Conditions: Leiomyosarcoma
Keywords: Leiomyosarcoma Pleomorphic sarcoma Myxofibrosarcoma Liposarcoma Angiosarcoma Epithelioid sarcoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 76
Healthy volunteers: no

Brief summary:
The purpose of this study is to learn about the safety and effects of the study medicine (called Ontorpacept or TTI-621) when given alone and when given in combination with doxorubicin for people with leiomyosarcoma. Leiomyosarcoma is a tumor of the smooth muscles.

This study is seeking participants who have:

* leiomyosarcoma that is advanced or has spread to other parts of the body (metastatic)
* not received prior treatment with anthracyclines (a drug commonly used in patients with some kinds of cancer, including leiomyosarcoma)
* not received more than one prior treatment for their leiomyosarcoma During the first 18 weeks of this study, participants will receive doxorubicin by IV infusion (given directly into a vein) at the study clinic every 3 weeks for a total of 6 doses. Participants will also receive Ontorpacept (TTI-621) by IV infusion at the study clinic on the same day as doxorubicin and again one week later for the first 18 weeks.

After the first 18 weeks, participants will stop receiving doxorubicin but will continue receiving Ontorpacept (TTI-621) as IV infusion every 14 days at the study clinic. They will keep receiving Ontorpacept (TTI-621) until their cancer is no longer responding to treatment.

We will examine the experiences of participants receiving Ontorpacept (TTI-621) in combination with doxorubicin in the first 18 weeks and then Ontorpacept (TTI-621) by itself after the doxorubicin is stopped. This will help us determine if the study medicine Ontorpacept (TTI-621) given with doxorubicin and then by itself is safe and effective.

Participants will be involved in the study for approximately one year, depending on how their cancer responds to the study treatment. They will have study visits about 12 times in the first 18 weeks (when the study medicine Ontorpacept is given with doxorubicin) and then every two weeks after the doxorubicin is stopped and the study medicine Ontorpacept (TTI-621) is given by itself.

Detailed description:
This trial will be conducted in 2 phases: Phase I (dose escalation of Ontorpacept in combination with fixed-dose doxorubicin) and Phase II (dose expansion of Ontorpacept in combination with fixed-dose doxorubicin).

Phase I will enroll patients with soft-tissue sarcomas including leiomyosarcoma, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma or epithelioid sarcoma to evaluate escalating doses of Ontorpacept (TTI-621) administered in combination with fixed-dose doxorubicin for up to six cycles followed by Ontorpacept (TTI-621) monotherapy.

Phase II will enroll patients with high-grade leiomyosarcoma and will evaluate two dose levels of Ontorpacept (TTI-621) in combination with fixed-dose doxorubicin for up to six cycles followed by Ontorpacept (TTI-621) monotherapy.

.

Arms:
arm 1: In the dose escalation portion of the study, participants with specific subsets of soft tissue sarcomas who have not received more than one prior line of therapy and have not received an anthracycline in any setting will be enrolled in three escalating dose cohorts to characterize the safety and tolerability of Ontorpacept (TTI-621) when administered in combination with doxorubicin for up to six cycles and followed by Ontorpacept (TTI-621) monotherapy arm 2: Participants with high-grade leiomyosarcoma will receive up to six cycles of Ontorpacept (TTI-621) at a pre-specified dose level (Dose Level A) in combination with fixed-dose doxorubicin followed by Ontorpacept (TTI-621) monotherapy to further characterize safety, tolerability, and clinical activity of the treatment regimen. arm 3: Participants with high-grade leiomyosarcoma will receive up to six cycles of Ontorpacept (TTI-621) at a pre-specified dose level (Dose Level B) in combination with fixed-dose doxorubicin followed by Ontorpacept (TTI-621) monotherapy to further characterize safety, tolerability, and clinical activity of the treatment regimen. arm 4: Participants with high-grade leiomyosarcoma will receive up to six cycles of Ontorpacept (TTI-621) at a pre-specified dose level (Dose Level C) in combination with fixed-dose doxorubicin followed by Ontorpacept (TTI-621) monotherapy to further characterize safety, tolerability, and clinical activity of the treatment regimen.

Interventions: intervention 1: Ontorpacept (TTI-621) intervention 2: Doxorubicin
Intervention descriptions: intervention 1: Ontorpacept (TTI-621) will be administered by intravenous infusion. intervention 2: 75 mg/m\^2 by intravenous infusion in 21-day cycles for a maximum of six cycles.

Protocol document:
Prot_000.pdf: 
T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 1 of 1 4 0  
 
 
 
 
 
 
 
 
 
I n v esti g ati o n al 
Pr o d uct 
T TI-
-I g G 1 Fc) 
Pr ot oc ol N u m b er 
T TI- 6 2 1- 0 3 
I N D N u m b er 
1 2 9 1 1 8  
P h as e of Cli nic al 
D e v el o p m e nt 
I/II 
Pr ot oc ol Titl e 
A P h as e I/II St u dy of T TI- 6 2 1 i n C o m bi n ati o n wit h D ox or u bici n i n P ati e nts wit h 
U nr es ect a bl e or M et ast atic Hi g h- Gr a d e L ei o m y os arc o m a  
V ersi o n a n d D at e 
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2 
S p o ns or C o nt act 
 M D, P h D 
 
Trilli u m T h er a p e utics, a Pfiz er C o m p a ny 
1 0 0 C a m bri d g e p ar k Driv e, S uit e 5 1 0 
C a m bri d g e, M A, 0 2 1 4 0 U S A 
 
 
 
 
 
 
 
 
C O N FI D E N TI ALI T Y S T A T E M E N T 
I nf or m ati o n c o nt ai n e d i n t his pr ot oc ol is c o nfi d e nti al i n n at ur e, a n d m a y n ot b e us e d, di v ul g e d, p u blis h e d or 
ot h er wis e discl os e d t o ot h ers exc e pt t o t h e ext e nt n ec ess ar y t o o bt ai n a p pr o v al of t h e I nstit uti o n al R e vi e w B o ar d 
or I n d e p e n d e nt Et hics C o m mitt e e, or as r e q uir e d b y l a w. P ers o ns t o w h o m t his i nf or m ati o n is discl os e d s h o ul d b e 
i nf or m e d t h at t his i nf or m ati o n is c o nfi d e nti al a n d m a y n ot b e f urt h er discl os e d wit h o ut t h e ex pr ess p er missi o n of 
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y. 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
P P D
P P D


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n 2. 0, 1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                      
p a g e 2 of 1 4 0
1.
P R O T O C OL A P P R O V AL
Pr ot oc ol N u m b er
T TI- 6 2 1- 0 3
V ersi o n a n d D at e
V ersi o n 2. 0,   1 7 J u n e 2 0 2 2
Pr ot oc ol Titl e
A P h as e I/II St u dy of T TI- 6 2 1 i n C o m bi n ati o n wit h D ox or u bici n i n a P ati e nts wit h 
U nr es ect a bl e or M et ast atic Hi g h- Gr a d e L ei o m y os arc o m a 
I h a v e r e a d t his pr ot oc ol a n d c o nfir m t h at it acc ur at ely d escri b es t h e pl a n n e d c o n d uct of t h e st u dy.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
D at e
Trilli u m T h er a p e utics, a Pfiz er C o m p a ny
P P D
P P D


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 3 of 140 
 
 
2.
SYNOPSIS
 
Protocol Number 
TTI-621-03 
Version and Date 
 2.0,  17 June 2022 
Phase of Clinical 
Development 
Phase I/II 
Protocol Title 
A Phase I/II Study of TTI-621 in Combination with Doxorubicin in Patients with 
Unresectable or Metastatic High-Grade Leiomyosarcoma  
Investigational 
Product 
TTI-621 (
-IgG1 Fc)  
IND Number 
129118 
Study Population 
 
 
 
Patients aged 18 years or older with unresectable or metastatic leiomyosarcoma  
who have not received prior treatment with anthracyclines (dose expansion); 
patients with leiomyosarcoma, undifferentiated pleomorphic sarcoma, 
myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma or epithelioid 
sarcoma will be allowed to enroll into the dose escalation portion of the study. 
General 
Investigative Plan 
A dose escalation will be undertaken in anthracycline-naïve patients with the high 
grade soft tissue sarcomas subtypes of leiomyosarcoma, undifferentiated 
pleomorphic 
sarcoma, 
myxofibrosarcoma, 
dedifferentiated 
liposarcoma, 
angiosarcoma or epithelioid sarcoma to evaluate safety of the planned dosing 
regimen of doxorubicin at 75 mg/m2 in combination with TTI-621.  The study will 
then be expanded to evaluate clinical activity and safety of TTI-621 at two dose 
levels in combination with doxorubicin  at 75 mg/m2 in patients with high-grade 
leiomyosarcoma.      
Investigative Sites 
Up to 20 centers in the US 
Planned Number of 
Subjects 
Up to approximately 80, including up to approximately 18 in the dose escalation 
portion of the study and approximately 62 subjects in the expansion portion of 
the study 
Enrollment Period 
The enrollment period is anticipated to be approximately 18 months in duration, 
with the first patient anticipated to be enrolled in July 2021 and completion of 
enrollment anticipated for December 2022   
Background and 
Rationale 
Soft tissue sarcomas are a rare, heterogeneous group of mesenchymal tumors, 
commonly the result of complex chromosomal abnormalities that play a role in 
disease progression and metastasis.   
 
Doxorubicin has been since the 1970s the standard of care for first-line treatment 
of patients with metastatic or advanced soft tissue sarcoma; however, 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 4 of 1 4 0  
 
 
d ox or u bici n activity is p o or, wit h a r es p o ns e r at e of 9 - 2 7 % 1, 2a n d pr o gr essi o n-
fr e e s urvi v al of 3- 5 m o nt hs,3- 5 wit h c u m ul ati v e c ar di ac t oxicit y t h at li mits its us e. 6   
T TI- 6 2 1 is a r ec o m bi n a nt s ol u bl e f usi o n pr ot ei n d esi g n e d t o  bl oc k t h e c ell- s urf ac e 
pr ot ei n C D 4 7, w hic h is f o u n d o n t h e s urf ac e of m a ny n or m al c ell ty p es a n d at hi g h 
l e v els o n m a ny m ali g n a nt t u m or c ells.  C D 4 7 bi n ds t o si g n al r e g ul at ory pr ot ei n 
 p h a g ocytic 
acti vity.  T his C D 4 7- m e di at e d i n hi biti o n of m acr o p h a g e p h a g ocyt osis activity is 
a n i m p ort a nt 
m ec h a nis m t hr o u g h w hic h c a nc er c ells c a n esc a p e i m m u n e-
m e di at e d cl e ar a nc e, a n d hi g h l e v els of C D 4 7 c orr el at e 
wit h p o or cli nic al 
pr o g n osis acr oss a n u m b er of c a nc er t y p es.  T TI- 6 2 1 c o m bi n es 
 (t h e bi n di n g d o m ai n f or C D 4 7) wit h t h e Fc r e gi o n of 
h u m a n I g G 1, g e n er ati n g a d ec oy r ec e pt or f or C D 4 7 o n t h e s urf ac e of t u m or c ells 
t h at b ot h o v er-ri d es t h e C D 4 7- m e di at e d i n hi biti o n of p h a g oc yt osis t hr o u g h t h e 
 p orti o n of t h e pr ot ei n a n d pr o vi d es a pr o-p h a g oc ytic sti m ul ati o n t hr o u g h 
t h e I g G 1 m oi ety. 
 
I n a n a n al ysis of 2 0 6 s arc o m as, t h e s u bty p es wit h t h e hi g h est m e di a n m acr o p h a g e 
sc or es i ncl u d e d n o n-tr a nsl oc ati o n-r el at e d s arc o m as, s uc h as l ei o my os arc o m a, 
u n diff er e nti at e d 
pl e o m or p hic s arc o m a, 
m yx ofi br os arc o m a, 
a n gi os arc o m a, 
d e diff er e nti at e d li p os arc o m a a n d e pit h eli o d s arc o m a. 7  I n a n ot h er st u dy of tiss u e 
micr o arr a ys of 1 2 4 2 s arc o m a s p eci m e ns c o n d uct e d t o f urt h er t h e u n d erst a n di n g 
of t h e s arc o m a i m m u n e l a n dsc a p e, t u m or- ass oci at e d m acr o p h a g e i nfiltr ati o n a n d 
ex pr essi o n 
of t h e t ar g et a bl e 
m acr o p h a g e- r el at e d i m m u n e 
c h ec k p oi nt 
C D 4 7/ SI R P
8   T his st u dy s h o w e d t h at t h e 
M 2-li k e ( C D 1 6 3 +) 
m acr o p h a g es w er e t h e pr e d o mi n a nt p h e n oty p e, w hic h a gr e es wit h fi n di n gs i n 
m el a n o m a, 9 n o n-s m all c ell l u n g c a nc er, 1 0 a n d c ol or ect al c a nc er.1 1, 1 2  T h e pr es e nc e 
of l ar g e n u m b ers of M 2-li k e m acr o p h a g es s u g g ests a hi g hl y i m m u n os u p pr essiv e 
t u m or 
micr o e nvir o n m e nt b ut d u e t o t h e pl asticity of t u m or-ass oci at e d 
m acr o p h a g e p ol ariz ati o n, t his c o ul d r e pr es e nt a nti-t u m or i m m u nit y 
t h at is 
s u p pr ess e d- b ut- p ois e d f or r e activ ati o n. 1 3  
 
M a ny s oli d t u m ors, i ncl u di n g br ai n, br e ast, c ol o n, g astric, ki d n e y, 
s oft tiss u e 
s arc o m as i ncl u di n g l ei o my os arc o m a, ost e os arc o m a, li v er, l u n g, 
m el a n o m a, 
o v ari a n, p a ncr e atic, a n d pr ost at e t u m ors h a v e als o b e e n f o u n d t o ex pr ess hi g h  
l e v els of C D 4 7.1 4- 1 8  I n m a ny of t h es e c as es, hi g h ex pr essi o n of C D 4 7 is ass oci at e d 
wit h p o or pr o g n osis, t h o u g ht t o b e t h e r es ult of C D 4 7- m e di at e d i n hi biti o n of 
m acr o p h a g e 
p h a g ocyt osis 
a n d 
esc a p e 
of i m m u n e- m e di at e d 
cl e ar a nc e.  
I nt err u pti o n of t h e C D 4 7-
t o C D 4 7 h as s h o w n a nti-t u m or activity i n h u m a n c a nc ers b ot h i n vitr o a n d i n viv o 
i n a ni m al m o d els of h u m a n m ali g n a nci es a n d i n s o m e e arl y cli nic al tri als.1 9   
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 5 of 1 4 0  
 
 
I n a n u m b er of a ni m al m o d els of h u m a n t u m ors, t h e c o m bi n ati o n of d ox or u bici n 
wit h C D 4 7-t ar g et e d a nti b o di es r es ults i n e n h a nc e d a nti- t u m or activity a n d 
i ncr e as e d 
m acr o p h a g e- m e di at e d 
c ell 
killi n g 
a n d 
m acr o p h a g e-m e di at e d 
p h a g oc yt osis of c a nc er c ell li n es i n vitr o,2 0- 2 3 s u g g esti n g t h at c o m bi ni n g T TI-6 2 1 
wit h d ox or u bici n c h e m ot h er a py mi g ht b e m or e eff ectiv e t h a n d ox or u bici n al o n e 
i n t u m or t y p es t h at ex pr ess C D 4 7 a n d h av e hi g h n u m b ers of m acr o p h a g es, s uc h 
as  l ei o my os arc o m a, u n diff er e nti at e d pl e o m or p hic s arc o m a, myx ofi br os arc o m a, 
a n gi os arc o m a, d e diff er e nti at e d li p os arc o m a a n d e pit h eli o d s arc o m a. 
 
It is hy p ot h esiz e d t h at bl oc k a d e of C D 4 7-m e di at e d i m m u n e ev asi o n a n d 
c o nc o mit a nt acti v ati o n of p h a g ocyt osis wit h T TI- 6 2 1 will b e cli nic all y b e n efici al i n 
p ati e nts wit h s arc o m a s u bt y p es i n w hic h C D 4 7 is ex pr ess e d a n d m acr o p h a g e 
sc or es ar e i ncr e as e d.  I n a d diti o n, 
 
 
 
 
 
 
 
 
 
  
 
T h us, t h e pri m ary g o als of t his cli nic al tri al ar e t o ev al u at e t h e s af et y of T TI- 6 2 1 
a d mi nist er e d i n c o m bi n ati o n wit h st a n d ar d- of-c ar e d ox or u bici n i n a nt hr acycli n e-
n aï v e p ati e nts wit h hi g h- gr a d e s oft tiss u e s arc o m as a n d t o f urt h er ev al u at e 
cli nic al activit y a n d s af et y i n t h e l ei o m y os arc o m a s u b p o p ul ati o n.    
St u d y D esi g n 
T his is a 
m ulti-c e nt er, o p e n-l a b el st u dy d esi g n e d t o ev al u at e T TI- 6 2 1 
a d mi nist er e d i n c o m bi n ati o n wit h d ox or u bici n.  T h e first p orti o n of t h e st u dy will 
e v al u at e t h e s af ety of i ncr e asi n g d os e l ev els of T TI- 6 2 1 i n c o m bi n ati o n wit h 
d ox or u bici n at t h e st a n d ar d d os e of at 7 5 m g/ m 2 i n p ati e nts wit h hi g h-gr a d e 
l ei o m y os arc o m a, u n diff er e nti at e d pl e o m or p hic s arc o m a, 
m yx ofi br os arc o m a, 
d e diff er e nti at e d li p os arc o m a, a n gi os arc o m a or e pit h eli oi d s arc o m a w h o h av e n ot 
r ec eiv e d m or e t h a n o n e pri or li n e of t h er a py f or a dv a nc e d dis e as e a n d h av e n ot 
r ec eiv e d a n a nt hr acycli n e i n a ny s etti n g ( n e o a dj uv a nt, a dj uv a nt or as tr e at m e nt 
f or a dv a nc e d of m et ast atic dis e as e).  T w o d os e l ev els of T TI-6 2 1 i n c o m bi n ati o n 
wit h d ox or u bici n will b e s el ect e d f or f urt h er ev al u ati o n i n a n ex p a nsi o n p h as e i n 
w hic h p ati e nts wit h l ei o m y os arc o m a w h o h a v e n ot r ec ei v e d m or e t h a n o n e pri or 
li n e of t h er a py f or a dv a nc e d dis e as e a n d h a v e n ot r ec eiv e d a n a nt hr acycli n e i n 
a ny s etti n g ( n e o a dj uv a nt, a dj u v a nt or as tr e at m e nt f or a dv a nc e d of m et ast atic 
dis e as e).  T h e di a g n osis of l ei o m y os arc o m a will b e c o nfir m e d at a c e ntr al 
l a b or at ory;  t h e p ati e nt m ay b e e nr oll e d b as e d o n a c urr e nt or m ost r ec e nt 
p at h ol o gy r e p ort t h at pr ovi d es s uffici e nt d et ail t o s u p p ort d eri v ati o n of t h e 
hist ol o gic i nt er pr et ati o n b ut a pr e- tr e at m e nt tiss u e s p eci m e n m ust b e m a d e 
a v ail a bl e f or c o nfir m ati o n  d uri n g scr e e ni n g or wit hi n t h e first cycl e of tr e at m e nt .  
I n t h e e v e nt t h at t h e di a g n osis is n ot c o nfir m e d d uri n g c e ntr al r evi e w, t h e p ati e nt 
m ust b e r e pl ac e d f or p ur p os es of m e eti n g t h e st atistic al r e q uir e m e nts of t h e 
st u dy b ut m a y b e all o w e d t o c o nti n u e o n tr e at m e nt aft er disc ussi o n wit h t h e 
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 6 of 1 4 0  
 
 
S p o ns or 
M e dic al 
M o nit or.  
A d diti o n al k ey i ncl usi o n crit eri a ar e E C O G 
p erf or m a nc e st at us 0- 1 ( A p p e n dix A
R E CI S T v 1. 1, a n d a d e q u at e c ar di ac a n d e n d or g a n f u ncti o n.  P ati e nts wit h pri or 
ex p os ur e t o a nt hr acycli n es will b e excl u d e d.   
 
I n t h e P h as e I d os e esc al ati o n p orti o n of t h e st u dy, t h e pri m ary o bj ecti v e is 
ass ess m e nt of t h e s af et y of esc al ati n g d os e l ev els of T TI- 6 2 1 i n c o m bi n ati o n wit h 
d ox or u bici n at t h e st a n d ar d d os e of 7 5 m g/ m 2.  U p t o a p pr oxi m at ely 1 8 p ati e nts 
ar e pl a n n e d t o b e e nr oll e d i n t his p orti o n of t h e st u dy t o ev al u at e t hr e e d os e 
l e v els of T TI- 6 2 1:  0. 2 m g/k g ( D os e L ev el 1), 0. 7 m g/k g ( D os e L ev el 2) a n d 2. 0 
m g/k g ( D os e L ev el 3).  E nr oll m e nt will b e o p e n t o p ati e nts wit h hi g h- gr a d e 
l ei o m y os arc o m a, u n diff er e nti at e d pl e o m or p hic s arc o m a, 
m yx ofi br os arc o m a, 
d e diff er e nti at e d li p os arc o m a, a n gi os arc o m a a n d e pit h eli oi d s arc o m a.  T w o d os e 
l e v els will b e s el ect e d f or e v al u ati o n i n p ati e nts wit h l ei o m y os arc o m a i n t h e P h as e 
II ex p a nsi o n p orti o n of t h e st u dy. 
 
T h e pri m ary o bj ecti v es of t h e P h as e II ex p a nsi o n p orti o n of t h e st u dy ar e 
e v al u ati o n of t h e s af ety a n d i nv esti g ati o n of cli nic al acti vity of t h e d ox or u bici n 
a n d T TI- 6 2 1 c o m bi n ati o n f or u p t o 1 8 w e e ks a n d T TI- 6 2 1 m o n ot h er a py gi v e n o n 
a n o n g oi n g b asis aft er c o m pl eti o n of t h e 1 8- w e e k c o m bi n ati o n i n p ati e nts wit h 
l ei o m y os arc o m a.  Cli nic al acti vity will b e b as e d o n ass ess m e nt of t h e o v er all 
r es p o ns e r at e by R E CI S T v 1. 1 i n ex p a nsi o n c o h orts:  d ox or u bici n at 7 5 m g/ m 2 i n 
c o m bi n ati o n wit h T TI- 6 2 1 at a l o w er d os e ( C o h ort A) a n d d ox or u bici n  at 7 5 
m g/ m
2 i n c o m bi n ati o n wit h T TI-6 2 1 at a hi g h er d os e ( C o h ort B).  U p t o 
a p pr oxi m at ely 3 1 p ati e nts will b e tr e at e d i n e ac h c o h ort, f or a t ot al of 
a p pr oxi m at ely 6 2 p ati e nts i n t his p orti o n of t h e st u dy. 
 
S ec o n d ary o bj ecti v es i ncl u d e f urt h er ev al u ati o n of t h e s af ety of t h e c o m bi n ati o n 
a n d ass ess m e nt of ot h er i n dic ati o ns of cli nic al b e n efit, i ncl u di n g pr o gr essi o n- fr e e 
s ur vi v al, o v er all s ur viv al, d ur ati o n of r es p o ns e, a n d cli nic al b e n efit r at e as d efi n e d 
by R E CI S T v 1. 1 crit eri a.   
 
 
 
 
 
 
 
 
 
 
 
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 7 of 1 4 0  
 
 
 
 
 
 
 
 
 
 
 
T h e st u dy will c o nsist of a 2 8- d a y scr e e ni n g p eri o d, a tr e at m e nt p eri o d i n w hic h 
p ati e nts will r ec ei v e d ox or u bici n i n c o m bi n ati o n wit h T TI- 6 2 1 i n 2 1- d ay cycl es f or 
a 
m axi m u m of six cycl es, f oll o w e d by c o nti n u e d tr e at m e nt wit h T TI- 6 2 1 
m o n ot h er a p y i n 2 8- d a y cycl es u ntil 
d oc u m e nt ati o n of o bj ectiv e dis e as e 
pr o gr essi o n or d ev el o p m e nt of u n acc e pt a bl e t oxicity, a n d a l o n g-t er m f oll o w- u p 
p eri o d t o ass ess ov er all s urvi v al.  
 
I n t h e c o m bi n ati o n p orti o n of t h e st u dy, Cycl e 1 t hr o u g h Cycl e 6, d ox or u bici n will 
b e a d mi nist er e d at 7 5 m g/ m 2 o n D ay 1 of e ac h 2 1- d ay c ycl e.  D ox or u bici n s h o ul d 
b e a d mi nist er e d t hr o u g h a fr e e-fl o wi n g c at h et er at 7 5 m g/ m 2 by i ntr a v e n o us 
i nf usi o n i n l ess t h a n 6 0 mi n ut es.  A m axi m u m of six cycl es of d ox or u bici n ( 1 8 
w e eks of tr e at m e nt) is p er mitt e d.  R e q uir e d pr o p hyl axis f or e m esis a n d 
c ar di o pr ot ecti o n, as w ell as g ui d eli n es f or pr o p hyl axis wit h G- C S F f or pr ev e nti o n 
of f e bril e n e utr o p e ni a, is d escri b e d i n S ecti o n 5. 2. 1 .  I n Cycl e 1 t hr o u g h Cycl e 6, 
f oll o wi n g pr o p hyl axis as d escri b e d i n S ecti o n 5. 2. 1  f or p ossi bl e i nf usi o n-r el at e d 
r e acti o ns, T TI- 6 2 1 will b e a d mi nist er e d by i ntr a v e n o us i nf usi o n o v er 1 2 0 mi n ut es 
o n D ay 1 a n d D ay 8 of e ac h 2 1- d a y cycl e.  B e gi n ni n g wit h Cycl e 2, t h e i nf usi o n 
p eri o d m ay b e r e d uc e d t o 6 0 mi n ut es at t h e I
i o n if t h e p ati e nt 
h as n ot ex p eri e nc e d i nf usi o n-r el at e d r e acti o n.   
 
F or t h e p ur p os es of s af ety d ecisi o ns t h at g ui d e c o h ort ex p a nsi o n a n d 
c o nsi d er ati o ns of T TI-6 2 1 d os e a dj ust m e nt i n t h e d os e esc al ati o n p orti o n of t h e 
st u dy, t h e d os e-li miti n g t oxicity s af et y e v al u ati o n p eri o d will c o nsist of t h e 2 1-d ay 
Cycl e 1.  S u bj ects will b e c o nsi d er e d e v al u a bl e f or d os e-li miti n g t oxicit y ( DL T) if 
t h e y r ec ei v e d d ox or u bici n o n D a y 1 of Cycl e 1 a n d T TI-6 2 1 o n D ay 1 a n d D a y 8 of 
Cycl e 1.  A p ati e nt w h o wit h dr a ws fr o m t h e s t u dy d uri n g Cycl e 1 i n t h e a bs e nc e 
of o bj ectiv e dis e as e pr o gr essi o n or DL T will b e r e pl ac e d.  If a d os e-li miti n g t oxicity  
as d efi n e d i n S ecti o n 5. 4  is e nc o u nt er e d i n o n e p ati e nt i n t h e i niti al t hr e e p ati e nts 
i n a d os e c o h ort, t hr e e a d diti o n al p ati e nts will b e e nr oll e d i n acc or d a nc e wit h t h e 
st a n d ar d 3 + 3 st u dy d esi g n. T h e m axi m u m t ol er at e d d os e ( M T D) f or t his st u dy will 
b e d efi n e d as t h e m axi m u m ev al u at e d T TI- 6 2 1 d os e l e v el at w hic h < 3 3 % of 
p ati e nts 
wit hi n a 
d os e c o h ort 
ex p eri e nc e 
d os e-li miti n g t oxicity 
w h e n 
a d mi nist er e d i n c o m bi n ati o n wit h d ox or u bici n at 7 5 m g/ m 2.  W hil e t hr e e pr e-
d efi n e d T TI- 6 2 1 d os e l ev els ar e a ntici p at e d, i nt er m e di at e d os e l ev els m ay b e 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 8 of 140 
 
 
studied to more closely characterize the safety profile of TTI-621 in combination 
with doxorubicin. 
 
After three patients in a dose cohort, or six patients in an expanded dose cohort, 
complete the 21-day dose-limiting toxicity assessment period, the incidence of 
dose-limiting toxicity, treatment-related safety observations and other available 
data, such as pharmacokinetic data, will be reviewed by the Sponsor Medical 
Monitor, Sponsor and Investigators.  If no patient in a three-patient cohort or no 
more than one patient in a six-patient dose cohort experiences treatment-related 
dose-limiting toxicity, the dose level will be deemed safe and dose escalation may 
proceed unless there are other unsuspected but concerning safety observations 
that suggest either an expansion of the current dose level or implementation of 
an intermediate dose level.    
 
After completion of Cycle 6, doxorubicin will be discontinued as per standard of 
care to avoid development of cumulative cardiac toxicity.  Thereafter, beginning 
with Cycle 7, TTI-621 will be administered as monotherapy on Day 1 and Day 15 
of 28-day cycles until documentation of disease progression or unacceptable 
toxicity. 
 
Objective disease assessments will be performed after every second cycle of 
treatment for approximately 50 weeks and after every third cycle thereafter.  A 
patient enrolled in an expansion cohort who withdraws or is withdrawn from the 
study prior to completion of two cycles of treatment and objective disease 
assessment after the second cycle for a reason other than disease progression or 
safety will be replaced in order to meet the statistical criteria for the Simon two-
stage study design.  Patients who withdraw from the study without objective 
evidence of disease progression will be followed until documentation of disease 
progression or initiation of another treatment.  All patients will be followed in the 
Long-Term Follow-Up period for survival. 
 
The mechanism of immunotherapy is mechanistically distinct from other types of 
therapy.  The patterns of response and progression to immunotherapeutic 
agents, such as TTI-621, often differ temporally, qualitatively and quantitatively 
from those observed with cytotoxic and targeted agents.  The goal of 
immunotherapy is to overcome immunosuppression induced by a tumor and its 
microenvironment, thereby allowing the immune system to develop or activate 
an immune response that targets and kills cancer cells.  Some patients have 
experienced pseudo-progression, in which tumor burden showed an initial surge 
followed by shrinkage, usually at around four weeks, that led to development of 
immune-related disease response criteria that supports continued treatment 
beyond progression in patients whose clinical conditions have not worsened and 
who have not experienced severe toxicities.  Recognizing that immunotherapy 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 9 of 140 
 
 
represents a paradigm shift in oncology treatment, patients with an early 
observation of disease progression but without deterioration in clinical conditions 
or unacceptable toxicity and who consent should continue treatment until 
disease progression is verified by a repeated disease assessment at least four
weeks later.   
Guidelines for 
Cohort Assignment  
The dose escalation portion of the study carries a traditional 3+3 design to 
evaluate three dose levels of TTI-621.  Standard guidelines for enrollment for the 
3+3 design will be followed, with requirement that three patients complete the 
21-day dose-limiting toxicity assessment period (six patients in the case of an 
expanded dose cohort) before the next dose cohort is open to enrollment. 
 
However, recognizing that leiomyosarcoma is a rare disease and expecting that 
patients with leiomyosarcoma may be eager to participate in the study, careful 
modifications to the enrollment schema have been developed to avoid having to 
withhold enrollment for these patients.  During the dose escalation portion of the 
study, eligible patients will be enrolled to the cohort that is open at the time they 
present to the study.  Based on known safety of the lowest planned dose of TTI-
621, 0.2 mg/kg, gleaned from other clinical trials, it is anticipated that this dose 
will serve as the TTI-621 dose level for Cohort A.  Thus, expansion Cohort A will 
open to enrollment once that dose level is judged to be safe in the dose escalation 
portion of the study and the next dose cohort is open to enrollment.  If a dose 
escalation cohort and expansion Cohort A are open to enrollment at the same 
time, priority for enrollment will be given to the dose escalation cohort and 
enrollment into expansion Cohort A will be strictly limited to those patients who 
present to the study after enrollment to a dose escalation cohort is closed and 
meet all the eligibility criteria for the expansion portion of the study (including 
documentation of the leiomyosarcoma indication). 
 
When both expansion cohorts are open to enrollment, assignment of eligible 
patients will be made on an alternating basis, with cohort assignment made by 
the contract research organization overseeing the study on behalf of the sponsor 
independent of investigator input and based strictly on chronology of verification 
of eligibility of patients as they complete screening assessments.   
Duration of 
Treatment and 
Subject 
Participation 
Subjects may receive TTI-621 in combination with doxorubicin for a maximum of 
six cycles (18 weeks), with six cycles providing the maximum cumulative exposure 
of doxorubicin.  It is intended that each patient will receive six cycles of 
doxorubicin as fewer than six cycles provides less benefit to the patient compared 
to six or more cycles24 and guidelines for prophylaxis for prevention of 
doxorubicin-mediated dose-limiting neutropenia are provided in Section 5.2.1.  
Patients may continue on study and receive TTI-621 monotherapy thereafter until 
disease progression.  With a 28-day screening period and an estimated 11 months 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 10 of 140 
 
 
of treatment, it is anticipated that patients may participate in the active portion 
of the study for up to approximately one year. 
Inclusion Criteria 
General 
1. Written informed consent obtained prior to performing any study-specific
procedure, including screening procedures 
2. 
 18 years of age 
3. ECOG Performance Status 0 or 1 
4. Patients enrolled onto the dose expansion cohorts must agree to pre-
treatment and on-treatment biopsies if deemed safe and feasible by the  
treating physician 
 Disease Characteristics 
5. Histologically-confirmed high-grade soft tissue sarcoma that is metastatic or 
locally advanced and not amenable to curative treatment with surgery or 
radiation 
 
In the dose escalation portion of the study, indications will be limited to 
high-grade leiomyosarcoma, undifferentiated pleomorphic sarcoma, 
myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma and 
epithelioid sarcoma  
 
In the expansion portion of the study, enrollment will be restricted to 
high-grade leiomyosarcoma that is histologically-confirmed at a central 
laboratory.  The patient may be enrolled based on a current or most 
recent pathology report that provides sufficient detail to support 
derivation of the histologic interpretation but a pre-treatment tissue 
specimen must be made available for confirmation during screening or 
within the first cycle of treatment    
6. Objective evidence of disease progression unless disease is newly-diagnosed 
7. Measurable disease per RECIST v1.1 (expansion cohorts);  target lesions must 
not be chosen from a previously-irradiated field unless there has been 
radiographically and/or pathologically documented tumor progression in that 
lesion prior to enrollment. 
Organ Function 
Adequate organ and hematologic function as defined below: 
8. 
 3 x upper limit of normal (ULN); 
5 x ULN in the 
presence of liver metastasis 
9. 
 1.5 x ULN ( 2 x ULN if hyperbilirubinemia is due to 
 
10. 
 x ULN OR creatinine clearance/estimated glomerular 
filtrati
2 if serum creatinine is >1.5 x ULN  
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 11 of 140 
 
 
11. 
the week preceding screening evaluation 
12. ANC  1.5 × 109/L 
13. Platelet count   100 × 109/L 
14. INR  1.5 x ULN  2.5 x ULN if on anti-
 5 seconds above 
the ULN unless receiving anti-coagulation therapy;  patients on full-dose anti-
coagulation must be on a stable dose of oral anti-coagulant or low molecular 
weight heparin, have therapeutic INR, no active bleeding (defined as within 
14 days prior to first dose of study medication) and no pathological condition 
that carries a high risk of bleeding (e.g., tumor involving major vessels or 
known varices)  
15. Left ventricular ejection fraction (LVEF) determined by echocardiogram or 
multigated acquisition scan >50% 
Previous Therapy
16. No more than one prior treatment regimen for advanced disease,  which is 
limited to gemcitabine with docetaxel 
17. Anthracycline-naïve:  anthracycline in the neoadjuvant/adjuvant setting 
renders the patient ineligible for participation 
18. Patients who were treated with a prior chemotherapy regimen must have 
been completed treatment at least three weeks before initiation of study 
treatment 
19. All adverse events from prior treatment must be NCI CTCAE v5 Grade 
1, 
2 or baseline 
20. Radiotherapy, including palliative radiotherapy, completed at least two
weeks prior to treatment; palliative radiation to non-target lesions while on
study is allowed   
Contraception 
21. Refer to Appendix D for reproductive criteria for male and female 
participants. Female patients of childbearing potential  must have a negative 
serum beta  human  chorionic gonadotropoin pregnancy test result at 
screening and at baseline before the first study drug administration. 
 
Exclusion Criteria 
General 
1. Investigator site staff directly involved in the conduct of the study and their 
family members, site staff otherwise supervised by the investigator, and 
sponsor and sponsor delegate employees directly involved in the conduct of 
the study and their family members. 
Cardiovascular System 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 12 of 140 
 
 
2. History of acute coronary syndromes, including myocardial infarction,  
coronary artery bypass graft, unstable angina, coronary angioplasty or 
stenting within 24 weeks prior to first administration of study drug 
3.   History of or current Class II, III or IV heart failure as defined by the New York 
Heart Association (NYHA) functional classification system or symptomatic or 
poorly controlled cardiac arrhythmia  
4.  Uncontrolled or poorly-controlled hypertension (defined as systolic blood 
pressure >160 mm Hg) for more than four weeks despite optimal medical 
management   
General and Infectious Disease 
5.   Child-Pugh Class C 
6.   Any comorbidity  or concomitant medication or other condition that in the 
opinion of the Investigator and/or Sponsor Medical Monitor renders the 
patient  unsuitable for participation in the trial or unlikely to fully comply with 
study procedures, restrictions and/or requirements that are considered 
relevant for evaluation of the efficacy or safety of the trial drug 
 
Consideration 
should 
be 
given 
to 
lack 
of 
currently-available 
immunoprotection against SARS-CoV-2 as a condition that may render a 
patient unsuitable for participation in the trial or unlikely or unable to fully 
comply with study procedures, restrictions and/or requirements that are 
considered relevant for the evaluation of the efficacy or safety of study 
treatment    
7.  Uncontrolled intercurrent illness, including active or chronic infection 
requiring systemic therapy or oral or systemic antibiotics within 14 days prior 
to study start 
8.   History of non-viral hepatitis or cirrhosis, alcohol abuse or active tuberculosis  
9.  Administration of live attenuated vaccines within 28 days prior to start of 
treatment or anticipated need for vaccination with live attenuated vaccine 
during the study 
10.  Major surgery within 28 days of scheduled Cycle 1 Day 1 dosing or minor 
surgery within seven days prior to initiation of study treatment or elective or 
planned major surgery to be performed during the course of the clinical trial 
CNS Disease Considerations 
11.  History or evidence of known CNS metastases or carcinomatous meningitis; 
patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms 
have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least seven days prior to study
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 13 of 140 
 
 
treatment; this exception does not include carcinomatous meningitis which 
is excluded regardless of clinical stability 
Coagulation Considerations 
12. Chronic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., 
indomethacin, ibuprofen, naproxen or similar agents) or other anti-platelet 
agents (e.g., clopidogrel, ticlopidine, dipyridamole, anagrelide);  aspirin up to 
325 mg per day is permitted 
13.  Significant bleeding disorders, vasculitis or a significant bleeding episode from 
the GI tract within three months prior to study entry 
Immune System 
14.  History of severe hypersensitivity reactions to antibodies 
15.  Systemic steroid therapy (> 10 mg daily prednisone or equivalent) or any 
other form of immunosuppressive therapy within seven days prior to the first 
dose of study treatment;  topical, inhaled, nasal and ophthalmic steroids are 
not prohibited 
16. History of autoimmune disease that has required systemic treatment with 
disease-modifying agents, corticosteroids, or immunosuppressive drugs 
unless in the opinion of the investigator the patient is in a complete and 
durable remission; physiologic replacement therapies, such as thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, is allowed 
17. Prior organ transplantation including allogeneic or autologous stem cell 
transplantation 
Oncology 
18. Concurrent or previous other malignancy within two years of study entry with 
the exception of cured basal or squamous cell skin cancer, superficial bladder 
cancer, prostate intra-epithelial neoplasm, carcinoma in situ of the cervix, or 
other non-invasive or indolent malignancy  
19.  Concurrent enrollment in another therapeutic clinical study 
20.  Prior treatment with anti-CD47 or anti-SIRP  therapy  
21.  Prior radiation to mediastinal/pericardial region 
Objectives 
Primary Objectives 
 
Evaluate the safety of escalating dose levels of TTI-621 when administered in 
combination with 75 mg/m2 doxorubicin in 21-day cycles and establish the 
maximum tolerated dose level of TTI-621 when administered in combination 
with doxorubicin 
 
Evaluate the safety of selected dose levels of TTI-621 when administered in 
combination with 75 mg/m2 doxorubicin in 21-day cycles and then as 
monotherapy in 28-day cycles until documentation of objective disease 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 1 4 of 1 4 0  
 
 
pr o gr essi o n 
 
I nv esti g at e cli nic al acti vity ass ess e d as ov er all r es p o ns e r at e of T TI-6 2 1 
a d mi nist er e d i n c o m bi n ati o n wit h 7 5 m g/ m 2 d ox or u bici n f or u p t o six cycl es 
( 1 8 w e e ks) a n d t h e n as m o n ot h er a py u ntil d oc u m e nt ati o n of o bj ectiv e 
dis e as e pr o gr essi o n  
S ec o n d ar y O bj ecti v es 
 
F urt h er ass ess s af ety of t h e s el ect e d d os e l ev els of T TI- 6 2 1 a d mi nist er e d i n 
c o m bi n ati o n wit h 7 5 m g/ m 2 d ox or u bici n 
 
D escri b e ot h er e vi d e nc e of cli nic al b e n efit 
E n d p oi nts 
Pri m ar y 
 
Ov er all s af ety pr ofil e as ass ess e d by t h e ty p e, fr e q u e ncy, s e v erit y, ti mi n g a n d 
c a us al r el ati o ns hi p of a ny a dv ers e ev e nts, c h a n g es i n vit al si g ns, E C G, s er u m 
c h e mistry 
or 
ot h er l a b or at ory 
ass ess m e nt, 
tr e at m e nt 
d el ays 
or 
disc o nti n u ati o ns f or p ati e nts e nr oll e d i nt o t h e d os e esc al ati o n p orti o n of t h e 
st u dy 
 
T h e p erc e nt a g e of p ati e nts wit h o bj ectiv e r es p o ns e ( C R + P R) as d efi n e d b y 
R E CI S T v 1. 1 crit eri a  
S ec o n d ar y 
 
Ov er all s af ety pr ofil e as ass ess e d by t h e ty p e, fr e q u e nc y, s ev erit y, ti mi n g a n d 
c a us al r el ati o ns hi p of a n y a dv ers e ev e nt s, c h a n g es i n vit al si g ns, E C G, s er u m 
c h e mistry 
or 
ot h er 
l a b or at ory 
ass ess m e nt, 
tr e at m e nt 
d el ays 
or 
disc o nti n u ati o ns f or p ati e nts e nr oll e d i nt o t h e s el ect e d d os e l ev el c o h orts i n 
t h e ex p a nsi o n p orti o n of t h e st u dy 
 
Pr o gr essi o n-fr e e s urvi v al ( P F S), ov er all s urviv al ( O S), dis e as e c o ntr ol r at e 
( D C R [ C R + P R + S D]), d ur ati o n of r es p o ns e ( D O R), d ur ati o n of dis e as e c o ntr ol, 
ti m e t o pr o gr essi o n a n d ti m e t o n e w m et ast as es as d efi n e d by R E CI S T v 1. 1 
crit eri a, ti m e t o w ors e ni n g of E C O G p erf or m a nc e st at us, ti m e t o w ors e ni n g 
of p ati e nt-r e p orti n g o utc o m es ass ess m e nts  
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 1 5 of 1 4 0  
 
 
Dr u g Pr o d uct       
T TI- 6 2 1 
T TI-
-I g G 1 Fc) 
c o m bi ni n g t h e s e q u e nc es 
bi n di n g d o m ai n f or C D 4 7) wit h t h e Fc r e gi o n of h u m a n I g G 1.  T TI- 6 2 1 Dr u g 
Pr o d uct is f or m ul at e d as
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 1 6 of 1 4 0  
 
 
 
 
 
, T TI- 6 2 1 Dr u g Pr o d uct is
 
 a d mi nist er e d by i ntr a v e n o us  i nf usi o n ov er 
1 2 0 mi n ut es.  T h e d os e of T TI- 6 2 1 will b e b as e d u p o n t h e d os e l ev el c o h ort t o 
w hic h t h e p ati e nt is assi g n e d.   
 
Pr o p hyl axis wit h ac et a mi n o p h e n, a nti- hist a mi n e a n d st er oi d will b e gi v e n pri or t o 
i niti ati o n of T TI- 6 2 1 i nf usi o n t o eli mi n at e or r e d uc e t h e occ urr e nc e or gr a d e of 
i m m u n e-r el at e d r e acti o n.  I n t h e a bs e nc e of i nf usi o n-r el at e d r e acti o n, th e 
d ur ati o n of i nf usi o n m ay b e r e d uc e d t o 6 0 mi n ut es b e gi n ni n g wit h C ycl e 2.   
 
O n d a ys w h e n T TI- 6 2 1 a n d d ox or u bici n ar e b ot h a d mi nist er e d, d ox or u bici n will 
b e a d mi nist er e d pri or t o i nf usi o n of T TI- 6 2 1.  O n e ac h d ay of T TI- 6 2 1 
a d mi nistr ati o n, a 6 0- mi n ut e o bs er v ati o n p eri o d will f oll o w T TI- 6 2 1 i nf usi o n a n d 
vit al si g ns will b e ass ess e d at 3 0- mi n ut e i nt erv als d uri n g t his o bs erv ati o n p eri o d ;  
d ecr e as e d af t er c o m pl eti o n of Cycl e 1 f or a p ati e nt w h o h as n ot ex p eri e nc e d 
i nf usi o n-r el at e d r e acti o n. 
R ef er e nc e Pr o d uct 
D o x or u bici n 
D ox or u bici n is c o nsi d er e d st a n d ar d of c ar e i n t h e i nt e n d e d p ati e nt p o p ul ati o n a n d 
will b e us e d i n acc or d a nc e wit h st a n d ar d of c ar e wit h i ntr a v e n o us i nf usi o n at a 
d os e of 7 5 m g/ m 2 o n D ay 1 of e ac h 2 1-d a y cycl e f or a m axi m u m of six cycl es ( 1 8 
w e eks).  D ox or u bici n s h o ul d b e m a d e u p t o a v ol u m e of 1 0 0 mL a n d a d mi nist er e d 
t hr o u g h a fr e e-fl o wi n g c at h et er at 7 5 m g/ m2 by i ntr a v e n o us i nf usi o n i n l ess t h a n 
6 0 mi n ut es.  T h e r at e of i nf usi o n s h o ul d b e d ecr e as e d if eryt h e m at o us str e aki n g 
al o n g t h e v ei n pr oxi m al t o t h e sit e of i nf usi o n or f aci al fl us hi n g occ ur.  D ox or u bici n 
is e m et o g e nic a n d pr o p h yl axis f or e m esis pri or t o eac h i nf usi o n of d ox or u bici n 
s h o ul d b e gi v e n.  I nstit uti o n al g ui d eli n es f or eff ectiv e pr o p hyl axis, i ncl u di n g 
s p ecific a g e nts, a d diti o n al a g e nts a n d r e gi m e ns, ar e acc e pt a bl e.  C ar di o pr ot ecti v e 
pr o p h yl axis m ust b e i m pl e m e nt e d n o l at er t h a n wit h i niti ati o n of Cycl e 5.   
 
A S C O g ui d eli n es f or us e of W B C gr o wt h f act ors 2 5 
of W B C gr o wt h f act ors f or pr e v e nti o n of f e bril e n e utr o p e ni a is w arr a nt e d w h e n 
t h e ris k of f e bril e n e utr o p e ni a is a p pr oxi m at ely 2 0 % or hi g h er a n d n o ot h er 
e q u all y eff ectiv e a n d s af e r e gi m e n t h at d o es n ot r e q uir e C S Fs is a v ail a bl e.  Pri m ary 
pr o p h yl axis is r ec o m m e n d e d f or t h e pr ev e nti o n of f e bril e n e utr o p e ni a i n p ati e nts 
w h o ar e at hi g h risk o n t h e b asis of a g e, m e dic al hist ory, dis e as e c h ar act eristics, 
a n d 
m y el ot oxicity of t h e c h e m ot h er a py r e gi m e n. T h e N C C N g ui d eli n es f or 
h e m at o p oi etic gr o wt h f act ors 2 6 cl assif y s oft tiss u e s arc o m a tr e at e d 
wit h 
d ox or u bici n as a n ex a m pl e of dis e as e s etti n g a n d c h e m ot h er a py r e g i m e n wit h a 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 17 of 140 
 
 
high risk for febrile neutropenia (>20%) and recommends G-CSF prophylaxis for 
patients with high risk (>20%) of febrile neutropenia. 
Thus, all patients receiving TTI-621 in combination with doxorubicin should 
receive prophylaxis with G-CSFs for prevention of febrile neutropenia.  Suggested 
prophylaxis is pegfilgrastim and discussion with the Sponsor Medical Monitor is 
encouraged.   
The Single Reference Safety Document (SRSD) for doxorubicin is the US Product 
Insert (USPI). 
Statistical 
Considerations  
Based on a standard 3+3 design, up to approximately six patients may be enrolled 
in each dose level cohort evaluated during the dose escalation portion of the 
study; a minimum of nine and a maximum of 18 patients who complete the safety 
review period is anticipated.  
 
The sample size for the dose level expansion cohorts is selected to obtain a 
reasonable estimate of clinical benefit, defined for this study as response rate 
defined by RECIST v1.1 criteria, to be used for planning future studies.  A Simon 
two-stage design will be used for each dose cohort; in the Simon two-stage design 
and assuming a baseline overall response rate of 10% with doxorubicin 
monotherapy and an alternative of 25%, a power of 90% and one-sided Type 1 
error set at 0.20, each dose level cohort will require 18 patients enrolled and 
evaluable for response in Stage 1.  With at least two clinical responses, an 
additional 13 patients will be enrolled in Stage 2.  The combination will be 
considered worthy of further study if at least five clinical responses observed in 
either 31-patient cohort.    
Dose Delays, Dose 
Modifications, 
Guidelines for 
Treatment 
Discontinuation 
and Study 
Withdrawal 
Patients who enter the study with symptoms or laboratory values equivalent to 
NCI CTCAE Grade 1 or Grade 2 should not have dose reductions related to the 
persistence or mild worsening of those symptoms or laboratory values.   
 
Dose reductions may be warranted if worsening of symptoms or laboratory 
values is clinically significant in the opinion of the Investigator and in the case of 
unacceptable treatment-related adverse events.  Recognizing that it may be 
difficult to make attribution to one agent or the other in the combination regimen 
and in collaboration with the Sponsor Medical Monitor, best efforts should be 
made to consider the underlying reason for the worsening of symptoms or 
development of a treatment-related adverse event so that dosing of the 
appropriate study drug can be modified.   
Except in the case of proteinuria, asymptomatic laboratory abnormalities should 
not result in dose interruptions, modifications, or discontinuation of study 
therapy unless determined by the Investigator to be clinically significant or life-
threatening. 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 18 of 140 
 
 
The Investigator should withdraw a patient from all study-related treatment for 
any of the following reasons: 
 
An unacceptable adverse event or safety observation, such as a persistent
moderate toxicity that is intolerable to the patient, that is in the opinion of 
the Investigator clearly attributed to TTI-621 
 
An unacceptable adverse event or safety observation, such as a persistent
moderate toxicity that is intolerable to the patient, that is in the opinion of 
the Investigator clearly attributed to doxorubicin and the patient has 
received fewer than four cycles of doxorubicin.  A patient who has completed 
four cycles of doxorubicin treatment and experiences an adverse event that 
requires discontinuation of doxorubicin treatment despite optimal 
prophylaxis and supportive care and is receiving clinical benefit may be 
eligible to continue to TTI-621 monotherapy with the next cycle (Cycle 5 or 
Cycle 6) after discussion with the Sponsor Medical Monitor and provided the 
patient has not experienced disease progression and TTI-621 re-treatment 
guidelines as described in Section 9.2.2 are met;  the patient may be replaced
or an additional patient may be enrolled for the purposes of having a 
heterogeneous population for evaluation of safety and clinical activity as
described in Section 6.7.   
 
Any event which would cause TTI-621 or doxorubicin to be modified by more 
than two dose reductions or to be held for more than 42 days from the last 
administered dose and is not attributable to a particular agent of the 
combination regimen; exception is made for patients who are receiving 
meaningful clinical benefit and the investigator feels, with Sponsor Medical 
Monitor concurrence, that continued treatment is in the best interest of the 
patient 
 
Any treatment-related adverse event that is deemed life-threatening, 
regardless of grade; exception is made for patients in whom the life-
threatening adverse event is attributed to doxorubicin and has occurred 
despite optimal prophylaxis and medical support and the patient is receiving 
clinical benefit and has received at least four cycles of doxorubicin treatment 
and the investigator feels, with Sponsor Medical Monitor concurrence, that 
continuation with TTI-621 monotherapy would be reasonable;  the patient 
may be replaced or an additional patient enrolled for the purposes of having 
a heterogeneous population for evaluation of safety and clinical activity as 
described in  Section 6.7. 
 
Documentation of objective (radiographic) disease progression; for patients
with asymptomatic progression and in the absence of unacceptable toxicity, 
the patient should continue treatment and a confirmation scan should be 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 19 of 140 
 
 
conducted at least four weeks later to document objective progression prior 
to removing patient from study treatment  
 
Unacceptable toxicity which in the opinion of the Investigator cannot be 
attributed to a specific study agent 
 
condition that renders the 
patient unsuitable for further treatment in the opinion of the Investigator; 
exception may be made for patients in whom the intercurrent illness or 
change in condition is thought to render the patient ineligible for continued 
treatment with doxorubicin and the patient has received at least four cycles 
of doxorubicin and is receiving clinical benefit and the investigator feels, with 
Sponsor Medical Monitor concurrence, that continuation with TTI-621 
monotherapy would be reasonable and the patient meets criteria for TTI-621 
re-treatment;  the patient may be replaced or an additional patient may be 
enrolled for the purposes of having a heterogeneous population for 
evaluation of safety and clinical activity as described in  Section 6.7. 
 
Significant noncompliance with study protocol 
 
Withdrawal of consent (patient may participate in Long-Term Follow-Up 
assessment of survival and disease status [if withdrawn prior to 
documentation of objective disease progression] if consent for this portion 
of the study is not withdrawn) 
 
Termination of the study by the sponsor 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 20 of 140 
 
 
STUDY SCHEMA SUMMARY
In the dose escalation portion of the study, eligible patients with high-grade leiomyosarcoma, 
undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, angiosarcoma 
or epithelioid sarcoma will receive doxorubicin at 75 mg/m2 and escalating doses of TTI-621 in a standard 
3+3 design.  For the expansion portion of the study, a low dose (Cohort A) and a high dose (Cohort B) of 
TTI-621 will be selected for evaluation with 75 mg/m2 doxorubicin in patients with high-grade 
leiomyosarcoma using a Simon two-stage design.  Due to cumulative toxicity that limits its use, 
doxorubicin is administered on Day 1 of 21-day cycles for a maximum of six cycles (18 weeks).  In Cycle 1 
through Cycle 6, TTI-621 will be administered on Day 1 and Day 8 of each 21-day cycle.  Beginning with 
Cycle 7, TTI-621 will be administered as monotherapy on Days 1 and 15 of 28-day cycles.    
 
During the dose escalation portion of the study, eligible patients will be enrolled to the cohort that is open 
at the time they present to the study.  Based on known safety of the lowest planned dose of TTI-621, 0.2 
mg/kg, gleaned from other clinical trials, it is anticipated that this dose will serve as the TTI-621 dose level 
for Cohort A.  Thus, expansion Cohort A will open to enrollment once that dose level is judged to be safe 
in the dose escalation portion of the study.  If a dose escalation cohort and expansion Cohort A are open 
to enrollment at the same time, priority for enrollment will be given to the dose escalation cohort and 
enrollment into expansion Cohort A will be limited to those patients who present to the study after 
enrollment to a dose escalation cohort is closed and meet all the eligibility criteria for the expansion 
portion of the study (including documentation of the leiomyosarcoma indication). 
 
When both expansion cohorts are open to enrollment, cohort assignment will be made on an alternating 
basis, with assignment made by the CRO overseeing the study on behalf of the sponsor independent of 
investigator input and based strictly on chronology of verification of eligibility of patients as they complete 
screening assessments.   
 
 
 
 
 
 
 
 
 
     Figure 1.  General Study Schema 
In the Simon two-stage design and assuming a baseline ORR of 10% with doxorubicin monotherapy and 
an alternative of 25%, a power of 90% and one-sided Type 1 error set at 0.20, each dose level cohort will 
require 18 patients enrolled and evaluable for response in Stage 1; with at least 2 clinical responses, an 
additional 13 patients will be enrolled in Stage 2.  The combination will be considered worthy of further 
study if at least five clinical responses are observed in either 31-patient cohort.   
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 2 1 of 1 4 0  
 
 
T A BL E O F C O N T E N T S
1.  
P R O T O C OL A P P R O V AL ........................................................................................................... 2  
2.  
S Y N O P SI S ................................................................................................................................ 3  
S T U D Y S C H E M A S U M M A R Y ........................................................................................................................ 2 0  
T A BL E O F C O N T E N T S ................................................................................................................................... 2 1  
LI S T O F FI G U R E S .................................................................................................................................. 2 6 
A B B R E VI A TI O N S .......................................................................................................................................... 2 7  
3.  
I N T R O D U C TI O N .................................................................................................................... 3 0 
3. 1.  
 .................................................................. 3 0 
3. 2.  R e g ul ati o n of M acr o p h a g e P h a g ocytic Acti vit y ........................................................................ 3 0  
3. 3.  T TI- 6 2 1 ...................................................................................................................................... 3 1  
3. 4.  R ati o n al e f or P ati e nt P o p ul ati o n a n d St u d y D esi g n ................................................................. 3 2  
3. 5.  I nv esti g ati o n al M e dici n al Pr o d uct T TI- 6 2 1 ............................................................................... 3 4 
3. 5. 1.  N o ncli nic al Ex p eri e nc e wit h T TI- 6 2 1 ............................................................................ 3 4  
3. 5. 1. 1.  
 .................................................... 3 4 
3. 5. 1. 2.  
 ....................................................... 3 5 
3. 5. 1. 3.  
N o ncli nic al T oxic ol o g y of T TI- 6 2 1 ................................................................... 3 5  
3. 5. 2.  Cli nic al Ex p eri e nc e wit h T TI- 6 2 1 .................................................................................. 3 6  
3. 5. 2. 1.  
St u d y T TI- 6 2 1- 0 1 (I ntr av e n o us R o ut e of A d mi nistr ati o n) .............................. 3 7  
3. 5. 2. 2.  
St u d y T TI- 6 2 1- 0 2 (I ntr at u m or al I nj ecti o n)...................................................... 4 1  
3. 6.  I nv esti g ati o n al M e dic al Pr o d uct D ox or u bici n .......................................................................... 4 1 
3. 7.  R ati o n al e f or Pl a n n e d R e gi m e ns of I nv esti g ati o n al M e dic al Pr o d ucts ..................................... 4 1  
3. 7. 1.  T TI- 6 2 1 ......................................................................................................................... 4 1  
3. 7. 2.  D ox or u bici n .................................................................................................................. 4 2  
3. 8.  B e n efit- Risk Ass ess m e nt ........................................................................................................... 4 3  
3. 8. 1.  Ex p ect e d Ris ks of T TI- 6 2 1 ............................................................................................ 4 3  
3. 8. 2.  Ex p ect e d B e n efits of T TI- 6 2 1 ....................................................................................... 4 3  
4.  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S ................................................................................... 4 5  
4. 1.  Pri m ar y O bj ectiv es .................................................................................................................... 4 5  
4. 2.  Pri m ar y E n d p oi nts .................................................................................................................... 4 5  
4. 3.  S ec o n d ary O bj ecti v es ............................................................................................................... 4 5  
4. 4.  S ec o n d ary E n d p oi nts ................................................................................................................ 4 5  
4. 5.  
 .............................................................................................................. 4 5 
4. 6.  
 .............................................................................................................. 4 6 
5.  
I N V E S TI G A TI O N AL PL A N ....................................................................................................... 4 7 
5. 1.  Ov er all St u dy D esi g n ................................................................................................................. 4 7  
5. 2.  D os es a n d Sc h e d ul e of A d mi nistr ati o n of I n v esti g ati o n al A g e nts ............................................ 5 0  
5. 2. 1.  Pr o p hyl axis ................................................................................................................... 5 1  
5. 2. 1. 1.  
D ox or u bici n Pr o p hyl axis ................................................................................. 5 1  
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI
C CI
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 22 of 140 
 
 
5.2.1.2.
TTI-621 Prophylaxis ........................................................................................51
5.2.2. Doxorubicin .................................................................................................................. 52 
5.2.3. TTI-621 ......................................................................................................................... 53 
5.3. 
Criteria for Treatment Discontinuation .................................................................................... 54 
5.4. 
Dose-Limiting Toxicity Criteria for the Dose Escalation Portion of the Study .......................... 56 
6. 
STUDY POPULATION............................................................................................................. 58 
6.1. 
Number of Patients ................................................................................................................... 58 
6.2. 
Inclusion Criteria ....................................................................................................................... 58 
6.3. 
Exclusion Criteria ...................................................................................................................... 59 
6.4. 
Re-Screening ............................................................................................................................. 61 
6.5. 
Waivers of Inclusion/Exclusion Criteria .................................................................................... 61 
6.6. 
Patients or Partners of Patients of Reproductive Potential ..................................................... 61 
6.7. 
Provisions for Enrollment of Additional Patients based on Emerging Data ............................. 62 
7. 
ENROLLMENT PROCEDURE AND METHOD OF ASSIGNING SUBJECTS TO TREATMENT 
GROUPS ................................................................................................................................ 63 
7.1. 
Enrollment Procedure............................................................................................................... 63 
7.2. 
Method of Assigning Subjects to Treatment Groups ............................................................... 63 
8. 
DESCRIPTION OF STUDY TREATMENT .................................................................................. 64 
8.1. 
Description of TTI-621 .............................................................................................................. 64 
8.2. 
Description of Doxorubicin ....................................................................................................... 64 
8.3. 
Preparation and Administration of Study Treatments ............................................................. 64 
8.3.1. TTI-621 ......................................................................................................................... 64 
8.3.2. Doxorubicin .................................................................................................................. 65 
8.4. 
Blinding of Treatment ............................................................................................................... 65 
8.5. 
Treatment Compliance ............................................................................................................. 65 
8.6. 
Study Drug Accountability ........................................................................................................ 66 
8.7. 
Concomitant Medications ........................................................................................................ 66 
8.7.1. Concomitant Corticosteroids ....................................................................................... 66 
8.7.2. Concomitant Hematopoietic Growth Factors and Blood Products ............................. 67 
8.7.3. Concomitant Anti-Coagulants ...................................................................................... 67 
8.8. 
Treatment of Overdose ............................................................................................................ 67 
9. 
MONITORING AND MANAGEMENT OF EXPECTED OR POTENTIAL ADVERSE EVENTS ........ 69 
9.1. 
Prophylaxis for Expected Adverse Events ................................................................................. 69 
9.2. 
Management of Adverse Events Associated with TTI-621 ....................................................... 69 
9.2.1. TTI-621 Treatment Interruptions ................................................................................. 69 
9.2.2. TTI-621 Re-Treatment Guidelines (Initiation of New Cycles of Treatment) ................ 70 
9.2.3. TTI-621 Dose Modification Guidelines ......................................................................... 70 
9.2.3.1. 
Infusion-Related Reactions Related to TTI-621 Administration ..................... 71 
9.2.3.2. 
Hematologic Adverse Events Related to TTI-621 Administration .................. 72 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 2 3 of 1 4 0  
 
 
9. 2. 3. 3.
N o n- H e m at ol o gic Ev e nts R el at e d t o T TI- 6 2 1 A d mi nistr ati o n........................ 7 4
9. 2. 3. 4.  
M a n a g e m e nt of Ot h er A dv ers e Ev e nts R el at e d t o T TI- 6 2 1 A d mi nistr ati o n .. 7 4  
9. 3.  M a n a g e m e nt of A dv ers e Ev e nts Ass oci at e d wit h D ox or u bici n ................................................ 7 4  
9. 3. 1.  D ox or u bici n Tr e at m e nt I nt err u pti o ns.......................................................................... 7 4  
9. 3. 2.  D ox or u bici n R e- Tr e at m e nt G ui d eli n es f or D ay 1 ......................................................... 7 5  
9. 3. 3.  D ox or u bici n D os e M o dific ati o n G ui d eli n es ................................................................. 7 5  
9. 3. 3. 1.  
C ar di ac T oxicity R el at e d t o D ox or u bici n A d mi nistr ati o n ................................ 7 6  
9. 3. 3. 2.  
S ec o n d ar y M ali g n a nci es R el at e d t o D ox or u bici n A d mi nistr ati o n .................. 7 7  
9. 3. 3. 3.  
Extr av as ati o n a n d Tiss u e N ecr osis R el at e d t o D ox or u bici n A d mi nistr ati o n .. 7 7  
9. 3. 3. 4.  
H e m at ol o gic T oxicity R el at e d t o D ox or u bici n A d mi nistr ati o n ....................... 7 7  
9. 3. 3. 5.  
T u m or L ysis Sy n dr o m e R el at e d t o D ox or u bici n A d mi nistr ati o n .................... 7 9  
9. 3. 3. 6.  
R a di ati o n S e nsitiz ati o n a n d R a di ati o n R ec all R el at e d t o D ox or u bici n 
A d mi nistr ati o n .............................................................................................. 7 9  
9. 3. 3. 7.  
M a n a g e m e nt of I nf usi o n- R el at e d R e acti o ns R el at e d t o D ox or u bici n 
A d mi nistr ati o n .............................................................................................. 7 9  
9. 4.  M a n a g e m e nt of A dv ers e Ev e nts n ot Attri b ut a bl e t o a S p ecific St u d y Tr e at m e nt ................... 8 0  
9. 5.  G ui d eli n es f or M a n a g e m e nt of T hr o m b ocyt o p e ni a Ass ess e d as R el at e d t o St u dy Tr e at m e nt 
( T TI- 6 2 1 a n d/ or D ox or u bici n).............................................................................................................. 8 1 
1 0.  
S T U D Y A S S E S S M E N T S ........................................................................................................... 8 5  
1 1.  
S C H E D UL E O F P R O C E D U R ES A N D A S S E SS M E N T S ................................................................ 9 1  
1 2.  
S T A TI S TI C AL C O N SI D E R A TI O N S ............................................................................................ 9 8  
1 2. 1.  S a m pl e Siz e ............................................................................................................................... 9 8  
1 2. 1. 1.  D os e Esc al ati o n ............................................................................................................ 9 8  
1 2. 1. 2.  Ex p a nsi o n C o h orts ....................................................................................................... 9 8  
1 2. 2.  A n alysis P o p ul ati o ns ................................................................................................................. 9 8  
1 2. 3.  Crit eri a f or Ev al u ati o n ............................................................................................................... 9 9  
1 2. 3. 1.  S af et y ........................................................................................................................... 9 9  
1 2. 3. 2
........................................................... 9 9 
1 2. 3. 3.  Cli nic al B e n efit ............................................................................................................. 9 9  
1 2. 3. 4.  P ati e nt- R e p ort e d O utc o m es ...................................................................................... 1 0 0  
1 2. 3. 5.
................................................................................................ 1 0 1 
1 2. 4.  St atistic al M et h o ds ................................................................................................................. 1 0 1  
1 3.  
S AF E T Y ................................................................................................................................ 1 0 2  
1 3. 1.  D efi niti o n of A dv ers e E v e nts .................................................................................................. 1 0 2  
1 3. 1. 1.  A dv ers e E v e nt ............................................................................................................ 1 0 2  
1 3. 1. 2.  S eri o us A dv ers e Ev e nt ............................................................................................... 1 0 2  
1 3. 2.  Cl arific ati o ns t o S eri o us A dv ers e Ev e nt R e p orti n g ................................................................. 1 0 3  
1 3. 3.  Ass ess m e nt of C a us alit y ......................................................................................................... 1 0 3  
1 3. 4.  Ass ess m e nt of S e v erit y ........................................................................................................... 1 0 4  
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 24 of 140 
 
 
13.5. Action Taken........................................................................................................................... 105
13.5.1. Other Specific Treatments of Adverse Event ............................................................. 105 
13.5.2. Outcome of Adverse Event ........................................................................................ 105 
13.5.3. Time Period and Frequency for Collecting AE and SAE Information ......................... 105 
13.5.4. Documentation .......................................................................................................... 106 
13.5.5. Follow-Up ................................................................................................................... 106 
13.5.6. Notification ................................................................................................................ 107 
13.5.7. Regulatory Requirements for SAEs ............................................................................ 108 
13.5.8. Adverse Events of Special Interest ............................................................................. 108 
13.5.9. Lack of Efficay............................................................................................................. 109 
13.5.10. 
Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure .............................................................................................. 109 
13.5.11. 
Medication Error ........................................................................................ 111 
13.6. Laboratory Abnormalities ....................................................................................................... 112 
13.7. Sponsor Safety Review ........................................................................................................... 112 
13.8. Overview of Safety Monitoring .............................................................................................. 112 
14. 
ETHICAL AND ADMINISTRATIVE CONSIDERATIONS ........................................................... 114 
14.1. Regulatory Authority Approvals ............................................................................................. 114 
14.2. Institutional Review Board ..................................................................................................... 114 
14.3. Confidentiality of Information ................................................................................................ 115 
14.4. Patient Informed Consent ...................................................................................................... 115 
14.5. Study Monitoring .................................................................................................................... 116 
14.6. Clinical Supplies ...................................................................................................................... 116 
14.7. Electronic Case Report Form .................................................................................................. 116 
14.8. Study Termination and Site Closure ....................................................................................... 117 
14.9. Modification of the Study Protocol ........................................................................................ 117 
14.10. Retention of Study Documents............................................................................................... 118 
14.11. Clinical Study Report ............................................................................................................... 118 
14.12. Study Publication .................................................................................................................... 118 
14.13. Quality Assurance Audits ........................................................................................................ 118 
14.14. Dissemination of Clinical Study Data ...................................................................................... 119 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 2 5 of 1 4 0  
 
 
1 5.
R E F E R E N C E S....................................................................................................................... 1 2 1
A P P E N DI X A:  E C O G P E R F O R M A N C E S T A T U S ........................................................................................... 1 2 5  
A P P E N DI X B:  R E S P O N S E E V AL U A TI O N C RI T E RI A I N S OLI D T U M O R ( R E CI S T) V E R SI O N 1. 1 ..................... 1 2 6  
 
 ................................................................ 1 3 1 
A P P E N DI X D:  C O N T R A C E P TI V E A N D B A R RI E R G UI D A N C E ....................................................................... 1 3 2  
A P P E N DI X E:  LI V E R S A F E T Y:  S U G G E S T E D A C TI O N A N D F OLL O W- U P A S S E S S M E N TS ............................. 1 3 5  
A P P E N DI X F:  KI D N E Y S AF E T Y:  M O NI T O RI N G G UI D ELI N E S ...................................................................... 1 3 7  
A P P E N DI X G:  P RI N CI P AL I N V E S TI G A T O R A C K N O WL E D G E M E N T F O R M .................................................. 1 3 9  
A P P E N DI X H:  D O C U M E N T HI S T O R Y ......................................................................................................... 1 4 0  
 
 
LI S T O F T A BL E S 
 ............. 3 8 
 2 % of S u bj ects ................... 3 8 
T a bl e 3.  S eri o us A d v ers e E v e nts of A n y Gr a d e Ass ess e d as R el at e d t o Tr e at m e nt i n 
 2 S u bj ects ....... 3 9 
T a bl e 4.  S u m m ar y of Cli nic al R es p o ns es Acr oss Dis e as e C o h orts  ........................................................... 3 9 
T a bl e 5.  T TI- 6 2 1 D os e L e v els Pl a n n e d f or E v al u ati o n i n C o m bi n ati o n wit h D o x or u bici n  ....................... 4 2 
T a bl e 6.  Pr o p h yl a xis R e gi m e n f or T TI- 6 2 1 t o R e d uc e i nci d e nc e a n d/ or Gr a d e of I nf usi o n- R el at e d 
R e acti o n  
 ..................................................................................................................................... 5 2 
T a bl e 7.  T TI- 6 2 1 D os e L e v els Pl a n n e d f or E v al u ati o n i n C o m bi n ati o n Wit h D o x or u bici n  ...................... 5 4 
T a bl e 8.  T TI- 6 2 1 I n v esti g ati o n al Dr u g Pr o d uct D escri pti o n  ..................................................................... 6 4 
T a bl e 9.  R e q uir e m e nts f or  I niti ati o n of a N e w C ycl e wit h T TI- 6 2 1  ......................................................... 7 0 
T a bl e 1 0.  T TI- 6 2 1 D os e M o dific ati o ns  ...................................................................................................... 7 0 
T a bl e 1 1.  D efi niti o n of I nf usi o n- R el at e d R e acti o n b y C T C A E Gr a d e  ........................................................ 7 1 
T a bl e 1 2.  M a n a g e m e nt of I nf usi o n- R el at e d R e acti o ns Ass oci at e d wit h T TI- 6 2 1 A d mi nistr ati o n  .......... 7 2 
T a bl e 1 3.  M a n a g e m e nt of H e m at ol o gic A d v ers e E v e nts Ass oci at e d wit h T TI- 6 2 1 A d mi nistr ati o n  ....... 7 3 
T a bl e 1 4.  M a n a g e m e nt of N o n- H e m at ol o gic A d v ers e E v e nts Ass oci at e d wit h T TI- 6 2 1 
A d mi nistr ati o n
 
 ..................................................................................................................................... 7 4 
T a bl e 1 5. M a n a g e m e nt of ot h er Tr e at m e nt- R el at e d A d v ers e E v e nts  ..................................................... 7 4 
T a bl e 1 6.  R e q uir e m e nts f or R e- Tr e at m e nt wit h D o x or u bici n o n D a y 1 ( C ycl e 2 t hr o u g h C ycl e 6)  ........ 7 5 
T a bl e 1 7. D o x or u bici n D os e M o dific ati o ns  ............................................................................................... 7 5 
T a bl e 1 8.  D o x or u bici n D os e M o dific ati o n G ui d eli n es  .............................................................................. 7 6 
T a bl e 1 9.  G e n er al G ui d eli n es f or D o x or u bici n D os e R e d ucti o n d u e t o N e utr o p e ni a  ............................. 7 9 
T a bl e 2 0.  M a n a g e m e nt of I R R Ass oci at e d wit h D o x or u bici n A d mi nistr ati o n  ......................................... 7 9 
T a bl e 2 1.  G e n er al G ui d eli n es f or M a n a g e m e nt of A d v ers e E v e nts w h e n Attri b uti o n is n ot P ossi bl e i n 
t h e O pi ni o n of t h e I n v esti g at or ......................................................................................................... 8 0 
T a bl e 2 2.  T TI- 6 2 1 a n d D o x or u bici n Tr e at m e nt G ui d eli n es B as e d o n T hr o m b oc yt o p e ni a Ass ess e d as 
R el at e d t o St u d y Tr e at m e nt i n C ycl es 1- 6 ( C o m bi n ati o n Tr e at m e nt)  .............................................. 8 1 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 2 6 of 1 4 0  
 
 
T a bl e 2 3.  T TI- 6 2 1 Tr e at m e nt G ui d eli n es b as e d o n T hr o m b oc yt o p e ni a Ass ess e d as R el at e d t o St u d y 
- 6 2 1 M o n ot h er a p y) ................................................................................ 8 4 
T a bl e 2 4.  Sc h e d ul e of Ass ess m e nts  .......................................................................................................... 8 6 
T a bl e 2 5.  S a m pl e C oll ecti o n Sc h e d ul e f or A n al ysis of
 ........................................ 8 9 
T a bl e 2 6.  S a m pl e C oll ecti o n Sc h e d ul e f or A n al ysis of 
 ............................. 8 9 
T a bl e 2 7.  S a m pl e C oll ecti o n Sc h e d ul e f or A n al ysis of
.............................. 9 0 
 
LI S T O F FI G U R E S 
Fi g ur e 1.  G e n er al St u d y Sc h e m a ....................................................................................................... 2 0 
Fi g ur e 1.  G e n er al St u d y Sc h e m a  ............................................................................................................... 2 0 
Fi g ur e 2.  Di a gr a m m atic Str uct ur e of T TI- 6 2 1  ........................................................................................... 3 1 
Fi g ur e 1.  M ec h a nis m of Acti o n of C D 4 7  ................................................................................................... 3 2 
Fi g ur e 4.  Cli nic al R es p o ns es i n S u bj ects wit h P T CL, M yc osis F u n g oi d es ( M F) a n d S éz ar y S y n dr o m e ( S S) 
( u p p er p a n el) a n d DL B CL (l o w er p a n el) ............................................................................................. 4 0 
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 2 7 of 1 4 0  
 
 
A B B R E VI A TI O N S
A B CL  
a g gr essi v e B -c ell l y m p h o m a   
A E  
a dv ers e ev e nt  
A E SI  
ALL 
a dv ers e ev e nt of s p eci al i nt er est  
ac ut e ly m p h o bl astic l e uk e mi a  
AL T  
al a ni n e a mi n otr a nsf er as e  
A ML  
ac ut e m y el oi d l e u k e mi a  
A N C  
a bs ol ut e n e utr o p hil c o u nt  
A S T  
as p art at e a mi n otr a nsf er as e  
A U C  
ar e a u n d er t h e c urv e  
B U N  
bl o o d ur e a nitr o g e n  
CLL  
c hr o nic ly m p h oc ytic l e uk e mi a 
C m ax  
m axi m u m bl o o d c o nc e ntr ati o n 
C N S  
c e ntr al n erv o us syst e m 
C R  
c o m pl et e r es p o ns e 
C R O  
c o ntr act r es e arc h or g a niz ait o n 
C T  
c o m p ut e d t o m o gr a p hy 
C T C A E  
C o m m o n T er mi n ol o gy Crit eri a f or A dv ers e E v e nts  
C T CL  
c ut a n e o us T-c ell l y m p h o m a 
D  
D a y  
D C R  
DILI 
dis e as e c o ntr ol r at e  
Dr u g I n d uc e d Liv er I nj ury 
DL B CL  
diff us e l ar g e B -c ell l y m p h o m a 
DL T 
d os e-li miti n g t oxicit y 
D O R 
d ur ati o n of r es p o ns e 
E C 5 0 
eff ectiv e h alf- m axi m al c o nc e ntr ati o n 
E C G 
el ectr oc ar di o gr a m 
E C O G 
E ast er n C o o p er ativ e O nc ol o gy Gr o u p 
e C R F 
E D B 
el ectr o nic c as e r e p ort f or m 
ex p os ur e d uri n g br e astf e e di n g 
E D C 
E D P 
el ectr o nic d at a c a pt ur e 
ex p os ur e d uri n g pr e g n a nc y 
e G F R  
esti m at e d gl o m er ul ar filtr ati o n r at e 
E OI 
E n d of I nf usi o n 
E O R T C 
E ur o p e a n Or g a nis ati o n f or R es e arc h a n d Tr e at m e nt of C a nc er 
F D A 
F o o d a n d Dr u g A d mi nistr ati o n 
F F P E 
fr es h-fix e d p ar affi n e m b e d d e d 
G- C SF 
gr a n ul ocyt e c ol o ny-sti m ul ati n g f act or 
G C P 
G o o d Cli nic al Pr actic e 
GL P 
G o o d L a b or at or y Pr actic e 
G M- C SF 
gr a n ul ocyt e- m acr o p h a g e c ol o ny-sti m ul ati n g f act or 
H Cl  
H y dr oc hl ori d e  
HI P A A 
H e alt h I nf or m ati o n P ort a bility a n d Acc o u nt a bility Act 
HL 
H o d g ki n ly m p h o m a 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 2 8 of 1 4 0  
 
 
I B CL
i n d ol e nt B-c ell l y m p h o m a
I C F 
i nf or m e d c o ns e nt f or m 
I C H 
I nt er n ati o n al C o u ncil f or H ar m o nis ati o n  
I E C 
I n d e p e n d e nt Et hics C o m mitt e e 
I g G 1 
i m m u n o gl o b ulin  G 1  
I N R 
I nt er n ati o n al N or m aliz e d R ati o 
I R B 
I nstit uti o n al R evi e w B o ar d 
I R R 
i nf usi o n-r el at e d r e acti o n 
I V 
i ntr a v e n o us(l y) 
L D H 
l act at e d e hy dr o g e n as e 
L VE F 
l eft v e ntric ul ar ej ecti o n fr acti o n 
M D S  
m y el o dys pl astic sy n dr o m es  
M e d D R A  
M e dic al Dicti o n ary f or R e g ul at ory Acti viti es  
M F  
m yc osis f u n g oi d es  
M H C  
m aj or hist oc o m p ati bilit y c o m pl ex  
M RI  
m a g n etic r es o n a nc e i m a gi n g  
M T D  
m axi m u m t ol er at e d d os e  
N A  
n ot av ail a bl e  
N B F  
n e utr al -b uff er e d f or m ali n  
N CI  
N ati o n al C a nc er I nstit ut e  
N E  
n ot ev al u a bl e  
N G S  
n ext -g e n er ati o n s e q u e nci n g  
N HL  
n o n -H o d g ki n ly m p h o m a  
N S AI D  
n o nst er oi d al a nti -i nfl a m m at ory dr u g 
O R R  
o v er all r es p o ns e r at e  
O S 
o v er all s urvi v al 
P- g p 
P- gl yc o pr ot ei n 
P D 
p h ar m ac o d y n a mics; pr o gr essi v e dis e as e 
P D- 1 
pr o gr a m m e d d e at h- 1  
P D-L 1 
pr o gr a m m e d d e at h-li g a n d- 1 
P E T 
p ositr o n e missi o n t o m o gr a p hy 
P F S 
pr o gr essi o n-fr e e s ur viv al 
P K 
p h ar m ac o ki n etics 
P R  
p arti al r es p o ns e  
P S 
p erf or m a nc e st at us 
P S S A 
P T CL 
Pfiz er S A E S u b missi o n Assist a nt 
p eri p h er al T-c ell ly m p h o m a 
QL Q- C 3 0 
Q u ality- of-Lif e Q u esti o n n air e C or e 3 0 
Q oL 
q u alit y of lif e 
R B C 
r e d bl o o d c ell 
R E CI S T 
R es p o ns e Ev al u ati o n Crit eri a i n S oli d T u m o urs 
S A E 
s eri o us a d v ers e e v e nt 
S A R S- C o V- 2 
s e v er e ac ut e r es pir at or y s y n dr o m e c or o n avir us 2 
S A P  
St atistic al A n alysis Pl a n  
S D 
st a bl e dis e as e 
 
si g n al r e g ul at ory pr ot ei n al p h a 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 2 9 of 1 4 0  
 
 
S M P C
S R S D 
S U S A R 
S u m m ary of Pr o d uct C h ar act eristics
Si n gl e R ef er e nc e S af ety D oc u m e nt 
s us p ect e d u n ex p ect e d s eri o us a d v ers e r e acti o ns 
t½  
t er mi n al h alf-lif e 
T A M  
t u m or-ass oci at e d m acr o p h a g e  
T CL  
T -c ell ly m p h o m a 
T H C/ C B D 
t etr a hy dr oc a n n a bi n ol/c a n n a bi di ol 
T E A E  
tr e at m e nt-e m er g e nt a dv ers e ev e nt  
T m ax  
ti m e t o Cm ax  
T -V ec  
t ali m o g e n e l a h er p ar e pv ec 
UL N  
u p p er li mit of n or m al  
U S  
U nit e d St at es  
U S P  
U nit e d St at es P h ar m ac o p ei a  
U S PI  
W B C 
W O C B P 
U nit e d St at es Pr o d uct I ns ert  
w hit e bl o o d c ell 
w o m a n of c hil d- b e ari n g p ot e nti al 
 
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 30 of 140 
 
 
3.
INTRODUCTION
3.1. 
 
CD47 is a transmembrane glycoprotein normally expressed on all hematopoietic cells and additionally on 
epithelial and mesenchymal cells in many tissues.27,28 CD47 binds several integrin proteins and the 
extracellular matrix protein thrombospondin-1 and is involved in a wide variety of physiologic processes 
including platelet and neutrophil activation, T-cell function, regulation of vascular signaling by nitric oxide, 
inhibition of dendritic cell activity, and inhibition of monocyte activation.29-34 
 
Hematologic malignancies have been shown to have high expression of CD47, including non-Hodgkin 
lymphoma (NHL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple 
myeloma, acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).35-41  Solid tumors have 
also been found to display high CD47 expression, including brain, breast, colon, gastric, kidney, soft tissue 
sarcomas including leiomyosarcoma, osteosarcoma liver, lung, melanoma, ovarian, pancreatic, and 
prostate tumors.14-18  In many of these cases, high expression of CD47 is associated with poor prognosis.  
 
, a transmembrane glycoprotein receptor consisting 
of 3 extracellular immunoglobulin-like domains and a cytoplasmic tail that triggers phosphatase-mediated 
signaling.  Signal regulatory protein alpha (
) is found on macrophages, monocytes, granulocytes, 
dendritic cells, and neurons.42  The interaction of CD47 with 
 on the surface of macrophages leads 
to inhibition of macrophage-mediated phagocytosis.43  The association between high levels of CD47 and 
poor clinical prognosis in patients is postulated to be due to the inhibitory CD47 signal, which serves as an 
important mechanism by which malignant cells escape immune-mediated clearance.  Interruption of the 
CD47-
thway using monoclonal antibodies to CD47 has shown anti-tumor activity in 
human cancers both in vitro and in vivo in animal models of human malignancies and in some early clinical 
trials.   
 
3.2. 
Regulation of Macrophage Phagocytic Activity 
Macrophage-mediated 
signals.  Of the latter, the best characterized inhibitory signal is CD47, which suppresses phagocytosis by 
43  Upon binding to CD47, immunoreceptor tyrosine-based 
activation of downstream phosphatases, including SHP-1 and SHP-2, ultimately leading to inhibition of 
phagocytosis.  The inhibition is thought to be mediated through deactivation of the contractile 
cytoskeletal activity involved in pulling the target cell into a macrophage for ingestion.44  Interestingly, this 
strategy of immune evasion is used by both differentiated cancer cells and cancer stem cells.45 
 
As noted above, elevated expression of CD47 has been correlated with poor clinical outcome.  For 
example, overall survival was significantly lower for diffuse large B-cell lymphoma (DLBCL) or mantle cell 
lymphoma patients who had elevated CD47 expression.36   CD47 expression was independently prognostic 
of DLBCL disease progression per multivariate analyses incorporating key prognostic factors.  Similarly, 
patients with CLL that expressed high levels of CD47 experienced a significantly worse event-free survival 
compared with those whose tumor expressed lower expression levels.36  Similar trends have been 
reported in other hematologic malignancies35,37,39 and in solid tumors.16,18,46,47  Indeed, evidence exists that 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n 2. 0, 1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                      
p a g e 3 1 of 1 4 0
i ncr e as e d C D 4 7 ex pr essi o n m a y b e i n v olv e d i n t h e tr a nsiti o n fr o m l o w-ris k t o hi g h-ris k M D S a n d p ossi bl e 
tr a nsf or m ati o n t o A ML.4 3 T h es e fi n di n gs ar e c o nsist e nt wit h t u m or c ells ex pl oiti ng t h e s u p pr essiv e C D 4 7-
- m e di at e d d estr ucti o n.  Bl oc ki n g C D 4 7 h as e m er g e d as a t h er a p e utic 
str at e gy a n d s ev er al a nti- C D 4 7 d ev el o p m e nt al pr o gr a ms ar e u n d er w ay t o ex pl or e t his a p pr o ac h.
3. 3.
T TI- 6 2 1
Trilli u m T h er a p e utics, a Pfiz er C o m p a ny is d ev el o pi n g T TI-
-I g G 1 Fc), a r ec o m bi n a nt s ol u bl e 
f usi o n pr ot ei n cr e at e d b y c o m bi ni n g s e q u e nc es 
h e 
C D 4 7 bi n di n g d o m ai n) wit h t h e Fc r e gi o n of h u m a n I g G 1 ( Fi g ur e 2
    
T TI- 6 2 1 f u ncti o ns as a d ec oy r ec e pt or, bi n di n g C D 4 7 o n t h e s urf ac e of t h e t u m or c ells a n d bl ocki n g its a nti-
p h a g oc ytic si g n al, all o wi n g t h e m acr o p h a g e t o i n g est t h e m ali g n a nt c ell .  T h e pr o p os e d m ec h a nis m of 
acti o n f or T TI- 6 2 1 is ill ustr at e d i n Fi g ur e 3
-ri di n g a ny pr o-
s ( St e p A).  T h e d ec o y r ec e pt or T TI- 6 2 1 bi n ds t o C D 4 7 o n t h e s urf ac e of t u m or 
c ells ( St e p B) a n d e n g a g es acti v ati n g Fc- g a m m a r ec e pt ors o n m acr o p h a g es ( St e p C).  T h e c o m bi n ati o n of 
C D 4 7 bl oc k a d e a n d acti v ati n g si g n als tri g g ers 
m acr o p h a g e p h a g ocyt osis of t u m or c ells ( St e p D).
M acr o p h a g es t h e n pr oc ess t h e i nt er n aliz e d t u m or c ells, r es ulti n g i n t h e pr es e nt ati o n of t u m or a nti g e n 
p e pti d e- M H C) c o m pl ex es at t h e c ell s urf ac e ( St e p E), tri g g eri n g T c ell acti v ati o n a n d t u m or c ell d estr ucti o n 
( St e p F). T h us, bl oc k a d e of C D 4 7 by T TI- 6 2 1 is pr o p os e d t o activ at e b ot h t h e i n n at e a n d a d a pti v e i m m u n e 
s yst e ms.
  
Fi g ur e 2.  Di a gr a m m atic Str uct ur e of T TI- 6 2 1                     
T TI- 6 2 1 c o nsists of t h e N-
(r e d) li n k e d t o a h u m a n I g G 1 Fc r e gi o n ( bl u e). 
C CI
C CI
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version 2.0, 17 June 2022                                        Confidential                                      
page 32 of 140
3.4.
Rationale for Patient Population and Study Design
Soft tissue sarcomas are a rare, heterogeneous group of mesenchymal tumors, commonly the result of 
complex chromosomal abnormalities that play a role in disease progression and metastasis.  Surgery with 
radiotherapy is the most common treatment for localized disease, with 5-year survival rates on the order 
of only 55% depending on the stage of disease.48 For patients diagnosed with advanced disease, survival 
is remarkably poor 
on the order of only one to two years.46-48 Doxorubicin is the standard of care for 
first-line treatment of patients with metastatic or advanced soft tissue sarcoma; however, doxorubicin 
activity is poor, with a response rate of 9 - 27%1,2and progression-free survival (PFS) of 3-5 months,3-5 with 
cumulative cardiac toxicity that limits its use.6 The cytotoxic chemotherapy regimen of gemcitabine with 
docetaxel is an alternative to doxorubicin, but does not lead to better results for patients.52
Several large Phase 3 studies conducted over the past decade have failed to identify a superior treatment 
and doxorubicin continues to be the mainstay of treatment for the general population of patients with 
soft tissue sarcoma despite poor survival and the potential for irreversible cardiotoxicity associated with 
its use.  Thus, there is a clear need for a more effective treatment option for patients with soft tissue 
sarcoma, leiomyosarcoma being one of the most common subtypes.
Soft tissue sarcoma lesions are often heavily infiltrated by tumor-associated macrophages (TAMs), which 
can outnumber tumor infiltrating lymphocytes by 10-fold.7,8,15
Studies have shown higher CD47 
expression in soft tissue sarcoma compared to benign tissue.15  Further, blockade of the CD47-SIRPa axis 
in preclinical models of leiomyosarcoma can decrease tumor growth and metastasis.15 Thus, blockade of 
Figure 3.  Mechanism of Action of CD47
CD47 on the tumor cell provides a suppressive, anti-
A). TTI-
-IgG1 Fc) binds CD47 on tumor cells (Step B) and engages Fc gamma receptors on
macrophages (Step C) resulting in tumor cell phagocytosis (Step D). Following phagocytosis, tumor cell 
antigens are processed and presented by macrophages as MHC-peptide complexes to T cells (Step E), 
resulting in T cell activation and tumor cell destruction (Step F).


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 33 of 140 
 
 
high CD47-expressing soft tissue sarcoma tumor cells by TTI-621 may enable phagocytosis of malignant 
cells by the infiltrating TAMs, potentially resulting in tumor cell destruction and better patient outcomes. 
 
The combination of doxorubicin and CD47-blockade has been shown to enhance anti-tumor activity in 
multiple solid tumor models, including ovarian, breast and hepatocellular carcinoma.20-22  In an invasive 
breast cancer model, anti-CD47 antibody therapy enhanced the effect of doxorubicin by reducing tumor 
growth and metastatic spread to the lungs.21 This anti-tumor effect was associated with increased 
macrophage-mediated killing of breast cancer cells.  Moreover, CD47 blockade was found to protect 
against doxorubicin-induced cytotoxicity by enhancing cardiac tissue viability and function in mice.  This 
cytoprotective effect was attributed to an increase in autophagic flux.  In another study, CD47 blockade 
enhanced macrophage-mediated phagocytosis of hepatocellular carcinoma cell lines in the presence of 
doxorubicin in vitro.22  
 
Together, these studies suggest that combining TTI-621 with doxorubicin chemotherapy may be more 
effective than doxorubicin alone in tumor types that have high CD47 expression and have high numbers 
of macrophages, such as leiomyosarcoma, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, 
angiosarcoma and dedifferentiated liposarcoma. 
 
In an ongoing clinical trial of TTI-621 in patients with relapsed or refractory hematologic malignancies and 
selected solid tumors (NCT02663518), as of 01 October 2020, 235 patients have been enrolled to evaluate 
escalating dose levels of TTI-621 and in combination with other treatment regimens.  In this study, TTI-
621 is administered weekly and doses ranging from 0.05 mg/kg to 2.0 mg/kg have been evaluated.  The 
safety profile is very similar across dose levels, with the primary 
 3 treatment-related adverse 
event being acute but reversible thrombocytopenia which occurred in 22% of patients treated at dose 
levels of 0.05 mg/kg up to 0.5 mg/kg alone and in combinations and in 24% of patients treated at dose 
levels ranging from 0.5 mg/kg up to 2.0 mg/kg.  Among patients with T cell lymphomas treated with TTI-
621 at a dose of 0.2 mg/kg, an overall response rate of 21% has been observed in the intent-to-treat 
patient.  At higher dose levels, up to 2.0 mg/kg, experience is more limited as this portion of the study is 
still ongoing. As of 12 April 2021, a 19% response rate has been observed in the intent-to-treat population 
of patients with cutaneous T cell lymphoma at dose levels between 0.7 mg/kg and 2.0 mg/kg;  five patients 
continue to receive treatment with TTI-621 at 2.0 mg/kg and this portion of the study remains open to 
enrollment.   
 
Thus, given the powerful rationale that supports CD47-targeted immune-based therapy in sarcoma, this 
study will now evaluate TTI-621 in patients with advanced high-grade leiomyosarcoma, one of the most 
common soft tissue sarcoma subtypes.  As a first step, the safety and activity of escalating doses of TTI-
21 in combination with doxorubicin administered under the medically-recognized standard dosing 
regimen (75 mg/m2 on Day 1 of 21-day cycles for up to six cycles) will be evaluated in the first part of this 
study, with expansion cohorts to evaluate the safety and activity of a high dose and a low dose of TTI-621 
in combination with doxorubicin with the goal of identifying the optimal combination for subsequent 
clinical evaluations. 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 3 4 of 1 4 0  
 
 
3. 5.
I n v esti g ati o n al M e dici n al Pr o d uct T TI- 6 2 1
3. 5. 1.  
N o ncli nic al E x p eri e nc e wit h T TI- 6 2 1 
3. 5. 1. 1.  
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 3 5 of 1 4 0  
 
 
A d diti o n
 
 
3. 5. 1. 2.  
A d
    
 
3. 5. 1. 3.  
N o ncli nic al T o xic ol o g y of T TI- 6 2 1 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 3 6 of 1 4 0  
 
 
A d diti o n al i nf or m ati o n wit h d escri pti o ns of e ac h st u dy i
 
 
3. 5. 2.  
Cli nic al E x p eri e nc e wit h T TI- 6 2 1 
As of 0 1 Oct o b er 2 0 2 0, 2 9 2 p ati e nts h av e b e e n tr e at e d wit h T TI- 6 2 1 acr oss t w o cli nic al tri als, i ncl u di n g ( a) 
2 3 5 s u bj ects i n St u dy T TI- 6 2 1- 0 1:  A P h as e 1 a/ 1 b Tri al of T TI- 6 2 1 i n S u bj ects wit h R el a ps e d or R efr act or y 
H e m at ol o gic M ali g n a nci es a n d S el ect e d S oli d T u m ors ( N C T 0 2 6 6 3 5 1 8) a n d ( b) 5 7 s u bj ects fr o m St u d y T TI-
6 2 1- 0 2: A P h as e 1 Tri al of I ntr at u m or al I nj ecti o ns of T TI- 6 2 1 i n S u bj ects wit h R el a ps e d a n d R efr act ory S oli d 
T u m ors a n d M yc osis F u n g oi d es ( M F) ( N C T 0 2 8 9 0 3 6 8).  
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 37 of 140 
 
 
3.5.2.1.
Study TTI-621-01 (Intravenous Route of Administration)
TTI-621-01 is a Phase 1a/b, open-label, multicenter study to evaluate the safety, tolerability, and 
preliminary efficacy of TTI-621 administered by weekly intravenous infusion.  The safety of TTI-621 at 
doses ranging from 0.05 mg/kg to 0.5 mg/kg was established in an initial dose escalation study and 
multiple expansion cohorts of subjects with various relapsed/refractory hematologic malignancies and 
selected solid tumors were enrolled in an expansion phase of the study in which TTI-621 was administered 
initially at a dose of 0.2 mg/kg;  through protocol amendment, higher dose levels of 0.5 mg/kg to 2.0 
mg/kg are now under evaluation.  Two additional cohorts have also been enrolled to characterize the 
safety and efficacy of TTI-621 at 0.1 mg/kg in combination with rituximab and in combination with 
nivolumab.  A total of 184 subjects have received TTI-621 as monotherapy, 40 subjects have received TTI-
621 in combination with rituximab and 11 subjects have received TTI-621 in combination with nivolumab.  
The most common diagnoses in these patients is non-Hodgkin lymphoma (NHL; 160 subjects, 68%), 
Hodgkin lymphoma (HL; 31 subjects, 13%) and AML (20 subjects, 9%). 
 
3.5.2.1.1. Pharmacokinetics 
Pharmacokinetic data are available at doses up to 1.4 mg/kg.  Preliminary PK data at dose levels of 0.5 to 
1.4 mg/kg suggest that TTI-621 serum exposure, as measured by Cmax and AUC0-168, increases with dose 
following both single and repeat infusions.  The available data suggests that there is no plateau in dose 
exposure relationship up to 1.4 mg/kg.  While the estimated serum half-life of TTI-621 appears to range 
between 3-4 days, a review of the trough profiles from 0.05 to 1.4 mg/kg suggests that steady state levels 
of serum TTI-621 exposure are achieved by Week 6+ suggesting that the effective serum half-life of TTI-
621 is minimally 3 to 4 days and as long as 7 days.  
 
3.5.2.1.2. Safety 
Not unexpected in this patient population, 223/235 subjects (95%) experienced at least one treatment-
emergent adverse event. Treatment-emergent adverse events 
 20% of subjects were 
infusion-related reaction (106 subjects, 45%), fatigue (82 subjects, 35%), chills (58 subjects, 25%), pyrexia 
(53 subjects, 23%), diarrhea (50 subjects, 21%), nausea (50 subjects, 21%) and anemia (49 subjects, 21%).  
The incidence of treatment-emergent adverse events was generally similar across disease cohorts, 
although a higher incidence of anemia was reported in the AML cohort compared with the other disease 
cohorts and the overall study population.   
 
The most frequently-reported treatment-related adverse events of any grade, summarized in Table 1, 
were infusion-related reaction (103 subjects, 44%), chills (49 subjects, 21%), platelet count decreased 
(37 subjects, 16%), fatigue (36 subjects, 15%), thrombocytopenia (34 subjects, 14%), anemia (30 subjects, 
13%), pyrexia (26 subjects, 11%), nausea (25 subjects (11%), diarrhea (22 subjects, 9%), headache (18 
subjects, 8%), vomiting (16 subjects, 7%) and hypotension (13 subjects, 6%).  The incidence of treatment-
related adverse events was generally similar across disease cohorts, although the incidence of treatment-
related anemia was higher in the AML and HL cohorts compared with other disease cohorts and the overall 
study population.   
 
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 38 of 140 
 
 
Table 1.  Adverse Events of Any Grade Assessed as Related to Treatment in 5% of Subjects
Treatment-Related Adverse Event 
(Preferred Term) 
Number of Subjects (Percent) 
Any 
193 (82%) 
Infusion-Related Reaction 
103 (44%) 
Chills 
49 (21%) 
Platelet Count Decreased 
37 (16%) 
Fatigue 
36 (15%) 
Thrombocytopenia 
34 (14%) 
Anemia 
30 (13%) 
Pyrexia 
26 (11%) 
Nausea 
25 (11%) 
Diarrhea 
22 (9%) 
Headache 
18 (8%) 
Vomiting 
16 (7%) 
Hypotension 
13 (6%) 
 
A total of 91 subjects (39%) experienced a treatment-related adverse event Grade  3, summarized in 
Table 2.  The most frequently-reported treatment-related Grade  3 adverse events were platelet count 
decreased (30 subjects, 13%), thrombocytopenia (23 subjects, 10%) and anemia (20 subjects, 9%).  The 
majority of infusion-related reactions observed across the overall study population were Grade 1 or Grade 
2, with only 8 patients (3%) experiencing 
 3 reaction.    
Table 2.  Adverse Events Grade  3 Assessed as Related to Treatment in  2% of Subjects 
 
 
 
 
 
 3 Treatment-Related Adverse Event 
(Preferred Term) 
Number of Subjects (Percent) 
Any 
91 (39%) 
Platelet Count Decreased 
30 (13%) 
Thrombocytopenia 
23 (10%) 
Anemia 
20 (9%) 
Infusion-Related Reaction 
8 (3%) 
Neutropenia 
8 (3%) 
Neutrophil Count Decreased 
7 (3%) 
WBC Count Decreased 
5 (2%) 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 39 of 140 
 
 
A total of 76 subjects (32%) experienced serious adverse events.  Treatment-related serious adverse 
events have been reported for 22 subjects (9%) and are summarized in Table 3.  Infusion-related reactions 
(7 subjects, 3%) and thrombocytopenia (4 subjects, 2%) were the most frequently-reported treatment-
related serious adverse events; all other preferred terms were reported for  2 subjects.  Only one 
infusion-related reaction led to treatment discontinuation; no thrombocytopenia observations led to 
treatment discontinuation. 
Table 3.  Serious Adverse Events of Any Grade Assessed as Related to Treatment in  2 Subjects 
  
There have been no deaths related to treatment with TTI-621.  At the time of data cut-off, 98 subjects 
(42%) enrolled in Study TTI-621-01 have died, with 70 of these deaths (71%) due to disease progression.  
The cause of death was unknown for 14 patients and seven of the 98 deaths (7%) were the result of 
adverse events that were unrelated to treatment with TTI-621 (respiratory failure in two subjects, sepsis 
in one subject, cardiorespiratory arrest in one subject, cardiovascular disease in one subject, diabetic 
ketoacidosis in one subject and hypoxemic respiratory failure in one subject).  More detailed information 
about the known and expected benefits and risks and reasonably expected adverse events of TTI-621 may 
be found in the TTI-621 Investigator Brochure, which is the SRSD for this study. 
 
3.5.2.1.3. Clinical Activity 
A summary of responses observed in the intent-to-treat population across all disease cohorts and all dose 
levels (0.05  2.0 mg/kg) in Study TTI-621-01 (reflecting a data cut-off of 01 October 2020) is presented in 
Table 4.  Overall, nine subjects (4%) had complete response (CR) and 21 subjects (9%) had partial response 
(PR).  An additional 84 subjects (36%) achieved stable disease (SD). 
Table 4.  Summary of Clinical Responses Across Disease Cohorts 
Treatment-Related  
Serious Adverse Event 
Number of Subjects 
(Percent) 
Serious Adverse Events Related to Treatment 
and Resulting in Treatment Discontinuation 
Number of Subjects (Percent) 
Any 
22 (9%) 
8 (3%) 
Infusion-Related Reaction 
7 (3%) 
1 (0.4%) 
Thrombocytopenia 
4 (2%) 
0 (0%) 
Cellulitis 
2 (1%) 
1 (0.4%) 
Response 
Category 
TCL 
n=40 
PTCL 
n=21 
CTCL 
n=38 
BCL 
n=21 
RTX 
n=40 
HL 
n=31 
AML 
n=29 
Other 
n=15 
Total 
N=235 
CR 
1 
2 
0 
0 
3 
1 
2 
0 
9 (4%) 
PR 
7 
0 
3 
2 
6 
3 
0 
0 
21 (9%) 
SD 
14 
3 
21 
11 
14 
15 
4 
2 
84 (36%) 
PD 
10 
8 
6 
6 
14 
8 
19 
8 
79 (34%) 
NA 
8 
8 
6 
2 
3 
4 
4 
5 
40 (17%) 
NE 
0 
0 
2 
0 
0 
0 
0 
0 
2 (1%) 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n 2. 0, 1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                      
p a g e 4 0 of 1 4 0
T CL ( T c ell l y m p h o m a), P T CL ( p eri p h er al T c ell l y m p h o m a), C T CL (c ut a n e o us T c ell l y m p h o m a), B CL ( B c ell l y m p h o m a), R T X ( T TI-
6 2 1 +rit uxi m a b), HL ( H o d gki n l y m p h o m a), A ML ( ac ut e m y el oi d l e u k e mi a)
A m o n g p ati e nts wit h T c ell ly m p h o m a, c ut a n e o us T c ell l y m p h o m a or p eri p h er al T c ell ly m p h o m a tr e at e d 
wit h T TI- 6 2 1 at a d os e of 0. 2 m g/ k g, a n ov er all r es p o ns e r at e of 2 1 % h as b e e n o bs er v e d i n t h e i nt e nt-t o-
tr e at p ati e nt p o p ul ati o n, a n d a 1 9 % r es p o ns e r at e i n p ati e nts wit h c ut a n e o us T c ell l y m p h o m a at d os e 
l e v els b et w e e n 0. 7 m g/ k g a n d 2. 0 m g/ k g, alt h o u g h t his p orti o n of t h e st u dy is o n g oi n g a n d r e m ai ns o p e n 
t o e nr oll m e nt.
Ti m e t o r es p o ns e a n d ti m e o n tr e at m e nt as a s urr o g at e f or d ur ati o n of r es p o ns e ar e s u m m ariz e d i n t h e 
f or m of s wi ml a n e pl ots f or p ati e nts wit h P T CL, Myc osis F u n g oi d es a n d S éz ar y Sy n dr o m e (Fi g ur e 4 , u p p er 
p a n el) a n d f or p ati e nts wit h DL B CL ( Fi g ur e 4 , l o w er p a n el). 
O nl y s u bj ects wit h av ail a bl e r es p o ns e 
ass ess m e nt d at a ar e i ncl u d e d i n t h e fi g ur es.
Fi g ur e 4.  Cli nic al R es p o ns es i n S u bj ects wit h P T CL, M yc osis F u n g oi d es ( M F) a n d S éz ar y S y n dr o m e ( S S)
( u p p er p a n el) a n d DL B CL (l o w er p a n el)
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 41 of 140 
 
 
3.5.2.2.
Study TTI-621-02 (Intratumoral Injection)
TTI-621-02 is a dose-escalation and expansion study was to evaluate the safety, tolerability, 
pharmacokinetics and anti-tumor activity of TTI-621 administered by intratumoral injection in subjects 
with relapsed or refractory percutaneously-accessible solid tumors or cutaneous lymphomas.  In the dose-
escalation phase, nine subjects received a single intratumoral injection of TTI-621 at 1 mg (n=3), 3 mg 
(n=3) or 10 mg (n=3).  Three subjects received intratumoral injections of TTI-621 at a dose of 10 mg given 
3 times per week for 1 week (total of three injections) and six subjects received intratumoral injections of 
TTI-621 at a dose of 10 mg given 3 times per week for two weeks (total of six injections).    
 
No dose limiting toxicities were reported and an maximum tolerated dose was not reached.  The 
maximum assessed dose based on the current formulation of TTI-621 and a 1 mL injection volume was 
10 mg administered three times per week for two weeks (total of six injections) and this dose and 
schedule was taken into expansion cohorts for evaluation as induction therapy as monotherapy or in 
combination with other anti-cancer agents, including programmed death 1 (PD-1) or programmed death 
ligand 1 (PD-L1) inhibitors, pegylated interferon-
-Vec) and local 
radiation as induction therapy.  Following TTI-621 induction therapy, continued weekly treatment with 
intratumoral TTI-621 was permitted at the Investigator s discretion. 
 
A total of 57 subjects were enrolled and treated with TTI-621 in this study: 19 subjects in the dose-
escalation part of the study and 38 subjects in the expansion part.  A total of 35 subjects (61%) had a 
diagnosis of cutaneous T-cell lymphoma (CTCL) and 22 subjects (39%) had non-CTCL disease.   
 
A decision was taken not to continue to develop the intratumoral route of administration and study was 
closed to enrollment with no safety concerns.    
3.6. 
Investigational Medical Product Doxorubicin 
Doxorubicin (doxorubicin hydrochloride) is an anthracycline topoisomerase II inhibitor indicated as a 
component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node 
involvement following resection of primary breast cancer and for the treatment of: acute lymphoblastic 
leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, metastatic breast 
bone sarcomas, metastatic ovarian carcinoma, metastatic transitional cell bladder carcinoma, metastatic 
thyroid carcinoma, metastatic gastric carcinoma and metastatic bronchogenic carcinoma.  
 
Refer to the Full Prescribing Information for information on the safety and clinical activity of doxorubicin. 
3.7. 
Rationale for Planned Regimens of Investigational Medical Products 
3.7.1. 
TTI-621 
In the dose escalation portion of the study, increasing doses of TTI-621 will be evaluated in combination 
with fixed-dose doxorubicin in a standard 3+3 dose escalation scheme.  The TTI-621 dose escalation will 
begin with 0.2 mg/kg (Dose Level 1) administered by intravenous infusion over two hours on Day 1 and 
Day 8 of each 21-day cycle in which doxorubicin is given on Day 1.  
scretion and in 
the absence of infusion-related reactions in prior cycles, the infusion duration may be reduced to not less 
than 60 minutes beginning with Cycle 2.  The planned dose levels are presented in Table 5. 
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 42 of 140 
 
 
Table 5.  TTI-621 Dose Levels Planned for Evaluation in Combination with Doxorubicin
Dose Level 
TTI-621 Dose 
1 
0.2 mg/kg 
2 
0.7 mg/kg 
3 
2.0 mg/kg 
 
If Dose Level 1, 0.2 mg/kg, is found to be intolerable, a lower dose level may be evaluated.  If Dose Levels 
2 or 3 are not tolerated, intermediate dose levels may be evaluated. 
 
To prevent development of cardiac toxicity, administration of doxorubicin is limited to a maximum of six 
cycles.  Beginning with Cycle 7, TTI-621 will be administered as monotherapy on Day 1 and Day 15 of 28-
day cycles until disease progression or development of unacceptable toxicity. 
 
These TTI-621 doses were identified as safe for weekly intravenous administration in study TTI-621-01, in 
which dose levels ranging from 0.05 to 2.0 mg/kg have been evaluated in over 235 patients to date with 
a wide range of hematologic and some solid tumor malignancies.  Enrollment and follow-up is ongoing in 
this study, but a preliminary data review shows that the safety profile is very similar across dose levels, 
 3 treatment-related adverse event being acute but reversible thrombocytopenia 
which occurred in 22% of patients treated at dose levels of 0.05 mg/kg up to 0.5 mg/kg alone and in 
combinations and in 24% of patients treated at dose levels ranging from 0.5 mg/kg up to 2.0 mg/kg.  This 
thrombocytopenia was found to be transient, occurring within hours after administration and resolving 
by the next planned weekly infusion.  To date, the average treatment duration of TTI-621 given on a 
weekly infusion schedule is 106 days (range, 1-1094).   
 
3.7.2. 
Doxorubicin 
Doxorubicin is considered standard of care in the intended patient population and will be used in 
accordance with standard of care with intravenous infusion at a dose of 75 mg/m2 on Day 1 of each 21-
day cycle for a maximum of six cycles (18 weeks).   It is intended that each patient will receive six cycles 
of doxorubicin as fewer than six cycles provides less benefit to the patient compared to six or more cycles24  
and guidelines for prophylaxis for prevention of doxorubicin-mediated dose-limiting neutropenia are 
provided in Section 5.2.1.  Investigators should consult the approved doxorubicin package insert for 
complete prescribing information (including warnings, precautions, contra-indications, adverse reactions 
and dose modifications) and may follow institutional procedures for the administration of doxorubicin.  
Doxorubicin should be made up to a volume of 100 mL and administered through a free-flowing catheter 
at 75 mg/m2 by intravenous infusion in less than 60 minutes.  The rate of infusion should be decreased if 
erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.  
  
Doxorubicin is emetogenic and prophylaxis for emesis prior to each infusion of doxorubicin should be 
given.  Institutional guidelines for effective prophylaxis, including specific agents, additional agents and 
regimens, are acceptable.  Cardioprotective prophylaxis must be implemented starting with no later than 
with initiation of Cycle 5.  In accordance with NCCN26 and ASCO25 guidelines, all patients should receive 
prophylaxis with G-CSFs for prevention of febrile neutropenia.  Suggested prophylaxis is pegfilgrastim but 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 4 3 of 1 4 0  
 
 
ot h er G- C SFs c a n b e c o n
S p o ns or 
M e dic al M o nit or is e nc o ur a g e d.   Pr o p hyl axis g ui d eli n es ar e pr ovi d e d i n S ecti o n 5. 2. 1 .    
3. 8.  
B e n efit- Ris k Ass ess m e nt 
D ox or u bici n is k n o w n t o h a v e cli nic al b e n efit i n p ati e nts 
wit h s oft tiss u e s arc o m a, i ncl u di n g 
l ei o m y os arc o m a, h o w ev er, wit h P FS of a p pr oxi m at el y fi v e m o nt hs a n d m e di a n o v er all s ur vi v al of l ess t h a n 
t w o y e ars,4 9- 5 1 t h er e is a sig nific a nt n e e d f or i m pr o v e m e nt.  It is hy p ot h esiz e d t h at bl oc k a d e of C D 4 7-
m e di at e d i m m u n e ev asi o n a n d c o nc o mit a nt activ ati o n of p h a g ocyt osis wit h T TI- 6 2 1 will b e cli nic all y 
b e n efici al i n p ati e nts wit h s arc o m a s u bty p es i n w hic h C D 4 7 is ex pr ess e d a n d m acr o p h a g e sc or es ar e 
i ncr e as e d.  I n a d diti o n, 
 
 
    
3. 8. 1.  
E x p ect e d Ris ks of T TI- 6 2 1   
I n cli nic al tri als t o d at e e nr olli n g al m ost 3 0 0 p ati e nts wit h a v ari et y of o nc ol o gic i n dic ati o ns acr oss a r a n g e 
of T TI- 6 2 1 d os e l e v els pri m aril y a d mi nist er e d by i ntr a v e n o us i nf usi o n w e e kly u ntil pr o gr essi o n, T TI- 6 2 1 
h as g e n er ally b e e n s af e a n d w ell-t ol er at e d.  I n T TI- 6 2 1- 0 1, i n w hic h T TI- 6 2 1 w as a d mi nist er e d 
i ntr a v e n o usly o n a w e e kl y sc h e d ul e i n p ati e nts wit h v ari o us r el a ps e d/r efr act ory h e m at ol o gic m ali g n a nci es 
a n d s el ect s oli d t u m ors, t h e m ost fr e q u e nt tr e at m e nt-r el at e d a dv ers e e v e nt w as i nf usi o n-r el at e d r e acti o n 
i n 4 4 % of p ati e nts.  T h e m aj ority of i nf usi o n-r el at e d r e acti o ns w er e mil d-t o- m o d er at e, wit h o nly 3 % of 
p ati e nts ex p eri e nci n g i nf usi o n-r el at e d r
 3.  T h e i nf usi o n-r el at e d r e acti o ns w er e r e p ort e d 
acr oss all d os e c o h orts a n d occ urr e d d es pit e pr e m e dic ati o n wit h a n a nti- hist a mi n e a n d ac et a mi n o p h e n.  
T his st u dy st u dy i nc or p or at es a st er oi d i nt o t h e pr o p hyl axis r e gi m e n, w hic h m a y b e r e d uc e d or eli mi n at e d 
at t h e discr eti o n of t h e I nv esti g at or i n p ati e nts w h o d o n ot ex p eri e nc e i nf usi o n-r el at e d r e acti o n.   
 
 3 tr e at m e nt-r el at e d a dv ers e ev e nt w as ac ut e b ut r ev ersi bl e t hr o m b ocyt o p e ni a 
w hic h occ urr e d i n 2 2 % of p ati e nts a n d w as n ot i m p act e d by d os e l ev el.  T h e tr a nsi e nt d ecr e as es i n pl at el et 
c o u nts occ urr e d i n t h e 2 4 h o urs f oll o wi n g i nf usi o n i n t h e m aj ority of s u bj ects f oll o wi n g i ntr av e n o us 
ex p os ur e t o T TI- 6 2 1, c o nsist e nt wit h a u g m e nt e d s yst e mic p h a g oc ytic cl e ar a nc e of pl at el ets.  I n t h e 
m aj orit y of c as es, pl at el et c o u nts r et ur n e d t o b as eli n e l e v els wit hi n 1 w e ek, e n a bli n g c o nti n u e d w e e kly 
d osi n g.  N o i ncr e as e d ris k of bl e e di n g or ot h er cli nic al s e q u el a e w er e o bs er v e d.  M or e d et ail e d i nf or m ati o n 
a b o ut t h e k n o w n a n d ex p ect e d ris ks a n d r e as o n a bly ex p ect e d a d v ers e ev e nts of T TI- 6 2 1 m a y b e f o u n d i n 
t h e T TI- 6 2 1 I nv esti g at or Br oc h ur e, w hic h is t h e S R S D f or t his st u dy. 
3. 8. 2.  
E x p ect e d B e n efits of T TI- 6 2 1  
 I n t h e e arl y- p h as e st u dy T TI- 6 2 1- 0 1 i n w hic h T TI- 6 2 1 w as a d mi nist er e d by w e e kly i ntr av e n o us i nf usi o n, a 
r es p o ns e r at e of 1 3 % h as b e e n o bs erv e d, i ncl u di n g ni n e p ati e nts wit h c o m pl et e r es p o ns e.  A cli nic al 
b e n efit r at e of 4 9 % h as b e e n o bs erv e d.  A m o n g 8 2 p ati e nts wit h P T CL , Myc osis F u n g oi d es, S éz ary 
S y n dr o m e or DL B CL r ec eivi n g T TI- 6 2 1 m o n ot h er a py a n d e v al u a bl e f or r es p o ns e, 1 5 r es p o ns es a n d a n 
a d diti o n al 4 2 c as es of dis e as e st a biliz ati o n w er e o bs er v e d.  Acr oss t h es e p ati e nt gr o u ps, 2 0 p ati e nts 
c o nti n u e d tr e at m e nt f or ov er 1 8 0 d a ys wit h o ut evi d e nc e of dis e as e pr o gr essi o n;  1 0 p ati e nts c o nti n u e d 
tr e at m e nt f or o v er 2 7 0 d ays wit h o ut evi d e nc e of dis e as e pr o gr essi o n s ev e n p ati e nts h av e c o nti n u e d o n 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 44 of 140 
 
 
treatment without evidence of disease progression for over one year, including one patient with partial 
response and one patient with complete response that has persisted over 900 days.  Thus, it is anticipated 
that TTI-621 may offer clinical benefit to patients with soft tissue sarcoma, including leiomyosarcoma, and 
the preclinical data suggesting synergy with anthracycline offers hope that the combination will provide 
a safe and effective treatment option for this patient population.  More detailed information about the 
known and expected benefits and reasonably expected adverse events of TTI-621 may be found in the 
TTI-621 Investigator Brochure, which is the SRSD for this study. 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 4 5 of 1 4 0  
 
 
4.
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S
4. 1.  
Pri m ar y O bj ecti v es 
 
E v al u at e t h e s af ety of esc al ati n g d os e l e v els of T TI- 6 2 1 w h e n a d mi nist er e d i n c o m bi n ati o n 
wit h 7 5 m g/ m 2 d ox or u bici n i n 2 1- d ay c ycl es a n d est a blis h t h e m axi m u m t ol er at e d d os e l e v el 
of T TI- 6 2 1 w h e n a d mi nist er e d i n c o m bi n ati o n wit h d ox or u bici n 
 
E v al u at e t h e s af et y of s el ect e d d os e l e v els of T TI- 6 2 1 w h e n a d mi nist er e d i n c o m bi n ati o n wit h 
7 5 m g/ m 2 d ox or u bici n i n 2 1- d a y cycl es a n d t h e n as m o n ot h er a p y i n 2 8- d ay c ycl es u ntil 
d oc u m e nt ati o n of o bj ectiv e dis e as e pr o gr essi o n 
 
I nv esti g at e cli nic al activity ass ess e d as ov er all r es p o ns e r at e of T TI- 6 2 1 a d mi nist er e d i n 
c o m bi n ati o n wit h 7 5 m g/ m 2 d ox or u bici n f or u p t o six cycl es ( 1 8 w e e ks) a n d t h e n as 
m o n ot h er a p y u ntil d oc u m e nt ati o n of o bj ecti v e dis e as e pr o gr essi o n  
4. 2.  
Pri m ar y E n d p oi nts  
 
Ov er all s af ety pr ofil e as ass ess e d b y t h e ty p e, fr e q u e ncy, s ev erit y, ti mi n g a n d c a us al 
r el ati o ns hi p of a ny a dv ers e ev e nts, c h a n g es i n vit al si g ns, E C Gs, s er u m c h e mistr y or ot h er 
l a b or at ory ass ess m e nt, tr e at m e nt d el a ys or disc o nti n u ati o ns f or p ati e nts e nr oll e d i nt o t h e 
d os e esc al ati o n p orti o n of t h e st u dy 
 
T h e p erc e nt a g e of p ati e nts wit h o bj ectiv e r es p o ns e ( C R + P R) as d efi n e d by R E CI S T v 1. 1 
crit eri a 
4. 3.  
S ec o n d ar y O bj ecti v es 
 
F urt h er ass ess s af et y of t h e s el ect e d d os e l ev els of T TI- 6 2 1 a d mi nist er e d i n c o m bi n ati o n wit h 
7 5 m g/ m 2 d ox or u bici n  
 
D escri b e ot h er e vi d e nc e of cli nic al b e n efit 
4. 4.  
S ec o n d ar y E n d p oi nts  
 
Ov er all s af ety pr ofil e as ass ess e d b y t h e ty p e, fr e q u e ncy, s ev erit y, ti mi n g a n d c a us al 
r el ati o ns hi p of a ny a dv ers e ev e nts, c h a n g es i n vit al si g ns, E C Gs, s er u m c h e mistr y or ot h er 
l a b or at ory ass ess m e nt, tr e at m e nt d el a ys or disc o nti n u ati o ns f or p ati e nts e nr oll e d i nt o t h e 
s el ect e d d os e l e v el c o h orts i n t h e ex p a nsi o n p orti o n of t h e st u d y 
 
Pr o gr essi o n-fr e e s ur viv al ( P F S), ov er all s urviv al ( O S), dis e as e c o ntr ol r at e ( D C R [ C R + P R + S D]), 
d ur ati o n of r es p o ns e ( D O R), d ur ati o n of dis e as e c o ntr ol, ti m e t o pr o gr essi o n a n d ti m e t o n e w 
m et ast as es as d efi n e d by R E CI S T v 1. 1 crit eri a, ti m e t o w ors e ni n g of E C O G p erf or m a nc e st at us 
(A p p e n dix A ), ti m e t o w ors e ni n g of p ati e nt-r e p orti n g o utc o m es ass ess m e nts 
4. 5.  
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 4 6 of 1 4 0  
 
 
4. 6.  
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 4 7 of 1 4 0  
 
 
5.
I N V E S TI G A TI O N AL PL A N
5. 1.  
O v er all St u d y D esi g n 
T his is a m ulti-c e nt er, o p e n-l a b el st u dy d esi g n e d t o e v al u at e T TI- 6 2 1 a d mi nist er e d i n c o m bi n ati o n wit h 
d ox or u bici n.  T h e first p orti o n of t h e st u dy will e v al u at e t h e s af et y of i ncr e asi n g d os e l ev els of T TI- 6 2 1 i n 
c o m bi n ati o n wit h d ox or u bici n at t h e st a n d ar d d os e of at 7 5 m g/ m 2 i n p ati e nts wit h hi g h- gr a d e s oft tiss u e 
s arc o m a w h o h av e n ot r ec ei v e d m or e t h a n o n e pri or li n e of t h er a py ( g e mcit a bi n e wit h d oc et ax el) a n d 
h a v e n ot r ec eiv e d a n a nt hr acycli n e i n a ny s etti n g ( n e o a dj uv a nt, a dj uv a nt or as tr e at m e nt f or a dv a nc e d of 
m et ast atic dis e as e).  T w o d os e l ev els of T TI- 6 2 1 i n c o m bi n ati o n wit h d ox or u bici n will b e s el ect e d f or 
f urt h er e v al u ati o n i n a n ex p a nsi o n p h as e i n w hic h p ati e nts wit h hi g h- gr a d e l ei o m y os arc o m a w h o h av e 
n ot r ec eiv e d m or e t h a n o n e pri or li n e of t h er a py ( g e mcit a bi n e wit h d oc et ax el) a n d h a v e n ot r ec eiv e d a n 
a nt hr ac ycli n e i n a n y s etti n g ( n e o a dj uv a nt, a dj uv a nt or as tr e at m e nt f or a dv a nc e d of m et ast atic dis e as e).  
A d diti o n al k e y i ncl usi o n crit eri a ar e E C O G p erf or m a nc e st at us 0- 1, a g e 
1 8 y e ars, m e as ur a bl e dis e as e by 
R E CI S T v 1. 1 ( ex p a nsi o n c o h orts o nl y), a n d a d e q u at e c ar di ac a n d e n d or g a n f u ncti o n.  P ati e nts wit h pri or 
ex p os ur e t o a nt hr acycli n es will b e excl u d e d.   
 
I n t h e P h as e I d os e esc al ati o n p orti o n of t h e st u dy, t h e pri m ary o bj ecti v e is ass ess m e nt of t h e s af et y of 
esc al ati n g d os e l ev els of T TI- 6 2 1 i n c o m bi n ati o n wit h d ox or u bici n at t h e st a n d ar d d os e of 7 5 m g/ m 2.  U p 
t o a p pr oxi m at el y 1 8 p ati e nts ar e pl a n n e d t o b e e nr oll e d i n t his p orti o n of t h e st u dy t o ev al u at e t hr e e d os e 
l e v els of T TI- 6 2 1:  0. 2 m g/k g ( D os e L ev el 1), 0. 7 m g/k g ( D os e L ev el 2) a n d 2. 0 m g/k g ( D os e L e v el 3).  
E nr oll m e nt will b e o p e n t o p ati e nts wit h hi g h- gr a d e l ei o my os arc o m a, u n diff er e nti at e d pl e o m or p hic 
s arc o m a, m yx ofi br os arc o m a, d e diff er e nti at e d li p os arc o m a, a n gi os arc o m a a n d e pit h eli oi d s arc o m a.  T w o 
d os e l e v els will b e s el ect e d f or ev al u ati o n i n p ati e nts wit h hi g h- gr a d e l ei o m y os arc o m a i n t h e P h as e II 
ex p a nsi o n p orti o n of t h e st u dy. 
 
T h e pri m ary o bj ectiv es of t h e P h as e II ex p a nsi o n p orti o n of t h e st u d y ar e c o nti n u e d e v al u ati o n of t h e 
s af et y a n d i nv esti g ati o n of cli nic al activity of t h e d ox or u bici n a n d T TI- 6 2 1 c o m bi n ati o n f or u p t o 1 8 w e e ks 
a n d T TI- 6 2 1 m o n ot h er a p y giv e n o n a n o n g oi n g b asis aft er c o m pl eti o n of t h e 1 8- w e e k c o m bi n ati o n i n 
p ati e nts wit h hi g h- gr a d e l ei o m y os arc o m a.  Cli nic al acti vity will b e b as e d o n ass ess m e nt of t h e ov er all 
r es p o ns e r at e ( O R R by R E CI S T v 1. 1 i n t w o 2 ex p a nsi o n c o h orts:   d ox or u bici n at 7 5 m g/ m 2 i n c o m bi n ati o n 
wit h T TI- 6 2 1 at a l o w er d os e ( C o h ort A) a n d d ox or u bici n at 7 5 m g/ m
2 i n c o m bi n ati o n wit h T TI- 6 2 1 at a 
hi g h er d os e ( C o h ort B).  U p t o a p pr oxi m at el y 3 1 p ati e nts will b e tr e at e d i n e ac h c o h ort, f or a t ot al of 
a p pr oxi m at ely 6 2 p ati e nts i n t his p orti o n of t h e st u dy. 
 
S ec o n d ar y o bj ecti v es i ncl u d e f urt h er ev al u ati o n of t h e s af et y of t h e c o m bi n ati o n a n d ass ess m e nt of ot h er 
i n dic ati o ns of cli nic al b e n efit, i ncl u di n g pr o gr essi o n-fr e e s ur viv al, o v er all s urvi v al, dis e as e c o ntr ol r at e, 
d ur ati o n of r es p o ns e, d ur ati o n of dis e as e c o ntr ol, ti m e t o pr o gr essi o n a n d ti m e t o n e w m et ast as es as 
d efi n e d b y R E CI S T v 1. 1 crit eri a, ti m e t o w ors e ni n g of E C O G p erf or m a nc e st at us, a n d ti m e t o w ors e ni n g of 
p ati e nt-r e p orti n g o utc o m es ass ess m e nts.   
 
O R R a n d
will b e a n al yz e d as a n ex pl or at ory 
o bj ectiv e.  Ot h er ex pl or at or y o bj ecti v es i ncl u d e 
 
 
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 4 8 of 1 4 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T h e st u dy will c o nsist of a 2 8- d ay scr e e ni n g p eri o d, a tr e at m e nt p eri o d i n w hic h p ati e nts will r ec ei v e 
d ox or u bici n i n c o m bi n ati o n wit h T TI- 6 2 1 i n 2 1- d ay c ycl es f or a m axi m u m of six c ycl es, f oll o w e d by 
c o nti n u e d tr e at m e nt wit h T TI- 6 2 1 as m o n ot h er a py i n 2 8- d ay cycl es u ntil d oc u m e nt ati o n of o bj ectiv e 
dis e as e pr o gr essi o n or d ev el o p m e nt of u n acc e pt a bl e t oxicit y, a n d a l o n g-t er m f oll o w- u p p eri o d f or 
ass ess m e nt of ov er all s ur viv al. 
 
I n t h e c o m bi n ati o n p orti o n of t h e st u dy, Cycl e 1 t hr o u g h Cycl e 6, d ox or u bici n will b e a d mi nist er e d aft er 
e m esis pr o p hyl axis at 7 5 m g/ m 2 o n D a y 1 of e ac h 2 1- d a y C ycl e.  It is i nt e n d e d t h at e ac h p ati e nt will r ec ei v e 
six cycl es of d ox or u bici n as f e w er t h a n six cycl es pr o vi d es l ess b e n efit t o t h e p ati e nt c o m p ar e d t o six or 
m or e c ycl es
2 4  a n d g ui d eli n es f or pr o p h yl axis f or pr e v e nti o n of d ox or u bici n- m e di at e d d os e-li miti n g 
n e utr o p e ni a ar e pr ovi d e d i n S ecti o n 5. 2. 1 .  D ox or u bici n is a d mi nist er e d t hr o u g h a fr e e-fl o wi n g 
i ntr a v e n o us c at h et er i n a v ol u m e of 1 0 0 mL b y i nf usi o n o v er l ess t h a n 6 0 mi n ut es; pr o p hyl axis f or e m esis 
s h o ul d b e giv e n pri or t o e ac h i nf usi o n a n d t h e sit e m ay f oll o w i nstit uti o n al g ui d eli n es f or pr o p hyl axis a n d 
i nf usi o n as l o n g as t h ey d o n ot c o ntr a dict t his r e q uir e m e nt.  T h e r at e of i nf usi o n s h o ul d b e d ecr e as e d if 
er yt h e m at o us str e aki n g al o n g t h e v ei n pr oxi m al t o t h e sit e of i nf usi o n or f aci al fl us hi n g occ ur.  As 
d escri b e d i n S ecti o n 5. 2. 1. 1 , pr o p hyl axis wit h d exr az ox a n e f or c ar di ot oxicity will b e gi n n o l at er t h a n wit h  
i niti ati o n of Cycl e 5 w h e n c u m ul ati v e d ox or u bici n will h a v e r e ac h e d 3 0 0 m g/ m2.  B ec a us e of t h e p ot e nti al 
f or c u m ul ativ e c ar di ac t oxicit y, a m axi m u m of six cycl es of d ox or u bici n ( 1 8 w e eks of tr e at m e nt) is 
p er mitt e d as p er st a n d ar d of c ar e.   
 
I n Cycl e 1 t hr o u g h Cycl e 6, T TI- 6 2 1 will b e a d mi nist er e d b y i ntr av e n o us i nf usi o n ov er 1 2 0 mi n ut es o n D ay 
1 a n d D a y 8 of e ac h 2 1- d ay c ycl e.  P ati e nts will r ec ei v e pr o p hyl axis as d escri b e d i n S ecti o n 5. 2. 1. 2 o n e ac h 
d a y of T TI- 6 2 1 i nf usi o n f or pr ev e nti o n of p ossi bl e i nf usi o n-r el at e d r e acti o ns.  B e gi n ni n g wit h C ycl e 2, t h e 
n if t h e p ati e nt h as n ot 
ex p eri e nc e d i nf usi o n-r el at e d r e acti o n.  I n a ny cycl e i n w hic h d ox or u bici n a n d T TI- 6 2 1 ar e a d mi nist er e d o n 
t h e s a m e d a y, d ox or u bici n tr e at m e nt will pr ec e d e a d mi nistr ati o n of T TI- 6 2 1; T TI- 6 2 1 pr o p hyl axis m a y 
b e gi n pri or t o i niti ati o n 
. 
 
F or t h e p ur p os es of s af ety d ecisi o ns t h at g ui d e c o h ort ex p a nsi o n a n d c o nsi d er ati o ns of T TI- 6 2 1 d os e 
a dj ust m e nt i n t h e d os e esc al ati o n p orti o n of t h e st u dy, t h e s af ety p eri o d will c o nsist of t h e 2 1- d ay C ycl e 
1.  S u bj ects will b e c o nsi d er e d e v al u a bl e f or d os e-li miti n g t oxicit y if t h ey r ec ei v e d d ox or u bici n o n D ay 1 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 49 of 140 
 
 
and TTI-621 on Day 1 and Day 8 of Cycle 1.  A patient who withdraws from the study during Cycle 1 in the 
absence of objective disease progression or dose-limiting toxicity will be replaced.  If a dose-limiting 
toxicity as defined in Section 5.4 is encountered in one patient in the initial three patients in a dose cohort, 
three additional patients will be enrolled in accordance with the standard 3+3 study design.   
 
After three patients in a dose cohort, or six patients in an expanded dose cohort, complete the 21-day 
DLT assessment period, the incidence of dose-limiting toxicity, treatment-related safety observations and 
other available data, such as pharmacokinetic data, will be reviewed by the Sponsor Medical Monitor, 
Sponsor and Investigators.  If no patient in a three-patient cohort or no more than one patient in a six-
patient dose cohort experiences treatment-related dose-limiting toxicity, the dose level will be deemed 
safe and dose escalation may proceed unless there are other safety observations or data that suggest 
either an expansion of the current dose level or implementation of an intermediate dose level.   Thus, 
three TTI-621 dose levels are anticipated, but additional dose levels may be studied to more closely 
characterize the combination of TTI-621 with doxorubicin. 
 
After completion of Cycle 6, doxorubicin will be discontinued as per standard of care to avoid development 
of cumulative cardiac toxicity.  However, beginning with Cycle 7, treatment will TTI-621 monotherapy will 
continue until documentation of progression or unacceptable toxicity; TTI-621 will be administered on 
Day 1 and Day 15 of 28-day cycles.  Patients who are unable to complete the planned six cycles of 
doxorubicin due to doxorubicin-related toxicity that has occurred despite optimal prophylaxis and medical 
support and the patient has received at least four cycles of combination treatment may be eligible to 
begin TTI-621 monotherapy in the next cycle after discussion with the Sponsor Medical Monitor provided 
the patient is receiving clinical benefit, has not experienced disease progression and TTI-621 re-treatment 
guidelines as described in Section 9.2.2 are met.  The patient may be replace or an additional patient may 
be enrolled d for the purposes of having a heterogeneous population for evaluation of safety and clinical 
activity as described in Section 6.7.   
 
Objective disease assessments will be performed after every second cycle of treatment for 50 weeks and 
after every third cycle thereafter.  A patient enrolled in an expansion cohort who withdraws or is 
withdrawn from the study prior to the first objective disease assessment for a reason other than disease 
progression or safety will be replaced in order to meet the statistical criteria for the Simon two-stage 
design.  In the event that the LMS diagnosis is not confirmed during central review for a patient enrolled 
in the dose expansion portion of the study, the patient must be replaced for purposes of meeting the 
statistical requirements of the study but may be allowed to continue on treatment after discussion with 
the Sponsor Medical Monitor.  Patients who withdraw from the study without evidence of disease 
progression will be followed in the Long-Term Follow-Up period for documentation of disease progression 
or initiation of another treatment as well as survival. 
 
The mechanism of immunotherapy is mechanistically distinct from other types of therapy.  The patterns 
of response and progression to immunotherapeutic agents, such as TTI-621, often differ temporally, 
qualitatively and quantitatively from those observed with cytotoxic and targeted agents.  The goal of 
immunotherapy is to overcome immunosuppression induced by a tumor and its microenvironment, 
thereby allowing the immune system to develop or activate an immune response that targets and kills 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 5 0 of 1 4 0  
 
 
c a nc er c ells. S o m e p ati e nts h a v e ex p eri e nc e d ps e u d o- pr o gr essi o n, i n w hic h t u m or b ur d e n s h o w e d a n 
i niti al s ur g e f oll o w e d by s hri nk a g e, us u ally at ar o u n d w e eks, t h at l e d t o d ev el o p m e nt of i m m u n e-r el at e d 
dis e as e r es p o ns e crit eri a t h at s u p p orts c o nti n u e d tr e at m e nt b ey o n d pr o gr essi o n i n p ati e nts w h os e cli nic al 
c o n diti o ns h a v e n ot w ors e n e d a n d w h o h a v e n ot ex p eri e nc e d s ev er e t oxiciti es.  R ec o g nizi n g t h at 
i m m u n ot h er a py r e pr es e nts a p ar a di g m s hift i n o nc ol o g y tr e at m e nt, p ati e nts wit h a n e arl y o bs erv ati o n of 
dis e as e pr o gr essi o n b ut wit h o ut d et eri or ati o n i n cli nic al c o n diti o ns or u n acc e pt a bl e t oxicity a n d w h o 
c o ns e nt s h o ul d c o nti n u e tr e at m e nt u ntil dis e as e pr o gr essi o n is v erifi e d by a r e p e at e d dis e as e ass ess m e nt 
at l e ast f o ur w e e ks l at er.   
 
Tiss u e bi o psi es will b e c oll ect e d d uri n g t h e scr e e ni n g p eri o d a n d aft er Cycl e 2 f or p ati e nts e nr oll e d i n t h e 
ex p a nsi o n c o h orts; o pti o n al bi o psi es at t h e ti m e of r es p o ns e a n d pr o gr essi o n will b e off er e d t o p ati e nts.  
S eri al bl o o d s a m pl es will b e o bt ai n e d at b as eli n e, d uri n g a n d aft er tr e at m e nt f or ass ess m e nt of T TI- 6 2 1 
p h ar m ac o ki n etic a n d p h ar m ac o dy n a mic e n d p oi nts as w ell as
 
 
R ec o g nizi n g t h at l ei o m y os arc o m a is a r ar e dis e as e a n d ex p ecti n g t h at p ati e nts wit h l ei o m y os arc o m a m ay 
b e e a g er t o p artici p at e i n t h e st u dy, c ar ef ul m o dific ati o ns t o t h e e nr oll m e nt sc h e m a h av e b e e n d ev el o p e d 
t o av oi d h avi n g t o wit h h ol d e nr oll m e nt f or t h es e p ati e nts.  D uri n g t h e d os e esc al ati o n p orti o n of t h e st u dy, 
eli gi bl e p ati e nts will b e e nr oll e d t o t h e c o h ort t h at is o p e n at t h e ti m e t h ey pr es e nt t o t h e st u dy.  B as e d 
o n k n o w n s af et y of t h e l o w est pl a n n e d d os e of T TI- 6 2 1, 0. 2 m g/ k g, gl e a n e d fr o m ot h er o n g oi n g cli nic al 
tri als, it is a ntici p at e d t h at t his d os e will s erv e as t h e T TI- 6 2 1 d os e l ev el f or C o h ort A.  T h us, ex p a nsi o n 
C o h ort A will o p e n t o e nr oll m e nt o nc e t h at d os e l ev el is j u d g e d t o b e s af e i n t h e d os e esc al ati o n p orti o n 
of t h e st u dy; if a d os e fi n di n g c o h ort a n d ex p a nsi o n C o h ort A ar e o p e n t o e nr oll m e nt at t h e s a m e ti m e, 
pri ority f or e nr oll m e nt will b e gi v e n t o t h e d os e esc al ati o n c o h ort a n d e nr oll m e nt i nt o ex p a nsi o n C o h ort 
A will b e li mit e d t o t h os e p ati e nts w h o pr es e nt t o t h e st u dy aft er e nr oll m e nt t o a d os e esc al ati o n c o h ort 
is cl os e d a n d 
m e et all t h e eli gi bility crit eri a f or t h e ex p a nsi o n p orti o n of t h e st u dy (i ncl u di n g 
d oc u m e nt ati o n of t h e l ei o m y os arc o m a i n dic ati o n). 
 
W h e n b ot h ex p a nsi o n c o h orts ar e o p e n t o e nr oll m e nt, assi g n m e nt of eli gi bl e p ati e nts will b e m a d e o n a n 
alt er n ati n g b asis, wit h c o h ort assi g n m e nt m a d e by t h e c o ntr act r es e arc h or g a niz ati o n ov ers e ei n g t h e 
st u dy o n b e h alf of t h e s p o ns or i n d e p e n d e nt of i nv esti g at or i n p ut a n d b as e d strictl y o n c hr o n ol o g y of 
v erific ati o n of eli gi bility of p ati e nts as t h ey c o m pl et e scr e e ni n g ass ess m e nts.   
 
5. 2.  
D os es a n d Sc h e d ul e of A d mi nistr ati o n of I n v esti g ati o n al A g e nts 
I n Cycl e 1 t hr o u g h Cycl e 6, p ati e nts will r ec ei v e T TI- 6 2 1 a n d d ox or u bici n.  Pr o p hyl axis f or k n o w n a dv ers e 
e v e nts ass oci at e d wit h e ac h a g e nt is r e q uir e d as d escri b e d b el o w i n S ecti o ns 5. 2. 1. 1  a n d 5. 2. 1. 2 . 
 
D ox or u bici n is a d mi nist er e d o n D a y 1 of e ac h cycl e.  D ox or u bici n tr e at m e nt is li mit e d t o a m axi m u m of six 
cycl es t o av oi d d e v el o p m e nt of c ar di ac t oxicity.  It is i nt e n d e d t h at e ac h p ati e nt will r ec ei v e six cycl es of 
d ox or u bici n as f e w er t h a n six cycl es pr ovi d es l ess b e n efit t o t h e p ati e nt c o m p ar e d t o six or m or e cycl es 2 4 
a n d g ui d eli n es f or pr o p hyl axis f or pr e v e nti o n of d ox or u bici n- m e di at e d d os e-li miti n g n e utr o p e ni a ar e 
pr o vi d e d i n S ecti o n 5. 2. 1 .   
 
I n Cycl e 1 t hr o u g h C ycl e 6, T TI- 6 2 1 will b e a d mi nist er e d o n D ay 1 aft er c o m pl eti o n of t h e d ox or u bici n 
i nf usi o n a n d o n D ay 8.  F or cl arity, d ox or u bici n is n ot a d mi nist er e d o n D ay 8. 
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 51 of 140 
 
 
In Cycle 2 through Cycle 6, in the event that doxorubicin dosing is held due to an adverse event from which 
the investigator believes the patient will recover and continue treament, TTI-621 treatment will also be 
held. The day on which doxorubicin is re-initiated will then be considered Day 1 of the cycle, and TTI-621 
will also be administered as planned on the new Day 1 and subsequent Day 8. Initiation of subsequent 
cycles will be reset according to the new Day 1.      
 
Beginning with Cycle 7, TTI-621 will be administered as monotherapy on Day 1 and Day 15 of 28-day cycles. 
5.2.1. 
Prophylaxis 
5.2.1.1. 
Doxorubicin Prophylaxis 
Doxorubicin is emetogenic and prophylaxis for emesis prior to each infusion of doxorubicin should be 
given.  Institutional guidelines for effective prophylaxis, including specific agents, additional agents and 
regimens, are acceptable.  As described in the following section, TTI-621 prophylaxis includes a 
requirement for steroid (80 mg oral methylprednisolone or 20 mg intravenous dexamethasone).  If site 
guidelines for doxorubicin prophylaxis include steroid, the steroid dose level should be at least equivalent 
to that required for TTI-621 prophylaxis as presented in Table 6.   
 
Prophylaxis with dexrazoxane for cardiotoxicity will begin no later than with the initiation of Cycle 5 when 
cumulative doxorubicin will have reached 300 mg/m2.  Dexrazoxane is administered via intravenous 
infusion over 15 minutes and should not be administered via intravenous push.  The dosage ratio of 
dexrazoxane to doxorubicin is 10:1 (e.g., 750 mg/m2 dexrazoxane to 75 mg/m2 doxorubicin).  Do not 
administer doxorubicin before dexrazoxane; administer doxorubicin 30 minutes after the completion of 
dexrazoxane infusion. 
In accordance with NCCN26 and ASCO25 guidelines, all patients should receive prophylaxis with G-CSF for 
prevention of febrile neutropenia.  Suggested prophylaxis is pegfilgrastim but other G-CSFs can be 
Sponsor Medical Monitor is 
encouraged.   
 
5.2.1.2. 
TTI-621 Prophylaxis 
Prophylaxis for infusion-related reactions related to administration of TTI-621 will be given prior to 
infusion of TTI-621 on each day of scheduled treatment.  Prophylaxis will consist of acetaminophen, anti-
histamine and steroid as described in Table 6.  TTI-621 prophylaxis may be initiated prior to doxorubicin 
infusion on days when doxorubicin and TTI-621 are both given to accommodate site preference and 
scheduling.  While steroid is not required for patients who have not experienced Grade 1 or 2 infusion-
related reactions, the Investigator may incorporate steroid into the prophylaxis regimen. 
 
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 52 of 140 
 
 
Table 6.  Prophylaxis Regimen for TTI-621 to Reduce incidence and/or Grade of Infusion-Related 
Reaction 
Cycle 
Day of Treatment 
Patients Requiring 
Premedication 
Premedication 
Administration 
Cycle 1 
 
Day 1 
Day 8 
All patients 
80 mg methylprednisolone (oral)     
OR 
20 mg dexamethasone (IV) 
At least one hour prior to 
initiation of TTI-621 infusion 
650  1000 mg acetaminophen 
At least 30 minutes prior to 
initiation of TTI-621 infusion 
Anti-histamine  
(e.g., 50 mg diphenhydramine) 
All subsequent 
cycles 
Day 1 
Day 8 
All patients 
650  1000 mg acetaminophen 
At least 30 minutes prior to 
initiation of TTI-621 infusion 
Anti-histamine  
(e.g., 50 mg diphenhydramine) 
Patients with Grade 3 
or Grade 4 IRR in 
previous infusion1 
80 mg methylprednisolone (oral)      
OR 
20 mg dexamethasone (IV) 
At least one hour prior to 
initiation of TTI-621 infusion 
650  1000 mg acetaminophen 
At least 30 minutes prior to 
initiation of TTI-621 infusion 
Anti-histamine (e.g., 50 mg 
diphenhydramine) 
1  Not required for patients who have not experienced Grade 3 or Grade 4 infusion-related reaction, but may be incorporated at 
 
 
5.2.2. 
Doxorubicin 
Doxorubicin will be administered with prophylaxis as described in Section 5.2.1.1.  In Cycle 1 through Cycle 
6, doxorubicin will be used in accordance with standard of care with intravenous infusion at a dose of 75 
mg/m2 on Day 1 of each 21-day cycle for a maximum of six cycles (18 weeks).  It is intended that each 
patient will receive six cycles of doxorubicin as fewer than six cycles provides less benefit to the patient 
compared to six or more cycles24  and guidelines for prophylaxis for prevention of doxorubicin-mediated 
dose-limiting neutropenia are provided in Section 5.2.1.  Investigators should consult the approved 
doxorubicin hydrochloride package insert for complete prescribing information (including warnings, 
precautions, contra-indications, adverse reactions and dose modifications) and may follow institutional 
procedures for the administration of doxorubicin.  Doxorubicin should be made up to a volume of 100 mL 
and administered through a free-flowing catheter at 75 mg/m2 by intravenous infusion in less than 60 
minutes.  The rate of infusion should be decreased if erythematous streaking along the vein proximal to 
the site of infusion or facial flushing occur.   
 
In any cycle in which doxorubicin and TTI-621 are administered on the same day, doxorubicin treatment 
will precede administration of TTI-621.  A delay before initiation of TTI-621 is not mandated. 
 
As described below in Section 5.2.3, it is intended that after completion of the planned six cycles of 
doxorubicin treatment, patients will transition to TTI-621 monotherapy and continue on monotherapy 
until progression.  Patients who are unable to complete the planned six cycles of doxorubicin treatment 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 53 of 140 
 
 
due to doxorubicin-related toxicity despite optimal prophylaxis and medical support but have received at 
least four cycles of combination treatment and are receiving clinical benefit may be eligible to revert to 
TTI-621 monotherapy with the next cycle (Cycle 5 or Cycle 6) after discusssion with the Sponsor Medical 
Monitor provided the patient has not experienced disease progression and TTI-621 re-treatment 
guidelines as described in Section 9.2.2 are met.  The patient may be replaced or an additional patient 
may be enrolled for the purposes of having a heterogeneous population for evaluation of safety and 
clinical activity as described in Section 6.7.  The Investigator may consult with the Sponsor Medical 
Monitor on a patient-by-patient basis in the event that early evidence of doxorubicin-related toxicity 
arises.  
 
The dose of doxorubicin should be calculated at the beginning of each cycle.   
 
5.2.3. 
TTI-621 
In Cycle 1 through Cycle 6, following administration of prophylaxis medications as described in Section 
5.2.1.2, TTI-621 will be administered by intravenous infusion over 120 minutes on Day 1 and Day 8 of each 
21-day cycle.  Beginning with Cycle 2, the infusion period may be reduced to 60 minutes at the 
 infusion-related reaction during prior infusions.   
 
For the purposes of safety decisions that guide cohort expansion and considerations of TTI-621 dose 
adjustment, the safety period will consist of the 21-day Cycle 1.  During the dose escalation portion of the 
study, dosing of the first patient in a dosing cohort should be followed by a one-week observation period 
before enrollment of the second and subsequent patients within the dosing cohort.  
 
After completion of Cycle 6, doxorubicin will be discontinued as per standard of care to avoid development 
of cumulative cardiac toxicity.  However, treatment with TTI-621 monotherapy will continue until 
documentation of progression or unacceptable toxicity.  Beginning with Cycle 7, following administration 
of prophylaxis medications as described in Section 5.2.1.2, TTI-621 will be administered on Day 1 and Day 
15 of 28-day cycles. 
 
Patients who are unable to complete the planned six cycles of doxorubicin treatment due to doxorubicin-
related toxicity despite optimal prophylaxis and medical support but have received at least four cycles of 
combination treatment and are receiving clinical benefit may be eligible to revert to TTI-621 monotherapy 
with the next cycle after discussion with the Sponsor Medical Monitor provided the patient has not 
experienced disease progression and TTI-621 re-treatment guidelines as described in Section 9.2.2 are 
met. 
 
The dose of TTI-621 is based on body weight and should be calculated at the beginning of each cycle and 
may be used throughout the cycle unless a patient experiences a >10% variation in weight within a cycle.   
 
As described previously and presented below in Table 7, three dose levels of TTI-621 are planned to be 
evaluated in combination with fixed-dose doxorubicin in a 3+3 study design in the dose escalation portion 
of the study.  After review of emergent safety and other data from these dose levels, alternate TTI-621 
dose levels may be evaluated to more fully understand safety or pharmacodynamics of TTI-621 in 
combination with doxorubicin, to more fully identify dose-limiting toxicities, to more clearly define the 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 54 of 140 
 
 
maximum tolerated dose, and/or to optimize selection of the most appropriate dose(s) for evaluation in 
the expansion cohorts.    
Table 7.  TTI-621 Dose Levels Planned for Evaluation in Combination With Doxorubicin 
Dose Level 
TTI-621 Dose 
1 
0.2 mg/kg 
2 
0.7 mg/kg 
3 
2.0 mg/kg 
 
During the dose expansion portion of the study, two dose levels of TTI-621 are planned to be evaluated 
in combination with fixed-dose doxorubicin in 31-patient expansion cohorts in a Simon two-stage model.  
The low dose of TTI-621 is anticipated to be 0.2 mg/kg and the high dose is anticipated to be the maximum 
of other TTI-621 dose levels evaluated in the dose escalation portion of the study, prospectively planned 
to be 2.0 mg/kg, but alternate dose levels may require evaluation and a different dose may be taken 
forward based after discussion with treating physicians and the Sponsor. 
 
5.3. 
Criteria for Treatment Discontinuation 
Patients may withdraw voluntarily from participation in the study or from study treatment at any time 
be terminated at his/her request or on the 
cal judgment.  The reason for patient withdrawal will be documented in the 
source data and noted on the electronic case report form (eCRF). 
 
At a minimum, all patients who discontinue study treatment, including those who refuse to return for a 
final visit, will be contacted for safety evaluations at the 30-Day Safety Follow-Up Visit.   
 
If such withdrawal occurs, or if the patient fails to return for visits, the investigator must determine the 
ord the information on the eCRF.  If the 
reason for withdrawal is an adverse event, monitoring should continue until the outcome is evident.  The 
specific event or test result(s) must be recorded in the eCRF.  At the discretion of the Sponsor, patients 
may also be removed from the study. 
 
It should be clearly documented in the source data whether patients withdrew their consent and will not 
enter the follow-up phase, including objective disease assessment for patients who withdrew from the 
study in the absence of objective disease assessment and survival, or if patients withdrew their consent 
for study treatment but will continue further participation in the follow-up phase. 
 
Treatment may be continued until one of the following criteria applies: 
 
Completion of six cycles of doxorubicin treatment, at which point doxorubicin treatment must be 
discontinued but the patient may continue with TTI-621 monotherapy 
 
Objective (radiographic) disease progression:  for patients with asymptomatic progression and in the 
absence of unacceptable toxicity, a consenting patient should continue treatment and a confirmation 
scan should be conducted at least 4 weeks later to document objective progression prior to removing 
patient from study treatment 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 55 of 140 
 
 
 
An unacceptable adverse event or safety observation, such as a persistent moderate toxicity that is 
intolerable to the patient, that is in the opinion of the Investigator clearly attributed to TTI-621 
 
An unacceptable adverse event or safety observation, such as a persistent moderate toxicity that is 
intolerable to the patient, that is in the opinion of the Investigator clearly attributed to doxorubicin 
and the patient has received fewer than four cycles of doxorubicin.  A patient who has completed four 
cycles of doxorubicin treatment and experiences an adverse event that requires discontinuation of 
doxorubicin treatment despite optimal prophylaxis and medical support and who is receiving clinical 
benefit may be eligible to continue on study receiving TTI-621 monotherapy after discussion with the 
Sponsor Medical Monitor but may be replaced or an additional patient may be enrolled for the 
purposes of evaluating safety and activity of the combination of doxorubicin and TTI-621 as described 
in Section 6.7. 
 
Unacceptable toxicity which in the opinion of the Investigator cannot be attributed to a specific study 
agent 
 
Any event which would cause TTI-621 or doxorubicin to be modified by more than two dose 
reductions or to be held for more than 21 days from the last administered dose and is not attributable 
to a particular agent of the combination regimen; exception is made for patients who are receiving 
meaningful clinical benefit and the investigator feels, with Sponsor Medical Monitor concurrence, that 
continued treatment is in the best interest of the patient 
 
Any treatment-related adverse event that is deemed life-threatening, regardless of grade; exception 
is made for patients in whom the life-threatening adverse event is attributed to doxorubicin despite 
optimal prophylaxis and medical support and the patient is receiving clinical benefit and the patient 
has received at least four cycles of doxorubicin treatment and the investigator feels, with Sponsor 
Medical Monitor concurrence, that continuation with TTI-621 monotherapy would be reasonable and 
the patient meets guidelines for re-treatment with TTI-621 as described in Section 9.2.2   
 
Discontinuation of TTI-621 treatment 
 
further treatment in the opinion of the Investigator; exception may be made for patients in whom the 
intercurrent illness or change in condition is thought to render the patient ineligible for continued 
treatment with doxorubicin despite optimal prophylaxis and medical support and the patient has 
received at least four cycles of doxorubicin and is receiving clinical benefit and the investigator feels, 
with Sponsor Medical Monitor concurrence, that continuation with TTI-621 monotherapy would be 
reasonable and the patient meets criteria for TTI-621 re-treatment as described in Section 9.2.2 
 
Significant non-compliance with protocol 
 
Pregnancy 
 
Withdrawal of consent (patient may participate in long-term assessment of survival and disease status 
[if withdrawn prior to documentation of objective disease progression] if consent for this portion of 
the study is not withdrawn) 
 
Subject is lost to follow-up 
 
Termination of the study by the sponsor 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 5 6 of 1 4 0  
 
 
S p o ns or M e dic al M o nit or, tr e at m e nt aft er 
o bj ectiv e dis e as e pr o gr essi o n m ay c o nti n u e f or a p ati e nt w h o is cli nic ally st a bl e a n d r ec eivi n g m e a ni n gf ul 
r e as o n f or c o nti n ui n g tr e at m e nt m ust b e t h or o u g hl y disc uss e d, a gr e e d wit h t h e S p o ns or M e dic al M o nit or, 
a n d cl e arl y d oc u m e nt e d i n t h e st u dy fil es. 
5. 4.  
D os e-Li miti n g T o xicit y Crit eri a f or t h e D os e Esc al ati o n P orti o n of t h e St u d y 
D os e-li miti n g t oxicit y is d efi n e d as a ny of t h e f oll o wi n g tr e at m e nt- e m er g e nt a dv ers e ev e nts t h at occ urs 
d uri n g t h e 2 1- d ay Cycl e 1 a n d t h at ar e j u d g e d by t h e I n v esti g at or as r el at e d t o T TI- 6 2 1 or t h e c o m bi n ati o n 
of T TI- 6 2 1 a n d d ox or u bici n.  A dv ers e e v e nts t h at ar e i n t h e o pi ni o n of t h e I nv esti g at or attri b ut a bl e 
excl usi v el y t o i ntr a v e n o us i nf usi o n of d ox or u bici n or a ny d ox or u bici n pr o p hyl axis m e dic ati o n will n ot b e 
c o nsi d er e d a d os e-li miti n g t oxicity.   
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 5 7 of 1 4 0  
 
 
I nf usi o n-r el at e d r e acti o ns wit h T TI- 6 2 1 ar e n ot u n ex p ect e d a n d pr o p h yl axis g ui d eli n es ar e pr o vi d e d i n 
S ecti o n 5. 2. 1. 2 t o miti g at e t h eir occ urr e nc e a n d/ or s e v erity.  W hil e t h e I nv esti g at or m ay d ecr e as e t h e 
d ur ati o n of T TI- 6 2 1 i nf usi o n a n d/ or m ay d ecr e as e or eli mi n at e t h e st er oi d c o m p o n e nt of T TI- 6 2 1 
pr o p h yl axis i n a p ati e nt w h o h as n ot ex p eri e nc e d i nf usi o n-r el at e d r e acti o n, c a uti o n is ur g e d wit h r es p ect 
t o i m pl e m e nti n g b ot h c h a n g es si m ult a n e o usl y a n d a st e p wis e a p pr o ac h is r ec o m m e n d e d. 
 
I n t h e e v e nt t h at o n e p ati e nt i n a c o h ort of t hr e e p ati e nts ex p eri e nc es a d os e-li miti n g t oxicit y, t h e c o h ort 
will b e ex p a n d e d t o a t ot al of six p ati e nts.  If at l e ast t w o p ati e nts wit hi n a d os e c o h ort ex p eri e nc e a d os e-
li miti n g t oxicity d uri n g t h e d os e-li miti n g t oxicity p eri o d, t h e c o ncl usi o n m a y b e dr a w n t h at t h e m axi m u m 
t ol er at e d d os e of T TI- 6 2 1 i n c o m bi n ati o n wit h 7 5 m g/ m2 d ox or u bici n h as b e e n exc e e d e d; a ny f urt h er d os e 
esc al ati o n, d e- esc al ati o n or c o h ort ex p a nsi o n will b e d eci d e d i n c o ns ult ati o n b et w e e n I nv esti g at ors, t h e 
S p o ns or M e dic al M o nit or a n d t h e S p o ns or aft er c o nsi d er ati o n of t h e p artic ul ar p ati e nts a n d a dv ers e 
e v e nts ex p eri e nc e d, as w ell as all av ail a bl e s af ety a n d p h ar m ac o ki n etic d at a of all c o h orts. 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 58 of 140 
 
 
6.
STUDY POPULATION
6.1. 
Number of Patients 
Up to approximately 80 patients are anticipated to participate in the study, with up to 18 in the dose 
escalation portion of the study and 31 in each of two expansion cohorts. Based on patient outcomes in 
the dose expansion portion of the study, additional patients may be added to further explore response 
and/or tolerability of study treatment at one or more dose levels of TTI-621.  
 
6.2. 
Inclusion Criteria  
Patients must meet all the following criteria to be enrolled in the study: 
 
General 
1. Written informed consent obtained prior to performing any study-specific procedure, including 
screening procedures 
2. Men 
 18 years of age 
3. ECOG  Performance Status 0 or 1 
4. Patients enrolled onto the dose expansion cohorts must agree to pre-treatment and on-treatment 
biopsies if deemed safe and feasible by the treating physician 
Disease Characteristics 
5. Histologically-confirmed high-grade soft tissue sarcoma that is metastatic or locally advanced and not 
amenable to curative treatment with surgery or radiation 
 
In the dose escalation portion of the study, indications will be limited to high-grade 
leiomyosarcoma, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated 
liposarcoma, angiosarcoma and epithelioid sarcoma 
 
In the expansion portion of the study, enrollment will be restricted to high-grade leiomyosarcoma 
that is histologically-confirmed at a central laboratory.  The patient may be enrolled based on a 
current or most recent pathology report that provides sufficient detail to support derivation of 
the histologic interpretation but a pre-treatment tissue specimen must be made available for 
confirmation during screening or within the first cycle of treatment   
6. Objective evidence of disease progression unless disease is newly-diagnosed 
7. Measurable disease per RECIST v1.1 (expansion cohorts);  target lesions must not be chosen from a 
previously-irradiated field unless there has been radiographically and/or pathologically documented 
tumor progression in that lesion prior to enrollment 
Organ Function 
Adequate organ and hematologic function as defined below: 
8. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT)  3 x ULN;   5 x ULN in 
the presence of liver metastasis 
9. 
 1.5 x ULN (  2 x 
 
10. 
 1.5 x ULN OR creatinine clearance/estimated glomerular filtration rate (eGFR) 
 40 mL/min/1.73 m2 if serum creatinine is > 1.5 x ULN  
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 59 of 140 
 
 
11. 
 9 g/dL; packed RBC transfusions are not allowed in the week preceding screening 
evaluation 
12. 
 1.5 × 109/L 
13. Platelet count  100 × 109/ L 
14. 
 1.5 x ULN 
 x ULN if on anti-coagulants) and PTT 
anti-coagulation therapy; patients on full-dose anti-coagulation must be on a stable dose of oral anti-
coagulant or low molecular weight heparin, have therapeutic INR, no active bleeding (defined as 
within 14 days prior to first dose of study medication) and no pathological condition that carries a 
high risk of bleeding (e.g., tumor involving major vessels or known varices) 
15. LVEF determined by echocardiogram or multigated acquisition scan > 50% 
 
Previous Therapy 
16. No more than 1 prior treatment regimen for advanced disease, which is limited to gemcitabine with 
docetaxel  
17. Anthracycline-naïve; anthracycline in the neoadjuvant/adjuvant setting renders the patient ineligible 
for participation 
18. Patients who were treated with a prior chemotherapy regimen must have been completed treatment 
at least three weeks before initiation of study treatment 
19. All adverse events from prior treatment must be NCI CTCAE v5 Grade  1, except alopecia and stable 
neuropathy, which must have re
 2 or baseline  
20. Radiotherapy, including palliative radiotherapy, completed at least two weeks prior to treatment; 
palliative radiation to non-target lesions while on study is allowed  
 
Contraception 
21. Refer to Appendix D for reproductive criteria for male and female patients.  Female patients of 
childbearing potential must have a negative serum beta-human chorionic gonadotropin pregnancy 
test result at screening and at baseline before the first study drug administration 
 
6.3. 
Exclusion Criteria 
Patients who meet any of the following criteria may not be enrolled: 
General 
1. Investigator site staff directly involved in the conduct of the study and their family members, site 
staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly 
involved in the conduct of the study and their family members 
Cardiovascular System 
2.  History of acute coronary syndromes, including myocardial infarction, coronary artery bypass graft, 
unstable angina, coronary angioplasty or stenting within 24 weeks prior to first administration of 
study drug 
3.   History of or current Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) 
functional classification system or symptomatic or poorly-controlled cardiac arrhythmia   
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 60 of 140 
 
 
4.   Uncontrolled or poorly-controlled hypertension (defined as systolic blood pressure >160 mm Hg) for 
more than four weeks despite optimal medical management   
General and Infectious Disease 
5.   Child-Pugh Class C 
6.   Any comorbidity or concomitant medical or other condition that in the opinion of the Investigator 
and/or Sponsor Medical Monitor renders the patient unsuitable  for participation in the trial or 
unlikely or unable to fully comply with study procedures, restrictions and/or requirements that are 
considered relevant for the evaluation of the efficacy or safety of the trial drug 
Consideration should be given to lack of currently-available immunoprotection against SARS-CoV-2 as 
a condition that may render a patient unsuitable for participation in the trial or unlikely or unable to 
fully comply with study procedures, restrictions and/or requirements that are considered relevant for 
the evaluation of the efficacy or safety of study treatment   
7.   Uncontrolled intercurrent illness, including active or chronic infection requiring systemic therapy or 
oral or systemic antibiotics within 14 days prior to study start 
8.   History of non-viral hepatitis or cirrhosis, alcohol abuse or active tuberculosis   
9.   Administration of live attenuated vaccines within 28 days prior to start of treatment or anticipated 
need for vaccination with live attenuated vaccine during the study 
10.   
Major surgery within 28 days of scheduled Cycle 1 Day 1 dosing or minor surgery within seven 
days prior to initiation of study treatment or elective or planned major surgery to be performed during 
the course of the clinical trial 
CNS Disease Considerations 
11.  History or evidence of known CNS metastases or carcinomatous meningitis; patients with previously 
treated brain metastases may participate provided they are stable (without evidence of progression 
by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic 
symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and 
are not using steroids for at least seven days prior to trial treatment; this exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability 
Coagulation Considerations 
12.  Chronic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., indomethacin, ibuprofen, 
naproxen or similar agents) or other anti-platelet agents (e.g., clopidogrel, ticlopidine, dipyridamole, 
anagrelide);  aspirin up to 325 mg per day is permitted 
13.  Significant bleeding disorders, vasculitis or a significant bleeding episode from the GI tract within 
three months prior to study entry  
Immune System 
14.  History of severe hypersensitivity reactions to antibodies 
15. Systemic steroid therapy (>10 mg daily prednisone or equivalent) or any other form of 
immunosuppressive therapy within seven days prior to the first dose of study treatment; topical, 
inhaled, nasal and ophthalmic steroids are not prohibited 
16.  History of autoimmune disease that has required systemic treatment with disease-modifying agents, 
corticosteroids, or immunosuppressive drugs unless in the opinion of the investigator the patient is in 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 61 of 140 
 
 
a complete and durable remission; physiologic replacement therapies, such as thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, is allowed 
17.  Prior organ transplantation including allogeneic or autologous stem cell transplantation 
 
Oncology 
18.  Concurrent or previous other malignancy within two years of study entry with the exception of cured 
basal or squamous cell skin cancer, superficial bladder cancer, prostate intra-epithelial neoplasm, 
carcinoma in situ of the cervix, or other non-invasive or indolent malignancy  
19.  Concurrent enrollment in another therapeutic clinical study 
20.  Prior treatment with anti-CD47 or anti-SIRP  therapy  
21.  Prior radiation to mediastinal/pericardial region 
6.4. 
Re-Screening 
A subject who fails to qualify for the study based on laboratory tests may be considered for re-screening 
at the discretion of the Investigator and after consultation with the Sponsor Medical Monitor if it is 
considered that the subject status has changed and the subject may now qualify for the study.  Screening 
is limited to two attempts (initial screening and one re-screening attempt). 
6.5. 
Waivers of Inclusion/Exclusion Criteria 
In general, waivers of inclusion or exclusion criteria will not be granted; the Investigator may consult with 
the Sponsor Medical Monitor on a case-by-case.   
6.6. 
Patients or Partners of Patients of Reproductive Potential   
This is an exclusion criterion and women of child-bearing potential must not be considering becoming 
pregnant during the study. 
 
All women of childbearing potential who participate in the study should be counseled on the need to 
practice adequate birth control and on the importance of avoiding pregnancy during study participation. 
Women should be instructed to contact the investigator or study staff immediately if pregnancy occurs or 
is suspected. 
 
Pregnancy testing will be conducted prior to administration of IP and throughout study participation on 
every woman of childbearing potential.  A woman who is found to be pregnant at the Screening Visit will 
be excluded from the study and considered to be a screening failure. 
 
A serum pregnancy test is required at screening.  Following screening, pregnancy tests may be urine or 
serum tests, and must have a sensitivity of at least 25 mIU/mL.  Pregnancy tests will be performed in 
WOCBP at the times listed in the Schedule of Assessments (Table 24).  Following a negative pregnancy 
test result at screening, appropriate contraception must be commenced and a second negative pregnancy 
test result will be required at the baseline visit prior to the patient receiving the study treatment.  
Pregnancy tests will also be done whenever one menstrual cycle is missed during the active treatment 
period (or when potential pregnancy is otherwise suspected) and at the end of the study.  Pregnancy tests 
may also be repeated if requested by IRBs/ECs or if required by local regulations.  If a urine test cannot be 
confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required.  In such cases, the 
patient must be excluded if the serum pregnancy result is positive.  
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 62 of 140 
 
 
Patients will be instructed to notify the Investigator if pregnancy is discovered either during or within  45 
days of the last dose of study treatment TTI-621 (or as per USPI for doxorubicin  combination treatment), 
which corresponds to the time needed to eliminate any reproductive safety risk of the study 
intervention(s). 
6.7. 
Provisions for Enrollment of Additional Patients based on Emerging Data 
Because this study has a relatively small sample size and patient heterogeneity may impact on 
interpretation of safety, clinical activity and/or other study objectives, provision is made that additional 
patients may be enrolled under certain conditions in order to have a sufficient number of patients to 
support the planned study objectives. 
 
It is intended that each patient will receive six cycles of doxorubicin as fewer than six cycles has been 
shown to provide less benefit to the patient compared to six or more cycles.24  If emerging data 
suggests that reduced exposure to doxorubicin has an impact on patient outcome with combined with 
TTI-621, additional  patients may be enrolled to support an evaluation of TTI-621 when combined with 
doxorubicin for six cycles.   
 
If emerging data suggests that safety, activity or other study objective is different for patients who 
have received prior treatment versus no prior treatment, the inclusion criterion may be modified or 
additional patients may be enrolled to generate a more homogenous patient population. 
 
If emerging data suggest other patient characteristics may impact on safety, activity or other study 
objective, additional patients may be enrolled to more fully investigate the observation.   
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 63 of 140 
 
 
7.
ENROLLMENT PROCEDURE AND METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
7.1. 
Enrollment Procedure 
At the time a prospective subject signs the informed consent form, a unique subject number will be 
assigned and the appropriate portion of a Registration/Enrollment form will be completed and sent to the 
Sponsor or designee.  Subjects will be screened for eligibility according to the criteria outlined in Section 
6.  Once a subject is deemed eligible, the completed Registration/Enrollment form will be sent to the 
Sponsor or designee, at which time the TTI-621 dose level and cohort or expansion arm will be assigned.  
7.2. 
Method of Assigning Subjects to Treatment Groups  
The dose escalation portion of the study carries a traditional 3+3 design to evaluate three dose levels of 
TTI-621.  Standard guidelines for enrollment for the 3+3 design will be followed, with requirement that 
three patients complete the 21-day safety assessment period before the next dose cohort is open to 
enrollment and expansion to six patients in the case of a treatment-related dose-limiting toxicity.   
 
However, recognizing that leiomyosarcoma is a rare disease and expecting that patients with 
leiomyosarcoma may be eager to participate in the study, careful modifications to the enrollment schema 
have been developed to avoid having to withhold enrollment for these patients.  During the dose 
escalation portion of the study, eligible patients will be enrolled to the cohort that is open at the time 
they present to the study.  Based on known safety and clinical activity of the lowest planned dose of TTI-
621, 0.2 mg/kg, gleaned from other ongoing clinical trials, it is anticipated that this dose will serve as the 
TTI-621 dose level for Cohort A.  Thus, expansion Cohort A will open to enrollment once that dose level is 
judged to be safe in the dose escalation portion of the study; if a dose escalation cohort and expansion 
Cohort A are open to enrollment at the same time, priority for enrollment will be given to the dose 
escalation cohort and enrollment into expansion Cohort A will be limited to those patients who present 
to the study after enrollment to an escalation cohort is closed and meet all the eligibility criteria for the 
expansion portion of the study (including documentation of the leiomyosarcoma indication). 
 
When both expansion cohorts are open to enrollment, assignment of eligible patients will be made on an 
alternating basis, with cohort assignment made by the CRO overseeing the study on behalf of the sponsor 
independent of investigator input and based strictly on chronology of verification of eligibility of patients 
as they complete screening assessments.   
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 6 4 of 1 4 0  
 
 
8.
D E S C RI P TI O N O F S T U D Y T R E A T M E N T
8. 1.  
D escri pti o n of T TI- 6 2 1 
A d escri pti o n of T TI- 6 2 1 I n v esti g ati o n al Dr u g Pr o d uct is pr ovi d e d i n T a bl e 8 .  T TI- 6 2 1 is a s ol u bl e 
r ec o m bi n a nt f usi o n pr ot ei n cr e at e d by c o m bi ni n g t h e 
d o m ai n f or C D 4 7) wit h t h e Fc r e gi o n of h u m a n I g G 1.  
 
 
 
   
T a bl e 8.  T TI- 6 2 1 I n v esti g ati o n al Dr u g Pr o d uct D escri pti o n 
D os a g e F or m 
 
 
 
  
U nit D os e 
T TI- 6 2 1 wit h a t ar g et pr ot ei n c o nc e ntr ati o n of 
m g/ mL i n 
m M 
m M
a n d
f or I nj ecti o n, p H 
 
R o ut e of A d mi nistr ati o n 
I ntr a v e n o us 
P h ysic al D escri pti o n 
Pr ot ei n s ol uti o n  
St or a g e C o n diti o ns 
St or e fr oz e n at -
° C t o -
° C (
F t o 
° F) or c ol d er 
8. 2.  
D escri pti o n of D o x or u bici n 
D ox or u bici n hy dr oc hl ori d e is a n a nt hr acycli n e t o p ois o m er as e II i n hi bit or.  D ox or u bici n H Cl I nj ecti o n is 
s u p pli e d i n vi als c o nt ai ni n g 1 0 m g/ 5 mL, 2 0 m g/ 1 0 mL, 5 0 m g/ 2 5 mL, 1 5 0 m g/ 7 5 mL, a n d 2 0 0 m g/ 1 0 0 mL 
d ox or u bici n H Cl as a cl e ar r e d s ol uti o n.  D ox or u bici n hy dr oc hl ori d e f or I nj ecti o n is s u p pli e d i n vi als 
c o nt ai ni n g 1 0 m g, 2 0 m g, 5 0 m g, a n d 1 5 0 m g d ox or u bici n hy dr oc hl ori d e as a r e d- or a n g e ly o p hiliz e d 
p o w d er.  D ox or u bici n hy dr oc hl ori d el f or I nj ecti o n is r ec o nstit ut e d wit h 0. 9 % S o di u m C hl ori d e I nj ecti o n, 
U S P t o o bt ai n a fi n al c o nc e ntr ati o n of 2 m g/ mL.   
 
A d diti o n al d et ails ar e pr o vi d e d i n t h e P h ar m acy M a n u al.  Sit es m a y f oll o w i nstit uti o n al g ui d eli n es f or 
s el ecti o n of pr o d uct ( D ox or u bici n H Cl I nj ecti o n or D ox or u bici n H y dr oc hl ori d e f or I nj ecti o n). 
 
8. 3.  
Pr e p ar ati o n a n d A d mi nistr ati o n of St u d y Tr e at m e nts 
All a d mi nistr ati o n of st u d y tr e at m e nts s h o ul d b e p erf or m e d i n a s etti n g wit h e m er g e ncy m e dic al f aciliti es 
a n d st aff w h o ar e tr ai n e d t o m o nit or f or a n d r es p o n d t o m e dic al e m er g e nci es.   
 
8. 3. 1.  
T TI- 6 2 1    
As d escri b e d i n S ecti o n 5. 2. 1. 2 , pr e m e dic ati o n wit h ac et a mi n o p h e n, a nti- hist a mi n e, st er oi d or a s u bs et of 
t h es e t hr e e a g e nts is r e q uir e d f or all s u bj ects pri or t o e ac h i nf usi o n of T TI- 6 2 1.  M o dific ati o n of t h e s p ecific 
a g e nt a n d/ or d os a g es m ay b e m a d e u p o n disc ussi o n wit h t h e S p o ns or M e dic al M o nit or.   
 
T TI- 6 2 1 Dr u g Pr o d uct will b e
 a n d t h e r e q uir e d d os e dil ut e d i nt o
mL
% 
f or i nj ecti o n U S P as f urt h er d escri b e d i n t h e P h ar m acy M a n u al.  If n ot us e d i m m e di at ely, 
t h e pr e p ar e d
 m a y b e st or e d as d escri b e d i n t h e P h ar m ac y M a n u al.  T h e assi g n e d d os e of T TI- 6 2 1 
will b e a d mi nist er e d i ntr av e n o usl y ov er 1 2 0 mi n ut es, alt h o u g h a r e d ucti o n i n d ur ati o n of i nf usi o n t o n ot 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 65 of 140 
 
 
less than 60 minutes is permitted after completion of Cycle 1 at the discretion of the Investigator in the 
absence of infusion-related reaction.  The start of the infusion (Time 0) is defined as after priming, 
immediately before commencement of the infusion.  End of Infusion is defined as the time immediately 
after flush.  
 
The individual dose is det
 Body weight can be 
rounded per institutional procedures when calculating doses.  Body weight will be taken on Day 1 of each 
cycle for purposes of calculating dosage preparation.   
 
Each subject will receive TTI-621 in accordance with the assigned dose until objective assessment of 
disease progression, unacceptable toxicity or other reason for treatment discontinuation.  
 
In Cycle 1 through Cycle 6, in which TTI-621 is given in combination with doxorubicin, doxorubicin will be 
administered first.  An observation period is not required before initiation of TTI-621 infusion; however, 
prophylaxis for infusion-related reaction prior to initiation of TTI-621 infusion is required as described in 
Section 5.2.1.2.   
 
In Cycle 2 through Cycle 6, in the event that doxorubicin dosing is held due to an adverse event from which 
the investigator believes the patient will recover and continue treament, TTI-621 treatment will also be 
held.  The day on which doxorubicin is re-initiated will be considered Day 1 of the cycle, and TTI-621 will 
be administered as planned on the new Day 1 and subsequent Day 8.  Initiation of subsequent cycles will 
be reset according to the new Day 1.      
 
8.3.2. 
Doxorubicin 
Doxorubicin is standard of care in this patient population and sites may use institutionally-accepted 
methods for preparation of doxorubicin for infusion to the patient.  Doxorubicin should be made up to a 
volume of 100 mL and administered through a free-flowing catheter at 75 mg/m2 by intravenous infusion 
in less than 60 minutes.  The rate of infusion should be decreased if erythematous streaking along the 
vein proximal to the site of infusion or facial flushing occur.  Doxorubicin is emetogenic and prophylaxis 
for emesis prior to each infusion of doxorubicin should be given as described in Section 5.2.1.1.  
Institutional guidelines for effective prophylaxis, including specific agents, additional agents and regimens, 
are acceptable.  Cardioprotective prophylaxis must be implemented no later than initiation of Cycle 5 as 
described in Section 5.2.1.1.  In accordance with NCCN26 and ASCO25 guidelines, all patients should receive 
prophylaxis with G-CSF for prevention of febrile neutropenia.  Suggested prophylaxis is pegfilgrastim but 
other G-
Sponsor 
Medical Monitor is encouraged.   
 
8.4. 
Blinding of Treatment 
This is an open-label study; study treatments will not be blinded. 
 
 
8.5. 
Treatment Compliance 
The study treatments will be administered by personnel at the study site to ensure compliance. 
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 66 of 140 
 
 
8.6.
Study Drug Accountability 
Study personnel will maintain accurate records of study treatment shipments, receipts and 
administration.  The site is responsible for the return or destruction of TTI-621 as required.  
 
8.7. 
Concomitant Medications 
Patients are allowed to continue medications that they are taking at baseline.  Patients may also receive 
concomitant medications that are medically indicated as standard care for the treatment of symptoms 
and intercurrent illnesses.  Medications to treat concomitant diseases, e.g., diabetes, hypertension, 
chronic obstructive pulmonary disease, are allowed.  Patients will receive prophylaxis medications to 
prevent development of infusion-related reactions prior to infusions of TTI-621 and may also receive 
therapy for symptom control and/or to mitigate side effects of the study medication as clinically indicated, 
as well as best supportive care as per institutional guidelines.  This may include, e.g., anti-emetics, anti-
diarrheals, anti-cholinergics, anti-spasmodics, anti-pyretics, anti-histamines, analgesics, antibiotics and 
other medications such as analgesics, electrolyte replacement, hydration, and/or blood product 
transfusions intended to treat symptoms.  Other prescribed medications for non-neoplastic conditions 
are allowed, as well as vitamins and nutritional supplements (at doses per the Recommended Dietary 
Allowance or supplementing a known deficiency).  The Investigator should instruct the patient not to take 
any additional medications (including over-the-counter products) during the study without prior 
consultation.  
  
Patients must not receive live, attenuated vaccines (e.g., FluMist ) within four weeks prior to first day of 
study treatment, at any time during the study, or through 90 days after the last dose of TTI-621.  
Inactivated vaccines are allowed.  Influenza vaccination should be given during influenza season only 
(approximately October to March). 
 
Doxorubicin is a major substrate of cytochrome P450 CYP3A4 and CYP2D6, and P-glycoprotein (P-gp).  
Clinically significant interactions have been reported with inhibitors of CYP3A4, CYP2D6, and/or P-gp (e.g., 
verapamil), resulting in increased concentration and clinical effect of doxorubicin.  Inducers of CYP3A4 
-gp inducers may decrease the concentration of 
doxorubicin.  Concurrent use of inhibitors and inducers of CYP3A4, CYP2D6 or P-gp must be avoided when 
doxorubicin is being administered.  
  
Due to potential impact on metabolism of both TTI-621 and doxorubicin, THC/CBD and herbal products 
are prohibited while the patient is receiving treatment on study.  The Investigator may discuss specific 
patients with the Sponsor Medical Monitor. 
 
All concomitant medications, including dose and reason for administration, will be recorded in the eCRF. 
 
8.7.1. 
Concomitant Corticosteroids 
Chronic use of steroid above a daily equivalent dose of 20 mg prednisone is not permitted on study.  
 
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8.7.2.
Concomitant Hematopoietic Growth Factors and Blood Products
Myeloid growth factors are permitted for treatment-emergent Grade 3 or Grade 4 neutropenia.  Likewise, 
erythropoiesis-stimulating or megakaryopoiesis-stimulating agents may be used for treatment-emergent 
anemia or thrombocytopenia, respectively.  Transfusion thresholds for blood product support will be in 
accordance with institutional guidelines.   
 
ASCO guidelines for use of WBC growth factors25 
prevention of febrile neutropenia is warranted when the risk of febrile neutropenia is approximately 20% 
or higher and no other equally effective and safe regimen that does not require CSFs is available.  Primary 
prophylaxis is recommended for the prevention of febrile neutropenia in patients who are at high risk on 
The NCCN guidelines for hematopoietic growth factors26 classify soft tissue sarcoma treated with 
doxorubicin as an example of disease setting and chemotherapy regimen with a high risk for febrile 
neutropenia (>20%) and recommends G-CSF prophylaxis for patients with high risk (>20%) of febrile 
neutropenia.   
Thus, all patients receiving TTI-621 in combination with doxorubicin should receive prophylaxis with G-
CSFs for prevention of febrile neutropenia associated with doxorubicin.  Suggested prophylaxis is 
pegfilgrastim and discussion with the Sponsor Medical Monitor regarding the specific agent is encouraged.   
8.7.3. 
Concomitant Anti-Coagulants 
Use of selected reversible anti-coagulants (low molecular weight heparin, heparin, warfarin or dabigatran) 
for prevention or treatment of thrombosis is permitted per the 2017 NCCN 
-Associated 
guidelines.   
8.8. 
Treatment of Overdose 
There are no known antidotes for overdoses of TTI-621 or doxorubicin.  In the event of an overdose of 
either of these agents, discontinuation of treatment may not have immediate therapeutic effect.  In the 
event of a known or suspected overdose, the patient should be monitored with appropriate hematology 
and clinical chemistry and should receive supportive therapy, as necessary.  
 
The doxorubin Full Prescribing Information describes some cases of doxorubicin overdose, treatment and 
outcome.  A 58-year-old man with acute lymphoblastic leukemia received 10-fold overdose of doxorubicin 
(300 mg/m2 ) in one day.  He was treated with charcoal filtration, hemotopoietic growth factor (G-CSF), 
proton pump inhibitor and antimicrobial prophylaxis.  The patient suffered sinus tachycardia, Grade 4 
neutropenia and thrombocytopenia for 11 days, severe mucositis and sepsis.  The patient recovered 
completely 26 days after the overdose.  A 17-year-old girl with osteogenic sarcoma received 150 mg of 
doxorubicin HCl daily for 2 days (intended dose was 50 mg per day for 3 days).  The patient developed 
severe mucositis on Days 4-7 after the overdose and chills and pyrexia on Day 7.  The patient was treated 
with antibiotics and platelets and recovered 18 days after overdose. 
 
Acute overdosage with doxorubicin enhances mucositis, leukopenia and thrombocytopenia.  Treatment 
of a severely myelosuppressed patient require hospitalization, antimicrobials, platelet transfusions and 
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symptomatic treatment of mucositis. Use of hematopoietic growth factor (G-CSF, GM-CSF) may be 
considered. 
 
Dexrazoxane may be considered for cardioprotection in patients who have received an excess of 
doxorubicin.   
 
Decisions regarding dose interruptions or modifications for TTI-621 and/or doxorubicin in the case of a 
suspected overdose will be made by the Investigator in consultation with the Sponsor Medical Monitor 
based on the clinical evaluation of the patient. 
 
Information regarding the quantity of the excess dose as well as the duration of the overdosing should be 
documented in the appropriate eCRF. 
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9.
MONITORING AND MANAGEMENT OF EXPECTED OR POTENTIAL ADVERSE EVENTS
Patient safety will be monitored throughout the study.  Documented adverse events observed, mentioned 
or spontaneously reported by the subject will be documented.  The Investigator will be responsible for 
monitoring the safety of patients and for alerting the Sponsor or its designee to any event that seems 
unusual, even if this event may be considered an unanticipated benefit to the patient.  The investigator is 
responsible for appropriate medical care of patients during the study and for adverse events that are 
serious in nature, considered related or unrelated to the study intervention, or that caused the patient to 
discontinue before completing the study.  The patient should be followed until such an adverse event is 
resolved or explained.  
 
All laboratory abnormalities and adverse events will be graded according to NCI CTCAE version 5.0.   
 
In the following section, guidelines are presented for management of adverse events attributed to TTI-
621 (Section 9.2) or doxorubicin (Section 9.3) and management of adverse events when attribution to 
neither agent is possible in the opinion of the Investigator (Section 0). 
 
9.1. 
Prophylaxis for Expected Adverse Events 
Prophylaxis for known adverse events associated with doxorubicin or TTI-621 are described in Section 
5.2.1.  All supportive measures consistent with optimal patient care according to institutional standards 
should be provided throughout the study.  Emergency resuscitation equipment and medications should 
be readily available.  Additional supportive measures should also be available and may include 
epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators and 
acetaminophen. 
 
9.2. 
Management of Adverse Events Associated with TTI-621  
9.2.1. 
TTI-621 Treatment Interruptions 
Treatment with TTI-621 may be interrupted for up to 42 days for toxicity; treatment may be interrupted 
for up to 21 days for reasons unrelated to toxicity if the patient is receiving clinical benefit and after 
discussion with the Sponsor Medical Monitor.  Treatment may be re-instated after discussion with the 
Sponsor Medical Monitor.  In general, if an interruption of more than 42 days is required due to adverse 
events, TTI-621 will be permanently discontinued; however, if in the judgment of the Investigator, the 
patient is likely to derive clinical benefit from TTI-621 after a hold of more than 42 days, study drug may 
be re-started with the approval of the Sponsor Medical Monitor.  The infusion duration may be increased 
and the prophylaxis regimen may be altered after discussion with the Sponsor Medical Monitor, but the 
TTI-621 dose level does not require modification when administration is re-started.  Longer interruptions 
may be acceptable on a patient-by-patient basis at the discretion of the Investigator after discussion with 
the Sponsor Medical Monitor. 
 
In Cycle 2 through Cycle 6, in the event that doxorubicin dosing is held due to an adverse event from which 
the investigator believes the patient will recover and continue treament, TTI-621 treatment will also be 
held.  The day on which doxorubicin is re-initiated will be considered Day 1 of the cycle, and TTI-621 will 
be administered as planned on the new Day 1 and subsequent Day 8.  Initiation of subsequent cycles will 
be reset according to the new Day 1.      
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9.2.2. 
TTI-621 Re-Treatment Guidelines (Initiation of New Cycles of Treatment) 
The parameters described in Table 9 should be met for initiation of a new cycle of treatment with TTI-621.  
Guidelines for intra-cycle dosing, dosing delays and dosing modifications in response to specific 
treatment-emergent adverse events are provided in Tables 12, 13, 14, 15, 21, 22 and 23. 
Table 9.  Requirements for  Initiation of a New Cycle with TTI-621  
Parameter 
Criterion 
ANC 
 1.0 × 109/L 
Platelet Count 
 75 × 109/L 
Bilirubin 
 1.5 × ULN 
AST, ALT 
 3 × ULN (< 5 × ULN if liver metastases) 
Treatment-Related  
Adverse Event 
NCI CTCAE Grade < 2 or baseline level (except for alopecia) 
9.2.3. 
TTI-621 Dose Modification Guidelines 
The expansion portion of the study is intended to evaluate two dose levels of TTI-621.  The lower dose 
level will be 0.2 mg/kg but the higher dose level is not yet known.  Therefore, Table 10 describes 
modifications for a range of target starting dose levels (Dose Level 1).  Provision is not made for treatment 
with TTI-621 at a dose level below 0.2 mg/kg, but a lower dose level may be allowed after consultation 
with the Sponsor Medical Monitor for a patient who is receiving clinical benefit and remaining on 
treatment is, in the opinion of the Investigator,  a reasonable treatment option for the patient.   
 
Table 10.  TTI-621 Dose Modifications 
 
 
 
 
 
 
 
 
 
Dose Level 
Dose Level -1 
Dose Level -2 
2.0 mg/kg 
1.4 mg/kg 
1.0 mg/kg 
1.4 mg/kg 
1.0 mg/kg 
0.7 mg/kg 
1.0 mg/kg 
0.7 mg/kg 
0.5 mg/kg 
0.7 mg/kg 
0.5 mg/kg 
0.2 mg/kg 
0.5 mg/kg 
0.2 mg/kg 
Discontinue 
0.2 mg/kg 
Discontinue 
Discontinue 
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9.2.3.1.
Infusion-Related Reactions Related to TTI-621 Administration
Infusion-related reactions will be graded as described in Table 11.   
 
Table 11.  Definition of Infusion-Related Reaction by CTCAE Grade 
CTCAE Grade 
Definition 
Grade 1 IRR 
Mild transient reaction; infusion interruption not indicated; intervention not indicated 
Grade 2 IRR 
Therapy or infusion interruption indicated but responds promptly to symptomatic 
treatment (e.g., anti-histamines, NSAIDS, narcotics, IV fluids); prophylactic medications 
 24 hours 
Grade 3 IRR 
Prolonged (i.e., not rapidly responsive to symptomatic medication, brief interruption of 
infusion, or both); recurrence of symptoms following initial improvement; hospitalization 
indicated for clinical sequelae 
Grade 4 IRR 
Life-threatening consequences; urgent intervention indicated 
Note:  An acute infusion reaction may occur with an agent that causes cytokine release (e.g., monoclonal antibodies or other 
biological agents).  Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.  Signs/symptoms may include: allergic reaction/hypersensitivity 
(including drug fever); arthralgia (joint pain); bronchospasm; cough; dizziness; dyspnea (shortness of breath); fatigue 
(asthenia, lethargy, malaise); headache; hypertension; hypotension; myalgia (muscle pain); nausea; pruritis/itching; 
rash/desquamation; rigors/chills; sweating (diaphoresis); tachycardia; tumor pain (onset or exacerbation of tumor pain 
due to treatment); urticaria (hives, welts, wheals); vomiting. 
 
As described in Section 5.2.1, prophylaxis is required prior to infusion of TTI-621.  Patients will be closely 
monitored for signs and symptoms of hypersensitivity or allergic reactions.  Guidelines for management 
of infusion-related reactions are presented in Table 12. 
 
 
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Table 12.  Management of Infusion-Related Reactions Associated with TTI-621 Administration  
CTCAE Grade 
Management Guidelines 
Grade 1 Infusion-
Related Reaction 
 
The infusion may be stopped or continued at a reduced (50%) infusion rate at the 
discretion of the Investigator. 
 
If symptoms resolve, the infusion can be re-started or increased, as tolerated, to the 
baseline rate. 
 
The patient may receive appropriate further treatment for infusion-related reaction 
 
Grade 2 Infusion-
Related Reaction 
 
The infusion should be stopped. 
 
The patient should receive appropriate further treatment with an anti-histamine 
management of IRR.  Further medications can be administered if necessary.   
 
Once symptoms have resolved or reduced to Grade 1, the infusion can be continued 
return and vital signs are stable, the infusion rate may be increased every 30 minutes, 
as tolerated, to the baseline rate. 
Grade 3 Infusion-
Related Reaction 
 
The infusion should be stopped promptly. 
 
The patient must receive appropriate treatment with an anti-histamine and/or 
acetaminophen and/or methylprednisolone or equivalent and, if necessary, further 
medications (i.e., epinephrine, bronchodilator).   
 
Only after the complete resolution to Grade 
1, and after having received 
appropriate prophylactic medication(s) as described above, the infusion may be 
return and vital signs are stable, the infusion rate may be increased to a maximum of 
50%. 
 
If after the resumption of infusion, symptoms return (irrespective of grade), the 
infusion must be stopped and the infusion tubing should be disconnected.  
 
The duration of infusion may be prolonged in order to ameliorate IRR but TTI-621 
dose does not require reduction. 
Grade 4 Infusion-
Related Reaction 
 
The infusion should be stopped promptly and the infusion tubing should be 
disconnected. 
 
The patient should receive appropriate treatment with an anti-histamine and/or 
acetaminophen and/or methylprednisolone (or equivalent) and, if necessary, further 
medications (i.e., epinephrine, bronchodilator).   
 
After discussion with the Sponsor Medical Monitor, the patient must not receive 
further infusions of TTI-621 if TTI-621 is judged by the Investigator to be the cause of 
the infusion-related reaction and the investigator feels that implementation of 
alternative or more aggressive prophylaxis would not be sufficient.   
9.2.3.2. 
Hematologic Adverse Events Related to TTI-621 Administration 
Blood counts should be monitored regularly as outlined in Table 24, with additional testing obtained 
according to standard clinical practice.  Management of hematologic adverse events associated with TTI-
621 administration is summarized in Table 13, Table 22 and Table 23.  Platelet transfusion is allowed to 
manage severe thrombocytopenia to prevent and minimize bleeding according to ASH and ASCO 
guidelines.  Per these guidelines, the platelet count threshold for prophylactic platelet transfusion is 
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<10,000 × 109/L. Investigators should consider the patient
medical history, concomitant medications 
and concurrent conditions to provide support for thrombocytopenia.  
Table 13.  Management of Hematologic Adverse Events Associated with TTI-621 Administration    
Note that specific guidelines for management of thrombocytopenia regardless of attribution to TTI-621 
and/or doxorubicin are provided in Table 22 and Table 23 and are not described here. 
 
 
 
 
Observation 
Management Guidelines 
Grade 4 neutropenia lasting > 72 hours 
 
 
Delay TTI-621 dosing until the re-treatment criterion (ANC >
1.0 × 109/L) is met, then resume TTI-621:  
o A
 
o One dose level reduction if dose delay was > 1 week 
o One dose level reduction if the event recurs 
Grade 3 febrile neutropenia lasting > 
72 hours 
 
Grade 3 neutropenia with clinical evidence 
of infection 
 
Grade 4 febrile neutropenia 
 
 
Delay TTI-621 dosing until the re-treatment criterion (ANC > 
1.0 × 109/L) is met, then resume TTI-621 at one dose level 
reduction 
Grade 3 anemia 
 
Delay TTI-
 1 or baseline, 
then resume TTI-621 treatment: 
o A
 1 week 
o One dose level reduction if dose delay was > 1 week 
o One dose level reduction if the event recurs  
Grade 4 anemia 
 
For Grade 4 events, discontinuation of TTI-621 should be 
considered.  If, per I
-621 
treatment can be resumed when the AE resolves to a level 
that meets re-treatment criteria 
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9.2.3.3.
Non-Hematologic Events Related to TTI-621 Administration
TTI-621 dose adjustments based on the occurrence of non-hematologic treatment-related adverse events 
are described in Table 14. 
Table 14.  Management of Non-Hematologic Adverse Events Associated with TTI-621 Administration   
Observation 
Management Guidelines 
exceptions: 
 
Nausea and/or vomiting lasting 
<72 hours with supportive care 
 
F
 hours 
 
Laboratory abnormalities lasting 
<72 hours and judged by the 
Investigator 
as 
not 
clinically 
significant  
 
For Grade 3 events, delay TTI-621 dosing until the re-treatment 
criteria are met, then resume TTI-621 at one dose level reduction  
 
No dose reduction is required for the exceptions listed 
 
For Grade 4 events, discontinuation of TTI-621 should be 
considered.  If, per I
best interest to continue the treatment, TTI-621 treatment can be 
resumed when the AE resolves to a level that meets re-treatment 
criteria 
9.2.3.4. 
Management of Other Adverse Events Related to TTI-621 Administration 
TTI-621 dose adjustments based on the occurrence of other treatment-related adverse events are 
described in Table 15. 
Table 15. Management of other Treatment-Related Adverse Events 
Severity of Event 
Management Guidelines 
Grade 1 
 
Maintain TTI-621 dose level 
 
Provide treatment to control symptoms if applicable 
Grade 2 (tolerable) 
 
Maintain TTI-621 dose level 
 
Provide treatment to control symptoms if applicable 
Grade 2 
(intolerable) 
 
Hold administration of TTI-621 until the adverse event r
 1 or to 
baseline level, then resume treatment with TTI-621 
Grade 3 
 
Hold administration of TTI-621 until the adverse event 
 1 or to 
baseline level, then resume treatment with TTI-621 
Grade 4 
 
Discontinue TTI-621 unless patient is receiving clinical benefit, adverse event recovers 
to baseline level and treating physician recommends continuation of treatment at a 
lower dose level or under a modified schedule 
9.3. 
Management of Adverse Events Associated with Doxorubicin  
9.3.1. 
Doxorubicin Treatment Interruptions 
Treatment with doxorubicin may be temporarily suspended for up to 42 days to allow for resolution of 
adverse events.  Dose interruptions for reason(s) other than toxicity and re-treatment may be allowed in 
accordance with standard of care if the patient is receiving clinical benefit and after discussion with the 
Sponsor Medical Monitor.  In general, if an interruption of more than 42 days is required due to adverse 
events, doxorubicin will be permanently discontinued; however, if in the judgment of the Investigator, 
the patient is likely to derive clinical benefit from doxorubicin after a hold of more than 42 days, study 
drug may be re-started with approval of the Sponsor Medical Monitor.  Longer interruptions may be 
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acceptable on a patient-by-patient basis at the discretion of the Investigator after discussion the Sponsor 
Medical Monitor. 
 
9.3.2. 
Doxorubicin Re-Treatment Guidelines for Day 1 
The laboratory parameters described in Table 16 should be met for re-treatment with doxorubicin. 
 
Table 16.  Requirements for Re-Treatment with Doxorubicin on Day 1 (Cycle 2 through Cycle 6)  
Parameter 
Criterion 
Platelets 
 109/L 
ANC 
 109/L 
Organ toxicity or other treatment-related    
adverse event 
Grade  2 
Bilirubin 
 1.5 × ULN 
AST, ALT 
 3 × ULN (< 5 × ULN if liver metastases) 
9.3.3. 
Doxorubicin Dose Modification Guidelines 
In general, doses should not be reduced for Grade 1 or Grade 2 adverse events, but treatment to manage 
symptoms should be provided, if applicable.   
 
For the purposes of doxorubicin dose modification in response to adverse events, the dose modification 
schema presented in Table 17 will be used. 
Table 17. Doxorubicin Dose Modifications 
Dose Level 
Doxorubicin Dose 
Dose Level 1 
75 mg/m2 
Dose Level -1 
60 mg/m2 
Dose Level -2 
45 mg/m2 
 
General guidelines for dose modifications in response to observed adverse events in presented in Table 
18.  In consideration that doxorubicin is being used as a standard of care anti-cancer therapy in the 
enrollment patient population and based on Investigator and site experience with doxorubicin in the 
enrolled patient population, alternate dose modifications may be implemented after discussion with the 
Sponsor Medical Monitor.   
 
 
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Table 18.  Doxorubicin Dose Modification Guidelines
Worst Toxicity in Prior Cycle 
Doxorubicin Dose for Next Cycle 
Febrile neutropenia 
Thrombocytopenia with bleeding 
ANC Grade 4 for  7 days 
Decrease doxorubicin one dose level 
Cardiotoxicity, including any signs and symptoms of heart failure, 
greater than 10% decline in LVEF to below the LLN, greater than 20% 
 45% 
Discontinue doxorubicin 
Consider initiation of dexrazoxane 
Grade 3 organ toxicity 
Decrease doxorubicin one  dose level 
Grade 4 organ toxicity 
Discontinue doxorubicin 
Hepatic impairment 
     Serum bilirubin 1.5  3.0 mg/dL 
     Serum bilirubin 3.1  5.0 mg/dL 
     Serum bilirubin > 5.0 mg/dL 
 
50% dose reduction 
75% dose reduction 
Discontinue doxorubicin 
9.3.3.1. 
Cardiac Toxicity Related to Doxorubicin Administration 
Cardiotoxicity is a recognized risk of doxorubicin that increases with higher cumulative drug exposure.  
Cardiac monitoring is conducted by a combination of monitoring of clinical parameters, ECG and 
echocardiogram (ECHO) / multigated acquisition (MUGA) scan.  ECG changes, arrhythmias, tachycardia, 
and/or chest pain should be managed according to clinical practice based on the specific findings. 
 
Patients will undergo baseline LVEF determination by ECHO or MUGA scan.  This evaluation may be 
repeated at any time during the study if clinically indicated.  A decrease in LVEF of  10% and below the 
lower limit of normal, or an absolute decrease of 20%, or if the absolute LVEF decreases to or below 40%, 
doxorubicin will be discontinued.  Doxorubicin should also be discontinued if the patient develops Grade 
 3 left ventricular systolic dysfunction (symptomatic congestive heart failure).  
 
If doxorubicin is discontinued for the above changes in LVEF despite optimal prophylaxis, the patient may 
be eligible to continue on study with TTI-621 monotherapy after discussion with the Sponsor Medical 
Monitor, provided that the patient has completed at least four cycles of doxorubicin therapy, is receiving 
clinical benefit and meets guidelines for re-treatment with TTI-621.   
 
The diagnostic method used at baseline for cardiovascular assessments (for example ECHO or MUGA 
scans) should be the same method used throughout the study, unless there is clinical or instrumental 
evidence that further investigations are needed.
The use of dexrazoxane to reduce the incidence and severity of cardiomyopathy due to doxorubicin 
administration in patients who have received a cumulative doxorubicin dose of 300 mg/m2 and who will 
continue to receive doxorubicin is recommended and will be implemented in this study.  As described in 
Section 5.2.1.1, prophylaxis with dexrazoxane for cardiotoxicity must begin no later than with initiation of 
Cycle 5 when cumulative doxorubicin will have reached 300 mg/m2.  Do not administer dexrazoxane as a 
cardioprotectant at the initiation of doxorubicin treatment unless that is the standard of care at a 
particular institution.   
 
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Doxorubicin can result in arrhythmias, including life-threatening arrhythmias, during or within a few hours 
after doxorubicin administration and at any timepoint during treatment.  Tachyarrhythmias, including 
sinus tachycardia, premature ventricular contractions and ventricular tachycardia, as well as bradycardia 
may occur.  Electrocardiographic changes including non-specific ST-T wave changes, atrioventricular and 
bundle-branch block can also occur.  These electrocardiographic changes may be transient and self-limited 
and may not require dose modifications of doxorubicin. 
 
9.3.3.2. 
Secondary Malignancies Related to Doxorubicin Administration 
The risk of developing secondary acute myelogenous leukemia and is increased following treatment with 
doxorubicin.  Cumulative incidences ranged from 0.2% at five years to 1.5% at 10 years in two separate 
trials involving the adjuvant treatment of women with breast cancer.  These leukemias generally occur 
within 1 to 3 years of treatment.  
 
9.3.3.3. 
Extravasation and Tissue Necrosis Related to Doxorubicin Administration 
Extravasation of doxorubicin can result in severe local tissue injury manifesting as blistering, ulceration, 
and necrosis requiring wide excision of the affected area and skin grafting.  When given via a peripheral 
venous line, infuse doxorubicin over 10 minutes or less to minimize the risk of thrombosis or perivenous 
extravasation.  If signs or symptoms of extravasation occur, immediately terminate the injection or 
infusion.  Extravasation may be present in patients who do not experience a stinging or burning sensation 
or when blood return is present on aspiration of the infusion needle.  If extravasation is suspected, apply 
ice to the site intermittently for 15 minutes, 4 times a day for 3 days.  If appropriate, administer 
dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after 
extravasation.  
 
9.3.3.4. 
Hematologic Toxicity Related to Doxorubicin Administration 
ASCO guidelines for use of WBC growth factors26 provide 
prevention of febrile neutropenia is warranted when the risk of febrile neutropenia is approximately 20% 
or higher and no other equally effective and safe regimen that does not require CSFs is available.  Primary 
prophylaxis is recommended for the prevention of febrile neutropenia in patients who are at high risk on 
the basis of age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. 
The NCCN guidelines for hematopoietic growth factors26 classify soft tissue sarcoma treated with 
doxorubicin as an example of disease setting and chemotherapy regimen with a high risk for febrile 
neutropenia (>20%) and recommends G-CSF prophylaxis for patients with high risk (>20%) of febrile 
neutropenia. 
Thus, all patients receiving TTI-621 in combination with doxorubicin should receive prophylaxis with G-
CSFs for prevention of febrile neutropenia associated with doxorubicin.  Suggested prophylaxis is 
pegfilgrastim and discussion with the Sponsor Medical Monitor regarding the specific agent is encouraged.   
 
Doxorubicin will not be administered in Cycles 2  6 
 1 x 109 cells/L or if the platelet 
count is < 75 x 109 cells/L.  When necessary, the next treatment cycle should be delayed until the ANC is 
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1 x 109 cells/L 
75 x 109 cells/L and non-hematologic toxicities have resolved.
For patients who experience Grade 3 neutropenic fever or infection or Grade 4 neutropenia without 
fever lasting more than 1 week, doxorubicin should be reduced to 75% of the starting dose (to 
approximately 60 mg/m2).  If a patient experiences a second incidence of neutropenic fever or infection 
or has another episode of Grade 4 neutropenia lasting >1 week, then a second dose reduction to 45 mg/m2 
should be implemented.  Doxorubicin dose reductions for neutropenia are described in Table 19.  
 
Therapeutic and prophylactic use of G-CSFs will be allowed per current ASCO and NCCN guidelines.  For 
patients with Grade 4 ANC without fever/infection lasting less than one week, re-treatment will be 
allowed at the I
2) with recommended 
use of G-CSFs per current ASCO guidelines.   
 
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 79 of 140 
 
 
Table 19.  General Guidelines for Doxorubicin Dose Reduction due to Neutropenia
Observation 
Management Guidelines 
ANC < 1 x 109 cells/L 
 
Doxorubicin not administered; treatment cycle delayed 
At Re-Treatment: 
 
Grade 3 neutropenic fever/infection 
has occurred 
 
If Grade 4 neutropenia lasting > 1 
week has occurred 
 
Grade 4 ANC without fever/infection 
 
 
Reduce doxorubicin dose to 60 mg/m2 
 
 
Reduce doxorubicin dose to 60 mg/m2 
 
 
Re-
discretion with prophylactic G-CSF 
Second Incidence of either 
 3 
neutropenic fever/infection or Grade 4 
neutropenia lasting > 1 week 
 
Reduce doxorubicin dose to 45 mg/m2 
 
9.3.3.5. 
Tumor Lysis Syndrome Related to Doxorubicin Administration 
Doxorubicin may induce tumor lysis syndrome in patients with rapidly growing tumors and should be 
managed according to institutional guidelines. 
 
9.3.3.6. 
Radiation Sensitization and Radiation Recall Related to Doxorubicin 
Administration 
Doxorubicin can increase radiation-induced toxicity to the myocardium, mucosa, skin and liver.  Radiation 
recall, including but not limited to cutaneous and pulmonary toxicity, can occur in patients who receive 
doxorubicin after prior radiation therapy.  Patients should not receive radiation unless there is an urgent 
or emergent need. 
 
9.3.3.7. 
Management of Infusion-Related Reactions Related to Doxorubicin 
Administration 
Infusion-related reactions will be graded as described in Table 11 in Section 9.2.3.1.  Management of 
infusion-related reactions associated with doxorubicin administration are described in Table 20. 
Table 20.  Management of IRR Associated with Doxorubicin Administration   
CTCAE Grade 
Management Guidelines 
Grade 1 or Grade 2 
 
Slow or stop the infusion rate. 
 
Provide appropriate further treatment for infusion-related reaction if clinically-
 
 
If symptoms resolve, the infusion can be re-started or increased, as tolerated, to the 
baseline rate. 
 
Consider premedications and reduced infusion rate 
Grade 3 or Grade 4 
 
The infusion should be stopped. 
 
doxorubicin-associated infusion-related reaction. 
 
Re-challenge is discouraged, especially if vital symptoms have been affected. 
 
Consider de-sensitization if therapy is consider essential and patient and physician 
concur on treatment goals 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 80 of 140 
 
 
9.4. 
Management of Adverse Events not Attributable to a Specific Study Treatment 
Guidelines for managing adverse events when attribution to either TTI-621 or doxorubicin is not possible 
in the opinion of the Investigator are provided in Table 21.  Guidelines for management of treatment 
emergent thrombocytopenia are provided in Table 22 and Table 23 in Section 9.5.  Discussion with the 
Sponsor Medical Monitor is recommended to ensure homogeneity in adverse event management across 
all patients to the extent possible.   
 
Table 21.  General Guidelines for Management of Adverse Events when Attribution is not Possible in 
the Opinion of the Investigator   
Note that guidelines for management of thrombocytopenia are provided in Table 22 and Table 
23 in Section 9.5 
Observation 
Management Guidelines 
Hematologic Toxicity1 
 
 3 neutropenia 
(ANC < 1 x 109/L) 
 
 3 anemia 
 
Hemoglobin < 8 g/dL 
 
Non-Hematologic Toxicity1 
 3 events excluding: 
 
Sub-optimally treated nausea, 
vomiting, diarrhea 
 
Alopecia 
 
Transient fatigue of a duration 
consistent with that associated with 
doxorubicin treatment (1-2 weeks) 
 
Infusion-related 
reaction 
in 
the 
absence of described prophylaxis 
 
Laboratory abnormalities that are 
asymptomatic and/or judged by the 
Investigator 
as 
not 
clinically 
significant for the patient 
First Appearance 
 
 1 or baseline 
with ANC > 1.0  x 109/L .  If no recovery after a delay of > 21 days, 
discontinue all study treatment. 
 
Reduce doxorubicin and TTI-621 dose levels by one dose level.   
 
First Re-Appearance 
 
 1 or baseline.  If 
no recovery after a delay of > 21 days, discontinue all study 
treatment. 
 
Reduce doxorubicin and TTI-621 dose levels by one additional 
dose level.   
 
Second Re-Appearance 
 
Discontinue all study treatment. 
Hematologic Toxicity 
 
Grade 1 or Grade 2 
 
Non-Hematologic Toxicity 
 
Grade 1 or Grade 2 
 
No treatment delay 
 
No change in dose level 
1  Interventional or supportive care may be introduced (e.g., G-CSF for neutropenia) 
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 81 of 140 
 
 
9.5.
Guidelines for Management of Thrombocytopenia Assessed as Related to Study Treatment 
(TTI-621 and/or Doxorubicin) 
Guidelines for management of treatment-emergent thrombocytopenia occurring in Cycles 1  6 or any 
cycle when doxorubicin and TTI-621 are administered together are provided in Table 22.  Guidelines for 
management of treatment-emergent thrombocytopenia occuring in Cycles 
7 or when TTI-621 is 
administered as monotherapy are provided in Table 23. 
Table 22.  TTI-621 and Doxorubicin Treatment Guidelines Based on Thrombocytopenia Assessed as 
Related to Study Treatment in Cycles 1-6 (Combination Treatment) 
Platelet Count on Day 8 
Management Guidelines 
<LLN  75 x 109/L 
 Continue TTI-621 and doxorubicin at same dose 
<75 x 109  50 x 109/L 
 Continue TTI-621 and doxorubicin at same dose 
<50 x 109  25 x 109/L 
 Omit TTI-621 on Day 8 
 Monitor platelet recovery (CBC twice weekly recommended) 
 Consider platelet transfusion per ASCO guidelines if clinically indicated 
 On Day 1 of next cycle: 
o 
9/L, initiate cycle with doxorubicin at 
the same dose and TTI-621 at one dose level reduction 
o 
9/L, hold doxorubicin and TTI-621 
and monitor platelets;  initiate the cycle when platelets recover to  
9/L with doxorubicin at same dose and TTI-621 at one dose level 
reduction 
 In the case of a second occurrence of platelet count decrease to <50 x 109, follow 
the guidelines above or consult with the Sponsor Medical Monitor regarding 
management 
 The reduced dose of TTI-621 should be used for the remaining combination cycles
 When the subject completes the combination portion of the study and moves to 
TTI-621 monotherapy: 
o 
the original TTI-621 dose level should be re-instated and platelet counts 
monitored 
o 
in the case of platelets < 50 x 109/L without other causality on Day 15, hold 
TTI-621 un
9/L and then continue with TTI-621 at a 
one dose level reduction 
o 
on second occurrence of platelets < 50 x 109/L without other causality, 
reduce TTI-621 by an additional dose level and monitor for tolerability or 
consult with the sponsor medical monitor regarding management 
o 
in the absence of disease progression, further dose reductions may be 
implemented after discussion with the sponsor medical monitor 
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 82 of 140 
 
 
Platelet Count on Day 8 
Management Guidelines 
<25 x 109/L 
 Omit TTI-621 on Day 8 
 Monitor platelet recovery (CBC twice weekly recommended) 
 Consider platelet transfusion per ASCO guidelines if clinically indicated 
 On Day 1 of next cycle: 
o 
9/L, reduce doxorubicin and TTI-621 
each by one dose level and initiate cycle  
o 
9/L, hold doxorubicin and TTI-621 
and monitor platelets;  initiate the cycle when platelets recover to      
109/L with doxorubicin and TTI-621 each at one dose level reduction 
 In the case of a second occurrence of platelet decrease to <25 x 109/L, consult 
with the Sponsor Medical Monitor regarding management 
 The reduced dose levels of doxorubicin and TTI-621 should be used for the
remaining combination cycles 
 When the subject completes the combination portion of the study and moves to 
TTI-621 monotherapy: 
o 
the original TTI-621 dose level should be re-instated and platelet counts 
monitored 
o 
in the case of platelets < 50 x 109/L on D15, hold TTI-621 until platelets are 
9/L and then continue with TTI-621 at a one dose level reduction 
o 
on second occurrence of platelets < 50 x 109/L without other causality, 
reduce TTI-621 by an additional dose level and monitor for tolerability or 
consult with the sponsor medical monitor regarding management 
o 
in the absence of disease progression, further dose reductions may be 
implemented after discussion with the sponsor medical monitor. 
 
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 83 of 140 
 
 
Day 8 Platelet Count 
Management Guidelines 
Any platelet count with 
clinically-relevant bleeding 
(more than easily-controlled 
epistaxis, mild gum bleeding 
or menses) 
 Hold TTI-621 on Day 8 
 Monitor platelet recovery (CBC twice weekly recommended) 
 Consider platelet transfusion per ASCO guidelines 
 On Day 1 of next cycle: 
o 
9/L and bleeding has resolved, reduce 
doxorubicin and TTI-621 by one dose level and initiate cycle  
o 
9/L and/or bleeding has not 
resolved, hold doxorubicin and TTI-621 and monitor platelets;  initiate the 
9/L with doxorubicin and TTI-621 
each at one dose level reduction 
 In the case of a second occurrence of platelet count decreased with bleeding 
attributed to study drug treatment, consult with the sponsor medical monitor 
regarding management 
 The reduced dose levels of doxorubicin and TTI-621 should be used for the 
remaining combination cycles 
 When the subject completes the combination portion of the study and moves to 
TTI-621 monotherapy: 
o 
the original TTI-621 should be re-instated and platelet counts monitored 
o 
in the case of platelets < 50 x 109/L on D15, hold TTI-621 until platelets are 
9/L and then continue with TTI-621 at one dose level reduction 
o 
on Day 1 
9/L, the reduced 
TTI-
9/L, reduce TTI-621 
by another dose level and monitor for tolerability.   
o 
in the absence of disease progression, further dose reductions may be 
implemented after discussion with the Sponsor Medical Monitor. 
 
 
 
 
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,  17 June 2022                                        Confidential                                          
page 84 of 140 
 
 
Table 23. TTI-621 Treatment Guidelines based on Thrombocytopenia Assessed as Related to Study 
-621 Monotherapy)     
Note that these guidelines are intended to address a patient who has not experienced 
thrombocytopenia in the combination portion of the study but presents with thrombocytopenia 
during monotherapy treatment. 
 
Day 15 Platelet Count 
Management Guidelines 
<LLN  75 x 109/L 
 Continue TTI-621 at same dose 
<75 x 109  50 x 109/L 
 Continue TTI-621 at same dose 
<50 x 109  25 x 109/L 
OR 
Any platelet count with 
bleeding attributed to study 
drug treatment 
 Monitor platelet recovery (CBC twice weekly recommended) 
 Consider platelet transfusion per ASCO guidelines if clinically indicated 
 Hold TTI-
9/L and then continue with TTI-621 at a 
one dose level reduction   
 On second occurrence of platelets < 50 x 109/L without other causality, reduce 
TTI-621 by an additional dose level and monitor for tolerability;  in the absence 
of disease progression, further dose reductions may be implemented after 
discussion with the Sponsor Medical Monitor 
<25 x 109/L 
 Monitor platelet recovery (CBC twice weekly recommended) 
 Consider platelet transfusion per ASCO guidelines if clinically indicated 
 Hold TTI-
9/L and then continue with TTI-621 at a 
one dose level reduction.   
 On second occurrence of platelets < 25 x 109/L without other causality, reduce 
TTI-621 by an additional dose level and monitor for tolerability or consult with 
the Sponsor Medical Monitor regarding management.  In the absence of disease 
progression, further dose reductions may be implemented after discussion with 
the Sponsor Medical Monitor. 
 
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,  1 7 J u n e 2 0 2 2                                        C o nfi d e nti al                                          
p a g e 8 5 of 1 4 0  
 
 
1 0.
S T U D Y A S S E S S M E N T S
T h e pr oc e d ur es a n d ass ess m e nts t h at will b e c o n d uct e d d uri n g t his st u dy ar e d escri b e d i n t his s ecti o n a n d 
s u m m ariz e d i n t h e Sc h e d ul e of Ass ess m e nts (T a bl e 2 4 ).  D et ail e d i nstr ucti o ns r e g ar di n g all l a b or at or y 
pr oc e d ur es, i ncl u di n g c oll ecti o n a n d h a n dli n g of s a m pl es, will b e i ncl u d e d i n t h e st u dy L a b or at ory M a n u al 
pr o vi d e d by t h e S p o ns or. 
 
T h e sc h e d ul e f or c oll ecti o n of bl o o d s a m pl es f or a n al ysis of 
is pr es e nt e d i n T a bl e 
2 5 .  T h e sc h e d ul e f or c oll ecti o n of s a m pl es f or 
 a n al ys es is pr es e nt e d i n T a bl e 2 6 .  T h e 
sc h e d ul e f or c oll ecti o n of s a m pl es f or 
 a n alys es is pr es e nt e d i n T a bl e 2 7 .   
 
Writt e n i nf or m e d c o ns e nt m ust b e gr a nt e d by e ac h p ati e nt pri or t o t h e i niti ati o n of a n y st u dy pr oc e d ur e 
or ass ess m e nt, i ncl u di n g ass ess m e nt of hist ol o g y.   
 
Pl a n n e d ti m e p oi nts f or all s af ety ass ess m e nts ar e pr o vi d e i n t h e Sc h e d ul e of Ass ess m e nts ( T a bl e 2 4 ).  
U nsc h e d ul e d s af et y m e as ur e m e nts m a y b e o bt ai n e d at a ny ti m e d uri n g t h e st u dy t o ass ess a ny p erc eiv e d 
s af et y iss u es. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI
C CI


TTI-621 (
-IgG1 Fc) 
 
Trillium Therapeutics, a Pfizer Company 
Clinical Protocol TTI-621-03 
Version  2.0,    17 June 2022                                                                                         Confidential                                             
page 86 of 140 
 
 
Table 24.  Schedule of Assessments 
 
 
ACTIVITY 
Screening 
Cycle 1 
Day in Cycle 
21-day cycle 
Cycle 2  Cycle 6 
Day in Cycle (± 1 day) 
21-day cycles 
Subsequent Cycles 
Day in Cycle (± 3 days) 
28-day cycles 
Safety Follow-Up 
Visitff 
Long-Term Follow-
Up 
Day -28 to -1 
1 
8 
1 
8 
1 
15 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Cancer history 
X 
 
 
 
 
 
 
 
 
Physical exam, vital signsa 
X 
X 
 
X 
 
X 
 
X 
 
Confirmation of histology in an 
archival or fresh tissue specimenb 
X 
 
 
 
 
 
 
Brief physical exam, vital signsc 
 
 
X 
 
X 
 
X 
 
 
LVEFd  
X 
 
 
Xw 
 
Xw 
 
X 
 
ECOG PS 
X 
X 
 
X 
 
X 
 
X 
 
Serum chemistrye 
X 
Xt 
Xt 
Xt 
Xt 
Xt 
Xt 
X 
 
Hematologyf 
X 
Xt 
Xt 
Xt 
Xt 
Xt 
Xt 
X 
 
Coagulationg 
X 
Xt 
 
 
 
 
 
 
 
ECGh 
X 
Xt 
 
Xu 
 
Xv 
 
X 
 
Pregnancy testi 
X 
X  
 
X  
 
X  
 
X 
 
Radiologic assessment of disease 
statusj 
X 
X 
X 
X 
PRO QoL assessmentk 
 
X 
 
X 
 
X 
 
X 
 
Administer doxorubicin with 
prophylaxisl 
 
X 
 
X 
 
 
 
 
 
Cardiotoxicity prophylaxism 
 
 
 
Xm 
 
 
 
 
 
Administer TTI-621 with 
prophylaxisn 
 
X 
X 
X 
X 
X 
X 
 
 
Adverse events 
 
 
Ongoing 
 
Concomitant medications and 
procedures 
 
 
Ongoing 
 
090177e19b809d54\Final\Final On: 09-Oct-2022 03:49 (GMT)


T TI- 6 2 1 (
-I g G 1 Fc) 
 
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y 
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3 
V ersi o n  2. 0,    1 7 J u n e 2 0 2 2                                                                                         C o nfi d e nti al                                             
p a g e 8 7 of 1 4 0  
 
 
a. 
C o m pl et e p h ysic al ex a mi n ati o n b y b o d y s yst e m, i ncl u di n g vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at or y r at e, w ei g ht, p uls e oxi m etr y); 
h ei g ht c oll ect e d d uri n g scr e e ni n g o nl y 
b 
Ex p a nsi o n p h as e o nl y a n d p ati e nts wit h a di a g n osis of l ei o m y os arc o m a;  t o b e p erf or m e d i n a c e ntr al l a b or at or y;  p ati e nt m ay b e e nr oll e d b as e d o n a c urr e nt 
or m ost r ec e nt p at h ol o g y r e p ort t h at pr o vi d es s uffici e nt d et ail t o s u p p ort d eri v ati o n of t h e hist ol o gic i nt er pr et ati o n b ut a pr e-tr e at m e nt tiss u e s p eci m e n 
m ust b e m a d e a v ail a bl e f or c o nfir m ati o n d uri n g scr e e ni n g or wit hi n t h e first cycl e of tr e at m e nt   
c 
S y m pt o m- dir ect e d p h ysic al ex a mi n ati o n, wit h vit al si g ns li mit e d t o t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at or y r at e 
d 
Ass ess e d b y tr a nst h or acic ec h oc ar di o gr a m or M U G A 
e 
Gl uc os e, s o di u m, p ot assi u m, c alci u m, c hl ori d e, p h os p h at e, bic ar b o n at e, bl o o d ur e a nitr o g e n or ur e a, cr e ati ni n e, t ot al pr ot ei n, al b u mi n, al k ali n e p h os p h at as e, 
as p art at e a mi n otr a nsf er as e ( A S T), al a ni n e a mi n otr a nsf er as e ( AL T), t ot al bilir u bi n, i n dir ect bilir u bi n, uric aci d, c alci u m, m a g n esi u m, l act at e d e h y dr o g e n as e 
(L D H) 
f 
H e m o gl o bi n, h e m at ocrit, pl at el ets, w hit e bl o o d c ells ( W B C), n e utr o p hils, l y m p h ocyt es, e osi n o p hils, b as o p hils, m o n oc yt es, W B C wit h a ut o m at e d 5- p art 
diff er e nti al, R B C, a bs ol ut e r etic ul oc yt es, r etic ul ocyt es %, M C H, M C V, R D W 
g  
I nt er n ati o n al n or m aliz e d r ati o (I N R)/ pr ot hr o m bi n ti m e ( P T), p arti al t hr o m b o pl asti n ti m e ( P T T).  T o b e r e p e at e d m or e fr e q u e ntl y if cli nic all y-i n dic at e d ( e. g., 
I N R/ P T f or p ati e nts o n a nti-c o a g ul a nts)     
h  
1 2-l e a d E C G, a v er a g e of tri plic at e ass ess m e nts o bt ai n e d wit h p ati e nt i n s u pi n e p ositi o n a n d wit hi n 1 0 mi n ut es t ot al ti m e; t o b e p erf or m e d pri or t o Cycl e 1, 
Cycl e 3, Cycl e 4 a n d C ycl e 6; pri or t o e v er y t hir d cycl e b e gi n ni n g wit h Cycl e 7; a n d at t h e S af et y F oll o w- U p Visit. 
i 
Pr e g n a nc y t ests will b e p erf or m e d i n W O C B P.  A s er u m pr e g n a nc y t est is r e q uir e d at scr e e ni n g. F oll o wi n g scr e e ni n g, pr e g n a ncy t ests m a y b e uri n e or s er u m 
t ests, a n d m ust h a v e a s e nsiti vit y of at l e ast 2 5 mI U/ mL. At b as eli n e a n d w h e n sc h e d ul e d at tr e at m e nt visits, m ust b e p erf or m e d pri or t o tr e at m e nt. 
j 
Ass ess e d o bj ecti v el y b y C T, M RI or P E T/ C T; t h e m et h o d us e d at b as eli n e s h o ul d b e us e d f or t h e d ur ati o n of p ati e nt p artici p ati o n.  P erf or m e d ev er y 6 ± 1 
w e ek f or t h e first 1 8 w e eks ( d uri n g c o m bi n ati o n tr e at m e nt), e v er y 8 ± 1 w e e k u ntil W e ek 5 0 or p ati e nt h as b e e n o n st u d y f or o n e y e ar, a n d ev er y 1 2 ± 2 
w e eks t h er e aft er.  C R or P R s h o ul d b e c o nfir m e d b y r e p e at ass ess m e nt at l e ast f o ur w e e ks aft er i niti al o bs er v ati o n; tr e at m e nt c a n c o nti n u e d uri n g t h e 
i nt er v al b et w e e n i niti al o bs er v ati o n a n d c o nfir m ati o n.  I n t h e e v e nt t h at a p ati e nt is r e m o v e d fr o m t h e st u d y i n t h e a bs e nc e of r a di ol o gic dis e as e pr o gr essi o n, 
a r a di ol o gic dis e as e ass ess m e nt s h o ul d b e p erf or m e d at t h e S af et y F oll o w- U p Visit if n ot p erf or m e d wit hi n t h e pr e vi o us f o ur w e eks a n d dis e as e st at us s h o ul d 
b e ass ess e d d uri n g L o n g- T er m F oll o w- U p u ntil r a di ol o gic d e m o nstr ati o n of pr o gr essi o n or i niti ati o n of n e w a nti-c a nc er t h er a p y, w hic h e v er occ urs first 
k 
P ati e nt-r e p ort e d h e alt h-r el at e d q u alit y of lif e will b e ass ess e d wit h t h e E O R T C QL Q- C 3 0 t o ol o n D a y 1 of ev er y c ycl e a n d at t h e S af et y F oll o w- U p visit pri or 
t o i niti ati o n of st u d y tr e at m e nt or ot h er st u d y acti viti es 
A C TI VI T Y  
Scr e e ni n g  
C ycl e 1  
D a y i n C ycl e 
2 1- d a y c ycl e  
C ycl e 2  C ycl e 6  
D a y i n C ycl e ( ± 1 d a y) 
2 1- d a y c ycl es  
S u bs e q u e nt C ycl es  
D a y i n C ycl e ( ± 3 d a ys) 
2 8- d a y c ycl es  
S af et y F oll o w- U p 
Visit ff 
L o n g- T er m F oll o w-
U p  
D a y - 2 8 t o - 1  
1  
8  
1  
8  
1  
1 5  
S ur vi v al, i niti ati o n of n e w a nti -
c a nc er t h er a py s 
 
 
 
 
 
 
 
 
X 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


T TI- 6 2 1 (
-I g G 1 Fc) 
 
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y 
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3 
V ersi o n  2. 0,    1 7 J u n e 2 0 2 2                                                                                         C o nfi d e nti al                                             
p a g e 8 8 of 1 4 0  
 
 
l  
D ox or u bici n s h o ul d b e a d mi nist er e d t hr o u g h a fr e e-fl o wi n g c at h et er at 7 5 m g/ m2 b y i ntr av e n o us i nf usi o n i n l ess t h a n 6 0 mi n ut es.  Pr o p h yl axis a g ai nst e m esis 
a n d f or pr e v e nti o n of f e bril e n e utr o p e ni a s h o ul d b e a d mi nist er e d as d escri b e d i n S ecti o n 5. 2. 1. 1 ; a d diti o n al pr o p h yl axis i n acc or d a nc e wit h i nstit uti o n al 
g ui d eli n es is acc e pt a bl e  
m  
C ar di o pr ot ecti v e a d mi nistr ati o n of d e xraz o xa n e  s h o ul d b e i niti at e d n o l at er t h a n i niti ati o n of Cycl e 5 u nl ess e arli er i niti ati o n is m e dic all y a d vis e d or st a n d ar d 
of c ar e at a p artic ul ar i nstit uti o n 
n 
Pr o p h yl axis as d escri b e d i n S ecti o n 5. 2. 1. 2 will b e i niti at e d at l e ast 3 0- 6 0 mi n ut es pri or t o i niti ati o n of T TI- 6 2 1 i nf usi o n.  T TI- 6 2 1 is a d mi nist er e d i ntr a v e n o usl y 
o v er 2 h o urs.  At t h e I
-r el at e d r e acti o n i n pri or cycl es, d ur ati o n of i nf usi o n m ay b e r e d uc e d t o 6 0 
mi n ut es b e gi n ni n g wit h Cycl e 2.  P ati e nts s h o ul d b e o bs er v e d f or o n e h o ur aft er i nf usi o n wit h vit al si g ns ass ess m e nt i n 3 0- mi n ut es f or si g ns of i nf usi o n-
r el at e d r e acti o n 
 a n d d o n ot 
ex p eri e nc e i nf usi o n-r el at e d r e acti o n. 
o  
D et ail e d s a m pl e c oll ecti o n sc h e d ul e pr o vi d e d i n T a bl e 2 5  
p 
D et ail e d s a m pl e c oll ecti o n sc h e d ul e pr o vi d e d i n T a bl e 2 7  
q 
D et ail e d s a m pl e c oll ecti o n sc h e d ul e pr o vi d e d i n T a bl e 2 6  
r 
D et ail e d s a m pl e c oll ecti o n sc h e d ul e pr o vi d e d i n T a bl e 2 7  
s 
Ass ess e d ev er y 1 2 ± 2 w e e ks; t el e p h o n e c o nt act is acc e pt a bl e 
t  
D o es n ot n e e d t o b e p erf or m e d if pr evi o us ass ess m e nt w as wit hi n 7 2 pr evi o us h o urs 
u 
Pri or t o i niti ati o n of Cycl e 3, C ycl e 4 a n d Cycl e 6; d o es n ot n e e d t o b e p erf or m e d if pr e vi o us ass ess m e nt w as wit hi n s ev e n d a ys 
v 
Pri or t o i niti ati o n of e v er y t hir d cycl e ( Cycl e 7, Cycl e 1 0, Cycl e 1 3, etc.); d o es n ot n e e d t o b e p erf or m e d if pr e vi o us ass ess m e nt w as wit hi n s e v e n d a ys 
w  
Pri or t o i niti ati o n of Cycl es 5 a n d 8; d o es n ot n e e d t o b e p erf or m e d if pr evi o us ass ess m e nt w as pr e vi o us f o ur w e eks 
x 
 P artici p a nts wit h a n u nr es ol v e d A E c o nsi d er e d b y t h e I n v esti g at or as p ossi bl y r el at e d t o or ass oci at e d wit h 
will b e as k e d t o r et ur n f or 
bl o o d s a m pli n g at a p pr oxi m at el y 3- m o nt h i nt er v als (if f e asi bl e gi v e n t h e u n d erl yi n g dis e as e) u ntil t h e l ast f oll o w- u p of t h e A E u p t o a m axi m u m of 1 2 m o nt hs.  
y 
Cycl es 2, 3, 4, 5 o nl y 
z 
Cycl e 2 a n d Cycl e 3 o nl y 
a a 
E v er y s ec o n d cycl e ( Cycl e 7, C ycl e 9, Cycl e 1 1, etc.) 
b b  
Cycl e 7 o nl y 
d d  
M a y b e c oll ect e d a n yti m e wit hi n s ev e n d a ys pri or t o a n d 1 4 d a ys aft er Cycl e 3 D a y 1; ot h er ti m es m a y b e acc e pt a bl e aft er c o ns ult ati o n wit h S p o ns or 
ff 
T o b e p erf or m e d 3 0 + fi v e d a ys aft er l ast a d mi nistr ati o n of st u d y tr e at m e nt or b ef or e i niti ati o n of s u bs e q u e nt a nti-c a nc er t h er a py, w hic h ev er occ urs first 
 
  
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C
CI
C
CI
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc) 
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y 
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3 
V ersi o n  2. 0,    1 7 J u n e 2 0 2 2 
 C o nfi d e nti al 
p a g e 8 9 of 1 4 0  
T a bl e 2 5.  S a m pl e C oll ecti o n Sc h e d ul e f or A n al ysis of
T a bl e 2 6.  S a m pl e C oll ecti o n Sc h e d ul e f or A n al ysis of
C ycl e 
D a y of Cycl e  
Ti m e p oi nt 
C ycl e 
D a y of Cycl e 
Ti m e p oi nt(s) 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc) 
 
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y 
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3 
V ersi o n  2. 0,    1 7 J u n e 2 0 2 2                                                                                         C o nfi d e nti al                                             
p a g e 9 0 of 1 4 0  
 
 
T a bl e 2 7.  S a m pl e C oll ecti o n Sc h e d ul e f or A n al ysis of
 
Scr e e ni n g 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C
CI
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2                                                     C o nfi d e nti al                       
p a g e 9 1 of 1 4 0  
 
 
1 1.
S C H E D UL E O F P R O C E D U R E S A N D A S S E S S M E N T S
T h e f oll o wi n g pr oc e d ur es a n d ass ess m e nts will b e p erf or m e d at t h e i n dic at e d ti m e p oi nts.  
 
Scr e e ni n g Visit ( D a y - 2 8 t o - 1) 
 
I nf or m e d c o ns e nt 
 
D e m o gr a p hics 
 
I ncl usi o n a n d excl usi o n crit eri a 
 
M e dic al hist ory 
 
C a nc er hist or y 
 
C o m pl et e p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e, w ei g ht, p uls e oxi m etry), 
h ei g ht 
 
 
L V E F by tr a nst h or acic ec h oc ar di o gr a m or M U G A 
 
E C O G P S 
 
S er u m c h e mistr y 
 
H e m at ol o g y  
 
C o a g ul ati o n  
 
1 2-l e a d E C G 
 
Uri n e or s er u m pr e g n a ncy t est (f e m al e p ati e nts of c hil d b e ari n g p ot e nti al o nly) 
 
R a di ol o gic ass ess m e nt of dis e as e st at us usi n g C T, M RI or P E T/ C T; t h e m et h o d us e d at b as eli n e 
s h o ul d b e us e d f or t h e d ur ati o n of p ati e nt p artici p ati o n 
 
Bl o o d c oll ecti o n f or
 
C ycl e 1 D a y 1  
 
P ati e nt-r e p ort e d q u ality- of-lif e ass ess m e nt 
 
C o m pl et e p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e, w ei g ht, p uls e oxi m etry) 
 
E C O G P S 
 
S er u m c h e mistr y ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr e vi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
C o a g ul ati o n ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
1 2-l e a d E C G ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
Uri n e or s er u m pr e g n a ncy t est (f e m al e p ati e nts of c hil d b e ari n g p ot e nti al o nl y; m ust b e 
p erf or m e d pri or t o tr e at m e nt) A d mi nist er d ox or u bici n wit h pr o p hyl axis 
 
A d mi nist er T TI- 6 2 1 wit h pr o p hyl axis 
 
6 0- mi n ut e o bs erv ati o n p eri o d aft er T TI- 6 2 1 i nf usi o n; vit al si g ns ass ess e d i n 3 0- mi n ut e i nt erv als 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2                                                     C o nfi d e nti al                       
p a g e 9 2 of 1 4 0  
 
 
C ycl e 1 D a y 8 
 
Bri ef p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e) 
 
S er u m c h e mistr y ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr e vi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
A d mi nist er T TI- 6 2 1 wit h pr o p hyl axis 
 
6 0- mi n ut e o bs erv ati o n p eri o d aft er T TI- 6 2 1 i nf usi o n; vit al si g ns ass ess e d i n 3 0- mi n ut e i nt erv als 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
C ycl e 2 D a y 1 
 
P ati e nt-r e p ort e d Q oL ass ess m e nt 
 
C o m pl et e p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e, w ei g ht, p uls e oxi m etry) 
 
E C O G P S 
 
S er u m c h e mistr y ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr e vi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
Uri n e or s er u m pr e g n a ncy t est (f e m al e p ati e nts of c hil d b e ari n g p ot e nti al o nly;  m ust b e 
p erf or m e d pri or t o tr e at m e nt)  
 
A d mi nist er d ox or u bici n wit h pr o p hyl axis 
 
A d mi nist er T TI- 6 2 1 wit h pr o p hyl axis 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
C ycl e 2 D a y 8 
 
Bri ef p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, a n d r es pir at ory r at e) 
 
S er u m c h e mistr y ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr e vi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
A d mi nist er T TI- 6 2 1 wit h pr o p hyl axis 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
Bl o o d c oll ecti o n f or
C ycl e 3 D a y 1  
 
P ati e nt-r e p ort e d Q oL ass ess m e nt 
 
C o m pl et e p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e, w ei g ht, p uls e oxi m etry) 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2                                                     C o nfi d e nti al                       
p a g e 9 3 of 1 4 0  
 
 
 
E C O G P S 
 
S er u m c h e mistr y ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr e vi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
Uri n e or s er u m pr e g n a ncy t est (f e m al e p ati e nts of c hil d b e ari n g p ot e nti al o nly;  m ust b e 
p erf or m e d pri or t o tr e at m e nt)  1 2-l e a d E C G ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d 
wit hi n pr e vi o us 7 d ays) 
 
R a di ol o gic ass ess m e nt of dis e as e st at us ( u nl ess p erf or m e d wit hi n pr evi o us 7 d ays) 
 
A d mi nist er d ox or u bici n wit h pr o p hyl axis  
 
A d mi nist er T TI- 6 2 1 wit h pr o p hyl axis 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
Tiss u e c oll ecti o n f or 
 
 
 
C ycl e 3 D a y 8  
 
Bri ef p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, a n d r es pir at ory r at e) 
 
S er u m c h e mistr y ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr e vi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
A d mi nist er T TI- 6 2 1 wit h pr o p hyl axis 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2                                                     C o nfi d e nti al                       
p a g e 9 4 of 1 4 0  
 
 
C ycl e 4 D a y 1 
 
P ati e nt-r e p ort e d Q oL ass ess m e nt 
 
C o m pl et e p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e, w ei g ht, p uls e oxi m etry) 
 
E C O G P S 
 
S er u m c h e mistr y ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr e vi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
1 2-l e a d E C G ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 d ays) 
 
Uri n e or s er u m pr e g n a ncy t est (f e m al e p ati e nts of c hil d b e ari n g p ot e nti al o nl y;  m ust b e 
p erf or m e d pri or t o tr e at m e nt)  
 
A d mi nist er d ox or u bici n wit h pr o p hyl axis 
 
A d mi nist er T TI- 6 2 1 wit h pr o p hyl axis 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
C ycl e 4 D a y 8 
 
Bri ef p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e) 
 
S er u m c h e mistr y ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr e vi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
A d mi nist er T TI- 6 2 1 wit h pr o p hyl axis  
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
 
 
 
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2                                                     C o nfi d e nti al                       
p a g e 9 5 of 1 4 0  
 
 
C ycl e 5 D a y 1
 
P ati e nt-r e p ort e d Q oL ass ess m e nt 
 
C o m pl et e p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e, w ei g ht, p uls e oxi m etry) 
 
L V E F by tr a nst h or acic ec h oc ar di o gr a m or M U G A ( u nl ess p erf or m e d wit hi n pr e vi o us 4 w e eks) 
 
E C O G P S 
 
S er u m c h e mistr y ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr e vi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
Uri n e or s er u m pr e g n a ncy t est (f e m al e p ati e nts of c hil d b e ari n g p ot e nti al o nl y;  m ust b e 
p erf or m e d pri or t o tr e at m e nt) R a di ol o gic ass ess m e nt of dis e as e st at us ( u nl ess p erf or m e d 
wit hi n pr e vi o us 7 d ays) 
 
A d mi nist er d ox or u bici n 
wit h pr o p hyl axis, i ncl u di n g c ar di o pr ot ect a nt ( a d mi nistr ati o n of 
c ar di o pr ot ect a nt m ust b e i niti ati o n n o l at er t h a n wit h C ycl e 5, b ut m a y b e i niti at e d e arli er p er 
i nstit uti o n al st a n d ar d of c ar e) 
 
A d mi nist er T TI- 6 2 1 wit h pr o p hyl axis 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
C ycl e 5 D a y 8 
 
Bri ef p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e) 
 
S er u m c h e mistr y ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr e vi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
A d mi nist er T TI- 6 2 1 wit h pr o p hyl axis 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
C ycl e 6 D a y 1 
 
P ati e nt-r e p ort e d Q oL ass ess m e nt 
 
C o m pl et e p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e, w ei g ht, p uls e oxi m etry) 
 
E C O G P S 
 
S er u m c h e mistr y ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr e vi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
1 2-l e a d E C G ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 d ays) 
 
Uri n e or s er u m pr e g n a ncy t est (f e m al e p ati e nts of c hil d b e ari n g p ot e nti al o nl y;  m ust b e 
p erf or m e d pri or t o tr e at m e nt)  
 
A d mi nist er d ox or u bici n wit h pr o p hyl axis, i ncl u di n g c ar di o pr ot ect a nt 
 
A d mi nist er T TI- 6 2 1 wit h pr o p hyl axis 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2                                                     C o nfi d e nti al                       
p a g e 9 6 of 1 4 0  
 
 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
C ycl e 6 D a y 8 
 
Bri ef p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, a n d r es pir at ory r at e) 
 
S er u m c h e mistr y ( u nl ess pr e vi o us ass ess m e nt w as p erf or m e d wit hi n pr e vi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess pr evi o us ass ess m e nt w as p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
A d mi nist er T TI- 6 2 1 wit h pr o p hyl axis  
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
C ycl e 7 a n d S u bs e q u e nt C ycl es, D a y 1 
 
P ati e nt-r e p ort e d Q oL ass ess m e nt 
 
C o m pl et e p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e, w ei g ht, p uls e oxi m etry) 
 
E C O G P S 
 
S er u m c h e mistr y ( u nl ess p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
Uri n e or s er u m pr e g n a ncy t est (f e m al e p ati e nts of c hil d b e ari n g p ot e nti al o nl y;  m ust b e 
p erf or m e d pri or t o tr e at m e nt)   
 
A d mi nist er T T- 6 2 1 wit h pr o p hyl axis 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
C ycl e 7, C ycl e 9, C ycl e 1 1, etc. D a y 1 
 
R a di ol o gic ass ess m e nt of dis e as e st at us ( u nl ess p erf or m e d wit hi n pr evi o us 7 d ays) 
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
Bl o o d c oll ecti o n f or
 
C ycl e 7, C ycl e 1 0, C ycl e 1 3, etc. D a y 1 
 
1 2-l e a d E C G ( u nl ess p erf or m e d wit hi n pr evi o us 7 d ays) 
 
C ycl e 7, C ycl e 1 1, C ycl e 1 5, etc. D a y 1 
 
Bl o o d c oll ecti o n f or
 
C ycl e 7 a n d s u bs e q u e nt c ycl es, D a y 1 5 
 
Bri ef p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e) 
 
S er u m c h e mistr y ( u nl ess p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
A d mi nist er T T- 6 2 1 wit h pr o p hyl axis 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2                                                     C o nfi d e nti al                       
p a g e 9 7 of 1 4 0  
 
 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
C ycl e 8 D a y 1 
 
L V E F by tr a nst h or acic ec h oc ar di o gr a m or M U G A ( u nl ess p erf or m e d wit hi n pr e vi o us 4 w e eks) 
 
S af et y F oll o w- U p Visit ( 3 0 + 5 d a ys aft er l ast a d mi nistr ati o n of st u d y tr e at m e nt or b ef or e i niti ati o n 
of s u bs e q u e nt a nti-c a nc er t h er a p y, w hic h e v er occ urs s o o n est) 
 
P ati e nt-r e p ort e d Q oL ass ess m e nt 
 
C o m pl et e p h ysic al ex a mi n ati o n   
 
Vit al si g ns (t e m p er at ur e, bl o o d pr ess ur e, p uls e r at e, r es pir at ory r at e, w ei g ht, p uls e oxi m etry) 
 
L V E F by tr a nst h or acic ec h oc ar di o gr a m or M U G A ( u nl ess p erf or m e d wit hi n pr evi o us 4 w e eks 
wit h n o a b n or m aliti es) 
 
E C O G P S 
 
S er u m c h e mistr y ( u nl ess p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
H e m at ol o g y ( u nl ess p erf or m e d wit hi n pr evi o us 7 2 h o urs) 
 
1 2-l e a d E C G 
 
Uri n e or s er u m pr e g n a ncy t est (f e m al e p ati e nts of c hil d b e ari n g p ot e nti al o nly  
 
R a di ol o gic ass ess m e nt of dis e as e st at us ( u nl ess p erf or m e d wit hi n pr evi o us 7 d ays) 
 
A dv ers e ev e nts 
 
C o nc o mit a nt m e dic ati o ns a n d pr oc e d ur es 
 
Bl o o d c oll ecti o n f or
 
L o n g- T er m F oll o w- U p 
 
R a di ol o gic ass ess m e nt of dis e as e st at us ( p ati e nts 
w h o h av e n ot ex p eri e nc e d dis e as e 
pr o gr essi o n) 
 
Bl o o d c oll ecti o n f or
 i n p artici p a nts wit h a n u nr es olv e d A E c o nsi d er e d by 
t h e I nv esti g at or as p ossi bl y r el at e d t o or ass oci at e d wit h
at t h e 
S af et y F oll o w- U p Visit will b e ask e d t o r et ur n f or
bl o o d s a m pli n g at a p pr oxi m at ely 3- m o nt h 
i nt erv als (if f e asi bl e gi v e n t h e u n d erl yi n g dis e as e) u ntil t h e l ast f oll o w- u p of t h e A E u p t o a 
m axi m u m of 1 2 m o nt hs. 
 
S ur vi v al ( ass ess e d ev ery 1 2 ± 2 w e e ks; t el e p h o n e c o nt act is acc e pt a bl e) 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2                                                     C o nfi d e nti al                       
p a g e 9 8 of 1 4 0  
 
 
1 2.
S T A TI S TI C AL C O N SI D E R A TI O N S
1 2. 1.  
S a m pl e Siz e 
1 2. 1. 1.  
D os e Esc al ati o n 
T h e n u m b er of p ati e nts will d e p e n d o n t h e n u m b er of d os e c o h orts t h at will b e e nr oll e d b ef or e r e ac hi n g 
t h e M T D.  It is a ntici p at e d t h at t hr e e d os e l ev els of T TI- 6 2 1 giv e n i n c o m bi n ati o n wit h a fix e d d os e of 
d ox or u bici n will b e e v al u at e d a n d t h at at l e ast ni n e a n d u p t o a p pr oxi m at ely 1 8 p ati e nts will b e e nr oll e d 
t o ev al u at e t h es e t hr e e d os e l e v els.  O n t his b asis of e m er gi n g s af et y d at a, a d diti o n al d os e l e v els m ay 
b e a d d e d.  T h e siz e a n d d esi g n of t h e d os e esc al ati o n p h as e of t h e st u dy is c o nsist e nt wit h st a n d ar d 3 + 3 
d esi g n wit h t h e o bj ectiv e of d et er mi ni n g t h e s af et y of esc al ati n g d os es of T TI- 6 2 1 i n c o m bi n ati o n wit h 
fix e d d os e d ox or u bici n a n d est a blis hi n g T TI- 6 2 1 d os es f or f urt h er e v al u ati o n i n t h e i nt e n d e d p ati e nt 
p o p ul ati o n. 
 
1 2. 1. 2.  
E x p a nsi o n C o h orts 
Ex p a nsi o n c o h orts ar e pl a n n e d t o ev al u at e t w o T TI- 6 2 1 d os e l ev els i n c o m bi n ati o n wit h d ox or u bici n:  a 
l o w d os e of T TI- 6 2 1 ( C o h ort A) a n d a hi g h er d os e ( C o h ort B).  A Si m o n t w o-st a g e d esi g n will b e us e d f or 
e ac h d os e c o h ort, ass u mi n g a b as eli n e ov er all r es p o ns e r at e of 1 0 % wit h d ox or u bici n m o n ot h er a py.  I n 
t h e Si m o n t w o-st a g e d esi g n a n d a n alt er n ativ e of 2 5 %, a p o w er of 9 0 % a n d o n e-si d e d Ty p e 1 err or s et 
at 0. 2 0, e ac h d os e l ev el c o h ort will r e q uir e 1 8 p ati e nts e nr oll e d a n d e v al u a bl e f or r es p o ns e i n St a g e 1; 
wit h at l e ast t w o cli nic al r es p o ns es, a n a d diti o n al 1 3 p ati e nts will b e e nr oll e d i n St a g e 2.  T h e 
c o m bi n ati o n will b e c o nsi d er e d w ort hy of f urt h er st u dy if at l e ast fiv e cli nic al r es p o ns es ar e o bs erv e d i n 
eit h er 3 1- p ati e nt c o h ort.   
 
1 2. 2.  
A n al ysis P o p ul ati o ns 
T h e f oll o wi n g a n al ysis p o p ul ati o ns ar e d efi n e d f or t h e st u d y: 
S af et y p o p ul ati o n : all p ati e nts w h o r ec eiv e d at l e ast 1 d os e of T TI- 6 2 1  
 
Effic ac y p o p ul ati o n:  all p ati e nts w h o r ec eiv e d at l e ast 1 d os e of T TI- 6 2 1  
 
DL T- e v al u a bl e p o p ul ati o n : all p ati e nts w h o r ec eiv e d t h e f ull d os e of d ox or u bici n a n d t h e pl a n n e d d os es 
of T TI- 6 2 1 o n D a y 1 a n d D ay 8 a n d h a v e b e e n f oll o w e d f or t h e e ntir e 2 1- d a y DL T p eri o d (i. e., Cycl e 1) or 
w h o h av e a DL T d uri n g Cycl e 1 will b e c o nsi d er e d DL T- e v al u a bl e 
 
R es p o ns e- e v al u ati o n p o p ul ati o n f or Si m o n t w o-st a g e d esi g n:   all p ati e nts i n eit h er Ex p a nsi o n C o h ort 
A (l o w d os e T TI- 6 2 1) or Ex p a nsi o n C o h ort B ( hi g h d os e T TI- 6 2 1) w h o c o m pl et e at l e ast t w o c ycl es of 
tr e at m e nt as d escri b e d i n t h e pr ot oc ol a n d h av e a p ost-tr e at m e nt o bj ecti v e dis e as e ass ess m e nt u nl ess 
t h e y w er e wit h dr a w n pri or t o m e eti n g t his crit eri o n f or s af ety or e arli er d e m o nstr ati o n of o bj ectiv e 
dis e as e pr o gr essi o n 
 
: all p ati e nts w h o r ec ei v e d at l e ast o n e d os e of T TI- 6 2 1 a n d 
h a v e at l e ast o n e ev al u a bl e bl o o d s a m pl e f or a n alysis c oll ect e d 
   
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2                                                     C o nfi d e nti al                       
p a g e 9 9 of 1 4 0  
 
 
1 2. 3.
Crit eri a f or E v al u ati o n
1 2. 3. 1.  
S af et y  
All p ati e nts w h o r ec ei v e at l e ast d os e of T TI- 6 2 1 will b e i ncl u d e d i n t h e s af et y a n al ys es.  
 
A dv ers e e v e nts, E C Gs, L V EF ass ess m e nts a n d l a b or at ory d at a will b e s u m m ariz e d a n d r e vi e w e d o n a n 
o n g oi n g b asis d uri n g t h e st u dy.  All a dv ers e ev e nts, E C Gs, L V E F ass ess m e nts a n d s af ety l a b or at ory 
a b n or m aliti es of p ot e nti al cli nic al c o nc er n will b e d escri b e d.  S af et y d at a will b e pr es e nt e d i n t a b ul ar 
a n d/ or gr a p hic al f or m at a n d s u m m ariz e d d escri ptiv el y by d os e c o h ort a n d ti m e w h er e a p pr o pri at e.  
A bs ol ut e v al u e d at a a n d c h a n g es fr o m b as eli n e d at a will b e s u m m ariz e d as a p pr o pri at e.  
 
A Es will b e c o d e d usi n g t h e M e dic al Dicti o n ary f or R e g ul at or y Acti viti es ( M e d D R A) a n d s e v erit y of A Es 
a n d l a b or at ory a b n or m aliti es will b e gr a d e d usi n g N CI C T C A E v 5 as a p pr o pri at e.  I nci d e nc e t a bl es of 
p ati e nts wit h A Es will b e pr es e nt e d f or all A Es by m axi m u m s ev erity, S A Es, A Es ass ess e d as r el at e d t o 
st u dy dr u g a n d a dv ers e e v e nts r es ulti n g i n disc o nti n u ati o n of st u dy dr u g.  
 
F or E C G a n al ys es, t h e m e a n of t h e tri plic at e E C G p ar a m et ers will b e us e d as t h e o bs er v ati o n f or a p ati e nt 
at a n o mi n al ti m e p oi nt.  C h a n g es i n E C G a n d l a b or at or y m e as ur e m e nts will b e s u m m ariz e d. 
 
Listi n gs of all s af ety d at a s ort e d by d os e c o h ort, p ati e nt a n d ass ess m e nt d at e will b e pr ovi d e d. 
 
1 2. 3. 2.  
 
 will b e ev al u at e d aft er si n gl e a n d m ulti pl e d os es of T TI- 6 2 1 d uri n g t h e 
c o urs e of t h e st u dy.  T h e
 of T TI- 6 2 1, m e as ur e d as 
 
, als o will b e i nv esti g at e d d uri n g t h e c o urs e of t h e st u dy. 
 
will b e list e d a n d s u m m ariz e d at e ac h ti m e p oi nt usi n g d escri ptiv e 
st atistics; gr a p hic al r e pr es e nt ati o ns will als o b e pr o vi d e d.  A n al ys es will b e p erf or m e d o n t h e 
 
 a n d will b e o utli n e d i n t h e St atistic al A n alysis Pl a n. 
 
Ex pl or at ory a n alys es m ay b e c o n d uct e d t o ev al u at e t h e r el ati o ns hi p b et w e e n T TI- 6 2 1 e n d- of-i nf usi o n 
a n d/ or tr o u g h c o nc e ntr ati o ns a n d v ari o us effic acy a n d s af ety e n d p oi nts. 
 
fr o m t his st u dy m a y b e p o ol e d wit h d at a fr o m ot h er st u di es a n d a n al yz e d 
usi n g p o p ul ati o n P K a p pr o ac h es.  I n a d diti o n, a m o d el- b as e d a p pr o ac h m ay b e us e d t o ex pl or e t h e 
p ot e nti al r el ati o ns hi p T TI- 6 2 1 ex p os ur e m etrics a n d effic acy, s af ety, a n d/ or bi o m ar k er e n d p oi nts a n d 
r e p ort e d s e p ar at el y. 
 
T h e 
will b e s u m m ariz e d 
d escri pti v ely.  Ex pl or at ory a n al ysis m ay b e c o n d uct e d t o e v al u at e t h e p ossi bl e eff ects of 
 
 effic ac y a n d s af et y e n d p oi nts. 
 
1 2. 3. 3.  
Cli nic al B e n efit 
Cli nic al effic acy will b e e v al u at e d by t u m or r es p o ns e f or p ati e nts wit h m e as ur a bl e dis e as e as ass ess e d 
by t h e I nv esti g at ors usi n g R E CI S T v 1. 1 ( A p p e n dix B ).  D ur ati o n of r es p o ns e will b e c alc ul at e d f or p ati e nts 
w h o ac hi ev e a C R or P R a n d is d efi n e d as t h e ti m e fr o m t h e d at e of first d oc u m e nt e d r es p o ns e ( C R or 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2                                                     C o nfi d e nti al                       
p a g e 1 0 0 of 1 4 0  
 
 
P R) t o t h e d at e of d oc u m e nt e d pr o gr essi o n or d e at h aft er ac hi evi n g r es p o ns e.  Dis e as e c o ntr ol r at e is 
d efi n e d as t h e p erc e nt a g e of p ati e nts w h o h av e ac hi ev e d C R, P R, or S D l asti n g at l e ast 1 2 w e e ks. 
Cli nic al acti vit y b as e d o n
will b e ass ess e d as a n 
of t h e 
st u dy. 
P ati e nts e nr oll e d i n a n ex p a nsi o n c o h ort w h o wit h dr a w fr o m t h e st u dy pri or t o t h e first o bj ecti v e 
dis e as e ass ess m e nt f or a r e as o n ot h er t h a n dis e as e pr o gr essi o n or s af et y will b e r e pl ac e d i n or d er t o 
m e et t h e st atistic al crit eri a f or t h e Si m o n t w o-st a g e d esi g n; t h es e p ati e nts  will n ot b e i ncl u d e d i n t h e 
r es p o ns e- e v al u a bl e p o p ul ati o n.  F or a p ati e nt e nr oll e d i nt o t h e d os e ex p a nsi o n p orti o n of t h e st u dy 
b as e d o n l oc al p at h ol o gy t h at is n ot c o nfir m e d d uri n g c e ntr al r evi e w, t h e p ati e nt m ust b e r e pl ac e d f or 
p ur p os es of m e eti n g t h e st atistic al r e q uir e m e nts of t h e st u dy b ut m a y b e all o w e d t o c o nti n u e o n 
tr e at m e nt aft er disc ussi o n wit h t h e S p o ns or M e dic al M o nit or.   
 
F or p ati e nts wit h asy m pt o m atic pr o gr essi o n o nl y or s us p ect e d ps e u d o pr o gr essi o n, t h e p ati e nt m a y 
c o nti n u e tr e at m e nt b e y o n d pr o gr essi o n u ntil a c o nfir m ati o n sc a n at l e ast f o ur w e eks l at er h as 
c o nfir m e d pr o gr essi o n. 
 
Effic acy a n alys es will b e b as e d o n t h e effic acy a n alysis p o p ul ati o n, i. e. all p ati e nts w h o r ec eiv e d at l e ast 
o n e d os e of st u dy tr e at m e nt, u nl ess ot h er wis e s p ecifi e d. 
1 2. 3. 4.  
P ati e nt- R e p ort e d O utc o m es 
P ati e nt-r e p ort e d h e alt h-r el at e d q u ality of lif e will b e ass ess e d wit h t h e E ur o p e a n Or g a nis ati o n f or 
R es e arc h a n d Tr e at m e nt of C a nc er ( E O R T C) Q u ality- of-Lif e Q u esti o n n air e C or e 3 0 ( QL Q- C 3 0) t o ol. 5 3  T h e 
P R O m e as ur es will b e c oll ect e d o n D a y 1 of e v er y cycl e a n d at t h e E n d- of- Tr e at m e nt visit.  P a p er v ersi o ns 
of t h e q u esti o n n air e will b e us e d.  T h e q u esti o n n air e s h o ul d b e c o m pl et e d pri or t o i niti ati o n of st u dy 
tr e at m e nt.  W h e n ev er p ossi bl e, if a d mi nistr ati o n is n ot p ossi bl e pri or t o all ot h er pr oc e d ur es, ev er y 
eff ort s h o ul d b e m a d e t o a d mi nist er at t h e s a m e ti m e p oi nt i n e ac h visit.  P ati e nt-r e p ort e d q u esti o n n air e 
s h o ul d b e c o m pl et e d by p ati e nts w h e n a l a n g u a g e tr a nsl ati o n is a v ail a bl e i n w hic h t h e p ati e nt is fl u e nt 
or lit er at e. 
 
Br o a dl y us e d i n c a nc er tri als, v ali d at e d, a n d av ail a bl e i n o v er 8 0 diff er e nt l a n g u a g es, t h e E O R T C QL Q-
C 3 0 is a r eli a bl e a n d v ali d at e d t o ol.  T h e E O R T C QL Q- C 3 0 is a s elf- a d mi nist er e d, s elf-r e p ort e d g e n er al 
c a nc er-s p ecific q u esti o n n air e c o nsisti n g of 3 0 it e ms c ov er e d by o n e of t hr e e di m e nsi o ns: 
 
Gl o b al h e alt h st at us/ (t w o it e ms) 
 
F u ncti o n al sc al es ( 1 5 t ot al it e ms a d dr essi n g eit h er p hysic al, r ol e, e m oti o n al, c o g niti v e or s oci al 
f u ncti o ni n g) 
 
S y m pt o m sc al es ( 1 3 t ot al it e ms a d dr essi n g eit h er f ati g u e, n a us e a/ v o miti n g, p ai n, dys p n e a, 
i ns o m ni a, a p p etit e l oss, c o nsti p ati o n, di arr h e a, or fi n a nci al i m p act) 
 
T h e r ec all p eri o d is t h e p ast w e e k a n d c o m pl eti o n ti m e is t y pic ally fiv e t o s e v e n mi n ut es.  T h e 
q u esti o n n air e will b e sc or e d as d escri b e d b y t h e E O R T C sc ori n g m a n u al. 5 4  
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI
C CI


T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2                                                     C o nfi d e nti al                       
p a g e 1 0 1 of 1 4 0  
 
 
1 2. 3. 5.
 
   
 
1 2. 4.  
St atistic al M et h o ds 
T a b ul ar s u m m ari es of d at a will b e d escri pti v e i n n at ur e (i. e., n u m b er of p ati e nts [ n], m e a n, st a n d ar d 
d e vi ati o n, m e di a n, mi ni m u m a n d m axi m u m f or c o nti n u o us v ari a bl es a n d n a n d p erc e nt f or c at e g oric al 
v ari a bl es).  F or effic acy p ar a m et ers, i ncl u di n g o bj ectiv e r es p o ns e r at e a n d dis e as e c o ntr ol r at e, 9 5 % 
 
 
Pr ot oc ol d e vi ati o ns will b e list e d.  Pr ot oc ol d evi ati o ns t h at mi g ht s u bst a nti ally aff ect effic acy a n al ys es 
will b e d et er mi n e d pri or t o d at a b as e l oc k.  
 
A m or e d et ail e d d escri pti o n of a n alysis m et h o ds will b e pr o vi d e d i n t h e S A P t o b e c o m pl et e d pri or t o 
t h e cli nic al d at a b as e l ock. 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
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13.
SAFETY
Adverse events observed, mentioned on open questioning by a member of the Investigator team or 
spontaneously reported by the subject will be documented.  Adverse events will be documented event 
based.  The observation phase for adverse events will start with signing the informed consent and will 
end at the completion of the active reporting period.  Planned timepoints for all safety assessments are 
provided in the Study Assessments (Section 10).  Unscheduled safety measurements may be obtained 
at any time during the study to assess any perceived safety issues. 
 
 
13.1. 
Definition of Adverse Events 
13.1.1. 
Adverse Event 
An adverse event is any untoward medical occurrence or the worsening of a pre-existing medical 
condition following or during exposure to a pharmaceutical product, whether or not considered causally 
related to the product.  Development of new disease lesions or disease progression is not considered 
an adverse event. 
 
All AEs and SAEs occurring in a patient during the active collection period as described in Section 13.5.3. 
will be recorded on the appropriate CRF from the signature of the informed consent.  All SAEs must be 
reported on the CT SAE Report Form to Pfizer Safety immediately upon awareness and under no 
circumstance should this exceed 24 hours.  A worsening of a condition/disease recorded in the medical 
medical records.  Laboratory abnormalities requiring treatment or considered by the investigator to be 
clinically relevant should be reported in the CRF as an AE.  Each AE is to be evaluated for duration, 
severity and causal relationship with the IP. 
 
For the purposes of this study, events that are unequivocally due to disease progression should not be 
reported as AEs unless the outcome is fatal within the active collection period.  Hospitalization due to 
signs and symptoms of disease progression should not be reported as an SAE.  If the malignancy has a 
fatal outcome during the study, the event leading to death must be recorded as an AE on the CRF, and 
as an SAE with CTCAE Grade 5 if it occurs during the active collection period.  Symptoms of the disease 
under study/lack of efficacy should not be classified as AEs as long as they are within normal day-to-day 
fluctuations or expected progression of the disease.  
 
The development of a new cancer should be regarded as an AE and will generally meet at least one of 
the SAE criteria.  New cancers are those that are not the primary reason for study treatment and have 
cancer. 
 
13.1.2. 
Serious Adverse Event  
A serious adverse event is an adverse event occurring during any study at any dose of the investigational 
product(s) that fulfills one or more of the following: 
 
Results in death 
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Is immediately life-threatening (the subject was at risk of death at the time of the event; this does 
not refer to an event which hypothetically might have caused death if it were more severe) 
 
Requires in-patient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability or incapacity 
 
Results in a congenital abnormality or birth defect 
 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above 
 
Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other 
situations, such as important medical events that may not be immediately life threatening or result in 
death or hospitalization but may jeopardize the patient or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition.  These should also be considered 
serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse.  
 
 
All serious adverse events that occur after any patient has signed informed consent, been enrolled, 
before treatment, during treatment, or within 30 days following the cessation of treatment, whether or 
not they are related to the study intervention, must be recorded on a Serious Adverse Event form. 
13.2. 
Clarifications to Serious Adverse Event Reporting 
 
Death is an outcome of a serious adverse event and not a serious adverse event in itself.  When 
death is an outcome, report the event(s) resulting in death as the serious adverse event term (e.g., 
serious adverse event term. 
 
Pre-planned or elective hospitalizations including social and/or convenience situations (e.g., respite 
care) are excluded from serious adverse event reporting.  In addition, emergency room visits and 
admission under 23-hour observation are excluded from serious adverse event reporting; however, 
such events should still be reported on the appropriate adverse event eCRF page. 
 
An isolated  laboratory abnormality is not reportable as a serious adverse event unless the 
Investigator assesses that the event meets the standard ICH criteria for a serious adverse event. 
 
 
13.3. 
Assessment of Causality 
The relationship of each adverse event to administration of the study drug(s) will be assessed by the 
Investigator after careful consideration of all relevant factors such as (but not limited to) the underlying 
study indication, co-existing disease, concomitant medication, relevant history, pattern of the adverse 
event, temporal relationship to receipt of the study medication(s) and de-challenge or re-challenge. 
 
Study drug or study treatment refers to intravenously-administered doxorubicin and intravenously-
administered TTI-621.  The assessment of relationship to study drug or study treatment will be done for 
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each drug separately.  If the Investigator feels such a distinction cannot be made, the assessment will 
be based on the combination of the two drugs. 
 
The assessment of causality is based on the question of whether there was a reasonable causal 
relationship to the study drug in question according to the following guidelines: 
  
RELATED (possible, probably or definitely related): there is a reasonable possibility that the study 
treatment caused the event; one or more of the following criteria apply:  
 
The event follows a reasonable temporal sequence from administration of study treatment 
 
The event could not be reasonably attributed to the known characteristi
state, environment or toxic factors or other modes of therapy administered to the patient 
 
The event follows a known pattern of response to study treatment 
 
The event disappears or decreases on cessation or reduction in dose of the study treatment.  In 
some situations, an AE will not disappear or decrease in intensity upon discontinuation of the study 
treatment despite other clear indications of relatedness 
 
UNRELATED (unlikely related or definitely not related): There is no reasonable possibility that the study 
treatment caused the event; one or more of the following criteria apply:  
 
The event does not follow a reasonable temporal sequence from administration of study treatment  
 
concurrent illness, environment or toxic factor or other therapies administered to the patient 
 
The event does not follow a known pattern of response to study treatment 
 
The event does not disappear or decrease on cessation or reduction in dose of the study treatment, 
and it does not reappear or worsen when the study treatment is re-administered 
 
There is a clear alternative explanation 
13.4. 
Assessment of Severity 
The severity rating of an adverse event refers to its intensity.  The severity of each adverse event will be 
categorized using the NCI CTCAE v5.  For any term that is not specifically listed in the CTCAE scale, 
intensity should be assigned a grade of 1 through 5 using the following CTCAE guidelines: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living 
Grade 3: 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to adverse event 
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It is important to distinguish between serious adverse events and severe adverse events. Severity is a 
measure of intensity whereas seriousness is defined by the criteria under Section 13.1.2.  An adverse 
event of severe intensity may not be considered a serious adverse event. 
13.5. 
Action Taken 
Any action with study treatment to resolve the adverse event is to be documented using the categories 
listed below.  The study drug action should be recorded separately for each component as detailed in 
the eCRF. 
 
Drug withdrawn 
 
Drug interrupted 
 
Dose reduced 
 
Dose not changed 
 
Not applicable 
 
Unknown 
13.5.1. 
Other Specific Treatments of Adverse Event 
 
None 
 
Remedial drug therapy 
 
Other 
13.5.2. 
Outcome of Adverse Event 
The outcome of the AE is to be documented as follows: 
 
Recovered / resolved 
 
Recovering / resolving 
 
Recovered / resolved with sequelae 
 
Not recovered / not resolved 
 
Fatal 
 
Unknown 
 
13.5.3. 
Time Period and Frequency for Collecting AE and SAE Information 
patient begins  from the time the patient provides informed-consent, which is obtained before 
undergoing any study-related procedure and/or receiving study intervention, through and including a 
minimum of 30 calendar days after the last administration of the study intervention.   
For patients who are screen failures, the active collection period ends when screen failure status is 
determined. 
If the patient withdraws from the study and also withdraws consent for the collection of future 
information, the active collection period ends when consent is withdrawn. 
If a patient permanently discontinues or temporarily discontinues study intervention because of an AE 
or SAE, the AE or SAE must be recorded on the CRF and the SAE reported using the CT SAE Report Form. 
Investigators are not obligated to actively seek information on AEs or SAEs after the patient has 
concluded study participation.  However, if the investigator learns of any SAE, including a death, at any 
time after a patient has completed the study, and they consider the event to be reasonably related to 
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the study intervention, the investigator must promptly report the SAE to Pfizer using the CT SAE Report 
Form. 
13.5.4. 
Documentation 
All AEs (serious and non-serious) occurring within the period of observation for the study must be 
documented in the CRF with the following information, where appropriate. (The period of observation 
for the study is described in Section 13.5.3). 
 
AE name or term 
 
When the AE first occurred (start date) 
 
 
 
Severity of the AE 
 
Seriousness (hospitalization, death, etc.) 
 
Actions taken 
 
Outcome 
 
Investigator opinion regarding the AE relationship to the IP(s) 
 
All nonserious AEs and SAEs occurring in a patient during the active collection period which begins after 
obtaining informed consent as described in Section 13.5.3, will be recorded on the AE section of the 
CRF.  
The investigator or designee is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the patient. 
 
The investigator must record his or her reasoning for 
as a comment on the CRF 
 
Reporting of AEs and SAEs for patients who fail screening are subject to the CRF requirements as 
described in Section 13.5.3. 
 
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is determined by 
the sponsor to be serious will be reported by the sponsor as an SAE. To assist in the determination of 
case seriousness, further information may be requested from the investigator to provide clarity and 
understanding of the event in the context of the clinical study. 
 
If a patient begins a new anti-cancer therapy, the recording period for nonserious AEs ends at the time 
the new treatment is started;  however, SAEs must continue to be recorded on the CRF during the above 
indicated active collection period.  Note that a switch to a commercially available version of the study 
intervention is considered as a new anti-cancer therapy for the purposes of SAE reporting. 
 
13.5.5. 
Follow-Up 
Follow-up by the investigator continues throughout and after the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator. 
 
If a patient is lost to follow-up, this should be captured accordingly within the adverse event eCRF and 
on the follow-up serious adverse event report 
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When a clinically important AE remains ongoing at the end of the active collection period, follow-up by 
the investigator continues until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to 
the investigator and Pfizer concurs with that assessment. 
After the initial AE or SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts.  For each event, the investigator must pursue and obtain adequate 
information until resolution, stabilization, the event is otherwise explained, or the participant is lost to 
follow-up. 
In general, follow-up information will include a description of the event in sufficient detail to allow for 
a complete medical assessment of the case and independent determination of possible causality.  Any 
information relevant to the event, such as concomitant medications and illnesses, must be provided. 
This may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other healthcare providers.  
dical record and 
recorded on the eCRF page 
New and ongoing treatment-related serious adverse events should be followed beyond the 30-day 
Safety Follow-Up Visit.  If the patient dies, this should be captured as the outcome of the adverse 
event unless no link between the adverse event and the patient death can be established, in which 
case the adverse event will be marked as ongoing and the death will be reported as a separate event.  
In the case of a participant death, a summary of available autopsy findings must be submitted as soon 
as possible to Pfizer Safety. 
  
13.5.6. 
Notification 
Serious Adverse Events 
The investigator or designee must report all SAEs  (related and unrelated) promptly to Pfizer Safety 
within 24 hours of the knowledge of the occurrence.  
To report the SAE, complete the CT SAE form electronically in the Pfizer SAE Submission Assistant (PSSA) 
tool.  When the form is completed, Pfizer Safety personnel will be notified electronically.  If the event 
meets serious criteria and it is not possible to access the PSSA tool, then fax the completed paper CT 
SAE form to Pfizer Safety within 24 hours of awareness.  When the PSSA tool becomes available, the 
SAE information must be entered within 24 hours of the PSSA system becoming available. 
At the time of first notification, the investigator or designee should provide the following information, 
if available: 
 
Protocol number 
 
Reporter (study site and investigator) 
 
 
 
 
 
 
 
Date of first dose of IP(s) 
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Date of last dose of IP(s), if applicable
 
AE term 
 
Date of occurrence of the event 
 
A brief description of the event, outcome to date, and any actions taken 
 
The seriousness criteria(on) that were met 
 
Concomitant medication at onset of the event 
 
Relevant medical history information 
 
Relevant laboratory test findings 
 
 
 
It should be noted that the CT SAE Report Form for reporting of SAE information is not the same as the 
AE page of the CRF.  When the same data are collected, the forms must be completed in a consistent 
manner.  AEs should be recorded using concise medical terminology and the same AE term should be 
used on both the CRF and the CT SAE Report Form for reporting of SAE information. 
13.5.7. 
Regulatory Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal obligations and 
ethical responsibilities toward the safety of patients and the safety of a study intervention under clinical 
investigation are met. 
 
The sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a study intervention under clinical investigation.  The sponsor will comply 
with country specific regulatory requirements relating to safety reporting to the regulatory authority, 
IRBs/ECs, and investigators. 
 
Investigator safety reports must be prepared for SUSARs according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
 
An investigator who receives SUSARs or other specific safety information (e.g., summary or listing of 
SAEs) from the sponsor will review and then file it along with the SRSD(s) for the study and will notify 
the IRB/EC, if appropriate according to local requirements. 
 
13.5.8. 
Adverse Events of Special Interest 
The following events are considered AEs of special interest based on preclinical toxicology studies with 
TTI-621.  Additional details are provided in the current version of the IB for TTI-621.  
 
Infusion-related reaction 
 
Thrombocytopenia 
 
Hemorrhage 
 
Anemia 
 
AESIs are examined as part of routine safety data review procedures throughout the clinical trial and as 
part of signal detection processes.  Should an aggregate analysis indicate that these pre-specified events 
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occur more frequently than expected, e.g., based on epidemiological data, literature or other data, then 
Aggregate analyses of safety data will be performed on a regular basis per internal SOPs. 
 
All AESIs must be reported as an AE or SAE following the procedures described in Sections 13.5.4 and 
13.5.6.  An AESI is to be recorded as an AE or SAE on the CRF.  In addition, an AESI that is also an SAE 
must be reported using the CT SAE Report Form. 
 
13.5.9. 
Lack of Efficay 
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of efficacy.  
Lack of efficacy or failure of expected pharmacological action is reportable to Pfizer Safety only if 
associated with an SAE.   
 
13.5.10. 
Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure 
Environmental exposure, occurs when a person not enrolled in the study as a patient receives 
unplanned direct contact with or exposure to the study intervention.  Such exposure may or may not 
lead to the occurrence of an AE or SAE.  Persons at risk for environmental exposure include healthcare 
providers, family members and others who may be exposed.  An environmental exposure may include 
Exposure During Pregnancy (EDP), Exposure During Breastfeeding (EDB) and occupational exposure. 
 
Any such exposure to the study intervention under study are reportable to Pfizer Safety within 24 hours 
of investigator awareness. 
 
Exposure During Pregnancy (EDP) 
 An EDP occurs if: 
 
A female patient is found to be pregnant while receiving or within 45 days after discontinuing study 
intervention TTI-621 (for combination therapy, consult the Doxorubicin USPI).  
 
A male patient who is receiving or has discontinued study intervention inseminates a female partner 
prior to or around the time of conception (not applicable for TTI-621 as is known not to be 
transmitted through semen;  for combination therapy, consult the applicable product label).   
 
A female nonpatient is found to be pregnant while being exposed or having been exposed to study 
intervention because of environmental exposure.  Below are examples of environmental EDP:   
o A female family member or healthcare provider reports that she is pregnant after having been 
exposed to the study intervention by ingestion, inhalation or skin contact.   
o A male family member or healthcare provider who has been exposed to the study intervention 
by ingestion, inhalation or skin contact then inseminates his female partner prior to or around 
the time of conception (not applicable for TTI-621 as is known not to be transmitted through 
semen;  for combination therapy, consult the Doxorubicin USPI).    
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irrespective of whether an SAE has occurred.  The initial information submitted should include the 
anticipated date of delivery (see below for information related to termination of pregnancy).  
 
 
Safety through PSSA, regardless of whether an SAE has occurred.  Details of the pregnancy in a 
patient will be collected after the start of study intervention (TTI-621 or combination therapy) or 
-621 (consult 
relevant product label for combination therapies).    
 
If EDP occurs in the setting of environmental exposure, the investigator must report information to 
Pfizer Safety through PSSA using the CT SAE Report Form and EDP Supplemental Form.  Since the 
exposure information does not pertain to the patient enrolled in the study, the information is not 
recorded on a CRF.  
 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for all EDP 
reports with an unknown outcome.   The investigator will follow the pregnancy until completion (or until 
pregnancy termination) and notify Pfizer Safety of the outcome as a follow-up to the initial EDP 
Supplemental Form.  In the case of a live birth, the structural integrity of the neonate can be assessed 
at the time of birth.  In the event of a termination, the reason(s) for termination should be specified 
and, if clinically possible, the structural integrity of the terminated fetus should be assessed by gross 
visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly and the 
findings are reported). 
 
Abnormal pregnancy outcomes are considered SAEs.  If the outcome of the pregnancy meets the criteria 
for an SAE (i.e., ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death or 
congenital anomaly), the investigator should follow the procedures for reporting SAEs.  Additional 
information about pregnancy outcomes that are reported to Pfizer Safety as SAEs follows:  
 
Spontaneous abortion including miscarriage and missed abortion should be reported as an SAE 
 
Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1 month should be reported as SAEs when 
the investigator assesses the infant death as related or possibly related to exposure to the study 
intervention.  
Additional information regarding the EDP may be requested by the sponsor.  Further follow-up of birth 
outcomes will be handled on a case-by-case basis (e.g., follow-up on preterm infants to identify 
developmental delays).  In the case of paternal exposure, the investigator will provide the patient with 
the Pregnant Partner Release of Information Form to deliver to his partner.  The investigator must 
document in the source documents that the patient was given the Pregnant Partner Release of 
Information Form to provide to his partner. 
 
Exposure During Breastfeeding (EDB) 
An EDB occurs if:   
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A female patient is found to be breastfeeding while receiving or after discontinuing study 
intervention 
 
A female non-patient is found to be breastfeeding while being exposed or having been exposed to 
study intervention (i.e., environmental exposure).  An example of environmental EDB is a female 
family member or healthcare provider who reports that she is breastfeeding after having been 
exposed to the study intervention by ingestion, inhalation or skin contact.  
 
irrespective of whether an SAE has occurred.  The information must be reported through PSSA.  When 
EDB occurs in the setting of environmental exposure, the exposure information does not pertain to the 
patient enrolled in the study, so the information is not recorded on a CRF.  However, a copy of the 
completed CT SAE Report Form (extracted from PSSA) is maintained in the investigator site file. 
 
An EDB report is not created when a Pfizer drug specifically approved for use in breastfeeding women 
(e.g., vitamins) is administered in accordance with authorized use.  However, if the infant experiences 
an SAE associated with such a drug, the SAE is reported together with the EDB. 
 
Occupational Exposure 
The investigator must report any instance of occupational exposure to Pfizer Safey within 24 hours of 
the information about the occupational exposure does not pertain to a patient enrolled in the study, 
the information is not recored on a CRF;  however, a copy of the completed CT SAE Report Form 
(extracted from PSSA) must be maintained in the investigator site file. 
 
13.5.11. 
Medication Error 
Medication errors may result from the administration or consumption of the study intervention by the 
wrong patient, or at the wrong time, or at the wrong dosage strength.   
 
 Medication errors include: 
 Medication errors involving participant exposure to the study intervention 
 
Potential medication errors or uses outside of what is foreseen in the protocol that do or do not 
involve the study participant 
 
The administration of expired study intervention 
 
The administration of an incorrect study intervention 
 
The administration of an incorrect dosage 
 
The administration of study intervention that has undergone temperature excursion from the 
specified storage range, unless it is determined by the sponsor that the study intervention under 
question is acceptable for use. 
 
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
 
Whether or not the medication error is accompanied by an AE, as determined by the investigator, the 
medication error and associated AE(s), serious and non-serious, are recorded on the AE page of the CRF.  
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Medication errors should be reported to Pfizer Safety within 24 hours through PSSA only when 
associated with an SAE. 
 
13.6. 
Laboratory Abnormalities 
To the extent possible, all laboratory abnormalities observed during the course of the study will be 
included under a reported adverse event term describing a clinical syndrome (e.g., elevated blood urea 
nitrogen and creatinine in the setting of an adverse event 
 In these cases (e.g., an 
adverse event of renal failure), the laboratory abnormality itself (e.g., elevated creatinine) does not 
need to be recorded as an adverse event.  
 
If a laboratory abnormality cannot be reported as a clinical syndrome, AND if the laboratory abnormality 
results in a therapeutic intervention (i.e., concomitant medication or therapy), is a dose-limiting toxicity 
or is judged by the Investigator to be of other particular clinical relevance, then the laboratory 
abnormality should be reported as an adverse event.  Laboratory Abnormalities requiring treatment or 
considered by the Investigator to be clinically-relevant should be reported inthe CRF as an AE. 
 
See Appendix E for suggested actions and follow-up assessments in the event of potential Drug Induced 
Liver Injury (DILI). 
 
See Appendix F for instructions for laboratory testing to monitor kidney function and reporting 
laboratory test abnormalities.  
  
Patients experiencing adverse events or clinically-significant laboratory abnormalities will be assessed 
and appropriate evaluations performed until all parameters have returned to baseline levels or are 
-current physical condition.   
 
13.7. 
Sponsor Safety Review 
The Medical Monitor or designee will be responsible for the ongoing review and evaluation of safety 
throughout the study (this includes all laboratory, ECG and echocardiogram/MUGA data as well as all 
adverse events). 
 
13.8. 
Overview of Safety Monitoring 
Throughout the study, investigators, site staff and the study Sponsor will meet regularly to review the 
status of all active patients on study.  During the dose escalation portion of the study, a weekly safety 
and information call will be held with participating investigators and site staff to discuss safety, review 
any questions, provide updates and to share information across sites.  At the completion of each dose 
escalation cohort, safety data will be summarized and presented for discussion with all investigators for 
the purpose of determining whether the observed safety in each cohort warrants escalation to the next 
higher dose level or whether an alternate dose level or other action should be considered. 
 
During the dose expansion portion of the study, these regularly-scheduled safety and information calls 
will continue;  the calls will initially be held at two-week intervals although ad hoc meetings may be held 
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as necessary to review specific safety or other issues that might arise during the course of the study.  As 
the study progresses, the frequency of these safety and information calls may be adjusted to reflect 
need on the basis of safety observations observed, the rate of enrollment and investigator or Sponsor 
request or need.   
 
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14.
ETHICAL AND ADMINISTRATIVE CONSIDERATIONS
This study will be conducted in accordance with applicable national and local regulations and guidelines, 
Good Clinical Practice (GCP), including ICH guidelines (Integrated Addendum To ICH E6[R1]: Guideline 
For Good Clinical Practice, E6[R2], Current Step 4 version [2016]), the National Statement on Ethical 
Conduct in Human Research 2007, and The Declaration of Helsinki (Brazil, 2013).   
signature on the Principal Investigator Acknowledgement Form (Appendix G) documents each 
 
 
14.1. 
Regulatory Authority Approvals 
The Sponsor or designee will submit the study protocol plus all relevant study documents to applicable 
regulatory agencies for approval before the study start.  No patient will be admitted to the study until 
appropriate regulatory approval of the study protocol has been received. 
 
Each Investigator must complete a Form FDA 1572 or equivalent and provide the completed form 
according to written instructions to the Sponsor (or designee).  Each Investigator must submit to the 
Sponsor (or designee) financial disclosure information according to national law and/or local 
regulations. 
 
Data generated in the US will be handled in accordance with the Health Information Portability and 
Accountability Act (HIPAA).  The study will be registered at www.clinicaltrials.gov using the Protocol 
Registration System. 
 
14.2. 
Institutional Review Board  
This protocol and any material to be provided to the patient (such as advertisements, patient 
information sheets, or descriptions of the study used to obtain informed consent) will be submitted by 
the Investigator to an IRB.  This also applies to protocol amendments. 
 
The Sponsor will supply relevant data for the Investigator to submit the study protocol and additional 
study documents to the IRB.  The Principal Investigator will submit the study protocol for review and 
approval by an IRB, according to national law and/or local regulations, and will provide the IRB with all 
appropriate materials. 
 
transmitted to the Sponsor.  This approval must refer to the study by exact study protocol title and 
number, identify the documents reviewed, and state the date of the review. 
 
No patient will be admitted to the study until appropriate IRB approval of the study protocol has been 
received, the Investigator has obtained the signed and dated ICF, and the Sponsor is notified. 
 
The Principal Investigator will submit appropriate reports on the progress of the study to the IRB at least 
annually in accordance with applicable national law and/or local regulations and in agreement with the 
policy established by the IRB and Sponsor. 
 
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The IRB must be informed by the Principal Investigator of all subsequent study protocol amendments 
and of serious adverse events or SUSARs occurring during the study that are likely to affect the safety 
of the patients or the conduct of the study. 
14.3. 
Confidentiality of Information 
protected from unauthorized parties.  Only patient initials and an identification code (i.e., not names) 
should be recorded on any form submitted to the Sponsor and the IRB.  The Investigator must keep logs 
on screened and enrolled patients.  In addition, the Investigator must have a list where the identity of 
all treated patients can be found. 
 
The Investigator agrees that all information received from the Sponsor, including, but not limited to, the 
-specified treatment, and any other study 
information, remain the sole and exclusive property of the Sponsor during the conduct of the study and 
thereafter.  This information is not to be disclosed to any third party (except employees or agents 
directly involved in the conduct of the study or as required by law) without prior written consent from 
the Sponsor.  The Investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study center to any third party or otherwise into the public 
domain.  The Investigator shall be under additional obligations related to non-disclosure confidential 
information and the handling of intellectual property as set forth in the Clinical Trial Agreement. 
 
14.4. 
Patient Informed Consent 
All information about the clinical study, including the patient information and the informed consent 
form, is prepared and used for the protection of the human rights of the patient according to ICH GCP 
guidelines and the Declaration of Helsinki. 
 
It is the responsibility of the Investigator to obtain signed informed consent forms from each patient 
participating in this study after adequate explanation of the aims, methods, objectives, and potential 
hazards of the study and before undertaking any study-related procedures. 
 
The informed consent form, prepared by the Investigator with the assistance of the Sponsor, must be 
approved along with the study protocol by the IRB and be acceptable to the Sponsor. 
 
The patient must be provided with the patient information and informed consent form consistent with 
the study protocol version used and approved by the relevant IRB.  The informed consent form must be 
in a language fully-comprehensible to the prospective patient.  Patients (and/or relatives, guardians, or 
legal representatives, if necessary) must be given sufficient time and opportunity to inquire about the 
details of the study and to discuss with the Investigator and decide on their participation in the study.  
The patient and the person explaining about the study and with whom they discuss the informed 
consent will sign and date the informed consent form.  A copy of the signed informed consent form will 
be retained by the patient and the original will be filed in the Investigator file unless otherwise agreed.  
The consenting process will be documented. 
 
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14.5.
Study Monitoring
On behalf of the Sponsor, a clinical research organization monitor will contact and visit the Investigator 
at the study center as necessary before the entry of the first patient and at predetermined appropriate 
intervals during the study until after the last patient has completed.  The clinical research organization 
will employ a risk-based monitoring approach that combines centralized remote monitoring and 
adaptive, on-site monitoring activities including source document verification to support and oversee 
activities being undertaken at the study center.  The monitor will also perform a study closure visit. 
 
In accordance with ICH GCP guidelines, the Investigator must ensure provision of sufficient time, 
reasonable space, and adequate qualified personnel for the monitoring visits.  The visits are for the 
purpose of verifying adherence to the study protocol and the completeness, consistency, and accuracy 
of data entered on the eCRF and other documents. 
 
The Investigator will make all source data (i.e, the various study records, the eCRFs, laboratory test 
reports, other patient records, drug accountability forms, and other pertinent data) available for the 
monitor and allow access to them throughout the entire study period.  Monitoring is done by comparing 
the relevant site records of the patients with the entries on the eCRF (i.e., source data verification).  It 
consistency, and accuracy of the data recorded on the eCRFs. 
 
By agreeing to participate in the study, the Investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of the monitoring visits are resolved.  Contact information for 
the study monitor is located in the Investigator file.  Representatives from the Sponsor may also contact 
and visit the Investigators and monitor data during the study. 
 
14.6. 
Clinical Supplies 
The Principal Investigator will be responsible for the dispensing, inventory and accountability of all 
clinical supplies, ensuring that accepted medical and pharmaceutical practices are followed.  An 
accurate and timely accountability record of the disposition of all clinical supplies must be maintained.  
The supplies and inventory record must be made available for inspection by the Sponsor or the 
 Under no circumstances will the Principal 
Investigator allow the investigational product to be used other than as directed by this protocol.   
 
14.7. 
Electronic Case Report Form  
The data will be collected using an electronic data capture (EDC) system by remote data entry on eCRFs 
and by agreeing to participate in the study, the Investigator agrees to maintain accurate eCRF and 
source documents as part of the case history for each patient who participates in the study.  Sites will 
receive training on the EDC system.  All users will be supplied with unique login credentials. 
 
Before study start, the Investigator will prepare a list showing the signature and handwritten initials of 
all individuals authorized to make or change entries on eCRFs.  
 
 
 
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For each patient enrolled, an eCRF must be completed, reviewed, signed and dated by the Principal 
Investigator or Co-Investigator.  Data entry into the CRF should be completed within a reasonable time 
period after data collection, generally on the order of approximately two weeks.  This also applies to 
records for those patients who fail to complete the study.  If a patient withdraws from the study, the 
reason must be noted on the eCRF.  If a patient is withdrawn from the study because of a treatment-
limiting AE, thorough efforts should be made to clearly document the outcome. 
 
All laboratory data and Investigator observations on the results and any other clinically significant test 
results must be documented on eCRFs. 
 
Full information regarding EDC and completing eCRFs is included in the Investigator files.  All questions 
or comments related to electronic capture should be directed to the assigned monitor. 
 
14.8. 
Study Termination and Site Closure 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time.  Should this 
be necessary, both parties will arrange discontinuation procedures.  In terminating the study, the 
Sponsor and the Investigator will ensure that adequate consideration is given to the protection of the 
 
 
The Sponsor reserves the right to discontinue the study at any time for medical or administrative 
reasons.  When feasible, a 30-day written notification will be given. 
 
The entire study will be stopped if: 
 
The protocol-specified treatment is considered too toxic to continue the study 
 
Evidence has emerged that, in the opinion of the Sponsor or the Investigator(s), makes the 
continuation of the study unnecessary or unethical 
 
The stated objectives of the study are achieved 
 
The Sponsor discontinues the development of study drug 
 
Regardless of the reason for termination, all data available for the patient at the time of discontinuation 
of follow-up must be recorded on the eCRF.  All reasons for discontinuation of treatment must be 
documented.  In terminating the study, the Investigator will ensure that adequate consideration is given 
 
 
14.9. 
Modification of the Study Protocol 
Protocol amendments, except when necessary to eliminate an immediate hazard to patients, must be 
made only with the prior approval of the Sponsor.  Agreement from the Investigator must be obtained 
for all protocol amendments and amendments to the informed consent document.  The IRB must be 
informed of all amendments and give approval before their implementation.  The Sponsor will submit 
any study protocol amendments to the concerned regulatory authorities for approval and keep the 
Investigator(s) updated as detailed in the ICH GCP guidelines. 
 
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14.10. Retention of Study Documents
The study site will maintain a study file, which should contain, at minimum, the IB, the protocol and any 
amendments, drug accountability records, correspondence with the IRB and the Sponsor, and other 
study-related documents. 
 
The Investigator agrees to keep records and those documents that include (but are not limited to) the 
identification of all participating patients, medical records, study-specific source documents, source 
worksheets, all original signed and dated ICFs, copies of all eCRFs, query responses, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities and the Sponsor or its 
designees. 
 
The Investigator shall retain records required to be maintained for a period of 5 years after the date a 
marketing application in an ICH region is approved for the drug for the indication for which it is being 
investigated or, if no application is to be filed or if the application is not approved for such indication, 
until at least 5 years after the investigation is discontinued.  However, these documents should be 
retained for a longer period if required by the applicable regulatory requirement(s) or if needed by the 
Sponsor.  
for the same period of time. 
 
No data should be destroyed without the agreement of the Sponsor.  Should the Investigator wish to 
assign the study records to another party or move them to another location, the Sponsor must be 
notified in writing of the new responsible person and/or the new location.  The Sponsor will inform the 
Investigator, in writing, when the study-related records are no longer needed. 
 
regulations or facilities of the investigational site. 
 
14.11. Clinical Study Report 
A clinical study report will be prepared under the responsibility and supervision of the Sponsor and 
signed by a Sponsor representative, thereby indicating their agreement with the analyses, results, and 
conclusions of the clinical study report. 
 
14.12. Study Publication 
The conditions regulating dissemination of the information derived from this study are described in the 
Clinical Trial Agreement. 
 
14.13. Quality Assurance Audits 
An audit visit to clinical centers may be conducted by a quality control auditor appointed by the Sponsor.  
The purpose of an audit, which is independent of and separate from routine monitoring or quality 
control functions, is to evaluate study conduct and compliance with the protocol, standard operating 
procedures, ICH GCP and the applicable regulatory requirements.  The Investigator and the Sponsor may 
also be subject to an inspection by the US Food and Drug Administration (FDA), Health Canada, 
European regulatory authorities or other applicable regulatory authorities at any time. 
 
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The auditor and regulatory authorities will require authority from the Investigator to have direct access 
 It is important that the Investigator(s) and their staff cooperate with 
the auditor or regulatory authorities during this audit or inspection. 
 
14.14. Dissemination of Clinical Study Data 
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the results of 
studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or www.pfizer.com, and 
other public registries and websites in accordance with applicable local laws/regulations.  In addition, 
Pfizer reports study results outside of the requirements of local laws/regulations pursuant to its SOPs. 
 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced and complete manner 
and are reported regardless of the outcome of the study or the country in which the study was 
conducted. 
 
www.clinicaltrials.gov 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional studies 
(conducted in patients) that evaluate the safety and/or efficacy of a product, regardless of the 
geographical location in which the study is conducted.  These results are submitted for posting in 
accordance with the format and timelines set forth by US law. 
 
EudraCT/CTIS 
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.   
 
www.pfizer.com 
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are posted to 
www.clinicaltrials.gov.  CSR synopses will have personally-identifiable information anonymized. 
 
Documents within Marketing Authorization Applications  
Pfizer complies with applicable local laws/regulations to publish clinical documents included in 
marketing applications. Clinical documents include summary documents and CSRs including the 
protocol and protocol amendments, sample CRFs, and SAPs. Clinical documents will have personally 
identifiable information anonymized. 
 
Data Sharing 
Pfizer provides researchers secure access to patient-level data or full clinical study reports for the 
-
disease, target or compound class.  Pfizer will make data available from these trials 24 months after 
study completion.  Patient-level data will be anonymized in accordance with applicable privacy laws and 
regulations.  Clinical study reports will have personally-identifiable information anonymized. 
 
Data requests are considered from qualified researchers with the appropriate competencies to perform 
the proposed analyses.  Research teams must include a biostatistician.  Data will not be provided to 
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applicants with significant conflicts of interest, including individuals requesting access for 
commercial/competitive or legal purposes. 
 
 
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15.
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47.
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Seddon B, Strauss SJ, Whelan J et al.  Gemcitabine and docetaxel versus doxorubicin as first-line 
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53. 
Aaronson NK, Ahmedzai S, Bergman B et al.  The European Organisation for Research and 
Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst. 1993;85:365-376. 
54. 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: 
European Organisation for Research and Treatment of Cancer, Brussels 2001. 
 
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APPENDIX A:
ECOG PERFORMANCE STATUS 
 
ECOG 
Performance 
Status 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on selfcare.  Totally confined to bed or 
chair. 
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APPENDIX B:
RESPONSE EVALUATION CRITERIA IN SOLID TUMOR (RECIST) VERSION 1.1
 
The 
RECIST 
guidelines 
(Version 
1.1) 
are 
described 
in 
Eisenhauer 
(2009) 
and 
at 
http://www.eortc.be/Recist/Default.htm. A short summary is given below. 
 
 
Measurable Disease 
Tumor lesions: measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) with the following: 
 
A minimum size of 10 mm by CT scan (CT scan thickness no greater than 5 mm); 
 
A minimum size of 10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable); 
 
A minimum size of 20 mm by chest X-ray. 
 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph node must 
greater than 5 mm). At baseline and in follow up, only the short axis will be measured and followed. 
 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or pathological 
 10 to < 15 mm short axis), as well as truly nomeasurable lesions, are considered 
nomeasurable disease.  Lesions considered truly nomeasurable include leptomeningeal disease, ascites, 
pleural/pericardial effusions, inflammatory breast disease, lymphangitic involvement of skin and lung, 
and abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
 
Bone Lesions 
Bone lesions, cystic lesion, and lesions previously treated with local therapy require particular comment. 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure bone 
lesions. However, these techniques can be used to confirm the presence or disappearance of bone 
lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components that can be 
evaluated by cross-sectional imaging techniques such as CT or MRI can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described above. 
Blastic bone lesions are nonmeasurable. 
 
Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-measurable) because they are, by definition, simple 
cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions if they 
meet the definition of measurability described above. However, if non-cystic lesions are present in the 
same patient, these are preferred as target lesions. 
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Lesions with Prior Local Treatment
Tumor lesions situated in a previous irradiated area or in an area subjected to other locoregional therapy 
are usually not considered measurable unless there has been demonstrated progression in the lesion. 
 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of 
all involved organs, should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of 
the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. 
The baseline sum LD will be used as reference by which to characterize the overall tumor response. 
 
Non-Target Lesions 
RECIST criteria require unequivocal quantification of the changes in tumor size for adequate 
interpretation of the sum of target lesions. Consequently, when the boundaries of the primary are 
difficult to delineate, this tumor should not be considered a target lesion. 
 
Guidelines for Evaluation of Measurable Disease 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow up. Imaging-based evaluation is preferred to 
evaluation by clinical examination when both methods have been used to assess the antitumor effect 
of a treatment. 
 
Evaluation of Target Lesions 
Complete Response 
Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response 
At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD. 
Stable Disease 
Neither sufficient shrinkage to qualify for partial response nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD since the 
treatment started. 
Progressive Disease 
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. The appearance of one 
or more new lesions is also considered progression. 
 
 
 
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Evaluation of Non-Target Lesions
Complete Response
Disappearance of all non-target lesions and normalization of tumor marker 
level. 
Stable Disease/ 
Incomplete Response 
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits. 
Progressive Disease
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. 
 
If tumor markers are initially above the institutional ULN, they must normalize for a patient to be 
considered a complete responder. 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
measurement and confirmation criteria. 
 
Timepoint Response 
A response assessment will occur at the protocol-specified timepoints. The tables below provide a 
summary of the overall response status calculation at each timepoint for patients who have 
measureable and non-measureable disease (non-target disease only). 
 
Timepoint Response: Patients with Target (± Non-Target) Disease 
Target Lesions
Non-target Lesions
New Lesions 
Overall Response
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not evaluated 
No 
PR 
SD 
Non-PD or not evaluated 
No 
SD 
Not Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; NE, Not evaluable. 
 
 
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Evaluation of Best Overall Response When Confirmation of CR and PR Required
Overall 
Response 
First Timepoint 
Overall Response 
Subsequent Timepoint 
Best Overall Response 
CR
CR 
CR
CR
PR 
SD, PD or PRa
CR 
SD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise, NE 
PR
CR 
PR
PR
PR 
PR
PR
SD 
SD
PR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise, NE 
NE
NE 
NE
 
a   If a CR is truly met at first timepoint, then any disease seen at a subsequent timepoint, even disease 
meeting PR criteria relative to baseline, makes this disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
still present and in fact the patient had PR, not CR at the first time point.  Under these circumstances, 
the original CR should be changed to PR and the best response is PR. 
 
Timepoint Response: Patients with Non-Target Lesion Assessments 
Non-Target 
Lesions 
New Lesions 
Overall Response 
Best Response for this  
Category also Requires 
CR 
No 
CR 
Normalization of tumor markers, tumor 
nodes < 10 mm 
Non-CR/non-PD 
No 
Non-CR/non-PD 
 
Not all evaluated 
No 
NE 
 
Unequivocal PD 
Any 
PD 
 
Any 
Yes 
PD 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of 
. 
This is a reason for stopping therapy, but is NOT objective PD.  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
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Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable 
(NE) at that time point. If only a subset of lesion measurements are made at an assessment, usually the 
case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point response, 
which is most likely to occur in the case of PD; e.g, if only 2 of 3 baseline target lesions are assessed and 
result in a > 20% increase in the sum, then the patient would be assessed as a PD regardless of the 
missing lesion. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having symptomatic 
deterioration.  Every effort should be made to document the objective progression, even after 
discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  When the 
evaluation of CR depends on this determination, it is recommended that the residual lesion be 
investigated (fine needle aspiration/biopsy) before confirming the CR status. 
 
Confirmatory Measurement/Duration of Response 
Confirmation 
Radiographic tumor assessments are required. If an initial CR or PR is noted, confirmatory scans must 
be performed at least 4 weeks later.  In the case of SD, follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of no less than 4 weeks. 
 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or PD is objectively documented (taking as 
reference for PD the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR until the 
first date that recurrent disease is objectively documented. 
 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started. 
 
 
Reference:  Eisenhauer EA, Therasse P, Bogaerts J et al.  New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247. 
 
 
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T TI- 6 2 1 (
-I g G 1 Fc)
Trilli u m T h er a p e utics, a Pfiz er C o m p a n y
Cli nic al Pr ot oc ol T TI- 6 2 1- 0 3
V ersi o n  2. 0,   1 7 J u n e 2 0 2 2                                                     C o nfi d e nti al                       
p a g e 1 3 1 of 1 4 0  
 
 
0 9 0 1 7 7 e 1 9 b 8 0 9 d 5 4\ Fi n al\ Fi n al O n: 0 9- O ct- 2 0 2 2 0 3: 4 9 ( G M T)
C CI


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APPENDIX D:  CONTRACEPTIVE AND BARRIER GUIDANCE
 
Male Patient Reproductive Inclusion Criteria 
No contraception methods are required for male patients in this study, as the calculated safety margin 
-fold between the estimated maternal exposure due to seminal transfer and the NOAEL for 
serious manifestations of developmental toxicity in nonclinical studies.  For combination treatments in 
this study, consult the Doxorubicin USPI, for contraceptive method.  
 
 
Female Patient Reproductive Inclusion Criteria 
The criteria below are part of Inclusion Criterion Number 21 (Section Contraception) and specify the 
reproductive requirements for including female patients.    
 
A female patient is eligible to participate if she (a) is not pregnant or breastfeeding;  (b) agrees to not 
donate eggs (ova, oocytes) for the purpose of reproduction from the time of screening through 45 days 
after the last dose of TTI-621 AND consult the Doxorubicin USPI;  and (c) at least one of the following 
conditions applies: 
 
Is not a WOCBP 
OR 
 
Is a WOCBP who agrees to use a highly effective contraceptive method (failure rate of <1% per 
year) with low user dependency during the intervention period and for at least 45 days after the 
last dose of TTI-621 AND as per the relevant product label for the Doxorubicin USPI, which 
corresponds to the time needed to eliminate any reproductive safety risk of the study 
intervention(s).  The investigator should evaluate the effectiveness of the contraceptive method 
in relationship to the first dose of study intervention. 
 
OR 
 
Is a WOCBP and agrees to use a highly effective (failure rate of <1% per year) user-dependent 
method of contraception during the intervention period and for at least 45 days after the last 
dose of TTI-621 (or as per the product label for the respective combination treatment), which 
corresponds to the time needed to eliminate any reproductive safety risk of the study 
intervention(s).  In addition to her use of the highly effective method above, she agrees to 
concurrently use an effective barrier method.  The investigator should evaluate the effectiveness 
of the contraceptive method in relationship to the first dose of study intervention. 
The investigator is responsible for reviewing the woma
recent sexual activity in order to decrease the risk of enrolling a woman with an early, undetected 
pregnancy. 
  
 
 
Woman of Childbearing and Non-Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
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If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Pre-menopausal female with 1 of the following:  
 
Documented hysterectomy 
 
Documented bilateral salpingectomy 
 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to a medical cause other than the above (eg, 
mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry. 
Note:  Documentation for any of the above categories can come from the 
study. 
 
2. Post-menopausal female: 
 
A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause.  In addition 
 
A high FSH level in the post-menopausal range must be used to confirm a post-menopausal 
state in women under 60 years of age and not using hormonal contraception or HRT 
 
A female on HRT and whose menopausal status is in doubt will be required to use one of 
the highly effective non-estrogen hormonal contraception methods if she wishes to 
continue her HRT during the study.  Otherwise, she must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment 
 
Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations regarding 
the use of contraceptive methods for those participating in clinical trials. 
The following contraceptive methods are appropriate for this study: 
Highly Effective Methods That Have Low User Dependency  
1. 
Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
2. 
Intrauterine device 
3. 
Intrauterine hormone-releasing system 
4. 
Bilateral tubal occlusion 
5. 
Vasectomized partner 
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Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the WOCBP and the absence of sperm has been confirmed.  If not, an 
additional highly effective method of contraception should be used.  The spermatogenesis cycle is 
approximately 90 days. 
Highly Effective Methods That Are User-Dependent 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation: 
 
Oral + barrier* 
 
Intravaginal + barrier* 
 
Transdermal + barrier* 
7. Progestogen-only hormone contraception associated with inhibition of ovulation: 
 
Oral + barrier* 
 
Injectable + barrier* 
Sexual Abstinence 
 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention.  
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the patient. 
 
 
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APPENDIX E:  LIVER SAFETY:  SUGGESTED ACTION AND FOLLOW-UP ASSESSMENTS
 
Potential Cases of Drug Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
serious 
potential outcome.  These patients fail to adapt and therefore are "susceptible" to progressive and 
serious liver injury, commonly referred to as DILI.  Patients who experience a transaminase elevation 
above 3 × ULN should be monitored more frequen
 
 
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations (>2 × ULN) by several 
days or weeks.  The increase in T bili typically occurs while AST/ALT is/are still elevated above 3 × ULN 
(i.e., AST/ALT and T bili values will be elevated within the same laboratory sample).  In rare instances, 
by the time T bili elevations are detected, AST/ALT values might have decreased.  This occurrence is still 
regarded as a potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to T bili 
 
and should always be considered important medical events, even before all other possible causes of 
liver injury have been excluded. 
 
baseline values and underlying conditions.  Patients who present with the following laboratory 
the etiology of the abnormal laboratory values: 
 
Patients with AST/ALT and T bili baseline values within the normal range who subsequently present 
 × ULN with no evidence of hemolysis and an 
alkaline phosphatase value <2 × ULN or not available. 
 
For patients with baseline AST OR ALT OR T bili values above the ULN, the following threshold values 
are used in the definition mentioned above, as needed, depending on which values are above the ULN 
at baseline: 
 
Pre-existing AST or ALT baseline values above the normal range:  
 times the 
 ULN;  or 
 × ULN (whichever is smaller) 
 
Pre-existing values of T bili above the normal range:  T bili level increased from baseline value by an 
 × ULN (whichever is smaller) 
Rises in AST/ALT and T bili separated by more than a few weeks should be assessed individually based 
law case should be reviewed with the sponsor.   
 
The patient should return to the investigator site and be evaluated as soon as possible, preferably within 
48 hours from awareness of the abnormal results.  This evaluation should include laboratory tests, 
detailed history and physical assessment.   
  
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In addition to repeating measurements of AST and AL
laboratory tests should include albumin, CK, direct and indirect bilirubin, GGT, PT/INR, total bile acids, 
and alkaline phosphatase.  Consideration should also be given to drawing a separate tube of clotted 
blood and an anti-coagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.   
 
A 
detailed 
history, 
including 
relevant 
information, 
such 
as 
review 
of 
ethanol, 
acetaminophen/paracetamol (either by itself or as a co-formulated product in prescription or 
over-the-counter medications), recreational drug or supplement (herbal) use and consumption, family 
history, sexual history, travel history, history of contact with a jaundiced person, surgery, blood 
transfusion, history of liver or allergic disease, and potential occupational exposure to chemicals, should 
be collected.  Further testing for acute hepatitis A, B, C, D and E infection, liver imaging (e.g., biliary 
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein adduct 
levels may be warranted.  
 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and T bili 
elevation defined ab
irrespective of availability of all the results of the investigations performed to determine etiology of the 
LFT abnormalities.  
 
investigations have been received and have excluded an alternative etiology. 
   
 
 
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APPENDIX F:  KIDNEY SAFETY:  MONITORING GUIDELINES
Laboratory Assessment of Change in Kidney Function and Detection of Kidney Injury 
Standard kidney safety monitoring requires assessment of baseline and post-baseline (Scr measurement 
to eGFR [Scr-based eGFR]) or eCrCl.   
Regardless of whether kidney function monitoring tests are required as a routine safety monitoring 
procedure in the study, if the investigator or sponsor deems it necessary to further assess kidney safety 
and quantify kidney function, then these test results should be managed and followed per standard of 
care. 
Age-Specific Kidney Function Calculation Recommendations 
Adults (18 Years and Above)
2021 CKD-EPI Equations 
2021 CKD-EPI  
Scr only 
Scr 
(mg/dL) 
Scys 
(mg/L) 
Recommended eGFR Equation 
Female 
 
N/A 
eGFR = 143 × (Scr/0.7)-0.241   ×  (0.9938)Age 
Female 
if > 0.7 
N/A 
eGFR = 143 × (Scr/0.7)-1.200   ×  (0.9938)Age 
Male 
 
N/A 
eGFR = 142 × (Scr/0.9)-0.302   ×  (0.9938)Age 
Male 
if > 0.9 
N/A 
eGFR = 142 × (Scr/0.9)-1.200   ×  (0.9938)Age 
2021 CKD-EPI 
 Scr-Scys Combined 
Scr 
(mg/dL) 
Scys 
(mg/L) 
Recommended eGFR Equation 
Female 
 
 
eGFR = 130 × (Scr/0.7)-0.219  × (Scys/0.8)-0.323  × (0.9961)Age 
Female 
 
if > 0.8 
eGFR = 130 × (Scr/0.7)-0.219  × (Scys/0.8)-0.778  × (0.9961)Age 
Female 
if > 0.7 
 
eGFR = 130 × (Scr/0.7)-0.544  × (Scys/0.8)-0.323  × (0.9961)Age 
Female 
if > 0.7 
if > 0.8 
eGFR = 130 × (Scr/0.7)-0.544  × (Scys/0.8)-0.778  × (0.9961)Age 
Male 
 
 
eGFR = 135 × (Scr/0.9)-0.144  × (Scys/0.8)-0.323  × (0.9961)Age 
Male 
 
if > 0.8 
eGFR = 135 × (Scr/0.9)-0.144  × (Scys/0.8)-0.778  × (0.9961)Age 
Male 
if > 0.9 
 
eGFR = 135 × (Scr/0.9)-0.544  ×  (Scys/0.8)-0.323  × (0.9961)Age 
Male 
if > 0.9 
if > 0.8 
eGFR = 135 × (Scr/0.9)-0.544  ×  (Scys/0.8)-0.778  × (0.9961)Age 
Inker LA et al. N Engl J Med. 2021; 385:1737-49.  
 
Adolescents (12 Years to <18 Years)
Cockcroft-Gault Formula 
CrCl (mL/min)  
Males:  CrCl = [(140-age) × body weight (in kg)] / [Scr (in mg/dL) × 72] 
Females:  CrCl = 0.85 × [(140-age) x body weight (in kg)] / [Scr (in mg/dL) × 72] 
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Children (2 years to <12 years)
Modified Schwartz Equation 
CrCl normalized to BSA (mL/min/1.73 m2) = (K × Ht)/ Scr 
Ht in cm;  Scr in mg/dL. 
K (proportionality constant):  Female Child < 12 years: K = 0.55.  Male Child < 12 years: K = 0.70 
Infants (1 month to <2 years) and Neonates (<1 month)
Bedside Schwartz Equation 
eGFR (mL/min/1.73 m2) = 0.413 × (Ht/Scr) 
Ht in cm ; Scr in mg/dL. 
Adverse Event Grading for Kidney Safety Laboratory Abnormalities 
AE grading for decline in kidney function (i.e., eGFR or eCrCl) will be according to CTCAE criteria. 
 
 
 
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APPENDIX G:  PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT FORM
 
Protocol Title 
A Phase I/II Study of TTI-621 in Combination with Doxorubicin in Patients with 
Unresectable or Metastatic High-Grade Leiomyosarcoma 
Protocol Number 
TTI-621-03 
Protocol Date 
17 June 2022 
Protocol Version 
Version 2.0 
Study Drug 
TTI-
-IgG1 Fc) 
IND Number 
129118  
Sponsor: 
Trillium Therapeutics, a Pfizer Company.
100 Cambridgepark Drive, Suite 510 
Cambridge, MA, 02140 
USA 
 
 
ACKNOWLEDGEMENT 
 
By signing this protocol, I confirm that I have read and agree to conduct the clinical trial as outlined in 
the protocol and in compliance with Good Clinical Practice, the Declaration of Helsinki as amended, and 
all other applicable regulatory requirements.  Confidentiality of all information received or developed in 
connection with this protocol will be maintained by me, as well as all other personnel involved in the 
clinical trial who are employed by me. 
 
The signature of the Principal Investigator below constitutes his/her agreement. 
 
 
____________________________________ 
 
 
____________________________________ 
Print Name of Principal Investigator 
Signature of Principal Investigator 
 
 
 
____________________________________ 
Date 
 
 
 
 
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TTI-621 (
-IgG1 Fc)
Trillium Therapeutics, a Pfizer Company
Clinical Protocol TTI-621-03
Version  2.0,   17 June 2022                                                     Confidential                       
page 140 of 140 
 
 
APPENDIX H:
DOCUMENT HISTORY 
 
 
 
 
Summary of changes for Version 2.0, dated 17 June 2022 provided in a separate document. 
 
Version 
Date 
1.0 
15 April 2021 
2.0 
17 June 2022 
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SAP_001.pdf: 
Statistical Analysis Plan 
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Pfizer Inc. 
Protocol #: TTI-621-03/C4961003 
A Phase I/II Study of PF-07901800 (TTI-621) in Combination with Doxorubicin 
in Patients with Unresectable or Metastatic High-Grade Leiomyosarcoma 
Statistical Analysis Plan 
Version 2.0 
Document last saved: 08-Nov-2023
Prepared by:
 
 
 
 M.Sc., Stats. Sp.
IQVIA Biotech 
 
Approved by:
 
 
MS, MSPH
  
 
Pfizer, Inc.
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Statistical Analysis Plan 
  
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CONTENTS
List of Abbreviations ................................................................................................... 4
1.Introduction ............................................................................................................. 7
1.1Background ................................................................................................ 7
1.2Protocol and Amendment History .............................................................. 8
2.Study Objectives ..................................................................................................... 8
2.1Primary Objectives ..................................................................................... 8
2.2Secondary Objectives ................................................................................ 8
2.3
 ............................................................................... 8
3.Study Endpoints ...................................................................................................... 9
3.1Primary Endpoints ..................................................................................... 9
3.2Secondary Endpoints ................................................................................. 9
3.3
 ................................................................................ 9
4.Study Design......................................................................................................... 11
4.1Design Overview ...................................................................................... 11
4.2Study Population ...................................................................................... 11
4.3Sample Size Estimation ........................................................................... 12
4.4Treatment Group Assignation .................................................................. 12
4.5Assessment Schedule ............................................................................. 13
5.Interventions ......................................................................................................... 14
5.1Study Procedures .................................................................................... 14
6.General Analytical Considerations ........................................................................ 14
6.1Study Summaries and Tabulations .......................................................... 14
6.2Data Sources ........................................................................................... 15
6.3Definition of Baseline ............................................................................... 15
6.4Definition of on-treatment period .............................................................. 15
6.5Missing Data ............................................................................................ 15
6.6Timing of Analyses .................................................................................. 17
6.7Analysis Populations ................................................................................ 18
6.8Data Display Characteristics .................................................................... 19
7.Subject Accountability ........................................................................................... 21
7.1Subject Characteristics ............................................................................ 21
7.2Disposition ............................................................................................... 23
7.3Protocol Deviations .................................................................................. 24
8.Efficacy Analyses .................................................................................................. 24
8.1Efficacy Outcomes ................................................................................... 24
8.2Primary Efficacy Outcome Analysis ......................................................... 27
8.3Secondary Efficacy Analyses ................................................................... 28
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9.Safety Analyses .................................................................................................... 31
9.1Exposure .................................................................................................. 31
9.2Dose-Limiting Toxicity .............................................................................. 32
9.3Adverse Events ........................................................................................ 33
9.4Deaths ..................................................................................................... 36
9.5Clinical Laboratory Results ...................................................................... 36
9.6Vital Signs ................................................................................................ 37
9.7ECOG ...................................................................................................... 37
9.8Electrocardiograms .................................................................................. 38
9.9Transthoracic echocardiogram or Multigated Acquisition Scan ............... 38
10.References.......................................................................................................... 39
11.
 ...... 41
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List of Abbreviations  
Abbreviation Definition 
AE
Adverse Event 
AESI
Adverse Event of Special Interest 
ANC 
Absolute Neutrophil Count
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CEC 
Clinical Evaluation Committee 
CI
Confidence Interval 
CM
Concomitant Medications 
CR
Complete Response 
CRF
Case Report Form 
CRO
Contract Research Organization 
CSR 
Clinical Study Report 
CT
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCO
Data Cut-Off 
DCR
Disease Control Rate 
DES 
DLT-Evaluable Set 
DLT 
Dose-Limiting Toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOS 
End of Study 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
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h 
hour
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IgG1 
immunoglobulin G1 
IL
Interleukin 
IP
Investigational Product 
IR
Immune Response 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IU
International Units 
IV
Intravenous 
L 
liter(s) 
LVEF 
Left Ventricular Ejection Fraction 
m2
meter(s) squared 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/mL 
Milligrams per milliliter 
min 
minute(s) 
MTD 
Maximum Tolerated Dose 
MUGA 
Multi-gated Acquisition Scan 
NA
Not Available 
 
NCI
National Cancer Institute 
NE
Not Evaluable 
ORR 
Objective Response Rate 
OS
Overall Survival 
PD
Progressive Disease; Pharmacodynamics 
PET
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PI
Principal Investigator 
PK
Pharmacokinetics 
PP
Per Protocol 
PR
Partial Response 
PRO 
Patient-Reported Outcomes 
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PT
Preferred Term 
QA
Quality Assurance 
QLQ-C30 
Quality-of-Life Questionnaire Core 30 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan 
SAS
Safety Analysis Set 
SD
Stable Disease 
SIRPĮ
Signal Regulatory Protein Į
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Events 
TLF 
Tables, Listings, and Figures 
71)Į
Tumor Necrosis FDFWRUĮ
TTP
Time to Progression 
WHO 
World Health Organization 
WHO-DD
World Health Organization Drug Dictionary 
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1. Introduction 
1.1 Background 
Soft tissue sarcomas are a rare, heterogeneous group of mesenchymal 
tumors, commonly the result of complex chromosomal abnormalities that 
play a role in disease progression and metastasis. 
Doxorubicin has been since the 1970s the standard of care for first-line 
treatment of patients with metastatic or advanced soft tissue sarcoma; 
however, doxorubicin activity is poor, with a response rate of 9 - 27% 
(Schoenfeld, 1982; Judson, 2001) and progression-free survival of 3-5 
months ('¶$PEURVLR3HQHO,WDOLDQR), with cumulative 
cardiac toxicity that limits its use (Borden, 1987). 
Ontorpacept, also known as TTI-621 or PF-07901800, is a recombinant 
soluble fusion protein designed to block the cell-surface protein CD47, 
which is found on the surface of many normal cell types and at high levels 
on many malignant tumor cells. CD47 binds to signal regulatory protein 
DOSKD6,53ĮRQWKHsurface of macrophages and inhibits their 
phagocytic activity. This CD47-mediated inhibition of macrophage 
phagocytosis activity is an important mechanism through which cancer 
cells can escape immune-mediated clearance, and high levels of CD47 
correlate with poor clinical prognosis across a number of cancer types. 
PF-07901800 (TTI-621) combines
KXPDQ6,53Į
(the binding domain for CD47) with the Fc region of human IgG1, 
generating a decoy receptor for CD47 on the surface of tumor cells that 
both over-rides the CD47-mediated inhibition of phagocytosis through the 
6,53ĮSRUWLRQRIWKHSURWHLQDQGSURYLGHVDSUR-phagocytic stimulation 
through the IgG1 moiety. 
It is hypothesized that blockade of CD47-mediated immune evasion and 
concomitant activation of phagocytosis with PF-07901800 (TTI-621) will 
be clinically beneficial in patients with sarcoma subtypes in which CD47 is 
expressed and macrophage scores are increased. 
 
 
 
Thus, the primary goals of this clinical trial are to evaluate the safety of 
PF-07901800 (TTI-621) administered in combination with standard-of-
care doxorubicin in anthracycline-naïve patients with high-grade soft 
tissue sarcomas and to further evaluate clinical activity and safety in the 
leiomyosarcoma subpopulation. 
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1.2 Protocol and Amendment History 
This Statistical Analysis Plan (SAP) is based on version 2.0 of Protocol 
TTI-621-03 (17JUN2022). This SAP will govern the analysis of data from 
this study. The plan for efficacy analyses may be modified prior to the 
clinical database lock. Any deviations from the analysis plan, will be 
documented as such in the clinical study report.   
2. Study Objectives 
2.1 Primary Objectives 
- 
To evaluate the safety of escalating dose levels of PF-07901800 when 
administered in combination with 75 mg/m2 doxorubicin in 21-day
cycles and establish the maximum tolerated dose level of PF-
07901800 when administered in combination with doxorubicin (Phase 
I Dose Escalation) 
- 
To evaluate the safety of selected dose levels of PF-07901800 when 
administered in combination with 75 mg/m2 doxorubicin in 21-day 
cycles and then as monotherapy in 28-day cycles until documentation 
of objective disease progression (Phase II Expansion) 
- 
To investigate clinical activity assessed as overall response rate of 
PF-07901800 administered in combination with 75 mg/m2 doxorubicin 
for up to six cycles (18 weeks) and then as monotherapy until 
documentation of objective disease progression (Phase II Expansion) 
2.2 Secondary Objectives 
- 
To further assess safety of the selected dose levels of PF-07901800 
administered in combination with 75 mg/m2 doxorubicin 
- 
To describe other evidence of clinical benefit 
2.3
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3. Study Endpoints 
3.1 Primary Endpoints 
- 
Overall safety profile as assessed by the type, frequency, severity, 
timing and causal relationship of any adverse events, changes in vital 
signs, ECGs, serum chemistry or other laboratory assessment, 
treatment delays or discontinuations for patients enrolled into the dose 
escalation portion of the study 
- 
Percentage of patients with objective response (CR + PR) as defined 
by RECIST v1.1 criteria  
3.2 Secondary Endpoints 
- 
Overall safety profile as assessed by the type, frequency, severity, 
timing and causal relationship of any adverse events, changes in vital 
signs, ECGs, serum chemistry or other laboratory assessment, 
treatment delays or discontinuations for patients enrolled into the 
selected dose level cohorts in the expansion portion of the study 
- 
Progression-free survival (PFS), overall survival (OS), disease control 
rate (DCR: CR + PR + SD), duration of response (DOR), duration of 
disease control, time to progression and time to new metastases as 
defined by RECIST v1.1 criteria, time to worsening of ECOG 
performance status, time to worsening of patient-reported outcomes 
assessments 
3.3
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4. Study Design 
4.1 Design Overview  
Multi-center, open-label study designed to evaluate PF-07901800 
administered in combination with doxorubicin. The first portion of the 
study will evaluate the safety of increasing dose levels of PF-07901800 in 
combination with doxorubicin at the standard dose of at 75 mg/m2 in 
patients with high-grade soft tissue sarcoma. Two dose levels of PF-
07901800 in combination with doxorubicin will be selected for further 
evaluation in an expansion phase in which patients with high-grade 
leiomyosarcoma. 
The study will consist of a 28-day screening period, a treatment period in 
which patients will receive doxorubicin in combination with PF-07901800 
in 21-day cycles for a maximum of six cycles, followed by continued 
treatment with PF-07901800 as monotherapy in 28-day cycles until 
documentation of objective disease progression or development of 
unacceptable toxicity, and a long-term follow-up period for assessment of 
overall survival. 
4.2 Study Population 
Eligible patients are those with high-grade soft tissue sarcoma who have 
not received more than one prior line of therapy (gemcitabine with 
docetaxel) and have not received an anthracycline in any setting 
(neoadjuvant, adjuvant or as treatment for advanced of metastatic 
disease). Up to approximately 80 patients are anticipated to participate in 
the study, with up to 18 in the dose escalation portion of the study and 31 
in each of two expansion cohorts. 
The protocol provides additional inclusion and exclusion criteria in its 
Section 6. 
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4.3 Sample Size Estimation 
4.3.1 Dose Escalation cohorts 
The number of patients will depend on the number of dose cohorts that 
will be enrolled before reaching the MTD. It is anticipated that three dose 
levels of PF-07901800 given in combination with a fixed dose of 
doxorubicin will be evaluated and that at least nine and up to 
approximately 18 patients will be enrolled to evaluate these three dose 
levels. On this basis of emerging safety data, additional dose levels may 
be added. The size and design of the dose escalation phase of the study 
is consistent with standard 3+3 design with the objective of determining 
the safety of escalating doses of PF-07901800 in combination with fixed 
dose doxorubicin and establishing PF-07901800 doses for further 
evaluation in the intended patient population. 
4.3.2 Expansion cohorts 
Expansion cohorts are initially planned to evaluate two PF-07901800 
dose levels in combination with doxorubicin: a low dose of PF-07901800 
(Cohort A) and a higher dose (Cohort B). A Simon two-stage design will 
be used for each dose cohort, assuming a baseline overall response rate 
of 10% with doxorubicin monotherapy in the Simon two-stage design and 
an alternative of 25%, a power of 90% and one-sided Type 1 error set at 
0.20, each dose level cohort will require 18 patients enrolled and 
evaluable for response in Stage 1; with at least two clinical responses, an 
additional 13 patients will be enrolled in Stage 2. The combination will be 
considered worthy of further study if at least five clinical responses are 
observed in either 31-patient cohort. 
To mitigate the risk of thrombocytopenia Grade 3 or Grade 4 observed at 
PF-07901800 highest dose 2mg/kg (Cohort B) on Day 8 during the 
combination therapy, PACL No 5 was issued to terminate enrollment into 
Cohort B after enrollment of the 18 patients (Stage 1) was completed. 
The remaining 13 patients, who were initially planned to be enrolled in 
Stage 2 Cohort B, were enrolled in an expansion Cohort C which was 
added to the study to evaluate a medium dose of PF-07901800 at 1 
mg/kg. 6LPRQ¶V-stage design was not applicable for Cohort C.   
4.4 Treatment Group Assignation 
The dose escalation portion of the study carries a traditional 3+3 design 
to evaluate three dose levels of PF-07901800. Standard guidelines for 
enrollment for the 3+3 design will be followed, with requirement that three 
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patients complete the 21-day safety assessment period before the next 
dose cohort is open to enrollment and expansion to six patients in the 
case of a treatment-related dose-limiting toxicity. 
However, recognizing that leiomyosarcoma is a rare disease and 
expecting that patients with leiomyosarcoma may be eager to participate 
in the study, careful modifications to the enrollment schema have been 
developed to avoid having to withhold enrollment for these patients.  
During the dose escalation portion of the study, eligible patients will be 
enrolled to the cohort that is open at the time they present to the study. 
Based on known safety and clinical activity of the lowest planned dose of 
PF-07901800, 0.2 mg/kg, gleaned from other ongoing clinical trials, it is 
anticipated that this dose will serve as the PF-07901800 dose level for 
Cohort A. Thus, expansion Cohort A will open to enrollment once that 
dose level is judged to be safe in the dose escalation portion of the study; 
if a dose escalation cohort and expansion Cohort A are open to 
enrollment at the same time, priority for enrollment will be given to the 
dose escalation cohort and enrollment into expansion Cohort A will be 
limited to those patients who present to the study after enrollment to an 
escalation cohort is closed and meet all the eligibility criteria for the 
expansion portion of the study (including documentation of the 
leiomyosarcoma indication). 
When both expansion cohorts are open to enrollment, assignment of 
eligible patients will be made on an alternating basis, with cohort 
assignment made by the CRO overseeing the study on behalf of the 
sponsor independent of investigator input and based strictly on 
chronology of verification of eligibility of patients as they complete 
screening assessments. 
4.5 Assessment Schedule 
The study participation for a patient might include the Screening Visit 
(Day -28 to -1); Cycle 1 (21-days cycle), Day 1 and Day 8; Cycle 2 to 6 
(21-days cycles), Day 1 and Day 8 (± 1 day); Subsequent Cycles (28-
days cycles), Day 1 and Day 15 (±  3 days); 7 (± 3 days) after last 
administration of study treatment; Safety Follow-up Period (30 + 5 days 
after last administration of study treatment or before initiation of 
subsequent anti-cancer therapy, whichever occurs soonest); and Long-
Term Follow-Up, assessed every 12 ± 2 weeks. 
The protocol provides additional details in Section 11. 
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5. Interventions 
5.1 Study Procedures 
Written informed consent must be granted by each patient prior to the 
initiation of any study procedure or assessment, including assessment of 
histology.  
The study will consist of a 28-day screening period, a treatment period in 
which patients will receive doxorubicin in combination with PF-07901800 
in 21-day cycles for a maximum of six cycles, followed by continued 
treatment with PF-07901800 as monotherapy in 28-day cycles until 
documentation of objective disease progression or development of 
unacceptable toxicity, and a long-term follow-up period for assessment of 
overall survival. 
Serial blood samples will be obtained at baseline, during and after 
treatment for assessment of PF-07901800 pharmacokinetic and 
pharmacodynamic endpoints, as well as 
 
. End-of-Treatment (under protocol V1 only), Safety Follow-up
and Long-Term Follow-Up Assessments will be performed. 
Tissue biopsies will be collected during the screening period and after 
Cycle 2 for patients enrolled in the expansion cohorts; optional biopsies at 
the time of response and progression will be offered to patients. 
  
The protocol v2.0 provides additional details on the activities and timing in 
Section 10, table 24 through 27. 
6. General Analytical Considerations 
6.1 Study Summaries and Tabulations 
7KHGHILQLWLRQRI³WUHDWPHQWJURXS´will be tabulated as follows: 
x Dose escalation cohorts (Phase 1) 
R Dose 1 (0.2 mg/kg)
R Dose 2 (0.7 mg/kg) 
R Dose 3 (2.0 mg/kg) 
x Expansion cohorts (Phase 2) 
R Cohort A (0.2 mg/kg) 
R Cohort B (1.0 mg/kg) 
R Cohort C (2.0 mg/kg) 
x Pooled cohorts by dose level 
R Lower dose (0.2 mg/kg) 
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R
Higher dose (2.0 mg/kg)
x Overall  
R Phase 1 total 
R
Phase 2 total 
R
Phases 1 + 2 total (for non-efficacy summaries only)
Data will be summarized by treatment group as above, as applicable.
6.2 Data Sources 
All reported study data will be recorded on the electronic case report 
forms (eCRF) using Medidata Rave. During the data collection process, 
automated quality assurance programs will be used to identify missing 
data, out-of-range data, and other data inconsistencies. Lab data 
(chemistry and hematology) will come from local labs through the EDC. 
6.3 Definition of Baseline 
Baseline is defined as the last measurement taken prior to the first 
infusion of study medication (Cycle 1 Day 1).  
The average of the pre-infusion results will be considered as the baseline 
value for vital signs taken at different timepoints on the same pre-infusion 
day. 
6.4 Definition of on-treatment period 
Safety endpoints will be summarized based on the on-treatment period, 
unless otherwise specified. 
On-treatment period is defined as the time from the first dose of study 
treatment through minimum (30 days + last dose of study treatment, start 
day of new anti-cancer therapy FDSWXUHGRQWKH³Survival Status´ CRF). 
6.5 Missing Data 
Due to the study design, data will be reported as collected and no 
imputation methods of missing values will be performed, except for partial 
dates. Below it is addressed how missing information will be handled for 
partial dates and incomplete disease assessments. 
When no imaging/measurement is done at all at a particular time point, 
the patient is not evaluable (NE) at that time point. If only a subset of 
lesion measurements are made at an assessment, usually the case is 
also considered NE at that time point, unless a convincing argument can 
be made that the contribution of the individual missing lesion(s) would not 
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change the assigned time point response, which is most likely to occur in 
the case of PD (e.g., if only 2 of 3 baseline target lesions are assessed 
and result in a > 20% increase in the sum, then the patient would be 
assessed as a PD regardless of the missing lesion). 
Partial dates are allowed on the eCRF for prior disease therapy start and 
stop dates, adverse event (AE) onset and end dates, concomitant 
medication start and stop dates, and concomitant procedure, procedure 
dates. An entry for the year is required in the eCRF system for each of 
these dates. Only the month and day may be entered as unknown. Dates 
from these forms will be reported in listings as collected. Every effort will 
be made to query missing dates. 
For records with missing AE onset date, the following procedure will be 
employed for use in determining whether the AE is treatment emergent: 
x AE onset dates with missing day and non-missing month will be 
assumed to occur on the first day of the non-missing month, 
except for AEs occurring in the month and year of first dosing, in 
which case the date will be imputed using the date of first dosing.  
x AE onset dates with missing day and month will be assumed to 
occur on the first day of the non-missing year (i.e., January 1), 
except for AEs occurring in the year of first dosing, in which case 
the date will be imputed using the date of the first dosing. 
x AEs that are not ongoing and have an end date with missing day 
and non-missing month, they will be assumed to occur on the last 
day of the month, except when the end of study date or date of 
death is prior to the last day of the month. The date will be imputed 
as end of study date, or death date, whichever happens the 
earliest. 
x AEs that are not ongoing and have missing month in the end date, 
the imputed end date should be set to the last day of the year 
31DECYYYY, except when the end of study date or date of death 
is prior to the last day of the year. The date will be imputed as end 
of study date, or death date, whichever happens the earliest. 
For records with a missing medication start and/or stop date, the following 
procedure will be employed for use in determining whether the medication 
is prior or concomitant: 
 Medication start dates with a missing day and non-missing 
month will be assumed to occur on the first day of the non-
missing month, except for medications occurring in the month of 
first dosing, in which case the date will be the date of first 
dosing. 
090177e1a009d2d3\Approved\Approved On: 27-Feb-2024 15:14 (GMT)


Statistical Analysis Plan 
  
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Page 17 of 42
 Medication start dates with missing day and month will be 
assumed to occur on the first day of the non-missing year (i.e., 
January 1), except for medications occurring in the year of first 
dosing, in which case the date will be the date of first dosing. 
 Medications that are not ongoing and have a medication stop 
date with a missing day and non-missing month will be assumed 
to occur on the last day of the non-missing month. 
 Medications that are not ongoing and have a medication stop 
date with missing day and month will be assumed to occur on 
the last day of the non-missing year (i.e., December 31). 
For records with a missing procedure date, the following procedure will be 
employed for use in determining whether the procedure is prior or 
concomitant: 
 Procedure dates with a missing day and non-missing month will 
be assumed to occur on the first day of the non-missing month, 
except for procedures occurring in the month of first dosing, in 
which case the date will be the date of first dosing. 
 Procedure dates with missing day and month will be assumed to 
occur on the first day of the non-missing year (i.e., January 1), 
except for procedures occurring in the year of first dosing, in 
which case the date will be the date of first dosing. 
For records with a missing disease progression date from prior therapy, 
the following procedure will be employed for use in analyzing time to 
event endpoints: 
x If the disease progression date is completely missing OR only 
the year is available, set as missing. 
x If both year and month of disease progression date from are 
available and only day is missing, the date of disease 
progression will be imputed by the last day of the month. 
For records with a partial death date, the following procedure will be 
employed for use in deriving time to event variables. 
x The death date will be imputed by the earliest possible date that 
is not contradicting with any other available data in the 
database. 
6.6 Timing of Analyses 
This is an open-label study, so analyses may be performed as the study 
progresses, such as efficacy and safety analysis for publication purposes. 
No formal interim analysis will be performed. 
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Page 18 of 42
Details of analysis will follow each section described in this SAP and may 
include the following components: 
- 
Disposition 
- 
Protocol deviations 
- 
Baseline characteristics: demographics, medical history, cancer 
history, concomitant medications and concomitant procedures 
- 
Key components from efficacy analysis 
- 
Key components from safety analysis 
  
6.7 Analysis Populations  
6.7.1 Full Analysis Set (FAS) 
The FAS will include patients who were enrolled, allocated to 
treatment, and received at least one non-zero dose of study 
treatment.  
This analysis population will be used for baseline summaries and the 
analysis of efficacy endpoints. 
Patients will be classified according to the study treatment actually 
received. For patients who received a wrong study dose, they would 
be recoded in protocol deviation and dosing compliance; if the wrong 
dose occurred only once, the analysis will use the patientV¶LQLWLDO
planned dose as summary cohorts. If more than one wrong dose 
RFFXUUHGWKHDQDO\VLVZLOOXVHSDWLHQWV¶DFWXDOGRVHDVVXPPDU\
FRKRUWV,ISDWLHQWV¶GRVHVZHUHUHGXFHGVDIHW\DQDO\VLVZLOOXVHWKH
initial planned dose as summary cohorts. Patients receiving different 
dosing schedules will be presented in the listings only. 
6.7.2 Safety Analysis Set (SAS) 
The SAS is identical to the FAS, which will include patients who were 
enrolled, allocated to treatment, and received at least one non-zero 
dose of study treatment.  
This analysis population will be used for the analysis of safety and 
exposure. 
6.7.3 DLT-Evaluable Set (DES) 
The DES is applicable to dose-escalation cohorts only. It will include 
patients who received the full dose of doxorubicin in Cycle 1 Day 1 
and the planned doses of PF-07901800 on Day 1 and Day 8, and 
090177e1a009d2d3\Approved\Approved On: 27-Feb-2024 15:14 (GMT)


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Page 19 of 42
have been followed for the entire 21-day DLT period (Cycle 1) or who 
have a DLT during Cycle 1. 
6.8 Data Display Characteristics 
Data displays produced for this study will include three types²summary 
tables, data listings, and figures.  Unless stated otherwise, data listings 
will be produced for all recorded data. Additional data listings will be 
produced for outcome measures that involve extensive procedures to 
derive the analyzed outcomes.  Summary tables and figures will be 
produced when specified in sections to follow. All analyses will be 
performed using SAS (Statistical Analysis Software). 
Data listings will simply list the data recorded on the CRF or derived for 
each subject.  As needed, they can be ordered by dose cohort, site, 
subject number, and time of assessment, and additional levels of ordering 
hierarchy may reflect subsets of assessments within subject.  Subject-
level identifiers appear on the first line of data, and identifiers for 
subgroups within subject appear only on the first line of each subgroup 
value. 
Tables will display summary statistics calculated for each dose cohorts 
per study phase (escalation/expansion), unless described otherwise in 
the following sections. For most summary tables, the dose group will be 
presented in column and the summary statistics of interest will be 
presented in rows. About tables ODEHOOLQJWKHWH[W³1XPEHURI
6XEMHFWV´ZLOOEHLQFRUSRUDWHGLQWKHWLWOHHLWKHUWKHSULPDU\WLWOHRUDVD
separate subtitle, and no further labeling (e.g., ³Q´ZLOODSSHDULQWKH
body of the table. 
The summary statistics displayed will be a function of the type of data 
associated with the summarized assessment.  Unless stated otherwise in 
relevant sections to follow, continuous data will be summarized with the 
number of non-missing values, mean, standard deviation, minimum, 
median, and maximum.  Categorical data will be summarized with the 
number of non-missing values and the numbers of values equal to each 
of the possible values.  Percentages of subjects with each of the possible 
values will be calculated from the number of subjects in the 
corresponding analysis population, unless stated otherwise, and those 
percentages will be presented with one decimal (XX.X%). Some 
continuous variables may also be grouped into categorical levels and 
evaluated in frequency tables. 
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Page 20 of 42
Dates in the clinical database are classified into the categories of 
procedure dates, log dates, milestone dates, outcome dates, and special 
dates: 
x Procedure Dates (TARGET DATE): Dates on which given 
protocol-specified procedure are performed.  They include the 
dates of laboratory testing, physical examinations, disease 
assessments, etc. They should be present whenever data for a 
protocol-specified procedure is present and should only be missing 
when a procedure is marked as NOT DONE in the database.  
Procedure dates will not be imputed. 
x Log Dates: Dates recorded in CRF data logs.  Specifically, they 
are the start and end dates for adverse events and concomitant 
medications/procedures. They should not be missing unless an 
event or medication is marked as ongoing in the database.  
Otherwise, incomplete log dates will be imputed according to the 
rules in Section 6.3 above. However, in listings, log dates will be 
shown as recorded without imputation. 
x Milestone Dates: Dates of protocol milestones such as study drug 
start date, study drug termination date, study closure date, etc.  
They should not be missing if the milestone occurs for a subject.  
They will not be imputed. 
x Outcome Dates: Dates corresponding to study endpoints such as 
survival, progression, etc.  In most cases, they are derived either 
from a milestone (e.g., the survival date is derived from the death 
date), or a procedure date (e.g., the progression date is derived 
from the date of the tumor scan that was used to determine 
progression).  They may be subject to endpoint-specific censoring 
rules if the outcome did not occur but are not otherwise subject to 
imputation. 
x Special Dates: Dates that cannot be classified in any of the above 
categories and they include the date of birth. They may be subject 
to variable-specific censoring and imputation rules. 
&DOFXODWLRQVXVLQJGDWHVHJVXEMHFW¶VDJHRUUHODWLYHGD\DIWHUWKHILUVW
dose of study medication) will adhere to the following conventions:  
x Trial Day 1 of Cycle 1 is defined as the day on which the dose of 
Doxorubicin and PF-07901800 is administered after screening. 
Study days after trial day 1 will be calculated as the difference 
between the date of interest and the first date of dosing of study 
medication plus 1 day. The generalized calculation algorithm for 
relative day: STUDY DAY = [(TARGET DATE ± DSTART) + 1 
where DSTART = the start day of study drug].   
x For dates of interest before the first date of dosing of study 
medication, the study day will be calculated as: STUDY DAY = 
TARGET DATE ± DSTART. Negative study days are reflective of 
090177e1a009d2d3\Approved\Approved On: 27-Feb-2024 15:14 (GMT)


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Page 21 of 42
observations obtained prior to first study drug administration.  
Note: Partial date for the first study drug is not imputed in general. 
All effort should be tried to avoid incomplete study drug start date.  
x Age (years) at informed consent will be calculated as: (Date of 
informed consent ± date of birth + 1) / 365.25, and then truncated 
to an integer. In case of partial birth date: impute missing day as 
15th of the month; impute missing month as July (month 7); set 
missing age in case of missing year. 
x Duration will be calculated by the difference of start and stop date 
+ 1. AE duration (days) = AE end date ± AE start date +1 
x Study drug exposure duration (weeks) is detailed in section 9.1. 
Exposure. 
x Time since disease diagnosis (months) will be calculated as 
(Informed Consent Date ± Diagnosis Date + 1) / 30.4167. 
x The time to event will be calculated as date of event minus 
reference date + 1. The specific censoring rules on time to event 
endpoints will follow Section 8 (for efficacy and PRO) and Section 
9 (for ECOG performance status). 
x The following conversion factors will be used to convert days to 
months or years:  
R 1 month = 30.4375 days 
R 1 week = 7 days 
R 1 year = 365.25 days 
6.8.1 Multiple Assessments for the Same Assessment Time Point 
In the case of multiple observations (e.g., scheduled vs. unscheduled) at 
a specific visit, the first non-missing measurement will be used for 
analysis, unless multiple study assessments are expected (e.g., pre-dose 
vs. post-dose). When multiple study assessments are expected, the first 
non-missing measurement for the visit and assessment time point will be 
used for analysis. 
7. Subject Accountability 
7.1 Subject Characteristics 
Subject characteristics will be summarized by treatment group based on 
the FAS, which consist of all subjects who received at least one non-zero 
dose of study treatment. 
Demography. Data collected about the following subject characteristics at 
the screening visit will be summarized: 
x Age (in years). Age will be calculated as the number of years elapsed 
between birth date and the date of the screening visit. 
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Page 22 of 42
x Age strata: 
R
< 40
R
40 - < 65 years 
R
65 - <75 years 
R
75 - <85 years 
R
\HDUV
x Sex  
x Race. If more than one race selected, summarize race as multiple. 
x Ethnicity 
x Height (cm) 
x Weight (kg) 
x Body Surface Area (BSA) (m2) = ([height (cm) × weight (kg)] / 3600)0.5
Medical History. Medical Histories will be summarized as the numbers 
and percentages of subjects with histories significant for each of the 
medical-history elements recorded on the MH CRF form. Coding will be 
performed using Medical Dictionary for Regulatory Activities (MedDRA), 
latest version. System Organ Class (SOC) and Preferred Term (PT) will 
be summarized by number and percentage of patients having at least one 
occurrence of a disease. All Medical history information, including 
diagnosis and start/end date will be listed for the FAS.  
Disease Characteristics. Disease characteristics   will be summarized as 
the numbers and percentages of subjects with significant medical-history 
elements recorded on the Disease History CRF form, and target tumor 
sites at baseline from disease assessment CRFs. Disease History 
information, including histology information, stages, progressive disease 
date of most recent progression, and target tumor site will be listed.  
Prior anti-cancer therapies. The prior anti-cancer therapies are collected 
XQGHUWKHµ3ULRUTreatment for Disease Under Study¶DQGµ3ULRU6XUJHUies 
for Current Diagnosis¶H&5)SDJHV
The number and percentage of participants in each of the following anti-
cancer therapy categories will be tabulated: 
x Participants with at least one prior anti-cancer drug therapy 
x Participants with at least one prior anti-cancer surgery 
Prior anti-cancer drug therapy will be summarized as follows based on the 
number and percentage of participants with the following: 
x One prior anti-cancer drug therapy 
x Two prior anti-cancer drug therapy regimens 
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Page 23 of 42
x Best response for each regimen: CR, PR, SD, PD, Unknown, Not 
applicable. 
Prior treatment regimens can include Docetaxel, Gemcitabine, or/and 
other. If the starting date for Docetaxel and Gemcitabine and other anti-
cancer drugs is the same or occurred within 14 days, these two treatments 
are considered as part of the same regimen. 
Concomitant Medication. Concomitant medication is defined as any 
medication with a start date prior to the date of the first dose of study 
treatment and continuing after the first dose of study treatment or with a 
start date between the dates of the first and last dose of study treatment.  
Any medication with a start date after the date of the last dose of study 
treatment will not be considered a concomitant medication. Any 
medication with a stop date prior to the first dose of study treatment is 
defined as a prior treatment. 
All concomitant medications and dietary supplements received within 28 
days prior to the first dose of study treatment through 30 days after the 
last dose of study treatment will be recorded in the eCRFs, using generic 
drug names when possible. Concomitant medications will be coded using 
the WHO-DD current version and will be summarized by the 2nd ATC 
level and by preferred drug name of the coded medication. Patients are 
counted only once in each therapeutic class category. Concomitant 
medication will be summarized using the FAS and be tabulated for each 
dose level using frequencies and percentages. Percentages will be based 
on the number of patients in each dose level. 
7.2 Disposition 
                 The percentages below will be calculated based on the number of 
patients in the FAS. 
End of Treatment (EOT): 6XEMHFW¶Vstatus (completed treatment [for 
doxorubicin only] or discontinued treatment), as well as the reasons for 
discontinuation of each study drug (Doxorubicin and PF-07901800 
captured on separated forms) will be summarized. 
End of Study (EOS): Subjects who discontinued or withdrew from the 
study, as well as the reasons, will be summarized. 
All disposition data will be presented in a listing. 
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Page 24 of 42
7.3 Protocol Deviations 
A listing will identify subjects who were enrolled even though they did not 
meet one or more eligibility criteria (Data recorded in the EOS eCRF 
page), or any other situations that were not compliant with the protocol. 
This data will be classified as major or minor deviation by the clinical 
team, that will review periodically the protocol deviations and finalize the 
deviations prior to the database lock and efficacy analyses. 
A summary table of major protocol deviations will be provided. A listing of 
protocol deviations related to COVID-19 will also be provided. 
8. Efficacy Analyses  
Efficacy analyses will use data from the FAS (for all efficacy endpoints) and 
will be descriptive in nature. Summary tables and figures will be presented by 
treatment group as described in Section 6.1, as applicable. 
8.1 Efficacy Outcomes 
For the primary endpoint, the clinical efficacy of PF-07901800 in
combination with doxorubicin will be evaluated by tumor response as 
assessed by the investigators using RECIST v1.1, according to protocol 
appendix B (Eisenhauer, 2009). 
The response categories of target lesions and its definitions are described 
below: 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to < 10 mm.  
Partial Response 
(PR) 
At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum 
LD.  
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for partial response nor 
sufficient increase to qualify for PD, taking as reference the 
smallest sum LD since the treatment started.  
Progressive 
Disease (PD) 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study). In addition to 
the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. The appearance of one 
or more new lesions is also considered PD. 
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Page 25 of 42
Not Evaluable 
(NE) 
No imaging/measurement is done at all at a particular time 
point. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered NE at that 
time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not 
change the assigned time point response, which is most likely 
to occur in the case of PD. 
The response categories of non-target lesions and its definitions are 
described below: 
Complete Response 
(CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  
Stable Disease/  
Incomplete Response  
(Non-CR/Non-PD) 
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal 
limits.  
Progressive Disease 
(PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  
Best overall response (BOR) will be assessed based on reported 
overall lesion responses at different evaluation time points from the 
date of first study treatment until the first documentation of PD, 
according to the following rules. Only tumor assessments performed 
on or before the start date of any subsequent anti-cancer therapies 
(from WKH³Survival Status´ eCRF) will be considered in the assessment 
of BOR. Clinical deterioration will not be considered as documentation 
of disease progression. 
BOR based on confirmed responses (primary definition): 
Best Overall Response (BOR) is defined as the best response 
recorded (CR, PR, SD, PD, NE per RECIST) from the start of 
the treatment until disease progression, taking as reference for 
PD the smallest measurements recorded since the treatment 
VWDUWHG7KHSDWLHQW¶VEHVWUHVSRQVHDVVLJQPHQWZLOOGHSHQGRQ
the achievement of both measurement and confirmation 
criteria. 
The tumor responses are required to be confirmed by 
radiographic tumor assessments. If an initial CR or PR is noted, 
confirmatory scans must be performed at least 4 weeks later. In 
the case of SD, follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 
no less than 4 weeks. 
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Page 26 of 42
x CR = at least two determinations of CR at least 4 weeks 
apart and before first documentation of PD.  
x PR = at least two determinations of PR or better (PR 
followed by PR or PR followed by CR) at least 4 weeks 
apart and before first documentation of PD (and not 
qualifying for a CR).  
x SD (applicable only to patients with measurable disease 
DWEDVHOLQH DWOHDVWRQH6'DVVHVVPHQWRUEHWWHU4 
weeks after the date of first study treatment and before 
first documentation of PD (and not qualifying for CR or 
PR).    
x Non-CR/non-PD (applicable only to patients with non-
measurable disease at baseline) = at least one non-
CR/non-3'DVVHVVPHQWRUEHWWHU4 weeks after the 
date of first study treatment and before first 
documentation of PD (and not qualifying for CR or PR). 
x
3' ILUVWGRFXPHQWDWLRQRI3'ZHHNVDIWHUWKHGDWH
of first study treatment (and not qualifying for CR, PR, SD 
or non-CR/non-PD4 
x NE:  all other cases.   
Objective Response (OR) is defined as confirmed BOR of CR or PR 
according to RECIST v1.1. OR rate (ORR) is the proportion of patients 
with OR in the analysis set. 
BOR based on unconfirmed responses (secondary definition): 
x Unconfirmed CR (uCR) = one objective status of CR 
before first documentation of PD.  
x Unconfirmed PR (uPR) = one objective status of PR 
before first documentation of PD (and not qualifying for 
uCR). 
x SD (applicable only to patients with measurable disease 
at EDVHOLQH DWOHDVWRQH6'DVVHVVPHQWRUEHWWHU
weeks after the date of first study treatment and before 
first documentation of PD (and not qualifying for uCR or 
uPR).   
x Non-uCR/non-PD (applicable only to patients with non-
measurable disease at baseline) = at least one non-
uCR/non-3'DVVHVVPHQWRUEHWWHU4 weeks after the 
date of first study treatment and before first 
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Statistical Analysis Plan 
  
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Page 27 of 42
documentation of PD (and not qualifying for uCR or 
uPR).   
x
3' ILUVWGRFXPHQWDWLRQRI3'ZHHNVDIWHUWKHGDWH
of r first study treatment (and not qualifying for uCR, uPR, 
SD or non-CR/non-PD).   
x NE:  all other cases.   
An objective status of uPR or SD cannot follow one of uCR. SD 
can follow uPR only in the rare case that tumor increases by 
less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.   
Unconfirmed Objective Response (uOR) is defined as unconfirmed 
BOR (uBOR) of uCR or uPR according to RECIST v1.1.  Unconfirmed 
OR rate (uORR) is the proportion of patients with uOR in the analysis 
set. 
8.2 Primary Efficacy Outcome Analysis 
%DVHOLQHGRFXPHQWDWLRQRI³WDUJHW´DQG³QRQ-WDUJHW´OHVLRQVOHVLRQFRXQW
and maximum lesion length) will be recorded in listings. The sum of 
diameters will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. The 
baseline lesion size value will be used as reference by which to 
characterize the lesion response. 
Other lesions (or sites of disease) not selected as target lesions 
(measurable or non-measurable), including pathological lymph nodes, 
should be identified as non-target lesions and should also be recorded 
during screening. Measurements of these lesions are not recorded, but 
the presence or absence of each, including any progression, should be 
noted throughout the study. The appearance of new malignant lesions 
denotes disease progression. 
3HU5(&,67FULWHULDWDUJHWOHVLRQVFRQVLGHUHGµWRRVPDOOWRPHDVXUH¶ZLOO
be assigned a default value of 5 mm and those identifieGDVµQRWSUHVHQW¶
will be assigned 0 mm for purposes of analysis.  
All FAS patients will be included in the denominators for percentage, even 
if the patient had a NE response. The ORR and uORR will be 
summarized descriptively for RECIST assessment method, with a 95% 
confidence interval (CI) using :LOVRQ¶VVFRUHPHWKRG. 
Overall tumor response assessment data will be presented in listings. 
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Statistical Analysis Plan 
  
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8.3 Secondary Efficacy Analyses 
Duration of response (DOR) will be calculated for patients who achieve a 
CR or PR, and is defined as the time from the date of first documented 
response (CR or PR) to the date of documented progression or death of 
any cause after achieving response. Patients who discontinue the study 
without disease progression or death or patients with an event after 2 or 
more missing/inadequate disease assessment or patients with an event 
after the start date of alternate anti-cancer therapy will be censored at 
their last response assessment date or last assessment prior to the start 
date of alternate anti-cancer therapy, whichever is earlier. The number of 
events and the number of censored patients will be summarized, and the 
median time to PD or death event (reported in days), its 95% confidence 
interval, and the 25th and 75th percentiles on the time to event will be 
summarized using Brookmeyer-Crowley method. 
Disease Control Rate (DCR) is defined as the percentage of patients who 
have achieved CR, PR, or SD lasting at least 4 weeks. DCR at any time 
during the study will be summarized, as per the RECIST assessment 
method. 
Progression Free Survival (PFS) is defined as the time from the first PF-
07901800 infusion (Cycle 1 Day 1) to PD or death of any cause, 
whichever is first. Patients without disease progression or death or 
patients with an event after 2 or more missing/inadequate disease 
assessment or patients with an event after the start date of alternate anti-
cancer therapy will be censored at their last response assessment date or 
last assessment prior to the start date of alternate anti-cancer therapy, 
whichever is earlier. 
The number of events and the number of censored patients will be 
summarized. PFS rate at selected times, as well as the median time to 
event (reported in days), its 95% confidence interval, and the 25th and 
75th percentiles on the time to event will be summarized using 
Brookmeyer-Crowley method. Kaplan-Meier plot of PFS will also be 
provided. 
Overall Survival (OS) is defined as the time from the first PF-07901800 
infusion (Cycle 1 Day 1) to death of any cause. Patients last known to be 
alive will be censored at their last known alive date. Kaplan-Meier 
methodology similar to the PFS analysis will be used to summarize the 
results.  
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Duration of Disease Control (DDC) is defined in patients who achieved a 
best overall response of SD or better, as the time from the first PF-
07901800 infusion (Cycle 1 Day 1) to the date of documented 
progression or death of any cause, and will be calculated for patients who 
achieve a CR, PR or SD lasting at least 4 weeks.  Patients without 
disease progression or death or patients with an event after 2 or more 
missing/inadequate disease assessment or patients with an event after 
the start date of alternate anti-cancer therapy will be censored at their last 
response assessment date or last assessment prior to the start date of 
alternate anti-cancer therapy, whichever is earlier. The number of events 
and the number of censored patients will be summarized, and the median 
time to PD or death event (reported in days), its 95% confidence interval, 
and the 25th and 75th percentiles on the time to event will be summarized 
using Brookmeyer-Crowley method. 
Time to progression (TTP) is defined the same as PFS, except that death 
is not considered an event.  Patients who die without PD or patients with 
PD after 2 or more missing/inadequate disease assessment or patients 
with PD after the start date of alternate anti-cancer therapy will be 
censored at their last disease assessment prior to the start date of 
alternate anti-cancer therapy, whichever is earlier. The number of events 
and the number of censored patients will be summarized. The median 
TTP (reported in days), its 95% confidence interval, and the 25th and 75th
percentiles on the time to event will be summarized using Brookmeyer-
Crowley method. 
Time to new lesion is defined as the time from the first PF-07901800 
infusion (Cycle 1 Day 1) to a new  lesion appearance. Patients without 
new lesion or patients with new metastases after 2 or more 
missing/inadequate disease assessment or patients with new metastases 
after the start date of alternate anti-cancer therapy will be censored at 
their last response assessment date or last assessment prior to the start 
date of alternate anti-cancer therapy whichever is earlier. The number of 
events and the number of censored patients will be summarized. The 
median time to event (reported in days), its 95% confidence interval, and 
the 25th and 75th percentiles on the time to event will be summarized 
using Brookmeyer-Crowley method. 
Waterfall plot for target lesion tumor response by individual will be 
presented, indicating best tumor response (maximum tumor reduction 
from baseline) at any time point for each subject. The plot will have one 
bar per subject sorted from worst to best response with color by dose 
administered.  Tumor response will be calculated based on the type of 
cancer that the patient has, with the appropriate measure using RECIST. 
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Swimmer plots for tumor response will be generated with RECIST 
assessment. The plots will have one horizontal bar per subject firstly 
sorted by Best Response, and then sorted from earliest to latest time to 
start of response for CR and PR; within categories of SD, PD and NE, 
patients will be sorted by maximum observation duration. Symbols within 
the swimmer plot will indicate time to start and end of each new level of 
response (if the end of one response is the start of a new type of 
response by definition, only the start will be shown). The plots will also 
show the length of treatment duration a patient had. 
8.3.1 Patient-Reported Outcomes 
Patient-Reported Outcomes (PRO) analyses will use data from the FAS. 
PRO will be assessed at Cycle 1 Day 1, at all study treatment day 1 of 
each cycle, and at Safety Follow up visit, following the European 
Organisation for Research and Treatment of Cancer (EORTC) Quality-of-
Life Questionnaire Core 30 (QLQ-C30) tool (Aaronson, 1993). 
Fifteen separate scales/items within 3 broad categories (9 multi-item 
scales and 6 single-item symptom measures) will be assessed (Fayers, 
2001):   
x Global health status / QoL (revised) (Items 29 and 30) 
x
Functional scales 
R Physical functioning (revised) (Items 1 to 5) 
R Role functioning (revised) (Items 6 and 7) 
R Emotional functioning (Items 21 to 24) 
R Cognitive functioning (Items 20 and 25) 
R Social functioning (Item 26 and 27) 
x Symptom scales 
R Fatigue (Items 10, 12 and 18) 
R Nausea and vomiting (Items 14 and 15) 
R Pain (Items 9 and 19)
R Dyspnea (Item 8) 
R Insomnia (Item 11) 
R Appetite loss (Item 13) 
R Constipation (Item 16) 
R Diarrhea (Item 17) 
R Financial difficulties (Item 28)   
The EORTC QLQ-C30 will be scored according to its user guides 
(https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf) 
(Fayers, 2001).  
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Time to first worsening of PRO assessments is defined as the time from 
the first PF-07901800 infusion (Cycle 1 Day 1) to the first observation of 
at least a 10-point decrease from baseline in the standardized score 
(linear transformation) of Global Health Status/QoL (Osoba, 1998). 
Patients without a worsening event will be censored on the last date of 
PRO assessments or the date of first study treatment, whichever is the 
latter. The number of events and the number of censored patients will be 
summarized only for expansion cohorts. The median time to event 
(reported in days), its 95% confidence interval, and the 25th and 75th
percentiles on the time to event will be summarized using Brookmeyer-
Crowley method.  
9. Safety Analyses 
Summary of AEs and other safety parameters will be based on the SAS by 
treatment group as described in Section 6.1, except for the DLT, which will be 
based on DLT-Evaluable Set (DES) by treatment group.  
9.1 Exposure 
In the combination portion of the study, Cycle 1 through Cycle 6, 
doxorubicin will be administered at 75 mg/m2 on Day 1 of each 21-day 
cycle.  A maximum of six cycles of doxorubicin (18 weeks of treatment) is 
permitted.  
In Cycle 1 through Cycle 6, PF-07901800 will be administered by 
intravenous infusion over 120 minutes on Day 1 and Day 8 of each 21-
day cycle.  Beginning with Cycle 7, PF-07901800 will be administered as 
monotherapy on Day 1 and Day 15 of 28-day cycles until documentation 
of disease progression or unacceptable toxicity. Monotherapy will be 
considered starting on the first cycle without doxorubicin. 
PF-07901800 dose levels planned for evaluation in combination with 
doxorubicin in the dose escalation portion of the study are as follow: 
Dose Level 
PF-07901800 Dose 
1 
0.2 mg/kg 
2 
0.7 mg/kg 
3 
2.0 mg/kg 
During the dose expansion portion of the study, two dose levels of PF-
07901800 are planned to be evaluated in combination with fixed-dose 
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doxorubicin. The low dose of PF-07901800 is anticipated to be 0.2 mg/kg 
and the high dose is anticipated to be the maximum of other PF-
07901800 dose levels evaluated in the dose escalation portion of the 
study, prospectively planned to be 2.0 mg/kg, but alternate dose levels 
may require evaluation and a different dose may be taken forward based 
after discussion with treating physicians and the Sponsor. 
Exposure to PF-07901800 and doxorubicin will be summarized with 
descriptive statistics for the number of non-zero doses received, duration 
of dosing (weeks), total cumulative dose (mg/kg for PF-07901800, mg/m2
for doxorubicin).  
Total cumulative dose is the sum of the actual doses of PF-07901800 or 
doxorubicin received. 
Duration of dosing is defined as the time (in weeks) from first dose of 
study drug in cycle 1 to the last dose of study drug in the last cycle a 
patient had.  
The calculation algorithm for duration of exposure (in days) for each drug 
will be:
- 
Doxorubicin:  
R Last Doxorubicin dose date ± first Doxorubicin dose date + 21 
- 
PF-07901800: 
R If the last dose is on Day 1 of Cycles 1-6: (Last PF-07901800 
dose date ± first PF-07901800 dose date + 7)
R If the last dose is on Day 8 of Cycles 1-6, and any time after 
Cycle 6: (Last PF-07901800 dose date ± first PF-07901800 
dose date + 14) 
The number of participants with infusion interruption, dose reduction, 
infusion held (i.e. dose omitted) from study drug administration CRFs and 
number of participants with cycle delayed from date of visit CRF will also 
be summarized descriptively for each study drug by treatment group.  
In addition, the planned dosing date and the actual dosing date will be 
listed. Listings will be provided with the information from all the study drug 
administration eCRFs.  Reasons for missed doses, and reasons for dose 
reduction, infusion interruption, and cycle delay of PF-07901800 and 
Doxorubicin will be listed.  
9.2 Dose-Limiting Toxicity 
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Dose-limiting toxicity (DLT) is defined as a hematologic and/or non-
hematologic treatment-emergent adverse event that occurs during the 21-
day Cycle 1 and that are judged by the Investigator as related to PF-
07901800 or the combination of PF-07901800 and doxorubicin, in those 
patients receiving the full dose of doxorubicin and the planned doses of 
PF-07901800 on Cycle 1 Day 1 and Day 8 and have been followed for 
the entire 21-day DLT period. Hematologic and Non-Hematologic AEs to 
be considered as DLT are listed in the study protocol. These DLT will be 
summarized, including number and percentage of patients, in the DES. 
Adverse events that are in the opinion of the investigator attributable 
exclusively to intravenous infusion of doxorubicin or any doxorubicin 
prophylaxis medication will not be considered a dose-limiting toxicity. AEs 
and Serious AEs (SAE) will be determined to be dose-limiting if they 
occur in this timeframe and meet the described criteria. AEs or SAEs 
experienced after the end of Cycle 1 will not be reported as DLTs but will 
be documented. Patients who experience a DLT (other than grade 5) will 
remain on the study to complete the safety evaluations and follow-up until 
resolution or stabilization of the DLT. 
9.3 Adverse Events 
Adverse events (AEs) will be documented on the AE eCRF and 
monitored continuously throughout the study. Adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
latest version, associating lower-level terms with PT and SOC by the 
primary hierarchy.  
Treatment Emergent Adverse Events (TEAEs) are those events with 
onset date occurring during the on-treatment period. The tables will 
display counts and percentages of patients who reported at least one 
TEAE in each SOC represented in the AE data. Within each SOC, the 
tables will display the counts and percentages of patients reporting at 
least one TEAE, as designated by the PT.   
The severity of adverse events will be graded using the NCI Common 
Toxicity Criteria for Adverse Events (CTCAE version 5.0). The intensity is 
assigned a grade of 1 through 5 using the following CTCAE guidelines: 
Grade 1 ± Mild; Grade 2 ± Moderate; Grade 3 ± Severe; Grade 4 ± Life-
threatening; Grade 5 ± Death. 
The causality of AE are reported as either related to study drug or not 
related to study drug for each study drug. Related AEs are those related 
to any study drug (i.e., at least one of the study drugs).  
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If a patient has multiple occurrences of an adverse event, the strongest 
level of relationship to study drug(s) and the worst toxicity grade a patient 
experiences for a given AE will be used in these tables. No imputation will 
be performed for missing toxicity grade or causality data. 
AEs that have missing onset dates will be considered as TEAE unless the 
stop date is known to be prior to the first administration of the study 
medication. If the AE onset date is partial, the date will be correlated as 
far as possible with the date of first dose of study medication. AE will be 
assumed to be TEAE, unless there is clear evidence (through comparison 
of partial dates) to suggest that the adverse event started prior to the first 
dose of study medication. Detailed imputation rules can be found in 
section 6.3. If patients died during the study and experienced AEs at the
time of death, the AEs that lead to death will use death date as the AE 
end date; otherwise, AEs that do not lead to death will be reported as 
ongoing. 
Adverse Events of Special Interest (AESI) include the following: 
R Thrombocytopenia: Haematopoietic thrombocytopenia ±
SMQ Broad  
R Anemia: Haematopoietic erythropenia ± SMQ broad  
R Hemorrhage: Haemorrhage terms (excl. laboratory terms) ±
SMQ narrow 
R Infusion related reactions (PT of Infusion-related reaction as 
recorded on the Adverse Event CRF) 
The following TEAE summary tables will be produced by treatment group 
as described in Section 6.1: 
a. An overall summary of safety will summarize the numbers (and 
percentages) of patients with the following: 

TEAEs (separately for combination period and monotherapy period, 
and overall), where combination period is defined as from the date 
of first study treatment to the date of last doxorubicin + 21 days 
 
Grade TEAEs (separately for combination period and 
monotherapy period, and overall) 
 
Treatment-related TEAEs (separately for combination period and 
monotherapy period, and overall)  
 
Treatment-related grade TEAEs (separately for combination 
period and monotherapy period, and overall)  
 
Serious TEAEs 
 
Treatment-related Serious TEAEs  

TEAEs leading to dose reduction (of PF-07901800 and doxorubicin, 
separately) 

TEAEs leading to drug interruption (of PF-07901800 and 
doxorubicin, separately) 
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 
TEAEs leading to permanently discontinued study drug (PF-
07901800, doxorubicin, and both)    
 
Treatment related TEAEs leading to permanent discontinuation of 
PF-07901800 
 
Treatment-related TEAEs leading to permanent discontinuation of 
doxorubicin 
 
Treatment-related TEAEs leading to permanent discontinuation of 
both drugs 

TEAEs leading to death  
 
Treatment-related TEAEs leading to death 
 
At least one TEAE of special interest: Thrombocytopenia SMQ 
(broad) 
 
At least one TEAE of special interest: Anemia SMQ (broad) 
 
At least one TEAE of special interest: Hemorrhage SMQ (narrow) 
 
At least one TEAE of special interest: Infusion related reactions 
b. Separate summaries of TEAEs by SOC and PT, as follows: 
x TEAEs by maximum severity (separately for combination period 
and monotherapy period, and overall) 
x Treatment-related TEAEs (separately for combination period and 
monotherapy period, and overall) 
x DLT 
x Serious TEAEs 
x Treatment-related Serious TEAEs  
x TEAEs leading to dose reduction (of PF-07901800 and doxorubicin 
separately) 
x TEAEs leading to drug interruptions (of PF-07901800 and 
doxorubicin separately) 
x TEAEs leading to permanent discontinuation (of PF-07901800 and 
doxorubicin separately, and both) 
x Treatment-related TEAEs leading to permanent discontinuation of 
(of PF-07901800 and doxorubicin separately, and both) 
x TEAEs leading to death 
x Treatment-related TEAEs leading to death 
c. Separate summaries of TEAEs by PT, as follows: 
 
Most common 7($(V$Q\JUDGHDQG*UDGH  
Most common Treatment-related 7($(V$Q\JUDGHDQG*UDGH
3)  
d. Summary of TEAEs (any grade DQG*UDGH of special interest will 
be summarized by SMQ and PT, as appliable: 
 
Thrombocytopenia (broad) 
 
Anemia (broad) 
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 
Hemorrhage (narrow) 
e. Summary of infusion related reactions (any JUDGHDQG*UDGH by 
SOC and PT 
The following AE listings will be produced, sorted by dose cohort, patient, 
and timing, with relevant information: 
 
All AEs  
 
All DLTs 
 
AEs leading to death 
 
COVID-19 related AEs 
9.4 Deaths  
The frequency (number and percentage) of subjects in the SAS who died 
and who died within 30 days after last dose of study treatment as well as 
the reason for death, will be tabulated: 
 
All deaths  
 
Deaths within 30 days after last dose of study treatment 

Reason for death  
In addition, date and cause of death will be provided in individual 
participant data listing together with selected dosing information (study 
treatment received, date of first / last administration, dose) and will 
include the following information: 
 
AEs with fatal outcome (Listing of PTs of AEs with outcome=Fatal, 
as well as AEs of Grade 5) 
 
Flag for death within 30 days of last dose of study treatment.  
 
Flag for death related to COVID-19
9.5 Clinical Laboratory Results 
Clinical laboratory tests (serum chemistry and hematology) will be 
performed at Screening and each cycle Day 1 and 8, unless otherwise 
specified, as indicated in Section 10 of the protocol. Baseline laboratory 
measurements do not need to be repeated if screening measurements 
were performed within 3 days prior to Cycle 1 Day 1. All laboratory data 
will be converted to standardized conventional units for reporting 
purposes.  
Hematology and chemistry evaluations which cannot be graded per 
CTCAE criteria will be summarized as counts and percentages of patients 
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with shifts from baseline to worst on-treatment assessment 
(normal/low/high).    
For hematology and chemistry evaluations which can be graded per 
CTCAE v5.0, the following summary table will be created: 
x Shift summary of baseline CTCAE grade versus the worst on-
treatment CTCAE grade (The highest CTCAE grade during the on-
treatment period is considered as the worst grade [Grade 0, 1, 2, 3, 
or 4] for the summary) 
x 6KLIWVXPPDU\IURP*UDGHDWEDVHOLQHWR*UDGH postbaseline 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will 
also be created, with different symbols for different treatment groups, by 
graphically displaying: 
x peak serum ALT(/ULN) vs peak total bilirubin (/ULN), including 
reference lines at ALT=3×ULN and total bilirubin =2×ULN.  
x peak serum AST(/ULN) vs peak total bilirubin (/ULN), including 
reference lines at AST=3×ULN and total bilirubin =2×ULN . 
9.6 Vital Signs 
Vital signs (weight, systolic blood pressure, diastolic blood pressure) will 
be summarized with continuous descriptive statistics at Screening, on 
Cycle 1 Day 1 (assessed in 30-minute intervals), on all study treatment 
day 1 of each cycle, at EOT/Early Termination, and at Safety Follow up 
visit. 
Vital Signs will be listed by patient and summarized by treatment and visit 
in the SAS.  
9.7 ECOG 
ECOG Performance Status will be assessed as described in the protocol 
Appendix A, at Screening, on Cycle 1 Day 1, on all study treatment day 1 
of each cycle, at EOT/Early Termination, and at Safety Follow up visit.  
Time to first worsening of ECOG performance status is defined as the 
time from the first PF-07901800 infusion (Cycle 1 Day 1) to the first date 
when a worsening from baseline (i.e., increase) in the ECOG assessment 
level is recorded in two consecutive assessments. Patients without a 
worsening event will be censored on the last date of ECOG assessments 
or the date of first study treatment, whichever is the later. 
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The number of events and the number of censored patients will be 
summarized, and the median time to worsening event (reported in days), 
its 95% confidence interval, and the 25th and 75th percentiles on the time 
to event will be summarized using Brookmeyer-Crowley method. 
9.8 Electrocardiograms 
Supine position 12-lead ECGs will be performed at screening and 
reviewed locally at each visit. 
Corrected QT, PR and QRS data will be collected on the ECG eCRF 
page. Data will be summarized using QTc. 
The frequency (number and percentage) of participants with notable ECG 
values according to the following categories will be summarized:            
- 
QTc increase from baseline >30 ms, >60 ms 
- 
QTc > 450 ms, > 480 ms, > 500 ms 
- 
35PVDQGLQFUHDVHIURPEDVHOLQHPV
- 
456PV
Participants with notable ECG interval values and qualitative ECG 
abnormalities will be listed for each participant and time point and the 
corresponding notable values and abnormality findings will be included in 
the listings. 
9.9 Transthoracic echocardiogram or Multigated Acquisition Scan 
Patients must undergo a Transthoracic Echocardiogram (ECHO) or 
Multigated Acquisition (MUGA) Scan during the screening period, as well 
as in Cycle 5 day 1, Cycle 8 day 1 and in the Safety Follow-Up Visit, 
unless performed within previous 4 weeks. Left Ventricular Ejection 
Fraction (LEVF) and an overall interpretation (normal/abnormal) will be 
summarized by visit. 
 
 
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10. 
References 
Aaronson NK, Ahmedzai S, Bergman B et al. The European Organisation for 
Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365-
376.  
Borden EC, Amato DA, Rosenbaum C et al. Randomized comparison of three 
adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 
1987;5:840-50.  
D'Ambrosio L, Touati N, Blay JY et al. Doxorubicin plus dacarbazine, 
doxorubicin plus ifosfamide, or doxorubicin alone as a first-line treatment for 
advanced leiomyosarcoma: A propensity score matching analysis from the 
European Organization for Research and Treatment of Cancer Soft Tissue 
and Bone Sarcoma Group. Cancer 2020;126:2637-47.
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 2009; 45:228-247. 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on 
behalf of the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring 
Manual (3rd Edition). Published by: European Organisation for Research and 
Treatment of Cancer, Brussels 2001.  
Italiano A, Toulmonde M, Cioffi A et al. Advanced well-differentiated 
/dedifferentiated liposarcomas: role of chemotherapy and survival. Ann Oncol 
2012;23:1601-7.
Judson I, Radford JA, Harris M et al. Randomised phase II trial of pegylated 
liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment 
of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft 
Tissue and Bone Sarcoma Group. Eur J Cancer 2001;37:870-7.
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance 
of changes in health-related quality-of-life scores. J Clin Oncol. 1998 
Jan;16(1):139-44. 
Penel N, Italiano A, Ray-Coquard I et al. Metastatic angiosarcomas: 
doxorubicin-based regimens, weekly paclitaxel and metastasectomy 
significantly improve the outcome. Ann Oncol 2012;23:517-23. 
Schoenfeld DA, Rosenbaum C, Horton J et al. A comparison of adriamycin 
versus vincristine and adriamycin, and cyclophosphamide versus vincristine, 
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Pfizer Inc. / Protocol: TTI-621-03/C4961003 
IQVIA Biotech (Confidential) Project # YXA42460
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
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actinomycin-D, and cyclophosphamide for advanced sarcoma. Cancer 
1982;50:2757-62. 
Somarouthu B, Lee SI, Urban T et al. Immune-related tumour response 
assessment criteria: a comprehensive review. Br J Radiol 2018;91:20170457. 
090177e1a009d2d3\Approved\Approved On: 27-Feb-2024 15:14 (GMT)


Statistical Analysis Plan 
  
 Pfizer Inc. / Protocol: TTI-621-03/C4961003 
IQVIA Biotech (Confidential) Project # YXA42460
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
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11. 
 
 
090177e1a009d2d3\Approved\Approved On: 27-Feb-2024 15:14 (GMT)
CCI
CCI


Statistical Analysis Plan 
  
 Pfizer Inc. / Protocol: TTI-621-03/C4961003 
IQVIA Biotech (Confidential) Project # YXA42460
Template No.: NVA_TP_CR694 Revision 3 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Reference: SOPCR008, WPCR013 
 
Page 42 of 42
090177e1a009d2d3\Approved\Approved On: 27-Feb-2024 15:14 (GMT)
CCI