3 8 partici pa nts wit h l ocall y  a d va nce d or metastatic ur ot helial carci n o ma ( U C) 
w h o were a nti -P D -1 or a nti -P D -L 1  treat me nt-naï ve a n d w h o ha d pr o gres si ve disease o n or 
were i nt olera nt t o s y ste mic t hera p y or f or w h o m sta n dar d of care sys te mic t hera p y was 
ref use d or u na vaila ble. Patie nts wit h N S C LC c o ul d ha ve recei ve d u p t o o ne li ne of pri or 
s yste mic t hera p y f or l ocall y a d va nce d or metastatic disease a n d if t he y ha d k n o w n e pi der mal 
gr o wt h fact or rece pt or ( E G F R) acti vati n g m utati o n or a n a na plastic l y m p h o ma ki nase ( A L K) 
rearra n ge me nt were re q uire d t o ha ve, i n a d diti o n, at least o ne tar gete d t hera p y f or t heir 
disease. Patie nts wit h U C c o ul d ha ve recei ve d u p t o 2 li nes of pri or sys te mic t hera pies f or 
l ocall y a d va nce d or metastatic disease. T he selecte d partici pa nts ha d a de q uate re nal, b o ne 
marr o w, li ver, a n d car diac f u ncti o n, wit h E C O G perf or ma nce stat us 0 or 1. All partici pa nts 
recei ve d 3 0 0 m g of P F -0 6 8 0 1 5 9 1 S C e ver y  4 wee ks. 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 0
Cli nic al O ver vie w
St u d y  B 8 0 1 1 0 0 1 is a n o n g oi n g P hase 1, o pe n-la bel, d ose escalati o n a n d e x pa nsi o n st u d y of 
sasa nli ma b i n partici pa nts wit h l ocall y a d va nce d or metastatic mela n o ma, s q ua m o us cell 
carci n o ma of t he hea d a n d nec k, o varia n c a ncer, sarc o ma, N S C L C, U C, or ot her s oli d 
t u m ors.  T he pri mar y p ur p ose of t he st u d y was t o e val uate safety a n d earl y si g ns of efficac y 
of sasa nli ma b.  T he cli nical st u d y  was di vi de d i nt o a d ose escalati o n ( Part 1) p hase, a n d a 
d ose e x pa nsi o n ( Part 2) p hase .  O ne h u n dre d f ort y-si x ( 1 4 6) partici pa nts ha ve bee n d ose d o n 
t he st u d y.  F orty ( 4 0) partici pa nts were e nr olle d i nt o Part 1 a n d 1 0 6 partici pa nts ( 6 8 wit h 
N S C L C a n d 3 8 wit h U C) were e nr olle d i nt o Part 2.  I n Part 1, 4 pre -s pecifie d I V d ose le vels 
( 0. 5, 1, 3, a n d 1 0 m g / k g a d mi nistere d Q 3 W), a n d 1 S C d ose le vel ( 3 0 0 m g a d mi nistere d 
Q 4 W) were e val uate d f or safet y.  N o D L Ts were o bser ve d a n d t h us, t here was n o ma xi m u m 
t olerate d d ose i de ntifie d.  T he 3 0 0 m g S C d ose was selecte d base d o n be nefit/ris k 
assess me nt.
As of t he data c ut off of 2 8 A u g ust 2 0 1 9, 1 3 of 1 5 partici pa nts treate d wit h sasa nli ma b 
3 0 0 m g S C d ose ( Part 1) e x perie nce d at least 1 treat me nt-relate d A E.  T he m ost c o m m o n 
treat me nt-relate d A Es re p orte d were diarr hea, fati g ue a n d decrease a p petite 
( n = 4 partici pa nts eac h, 2 6. 7 %), a n d na usea, c o u g h, a n d d ys p nea ( n = 3 partici pa nts eac h, 
2 0. 0 %).  O ne partici pa nt e x perie nce d a Gra de 3 treat me nt -relate d A E (a ne mia).  T here were 
n o Gra de 4 or Gra de 5 treat me nt -relate d A Es.
A t otal of 6 0 of 1 0 6 partici pa nts e x p erie nce d at least 1 treat me nt-relate d A E i n Part-2.  M ost 
c o m m o nl y re p orte d treat me nt-relate d A Es e x perie nce d by > 5 % of partici pa nts were 
h y pert h y r oi dis m ( n = 1 1; 1 0. 4 %), li pase i ncrease d a n d pr urit us ( n = 7; 6. 6 %) eac h a n d 
a m ylase i ncrease d, h yp ot h y r oi dism, a n d a ne mia ( n = 6; 5. 7 %) eac h.  Gra de 3 treat me nt -
relate d A Es i ncl u de d li pase i ncrease, a myl ase i ncrease d (eac h n = 2, 1. 9 %), bl o o d al kali ne 
p h os p hatase i ncrease d, decrease d a p petite, h y per ma g nese mia, p ne u m o nitis, a ge usia, 
a n os mia, a n d ja u n dice (eac h n = 1, 0. 9 %).  Gra de 4 treat me nt -relate d A Es i ncl u de d li pase 
i ncrease d, ne utr o p hil c o u nt decrease d, w hite bl o o d cell c o u nt decrease d (eac h n = 1, 0. 9 %). 
Gra de 5 treat me nt -relate d A E i ncl u de d arr hyt h mia ( n = 1, 0. 9 %).  F or treat me nt -relate d S A Es 
re p orte d, refer t o t he sasa nli ma b ( P F- 0 6 8 0 1 5 9 1) I B.
N o si g nifica nt i njecti o n site reacti o ns were re p orte d, e xce pt f or 1 case of Gra de 1 i njecti o n 
site pai n.  Safety data i ncl u di n g p ossi ble ir A E are m ostl y  c o nsiste nt wit h t he k n o w n safet y 
pr ofile of a nti -P D -1 treat me nt .
Detaile d safet y i nf or mati o n fr o m cli nical st u dies, as well as n o ncli nical i nf or mati o n, ca n be 
f o u n d i n t he sasa nli ma b ( P F-0 6 8 0 1 5 9 1) I B .
C o ncl usi o ns:
Base d o n t he a vaila ble safet y  a n d efficac y data f or P F-0 6 8 0 1 5 9 1, t he be nefit ris k pr ofile of 
P F - 0 6 8 0 1 5 9 1 is e x pecte d t o be fa v ora ble.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 1
1 0. 1 0. A p pe n di x 1 0: Det aile d D ose Esc al ati o n/ Fi n di n g Sc he me f or B L R M 
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 dec isi 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. 1 0. 1. St atistic al M o del
Let π ( d) be t he ris k of D L T f or P F - 0 7 0 6 2 1 1 9 gi ve n as a si n gle a ge nt at d ose d. T he 
d ose -D L T m o del is l o gistic:
l o git ( π ( d)) =l o g () +l o g( d ⁄ d *)
d * = 1 8 0 0 µ g a n d use d t o scale t he d oses of P F- 0 7 0 6 2 1 1 9. He nce, ( > 0) are t he 
P F -0 7 0 6 2 1 1 9 o d ds of a D L T at d * µ g; a n d ( > 0) is t he i ncrease i n t he l o g-o d ds o f a D L T by 
a u nit i ncrease i n l o g- d ose.
1 0. 1 0. 2. Pri or S pecific ati o ns f or M o n ot her a p y Wit h o ut Pri mi n g
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 all m o del 
para meters, w hic h i ncl u de t he para meters a n d . A wea kly i nf or mati ve pri or was use d as 
t here were n o rele va nt h u ma n hist orical D L T data a vaila ble. It was ass u me d t hat m o del 
para meters will f oll o w a bi variate n or mal ( B V N) distri b uti o n
(l o g(),l o g( )) ~ N2 ( m, S)
wit h pri or mea ns m = ( m 1, m2), a n d pri or c o varia nce matri x S c o m p osed of sta n dar d 
de viati o ns s 1, s2 a n d c orrelati o n ρ. It was ass u me d t hat
( m1, m2, s1, s2, ρ) = (l o git( p *), 0, 2, 1, 0)
Here, p * is t he a ntici pate d D L T rate at t he scali n g d ose d *. I t was ass u me d base d o n 
pre -cli nical data t hat D L T rate at 1 8 0 0 µ g  was 0. 3 3.
T his pri or is c o nsi dere d t o be wea kl y i nf or mati ve ( Ne ue nsc h wa n der et al. 2 0 1 4). 3 1
T he pri or distri b uti o ns of t he m o del para meters are pr o vi de d i n Ta ble 1 6 . Ta ble 1 7 ill ustrates 
t he res ulti n g pri or distri b uti o n of D L T rate deri ve d fr o m t he pri or gi ve n i n Ta ble 1 6 a n d 
r o u n de d t o 3 deci mal p oi nts. Base d o n t he a vaila ble i nf or mati o n t he starti n g d ose of 
P F - 0 7 0 6 2 1 1 9 of 4 5 µ g satisfies t he E W O C cri teria.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 2
T a ble 1 6 .
Pri or Distri b uti o n f or t he M o del P ar a meters
P F -0 7 0 6 2 1 1 9 si n gle a ge nt p ar a m eters: B V N we a kl y i nf or m ati ve pri or
Para meters
Mea ns
Sta n dar d de viati o ns
C orrelati o n
(l o g (α ),l o g (β  ))
-0. 7 0 8, 0
2, 1
0
T a ble 1 7 .
S u m m ar y of Pri or Distri b uti o n of D ose Li miti n g T o xicit y R ates f or 
P F -0 7 0 6 2 1 1 9
              ( ∗=      μ   )
P F -0 7 0 6 2 1 1 9 
D ose ( µ g)
Pri or Pr o b a bilities t h at D L T R ate is i n 
t he I nter v al
Me a n
S D
Q u a ntiles
[ 0, 0. 1 6)
[ 0. 1 6, 0. 3 3)
[ 0. 3 3, 1]
2. 5 %
5 0 %
9 7. 5 %
4 5
0. 8 2 9 
0. 0 7 4 
0. 0 9 7 
0. 0 9 3 
0. 1 8 6 
0. 0 0 0 
0. 0 0 8 
0. 7 2 7
9 0
0. 7 8 8 
0. 0 9 1 
0. 1 2 1 
0. 1 1 3 
0. 2 0 3 
0. 0 0 0 
0. 0 1 6 
0. 7 8 0
1 8 0
0. 7 3 6 
0. 1 0 7 
0. 1 5 7 
0. 1 4 1 
0. 2 2 3 
0. 0 0 0 
0. 0 3 0 
0. 8 2 8
3 6 0
0. 6 6 4 
0. 1 2 7 
0. 2 0 9 
0. 1 8 1 
0. 2 4 7 
0. 0 0 0 
0. 0 6 0 
0. 8 7 4
7 2 0
0. 5 5 3 
0. 1 5 8 
0. 2 8 8 
0. 2 4 2 
0. 2 7 3 
0. 0 0 0 
0. 1 2 2 
0. 9 1 4
1 4 4 0
0. 3 8 2 
0. 1 8 6 
0. 4 3 1 
0. 3 4 6 
0. 2 9 7 
0. 0 1 0 
0. 2 5 8 
0. 9 5 0
2 8 8 0
0. 2 1 4 
0. 1 5 3 
0. 6 3 3 
0. 5 0 4 
0. 3 2 4 
0. 0 1 6 
0. 5 0 0 
0. 9 8 9
Fi g ure 4.
S u m m ar y of D L T R ates f or P F -0 7 0 6 2 1 1 9
1 0. 1 0. 3. Pri or S pecific ati o ns f or M o n ot her a p y wit h Pri mi n g
A wea kl y i nf or mati ve pri or si milar t o o ne descri be d i n pre vi o us secti o n was use d. T he 
scali n g d ose f or t he re gi me n wit h pri mi n g is 8 0 0 µ g
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 3
As pre vi o usl y , it was ass u me d t hat ( m 1, m 2, s 1, s 2, ρ) = (l o git( p *), 0, 2, 1, 0)
Here, p * is t he a ntici pate d D LT rate at t he scali n g d ose d *. I t was ass u me d base d o n a nalys is 
of m o n ot hera p y d ose escalati o n wit h o ut pri mi n g t hat D L T rate at f ull d ose 8 0 0 µ g after 
pri mi n g wit h 4 0 0 µ g  was 0. 0 4 8 via matc hi n g D L T rates at 4 0 0 µ g  m o n ot hera p y wit h o ut 
pr i mi n g wit h pri mi n g/f ull d ose of 4 0 0 µ g/ 8 0 0 µ g.
T he pri or distri b uti o ns of t he m o del para meters are pr o vi de d i n Ta ble 1 8. Ta ble 1 9 ill ustrates 
t he res ulti n g pri or distri b uti o n of D LT rate deri ve d fr o m t he pri or gi ve n i n Ta ble 1 8 a n d 
r o u n de d t o 3 deci mal p oi nts. Base d o n t he a vaila ble i nf or mati o n t he starti n g d ose of 
P F - 0 7 0 6 2 1 1 9 of 4 0 0 µ g/ 8 0 0 µ g satisfies t he E W O C criteria.
T a ble 1 8 .
Pri or Distri b uti o n f or t he M o del P ar a meters ( Wit h Pri mi n g)
P F -0 7 0 6 2 1 1 9 si n gle a ge nt p ar a m eters: B V N we a kl y i nf or m ati ve pri or
Para meters
Mea ns
Sta n dar d de viati o ns
C orrelati o n
(l o g(α ),l o g(β ))
-2. 9 8 7 , 0
2, 1
0
T a ble 1 9 .
S u m m ar y of Pri or Distri b uti o n of D ose Li miti n g T o xicit y R ates f or 
P F -0 7 0 6 2 1 1 9 ( Wit h Pri mi n g D ose of 4 0 0 µ g)
( ∗=    μ  )
P F -0 7 0 6 2 1 1 9 
D ose ( µ g)
Pri or Pr o ba bilities t hat D L T Rate is i n t he 
I nter val
Mea n
S D
Q ua ntiles
[ 0, 0. 1 6)
[ 0. 1 6, 0. 3 3)
[ 0. 3 3, 1]
2. 5 %
5 0 %
9 7. 5 %
8 0 0
0. 7 4 7 
0. 1 2 5 
0. 1 2 8 
0. 1 3 1 
0. 1 8 8 
0. 0 0 1 
0. 0 4 7 
0. 7 1 6
1 0 0 0
0. 6 8 4 
0. 1 4 0 
0. 1 7 6 
0. 1 6 5 
0. 2 1 8 
0. 0 0 1 
0. 0 6 7 
0. 8 0 6
1 2 0 0
0. 6 3 1 
0. 1 4 9 
0. 2 2 0 
0. 1 9 8 
0. 2 4 6 
0. 0 0 2 
0. 0 8 5 
0. 8 9 0
1 4 0 0
0. 5 9 0 
0. 1 5 1 
0. 2 5 9 
0. 2 2 7 
0. 2 6 9 
0. 0 0 2 
0. 1 0 4 
0. 9 3 7
1 6 0 0
0. 5 5 8 
0. 1 5 2 
0. 2 9 0 
0. 2 5 2 
0. 2 8 7 
0. 0 0 2 
0. 1 2 0 
0. 9 6 4
1 8 0 0
0. 5 3 2 
0. 1 5 2 
0. 3 1 7 
0. 2 7 3 
0. 3 0 1 
0. 0 0 2 
0. 1 3 7 
0. 9 8 1
2 0 0 0
0. 5 0 9 
0. 1 5 0 
0. 3 4 1 
0. 2 9 2 
0. 3 1 2 
0. 0 0 2 
0. 1 5 3 
0. 9 8 9
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 4
1 0. 1 1. A p pe n di x 1 1: S u g geste d C yt o ki ne Rele ase S y n dr o me M a n a ge me nt Al g orit h m 
a n d Re vise d C R S Gr a di n g S yste m
A d a pte d fr o m Lee D W, et al: A S T C T C o nse ns us Gr a di n g f or Cyt oki ne Rele ase Sy n dr o me a n d 
Ne ur ol o gic T oxicity Ass oci ate d wit h I m m u ne Effect or Cells 2 0 1 9. 2 5: 6 2 5 -6 3 8.
* N ote – H y p o xia re q uiri n g l o w -fl o w si m ple face mas k defi ne d as o x y ge n deli vere d at ≤6 L/ mi n ute is Gra de 2 
C R S, w hereas h y p o xia re q uiri n g hi g h -fl o w sim ple face mas k defi ne d as o x y ge n deli vere d at > 6 L/ mi n ute is 
Gra de 3 C R S.
C R S m a n a ge me nt g ui deli nes
A S T C T Gr a de 1 C R S:

M o nit or vital si g ns f or w orse ni n g of c o n diti o n.
Fe ver

Aceta mi n o p he n/ paraceta m ol a n d h y p ot her mia bla n ket f or t he treat me nt of fe ver.

N o n- ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds) s uc h as i b u pr ofe n ca n be use d as 
sec o n d treat me nt o pti o n f or fe ver if n ot c o ntrai n dicate d.

Assess f or i nfecti o n usi n g bl o o d a n d uri ne c ult ures, a n d c hest ra di o gra p h y.

E m piric br oa d -s pectr u m a nti bi otics a n d fil grasti m if ne utr o pe nic.

Mai nte na nce I V fl ui ds f or h y drati o n.

S y m pt o matic ma na ge me nt of c o nstit uti o nal s y m pt o ms or or ga n t o xicit y .

C o nsi der t ociliz u ma b 8 m g/ k g * I V or silt u xi ma b 1 1 m g/ k g I V f or persiste nt (lasti n g 
> 3 da y s) a n d refract or y fe ver.
A S T C T Gr a de 2 C R S:

M o nit or vital si g ns e ver y 4 h o urs f or w orse ni n g of c o n diti o n.
Fe ver

Ma na ge as i n Gra de 1 C R S.
H y p ote nsi o n

I V fl ui d b ol us of 5 0 0-1 0 0 0 m L of n or mal sali ne. Ca n gi ve sec o n d I V fl ui d b ol us if
s yst olic bl o o d press ure re mai ns < 9 0 m m H g.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 5

C o nsi der t ociliz u ma b 8 m g/ k g ( ma xi m u m d ose 8 0 0 m g) I V or silt u xi ma b 1 1 m g/ k g 
I V f or treat me nt of hy p ote nsi o n refract or y t o fl ui d b ol uses; t ociliz u ma b ca n be 
re peate d after 6 h if nee de d.

If hy p ote nsi o n persists after 2 fl ui d b ol uses a n d a nti -I L-6 t hera p y, start vas o press ors, 
c o nsi der tra nsfer t o i nte nsi ve care u nit (I C U), o btai n ec h ocar di o gra m ( E C H O), a n d 
i nitiate ot her met h o ds of he m o d y na mic m o nit ori n g.

I n patie nts at hi g h-ris k ( b ul k y disease, ol der a ge or c o m or bi dities) or if h y p ote nsi o n 
persists after 1 -2 d oses of a nti -I L-6 t hera p y , de xa met has o ne ca n be use d at 1 0 m g I V 
e ver y 6 hrs.
H y p o xi a

S u p ple me ntal o x y ge n.

T ociliz u ma b or silt u xi ma b ±
c ortic oster oi ds a n d s u p p orti ve care, as i n dicate d f or
h y p ote nsi o n.
A S T C T Gr a de 3 C R S:

M o nit or patie nt (i ncl u di n g c o nti n u o us E C G m o nit ori n g) i n a n I C U a n d o btai n E C H O
if n ot d o ne alrea dy.
Fe ver

Ma na ge as i n Gra de 1 C R S.
H y p ote nsi o n

I V b ol uses, as nee de d, as rec o m me n de d f or Gra de 2 C R S.

T ociliz u ma b a n d silt u xi ma b as rec o m me n de d f or Gra de 2 C R S if n ot a d mi nistere d 
pre vi o usl y .

Vas o press ors as nee de d.

De xa met has o ne 1 0 m g I V e ver y 6 hrs; if refract or y, i ncrease t o 2 0 m g I V e ver y 6 hrs.
H y p o xi a

S u p ple me ntal o x y ge n i ncl u di n g hi g h -fl o w o xy ge n deli ver y.

T ociliz u ma b or silt u xi ma b pl us c ortic oster oi ds a n d s u p p orti ve care, as desc ri be d
a b o ve.
A S T C T Gr a de 4 C R S:

M o nit or patie nt (i ncl u di n g c o nti n u o us E C G m o nit ori n g) i n a n I C U a n d o btai n E C H O
if n ot d o ne alrea dy.
Fe ver

Ma na ge as i n Gra de 1 C R S.
H y p ote nsi o n

I V b ol uses, a nti-I L-6 t hera p y , vas o press ors, a n d he m o d yna mic m o nit ori n g as
rec o m me n de d f or gra de 3 C R S.

Met h y l pre d nis ol o ne 1 g/ da y IV.
H y p o xi a

S u p ple me ntal o x y ge n via p ositi ve press ure/ mec ha nical ve ntilati o n.

T ociliz u ma b or silt u xi ma b pl us c ortic oster oi ds a n d s u p p orti ve care, as descri be d
a b o ve.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 6
1 0. 1 2. A p pe n di x 1 2: E C O G Perf or m a nce St at us
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)
C O P Y RI G H T E D M A T E RI A L


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 7
1 0. 1 3. A p pe n di x 1 3: S u p p orti ve C are f or I m m u ne - Rel ate d A d verse E ve nts (ir A Es)
T a ble 2 0 .
M a n a ge me nt of I m m u ne Rel ate d A d verse E ve nts (ir A Es)
Gr a de
M a n a ge m e nt
F oll o w u p
Gastr oi ntesti nal 
ir A Es
Gr a de 1
Diarr hea: 
< 4 st o ols/ da y o ver 
baseli ne;
C olitis: 
as y m pt o matic
A nti -diarr heal me dicati o n 
(e g, l o pera mi de 4 m g i nitial 
d ose f oll o w e d b y 2 m g after 
e ver y s u bse q ue nt l o ose st o ol 
wit h n o m ore t ha n 1 6 m g 
dail y)
C o nti n ue st u d y i nter ve nti o n 
t hera p y.
If persists >4 8 h o urs, a d d sec o n d 
a nti -diarr heal me dicati o n (e g, 
L o m o til 2 ta blets 4 ti mes dail y).
Gr a de 2
Diarr hea: 4 t o 6 
st o ols per da y o ver 
baseli ne; I V fl ui ds 
i n dicate d < 2 4 
h o urs; n ot 
i nterferi n g wit h 
A D L
C olitis: a b d o mi nal 
pai n; bl o o d i n st o ol
Wit h h ol d st u d y i nter ve nti o n 
t hera p y.
A nti -diarr heal me dicati o n 
(e g, l o pera mi de 4 m g i nitial 
d ose f oll o w e d b y 2 m g after 
e ver y s u bse q ue nt l o ose st o ol 
wit h n o m ore t ha n 1 6 m g 
dail y) .
If i m pr o ves t o Gra de 1: 
Res u me st u d y  i nter ve nti o n 
t hera p y.
If persists >4 8 h o urs, a d d sec o n d 
a nti -diarr heal me dicati o n (e g, 
L o m o til 2 ta blets 4 ti mes dail y).
If persists >9 6 h o urs or rec ur s:
Met h yl pre d nis ol o ne 0. 5 t o 
1. 0 m g/ k g/ da y or e q ui vale nt. 
W he n s y m pt o ms i m pr o ve t o 
Gra de 1, ta per ster oi ds o ver at 
least 1 m o nt h, c o nsi der 
pr o p h ylactic a nti bi otics f or 
o p p ort u nistic i nfecti o ns, a n d 
res u me st u d y i nter ve nti o n 
t hera p y per pr ot oc ol.
If worse ns or persists > 3 da ys 
wit h ster oi ds:
Treat as Gra de 3 t o 4.
Gr a de 3 t o 4
Diarr hea ( Gra de 3): 
≥7 st o ols per da y 
o ver baseli ne; 
i nc o nti ne nce; I V 
fl ui ds ≥2 4 hrs.; 
i nterferi n g wit h 
A D L
C olitis ( Gra de 3): 
se vere a b d o mi nal 
pai n, me dical 
i nter ve nti o n 
i n dicate d, perit o neal 
si g ns
Wit h h ol d st u d y i nter ve nti o n 
t hera p y.
A nti -diarr heal me dicati o n 
(e g, l o pera mi de 4 m g i nitial 
d ose f oll o w e d b y 2 m g after 
e ver y s u bse q ue nt l o ose st o ol 
wit h n o m ore t ha n 1 6 m g 
dail y) .
Met h yl pre d nis ol o ne
1. 0 t o 
2. 0 m g/ k g/ da y I V or 
e q ui vale nt.
C o nsi der a d d iti o n of
pr o p h ylactic a nti bi otics f or 
o p p ort u nistic i nfecti o ns .
C o nsi der e n d osc o p y.
I n vesti gati o nal pr o d uct t hera p y –
See Ta ble 1 2 – D ose 
M o dificati o ns f or S pecific 
I m m u ne Relate d T o xicit y.
C o nti n ue ster oi ds u ntil Gra de 1, 
t he n ta per o ver at least 1 m o nt h.
If persists > 4 8 h o urs, a d d sec o n d 
a nti -diarr heal me dicati o n (e g, 
L o m o til 2 ta blets 4 ti mes dail y).
If persists > 9 6 h o urs or rec urs:
C o nsi der a d diti o n of i nfli xi ma b 
5 m g/ k g (if n o c o ntrai n dicati o n). 
N ote: I nfli xi ma b s h o ul d n ot be 
use d i n cases of perf orati o n or 
se psis.
Der m atitis ir A E
Gr a de 1 t o 2 
C o veri n g 3 0 % 
b o d y s urface area
S y m pt o matic t hera p y 
(e g, a nti hista mi nes, t o pical 
ster oi ds) C o nti n ue st u d y
i nter ve nti o n t hera p y
If persists > 1 t o 2 wee ks or 
rec urs: C o nsi der s ki n bi o ps y 
Wit h h ol d st u d y i nter ve nti o n 
t hera p y.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 8
T a ble 2 0 .
M a n a ge me nt of I m m u ne Rel ate d A d verse E ve nts (ir A Es)
Gr a de
M a n a ge m e nt
F oll o w u p
C o nsi der 0. 5 t o 1. 0 m g/ k g/ da y 
met h yl pre d nis ol o ne I V or oral 
e q ui vale nt. O nce i m pr o vi n g, 
ta per ster oi ds o ver at least 
1 m o nt h, c o nsi der pr o p h ylactic 
a nti bi otics f or o p p ort u nistic 
i nfecti o ns, a n d res u me st u d y 
i nter ve nti o n t hera p y
If worse ns: 
Treat as Gra de 3 t o 4.
Gr a de 3 t o 4
C o veri n g > 3 0 % 
b o d y s urface area; 
life t hreate ni n g 
c o nse q ue nces
Wit h h ol d or disc o nti n ue 
st u d y i nter ve nti o n t hera p y 
C o nsi der s ki n bi o ps y 
Der m at ol o g y c o ns ult 
1. 0 t o 2. 0 m g/ k g/ da y 
met h yl pre d nis ol o ne I V or 
I V e q ui vale nt
If i m pr o ves t o Gra de 1: 
Ta per ster oi ds o ver at least 
1 m o nt h a n d a d d pr o p h ylactic 
a nti bi otics f or o p p o rt u nistic 
i nfecti o ns.
Res u me st u d y i nter ve nti o n 
t hera p y.
P ne u m o nitis 
ir A Es
Gr a de 1
Ra di o gra p hic 
c ha n ges o nl y
C o nsi der dela y of st u d y 
i nter ve nti o n t hera p y 
M o nit or f or s y m pt o ms e ver y 
2 t o 3 da ys 
C o nsi der P ul m o nar y a n d 
I nfecti o us Disease c o ns ults
Re -i ma ge at least e ver y 3 wee ks 
If worse ns, treat as Gra de 2 or 
Gra de 3 t o 4
Gr a de 2
Mil d t o m o derate 
ne w s y m pt o ms
Wit h h ol d st u d y i nter ve nti o n 
t hera p y
P ul m o nar y a n d I nfecti o us 
Disease c o ns ults
M o nit or s y m pt o ms dail y, 
c o nsi der h os pitalizati o n 
1. 0 m g/ k g/ da y 
met h yl -pre d nis ol o ne I V or 
oral e q ui vale nt 
C o nsi der br o nc h osc o p y, 
l u n g bi o ps y
Re -i ma ge e ver y 1 t o 3 da ys 
If i m pr o ves: 
W he n s y m pt o ms ret ur n t o near 
baseli ne, ta per ster oi ds o ver at 
least 1 m o nt h a n d t he n res u me 
st u d y i nter ve nti o n t hera p y a n d 
c o nsi der pr o p h ylacti c a nti bi otics 
If n ot i m pr o vi n g after 2 wee ks or 
w orse ni n g: 
Treat as Gra de 3 t o 4
Gr a de 3 t o 4
Se vere ne w 
s y m pt o ms; 
Ne w/ w orse ni n g 
h y p o xia; 
life-t hreate ni n g
Disc o nti n ue st u d y 
i nter ve nti o n t hera p y
H os pitalize 
P ul m o nar y a n d I nfecti o us 
Disease c o ns ults
2 t o 4 m g/ k g/ da y 
met h yl pre d nis ol o ne I V or 
I V e q ui vale nt 
A d d pr o p h ylactic a nti bi otics 
f or o p p ort u nistic i nfecti o ns 
C o nsi der br o nc h osc o p y, 
l u n g bi o ps y
If i m pr o ves t o baseli ne: 
Ta per ster oi ds o ver at least 
6 we e ks. If n ot i m pr o vi n g after 
4 8 h o urs or w orse ni n g: 
A d d a d diti o nal 
i m m u n os u p pressi o n 
(e g, i nfli xi ma b, 
c ycl o p h os p ha mi de, i ntra ve n o us 
i m m u n o gl o b uli n, or 
m yc o p he n olate m ofetil).
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4 9
T a ble 2 0 .
M a n a ge me nt of I m m u ne Rel ate d A d verse E ve nts (ir A Es)
Gr a de
M a n a ge m e nt
F oll o w u p
He patitis ir A Es
Gr a de 1
Gra de 1 A S T or 
A L T > U L N t o 
3. 0 x U L N a n d/ or 
T otal bilir u bi n 
> U L N t o 1. 5 x 
U L N
C o nti n ue st u d y i nter ve nti o n 
t hera p y
C o nti n ue li ver f u ncti o n 
m o nit ori n g . If worse ns, treat as 
Gra de 2 or 3 t o 4.
Gr a de 2
A S T or A L T > 3. 0 
t o ≤5 x U L N a n d/ or 
t otal bilir u bi n 
> 1. 5 t o ≤3 x U L N
Wit h h ol d st u d y i nter ve nti o n 
t hera p y
I ncrease fre q ue nc y of 
m o nit ori n g t o e ver y 3 da ys
If ele vati o ns ret ur n w it hi n ≤7 
da ys t o G ra de ≤1:
Res u me r o uti ne m o nit ori n g a n d
treat me nt at sa me d ose le vel.
If ele vati o ns d o n ot i m pr o ve 
wit hi n ≤7 da ys t o Gra de ≤1 :
M et h yl pre d nis ol o ne 0. 5 t o 1 
m g/ k g/ da y ( or oral /I V
e q ui vale nt ) a n d , w he n ele vati o ns
i mpr o ve t o Gra de ≤1 , ta per 
ster oi ds o ver at least 1 m o nt h, 
c o nsi der pr o p h ylactic a nti bi otics 
f or o p p ort u nistic i nfecti o ns, a n d 
re d uce d ose of P F -0 7 0 6 2 1 1 9 b y 
1 le vel.
Gr a de 3 t o 4
A S T or A L T > 5 x 
U L N a n d/ or t otal 
bilir u bi n > 3 x U L N
Disc o nti n ue st u d y 
i nter ve nti o n t hera p y.
I ncrease fre q ue nc y of 
m o nit ori n g t o e ver y 1 t o 2 
da ys.
1. 0 t o 2. 0 m g/ k g/ da y 
met h yl pre d nis ol o ne I V or 
I V e q ui vale nt.
A d d pr o p h ylactic a nti bi otics 
f or o p p ort u nistic i nfecti o ns. 
C o ns ult gastr oe nter ol o gist.
C o nsi der o btai ni n g M RI/ C T 
sca n of li ver a n d li ver 
bi o ps y if cli nicall y 
warra nte d.
If ret ur ns t o Gra de 2: 
Ta per ster oi ds o ver at least 
1 m o nt h. If d oes n ot i m pr o ve i n 
> 3 t o 5 da ys, w orse ns or 
re b o u n ds: 
A d d m yc o p he n olate m ofetil 
1 gra m ( g) t wice dail y.
If n o res p o nse wit hi n a n 
a d diti o nal 3 t o 5 da ys, c o nsi der 
ot her i m m u n os u p pressa nts per 
l ocal g ui deli nes.
E n d ocri ne ir A Es
As y m pt o matic 
t h yr oi d-sti m ulati n g 
h or m o ne ( T S H) 
a b n or malit y
C o nti n ue st u d y i nter ve nti o n 
t hera p y
If T S H < 0. 5 x l o wer li mit of 
n or m al ( L L N), or T S H 
> 2 x U L N, or c o nsiste ntl y o ut of 
ra n ge i n 2 s u bse q ue nt 
meas ure me nts: i ncl u de free 
t h yr o xi ne ( T 4) at s u bse q ue nt 
c ycles as cli nicall y i n dicate d; 
c o nsi der e n d ocri n ol o g y c o ns ult.
S y m pt o matic 
e n d ocri n o pat h y
E val uate e n d ocri ne f u ncti o n 
C o nsi der pit uitar y M RI 
sca n.
If i m pr o ves ( wit h or wit h o ut 
h or m o ne re place me nt): 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 0
T a ble 2 0 .
M a n a ge me nt of I m m u ne Rel ate d A d verse E ve nts (ir A Es)
Gr a de
M a n a ge m e nt
F oll o w u p
If s y m pt o matic wit h 
a b n or mal la b/ pit uitar y sca n: 
Wit h h ol d st u d y i nter ve nti o n 
t hera p y:
1 t o 2 m g/ k g/ da y 
met h yl pre d nis ol o ne I V or 
oral e q ui vale nt.
I nitiate a p pr o priate h or m o ne 
re place me nt t herap y .
If n or mal la b/ pit uitar y M RI 
sca n b ut s y m pt o ms persist: 
Re peat la bs i n 1 t o 3 
wee ks/ M RI i n 1 m o nt h.
Ta per ster oi ds o ver at least 
1 m o nt h a n d c o nsi der 
pr o p h ylactic a nti bi otics f or 
o p p ort u nistic i nfecti o ns.
Res u me st u d y i nter ve nti o n 
t hera p y.
Partici pa nts wit h a dre nal 
i ns ufficie nc y ma y nee d t o 
c o nti n ue ster oi ds wit h 
mi neral oc ortic oi d c o m p o ne nt.
S us pici o n of 
a dre nal crisis (e g, 
se vere de h y drati o n, 
h y p ote nsi o n, s h oc k 
o ut of pr o p orti o n t o 
c urre nt ill ness)
Wit h h ol d or disc o nti n ue 
st u d y i nter ve nti o n t hera p y.
R ule o ut se psis 
Stress d ose of I V ster oi ds 
wit h mi neral oc ortic oi d 
acti vit y I V fl ui ds.
C o ns ult e n d ocri n ol o gist 
If a dre nal crisis r ule d o ut, 
t he n treat as a b o ve f or 
s y m pt o matic 
e n d ocri n o pat h y.
A D L =acti vities of dail y li vi n g, A L T =ala ni ne a mi n otra nsferase, A S T =as partate a mi n otra nsferase, 
C T =c o m p ute d t o m o gra p h y, ir A E =i m m u ne -relate d a d verse e ve nt, I V =i ntra ve n o us, L F T =li ver f u ncti o n test, 
L L N =l o wer li mit of n or mal, M RI = ma g netic res o na nce i ma gi n g, N CI -C T C A E = Nati o nal Ca ncer 
I nstit ute-C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts, N S AI Ds = n o nster oi dal a nti -i nfla m mat or y 
dr u gs, T 4 =t h yr o xi ne, T S H =t h yr oi d -sti m ulati n g h or m o ne, U L N = u p per li mit of n or mal.
* N ote – See Ta ble 1 2 – D ose M o dificati o ns f or S pecific I m m u ne Relate d T o xicit y Attri b ute d t o 
I n vesti gati o nal Pr o d uct or C o m bi nati o n I n vesti gati o nal T hera p y f or a d diti o nal details o n d ose 
c o nsi derati o ns wit h st u d y i nter ve nti o n t hera p y.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 1
1 0. 1 4. A p pe n di x 1 4: R E CI S T ( Res p o nse E v al u ati o n Criteri a i n S oli d T u m ors) 
Versi o n 1. 1 G ui deli nes
A d a pte d fr o m E. A. Eise n h a uer, et al: Ne w res p o nse ev al u ati o n criteri a i n s oli d t u m ors: 
Revise d R E CI S T g ui deli ne (versi o n 1. 1). E ur o pe a n J o ur n al of C a ncer 4 5 ( 2 0 0 9) 2 2 8– 2 4 7.
C ate g orizi n g Lesi o ns at B aseli ne
Me as ur a ble Lesi o ns
Lesi o ns t hat ca n be acc uratel y  meas ure d i n at least o ne di me nsi o n.

Lesi o ns wit h l o n gest dia meter t wice t he slice t hic k ness a n d at least 1 0 m m or greater 
w he n assesse d b y  C T or M RI (slice t hic k ness 5-8 m m).

Lesi o ns wit h l o n gest dia meter at least 2 0 m m w he n assesse d b y  C hest X-ra y.

S u perficial lesi o ns wit h l o n gest dia meter 1 0 m m or greater w he n assesse d b y  cali per.

Mali g na nt l y m p h n o des wit h t he s h ort a xis 1 5 m m or great er w he n assesse d b y C T.
N O T E: T he s h ortest axis is use d as t he di a meter f or m ali g n a nt ly m p h n o des, l o n gest axis f or 
all ot her me as ur a ble lesi o ns.
N o n - me as ur a ble Dise ase 

N o n -meas ura ble disease i ncl u des lesi o ns t o o s mall t o be c o nsi dere d meas ura ble
(i ncl u din g n o des wit h s h ort a xis bet wee n 1 0 a n d 1 4. 9 m m) a n d tr ul y  n o n-meas ura ble 
disease s uc h as ple ural or pericar dial eff usi o ns, ascites, i nfla m mat or y  breast disease, 
le pt o me ni n geal disease, l y m p ha n gitic i n v ol ve me nt of s ki n or l u n g, cli nical lesi o ns 
t hat ca n n ot be acc uratel y meas ure d wit h cali pers, a b d o mi nal masses i de ntifie d b y 
p h y sical e xa m t hat are n ot meas ura ble b y re pr o d uci ble i ma gi n g tec h ni q ues.

B o ne disease: B o ne disease is n o n- meas ura ble wit h t he e xce pti o n of s oft tiss ue 
c o m p o ne nts t hat ca n be e val uate d b y  C T or M RI a n d meet t he defi niti o n of 
meas ura bilit y  at baseli ne.

Pre vi o us l ocal treat me nt: A pre vi o usl y irra diate d lesi o n ( or lesi o n patie nti ve t o ot her 
l ocal treat me nt) is n o n-meas ura ble u nless it has pr o gresse d si nce c o m pleti o n of 
treat me nt.
N or m al Sites

C y stic lesi o ns: Si m ple c ysts s h o ul d n ot be c o nsi dere d as mali g na nt lesi o ns a n d s h o ul d 
n ot be rec or de d eit her as tar get or n o n -tar get disease. C ystic lesi o ns t h o u g ht t o 
re prese nt c ystic metastases ca n be meas ura ble lesi o ns, if t he y meet t he s pecific 
d efi niti o n a b o ve. If n o nc ystic lesi o ns are als o prese nt, t hese are preferre d as tar get 
lesi o ns.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 2

N or mal n o des: N o des wit h s h ort a xis < 1 0 m m are c o nsi dere d n or mal a n d s h o ul d n ot 
be rec or de d or f oll o we d eit her as meas ura ble or n o n -meas ura ble disease.
Rec or di n g T u m or Assess me nts 
All sites of disease m ust be assesse d at baseli ne. Baseli ne assess me nts s h o ul d be d o ne as 
cl ose as p ossi ble pri or t o st u d y  start. F or a n a de q uate baseli ne assess me nt, all re q uire d sca ns 
m ust be d o ne wit hi n 2 8 da y s pri or t o treat me nt a n d all disease m ust be d oc u me nte d 
a p pr o priatel y. If baseli ne assess me nt is i na de q uate, s u bse q ue nt stat uses ge nerall y s h o ul d be 
i n deter mi nate.
N ote: F or t he p artici p a nt p o p ul ati o n bei n g ev al u ate d i n t his pr ot oc ol, t he b aseli ne 
assess me nt m ay be c o m plete d wit h i n 6 weeks pri or t o r a n d o miz ati o n.
T ar get Lesi o ns
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, 5 lesi o ns i n t otal, 
re prese ntati ve of all i n v ol ve d or ga ns, s h o ul d be i de ntifie d as tar get lesi o ns at baseli ne. Tar get 
lesi o ns s h o ul d be selecte d o n t he basis of size (l o n gest lesi o ns) a n d s uitabilit y  f or acc urate 
re peate d meas ure me nts. Rec or d t he l o n gest dia meter f or eac h lesi o n, e xce pt i n t he case of 
pat h ol o gical l y m p h n o des f or w hic h t he s h ort a xis s h o ul d be rec or de d. T he 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 da l lesi o ns) f or all tar get lesi o ns at 
baseli ne will be t he basis f or c o m paris o n t o assess me nts perf or me d o n st u d y.

If t w o tar get lesi o ns c oalesce t he meas ure me nt of t he c oalesce d mass is use d. If a 
lar ge tar get lesi o n s plits, t he s u m of t he parts is use d.

Meas ure me nts f or tar get lesi o ns t hat bec o me s mall s h o ul d c o nti n ue t o be rec or de d. If 
a tar get lesi o n bec o mes t o o s mall t o meas ure, 0 m m s h o ul d be rec or de d if t he lesi o n is 
c o nsi dere d t o ha ve disa p peare d; ot her wise a defa ult val ue of 5 m m s h o ul d be 
rec or de d.
N O T E: W he n n o d al lesi o ns decre ase t o < 1 0 m m ( n or m al), t he act u al me as ure me nt s h o ul d 
still be rec or de d.
N o n -t ar get Dise ase 
All n o n - meas ura ble disease is n o n-tar get. All meas ura ble lesi o ns n ot i de ntifie d as tar get 
lesi o ns are als o i ncl u de d as n o n-tar get disease. Meas ure me nts are n ot re q uire d b ut rat her 
assess me nts will be e x presse d as A B S E N T, I N D E T E R MI N A T E, P R E S E N T/ N O T 
I N C R E A S E D, I N C R E A S E D. M ulti ple n o n-tar get lesi o ns i n o ne or ga n ma y be rec or de d as a 
si n gle ite m o n t he case re p ort f or m (e g, ‘ m ulti ple e nlarge d pel vic l y m p h n o des’ or ‘ m ulti ple 
li ver metastases’).
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 3
O bjecti ve Res p o nse St at us at E ac h E v al u ati o n
Disease sites m ust be assesse d usi n g t he sa me tec h ni q ue as baseli ne, i ncl u di n g c o nsiste nt 
a d mi nistrati o n of c o ntrast a n d ti mi n g of sca n ni n g. If a c ha n ge nee ds t o be ma de t he case m ust 
be disc usse d wit h t he ra di ol o gist t o deter mi ne if s u bstit uti o n is p ossi ble. I f n ot, s u bse q ue nt 
o bjecti ve stat uses are i n deter mi nate.
T ar get Dise ase

C o m plete Res p o nse ( C R): C o m plete disa p peara nce of all tar get lesi o ns wit h t he 
e xce pti o n of n o dal disease. All tar get n o des m ust decrease t o n or mal size (s h ort a xis 
< 1 0 m m). All tar get lesi o ns m ust be assesse d.

Partial Res p o nse ( P R): Greater t ha n or e q ual t o 3 0 % decrease u n der baseli ne of t he 
s u m of dia meters of all tar get meas ura ble lesi o ns. T he s h ort dia meter is use d i n t he 
s u m f or tar get n o des, w hile t he l o n gest dia meter is use d i n t he s u m f or all ot her tar get 
lesi o ns. All tar get lesi o ns m ust be assesse d.

Sta ble: D oes n ot q ualif y f or C R, P R or Pr o gressi o n. All tar get lesi o ns m ust b e 
assesse d. Sta ble ca n f oll o w P R o nl y i n t he rare case t hat t he s u m i ncreases b y less 
t ha n 2 0 % fr o m t he na dir, b ut e n o u g h t hat a pre vi o usl y d oc u me nte d 3 0 % decrease n o 
l o n ger h ol ds.

O bjecti ve Pr o gressi o n ( P D): 2 0 % i ncrease i n t he s u m of dia meters of tar get 
meas ura ble lesi o ns a b o ve t he s mallest s u m o bser ve d ( o ver baseli ne if n o decrease i n 
t he s u m is o bser ve d d uri n g t hera py), wit h a mi ni m u m a bs ol ute i ncrease of 5 m m.

I n deter mi nate. Pr o gressi o n has n ot bee n d oc u me nte d, a n d 
o ne or m ore tar get meas ura ble lesi o n s ha ve n ot bee n assesse d; 
or assess me nt met h o ds use d were i nc o nsiste nt wit h t h ose use d at baseli ne;
or o ne or m ore tar get lesi o ns ca n n ot be meas ure d acc uratel y (e g, p o orl y visi ble u nless d ue t o 
bei n g t o o s mall t o meas ure);
or o ne or m ore tar get lesi o ns were e xcise d or irra diate d a n d ha ve n ot rea p peare d or i ncrease d.
N o n -t ar get Dise ase

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 vels. All l ym p h n o des m ust be ‘ n or mal’ 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 a n y  n o n-tar get lesi o ns a n d/ or t u m or mar ker le vel 
a b o ve t he n or mal li mits.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 4

P D: U ne q ui v ocal pr o gressi o n of pre- e xisti n g lesi o ns. Ge nerall y, t he o verall t u m or 
b ur de n m ust i ncrease s ufficie ntl y  t o merit disc o nti n uati o n of t hera p y. I n t he prese nce 
of S D or P R i n tar get disease, pr o gressi o n d ue t o u ne q ui v ocal i ncrease i n n o n -tar get 
disease s h o ul d be rare.

I n deter mi nate: Pr o gressi o n has n ot bee n deter mi ne d a n d o ne or m ore n o n-tar get sites 
were n ot assesse d or assess me nt met h o ds were i nc o nsiste nt wit h t h ose use d at 
baseli ne.
Ne w Lesi o ns 
T he a p peara nce of a n y ne w u ne q ui v ocal mali g na nt lesi o n i n dicates P D. 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 assess me nt will clarif y  t he eti ol o g y. If 
re peat assess me nts c o nfir m t he lesi o n, t he n pr o gressi o n s h o ul d be rec orde d o n t he date of t he 
i nitial assess me nt. A lesi o n i de ntifie d i n a n area n ot pre vi o usl y  sca n ne d will be c o nsi dere d a 
ne w lesi o n.
S u p ple me nt al I n vesti g ati o ns

If C R deter mi nati o n de pe n ds o n a resi d ual lesi o n t hat decrease d i n size b ut di d n ot 
disa p pear c o m p letely, it is rec o m me n de d t he resi d ual lesi o n be i n vesti gate d wit h 
bi o ps y  or fi ne nee dle as pirate. If n o disease is i de ntifie d, o bjecti ve stat us is C R.

If pr o gressi o n deter mi nati o n de pe n ds o n a lesi o n wit h a n i ncrease p ossi bl y d ue t o 
necr osis, t he lesi o n m a y be i n vesti gate d wit h bi o ps y or fi ne nee dle as pirate t o clarif y 
stat us.
S u bjecti ve Pr o gressi o n
Patie nts 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 s h o ul d n ot be re p orte d as P D o n t u m or assess me nt C R Fs. T his s h o ul d be 
i n dicate d o n t he e n d of treat me nt C R F as off treat me nt d ue t o Gl o bal Deteri orati o n of Healt h 
Stat us. 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.
T a ble 2 1 . O bjecti ve Res p o nse St at us at E ac h E v al u ati o n
T ar get Lesi o ns
N o n -t ar get Dise ase
Ne w 
Lesi o ns
O bjecti ve St at us
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
I n deter mi nate or Missi n g
N o
P R
P R
N o n -C R/ N o n -P D, I n deter mi nate, or Missi n g
N o
P R
S D
N o n -C R/ N o n -P D, I n deter mi nate, or Missi n g
N o
Sta ble
I n deter mi nate or Missi n g
N o n -P D
N o
I n deter mi nate
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
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 5
T a ble 2 2 . O bjecti ve Res p o nse St at us at E ac h E v al u ati o n f or P atie nts wit h N o n 
T ar get Dise ase O nl y
N o n -t ar get Dise ase
Ne w Lesi o ns
O bjecti ve St at us
C R
N o
C R
N o n -C R/ N o n -P D
N o
N o n -C R/ N o n -P D
I n deter mi nate
N o
I n deter mi nate
U ne q ui v ocal pr o gressi o n
Yes or N o
P D
A n y
Yes
P D
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 6
1 0. 1 5. A p pe n di x 1 5: I m m u ne- Rel ate d Res p o nse Criteri a Deri ve d fr o m R E CI S T 1. 1 
(ir R E CI S T)
I ncreasi n g cli nical e x perie nce i n dicates t hat tra diti o nal res p o nse criteria ma y n ot be s ufficie nt 
t o f ull y c haracterize acti vit y i n t his ne w era of tar gete d t hera pies a n d/ or bi ol o gics.
T his is partic ularl y  tr ue f or i m m u n ot hera pe utic a ge nts s uc h as a nti- CT L A 4 a n d 
a nti-P D -1/a nti -P D -L 1 a nti b o dies w hic h e xert t he a ntit u m or acti vit y  b y a u g me nti n g acti vati o n 
a n d pr oliferati o n of T cells, t h us lea di n g t o t u m or i nfiltrati o n b y  T cells a n d t u m or re gressi o n 
rat her t ha n direct c yt ot o xic effects.1 8 ,1 9  Cli nical o bser vati o ns of partici pa nts wit h a d va nce d 
mela n o ma treate d wit h i pili m u ma b, f or e xa m ple, s u g geste d t hat c o n ve nti o nal res p o nse 
assess me nt criteria s uc h as Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) a n d 
W H O criteria are n ot s ufficie nt t o f ull y  c haracterize patter ns of t u m or res p o nse t o 
i m m u n ot hera p y beca use t u m ors treate d wit h i m m u n ot hera pe utic a ge nts ma y s h o w a d diti o nal 
res p o nse patter ns t hat are n ot descri be d i n t hese c o n ve nti o nal criteria.4 6 ,2 9
F urt her m ore, t he c o n ve nti o nal t u m or assess me nt criteria ( R E CI S T a n d W H O criteria) ha ve 
bee n re p orte d as n ot ca pt uri n g t he e xiste nce of a s u bset of partici pa nts w h o ha ve a n O S 
si milar t o t h ose w h o ha ve e x perie nce d C R or P R b ut were fla g ge d as P D b y W H O 
criteria. 4 9 ,2 9
O n t hese gr o u n ds, a t u m or assess me nt s ys te m has bee n de vel o pe d t hat i nc or p orates t hese 
dela y e d or flare -t ype res p o nses i nt o t he R E CI S T v 1. 1 (ir R E CI S T). 3 0
F or ir R E CI S T, o nl y  tar get a n d meas ura ble lesi o ns are ta ke n i nt o acc o u nt. I n c o ntrast t o 
R E CI S T v 1. 1, ir R E CI S T: 

Re q uires c o nfir mati o n of b ot h pr o gressi o n a n d res p o nse b y i ma gi n g at least 4 wee ks 
fr o m t he date first d oc u me nte d, a n d 

D oes n ot necessaril y sc ore t he a p peara nce of ne w lesi o ns as pr o gressi ve disease if t he 
s u m of lesi o n dia meters of tar get lesi o ns ( mi ni m u m of 1 0 m m l o n gest dia meter per 
n o n -n o dal lesi o n a n d 1 5 m m s h ortest dia mete r per n o dal lesi o n, ma xi m u m of 5 tar get 
lesi o ns, ma xi m u m of 2 per or ga n) a n d meas ura ble ne w lesi o ns d oes n ot i ncrease b y 
≥2 0 %.
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haracterize eac h 
i de ntifie d a n d re p orte d tar get lesi o n(s) at baseli ne a n d t hr o u g h o ut t he trial.
ir R E CIS T is defi ne d as f oll o ws: 
1.
O verall i m m u ne -relate d c o m plete res p o nse (ir C R): C o m plete disa p peara nce of all 
lesi o ns ( w het her meas ura ble or n ot) a n d n o ne w lesi o ns. All meas ura ble ly m p h n o des 
als o m ust ha ve a re d ucti o n i n s h ort a xis t o < 1 0 m m.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 7
2.
O verall i m m u ne -relate d partial res p o nse (ir P R): 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 ortest f or n o dal lesi o ns) of tar get a n d ne w meas ura ble lesi o ns 
decreases ≥3 0 %.
3.
O verall i m m u ne -relate d sta ble disease (ir S D): 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 ortest f or n o dal lesi o ns) of tar get a n d ne w meas ura ble lesi o ns is 
neit her ir C R, ir P R, (c o m pare d t o baseli ne) or i m m u ne -relate d pr o gressi ve disease 
(ir P D, c o m pare d t o na dir).
4.
O verall i m m u ne -relate d pr o gressi ve disease (ir P D): 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 ortest f or n o dal lesi o ns) of tar get a n d ne w meas ura ble lesi o ns 
i ncreases ≥2 0 % (c o m pare d t o na dir), c o nfir me d b y  a re peat, c o nsec uti ve o bser vati o n 
at least 4 wee ks fr o m t he d ate first d oc u me nte d.
Ne w meas ura ble lesi o ns: I nc or p orate d i nt o t u m or b ur de n (ie, a d de d t o t he tar get lesi o n 
meas ure me nts). A l y m p h n o de has t o be ≥1 5 m m i n s h ort a xis t o be a meas ura ble ne w lesi o n 
a n d its s h ort a xis meas ure me nt is i ncl u de d i n t he s u m. U p t o 2 ne w lesi o ns per or ga n a n d u p 
t o 5 ne w lesi o ns i n t otal ca n be a d de d t o t he meas ure me nts.
Ne w n o n - meas ura ble lesi o ns: D o n ot defi ne pr o gressi o n b ut precl u de ir C R.
O verall res p o nses deri ve d fr o m c ha n ges i n i n de x, n o n- i n de x, a n d ne w lesi o ns are o utli nes i n 
Ta ble 2 3 .
T a ble 2 3 . O ver all Res p o nse Deri ve d fr o m C h a n ges i n I n de x, N o n i n de x a n d Ne w 
Lesi o ns
M e as ur a ble Res p o nse
N o n -me as ur a ble Res p o nse
O ver all Res p o nse 
Usi n g ir R E CI S T b
I n de x a n d Ne w 
M e as ur a ble Lesi o ns 
( T u m or B ur de n)a
N o n -I n de x Lesi o ns
Ne w N o n -M e as ur a ble 
Lesi o ns
Decrease 1 0 0 %
A bse nt
A bse nt
ir C R
Decrease 1 0 0 %
Sta ble
A n y
ir P R
Decrease 1 0 0 %
U ne q ui v ocal pr o gressi o n
A n y
ir P R
Decrease ≥3 0 %
A bse nt/sta ble
A n y
ir P R
Decrease ≥3 0 %
U ne q ui v ocal pr o gressi o n
A n y
ir P R
Decrease < 3 0 % a n d 
i ncrease < 2 0 %
A bse nt/sta ble
A n y
ir S D
Decrease < 3 0 % a n d 
i ncrease < 2 0 %
U ne q ui v ocal pr o gressi o n
A n y
ir S D
I ncrease ≥2 0 %
A n y
A n y
ir P D
a.
Decrease assesse d relati ve t o baseli ne.
b.
Res p o nse (ir C R a n d ir P R) a n d pr o gressi o n (ir P D) m ust be c o nfir me d b y a sec o n d, c o nsec uti ve 
assess me nt at least 4 wee ks a part.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 8
1 0. 1 6. A p pe n di x 1 6: 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
A b
a nti b o d y
A C RI N
A merica n C olle ge of Ra di ol o g y  Ima gi n g Net w or k
A D A
a nti dr u g a nti b o dies
A E
a d verse e ve nt(s)
AI D S
ac q uire d i m m u n o deficie nc y  sy n dr o me
A L L
Ac ute L y m p h oc y tic Le u ke mia
A L T
ala ni ne a mi n otra nsferase
A M L
Ac ute M yel oi d Le u ke mia
A N C
a bs ol ute ne utr o p hil c o u nt
a nti-P D -1
a nti-pr o gra m me d cell deat h pr otei n -1
a nti-E G F R
A nti -e pi der mal gr o wt h fact or rece pt or pat h wa y
a nti-V E G F
A nti – vasc ular e n d ot helial gr o wt h fact or t hera p y
A PI
acti ve p har mace utical i n gre die nt
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 S T C T
A merica n S ociet y f or Tra ns pla ntati o n a n d Cell ular T hera py
A U C
area u n der t he c ur ve
A U C i nf
A U C fr o m ti me zer o e xtra p olate d t o i nfi nite ti me
A U C last
A U C fr o m ti me zer o t o t he last q ua ntifia ble c o nce ntrati o n
A U C ta u
A U C wit hi n t he first d osi n g i nter val
A V
atri o ve ntric ular
B A
bi oa vaila bilit y
B B S
Bi os peci me n Ba n ki n g S yste m
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 R A F
seri ne/t hre o ni ne-pr otei n ki nase B -Raf.
B S A
b o d y  s urface area
B U N
bl o o d urea nitr o ge n
C A R
c hi meric a nti ge n rece pt or
C E A
carci n oe m br yo nic a nti ge n
Ceff
cli nical efficaci o us c o nce ntrati o n 
C D S
c ore data s heet 
C F R
C o de of Fe deral Re g ulati o ns
c G M P
c yclic g ua n osi ne m o n o p h o s p hate
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 cleara nce
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5 9
A b bre vi ati o n
Ter m
Cl x
Cell li ne xe n o graft 
C ma x
ma xi m u m o bser ve d c o nce ntrati o n
C M C
C he mistr y , Ma n ufact uri n g, a n d C o ntr ols
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 R
c o m plete res p o nse
C R A
cli nical researc h ass ociate
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 R U
cli nical researc h u nit
C S F
cere br os pi nal fl ui d
C S R
cli nical st u d y re p ort
C T
c o m p ute d t o m o gra p h y
C T C
circ ulati n g t u m or cells
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 T L s
C y t ot o xic T l ym p h oc y tes 
C T M S
cli nical trial ma na ge me nt s yste m
C tr o u g h
pre dicte d tr o u g h c o nce ntrati o n 
C V
Car di o vasc ular
C # D #
c ycle #, Da y#
D C R
disease c o ntr ol rate
D C T
data c ollecti o n t o ol
Df
defer o xa mi ne
DI LI
dr u g -i n d uce d li ver i nj ur y
D LI
D o n or L y m p h oc y te I nf usi o n
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 R E
disease -relate d e ve nt
D U
dis pe nsa ble u nit
E C
et hics c o m mittee
E C 5 0
c o nce ntrati o n c orres p o n di n g t o 5 0 % of t he ma xi m u m effect
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 M C
e xter nal data m o nit ori n g c o m mittee 
E D P
e x p os ure d uri n g pre g na nc y
E F S
E ve nt -Free S ur vi val
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 0
A b bre vi ati o n
Ter m
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 Trial 
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
FI H
first-i n-h u ma n
FI P
first-i n-patie nt
FI S H
Fl u oresce nt i n sit u h y bri dizati o n
F S H
f ollicle-sti m ulati n g h or m o ne
G C P
G o o d Cli nical Practice
G C S F
gra n ul oc y te c ol o ny -sti m ulati n g fact or
G G T
ga m ma -gl uta m y l tra nsferase
G L P
G o o d La b orat or y  Practice
G U C Y 2c
a nti-G ua n yl yl  Cycl ase 2 C ( G U C Y 2c)/a nti -C D 3 bis pecific Fc 
dia b o d y
G V H D
graft vers us h ost disease
H b A 1c
he m o gl o bi n A 1c
H bc A b
he patitis B c ore a nti b o d y
H bs A g 
he patitis B s urface a nti ge n
H B V
he patitis B vir us
H C V
he patitis C vir us
H C V A b
he patitis C a nti b o d y
H E R
h u ma n e pi der mal gr o wt h fact or rece pt or
H E R 2
h u ma n e pi der mal gr o wt h fact or rece pt or 2
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
In vesti gat or’s B r oc h ure
I C D
i nf or me d c o nse nt d oc u me nt
I C U
I nte nsi ve care u nit
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts 
f or P har mace uticals f or H u ma n Use
I F N
i nterfer o n-ga m ma
I g G
i m m u n o gl o b uli n G
I g G 1
i m m u n o gl o b uli n 1
I g G 4
i m m u n o gl o b uli n 4
I H C
i m m u n o hist oc he mistr y
I L
i nterle u ki n
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 1
A b bre vi ati o n
Ter m
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 a p plicati o n
I N R
i nter nati o nal n or malize d rati o
I P 
i n vesti gati o nal pr o d uct 
ir A E
i m m u ne-relate d a d verse e ve nts
I RB
Instit uti o nal R e vie w B oar d
I R C
i nter nal re vie w c o m mittee
ir P F S
i m m u ne-relate d P F S
I R R
i nf usi o n relate d reacti o n
ir R E CIS T
I m m u ne Relate d Res p o nse Criteria i n S oli d T u m or
I R T
i nteracti ve res p o nse tec h n ol o g y
I S R
injecti o n site reacti o n 
I UD
i ntra uteri ne de vice
I U S
i ntra uteri ne h or m o ne-releasi n g sys te m
I V
intra ve n o us
I W R
i nteracti ve We b-base d res p o nse
K R A S
Kirste n Rat Sarc o ma viral o nc o ge ne
L B B B
left b u n dle bra nc h bl oc k
L D H
lactate de hy d r o ge nase
L F T
li ver f u ncti o n test
L V E F
left ve ntric ular ejecti o n fracti o n
m A b
m o n ocl o nal a nti b o d y
M A B E L
mi ni m u m a ntici pate d bi ol o gical effect le vel
M A C
maj or hist oc o m pati bilit y  c o m ple x
M A D
ma xi m u m a d mi nistere d d ose
M A P
meta -a nal yt ic-pre dicti ve
M b
m i ni b o d y
M H C
maj or hist oc o m pati bilit y  c o m ple x
M D
m ulti ple d ose
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
M F D
ma xi m u m feasi ble d ose
mI T T
m o difie d i nte nt t o treat
M RI
ma g netic res o na nce i ma gi n g
M SI -H
micr osatellite i nsta ble – hi g h
M S S
micr osatellite sta ble
M T D
ma xi m u m t olerate d d ose
m T PI
m o difie d t o xicit y  pr o ba bilit y i nter val
M U G A
m ulti gate d ac q uisiti o n sca n
N/ A
n ot a p plica ble
N A b
ne utralizi n g a nti b o dies
N CI
Nati o nal Ca ncer I nstit ute
NI M P
n o n -i n vesti gati o nal me dici nal pr o d uct
N K
nat ural killer
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 2
A b bre vi ati o n
Ter m
N M C T G
N uclear Me dici ne Cli nical Trial Gr o u p, L L C
N O A E L
n o -o bser ve d -a d verse-effect le vel
N S AI D
n o n ster oi dal a nti-i nfla m mat or y dr u g
N S C L C
n o n -s mall cell l u n g ca ncer
N S G
Fe male N O D -sci d I L-2 R n ull
O R
o bjecti ve res p o nse
O R R
o verall res p o nse rate
O S
o verall s ur vi val
P A C L
Pr ot oc ol A d mi nistrati ve C ha n ge Letter
P B M C
peri p heral bl o o d m o n o n uclear cell
P C D
pri mar y  c o m pleti o n date
P D
p har mac o d y n a mics(s)
P D L -1
pr o gra m me d cell deat h pr otei n -1
P D L -2
pr o gra m me d cell deat h pr otei n -2
P D X
partici pa nt deri ve d xe n o graft 
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 x 
p har mac o ge n o mic(s)
PI
pri nci pal i n vesti gat or
PI B
p o w der i n b ottle
P K
p har mac o ki netic(s)
P R
partial res p o nse
P R E S
P osteri or Re versi ble E nce p hal o pat h y S y n dr o me
P S
perf or ma nce stat us
P T
pr ot hr o m bi n ti me
P V C
pre mat ure ve ntric ular c o ntracti o n/c o m ple x
Q 2 W
e ver y 2 wee ks
Q 4 W
e ver y 4 wee ks
Q D
e ver y da 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)
R ac
acc u m ulati o n rati o
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 F S
Rela pse -Free S ur vi val
R N A
ri b o n ucleic aci d
R O
rece pt or occ u pa nc y
R P 2 D
rec o m me n de d P hase 2 d ose
R R
res p o nse rate
S A E
seri o us a d verse e ve nt
S A P
Statistical A nal y sis Pla n
S C
S u bc uta ne o us(l y)
S D
si n gle d ose
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 3
A b bre vi ati o n
Ter m
S o A
sc he d ule of acti vities
S O P
sta n dar d o perati n g pr oce d ure(s)
S R S D
si n gle refere nce safety d oc u me nt
S U S A R
S us pecte d U ne x pecte d S eri o us A d verse R eacti o n
S U V
sta n dar d u pta ke v al ues
t1/ 2
ter mi nal half-life
T bili
t otal bilir u bi n
T B R
t u m or bac k gr o u n d rati o
T C Rs
t-cell rece pt ors 
TI L
T u m or i nfiltrati n g l y m p h oc y tes 
T M E
t u m or micr oe n vir o n me nt
T N F
t u m or necr osis fact or
T ma x
ti me t o ma xi m u m c o nce ntrati o n
T M D D
Tar get me dicati o n dr u g dis p ositi o n 
T M E
t u m or micr oe n vir o n me nt
T S H
t h yr oi d sti m ulati n g h or m o ne
T T P
ti me t o pr o gressi o n
U C
ur ot helial carci n o ma
U L N
u p per li mit of n or mal
U S
U nite d States
U S PI
U nite d States Pac ka ge I nsert 
U V B
ultra vi olet B
V E G F -A
vasc ular e n d ot helial gr o wt h fact or
Vss
stea d y state v ol u me distri b uti o n 
W B C
w hite bl o o d cell
W B S
w h ole b o d y  sca n
W N L
wit hi n n or mal li mits
W O C B P
w o ma n / w o me n of c hil d beari n g p ote ntial
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 4
1 0. 1 7. A p pe n di x 1 7: J a p a n S pecific M atters
J a p a n p artici p ati o n
a)
S u g geste d C yt o ki ne Rele ase S y n dr o me M a n a ge me nt
T ociliz u ma b is n ot a p pr o ve d i n Ja pa n f or t he treat me nt of C R S ot her t ha n t he e ve nts 
ass ociate d wit h c hi meric a nti ge n rece pt or ( C A R) T cell t hera p y.
b)
C o n diti o n t o be disc h ar ge d:
W he n a partic i pa nt is disc har ge d fr o m t he h os pital d uri n g t he D L T e val uati o n peri o d, t he 
f oll o wi n g c o n diti o ns (tests, me dical e xa mi nati o ns, etc.) s h o ul d be perf or me d o n t he da y of 
t he sc he d ule d disc har ge b y t he i n vesti gat ors, a n d t he pr o priety of disc har ge s h o ul d be 
de ter mi ne d. T he tests/ me dical e xa mi nati o ns w hic h are nee de d t o c o nfir m t he partici pa nt’s 
stat us will be c o n d ucte d per cli nical practice i n t he st u d y site as a p pr o priate.

T here are n o c urre nt cli nicall y  si g nifica nt a d verse or si de effects, i ncl u di n g C R S, or 
me dical reas o ns t hat re q uire m o nit ori n g i n a h os pital setti n g.

If a cli nicall y si g nifica nt a d verse or si de effect has occ urre d or c o nti n ues t o be 
prese nt, t he i n vesti gat or will deter mi ne t hat t he e ve nt is ma na gea ble b y a p pr o priate 
treat me nt or pr o p hyl a xis i n a n o ut of t he h os pital setti n g.

O verall p h ys ical c o n diti o n is sta ble a n d acce pta ble.

I n case of e mer ge nc y, t he partici pa nt ma y ret ur n t o t he cli nical st u d y site or ot her 
me dical i nstit uti o n. If partici pa nts g o t o a me dical i nstit uti o n ot her t ha n t he cli nical 
st u d y site, t he cli nical st u d y site as ks t hat t he partici pa nts c o ntact t he st u d y site, st u d y 
i n vesti gat or a n d t he d oct or at t he me dical i nstit uti o n w h o will c o m m u nicate t o disc uss 
a p pr o priate treat me nts. A st u d y  site kee ps fra me w or k t o rea d y f or e merge nc y  
sit uati o ns t hat is a vaila ble e ve n d uri n g ni g hts a n d h oli da ys, a n d t he s p o ns or will 
e ns ure t hat t he selecte d st u d y  site will t h or o u g hl y f oll o w all partici pa nts acc or di n g t o 
st u d y pr oce d ures.
c)
Secti o n 8. 7 - Ge netics a n d Secti o n 8. 8 – Bi o m ar kers:
Gi ve n t he ge netic testi n g is f or e x pl orat or y  p ur p oses o nl y a n d f oll o wi n g Pfizer pr ocess, t here 
is n o e x pectati o n t o discl ose t hese ge netic testi n g res ults t o t he st u d y partici pa nts, at a n y 
ti me.
A st u d y  partici pa nt’s partici pati o n i n a cli nical st u d y s hall n ot be c o n diti o ne d o n his or her 
i nf or me d c o nse nt f or t he use of bi os peci me ns that is n ot relate d t o a cli nical e n d p oi nt, t he 
dr u g bei n g i n vesti gate d i n t he trial, or t he i ncl usi o n/e xcl usi o n criteria f or t he st u d y .
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 5
1 0. 1 8. A p pe n di x 1 8: 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 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.
T hese pla n ne d c ha n ges are bei n g i m ple me nte d i m me diatel y  i n res p o nse t o t he C O VI D- 1 9 
pa n de mic a n d are pla n ne d f or t he d urati o n of t he C O VI D- 1 9 pa n de mic. T his a p plies t o 
partici pa nts w h o are q uara nti ne d or wis h t o n ot atte n d sc he d ule d visits or perf or m st u d y  
pr oce d ures or tests o n site d ue t o safet y  c o ncer ns a n d/ or l ocal g o ver n me nt healt h or healt h 
i nstit ute s u g gesti o ns a n d/ or g ui deli nes iss ue d i n a n eff ort t o li mit e x p os ure of v ul nera ble 
p o p ulati o ns t o t he vir us.
Use of t hese alter nati ve st u d y  meas ures are e x pected 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 n y q uara nti nes a n d tra vel ba ns/a d vis ories).
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 partici pa 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 # 6: “ Acti ve a n d cli nicall y  si g nifica nt 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, 
wit h p ositi ve ser ol o g y , t h ose partici pa nts wit h a ne gati ve viral l oa d are p otentiall y  eli gi ble 
pr o vi de d t he ot her e ntr y  criteria are met.
Tele he alt h Visits
St u d y  partici pa nts w h o ca n atte n d sc he d ule d st u d y visits o n site a n d c o m plete all st u d y 
pr oce d ures as descri be d i n t he pr ot oc ol per t he Sc he d ule of t he Acti vities s h o ul d d o s o; all 
ot her partici pa nts s h o ul d ma ke e ver y  eff ort t o partici pate i n st u d y visits b y tele p h o ne via a 
tele healt h visit. Vi de o c o ntact ca n be use d if a vaila ble a n d per mitte d b y l ocal re g ulati o ns.
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 t he 
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 a n y A Es a n d S A Es since t he last c o ntact. Refer t o Secti o n 8. 1 .

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.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 6

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 of t h is a p pe n di x re gar di n g pre g na nc y tests.

Re vie w of p h ys ical sy m pt o ms i n place of ma n date d p h y sical e xa ms
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 ny c ha n ge i n t heir 
healt h stat us.
Alter n ati ve F acilities f or S afet y Assess me nts
If t he st u dy partici pa nt is u na ble t o visit t he st u d y  site, pr ot oc ol s pecifie d safet y la b orat or y 
tests a n d/ or t u m or assess me nts ma y alter nati vely be perf or me d at a n alter nati ve l ocal 
la b orat or y or facility, w here all o wa ble b y la w or l ocal g ui da nce. I n t hese cases: 

L ocal la b orat or y  refere nce ra n ges nee d t o be d oc u me nte d a n d s u b mitte d t o st u d y 
tea m. 

Rec or ds of l ocal la b orat or y  tests, la b accre ditati o n, a n d re p orts of t u m or assessme nts 
s h o ul d be retrie ve d a n d d oc u me nte d i n site me dical rec or ds.

Rele va nt data fr o m l ocal la b orat ories a n d testi n g facilities are t o be e ntere d i n t he 
C R F.

Visits m ust be c o n d ucte d b y  staff w h o are a p pr o priatel y q ualifie d a n d trai ne d o n t he 
st u d y pr ot oc ol

A n y  res ults t hat are c o nsi dere d cli nicall y si g nifica nt m ust be re p orte d i n a ti mel y 
ma n ner a n d as directe d i n t he pr ot oc ol.
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. At t he discreti o n of 
t he treati n g p hys icia n h o me bl o o d dra ws ma y be per mitte d. All safety la b orat or y  tests
o utli ne d i n t his pr ot oc ol ca n be d o ne at a l ocal la b orat or y .
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 
certificati 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 ocal 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 I U/ m L ma y be 
use d b y  t he p artici 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 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 7
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.
A n y  res ults t hat are c o nsi dere d cli nicall y si g nifica nt m ust be re p orte d i n a ti mel y ma n ner a n d 
as directe d i n t he pr ot oc ol.
I m a gi n g a n d 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 pla n ne d or u n pla n ne d i ma gi n g 
assess me nts t he partici pa nt ma y  visit a n alter nati ve facility t o ha ve t hese assess me nts 
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 a n d a n y 
a b n or malities, i nclu di n g pr o gressi o n of disease m ust be re p orte d t o t he Pfizer cli nical ti me i n 
a ti mel y ma n ner a n d as directe d i n t he pr ot oc ol.
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.
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.
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 P F - 0 7 0 6 2 1 1 9, P F-0 6 8 0 1 5 9 1, a n d 
Be vaciz u ma b -Pfizer, 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 uth orit y - a p pr o ve d test) or 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, st u d y  i nter ve nti o n s h o ul d 
be dela y e 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 nten de d t o all o w t he 
res ol uti o n of s ym 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 t his pr ot oc ol 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.
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 at t he discreti o n of t he treati n g p h ys icia n a n d i n c o ns ultati o n wit h t he S P O N S O R. 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 8
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(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. 2 . 

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 d verse E ve nts a n d Seri o us A d verse E ve nts
St u d y  treat me nt s h o ul d c o nti n ue u nless t he i n vesti gat or/treati n g p h ysicia n is c o ncer ne d a b o ut 
t he safety of t he partici pa nt , i n w hic h case te m p orar y or per ma ne nt disc o nti n uati o n ma y be 
re q uire d.
It is rec o m me n de d that 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 0. 8 P atie nt D at a M o nit ori n g a n d Pr ot oc ol De vi ati o ns 
E ver y  eff ort s h o ul d be ma de t o e ns ure t hat re q uire d pr ot oc ol tests a n d pr oce dures are 
c o m plete d as descri be d wit h t he pr ot oc ol. H o we ver, t he circ u msta nces ar o u n d t he o n g oi n g 
C O VI D -1 9 pa n de mic ma y  ma ke it u nfeasi ble t o perf or m s o me of t he tests a n d pr oce d ures. I n 
t hese cases, t he i n vesti gat or m ust ta ke all of t he necessar y ste ps t o e ns ure t he safet y a n d 
well bei n g of t he st u d y partici pa nt. W he n a re q uire d pr ot oc ol test or pr oce d ure ca n n ot be 
perf or me d, t he i n vesti gat or will pr o m ptl y  d oc u me nt t he reas o n f or t he misse d test or 
pr oce d ure a n d a n y c orrecti ve a n d pre ve nti ve acti o ns t he y ha v e ta ke n t o e ns ure t hat re q uire d 
pr ocesses will be 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.
If t he st u dy partici pa nt is u na ble t o visit t he st u d y site, re q uire d pr ot oc ol pr oce d ures t hat ca n 
be pe rf or me d t o t he best of st u d y site’s a bilit y via tele p h o ne c o ntact or vi de o ( w here all o we d) 
s h o ul d be c o nsi dere d, if i n t he o pi ni o n of t he i n vesti gat or it is t he safest a p pr oac h, e g, 
e val uati o n of p h ys ical sy m pt o ms i n place of pr ot oc ol ma n date d p h ys ical e xami nati o ns, 
re vie w of a d verse e ve nts or seri o us a d verse e ve nts, d osi n g c o m plia nce, c o ntrace pti o n c hec k, 
a n d c o nc o mita nt me dicati o n c hec ks, etc. St u d y partici pa nts s h o ul d ma ke e ver y  atte m pt t o 
c o nti n ue t o mai ntai n a d osi n g diar y ( w here a p pr o priate) a n d ma y se n d t his t o t he site 
electr o nicall y or via mail.
Patie nt data m o nit ori n g will c o nti n ue wit h o ut i nterr u pti o n. Re m ote data m o nit ori n g will be 
per mitte d, w here ver p ossi ble. T he C R A will c o nti n ue m o nit ori n g data i n a n o n g oi n g ma n ner 
via re m ote access f oll o wi n g all i nstit uti o nal pr ocesses, if a p plica ble.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6 9
A n y  ot her de viati o ns t o t he pr ot oc ol, e xce pt f or t hese a p pr o ve d m o dificati o ns, m ust be 
d oc u me nte d as pr ot oc ol de viati o ns, a n d if relate d t o t he pa n de mic, t he reas o n s h o ul d clearl y 
state “ C O VI D-1 9”. T hese are n ot i m me diately re q uire d t o be re p orte d t o healt h a ut h orities or 
I RB/ E Cs u nless re q ueste d l ocall y .
T he i m pact of C O VI D -1 9 o n pr ot oc ol visits a n d st u d y  tests or pr oce d ures a n d ass ociate d 
ti mefra mes s h o ul d be re p orte d, prefera bl y, o n a case re p ort f or m ( C R F) if at all p ossi ble. F or 
partici pa nt disc o nti n uati o n re p orti n g i n t he C R F: Please select t he m ost a p pr o priate stat us f or 
disc o nti n uati o n. I f t he disc o nti n uati o n is ass ociate d wit h t he c urre nt C O VI D-1 9 pa n de mic, 
e nter “ C O VI D -1 9” i n t he “ S pecif y  Stat us” fiel d.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 0
1 0. 1 9. P E T I ma gi n g S u b st u d y wit h 8 9Zr -Df -I A B 2 2 M 2 C
1 0. 1 9. 1. O ver all desi g n a n d Scie ntific R ati o n al f or S u bs t u d y 
T his s u bst u d y  will e val uate C D 8 P E T tracer u pta ke, at b aseli ne a n d o n- treat me nt, i n t u m or 
lesi o ns a n d refere nce tiss ues (i ncl u di n g T-cell ric h tiss ues a n d t h ose e x pecte d t o e x press 
G U C Y 2c) wit h t he ai m t o meas ure p ote ntial c ha n ge i n C D 8 P E T tracer u pta ke i n t u m or 
lesi o ns bet wee n b aseli ne a n d o n -treat me nt a n d i n refere nce tiss ues.
T he P E T i ma gi n g s u bst u d y will be o pe ne d i nitiall y at a s ubset of U S sites partici pati n g i n 
St u d y C 3 8 6 1 0 0 1 , w hic h ha ve bee n q ualifie d f or use wit h 8 9Zr -Df -I AB 2 2 M 2 C.  
Site s q ualifie d f or use m ust ha ve lice nses w hic h i ncl u de ha n dli n g of Zirc o ni u m - 8 9 a n d 
a p pr o priate pr oce d ures i n place f or ha n dli n g of sa m ples t hat are c o nsi dere d ra di oacti ve . T his 
i nclu des pr ocessi n g a n d a nal ys is of bl o o d sa m ples t hat are c ollecte d wit hi n 3 0 da y s of C D 8 
P E T tracer i nf usi o n.
St u d y  p o p ulati o n: A p pr o xi matel y  1 0 t o 1 5 partici pa nts e nr olle d acr oss t he st u d y ( prefera bly 
t h ose e nr olle d i n t he ma n dat or y  bi o psy c o h orts i n P art 1 a n d P art 2) will als o be eli gi ble f or 
e nr oll me nt i n t he P E T i ma gi n g s u bst u dy wit h t he C D 8 T cell s pecific 8 9Zr -Df -I AB 2 2 M 2 C 
P E T tracer ( C D 8 P E T tracer).
As part of its mec ha nis m of acti o n, P F - 0 7 0 6 2 1 1 9 is e x pecte d t o i ncrease T-cell i nfiltrati o n 
selecti vely i nt o t u m ors e x pressi n g G U C Y 2c.  C D 8 P E T tracer st u dies are i nte n de d t o e na ble 
meas ure me nt of C D 8 + T cells t hr o u g h o ut t he b o d y, per mitti n g t he c o m paris o n of C D 8 + T -
cell le vels i n t u m ors (bef ore a n d after a d mi nistrati o n of P F - 0 7 0 6 2 1 1 9) wit h C D 8 T cell 
distri b uti o n i n refere nce tiss ues.  A d diti o nall y , C D 8 P E T tracer met h o d ol o g y  i ma ges m ulti ple 
t u m or lesi o ns si m ulta ne o usl y i n c o m paris o n t o paire d bi o ps y pr oced ures w hic h are us uall y  
li mite d t o a si n gle accessi ble lesi o n.   C D 8 P E T tracer st u dies ma y t heref ore c o ntri b ute 
t o war d a br oa der u n dersta n di n g of t he P D effects of P F -0 7 0 6 2 1 1 9 al o ne a n d p ote ntiall y  i n 
c o m bi nati o n wit h ot her a ge nts.  T his i nf or mati o n is i nte n de d t o c haracterize t he mec ha nis m 
of acti o n P F - 0 7 0 6 2 1 1 9, i de ntif y partici pa nts w h o are m ost li kel y t o be nefit fr o m treat me nt, 
a n d i de ntif y p ote ntial resista nce mec ha nis ms t o P F -0 7 0 6 2 1 1 9 al o ne a n d i n c o m bi nati o n wit h 
ot her a ge nts.
T he C D 8 P E T tracer is a ~ 8 0 k Da mi ni b o d y  ( M b) wit h hi g h affi nit y ( bi n di n g E C5 0 = 0. 4 n M) 
f or t he C D 8 glyc o pr otei n t hat is c o nj u gate d wit h Df a n d ra di ola bele d wit h 8 9Zr f or i ma gi n g 
C D 8 + T cells i n h u ma ns. It bi n ds t o b ot h C D 8 α α a n d C D 8 α β a n d will t heref ore bi n d t o 
mat ure T cells, de vel o pi n g t h y m o c y tes, T C R α β -e x pressi n g g ut i ntrae pit helial T cells, s o me 
γ δ T cells a n d s o me N K a n d de n dritic cells. T he M b desi g n of t he C D 8 P E T tracer is 
i nte n de d t o a d dress t he li mitati o ns of m olec ular i ma gi n g usi n g i ntact m o n ocl o nal a nti b o dies
( pr ol o n ge d bl o o d circ ulati o n, si g nifica nt bac k gr o u n d si g nal) a n d t o pre ve nt acti vati o n of 
i m m u ne cell Fc effect or f u ncti o ns. T he s maller size a n d i na bilit y  of t he M b t o i nteract wit h 
t he Fc R a n d t he ne o natal Fc rec ycli n g rece pt or res ults i n a relati vel y  i nert i ma gi n g a ge nt 
wit h ra pi d cleara nce. I A B 2 2 M 2 C was e n gi neere d fr o m t he h u ma nize d hea v y  a n d li g ht c hai n 
se q ue nces of t he m uri ne O K T 8 a nti b o d y  t hat tar gets h u man C D 8.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 1
T he C D 8 P E T tracer has c o m plete d a P hase 1 st u d y ( N C T 0 3 1 0 7 6 6 3) a n d is c urre ntly bei n g 
e val uate d i n a P hase 2 , o pe n -la bel st u d y (N C T 0 3 8 0 2 1 2 3 ) i n partici pa nts wit h select a d va nce d 
or metastatic s oli d t u m ors selecte d t o recei ve sta n dar d of care i m m u n ot hera p y o nly. T his 
st u d y is e val uat i n g t he safet y of re peat d oses of t he C D 8 P E T tracer a n d ai mi n g t o assess a n d 
q ua ntif y  a n y detecta ble c ha n ges i n u pta ke bet wee n b aseli ne a n d o n -treat me nt.  Interi m res ults 
fr o m t his st u d y ha ve esta blis he d t he a bility of t he C D 8 P E T tracer t o detect C D 8 + T cells i n 
t u m ors a n d c o nfir me d t he safet y pr ofile of t he C D 8 P E T tracer after re peat d oses. A d diti o nal 
i nf or mati o n relate d t o safet y a n d i ma gi n g res ults is prese nte d i n t he 8 9Zr -Df -I AB 2 2 M 2 C 
i n vesti gat or br oc h ure.  T h ese data ha ve esta blis he d t he p ote ntial utilit y  of usi n g t he C D 8 P E T 
tracer f or partici pa nts i n St u d y C 3 8 6 1 0 0 1 .
1 0. 1 9. 2. Be nefit /Ris k Asse ssme nt
P E T Sc a ns wit h 8 9 Zr -Df -I A B 2 2 M 2 C
Base d o n t he a vaila ble data, t he pri nci pal ris k is e x p os ure t o i o nizi n g ra diati o n release d b y 
8 9Zr . Ad diti o nall y , t here is l o w li keli h o o d t hat t he C D 8 P E T tracer m a y be ass ociate d wit h a n 
a d verse reacti o n or i m m u n o ge nic res p o nse. T he n o ncli nical data ha ve de m o nstrate d t hat 
I AB 2 2 M 2 C a n d Df- I AB 2 2 M 2 C ha d n o meas ura ble effects o n T cell pr oliferati o n/ acti vati o n 
or c y t o ki ne release. As of 0 4 A u g u st 2 0 2 1 , 8 8 patie nts ha ve recei ve d t he C D 8 P E T t racer. 
M o nit ori n g of partici pa nts is rec o m me n de d. T he p ote ntial ris ks after i nf usi o n wit h t he C D 8 
P E T tracer i ncl u de i nf usi o n site reacti o ns of re d ness, itc hi n g a n d pai n, aller gic reacti o n 
(i ncl u di n g a na p hyl a xis), ki d ne y /li ver/res pirat or y fail ure, t hr o m b oc yt o pe nia, art hritis, a n d/ or 
h y p ote nsi o n. I nserti o n of I V cat heters f or i nf usi o n s a n d bl o o d dra ws m a y  ca use mi n or pai n, 
br uisi n g, a n d/ or i nfecti o n at t he i nf usi o n site.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 2
1 0. 1 9. 3. P E T I ma gi n g S u b st u d y O bjecti ves
I n a d diti o n t o t he c ore st u d y o bjecti ves (Secti o n 3 ), t he P E T i ma gi n g su b st u d y
(Secti o n 1 0. 1 9 ) will i ncl u de t he f oll o wi n g e x pl orat or y o bjecti ves:
O bjecti ves:
Terti ar y/ E x pl or at or y
E n d p oi nts:
Terti ar y/ E x pl or at or y
• Meas ure p ote ntial c ha n ge i n C D 8 P E T tracer u pta ke 
a n d bi o distri b uti o n i n t u m or lesi o ns a n d refere nce 
tiss ues, i ncl u di n g C D 8 + T cell ric h refere nce tiss ues 
bet w ee n baseli ne a n d o n- treat me nt wit h 
P F -0 7 0 6 2 1 1 9 .
• Meas ure p ote ntial c ha n ges i n C D 8 P E T tracer 
u pta ke o n baseli ne a n d o n -treat me nt P E T sca ns 
c o m pare d t o c ha n ge i n C D 8 + T cells i n t u m or 
lesi o ns b y I H C if t he sa me lesi o n was bi o psie d at 
b aseli ne a n d o n-t reat me nt visits.
• Ex pl ore t he q ualitati ve a n d q ua ntitati ve C D 8 P E T 
tracer meas ure me nts wit h cli nical o utc o mes of 
P F -0 7 0 6 2 1 1 9 treat me nt.
• Eval uate t he ass ociati o n of  C D 8 P E T tracer u pta ke 
wit h i m m u ne i nfiltrates a n d ot her m olec ular 
bi o mar kers (s uc h as C D 4, C D 8, P D -1 a n d P D -L 1) .
Bi o ps y lesi o n :  S U V meas ure me nt at baseli ne vs 
S U V meas ure me nt f oll o wi n g treat me nt .
Tar get lesi o n :  S U V meas ure me nt at baseli ne vs 
S U V meas ure me nt
f oll o wi n g treat me nt.
N o ntar get lesi o ns (if a p plica ble) :  S U V meas ure me nt
at baseli ne vs S U V meas ure me nt f oll o wi n g 
treat me nt.
Refere nce tiss ues (i ncl u di n g b ut n ot li mite d t o 
n or m al c ol o n a n d ot her G U C Y 2c e x pressi n g tiss ues 
w here a p plica ble) :  S U V meas ure me nt at baseli ne vs 
S U V meas ure me nt f oll o wi n g treat me nt
C ha n ge i n S U V meas ure me nt at baseli ne vs cli nical 
bi o mar ker or ra di o gra p hic res p o nses
S U V = sta n dar d u pta ke val ues 
1 0. 1 9. 4. P E T I ma gi n g S u b st u d y Desi g n 
Partici pa nts i n t his s u bst u d y will ha ve 2 pla n ne d i ma gi n g sessi o ns:
1.
T he f irst i ma gi n g sessi o n will ta ke place pri or t o t hera py ( P E T Baseli ne ).  C D 8 P E T 
tracer will be a d mi nistere d wit h w h ole b o d y  P E T/ C T i ma gi n g ac q uire d 2 4 hr ( ± 3 hr) 
later a n d 7 t o 9 da y s pri or t o t he i nitiati o n of treat me nt wit h P F - 0 7 0 6 2 1 1 9.
2.
T he s ec o n d i ma gi n g sessi o n will ta ke place after recei vi n g t he first 3 d oses of 
P F - 0 7 0 6 2 1 1 9, o n C 2 D 8 , w hic h will be a p pr o xi matel y 5 t o 6 wee ks after i nitiati o n of 
treat me nt. C D 8 P E T tracer i ma gi n g a ge nt will be a d mi nistere d o n C 2 D 8 a n d w h ole 
b o d y P E T/ C T i ma gi n g ac q uire d 2 4 hr ( ± 3 hr) later.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 3
3.
A n a d diti o nal t hir d o pti o nal i ma gi n g sessi o n is i ncl u de d i n C y cle 3 or later. T he 
o pti o nal t hir d i ma gi n g sessi o n ma y  o nly be perf or me d after disc ussi o n a n d a gree me nt 
bet wee n t he i n vesti gat or a n d s p o ns or .
Partici pa nts i n t he P E T i ma gi n g s u bst u d y s h o ul d be e nr olle d , if p ossi ble, i n c o h orts re q uiri n g 
ma n dat or y  pretreat me nt a n d on -treat me nt bi o psies a n d will ha ve 2 pla n ne d bi o ps y  
pr oce d ures t o c oi nci de wit h P E T i ma gi n g sessi o ns.
1.
Baseli ne d e n o v o bi o ps y c ollecti o ns will occ ur after t he first i nf usi o n of t he C D 8 P E T 
tracer a n d its ass ociate d P E T sca n.
2.
O n treat me nt bi o ps y c ollecti o n will o cc ur wit hi n 1 wee k after t he sec o n d i nf usi o n of 
t he C D 8 P E T tracer a n d its ass ociate d P E T sca n.
I ncl usi o n Criteri a 
1.
Part ici pa nts m ust meet all eli gi bilit y criteria f or e nr oll me nt i n St u d y C 3 8 6 1 0 0 1 pri or 
t o bei n g e nr olle d i n t he P E T i ma gi n g s u bst u dy a n d i nitiati o n of pr oce d ures.
2.
Partici pa nts s h o ul d ha ve a t u m or a me na ble t o bi o ps y  a n d c o nse nt t o t hese pla n ne d 
bi o ps y  pr oce d ures. Partici pa nts wit h o ut a t u m or a me na ble t o bi o ps y  m ust be 
a p pr o ve d b y t he s p o ns or.
E xcl usi o n Criteri a
1.
Partici pa nts are e xcl u de d fr o m t he P E T i ma gi n g s u bst u d y  if a ny of t he e xcl usi o n 
criteria are met f or St u d y C 3 8 6 1 0 0 1.
2.
Partici pa nts f or w h o m t he o nl y  t u m or a me na ble t o bi o ps y is als o a tar get lesi o n.
3.
Partici pa nts w h o ha ve pre vi o usl y  recei ve d C D 8 P E T tracers or ot her 8 9Zr la bele d P E T 
tracers i n t he pri or 4 5 da y s.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 4
1 0. 1 9. 5. C D 8 P E T Tr acer I m a gi n g Pr oce d ures :
T a ble 2 4 . O ver vie w of P E T I m a gi n g S u bst u d y Visits
P E T I m a gi n g 
Pr oce d ures
B aseli ne Sc a n / Bi o ps y
St u d y 
St art
O n -Tre at m e nt Sc a ns / Bi o ps y
Visit 1 
Visit 2
Visit 3
C 1 D 1
Visit 4
Visit 5
Visit 6
D a y -7 t o -
9
fr o m 
C 1 D 1
2 4 hr 
( ± 3 hr) 
p ost 
i nf usi o n
P ost C D 8 
Tracer 
C T/ P E T 
sca n pri or 
t o C 1 D 1 
C 2 D 8
( ± 2 
da ys)
2 4 hr
( ± 3 hr) 
p ost 
i nf usi o n
C 2 D 1 5
( ±7 da ys ) 
p ost C D 8 
Tracer 
C T/ P E T Sca n
Vit al Si g ns 1
( bef ore a n d after 
i nf usi o n)
X
X
C D 8 P E T Tr acer 
inf usi o n
X
X
C D 8 P E T Tr acer
P E T/ C T sc a n 2
X
X
T u m or Bi o ps y 3
X
X
1 . Vital si g ns assesse d 1 5 ( ± 5) mi n utes pri or t o i nf usi o n a n d wit hi n 6 0 mi n utes after i nf usi o n of t he C D 8 P E T 
tracer.
2 . T u m or assess me nt sca ns sc he d ule d per pr ot oc ol f or e val uati o n of res p o nse per R E CI S T criteria are t o be 
c ollecte d se paratel y fr o m C D 8 P E T tracer s u bst u d y sca ns .
3 . T u m or bi o psies ca n be c ollecte d o n t he sa me da y as i ma gi n g as l o n g as t he y occ ur after t he P E T/ C T sca n
C D 8 P E T tr acer i nf usi o n:
D osi n g i nf or mati o n:
T he C D 8 P E T tracer is a n ~ 8 0 k Da M b wit h hi g h affi nit y  t o C D 8 glyc o pr otei n ( bi n di n g 
E C 5 0 = 0. 4 n M) t hat is c o nj u gate d wit h D f a n d ra di ola bele d wit h 8 9Zr f or i ma gi n g C D 8 + 
T- cells i n h u ma ns. 
A d ose of 1. 0 ( ± 2 0 %) m Ci of C D 8 P E T tracer as 1. 5 m g of A PI will be a d mi nistere d I V o ver 
5 t o 1 0 mi n utes, wit hi n 1 w ee k pri or t o t he i nitiati o n of t hera py wit h P F -0 7 0 6 2 1 1 9 , a n d 
a p pr o xi matel y 5 wee ks after start of treat me nt wit h P F- 0 7 0 6 2 1 1 9.
Dis pe nsati o n of C D 8 P E T tracer
T he C D 8 P E T tracer will be deli ve re d fr o m a ce ntral ma n ufact uri n g facilit y t o t he 
i n vesti gati o nal site’s ra di o p har mac y or N uclear Me dici ne De part me nt. U p o n recei pt, 
q ualifie d pers o n nel will e ns ure t hat t he st u d y  dr u g has bee n deli vere d i n g o o d c o n diti o n, 
i n ve nt orie d, st ore d pr o perl y, la bele d a n d dis pe nse d i n c o m plia nce wit h t he p har mac y ma n ual, 
all re g ulat or y a ge ncies a n d per t he i n vesti gat or’s prescri pti o n or der.
T he 8 9Zr d ose will be meas ure d b y t he q ualifie d pers o n nel i n a d ose cali brat or pri or t o 
dis pe nsi n g. T he n t he s yri n ge will be pl ace d i n a s hiel de d carrier al o n g wit h a desi g nate d I V 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 5
i nf usi o n p u m p f or ra di oacti ve i nf usi o n a n d a d mi nistrati o n. After d ose a d mi nistrati o n, t he 
q ualifie d pers o n nel will ret ur n t he s yri n ge f or resi d ual meas ure me nt b y t he q ualifie d 
pers o n nel (s uc h as t he n uc lear me dici ne tec h n ol o gist) at t he site. Meas ure d ra di oacti vit y 
val ues a n d ti mes of meas ure me nt will be d oc u me nte d, as well as t he t otal i njecte d v ol u me.
Re g ulat or y  a ge ncies re q uire acc o u nti n g f or t he dis p ositi o n of all i n vesti gati o nal dr u gs 
recei ve d by ea c h cli nical site. Inf or mati o n o n dr u g dis p ositi o n re q uire d b y  la w c o nsists of t he 
date recei ve d, date dis pe nse d, q ua ntit y  dis pe nse d, a n d t he partici pa nt i de ntificati o n n u m ber t o 
w h o m t he dr u g was dis pe nse d. T he I n vesti gat or is res p o nsi ble f or acc o u nti n g f o r all u n use d 
st u d y dr u g a n d destr oyi n g all use d st u d y  dr u g c o ntai ners i n c o m plia nce wit h t he 
Ra di o p har mac y  M a n ual.
I nf usi o n of C D 8 P E T tracer
T he dis pe nse d d ose will be i nf use d u n der t he s u per visi o n of a q ualifie d n uclear me dici ne 
pers o n nel as a n I V i nf usi o n wit h a n i nf usi o n p u m p o ver n o less t ha n 5 mi n utes f oll o we d b y a 
sali ne fl us h. T he t otal i nf usi o n ti me s h o ul d be bet wee n 5 a n d 1 0 mi n utes. V ital si g ns will be 
assesse d 1 5 ( ± 5) mi n utes pri or t o i nf usi o n a n d wit hi n 6 0 mi n utes after i nf usi o n of t he C D 8 
P E T tracer.
Pre me dicati o n (f or e xa m ple, wit h aceta mi n o p he n a n d di p he n h y dra mi ne) is n ot re q uire d b ut 
ma y  be a d mi nistere d at t he discreti o n of t he i n vesti gat or a p pr o xi matel y 1 h o ur pri or t o 
i nf usi o n of t he C D 8 P E T tracer.
8 9Zr -Df -I A B 2 2 M 2 C P E T/ C T sc a n:
P E T/ C T sca n ner vali dati o n:
I n a n eff ort t o ge nerate t he m ost acc urate a n d c o nsiste nt i ma gi n g data acr oss all partici pati n g 
i n vesti gati ve sites, t o s u p p ort t he data c ollecti o n a n d a nalys is f or t his cli nical st u d y, t he 
S p o ns or is c o ntracti n g wit h t he N uclear Me dicine Cli nical Trial Gr o u p, L L C ( N M C T G) t o 
c o n d uct t he vali dati o n of P E T/ C T sca n ners at eac h partici pati n g site t hat will be use d i n t his 
st u d y.
T he N M C T G will pr o vi de a p ha nt o m al o n g wit h detaile d i nstr ucti o ns of t he P E T/ C T 
vali dati o n pr oce d ures o n h o w t o fi ll a n d sca n t he p ha nt o m a n d c o or di nate deli ver y of a d ose 
of 8 9Zr t o t he site. Eac h P E T/ C T sca n ner i nte n de d f or use i n t his cli nical st u d y will be 
vali date d b y t he N M C T G. O nce t he vali dati o n is c o m plete d, t he site will s u b mit t he data t o 
t he N M C T G f or a nalys is. T he site will st ore t he p ha nt o m i n a sec ure, dr y area f or 3 3 d a y s 
( u ntil t he ra di oacti vit y has deca y e d t o a n u n detecta ble le vel) bef ore tra ns p orti n g bac k t o t he 
N M C T G.
U p o n c o m pleti o n of t he P E T/ C T sca n ner vali dati o n, t he N M C T G will pr o vi de a vali dat i o n 
certificate a n d t he setti n g para meters s pecific t o t he vali date d sca n ner t hat s h o ul d be sa ve d 
i nt o t he site’s sca n ner pr ot oc ol f or t his cli nical trial bef ore  i ma gi n g t he first e nr olle d 
partici pa nt . It is re q uire d t hat sites o nl y use N M C T G-vali date d P E T/ C T sca n ner(s) , wit h t he 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 6
setti n g para meters ge nerate d fr o m t he p ha nt o m-vali dati o n pr oce d ure , t o i ma ge partici pa nts 
e nr olle d i n t his trial as per pr ot oc ol.
Pri or P E T/ C T sca n ner vali dati o n b y  N M C T G f or use wit h t he C D 8 P E T tracer is acce pta ble 
f or use of a P E T/ C T sca n ner i n t his trial as l o n g as P E T/ C T sca ns ta ke place pri or t o 
e x pirati o n of sca n ner certificati o n.
P E T/ C T Sca ns:
8 9Zr -Df -I AB 2 2 M 2 C ( C D 8 P E T Tracer) P E T / C T sca n i ma ges m ust o nl y  be ac q uire d o n 
P E T/ C T sca n ners t hat ha ve bee n a p pr o ve d b y t he s p o ns or. T he S p o ns or m ust be c o ntacte d 
f or per missi o n t o use alter nate sca n ners i n case of e q ui p me nt fail ure a n d/ or maj or e q ui p me nt 
u p gra des or re place me nt. Ac q uisiti o n a n d rec o nstr ucti o n para meters s h o ul d be o btai ne d 
acc or di n g t o t he rec o m me n dati o n pr o vi de d t o eac h site base d u p o n p ha nt o m vali dati o n of t he 
sca n ner a n d s h o ul d be o btai ne d i n List M o de, w he ne ver p ossi ble, t o all o w f or virt ual 
ra di oacti ve d ose rec o nstr ucti o n at a later date.
Sca ns are prefera b l y w h ole b o d y sca ns fr o m t he base of t he s k ull t hr o u g h u p per-t hi g hs 
(e nc o m passi n g t he pel vis). A d diti o nal areas of k n o w n or s us pecte d disease s h o ul d be 
o btai ne d (if t he y  are o utsi de of t his area) at e ver y sca n visit usi n g ac q uisiti o n setti n gs 
o pti mize d f or 8 9Zr i ma gi n g. Please refer t o t he i ma gi n g ma n ual re gar di n g partici pa nt
pre parati o n, sca n ni n g ti mes per be d p ositi o n, 8 9Zr -o pti mizati o n, ac q uisiti o n a n d 
rec o nstr ucti o n para meters, slice t hic k ness, a n d ot her para meters as well as t he i nstr ucti o ns f or 
h o w t o s u b mit i ma ges f or ce ntral re vie w.
P E T/ C T sca ns as part of t he C D 8 P E T tracer st u d y ma y  be c ollecte d f or ce ntral re vie w. 
A d diti o nall y , baseli ne a n d t u m or assess me nt sca ns sc he d ule d per pr ot oc ol f or e val uati o n per 
R E CI S T criteria s h o ul d be c ollecte d se parat el y fr o m C D 8 P E T tracer s u bst u d y sca ns a n d 
s h o ul d be perf or me d i n acc or da nce wit h i nstit uti o nal practices.
T u m or Bi o ps ies:
Pretreat me nt a n d o n -treat me nt de n o v o t u m or bi o psies s h o ul d be c ollecte d as descri be d i n 
Bi o mar ker Secti o n 8. 8. 2 a n d t he La b orat or y Ma n ual wit h t he f oll o wi n g a d diti o nal 
re q uire me nts:

Pretreat me nt de n o v o t u m or bi o psies m ust be c ollecte d at least 2 4 hr after C D 8 P E T 
tracer i nf usi o n a n d after t he ass ociate d baseli ne P E T/ C T sca n. Bi o psies s h o ul d n ot be 
c ollecte d bef ore C D 8 P E T tracer i nf usi o n. Pretreat me nt t u m or bi o psies m ust als o be 
c ollecte d pri or t o treat me nt wit h P F - 0 7 0 6 2 1 1 9.

O n -treat me nt bi o psies are sc he d ule d f or c ollecti o n o n C 2 D 1 5 ( ± 7 d a y s).  O ntreat me nt 
bi o psies m ust be c ollecte d after C 2 D 8 a n d at least after 2 4 hr p ost i nf usi o n, a n d 
wit hi n 2 wee ks after i nf usi o n of C D 8 P E T tracer f or t he o n- treat me nt P E T/ C T sca n.  
All eff ort s h o ul d be ma de t o c ollect o n -treat ment bi o psies fr o m t he sa me lesi o n t hat 
was bi o psie d bef ore t hera p y . If bi o psy of t he sa me lesi o n is n ot p ossi ble, t he bi o ps y 
s h o ul d be prefera bly c ollecte d fr o m a lesi o n at t he sa me metastatic or ga n.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 7

After bi o ps y  tiss ues (fr o m b ot h pretreat me nt a n d o n-treatme nt sa m ples) ha ve bee n 
c ollecte d a n d u n der g o ne pr ocessi n g pr oce d ures as o utli ne d i n t he La b orat or y Ma n ual, t he 
bi o ps y  m ust be st ore d o n site at r o o m te m perat ure f or 3 0 da y s ( p ost i nf usi o n of C D 8 P E T 
tracer) bef ore bei n g s hi p pe d (t o all o w f or deca y of ra dioacti vit y).
A d diti o nal details ca n be f o u n d bel o w i n Ta ble 2 5 , a n d i n t he La b orat or y Ma n ual.  
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 8
T a ble 2 5 .
Sc he d ule of Assess me nts f or 8 9Zr -Df -I A B 2 2 M 2 C I m m u n o-P E T C D 8 Mi ni -b o d y I m a gi n g S u bst u d y
Visit I de ntifier
Scree ni n g
Pre -Tre at me n t P E T S u b St u d y 
Assess me nts
C ycle 1
C ycle 2
C ycle ≥3
Tr acer 
I nf usi o n
P E T 
I ma gi n g
Pre -tre atme nt 
Bi o ps y
Tr acer 
I nf usi o n
P E T 
I ma gi n g
O n Tre at me nt 
Bi o ps y
Tr acer 
I nf usi o n
P E T 
I ma gi n g
E O T/
Wit h dr a w al
P ost 
tre atme nt 
f oll o w u p
St u d y D a y
-2 8 t o - 9
d a ys
- 7- 9
- 6
-6 t o - 1
1
1 5
1
8
9
1 5
8
9
H o urs Pre -/P ost -D ose 1
0
0
0
0
Visit wi n d o w 2
Tracer i nf usi o n starti n g - 9 t o -7 
da ys pre treat me nt
± 2 4 hrs
± 7 d a ys
E nr oll me nt eli gi bilit y 
c o nfir mati o n pri or t o e nteri n g 
P E T S u b -St u d y
X
P K a n d P D  sa m ples
P atie nts s h o ul d f oll o w all sc he d ule d assess me nt, i ncl u di n g s afety l a bs, b ase d o n t he tri al c o h ort 
t h at t hey are p artici p ati n g i n
Ma n dat or y Pre -treat me nt  a n d 
o n treat me nt T u m or Bi o ps y 3,
X
X
( ± 7 da ys)
O pti o nal Sec o n d 
O n -Treat me nt T u m or 
Bi o ps y 3 , 4,
X
Vital Si g ns bef ore a n d after 
i nf usi o n
X
X
X
8 9Zr -Df -I AB 2 2 M 2 C i nf usi o n5
X
X
8 9Zr -Df -I AB 2 2 M 2 C 6      
P E T/ C T sca n
X
X
O pti o nal Re peat P E T I ma gi n g 
Assess me nts 7
X  
X
1 Sa m pli n g ti mes i n dicate d are relate d t o t he e n d of t he S C i njecti o n. All eff orts s h o ul d be ma de t o o btai n sc he d ule d P E T assess me nts i ncl u di n g bi o psies pri or t o treat me nt if 
c ollecti o n occ urs o n a da y of a sc he d ule d d ose of P F- 0 7 0 6 2 1 1 9.
2 Visit wi n d o w is base d o n t he i nitiati o n of P E T tracer i nf usi o n.
3 Bi o psies ca n be c ollecte d o n t he sa me da y as P E T i ma gi n g b ut m ust be c ollecte d after P E T i ma gi n g has occ urre d.
4 O pti o nal sec o n d o n treat me nt bi o ps y ma y be c ollecte d eit her after o pti o nal re peat P E T i ma gi n g or at E O T.
5 Pretreat me nt i nf usi o n m ust occ ur wit hi n 7- 9 da ys bef ore treat me nt ( C 1 D 1), a n d wit hi n 2 4 hrs of C 2 D 8.
6 P E T sca n m ust ta ke place 2 4 h o urs ± 3 hrs after i nf usi o n of 8 9Zr -Df -I AB 2 2 M 2 C, t u m or assess me nt sca ns sc he d ule d per pr ot oc ol f or e val uati o n of R E CI S T criteria s h o ul d b e 
c ollecte d se paratel y fr o m C D 8 P E T tracer s u bst u d y.
7 O pti o nal re peat P E T i ma gi n g ma y o nl y be perf or me d after disc ussi o n a n d a gree me nt bet wee n t he i n vesti gat or a n d s p o ns or.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7 9
1 0. 2 0. S u bc ut a ne o us I njecti o n Site L oc ati o ns
I njecti o n site l ocati o ns i ncl u de a ma xi m u m of 8 u ni q ue a d mi nistrati o n sites distri b ute d acr oss 
4 a b d o mi nal q ua dra nts wit h a p ossi bilit y  of u p t o 2 i njecti o n l ocati o ns per q ua dra nt. F or a 
gi ve n q ua dra nt, L o cati o n 1 is pr o xi mal t o t he u m bilic us a n d L ocati o n 2 is distal t o t he 
u m bilic us. 
I njecti o ns t o t he a b d o me n are preferre d. If S C i njecti o ns i n t he a b d o mi nal l ocati o n are n ot 
p ossi ble, S C i njecti o ns ca n be a d mi nistere d i n a distri b ute d ma n ner i n t he t hi g hs after 
disc ussi o n a n d a gree me nt bet wee n i n vesti gat or a n d t he S p o n s or. S C i njecti o ns i n t he u p per 
e xtre mities (e g, delt oi d, u p per a n d l o wer ar m) are n ot per mitte d.
T he f oll o wi n g pri nci ples  s h o ul d g ui de selecti o n of sites f or S C i njecti o n:
Pri nci ple [ 1]:  F or partici pa nts recei vi n g c o m bi nati o n t hera p y i n v o l vi n g > 1 dr u g a d mi nistere d 
s u bc uta ne o usly (f or e xa m ple, b ot h P F - 0 7 0 6 2 1 1 9 a n d P F-0 6 8 0 1 5 9 1), eac h dr u g s h o ul d be 
a d mi nistere d i n se parate a b d o mi nal q ua dra nt(s).
Pri nci ple [ 2]:  I f t he t otal n u m ber of S C i njecti o ns per mits, t he n i njecti o n sites (e ve n f or t he 
sa me dr u g) s h o ul d be distri b ute d a m o n g q ua dra nts t o t he e xte nt p ossi ble bef ore utilizi n g 2 
sites wit hi n t he sa me q ua dra nt, s u bject t o c o nstrai nt of pri nci ple [ 1].
Pri nci ple [ 3]:  I n t he e ve nt of s pecial circ u msta nces (f or e xa m ple, a n i ns ufficie nt n u m ber of
s uita ble i njecti o n sites o n t he a b d o me n), t he n t he i n vesti gat or s h o ul d c o ns ult wit h t he 
S p o ns or f or f urt her g ui da nce.
Trac k t he partici pa nt’s i njecti o n sites (s) se q ue ntiall y  o n t his dia gra m wit h a re d pe n a n d 
mar k t he i njecti o n sites o n t he partici pa nt’s a b d o me n acc or di n g t o yo ur cli nic’s sta n dar d 
practice.
Rec or d t he l ocati o n a n d ti me of eac h i njecti o n a n d a n y  IS R i n t he partici pa nt’s s o urce rec or ds 
a n d st u d y C R F. See e C R F g ui deli nes f or m ore i nf or mati o n.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 0
1 0. 2 1. 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 h r o u g h A me n d me nt 6
D oc u me nt Hist or y:
Pr ot oc ol A me n d me nt 6 ( 0 8 -Oct -2 0 2 1)
R ati o n ale f or Pr ot oc ol A me n d me nt 6 : T his a me n d me nt descri be d a ne w C D 8 P E T tracer 
s u bst u d y i nte n de d t o pr o vi de e x pl orat or y data t o e na ble n o ni n vasi ve vis ualizati o n of t he 
rele va nt C D 8 + T-cell p o p ulati o n of t he i m m u ne s yste m. I n a d diti o n, t his a me n d me nt 
pr o vi des m o difie d g ui da nce o n ( 1) i njecti o n site l ocati o ns a n d m o nit ori n g f or I S Rs; a n d ( 2) 
m a na ge me nt of diarr hea.
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
Sc he d ule of 
Acti vities 
Ta ble 2 i n 
Secti o n 1
C ha n ge d uri nal ys is c ollecti o n 
da y  fr o m C 1 D 1 9 t o C 1 D 1 5
C ha n ge descri be d i n 0 6 A pril 2 0 2 1 
P A C L
Sc he d ule of 
Acti vities 
Ta ble 2 i n 
Secti o n 1
Re m o ve d te xt fr o m f o ot n ote 
n u m ber 2 pertai ni n g t o 
a d diti o nal si g ni n g of c o nse nt 
d oc u me nt i n Ja pa n after at 
least C ycle 1 of Part 1 A bef ore 
c o nti n ui n g wit h C ycle 2.
C ha n ge descri be d i n 0 6 A pril 2 0 2 1 
P A C L
Sc he d ule of 
Acti vities 
Ta ble 4 i n 
Secti o n 1
Bl o o d sa m ples f or 
P K/ A D A/ N A b f or 
P F - 0 6 8 0 1 5 9 1 a n d 
be vaciz u ma b -Pfizer will n ot be 
re q uire d o n C 1 D 1.
O n C 2 D 1 (a n d all s u bse q ue nt 
c ycles wit h sc he d ule d 
c ollecti o ns) “ Bl o o d sa m ples 
f or P K/ A D A/ NA b a gai nst 
P F - 0 6 8 0 1 5 9 1” will n ot be 
re q uire d. I nstea d, “ Bl o o d 
sa m ples f or P K/ A D A/ NA b 
a gai nst P F-0 6 8 0 1 5 9 1” will be 
c ollecte d o n Da y 1 5 of all 
c ycles
C ha n ge descri be d i n 0 6 A pril 2 0 2 1 
P A C L
Sc he d ule of 
Acti vities 
Ta ble 4 i n 
Secti o n 1
F o ot n ote # 3 is clarifie d as 
f oll o ws: All pre-d ose bl o o d 
sa m ples f or P F-0 6 8 0 1 5 9 1 will 
b e c ollecte d o n Da y 1 5 visit of 
C ha n ge descri be d i n 0 6 A pril 2 0 2 1 
P A C L
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 1
D oc u me nt Hist or y:
Pr ot oc ol A me n d me nt 6 ( 0 8 -Oct -2 0 2 1)
R ati o n ale f or Pr ot oc ol A me n d me nt 6 : T his a me n d me nt descri be d a ne w C D 8 P E T tracer 
s u bst u d y i nte n de d t o pr o vi de e x pl orat or y data t o e na ble n o ni n vasi ve vis ualizati o n of t he 
rele va nt C D 8 + T-cell p o p ulati o n of t he i m m u ne s yste m. I n a d diti o n, t his a me n d me nt 
pr o vi des m o difie d g ui da nce o n ( 1) i njecti o n site l ocati o ns a n d m o nit ori n g f or I S Rs; a n d ( 2) 
m a na ge me nt of diarr hea.
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
eac h sc he d ule d c ollecti o n 
C y cle. Pre-d ose bl o o d sa m ples 
f or be vaciz u ma b-Pfizer will be 
c ollecte d o n Da y 1 5 visit i n 
C y cle 1 a n d s u bse q ue ntl y o n 
D a y  1 visit of eac h sc he d ule d 
c ollecti o n C ycle. T he c ha n ges 
t o Ta ble 4 were ma de t o better 
ali g n wit h t he d ose pri mi n g 
strate g y, w here P F-0 6 8 0 1 5 9 1 
or be vaciz u ma b -Pfizer will be 
a d mi nistere d f or t he first ti me 
o n C 1 D 1 5, t heref ore 
c ollecti o ns fr o m C 1 D 1 were 
re m o ve d a n d/ or m o ve d t o 
acc o m m o date t hese c ha n ges
Sc he d ule of 
Acti vities 
Ta ble 4 i n 
Secti o n 1
F o ot n ote # 3 was re vise d t o 
clarif y t he c ollecti o n sc he d ules 
f or P K/ A D A/ N A b f or 
P F -0 7 0 6 2 1 1 9/ be vaciz u ma b -
Pfizer a n d P F -0 6 8 0 1 5 9 1 i n 
C y cles 5 a n d be yo n d.
Clarifie d bl o o d c ollecti o n sc he d ule f or 
P K/ A D A/ N A b f o r 
P F -0 7 0 6 2 1 1 9/ be vaciz u ma b -Pfizer a n d 
P F -0 6 8 0 1 5 9 1 i n C y cles 5 a n d be yo n d.
Sc he d ule of 
Acti vities 
Ta ble 6 i n 
Secti o n 1
Bl o o d sa m ples f or 
P K/ A D A/ N A b f or 
P F - 0 6 8 0 1 5 9 1 a n d 
be vaciz u ma b -Pfizer will n ot be 
re q uire d o n C 1 D 1.
O n C 2 D 1 (a n d all s u bse q ue nt 
c ycles wit h sc he d ule d 
c ollecti o ns) “ Bl o o d sa m ples 
f or P K/ A D A/ NA b a gai nst 
P F -0 6 8 0 1 5 9 1” will n ot be 
C ha n ge descri be d i n 0 6 A pril 2 0 2 1 
P A C L
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 2
D oc u me nt Hist or y:
Pr ot oc ol A me n d me nt 6 ( 0 8 -Oct -2 0 2 1)
R ati o n ale f or Pr ot oc ol A me n d me nt 6 : T his a me n d me nt descri be d a ne w C D 8 P E T tracer 
s u bst u d y i nte n de d t o pr o vi de e x pl orat or y data t o e na ble n o ni n vasi ve vis ualizati o n of t he 
rele va nt C D 8 + T-cell p o p ulati o n of t he i m m u ne s yste m. I n a d diti o n, t his a me n d me nt 
pr o vi des m o difie d g ui da nce o n ( 1) i njecti o n site l ocati o ns a n d m o nit ori n g f or I S Rs; a n d ( 2) 
m a na ge me nt of diarr hea.
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
re q uire d. I nstea d, “ Bl o o d 
sa m ples f or P K/ A D A/ NA b 
a gai nst P F-0 6 8 0 1 5 9 1” will be 
c ollecte d o n Da y 1 5 of all 
c ycles
Sc he d ule of 
Acti vities 
Ta ble 6 i n 
Secti o n 1
F o ot n ote # 3 is clarifie d as 
f oll o ws: All pre-d ose bl o o d 
sa m ples f or P F-0 6 8 0 1 5 9 1 will 
be c ollecte d o n Da y  1 5 visit of 
eac h sc he d ule d c ollecti o n 
C y cle. Pre-d ose bl o o d sa m ples 
f or be vaciz u ma b-Pfizer will be 
c ollecte d o n Da y 1 5 visit i n 
C y cle 1 a n d s u bse q ue ntl y o n 
D a y  1 visit of eac h sc he d ule d 
c ollecti o n C ycle. T he c ha n ges 
t o Ta ble 6 were ma de t o better 
ali g n wit h t he d ose pri mi n g 
strate g y, w here P F-0 6 8 0 1 5 9 1 
or be vaciz u ma b -Pfizer will be 
a d mi nistere d f or t he first ti me 
o n C 1 D 1 5, t heref ore 
c ollecti o ns fr o m C 1 D 1 were 
re m o ve d a n d/ or m o ve d t o 
acc o m m o date t hese c ha n ges
C ha n ge descri be d i n 0 6 A pril 2 0 2 1 
P A C L
Sc he d ule of 
Acti vities 
Ta ble 6 i n 
Secti o n 1
F o ot n ote # 3 was re vise d t o 
clarif y t he c ollecti o n sc he d ules 
f or P K/ A D A/ N A b f or 
P F - 0 7 06 2 1 1 9/ be vaciz u ma b -
Pfizer a n d P F -0 6 8 0 1 5 9 1 i n 
C y cles 5 a n d be yo n d.
Clarifie d bl o o d c ollecti o n sc he d ule f or 
P K/ A D A/ N A b f or 
P F -0 7 0 6 2 1 1 9/ be vaciz u ma b -Pfizer a n d 
P F -0 6 8 0 1 5 9 1 i n C y cles 5 a n d be yo n d.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 3
D oc u me nt Hist or y:
Pr ot oc ol A me n d me nt 6 ( 0 8 -Oct -2 0 2 1)
R ati o n ale f or Pr ot oc ol A me n d me nt 6 : T his a me n d me nt descri be d a ne w C D 8 P E T tracer 
s u bst u d y i nte n de d t o pr o vi de e x pl orat or y data t o e na ble n o ni n vasi ve vis ualizati o n of t he 
rele va nt C D 8 + T-cell p o p ulati o n of t he i m m u ne s yste m. I n a d diti o n, t his a me n d me nt 
pr o vi des m o difie d g ui da nce o n ( 1) i njecti o n site l ocati o ns a n d m o nit ori n g f or I S Rs; a n d ( 2) 
m a na ge me nt of diarr hea.
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
Secti o n 2. 5 
Be nefit/ Ris k 
Assess me nt
Para gra p h 2 was re vise d t o 
clarif y t hat C R S a n d diarr hea 
has alrea d y bee n o bser ve d i n 
t he st u d y. F urt her m ore, t he 
q ualif y i n g te xt, “ p ote ntiall y at 
hi g her d oses” has bee n 
re m o ve d.
T o u p date t he pr ot oc ol t hat C R S a n d 
diarr hea are n o l o n ger e x pecte d A Es 
of P F -0 7 0 6 2 1 1 9.  Rat her t he y  ha ve
bee n o bser ve d i n t he st u d y. 
F urt her m ore, t hat as of t he date of t his 
pr ot oc ol a me n d me nt, t here is n o clear 
d ose -A E relati o ns hi p.
Secti o n 2. 5 
Be nefit/ Ris k 
Assess me nt
I n para gra p h 4, ne w te xt was 
i nc or p orate d t hat refers t he 
rea der t o t he I ma gi n A B I B f or 
d etaile d i nf or mati o n o n t he 
e x pecte d be nefits a n d ris ks a n d 
e x pecte d A Es of t he P E T 
tracer.
T o direct rea der t o c o m plete 
i nf or mati o n o n t he be nefits, ris ks a n d 
e x pecte d A Es of t he P E T tracer f or 
t he ne wly i nc or p orate d s u bst u d y.
Secti o n 3, 
O bjecti ves a n d 
E n d p oi nts
A d de d ne w tertiar y  / 
e x pl orat or y e n d p oi nt of 
meas uri n g c ha n ges i n C D 8 
P E T tracer u pta ke f or b ot h 
Part 1 ( d ose escalati o n) a n d 
Part 2 ( d ose e x pa nsi o n)
D oc u me nts t he a d diti o n of ne w 
e n d p oi nts pertai ni n g t o C D 8 P E T 
tracer s u bst u d y.
Secti o n 4. 1, 
O verall Desi g n
A d de d para gra p h s u m marizi n g 
t he C D 8 P E T tracer s u bst u d y, 
al o n g wit h a n i ntra-d oc li n k t o 
t he c o m plete descri pti o n of t he 
s u bst u d y i n Secti o n 1 0. 1 9
Ca pt ures t he ne w C D 8 P E T tracer 
s u bst u d y i n t he hi g h-le vel st u d y 
descri pti o n.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 4
D oc u me nt Hist or y:
Pr ot oc ol A me n d me nt 6 ( 0 8 -Oct -2 0 2 1)
R ati o n ale f or Pr ot oc ol A me n d me nt 6 : T his a me n d me nt descri be d a ne w C D 8 P E T tracer 
s u bst u d y i nte n de d t o pr o vi de e x pl orat or y data t o e na ble n o ni n vasi ve vis ualizati o n of t he 
rele va nt C D 8 + T-cell p o p ulati o n of t he i m m u ne s yste m. I n a d diti o n, t his a me n d me nt 
pr o vi des m o difie d g ui da nce o n ( 1) i njecti o n site l ocati o ns a n d m o nit ori n g f or I S Rs; a n d ( 2) 
m a na ge me nt of diarr hea.
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
Secti o n 4. 2 
Sci e ntific 
Rati o nale f or 
St u d y  Desi g n
A d de d italicize d te xt t o sec o n d 
para gra p h.  “ T he bi o mar ker 
assess me nts, i ncl u di n g t he P E T 
i m a gi n g s u bst u dy, ma y  
c o ntri b ute t o c o nfir mi n g tar get 
e n ga ge me nt….”
T o pr o vi de a f ull descri pti o n of t he 
bi o mar ker g oals i n t he o ve r vie w 
secti o n.
Secti o n 6. 1. 1. 2 
P F - 0 6 8 0 1 5 9 1
Te xt was re vise d pertai ni n g t o 
sit uati o ns w here a b d o mi nal 
i njecti o n site l ocati o ns are n ot 
p ossi ble.
Te xt was re vise d t o ali g n wit h t he ne w 
Secti o n 1 0. 2 0 A p pe n di x 2 0 
S u bc uta ne o us I njecti o n Site 
L ocati o ns. T his a n d t he a d de d 
A p pe n di x 2 0, facilitate l ocati o n of 
i njecti o n sites l ocati o ns w he n 
i n vesti gati o nal c o m bi nati o n t hera pies 
are a d mi nistere d. T his will facilitate 
m o nit ori n g f or I S Rs t o eit her 
i n vesti gati o nal t hera py.
Secti o n 6. 6. 4, 
A nti Diarr heal, 
A nti E metic 
T hera p y a n d
Secti o n 6. 7. 3 
D ose 
Re d ucti o ns –
Ta ble 1 2
A d de d te xt wit h a d diti o nal 
g ui da nce f or ma na gi n g 
diarr hea A Es ( Secti o n 6. 6. 4), 
re vise d Ta ble 1 2 ( Secti o n 
6. 7. 3)
E m p hasizes i m p orta nce of m o nit ori n g 
f or diarr hea a n d prescri bi n g 
i m me diate i nter ve nti o n t o war ds earl y 
res ol uti o n.
Secti o n 1 0. 1 3 
A p pe n di x 1 3
S u p p orti ve Care 
f or I m m u ne-
Relate d 
A d verse E ve nts 
(ir A Es)
T o Ta ble 2 0, a d de d te xt wit h 
a d diti o nal g ui da nce f or 
ma na gi n g diarr hea A Es
Pr o vi des detaile d i nstr ucti o ns f or 
treat me nt of diarr hea i ncl u di n g d osi n g
a dj ust me nts, a n d use of a nti- diarr heal 
me dicati o ns (l o pera mi de, L o m otil, 
a n d met h yl pre d nis ol o ne).
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 5
D oc u me nt Hist or y:
Pr ot oc ol A me n d me nt 6 ( 0 8 -Oct -2 0 2 1)
R ati o n ale f or Pr ot oc ol A me n d me nt 6 : T his a me n d me nt descri be d a ne w C D 8 P E T tracer 
s u bst u d y i nte n de d t o pr o vi de e x pl orat or y data t o e na ble n o ni n vasi ve vis ualizati o n of t he 
rele va nt C D 8 + T-cell p o p ulati o n of t he i m m u ne s yste m. I n a d diti o n, t his a me n d me nt 
pr o vi des m o difie d g ui da nce o n ( 1) i njecti o n site l ocati o ns a n d m o nit ori n g f or I S Rs; a n d ( 2) 
m a na ge me nt of diarr hea.
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
Secti o n 1 0. 1 9 
P E T I ma gi n g 
S u bst u d y  wit h 
8 9Zr -Df -
I AB 2 2 M 2 C
A d de d c o m plete descri pti o n of 
t he ne w C D 8 P E T tracer 
s u bst u d y i ncl u di n g an S o A
de dicate d t o t he s u b st u d y 
pr oce d ures
Pr o vi de c o m pre he nsi ve i nf or mati o n t o 
t he sites f or c o n d ucti n g t he C D 8 P E T 
tracer s u bst u d y
Secti o n 1 0. 2 0 
S u bc uta ne o us 
I njecti o n Site 
L ocati o ns
A d de d clarif y i n g i nstr ucti o ns 
o n a b d o mi nal s u bc uta ne o us 
i njecti o ns i n t he c o m bi nati o n 
st u dies ( Parts 1 B a n d 2)
T he m ore detaile d i nstr ucti o ns will 
facilitate m o nit ori n g f or a n d 
d oc u me nti n g I S Rs f oll o wi n g 
c o m bi nati o n re gi me ns wit h 
P F -0 7 0 7 6 2 1 1 9 t hat are i njecte d 
S u bc uta n e o us
M ulti ple 
Secti o ns
Mi n or e dit orial c ha n ges a n d 
c orrecti o ns
Mi n or re visi o ns a n d
c orrecti o ns f or 
i m pr o vi n g u n dersta n di n g
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
A me n d me nt 5
1 6 Marc h 2 0 2 1
T he pri mar y  p ur p ose of t he a me n d me nt is 
t o re vise t he st u d y desi g n t o i nc or p orate 
c o h orts t hat recei ve a pri mi n g d ose 2 
wee ks bef ore recei vi n g a f ull d ose of P F-
0 7 0 6 2 1 1 9. T he pri mi n g d ose is a d de d t o 
miti gate t he occ urre nce of c y t o ki ne-
me diate d A Es f oll o wi n g s u bse q ue nt 
a d mi nistrati o ns of hi g her d oses.
S O A f or P art 1 A, 1 B, a n d P art 2 
Wit h o ut a Pri mi n g D ose ( T a ble 1)
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 6
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
A r o w f or pre me dicati o n was a d de d wit h 
a c orres p o n di n g f o ot n ote (als o a d de d t o 
Secti o n 6. 1. 1. 1). Pre me dicati o n has bee n 
i m ple me nte d i nt o t his st u d y t o f urt her 
i m pr o ve t olera bilit y a n d partici pa nt 
e x perie nce.
F or partici pa nts recei vi n g P F - 0 6 8 0 1 5 9 1, a
pre g na nc y  test is re q uire d 3 0 da ys after 
E O T a n d t he f oll o w -u p visit will occ ur 
3 0, 9 0, a n d 1 8 0 da y s after E O T.
P K, P D, a n d I m m u n o ge nicit y 
Assess me nts f or P art 2 Wit h o ut a 
Pri mi n g D ose ( T a ble 5)
T he 4 -h o ur ti me p oi nt o n Da y  1 was 
re m o ve d.
S O As f or P art 1 A, P art 1 B, a n d P art 2 
Wit h a Pri mi n g D ose ( T a ble 2);
P K, P D, a n d I m m u n o ge nicit y 
Assess me nts f or P art 1 a n d P art 1 B 
Wit h a Pri mi n g D ose S O A ( T a ble 4); 
a n d P K, P D, a n d I m m u n o ge nicit y 
Assess me nts f or P art 2 Wit h a Pri mi n g 
D ose ( T a ble 6)
T hese ta bles were a d de d f or t he c o h ort 
wit h a pri mi n g d ose; sc he d ules are si milar 
t o Ta ble 1 e xce pt m o difie d t o 
acc o m m o date t he pri mi n g d ose. 
Secti o n 2. 2. 8 S u m m ar y of C urre nt 
Cli nic al D at a fr o m St u d y 3 8 6 1 0 0 1
S u m mar y  of data as of 2 8 Dece m ber 2 0 2 0 
was a d de d.
Secti o n 2. 3. 1 P F -0 6 8 0 1 5 9 1, a n A nti -P D -
1 A nti b o d y: Cli nic al E x perie nce i n 
St u d y B 8 0 1 1 0 0 1 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 7
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
( N C T 0 2 5 7 3 2 5 9)/ A p pe n di x 9
Preli mi n ar y Cli nic al S u m m ar y f or 
St u d y B 8 0 1 1 0 0 1 P h ase 1 FI H ( P F 
0 6 8 0 1 5 9 1)
Data as of 1 0 Fe br uar y  2 0 2 1 was 
i ncl u de d.
Secti o n 2. 5 Be nefit/ Ris k Assess me nt
E x pa n de d t o i ncl u de t he be nefit/ris k 
assess me nt f or c o h orts wit h a pri mi n g 
d ose.
Secti o n 3 O bjecti ves a n d E n d p oi nts
Pri mar y  o bjecti ve was m o difie d t o 
i ncl u de t he c o h ort wit h a pri mi n g d ose.
Secti o n 4 St u d y Desi g n
U p date d a n d re or ga nize d t o i ncl u de 
details of t he c o h orts wit h t he pri mi n g 
d ose, i ncl u di n g D L T o bser vati o n peri o d 
f or Part 1 c o h orts wit h a pri mi n g d ose ( 4 2 
da y s), j ustificati o n f or t he starti n g d ose 
( m o n ot hera py, c o m bi nati o n d ose -fi n di n g, 
a n d d ose e x pa nsi o n [ Part 2]), criteria f or 
d ose escalati o n, a n d t he t otal n u m ber of 
st u d y partici pa nts.
Fi g ure 3 C 3 8 6 1 0 0 1 St u d y Sc he m a
U p date d t o i ncl u de t he c o h orts wit h a 
pri mi n g d ose.
Secti o n 5 St u d y P o p ul ati o n
I ncl usi o n criteri o n 5: t u m or tiss u e is n o w 
re q uire d f or Part 2 d ose e x pa nsi o n.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 8
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
E xcl usi o n criteri o n 1 2: partici pati o n i n 
me dical i ma gi n g st u dies wit hi n 2 wee ks 
of st u d y  e ntr y is all o we d.
Secti o n 6. 1. 1. 1 P F -0 7 0 6 2 1 1 9
Pre me dicati o n t o i m pr o ve partici pa nt 
t olera bilit y has bee n a d de d. 
Secti o n 6. 6 C o nc o mit a nt T her a p y
G ui deli nes ar o u n d C O VI D -1 9 vacci nes 
ha ve bee n a d de d.
Secti o n 6. 6. 4 A nti -Di arr he al, A nti -
E metic T her a p y
A d diti o nal details were pr o vi de d 
re gar di n g ma na ge me nt of diarr hea.
Secti o n 7. 1. 1 E C G C h a n ges
T his secti o n was re m o ve d si nce it was
u n necessar y . Rele va nt E C G re q uire me nts 
are i n t he I/ E criteria a n d D LT 
defi niti o ns.
Secti o n 8. 1. 4 E C G
Te xt clarifie d t o i n dicate t hat Q Tc F will 
be t he c orrecti o n fact or f or deter mi ni n g 
Q Tc.
Secti o n 8. 1. 7 I njecti o n Site T oler a bilit y 
Assess me nt
T o be perf or me d after P F- 0 6 8 0 1 5 9 1 
i njecti o ns as well.
Secti o n 8. 3 Tre at me nt of O ver d ose
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8 9
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
U p date d t o i ncl u de defi niti o n of o ver d ose 
f or P F-0 6 8 0 1 5 9 1 a n d 
be vaciz u ma b -Pfizer.
Secti o n 9 St atistic al 
C o nsi der ati o ns/ A p pe n di x 1 0
U p date d t o i ncl u de statistical 
c o nsi derati o ns f or t he c o h orts wit h a 
pri mi n g d ose.
A p pe n di x 4: C o ntr ace pti ve G ui d a nce 
a n d C ollecti o n of Pre g n a nc y 
I nf or m ati o n
I ncrease d le n gt h of ti me t hat a hi g hl y 
effecti ve c o ntrace pti ve met h o d m ust be 
use d after t he last d ose of P F - 0 6 8 0 1 5 9 1 
a n d be vaciz u ma b- Pfizer.
A p pe n di x 9  Preli mi n ar y Cli nic al 
S u m m ar y f or St u d y B 8 0 1 1 0 0 1 P h ase 1 
FI H ( P F - 0 6 8 0 1 5 9 1)
A p pe n di x 9 has bee n u p date d t o i ncl u de 
m ore rece nt safet y i nf or mati o n a n d t o 
ali g n wit h all ot her P F-0 6 8 7 0 1 5 9 1 
pr ot oc ols refers directl y  t o t he m ost 
rece nt P F- 0 6 8 0 1 5 9 1 I B f or ot her 
i m p orta nt i nf or mati o n. 
Ot her mi n or clarificati o ns, a d mi nistrati ve, 
a n d t yp o gra p hical c ha n ges were ma de. 
T he ter m ‘ patie nt’ was re place d wit h 
‘ partici pa nt t hr o u g h o ut t he pr ot oc ol.
A me n d me nt 4
0 5 Oct o ber 2 0 2 0 
T he pri mar y  p ur p ose of t he a me n d me nt is 
t o i nc or p orate fee d bac k recei ve d fr o m t he 
U nite d States ( U S) F o o d a n d Dr u g 
A d mi nistrati o n ( F D A).
S O A f or P art 1 A, 1 B, a n d P art 2
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 0
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
T he f oll o wi n g re visi o ns were m a de :
Ma n dat or y  pr otei n uria assess me nt 
( di pstic k is acce pta ble) assess me nt is 
re q uire d pri or t o e ver y be vaciz u ma b-
Pfizer d ose t hr o u g h o ut t he c o urse of t he 
st u d y. If uri nalys is de m o nstrates pr otei n >
2 +, t he n a 2 4 -h o ur uri ne pr otei n 
c ollecti o n s h o ul d f oll o w. I n p atie nts wit h 
pr otei n uria greater t ha n or e q ual t o 2 
gra ms per 2 4 h o urs, be vaciz u ma b- Pfizer 
s h o ul d be hel d u ntil rec o ver y (less t ha n 2 
gra ms per 2 4 h o urs). Patie nts w h o 
de vel o p ne p hr otic s y n dr o me s h o ul d 
disc o nti n ue be vaciz u ma b -Pfizer.
I n a d diti o n, t his i nf or mati o n was als o 
a d de d t o: 

Secti o n 6. 1. 1. 3 Be vaciz u ma b-
Pfizer.

Secti o n 6. 7. 1 D osi n g I nterr u pti o ns

A p pe n di x 2: Cli nical L a b orat or y 
Tests
Secti o n 6. 7. 3 D ose Re d ucti o ns:
Ta ble 5 D ose M o dificati o ns f or A d verse 
Reacti o ns relate d t o Be vaciz u ma b -Pfizer 
was a d de d t o t he pr ot oc ol f or a d diti o nal 
g ui da nce. 
Ot her, mi n or clarificati o ns, a d mi nistrati ve 
a n d t yp o gra p hical c ha n ges were ma de. 
A me n d me nt 3
1 7 A u g ust 2 0 2 0
T he pri mar y  p ur p ose of t he a me n d me nt is 
t o u p date t he pr ot oc ol t o i ncl u de 
o perati o nal details nee de d f or t he 
pre pla n ne d e x pa nsi o n of t he st u d y  
( Part 2).
S O A f or P art 1 A, 1 B, a n d P art 2
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 1
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
F or p artici p a nts i n P art 2 t he f oll o wi n g 
re visi o ns were m a de : 

A ± 1 da y  wi n d o w was a d de d t o t he 
Da y  5 visit (f o ot n ote 2 3).

S u bjects i n Part 2 will n ot re q uire a 
Da y  3 visit, s o f or clarity, t he f o ot n ote 
f or t he E C G assess me nt was m o difie d 
(f o ot n ote 6).

T he la n g ua ge detaili n g t he fre q ue nc y  
of C T/ M RI  sca ns was clarifie d i n t he 
ta ble r o w.

T he la n g ua ge i n f o ot n ote 1 4 was 
clarifie d.

T he C E A assess me nts were m o ve d 
fr o m t he P K Assess me nts ta ble t o t he 
sta n dar d assess me nts ta ble.
S O A f or P K, P D, a n d I m m u n o ge nicit y 
f or P art 1 A a n d P art 1 B

C ha n ge d wi n d o w of Da y 5 ( 9 6 h o ur) 
P K c ollecti o n t o ± 2 4 h o urs.

T he o pti o nal or ma n dat or y 
o ntreat me nt bi o ps y  sa m ple c ollecti o n 
sc he d ule f or wit hi n 2 8 da ys pri or t o 
re gistrati o n was re m o ve d.

A Da y  1 5, 8 h o ur sa m ple c ollecti o n 
f or P F-0 7 0 6 2 1 9 9 c o nce ntrati o n 
c yt o ki nes a n d circ ulati n g mar kers was 
a d de d f or partici pa nts i n Part 1 B.

A d de d c ollecti o n of P K sa m ple s t o 
t he alrea dy s c he d ule d A D A/ N A b 
c ollecti o ns f or Part 1 B.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 2
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
o
F o ot n ote 3 u p date d t o reflect 
t he a b o ve c ha n ge t o P K 
sa m pli n g f or Part 1 B

F o ot n otes 5 a n d 6 u p date d t o clarif y  
t u m or sa m ple c ollecti o n re q uire me nts.

S O A a n d f o ot n otes f or P K, P D, a n d 
I m m u n o ge nicity Assess me nts f or 
P art 2 a d de d.
Secti o n 3 O bjecti ves a n d E n d p oi nts

Tertiar y / E x pl orat or y O bjecti ve a d de d 
f or Part 1 B a n d Part 2. T he tertiar y 
e n d p oi nt f or Part 1 B a n d Part 2 ha ve 
bee n u p date d t o reflect t he o ut p ut f or 
t hese pres pecifie d c ollecti o ns.
Secti o n 4. 1 O ver all Desi g n

T u m or tiss ue sa m ple la n g ua ge 
m o difie d t o i nc or p orate Part 2 
re q uire me nts.

La n g ua ge was a d de d t o clarif y  
i n patie nt o bser vati o n peri o d f or 
Part 2.
Secti o n 4. 3. 3 Fi xe d D osi n g A p pr o ac h

La n g ua ge was a d de d t o all o w f or  
b o d y  wei g ht or B S A base d d osi n g.
Secti o n 5. 1 I ncl usi o n Criteri a

I C # 5 was re vise d t o i nc or p orate 
t u m or tiss ue sa m ple re q uire me nts.
Secti o n 5. 2 – E xcl usi o n Criteri a
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 3
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
Clarificati o n was a d de d t o E C # 6 t o 
i nc or p orate C O VI D-1 9 testi n g 
re q uire me nts.
Secti o n 6. 1. 1. 1 – P F -0 7 0 6 2 1 1 9

La n g u a ge was a d de d t o clarif y 
i n patie nt o bser vati o n peri o d f or 
Part 2.
Secti o n 6. 1. 1. 3 – Be v aciz u m a b -Pfizer

A d mi nistrati o n i nstr ucti o ns were 
u p date d.
Secti o n 6. 6. 3 He m at o p oietic Gr o wt h 
F act ors

Clarifie d t hat er y t hr o p oieti n is n ot 
a p pr o ve d i n Ja pa n.
A d de d Secti o n 6. 7. 1. 1 – D ose 
I nterr u pti o n of P artici p a nts wit h 
Pres u me d or Acti ve C O VI D -1 9/ S A R S 
C o V 2 I nfecti o n
A d de d Secti o n 8. 1. 2 C O VI D -1 9: Use of 
Alter n ati ve Met h o ds f or I n- Pers o n 
Visits
Secti o n 8. 2. 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

U p date d t he te xt i n dicati n g h o w t he 
i n vesti gat or s h o ul d n otif y Pfizer of a n 
S A E, ie, usi n g t he C T S A E Re p ort 
F or m.
Secti o n 8. 2. 6 Me dic ati o n Err ors
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 4
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale

Clarifie d t hat me dicati o n d osi n g 
err ors s h o ul d be re p orte d t o t he 
s p o ns or wit hi n 2 4 h o urs.
Secti o n 8. 3 Tre at me nt of O ver d ose

Cl arifie d t h at m o nit ori n g of a n y 
p artici p a nt s h o ul d c o nti n ue f or 5 
h alf -li ves or 2 8 c ale n d ar d a ys after 
t he o ver d ose.
Secti o n 8. 8, 8. 8. 1, 8. 8 2 - T u m or tiss ue 
sa m ple la n g ua ge re vise d t o i nc or p orate 
Part 2 re q uire me nts.
Secti o n 1 0. 3. 2 Defi niti o n of S A E

Te xt a d de d t o i ncl u de t he e ve nt of 
s us pecte d tra ns missi o n of a n 
i nfecti o us a ge nt, via a Pfizer pr o d uct.
Secti o n 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 

U p date d E x p os ure d uri n g 
pre g na nc y/ breastfee di n g A E/ S A E 
rep orti n g pr oce d ures.
Secti o n 9. 5. 1 D at a M o nit ori n g 
C o m mittee:

La n g ua ge a d de d t o clarif y  c ollecte d 
data w hic h will be re vie we d d uri n g 
t he peri o dic safety re vie w tea m.
Secti o n 1 0. 4. 3 W o m a n of C hil d be ari n g 
P ote nti al

La n g ua ge was a d de d t o clarif y  t he 
pr oce d ure f or partici pa nts wit h a hi g h 
F S H.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 5
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
Secti o n 1 0. 4. 4 C o ntr ace pti o n Met h o d

Clarifie d  c o ntrace pti o n met h o ds n ot 
a p pr o ve d i n Ja pa n.
Secti o n 1 0. 1 0. 2 Pri or S pecific ati o ns

T he D L T rate was c orrecte d.
A d de d Secti o n 1 0. 1 7 J a p a n S pecific 
M atters
A d de d Secti o n 1 0. 1 8: Alter n ati ve 
Me as ures D uri n g P u blic E mer ge ncies
Ot her, mi n or clarificati o ns, a d mi nistrati ve 
a n d t yp o gra p hical c ha n ges were ma de.
A me n d me nt 0 2
1 0 Oct o ber 2 0 1 9 
T he pri mar y  p ur p ose of t he a me n d me nt is 
t o i nc or p orate fee d bac k recei ve d fr o m t he 
U nite d States ( U S) F o o d a n d Dr u g 
A d mi nistrati o n ( F D A).
I n a d diti o n, clarificati o ns, a d mi nistrati ve 
a n d t yp o gra p hical m o dificati o ns were 
ma de.
4. 3. 7 Criteria f or D ose Escalati o n 

Clarificati o n, i ncl u di n g 
t yp o gra p hical m o dificati o ns 
ar o u n d i ntra -partici pa nt d ose 
escalati o n c o nsi derati o ns were 
ma de.
Secti o n 4. 3. 8 D ose L i miti n g T o xicit y 
Defi niti o n

Clarificati o n ma de t hat all C R S 
e ve nts Gra de 3 or hi g her, 
re gar dless of d urati o n will be 
c o nsi dere d a D L T.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 6
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale

Gra de 3 i nf usi o n relate d reacti o ns 
(II R), aller gic reacti o ns or 
a na p h yl a xis will n o w be 
c o nsi dere d D L Ts.
Secti o n 5. 1 I ncl usi o n Criteria

T y p o gra p hical err or was c orrecte d 
s plitti n g i ncl usi o n criteria # 3 a n d 
# 4 i nt o t w o se parate criteri o n.
Secti o n 6. 7. 3 D ose Re d ucti o ns
T y p o gra p hical err or was c orrecte d 
pr o perl y li n k Ta bl e 3 i n t he te xt f or t he 
n o n -i m m u ne-relate d t o xicities.
A me n d me nt 0 1
0 8 Oct o ber 2 0 1 9 
T he pri mar y  p ur p ose of t he a me n d me nt is 
t o i nc or p orate fee d bac k recei ve d fr o m t he 
U nite d States ( U S) F o o d a n d Dr u g 
A d mi nistrati o n ( F D A).
I n a d diti o n, clarificati o ns, a d ministrati ve 
a n d t yp o gra p hical m o dificati o ns were 
ma de.
S C H E D U L E O F A C TI VI TI E S ( S O A)

I n patie nt m o nit ori n g f or C ycle 1 
Da y  1 5 ( C 1 D 1 5) has bee n 
e xte n de d t o 8 h o urs p ost d ose. 
Patie nts ma y  be release d o nl y 
after t he i n vesti gat or has 
c o nfir me d t he partici pa nt has n ot 
e x hi bite d si g ns a n d s ym pt o ms of a 
c yt o ki ne reacti o n.

C 1 D 1 2 -h o ur ti me p oi nt has bee n 
re m o ve d, w hic h was rele va nt t o 
I n vtra ve n o us (I V) d osi n g o nl y, 
w hic h has bee n re m o ve d fr o m t he 
pr ot oc ol.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 7
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale

I n- h o use m o nit ori n g re q uire me nts  
a n d I V i nf usi o n i nstr ucti o ns f or I V 
d osi n g ha ve bee n re m o ve d fr o m 
t he S O A, wit h re m o val of I V 
d osi n g fr o m t he pr ot oc ol.

Sc he d ule of P har mac o ki netic, 
P har mac o d y na mic, a n d 
I m m u n o ge nicit y Assess me nts f or 
Parts 1 A a n d 1 B -f o ot n ote 7 
“ Bl o o d Sa m ple f or C yt o ki nes & 
Circ ulati n g Mar kers (c e ntral la b) 
a n d Bl o o d sa m ple f or T cell 
I m m u n o p he n oty pi n g” clarifies 
t hat: t w o ( 5 m L) bl o o d sa m ples 
will be c ollecte d t o is olate ser u m 
f or ce ntral la b orat or y tests f or 
safety c ollecte d pre -d ose o n 
C 1 D 1.
Secti o n 2. 5 Be nefit/ Ris k Assess me nt

I n patie nt o bser vati o n of I V d osi n g 
was re m o ve d fr o m t he pr ot oc ol.
Secti o n 4. 1 O verall Desi g n

Clarificati o n was a d de d ar o u n d 
t he Ba ye sia n l o gistic re gressi o n 
m o del ( B L R M) a n d ma xi m u m 
d ose i ncreases i n Part 1 A a n d 1 B.

Clarificati o n was a d de d ar o u n d 
c o h ort size f or d ose le vel of Part 
1 B a n d Part 2.

Clarificati o n t hat Part 1 B will 
ha ve at least 3 D ose Li miti n g 
T o xicit y  ( D L T) e val ua ble 
partici pa nts, w hic h was c ha n ge d 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 8
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
fr o m pre vi o us at least 2 D LT 
e val ua ble partici pa nt.

Fi g ure 3: C 3 8 6 1 0 0 1 St u d y 
Sc he ma was u p date d t o refl ect 
n u m ber of partici pa nts i n Part 1 B.

I n patie nt m o nit ori n g f or C 1 D 1 5 
has bee n e xte n de d t o 8 h o urs p ost 
d ose. Patie nts ma y  be release d 
o nl y  after t he i n vesti gat or has 
c o nfir me d t he partici pa nt has n ot 
e x hi bite d si g ns a n d s ym pt o ms of a 
c yt o ki ne reacti o n.
Secti o n 4. 3. 2 S u bc uta ne o us R o ute

T he pr ot oc ol has bee n u p date d t o 
clarif y t he use of s u bc uta ne o us 
d osi n g o nl y at t his ti me. If 
i ntra ve n o us d ose a d mi nistrati o n, 
i ncl u di n g i ntra ve n o us d ose 
pri mi n g is g oi n g t o be e x pl ore d i n 
t his st u d y, a f ut ure pr ot oc ol 
a men d me nt w o ul d occ ur pri or t o 
pr ocee di n g.
Secti o n 4. 3. 5 Starti n g D ose f or 
C o m bi nati o n D ose Fi n di n g ( Part 1 B)

Clarificati o n a d de d ar o u n d d ose 
a dj ust me nts usi n g B L R M wit h 
res pect t o P F- 0 7 0 6 2 1 1 9.
Secti o n 4. 3. 7 Criteria f or D ose Escalati o n

Clarificati o n t hat Part 1 B will 
ha ve at least 3 D L T e val ua ble 
partici pa nts, w hic h was c ha n ge d 
fr o m pre vi o us at least 2 D LT 
e val ua ble partici pa nt.
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9 9
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale

F o ot n ote was a d de d t o Ta ble 1 f or 
clarificati o n, if t he 4 5 μ g 
s u bc uta ne o us ( S C) Q 2 W d ose is 
n ot t olerate d, t he n a l o wer d ose of 
3 0 μ g Q 2 W via S C r o ute will be 
e val uate d.

I ntra-partici pa nt d ose escalati o n 
g ui deli nes ha ve bee n re vise d s o 
t hat at least 2 c ycles be y o n d t he 
D L T peri o d f or t he ne xt 
i m me diate hi g her d ose le vel ha ve 
passe d pri or t o pr ocee di n g t o a 
hi g her d ose.
Secti o n 4. 3. 8 D ose L i miti n g T o xicit y 
Defi niti o n

T he defi niti o n of D L T e val ua ble 
partici pa nts ha ve bee n re vise d t o 
i ncl u de a ny partici pa nt t hat has a 
D L T irres pecti ve of w het her t he y  
recei ve d all pla n ne d d oses a n d 
recei ve d t he sc he d ule d safet y 
assess me nts.

D L T criteria ha ve bee n clarifie d 
f or c o nsiste nc y.

Gra de 4 v o miti n g or Gra de 4 
diarr hea has bee n a d de d as a D L T.

Gra de 3 C yt o ki ne Release 
S y n dr o me ( C R S) e ve nt criteria 
ha ve bee n clarifie d.
Secti o n 5. 1 I ncl usi o n Criteria 

I ncl usi o n criteria # 2 a n d # 3 ha ve 
bee n u p date d t o i ncl u de t hat f or 
Parts 1 A a n d 1 B partici pa nts m ust 
ha ve e x ha uste d all F D A or l ocal 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 0
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale
re g ulat or y a p pr o ve d treat me nts 
t hat w o ul d c o nfer si g nifica nt 
cli nicall y be nefit f or t heir disease.
Secti o n 5. 2 E xcl usi o n Criteria
E xcl usi o n criteri o n # 1 3 has bee n 
a d de d t o i ncl u de t he e xcl usi o n of 
partici pa nts wit h acti ve or hist or y  
of cli nicall y  si g nifica nt 
a ut oi m m u ne disease t hat re q uire d 
s yste mic i m m u n os u p pressi ve 
t hera py or a n ot her me dical 
c o n diti o n t hat re q uire d 
i m m u n os u p pressi o n wit hi n 2 
ye ars of treat me nt.
Secti o n 6. 1 St u d y  Inter ve nti o ns 
A d mi nistere d

Secti o n has bee n u p date d t o 
re m o ve i ntra ve n o us d ose 
a d mi nistrati o n a n d  i ntra ve n o us 
d ose pri mi n g.
Secti o n 6. 1. 1 A d mi nistrati o n 

Secti o n has bee n u p date d t o 
re m o ve i ntra ve n o us i nf usi o n 
a d mi nistrati o n a n d i ntra ve n o us 
d ose pri mi n g.

G ui da nce o n w here S C i njecti o ns 
s h o ul d be a d mi nistere d was a d de d 
f or clarificati o n.

I n patie nt m o nit ori n g f or C 1 D 1 5 
has bee n e xte n de d t o 8 h o urs p ost 
d ose.
Secti o n 6. 7 D ose M o dificati o n 
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 1
D oc u me nt Hist or y
Pr ot oc ol A me n d me nt s -0 1 t hr o u g h - 0 5
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges a n d R ati o n ale

Clarificati o n of d ose 
m o dificati o ns a n d d osi n g o pti o ns 
as a res ult of D L T ha ve bee n 
i ncl u de d.
Secti o n 8. 1. 6 I njecti o n Site T olera bilit y  
Assess me nt

Clarificati o n ma de f or S C d osi n g 
o nl y .
Secti o n 9. 2. 1 Part 1 D ose Escalati o n

Clarificati o n ar o u n d t otal n u m ber 
of partici pa nts i n t he c o m bi nati o n 
ar ms of Part 1 B.
Secti o n 9. 4. 1 Ma xi m u m T olerate d D ose 
Deter mi nati o n

Clarificati o n of t he starti n g d ose 
i n Part 1 A ( 4 5 µ g).
Secti o n 9. 4. 4. 1 P har mac o ki netic A nal ys es 

P har mac o ki netic ( P K) para meters 
i n v ol vi n g I V d osi n g (e g, C L a n d 
Vss) ha ve bee n re m o ve d.
Ori gi nal Pr ot oc ol
2 0 A u g ust 2 0 1 9
n/a
0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 2
1 1. R E F E R E N C E S
1.  
A h me di n, J., et al., Ca ncer Statistics. C A A Ca ncer J o ur nal f or Cli nicia ns.
2 0 0 9 ;5 9( 4): 2 2 5 - 4 9.
2.
Alle gra CJ, Jess u p J M, S o merfiel d M R, et al. A merica n S ociet y of Cli nical O nc ol o g y 
pr o visi o nal cli nical o pi ni o n: testi n g f or K R A S ge ne m utati o ns i n partici pa nts wit h 
metastatic c ol orectal carci n o ma t o pre dict res p o nse t o a nti- e pi der mal gr o wt h fact or 
rece pt or m o n ocl o nal a nti b o d y t hera p y. J Cli n O nc ol. 2 0 0 9;2 7( 1 2): 2 0 9 1 - 6.
3.
Alle n E, Ja b o uill e A, Ri vera L B et al. C o m bi ne d a ntia n gi o ge nic a n d a nti – P D -L 1 
t hera py sti m ulates t u m or i m m u nit y  t hr o u g h H E V f or mati o n. Sci Tra nsl Me d .
2 0 1 7 ;9( 3 8 5) :eaa k 9 6 7 9.
4. 
Ba n h olzer M L, Wa n del C, Barr o w P, et al. Cli nical trial c o nsi derati o ns o n male 
c o ntrace pti o n a n d c ollecti o n of pre g na nc y i nf or mati o n fr o m fe male part ner: u p date. 
Cli n Tra nsl Me d/ 2 0 1 6; 5( 1) : 2 3- 3 7.
5.
Bas hir et al. Sile nci n g t he G U C A 2 A -G U C Y 2 C t u m or s u p press or a xis i n CI N, serrate d, 
a n d M SI c ol orectal ne o plasia. H u ma n Pat h ol o g y. 2 0 1 9;8 7: 1 0 3 - 1 4.
6.
E M D Ser o n o, I nc ( 2 0 1 9). Hi g hli g hts of prescri bi n g i nf or mati o n. Ba ve nci o ® (a vel u ma b) 
i njecti o n. Retrie ve d fr o m htt ps:// w w w.e m dser o n o.c o m/c o nte nt/ da m/ we b/c or p orate/ n o n -
i ma ges/c o u ntr y-s pecifics/ us/ pi/ ba ve nci o-pi. p df.
7.
Be ns o n A B 3 r d, Aja ni J A, Catala n o R B et al. Rec o m me n de d g ui deli nes f or t he treat me nt 
of ca ncer treat me nt -i n d uce d diarr hea. J Cli n O nc ol. 2 0 0 4;2 2( 1 4): 2 9 1 8 - 2 6.
8.
A m ge n, I nc ( 2 0 1 9). Bli nc yt o ™ ( bli nat u m o ma b). Hi g hli g hts of prescri bi n g i nf or mati o n.
Retrie ve d fr o m htt ps:// w w w. pi.a m ge n.c o m/ ~/ me dia/a m ge n/re p osit or y sites/ pi-a m ge n-
c o m/ bli nc yt o/ bli nc yt o _ pi _ hc p _e n glis h. p df.
9. 
Bir be R, Palazz o J P, Walters R et al. H u m Pat h. 2 0 0 5; 3 6( 2): 1 7 0 - 9.
1 0.
Bra y F, Ferla y  J, S oerj o matara m I, et al. Gl o bal Ca ncer Statistics 2 0 1 8: G L O B O C A N 
esti mates of i nci de nce a n d m ortalit y  w orl d wi de f or 3 6 ca ncers i n 1 8 5 c o u ntries. Ca 
Ca ncer J Cli n. 2 0 1 8 ;6 8: 3 9 4 - 2 4.
1 1.
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P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 3
1 4.
Di Nic ola nt o ni o F, Marti ni M,
M oli nari F,
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1 6.
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(atez oliz u ma b) i njecti o n. Retrie ve d fr o m 
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3 7 5 9 3 9 4 0 0. 1 5 6 3 4 0 9 7 1 8 & _ gac = 1. 2 2 1 8 2 8 3 3 0. 1 5 6 3 4 0 9 7 1 8. Cj 0 K C Qj wjr v p B R C 0 A RI s A
Fr F u V _ U K K 7 L- U 7 w Sl 4 S A p M V 6 -
3c T G H 0 k S M 5 U Oc H v 8 n S b X N Nl 7 F N _ _t 0 V F 8a Ar d S E A L w _ wc B.
1 7.
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2 1.
Ge ne ntec h, I nc ( 2 0 1 9). Hi g hli g hts of prescri bi n g i nf or mati o n. Ke y tr u da®
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htt p:// w w w. merc k. c o m/ pr o d uct/ usa/ pi _circ ulars/ k/ ke y tr u da/ ke ytr u da _ pi. p df.
2 2.
Astra Ze neca ( 2 0 1 8). Hi g hli g hts of prescri bi n g i nf or mati o n. I mfi nzi ® ( d ur val u ma b) 
i njecti o n. Retrie ve d fr o m htt ps:// w w w.i mfi nzi hc p.c o m/ n o n-s mall-cell-l u n g-
ca ncer/sta ge -3/ d ur val u ma b -nsclc -cli nical-
trials. ht ml?s o urce =i mz _ n _ h _ 9 & u me di u m =c pc & ua d p u b = g o o gle & uca m pai g n = 2 0 1 9i mfi
nzi hc p nsclc bra n de d _ ge neral _ hc p & ucreati ve = bra n de d _al o ne _ p h & u place =i mfi nzi & o utc
o me = hc p &c m pi d = 1.
2 3.
Ki y oz u mi Y, I wats u ki M, Ya mas hita K, et al. U p date o n tar gete d t hera p y a n d i m m u ne 
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0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)


P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
Fi nal Pr ot oc ol A me n d me nt 7, 1 9 N o ve m ber 2 0 2 1
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0 4
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Lee D W, Sa nt o mass o B D, L oc ke F L, et al: A S T C T C o nse ns us Gra di n g f or C y t o ki ne 
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2 0 1 9 ;2 5: 6 2 5 - 3 8.
2 6.
“ Meta b olis m a n d Tra ns p ort, Dr u g I nteracti o n Data base”, De part me nt of P har mace utics, 
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2 7.
M o ore P A, S ha h K, Ya n g Y, Al ders o n R et al.
De vel o p me nt of M G D 0 0 7, a g p A 3 3 x 
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P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
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4 7.
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P F -0 7 0 6 2 1 1 9
C 3 8 6 1 0 0 1
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0 9 0 1 7 7 e 1 9 8 a 5 b 3 4 8\ A p pr o v e d\ A p pr o v e d O n: 1 9- N o v- 2 0 2 1 1 8: 4 9 ( G M T)

SAP_001.pdf: 
Protocol C3861001 (PF-07062119) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
Protocol C3861001 
 
 
 
 
A PHASE 1 DOSE ESCALATION AND EXPANSION STUDY EVALUATING THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS 
AND ANTI TUMOR ACTIVITY  OF PF-07062119 IN PATIENTS WITH 
ADVANCED GASTROINTESTINAL TUMORS 
 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
 
 
 
 
Version: 
1 
Date:  
14 Oct 2019
090177e19404d8e3\Approved\Approved On: 24-Jun-2020 12:17 (GMT)


Protocol C3861001 (PF-07062119) Statistical Analysis Plan 
 
 
PFIZER CONFIDENTIAL 
Page 2 
TABLE OF CONTENTS 
LIST OF TABLES .....................................................................................................................4 
LIST OF FIGURES ...................................................................................................................4 
APPENDICES ...........................................................................................................................4 
1. VERSION HISTORY ............................................................................................................5 
2. INTRODUCTION .................................................................................................................5 
2.1. Study Objectives, Endpoints and Estimands (part 1) ................................................5 
2.1.1. Primary Objectives .......................................................................................5 
2.1.2. Secondary Objectives ...................................................................................5 
2.1.3. Exploratory Objectives .................................................................................5 
2.2. Study Objectives, Endpoints, and Estimands (part 2) ...............................................6 
2.2.1. Primary Objectives .......................................................................................6 
2.2.2. Secondary Objectives ...................................................................................6 
2.2.3. Exploratory Objectives .................................................................................6 
2.3. Study Design .............................................................................................................7 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS (PART 1) ...............................................................................................10 
3.1. Primary Endpoint(s) ................................................................................................10 
3.2. Secondary Endpoint(s) ............................................................................................12 
3.3. Other Endpoint(s) ....................................................................................................12 
4. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS (PART 2) ...............................................................................................13 
4.1. Primary Endpoint(s) ................................................................................................13 
4.2. Secondary Endpoint(s) ............................................................................................13 
4.3. Other Endpoint(s) ....................................................................................................13 
4.4. Baseline Variables ...................................................................................................14 
4.5. Safety Endpoints .....................................................................................................14 
4.5.1. Adverse Events ...........................................................................................14 
4.5.2. Laboratory Data ..........................................................................................15 
5. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ...................................................15 
6. GENERAL METHODOLOGY AND CONVENTIONS ....................................................16 
6.1. Hypotheses and Decision Rules ..............................................................................16 
6.2. General Methods .....................................................................................................16 
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6.2.1. Analyses for Continuous Data ....................................................................16 
6.2.2. Analyses for Categorical Data ....................................................................16 
6.2.3. Analyses for Binary endpoints ....................................................................16 
6.2.4. Analyses for time-to-event data ..................................................................17 
6.3. Methods to Manage Missing Data ..........................................................................17 
6.3.1. Missing Dates .............................................................................................17 
6.3.2. Efficacy Analysis ........................................................................................17 
6.3.3. Pharmacokinetics ........................................................................................17 
6.3.3.1. Concentrations Below the Limit of Quantification ...................17 
6.3.3.2. Deviations, Missing Concentrations and Anomalous 
Values ................................................................................................18 
6.3.4. Pharmacokinetic Parameters .......................................................................18 
6.3.5. QTc .............................................................................................................18 
7. ANALYSES AND SUMMARIES ......................................................................................18 
7.1. Primary Endpoint(s) ................................................................................................18 
7.1.1. Dose Limiting Toxicities (DLTs) ...............................................................18 
7.1.2. Adverse Events ...........................................................................................20 
7.1.3. Laboratory abnormalities ............................................................................20 
7.2. Secondary Endpoint(s) ............................................................................................21 
7.2.1. Pharmacokinetic Analysis ..........................................................................21 
7.2.2. Pharmacodynamics Analysis ......................................................................21 
7.2.3. Immunogenicity Data Analysis ...................................................................21 
7.2.4. Tumor Response .........................................................................................21 
7.3. Baseline and Other Summaries and Analyses .........................................................22 
7.3.1. Baseline Summaries ....................................................................................22 
7.3.2. Study Conduct and Participant Disposition ................................................22 
7.3.3. Study Treatment Exposure .........................................................................22 
7.3.4. Concomitant Medications and Nondrug Treatments ..................................23 
7.4. Safety Summaries and Analyses .............................................................................23 
7.4.1. Adverse Events ...........................................................................................24 
7.4.2. Laboratory Data ..........................................................................................24 
7.4.3. Vital Signs ..................................................................................................24 
8. ELECTROCARDIOGRAMS ..............................................................................................24 
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8.1.1. Physical Examination .................................................................................27 
9. INTERIM ANALYSES .......................................................................................................27 
10. REFERENCES ..................................................................................................................27 
11. APPENDICES ...................................................................................................................28 
 
LIST OF TABLES 
Table 1. 
Analysis Sets .............................................................................................15 
Table 2. 
Safety QTc Assessment ............................................................................26 
Table 3. 
Progression Free Survival and Duration of Response ..............................29 
Table 4. 
Time to Progression ..................................................................................29 
Table 5. 
Response Evaluation Criteria in Solid Tumors by RECIST 1.1 ...............34 
Table 6. 
Objective Response Status at Each Evaluation for Patients with Non 
Target Disease Only .................................................................................34 
Table 7.  
Overall Response Derived from Changes in Index, Non-index and 
New Lesions .............................................................................................36 
 
LIST OF FIGURES 
Figure 1. 
Dose Escalation (BLRM design) ................................................................9 
 
APPENDICES 
Appendix 1. Summary of Efficacy Analyses ...........................................................................28 
Appendix 2. Time to Event Data Analysis Censoring Rules ...................................................29 
Appendix 3. Categorical Classes for ECG and Vital Signs .....................................................30 
Appendix 4. RECIST 1.1 Tumor Assessment Criteria ............................................................31 
Appendix 5. Immune-Related Response Criteria Derived from RECIST 1.1 
(irRECIST) ...............................................................................................35 
 
 
 
 
 
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1. VERSION HISTORY 
This is the first version. 
2. INTRODUCTION 
PF-07062119 is an anti-Guanylyl Cyclase 2C (GUCY2c)/anti-CD3 bispecific Fc diabody 
targeting CD3 on T cells with one binding domain and GUCY2c with the other binding 
domain. PF-07062119 acts as a T cell redirecting bispecific for the treatment of 
gastrointestinal tumors including colorectal, gastric and esophageal adenocarcinomas. 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3861001.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment. 
2.1. Study Objectives, Endpoints and Estimands (part 1) 
2.1.1. Primary Objectives  
To assess safety and tolerability of increasing dose levels of PF-07062119 administered in 
patients with advanced gastrointestinal tumors, including colon, gastric and esophageal 
adenocarcinomas, for whom no standard therapy is available in order to estimate the 
Maximum Tolerated Dose (MTD) and select the Recommended Phase 2 Dose (RP2D) (as a 
monotherapy in Part 1A and in combination therapy in Part 1B with select tumor(s)). 
2.1.2. Secondary Objectives 
• To characterize the single and multiple dose pharmacokinetics (PK) of PF-07062119. 
• To evaluate the immunogenicity of PF-07062119.  
• To evaluate the immunogenicity of PF-06801591 and bevacizumab-Pfizer given in 
combination with PF-07062119 (part 1B). 
• To evaluate immune cells in archival biopsies and/or pre and post treatment biopsies 
(if available). 
• To evaluate preliminary anti-tumor activity. 
2.1.3. Exploratory Objectives 
• To explore preliminary anti-tumor activity by standard and immune related response 
criteria and time to event endpoint.  
• To explore the relationship between target expression and biomarkers in archival 
tumor biopsies and/or pre and post treatment tumor biopsies (if available), whole 
blood and serum samples in order to elucidate mechanism of action and response to 
therapy.  
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• To explore additional biomarkers related to clinical response, in order to elucidate 
the mechanism of action of PF-07062119, predict response to therapy and to 
understand resistance mechanisms that may predict escape from therapy. 
• To evaluate T, B, and Natural Killer (NK) subtypes for immunophenotyping in 
addition to T cell proliferation, activation, and exhaustion markers in whole blood.  
• To explore cytokines and chemokines as pharmacodynamic (PD) markers in pre and 
on treatment serum samples. 
• To explore the tumor biomarker carcinoembryonic antigen (CEA) levels. 
• To enable exploratory research through collection of banked biospecimens, unless 
prohibited by local regulations or ethics committee decision. 
 
2.2. Study Objectives, Endpoints, and Estimands (part 2) 
2.2.1. Primary Objectives  
• To confirm safety and tolerability and explore preliminary evidence of anti-tumor activity 
of PF-07062119 at the RP2D in patients with advanced colorectal adenocarcinomas (as 
a monotherapy and in combination therapy). 
2.2.2. Secondary Objectives 
• To evaluate the PK of PF-07062119 at the RP2D. 
• To evaluate the immunogenicity of PF-07062119. 
• To evaluate the immunogenicity of PF-06801591 and bevacizumab-Pfizer given in 
combination with PF-07062119. 
• To evaluate immune PD effects of PF-07062119 between pre-treatment and post 
treatment tumor biopsies. 
• To evaluate preliminary anti-tumor activity through time to event endpoints. 
2.2.3. Exploratory Objectives 
• To document any anti-tumor activity as assessed by immune related response criteria. 
 
• To explore the relationship between target expression and biomarkers in archival 
tumor biopsies and/or pre and post treatment tumor biopsies, whole blood and serum 
samples in order to elucidate mechanism of action and response to therapy. 
• To explore additional biomarkers related to clinical response, in order to elucidate 
the mechanism of action of PF-07062119, predict response to therapy and to 
understand resistance mechanisms that may predict escape from therapy. 
 
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• To evaluate T, B and NK subtypes for immunophenotyping in addition to T cell 
proliferation, activation and exhaustion markers in whole blood. 
 
• To explore cytokine and chemokine PD markers in pre and on treatment serum 
samples. 
 
• To explore the tumor biomarker carcinoembryonic antigen (CEA) levels. 
 
• To enable exploratory research through collection of banked biospecimens, unless 
prohibited by local regulations or ethics committee decision.  
2.3. Study Design 
This is a phase I, open-label, multi-center, multiple-dose, safety, PK and PD study of 
PF-07062119.  This study contains two parts, single agent dose escalation (Part 1A) and 
dose finding in combination with anti-PD-1 and in combination with anti-VEGF (Part 1B) 
followed by dose expansion (part 2).  
Part 1A will estimate the MTD and/or RP2D of PF-07062119 as a monotherapy. In Part 1A, 
sequential cohorts of patients with advanced gastrointestinal tumors, including colorectal, 
gastric and esophageal adenocarcinomas, who are not candidates for regimens known to 
provide clinical benefit will receive escalating doses of PF-07062119 administered as 
subcutaneous (SC) injection as guided by the Bayesian Logistic Regression Model 
(BLRM).With the determination that a dose level is safe following a DLT observation period 
of 28 days and based on the discussion by the safety review team, dose escalation will 
proceed to the next dose level. The SC route has the potential to reduce the Cmax which is 
believed to be associated with CRS and inflammatory responses, a common adverse event for 
bispecific antibodies. The starting SC dose is 45 μg Q2W. Maximum dose increases from the 
previous dose levels will be up to 200%, which is a consistent approach with biologic 
compounds including an anti CD3 bispecific (Saber et al, 2017),37 but will be adjusted to no 
more than 100% following the observation of a DLT or if there are two Grade 2 or higher 
clinically significant treatment related AEs. Cohort size will be approximately 3 participants. 
The first cohort of 45 μg Q2W in Part 1A will have at least 1 DLT-evaluable participant. All 
other cohorts in Part 1A will have at least 2 DLT evaluable participants. Part 1A is 
estimated to enroll approximately 30 participants, but the actual number of participants 
enrolled will depend on the tolerability of PF-07062119 and the number of dose levels 
required to identify the MTD, but will include at least 6 participants treated at the 
recommended RP2D/MTD. 
 
 In Part 1B, the dose finding evaluation with PF-07062119 in combination with anti-PD-1 
[PF-06801591] and in combination with anti-VEGF [bevacizumab-Pfizer]) will occur in 
patients with colorectal, gastric and esophageal adenocarcinomas.  
Upon determining the single agent PF-07062119 RP2D/MTD, the Part 1B cohort will be 
initiated to explore safety, tolerability and preliminary anti-tumor activity of PF-07062119 in 
combination with in combination with PF-06801591and bevacizumab-Pfizer according to 
the following considerations: 
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• BLRM will be used to guide the dose escalation/de-escalation process for each 
combination (PF-07062119/PF-06801591 and PF-07062119/ bevacizumab-Pfizer ) 
separately. The determination of the safety for a given dose level for each combination 
will be based on the discussion by the safety review team. 
• For the PF-07062119 and /PF-06801591combination, the starting dose of PF-07062119 
in combination with PF-06801591 will be one dose level lower than the PF-07062119 
monotherapy MTD in order to account for any potential increase in CRS that might be 
associated with the PF-07062119/PF-06801591 combination. If the PF-07062119 RP2D 
from Part 1A is lower than the MTD, the RP2D will be used in combination with PF-
06801591. Study participants will be evaluated for the safety and tolerability of the 
combination and for appropriate PF-07062119 dose adjustment; the PF-07062119 dose 
used in the next cohort may remain the same, escalated, or de-escalated as guided by 
emerging clinical data and the BLRM design. Maximum increases of PF-07062119 from 
the previous level will be 100%. However, PF-07062119 will not be dose escalated 
beyond the MTD/RP2D for PF-07062119 as a single agent in Part 1A. The dose of PF-
06801591 will remain unchanged at 300 mg Q4W SC throughout the safety assessment 
period. Additionally, a less frequent PF-07062119 dosing regimen (eg, Q4W) or a 
staggered dosing approach (eg, PF-07062119 to be initiated alone on C1D1 and PF-
06801591 to be initiated after 1or 2 weeks) may be attempted as guided by the clinical 
data. 
The cohort size at each dose level of Part 1B for the PF-07062119/PF-06801591 and 
PF-07062119/bevacizumab-Pfizer combination will each be approximately 3 
participants; all cohorts in Part 1B will each have at least 3 DLT evaluable participants. 
Part 1B is estimated to enroll approximately 20 participants (10 for each combination), 
but the actual number of participants enrolled will depend on the tolerability of 
PF-07062119 in combination with PF-06801591 and with bevacizumab-Pfizer and the 
number of dose levels required to identify the corresponding PF-07062119 MTDs in the 
combination setting, but will include at least 6 participants treated at the corresponding 
recommended RP2D/MTDs. As the RP2D/MTD is approached or the RP2D/MTD of 
PF-07062119 has been determined, an optional subset of participants may be enrolled 
(approximately 6-12 patients) with the requirement of providing mandatory paired fresh 
pre-treatment and on-treatment biopsy samples in Parts 1A and 1B to enable evaluation 
of tissue biomarker PD activity.  The option to enroll the subset of participants for 
mandatory paired tumor samples will be based on evaluation of emerging clinical data 
including available safety/tolerability, PK, and PD findings by the sponsor. 
In Part 2, the dose expansion phase will evaluate the RP2D of PF-07062119 as 
monotherapy and with a combination agent (anti-PD-1 [PF-06801591] and anti-VEGF 
[bevacizumab-Pfizer]) in patients with colorectal adenocarcinoma.  In Part 2, 
approximately 60 patients will be enrolled; 20 patients in each monotherapy and  
combination cohorts.  Responses in these initial dose expansion arms may lead to further 
evaluation of PF-07062119 in additional tumor indications and combination therapies. 
 
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Fresh pre-treatment biopsies in Part 2 will be required from all patients in all cohorts in 
order to establish relationship between target expression and efficacy observations.  For a 
subset of patients in all cohorts (approximately 10 patients) mandatory fresh pre-treatment 
and on-treatment biopsy samples will be collected in order to confirm the mechanism of 
action and evaluate potential resistance mechanism during treatment.  
Number of Participants: In the overall first -in-patient (FIP) study, up to approximately 
110 patients are expected to be enrolled. Part 1 is estimated to enroll approximately 50 
participants (30 participants in Part 1A and 10 patients in Part 1B for each of combination 
partners).  In Part 2, approximately 20 patients will be enrolled in each monotherapy and 
combination cohorts.   
C3861001 Study Schema  
Figure 1. Dose Escalation (BLRM design) 
 
There will also be a minimum 72-hour interval between the first dose administered to each of 
the initial patients (ie, patients contributing to initial DLT evaluation) enrolled at a new dose 
level to allow the detection of possible infusion-site reactions or possible cytokine release 
syndrome.  All patients will be observed in-patient for at least 48 hours after the first SC dose 
on Cycle 1 Day 1 (C1D1) for Part 1 and for at least 8 hours after the second SC dose on 
Cycle 1 Day 15 (C1D15).  Patients should remain in house for observation for at least 
1-hour post dose for all visits after C1D15 and may only be released after the investigator 
has confirmed the patient has not exhibited signs of cytokine reaction.  
Treatment with study intervention will continue until either disease progression, patient 
refusal, or unacceptable toxicity occurs, whichever is earliest, unless the investigator and 
medical monitor agree to treatment beyond disease progression based on individual 
benefit/risk assessments. 
The biomarker studies will be used to help understand the in vivo mechanism of action of the 
agent(s) studied as well as potential mechanisms of resistance.  The studies may help in the 
future development of PF-07062119 as a single agent, or in combination with other 
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compounds, and may provide information on tumor sub-types that may respond to the 
Investigational Product.  
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS (PART 1) 
3.1. Primary Endpoint(s) 
•  First cycle Dose Limiting Toxicities (DLTs). 
A participant is classified as dose-limiting toxicity (DLT)-evaluable if he/she 
experiences a DLT (irrespective of whether they received all of the planned doses of 
each investigational product and study intervention and scheduled safety assessments 
during the DLT window) or if he/she otherwise in the absence of a DLT receives all of 
the planned doses of each investigational product and study intervention and has 
received scheduled safety assessments during the DLT window.  If a participant fails 
to meet these criteria, he/she may be replaced.   
Dose limiting toxicities (DLT) will be assessed through Cycle 1 (28-day cycle with 
Day 29 (eg, C2D1) laboratory assessments).   
For the purpose of dose escalation, the DLT observation period for Q2W SC regimen 
will be during the first cycle (28 days after the start of study treatment) in each 
participant. 
Significant adverse events considered to be related to the investigational product or 
treatment under investigation that occur after the DLT observation period will be 
reviewed in context of all safety data available.  That review may result in re-
evaluation of the dosing level or regimen.  
Severity of adverse events will be graded according to Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0.   
For the purpose of dose escalation, any of the following AEs with the associated 
parameters that occur in the first cycle of treatment or within 28 days after the start 
of the study treatment which are attributable to one, the other, or both agents in the 
combination will be classified as DLTs:  
: 
Hematological DLTs: 
1.  Grade 3 neutropenia must last >5 days. 
2.  Febrile neutropenia is a DLT defined as an absolute neutrophil count (ANC) <1.0 x 109/L 
with a single temperature of >38.3C, or 101oF, or a sustained temperature of 38C, or 
100.4F, for more than one hour. 
3.  Grade 3 neutropenia with infection is a DLT.  
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4.  Grade 3 thrombocytopenia with Grade 2 (clinically significant) bleeding is a DLT. 
5.  Grade 4 thrombocytopenia is a DLT. 
6.  Anemia or thrombocytopenia requiring transfusion. 
Non-hematological Exceptions: 
1. Grade ≥3 fatigue lasting ≥7 days is a DLT. 
 
2. For participants with liver, bone, or lung metastasis, an AST or ALT increase 
>8 x ULN or alkaline phosphatase >10 x ULN is a DLT. 
 
3. Confirmed drug induced liver injury (DILI) meeting Hy’s law criteria is a DLT. 
 
4.  Grade ≥3 vomiting or diarrhea lasting ≥3 days despite adequate treatment 
(eg, antiemetic or antidiarrheal medications, respectively) and other supportive care is 
a DLT. 
 
5. Grade ≥3 CRS considered not to be due to an IRR, allergic reaction or anaphylaxis 
[unless i) not maximally treated or ii) events that are maximally treated, 
(eg, including the use of indicated immunosuppressive therapy and/or vasopressors), 
and resolve to ≤ Grade 2 within 72 hours] is a DLT. 
 
6.  Grade ≥3 QTcF prolongation irrespective of duration is a DLT. 
 
7.  Any death not clearly due to the underlying disease or extraneous causes is a DLT. 
 8.  Clinically important or persistent toxicities (e.g., toxicities responsible for significant 
dose delay) that are not included in the above criteria may also be considered a DLT 
following review by the investigators and the Sponsor.  All DLTs need to represent a 
clinically significant shift from baseline. 
Otherwise, adverse events of CTCAE Grade greater than or equal to 3 will be considered to 
be DLTs, with the exception of the AE’s listed below. 
The following AEs will not be adjudicated as DLTs: 
 1.  Isolated Grade 3 laboratory abnormalities that are not associated with clinical sequelae 
and are corrected with supplementation/appropriate management within 72 hours of their 
onset. 
2.  Grade 3 amylase or lipase elevation not associated with clinical symptoms or clinical 
manifestations of pancreatitis. 
3.  Grade 3 infusion related reaction (IRR), allergic reaction or anaphylaxis will not be 
considered as DLTs but may be a reason for study discontinuation and will be reviewed with 
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the sponsor. The MTD is defined as a dose with probability of DLT from the target toxicity 
internal.  The target interval for the DLT rate is defined as [0.16, 0.33].  
• Adverse Events as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
version [v.5.0], timing, seriousness, and relationship to study therapy. Detailed 
description is available in section 4.5.1. 
• Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE version [v.5.0]), and timing. 
3.2. Secondary Endpoint(s) 
• Pharmacokinetic parameters of PF-07062119: 
• Cycle 1 and Cycle 4 PK parameters maximum concentration (Cmax), time to achieve 
Cmax (Tmax), area under the concentration versus time curve from time zero to the last 
quantifiable concentration (AUClast). If data permits, other PK parameters will be 
derived such as apparent clearance (CL/F), terminal half-life (t1/2), and the area 
under the plasma concentration-time profile from time zero extrapolated to infinite 
time (AUC inf). 
• Pre-dose trough concentrations after multiple doses of PF-07062119. 
• Incidence and titers of anti-drug antibodies (ADA) and neutralizing antibodies 
against PF-07062119. 
• Incidence and titers of ADA and Nab against PF-06801591 and bevacizumab-Pfizer 
given in combination with PF-07062119 (Part 1B). 
• Assessment of intra-tumor T cells (eg, CD8 IHC). 
• Objective response, as assessed using the Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1. 
3.3. Other Endpoint(s) 
The exploratory endpoints are: 
• Progression free survival (PFS) and duration of response (DOR) by RECIST version 
1.1. 
• Overall Tumor assessment by the Immune Related Response Criteria in Solid Tumor 
(irRECIST) (criteria and immune-related progression free survival (irPFS). 
• GUCY2c expression levels in archival and/or pre and on/post treatment tumor 
biopsies. 
• Immunophenotyping of blood Immune cell subtypes frequency and activation.   
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• Intra-tumor immune pathway modulation, gene expression profiles, DNA mutations 
and immune cell biomarkers in pre- and post-dose tumor biopsies. 
• Cytokine and chemokine PD markers in pre and on treatment serum samples. 
•  CEA levels in serum. 
• Potential results from exploratory analysis of banked biospecimens (these results may 
or may not be generated in the context of the present study). 
Detailed methodology for summary and statistical analyses of the exploratory endpoints 
collected in this study will be further detailed in a biomarker statistical analysis plan (bSAP), 
which will be maintained by the sponsor. 
4. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS (PART 2) 
4.1. Primary Endpoint(s) 
• Adverse Events as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 
[v.5.0])), timing, seriousness, and relationship to study therapy. 
• Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE version [v.5.0]), and timing. 
• Objective response rate (ORR) as determined by the Response Evaluation Criteria in 
Solid Tumor (RECIST) version 1.1 criteria. 
4.2. Secondary Endpoint(s) 
• Pharmacokinetic parameters and concentrations of PF-07062119.  
o Pre-dose trough concentrations after multiple doses of PF-07062119. 
• Incidence and titers of ADA and Nab against PF-07062119. 
• Incidence and titers of ADA and Nab against PF-06801591 and bevacizumab-Pfizer 
given in combination with PF-07062119. 
• Assessment of increased intra-tumor T cells following PF-07062119 treatment (eg, CD8 
IHC). 
• PFS and DOR by RECIST version 1.1. 
4.3. Other Endpoint(s) 
• irRECIST and irPFS. 
 
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• GUCY2c expression levels in archival and/or pre- and on/post-treatment tumor 
biopsies. 
 
• Immunophenotyping of blood Immune cell subtypes frequency and activation.  
  
• Intra-tumor immune pathway modulation, gene expression profiles, DNA mutations 
and immune cell biomarkers in pre- and post-dose tumor biopsies. 
 
• Cytokine and chemokine PD markers in pre- and on-treatment serum samples. 
 
• Serum CEA levels. 
 
• Potential results from exploratory analysis of banked biospecimens (these results may 
or may not be generated in the context of the present study). 
4.4. Baseline Variables 
Baseline characteristics will be collected according to Schedule of Activities as specified in 
the protocol.  No baseline variable will be used for stratification or as covariates in the 
statistical analysis.  Unless otherwise specified, the baseline value is defined as the value 
collected at the time closest to, but prior to, the start of study drug administration in the first 
cycle.  
Laboratory baseline will be the last predose measurement of before the first dose of any 
component of the study treatment. 
Baseline for ECG is defined as Cycle 1 Day 1 predose. ECG measurements (an average of 
the triplicate measurements) will be used for the statistical analysis and all data presentations.  
4.5. Safety Endpoints 
4.5.1. Adverse Events 
Severity of adverse events will be graded according to Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0.  
For the purpose of dose escalation, any of the following AEs occurring in the first cycle of 
treatment or within 28 days after the start of the study treatment which are attributable to 
one, the other, or both agents in the combination will be classified as DLTs. 
 
The definitions of an AE and an SAE can be found in Appendix 3 of the protocol. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE or that caused the participant to discontinue 
the study. 
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In addition, the investigator may be requested by Pfizer Safety to obtain specific follow up 
information in an expedited fashion. 
4.5.2. Laboratory Data 
 
Temperature (oral, tympanic, temporal or axillary), blood pressure (BP) and pulse rate will 
be assessed.  
Further details of the laboratory tests can be found in Appendix 2 of the protocol. 
5. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior releasing the database and classifications will be 
documented per standard operating procedures. 
Table 1. 
Analysis Sets 
 
Population 
Description 
Full analysis set 
The full analysis set includes all enrolled participants. 
Per protocol analysis set 
(Evaluable for MTD) 
The per protocol analysis set includes all enrolled participants 
who had at least one dose of study treatment and either 
experienced DLT or do not have major treatment deviations 
during the DLT observation period.  
Safety set 
The safety analysis set includes all enrolled participants who 
receive at least one dose of study treatment. Unless otherwise 
specified the safety analysis set will be the default analysis set 
used for all analyses. 
Modified Intent to Treat 
(mITT) 
The modified intent to treat (mITT) is the analysis population 
that will follow the ITT principle and include participants 
receiving at least 1 dose of study medication with baseline 
assessment and at least 1 post baseline assessment, disease 
progression, or death before the first tumor assessment.  The 
mITT population may be used for interim analysis and 
conference presentations when the study is still ongoing. 
PK analysis 
The PK parameter analysis population is defined as all enrolled 
participants treated who do not have protocol deviations 
influencing PK assessment, and have sufficient information to 
estimate at least 1 of the PK parameters of interest. 
The PK concentration population is defined as all enrolled 
participants who are treated and have at least 1 analyte 
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Population 
Description 
concentration. 
Response Evaluable 
The response evaluable population will include all participants 
who received at least one dose of study treatment and had 
baseline disease and at least one post baseline disease 
assessment. 
PD/Biomarker 
The PD/Biomarker analysis population is defined as all enrolled 
participants with at least 1 of the PD/Biomarkers evaluated at 
pre and/or post dose. 
Immunogenicity analysis 
set 
The immunogenicity analysis set includes all enrolled 
participants who receive at least one dose of study treatment 
and have at least one sample tested for ADA. 
 
6. GENERAL METHODOLOGY AND CONVENTIONS 
6.1. Hypotheses and Decision Rules 
There will be no formal hypothesis testing in this study. 
6.2. General Methods 
The data are summarized by cohort defined by the initial dose of the study drug.  DLT rates 
at the study dose levels will be presented via mean and medians and a Bayesian credible 
interval based on the posterior density from the full probability model and will be used for 
the dose escalation decision meetings.  
6.2.1. Analyses for Continuous Data 
Continuous data will be summarized with the mean, median, minimum, maximum, 
coefficient of variation and standard deviation.  Missing values will be excluded from the 
analysis. 
6.2.2. Analyses for Categorical Data  
Categorical data will be summarized by number of unique patient incidence.  Missing data 
will be excluded from the analysis.  
6.2.3. Analyses for Binary endpoints 
Binary data will be summarized using number of unique patient incidence, and Wilson’s 
confidence interval for binomial proportions will be presented if warranted. 
Binary endpoints in this study include ORR, complete response (CR), partial response (PR) 
based on RECIST 1.1.  Descriptive statistics along with the corresponding 2-sided 
95% confidence intervals using an exact method will be provided for these endpoints if the 
sample size per cohort permits. 
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6.2.4. Analyses for time-to-event data 
The time-to-event data will be presented for individual patient and by cohort when 
applicable.   
6.3. Methods to Manage Missing Data 
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied. 
6.3.1. Missing Dates 
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the 
calculation results in a negative time duration (eg, date of onset cannot be prior to day one 
date).  In this case, the date resulting in 0 time duration will be used.  Pfizer standards are 
also used if both month and day are missing (Jan 1 unless negative time duration).  This 
excludes the pharmacokinetic, ECG, and pharmacodynamic analyses, which will only use the 
actual date collected or if date not available deem the data missing. 
6.3.2. Efficacy Analysis 
Response Evaluable Set will be used for all response related analyses including ORR, DOR, 
and PFS.  
Tumor response will be presented in the form of participant data listings that include, but are 
not limited to tumor type, dose on Day 1, tumor response at each visit, and best overall 
response. 
Part 1A and Part 1B: Progression date, death date, date of first response and last tumor 
assessment date and date of last contact will be listed. 
Part 2: The Kaplan-Meier methods will be used to analyze all time to event endpoints. 
Median PFS (if reached).  
PFS is defined the time from start date to date of first documentation of progression, or death 
due to any cause. Progression is defined as the appearance of local, regional or distant 
disease of the same type after complete response or progression of pre-existing lesions. It 
does not include second primary malignancies of unrelated types. 
For the time-to-event endpoints, the missing data handling method will be censoring. 
Censoring rules for time-to-event endpoints are detailed in Appendix 2. 
6.3.3. Pharmacokinetics  
6.3.3.1. Concentrations Below the Limit of Quantification 
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.) 
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6.3.3.2. Deviations, Missing Concentrations and Anomalous Values 
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true: 
1. A concentration has been collected as ND (ie not done) or NS (ie no sample), 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist. 
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing. 
6.3.4. Pharmacokinetic Parameters 
Actual PK sampling times will be used in the derivation of PK parameters. 
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie not calculated). (Note that NC values will not be generated beyond the 
day that a subject discontinues.) 
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular dose with ≥3 evaluable measurements. 
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses. 
6.3.5. QTc 
For the QTc analyses, no values will be imputed for missing data. 
7. ANALYSES AND SUMMARIES 
7.1. Primary Endpoint(s) 
7.1.1. Dose Limiting Toxicities (DLTs) 
• Analysis set: Per protocol analysis set. Dose limiting toxicities (DLT) will be 
assessed during Cycle 1 (the first 28 days) to inform dose escalation and determine 
the MTD.   
• Analysis methodology:  
Statistical Methods:  
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The dose escalation in the Part 1A and Part 1B of the study will be guided by a Bayesian 
analysis of dose limiting toxicity (DLT) data for PF-07062119. Toxicity is modelled using 
two-parameter logistic regression for the probability of a participant experiencing a DLT at 
the given dose.   
Assessment of participant risk (the three dosing intervals boundaries can be modified): 
After each cohort of participants, the posterior distribution for the risk of DLT for new 
participants at different doses of interest for PF-07062119 will be evaluated.  The posterior 
distributions will be summarized to provide the posterior probability that the risk of DLT lies 
within the following intervals:  
 
Under-dosing: 
[0, 0.16] 
Targeted dosing: 
[0.16, 0.33] 
Overdosing: 
[0.33, 1] 
 
The escalation with overdose control (EWOC) principle: 
Dosing decisions are guided by the escalation with overdose control principal (Rogatko 
2007).  A dose may only be used for newly enrolled participants if the risk of excessive 
toxicity at that dose is less than 25%. 
Prior distributions: 
Weakly informative prior distributions based on pre-clinical/expert opinion information will 
be chosen for the logistic parameters for prior distribution in Part 1A, see Appendix 10.10. 
A meta-analytic-predictive (MAP) approach will be used to derive the prior distribution for 
model parameters used in Part 1B based on the data collected in Part 1A.  The MAP prior 
for the logistic model parameters for this study is the conditional distribution of the 
parameters given the historical data (see Spiegelhalter 2004, Neuenschwander 2010, 
Neuenschwander 2014).  MAP priors are derived from hierarchical models, which take into 
account possible differences between the studies.  A full description of the application of the 
MAP approach to derive the prior distributions of the model parameters is given in Appendix 
10.9.  
Starting dose: 
The starting dose is 45 µg. For this dose the prior risk of overdosing is 9.7%, which satisfies 
the EWOC criterion.  A full assessment of the prior risk to participants is given in Appendix 
10.9.  
The maximum number of participants in dose escalation part of the trial was set to 50.  The 
trial will be stopped when the following criteria are met: 
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• At least 6 participants have been treated at the recommended MTD/RP2D, ď. 
• The dose ď satisfies one of the following conditions: 
• The probability of target toxicity at dose ď exceeds 50%,  
i.e. Pr(0.16 ≤ πd <0.33)≥50%.  
• A minimum of 15 participants have been treated in the trial. 
Intercurrent events and missing data: Cohort size will be approximately 3 participants, with 
at least 1 DLT-evaluable participant per cohort in the first dose level of Part 1A and at least 2 
DLT evaluable participants per cohort in the remaining cohorts of Part 1A  and at least 3 
DLT-evaluable participants per cohort in Part 1B.  The actual number of patients enrolled 
will depend on the tolerability of PF-07062119 and the number of dose levels required to 
identify the MTD. Missing values will not be imputed. 
7.1.2. Adverse Events 
• Analysis set: Safety analysis set.    
• Analysis methodology:  characterized by type, frequency, severity (as graded by 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI 
CTCAE version 5.0]) timing, seriousness, and relationship to study therapy. Further 
description is given in section 7.4.1.  The treatment emergent adverse events will be 
defined according to Pfizer’s standard definition.  
• Intercurrent events and missing data: intermediate missing values will not be imputed. 
7.1.3. Laboratory abnormalities 
• Analysis set: safety analysis set.   
• Analysis methodology: Presented as tables and characterized by type, frequency, 
severity (as graded by NCI CTCAE version 5.0), and timing.  The number and 
percentage of participants who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay.  
The analyses will summarize laboratory tests both on the entire study period and by 
cycle (Cycle 1 and Cycles beyond 1).  For laboratory tests without CTCAE grade 
definitions, results will be categorized as normal, abnormal, or not done.  Shift tables 
or figures may be created for select laboratory abnormalities.  Results meeting the 
Hy’s Law as defined in the protocol may also be presented as tables or listings. 
• Intercurrent events and missing data: intermediate missing values will not be imputed. 
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7.2. Secondary Endpoint(s) 
7.2.1. Pharmacokinetic Analysis 
The concentrations of PF-07062119 will be summarized by descriptive statistics (n, mean, 
standard deviation, coefficient of variation, median, minimum maximum, and geometric 
mean) by dosing cohort, cycle, and nominal time.  Individual patient and median profiles of 
the concentration-time data will be plotted by dosing cohort and cycle using nominal times.  
Median profiles will be presented on both linear-linear and log-linear scales. 
The individual concentration-time data of PF-07062119 following the Cycle 1 Day 1 dose 
and Cycle 4 Day 1 dose will be analyzed separately using non-compartmental analysis to 
estimate the PK parameters.  The PK parameters estimated will include Cmax, time to 
maximum concentration (Tmax), and concentration versus time curve (AUClast).  If data permit 
or if considered appropriate, other PK parameters including terminal elimination half-life 
(t1/2), clearance (CL or CL/F), and volume of distribution at steady state (Vss or Vss/F) may be 
determined.  Actual sample collection times will be used for the parameter calculations. 
The concentrations of PF-06801591 or bevacizumab-Pfizer from Part 1B and Part 2 will be 
summarized by descriptive statistics (n, mean, standard deviation, coefficient of variation, 
median, minimum maximum, and geometric mean) by dosing cohort, cycle, and nominal 
time. 
Pharmacokinetic/Pharmacodynamic (PK/PD) Correlation 
PK and data from this study may be analyzed using population modeling approaches and 
may also be pooled with data from other future studies to investigate any association 
between PF-07062119 exposure and biomarkers or selected safety and/or efficacy endpoints.  
The results of these analyses, if performed, may be reported separately from the clinical 
study report. 
7.2.2. Pharmacodynamics Analysis 
For biopsy samples, summary statistics (eg, the mean and standard deviation, median, and 
minimum/maximum levels of continuous, and frequencies and percentages of categorical 
biomarker measures) will be determined at baseline and post-treatment. 
7.2.3. Immunogenicity Data Analysis 
For the immunogenicity data, the percentage of patients with positive ADA will be 
summarized.  Listings and summary tabulations of the ADA data at baseline and 
post-randomization will be generated.  Samples may also be analyzed for the presence of 
neutralizing antibodies (NAb), and any data will be similarly summarized.  For patients with 
positive ADA or NAb, the magnitude (titer), time of onset, and duration of ADA or NAb 
response will also be described, if data permit.  The potential impact of immunogenicity on 
PK and clinical response including pharmacodynamic markers, safety/tolerability and 
efficacy will be explored, if warranted by the data. 
7.2.4. Tumor Response  
• Overall Response Rate (ORR).   
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• ORR as assessed using RECIST version 1.1. ORR is defined as the proportion of 
patients who achieved completed response (CR) or partial response (PR) per RECIST 
1.1. 
• Duration of Response (DOR). 
• Duration of response is defined as the time from start date (which is the date of first 
documentation of PR or CR) to date of first documentation of objective progression 
or death.  DOR is only applicable to those patients with an objective response. 
• Analysis set: Response Evaluable.  
• Intercurrent events and missing data: Data after study drug discontinuation and rescue 
will be excluded; intermediate missing values will not be imputed. 
7.3. Baseline and Other Summaries and Analyses 
7.3.1. Baseline Summaries 
Baseline characteristics such as demographics, prior medication, medical history, ECOG 
performance status, and primary diagnosis will be tabulated and listed.  For ECOG 
performance status a shift table (worst post-baseline vs baseline) may be produced.  The 
Safety Analysis Set will be used. 
7.3.2. Study Conduct and Participant Disposition 
An accounting of the study patients will be tabulated.  The subject evaluation groups will be 
listed.  The Full Analysis Set will be used.  
Subject discontinuation from treatment and study will be tabulated and listed separately with 
their reason for discontinuation.  The Safety Analysis Set will be used. 
7.3.3. Study Treatment Exposure 
The safety analysis set will be used. 
Dose modifications are described in the protocol.  The following will be summarized by 
subject for overall and each dose level: 
• Number of subjects per dose level;  
• Median and range of number of cycles started per subject;  
• Number (%) of subjects starting a cycle (1, 2, 3…);  
• Number (%) of dose interruptions (include both known and unknown dates);  
• Number (%) of subjects with dose reductions;  
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• Number (%) of each reason (drug related AE vs AE vs. Other) dose interruptions and 
dose reductions;  
• Time on treatment (median, range). 
The following will be summarized by cycle received for overall and each dose level:  
• Total number of cycles started;  
• Number of cycles started per subject (median, range);  
• Number of cycles before 1st reduction (median, range);  
• Number of cycles before 1st interruption (median, range).  
The following will be summarized for cumulative dose by dose level and cycle:  
• Summary statistics (mean, median, standard deviation and range) of cumulative dose 
and cumulative percent of administered dose (compared to planned dose) by cycle 
and overall. 
Listings by subject (ordered by dose level): start date and stop date of each dosing period 
within each cycle (including records with 0 mg), administered total daily dose for each 
period, any missed doses with unknown dates (Y/N), number of missed doses with unknown 
dates, reason for any dosing changes.  
Listings by subject and each cycle (ordered by dose level): cycle length, total planned dose, 
administered total dose, percentage of planned dose, dose reduction (yes/no), and dose 
interruption (yes/no). 
7.3.4. Concomitant Medications and Nondrug Treatments 
Prior, concomitant, and further therapies (drug and non-drug treatments) will be coded by the 
World Health Organization (WHO) medical dictionary. Listings of prior, concomitant, and 
further therapies will be provided separately. 
 
7.4. Safety Summaries and Analyses 
All safety analyses will be performed on the safety population. 
Summaries and analyses of safety parameters will include all participants in the safety 
analysis set. 
AEs, ECGs, BP, PR, continuous cardiac monitoring, and safety laboratory data will be 
reviewed and summarized on an ongoing basis during the study to evaluate the safety of 
participants.  Any clinical laboratory, ECG, BP, and PR abnormalities of potential clinical 
concern will be described.  Safety data will be presented in tabular and/or graphical format 
and summarized descriptively, where appropriate. 
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Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted.  However, any untoward findings 
identified on physical/or neurological examinations examinations conducted during the 
active collection period will be captured as AEs, if those findings meet the definition of an 
AE.  Data collected at screening that are used for inclusion/exclusion criteria, such as 
laboratory data, ECGs, and vital signs, will be considered source data, and will not be 
required to be reported, unless otherwise noted. Demographic data collected at screening 
will be reported. 
7.4.1. Adverse Events  
AEs will graded by the investigator according to the CTCAE version 5.0 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  Adverse event data will be 
reported in tables and listings.  Summaries of adverse event by mapped terms, appropriate 
thesaurus level, toxicity grade, and seriousness and relationship to study treatment will be 
presented, as well as summaries of adverse events leading to death and premature 
withdrawal from study treatment.  The number and percentage of participants who 
experienced any AE, SAE, treatment related AE, and treatment related SAE will be 
summarized according to worst toxicity grades.  The summaries will present AEs both on the 
entire study period and by cycle (Cycle 1 and Cycles beyond 1).  Listings of DLTs and deaths 
will be provided. 
7.4.2. Laboratory Data 
Safety laboratory tests will be performed as described in the protocol. 
To determine if there are any clinically significant laboratory abnormalities, the 
hematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 
the criteria specified in the sponsor reporting standards.  The assessment will take into 
account whether each subject’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter. 
The data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, 
pharmacokinetic and biomarker measurements. 
7.4.3. Vital Signs 
Vital signs will be measured with the participant in a semi-supine position after 5 minutes of 
rest and will include temperature, systolic and diastolic blood pressure, and pulse rate.   
8. ELECTROCARDIOGRAMS 
The analysis of ECG results will be based on participants in the safety analysis set with 
baseline and on-treatment ECG data. Baseline is defined as a Cycle 1 Day 1 pre-dose.  
Standard 12-Lead ECGs utilizing limb leads (with a 10-second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QT, and QTc intervals and QRS 
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complex.  Alternative lead placement methodology using torso leads (e.g. Mason-Likar) is 
not recommended given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement.  All scheduled ECGs should be performed after the 
participant has rested quietly for at least 10 minutes in a supine position.  
At each time point, 3 consecutive ECGs will be performed at approximately [1-4] minutes 
apart to determine the mean QTc interval.  To ensure safety of the participants, a qualified 
individual at the investigator site will make comparisons to baseline measurements.  
Additional ECG monitoring will occur if a) the mean value from the triplicate measurements 
for any postdose QTc interval is increased by 60 msec from the baseline and is >450 msec; 
or b) an absolute QTc value is 500 msec for any scheduled ECG.  If either of these 
conditions occurs, then a single ECG measurement must be repeated at least hourly until 
QTc values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement.  In addition, if verified QTc values continue to exceed the criteria above, 
immediate correction for reversible causes including electrolyte abnormalities, hypoxia and 
concomitant medications for drugs with the potential to prolong the QTcF interval should be 
performed. 
If the QTc interval reverts to less than the threshold criteria listed above, and in the 
judgment of the investigator(s) and sponsor, it is determined that the cause(s) of QTc 
prolongation is something other than investigational product, treatment may be continued 
with regular ECG monitoring.  If in that timeframe the QTcF intervals rise above the 
threshold values, the investigational product will be held until the QTc interval decreases to 
below the threshold values.  Participants will then restart the investigational product at the 
next lowest dose level.  If the QTc interval has still not decreased to 501 msec after 2 weeks, 
or if at any time a participant has a QTcF interval >515 msec or becomes symptomatic, the 
participant will be removed from the study.  Additional triplicate ECGs may be performed as 
clinically indicated. 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in 
the same positions each time in order to achieve precise ECG recordings.  If a machine-read 
QTc value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range. 
If a participant experiences a cardiac or neurologic AE (specifically syncope, dizziness, 
seizures, or stroke), an ECG (triplicate) should be obtained at the time of the event.  
For each patient and by treatment, the maximum change from baseline will be calculated as 
well as the maximum post-baseline interval across time points.  Categorical analysis will be 
conducted for the maximum change from baseline in corrected QT and the maximum 
post-baseline QT interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction methods will be used) using maximum absolute QTc results.  Shift tables will also 
be provided for ECG abnormality at baseline vs. on treatment (yes, no, not done: (n, %). 
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If more than 1 ECG is collected at a nominal time after dose administration (for example, 
triplicate ECGs), the mean of the replicate measurements will be used to represent a single 
observation at that time point.  If any of the 3 individual ECG tracings has a QTc value 
>500 msec, but the mean of the triplicates is not >500 msec, the data from the participant’s 
individual tracing will be described in a safety section of the clinical study report (CSR) in 
order to place the >500-msec value in appropriate clinical context.  However, values from 
individual tracings within triplicate measurements that are >500 msec will not be included in 
the categorical analysis unless the average from the triplicate measurements is also 
>500 msec.  Changes from baseline will be defined as the change between the postdose QTc 
value and the average of the time-matched baseline triplicate values on Day -1, or the 
average of the predose triplicate values on Day 1.   
In addition, an attempt will be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK/PD modeling approach.  If a 
PK/PD relationship is found, the impact of participant factors (covariates) on the 
relationship will be examined. 
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points. 
QT intervals will be corrected for heart rate (HR) (QTc) using standard correction factors 
(ie, Fridericia’s (default correction), Bazett’s, and possibly a study-specific factor, as 
appropriate).  Data will be summarized and listed for QT, HR, response rate (RR), partial 
response (PR), QRS, QTcF (and other correction factors, eg, QTcB as appropriate) by study 
arm and presented by time and dose.  Individual QT (all evaluated corrections) intervals will 
be listed by study, time and dose.  The most appropriate correction factor will be selected 
and used for the following analyses of central tendency and outliers and used for the study 
conclusions.  Descriptive statistics (n, mean, median, standard deviation, minimum, and 
maximum) will be used to summarize the absolute corrected QT interval and changes from 
baseline in corrected QT after treatment by dose and time point. 
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by treatment and time. 
The number (%) of participants with maximum postdose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Table 2. 
Safety QTc Assessment 
Degree of Prolongation 
Mild (msec) 
Moderate (msec) 
Severe (msec) 
Absolute value 
>450-480 
>480-500 
>500 
Increase from baseline 
30-60 
>60 
 
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In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized. 
Patients experiencing clinically-relevant morphological ECG changes will be summarized 
(including frequency and percentage).  
Categorical data analysis will follow Appendix 3.  
8.1.1. Physical Examination 
Participants will have a physical examination to include weight, vital signs, assessment of 
ECOG performance status and height; height will be measured at screening only. 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems.  
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
9. INTERIM ANALYSES 
No formal interim analysis will be conducted for this study.  As this is an open-label study, 
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating dose-escalation decisions, facilitating PK/PD 
modeling, and/or supporting clinical development. 
10. REFERENCES 
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11. APPENDICES 
Appendix 1. Summary of Efficacy Analyses 
Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules 
for Handling Intercurrent 
Events and Missing Data  
Analysis 
Model 
Tumor response: 
Objective response 
rate (ORR) and 
duration of response 
(DoR), as assessed 
using the Response 
Evaluation Criteria 
in Solid Tumors 
(RECIST 
Appendix 4) version 
1.1, PFS 
Summary 
Response 
Evaluable 
Separately for 
observed data. 
N/A 
 
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Appendix 2. Time to Event Data Analysis Censoring Rules 
Table 3. 
Progression Free Survival and Duration of Response 
Situation 
Date of Progression/Censoring1 
Outcome 
Inadequate baseline assessment  
First dosing date in Cycle 1 
Censored 
No on-study assessments 
First dosing date in Cycle 1 
Censored 
Alive, on treatment2 and no 
Progression  
Date of last objective tumor 
assessment 
Censored 
Progression Documented on or 
between scheduled tumor 
assessments prior to treatment 
discontinuation2 
Date of first objective tumor 
assessment showing objective 
progression 
 
Progressed (Event) 
Treatment discontinuation for 
undocumented progression 
Date of last objective tumor 
assessment prior to 
discontinuation2 
Censored 
Treatment discontinuation due 
to toxicity or other reason 
Date of last objective tumor 
assessment prior to 
discontinuation2 
Censored 
Death prior to first planned 
tumor assessment  
Date of death 
Death (Event) 
Death without objective 
progression prior to treatment 
discontinuation2 
Date of death 
Death (Event) 
Death or progression after 2 or 
more missed tumor assessments 
Date of last objective tumor 
assessment prior to the event 
Censored 
1. 
For date of censorship, if a tumor assessment takes place over a number of days (eg, superficial lesions one day, scans 
another), the last date is used as the assessment date. 
2. or within 28 days of discontinuation of treatment.   
Table 4. 
Time to Progression 
Situation 
Date of Progression/Censoring1 
Outcome 
Inadequate baseline assessment  
First dosing date in Cycle 1 
Censored 
No on-study assessments 
First dosing date in Cycle 1 
Censored 
Alive, on treatment2 and no 
Progression  
Date of last objective tumor 
assessment 
Censored 
Progression Documented on or 
between scheduled tumor 
assessments prior to  treatment 
discontinuation2 
Date of first objective tumor 
assessment showing objective 
progression 
 
Progressed (Event) 
Treatment discontinuation for 
undocumented progression 
Date of last objective tumor 
assessment prior to 
discontinuation2 
Censored 
Treatment discontinuation due 
Date of last objective tumor 
Censored 
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to toxicity or other reason 
assessment prior to discontinuation 
New anticancer treatment <28 
days after discontinuation of 
treatment without progression 
Date of last objective tumor 
assessment prior to new anticancer 
treatment 
Censored 
Death prior to first planned 
tumor assessment  
Start date (C1D1) 
Censored 
Death without objective 
progression prior to treatment 
discontinuation2 
Date of last objective tumor 
assessment prior to death 
Censored 
Progression after 2 or more 
missed tumor assessments 
Date of last objective tumor 
assessment prior to the event 
Censored 
3. 
For censoring date, if a tumor assessment takes place over a number of days (eg, superficial lesions one day, scans 
another), the last date is used as the assessment date. 
4. or within 28 days of discontinuation of treatment. 
DOSD and DOR 
Censoring rules for DOSD and DOR will be the same as for PFS.  
Appendix 3. Categorical Classes for ECG and Vital Signs  
Categories for QTcB and QTcF 
QTcB/QTcF 
(ms) 
max. ≤450 
450<max. ≤480 
480<max.≤500 
max. >500 
QTcB/QTcF 
(ms) increase 
from baseline 
max. <30 
30≤max. <60 
max. ≥60 
 
 
Categories for PR and QRS 
PR (ms) 
max ≥300 
 
PR (ms) increase 
from baseline 
Baseline >200 
and max. 
≥25% increase 
Baseline ≤200 and 
max. ≥50% 
increase 
QRS (ms) 
Max. ≥200 
  
QRS (ms) 
increase from 
baseline 
Baseline >100 
and max. 
≥25% increase 
Baseline ≤100 and 
max. ≥50% 
increase 
 
 
 
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Categories for Vital Signs 
Systolic BP (mm Hg) 
min. <90 
 
Systolic BP (mm Hg) 
change from baseline 
max. decrease ≥30 
max. increase ≥30 
Diastolic BP (mm Hg) 
min. <50 
 
Diastolic BP (mm Hg) 
change from baseline 
max. decrease ≥20 
max. increase ≥20 
Supine pulse rate (bpm) 
min. <40 
max. >120 
 
Measurements that fulfil these criteria are to be listed in the study report. 
Appendix 4. RECIST 1.1 Tumor Assessment Criteria 
Adapted from E.A. Eisenhauer, P. Therasseb, J. Bogaerts, L.H. Schwartz, D. Sargent, R. 
Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. 
Kaplan, D. Lacombe, J. Verweij: New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247.  
At baseline, individual tumor lesions will be categorized by the investigator as either 
measurable or not, according to the criteria summarized below: 
Measurable Lesions 
Lesions that can be accurately measured in at least one dimension. 
•  Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm). 
•  Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 
•  Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 
•  Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions 
 Non-measurable Lesions  
• Non-measurable disease includes lesions too small to be considered measurable 
(including nodes with short axis between 10 and 14.9 mm) and truly non-measurable 
disease such as pleural or pericardial effusions, ascites, inflammatory breast disease, 
leptomeningeal disease, lymphangitic involvement of skin or lung, clinical lesions 
that cannot be accurately measured with calipers, abdominal masses identified by 
physical exam that are not measurable by reproducible imaging techniques. 
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•  Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of measurability 
at baseline. 
•  Previous local treatment: A previously irradiated lesion (or lesion patientive to other 
local treatment) is non-measurable unless it has progressed since completion of treatment.  
Normal sites: 
• Cystic lesions: Simple cysts should not be considered as malignant lesions and should not 
be recorded either as target or non-target disease. Cystic lesions thought to represent 
cystic metastases can be measurable lesions, if they meet the specific definition above. If 
non-cystic lesions are also present, these are preferred as target lesions. 
•  Normal nodes: Nodes with short axis <10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease. 
Recording Tumor Assessments 
All sites of disease must be assessed at baseline. Baseline assessments should be done 
asclose as possible prior to study start. For an adequate baseline assessment, all required 
scans must be done within 28 days prior to treatment and all disease must be documented 
appropriately. If baseline assessment is inadequate, subsequent statuses generally should 
beindeterminate. 
Note: For the patient population being evaluated in this protocol, the baseline assessment 
may be completed within 6 weeks prior to randomization. 
Target Lesions 
Response in target lesions is defined as follows: 
•  Complete Response (CR): Complete disappearance of all target lesions with 
theexception of nodal disease. All target nodes must decrease to normal size (short 
axis<10 mm). All target lesions must be assessed. 
•  Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions. The short diameter is used in the sum 
for target nodes, while the longest diameter is used in the sum for all other target lesions. 
All target lesions must be assessed. 
•  Stable Disease (SD): Does not qualify for CR, PR or Progression. All target lesions 
must be assessed. Stable can follow PR only in the rare case that the sum increases by 
less than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds. 
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•  Objective Progression (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5 mm. 
•  Indeterminate: Progression has not been documented, and one or more target 
measurable lesions have not been assessed; or assessment methods used were 
inconsistent with those used at baseline; or one or more target lesions cannot be measured 
accurately (eg, poorly visible unless due to being too small to measure); or one or more 
target lesions were excised or irradiated and have not reappeared or increased. 
Non-Target Lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol.  
Response in non-target lesions is defined as follows: 
• Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis).  
• Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 
• PD: Unequivocal progression of pre-existing lesions. Generally, the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy. In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 
• Indeterminate: Progression has not been determined and one or more non-target 
sites were not assessed or assessment methods were inconsistent with those used at 
baseline. 
New Lesions  
The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion 
isequivocal, for example due to its small size, continued assessment will clarify the etiology. 
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment. A lesion identified in an area not previously scanned will be 
considered a new lesion. 
Supplemental Investigations 
•  If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate. If no disease is identified, objective status is CR. 
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•  If progression determination depends on a lesion with an increase possibly due 
tonecrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective Progression 
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs. This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status. Every effort should be made to document objective progression even 
afterdiscontinuation of treatment. 
Determination of Overall Response by the RECIST 1.1 Criteria 
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  The overall assessment of response will involve all parameters as depicted in the 
following table. 
Table 5. 
Response Evaluation Criteria in Solid Tumors by RECIST 1.1 
Target lesions 
Non-target lesions 
New Lesions 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Indeterminate or Missing 
No 
PR 
PR 
Non-CR/Non-PD, Indeterminate or Missing 
No 
PR 
SD 
Non-CR/Non-PD, Indeterminate or Missing 
No 
SD 
Indeterminate or Missing 
Non-PD 
No 
Indeterminate 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease 
Table 6. 
Objective Response Status at Each Evaluation for Patients with Non Target 
Disease Only  
Non-target Disease 
New Lesions 
Objective Status 
CR  
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Indeterminate  
No 
Indeterminate 
Unequivocal progression 
Yes or No 
PD 
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Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease 
 
Appendix 5. Immune-Related Response Criteria Derived from RECIST 1.1 (irRECIST) 
Increasing clinical experience indicates that traditional response criteria may not be sufficient 
to fully characterize activity in this new era of targeted therapies and/or biologics. 
This is particularly true for immunotherapeutic agents such as anti-CTLA4 and anti-PD-
1/anti-PD-L1 antibodies which exert the antitumor activity by augmenting activation and 
proliferation of T cells, thus leading to tumor infiltration by T cells and tumor regression 
rather than direct cytotoxic effects.18,19 Clinical observations of patients with advanced 
melanoma treated with ipilimumab, for example, suggested that conventional response 
assessment criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) and 
WHO criteria are not sufficient to fully characterize patterns of tumor response to 
immunotherapy because tumors treated with immunotherapeutic agents may show additional 
response patterns that are not described in these conventional criteria. 
Furthermore, the conventional tumor assessment criteria (RECIST and WHO criteria) 
havebeen reported as not capturing the existence of a subset of patients who have an OS 
similar to those who have experienced CR or PR but were flagged as PD by WHO criteria. 
On these grounds, a tumor assessment system has been developed that incorporates 
thesedelayed or flare-type responses into the RECIST v1.1 (irRECIST). 
For irRECIST, only target and measurable lesions are taken into account. In contrast to 
RECIST v1.1, irRECIST: 
•  Requires confirmation of both progression and response by imaging at least 4 weeks 
from the date first documented, and 
•  Does not necessarily score the appearance of new lesions as progressive disease if 
thesum of lesion diameters of target lesions (minimum of 10 mm longest diameter per 
non-nodal lesion and 15 mm shortest diameter per nodal lesion, maximum of 5 
targetlesions, maximum of 2 per organ) and measurable new lesions does not increase by 
≥20%. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline and throughout the trial. irRECIST is 
defined as follows: 
1. Overall immune-related complete response (irCR): Complete disappearance of all lesions 
(whether measurable or not) and no new lesions. All measurable lymph nodes also must have 
a reduction in short axis to <10 mm. 
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2. Overall immune-related partial response (irPR): Sum of the diameters (longest for non-
nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases 
≥30%. 
3. Overall immune-related stable disease (irSD): Sum of the diameters (longest for non-nodal 
lesions, shortest for nodal lesions) of target and new measurable lesions is neither irCR, irPR, 
(compared to baseline) or immune-related progressive disease (irPD, compared to nadir). 
4. Overall immune-related progressive disease (irPD): Sum of the diameters (longest for non-
nodal lesions, shortest for nodal lesions) of target and new measurable lesions increases 
≥20% (compared to nadir), confirmed by a repeat, consecutive observation at least 4 weeks 
from the date first documented.  
New measurable lesions: Incorporated into tumor burden (ie, added to the target lesion 
measurements). A lymph node has to be ≥15 mm in short axis to be a measurable new lesion 
and its short axis measurement is included in the sum. Up to 2 new lesions per organ and up 
to 5 new lesions in total can be added to the measurements. 
New non-measurable lesions: Do not define progression but preclude irCR. 
Table 7.  
Overall Response Derived from Changes in Index, Non-index and New 
Lesions 
Index and New 
Measurable Lesions1 
Non-Index Lesions 
Measurable 
Lesions 
Overall 
response 
using 
irRECIST2 
Decrease 100% 
CR 
No 
CR 
Decrease 100% 
Non-CR/Non-PD 
No 
PR 
Decrease 100% 
Indeterminate or Missing 
No 
PR 
Decrease ≥30% 
Non-CR/Non-PD, Indeterminate or Missing 
No 
PR 
Decrease ≥30% 
Non-CR/Non-PD, Indeterminate or Missing 
No 
SD 
Decrease <30% and 
increase <20% 
Non-PD 
No 
Indeterminate 
Decrease <30% and 
increase <20% 
Any 
Yes or No 
PD 
Increase ≥20% 
PD 
Yes or No 
PD 
 
 
                                                 
1 Decrease assessed relative to baseline. 
2 Response (irCR and irPR) and progression (irPD) must be confirmed by a second consecutive  assessment at least 4 weeks apart. 
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