Clinical trial NCT03250832
Conditions: Neoplasms
Keywords: Advanced solid tumors Dostarlimab Ovarian cancer Colorectal cancer Lung cancer Dose escalation Dose expansion
Sponsor: Tesaro, Inc.
Start date: 2017-08-08; Completion date: 2023-02-13
Enrollment: 111 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a multicenter, open-label, first-in-human Phase 1 study evaluating the anti-lymphocyte activation gene-3 (LAG-3) antibody TSR-033 alone, in combination with the anti-PD-1 antibody dostarlimab, and in combination with dostarlimab, modified folinic acid (FOL)/leucovorin, 5-fluorouracil and oxaliplatin (OX) (mFOLFOX6) or FOL/leucovorin, 5-fluorouracil and irinotecan (IRI) (FOLFIRI), and bevacizumab in participants with advanced solid tumors in a broad range of solid tumors. Participants with disease types selected for evaluation in this study are expected to derive clinical benefit with addition of an anti-PD-1. The study will be conducted in two parts with Part 1 consisting of dose escalation to determine the recommended phase 2 dose (RP2D) of TSR-033 as a single agent (Part 1a) and in combination with dostarlimab (Part 1c). RP2D decisions will be based on the occurrence of dose-limiting toxicities (DLTs), pharmacokinetics (PK), as well as pharmacodynamics (PDy) data. Part 2A of the study will investigate the anti-tumor activity of TSR-033 and dostarlimab in combination in participants with advanced or metastatic microsatellite stable colorectal cancer (MSS-CRC). Part 2B of the study will investigate the safety and anti-tumor activity of TSR-033 and dostarlimab in combination with chemotherapy (Cohort B1: mFOLFOX6 and Cohort B2: FOLFIRI) and bevacizumab in participants with advanced or metastatic MSS-CRC.

Detailed description:

Arms: arm 1: Part 1a will evaluate TSR-033 at ascending doses (20 milligrams \[mg\], 80 mg and 240 mg) every 2 weeks. Cohorts will be enrolled sequentially and will initially follow a 3+3 design at a starting dose of 20 mg. arm 2: Part 1b will evaluate the PK profile and assess PDy data from blood and tumor tissue samples following TSR-033 treatment. The participants will begin treatment with TSR-033 on Day 1 followed by 28 days observation for collection of blood sampling for PK/PDy. Participants will receive their second dose of TSR-033 on Day 29 and every 14 days thereafter. arm 3: Participants will be administered ascending doses of TSR-033 in combination with dostarlimab 500 mg every 3 weeks. Planned dose levels of TSR-033 include 80 and 240 mg. arm 4: Part 2 Cohort A will evaluate the preliminary activity of TSR-033 in combination with dostarlimab in anti-PD-1 naive participants with third and fourth line MSS-CRC. TSR-033 will be administered every 2 weeks and dostarlimab every 6 weeks. arm 5: Part 2 Cohort B1 will evaluate the preliminary activity of TSR-033 administered every 2 weeks (Q2W) in combination with dostarlimab administered every 6 weeks (Q6W) along with mFOLFOX6 and bevacizumab (standard of care \[SOC\]) in anti-PD-1 naive second line MSS-CRC participants who have progressed on frontline treatment with FOLFIRI, with or without biologics. arm 6: Part 2 Cohort B2 will evaluate the preliminary activity of TSR-033 in combination with FOLFIRI and bevacizumab (SOC) in anti-PD-1 naive second line MSS-CRC participants who have progressed on frontline treatment with FOLFOX, with or without biologics.
Interventions: intervention 1: TSR-033 intervention 2: Dostarlimab intervention 3: mFOLFOX6 intervention 4: FOLFIRI intervention 5: Bevacizumab
Intervention descriptions: intervention 1: TSR-033 is a humanized monoclonal antibody immunoglobulin (Ig) G4. intervention 2: Dostarlimab (previously referred to as TSR-042) is an IgG4 antibody. intervention 3: mFOLFOX6 is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and oxaliplatin (OX) which acts as systemic cytotoxic agent. intervention 4: FOLFIRI is combination of folinic acid (FOL)/leucovorin, 5-fluorouracil and irinotecan (IRI) which acts as systemic cytotoxic agent. intervention 5: Bevacizumab is a humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor (VEGF)-A to inhibit angiogenesis.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE 
Protocol Title: A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-033, an 
Anti-LAG-3 Monoclonal Antibody, Alone and in Combination With an Anti-PD-1 in Patients 
With Advanced Solid Tumors (CITRINO) 
Protocol Number: 213349 (4040-01-001)/Amendment 05 (Version 6.0) 
Compound Names: TSR-033 (also known as: encelimab, GSK4074386A) 
 
Dostarlimab (also known as: TSR-042, GSK4057190A) 
Study Phase: Phase 1 
Sponsor Name and Legal Registered Address: 
TESARO, Inc. 
1000 Winter Street 
Suite 3300 
Waltham, MA 02451 
+1 339 970 0900 
TESARO Bio Netherlands B.V. 
Joop Geesinkweg 901 
1114AB Amsterdam-Duivendrecht 
The Netherlands 
+45 31664608 
Regulatory Agency Identification Numbers: 
Registry 
ID 
IND 
134,547 
EudraCT 
2017-001622-18  
Medical Monitor Name and Contact Information: Can be found in the Study Reference 
Manual 
Sponsor Signatory: 
Hagop Youssoufian, MD, MSc 
Medical Director 
Approval Date: 23 Feb 2022 
©2022 GSK group of companies or its licensor. All rights reserved. Unauthorized copying or 
use of this information is prohibited. 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Document Number 
Amendment 05 (Version 6.0) 
23 Feb 2022 
TMF-14403236 
Amendment 04 (Version 5.0) 
29 Jan 2020 
TMF-11848538 
Amendment 03 (Version 4.0) 
24 Jun 2019 
RPS-SA-1586848 
Amendment 02 (Version 3.0) 
02 Jan 2018 
RPS-SA-1586671 
Amendment 01 (Version 2.0) 
19 Jun 2017 
RPS-SA-1586272 
Original Protocol (Version 1.0) 
19 Apr 2017 
RPS-SA-1586523 
Amendment 05 (23 Feb 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
Amendment 05 is a global protocol amendment to refine the study endpoints and provide 
operational details for the study after the planned final analysis/database closure. Additional 
clarifications have also been provided. A description and rationale for all changes is provided in 
the following Protocol Amendment Summary of Changes table. 
Protocol Amendment Summary of Changes 
Section # and Name 
Description of Change 
Brief Rationale 
Document headers, Title Page, 
Sponsor Signatory page 
(removed), Protocol 
Amendment Summary of 
Changes section (new), and 
throughout 
Document headers, Title Page, 
and Sponsor Signatory page 
(removed) were updated 
according to the Sponsor’s 
template; Protocol Amendment 
Summary of Changes section 
was added according to the 
Sponsor’s template; editorial 
revisions were made for 
consistency with the Sponsor’s 
ways of working and to add 
clarification and/or remove 
discrepancies 
Editorial changes to align with 
the Sponsor’s standard protocol 
template and ways of working 
and for accuracy, clarity, 
conformity, flow, and 
typographical error correction 


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Secti o n  # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
S y n o psis →O bjecti ves  
Secti o n  2. 1. Pri mar y O bj ecti ve, 
Secti o n  2. 2. Sec o n dar y 
O bjecti ves, a n d Secti o n  2. 3.  
Secti o n  6. 3. 2. Efficac y 
E n d p oi nts  
Secti o n  8. 5. 2. Sec o n dar y 
Efficac y Para meters  
( Pri mar y a n d Sec o n dar y) 
Pr o vi de d e xa m ple para meters t o 
be use d f or safet y/t ol era bilit y 
a nal yses; pr o vi de d clarificati o n 
a n d e xa m ple f or P K 
c haracterizati o n 
( Sec o n dar y) Restricte d D O R 
a n d D C R a nal yses b y 
R E CI S T  v 1. 1 t o Part  2 o nl y  
T o pr o vi de a d diti o nal 
clarificati o n of e xa m ple 
para meters, Part  2 e n d p oi nts, 
a n d  
e n d p oi nts.  
S y n o psis → Met h o d ol o g y  
Secti o n  3 . 3. 3. E n d of St u d y a n d 
Fi nal A nal ys is ( ne w secti o n) 
Secti o n  5. 7.  C o nti n ue d Access 
t o St u d y Treat me nt After Fi nal 
A nal ys is ( ne w secti o n) 
Secti o n  6. 1. 1 2 . C ollecti o n of 
Safet y I nf or mati o n After Fi nal 
A nal ys is ( ne w secti o n) 
Secti o n  7. 1. Sc he d ule of E ve nts  
( Delete d) Secti o n 9. 1 5 . E n d of 
St u d y (secti o n m o ve d t o ne w 
Secti o n  3. 3. 3 ) 
A d de d g ui deli nes f or patie nts 
w h o c o nti n ue treat me nt after t he  
D C O  date of t he pla n ne d fi nal 
a nal ys is/ data base cl os ure 
T o pr o vi de c o nti n ue d treat me nt 
o pti o ns t o patie nts still deri vi n g 
cli nical be nefit fr o m treat me nt 
w he n t he D C O date is reac he d 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis→ Pharmacokinetics 
and Antidrug Antibody Analysis 
Synopsis→Statistical Methods 
(Pharmacokinetic Analysis) 
Section 3.3.1.4. 
Pharmacokinetics and Antidrug 
Antibody Assessments 
Section 6.4.1. Pharmacokinetic 
Analysis 
Section 8.1. Study Populations 
Section 8.3. Pharmacokinetic 
Analyses 
Removed duplicated PK 
analysis information and 
clarified existing PK analysis 
information 
Updated PK Population 
definition and added 
Immunogenicity Population 
definition 
Reduced repeated details of PK 
analyses for clarity and updated 
existing details in line with 
Sponsor’s ways of working/for 
accuracy 
Updated study population 
details in line with planned 
statistical analyses 
Synopsis→Investigational 
Product, Dosage, and Mode of 
Administration 
Section 3.1.3.1 Part 1a: 
TSR-033 Monotherapy (Q2W) 
Section 5.2. Administration 
Revised the text to note that the 
infusion times provided for 
TSR-033 and the study 
treatments in Part 2B are 
approximate and to remove the 
15-minute observation period 
after an infusion of TSR-033 
Per study Protocol Clarification 
Letter issued 22 June 2021: 
Approximate infusion timing is 
deemed sufficient for TSR-033 
and all study treatments in 
Part 2B and the observation 
period after TSR-033 
administration is not required 
for patient safety 
Synopsis→Statistical Methods 
(Safety Analyses) 
Section 8.2. Safety Analyses 
Removed coagulation, 
urinalysis, vital signs, and 
physical examinations from 
descriptions of statistical 
analyses 
These parameters will not be 
statistically analyzed 
Section 5.1.2. 
Non-investigational Products 
Added a note that biosimilars of 
bevacizumab are permitted for 
administration as a substitute for 
bevacizumab 
Per study Protocol Clarification 
Letter issued 28 June 2021: This 
clinical practice is deemed 
allowable 


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Secti o n  # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Secti o n  5. 3 D ose M o dificati o n 
( Ta ble 2 D ose M o dificati o ns f or 
N o n -He mat ol o gic T o xiciti es –  
A p plies t o B ot h St u d y Dr u g 
C o m p o ne nts ( T S R -0 3 3 a n d 
D ostarli ma b))  
Secti o n  5. 6. 4.  Resc ue 
Me dicati o ns a n d S u p p orti ve 
Care G ui deli nes  
A d de d d ose m o dificati o ns a n d, 
as a p pr o priate, s u p p orti ve care 
g ui deli nes f or t he f oll o wi n g A E 
cate g ories: a dre nal 
i ns ufficie nc y; he m o p ha g oc ytic 
l y m p h o histi oc yt osis; 
m y ocar ditis; se vere e xf oliati ve 
der mat ol o gic e ve nts, se vere 
ne ur ol o gical e ve nts; u veitis; a n d 
ot her ir A Rs  
Reclassifie d d ose m o dificati o ns 
f or i m m u ne-relate d ras h t o 
se vere e xf oliati ve der mat ol o gic 
e ve nts a n d i ncl u de d d ose 
m o dificati o ns a n d s u p p orti ve 
care g ui deli nes f or s us pecte d 
a n d c o nfir me d cases of D R E S S, 
SJ S, a n d T E N.  
Reclassifie d d ose m o dificati o ns 
f or i m m u ne-relate d e nce p halitis 
t o i ncl u de se veral se vere 
ne ur ol o gical e ve nts ( m yast he nic 
s y n dr o me/ m yast he nia gra vis, 
G uillai n Barré s y n dr o me, 
i m m u ne-relate d e nce p halitis, 
a n d tra ns verse m yelitis)  
Ma de mi n or clarif yi n g u p dates 
t o d ose m o dificati o ns f or t he 
f oll o wi n g A E cate g ories: 
diarr hea/c olitis; A S T, A L T, or 
i ncrease d bilir u bi n; 
h y pert h yr oi dis m; a n d re nal 
fail ure or ne p hritis. 
Clarificati o ns, c orrecti o ns, a n d 
pr o gra m u p dates. N ote, r as h a n d 
s ki n reacti o ns are n o w c o vere d 
b y t he ne w “ Ot her ir A Rs” A E 
cate g or y. 
A b bre viati o ns:  A E =a d verse e ve nt;  A L T =ala ni ne a mi n otra nsferase; A S T =as partate a mi n otra nsferase;  D C O = data 
c ut -off ; D C R = disease c o ntr ol rate; D O R = d urati o n of res p o nse; D R E S S = dr u g reacti o n wit h e osi n o p hilia a n d 
s yste mic s y m pt o ms; ir A R =i m m u ne-relate d a d verse reacti o n;
Criteria i n S oli d T u m ors; O S = o verall s ur vi val; P F S = p r o gressi o n-free s ur vi val; P K = p har mac o ki netic; 
R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors .; SJ S = Ste ve ns-J o h ns o n s y n dr o me; T E N =t o xic e pi der mal 
necr ol ysi s. 
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SYNOPSIS 
Name of Sponsor/Company: TESARO, Inc. 
Name of Investigational Product: TSR-033 and dostarlimab 
Name of Active Ingredients: TSR-033 and dostarlimab 
Title of Study: A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-033, an Anti-LAG-3 
Monoclonal Antibody, Alone and in Combination With an Anti-PD-1 in Patients With Advanced Solid 
Tumors 
Study Center(s): Up to 10 sites in Part 1 and up to 20 sites in Part 2 
Studied period (years): 
Estimated date first patient enrolled: July 2017 
Estimated date last patient completed: May 2021 
Phase of development: 1 
 
Proposal/Rationale: The recognition of tumors by the immune system has been appreciated for 
multiple decades and has provided an impetus to utilize the immune system to control tumor growth. 
Studies have reported the presence of tumor-infiltrating lymphocytes (TILs) as a positive prognostic 
feature in multiple tumors, supporting a role for the immune system in limiting tumor growth. Despite 
evidence of immune reactivity, tumors are able to grow in the presence of an immune system, 
suggesting a suboptimal innate immune response. 
Emerging research into this inadequate immune response has identified an important family of proteins 
that play key roles in immune checkpoint pathways, regulatory cascades that ordinarily maintain 
immune homeostasis, but are co-opted by cancer cells so that they may evade detection and subsequent 
destruction by the immune system. Prominent proteins within this immune checkpoint family include 
programmed cell death receptor (PD-1), associated with immune system downregulation and self-
tolerance, and lymphocyte activation gene-3 (LAG-3) which is widely associated with exhausted or 
dysfunctional T cells that show varying degrees of functional impairment in the context of chronic 
antigen exposure. 
To date, PD-1 has been a popular development target of anti-cancer therapies. However, despite 
favorable response rates observed with these therapies, there remains a large number of patients who 
derive little clinical benefit from this treatment approach (primary resistance) or suffer a relapse post-
treatment (acquired or adaptive immune resistance). To potentially engender a stronger and more 
durable anti-tumor response, it is thought that a combined treatment approach that targets both PD-1 and 
LAG-3, complementary immune pathways in intrinsic tumor-cell resistance, may be successful. This 
belief is bolstered by internal results in the mixed lymphocyte reaction (MLR) assay and efficacy in 
syngeneic tumor models, which, taken together, provide a rationale for combination therapy with anti-
PD-1 and anti-LAG-3 antibodies in cancer. 
Two such therapeutic antibodies that target PD-1 and LAG-3 are dostarlimab and TSR-033, 
respectively. Dostarlimab is a potent humanized immunoglobulin G4 (IgG4) κ monoclonal antibody 
(mAb) that binds to PD-1 and blocks the interaction between PD-1 and its ligands, programmed cell 
death ligand-1 (PD-L1) and programmed cell death ligand-2 (PD-L2). The functional antagonist activity 
of dostarlimab was confirmed in a MLR assay demonstrating enhanced interleukin-2 (IL-2) production 
upon addition of dostarlimab. Dostarlimab is being studied as monotherapy and in combination in 
several tumor types to evaluate its safety and tolerability, pharmacokinetics (PK), pharmacodynamics 
(PDy), and clinical activity in patients with advanced or metastatic solid tumors. TSR-033 is a potent 
and selective humanized IgG4κ mAb that will undergo dose-limiting studies and safety and tolerability 


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assessment in patients with advanced or metastatic solid tumors, both alone and in combination with 
dostarlimab, in Part 1 of this study. 
Colorectal cancer (CRC) is one of the most common malignancies worldwide and remains a deadly 
disease (second most common cause of cancer death in the United States [US]) despite current 
therapeutic options1, which include the current standard of care (SOC), chemotherapy with or without 
anti-angiogenic antibodies or anti-epidermal growth factor receptor (EGFR) antibodies2 as first- and 
second-line regimens. In the US, although the incidence rate of CRC in adults aged ≥50 years has 
declined in recent decades, it has increased by 13% in those aged <50 years. In addition, if the disease 
progresses to become metastatic CRC (mCRC), it is usually incurable. While colorectal cancers with 
microsatellite instability are frequently sensitive to check point inhibitor therapy, they make up only 
about 3% of patients with metastatic disease.3 Unfortunately, in contrast to many other areas of cancer 
therapy, the advances achieved with immunotherapy have not yet been replicated in the remaining 97% 
of patients whose mCRC is microsatellite stable CRC (MSS-CRC). Therefore, MSS-CRC remains an 
area of great and urgent medical need. 
Based on the growing body of evidence from preclinical models, the anti-tumor effects of conventional 
chemotherapy, used as part of the SOC in CRC, are derived not only from direct tumor cell killing, but 
also from increased priming of the immune response. This can occur through immunogenic cell death 
(ICD) which (a) releases a host of antigens/neoantigens and highly immunostimulatory molecules 
which attract leukocytes and (b) stimulates a type I interferon response which promotes improved 
antigen presentation and T cell activation. This suggests that chemotherapy can synergize with 
checkpoint blockade pathways to boost tumor immunosurveillance and improve anti-tumor efficacy. By 
harnessing the host immune system, immunotherapy may therefore add a complementary and distinct 
mechanism of action to the currently utilized standard chemotherapeutic and biologic regimens used to 
treat CRC. Therefore, immunotherapeutic agents warrant further investigation in the clinic to test the 
hypothesis that the combination of immunotherapy and chemotherapy can synergistically potentiate 
antitumor responses in patients with MSS-CRC. 
Among the cytotoxic chemotherapy choices for CRC, oxaliplatin- and irinotecan-based chemotherapy 
regimens are most commonly utilized, with clinical outcomes improved by the addition of biologics 
targeting EGFR or vascular endothelial growth factor (VEGF) or its receptor (VEGFR) in appropriate 
patients.4 With regard to oxaliplatin-based regimens, FOLFOX and its variants (ie, modified FOLFOX6 
[mFOLFOX6], FOLFOX4) remain popular and are used globally.5,6 FOLFOX consists of folinic acid 
(FOL) or leucovorin, 5-fluorouracil (F), and oxaliplatin (OX). mFOLFOX6, given with or without 
bevacizumab (anti-VEGF mAb), is by far the most commonly used regimen, clinically and in studies, 
for first-line therapy in CRC.7 An alternative 3-drug combination is FOLFIRI, which consists of 
irinotecan (IRI) in addition to FOL and F.8 This combination can also be given with biologics. While it 
is generally considered that FOLFOX and FOLFIRI are equivalent regimens, particularly with regard to 
overall survival (OS)6, the oxaliplatin-based regimens are utilized more frequently than irinotecan-based 
regimens in the first-line metastatic setting globally. In the second-line metastatic setting, a number of 
contemporary trials have established reliable benchmarks for overall response rates and progression-free 
survival (PFS), as well as OS, with FOLFOX- or FOLFIRI-based regimens. Taken together, the overall 
response rate with FOLFOX or FOLFIRI chemotherapy with or without biologics appears to be modest 
in CRC, in the 4% to 15% range.6,9,10,11,12,13,14 
Beyond second-line therapy, TAS-102, an oral fluoropyrimidine analogue and thymidine phosphorylase 
inhibitor, has demonstrated an improvement of OS by 1.8 months in patients with refractory disease 


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versus best supportive care (5.3 versus 7.1 months [HR 0.68, 95% CI 0.58 to 0.81; p<0.001]).15 In 
addition, two anti-EGFR monoclonal antibodies, cetuximab and panitumumab, have shown efficacy as 
monotherapy in the third-line setting in patients with KRAS wild type tumors.16,17,18 Monotherapy with 
the anti-angiogenic drug regorafenib has also yielded a modest survival benefit of 1.4 months (6.4 
versus 5.0 months [HR ratio 0.77; 95% CI 0.64 to 0.94; one-sided p=0.0052).19 Finally, immunotherapy 
with checkpoint inhibitors as monotherapy appears to be active only in patients with microsatellite 
instability–high (MSI-H) or mismatch repair–deficient (dMMR) CRC.20,21 Both nivolumab and 
pembrolizumab are currently approved for MSI-H or dMMR CRC that has progressed following 
treatment with fluoropyrimidine, oxaliplatin, and irinotecan. In summary, the current treatment options 
in first- through fourth-line CRC, their response rates, and the growing knowledge around subtypes of 
CRC patients, highlight the need for more efficacious therapeutics and support the decision to study 
TSR-033 and dostarlimab combination therapy in MSS-CRC. 
The purpose of Part 2A of the study is to assess the safety and initial efficacy of the combination of 
TSR-033 and dostarlimab in third- or fourth-line MSS-CRC. Part 2B will assess the safety profile and 
initial efficacy of mFOLFOX6 (Cohort B1) or FOLFIRI (Cohort B2) plus bevacizumab in combination 
with TSR-033 and dostarlimab in patients with second-line MSS-CRC who have progressed on a prior 
first-line regimen.20 
Objectives: 
Primary: 
Part 1 (Dose Escalation Cohorts 1a, 1b, and 1c): 
• 
To define the recommended Phase 2 dose (RP2D) and schedule of TSR-033 as 
monotherapy and in combination with dostarlimab. 
• 
To evaluate the safety and tolerability (eg, number of patients experiencing dose-limiting 
toxicities [DLTs], adverse events [AEs]/serious adverse events [SAEs]/immune-related 
adverse events [irAEs], and abnormal hematology/clinical chemistry results) of TSR-033 as 
monotherapy and in combination with dostarlimab in patients with advanced or metastatic 
solid tumors. 
Part 2A (Dose Expansion Cohort): 
• 
To evaluate the anti-tumor activity of TSR-033 in combination with dostarlimab in anti-
PD(L)-1 naïve patients with advanced or metastatic MSS-CRC who have progressed 
following 2 or 3 prior lines of therapy as measured by objective response rate (ORR) 
assessed by the Investigators using Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1. 
Part 2B (Dose Expansion Cohorts B1 and B2): 
• 
B1: 
− 
To evaluate the safety and tolerability (eg, number of patients experiencing DLTs, 
AEs/SAEs/irAEs, and abnormal hematology/clinical chemistry results) of TSR-033 and 
dostarlimab in combination added to mFOLFOX6 and bevacizumab in anti-PD(L)-1 
naïve patients with advanced or metastatic MSS-CRC following progression on 
frontline treatment with FOLFIRI (or variant), with or without biologics. 
• 
B2: 
− 
To evaluate the safety and tolerability (eg, number of patients experiencing DLTs, 
AEs/SAEs/irAEs, and abnormal hematology/clinical chemistry results) of TSR-033 and 


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d ostarli ma b  i n c o m bi nati o n a d de d t o F O L FI RI a n d be vaciz u ma b i n a nti-P D( L) -1 n aï ve 
patie nts  wit h a d va nce d or metastatic M S S -C R C f oll o wi n g pr o gressi o n o n fr o ntli ne 
treat me nt wit h F O L F O X ( or varia nt), wit h or wit h o ut bi ol o gics. 
Sec o n dar y:  
I n P art 1 a n d P art 2, u nless ot her wise s pecifie d: 
•  
T o c haracterize t he P K  (e g, ser u m c o nce ntrati o ns f or Part  1 a n d Part  2 a n d deri ve d P K 
para meters  for Part  1, as data per mit)  a n d i m m u n o ge nicit y of T S R -0 3 3 al o ne, T S R -0 3 3 a n d 
d ostarli ma b  i n c o m bi nati o n, a n d T S R-0 3 3 a n d d ostarli ma b  i n c o m bi nati o n wit h 
c he m ot hera p y a n d be vaciz u ma b.  
•  
T o ev al uate ad diti o n al measure s o f cli nical ben efit, i ncl u di n g 
− O R R b y  R E C IS T  v 1. 1 ( P art 1) 
− D u rati o n of res p o nse ( D O R)  b y  R E C IS T  v 1. 1  ( P art 2)  
− Disease c o ntr ol rate ( D C R)  b y R E CI S T  v 1. 1 ( P art 2 ) 
•  
B 1:  
− T o e val uate t he a nti -t u m or acti vit y of T S R-0 3 3 a n d d ostarli ma b  i n c o m bi nati o n a d de d 
t o m F O L F O X 6 a n d be vaciz u ma b i n patie nts wit h a d va nce d or metastatic M S S-C R C 
f oll o wi n g pr o gressi o n o n fr o ntli ne treat me nt wit h F O L FI RI, wit h or wit h o ut bi ol o gics, 
meas ure d b y t he O R R  as assessed b y  t he In v esti gat or usi n g  R E C IS T v 1. 1.  
•  
B 2:  
− T o e val uate t he a nti -t u m or acti vit y of T S R-0 3 3 a n d d ostarli ma b  i n c o m bi nati o n a d de d 
t o F O L FI RI a n d be vaciz u ma b i n patie nts wit h a d va nce d or metastatic M S S-C R C 
f oll o wi n g pr o gressi o n o n fr o ntli ne treat me nt wit h F O L F O X ( or varia nt), wit h or 
wit h o ut bi ol o g ics, meas ure d b y t he O R R  as assessed b y  t he In v esti gat or usi n g  R E C IS T 
v 1. 1.  
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
1 0  
 
Met h o d ol o g y:  
T his is a  m ulti -cent er, op en -lab el, first-in -h u m an,  P h ase 1 st u d y  ev al uatin g t he  anti -L A G -3 anti b o d y  
T S R -0 3 3 1) al o ne, 2) i n c o m bi nati o n wit h t he a nti -P D 1 a nti b o d y d ostarli ma b , a n d 3) i n c o m bi nati o n 
wit h d ostarli ma b , m F O L F O X 6 or F O L FI RI, a n d be vaciz u ma b. T he st u d y will be c o n d ucte d i n 2 parts, 
wit h Part 1 c o nsisti n g of d ose escalati o n t o deter mi ne t he R P 2 D of  T S R -0 3 3 as a si n gle a ge nt ( Part 1a) 
a n d i n c o m bi nati o n wit h d ostarli ma b  ( Part 1c). R P 2 D decisi o ns will be base d o n t he occ urre nce of 
D L Ts or P K/ P D y data, as a vaila ble. Part 1 b of t he st u d y will ai m t o better c haracterize t he P K pr ofile of 
T S R -0 3 3
 T hese a d diti o nal patie nts will n ot be 
c o nsi dere d e val ua ble f or d ose escalati o n p ur p oses ( ie, n ot i ncl u de d i nt o t he D L T-e val ua ble p o p ulati o n), 
b ut will c o ntri b ute t o t he o verall safet y assess me nt at t he d ose le vel be i n g e val uate d. T hese re gi me ns 
will be e val uate d i n p atients w it h ad v an ced or metastatic s oli d  t u m ors w h o h ave  li mited av ailable 
treat ment o pti o ns as determi n ed b y  t he In v estig ato r. 
Part 2 A of t he st u d y will i n vesti gate t he a nti -t u m or acti vit y of T S R-0 3 3 a n d d ostarli ma b  i n c o m bi nati o n 
i n patie nts wit h a d va nce d or metastatic M S S-C R C. W hile t he pri mar y o bjecti ve of t his part of t he st u d y 
is O R R b y I n vesti gat or assess me nt, c o pies of sca ns will be c ollecte d a n d st ore d at a re p osit or y f or 
p ote ntial e val uati o n.  
Part 2 B of t he st u d y will i n vesti gate t he safet y a n d a nti -t u m or acti vit y of T S R-0 3 3 a n d d ostarli ma b  i n 
c o m bi nati o n wit h c he m ot hera p y ( C o h ort B 1: m F O L F O X 6, C o h ort B 2: F O L FI RI) a n d be vaciz u ma b i n 
patie nts wit h a d va nce d or metastatic M S S -C R C. As t he pri mar y o bjecti ve of t his part of t he st u d y will 
be safet y a n d t olera bilit y, b ot h Part 2 B c o h orts will be gi n  b y e nr olli n g 6 patie nts eac h, wit h e nr oll me nt 
bei n g pa use d u ntil t he e n d of t he D L T o bser vati o n peri o d bef ore a n y f urt her e nr oll me nt i n t his ar m. 
W hile t he sec o n dar y o bjecti ve of t his part of t he st u d y is O R R b y I n vesti gat or assess me nt, c o pies of 
sca ns will be c ollecte d a n d st ore d at a re p osit or y f or p ote ntial e val uati o n. 
D L T criteria are detaile d i n t he pr ot oc ol. T o xicities will be assesse d acc or di n g t o C o m m o n T er mi n ol o g y 
Criteria f or A d verse E ve nts ( C T C A E) v 5. 0 . 
T he  st ud y  w ill be co n d u cted i n co n fo rm an ce w it h G o o d Cli ni cal Practice ( G C P) . 
T he desi g n sc he ma is prese nte d bel o w. T he starti n g d oses f or Part 2 ha ve bee n deter mi ne d base d o n 
safet y fi n di n gs i n earlier c o h orts. 
T he e n d of st u d y is defi ne d as t he date w he n t he last patie nt o n st u d y has c o m plete d h is/ her last st u d y 
visit.  
T he fi nal data c ut -off ( D C O) date f or t he st u d y wi ll be defi ne d b y t he S p o ns or a n d will be 
c o m m u nicate d t o all sites . T he D C O date re prese nts t he e n d of data c ollecti o n f or t he st u d y a n d t he date 
o n w hic h t he cli nical st u d y data bas e will be cl ose d t o ne w data.  
Patie nts i n S ur vi val F oll o w -U p at t he ti me of t he D C O date will be c o nsi dere d t o ha ve c o m plete d t he 
st u d y. Patie nts still o n treat me nt at t he ti me of t he D C O date ma y c o nti n ue t o recei ve st u d y treat me nt  
f or u p t o 2 years u nles s s pecific wit h dra wal criteria are met; patie nts ma y als o c h o ose t o disc o nti n ue 
st u d y treat me nt at a n y ti me. N ote:  St u d y treat me nt m ust be disc o nti n ue d bef ore t he T S R -0 3 3  st u d y dr u g 
s u p pl y e x pires. 
Patie nts w h o c o nti n ue st u d y treat me nt will be m o nit ore d a n d recei ve f oll o w -u p care i n acc or da nce wit h 
sta n dar d l ocal cli nical practice. Assess me nts will re vert t o t he sta n dar d of care at a patie nt’s partic ular 
st u d y site, a n d o nl y S A Es , A Es lea di n g t o disc o nti n uati o n of st u d y treat me nt, o ver d oses, a n d 
pre g na nci es will be re p orte d directl y t o t he S p o ns or via pa per f or ms. Alt h o u g h t he cli nical st u d y 
data base will be cl ose d at t he ti me of t he D C O date, t he st u d y will re mai n o pe n u ntil all patie nts 
disc o nti n ue st u d y treat me nt a n d t he e n d of st u d y defi niti o n ( n ote d a b o ve) is reac he d.  
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CONFIDENTIAL 
213349 (4040-01-001, CITRINO) 
Amd 05 (Version 6.0) 
11 
 
Overall Study Schema 
 
Abbreviations: CRC=colorectal cancer; DLT=dose-limiting toxicity; mg=milligrams; MSS=microsatellite stable; 
PDy=pharmacodynamics; PK=pharmacokinetics; Q2W=every 2 weeks; Q3W=every 3 weeks; Q6W=every 6 weeks; 
RP2D=recommended Phase 2 dose. 
a Approximately 72 patients in Parts 1a, 1b and 1c are expected, but this may increase to approximately 132 patients in total if 
the Sponsor and Investigators determine that additional safety and/or PK/PDy data are needed to confirm the RP2D for 
monotherapy. These enrollment numbers could increase if the Sponsor, in consultation with the Investigator, determine that 
additional cohorts consisting of 6-12 patients are needed to examine additional dose levels. At any dose level, where DLTs 
were observed in less than ⅓ of patients, in Part 1b, up to 6 additional patients may be enrolled to enable a better 
characterization of the PK/PDy data in order to confirm the RP2D. These enrollment numbers could further increase if the 
Sponsor, in consultation with the Investigators determine that an intermediate dose level(s), consisting of approximately 
6 patients requires exploration to better understand PK/PDy. 
b The starting dose of TSR-033 when used in combination with dostarlimab must be one dose level below the highest dose at 
which <⅓ of 6-12 patients experienced DLTs with single-agent TSR-033. 
c Doses presented in the schema represent the planned TSR-033 dose levels (subject to change based on safety and/or PK/PDy 
data). Dostarlimab will be given at a dose of 500 mg (Q3W) in Part 1c and 1000 mg Q6W in Part 2 of the study. These 
enrollment numbers could increase if the Sponsor, in consultation with the Investigator, determine that additional cohorts 
consisting of 6-12 patients are needed to examine additional dose levels. 
d Part 2 will enroll 2 disease-specific cohorts: Cohort A (third- or fourth-line MSS-CRC) and Cohort B (second-line 
MSS-CRC). The opening of enrollment of the expansion cohorts may not be simultaneous and is dependent on emerging data 
from ongoing studies. 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
1 2  
 
N u m ber  of P atie nts ( Pl a n ne d):  
A p pr o xi matel y 1 2 7 -1 8 7 patie nts are e x pecte d t o e nr oll i n t his st u d y i n t otal (all o wi n g f or re place me nt of 
patie nts a n d d ose e x pa nsi o n).  
Part 1: A t otal of u p t o a p pr o xi matel y 7 2 -1 3 2 patie n ts are a ntici pate d: 
P art 1 a ( T S R -0 3 3 m o n ot her a py d ose esc al ati o n):  A p pr o xi matel y 3 0 -5 4 patie nts  
P art 1 b ( T S R -0 3 3 m o n ot her a py P K/
): A p pr o xi matel y 1 8 -3 0 patie nts  
P art 1c ( T S R -0 3 3 + d ost arli m a b  c o m bi n ati o n d ose esc al ati o n):  A p pr o xi matel y 2 4 -4 8 patie nts  
T hese e nr oll me nt n u m bers c o ul d i ncrease if t he S p o ns or, i n c o ns ultati o n wit h t he I n vesti gat or, 
deter mi nes t hat a d diti o nal c o h orts c o nsisti n g of 6 -1 2 patie nts are nee de d t o e xa mi ne a d diti o nal d ose 
le vels. 
Part 2: A t otal of u p t o a p pr o xi matel y 5 5 patie nts are a ntici pate d: 
P art 2 C o h ort A ( T S R -0 3 3 + d ost arli m a b  c o m bi n ati o n d ose ex p a nsi o n i n a nti -P D -1 -n aïve t hir d - or 
f o urt h-li ne M S S-C R C p atie nts):  A p pr o xi matel y 3 1 patie nts . 
P art 2 C o h ort B 1 ( T S R -0 3 3 + d ost arli m a b  c o m bi n ati o n give n  wit h m F O L F O X 6 a n d bev aciz u m a b 
[ S O C] i n a nti-P D -1 -n aïve sec o n d -li ne M S S-C R C p atie nts w h o h ave pr o gresse d o n fr o ntli ne tre at me nt 
wit h F O L FI RI, wit h or wit h o ut bi ol o gics ): A p pr o xi matel y 1 2 patie nts.  
P art 2 C o h ort B 2 ( T S R -0 3 3 + d ost arli m a b  c o m bi n ati o n give n w it h F O L FI RI a n d bev aciz u m a b [ S O C] 
i n a nti-P D -1 -n aïve sec o n d -li ne M S S-C R C p atie nts w h o h ave pr o gresse d o n fr o ntli ne tre at me nt wit h 
F O L F O X [ or v ari a nt], wit h or wit h o ut bi ol o gics ): A p pr o xi matel y 1 2 patie nts.  
S h o ul d e nr oll me nt i n C o h ort B 1 la g, all o wa nce will  be ma de t o i ncrease t he n u m b er of patie nts e nr olle d 
i n C o h ort B 2 after D L T cleara nce of t he first 6 patie nts, s uc h t hat a n a d diti o nal 6 t o 1 8 ma y be e nr olle d. 
T he t otal f or Part 2 B as a w h ole re mai ns at 2 4.  
M ai n P atie nt Selecti o n Criteri a  
•  
Ke y I ncl usi o n C riteria f or Patie nts i n Part 1: 
− T he patie nt has a n y hist ol o gicall y or c yt ol o gicall y c o nfir me d a d va nce d ( u nresecta ble) 
or metastatic s oli d t u m or a n d has pr o gressi ve disease  ( P D) after treat me nt wit h 
a vaila ble t hera pies t hat are k n o w n t o c o nfer cli nical be nefit or w h o are i nt olera nt t o 
treat me nt. 
− T he patie nt m ust ha ve a n arc hi val t u m or tiss ue sa m ple t hat is f or mali n -fi xe d a n d 
paraffi n -e m be d de d ( F F P E) ( bl oc ks preferre d o ver sl i des) a n d re q ueste d a n d c o nfir me d 
a vaila ble fr o m offsite l ocati o ns pri or t o d osi n g. T he q ualit y a n d q ua ntit y of t he sa m ple 
m ust be c o nfir me d s ufficie nt as per t he St u d y La b orat or y Ma n ual. Patie nts w h o d o n ot 
ha ve arc hi val tiss ue m ust a gree t o a ne w bi o ps y t o o btai n fres h t u m or tiss ue pri or t o 
d osi n g.  
− Part 1 b ( P K/ P D y  c o h ort): T he patie nt m ust ha ve lesi o ns a me na ble f or bi o ps y a n d a gree 
t o u n der g o bi o psies f or fres h t u m or tiss ue pri or t o treat me nt, a p pr o xi matel y 4 t o 
6  wee ks after i nitiati n g st u d y treat me nt, a n d, w he ne ver p ossi ble, at e n d of treat me nt 
(E O T ) a n d/ or t he ti me of P D. Serial bi o psies are o pti o nal f or patie nts i n Part 1a a n d 1c.  
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CONFIDENTIAL 
213349 (4040-01-001, CITRINO) 
Amd 05 (Version 6.0) 
13 
 
• 
Key Inclusion Criteria for Patients in Part 2: 
− 
The patient has any histologically or cytologically confirmed CRC that is metastatic or 
not amenable to potentially curative resection (advanced), in the opinion of the 
Investigator. 
− 
The patient has a primary and/or metastatic tumor(s) that is known to be MSS, as 
determined locally. 
− 
The patient must have lesions amenable for biopsy and agree to undergo biopsies for 
fresh tumor tissue prior to treatment, approximately 4 to 6 weeks after initiating study 
treatment, and, whenever possible, at EOT and/or the time of PD. If the patient has had 
a biopsy prior to entering the 28-day screening period, and within approximately 12 
weeks of study treatment, that biopsy sample may be accepted as the baseline fresh 
biopsy. Additionally, submission of sufficient high-quality archival tissue is 
recommended, if available, to enable a longitudinal analysis of tumor biomarkers. 
− 
The patient has measurable disease by RECIST v1.1. 
− 
The patient must have a baseline albumin ≥3.0 g/dL. 
• 
Key Inclusion Criteria for Patients in Part 2A: 
− 
The patient must have had at least 2, but no more than 3, prior lines of therapy in the 
advanced or metastatic setting. Adjuvant chemotherapy with radiographic progression 
>12 months after the last dose will not be considered a line of therapy. 
− 
The patient has progressed on standard therapies or withdrawn from standard treatment 
due to unacceptable toxicity. Previous standard treatment must include all of the 
following: a) fluoropyrimidine, b) oxaliplatin (patients treated with oxaliplatin in 
adjuvant setting should have progressed after 12 months of completion of adjuvant 
therapy or they must have been treated with oxaliplatin for metastatic disease), c) 
irinotecan, d) patients whose disease is known to be RAS-wild-type must have been 
treated with cetuximab, panitumumab, or other EGFR inhibitor for metastatic disease, 
and e) bevacizumab and/or another anti-angiogenic agent, and f) previous treatment 
with regorafenib and/or TAS-102 are allowed in the absence of contraindications and if 
these agents are available to the patient according to local standards. 
− 
The time between a patient’s last chemotherapy and enrollment must be ≤8 weeks. 
• 
Key Inclusion Criteria for Patients in Part 2B: 
− 
The patient has received ≤2 prior systemic chemotherapy regimens in any setting (only 
1 prior regimen for metastatic disease is permitted). 
• 
Key Inclusion Criteria for Patients in Part 2 Cohort B1: 
− 
The patient has received first-line combination therapy consisting of bevacizumab or 
anti-EGFR antibodies with FOLFIRI and has experienced radiographic progression 
during or after first-line therapy. Radiographic progression >12 months after the last 
dose of adjuvant therapy will not be considered a line of therapy. 


TMF-14403236 
CONFIDENTIAL 
213349 (4040-01-001, CITRINO) 
Amd 05 (Version 6.0) 
14 
 
− 
mFOLFOX6 therapy with bevacizumab is appropriate for the patient and is 
recommended by the Investigator. 
• 
Key Inclusion Criteria for Patients in Part 2 Cohort B2: 
− 
The patient has received first-line combination therapy consisting of bevacizumab or 
anti-EGFR antibodies with FOLFOX (or variant) and has experienced radiographic 
progression during or after first-line therapy. Radiographic progression >12 months 
after the last dose of adjuvant therapy will not be considered a line of therapy. 
− 
FOLFIRI therapy with bevacizumab is appropriate for the patient and is recommended 
by the Investigator. 
• 
Key Exclusion Criteria for all Patients: 
− 
The patient has previously been treated with an anti-LAG-3 antibody. 
− 
The patient has known uncontrolled central nervous system (CNS) metastases and/or 
carcinomatous meningitis. 
− 
The patient has a known concurrent, serious, uncontrolled medical disorder, 
nonmalignant systemic disease, or active infection requiring systemic therapy, 
including human immunodeficiency virus (HIV), known active hepatitis B or hepatitis 
C, active infection, or active autoimmune disease. 
− 
The patient is pregnant or breastfeeding, or expecting to conceive children within the 
projected duration of the study. 
− 
The patient has a history of interstitial lung disease. 
− 
The patient has not recovered (ie, to Grade ≤1 or to baseline) from radiation- and 
chemotherapy-induced AEs, has received transfusion of blood products (including 
platelets or red blood cells), or has received administration of colony stimulating factors 
(including granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage 
colony-stimulating factor, or recombinant erythropoietin) within 3 weeks prior to the 
first dose of study drug. 
− 
The patient is currently participating in an investigational study (therapy or device) or 
has participated in an investigational study within 4 weeks prior to the first dose of 
study drug. 
− 
The patient has received prior anti-cancer therapy (chemotherapy, targeted therapies, 
radiotherapy, or immunotherapy) within 21 days or less than 5 times the half-life of the 
most recent therapy prior to the first dose of the drug, whichever is shorter. 
− 
The patient has not recovered (Grade ≥1) from AEs and/or complications from any 
major surgery prior to the first dose of study drug. 
− 
The patient has received a vaccine within 7 days of the first dose of study drug. 
− 
The patient has known hypersensitivity to TSR-033, dostarlimab (Part 1c and Part 2), or 
associated excipients. 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
1 5  
 
•  
Ke y E xcl usi o n Criteria f or Patie nts i n Part 1:  
− Pri or treat me nt wit h a n a nti -P D -1, a nti -P D -L 1, a nti -P D -L 2, or a nti -L A G -3 a ge nt t hat 
res ulte d i n per ma ne nt disc o nti n uati o n d ue t o a n A E. 
•  
Ke y E xcl usi o n Criteri a f or Patie nts i n Part 2:  
− T he patie nt has bee n pre vi o usl y treate d wit h a n a nti -P D -1  or a nti -P D -L 1  a nti b o d y.  
•  
Ke y E xcl usi o n Criteria f or Patie nts i n Part 2 B:  
− T he patie nt has k n o w n h y perse nsiti vit y t o be vaciz u ma b, m F O L F O L X 6 ( C o h ort B 1) or 
F O L FI RI ( C o h ort B 2),  or ass ociate d e xci pie nts . 
− T he patie nt e x perie nce d P D wit hi n 1 2 m o nt hs of last d ose of a dj u va nt t hera p y.  
P h ar m ac o ki netics a n d A nti dr u g A nti b o d y A n al ysis  
Bl o o d sa m ples f or t he deter mi nati o n of ser u m le vels of T S R -0 3 3 a n d d ostarli ma b  will be c ollecte d fr o m 
patie nts i n b ot h Part 1 a n d Part 2. Sa m pli n g ti mes f or bl o o d P K a nal ysis are detaile d i n t he pr ot oc ol. All 
sa m pli n g ti mes are relati ve t o t he start of t he T S R-0 3 3 i nf usi o n.  
I n Part 1 b, a c o h ort(s) of u p t o 6 a d diti o nal patie nts ma y be e nr olle d i n a n y d ose le vel wit h D L Ts 
o bser ve d i n < ⅓ of patie nts t o better c haracterize t he P K pr ofile
. I n t his c o h ort(s), patie nts will recei ve t heir T S R-0 3 3 d oses o n Da y 1, Da y 2 9, a n d Q 2 W 
t hereafter. T he exte n de d treat me nt d urati o ns i n t he a bse nce of a Da y 1 5 d ose e na bles better 
c haracterizati o n of t he ter mi nal p hase of t he P K pr ofile, w hic h ca n lea d t o m ore acc urate calc ulati o ns of 
P K para meters (s uc h as  ter mi nal half-life [t½ ]). A d diti o nall y, t his e xte n ded treat me nt i nter val will 
pr o vi de a d diti o nal P D y  data t hat ma y c o ntri b ute t o t he deter mi nati o n of t he R P 2 D. T he decisi o n 
re gar di n g w hic h c o h ort(s) t o e x pa n d f or t his e val uati o n will be deter mi ne d b y t he S p o ns or a n d t he 
I n vesti gat ors. 
T he ser u m sa m ples f or P K deter mi nati o n will be a nal yze d usi n g e nz y me -li n ke d i m m u n os or be nt assa y 
( E LI S A). 
A nti dr u g A nti b o d y A nal ysis  
T he ser u m sa m ples f or t he deter mi nati o n of a nti -T S R -0 3 3 a nti b o dies a n d a nti -d ostarli ma b  a nti b o dies 
will be t he sa me sa m ples c ollecte d as f or P K. A nti dr u g a nti b o d ies ( A D As) will be a nal yze d usi n g 
electr oc he mil u mi nesce nce ( E C L) wit h pre -d ose sa m ples fr o m all d oses c ollecte d a n d ter mi nal p hase 
sa m ples, as a p pr o priate, fr o m t he first a n d si xt h d oses f or Part 1 patie nts. F or all patie nts, a d diti o nal 
sa m ples f or A D A deter mi nati o n will be c ollecte d u p o n treat me nt disc o nti n uati o n at a safet y f oll o w-u p 
( F U P) visit. 
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T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
1 6  
 
I n vesti g ati o n al Pr o d uct, D os a ge, a n d M o de of A d mi nistr ati o n:  
T S R -0 3 3 is a h u ma nize d m o n ocl o nal I g G 4 a nti b o d y a n d will be s u p plie d as a s ol uti o n i n vials 
c o ntai ni n g 8 0 a n d 1 6 0 m g ( 2 0  m g/ m L). T hr o u g h o ut t he st u d y, T S R -0 3 3 will be a d mi nistere d via a n 
a p pr o xi matel y 3 0 -mi n ute i ntra ve n o us (I V) i nf usi o n pri or t o t he a d mi ni strati o n of d ostarli ma b . 
D ostarli ma b ( pre vi o usl y referre d t o as T S R -0 4 2)  is a h u ma nize d m o n ocl o nal I g G 4 a nti b o d y a n d will be 
s u p plie d as a s ol uti o n i n vials c o ntai ni n g 5 0 0 m g ( 5 0 m g/ m L). T he 5 0 m g/ m L c o nce ntrati o n will o nl y 
be i ntr o d uce d after a p pr o val b y healt h a ut h orities. D ostarli ma b  will als o be a d mi nistere d via a 3 0 ( -5 
a n d + 1 5) mi n ute I V i nf usi o n , at e ver y t hir d d ose  of T S R -0 3 3 , wit h a 2 -h o ur o bser vati o n peri o d o n Da y 
1. S h o ul d n o i nf usi o n reacti o ns (Irs) occ ur, o bser vati o n ca n be re d uce d t o 1 h o ur, t he n t o 3 0 mi n utes.  
F or t he d o u blet c o m bi nati o n, T S R -0 3 3 will be a d mi nistere d first, f oll o we d b y d ostarli ma b . 
I n Part 2 B, t he i n vesti gati o nal dr u gs T S R-0 3 3 a n d d ostarli ma b  will be gi ve n i n c o m bi nati o n wit h t he 
c urre nt S O C i n C R C, c he m ot hera p y ( m F O L F O X 6 [ C o h ort B 1] or F O L FI RI [ C o h ort B 2]) wit h 
be vaciz u ma b.  
N ote: I nf usi o n ti mes descri be d bel o w are a p pr o xi mate. 
m F O L F O X 6 will be a d mi nistere d at a d ose of 8 5 m g/ m 2 of o xali plati n  I V o ver 2 h o ur s, 4 0 0 m g/ m 2 of 
le uc o v ori n I V o ver 2 h o urs, f oll o we d b y 4 0 0 m g/ m2 of 5 -fl u or o uracil I V b ol us o ver 2-4  mi n utes, a n d a 
c o nti n u o us i nf usi o n of 2 4 0 0 m g/ m 2 of 5 -fl u or o uracil o ver 4 6 h o urs. T his re gi me n will be re peate d e ver y 
2 wee ks ( Q 2 W).  Ot her variati o n o n t he a d mi nistrati o n sc he d ule ma y be c o nsi dere d u p o n disc ussi o n 
wit h t he Me dical M o nit or.  
F O L FI RI will be a d mi nistere d at a d ose of 1 8 0 m g/ m 2 of iri n oteca n I V o ver 9 0 mi n utes, wit h 
4 0 0  m g/ m 2 of le uc o v ori n I V o ver 9 0 mi n utes, f oll o we d b y 4 0 0 m g/ m2 of 5 -fl u or o uracil I V b ol us, a n d a 
c o nti n u o us i nf usi o n of 2 4 0 0 m g/ m 2 5 -fl u or o uracil I V o ver 4 6 h o urs. Ot her variati o n o n t he 
a d mi nistrati o n sc he d ule ma y be c o nsi dere d u p o n disc ussi o n wit h t he Me dical M o nit or.  
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T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
1 7  
 
F or t he d o u blet c o m bi nati o n wit h c he m ot hera p y,  t he c he m ot hera p y re gi me n will be a d mi nistere d 2 da ys 
pri or ( Da y 1) t o t he a d mi nistrati o n of T S R -0 3 3 a n d d ostarli ma b , w hic h will be gi ve n o n Da y 3 of t he 
d ose c ycle . 
Pre me dicati o n wit h a nti -e metics a n d atr o pi ne f or iri n oteca n are per mitte d . 
Be vaciz u ma b will be a d mi nistere d at 5 m g/ k g o n Da y 1 pri or t o c he m ot hera p y a n d re peate d Q 2 W. 
Be vaciz u ma b will be a d mi nistere d via a 3 0 ( -5 a n d + 1 5) mi n ute I V i nf usi o n ( u nless a l o n ger sc he d ule 
was pre vi o usl y t olerate d) wit h a 1 5 -mi n ute o bser vati o n peri o d (ass u mi n g pre vi o usl y t olerate d).  
T he ti me f or t he first t otal d ose f or patie nts recei vi n g t he treat me nt re gi me n i ncl u di n g m F O L F O X 6 
c he m ot hera p y is 8 -9 h o urs. T he ti me f or t he first t otal d ose f or patie nts recei vi n g t he treat me nt re gi me n 
i ncl u di n g F O L FI RI c he m ot hera p y is 7 t o 8 h o urs . 
G -C S F ca n be use d acc or di n g t o t he A merica n S ociet y of Cli nical O nc ol o g y g ui deli nes  
O xali plati n ma y be disc o nti n ue d after 6 c ycles t o re d uce t he p ote ntial f or ne ur o pat h y s h o ul d it be 
dee me d a p pr o priate b y t he In vesti gat or.  
C o h ort -s pecific dose a n d sc he d ule details  
P art 1 a : T S R-0 3 3 will be a d mi nistere d e ver y 1 4 da ys ± 1 da y ( Q 2 W) or e ver y 2 1 da ys ± 1 da y ( Q 3 W) . 
T he pla n ne d asce n di n g d oses i n Part 1a of t he st u d y are 2 0, 8 0, a n d 2 4 0 m g Q 2 W. F urt her d ose 
escalati o n t o 7 2 0 m g Q 2 W ma y als o be asses se d i n a n a d diti o nal c o h ort(s) f oll o wi n g a gree me nt 
bet wee n t he I n vesti gat ors a n d S p o ns or. A d diti o nal c o h orts c o nsisti n g of 6 -1 2 patie nts t o e xa mi ne 
a d diti o nal d ose le vels ma y als o be e x pl ore d, if warra nte d, f oll o wi n g a gree me nt bet wee n t he 
I n vesti gat ors a n d S p o ns or . 
P art 1 b: A c o h ort(s) of u p t o 6 a d diti o nal patie nts ma y be e nr olle d i n a n y d ose le vel wit h D L Ts 
o bser ve d i n < ⅓ of patie nts t o better c haracterize t he P K pr ofile of T S R -0 3 3 
 I n t his c o h ort(s) patie nts will recei ve t heir T S R-0 3 3 d ose o n  
Da y 1, Da y 2 9, a n d c o nti n ue Q 2 W t hereafter.  
P art 1c: T S R -0 3 3 will be a d mi nistere d wit h d ostarli ma b  Q 3 W t hr o u g h o ut Part 1c, a n d patie nts will 
recei ve d ost arli ma b at a d ose of 5 0 0 m g i n c o m bi nati o n wit h asce n di n g d oses of T S R -0 3 3 Q 3 W. T he 
starti n g d ose of T S R-0 3 3 w he n use d i n c o m bi nati o n wit h d ostarli ma b  m ust be o ne d ose le vel bel o w t he 
hi g hest d ose at w hic h < ⅓ of patie nts e x perie nce d D L Ts wit h si n gle -a ge nt T S R -0 3 3. Pla n ne d d ose le vels 
of T S R -0 3 3 i ncl u de 8 0 a n d 2 4 0 m g. A hi g her d ose le vel of 7 2 0 m g Q 3 W ma y be e x pl ore d, if warra nte d, 
base d o n tar get e x p os ure a n d safet y fi n di n gs. A d diti o nal c o h orts c o nsisti n g of 6 -1 2 patie nts t o e xa mi ne 
a d diti o nal d ose le vels ma y als o be e x pl ore d, if warra nte d, f oll o wi n g a gree me nt bet wee n t he 
I n vesti gat ors a n d S p o ns or. D ostarli ma b  at a d ose of 1 0 0 0 m g ma y als o be teste d wit h t he R P 2 D of 
T S R -0 3 3 gi ve n o n a n e ver y -6 -wee ks  (Q 6 W ) sc he d ule. F or all a d mi nistrati o ns of t he c o m bi nati o n 
re gi me n, T S R-0 3 3 will be gi ve n first, f oll o we d b y d ostarli ma b . 
P art 2 A : F oll o wi n g c o m pleti o n of t he T S R-0 3 3 i nf usi o n, d ostarli ma b  ( 1 0 0 0 m g) will be a d mi nistere d 
via a 3 0 -mi n ute I V i nf usi o n ( -5 mi n ute a n d + 1 5 mi n ute). T S R -0 3 3 will be gi ve n o n a Q 2 W sc he d ule 
a n d d ostarli ma b  o n a Q 6 W sc he d ule. If e mer gi n g safet y a n d/ or P K data i n dicate t hat e x pl orati o n of a 
l o wer T S R-0 3 3 d ose is warra n te d, a n a d diti o nal c o h ort ma y be o pe ne d. 
T he P har mac y Ma n ual c o ntai ns s pecific i nstr ucti o ns f or t he pre parati o n of eac h d ose a n d a d mi nistrati o n 
of t he i nf usi o n s ol uti o n.  
P art 2 C o h ort B 1: I nitiall y, a 6-patie nt r u n -i n wit h m F O L F O X 6 pl us be vaciz u ma b re gi me n will be 
teste d f or safet y, wit h t he p ote ntial t o a d d 6 a d diti o nal patie nts, f or a t otal of 1 2 patie nts. T he D L T 
o bser vati o n peri o d will be fr o m D ose 1, Da y 1, t hr o u g h D ose 3, Da y 3, pri or t o t he start of i nf usi o n. 
F oll o wi n g t he D L T o bser vati o n peri o d, if ≥2 D L Ts are o bser ve d, a d ose le vel re d ucti o n of T S R -0 3 3 t o 
2 4 0 m g ca n be c o nsi dere d ( d ose le vel -1). T his d ose le vel w o ul d t he n e nr oll 6 patie nts. Alter nati vel y, if 
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<2 DLTs are observed during the DLT observation period, 6 additional patients may be enrolled at that 
dose level to confirm safety and collect preliminary efficacy data. 
Part 2 Cohort B2: Initially, a 6-patient run-in with FOLFIRI plus bevacizumab regimen will be tested 
for safety, with the potential to add 6 additional patients, for a total of 12 patients. The DLT observation 
period will be from Dose 1, Day 1, through Dose 3, Day 3, prior to the start of infusion. Following the 
DLT observation period, if ≥2 DLTs are observed, a dose level reduction of TSR-033 to 240 mg can be 
considered (dose level -1). This dose level would then enroll 6 patients. Alternatively, if <2 DLTs are 
observed during the DLT observation period, 6 additional patients may be enrolled at that dose level to 
confirm safety and collect preliminary efficacy data. Should enrollment in Cohort B1 fall behind, 
allowance will be made to increase the number of patients enrolled in Cohort B2 after DLT clearance of 
the first 6 patients, such that an additional 6 to 18 may be enrolled. The total for Part 2B as a whole 
remains at 24. 
Please refer to the Pharmacy Manual for details on the preparation and administration of the infusion 
solutions for TSR-033 and dostarlimab. 
mFOLFOX6 or FOLFIRI and TSR-033 will be given on a Q2W schedule and dostarlimab on a Q6W 
schedule. 
The full infusion schedule will be as follows: 
Part 2 Cohort B1: Infusion times (per dose cycle): 
Note: Infusion times described below are approximate. 
1. Bevacizumab (Day 1): 30-minute infusion, unless a longer schedule was previously tolerated; 
15 minutes observation (assuming previously tolerated). 
2. Oxaliplatin with leucovorin (Day 1): 2-hour infusion. (Part of mFOLFOX6 regimen). 
3. 5-Fluorouracil (Day 1): 2-4 minutes. (Part of mFOLFOX6 regimen). 
4. 5-Fluorouracil (Day 1-3): continuous infusion, 46-hours. (Part of mFOLFOX6 regimen). 
5. TSR-033 (Day 3): 30-minute infusion. 
6. Dostarlimab (Day 3, every third dose of TSR-033): 30-minute infusion; 2-hour observation for 
first dose. Should no Irs occur, observation can be reduced to 1 hour for second dose, then to 30 
minutes thereafter. 
Part 2 Cohort B2: Infusion times (per dose cycle): 
Note: Infusion times described below are approximate. 
1. Bevacizumab (Day 1): 30-minute infusion, unless a longer schedule was previously tolerated; 
15 minutes observation (assuming previously tolerated). 
2. Irinotecan with leucovorin (Day 1): 90 minutes. (Part of FOLFIRI regimen). 
3. 5-Fluorouracil (Day 1): 2-4 minutes. (Part of FOLFIRI regimen). 
4. 5-Fluorouracil (Day1-3): continuous infusion, 46-hours. (Part of FOLFIRI regimen). 
5. TSR-033 (Day 3): 30-minute infusion. 
6. Dostarlimab (Day 3, every third dose of TSR-033): 30-minute infusion; 2-hour observation for 
first dose. Should no Irs occur, observation can be reduced to 1 hour for second dose, then to 30 
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Part 2B Dosing Schema: 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11a 
Dose 1b 
 
Dose 2b 
 
Dose 3b 
 
Dose 4b 
 
Dose 5b 
 
Dose 6b 
Bevacizumab 
 
Bevacizumab 
 
Bevacizumab 
 
Bevacizumab 
 
Bevacizumab 
 
Bevacizumab 
mFOLFOX6c 
or FOLFIRId 
 
mFOLFOX6c 
or FOLFIRId 
 
mFOLFOX6c 
or FOLFIRId 
 
mFOLFOX6c 
or FOLFIRId 
 
mFOLFOX6c 
or FOLFIRId 
 
mFOLFOX6c 
or FOLFIRId 
TSR-033 
(Day 3) 
 
TSR-033 
(Day 3) 
 
TSR-033 
(Day 3) 
 
TSR-033 
(Day 3) 
 
TSR-033 
(Day 3) 
 
TSR-033 
(Day 3) 
Dostarlimab 
(Day 3) 
 
 
 
 
 
Dostarlimab 
(Day 3) 
 
 
 
 
Abbreviation: Wk=week. 
a This treatment regimen may be continued for so long as the patient is, in the opinion of the Investigator, benefiting from 
treatment. 
b Drug administered on Day 1 unless otherwise noted. 
c Cohort B1. 
d Cohort B2. 
Duration of Treatment: 
Planned Study Conduct Duration: Approximately 42 months (time from first patient enrolled until 
study cut-off [when responder or discontinuation status for all patients is known]). 
Planned Study Treatment Duration: Enrolled patients may continue study treatment for up to 2 years or 
until PD, unacceptable toxicity, patient withdrawal, Investigator’s decision, or death. Continued study 
treatment beyond 2 years may be considered following discussion between the Sponsor and 
Investigator. 
Criteria for Evaluation: 
Pharmacokinetics: 
Serum samples for PK determination will be collected prior to, during, and after treatment with 
TSR-033 alone or in combination with dostarlimab, and the dual immunotherapy regimen in 
combination with chemotherapy and bevacizumab as described in the protocol. 
Serum samples for ADA assessments will be collected prior to, during, and after treatment with  
TSR-033 alone or in combination with dostarlimab, and the dual immunotherapy regimen in 
combination with chemotherapy and bevacizumab. Results of ADA assays (screening, confirmation, 
and neutralizing antibody [NAb]) will be correlated with clinical activity, PK, as well as safety 
assessments. 
Pharmacodynamics: 
During Part 1 and Part 2, blood cells may be assessed for LAG-3 receptor occupancy according to the 
schedule detailed in the protocol. 
In addition, these analyses may include, but are not limited to, assessing changes in circulating immune 
cells, serum cytokines, ctDNA, and soluble LAG-3 to better characterize the clinical activity of  
TSR-033 and may be considered for selection of the RP2D. 
Safety: 
Safety assessments conducted throughout the treatment period include symptom-directed physical 
examinations, AE and DLT assessment, vital signs, electrocardiograms (ECGs), ECOG PS, and clinical 
laboratory assessments, including complete blood count (CBC) with 5-part differential, coagulation 
factors, chemistry, thyroid panel (ie, thyroid-stimulating hormone [TSH], triiodothyronine [T3], free 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
2 0  
 
trii o d ot h yr o ni ne [ F T 3], t h yr o xi ne [ T4], free t h yr o xi ne [ F T 4], or e q ui vale nt tests, w here a p plica ble), 
u ri naly sis, an d p reg n an c y  testi n g. 
St atistic al Met h o ds:  
All descri pti ve statistical a nal yses will be perf or me d usi n g t he m ost rece ntl y release d a n d a vaila ble S A S 
statistical s oft ware, u nless ot her wise n ote d. F or cate g orical varia bles, t he n u m ber a n d perce nt of eac h 
cate g or y wit hi n a para meter will be calc ulate d. F or c o nti n u o us varia bles, t he sa m ple size ( n), mea n, 
me dia n, a n d sta n dar d de viati o n, as well as t he mi ni m u m a n d ma xi m u m val ues, will be prese nte d. 
Missi n g data will n ot be i m p ute d u nless ot her wise state d. T here will be a detaile d descri pti o n of patie nt 
dis p ositi o n; patie nt de m o gra p hics a n d baseli ne c haracteristics wil l be s u m marize d. 
N o f or mal i nteri m a nal ysis is pla n ne d f or t his st u d y. H o we ver, a re vie w of safet y data a n d a vaila ble 
preli mi nar y P K data will be c o n d ucte d b y t he S p o ns or a n d I n vesti gat ors f oll o wi n g c o m pleti o n of t he 
D L T o bser vati o ns peri o ds i n Part 1a, Pa rt 1c, a n d Part 2 B. Deter mi nati o n of t he R P 2 D will be base d o n 
re vie w of safet y, P K, a n d P D y  data. A statistical a nal ysis pla n ( S A P) will f ull y descri be t he pla n ne d 
a nal yses f or t his trial. All a nal yses will be perf or me d f or a n y patie nt t hat recei ve d a n y a m o u nt of st u d y 
dr u g. All a nal yses f or efficac y will use D ose 1, Da y 1 as t he start ti me.  
Sa m ple Size  
Asce n di n g d oses of T S R -0 3 3 i n Part 1a a n d i n c o m bi nati o n wit h d ostarli ma b  i n Part 1c will be 
e val uate d t o i de ntif y t he R P 2 Ds. T he act ual n u m ber of patie nts  accr ue d d uri n g t his p hase will be 
deter mi ne d lar gel y b y t he safet y a n d P K fi n di n gs o bser ve d d uri n g t he c o urse of t heir treat me nt. R P 2 D 
decisi o ns f or Part 1a a n d Part 1c will be base d o n a mi ni m u m of 6 patie nts f or eac h re gi me n. Patie nts i n 
Part 1 b ( P K/ P D y  c o h ort) will n ot be c o nsi dere d e val ua ble f or d ose escalati o n p ur p oses ( ie, n ot i ncl u de d 
i nt o t he D L T-e val ua ble p o p ulati o n) b ut will c o ntri b ute t o t he o verall safet y assess me nt at t he d ose le vel 
bei n g e val uate d. It is e x pecte d t hat u p t o a p pr o xi matel y 1 3 2 patie nts will be e nr olle d i n Part 1 as 
f oll o ws: 
P art 1 a ( T S R -0 3 3 m o n ot her a py d ose esc al ati o n):  A p pr o xi matel y 3 0 -5 4 patie nts  
P art 1 b ( T S R -0 3 3 P K/
: A p pr o xi matel y 1 8 -3 0 patie nts  
P art 1c ( T S R -0 3 3 + d ost arli m a b  d ose esc al ati o n):  A p pr o xi mate l y 2 4-4 8 patie nts  
A t otal of u p t o a p pr o xi matel y 5 5 patie nts are a ntici pate d i n t he 2 pla n ne d e x pa nsi o n c o h orts i n Part 2. 
I n eac h e x pa nsi o n c o h ort, a n e xact si n gle sta ge desi g n will be use d. Eac h c o h ort is desi g ne d wit h a o ne-
si de d t y pe I err or rate of 1 0% a n d a p o wer of 8 0 % . 
P art 2 A ( T S R -0 3 3 + d ost arli m a b  c o m bi n ati o n d ose ex p a nsi o n i n a nti -P D -1 -n aïve t hir d - or f o urt h -li ne 
M S S -C R C p atie nts):  A n ull h y p ot hesis of O R R 1 0 % will be teste d a gai nst a n alter nati ve h y p ot hesis of 
O R R 2 5 %. T he trial is desi g ne d usi n g a o ne -si de d e xact test t hat ac hie ves a mi ni m u m of 8 0 % p o wer at 
al p ha le vel of 0. 1. A sa m ple size of 3 1 will pr o vi de a n attai ne d p o wer of 8 2. 4 % a n d a n attai ne d t y pe -1 
err or of 0. 0 8 3. T he n ull h y p ot hesis will be rejecte d if 6 or m ore res p o nses are o bser ve d i n t he 3 1  
patie nts . 
P art 2 B ( T S R -0 3 3 + d ost arli m a b  c o m bi n ati o n give n i n wit h m F O L F O X 6 or F O L FI RI a n d bev aciz u m a b 
[ S O C] i n a nti-P D -1 -n aïve sec o n d-li ne M S S-C R C p atie nts) A n ull h y p ot hesis of O R R 2 0 % will be 
teste d a gai nst a n alter nati ve h y p ot hesis of O R R 4 0 %. T he trial is desi g ne d usi n g a o ne-si de d e xact test 
t hat ac hie ves a mi ni m u m of 8 0 % p o wer at al p ha le vel of 0. 1. A sa m ple size of 2 4 will pr o vi de a n 
attai ne d p o wer of 8 0. 8 % a n d a n attai ne d t y pe -1 err or of 0. 0 8 9. T he n ull h y p ot hesis will be rejecte d if 8 
or m ore res p o nses are o bser ve d i n t he 2 4 patie nts . 
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Pharmacokinetic Analysis 
Noncompartmental methods will be used to evaluate the PK characteristics of TSR-033 in Part 1a and 
Part 1b and TSR-033 and dostarlimab in Part 1c and Part 2, as appropriate. PK parameters such as 
maximum concentration (Cmax), time at maximum concentration (Tmax), area under the 
concentration-time curve (AUC), t½, volume of distribution at steady state (Vss), and clearance (CL) 
may be derived from serum concentrations using actual sampling times, as data permit. 
Concentration-time data and PK parameters will be listed and summarized descriptively by cohort, dose 
level, and dose number. Concentration data may be included in a population PK analysis, the results of 
which will be reported separately. 
Safety Analyses 
AEs, concomitant medication, and results from physical examination will be listed. 
AEs will also be coded with the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized per system organ class and preferred term. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(September 2016 or later version). A dictionary listing of all unique concomitant medications used in 
the study will be provided. 
All hematology, blood chemistry, and ECG results will be listed per patient for each assessment, and 
descriptive statistics will be tabulated for select criteria. Serum will be evaluated for the presence of 
ADAs. 
Efficacy Analyses 
ORR will be calculated for Part 2 and will be summarized and presented in tables and listings. All 
analyses will include summary statistics, including number of patients (n) and percentage (%) for 
categorical variables and number of patients, mean, standard deviation, median, minimum, and 
maximum for continuous variables. Time-to-event analyses will be performed using Kaplan-Meier 
(KM) methods.22 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
2 2  
 
T A B L E O F C O N T E N T S  
TI T L E P A G E  ...................................................................................................................................1  
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S  ..........................................................2  
S Y N O P SI S  6  
T A B L E O F C O N T E N T S  ...............................................................................................................2 2  
LI S T O F T A B L E S  .........................................................................................................................2 8  
LI S T O F FI G U R E S  .......................................................................................................................2 9  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  ................................................3 0  
1.  
I N T R O D U C TI O N ......................................................................................................3 5  
1. 1.  
Bac k gr o u n d  .................................................................................................................3 5  
1. 1. 1.  
L y m p h oc yte Acti vati o n Ge ne -3  .................................................................................3 5  
1. 1. 1. 1.  
T S R -0 3 3  ......................................................................................................................3 5  
1. 1. 2.  
Pr o gra m me d Cell Deat h -1 Pr otei n  ..............................................................................3 5  
1. 1. 2. 1.  
D ostarli ma b  .................................................................................................................3 6  
1. 2.  
Rati o nale f or E val u ati n g T S R -0 3 3 as C o m bi nati o n T hera p y  .....................................3 7  
1. 2. 1.  
T S R -0 3 3 a n d D ostarli ma b  ..........................................................................................3 7  
1. 2. 2.  
T S R -0 3 3 a n d C he m ot hera p y wit h A nti -Gr o wt h Fact or A nti b o dies  ...........................3 8  
1. 2. 3.  
Rati o nale f or Selecti o n of E x pa nsi o n C o h orts  ............................................................3 8  
2.  
T RI A L O BJ E C TI V E S  ................................................................................................4 0  
2. 1.  
Pri mar y O bj ecti ve  .......................................................................................................4 0  
2. 1. 1.  
Part 1: D ose Escalati o n C o h orts ( 1a, 1 b, a n d 1c)  .......................................................4 0  
2. 1. 2.  
Part 2 A: C R C D ose E x pa nsi o n C o h ort A  ...................................................................4 0  
2. 1. 3.  
Part 2 B: C R C D ose  E x pa nsi o n C o h orts B 1 a n d B 2  ...................................................4 0  
2. 2.  
Sec o n dar y O bj ecti ves  .................................................................................................4 0  
3.  
I N V E S TI G A TI O N A L P L A N .....................................................................................4 2  
3. 1. 1.  
D L T Criteria  ...............................................................................................................4 4  
3. 1. 2.  
R ati o nale f or t he T S R -0 3 3 Starti n g D ose  ...................................................................4 5  
3. 1. 3.  
Part 1 –  D ose Escal ati o n  .............................................................................................4 5  
3. 1. 3. 1.  
Part 1a: T S R -0 3 3 M o n ot hera p y ( Q 2 W)  .....................................................................4 5  
3. 1. 3. 2.  
Part 1 b: T S R -0 3 3 M o n ot hera p y P K/ P D y C o h ort ( Q 2 W Sc he d ule)  ...........................4 6  
3. 1. 3. 3.  
Part 1c: T S R -0 3 3 i n C o m bi nati o n wit h D ostar li ma b ( Q 3 W Sc he d ule) .....................4 7  
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3.1.4. 
Part 2 – Dose Expansion Cohorts – TSR-033 + Dostarlimab (Q2W + Q6W) ...........48 
3.2. 
Number of Subjects ....................................................................................................49 
3.3. 
General Study Conduct ...............................................................................................49 
3.3.1. 
Study Visits and Assessments ....................................................................................49 
3.3.1.1. 
Biopsies.......................................................................................................................49 
3.3.1.2. 
Safety Assessments .....................................................................................................50 
3.3.1.3. 
Radiographic Disease Assessments and Tumor Markers ...........................................50 
3.3.1.4. 
Pharmacokinetics and Antidrug Antibody Assessments ............................................51 
3.3.1.5. 
Pharmacodynamics Assessments................................................................................52 
3.3.1.6. 
End of Treatment and Follow-Up Assessments .........................................................52 
3.3.1.7. 
Adverse Events Follow-up .........................................................................................52 
3.3.2. 
Study Treatment Duration ..........................................................................................52 
3.3.3. 
End of Study and Final Analysis ................................................................................52 
4. 
STUDY POPULATION .............................................................................................54 
4.1. 
Inclusion Criteria ........................................................................................................54 
4.1.1. 
Inclusion Criteria for Patients in Part 1 ......................................................................54 
4.1.2. 
Inclusion Criteria for Patients in Part 2 ......................................................................55 
4.1.2.1. 
Inclusion Criteria for Patients in Part 2A ...................................................................56 
4.1.2.2. 
Inclusion Criteria for Patients in Part 2B ....................................................................57 
4.2. 
Exclusion Criteria .......................................................................................................57 
4.2.1. 
General Exclusion Criteria for All Patients ................................................................57 
4.2.1.1. 
Exclusion Criteria for Patients in Part 1 .....................................................................59 
4.2.1.2. 
Exclusion Criteria for Patients in Part 2 .....................................................................59 
4.2.1.3. 
Exclusion Criteria for Patients in Part 2B ...................................................................59 
4.3. 
Patient Withdrawal and Replacement .........................................................................59 
4.3.1. 
Discontinuation from Study Treatment ......................................................................59 
4.3.2. 
Discontinuation from the Study ..................................................................................60 
4.3.3. 
Replacement of Patients .............................................................................................60 
4.4. 
Patient Identification and Randomization ..................................................................60 
4.4.1. 
Patient Identification ...................................................................................................60 
4.4.2. 
Randomization Scheme ..............................................................................................60 
5. 
STUDY MEDICATION .............................................................................................61 


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5.1. 
Identity ........................................................................................................................61 
5.1.1. 
Investigational Products ..............................................................................................61 
5.1.2. 
Non-Investigational Products .....................................................................................61 
5.2. 
Administration ............................................................................................................61 
5.2.1. 
Post-Treatment Vital Signs Monitoring and Safety Observation ...............................64 
5.2.2. 
Dose of TSR-033 ........................................................................................................64 
5.2.2.1. 
TSR-033 Dose (Part 1a and Part 1b) – Q2W Schedule ..............................................64 
5.2.2.2. 
TSR-033 in Combination with Dostarlimab (Part 1c) – Q3W Schedule....................64 
5.2.2.3. 
TSR-033 in Combination with Dostarlimab (Part 2) ..................................................64 
5.3. 
Dose Modification ......................................................................................................65 
5.3.1. 
Dose Modification General Rules ..............................................................................65 
5.3.2. 
Dose Modification for Specific Immune-Related Adverse Events ............................65 
5.4. 
Packaging, Labeling and Storage ...............................................................................67 
5.5. 
Drug Accountability ...................................................................................................68 
5.6. 
Previous and Concomitant Medications .....................................................................68 
5.6.1. 
Recording of Previous and Concomitant Medications ...............................................68 
5.6.2. 
Prohibited Medications ...............................................................................................68 
5.6.3. 
Contraception ..............................................................................................................69 
5.6.4. 
Rescue Mediations and Supportive Care Guidelines ..................................................70 
5.7. 
Continued Access to Study Treatment After Final Analysis ......................................74 
6. 
ENDPOINTS AND METHODS OF ASSESSMENT ...............................................75 
6.1. 
Safety Endpoints .........................................................................................................75 
6.1.1. 
Definitions ..................................................................................................................75 
6.1.2. 
Assessment of Adverse Events ...................................................................................76 
6.1.2.1. 
Intensity ......................................................................................................................76 
6.1.2.2. 
Causality .....................................................................................................................76 
6.1.3. 
Collecting and Recording Adverse Events .................................................................77 
6.1.4. 
Reporting Disease Progression ...................................................................................78 
6.1.5. 
Reporting of Serious Adverse Events .........................................................................78 
6.1.5.1. 
Submission and Distribution of Serious Unexpected Suspected Adverse 
Reaction Reports .........................................................................................................79 
6.1.6. 
Pregnancy ...................................................................................................................79 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
2 5  
 
6. 1. 7.  
Cli nical La b orat or y Assess me nts  ...............................................................................8 0  
6. 1. 8.  
P h ysical E x a mi nati o n a n d Vital Si g ns  ........................................................................8 1  
6. 1. 8. 1.  
S y m pt o m -Direct e d P h ysi cal E x a mi nati o n  ..................................................................8 1  
6. 1. 9.  
Electr ocar di o gra m  .......................................................................................................8 1  
6. 1. 1 0.  
Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma n ce Stat us  ........................................8 2  
6. 1. 1 1.  
A d diti o nal Safet y Ass ess me nts ...................................................................................8 2  
6. 1. 1 2.  
C ollecti o n of Safet y I nf or mati o n After Fi nal A nal ysis  ..............................................8 2  
6. 2.  
De m o gra p hics a n d Baseli ne C haract eristics  ...............................................................8 2  
6. 2. 1.  
Patie nt Eli gi bilit y  ........................................................................................................8 2  
6. 2. 2.  
Patie nt De m o gra p hics  .................................................................................................8 2  
6. 2. 3.  
Ca ncer Hist or y  ............................................................................................................8 3  
6. 2. 4.  
Me dical a n d S ur gic al Hist or y  .....................................................................................8 3  
6. 2. 5.  
Pre vi o us a n d C o nc urre nt Me dicati o ns  ........................................................................8 3  
6. 3.  
Cli nical Acti vit y E n d p oi nts  ........................................................................................8 4  
6. 3. 1.  
E val uati o n of T u m or Res p o nse  ..................................................................................8 4  
6. 3. 1. 1.  
O ver vie w  .....................................................................................................................8 4  
6. 3. 1. 2.  
Ti mi n g of Ra di o gra p hi c E val uati o ns  ..........................................................................8 4  
6. 3. 1. 3.  
Assess me nt of Res p o nse b y R E CI S T  .........................................................................8 5  
6. 3. 1. 4.  
Assess me nt of Res p o nse b y I m m u ne -Relate d R E CI S T  .............................................8 5  
6. 3. 1. 5.  
Treat me nt a n d Assess me nt after Pr o gressi o n  .............................................................8 6  
6. 3. 2.  
Efficac y E n d p oi nts  ......................................................................................................8 6  
6. 3. 2. 1.  
O bjecti ve Res p o nse Rate  ............................................................................................8 6  
6. 3. 2. 2.  
D urati o n of Res p o nse  .................................................................................................8 6  
6. 3. 2. 3.  
Disease C o ntr ol Rate  ..................................................................................................8 7  
6. 4.  
P har mac o ki netics a n d A nti dr u g A nti b o dies  ...............................................................8 7  
6. 4. 1.  
P har mac o ki netic A n al ysis  ..........................................................................................8 7  
6. 4. 2.  
A nal ysis of A nti dr u g A nti b o dies  ................................................................................8 8  
6. 6. 1.  
Bl o o d Sa m ples  ............................................................................................................8 8  
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C O N FI D E N TI A L  
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A m d  0 5 ( Versi o n  6. 0)  
2 6  
 
6. 6. 2.  
T u m or Tiss ue  ..............................................................................................................8 8  
7.  
S T U D Y C O N D U C T  ...................................................................................................9 0  
7. 1.  
Sc he d ules of E ve nts  ....................................................................................................9 0  
7. 1. 1.  
Use of Sta n dar d of Care Assess me nts f or Scree ni n g  ..................................................9 0  
8.  
S T A TI S TI C A L M E T H O D S  .....................................................................................1 1 5  
8. 1.  
St u d y P o p ulati o ns  .....................................................................................................1 1 5  
8. 2.  
Safet y A nal yses  ........................................................................................................1 1 6  
8. 2. 1.  
C o nc o mita nt Me dicati o ns  .........................................................................................1 1 7  
8. 3.  
P har mac o ki netic A n al ys es  ........................................................................................1 1 7  
8. 4.  
A nti dr u g A nti b o d y A n al ysis  .....................................................................................1 1 7  
8. 5.  
Efficac y A nal yses  .....................................................................................................1 1 7  
8. 5. 1.  
Pri mar y Efficac y Para meter  ......................................................................................1 1 7  
8. 5. 2.  
Sec o n dar y Efficac y Para meters  ................................................................................1 1 8  
8. 7.  
Deter mi nati o n of Sa m ple Size  ..................................................................................1 1 8  
9.  
E T HI C A L, L E G A L, A N D A D MI NI S T R A TI V E A S P E C T S  ..................................1 1 9  
9. 1.  
Et hics Re vie w  ...........................................................................................................1 1 9  
9. 2.  
Data Q ualit y Ass ura nce  ............................................................................................1 1 9  
9. 3.  
I nstit uti o nal Re vie w B oar d .......................................................................................1 1 9  
9. 4.  
Access t o S o urce Dat a/ D oc u me nts  ...........................................................................1 1 9  
9. 5.  
Arc hi vi n g St u d y D o c u me nts  .....................................................................................1 2 0  
9. 6.  
G o o d Cli nical Practice  ..............................................................................................1 2 0  
9. 7.  
I nf or me d C o nse nt .....................................................................................................1 2 0  
9. 8.  
Pr ot oc ol A p pr o val a n d A me n d me nt  .........................................................................1 2 1  
9. 9.  
Patie nt C o nfi de ntialit y a n d Data Pr otecti o n  .............................................................1 2 1  
9. 1 0.  
St u d y M o nit ori n g  ......................................................................................................1 2 1  
9. 1 1.  
A u di ts a n d I ns p ecti o ns ..............................................................................................1 2 2  
9. 1 2.  
Et hical C o nsi derati o ns  ..............................................................................................1 2 2  
9. 1 3.  
Rete nti o n of Rec or ds  ................................................................................................1 2 2  
9. 1 4.  
St u d y Ter mi nati o n  ....................................................................................................1 2 2  
1 0.  
R E F E R E N C E S  .........................................................................................................1 2 3  
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APPENDIX 1. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST), V1.1 ........................................................................................................127 
APPENDIX 2. IMMUNE-RELATED RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS .....................................................................................................129 
APPENDIX 3. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS ...................................................................................................................130 
APPENDIX 4. COCKCROFT-GAULT FORMULA ...............................................................131 


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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................30 
Table 2: 
Dose Modifications for Non-Hematologic Toxicities – Applies to Both 
Study Drug Components (TSR-033 and Dostarlimab) ...............................................66 
Table 3: 
TSR-033 or Dostarlimab Infusion-Related Reaction Treatment Guidelines ..............73 
Table 4: 
Schedule of Clinical Events: TSR-033 Monotherapy, Part 1a and Part 1b 
(Q2W) .........................................................................................................................91 
Table 5: 
Schedule of Clinical Events: TSR-033 + Dostarlimab Combination Therapy, 
Part 1c (Q3W) .............................................................................................................95 
Table 6: 
Schedule of Clinical Events: Part 2A .........................................................................98 
Table 7: 
Schedule of Clinical Events: Part 2B (Cohorts B1 and B2) .....................................102 
Table 8: 
Sampling Schedule for Pharmacokinetic and ADA Analysis: Part 1a (Q2W) .........106 
Table 9: 
Sampling Schedule for Additional Pharmacokinetic and ADA Analysis: Part 
1b (Q2W) ..................................................................................................................107 
Table 10: Sampling Schedule for Pharmacokinetic and ADA Analysis: Part 1c (Q3W) .........108 
Table 11: Sampling Schedule for Pharmacokinetic and ADA Analysis: Part 2A (Q2W) ........109 
Table 12: Sampling Schedule for Pharmacokinetic and ADA Analysis: Part 2B 
(Cohorts B1 and B2) (Q2W).....................................................................................110 
Table 13: Sampling Schedule for Pharmacodynamics: Part 1a and Part 1b (Q2W) ................111 
Table 14: Sampling Schedule for Pharmacodynamics: Part 1c (Q3W) ....................................112 
Table 15: Sampling Schedule for Pharmacodynamics: Part 2A (Q2W) ...................................112 
Table 16: Sampling Schedule for Pharmacodynamics: Part 2B (Cohorts B1 and B2) 
(Q2W) .......................................................................................................................113 
Table 17: Sampling Schedule for Biomarkers and Biopsies: Part 1a, 1b, 1c, and Part 
2A .............................................................................................................................113 
Table 18: Sampling Schedule for Biomarkers and Biopsies: Part 2B (Cohorts B1 and 
B2) ............................................................................................................................114 
Table 19: RECIST Response for Patients with Measurable Disease (ie, Target Disease) .......128 
Table 20: RECIST Response for Patients with Nonmeasurable Disease .................................128 
Table 21: Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease ......................................................................................................................129 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
2 9  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
O verall St u d y Sc h e ma  ................................................................................................4 3  
Fi g ure  2:  
Part 1a D osi n g Sc h e ma –  T S R -0 3 3 M o n ot hera p y ( Q 2 W Sc he d ule)  ..........................4 6  
Fi g ure  3:  
Part 1 b D osi n g Sc he m a –  P K/
.................................................4 7  
Fi g ure  4:  
Part 1c D osi n g Sc h e ma –  T S R -0 3 3 C o m bi ne d wit h D ostarli ma b ( Q 3 W)  .................4 8  
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation 
Definition 
ADA 
antidrug antibody 
ADL 
activities of daily living 
AE 
adverse event 
ALC  
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BP 
blood pressure (resting) 
CBC 
complete blood count 
CEA 
carcinoembryonic antigen 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CrCL/Ccr 
creatinine clearance 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor deoxyribonucleic acid 
CIOMS 
Council for International Organizations of Medical Sciences 
DCR 
disease control rate 
DCO 
data cut-off 
DLT 
dose-limiting toxicity 
dMMR 
mismatch repair-deficient 
DOR 
duration of response 
DRESS 
drug reaction with eosinophilia and systemic symptoms 


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Abbreviation 
Definition 
ECG 
electrocardiogram 
ECL 
electrochemiluminescence 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
ELISA 
enzyme-linked immunosorbent assay 
EOT 
end of treatment 
F 
5-fluorouracil 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FOL 
folinic acid (leucovorin) 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
FUP 
follow-up 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
G-CSF 
granulocyte-colony stimulating factor 
GLP 
Good Laboratory Practice 
Hb 
hemoglobin 
HbsAg 
hepatitis B surface antigen 
HCV RNA 
hepatitis C virus ribonucleic acid 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICD 
immunogenic cell death 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG4 
immunoglobulin G4 
IL-2 
interleukin-2 
INR 
international normalized ratio 
IR 
infusion reaction 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
3 2  
 
A b bre vi ati o n  
Defi niti o n  
ir A E 
i m m u ne-relate d a d verse e ve nt 
ir A R 
i m m u ne-relate d a d verse reacti o n 
I R B 
I nstit uti o nal Re vie w B oar d 
ir C R 
i m m u ne-relate d c o m plete res p o nse 
I RI 
iri n oteca n 
ir P D 
i m m u ne-relate d pr o gressi ve disease 
ir P R 
i m m u ne-relate d partial res p o nse 
ir S D 
i m m u ne-relate d sta ble disease 
I V 
i ntra ve n o us(l y) 
K M  
Ka pla n -Meier  
L A G -3  
l y m p h oc yte acti vati o n ge ne-3  
m A b  
m o n ocl o nal a nti b o d y  
M A D  
ma xi m u m a d mi nistere d d ose  
m C R C  
metastatic c ol orectal ca ncer  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M H C  
maj or hist oc o m pati bilit y c o m ple x  
M L R  
mi xe d l y m p h oc yte reacti o n  
M RI  
ma g netic res o na nce i ma gi n g  
M SI -H  
micr osatellite i nsta bilit y -hi g h  
M S S  
micr osatellite sta ble  
M T D  
ma xi m u m t olerate d d ose  
N A b  
ne utralizi n g a nti b o d y  
N S AI D  
n o n -ster oi dal a nti-i nfla m mat or y dr u g 
N S C L C  
n o n -s mall cell l u n g ca ncer 
O R R  
o bj ecti ve res p o nse rate  
O S  
o verall s ur vi val  
O X  
o xali plati n  
P D  
pr o gressi ve disease  
P D -1  
pr o gra m me d cell deat h -1 rece pt or  
P D -L 1  
pr o gra m me d deat h li ga n d -1  
P D -L 2  
pr o gra m me d deat h li ga n d -2  
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Abbreviation 
Definition 
PDy 
pharmacodynamic(s) 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
per os (by mouth) 
PR 
partial response 
PS 
performance status 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q6W 
every 6 weeks 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SJS 
Stevens-Johnson syndrome 
SOC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal half-life 
T1DM 
type 1 diabetes mellitus 
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
TIL 
tumor-infiltrating lymphocytes 
TIM-3 
T-cell immunoglobulin and mucin-domain containing-3 receptor 
Tmax 
time at maximum concentration 
TRAE 
treatment-related adverse event 
TSH 
thyroid-stimulating hormone 


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Abbreviation 
Definition 
ULN 
upper limit of normal 
US 
United States 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 
Vss 
volume of distribution at steady state 
WHO 
World Health Organization 
WOCBP 
women of child bearing potential 


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1. 
INTRODUCTION 
1.1. 
Background 
The recognition of tumors by the immune system has been appreciated for multiple decades and 
provided an impetus to utilize the immune system to control tumor growth. Studies have reported 
the presence of tumor-infiltrating lymphocytes (TILs) as a positive prognostic feature in multiple 
tumors, supporting a role for the immune system in limiting tumor growth. Despite evidence of 
immune reactivity, tumors are able to grow in the presence of an immune system, suggesting a 
suboptimal immune response. 
Emerging research into this inadequate immune response has identified an important family of 
proteins that play key roles in immune checkpoint pathways, regulatory cascades that ordinarily 
maintain immune homeostasis, but are co-opted by cancer cells so that they may evade detection 
and subsequent destruction by the immune system. Prominent proteins within this immune 
checkpoint family include lymphocyte activation gene (LAG-3) and programmed cell death-1 
receptor (PD-1), which are widely associated with exhausted or dysfunctional T cells that show 
varying degrees of functional impairment in the context of chronic antigen exposure and are 
associated with immune system downregulation and self-tolerance. 
1.1.1. 
Lymphocyte Activation Gene-3 
LAG-3 was first identified on activated T cells and a subset of natural killer cells. Its engagement 
on T cells results in the attenuation of T cell signaling and reduced effector function, and it has 
thus been implicated in limiting anti-tumor immunity.23,24 LAG-3, along with other co-inhibitory 
receptors (eg, PD-1, T-cell immunoglobulin and mucin-domain containing-3 receptor [TIM-3]) 
is widely associated with exhausted or dysfunctional T cells, which show varying degrees of 
functional impairment in the context of chronic antigen exposure.25 
1.1.1.1. 
TSR-033 
TSR-033 is a potent and selective humanized monoclonal antibody (mAb) of the 
immunoglobulin G4 (IgG4) κ isotype that binds to human and cynomolgus monkey LAG-3 with 
high affinity and blocks the binding of LAG-3 to major histocompatibility complex (MHC) Class 
II-expressing Daudi cells. Functionally, as a single agent, TSR-033 enhances T cell activation (as 
determined by interleukin-2 [IL-2]) in a mixed lymphocyte reaction (MLR) with a half-maximal 
effective concentration of approximately 2 nM. Furthermore, the combination of TSR-033 with 
an anti-PD-1 antibody increased T cell activation in this assay, resulting in a 5- to 10-fold 
increase in potency of the combination versus TSR-033 alone. These data, together with other 
nonclinical data, support the evaluation of TSR-033 as a monotherapy, and in combination with 
anti-PD-1, in cancer patients. 
Please refer to the current version of the Tesaro TSR-033 Investigator’s Brochure (IB) for further 
nonclinical and clinical details about this investigational product. 
1.1.2. 
Programmed Cell Death-1 Protein 
Initial exploration of T cell activation in chronic viral models suggested that chronic viral 
infections led to a state of T cell hypo-responsiveness, termed T cell exhaustion, and involved 


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immune inhibitory receptors expressed by T cells.25,26 One of the proteins shown to be mediating 
T cell exhaustion in chronic viral models and subsequently tumor models was PD-1. The 
discovery and characterization of PD-1 revealed that PD-1 limits T cell activation through 
binding to programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2) and 
limiting tyrosine kinase signaling from the T cell antigen receptor and co-stimulatory 
receptors.27,28 
The identification of PD-L1 as the ligand for PD-1 was followed by the demonstration that 
PD-L1 expression by tumor cells enhances tumor growth.29 These data led to the hypothesis that 
PD-1/PD-L1 may be exploited to subvert the anti-tumor immune response. Nonclinical models 
where PD-1 signaling was blocked or deficient (PD-1 knockout mice) demonstrated improved 
immune-mediated tumor control.30,31 Thus, PD-1/PD-L1 represented an immune inhibitory 
mechanism employed by tumors to subvert the immune response and disruption of this axis 
enhanced the lysis of tumor cells by T cells. 
These nonclinical experiments led to the evaluation of anti-PD-1 antibodies in patients with solid 
tumors. From the first clinical study, the activity of an anti-PD-1 antibody, nivolumab, appeared 
to be higher compared to past immunotherapeutic approaches.32 Activity was demonstrated in 
tumors known to be responsive to immunotherapy, such as melanoma and renal cell carcinoma 
(RCC), as well as lung tumors which were traditionally insensitive to immunotherapy, like 
non-small cell lung cancer (NSCLC). This led to intense interest in PD-1/PD-L1 blockade in 
multiple tumor types resulting in the development of specific antibodies that block PD-1 or 
PD-L1 that have subsequently demonstrated clinical efficacy in multiple malignancies. 
Multiple clinical trials in melanoma, RCC, NSCLC and other cancer types have yielded positive 
data with 2 different antibodies targeting PD-1, nivolumab and pembrolizumab, demonstrating 
improved response rates and survival.33-38 Based on the clinical activity and manageable safety 
profile reported in these pioneering studies, nivolumab and pembrolizumab both have received 
approval by the US Food and Drug Administration (FDA) and European Medicinal Agency 
(EMA) in a number of indications (refer to current labels). Although nivolumab and 
pembrolizumab are distinct antibodies, the safety profiles are very similar across therapies and 
across tumor types demonstrating that the targeting of PD-1 was well-tolerated with manageable 
immune-related adverse events (irAEs) being the most noteworthy. 
1.1.2.1. 
Dostarlimab 
Dostarlimab is a potent humanized mAb of the IgG4κ isotype that binds to PD-1 and blocks the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. The functional antagonist activity 
of dostarlimab was confirmed in a MLR assay demonstrating enhanced IL-2 production upon 
addition of dostarlimab. 
Dostarlimab is being studied as monotherapy and in combination in several tumor types to 
evaluate its safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PDy), and 
clinical activity in patients with advanced or metastatic solid tumors. 
Dose escalation of dostarlimab as monotherapy continued to a maximally administered dose of 
10 mg/kg every 2 weeks (Q2W); no dose-limiting toxicities (DLTs) were observed and a 
maximum tolerated dose (MTD) was not reached. Flat doses of 500 mg every 3 weeks (Q3W) 
and 1000 mg every 6 weeks (Q6W) were also evaluated for safety in cohorts of 6 patients each 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
3 7  
 
a n d were f o u n d t o be s afe f or c urre ntl y o n g oi n g assess me nt i n t he Part 2 e x pa nsi o n c o h orts as n o 
D L Ts were o bser ve d. T h e 1 0 0 0  m g  flat d ose will als o be use d i n c o m bi nati o n wit h T S R-0 3 3 i n 
Part 2 of t his st u d y . 
T he c urre nt safet y d ata f or patie nts recei vi n g d ost arli ma b  m o n ot hera p y re p ort t he m ost 
c o m m o nl y o bser ve d ( > 1 5 %) a d verse e v e nts ( A Es) as: fati g ue, na us ea, diarr hea, decrease d 
a p petite, a ne mia, c o nsti pati o n , a n d v o miti n g. T hese A Es are t y pi cal of a n d see n i n patie nts 
recei vi n g ot her si milar dr u gs i n t his class ( P D-1 i n hi bit ors) . 
Please refer t o t he c urre nt versi o n of t he Tesar o d ostarli ma b  I B f or f urt h er n o ncli nical a n d 
cli nical details a b o ut t his i n vesti gati o nal pr o d u ct.  
1. 2.  
R ati o n ale f or E v al u ati n g T S R -0 3 3 as C o m bi n ati o n T her a p y  
1. 2. 1.  
T S R -0 3 3 a n d D ost arli m a b  
L A G -3 is e x presse d o n TI Ls acr oss a wi de ra n ge of t u m or t y pes, s u c h as c ol orectal, breast, 
o varia n, pr ostatic, re nal ca ncers, N S C L C, a n d mel a n o ma. 3 9 -4 3 L A G -3 is fre q ue ntl y c o -e x presse d 
wit h P D -1 o n TI Ls, a n d d ual bl oc ka de of P D -1 a n d L A G -3 e n h a nces C D 8 effect or f u n cti o n e x 
vi v o i n patie nt TI L s a n d p ote ntiates a nti-t u m or i m m u nit y i n pr ecli nical m o dels of o varia n ca ncer, 
c ol o n carci n o ma, a n d fi br osarc o ma. 4 4 ,4 5 
T o date, cli nical dat a are a vaila ble f or o ne st u d y i n vesti gati n g a nti -L A G -3 a n d a nti -P D -1 
a nti b o dies i n c o m bi nati o n. 4 6 T he safet y a n d P K of t he a nti -L A G -3 a nti b o d y B M S -9 8 6 0 1 6 was 
e val uate d as a si n gle a ge nt i n 2 3 patie nts wit h s oli d t u m ors, at t he f oll o wi n g d ose le vels: 2 0 m g, 
8 0 m g, 2 4 0 m g, or 8 0 0 m g. Fift y -se v e n patie nts w ere treate d wit h B M S-9 8 6 0 1 6 i n c o m bi nati o n 
wit h ni v ol u ma b ( O p di v o ® ) at t he f oll o wi n g d os e le vels ( B M S-9 8 6 0 1 6 d os e/ ni v ol u ma b d ose): 
2 0/ 8 0 m g, 2 0/ 2 4 0 m g, 8 0/ 2 4 0 m g, or 2 4 0/ 2 4 0 m g. W hile t he M T D was n ot ac hie ve d, a n d d ose 
escalati o n of t he c o m bi nati o n c o nti n ues, i m m u ne -me diate d D L Ts t y picall y ass ociate d wit h 
c hec k p oi nt i n hi bit ors were o bser ve d. Of t he 2 3 patie nts treate d wit h m o n ot hera p y, 3 patie nts 
were re p orte d wit h Gra d e ≥3 A Es; t hese i ncl u de d ele vate d li pase ( 2 patie nts) a n d mac ul o pa p ul ar 
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rash (1 patient). Of the 57 patients treated with BMS-986016 + nivolumab, 7 patients reported 
AEs Grade ≥3. These included Grade 3 or 4 elevated lipase, elevated amylase, colitis, 
dehydration, dyspnea, aseptic meningitis, mucosal inflammation, elevated troponin, and 
ventricular fibrillation (in one patient each). One patient treated at a dose of BMS-986016 
240 mg + nivolumab 240 mg experienced Grade 5 myocarditis; this patient had a history of heart 
disease. Preliminary evidence of clinical benefit was observed in patients with melanoma, 
NSCLC, cervical cancer, anal cancer, and cholangiocarcinoma. 
Despite favorable response rates observed with PD-1/PD-L1 checkpoint inhibitors, there remain 
large numbers of patients who derive little clinical benefit from such therapies (primary 
resistance) or suffer a relapse (acquired or adaptive immune resistance).47 LAG-3 is implicated in 
tumor cell extrinsic resistance mechanisms, suggesting that targeting this pathway, in addition to 
PD-1, may engender a stronger and more durable anti-tumor response.47 These data are 
consistent with our own results in the MLR assay and efficacy in syngeneic tumor models and, 
taken together, provide a rationale for combination therapy with anti-PD-1 and anti-LAG-3 
antibodies in cancer. 
1.2.2. 
TSR-033 and Chemotherapy with Anti-Growth Factor Antibodies 
Based on a growing body of evidence in preclinical models, the anti-tumor effects of 
conventional chemotherapy derive not only from direct tumor cell killing, but also from 
increased priming of the immune response.48 This can occur through immunogenic cell death 
(ICD) which (a) releases a host of antigens/neoantigens as well as highly immunostimulatory 
molecules which attract leukocytes and (b) stimulation of a type I interferon response which 
promotes improved antigen presentation and T cell activation.49 Chemotherapy can thus 
synergize with checkpoint blockade to boost tumor immunosurveillance and improve anti-tumor 
efficacy. Also harnessing the host immune system, immunotherapy may add a complementary 
and distinct mechanism of action to the currently utilized standard chemotherapeutic and 
biologic regimens used to treat many forms of cancer. Therefore, immunotherapeutic agents 
warrant further investigation in the clinic to test the hypothesis that the combination of 
immunotherapy and chemotherapy can synergistically potentiate antitumor responses. This idea 
will be studied in Part 2 of the current protocol, investigating the efficacy of TSR-033 and 
dostarlimab therapy in combination with chemotherapy in patients with advanced or metastatic 
colorectal cancer (CRC) (see Section 1.2.3). 
1.2.3. 
Rationale for Selection of Expansion Cohorts 
CRC is one of the most common malignancies worldwide and remains a deadly disease (second 
most common cause of cancer death in the United States [US]) despite current therapeutic 
options1, which include the current standard of care (SOC), chemotherapy with or without anti-
angiogenic antibodies or anti-epidermal growth factor receptor (EGFR) antibodies2 as first- and 
second-line regimens. In the US, although the incidence rate of CRC in adults aged ≥50 years 
has declined in recent decades, it has increased by 13% in those aged <50 years. In addition, if 
the disease progresses to become metastatic CRC (mCRC), it is usually incurable. While 
colorectal cancers with microsatellite instability are frequently are frequently sensitive to check 
point inhibitor therapy, they make up only about 3% of patients with metastatic disease.3 
Unfortunately, in contrast to many other areas of cancer therapy, the advances achieved with 


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immunotherapy have not yet been replicated in the remaining 97% of patients whose mCRC is 
microsatellite stable CRC (MSS-CRC). Therefore, MSS-CRC remains an area of great and 
urgent medical need. 
Among the cytotoxic chemotherapy choices for CRC, oxaliplatin- and irinotecan-based 
chemotherapy regimens are most commonly utilized, with clinical outcomes improved by the 
addition of biologics targeting EGFR or vascular endothelial growth factor (VEGF) or its 
receptor (VEGFR) in appropriate patients.4 With regard to oxaliplatin-based regimens, FOLFOX 
and its variants (ie, modified FOLFOX6 [mFOLFOX6], FOLFOX4) remain popular and are used 
globally.5,6 FOLFOX consists of folinic acid (FOL) or leucovorin, 5-fluorouracil (F), and 
oxaliplatin (OX). mFOLFOX6, given with or without bevacizumab (anti-VEGF mAb), is by far 
the most commonly used regimen, clinically and in studies, for first-line therapy in CRC.7 An 
alternative 3-drug combination is FOLFIRI, which consists of irinotecan (IRI) in addition to FOL 
and F.8 This combination can also be given with biologics. While it is generally considered that 
FOLFOX and FOLFIRI are equivalent regimens, particularly with regard to overall survival 
(OS)6, the oxaliplatin-based regimens are utilized more frequently than irinotecan-based 
regimens in the first-line metastatic setting globally. In the second-line metastatic setting, a 
number of contemporary trials have established reliable benchmarks for overall response rates 
and progression-free survival (PFS), as well as OS, with FOLFOX- or FOLFIRI-based regimens. 
Taken together, the overall response rate with FOLFOX or FOLFIRI chemotherapy with or 
without biologics appears to be modest in CRC, in the 4% to 15% range.6,9,10,11,12,13,14 
Beyond second-line therapy, TAS-102, an oral fluoropyrimidine analogue and thymidine 
phosphorylase inhibitor, has demonstrated an improvement of OS by 1.8 months in patients with 
refractory disease versus best supportive care (5.3 versus 7.1 months [HR 0.68, 95% CI 0.58 to 
0.81; p<0.001]).15 In addition, two anti-EGFR monoclonal antibodies, cetuximab and 
panitumumab, have shown efficacy as monotherapy in the third-line setting in patients with 
KRAS wild type tumors.16,17,18 Monotherapy with the anti-angiogenic drug regorafenib has also 
yielded a modest survival benefit of 1.4 months (6.4 versus 5.0 months [HR ratio 0.77; 95% CI 
0.64 to 0.94; one-sided p=0.0052).19 Finally, immunotherapy with checkpoint inhibitors as 
monotherapy appears to be active only in patients with microsatellite instability–high (MSI-H) or 
mismatch repair–deficient (dMMR) CRC.20,21 Both nivolumab and pembrolizumab are currently 
approved for MSI-H or dMMR CRC that has progressed following treatment with 
fluoropyrimidine, oxaliplatin, and irinotecan. In summary, the current treatment options in first- 
through fourth-line CRC, their response rates, and the growing knowledge around subtypes of 
CRC patients, highlight the need for more efficacious therapeutics and support the decision to 
study TSR-033 and dostarlimab combination therapy in MSS-CRC. 
The purpose of Part 2A of the study is to assess the safety and initial efficacy of the combination 
of TSR-033 and dostarlimab in third- or fourth-line MSS-CRC. Part 2B will assess the safety 
profile and initial efficacy of mFOLFOX6 (Cohort B1) or FOLFIRI (Cohort B2) plus 
bevacizumab in combination with TSR-033 and dostarlimab in patients with second-line MSS-
CRC who have progressed on a prior first-line regimen.20 The second part of the study will 
explore anti-tumor activity in the pre-specified tumor types and confirm the safety and 
tolerability of TSR-033 in combination with dostarlimab and/or chemotherapy. 


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2. 
TRIAL OBJECTIVES 
2.1. 
Primary Objective 
2.1.1. 
Part 1: Dose Escalation Cohorts (1a, 1b, and 1c) 
• To define the RP2D and schedule of TSR-033 as monotherapy (1a, 1b) and in 
combination with dostarlimab (1c). 
• To evaluate the safety and tolerability (eg, number of patients experiencing DLTs, 
AEs/serious adverse events [SAEs]/irAEs, and abnormal hematology/clinical 
chemistry results) of TSR-033 as monotherapy (1a, 1b) and in combination with 
dostarlimab (1c) in patients with advanced or metastatic solid tumors 
2.1.2. 
Part 2A: CRC Dose Expansion Cohort A 
• To evaluate the anti-tumor activity of TSR-033 in combination with dostarlimab in 
anti-PD(L)-1 naïve patients with advanced or metastatic MSS-CRC who have 
progressed following 2 or 3 prior lines of therapy as measured by objective response 
rate (ORR) assessed by the Investigators using Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 
2.1.3. 
Part 2B: CRC Dose Expansion Cohorts B1 and B2 
• B1: 
− To evaluate the safety and tolerability (eg, number of patients experiencing DLTs, 
AEs/SAEs/irAEs, and abnormal hematology/clinical chemistry results) of 
TSR-033 and dostarlimab in combination added to mFOLFOX6 and bevacizumab 
in anti-PD-1-naïve patients with advanced or metastatic MSS-CRC following 
progression on frontline treatment with FOLFIRI (or variant), with or without 
biologics. 
• B2: 
− To evaluate the safety and tolerability (eg, number of patients experiencing DLTs, 
AEs/SAEs/irAEs, and abnormal hematology/clinical chemistry results) of 
TSR-033 and dostarlimab in combination added to FOLFIRI and bevacizumab in 
anti-PD-1-naïve patients with advanced or metastatic MSS-CRC following 
progression on frontline treatment with FOLFOX (or variant), with or without 
biologics. 
2.2. 
Secondary Objectives 
In Part 1 and Part 2, unless otherwise specified: 
• To characterize the PK (eg, serum concentrations for Part 1 and Part 2 and derived 
PK parameters for Part 1, as data permit) and immunogenicity of TSR-033 alone, 
TSR-033 and dostarlimab in combination, and TSR-033 and dostarlimab in 
combination with chemotherapy and bevacizumab. 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
4 1  
 
•  T o ev al uate ad diti o n al measure s o f cli nical ben efit, i ncl u di n g 
− O R R b y  R E C IS T  v 1. 1  ( P art 1)  
− D urati o n of res p o ns e ( D O R)  b y  R E C IS T  v 1. 1  ( P art 2)  
− Disease c o ntr ol rate ( D C R)  b y R E CI S T  v 1. 1 ( P art 2 ) 
•  B 1:  
− T o e val uate t he a nti -t u m or acti vit y of T S R-0 3 3 a n d d ostarli ma b  a d de d t o 
m F O L F O X 6 a n d b e vaciz u ma b i n patie nts wit h a d va nce d or m etastatic M S S -C R C 
f oll o wi n g pr o gressi o n o n fr o ntli ne treat me nt wit h F O L FI RI, wit h or wit h o ut 
bi ol o gics, meas ur e d b y t he O R R  as assessed b y  t he In v esti gat or usi n g  R E C IS T 
v 1. 1.  
•  B 2:  
− T o e val uate t he a nti-t u m or acti vit y of T S R-0 3 3 a n d d ostarli ma b  a d de d t o 
F O L FI RI a n d b e vaciz u ma b i n patie nts wit h a d va n ce d or metast atic M S S -C R C 
f oll o wi n g pr o gressi o n o n fr o ntli ne treat me nt wit h F O L F O X ( or varia nt), wit h or 
wit h o ut bi ol o gics, meas ure d b y t he O R R  as assessed b y  t he In v esti gat or usi n g  
R E C IS T v 1. 1.  
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
4 2  
 
3.  
I N V E S TI G A TI O N A L P L A N 
T his is a  m ulti -cent er, op en -lab el, first-in -h u m an,  P h ase 1 st u d y  ev al uatin g t he  anti -L A G -3 
anti b o d y  T S R -0 3 3 al o ne, i n c o m bi nati o n wit h t he a nti -P D 1 a nti b o d y d ostarli ma b , a n d t he 
c o m bi nati o n of T S R -0 3 3 a n d d ostarli ma b  wit h m F O L F O X 6 or F O L FI RI a n d be vaciz u ma b. T he 
st u d y will be c o n d uct e d i n 2 parts, wit h Part 1 c o nsisti n g of d ose es calati o n t o deter mi ne t he 
R P 2 D of T S R -0 3 3 as a si n gle a ge nt ( Part 1 a) a n d i n c o m bi nati o n wit h d ostarli ma b  ( Part 1c). 
R P 2 D decisi o ns will be base d o n t he occ urre nce of D L Ts or P K/ P D y  dat a, as a vaila ble. Part 1 b 
of t he st u d y will ai m t o b etter c haracterize t he P K pr ofile of T S R -0 3 3 
 T hese a d diti o nal p atie nts will n ot be c o nsi dere d e v al ua ble f or 
d ose escal ati o n p ur p oses ( ie, n ot i ncl u de d i nt o t he D L T-e val u a ble p o p ulati o n) b ut will c o ntri b ute 
t o t he o verall safet y assess me nt at t he d ose le vel b ei n g e val uate d. I n Part 2, t hese re gi me ns will 
be e val uat e d i n p atients w it h a d va nce d or met astatic M S S-C R C w h o h ave  li mited av ailable 
treat ment o pti o ns as determi n ed b y  t he In v estig ato r. 
Part 2 A of t he st u d y will i n vesti gate t he a nti -t u m or acti vit y of T S R-0 3 3 a n d d ostarli ma b  i n 
c o m bi nati o n i n patie nts wit h a d va nce d or metastatic M S S -C R C. W hile t he pri mar y o bjecti ve of 
t his part of t he st u d y is O R R b y I n vesti gat or ass ess me nt, c o pies of sca ns will be c ollecte d a n d 
st ore d at a re p osit or y f or p ote ntial e val uati o n. 
Part 2 B of t he st u d y will i n vesti gate t he s afet y a n d a nti -t u m or acti vit y of T S R-0 3 3 a n d 
d ostarli ma b  i n c o m bi nati o n wit h c he m ot hera p y ( C o h ort B 1: m F O L F O X 6, C o h ort B 2: F O L FI RI) 
a n d be va ciz u ma b i n patie nts wit h a d va nce d or m etastatic M S S -C R C. As t he pri mar y o bjecti ve of 
t his part of t he st u d y will be safet y, b ot h Part 2 B C o h orts will be gi n b y e nr olli n g 6 patie nts eac h, 
wit h e nr oll me nt bei n g p a use d u ntil t he e n d of t he D L T o bs er vati o n peri o d bef ore a n y f urt h er 
e nr oll me nt i n t his ar m. W hile t he sec o n dar y o bjecti ve of t his part of t he st u d y is O R R b y 
I n v esti gat or assess me nt, c o pies of sca ns will be c ollecte d a n d st ore d at a re p osit or y f or p ote ntial 
e val uati o n.  
D L T criteri a are detaile d i n Sec ti o n 3. 1. 1 . T o xicities will be assesse d acc or di n g t o C o m m o n 
Ter mi n ol o g y Criteri a f or A d verse E v e nts ( C T C A E) v 5. 0 f or Part 1a, 1 c, a n d Part 2 B . 
T he  st ud y  w ill be co n d u c ted i n co n fo rm an ce w it h G o o d Cli ni cal Practice ( G C P). 
T he desi g n sc he ma prese nte d bel o w (starti n g d oses f or Part 1 b, Part 1c , a n d Part 2 are c o nti n ge nt 
o n safet y fi n di n gs i n earli er c o h orts).  
C CI
C CI


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Figure 1: 
Overall Study Schema 
 
Abbreviations: CRC=colorectal cancer; DLT=dose-limiting toxicity; mg=milligrams; MSS=microsatellite stable; 
PDy=pharmacodynamics; PK=pharmacokinetics; Q2W=every 2 weeks; Q3W=every 3 weeks; Q6W=every 6 weeks; 
RP2D=recommended Phase 2 dose. 
a Approximately 72 patients in Parts 1a, 1b and 1c are expected, but this may increase to approximately 132 patients 
in total if the Sponsor and Investigators determine that additional safety and/or PK/PDy data are needed to confirm 
the RP2D for monotherapy. These enrollment numbers could increase if the Sponsor, in consultation with the 
Investigator, determine that additional cohorts consisting of 6-12 patients are needed to examine additional dose 
levels. At any dose level, where DLTs were observed in less than ⅓ of patients, in Part 1b, up to 6 additional 
patients may be enrolled to enable a better characterization of the PK/PDy data in order to confirm the RP2D. These 
enrollment numbers could further increase if the Sponsor, in consultation with the Investigators determine that an 
intermediate dose level(s), consisting of approximately 6 patients requires exploration to better understand PK/PDy. 
b The starting dose of TSR-033 when used in combination with dostarlimab must be one dose level below the 
highest dose at which <⅓ of 6-12 patients experienced DLTs with single-agent TSR-033. 
c Doses presented in the schema represent the planned TSR-033 dose levels (subject to change based on safety 
and/or PK/PDy data). dostarlimab will be given at a dose of 500 mg (Q3W) in Part 1c and 1000 mg Q6W in Part 2 
of the study. These enrollment numbers could increase if the Sponsor, in consultation with the Investigator, 
determine that additional cohorts consisting of 6-12 patients are needed to examine additional dose levels. 
d Part 2 will enroll 2 disease-specific cohorts: Cohort A (third- or fourth-line MSS-CRC) and Cohort B (second-line 
MSS-CRC). The opening of enrollment of the expansion cohorts may not be simultaneous and is dependent on 
emerging data from ongoing studies. 


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3.1.1. 
DLT Criteria 
DLT Criteria for assessments in Part 1a, 1c, and 2B (unless noted) include treatment-related 
adverse events (TRAEs) as detailed below: 
• Grade ≥2 uveitis, eye pain, or blurred vision that does not resolve with topical therapy 
within 2 weeks. 
• Grade ≥2 immune-related endocrine toxicity that requires hormone replacement 
(except Grade 2 thyroiditis or thyroid dysfunction). 
• Grade 2 or 3 colitis or diarrhea that persists without resolution to Grade ≤1 for ≥7 
days despite adequate immune suppressive therapy. 
• Grade 3 or 4 irAE without resolution to Grade ≤1 or baseline within 8 days despite 
adequate immune suppressive therapy per Section 5.6.4 and Table 3. 
• Any Grade clinically significant irAE (eg, myocarditis, encephalitis) requiring 
treatment discontinuation. 
• Any other Grade ≥3 non-hematologic clinical (non-laboratory) toxicity excluding: 
− Nausea and vomiting resolving to Grade ≤1 within 48 hours. 
− Grade 3 fatigue with duration <7 days. 
− In Part 2B, events deemed by the Investigator to be related to the 
chemotherapeutic or biologic agents administered as SOC alongside the study 
drugs. 
• Any clinically-significant Grade ≥3 non-hematologic laboratory abnormality. 
• Any clinically-significant hematologic toxicity specifically defined as: 
− Grade 4 thrombocytopenia for ≥7 days, or Grade 3 or 4 associated with bleeding 
or requiring platelet transfusion. 
− Grade 4 neutropenia for ≥7 days, or Grade 3 or 4 associated with infection or 
febrile neutropenia. 
− Grade 4 anemia, or Grade 3 requiring blood transfusion. 
• Any death that is not clearly attributed to the underlying disease or extraneous causes. 
Treatment-related toxicity is defined as an AE that is not clearly attributable to other causes (eg, 
PD or a pre-existing medical condition). Toxicities will be assessed according to the CTCAE 
v5.0. If multiple toxicities occur, the presence of DLT will be graded based on the most severe 
toxicity observed. 
At the end of the respective DLT observation periods, each patient must be assessed by the 
Investigator as to whether the patient experienced a DLT to confirm the patient may continue 
treatment. Patients who experience DLTs may be considered for continuing treatment given the 
appropriate clinical context (eg, may continue treatment if a transient Grade 3 laboratory 
abnormality is asymptomatic and otherwise unremarkable) following discussion between the 
Investigators and Sponsor. 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
4 5  
 
F or t he p ur p os es of d ose escalati o n de cisi o n or det er mi ni n g R P 2 D, a ll safet y dat a fr o m t he d ose 
escalati o n c o h orts, i ncl u di n g all ir A Es, re gar dl ess of se verit y occ urre nce wit hi n t he D L T 
wi n d o w, will be c o nsi dere d. T hese c urre nt D L T criteria will be a p plie d retr oacti vel y f or all 
patie nts treate d wit h T S R -0 3 3 i n c o m bi nati o n  wit h d ostarli ma b  a n d f or patie nts treate d wit h 
T S R -0 3 3 m o n ot hera p y . 
3. 1. 2.  
R ati o n ale f or t he T S R -0 3 3 St arti n g D ose  
3. 1. 3.  
P art 1 –  D ose Esc al ati o n  
3. 1. 3. 1.  
P art 1 a: T S R -0 3 3 M o n ot her a p y ( Q 2 W)  
P art 1a ( m o n ot hera p y d ose escalati o n ) w ill ev al uate T S R -0 3 3 at ascen di n g  d o ses ( 2 0 m g, 8 0 m g, 
a n d 2 4 0 m g). A hi g her d ose le vel of 7 2 0 m g, or i nter me diate d ose l e vels ma y b e e x pl ore d, if 
warra nte d base d o n tar get e x p os ure a n d safet y fi n di n gs. T S R -0 3 3 will be a d mi nist ered  via  a n 
a p pr o xi matel y 3 0 -mi n ute IV i nfusi o n Q 2 W.  T he D L T o bs er vati o n peri o d i n Part 1a is defi ne d as 
2 8 da ys, e nc o m passi n g 2  Q 2 W a d mi nistrati o ns of T S R -0 3 3.  
C o h orts will be e nr olle d se q ue ntiall y a n d will i nitiall y f oll o w a 3 + 3 desi g n at a starti n g d ose of 
2 0 m g, as d eter mi ne d b y precli nical safet y a n d p h ar mac ol o g y st u dies. I niti all y, 3 patie nts will be 
a d mi nistere d T S R -0 3 3, a n d d ose escal ati o n or e x pa nsi o n t o 6 patie nts will be c o nsi dere d after all 
3 patie nts at t he 2 0 -m g le vel ha ve c o m plete d t he D L T o bser vati o n  peri o d a n d are f o u n d t o b e 
e val ua ble f or safet y u p o n re vie w of s afet y d ata c o n d ucte d b y t he I n vesti gat ors a n d S p o ns or. I n 
s u bse q ue nt d ose le vels, 6 patie nts will i nitiall y be e nr olle d i nt o eac h c o h ort t o e val uate as ce n di n g 
d oses of T S R -0 3 3. At a n y d ose le vel w here D L Ts a re o bser ve d i n ⅓ of p atie nts, u p t o 6 
a d diti o nal patie nts ma y b e e nr olle d i n t hat d ose le vel.  T he p ote ntial e nr oll me nt of a d diti o nal 
patie nts will ta ke place f oll o wi n g disc ussi o n wit h t he I n v esti gat ors, ta ki n g i nt o acc o u nt se verit y 
a n d d urati o n of o bser ve d  D L Ts as well as t he o v erall safet y of a d os e le vel.  
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Figure 2: 
Part 1a Dosing Schema – TSR-033 Monotherapy (Q2W Schedule) 
 
Abbreviations: DLT=dose limiting toxicity; Q2W=every 2 weeks. 
At any dose level, an initial 3 or 6 patients will be enrolled, then: 
• If the observed DLT rate is <⅓, the dose may be escalated. 
• If the observed DLT rate is >⅓, no further dose escalation will be considered, and this 
dose level will be considered the maximum administered dose (MAD). 
• If the observed DLT rate is ⅓, the Sponsor may enroll up to 6 additional patients 
following discussion with the Investigators. 
− If the observed DLT rate in a total cohort of 9 to 12 patients is >⅓, no further dose 
escalation will be considered, and this dose level will be considered the MAD. 
The MTD will be considered the dose one level below the MAD if ≥⅓ of patients experience 
DLTs, or, at MAD if <⅓ of patients experience DLTs. 
Accordingly, the RP2D may be at the MAD or 1 dose level below the MAD. Alternatively, an 
intermediate dose level below the MAD may be introduced and assessed for DLTs. Dose 
escalation will continue until the RP2D is reached or may be stopped at any dose level based on 
emerging safety and PK/PDy data, subject to agreement between the Investigators and Sponsor. 
A RP2D will be defined as the dose with DLTs observed in <⅓ of at least 6 patients and desired 
PK and
as determined by the Sponsor, in agreement with the Investigators. A 
patient will be considered non-evaluable if, for any reason other than safety, the patient is unable 
to complete the DLT observation period, or if the PK assessments were insufficient to define the 
PK profile. Patients in Part 1a considered non-evaluable may be replaced after consultation 
between the Investigators and Sponsor. 
3.1.3.2. 
Part 1b: TSR-033 Monotherapy PK/PDy Cohort (Q2W Schedule) 
CCI
CCI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
4 7  
 
Fi g ure  3 : 
P art 1 b D osi n g Sc he m a –  P K/
 
A b bre viati o ns: P D y = p har mac o d y na mic; P K = p har mac o ki netic; Q 2 W = e ver y 2 wee ks.  
3. 1. 3. 3.  
P art 1c: T S R -0 3 3 i n C o m bi n ati o n wit h D ost arli m a b  ( Q 3 W Sc he d ule) 
T he starti n g d os e of T S R -0 3 3 w he n use d i n c o m bi nati o n wit h d ostarli ma b m ust be 1 d ose le vel 
bel o w t he hi g h est d ose at  w hic h < ⅓ of at least 6 p atie nts e x perie nce d D L Ts wit h si n gle a ge nt 
T S R -0 3 3 . 
T S R -0 3 3 will be a d mi nistere d wit h d ostarli ma b  Q 3 W t hr o u g h o ut Part 1c, a n d patie nts will 
recei v e d ostarli ma b  at a d ose of 5 0 0 m g i n c o m bi nati o n wit h asce n di n g d oses of T S R -0 3 3 Q 3 W.  
T he starti n g d os e of T S R -0 3 3 w he n use d i n c o m bi nati o n wit h d ostarli ma b  m ust be o ne d ose 
le vel bel o w t he hi g hest d ose at w hic h < ⅓ of patie nts e x perie nce d D L Ts wit h si n gle-a ge nt T S R -
0 3 3. Pla n ne d d ose le vels of T S R -0 3 3 i ncl u de 8 0 a n d 2 4 0 m g. A hi g her d ose le vel of 7 2 0 m g 
Q 3 W ma y be e x pl ore d if warra nte d base d o n tar get e x p os ure a n d safet y fi n di n gs. A d diti o nal 
c o h orts c o nsisti n g of 6 -1 2 patie nts are n ee de d t o e x a mi ne a d diti o nal d ose le vels ma y als o be 
e x pl ore d if warra nte d f oll o wi n g a gree me nt b et wee n t he I n ves ti gat ors a n d S p o ns or. d ostarli ma b  
at a d ose of 1 0 0 0 m g ma y als o be t este d wit h t he R P 2 D of T S R -0 3 3 gi ve n o n a Q 6 W sc he d ule. 
F or all a d mi nistrati o ns of t he c o m bi nati o n re gi me n, T S R -0 3 3 will be gi ve n first, f oll o we d b y 
d ostarli ma b . 
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Figure 4: 
Part 1c Dosing Schema – TSR-033 Combined with Dostarlimab (Q3W) 
 
Abbreviations: DLT=dose-limiting toxicity; Q3W=every 3 weeks. 
The RP2D will be defined by the Sponsor in agreement with Investigators based on safety, PK, 
and PDy data in a minimum of at least 6 patients. If DLT is observed in ≥⅓ patients, additional 
cohort(s) may be opened where a lower dose of either TSR-033 or dostarlimab, or both, may be 
explored. 
3.1.3.3.1. Assessment of Renal Impairment 
During the conduct of the expansion cohorts, a safety assessment will be performed in 6-12 
patients with moderate chronic kidney damage (ie, creatinine clearance [CrCL] between 30 and 
50 mL/min). Patients meeting these criteria may be enrolled in any of the 4 expansion cohorts 
and will complete DLT observation for 42 days. If DLTs are observed in <⅓ of patients, then 
patients with CrCL ≥30 mL/min will be allowed throughout Part 2 of the study. 
3.1.4. 
 Part 2 – Dose Expansion Cohorts – TSR-033 + Dostarlimab (Q2W + Q6W) 
Part 2 will commence using the RP2D established for the combination regimen in Part 1c of the 
study. Study treatment in Part 2 will be administered on a Q2W schedule for TSR-033 and a 
Q6W schedule for dostarlimab. In Part 2B, TSR-033 and dostarlimab will be administered on Day 
3 of a dose cycle following chemotherapy and bevacizumab therapy on Day 1 of a dose cycle. 
The expansion cohorts will evaluate the preliminary activity of TSR-033 in combination with 
dostarlimab in anti-PD-1 naïve patients with a specific tumor type as follows: 
• Cohort A – Third- and fourth-line MSS-CRC 
• Cohort B –Second-line MSS-CRC 
In each disease-specific expansion cohort, a Simon’s 2-stage design will be used to provide 
initial assessment of the clinical activity of the TSR-033 in combination with dostarlimab50 (see 
Section 8.7). 
For Cohorts B1 and B2, if within 12 weeks of initiating study treatment, delayed irAEs 
consistent with DLT criteria occur in ≥⅓ of patients at a particular dose level, a lower dose level 
will be considered by the Sponsor following discussion with study Investigators for: 
• Further refinement of RP2D and dose for expansion cohorts and/or 
• All patients on treatment if in the best interest of the patient 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
4 9  
 
3. 2.  
N u m ber of S u bjects  
A p pr o xi matel y 1 2 7 -1 8 7 pa tie nts are e x pecte d t o e nr oll i n t his st u d y (all o wi n g f or re place me nt of 
patie nts a n d d ose e x pa nsi o n).  
Part 1: A t otal of u p t o 7 2 -1 3 2 patie nts are a ntici p ate d:  
P art 1 a ( T S R -0 3 3 m o n ot her a py d ose es c al ati o n): A p pr o xi matel y 3 0 t o 5 4 patie nts  
P art 1 b ( T S R -0 3 3  m o n ot her a py P K/
: A p pr o xi matel y 1 8 t o 3 0 patie nts  
P art 1c ( T S R -0 3 3 + d ost arli m a b  c o m bi n ati o n d ose esc al ati o n): A p pr o xi matel y 2 4 t o 4 8 p atie nts  
T hese e nr oll me nt n u m bers c o ul d i ncrease if t he S p o ns or, i n c o ns ultati o n wit h t he I n vesti gat o r, 
deter mi nes t hat a d diti o nal c o h orts c o nsisti n g of 6 -1 2 patie nts are n ee de d t o e x a mi ne a d diti o nal 
d ose le vels.  
Part 2 : A t otal of u p t o a p pr o xi matel y 5 5 p atie nts are a ntici p ate d:  
C o h ort A ( T S R -0 3 3 + d ost arli m a b  i n a nti-P D -1 -n aïve t hir d - a n d f o urt h -li ne C RC): 
A p pr o xi matel y 3 1 p atie nts  
C R C C o h ort B 1 ( T S R -0 3 3 + d ost arli m a b  give n i n c o m bi n ati o n wit h m F O L F O X 6 a n d 
bev aciz u m a b ( S O C) i n a nti -P D -1 -n aïve s ec o n d -li ne M S S-C R C p atie nts w h o h ave pr o gresse d o n 
fr o ntli ne tre at me nt wit h F O L FI RI, wit h or wit h o ut bi ol o gics): A p pr o xi matel y 1 2 p atie nts.  
C R C C o h ort B 2 ( T S R -0 3 3 + d ostarli ma b  gi ve n i n c o m bi nati o n wit h F O L FI RI a n d b e vaciz u ma b 
( S O C) i n a nti-P D -1 -naï v e sec o n d -li ne M S S-C R C patie nts w h o ha ve pr o gresse d o n fr o ntli ne 
treat me nt wit h F O L F O X [ or varia nt], wit h or wit h o ut biol o gics ): A p pr o xi matel y 1 2 p atie nts. 
S h o ul d e nr oll me nt i n C o h ort B 1 fall be hi n d, all o wa nce will be ma de t o i n creas e t he n u m ber of 
patie nts e nr olle d i n C o h ort B 2 aft er D L T cleara nce of t he first 6 patie nts, s uc h t hat a n a d diti o nal 
6 t o 1 8 ma y be e nr olle d. T he t otal f or Part 2 B as a w h ole re mai ns at 2 4.  
3. 3.  
Ge ner al St u d y C o n d uct  
F oll o wi n g t he i nf or me d c o nse nt pr ocess, all patie nts will u n der g o scree ni n g pr oce d ures wit hi n 
2 1 da ys ( Part 1) or 2 8 d a ys ( Part 2) pri or t o t he first d ose of st u d y tr eat me nt t o deter mi ne 
eli gi bilit y f or st u d y e ntr y. Scree ni n g pr oce d ures i ncl u de assess me nt of p atie nt hist or y ( me dical, 
s ur gic al, ca n cer, m e dicati o n), c o m plete p h ysical e x a mi nati o n (i ncl u di n g vital si g ns, hei g ht, a n d 
wei g ht), electr ocar di o gra m ( E C G), deter mi nati o n of patie nt Ea ster n C o o perati ve O nc ol o g y 
Gr o u p ( E C O G) p erf or ma nce stat us ( P S), a n d cli ni cal la b orat or y tests (see S ecti o n  6. 1. 7 ). 
3. 3. 1.  
St u d y Visits a n d Assess me nts  
3. 3. 1. 1.  
Bi o p sies 
Bi o psies are a n i nte gral c o m p o ne nt of t his st u d y t o e na ble a n assess me nt of t he P D y effects of  
T S R -0 3 3 as a m o n ot hera p y a n d i n c o m bi nati o n wit h d ostarli ma b . Data fr o m t hese i n vesti gati o ns 
ma y c o ntri b ute t o t he u n dersta n di n g of t he t u m or micr oe n vir o n m e nt, i ncl u di n g, b ut n ot li mite d 
t o, i m m u ne cells, t u m or c haract eristics, a n d i m m u ne-rel ate d ge n e a n d pr otei n e x pressi o n a n d 
h o w t he y relate t o T S R -0 3 3 cli nical acti vit y. Pre -d ose a n d o n -st u d y/ E O T bi o psies are o pti o nal 
f or patie nts i n Parts 1a a n d 1c. F or all patie nts i n 1 b a n d Part 2, fres h bi o psies are re q uir e d. F or 
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T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
5 0  
 
patie nts i n c o h orts A a n d B, 
 
 It is preferre d t hat f or t u m or bi o psies t hat are n ot si m pl y i ncisi o nal or 
e x cisi o nal, a 1 6 -ga u ge c ore bi o ps y n ee dle is use d; h o w e ver, a s maller b ore nee dle ma y b e use d if 
c o nsi dere d n ecess ar y f or t he patie nt’s safet y. F o ur c ore bi o psies nee d t o be o btai ne d. Fi ne nee dle 
bi o psies are n ot rec o m me n de d f or t his st u d y. Ple ural eff usi o ns or l u n g as pirate sa m ples ca n n ot 
be s u bstit ute d f or t u m or bi o psies. Patie nts u n der g oi n g t u m or bi o ps y m ust ha ve pr ot hr o m bi n ti me 
( P T)/acti vate d partial t hr o m b o plasti n ti me (a P T T) < 1. 5 × u p per li mit of n or mal ( U L N). Details 
re gar di n g t u m or tiss ue sa m ple c ollecti o n a n d ma na ge me nt are pr o vi de d i n t he St u d y La b orat or y 
Ma n ual a n d as f oll o ws:  
•  Arc hi val t u m or tiss ue is r e q uire d at scree ni n g f or all patie nts i n Part 1a, 1 b, a n d 1c. 
Arc hi val t u m or tiss ue ma y be s u b mitte d as f or mali n -fi x e d paraffi n-e m be d de d ( F F P E) 
bl oc k ( preferre d) or sli des. If arc hi val t u m or tiss ue is  n ot a vaila ble, patie nts m ust 
u n der g o a t u m or tiss ue bi o ps y at scree ni n g ( pri or t o d osi n g). F or Part 2, s u b missi o n of 
s ufficie nt hi g h-q ualit y F F P E arc hi v al tiss ue is rec o m me n de d, if a vaila ble, t o e na ble a 
l o n git u di nal a nal ysis of t u m or bi o mar kers. 
•  Se parate  fr o m arc hi val t u m or tiss ue, serial t u m or tiss ue bi o psies are O P TI O N A L f or 
Part 1a a n d 1c a n d R E Q UI R E D f or Part 1 b a n d Part 2. Fres h seri al t u m or tiss ue 
bi o psies are t o be c ollect e d pri or t o treat me nt, a p pr o xi matel y 4 t o 6  wee ks after 
treat me nt, a n d, w h e never p ossi ble, at t he ti me of P D a n d or E O T.  
T here ma y b e i nsta nces w here p atie nts are e nr oll e d a n d it is s u bse q ue ntl y deter mi ne d t hat, f or 
me dical reas o ns, a fres h t u m or tiss ue bi o ps y ca n n ot be o btai ne d. T he reas o n f or t he misse d 
bi o ps y m ust be d oc u me nte d i n t he me dical rec or d. Refer t o Secti o n 6. 6. 2 . 
3. 3. 1. 2.  
S afet y Assess me nts  
S afety  assess ments co n d u cted t h ro u g h o ut t he  trea t ment p eri o d i ncl u de sym pt o m -di recte d 
p h y sical ex ami n ati o ns, vital sig ns, E C G s, E C O G P S , an d cli nical lab o rat ory  assess ments, 
i ncl u di n g c o m plete bl o o d c o u nt ( C B C) wit h differe ntial (i n cl u di n g a bs ol ut e l y m p h o c yt e c o u nt 
[ A L C] a n d a bs ol ut e ne utr o p hil c o u nt [ A N C]), co ag ul ati o n pr ofile, ch emist ry , t h yr oi d pa n el (ie, 
t h yr oi d-sti m ulati n g h or m o ne [T S H] , trii o d ot h yr o ni ne [ T3], free trii o d ot h yr o ni ne [ F T 3],  
t h yr o xi n e [T 4], free t h yr o xi ne [ F T 4], or e q ui vale nt tests, w here a p plica ble), u ri nalysis, an d 
p reg n an c y  testi n g. 
3. 3. 1. 3.  
R a di o gr a p hic Dise ase Assess me nts  a n d T u m or M ar kers  
Ra di o gra p hic ev al uati o ns (c o m p ute d t o m o gra p h y [C T] / ma g netic res o n a nce i ma gi n g [ MR I] of  
ch est, ab d o m en, an d p el vis, or ot her re gi o ns k n o w n t o ha ve disease i n v ol ve me nt) t o assess ex tent 
of  dis ease w ill b e co n d u cted Q 6 W  ( 4 2 d a y s ± 7 da y s) f or t he first 3 assess m e nts a n d e ver y 
9  wee ks t hereaft er, or u ntil ra di o gra p hic c o nfir me d P D or i nitiati o n of ne w s yste mic a nti -ca ncer 
t hera p y, w hic h e ver occ urs first. A d diti o nall y, patie nts will ha ve a p p ro p riate testi n g of ser u m-
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T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
5 1  
 
base d t u m or mar kers w h e re a p plica ble (e g, carci n oe m br y o nic a nti ge n [ C E A] f or patie nts wit h 
C R C)  t o c oi nci de a p pr o xi matel y wit h ra di o gra p hi c assess me nts. All o n-st u d y t u m or ass ess me nts 
(ra di o gra p hi c a n d t u m or mar kers) will be perf or me d i n dep en d ent of  d os e  d ela y s an d/ or  d ose  
i nterru pti o ns, an d/ or  at an y  ti me w h en p ro g ressi o n of dis ease is s us pected.  B rai n scans w ill be 
co n d u cted if  cli nicall y i n dicated; b o ne s cans w ill be co n d u cted  p er S O C . A fter 1  y ear, p atients 
w h o rem ai n o n treat ment w ill have  i mag in g  p erfo rm ed ev ery  1 2  wee ks  (8 4  ± 7 d a ys). If a p atient 
dis co nti n u es treat ment for  a reas o n ot her th an p ro g ressi o n or d eat h, w it hd ra wal of co ns ent, or  
l oss t o f oll o w-u p ( F U P), ra di o gra p hic s cans an d ap p ro p riate testi n g of
s h o ul d co n ti n ue at t he s pecified i nt erv als. I n Part 2, c o pies of sca ns will be c ollecte d a n d st ore d 
at a re p osit or y f or p ote ntial e val uati o n.  
Per R E CI S T v 1. 1, patie nts w h o ac hie ve c o m plete res p o nse ( C R) or p artial r es p o nse ( P R) s h o ul d 
ha ve t he res p o nse c o nfir me d; t u m or i ma gi n g f or c o nfir mati o n o f res p o nse ma y b e perf or me d, at 
t he earliest, 4 w ee ks after t he first i n dicati o n of res p o nse, or at t he ne xt sc he d ule d sca n, 
w hic he ver is cli nicall y i n dicate d . 
Base d o n a rec o g niz e d p he n o me n o n of tra nsie nt t u m or flare i n t he first fe w m o nt hs after t he start 
of i m m u n ot hera p y wit h s u bse q ue nt disease res p o nse, patie nts treate d wit h T S R -0 3 3 will be 
per mitte d t o c o nti n ue treat me nt be y o n d i nitial R E CI S T v 1. 1 -defi ne d P D w hile a waiti n g 
c o nfir mati o n of P D. 5 1 I n i nsta nces w here pse u d o pr o gessi o n is s us pecte d, P D s h o ul d be 
co n firm ed a  mi ni m u m of 4 wee ks a n d u p t o 6 wee ks after t he first P D assess ment i n acc or da n ce 
wit h t he 
g ui deli nes (see Secti o n  6. 3. 1. 5  a n d A p pe n di x  2 ). Treat me nt ma y c o nti n ue 
base d o n I n vesti gat or j u d ge m e nt if t he patie nt is cli nicall y sta ble ( ie, n o si g ns or s y m pt o ms of 
cli nicall y si g n ifica nt or ra pi d pr o gressi o n of dise ase, i ncl u di n g w orse ni n g of la b orat or y v al ues or 
decli ne i n P S; n o pr o gressi ve t u m or at critical a nat o mical sites [ e g, c or d c o m pressi o n, 
i ntracra ni al t u m or he m orr ha ge, et c.] re q uiri n g ur ge nt me dical i nter ve nti o n). Cli nicall y st a ble 
patie nts s h o ul d n ot be disc o nti n ue d u ntil pr o gressi o n is c o nfir me d (see A p pe n di x  2  f or
detaile d g ui da nce).  
3. 3. 1. 4.  
P h ar m a c o ki netics a n d  A nti dr u g A nti b o d y Assess me nts  
Bl o o d sa m ples f or t he d eter mi nati o n of ser u m le vels of T S R -0 3 3 a n d d ostarli ma b , as well as 
a nti dr u g a nti b o dies ( A D A s) f or me d a gai nst t hese i n vesti gati o nal pr o d u cts, will be c ollecte d fr o m 
patie nts i n b ot h Part 1 a n d Part 2 . 
In Part 1 b, a c o h ort(s) of u p t o 6 a d diti o nal patie nts ma y be e nr olle d i n a n y d ose le vel wit h D L Ts 
o bser ve d i n < ⅓ of patie nts t o better c haracterize t he P K pr ofile 
 f oll o wi n g treat me nt 
wit h T S R -0 3 3. I n t his c o h ort(s), patie nts will recei ve t heir  T S R -0 3 3 d oses o n Da y 1, Da y 2 9, a n d 
c o nti n ue Q 2 W t hereafter. T he e xte n de d treat me nt d urati o ns i n t he a bse nce of a Da y 1 5 d os e 
e na bles better c haract erizati o n of t he ter mi nal p has e of t he P K pr ofile, w hic h ca n lea d t o m ore 
acc urate calc ulati o ns of P K para m eters (s uc h as t ½ ). A d diti o nall y, t his e xte n de d treat me nt 
i nter val will pr o vi de a d diti o nal  
 t hat ma y c o ntri b ute t o t he deter mi nati o n of t he R P 2 D. 
T he decisi o n re gar di n g w hic h c o h ort(s) t o e x pa n d f or t his e val uati o n will be deter mi ne d b y t he 
S p o ns or  a n d t he I n vesti gat ors.  
T he ser u m sa m ples f or P K deter mi nati o n will be a nal yze d usi n g e nz y m e -li n ke d i m m u n os or be nt 
assa y ( E LI S A).  
C CI
C CI
C CI
C CI
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
5 2  
 
3. 3. 1. 5.  
P h ar m a c o d y n a mi cs Ass ess me nts  
3. 3. 1. 6.  
E n d of Tre at me nt a n d F oll o w -U p Assess me nts  
T he E O T visit will  occ ur wit hi n 7 da ys of t he d ecisi o n t o disc o nti n ue st u d y treat me nt f or a n y 
reas o n. S h o ul d t he first d ose of a ne w a nti-ca ncer t hera p y occ ur wit hi n 1 4 da ys of t he decisi o n t o 
disc o nti n ue st u d y treat me nt, all assess me nts re q uire d f or t he Safet y F U P visit s h o ul d occ ur at t he 
E O T visit, a n d t his visit will be c o nsi dere d t he Safet y F U P visit. If t he first d ose of t he ne w a nti -
ca ncer t hera p y occ urs > 1 4 da ys after t h e decisi o n t o disc o nti n ue st u d y, t he Safet y F U P visit will 
occ ur 3 0 ± 7 da ys after t h e last d ose of  t he st u d y dr u g, or at t he start of a n y ne w a nti-ca ncer 
t hera p y, w hic h e ver occ ur first. 
3. 3. 1. 7.  
A d verse E ve nts F oll o w -u p  
All A Es a n d S A Es will be c ollecte d a n d rec or de d f or eac h patie nt fr o m t he da y of si g ni n g t he 
i nf or me d c o nse nt f or m (I C F) u ntil 9 0 da ys after ce ssati o n of st u d y treat me nt ( or u ntil alter nati ve 
a nti-ca ncer t hera p y is i nitiate d, w hic he v er occ urs first), a n d a n y pre g na nci es are t o be ca pt ure d 
t hr o u g h 1 5 0 d a ys p ost tr eat me nt. If a n I n v esti gat or bec o mes a ware of a n S A E after t he 9 0 -da y 
F U P peri o d f oll o wi n g treat me nt disc o nti n uati o n a n d c o nsi ders t he S A E relate d t o i n vesti gati o nal 
pr o d uct, t he I n vesti gat or s h o ul d re p ort t he S A E t o t he S p o ns or acc or di n g t o ti meli nes f or 
re p orti n g S A Es descri b e d i n Secti o n 6. 1. 5 . All A Es a n d S A Es e x perie nce d b y a p atie nt d uri n g 
t he st u d y peri o d, irres pecti ve of t he s us pecte d ca us alit y, will be m o nit ore d u ntil: t he A E or S A E 
has res ol ve d or st a biliz e d, a b n or mal la b orat o r y val ues ha ve ret ur ne d t o bas eli ne or n or malize d, 
t here is a satisfact or y e x pla nati o n f or t he c h a n ges o bser ve d, t he patie nt is l ost t o F U P, t he patie nt 
wit h dra ws c o nse nt, or t h e patie nt has die d.  
3. 3. 2.  
St u d y Tre at me nt D ur ati o n  
Patie nts i n Part 1 a n d 2 ma y c o nti n ue treat me nt wit h T S R -0 3 3 m o n ot hera p y or c o m bi nati o n 
treat me nt f or u p t o 2 years  u nless s pecific wit h dra wal criteri a are met ( Secti o n  4. 3 ). C o nti n ue d 
treat me nt be y o n d 2 years ma y b e c o nsi dere d f oll o wi n g disc ussi o n bet w ee n t he I n v esti gat ors a n d 
S p o ns or.  
3. 3. 3.  
E n d of St u d y a n d Fi n al A n al ys is 
T he e n d of st u d y is defi n e d as t he date w he n t he l ast patie nt o n st u d y has c o m plete d his/ her last 
st u d y visit. 
C CI


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The final data cut-off (DCO) date for the study will be defined by the Sponsor and will be 
communicated to all sites. The DCO date represents the end of data collection for the study and 
the date on which the clinical study database will be closed to new data. 
Patients in Survival Follow-Up at the time of the DCO date will be considered to have completed 
the study. Patients still on treatment at the time of the DCO date may continue to receive study 
treatment for up to 2 years unless specific withdrawal criteria are met (see Section 3.3.2 and 
Section 4.3.1); patients may also choose to discontinue study treatment at any time. Note: Study 
treatment must be discontinued before the TSR-033 study drug supply expires. 
Patients who continue study treatment will be monitored and receive follow-up care in 
accordance with standard local clinical practice. Assessments will revert to the standard of care 
at a patient’s particular study site, and only SAEs, AEs leading to discontinuation of study 
treatment, overdoses, and pregnancies will be reported directly to the Sponsor via paper forms 
(see Section 6.1.12; refer to the Study Reference Manual for further details on reporting using 
paper forms). Although the clinical study database will be closed at the time of the DCO date, 
the study will remain open until all patients discontinue study treatment and the end of study 
definition (noted above) is reached. 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
4.1.1. 
Inclusion Criteria for Patients in Part 1 
1. The patient is ≥18 years of age. 
2. The patient has any histologically or cytologically confirmed advanced (unresectable) or 
metastatic solid tumor and has PD after treatment with available therapies that are known 
to confer clinical benefit or who are intolerant to treatment. 
3. The patient must have an archival tumor tissue sample that is FFPE (blocks preferred 
over slides) and requested and confirmed available from offsite locations prior to dosing. 
The quality and quantity of the sample must be confirmed sufficient as per the Study 
Laboratory Manual. Patients who do not have archival tissue must agree to a fresh tumor 
tissue biopsy prior to dosing. 
4. Part 1b (PK/PDy cohort): The patient must have lesions amenable for biopsy and agree to 
undergo biopsies for fresh tumor tissue prior to treatment, approximately 4 to 6 weeks 
after treatment, and, whenever possible, at the time of PD and/or EOT. Serial biopsies are 
optional for patients in Part 1a and 1c. 
5. Female patients must have a negative serum or urine pregnancy test within 72 hours prior 
to the date of the first dose of study medication if of childbearing potential or be of non-
childbearing potential. Non-childbearing potential is defined as: 
a. ≥45 years of age and has not had menses for >1 year. 
b. Amenorrhoeic for <2 years without a hysterectomy and oophorectomy and a follicle-
stimulating hormone value in the postmenopausal range upon pre-study (screening) 
evaluation. 
c. Post hysterectomy, bilateral oophorectomy, or tubal ligation. Documented 
hysterectomy or oophorectomy must be confirmed with medical records of the actual 
procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with 
medical records of the actual procedure, otherwise the patient must fulfill the criteria 
in Inclusion Criterion 5. 
6. Female patients of childbearing potential (ie, those who do not meet a-c above) must 
agree to use 2 highly effective forms of contraception with their partners (See 
Section 5.6.3 for a list of acceptable contraception methods), starting with the screening 
visit through 150 days after the last dose of study therapy. 
7. The patient must have an ECOG PS of ≤1. 
8. The patient has adequate hematologic and organ function, defined as: 
a. ANC ≥1,500/µL. 
b. Platelets ≥100,000/µL. 
c. Hemoglobin (Hb) ≥9 g/dL or ≥5.6 mmol/L. 


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− Note: Patients with Hb 7 to ≤9 g/dL (without bleeding) may be transfused prior to 
dosing in order to meet eligibility criteria; however, Hb should remain stable and 
≥9 g/dL for at least 1 week. 
d. Serum creatinine ≤1.5 × ULN or calculated CrCL ≥50 mL/min using Cockcroft-Gault 
equation for patients with creatinine levels >1.5 × institutional ULN. 
e. Total bilirubin ≤1.5 × ULN and direct bilirubin ≤1 × ULN (in the event that the total 
bilirubin result exceeds the upper institutional limits of normal, direct bilirubin will 
be obtained to determine eligibility). 
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN 
unless liver metastases are present, in which case they must be ≤5 × ULN 
g. International normalized ratio (INR) of PT ≤1.5 × ULN, unless patient is receiving 
anticoagulant therapy, then PT or partial thromboplastin time (PTT) is within 
therapeutic range of intended use of anticoagulants; aPTT) ≤1.5 × ULN unless patient 
is receiving anticoagulant therapy, then PT or PTT is within therapeutic range of 
intended use of anticoagulants. 
4.1.2. 
Inclusion Criteria for Patients in Part 2 
1. The patient is ≥18 years of age. 
2. The patient has any histologically or cytologically confirmed CRC that is metastatic or 
not amenable to potentially curative resection (advanced), in the opinion of the 
Investigator. 
3. The patient has a primary and/or metastatic tumor(s) that is known to be MSS, as 
determined locally. 
4. The patient must have lesions amenable for biopsy and agree to undergo biopsies for 
fresh tumor tissue prior to treatment, approximately 4 to 6 weeks after treatment, and, 
whenever possible, at EOT and/or the time of PD. If the patient has had a biopsy prior to 
entering the 28-day screening period, and within approximately 12 weeks of study 
treatment, that biopsy sample may be accepted as the baseline fresh biopsy. Additionally, 
submission of sufficient high-quality archival tumor tissue is recommended, if available, 
to enable a longitudinal analysis of tumor biomarkers. 
5. The patient has measurable disease by RECIST v.1.1. 
6. The patient has resolution to Grade ≤1, per CTCAE v5.0, of all clinically significant toxic 
effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy, with the 
exception of peripheral neuropathy, which must have resolved to Grade ≤2, and except 
where otherwise noted in the eligibility criteria. 
7. Female patients must have a negative serum or urine pregnancy test within 72 hours prior 
to the date of the first dose of study medication if of childbearing potential or be of non-
childbearing potential. Non-childbearing potential is defined as: 
a. ≥45 years of age and has not had menses for >1 year. 
b. Amenorrhoeic for <2 years without a hysterectomy and oophorectomy and a follicle-
stimulating hormone value in the postmenopausal range upon pre-study (screening) 
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c. Post hysterectomy, bilateral oophorectomy, or tubal ligation. Documented 
hysterectomy or oophorectomy must be confirmed with medical records of the actual 
procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with 
medical records of the actual procedure, otherwise the patient must fulfill the criteria 
in Inclusion Criterion 5. 
8. Female patients of childbearing potential (ie, those who do not meet a-c above) must 
agree to use 2 highly effective forms of contraception with their partners (See 
Section 5.6.3 for a list of acceptable contraception methods), starting with the screening 
visit through 150 days after the last dose of study therapy. 
9. The patient has an ECOG PS of ≤1. 
10. The patient has adequate hematologic and organ function as defined: 
a. ANC ≥1,500/µL 
b. Platelets ≥100,000/µL. 
c. Hb ≥9 g/dL or ≥5.6 mmol/L. 
− Note: Patients with Hb 7 to ≤9 g/dL (without bleeding) may be transfused prior to 
dosing in order to meet eligibility criteria; however, Hb should remain stable and 
≥9 g/dL for at least 1 week. 
d. Serum creatinine ≤1.5 × ULN or calculated CrCL ≥50 mL/min using Cockcroft-Gault 
equation for patients with creatinine levels >1.5 × institutional ULN. 
e. Total bilirubin ≤1.5 × ULN and direct bilirubin ≤1 × ULN (in the event that the total 
bilirubin result exceeds the upper institutional limits of normal, direct bilirubin will 
be obtained to determine eligibility). 
f. AST and ALT ≤2.5 × ULN unless liver metastases are present, in which case they 
must be ≤5 × ULN 
g. INR of PT ≤1.5 × ULN, unless patient is receiving anticoagulant therapy, then PT or 
PTT is within therapeutic range of intended use of anticoagulants; aPTT) ≤1.5 × ULN 
unless patient is receiving anticoagulant therapy, then PT or PTT is within therapeutic 
range of intended use of anticoagulants. 
h. Urinary protein is ≤1+ on dipstick for routine urinalysis; if urine protein ≥2+, a 24-
hour urine sample must be collected and must demonstrate <1000 mg of protein in 24 
hours to allow participation in the study. 
i. Baseline albumin ≥3.0 g/dL. 
4.1.2.1. 
Inclusion Criteria for Patients in Part 2A 
1. The patient must have had at least 2, but no more than 3, prior lines of therapy in the 
advanced or metastatic setting. Adjuvant chemotherapy with radiographic progression 
>12 months after the last dose will not be considered a line of therapy. 
2. The patient has progressed on standard therapies or withdrawn from standard treatment 
due to unacceptable toxicity. Previous standard treatment must include all of the 
following: 
a. Fluoropyrimidine. 


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b. Oxaliplatin: Patients treated with oxaliplatin in adjuvant setting should have 
progressed after 12 months of completion of adjuvant therapy or they must have been 
treated with oxaliplatin for metastatic disease. 
c. Irinotecan. 
d. Patients whose disease is known to be RAS-wild-type must have been treated with 
cetuximab, panitumumab, or other EGFR inhibitor for metastatic disease. 
e. Bevacizumab and/or another anti-angiogenic agent. 
f. Previous treatment with regorafenib and/or TAS-102 are allowed in the absence of 
contraindications and if these agents are available to the patient according to local 
standards. 
3. Time between the patient’s last chemotherapy and enrollment must be ≤8 weeks. 
4.1.2.2. 
Inclusion Criteria for Patients in Part 2B 
4. The patient has received ≤2 prior systemic chemotherapy regimens in any setting (only 1 
prior regimen for metastatic disease is permitted). 
4.1.2.2.1. Inclusion Criteria for Patients in Part 2 Cohort B1 
1. The patient has received first-line combination therapy consisting of bevacizumab or 
anti-EGFR antibodies with FOLFIRI and has experienced radiographic progression 
during or after first-line therapy. Radiographic progression >12 months after the last dose 
of adjuvant therapy will not be considered a line of therapy. 
2. mFOLFOX6 therapy with bevacizumab is appropriate for the patient and is 
recommended by the Investigator. 
4.1.2.2.2. Inclusion Criteria for Patients in Part 2 Cohort B2 
1. The patient has received first-line combination therapy consisting of bevacizumab or 
anti-EGFR antibodies with FOLFOX (or a variant) and has experienced radiographic 
progression during first-line therapy. Radiographic progression >12 months after the last 
dose of adjuvant therapy will not be considered a line of therapy. 
2. FOLFIRI therapy with bevacizumab is appropriate for the patient and is recommended by 
the Investigator. 
4.2. 
Exclusion Criteria 
4.2.1. 
General Exclusion Criteria for All Patients 
1. The patient has previously been treated with an anti-LAG-3 antibody. 
2. The patient has known uncontrolled central nervous system (CNS) metastases and/or 
carcinomatous meningitis. 
3. The patient has a known concurrent, serious, uncontrolled medical disorder, 
nonmalignant systemic disease, or active infection requiring systemic therapy, including 
human immunodeficiency virus (HIV), known active hepatitis B or hepatitis C, active 
infection, or active autoimmune disease. 


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4. The patient is pregnant or breastfeeding, or expecting to conceive children within the 
projected duration of the study. 
5. The patient has a history of interstitial lung disease. 
6. The patient has not recovered (ie, to Grade ≤1 or to baseline) from radiation- and 
chemotherapy-induced AEs, has received transfusion of blood products (including 
platelets or red blood cells), or has received administration of colony stimulating factors 
(including granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage 
colony-stimulating factor or recombinant erythropoietin) within 3 weeks prior to the first 
dose of study drug. 
7. The patient is currently participating in an investigational study (therapy or device) or has 
participated in an investigational study within 4 weeks prior to the first dose of study 
drug. 
8. The patient has received prior anti-cancer therapy (chemotherapy, targeted therapies, 
radiotherapy, or immunotherapy) within 21 days or less than 5 times the half-life of the 
most recent therapy prior to the first dose of study drug, whichever is shorter. 
9. The patient has received wide-field (full-dose pelvic) radiotherapy within 28 days prior to 
the first dose of study drug. 
10. The patient has a history of uncontrolled hereditary or acquired bleeding or thrombotic 
disorders. 
11. The patient has experienced any arterial thrombotic or arterial thromboembolic events, 
including, but not limited to myocardial infarction, transient ischemic attack, or 
cerebrovascular accident, within 12 months prior to first dose of study drug. 
12. The patient has received a prior autologous or allogeneic organ or transplantation. 
13. The patient has undergone major surgery within 28 days or subcutaneous venous access 
device placement within 7 days prior to the first dose of study drug. 
14. The patient has had a serious nonhealing wound, ulcer, or bone fracture within 28 days 
prior to first dose of study drug. 
15. The patient has an elective or planned major surgery to be performed during the course of 
the trial. 
16. The patient has a history of inflammatory bowel disease or Crohn’s disease requiring 
medical intervention (immunomodulatory or immunosuppressive medications or surgery) 
in the 12 months prior to the first dose of study drug. 
17. The patient has an acute or subacute bowel obstruction, abdominal fistula, or history of 
chronic diarrhea which is considered clinically significant, in the opinion of the 
Investigator. 
18. The patient has experienced a Grade ≥3 bleeding event within 3 months prior to the first 
dose of study drug. 
19. The patient has either peptic ulcer disease associated with a bleeding event or known 
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20. The patient has not recovered (Grade ≥1) from AEs and/or complications from any major 
surgery prior to the first dose of study drug. 
21. The patient has received a vaccine within 7 days of the first dose of study drug. 
22. The patient has known hypersensitivity to TSR-033, dostarlimab (Part 1c and Part 2), or 
associated excipients. 
4.2.1.1. 
Exclusion Criteria for Patients in Part 1 
1. The patient’s prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-LAG-3 
agent resulted in permanent discontinuation due to an AE. 
4.2.1.2. 
Exclusion Criteria for Patients in Part 2 
1. The patient has been previously treated with an anti-PD-1 or anti-PD-L1 antibody. 
4.2.1.3. 
Exclusion Criteria for Patients in Part 2B 
1. The patient has known dihydropyrimidine dehydrogenase deficiency. 
2. The patient experienced an arterial thrombotic/thromboembolic event, Grade 4 
hypertension, Grade 4 proteinuria, a Grade 3-4 bleeding event, or bowel perforation 
during first-line therapy with a bevacizumab-containing regimen. 
3. The patient has known hypersensitivity to bevacizumab, mFOLFOLX6 (Cohort B1) or 
FOLFIRI (Cohort B2), or associated excipients. 
4. The patient experienced PD within 12 months of last dose of adjuvant therapy. 
4.3. 
Patient Withdrawal and Replacement 
4.3.1. 
Discontinuation from Study Treatment 
Patients may be discontinued from study treatment at any time. Specific reasons for 
discontinuing treatment include the following: 
• AE, which may include DLTs, irAEs per guidance in Table 3, and non-resolving AEs 
where continued treatment could be detrimental to patient’s well-being. 
• Disease progression as outlined in Section 6.3 or based on clinical criteria by 
Investigator. 
• Risk to patients as judged by the Investigator, Sponsor, or both. 
• Severe noncompliance with protocol as judged by the Investigator, Sponsor, or both 
• Patient request. 
• Patient becomes pregnant. 
• Withdrawal of consent by the patient, who is at any time free to discontinue 
participation in the study, without prejudice to further treatment. 


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• Withdrawal of consent from treatment, but agreement to participate in FUP visits 
(partial consent withdrawn). 
• Death. 
Patients who discontinue from study treatment will continue to receive FUP assessments (see 
Table 4, Table 5, Table 6, and Table 7) as part of the study unless they are discontinued from the 
study. 
4.3.2. 
Discontinuation from the Study 
Patients may be discontinued from the study for any of the following reasons: 
• Withdrawal of consent by the patient, who is at any time free to discontinue 
participation in the study, without prejudice to further treatment. 
• Loss to FUP. 
• Death. 
• Sponsor decision to terminate study. 
If a patient is thought to be lost to FUP, discontinues study treatment, or discontinues the study, 
attempts should be made to contact the patient to determine the reason for discontinuation. For 
patients who are thought to be lost to FUP, at least 3 documented attempts, including 1 via 
certified mail, should be made to contact the patient before the patient is deemed lost to FUP. 
4.3.3. 
Replacement of Patients 
After consultation between the Investigators and Sponsor, enrollment may be extended to replace 
patient(s) that become non-evaluable for safety or if there is insufficient PK data during Part 1a, 
Part 1b, and Part 1c. 
For Cohorts B1 and B2, if a patient discontinues study treatment prior to the first assessment of 
disease (either scheduled radiological assessment at 6- or 9-weeks post treatment initiation or 
clinically indicated disease assessment prior to 6 or 9 weeks), the patient may be replaced after 
consultation between the Investigators and Sponsor, unless the patient discontinued study 
treatment due to clear clinical progression without radiographic evidence of progression. In these 
patients, obtaining a subsequent confirmatory radiographic image is necessary if feasible (eg, 
patient’s condition allows for imaging). 
4.4. 
Patient Identification and Randomization 
4.4.1. 
Patient Identification 
All patients who enter screening (defined as the point at which the patient signs the ICF) will 
receive a unique patient identification number. This number will be used to identify the patient 
throughout the study and must be used on all study documentation related to that patient. A 
patient will be considered enrolled when the patient has consented, been screened, and all 
eligibility criteria have been confirmed by the Investigator. The patient identification number 
must remain constant throughout the entire study. 
4.4.2. 
Randomization Scheme 
Not applicable. 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
6 1  
 
5.  
S T U D Y M E DI C A TI O N  
5. 1.  
I de ntit y 
5. 1. 1.  
I n vesti g ati o n al Pr o d ucts 
T S R -0 3 3 is a h u ma nize d m o n ocl o nal I g G 4 a nti b o d y a n d will be s u p plie d as a s ol uti o n i n vials 
c o ntai ni n g 8 0  a n d 1 6 0 m g ( 4 m L a n d 8 m L fill v ol u mes at 2 0  m g/ m L, res p ecti vel y).  
D ostarli ma b  ( pre vi o usl y referre d t o as T S R-0 4 2) is a n I g G 4 a nti b o d y a n d will be s u p plie d as a 
s ol uti o n i n vials c o ntai ni n g 5 0 0 m g ( 5 0 m g/ m L).  
5. 1. 2.  
N o n -In vesti g ati o n al Pr o d ucts  
I n Part 2 B t he i n vesti gati o nal pr o d ucts T S R-0 3 3 a n d d ostarli ma b  will be a d mi nistere d i n 
c o m bi nati o n wit h t he c urre nt S O C treat me nt f or C R C, w hic h is c he m ot he ra p y ( m F O L F O X 6 or 
F O L FI RI) wit h be v aciz u ma b . 
m F O L F O X 6 a n d F O L F I RI are c o m bi nati o ns of f oli nic aci d ( F O L)/le uc o v ori n, 5-fl u or o uracil ( F), 
a n d eit her o xali plati n ( O X) or iri n oteca n (I RI), res pecti vel y, w hic h act as s yste mic c yt ot o xic 
a ge nts . 
Be vaciz u ma b is a  h u ma niz e d m o n ocl o nal I g G 1 a nti b o d y t hat tar gets V E G F -A t o i n hi bit 
a n gi o ge nesis . 
B ot h t he c he m ot hera p e utic a ge nts a n d t he bi ol o gic, be vaciz u ma b, a d mi nistere d i n t his st u d y, are 
n ot i n vesti gati o nal pr o d u cts a n d will be o btai ne d fr o m l ocal s o urces as c o m merc iall y a vaila bl e 
d osa ge f or m ulati o n . N ote:  Bi osi milars of be v aciz u ma b are p er mitte d f or a d mi nistrati o n as a 
s u bstit ute f or be vaciz u ma b. A d mi nistrati o n of a bi osi milar of be vaciz u ma b m ust be rec or de d i n 
t he electr o nic case re p ort f or m ( e C R F) as a c o nc o mita nt me dicati o n  (Secti o n  5. 6. 1 ). 
5. 2.  
A d mi nistr ati o n  
T S R -0 3 3 will be a d mi nistere d usi n g a n a p pr o xi matel y  3 0 -mi n ute I V i nf usi o n o n Da y 1. Start  a n d 
st o p ti mes f or i nf usi o n will be rec or de d i n t he e C R F. 
P art 1 a : T S R-0 3 3 will be a d mi nistere d e ver y 1 4 d a ys ± 1 d a y ( Q 2 W). T he pla n ne d asce n di n g 
d oses i n Part 1a of t he st u d y are 2 0, 8 0, a n d 2 4 0 m g Q 2 W. F urt h er d ose escalati o n t o 7 2 0 m g 
Q 2 W ma y als o be a ssess e d i n a n a d diti o nal c o h ort(s) f oll o wi n g a gree me nt bet wee n t he 
I n v esti gat ors a n d S p o ns or. A d diti o nal c o h orts c o nsisti n g of 6-1 2 patie nts t o e x a mi ne a d diti o nal 
d ose le vels ma y als o be e x pl ore d, if warra nte d, f oll o wi n g a gree me nt b et wee n t he I n vesti gat ors  
a n d S p o ns or . 
P art 1 b:  A c o h ort(s) of u p t o 6 a d diti o nal patie nts ma y b e e nr olle d i n a n y d ose le vel wit h D L Ts 
o bser ve d i n < ⅓ of patie nts t o better c haracterize t he P K pr ofile of T S R -0 3 3 
 I n t his c o h ort(s) patie nts will recei v e t heir T S R-0 3 3 d ose o n  
Da y 1, Da y 2 9 a n d c o nti n ue Q 2 W  t hereafter. 
P art 1c: T S R -0 3 3 will be a d mi nistere d wit h d ostarli ma b  Q 3 W t hr o u g h o ut Part 1c, a n d p atie nts 
will recei ve d ostarli ma b  at a d ose of 5 0 0 m g i n c o m bi nati o n wit h asce n di n g d oses of T S R -0 3 3 
Q 3 W. T he starti n g d ose of T S R -0 3 3 w he n use d i n c o m bi nati o n wit h d ostarli ma b  m ust be o ne 
C CI
C CI


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dose level below the highest dose at which <⅓ of patients experienced DLTs with single-agent 
TSR-033. Planned dose levels of TSR-033 include 80 and 240 mg. A higher dose level of 720 
mg Q3W may be explored, if warranted, based on target exposure and safety findings. 
Additional cohorts consisting of 6-12 patients to examine additional dose levels may also be 
explored, if warranted, following agreement between the Investigators and Sponsor. dostarlimab 
at a dose of 1000 mg may also be tested with the RP2D of TSR-033 given on a Q6W schedule. 
For all administrations of the combination regimen, TSR-033 will be given first, followed by 
dostarlimab. 
Part 2A: Following completion of the TSR-033 infusion, dostarlimab (1000 mg) will be 
administered via a 30-minute IV infusion (-5 minute and +15 minute) with a post-infusion 
observation period of 2 hours for Dose 1, Day 1. TSR-033 will be given on a Q2W schedule and 
dostarlimab on a Q6W schedule. If emerging safety and/or PK data indicate that exploration of a 
lower TSR-033 dose is warranted, an additional cohort may be opened. 
Part 2 Cohort B1: Initially, a 6-patient run-in with mFOLFOX6 plus bevacizumab regimen will 
be tested for safety, with the potential to add 6 additional patients, for a total of 12 patients. The 
DLT observation period will be from Dose 1, Day 1, through Dose 3, Day 3, prior to the start of 
infusion. Following the DLT observation period, if ≥2 DLTs are observed, a dose level reduction 
of TSR-033 to 240 mg can be considered (dose level -1). This dose level would then enroll 6 
patients. Alternatively, if <2 DLTs are observed during the DLT observation period, 6 additional 
patients may be enrolled at that dose level to confirm safety and collect preliminary efficacy 
data. 
Part 2, Cohort B2: Initially, a 6-patient run-in with FOLFIRI plus bevacizumab regimen will be 
tested for safety, with the potential to add 6 additional patients, for a total of 12 patients. The 
DLT observation period will be from Dose 1, Day 1, through Dose 3, Day 3, prior to the start of 
infusion. Following the DLT observation period, if ≥2 DLTs are observed, a dose level reduction 
of TSR-033 to 240 mg can be considered (dose level -1). This dose level would then enroll 6 
patients. Alternatively, if <2 DLTs are observed during the DLT observation period, 6 additional 
patients may be enrolled at that dose level to confirm safety and collect preliminary efficacy 
data. 
Should enrollment in Cohort B1 fall behind, allowance will be made to increase the number of 
patients enrolled in Cohort B2 after DLT clearance of the first 6 patients, such that an additional 
6 to 18 may be enrolled. The total for Part 2B as a whole remains at 24. 
Please refer to the Pharmacy Manual for details on the preparation and administration of the 
infusion solutions for TSR-033 and dostarlimab. 
The bevacizumab and the chemotherapy regimens will be administered following TSR-033 and 
dostarlimab administration. mFOLFOX6 or FOLFIRI and TSR-033 will be given on a Q2W 
schedule and dostarlimab on a Q6W schedule. 
The full infusion schedule will be as follows: 
Part 2 Cohort B1: Infusion times (per dose cycle): 
Note: Infusion times described below are approximate. 


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1. Bevacizumab (Day 1): 30-minute infusion, unless a longer schedule was previously 
tolerated; 15 minutes observation (assuming previously tolerated). 
2. Oxaliplatin with leucovorin (Day 1): 2-hour infusion. (Part of mFOLFOX6 regimen). 
3. 5-Fluorouracil (Day 1): 2-4 minutes. (Part of mFOLFOX6 regimen). 
4. 5-Fluorouracil (Day 1-3): continuous infusion, 46-hours. (Part of mFOLFOX6 regimen). 
5. TSR-033 (Day 3): 30-minute infusion. 
6. Dostarlimab (Day 3, every third dose of TSR-033): 30-minute infusion; 2 -hour 
observation for first dose. Should no infusion reactions (IRs) occur, observation can be 
reduced to 1 hour for second dose, then to 30 minutes thereafter. 
Part 2 Cohort B2: Infusion times (per dose cycle): 
Note: Infusion times described below are approximate. 
1. Bevacizumab (Day 1): 30-minute infusion, unless a longer schedule was previously 
tolerated; 15 minutes observation (assuming previously tolerated). 
2. Irinotecan with leucovorin (Day 1): 90 minutes. (Part of FOLFIRI regimen). 
3. 5-Fluorouracil (Day 1): 2-4 minutes. (Part of FOLFIRI regimen). 
4. 5-Fluorouracil (Day 1-3): continuous infusion, 46-hours. (Part of FOLFIRI regimen). 
5. TSR-033 (Day 3): 30-minute infusion. 
6. Dostarlimab (Day 3, every third dose of TSR-033): 30-minute infusion; 2-hour 
observation for first dose. Should no IRs occur, observation can be reduced to 1 hour for 
second dose, then to 30 minutes thereafter. 
Part 2B Dosing Schema: 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11a 
Dose 1b 
 
Dose 2b 
 
Dose 3b 
 
Dose 4b 
 
Dose 5b 
 
Dose 6b 
Bevacizumab 
 
Bevacizumab 
 
Bevacizumab 
 
Bevacizumab 
 
Bevacizumab 
 
Bevacizumab 
mFOLFOX6c 
or FOLFIRId 
 
mFOLFOX6c 
or FOLFIRId 
 
mFOLFOX6c 
or FOLFIRId 
 
mFOLFOX6c 
or FOLFIRId 
 
mFOLFOX6c 
or FOLFIRId 
 
mFOLFOX6c 
or FOLFIRId 
TSR-033 
(Day 3) 
 
TSR-033 
(Day 3) 
 
TSR-033 
(Day 3) 
 
TSR-033 
(Day 3) 
 
TSR-033 
(Day 3) 
 
TSR-033 
(Day 3) 
Dostarlimab 
(Day 3) 
 
 
 
 
 
Dostarlimab 
(Day 3) 
 
 
 
 
Abbreviation: Wk=week. 
a This treatment regimen may be continued for so long as the patient is, in the opinion of the Investigator, benefiting 
from treatment. 
b Drug administered on Day 1 unless otherwise noted. 
c Cohort B1. 
d Cohort B2. 


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5.2.1. 
Post-Treatment Vital Signs Monitoring and Safety Observation 
For all patients in Part 1, vital signs (ie, resting blood pressure [BP], pulse, respiratory rate, and 
temperature) will be monitored around the administration of the first and second doses of TSR-
033. These measurements should be collected prior to TSR-033 administration, 15 minutes after 
the start of the TSR-033 infusion (±5 mins), at the end of the TSR-033 infusion (±5 mins), 
60 minutes (±15 minutes) after the end of the TSR-033 infusion, and 150 minutes (±15 minutes) 
after the end of the TSR-033 infusion. Vital signs on subsequent treatment days will be assessed 
and documented prior to the TSR-033 infusion and at the end of the TSR-033 infusion. Vital 
signs should be collected prior to blood draws. 
For patients in Part 1 of the study, safety observation will take place for 4 hours post-TSR-033 or 
-TSR-033/dostarlimab administration, for Dose 1 and Dose 2 of TSR-033. For patients in Part 2, 
a 2-hour observation period will take place post-treatment administration for Dose 1; should no 
IRs occur, observation can be reduced to 1 hour for Dose 2, then to 30 minutes for all doses 
thereafter. Note that the observation period for patients receiving combination therapy (Part 1c 
and 2) will begin once the dostarlimab administration is completed. Also note that for patients in 
Part 2B, observation will be on Day 3 of the dose cycle when TSR-033/dostarlimab are 
administered post-Day 1/2 treatment with SOC chemotherapy and bevacizumab. 
5.2.2. 
Dose of TSR-033 
5.2.2.1. 
TSR-033 Dose (Part 1a and Part 1b) – Q2W Schedule 
Part 1a (dose escalation) will initially evaluate 3 ascending dose levels of TSR-033, 20 mg, 
80 mg, and 240 mg, administered via IV infusion. A 3 + 3 design will be used for the initial dose 
escalation (see Section 3.1.3.1 for details on dose escalation rules). Subsequent dose escalations 
will enroll 6-12 patients at each dose level. Further dose escalation may be considered in 
additional cohort(s) to 720 mg or an intermediate dose following agreement between the 
Investigators and Sponsor. 
Once the DLT observation period for the 20 mg dose level in Part 1a is complete, a cohort of up 
to 6 patients at a dose of 20 mg will be enrolled in Part 1b. Additional cohorts may be enrolled in 
Part 1b at 80 or 240 mg, or both, or an alternative dose level, such as 720 mg, to better 
understand the PK/PDy of TSR-033. 
5.2.2.2. 
TSR-033 in Combination with Dostarlimab (Part 1c) – Q3W Schedule 
The starting dose of TSR-033 when used in combination with dostarlimab must be one dose 
level below the highest dose at which <⅓ of at least 6 patients experienced DLTs globally with 
single agent TSR-033. A lower dose cohort (6-12 patients) may be evaluated if emerging data 
indicate that further dose exploration is warranted. In Part 1c TSR-033 will be administered in 
combination dostarlimab at a flat dose of 500 mg. On a day of treatment, TSR-033 will be 
administered first, followed by dostarlimab. 
5.2.2.3. 
TSR-033 in Combination with Dostarlimab (Part 2) 
Part 2 of the study will further explore the safety and clinical activity of TSR-033 in combination 
with dostarlimab. In Part 2B, the TSR-033 + dostarlimab combination will be administered with 


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bevacizumab and chemotherapy (Cohort B1: mFOLFOX or Cohort B2: FOLFIRI). In Part 2, the 
following 2 disease specific cohorts will be enrolled (all patients PD-1 naïve): 
• Cohort A: Third- or fourth-line CRC 
• Cohort B: Second-line CRC 
Dosing in Part 2 will be initiated using the RP2D established for TSR-033 in Part 1c of the study. 
Based on the analysis of TSR-033 exposure, receptor occupancy data, and PK/PDy modeling 
from Part 1, 720 mg Q2W is predicted to result in drug exposure sufficient to maintain adequate 
target engagement over the dosing interval in the majority of patients. The selection of the RP2D 
and schedule may subsequently be revised based on clinical and PK/PDy data initially obtained 
in Part 2. 
TSR-033 should not be administered before the visit-required assessments are completed and 
laboratory test results and assessments are reviewed by the Investigator or sub Investigator. 
5.3. 
Dose Modification 
5.3.1. 
Dose Modification General Rules 
• Intra-patient dose escalation to a TSR-033 dose that has been previously shown to be safe 
may be permitted following agreement between the Investigator and Sponsor. 
• Study treatment dosing delays are permitted in the case of medical/surgical events or 
logistical reasons not related to study therapy (eg, surgery, unrelated medical events, 
patient vacation, and/or holidays). Patients should be placed back on study therapy within 
28 days of the scheduled TSR-033 infusion. If a delay is >28 days, the patient should be 
placed back on study therapy only after discussion with the Sponsor. Reasons for 
treatment delays of >3 days should be documented in the eCRF. 
• TSR-033 and dostarlimab must be withheld for drug-related Grade 3 toxicities but may 
be resumed upon recovery to Grade ≤1 (see Table 2 for certain exceptions); TSR-033 and 
dostarlimab will be permanently discontinued for any drug-related Grade 4 event. TSR-
033 should be discontinued for some Grade 3 immunologic-mediated AEs as described in 
Table 2. 
• Specific AEs typically observed with anti-PD-1 antibodies will be managed according to 
the rules summarized below in Section 5.3.2. 
• In Part 2B, dose modification for bevacizumab, mFOLFOX6 (Cohort B1), or FOLFIRI 
(Cohort B2) should follow the product label. If, in the opinion of the Investigator, a 
patient may benefit from discontinuation of certain but not all elements of a regimen, for 
example, discontinue oxaliplatin but remain on the remainder of mFOLFOX6 plus 
bevacizumab and the immunotherapies, this will be allowed only after discussion with 
the Medical Monitor. 
5.3.2. 
Dose Modification for Specific Immune-Related Adverse Events 
• Any grade hypophysitis or hypothyroidism should be managed by endocrine 
replacement therapy. In case of new onset type 1 diabetes mellitus (T1DM)/Grade 3 


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or 4 hyperglycemia, holding the dose is required, but TSR-033 and dostarlimab may 
be resumed in appropriately managed clinically and metabolically stable patients. 
Please refer to Table 3 for details on the management of TSR-033 dose delays and 
discontinuation for specific events. 
• For TSR-033, dose reductions to a lower dose level (no reduction below 20 mg) may 
be permitted following consultation with the Sponsor based on emerging data. 
• All treatment delays (including any missed doses) and discontinuations, and the 
reason for delays or discontinuation of TSR-033 and/or dostarlimab, should be 
recorded in the eCRF. 
Table 2: 
Dose Modifications for Non-Hematologic Toxicities – Applies to Both Study 
Drug Components (TSR-033 and Dostarlimab) 
Toxicity 
Hold Treatment for 
Grade 
Restarting Treatment/Discontinuation 
Diarrhea/colitis 
2-3 
Restart dosing when toxicity resolves to Grade 1. 
4 or recurrent 3 
Permanently discontinue. 
AST, ALT, or increased 
bilirubin 
2 
with AST or ALT >3 
to ≤5 × ULN or  
total bilirubin >1.5 to 
≤3 × ULN 
Restart dosing when toxicity resolves to Grade 1. 
≥3 
with AST or ALT 
>5 × ULN  
or total bilirubin 
>3 × ULN 
Permanently discontinue (exception belowa).  
T1DM or hyperglycemia 
3-4 hyperglycemia or 
T1DM (associated 
with metabolic 
acidosis or ketonuria) 
Restart dosing in appropriately managed, clinically and 
metabolically stable patients; insulin replacement therapy is 
required. 
Severe neurological 
events (myasthenic 
syndrome/myasthenia 
gravis, Guillain-Barré 
syndrome, 
immune-related 
encephalitis, transverse 
myelitis) 
Any grade 
Permanently discontinue. 
Hypophysitis 
2-4 
For Grade 2-3 hold until hormonal therapy results in return 
to adequate levels by laboratory values and restart dosing 
when toxicity resolves to Grade 1. For recurrence or 
worsening of Grade ≥2 hypophysitis after steroid taper has 
been completed and is on adequate hormone replacement 
therapy, permanently discontinue. For Grade 4, permanently 
discontinue. 
Hyperthyroidism  
3 
Hold until return to adequate hormone levels based on 
laboratory values and restart dosing when toxicity resolves 
to Grade 1. 
4 
Permanently discontinue. 


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Table 2: 
Dose Modifications for Non-Hematologic Toxicities – Applies to Both Study 
Drug Components (TSR-033 and Dostarlimab) (Continued) 
Toxicity 
Hold Treatment for 
Grade 
Restarting Treatment/Discontinuation 
Infusion-related reaction 
2b 
Restart dosing when toxicity resolves to Grade 1. 
3-4 
Permanently discontinue. 
Pneumonitis 
2 
Restart dosing when toxicity resolves to Grade 1. If Grade 2 
recurs, permanently discontinue. 
3-4 
Permanently discontinue. 
Severe exfoliative 
dermatologic events 
Suspected DRESS, 
SJS, or TEN 
Withhold. 
Confirmed DRESS, 
SJS, or TEN 
Permanently discontinue. 
Renal failure or nephritis 
2 with creatine >1.5 to 
≤3 × ULN 
Restart dosing when toxicity resolves to Grade 1. 
≥3 with creatine >3 × 
ULN 
Permanently discontinue. 
Adrenal insufficiency 
2-3 
Hold until administration of hormone replacement therapy 
results in return to adequate hormone levels based on 
laboratory values and restart dosing when toxicity resolves 
to Grade 1. 
For recurrent or worsening Grade ≥2 adrenal insufficiency 
while adequate hormone replacement therapy is continuing, 
permanently discontinue. 
4 
Permanently discontinue. 
Hemophagocytic 
lymphohistiocytosis 
Any grade 
Permanently discontinue. 
Myocarditis 
2-4 
Permanently discontinue. 
Uveitis 
≥2 
Withhold. 
Other irARs 
Based on severity and 
type of reaction (2-3) 
Withhold. Restart dosing when toxicity resolves to Grade 1. 
4 or recurrent 3 
Permanently discontinue. 
Recurrence of AEs after 
resolution to Grade 1 
3-4 
Permanently discontinue. 
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; DRESS=drug 
reaction with eosinophilia and systemic symptoms; irAR=immune-related adverse reaction; SJS=Stevens-Johnson 
syndrome; T1DM=type 1 diabetes mellitus; TEN=toxic epidermal necrolysis; ULN=upper limit of normal 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by 
≥50% relative to baseline and lasts for at least 1 week then patient should be discontinued. 
b Upon resolution within 1 hour of stopping drug infusion, the infusion may be restarted at 50% of the original 
infusion rate (eg, from 100 mL/h to 50 mL/h). Otherwise dosing will be held until symptoms resolve and the patient 
should be premedicated for the next scheduled dose; refer to Section 5.6.4 Infusion-Related Reaction Treatment 
Guidelines for further management details (see Table 3). 
5.4. 
Packaging, Labeling and Storage 
TSR-033 for injection is supplied in vials containing 80 and 160 mg at a concentration of 
20 mg/mL. 


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Dostarlimab for injection is supplied in vials containing 500 mg at a concentration of 50 mg/mL. 
The 50 mg/mL concentration will be implemented after appropriate approval from competent 
health authorities. 
The label text of the study treatment will comply with Good Manufacturing Practice and national 
legislation to meet the requirements of the participating countries. The study treatment will be 
open-label and nonpatient-specific. 
All study treatment supplies must be stored in accordance with the Pharmacy Manual 
instructions and package labeling. Until dispensed or administered to the patients, the study 
treatment will be stored in a securely locked area, accessible to authorized personnel only. 
5.5. 
Drug Accountability 
The Investigator or designee is responsible for maintaining accurate dispensing records of the 
study treatments throughout the clinical study. 
Details of maintaining drug accountability, including information on the accountability log, will 
be provided in the Pharmacy Manual. 
All dispensing and accountability records will be available for Sponsor review. The study 
monitor will assume the responsibility to reconcile the study treatment accountability log. The 
pharmacist will dispense study treatment for each patient according to the protocol and 
Pharmacy Manual, if applicable. 
5.6. 
Previous and Concomitant Medications 
5.6.1. 
Recording of Previous and Concomitant Medications 
At screening, patients will be asked what medications they have taken during the last 30 days. At 
each subsequent study visit, patients will be asked what concomitant medications they are 
currently taking or have taken since the previous visit. 
Any medication the patient takes during the study other than the study treatment, including 
herbal and other nontraditional remedies, is considered a concomitant medication. All 
concomitant medications must be recorded in the eCRF. 
5.6.2. 
Prohibited Medications 
Known prior medications that exclude a patient from participating in the study are described in 
the exclusion criteria (Section 4.2). 
Patients are prohibited from receiving the following therapies during the screening and treatment 
phase of this study: 
• Systemic anti-cancer or biological therapy not specified in this protocol. 
• Immunotherapy not specified in this protocol. 
• Chemotherapy not specified in this protocol. 
• Investigational agents other than TSR-033 and dostarlimab. 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
6 9  
 
•  Ra diati o n t hera p y is pr o hi bite d wit hi n 3 wee ks pri or t o st u d y Da y 1 a n d d uri n g st u d y 
treat me nt. 
− Palli ati ve ra diati o n t hera p y t o a s mall fiel d > 1 wee k pri or t o Da y 1 of st u d y 
treat me nt ma y be all o we d after c o ns ultati o n wit h t he S p o ns or. D uri n g st u d y 
treat me nt, ra diati o n t hera p y is per mitte d t o pre-e xisti n g s mall areas of pai nf ul 
metastases t hat ca n n ot b e m a na ge d wit h l ocal or s yste mic a n al gesics, as l o n g as 
n o e vi de nce of P D is prese nt. T he patie nt m ust ha ve clear meas ura ble disease 
o utsi de t he ra diate d fi el d. A d mi nistrati o n of palliati ve ra diati o n t hera p y ma y be 
c o nsi dere d cli nical pr o gressi o n f or t he p ur p oses of deter mi ni n g 
 
•  S yste mic gl uc oc ortic oi ds f or a n y p ur p os e ot her t h a n t o m o d ulate s y m pt o ms of 
s us pecte d i m m u n ol o gic eti ol o g y are n ot p er mitte d. 
− T he use of p h ysi ol o gic d oses of c ortic oster oi ds ma y b e a p pr o ve d after 
c o ns ultati o n wit h t he S p o ns or. T he use of c ortic ost er oi ds is als o per mitte d f or 
patie nts wit h aller g y t o I V c o ntrast f or C T i ma gi n g sca ns. I n hal e d c ortic ost er oi ds 
(f or t he ma n a ge me nt of ast h ma), t o pical or l ocall y i njecte d ster oi ds, a n d 
c ortic oster oi d e ye dr o ps are per mitte d.  
•  Vacci n es wit hi n 7  da ys pri or t o t he first d ose of st u d y treat me nt are n ot per mitte d . 
− If t here is a cli nical i n dicati o n f or a n y me dicati o n or vacci n ati o n s pecificall y 
pr o hi bite d d uri n g t he st u d y, disc o nti n uati o n fr o m st u d y t hera p y ma y be re q uire d. 
T he I n vesti gat or s h o ul d  disc uss a n y q u esti o ns re gar di n g t his wit h t he S p o ns or. 
T he fi nal de cisi o n o n a n y s u p p orti ve t hera p y or vacci nati o n rests wit h t he 
I n v esti gat or or t he p atie nt’s pri mar y p h ysicia n, or b ot h. T he decisi o n t o c o nti n ue 
t he patie nt o n st u d y t hera p y, h o we ver, re quir es t he m ut ual a gree me nt of t he 
I n v esti gat or, t he S p o ns or, a n d t he patie nt. 
5. 6. 3.  
C o ntr ace pti o n  
It is n ot k n o w n if T S R-0 3 3 or d ostarli ma b  ma y ha ve a d verse effects o n a fet us i n uter o. 
H o we ver, bl oc ka d e of P D -L 1 si g n ali n g i n m uri ne m o dels of all o ge neic pre g na n c y ca n eli mi nate 
fet o mater n al t olera nce a n d ca use s p o nta n e o us a b orti o n, as i n dicate d b y i n crease i n e m br y o 
res or pti o n a n d a re d ucti o n i n litter siz e.5 2 T heref ore, n o n pre g na nt, n o n -breastfee di n g w o me n ma y  
o nl y be e nr olle d if t he y are willi n g t o use 2  hi g hl y effecti ve f or m s of c o ntrace pti o n (fr o m t he list 
bel o w) or are c o nsi d ere d hi g hl y u nli kel y t o c o ncei ve. Hi g hl y u nli kel y t o c o ncei ve is defi n e d as: 
s ur gic all y steriliz e d, p ost me n o pa usal (a w o ma n w h o is ≥4 5 years of a ge a n d has n ot ha d me nses 
f or > 1 year will be c o nsi dere d p ost me n o pa us al), or n ot heter ose x uall y acti ve f or t he d urati o n of 
t he st u d y. 
T he f oll o wi n g are c o nsi d ere d hi g hl y effecti ve f or ms of c o ntrace pti o n: h or m o nal c o ntrace pti ves 
t hat i ncl u de a n y re gistere d or mar kete d c o ntrace pti ve a ge nt t hat c o ntai ns a n estr o ge n a n d/ or a 
pr o gestati o nal a ge nt (i n cl u di n g oral, s u b c uta ne o us, i ntra uteri ne, or i ntra m usc ular a ge nts), 
i ntra uteri ne de vic e, vas ect o miz e d part ners, a n d a bsti ne nce, if t his is t he esta blis he d a n d preferre d 
c o ntrace pti o n f or t he pati e nt . 
Fe male p atie nts s h o ul d be i nf or me d t hat ta ki n g t h e st u d y dr u g m a y i n v ol ve u n k n o w n ris ks t o t he 
fet us ( u n b or n ba b y) if pre g n a nc y w ere t o o cc ur d uri n g t he st u d y. I n or der t o partici pate i n t he 
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study, they must adhere to the contraception requirement (described above) for the duration of 
the study and through 150 days after the last study treatment. If there is any question that a 
patient will not reliably comply with the requirements for contraception that patient should not 
be entered into the study. 
5.6.4. 
Rescue Mediations and Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator including, but not limited to, the items outlined below. Prophylactic cytokines (eg, 
G-CSF) should be administered according to current American Society of Clinical Oncology 
guidelines.51 
Note: It may be necessary to perform additional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of an event. 
The following text details specific treatment guidance by type of AE: 
• Pneumonitis: 
− Treat with systemic corticosteroids, oral for Grade 2 (eg, 0.5 to 1 mg/kg per day 
of prednisone or equivalent) and IV for Grade 3-4 (eg, 1 to 2 mg/kg per day of 
prednisone or equivalent). 
− Administer additional anti-inflammatory measures, as needed. 
− Taper corticosteroids when symptoms improve to Grade ≤1 over ≥4 weeks. 
− If Grade 2 and no improvement or worsening over 2 weeks, treat as Grade 3-4. 
− Consider prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
• Diarrhea/Colitis: 
− Monitor carefully for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, and blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
− All patients who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. 
− For Grade 2 diarrhea/colitis that persists >3 days, administer oral corticosteroids 
(eg, 0.5 to 1.0 mg/kg per day of prednisone or equivalent). If symptoms persist or 
worsen with steroids, treat as Grade 3-4. 
− For Grade 3 or 4 diarrhea/colitis that persists >3 days, treat with IV steroids (eg, 1 
to 2 mg/kg per day of prednisone or equivalent) followed by high-dose oral 
steroids. 
− Taper corticosteroids when symptoms improve to Grade ≤1 over ≥4 weeks. 


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• T1DM or Grade ≥3 Hyperglycemia: 
− For type I diabetes mellitus and for Grade 3-4 hyperglycemia associated with 
metabolic acidosis or ketonuria, insulin replacement therapy is required. 
• Hypophysitis: 
− Treat with systemic corticosteroids, oral for Grade 2 (eg, 0.5 to 1 mg/kg per day 
of prednisone or equivalent) and IV for Grade 3-4 (eg, 1 to 2 mg/kg per day of 
prednisone or equivalent). 
− Taper corticosteroids when symptoms improve to Grade ≤1 over ≥4 weeks. 
− Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
• Hyperthyroidism or Hypothyroidism: 
− Thyroid disorders have been reported with PD-1 inhibitors occurring at any time 
during treatment. Monitor patients for changes in thyroid function (at the start of 
treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
− Grade 2 Hyperthyroidism events: 
− Consider nonselective beta-blockers (eg, propranolol) as initial therapy. 
− Grade 3-4 Hyperthyroidism 
− Treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids (eg, 0.5 to 1 mg/kg per day of prednisone or equivalent). Taper 
corticosteroids when symptoms improve to Grade ≤1 over ≥4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
− Grade 2-4 Hypothyroidism 
− Thyroid hormone replacement therapy, with levothyroxine or liothyronine, is 
indicated per SOC. 
• Hepatitis: 
− Treat with systemic corticosteroids, oral for Grade 2 (initial dose of 1 to 2 mg/kg 
per day of prednisone or equivalent) and IV for Grade 3-4 (1 to 2 mg/kg per day 
of prednisone or equivalent) 
− Taper corticosteroids when symptoms improve to Grade ≤1 over ≥4 weeks. 
• Severe Exfoliative Dermatologic Events: 
− Suspected: Treat with high potency topical steroids to affected areas. Treat with 
oral prednisone or equivalent at an initial dose of 0.5 to 1 mg/kg/day and taper 
steroid when dermatitis is controlled. Ensure adequate evaluation (eg, urgent 
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− Confirmed: Administer 1 to 2 mg/kg/day IV methylprednisolone or equivalent 
and taper steroid when dermatitis is controlled. 
• Renal Failure or Nephritis: 
− Treat with systemic corticosteroids, oral for Grade 2 (initial dose of 
0.5 to 1 mg/kg per day of prednisone or equivalent) and IV for Grade 3-4 
(1 to 2 mg/kg per day of prednisone or equivalent). 
− Taper corticosteroids when symptoms improve to Grade ≤1 over ≥4 weeks. 
• Adrenal Insufficiency: 
− Start treatment with corticosteroids before other hormone replacement therapy to 
avoid adrenal crisis (hydrocortisone slowly titrating doses down according to 
symptoms or prednisone and fludrocortisone titrating up or down based on blood 
pressure, other symptoms, and laboratory results); patients with severe symptoms 
may require additional fluids (eg, saline >2 L). 
− Monitor for cortisol level (AM), comprehensive metabolic panel (Na, K, CO2, 
glucose), and renin. 
− Ensure adequate evaluation (eg, endocrine consultation). 
• Myocarditis: 
− Administer high-dose corticosteroids (1 g/day of IV methylprednisolone) for 3 to 
5 days, followed by oral prednisone taper over 4 to 6 weeks based on 
improvement in cardiac function and biomarkers. 
− If no improvement in 24 hours, consider adding other potent immunosuppressive 
agents. 
− Ensure adequate evaluation (eg, urgent cardiology consultation) to confirm 
etiology and/or exclude other causes. 
• Severe Neurological Events (Myasthenic Syndrome/Myasthenia Gravis, 
Guillain-Barré Syndrome, Immune-Related Encephalitis, Transverse Myelitis) 
− Consider high dose corticosteroids and other therapies as needed. 
− It is highly recommended that Investigators discuss any AEs with the Sponsor 
before using infliximab. 
− Ensure adequate evaluation (eg, neurology consultation). 
− Consider MRI of brain and/or spine depending on symptoms. 
− Consider inpatient management as clinically indicated. 
• Uveitis: 
− Urgent ophthalmology consultation. 
− Administer treatment with ophthalmic and systemic 
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• Management of Infusion-related Reactions: An infusion-related reaction is defined 
as an AE to the infusion of TSR-033 or dostarlimab that occurs during the infusion or 
within 2 hours of completion of the infusion. Signs and symptoms usually develop 
during or shortly after drug infusion and generally resolve completely. Table 3 shows 
treatment guidelines for patients who experience an infusion-related reaction 
associated with administration of TSR-033 or dostarlimab. 
Table 3: 
TSR-033 or Dostarlimab Infusion-Related Reaction Treatment Guidelines 
CTCAE Grade 
Treatmenta 
Premedication at Subsequent 
Treatment 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated. 
Increase monitoring of vital signs as 
medically indicated until the patient 
is deemed medically stable in the 
opinion of the Investigator. 
None. 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDS, narcotics, and/or IV 
fluids); prophylactic medications 
indicated for ≤24 hours. 
Stop infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include, but is not 
limited to: 
-IV fluids 
-Antihistamines 
-NSAIDS 
-Acetaminophen 
-Narcotics 
Increase monitoring of vital signs as 
medically indicated until the patient 
is deemed medically stable in the 
opinion of the Investigator. 
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the 
original infusion rate (eg, from 100 
mL/h to 50 mL/h). Otherwise, 
dosing will be held until symptoms 
resolve, and the patient should be 
premedicated for the next scheduled 
dose. 
The end of infusion PK sample 
should always be drawn at the end of 
the last study medication infusion, 
regardless if the infusion is slowed 
or temporarily stopped due to an 
infusion reaction. 
Patients who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study treatment 
administration. 
Patient may be premedicated 
1.5 hours (±30 minutes) prior to 
infusion of TSR-033 
±dostarlimab with: 
-Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine). 
-Acetaminophen 500-
1000 mg PO (or equivalent 
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Table 3: 
TSR-033 or Dostarlimab Infusion-Related Reaction Treatment Guidelines 
(Continued) 
CTCAE Grade 
Treatmenta 
Premedication at Subsequent 
Treatment 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly responsive 
to symptomatic medication or brief 
interruption of infusion, or both); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(eg, renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy 
may include, but is not limited to: 
-IV fluids 
-Antihistamines 
-NSAIDS 
-Acetaminophen 
-Narcotics 
-Oxygen 
-Pressors 
-Corticosteroids 
-Epinephrine 
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion 
of the Investigator. 
Hospitalization may be indicated. 
Patient is permanently discontinued 
from further study treatment 
administration 
No subsequent dosing. 
Abbreviations: CTCAE=Common Terminology Criteria for Adverse Events; IV=intravenous; NSAID=non-steroidal 
anti-inflammatory drug; PO=per os (by mouth). 
a Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
5.7. 
Continued Access to Study Treatment After Final Analysis 
For patients who continue to receive study treatment after the DCO date of the final analysis (see 
Section 3.3.3), dispensing of study treatment after the clinical study database has closed may be 
done with a manual resupply option (refer to the Study Reference Manual). Drug accountability 
data will also be collected at the site. Note: There will be no further access to TSR-033 study 
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6. 
ENDPOINTS AND METHODS OF ASSESSMENT 
6.1. 
Safety Endpoints 
Safety parameters evaluated during the conduct of the study include DLTs, SAEs, 
treatment-emergent AEs (TEAEs), irAEs, clinical laboratory assessments (hematology, 
chemistry, thyroid function, and urinalysis), vital signs, ECGs, physical examination, ECOG PS, 
and use of concomitant medications. 
6.1.1. 
Definitions 
Adverse event: An AE is any untoward medical occurrence that occurs in a patient or clinical 
investigation subject administered a pharmaceutical product, and which does not necessarily 
have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including clinically significant abnormal laboratory findings), symptom, or 
disease temporally associated with the use of an investigational product, whether or not 
considered related to the product. 
AEs may include the onset of new illness and the exacerbation of pre-existing medical 
conditions. An AE can include an undesirable medical condition occurring at any time, including 
baseline or washout periods, even if no study treatment has been administered. 
A TEAE will be defined as any new AE that begins, or any pre-existing condition that worsens in 
severity, after at least 1 dose of study treatment has been administered. 
Serious adverse event: An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening. 
− Note: This means that the patient is at immediate risk of death at the time of the 
event; it does not mean that the event hypothetically might have caused death if it 
were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
− Any AE that prolongs hospitalization will be considered an SAE. 
− Exception: Planned hospitalization (eg, for observation, protocol compliance, 
elective procedures, or social reasons) will not be considered an SAE; however, 
the reason for the planned hospitalization should be captured in medical history. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event(s). 
− An important medical event may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or require intervention to 
prevent one of the above outcomes. Examples of such events are intensive 
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dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
Suspected Unexpected Serious Adverse Reaction (SUSAR): A SUSAR is serious adverse 
reaction of which the nature and severity is not consistent with the information about the study 
drug set out in the IB Reference Safety Information section. 
6.1.2. 
Assessment of Adverse Events 
Each AE will be assessed by the Investigator with regard to the categories described in the 
following sections. 
6.1.2.1. 
Intensity 
Investigators should assess the severity of AEs according to CTCAE. In general, CTCAE v5.0 
severity grades are: 
• 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 (ADL). (Instrumental ADL 
refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.) 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated, disabling, limiting 
self-care ADL. (Self-care ADL refer to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden.) 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 
A distinction should be made between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria above in Section 6.1.1. For example, a mild degree 
of gastrointestinal bleeding requiring an overnight hospitalization for monitoring purposes may 
be considered an SAE but is not necessarily severe. Similarly, an AE that is severe in intensity is 
not necessarily an SAE. For example, alopecia may be assessed as severe in intensity but may 
not be considered an SAE. 
6.1.2.2. 
Causality 
The Investigator will assess the causality/relationship between the study drug and the AE. One of 
the following categories should be selected based on medical judgment, considering the 
definitions and all contributing factors: 
• Related: A clinical event, including laboratory test abnormality, occurs in a plausible 
time relationship to treatment administration, and which concurrent disease or other 
drugs or chemicals cannot explain. The response to withdrawal of the treatment 
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• Possibly related: A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the treatment, unlikely to be attributed 
to concurrent disease or other drugs or chemicals. 
• Unlikely related: A clinical event, including laboratory test abnormality, with a 
temporal relationship to treatment administration that makes a causal relationship 
improbable, or in which other drugs, chemicals, or underlying disease provide likely 
explanations. 
• Unrelated: A clinical event, including laboratory test abnormality, with little or no 
temporal relationship with treatment administration. Typically explained by 
extraneous factors (eg, concomitant disease, environmental factors, or other drugs or 
chemicals). 
6.1.3. 
Collecting and Recording Adverse Events 
All AEs, regardless of the source of identification (eg, physical examination, laboratory 
assessment, ECG, or reported by patient), must be documented in the eCRF. 
All AEs and SAEs will be collected and recorded in the eCRF for each patient from the day of 
signed informed consent until 90 days post treatment or until initiation of alternative anti-cancer 
therapy, whichever occurs first (see Table 4, Table 5, Table 6, and Table 7 for schedules of 
events). If an Investigator becomes aware of an SAE after the 90-day follow up period post 
treatment discontinuation and considers the SAE related to investigational product, the 
Investigator should report the SAE to the Sponsor according to timelines for reporting SAEs 
described in Section 6.1.5. All AEs and SAEs experienced by a patient during the study period, 
irrespective of the suspected causality, will be monitored until: the AE or SAE has resolved or 
stabilized, any abnormal laboratory values have returned to baseline or normal levels, there is a 
satisfactory explanation for the changes observed, the patient is lost to FUP or withdraws 
consent, or the patient has died. 
AEs may be volunteered spontaneously by the study patient, or discovered by the study staff 
during physical examinations or by asking an open, nonleading question such as: “How have you 
been feeling since you were last asked?” The Investigator will document the nature of the AE, 
date of onset of the AE (and time, if known), date of outcome of the AE (and time, if known), 
severity of the AE, assessment of the seriousness of the AE, and assessment of the causal 
relationship of the AE to study drug and/or study procedure. 
Each AE should be recorded in the source document and in the eCRF using the patient’s own 
words (verbatim) unless, in the opinion of the Investigator, the AEs constitute components of a 
recognized condition, disease, or syndrome. In the latter case, the condition, disease, or 
syndrome should be named rather than each individual symptom. 
Concomitant illnesses that existed before entry into the study will not be considered an AE 
unless the illness worsens during the treatment period. Pre-existing conditions will be recorded in 
the eCRF (in the medical history section or appropriate page) as well as on the SAE Report Form 
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6.1.4. 
Reporting Disease Progression 
The event of PD is an efficacy criterion and is therefore not considered an AE per se. Disease 
progression should be reported within the eCRF. If AEs/SAEs occur in relation to disease 
progression that are not consistent with the nature and natural progression of the patient’s 
disease, these AEs/SAEs must be reported per AE/SAE reporting requirements described in 
Section 6.1.2 and Section 6.1.5. Death due to PD that is consistent with the nature and natural 
progression of the patient’s disease is not reported as AE/SAE. 
6.1.5. 
Reporting of Serious Adverse Events 
The Investigator must report all SAEs within 24 hours of becoming aware of the initial SAE or 
any FUP information regarding the SAE using the SAE reporting contact information as printed 
on the SAE forms and in the SAE completion guidelines. 
For all SAEs, an SAE report form must be completed by the Investigator for all initial and FUP 
SAEs. A FUP SAE report must be completed each time an Investigator becomes aware of any 
additional information regarding the SAE. For the FUP SAE Report Form, the following fields 
must be completed on each form: FUP number, site number, patient/subject number, protocol 
number, and the SAE term(s) and date of awareness. Only the appropriate field(s) on the SAE 
Report Form where the Investigator received additional or updated information should be 
completed. Previously provided information does not have to be entered on the FUP SAE Report 
Form. 
Initial and FUP SAE reports and any additional supporting documentation (eg, hospital reports, 
consultant reports, death certificates, or autopsy reports) included with the SAE report should be 
sent to the Sponsor (or designee) within 24 hours of the Investigator/site awareness or receipt. If 
supporting documentation is provided, the Investigator should highlight all relevant and pertinent 
information. Also, any additional SAE documentation must be a clear photocopy with the 
patient’s personal identifiers removed. The Investigator must sign and date all SAE forms. 
The minimum information required for an initial SAE report is: 
• Identification of person sending the report (ie, name and address of Investigator) 
• Patient identification (screening number, initials [if permitted by local data privacy 
regulations], NOT patient name) 
• Protocol number 
• Description of SAE 
• Causality assessment 
In case the Investigator has no ability to either fax or email an SAE (eg, due to technical issues), 
pharmacovigilance can be contacted by phone. If an SAE is reported via phone and during usual 
business hours, the Sponsor pharmacovigilance (or designee) will capture the information on a 
telephone contact form or similar method. Outside usual business hours, the message will be 
recorded and the required FUP actions initiated during the next business day. Once technical 
issues are resolved, the Investigator should fax or email the completed SAE form to the Sponsor 
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After receipt of the initial report, the Sponsor (or designee) will review the information and, if 
necessary, contact the Investigator to obtain further information. 
6.1.5.1. 
Submission and Distribution of Serious Unexpected Suspected Adverse Reaction 
Reports 
All SAEs that are unexpected and considered by the Investigator or Sponsor to be reasonably 
associated (related or possibly related) with the use of the investigational study drug(s) are 
subject to expedited safety reporting to health regulatory agencies. Per regulatory requirements, 
if an SAE is assessed by TESARO as a SUSAR it will be submitted to the Regulatory 
Authorities. In addition to this, a copy of the report (Council for International Organizations of 
Medical Sciences [CIOMS] or MedWatch 3500A) will be distributed to the Investigators/site. A 
copy of the report will be submitted to the respective Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) and Investigators as per local regulation. 
Disease progression or AEs related to the underlying disease, as defined in the study 
protocol, unless resulting in death, should be considered as expected and are excluded from 
the regulatory requirements for expedited reporting. 
TESARO has delegated the reporting of some of the SUSARs reporting duties to a third party. 
Information about the third parties responsible for SUSAR reporting to Health Authorities, 
Investigators, IRBs, and IECs is listed in the application documentation submitted to regulatory 
authorities. 
6.1.6. 
Pregnancy 
Pregnancies occurring in patients enrolled in this study must be reported and followed to 
outcome. If a patient inadvertently becomes pregnant while on study treatment, the patient will 
immediately be removed from the study. Any pregnancies that occur within 150 days following 
the last dose of study treatment must be reported to the Sponsor. 
Pregnancy alone is not regarded as an AE unless there is a possibility that the study drug may 
have interfered with the effectiveness of a contraceptive medication. Elective abortions without 
complications should not be considered AEs unless they were therapeutic abortions. 
Hospitalization for normal delivery of a healthy newborn should not be considered an SAE. 
Pregnancy is not considered an SAE unless there is an associated serious outcome. Spontaneous 
abortions should always be reported as SAEs. 
Any SAE that occurs during pregnancy must be recorded on the SAE Report Form (eg, maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, or birth defect) and reported within 24 hours in accordance with the 
procedure for reporting SAEs. 
The Investigator should complete the Initial Pregnancy Notification report form and forward it to 
the Sponsor (or designee) within 24 hours of knowledge of the pregnancy. If there is an 
associated serious outcome, then both the Initial Pregnancy Notification report form and SAE 
report form should be completed. 
The Investigator should FUP with the patient until delivery or termination of pregnancy, even if 
the patient was withdrawn from the study or if the study has finished. At that time, the Pregnancy 


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Outcome report form should be completed and submitted to the Sponsor within 24 hours after 
the Investigator becomes aware of the pregnancy outcome. 
In the event the pregnancy outcome occurs following the end of the study and database lock, the 
Investigator will report the pregnancy outcome to the Sponsor (or designee) within 24 hours after 
the outcome of the pregnancy is known to the Investigator in accordance with the procedure for 
reporting SAEs (see Section 6.1.5). 
6.1.7. 
Clinical Laboratory Assessments 
The following laboratory variables will be determined in accordance with the schedule of events 
(see Table 4, Table 5, Table 6, and Table 7). These tests will be performed by the local 
laboratory at the clinical site. 
• CBC: 
− Hb 
− Mean corpuscular volume 
− White blood cell count 
− Platelets 
− 5-part differential white cell count (absolute or percentage) 
− Mean platelet volume (optional, but highly encouraged, especially for patients 
with high grade thrombocytopenia) 
• Coagulation factors: 
− INR 
− aPTT 
− PT 
• Chemistry: 
− Sodium 
− Potassium 
− Calcium 
− Magnesium 
− Chloride 
− Glucose (fasting at baseline); 
baseline may be screening or 
pre-dose (Dose 1, Day 1) 
− Creatinine and estimated 
CrCL using Cockcroft-Gault 
formula (see Appendix 4) 
− Urea or blood urea nitrogen 
− Bicarbonate 
− Amylase 
− Bilirubin (total and direct; in 
the event that a total bilirubin 
result >ULN, direct bilirubin 
will be obtained and recorded 
in the CRF) 
− Alkaline phosphatase (ALP) 
− AST 
− ALT 


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− Total protein 
− Albumin 
− Lactate dehydrogenase 
− Lipase 
• Urinalysis: 
− Specific gravity 
− Leukocyte esterase 
− Nitrite 
− Blood 
− Bilirubin 
− Protein 
− Glucose 
− Ketones 
− Urobilinogen 
− Microscopy (if clinically 
indicated) 
• Thyroid panel (ie, TSH, T3 or FT3, and FT4 [or T4 if FT4 is not available], or 
equivalent tests, where applicable) 
• Serum or urine pregnancy testing (women of childbearing potential [WOCBP] only) 
• Hepatitis B surface antigen (HBsAg) and hepatitis C virus ribonucleic acid (HCV 
RNA) testing (screening only if clinically indicated eg, patients with history of IV 
drug use) 
Any laboratory values assessed as clinically significant should be recorded as an AE. If SAE 
criteria are met, the event should be recorded and reported according to the SAE reporting 
process (see Section 6.1.5). 
6.1.8. 
Physical Examination and Vital Signs 
Complete physical examinations, including height (screening only), weight, and vital signs (BP, 
pulse, respiratory rate, and temperature) will be performed in accordance with the schedule of 
events (see Table 4, Table 5, Table 6, and Table 7). 
Any physical examination or vital signs assessed as clinically significant should be recorded as 
an AE or SAE. If any seriousness criteria are met, the event should be recorded and reported 
according to the SAE reporting process (see Section 6.1.5). 
6.1.8.1. 
Symptom-Directed Physical Examination 
Symptom-directed physical exams will be performed throughout the study as clinically indicated. 
6.1.9. 
Electrocardiogram 
A standard 12-lead ECG will be performed in accordance with the schedule of events (see 
Table 4, Table 5, Table 6, and Table 7). Any ECG result assessed as clinically significant should 
be recorded as an AE or SAE. If any seriousness criteria are met, the event should be recorded 
and reported according to the SAE reporting process (see Section 6.1.5). 


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6.1.10. 
Eastern Cooperative Oncology Group Performance Status 
PS will be assessed using the ECOG scale (see Appendix 3) in accordance with the schedule of 
events (see Table 4, Table 5, Table 6, and Table 7). The same observer should assess PS each 
time. 
6.1.11. 
Additional Safety Assessments 
All patients will undergo ECGs in accordance with the schedule of events (see Table 4, Table 5, 
Table 6, and Table 7). ECGs should be performed prior to any blood draws. Patients will be 
supine or in a semi-recumbent position (about 30 degrees of elevation) and rested for 
approximately 2 minutes before ECGs are recorded. 
Any ECG findings assessed as clinically significant should be recorded as an AE. If any 
seriousness criteria are met, the event should be recorded and reported according to the SAE 
reporting process (see Section 6.1.5). 
6.1.12. 
Collection of Safety Information After Final Analysis 
For patients who continue to receive study treatment after the DCO date of the final analysis (see 
Section 3.3.3), the Sponsor will continue to collect safety information including SAEs, AEs 
leading to discontinuation of study treatment, overdoses, and pregnancies; these events will be 
reported directly to the Sponsor via paper forms (refer to the Study Reference Manual). The 
events will be reported per defined time frames as follows: 
• SAEs, AEs leading to discontinuation of study treatment, and overdoses will be 
reported during the treatment period and for up to 90 days after last dose or until 
initiation of alternative anti-cancer therapy, whichever occurs first. 
• Pregnancies will be reported during the treatment period and for up to 150 days after 
last dose. 
Reporting of these events (SAEs, AEs leading to discontinuation of study treatment, overdoses, 
and pregnancies) will continue to be in accordance with the protocol. Additionally, any SAE that 
is ongoing at the time of the DCO date of the final analysis must be followed-up to resolution, 
unless the event is considered by the Investigator as unlikely to resolve or the patient is lost to 
follow-up. The Sponsor retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the time of the DCO date of the final analysis, if judged necessary. 
6.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics consist of those variables that are assessed at 
screening/baseline. 
6.2.1. 
Patient Eligibility 
Compliance with inclusion and exclusion criteria will be assessed as outlined in Section 4.1 and 
Section 4.2. 
6.2.2. 
Patient Demographics 
Patient demography consists of age at screening, race, ethnicity, and sex. 


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6.2.3. 
Cancer History 
For disease history the following will be documented: 
• Date of first diagnosis 
• Tumor type 
• Part 2, primary and/or metastatic tumor is known to be MSS as determined locally 
• Stage at time of initial diagnosis 
• Histology and grade of disease at diagnosis and most recent biopsy if additional 
biopsy performed 
• Information on first anti-cancer treatment: 
− Intent (adjuvant, neoadjuvant, curative, or palliative) 
− Date of start of first treatment 
− Agents used in first treatment 
− Date of last dose of first treatment 
• Information on second and subsequent anti-cancer treatments: 
− Intent (adjuvant, neoadjuvant, curative, or palliative) 
− Dates of start of all subsequent treatments 
− Agents used in all subsequent treatments 
− Dates of last dose of all subsequent treatments 
• Best response and toxicities for each prior anti-cancer treatment 
• Date of recurrence for each prior anti-cancer treatment 
6.2.4. 
Medical and Surgical History 
Major medical and surgical history (including medication history) will be collected. Details of 
any prior invasive malignancy will be collected. Medical and surgical history will be obtained by 
interviewing the patient or by reviewing the patient’s medical records. 
6.2.5. 
Previous and Concurrent Medications 
Previous and concomitant medication will be documented as described in Section 5.6. 
Medications will be coded using World Health Organization (WHO) Anatomical Therapeutic 
Chemical classification. 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
8 4  
 
6. 3.  
Cli nic al  Acti vit y E n d p oi nts  
6. 3. 1.  
E v al u ati o n of T u m or R es p o nse  
6. 3. 1. 1.  
O ver vie w  
T he cli nical a cti vit y of T S R -0 3 3 will be e val u
s me nt of t u m or res p o nse t o treat me nt 
acc or di n g t o R E CI S T v 1. 1 5 3 (A p pe n di x  1  a n d
[ Secti o n 6. 3. 1. 3 , Secti o n 6. 3. 1. 4 , a n d 
A p pe n di x  2 ]). Ser u m-base d t u m or mar ker data will n ot be use d f or defi ni n g o bjecti ve res p o nses 
or disease pr o gressi o n; h o we ver, t hes e ca n be use d f or cli nical decisi o ns . 
Res p o nse t o treat me nt will pri maril y be b ase d o n I n vesti gat or e val uati o n of ra di o gra p hic i ma ges. 
I n Part 2, all ra di o gra p hic i ma ges/sca ns at t he ti m e p oi nts s pecifie d (T a ble  4 , Ta ble  5 , Ta ble  6 , 
a n d Ta ble  7 ), as well as a n y u nsc h e d ule d i ma ges/s ca ns, will be c ollect e d a n d st ore d at a 
re p osit or y f or p ote ntial e val uati o n. 
T he pr ocess f or i ma ge c ollecti o n a n d tra ns missi o n t o t he  ce ntral i ma gi n g ve n d or ca n be f o u n d i n 
t he St u d y Ma n ual. 
T u m or i ma gi n g (c hest, a b d o me n, a n d pel vis, as w ell as brai n or ot her re gi o ns k n o w n t o ha ve 
disease i n v ol ve me nt) s h o ul d be perf or m e d usi n g t he sa me i ma gi n g tec h ni q ue i n a patie nt 
t hr o u g h o ut t he st u d y. C T sca n is t he m ore c o m m o nl y use d m o dalit y a n d is preferre d f or t he 
maj orit y of patie nts. A n M RI ca n be utilize d if cli nicall y a p pr o priat e M RI, ie w he n C T is 
c o ntrai n dicate d or f or i m a gi n g of t h e brai n . P ositr o n e missi o n t o m o gra p h y ( P E T)/ C T ma y b e 
use d a cc or di n g t o R E CI S T g ui deli nes . 
If brai n C T/ M RI is clear at scree ni n g, re peat i ma gi n g is n ot re q uire d i n t he a bse nce of cli nical 
i n dicati o n re q uiri n g F U P. 
B o ne sca ns s h o ul d be c o n d ucte d per S O C.  
6. 3. 1. 2.  
Ti mi n g of R a di o gr a p hic E v al u ati o ns  
All patie nts will u n der g o s erial ra di o gra p hic ass ess me nts t o assess t u m or res p o nse. I nitial t u m or 
i ma gi n g at scree ni n g m ust be perf or m e d wit hi n 2 8 da ys pri or t o t he date of t he first d ose of st u d y 
treat me nt. Sca ns perf or m e d pri or t o t he si g ni n g of t he I C F as p art of r o uti ne cli nical  ma na ge me nt 
are acce pta ble f or use as i nitial t u m or i ma gi n g if t he y are of dia g n ostic q ualit y a n d perf or me d 
wit hi n 2 8 da ys pri or t o first d ose date.  
T u m or i ma gi n g s h o ul d b e perf or me d Q 6 W  ( 4 2 ± 7 da ys) f or t he first 3 assess me nts a n d t he n 
e ver y 9 ( 6 3 ± 7 d a ys ) wee ks t hereaft er, or m or e fre q ue ntl y if cli nicall y i n dicate d a n d at t he ti me 
of s us pecte d P D. Aft er 1  year of ra di o gra p hic assess me nts, patie nts will ha ve i ma gi n g p erf or m e d 
e ver y 1 2 w ee ks ( 8 4 ± 7 d a ys). I ma gi n g s h o ul d n ot be dela ye d f or del a ys i n d osi n g . 
Per R E CI S T v 1. 1 (see A p pe n di x  1 ), C R or P R s h o ul d be c o nfir me d b y a re peat t u m or i ma gi n g 
assess me nt. T he t u m or i ma gi n g f or c o nfir m ati o n of res p o nse m a y b e perf or me d, at t he earliest, 
4  wee ks after t he first i n dicati o n of res p o nse, b ut n o later t ha n 3 5 da ys, w hi c he ver is cli nicall y 
i n dicate d. A d diti o nall y, PD s h o ul d als o be co n firm ed a  mi ni m u m of 4 wee ks, a n d u p t o 9 wee ks, 
after t he first P D assess ment . Patie nts ma y re mai n o n st u d y treat me nt w hile a waiti n g 
c o nfir mati o n, pr o vi de d t he patie nt is cli nicall y sta ble (see Secti o n  6. 3. 1. 5 ). 
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
8 5  
 
C o nti n ue t o perf or m i ma gi n g u ntil w hic he ver of t he f oll o wi n g o cc urs:  
•  T he start of ne w a nti -ca n cer treat me nt  
•  Wit h dra wal of c o nse nt  
•  Deat h  
•  E n d of t he st u d y ( w he n res p o n der or disc o nti n uati o n stat us f or all patie nts is k n o w n ) 
Patie nts w h o disc o nti n ue st u d y treat me nt f or r eas o ns ot her t ha n P D will c o nti n ue p ost -treat me nt 
i ma gi n g st u dies f or dise ase stat us F U P at t he sa me fre q ue n c y as alrea d y f oll o we d (e v er y 6, 9, or 
1 2 wee ks [ ± 7 da ys] de p e n di n g o n t he le n gt h of treat me nt wit h t he st u d y dr u g) u ntil P D , start of a 
n o n -st u d y anti -ca ncer treat me nt, wit h dra wal of c o nse nt t o st u d y partici pati o n, l oss t o F U P, deat h, 
or e n d of t he st u d y.  
6. 3. 1. 3.  
Assess me nt of Res p o nse b y R E CI S T  
R E CI S T v 1. 1 will be use d b y t he I n vesti gat or as t he pri mar y meas ure f or assess me nt of t u m or 
res p o nse, date of P D, a n d as a basis f or all pr ot oc ol g ui deli nes relate d t o disease stat us. N ote t hat 
 will be f oll o w e d i n cases of P D t o assess c o nti n uati o n of treat m e nt i n cli nicall y sta ble 
patie nts u ntil pr o gressi o n is c o nfir me d (see Secti o n  6. 3. 1. 5 ). 
Details o n R E CI S T v 1. 1, i ncl u di n g e v al uati o n of tar get a n d n o n -tar get lesi o ns a n d defi niti o ns of 
res p o nse, are pr o vi d e d i n A p pe n di x  1 . 
C CI
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
8 6  
 
6. 3. 1. 5.  
Tre at me nt a n d Assess me nt after Pr o g ressi o n  
T here is a cc u m ulati n g e vi de nce i n dicati n g cli nical be nefit i n a s u bset of p atie nts treate d wit h 
i m m u n ot hera p y d es pite i nitial e vi de nce of P D.5 4 D uri n g st u d y tr eat me nt, a patie nt wit h i nitial 
e vi de nce of ra di ol o gic al P D ma y c o nti n ue o n st u d y treat me nt u ntil re peat i ma gi n g is o btai ne d (at 
least 4 wee ks a n d u p t o 9 wee ks later, see A p pe n di x  2 ). T he I n vesti gat or’s decisi o n t o c o nti n ue 
treat me nt be y o n d t he i nitial assess me nt of pr o gressi o n s h o ul d be base d o n t he patie nt’s o verall 
cli nical c o n diti o n, i ncl u di n g P S, cli nical s y m pt o ms, a n d la b orat or y d ata. A patie nt ma y recei ve 
T S R -0 3 3 treat me nt w hile waiti n g f or c o nfir m at or y i ma gi n g if he or s he is cli nicall y sta ble p er 
t he f oll o wi n g criteria: 
•  A bse nce of si g ns a n d s y m pt o ms i n dicati n g cli nicall y si g nifica nt pr o gressi o n of  
disease, i ncl u di n g w orse ni n g of la b orat or y para m eters.  
•  N o decli ne i n P S.  
•  D oes n ot ha ve ra pi d P D . 
•  Treat me nt be y o n d pr o gressi o n will n ot dela y a n i m mi ne nt i nter ve nti o n t o pre ve nt 
seri o us c o m plicati o ns of disease pr o gressi o n (e g, C N S metastases, c or d c o m pressi o n) 
W he ne ver p ossi ble, patie nts s h o ul d n ot be disc o nti n ue d u ntil P D is c o nfir me d . 
6. 3. 2.  
Effic ac y E n d p oi nts  
6. 3. 2. 1.  
O bjecti ve R es p o nse R ate  
T he pri mar y effic ac y e n d p oi nt is O R R f or Part 2 A , defi ne d as t he pr o p orti o n of patie nts 
ac hie vi n g C R or P R as assesse d b y t he I n v esti gat or per R E CI S T v 1. 1 ( A p pe n di x  1 ). O R R i n 
Part  1 a n d Part 2 B  of t he st u d y is a sec o n dar y e n d p oi nt. T u m or assess me nts after t he i nitiati o n of 
f urt her a nti-ca n cer t hera p y are e x cl u de d f or t he ass ess me nt of best o verall res p o ns e. 
6. 3. 2. 2.  
D ur ati o n of Res p o nse  
D O R will be e val uate d as a sec o n dar y e n d p oi nt i n Part 2 a n d is defi ne d as t he ti me fr o m first 
d oc u me ntati o n of C R or P R b y R E CI S T v 1. 1 u ntil t he ti me of first d oc u me ntati o n of P D per 
R E CI S T v 1. 1 ( A p pe n di x  1 ). 
C CI
C CI
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
8 7  
 
6. 3. 2. 3.  
Dise ase C o ntr ol R ate  
D C R will be assesse d as a sec o n dar y e n d p oi nt i n Part 2 a n d is defi ne d as t he perce nta ge of 
patie nts ac hie vi n g C R, P R, or sta ble disease ( S D) as assesse d b y t he I n vesti gat or p er R E CI S T 
v 1. 1 ( A p pe n di x  1 ). S D per R E CI S T v 1. 1 f or a mi ni m u m of 12  we e ks is necessar y f or i ncl usi o n 
i n e val uati o n of D C R. 
6. 4.  
P h ar m ac o ki netics a n d A nti dr u g A nti b o dies  
C o m plete  i nstr ucti o ns f or c ollecti o n, pr ocessi n g, s hi p pi n g, a n d ha n dli n g of sa m ples f or P K a n d 
A D A a nal ysis are det aile d i n t he St u d y M a n ual.  
6. 4. 1.  
P h ar m a c o ki netic A n al ysis  
Bl o o d sa m ples f or d eter mi nati o n of ser u m le vels of T S R -0 3 3 a n d d ostarli ma b  will be c ollecte d 
fr o m patie nts i n b ot h Part 1 a n d Part 2. Sa m pli n g ti mes f or bl o o d f or P K a n al ysis are detaile d i n 
Ta ble  8 , Ta ble  9 , T a ble  1 0 , Ta ble  1 1 , a n d T a ble  1 2 . 
I n P art 1, all sa m pli n g ti mes are relati ve t o t he of t he T S R -0 3 3 i nf usi o n.  T he e n d of i nf usi o n 
s a m ple f or T S R-0 3 3 m ust be t a ke n bef ore st arti n g t he d ost arli m a b  i nf usi o n i n P art 1c of 
t he st u d y. If t h e e n d of t he d ostarli ma b  i nf usi o n is later t ha n 1 h o ur ( ± 5 min utes) relati ve t o t he 
start of t he T S R-0 3 3 i nf usi o n, a n e n d of i nf usi o n s a m ple m ust be ta ke n f or d ostarli ma b . I n Part 2, 
p ost -i nf usi o n sa m ples are ta ke n at t he e n d of t he d ostarli ma b  a d mi nistrati o n f or d oses/ wee ks 
w here T S R -0 3 3 a n d d ost arli ma b  are gi ve n i n c o m bi nati o n ( ie, D ose 1, D os e 4, etc.), a n d at t he 
e n d of t he T S R -0 3 3 f or d oses/ wee ks w h ere T S R -0 3 3 is a d mi nistere d al o ne ( ie, D ose 2, D os e 3, 
D ose 5, etc.) . 
I n Part 1 b, a c o h ort(s) of u p t o 6 a d diti o nal patie nts ma y be e nr olle d i n a n y d ose le vel wit h D LTs 
< ⅓ of patie nts t o better c haract erize t he P K pr ofil e of T S R -0 3 3
 I n t his c o h ort(s), T S R-0 3 3 will be a d mi nistere d o n Da y 1, Da y 2 9, a n d Q 2 W  
t hereafter ( wit h o ut a d mi nistrati o n of a Da y 1 5 d os e). T he e xte n de d treat ment d urati o ns i n t he 
a bse nce of t he sec o n d d ose o n Da y 1 5 e n a bles a b etter c haracterizati o n of t he ter mi nal p hase of 
t he P K pr ofile, w hic h ca n lea d t o m ore acc urate calc ulati o ns of P K para m eters (s uc h as t½ ). 
A d diti o nall y, t his e xte n de d treat me nt i nter v al w ill pr o vi de a d diti o nal  
 t hat ma y 
C CI
C CI
C CI
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
8 8  
 
c o ntri b ute t o t he deter mi nati o n of t he R P 2 D. T he decisi o n re gar di n g w hic h c o h ort(s) t o e x pa n d 
f or t his e val uati o n will be deter mi ne d b y t he S p o ns or a n d t he I n v esti gat ors. 
T he ser u m sa m ples f or P K deter mi nati o n will be a nal yze d usi n g E LI S A.  
T he e n d of i nf usi o n P K s a m ple s h o ul d al wa ys be dra w n at t he e n d of t he last st u d y m e dicati o n 
i nf usi o n, re gar dless if t he i nf usi o n is sl o we d or te m p oraril y st o p pe d d u e t o a n i nf usi o n reacti o n. 
6. 4. 2.  
A n al ysis of A nti dr u g A nti b o dies  
Ser u m s a m ples f or t he deter mi nati o n of a nti -T S R -0 3 3 a nti b o dies a n d a nti -d ostarli ma b  a nti b o dies 
will be t he sa me sa m ples c ollecte d as f or P K. Mi ni mall y, A D A s will be a n al yze d usi n g 
electr oc h e mil u mi nesce nce ( E C L) wit h pre -d ose sa m ples fr o m all d oses c ollecte d a n d t er mi nal 
p hase sa m ples, as a p pr o priate, fr o m first a n d si xt h d oses f or Part 1 patie nts. F or all patie nts, 
a d diti o nal sa m ples f or A D A deter mi nati o n will be c ollecte d u p o n treat me nt disc o nti n uati o n at a 
safet y F U P visit (ie, a p pr o xi matel y 3 0 a n d 9 0 d a ys after t he last d ose of T S R-0 3 3 or d ostarli ma b , 
or b ot h, t o c oi nci de wit h t he safet y F U P visits).  
C CI
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
8 9  
 
C CI


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7. 
STUDY CONDUCT 
7.1. 
Schedules of Events 
Schedules of events and procedures are provided in Table 4, Table 5, Table 6, Table 7, Table 8, 
Table 9, Table 10, Table 11, Table 12, Table 13, Table 14, Table 15, Table 16, Table 17, and 
Table 18. 
Patients who continue to receive study treatment after the DCO date of the final analysis (see 
Section 3.3.3) will be monitored and receive follow-up care in accordance with standard local 
clinical practice. Assessments will revert to the standard of care at a patient’s particular study site 
and only SAEs, AEs leading to discontinuation of study treatment, overdoses, and pregnancies 
will be reported directly to the Sponsor via paper forms (see Section 6.1.12; refer to the Study 
Reference Manual for further details on reporting using paper forms). 
7.1.1. 
Use of Standard of Care Assessments for Screening 
In some cases, clinical assessments performed prior to obtaining informed consent may be used 
to qualify the patient for the study, providing these assessments are performed within 21 days 
prior to the first dose of study treatment (within 28 days for radiologic assessments). These 
include radiological examinations, ECGs, physical examinations, vital signs, hematology, 
chemistry, coagulation studies, or urinalysis, which may be considered as part of normal SOC. In 
these cases, repeat assessments may not be necessary prior to enrollment unless individual 
parameters require further study or confirmation and are clinically appropriate. 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
9 1  
 
T a ble  4 : 
Sc he d ule of Cli nic al E ve nts: T S R -0 3 3 M o n ot her a p y, P a rt 1 a a n d P a rt 1 b ( Q 2 W)  
Visit/ D ose:  
Scree ni n g  
D ose 1  
D ose 2  
S u bse q ue nt 
D oses  
E O T a 
S afet y 
F U P b  
S ur vi v al 
F U P  
D a y:  
Pr o ce d ure ( Pr ot oc ol Secti o n):  
-2 1  t o -1  
1  
2  
3  
5  
( ± 2 4 
hr)  
8  
( ± 2 4 
hr)  
1  
( ± 2 4 
hr)  
8  
( ± 2 4 
hr)  
D ose n,  
D a y 1  
( E ver y 
3 0 a n d 
9 0 ± 7 
D a ys)  
( E ver y 
9 0  ± 1 4 
D a ys)  
I nf or me d c o nse nt ( Secti o n 9. 7 ) 
X  
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria re vie w 
( Secti o ns 4. 1  a n d  4. 2 ) 
X  
 
 
 
 
 
 
 
 
 
 
 
C o nfir m t hat patie nt c o nti n ues t o 
satisf y eli gi bilit y criteria 
( Secti o ns 4. 1  a n d  4. 2 ) 
 
X  
 
 
 
 
 
 
 
 
 
 
De m o gra p hics ( Secti o n  6. 2 ) 
X  
 
 
 
 
 
 
 
 
 
 
 
Ca ncer, Me dical, S ur gical a n d 
Me dicati o n hist or y ( Secti o ns  6. 2. 3 , 
6. 2. 4 , a nd  6. 2. 5 ) 
X  
 
 
 
 
 
 
 
 
 
 
 
T u m or  assessm e nt ( R E CIS T v 1. 1 
a n d
( Secti o n 6. 3. 1 , A p pe n di x  1 , a n d 
A p pe n di x  2 ) 
X  
 
 
 
 
 
 
 
P er 
Secti o n  6. 3. 1. 2  
X c 
 
C B C wit h 5 -part differe ntial –
P art  1 a  ( Secti o n 6. 1. 7 ) 
X  
X d 
X  
X  
X  
X  
X  
X  
X d 
X  
X  
 
C B C wit h 5 -part differe ntial –
P art  1 b  ( Secti o n 6. 1. 7 ) 
X  
X d 
X  
X  
X  
D a ys 
8, 1 5, 
& 2 2  
X  
X  
X d 
X  
X  
 
C he m istr y– P art 1 a  ( Secti o n 6. 1. 7 ) 
X  
X d 
X  
 
 
X  
X  
X  
X d 
X  
X  
 
C he m istr y– P art 1 b  ( Secti o n 6. 1. 7 ) 
X  
X d 
X  
 
 
D a ys 
8, 1 5, 
& 2 2  
X  
X  
X d 
X  
X  
 
C CI


TMF-14403236 
CONFIDENTIAL 
213349 (4040-01-001, CITRINO 
Amd 05 (Version 6.0) 
92 
 
Table 4: 
Schedule of Clinical Events: TSR-033 Monotherapy, Part 1a and Part 1b (Q2W) (Continued) 
Visit/Dose: 
Screening 
Dose 1 
Dose 2 
Subsequent 
Doses 
EOTa 
Safety 
FUPb 
Survival 
FUP 
Day: 
Procedure (Protocol Section): 
-21 to -1 
1 
2 
3 
5 
(±24 
hr) 
8 
(±24 
hr) 
1 
(±24 
hr) 
8 
(±24 
hr) 
Dose n, 
Day 1 
(Every
30 and 
90 ±7 
Days) 
(Every 
90 ±14 
Days) 
Coagulation (Section 6.1.7) 
X 
 
 
 
 
 
 
 
Per SOC for 
patients on 
anticoagulant 
therapy 
 
 
 
Pregnancy test in WOCBP only 
(Section 6.1.7) 
Within 
72 hours 
of Dose 1 
Every 3 months during study treatment 
X 
X 
 
HBV/HCV test (if clinically 
indicated; eg, history of IV drug 
use) (Section 6.1.7) 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (Section 6.1.7) 
X 
Xd 
 
 
 
 
X 
 
Xd 
X 
X 
 
Serum-based tumor markers 
(eg, CEA) (Section 3.3.1.3) 
X 
Xd 
 
 
 
 
 
 
Xd 
X 
 
 
Thyroid panel (Section 6.1.7) 
X 
Every 6 weeks and if clinically indicated 
X 
 
 
12-Lead ECG (Section 6.1.9)  
Patients will undergo ECG monitoring at screening, pre-dose on Dose 1, Day 1, every 28 days 
thereafter while on study treatment, at the EOT visit, and at any time it is clinically indicated 
 
 
Complete PE (Section 6.1.8) 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Symptom-directed PE 
(Section 6.1.8.1) 
 
Throughout the study as clinically indicated 
 
 
 
Vital signs, height (at screening 
only), and weight–Part 1a 
(Sections 5.2.1 and 6.1.8) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
9 3  
 
T a ble  4 : 
Sc he d ule of Cli nic al E ve nts: T S R -0 3 3 M o n ot her a p y, P a rt 1 a a n d P a rt 1 b ( Q 2 W) ( C o nti n ue d)  
Visit/ D ose:  
Scree ni n g  
D ose 1  
D ose 2  
S u bse q ue nt 
D oses  
E O T a 
S afet y 
F U P b  
S ur vi v al 
F U P  
D a y:  
Pr o ce d ure ( Pr ot oc ol Secti o n):  
-2 1  t o -1  
1  
2  
3  
5  
( ± 2 4 
hr)  
8  
( ± 2 4 
hr)  
1  
( ± 2 4 
hr)  
8  
( ± 2 4 
hr)  
D ose n,  
D a y 1  
( E ver y 
3 0 a n d 
9 0 ± 7 
D a ys)  
( E ver y 
9 0  ± 1 4 
D a ys)  
V ital sig ns, he ig h t (at scree ni n g 
o nl y), a n d w e ig h t– P art 1 b  
( Secti o ns 5. 2. 1  a n d  6. 1. 8 ) 
X  
X  
X  
X  
X  
D a ys 
8, 1 5, 
& 2 2  
X  
X  
X  
X  
 
 
E C O G P S (A p pe n di x  3 )  
X  
 
 
 
 
 
 
 
Pre -d ose  
X  
 
 
A E m o nit ori n g ( Secti o ns  6. 1. 2 , 
6. 1. 3 , 6. 1. 4 , a n d  6. 1. 5 )  
C ollecte d fr o m t he ti me of si g ne d i nf or me d c o nse nt ( Da y -2 1  t o Da y -1) a n d at all st u d y visits t hr o u g h t he 9 0 -da y S F U, 
or u ntil i nitiati o n of alter nati ve a nti -ca ncer t hera p y, w hic he ver occ urs first  
C o nc o mita nt me dicati o ns 
( Secti o ns 5. 6  a n d 6. 2. 5 ) 
C ollecte d at scree ni n g a n d at all st u d y visits t hr o u g h t he 3 0 -d a y S F U, or u ntil i nitiati o n of alter nati ve 
a nti-ca ncer t hera p y, w hic he ver occ urs first  
 
T S R -0 3 3 a d m in istere d– P art 1 a  
( Secti o ns 3. 1. 3. 1 , 5. 2 , a n d t he 
P har mac y Ma n ual)  
 
X  
 
 
 
 
Da y 
1 5  
 
E ver y 1 4 da ys 
( ± 1 da y) 
 
 
 
T S R -0 3 3 a d m in istere d– P art 1 b  
( Secti o ns 3. 1. 3. 2 , 5. 2 , a n d t he 
P har mac y Ma n ual)  
 
X  
 
 
 
 
Da y 
2 9  
 
E ver y 1 4 da ys 
( ± 1 da y) 
 
 
 
P ost -i nf usi o n, 4-h o ur o bser vati o n 
peri o d  ( Secti o n 5. 2. 1 ) 
 
X  
 
 
 
 
X  
 
 
 
 
 
S ur vi val assess me nt a n d a nti -ca ncer 
treat me nts ( Secti o n 3. 3. 1. 6 )  
 
 
 
 
 
 
 
 
 
 
 
Via 
tele p h o ne 
A b bre viati o ns: A E =a d verse e ve nt; C B C =c o m plete bl o o d c o u nt; C E A =carci n oe m br y o nic a nti ge n; C R C =c ol orectal ca nc er; C T =c o m p ute d t o m o gra p h y; 
E C G =electr ocar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; E O T =e n d of treat me nt; F U P =f oll o w -u p; H B V = he p atitis B vir us; H C V = he p atitis C 
vir us; hr = h o urs;
; I V =i ntra ve n o us; M RI = ma g netic res o na nce i ma gi n g; P D = pr o gressi ve disease; P E = p h ysical e xa mi nati o n; 
P S = perf or ma nce stat us; Q 2 W =e ver y 2 wee ks; R E CI S T = Res p o nse E val uat i o n Criteria i n S oli d T u m ors; S F U =st u d y f oll o w u p; S O C =sta n dar d of care; 
W O C B P = w o me n of c hil d beari n g p ote ntial.  
a T he E O T visit will occ ur wit hi n 7 da ys of t he decisi o n t o disc o nti n ue st u d y treat me nt f or a n y reas o n. 
b Safet y F U P visit s h o ul d be c o n d ucte d 3 0 ( ± 7) a n d 9 0 ( ± 7) da ys after last st u d y dr u g d ose. S h o ul d t he first d ose of a ne w a nti -ca ncer t hera p y occ ur wit hi n 1 4 
da ys of t h e decisi o n t o disc o nti n ue st u d y treat me nt, all assess me nts re q uire d f or t he Safet y F U P visit s h o ul d occ ur at t he E O T visit, a n d t his visit will b e 
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
9 4  
 
c o nsi dere d t he Safet y F U P visit. If t he first d ose of t he ne w a nti -ca ncer t hera p y occ urs > 1 4 da ys after t he d ecisi o n t o dis c o nti n ue st u d y, t he Safet y F U P visit will 
occ ur 3 0 ± 7 da ys after t he last d ose of t he st u d y dr u g, or at t he start of a n y ne w a nti -ca ncer t hera p y, w hic he ver occ urs first . 
c T u m or assess me nt p er R E CI S T v 1. 1  a n d 
 via C T or M RI (c hest, a b d o me n, a n d pel vis [as well as brai n or ot her re gi o ns k n o w n t o ha ve disease 
i n v ol ve me nt]) are re q uire d wit hi n 2 8 da ys pri or t o D ose 1, Da y 1. S u bse q ue nt i ma gi n g s h o ul d be perf or me d e ver y 6 wee ks ( 4 2 ± 7 da ys) f or t he first 3 
assess me nts a n d e ver y 9 wee ks ( 6 3 ± 7 da ys) t hereafter w hile o n st u d y treat me nt , or m ore fr e q ue ntl y if cli nicall y i n dicate d a n d at t he ti me of s us pecte d P D . After 
1 year, t u m or assess me nts ma y be perf or me d e ver y 1 2 wee ks ( 8 4 ± 7 da ys). I ma gi n g s h o ul d n ot be dela ye d f or dela ys i n d osi n g . If a p plica ble, testi n g of ser u m-
base d t u m or mar kers ( e g, C E A f or patie nts wit h C R C) s h o ul d c oi nci de a p pr o xi matel y ( ± 5 da ys) wit h ra di o gra p hic t u m or assess me nts. T he t u m or i ma gi n g for 
c o nfir mati o n  of res p o nse ma y be perf or me d at t he earliest 2 8 da ys after t he first i n dicati o n of res p o nse, b ut n o later t ha n 3 5 da ys, w hic h e ver is cli nicall y 
i n dicate d. T he s u bse q ue nt sca n after t he c o nfir mat or y sca n s h o ul d be o btai ne d per t he ori gi nal sc he d ule. Cli nicall y sta ble patie nts s h o ul d n ot b e disc o nti n ue d 
u ntil pr o gressi o n is c o nfir me d (Secti o n  6. 3. 1 ). P atie nts w h o disc o nti n ue st u d y treat me nt f or reas o ns ot her t ha n P D will c o nti n ue p ost -treat me nt i ma gi n g st u dies as 
descri be d i n Secti o n  6. 3. 1. 2 . 
d If scree ni n g la b orat or y testi n g ( C B C, c he mistr y, ser u m-base d t u m or mar kers, a n d uri nal ysis) perf or me d wit hi n 7 2 h o urs pri or t o o r o n D ose 1, Da y 1, re p eat 
testi n g is n ot re q uire d. La b orat or y testi n g ( C B C, c he mistr y, ser u m-base d t u m or mar kers, a n d uri nal ysis) is all o we d u p t o 2 4 h o urs pri or t o T S R -0 3 3 i nf usi o n 
d uri n g t he st u d y. Pre -d ose test res ults m ust b e re vie we d pri or t o d osi n g.  Starti n g wit h D ose 5 of T S R -0 3 3, la b orat or y testi n g is o nl y t o be perf or me d o n o d d 
n u m bere d d oses ( ie, e ver y 2 8 da ys). 
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
9 5  
 
T a ble  5 : 
Sc he d ule of Cli nic al E ve nts: T S R -0 3 3 + D ost arli m a b  C o m bi n ati o n T her a p y, P a rt 1c ( Q 3 W)  
Vi sit/ D ose: 
Scree ni n g  
D ose 1  
D ose 2  
S u bse q ue nt 
D oses  
E O T a 
S afet y 
F U P b  
S ur vi v al 
F U P  
D a y:  
Pr o ce d ure ( Pr ot oc ol Secti o n):  
-2 1  t o -1  
1  
2  
3  
5  
( ± 2 4 
hr)  
8 & 1 5  
( ± 2 4 
hr)  
1  
( ± 2 4 
hr)  
8 & 1 5  
( ± 2 4 
hr)  
D ose n,  
D a y 1  
( E ver y 
3 0 a n d 
9 0 ± 7 
D a ys)  
( E ver y 
9 0  ± 1 4 
D a ys)  
I nf or me d c o nse nt ( Secti o n 9. 7 )  
X  
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria re vie w 
( Secti o ns 4. 1  a n d  4. 2 ) 
X  
 
 
 
 
 
 
 
 
 
 
 
C o nfir m t hat patie nt c o nti n ues t o 
satisf y eli gi bilit y criteria 
( Secti o ns 4. 1  a n d  4. 2 ) 
 
X  
 
 
 
 
 
 
 
 
 
 
De m o gra p hics ( Secti o n  6. 2 ) 
X  
 
 
 
 
 
 
 
 
 
 
 
Ca ncer, Me dical, S ur gical a n d 
Me dicati o n hist or y ( Secti o ns  6. 2. 3 , 
6. 2. 4 , a n d  6. 2. 5 ) 
X  
 
 
 
 
 
 
 
 
 
 
 
T u m or  assessm e nt ( R E CIS T a n d 
( Secti o n 6. 3. 1 , A p pe n di x  1 , a n d 
A p pe n di x  2 ) 
X  
 
 
 
 
 
 
 
P er 
Secti o n  6. 3. 1. 2  
X c 
 
C B C wit h 5 -part differe ntial 
( Secti o n 6. 1. 7 ) 
X  
X d 
X  
X  
X  
X  
X  
X  
X d 
X  
X  
 
C he m istr y ( Secti o n 6. 1. 7 ) 
X  
X d 
X  
 
 
X  
X  
X  
X d 
X  
X  
 
C oa g u latio n ( Secti o n  6. 1. 7 ) 
X  
 
 
 
 
 
 
 
P er S O C f or 
patie nts o n 
a ntic oa g ula nt 
t h era p y 
 
 
 
Pre g na nc y  test f or W O C B P o nl y 
( Secti o n 6. 1. 7 ) 
Wit hi n  
7 2 h o urs 
of D ose 1  
E ver y 3 m o nt hs d uri n g st u d y treat me nt  
X  
X  
 
C CI


TMF-14403236 
CONFIDENTIAL 
213349 (4040-01-001, CITRINO 
Amd 05 (Version 6.0) 
96 
 
Table 5: 
Schedule of Clinical Events: TSR-033 + Dostarlimab Combination Therapy, Part 1c (Q3W) (Continued) 
Visit/Dose: 
Screening 
Dose 1 
Dose 2 
Subsequent 
Doses 
EOTa 
Safety 
FUPb 
Survival 
FUP 
Day: 
Procedure (Protocol Section): 
-21 to -1 
1 
2 
3 
5 
(±24 
hr) 
8&15 
(±24 
hr) 
1 
(±24 
hr) 
8&15 
(±24 
hr) 
Dose n, 
Day 1 
(Every 
30 and 
90 ±7 
Days) 
(Every 
90 ±14 
Days) 
HBV/HCV test (if clinically 
indicated; eg, history of IV drug 
use) (Section 6.1.7) 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (Section 6.1.7) 
X 
Xd 
 
 
 
 
X 
 
Xd 
X 
X 
 
Serum-based tumor markers (eg, 
CEA) (Section 3.3.1.3) 
X 
Xd 
 
 
 
 
 
 
Xd 
X 
 
 
Thyroid panel (Section 6.1.7) 
X 
Every 6 weeks and if clinically indicated 
X 
 
 
ECG (Section 6.1.9) 
Patients will undergo ECG monitoring at screening, pre-dose on Dose 1, Day 1, every 28 days 
thereafter while on study treatment, at the EOT visit, and at any time it is clinically indicated 
 
 
Complete PE (Section 6.1.8) 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Symptom-directed PE 
(Section 6.1.8.1) 
 
Throughout the study as clinically indicated 
 
 
 
Vital signs, height (at screening 
only), and weight (Sections 5.2.1 
and 6.1.8) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG PS (Appendix 3)  
X 
 
 
 
 
 
 
 
Pre-dose 
X 
 
 
AE monitoring (Sections 6.1.2, 
6.1.3, 6.1.4, and 6.1.5)  
Collected from the time of signed informed consent (Day -21 to Day -1) and at all study visits through the 90-day SFU, 
or until initiation of alternative anti-cancer therapy, whichever occurs first 
Concomitant medications 
(Sections 5.6 and 6.2.5) 
Collected at screening and at all study visits through the 30-day SFU, or until initiation of alternative 
anti-cancer therapy, whichever occurs first 
 
TSR-033 + dostarlimab 
administered 
(Section 5.2) 
 
X 
 
 
 
 
Day 
22 
 
Every 21 days 
 
 
 
 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
9 7  
 
T a ble  5 : 
Sc he d ule of Cli nic al E ve nts: T S R -0 3 3 + D ost arli m a b C o m bi n ati o n T her a p y, P a rt 1c ( Q 3 W) ( C o nti n ue d)  
Visit/ D ose:  
Scree ni n g  
D ose 1  
D ose 2  
S u bse q ue nt 
D oses  
E O T a 
S afet y 
F U P b  
S ur vi v al 
F U P  
D a y:  
Pr o ce d ure ( Pr ot oc ol Secti o n):  
-2 1  t o -1  
1  
2  
3  
5  
( ± 2 4 
hr)  
8 & 1 5  
( ± 2 4 
hr)  
1  
( ± 2 4 
hr)  
8 & 1 5  
( ± 2 4 
hr)  
D ose n,  
D a y 1  
( E ver y 
3 0 a n d 
9 0 ± 7 
D a ys)  
( E ver y 
9 0  ± 1 4 
D a ys)  
P ost -i nf usi o n, 4-h o ur o bs er vati o n 
peri o d  ( Secti o n 5. 2. 1 ) 
 
X  
 
 
 
 
X  
 
 
 
 
 
S ur vi val assess me nt a n d a nti -ca ncer 
treat me nts ( Secti o n 3. 3. 1. 6 ) 
 
 
 
 
 
 
 
 
 
 
 
Via 
tele p h o ne 
A b bre viati o ns: A E =a d verse e ve nt; C B C =c o m plete bl o o d c o u nt; C E A =carci n oe m br y o nic a nti ge n; C R C =c ol orectal ca nc er; C T =c o m p ute d t o m o gra p h y; 
E C G =electr ocar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; E O T =e n d of treat me nt; F U P =f oll o w -u p; H B V = he p atitis B vir us; H C V = he p atitis C 
vir us; hr = h o urs;
 I V =i ntra ve n o us; M RI = ma g netic res o na nce i ma gi n g; P D= pr o gressi ve disease; P E = p h ysical e xa mi n ati o n; 
P S = perf or ma nce stat us; Q 3 W =e ver y 3 wee ks; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors; S F U =st u d y f oll o w u p; S O C =sta n d ar d of care.  
a T he E O T visit will occ ur wit hi n 7 da ys of t he de cisi o n t o disc o nti n ue st u d y treat me nt f or a n y reas o n . 
b Safet y F U P visit s h o ul d be c o n d ucte d 3 0 ( ± 7) a n d 9 0 ( ± 7) da ys after last st u d y dr u g d ose. S h o ul d t he first d ose of a ne w a nti -ca ncer t hera p y occ ur wit hi n 1 4 
da ys of t he decisi o n t o disc o nti n ue st u d y treat me nt, all assess me nts re q uire d f or t he Safet y F U P visit s h o ul d occ ur at t he E O T visit, a n d t his visit will b e 
c o nsi dere d t he Safet y F U P visit. If t he first d ose of t he ne w a nti -ca ncer t hera p y occ urs > 1 4 da ys after t he decisi o n t o dis c o nti n ue st u d y, t he Safet y F U P visit will 
occ ur 3 0 ± 7 da ys after t he last d ose of t he st u d y dr u g, or at t he start of a n y ne w a nti -ca ncer t hera p y, w hic he ver occ urs first.  
c T u m or assess me nt p er R E CI S T v 1. 1  a n d 
 via C T or M RI (c hest, a b d o me n, a n d pel vis [as well as brai n or ot her re gi o ns k n o w n t o ha ve disease 
i n v ol ve me nt]) are re q uire d wit hi n 2 8 da ys pri or t o D ose 1, Da y 1. S u bse q ue nt i ma gi n g sh o ul d be perf or me d e ver y 6 wee ks ( 4 2 ± 7 da ys) f or t he first 3 
assess me nts a n d e ver y 9 wee ks ( 6 3 ± 7 da ys) t hereafter w hile o n st u d y treat me nt , or m ore fr e q ue ntl y if cli nicall y i n dicate d a n d at t he ti me of s us pecte d P D . After 
1 year, t u m or assess me nts ma y be perf or me d e ver y 1 2 wee ks ( 8 4 ± 7 da ys). I ma gi n g s h o ul d n ot be dela ye d f or dela ys i n d osi n g . If a p plica ble, testi n g of ser u m-
base d t u m or mar kers ( e g, C E A f or patie nts wit h C R C) s h o ul d c oi nci de a p pr o xi matel y ( ± 5 da ys) wit h ra di o gra p hic t u m or assess me nts. T he t u m or i ma gi n g f or 
c o nfir mati o n of res p o nse ma y be perf or me d at t he earliest 2 8 da ys after t he first i n dicati o n of res p o nse, b ut n o later t ha n 3 5 da ys, w hic he ver is cli nicall y 
i n dicate d. T he s u bse q ue nt sca n after t he c o nfir mat or y sca n s h o ul d be o btai ne d per t he ori gi nal sc he d ule. Cli nicall y sta ble patie nts s h o ul d n ot b e disc o nti n ue d 
u ntil pr o gressi o n is c o nfir me d ( Secti o n 6. 3. 1 ). P atie nts w h o disc o nti n ue st u d y treat me nt f or reas o ns ot her t ha n P D will c o nti n ue p ost -treat me nt i ma gi n g st u dies as 
descri be d i n Secti o n  6. 3. 1. 2 . 
d If scree ni n g la b orat or y testi n g ( C B C, c he mistr y, ser u m-base d t u m or mar kers, a n d uri nal ysis) perf or me d wit hi n 7 2 h o urs pri or t o or o n D ose 1, Da y 1, re p eat 
testi n g is n ot re q uire d. La b orat or y testi n g ( C B C, c he mistr y, ser u m-base d t u m or mar kers, a n d uri nal ysis) is all o we d u p t o 2 4 h o urs pri or t o T S R -0 3 3 i nf usi o n 
d uri n g t he st u d y. Pre -d ose test res ults m ust b e re vie we d pri or t o d osi n g. Starti n g wit h D ose 5 of T S R -0 3 3, la b orat or y testi n g is o nl y t o b e perf or me d o n o d d 
n u m bere d d oses ( ie, e ver y 2 8 da ys). 
C CI
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
9 8  
 
T a ble  6 : 
Sc he d ule of Cli nic al E ve nts: P art 2 A  
Visit/ D ose:  
Scree ni n g  
D ose 1  
S u bse q ue nt 
D oses  
E O T  
( Wit hi n 7 D a ys of 
Decisi o n t o 
Disc o nti n ue)  
S afet y F U P a 
F U P Assess me nts  
D a y:  
Pr o ce d ure ( Pr ot oc ol Secti o n):  
-2 8 t o -1  
1  
D ose n,  
D a y 1  ( ± 2 4 hr) 
( E ver y 3 0 a n d 
9 0 ± 7 D a ys)  
( E ver y 9 0 ± 1 4 
D a ys)  
I nf or me d c o nse nt ( Secti o n 9. 7 ) 
X  
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria re vie w 
( Secti o ns 4. 1  a n d 4. 2 ) 
X  
 
 
 
 
 
C o nfir mati o n t hat patie nt c o nti n ues t o satisf y 
eli gi bilit y criteria  
( Secti o ns 4. 1  a n d 4. 2 ) 
 
X  
 
 
 
 
De m o gra p hics ( Secti o n  6. 2 ) 
X  
 
 
 
 
 
Ca ncer, Me dical, S ur gical a n d Me dicati o n 
hist or y ( Secti o ns  6. 2. 3 , 6. 2. 4 , a n d  6. 2. 5 ) 
X  
 
 
 
 
 
T u m or  assessm e nt ( R E CIS T a n d
b 
( Secti o n 6. 3. 1 , A p pe n di x  1 , a n d A p pe n di x  2 ) 
X  
 
X c 
X b 
 
C B C wit h 5 -part differe ntial ( Secti o n  6. 1. 7 ) 
X  
X d  
X d  
X  
X  
 
C he m istr y ( Secti o n 6 . 1. 7) 
X  
X d  
X d  
X  
X  
 
C oa g u latio n fact ors ( Secti o n  6. 1. 7 ) 
X  
 
P er S O C f or 
patie nts o n 
a ntic oa g ula nt 
t hera p y 
 
 
 
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Table 6: 
Schedule of Clinical Events: Part 2A (Continued) 
Visit/Dose: 
Screening 
Dose 1 
Subsequent 
Doses 
EOT 
(Within 7 Days of 
Decision to 
Discontinue) 
Safety FUPa 
FUP Assessments 
Day: 
Procedure (Protocol Section): 
-28 to -1 
1 
Dose n,  
Day 1 (±24 hr) 
(Every 30 and 
90 ±7 Days) 
(Every 90 ±14 
Days) 
Pregnancy test for WOCBP only 
(Section 6.1.7) 
Within 72 
hours of Dose 
1 
 
Every 3 months 
during study 
treatment 
X 
X 
 
HBV/HCV test (Section 6.1.7) 
X 
 
 
 
 
 
Serum-based tumor markers (eg, CEA) 
(Section 3.3.1.3) 
X 
Xd 
Xd 
X 
 
 
Urinalysis (Section 6.1.7) 
X 
Xd 
Xd 
X 
X 
 
Thyroid panel (Section 6.1.7) 
X 
Every 6 weeks (ie Dose 1, 4, 
7, etc.) and if clinically 
indicated 
X 
 
 
ECG (Section 6.1.9) 
Patients will undergo ECG monitoring at screening, pre-dose on Dose 
1, Day 1, every 28 days thereafter while on study treatment, at the EOT 
visit, and at any time it is clinically indicated 
 
 
Physical examination (Section 6.1.8) 
X 
 
 
X 
X 
 
Symptom-directed PE (Section 6.1.8.1) 
 
Throughout the study as 
clinically indicated 
 
 
 
Vital signs, height (at screening only), and 
weight (Sections 5.2.1 and 6.1.8) 
X 
X 
X 
X 
 
 
ECOG-PS (Appendix 3) 
X 
 
Pre-dose 
X 
 
 
AE monitoring (Sections 6.1.3, 6.1.4 
and 6.1.5)  
Collected from the time of signed informed consent (Day -28 to Day -1) and at all study visits through the 90-
day SFU, or until initiation of alternative anti-cancer therapy, whichever occurs first 
Concomitant medications (Section 5.6 and 
6.2.5) 
Collected at screening and at all study visits through the 30-day SFU, or until initiation of 
alternative anti-cancer therapy, whichever occurs first 
 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
1 0 0  
 
T a ble  6 : 
Sc he d ule of Cli nic al E ve nts: P art 2 A ( C o nti n ue d)  
Visit/ D ose:  
Scree ni n g  
D ose 1  
S u bse q ue nt 
D oses  
E O T  
( Wit hi n 7 D a ys of 
Decisi o n t o 
Disc o nti n ue)  
S afet y F U P a 
F U P Assess me nts  
D a y:  
Pr o ce d ure ( Pr ot oc ol Secti o n):  
-2 8 t o -1  
1  
D ose n,  
D a y 1  ( ± 2 4 hr) 
( E ver y 3 0 a n d 
9 0 ± 7 D a ys)  
( E ver y 9 0 ± 1 4 
D a ys)  
T S R -0 3 3 a d mi nistrati o n Q 2 W ( Secti o n  5. 2 ) 
 
X  
X  
 
 
 
D ostarli ma b  a d mi nistrati o n Q 6 W 
( Secti o n 5. 2 ) 
 
X  
E ver y t hir d 
d ose ( D ose 1, 4, 
7, etc.)  
 
 
 
P ost -i nf usi o n, 2-h o ur o bs er vati o n peri o d 
( Secti o n 5. 2. 1 ) 
 
X  
X e 
 
 
 
S ur vi val assess me nt a n d a nti -ca ncer 
treat me nts ( Secti o n 3. 3. 1. 6 ) 
 
 
 
 
 
Via tele p h o ne  
A b bre viati o ns: A E =a d verse e ve nt; C B C =c o m plete bl o o d c o u nt; C E A =carci n oe m br y o nic a nti ge n; C R C =c ol orectal ca nc er; C T =c o m p ute d t o m o gra p h y; 
E C G =electr ocar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; E O T =e n d of treat me nt; F U P =f oll o w -u p; H B V = he p atitis B vir us; H C V = he p atitis C 
vir us; I R =i nf usi o n reacti o n;
; I V =i ntra ve n o us; M RI = ma g netic res o na nce i ma gi n g; P D= pr o gressi ve disease; P E = p h ysical 
e xa mi nati o n; P S = perf or ma nce stat us; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors; S F U =st u d y f oll o w u p; S O C =sta n dar d of care.  
a Safet y F U P visit s h o ul d be c o n d ucte d 3 0 ( ± 7) a n d 9 0 ( ± 7) da ys after last st u d y dr u g d ose. S h o ul d t he first d ose of a ne w a nti -ca ncer t hera p y occ ur wit hi n 1 4 
da ys of t he decisi o n t o disc o nti n ue st u d y treat me nt, all assess me nts re q uire d f or t he Safet y F U P visit s h o ul d occ ur at t he E O T visit, a n d t his visit will b e 
c o nsi dere d t he Safet y F U P visit. If t he first d ose of t he ne w a nti -ca ncer t hera p y occ urs > 1 4 d a ys after t he decisi o n t o dis c o nti n ue st u d y, t he Safet y F U P visit will 
occ ur 3 0 ± 7 da ys after t he last d ose of t he st u d y dr u g, or at t he start of a n y ne w a nti -ca ncer t hera p y, w hic he ver occ urs first.  
b T u m or assess me nt p er R E CI S T v 1. 1  a n d 
 via C T or M RI (c hest, a b d o me n, a n d pel vis [as well as brai n or ot her re gi o ns k n o w n t o ha ve disease 
i n v ol ve me nt]) are re q uire d wit hi n 2 8 da ys pri or t o D ose 1, Da y 1. S u bse q ue nt i ma gi n g s h o ul d be perf or me d e ver y 6 wee ks ( 4 2 ± 7 da ys) f or t he first 3 
assess me nts a n d e ver y 9 wee ks ( 6 3 ± 7 da ys) t hereafter w hile o n st u d y treat me nt , or m ore fr e q ue ntl y if cli nicall y i n dicate d a n d at t he ti me of s us pecte d P D . After 
1 year, t u m or assess me nts ma y be perf or me d e ver y 1 2 wee ks ( 8 4 ± 7 da ys). I ma gi n g s h o ul d n ot be dela ye d f or dela ys i n d osi n g . T esti n g of ser u m -base d t u m or 
mar kers ( e g, C E A f or patie nts wit h C R C) s h o ul d c oi nci de a p pr o xi matel y ( ± 5 da ys) wit h ra di o gra p hic t u m or assess me nts. T he t u m or i ma gi n g for c o nfir mati o n of 
res p o nse ma y be perf or me d at t he earliest 2 8 da ys after t he first i n dicati o n of res p o nse, b ut n o later t ha n 3 5 d a ys, w hic he ver is cli nicall y i n dicate d. T he 
s u bse q ue nt sca n after t he c o nfir mat or y sca n s h o ul d be o btai ne d per t he ori gi nal sc he d ule. Cli nicall y sta ble patie nts s h o ul d n ot b e disc o nti n ue d u ntil pr o gressi o n is 
c o nfir me d ( Secti o n 6. 3. 1 ). P atie nts w h o disc o nti n ue st u d y tr eat me nt f or reas o ns ot her t ha n P D will c o nti n ue p ost-treat me nt i ma gi n g st u dies as d escri be d i n 
Secti o n  6. 3. 1. 2 . 
c D ose 4, 7 , a n d 1 0  (± 1 wee k) ; t he n e ver y 9 ( ± 1) wee ks t hereafter (6 3 ± 7 da ys) . 
d If scree ni n g la b orat or y testi n g ( C B C, c he mistr y, ser u m-base d t u m or mar kers, a n d uri nal ysis) perf or me d wit hi n 7 2 h o urs pri or t o or o n D ose 1, Da y 1, re p eat 
testi n g is n ot re q uire d. La b orat or y testi n g ( C B C, c he mistr y, ser u m-base d t u m or mar kers, a n d uri nal ysis) is all o we d u p t o 2 4 h o urs pri or t o T S R -0 3 3 i nf usi o n 
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during the study. Pre-dose test results must be reviewed prior to dosing. Starting with Dose 5 of TSR-033, laboratory testing is only to be performed on odd 
numbered doses (ie, every 28 days). 
e Should no IRs occur during the 2-hour observation period for Dose 1, observation can be reduced to 1 hour for Dose 2, then to 30 minutes for all doses 
thereafter. If an IR does occur, patients must be observed for the full 2 hours post dose until no further IRs are observed. 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
1 0 2  
 
T a ble  7 : 
Sc he d ule of Cli nic al E ve nts: P art 2 B ( C o h orts B 1 a n d B 2)  
Visit / D ose: 
S cree ni n g  
D ose 1  
S u bse q ue nt 
D oses  
E O T  
( Wit hi n 7 D a ys of 
Decisi o n t o 
Disc o nti n ue)  
S afet y F U P a 
F U P Assess me nts  
D a y:  
Pr o ce d ure ( Pr ot oc ol Secti o n):  
-2 8 t o -1  
1  
3  
D ose 
n, 
D a y 1  
( ± 2 4 
hr)  
D ose 
n, 
D a y 3  
( E ver y 3 0 a n d 
9 0 ± 7 D a ys)  
( E ver y 9 0 ± 1 4 
D a ys)  
I nf or me d c o nse nt ( Secti o n 9. 7 ) 
X  
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria re vie w 
( Secti o ns 4. 1  a n d 4. 2 ) 
X  
 
 
 
 
 
 
 
C o nfir mati o n t hat patie nt c o nti n ues t o satisf y 
eli gi bilit y criteria  
( Secti o ns 4. 1  a n d 4. 2 ) 
 
X  
 
 
 
 
 
 
De m o gra p hics ( Secti o n  6. 2 ) 
X  
 
 
 
 
 
 
 
Ca ncer, Me dical, S ur gical a n d Me dicati o n 
hist or y ( Secti o ns  6. 2. 3 , 6. 2. 4 , a nd 6. 2. 5 ) 
X  
 
 
 
 
 
 
 
T u m or  assessm e nt ( R E CIS T a n d
 
( Secti o n 6. 3. 1 , A p pe n di x  1 , a n d A p pe n di x  2 ) 
X  
 
 
X c 
 
X b 
 
C B C wit h 5 -part differe ntial ( Secti o n  6. 1. 7 ) 
X  
X d 
 
X d  
 
X  
X  
 
C he m istr y ( Secti o n 6. 1. 7 ) 
X  
X d 
 
X d  
 
X  
X  
 
C oa g u latio n fact ors ( Secti o n  6. 1. 7 ) 
X  
 
 
P er S O C f or 
patie nts o n 
a ntic oa g ula nt 
t hera p y 
 
 
 
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Table 7: 
Schedule of Clinical Events: Part 2B (Cohorts B1 and B2) (Continued) 
Visit/Dose: 
Screening 
Dose 1 
Subsequent 
Doses 
EOT 
(Within 7 Days of 
Decision to 
Discontinue) 
Safety FUPa 
FUP Assessments 
Day: 
Procedure (Protocol Section): 
-28 to -1 
1 
3 
Dose 
n,  
Day 1 
(±24 
hr) 
Dose 
n,  
Day 3 
(Every 30 and 
90 ±7 Days) 
(Every 90 ±14 
Days) 
Pregnancy test for WOCBP only 
(Section 6.1.7) 
Within 72 
hours of Dose 
1 
 
 
Every 3 months 
during study 
treatment 
X 
X 
 
HBV/HCV test (Section 6.1.7) 
X 
 
 
 
 
 
 
 
Serum-based tumor markers (eg, CEA) 
(Section 3.3.1.3) 
X 
Xd 
 
Xd 
 
X 
 
 
Urinalysis (Section 6.1.7) 
X 
Xd 
 
Xd 
 
X 
X 
 
Thyroid panel (Section 6.1.7) 
X 
Every 6 weeks (ie, Dose 1, 4, 
7, etc.) and if clinically 
indicated 
X 
 
 
ECG (Section 6.1.9) 
Patients will undergo ECG monitoring at screening, pre-dose on Dose 
1, Day 1, every 28 days thereafter while on study treatment, at the EOT 
visit, and at any time it is clinically indicated 
 
 
Physical examination (Section 6.1.8) 
X 
 
 
 
 
X 
X 
 
Symptom-directed PE (Section 6.1.8.1) 
 
Throughout the study as 
clinically indicated 
 
 
 
Vital signs, height (at Screening only), and 
weight (Sections 5.2.1 and 6.1.8) 
X 
X 
 
X 
 
X 
 
 
ECOG PS (Appendix 3) 
X 
 
 
Pre-
dose 
 
X 
 
 
AE monitoring (Sections 6.1.3, 6.1.4, 
and 6.1.5)  
Collected from the time of signed informed consent (Day -28 to Day -1) and at all study visits through the 90-
day SFU, or until initiation of alternative anti-cancer therapy, whichever occurs first 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
1 0 4  
 
T a ble  7 : 
Sc he d ule of Cli nic al E ve nts: P art 2 B ( C o h orts B 1 a n d B 2) ( C o nti n ue d)  
Visit/ D ose:  
Scree ni n g  
D ose 1  
S u bse q ue nt 
D oses  
E O T  
( Wit hi n 7 D a ys of 
Decisi o n t o 
Disc o nti n ue)  
S afet y F U P  
F U P Assess me nts  
D a y:  
Pr o ce d ure ( Pr ot oc ol Secti o n):  
-2 8 t o -1  
1  
3  
D ose 
n,  
D a y 1  
D ose 
n,  
D a y 3  
( E ver y 3 0 a n d 
9 0 ± 7 D a ys)  
( E ver y 9 0 ± 1 4 
D a ys)  
C o nc o mita nt me dicati o ns ( Secti o n 5. 6  a n d 
6. 2. 5 ) 
C ollecte d at scr ee ni n g a n d at all st u d y visits t hr o u g h t he 3 0 -d a y S F U, or u ntil i nitiati o n of 
alter nati ve a nti -ca ncer t hera p y, w hic he ver occ urs first  
 
B e vaciz u ma b a n d m F O L F O X 6 ( C o h ort B 1) 
or F O L FI RI ( C o h ort B 2) a d mi nistrati o n 
Q 2 W ( Secti o n  5. 2 ) 
 
X  
 
X  
 
 
 
 
T S R -0 3 3 a d mi nistrati o n Q 2 W ( Secti o n  5. 2 ) 
 
 
X  
 
X  
 
 
 
D ostarli ma b a d mi nistrati o n Q 6 W 
( Secti o n 5. 2 ) 
 
 
X  
 
E ver y 
t hir d 
d ose 
( D ose 
1, 4, 
7, 
etc.)  
 
 
 
P ost -i nf usi o n, 2-h o ur o bs er vati o n peri o d  
( Secti o n 5. 2. 1 ) 
 
 
X  
 
X e 
 
 
 
S ur vi val assess me nt a n d a nti -ca ncer 
treat me nts ( Secti o n 3. 3. 1. 6 ) 
 
 
 
 
 
 
 
Via tele p h o ne  
A b bre viati o ns: A E =a d verse e ve nt; C B C =c o m plete bl o o d c o u nt; C E A =carci n oe m br y o nic a nti ge n; C R C =c ol orectal ca nc er; C T =c o m p ute d t o m o gra p h y; 
E C G =electr ocar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; E O T =e n d of treat me nt; F U P =f oll o w -u p; H B V = he p atitis B vir us; H C V = he p atitis C 
vir us; I R =i nf usi o n reacti o n;
; I V =i ntra ve n o us; M RI = ma g netic res o na nce i ma gi n g; P D = pr o gressi ve disease; P E = p h ysical 
e xa mi nati o n; P S = perf or ma nce stat us; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors; S F U =st u d y f oll o w u p; S O C =sta n dar d of care.  
a Safet y F U P visit s h o ul d be c o n d ucte d 3 0 ( ± 7) a n d 9 0 ( ± 7) da ys after last st u d y dr u g d ose. S h o ul d t he first d ose of a ne w a nti -ca ncer t hera p y occ ur wit hi n 1 4 
da ys of t he decisi o n t o disc o nti n ue st u d y treat me nt, all assess me nts re q uire d f or t he Safet y F U P visit s h o ul d occ ur at t he E O T visit, a n d t his visit will b e 
c o nsi dere d t he Safet y F U P visit. If t he first d ose of t he ne w a nti -ca ncer t hera p y occ urs > 1 4 da ys after t he decisi o n t o dis c o nti n ue st u d y, t he Safet y F U P visit will 
occ ur 3 0 ± 7 da ys after t he last d ose of t he st u d y dr u g, or at t he start of a n y ne w a nti -ca ncer t hera p y, w hic he ver occ urs first.  
b T u m or assess me nt p er R E CI S T v 1. 1  a n d 
via C T or M RI (c hest, a b d o me n, a n d pel vis [as well as brai n or ot her re gi o ns k n o w n t o ha ve disease 
i n v ol ve me nt]) are re q uire d wit hi n 2 8 da ys pri or t o D ose 1, Da y 1. S u bse q ue nt i ma gi n g s h o ul d be perf or me d e ver y 6 wee ks ( 4 2 ± 7 da ys) f or t he first 3 
assess me nts a n d e ver y 9 wee ks ( 6 3 ± 7 da ys) t hereafter w hile o n st u d y treat me nt , or m ore fr e q ue ntl y if cli nicall y i n dicate d a n d at t he ti me of s us pecte d P D . After 
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1 year, tumor assessments may be performed every 12 weeks (84 ±7 days). Imaging should not be delayed for delays in dosing. Testing of serum-based tumor 
markers (eg, CEA for patients with CRC) should coincide approximately (±5 days) with radiographic tumor assessments. The tumor imaging for confirmation of 
response may be performed at the earliest 28 days after the first indication of response, but no later than 35 days, whichever is clinically indicated. The 
subsequent scan after the confirmatory scan should be obtained per the original schedule. Clinically stable patients should not be discontinued until progression is 
confirmed (Section 6.3.1). Patients who discontinue study treatment for reasons other than PD will continue post-treatment imaging studies as described in 
Section 6.3.1.2. 
c Dose 4, 7, and 10 (±1 week); then every 9 (±1) weeks thereafter (63 ±7days). 
d If screening laboratory testing (CBC, chemistry, serum-based tumor markers, and urinalysis) performed within 72 hours prior to or on Dose 1, Day 1, repeat 
testing is not required. Laboratory testing (CBC, chemistry, serum-based tumor markers, and urinalysis) is allowed up to 24 hours prior to Day 1 of the dosing 
cycle during the study. Pre-dose test results must be reviewed prior to dosing. Starting with Dose 5 of TSR-033, laboratory testing is only to be performed on odd 
numbered doses (ie, every 28 days). 
e Should no IRs occur during the 2-hour observation period for Dose 1, observation can be reduced to 1 hour for Dose 2, then to 30 minutes for all doses 
thereafter. If an IR does occur, patients must be observed for the full 2 hours post dose until no further IRs are observed. 


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Table 8: 
Sampling Schedule for Pharmacokinetic and ADA Analysis: Part 1a (Q2W) 
Visit/Dose: 
Dose 1 
Doses 
2–5 
Dose 6 
Dose 
7 
Doses 
≥8a 
EOT 
Safety 
FUPb 
Day: 
Time Relative to Start of 
TSR-033 30-minute IV 
Infusion: 
Day 
1 
Day 
2 
Day 
3 
Day 
5 
Day 
8 
Day 
1 
Day 
1 
Day 
2 
Day 
3 
Day 
5 
Day 
8 
Day 
1 
Day 
1 
 
(Every 30 
and 90 ±7 
Days) 
Pre-dose (within 30 min) 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
0.25 hr (±5 min) 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
0.5 hr (±5 min) 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
1.5 hr (±5 min) 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
3 hr (±5 min) 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
24 hr (Day 2 ±2 hr) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
48 hr (Day 3 ±4 hr) 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
96 hr (Day 5 ±24 hr) 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
168 hr (Day 8 ±24 hr) 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
EOT 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
FUP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: ADA=antidrug antibody; EOT=end of treatment; FUP=follow up; hr=hours; IV=intravenous; min=minutes; Q2W=every 2 weeks. 
a Every other dose (eg, Dose 8, 10, 12, etc.). 
b For ADA sample collection, this sample collection time will coincide with the safety FUP visits. 


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Table 9: 
Sampling Schedule for Additional Pharmacokinetic and ADA Analysis: Part 1b (Q2W) 
Visit/Dose: 
Dose 1 
Doses 
2a–5 
Dose 6 
Dose 
7 
Doses 
≥8b 
EOT 
Safety 
FUPc 
Day: 
Time Relative to Start 
of TSR-033 30-minute 
IV Infusion: 
Day 
1 
Day 
2 
Day 
3 
Day 
5 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
1 
Day 
2 
Day 
3 
Day 
5 
Day 
8 
Day 
1 
Day 
1 
(Every 
30 and 
90 ±7 
Days) 
Pre-dose (w/in 30 min) 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
0.25 hr (±5 min) 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
0.5 hr (±5 min) 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
1.5 hr (±5 min) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
3 hr (±5 min) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
24 hr (Day 2 ±2 hr) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
48 hr (Day 3 ±4 hr) 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
96 hr (Day 5 ±24 hr) 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
168 hr (Day 8 ±24 hr) 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
336 hr (Day 15 ±24 hr) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
504 rh (Day 22 ±24 hr) 
 
 
 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
EOT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
FUP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: ADA=antidrug antibody; EOT=end of treatment; FUP=follow up; hr=hours; IV=intravenous; min=minutes; Q2W=every 2 weeks; w/in=within. 
a The second dose will be given 4 weeks after Dose 1 (on Day 29). 
b Every other dose (ie, Dose 8, 10, 12, etc.). 
c For ADA sample collection. This sample collection time will coincide with the safety FUP visits. 
d Pre-dose (Dose 2). 


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Table 10: 
Sampling Schedule for Pharmacokinetic and ADA Analysis: Part 1c (Q3W) 
Visit/Dose: 
Dose 1 
Doses 
2-5 
Dose 6 
Dose 
7 
Doses 
≥8a 
EOT 
Safety 
FUPb 
Day: 
Time Relative to 
Start of TSR-033 
30-minute IV 
Infusion: 
Day 
1 
Day 
2 
Day 
3 
Day 
5 
Day 
8 
Day 
15 
Day 
1 
Day 
1 
Day 
2 
Day 
3 
Day 
5 
Day 
8 
Day 
15 
Day 
1 
Day 
1 
(Every 
30 and 
90 ±7 
Days) 
Pre-dose (w/in 30 min) 
X 
 
 
 
 
 
Xc 
X 
 
 
 
 
 
Xd 
X 
 
 
0.25 hr (±5 min) 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
0.5 hr (±5 min)b,d 
Xd 
 
 
 
 
 
X 
Xd 
 
 
 
 
 
 
Xd,e 
 
 
1.0 hr (±5min) 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
Xc 
 
 
1.5 hr (±5 min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
3 hr (±5 min) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
24 hr (Day 2 ±2 hr) 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
48 hr (Day 3 ±4 hr) 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
96 hr (Day 5 ±24 hr) 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
168 hr (Day 8 ±24 hr) 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
336 hr (Day 15 ±24 hr) 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
EOT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
FUP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: ADA=antidrug antibody; EOT=end of treatment; FUP=follow up; hr=hours; IV=intravenous; min=minutes; Q3W=every 3 weeks; w/in=within. 
a Every other dose (Dose 8, 10, 12, etc.). 
b For ADA sample collection. This sample collection time will coincide with the safety FUP visits. 
c If the end of infusion for dostarlimab is later than 1.0 hr ±5 min relative to the start of TSR-033 infusion, an end of infusion sample must be taken for 
dostarlimab. 
d Important: End of infusion sample for TSR-033, must be taken before starting the dostarlimab infusion. 
e Pre-dose. 


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Table 11: 
Sampling Schedule for Pharmacokinetic and ADA Analysis: Part 2A (Q2W) 
Visit/Dose: 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
Dose 6 
Doses ≥8 
EOT 
Safety 
FUP 
Day: 
Timepoint: 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
(Every 30 
and 90 ±7 
Days) 
Pre-dose (within 30 min) 
X 
X 
X 
X 
X 
X 
Xa 
 
 
End of infusion (±5 min)b 
X 
X 
X 
X 
X 
X 
 
 
 
EOT 
 
 
 
 
 
 
 
X 
 
FUPc 
 
 
 
 
 
 
 
 
X 
Abbreviations: ADA=antidrug antibody; EOT=end of treatment; FUP=follow-up; hr=hours; min=minutes; Q2W=every 2 weeks. 
a Every other dose (Dose 8, 10, 12, etc, regardless if TSR-033 is administered alone or in combination with dostarlimab). 
b End of infusion of the last investigational drug, ie, on days when TSR-033 is administered alone, the draw is post end of TSR-033 infusion (Dose 2, Dose 3, 
Dose 5, Dose 6, etc), and when TSR-033 is given in combination with dostarlimab, the draw should be taken at the end of the dostarlimab infusion (Dose 1, Dose 
4, etc). The end of infusion PK sample should always be drawn at the end of the last study medication infusion, regardless if the infusion is slowed or temporarily 
stopped due to an infusion reaction. 
c For ADA sample collection. This sample collection time will coincide with the safety follow up visits. 


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Table 12: 
Sampling Schedule for Pharmacokinetic and ADA Analysis: Part 2B (Cohorts B1 and B2) (Q2W) 
Visit/Dose: 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
Dose 6 
Doses ≥8 
EOT 
Safety 
FUP 
Day: 
Timepoint: 
Day 3 
Day 3 
Day 3 
Day 3 
Day 3 
Day 3 
Day 3 
(Every 30 
and 90 ±7 
Days) 
Pre-dose (within 30 min) 
X 
X 
X 
X 
X 
X 
Xa 
 
 
End of infusion (±5 min)b 
X 
X 
X 
X 
X 
X 
Xa 
 
 
EOT 
 
 
 
 
 
 
 
X 
 
FUPc 
 
 
 
 
 
 
 
 
X 
Abbreviations: ADA=antidrug antibody; EOT=end of treatment; FUP=follow-up; hr=hours; min=minutes; Q2W=every 2 weeks. 
a Every other dose (Day 3 of Dose 8, 10, 12, etc., regardless if TSR-033 is administered alone or in combination with dostarlimab). 
b End of infusion of the last investigational drug, ie, on days when TSR-033 is administered alone, the draw is post end of TSR-033 infusion (Dose 2, Dose 3, 
Dose 5, Dose 6, et), and when TSR-033 is given in combination with dostarlimab, the draw should be taken at the end of the dostarlimab infusion (Dose 1, Dose 
4, etc). The end of infusion PK sample should always be drawn at the end of the last study medication infusion, regardless if the infusion is slowed or temporarily 
stopped due to an infusion reaction. 
c For ADA sample collection. This sample collection time will coincide with the safety follow up visits. 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
1 1 1  
 
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
1 1 2  
 
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
1 1 3  
 
T a ble  1 7 : 
S a m pli n g Sc he d ule f or Bi o m ar kers a n d Bi o psies: P art 1 a, 1 b, 1c, a n d P art 2 A  
Visit/ D ose:  
D a y:  
Pr o ce d ure ( Pr ot oc ol Secti o n):  
Scree ni n g  
D ose 1  
D ose 2  
D ose 3  
D ose 5  
D ose 7  
D ose 1 0  
E O T a  
D a y 1  
D a y 8  
D a y 1  
D a y 1  
D a y 1  
D a y 1  
D a y 1  
Fres h t u m or tiss ue bi o psies ( S ecti o n  6. 6. 2 ) 
X  
 
 
 
X c 
 
 
X  
Arc hi val t u m or tiss ue (re q uire d f or P art 1; 
rec o m me n de d, if a vaila ble f or P art 2 A) 
( Secti o n 3. 3. 1. 1 ) 
X  
 
 
 
 
 
 
 
A b bre viati o ns: E O T =e n d of treat me nt; P D = pr o gressi ve dise ase.  
a T he E O T visit s h o ul d occ ur wit hi n 7 da ys of t he decisi o n t o disc o nti n ue st u d y treat me nt f or a n y reas o n. Sa m ples will be o btai ne d o nl y f or patie nts w h o 
disc o nti n ue st u d y treat me nt d ue t o P D.  
b  T he  o n -st u d y ct D N A sa m ple s h o ul d be o btai ne d 4 t o 6 wee ks f oll o wi n g D ose 1 ( bet wee n D ose 3 -4).  
c T he o n -st u d y bi o ps y s h o ul d be o btai ne d 4 t o 6 wee ks f oll o wi n g D ose 1 ( bet wee n D ose 3 -4).  
C CI
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O  
A m d  0 5 ( Versi o n  6. 0)  
1 1 4  
 
T a ble  1 8 : 
S a m pli n g Sc he d ule f or Bi o m ar kers a n d Bi o psies: P art 2 B ( C o h orts B 1 a n d B 2)  
Visit/ D ose:  
D a y:  
Pr o ce d ure ( Pr ot oc ol Secti o n):  
Scree ni n g  
D ose 1  
D ose 2  
D ose 3  
D ose 5  
D ose 7  
D ose 1 0  
E O T a  
D a y 3  
D a y 1 0  
D a y 3  
D a y 3  
D a y 3  
D a y 3  
D a y 3  
Fres h t u m or tiss ue bi o psies ( S ecti o n  6. 6. 2 ) 
X  
 
 
 
X c 
 
 
X  
Arc hi val t u m or tiss ue (rec o m me n de d, if  
a vaila ble) ( Secti o n  3. 3. 1. 1 ) 
X  
 
 
 
 
 
 
 
A b bre viati o ns: E O T =e n d of treat me nt; P D = pr o gressi ve dise ase.  
a T he E O T visit s h o ul d occ ur wit hi n 7 da ys of t he decisi o n t o disc o nti n ue st u d y treat me nt f or a n y reas o n. Sa m ples will be o btai ne d o nl y f or patie nts w h o 
disc o nti n ue st u d y treat me nt d ue t o P D.  
b  T he o n -st u d y ct D N A sa m ple s h o ul d be o btai ne d 4 t o 6 wee ks f oll o wi n g D ose 1 ( bet wee n D ose 3 -4).  
c T he o n -st u d y bi o ps y s h o ul d be o btai ne d 4 t o 6 wee ks f oll o wi n g D ose 1 ( bet wee n D ose 3 -4).  
C CI


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
1 1 5  
 
8.  
S T A TI S TI C A L M E T H O D S  
All descri pti ve statistical a nal ys es will be perf or m e d usi n g t he m ost rece ntl y releas e d a n d 
a vaila ble S A S statistical s oft ware, u nless ot h er wis e n ote d. F or cate g orical v aria bles, t he n u m ber  
a n d perce nt of eac h cate g or y wit hi n a para m eter will be calc ulate d. F or c o nti n u o us varia bles, t he 
sa m ple siz e ( n), mea n, m e dia n, a n d sta n dar d de viati o n, as well as t he mi ni m u m a n d ma xi m u m 
val ues, will be prese nt e d. Missi n g data will n ot be i m p ute d u nless ot her wise state d. T here will be 
a detaile d des cri pti o n of patie nt dis p ositi o n; patie nt de m o gra p hics a n d b aseli ne c haracteristics 
will be s u m mariz e d.  
N o f or mal i nteri m a nal ysis is pla n ne d f or t his st u d y. H o we ver, a re vie w of safet y data a n d 
a vaila ble preli m i nar y P K data will be c o n d uct e d b y t he S p o ns or a n d I n vesti gat ors f oll o wi n g 
c o m pleti o n of t he D L T o bser vati o n peri o ds i n Part 1a a n d Part 1c. Deter mi nati o n of t he R P 2 D 
will be base d o n re vi e w of safet y, P K, a n d  
. All a nal yses will be perf or me d f or a n y 
patie nt t hat recei ve d a n y a m o u nt of st u d y dr u g. All a nal ys es f or efficac y will use D ose 1, Da y 1 
as t he start ti me.  
Details of t he statistical a nal yses prese nt e d bel o w will be pr o vi de d i n t he st u d y’s statistical 
a nal ysis pla n ( S A P). A c ha n ge t o t he data  a nal ysis met h o ds descri be d i n t h e pr ot oc ol will re q uire 
a pr ot oc ol a me n d me nt o nl y if it alters a pri nci pal feat ure of t he pr ot oc ol. T h e S A P will be 
fi nalize d pri or t o data bas e l oc k. A n y c h a n ges t o t he met h o ds descri be d i n t h e pla n will be 
descri be d a n d j u stifie d i n t he fi nal cli nical st u d y re p ort. 
8. 1.  
St u d y P o p ul ati o ns  
A nal ysis p o p ulati o ns will be defi ne d as f oll o ws f or Part 1 a n d Part 2, res p ecti vel y:  
•  Safet y P o p ulati o n: All patie nts w h o recei v e a n y a m o u nt of st u d y dr u g . 
•  Efficac y P o p ulati o n: All patie nts w h o r ecei ve a n y a m o u nt of T S R -0 3 3.  
•  D L T E v al ua ble P o p ulati o n: T he assess me nt of D L Ts i n Part 1a, Part 1c, a n d Part 2 B 
will i ncl u de o nl y t h ose p atie nts c o m pleti n g t he D L T o bser vati o n peri o d t hr o u g h o ut 
t he c o urse of 2 T S R-0 3 3 a d mi nistrati o ns ( ie, Da y 1 a n d Da y 1 5 i n t he first 2 8 da ys of 
st u d y treat me nt) f or Part 1a, t he c o urse of 2 T S R-0 3 3 + d ostarli ma b  a d mi nistrati o ns 
(ie, Da y 1 a n d Da y 2 1 i n t he first 4 2 da ys of st u d y treat me nt) f or Part 1c, t h e c o urse 
of 2 T S R -0 3 3 + d ostarli ma b  a d mi nistrati o ns ( ie, Da y 3 a n d Da y 1 7 i n t he first 3 0 da ys 
of st u d y tr eat me nt) u nless t he patie nt disc o nti n ue d T S R -0 3 3 ( Part 1a) or T S R -0 3 3 + 
d ostarli ma b  ( Part 1c a n d Part 2 B) d ue t o a D L T. 
•  Per Pr ot oc ol P o p ulati o n: All patie nts i n t he Efficac y P o p ulati o n w h o d o n ot ha ve 
pr ot oc ol vi olati o ns  d uri n g t he st u d y t hat ma y si g nifica ntl y i m pact t he i nter pretati o n of 
effic ac y res ults a n d ha ve ≥1 p ost -baseli ne disease assess me nt.  
•  P K P o p ulati o n: All patie nts w h o recei v e a n y a m o u nt of T S R -0 3 3 a n d/ or d ostarli ma b 
a n d ha ve ≥1  me as ura ble dr u g c o nce ntrati o n.  P K P o p ulati o ns will be defi ne d 
se parat el y f or eac h st u d y dr u g. 
•  I m m u n o ge nicit y ( A D A) P o p ulati o n: All patie nts w h o recei ve a n y a m o u nt of T S R-0 3 3 
a n d ha ve ≥1  A D A sa m pl e wit h a res ult.  
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Demographics, baseline characteristics, and medical history information will be summarized by 
dose level for Parts 1a, 1b, and 1c and by expansion cohorts for Part 2, for the Safety Population 
using descriptive statistics. No formal statistical comparisons among cohorts will be performed. 
Demographic, baseline characteristics, and medical history data for each patient will be provided 
in data listings. 
8.2. 
Safety Analyses 
The following key safety parameters will be evaluated by dose level, by expansion cohorts, and 
overall, unless noted otherwise: 
• DLTs (DLT-Evaluable Population) during the DLT-observation period in Part 1a, 
Part 1c, and Part 2B. 
• Incidence of TEAEs during the DLT-observation period (ie, the first 28 days of 
treatment for Part 1a and the first 42 days of treatment for Part 1c) compared to 
subsequent days with subsequent doses. 
• Incidence of TEAEs, irAEs, and SAEs occurring while patients are on treatment or up 
to 90 days after the last dose of study drug or until alternative anti-cancer therapy is 
initiated, whichever occurs first. 
• Clinical laboratory assessments (CBC with 5-part differential, chemistry, and thyroid 
panel), CTCAE graded laboratory toxicities, ECOG PS, ECG parameters, and usage 
of concomitant medications. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
system and displayed in tables and data listings using system organ class and preferred term. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined per protocol as any AE with onset after the first 
administration of study drug, throughout the treatment period, until 90 days after cessation of 
study treatment (or until the start of alternative anti-cancer therapy, whichever occurs earlier), or 
any event that was present at baseline but worsened in intensity or was subsequently considered 
drug-related by the Investigator through the end of the study. DLTs will be tabulated by dose 
level in Part 1a, Part 1c, and Part 2B. 
The number and percentage of patients with any TEAE, with any TEAE assessed by the 
Investigator as related to treatment (definite, probable, or possible relationship), and with any 
SAE will be summarized by treatment group and overall. In these tabulations, each patient will 
contribute only once (ie, the most related occurrence or the most intense occurrence) to each of 
the incidence rates in the descriptive analysis, regardless of the number of episodes. No formal 
hypothesis-testing analysis of AE incidence rates will be performed. 
The occurrence of and reasons for any requirement for dose interruption will be tabulated. 
All AEs occurring on-study will be listed in patient data listings. By-patient listings will also be 
provided for the following: patient deaths, SAEs, and AEs leading to withdrawal of study 
treatment. 


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8.2.1. 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug Dictionary (September 2016 or 
later version). A dictionary listing of all unique concomitant medications used in the study will 
be provided. 
8.3. 
Pharmacokinetic Analyses 
All patients who receive any amount of TSR-033 and/or dostarlimab and have ≥1 measurable 
drug concentration will be included in PK analyses. 
Noncompartmental methods will be used to evaluate the PK characteristics of TSR-033 in 
Part 1a and Part 1b and TSR-033 and dostarlimab in Part 1c and Part 2, as appropriate. PK 
parameters such as Cmax, time at maximum concentration (Tmax), AUC, t½, volume of distribution 
at steady state (Vss), and clearance (CL) may be derived from serum concentrations using actual 
sampling times, as data permit. Concentration data may be included in a population PK analysis, 
the results of which will be reported separately. 
Concentration-time data and PK parameters will be listed and summarized descriptively by 
cohort, dose level, and dose number. Summary statistics will include the mean, standard 
deviation, coefficient of variation, geometric mean, geometric mean coefficient of variation, 
median, minimum, and maximum. 
8.4. 
Antidrug Antibody Analysis 
The number and percent of patients who become positive for ADAs will be summarized by 
visit/time and overall. Similar analysis may be conducted for neutralizing antibodies (NAbs) if 
deemed appropriate. 
8.5. 
Efficacy Analyses 
All efficacy endpoints will be summarized on the data from patients in Part 2 by expansion 
cohort; in addition, data may be pooled for patients in Part 1 and Part 2, by tumor type. The 
primary efficacy analysis is based on the Efficacy Population defined in Section 8.1. All analyses 
will include summary statistics, including number of patients (n) and percentage (%) for 
categorical variables and number of patients, mean, standard deviation, median, minimum, and 
maximum for continuous variables. Time-to-event analyses will be performed using Kaplan-
Meier (KM) methods.22 Comparisons in the Part 1 portion of the study will be made using 
descriptive statistics. 
8.5.1. 
Primary Efficacy Parameter 
The primary efficacy endpoint will be ORR for Part 2A of the study, defined as the achievement 
of CR or PR using RECIST v1.1, as assessed by the Investigator. Point estimates and 2-sided 
95% CIs will be provided. The primary analysis of ORR will be performed for each expansion 
cohort and no multiplicity adjustment will be made since separate inferences will be drawn for 
each cohort. 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
1 1 8  
 
8. 5. 2.  
Sec o n d ar y Effic ac y P ar a meter s 
O R R i s a sec o n dar y e n d p oi nt f or Part 1 a n d Part 2 B of t he st u d y, defi ne d as t he ac hie ve me nt of 
C R or P R usi n g R E CI S T v 1. 1, as assesse d b y t he I n v esti gat or . 
D C R is a sec o n dar y e n d p oi nt f or Part 2 a n d is defi ne d as t he pr o p orti o n of patie nts ac hie vi n g 
C R, P R, or S D as assesse d b y t he I n vesti gat or per R E CI S T v 1. 1, wit h p oi nt esti mates a n d 
2 -si de d 9 5 % CIs. S D per R E CI S T v 1. 1 f or a mi ni m u m of 12  wee ks is necessar y f or i ncl usi o n i n 
e val uati o n of D C R.  
D O R  is a sec o n dar y e n d p oi nt f or Part 2 a n d  will be prese nt e d t hr o u g h use of s u m mar y statistics 
usi n g K M met h o ds, t o i ncl u de 2 5 t h, 5 0t h ( me dia n), a n d 7 5t h perce ntiles a n d ass ociate d 2 -si de d 
9 5 % CIs f or t he me dia n, n u m ber of e v e nts, a n d n u m ber of ce ns ore d o bs er vati o ns . 
8. 7.  
Deter mi n ati o n of S a m ple Size  
Asce n di n g d oses of T S R -0 3 3 i n Part 1a a n d i n c o m bi nati o n wit h d ostarli ma b  i n Part 1c will be 
e val uate d t o i de ntif y t he res pecti ve R P 2 Ds. T he act ual n u m ber of patie nts accr ue d d uri n g t his 
p hase will be deter mi ne d lar gel y b y t he safet y a n d P K fi n di n gs o bser v e d d uri n g t he c o urse of 
t heir treat me nt. R P 2 D decisi o ns f or Part 1a a n d Part 1c will be base d o n a mi ni m u m of 6  patie nts 
f or eac h re gi me n. Patie nts i n Part 1 b ( P K/ P D y c o h ort) will n ot be c o nsi dere d e val ua ble f or d ose 
escalati o n p ur p oses ( ie, n ot i ncl u de d i nt o t he D L T-e val ua ble p o p ul ati o n), b ut will c o ntri b ute t o 
t he o verall safet y assess me nt at t he d ose le vel bei n g e v al uate d. It is e x pect e d t hat u p t o 
a p pr o xi matel y 1 3 2 patie nts will be e nr olle d i n Part 1 as f oll o ws:  
P art 1 a ( T S R -0 3 3 m o n ot her a py d ose es c al ati o n):  A p pr o xi matel y 3 0 -5 4 patie nts  
P art 1 b ( T S R -0 3 3 m o n ot her a py P K/
: A p pr o xi matel y 1 8 -3 0 patie nts  
P art 1c ( T S R -0 3 3 + d ost arli m a b  c o m bi n ati o n d ose esc al ati o n):  A p pr o xi matel y 2 4 -4 8 patie nts  
A t otal of u p t o a p pr o xi matel y 5 5 p atie nts are a ntici pate d i n t he 2 pla n ne d e x pa nsi o n c o h orts i n 
Part 2 . 
P art 2 A ( T S R -0 3 3 + d ost arli m a b  c o m bi n ati o n d ose ex p a nsi o n i n a nti -P D -1 -n aïve t hir d - or 
f o urt h-li ne M S S-C R C p atie nts):  A n ull h y p ot hesis of O R R 1 0 % will be teste d a gai nst a n 
alter nati ve h y p ot hesis of O R R 2 5 %. T he trial is desi g ne d usi n g a o n e -si de d e x act test t hat 
ac hie ves a mi ni m u m of 8 0 % p o wer at al p ha le vel of 0. 1. A sa m ple siz e of 3 1 will pr o vi de a n 
attai ne d p o wer of 8 2. 4 % a n d a n attai ne d t y p e -1 err or of 0. 0 8 3. T he n ull h y p ot hesis will be 
rejecte d if 6 or m ore res p o nses are o bs er ve d i n t he 3 1 patie nts. 
P art 2 B ( T S R -0 3 3  + d ost arli m a b  c o m bi n ati o n give n wit h m F O L F O X 6 or F O L FI RI a n d 
bev aciz u m a b [ S O C] i n a nti -P D -1 -n aïve s ec o n d -li ne M S S-C R C p atie nts):  A n ull h y p ot hesis of 
O R R 2 0 % will be teste d a gai nst a n alter nati ve h y p ot hesis of O R R 4 0 %. T he trial is desi g n e d 
usi n g a o n e -side d e x act t est t hat ac hie ves a mi ni m u m of 8 0 % p o wer at al p h a le vel of 0. 1. A 
sa m ple siz e of 2 4 will pr o vi de a n attai ne d p o wer of 8 0. 8 % a n d a n attai ne d t y pe -1 err or of 0. 0 8 9. 
T he n ull h y p ot hesis will be reje cte d if 8 or m or e res p o nses are o bser ve d i n t he 2 4  patie nts . 
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9. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
9.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must submit 
written approval to TESARO, Inc. before he/she can enroll any patient/subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study. The protocol must be re-approved by the IRB or 
IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. TESARO, Inc. will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
9.2. 
Data Quality Assurance 
The Sponsor (or designee) will conduct a study initiation visit to verify the qualifications of the 
Investigator, inspect the facilities, and inform the Investigator of responsibilities and procedures 
for ensuring adequate and correct documentation. 
The Investigator must prepare and maintain adequate and accurate records of all observations 
and other data pertinent to the clinical study for each study participant. Frequent communication 
between the clinical site and the Sponsor is essential to ensure that the safety of the study is 
monitored adequately. The Investigator will make all appropriate safety assessments on an 
ongoing basis. The Sponsor’s Medical Monitor may review safety information as it becomes 
available throughout the study. 
All aspects of the study will be carefully monitored with respect to GCP and standard operating 
procedures for compliance with applicable government regulations. The Site Monitor will be an 
authorized individual designated by the Sponsor. The Study Monitor will have access to all 
records necessary to ensure integrity of the data and will periodically review the progress of the 
study with the Principal Investigator. 
9.3. 
Institutional Review Board 
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval 
and all materials approved by the IRB for this study, including the patient consent form and 
recruitment materials, must be maintained by the Investigator and made available for inspection. 
9.4. 
Access to Source Data/Documents 
An electronic data capture system to manage data collection will be utilized during this trial. The 
electronic data capture system is a software tool designed to ensure quality assurance and 


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facilitate data capture during clinical trials. The system is fully compliant with Code of Federal 
Regulations 21 Part 11. 
The Investigator will ensure the accuracy, completeness, and timeliness of the data reported to 
the Sponsor. Data collection processes and procedures will be reviewed and validated to ensure 
completeness, accuracy, reliability, and consistency. A complete audit trail will be maintained of 
all data changes. The Investigator or designee will cooperate with the Sponsor’s representative(s) 
for the periodic review of study documents to ensure the accuracy and completeness of the data 
capture system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the respective study sites by 
means of electronic or manual queries. 
The Investigator or designee will prepare and maintain adequate and accurate study documents 
(medical records, ECGs, AE and concomitant medication reporting, raw data collection forms, 
etc.) designed to record all observations and other pertinent data for each patient receiving study 
treatment. 
The Investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors, and the IRB to have direct access to all documents pertaining to the study. 
9.5. 
Archiving Study Documents 
Essential clinical documents will be maintained to demonstrate the validity of the study and the 
integrity of the data collected. Master files should be established at the beginning of the study, 
maintained for the duration of the study, and retained according to the appropriate regulations. 
Trial subject’s medical files should be retained for at least 5 years (recommended to be in their 
original format) and in accordance with the maximum period of time permitted by the hospital, 
institution, or private practice. If the Investigator becomes unable to respond for their essential 
documents (eg, relocation, retirement), the Sponsor should be notified of this change and 
informed as to whom the responsibility has been transferred. 
9.6. 
Good Clinical Practice 
This study will be conducted in accordance with the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) for GCP and the Declaration 
of Helsinki (Version 2008). The clinical study will also be carried out in accordance with 
national and local regulatory requirement(s). 
9.7. 
Informed Consent 
Before each patient is enrolled in the clinical study, written informed consent will be obtained 
from the patient according to the regulatory and legal requirements of the participating country. 
As part of this procedure, the Investigator must explain orally and in writing the nature, duration, 
and purpose of the study, and the action of the study treatment in such a manner that the patient 
is aware of the potential risks, inconveniences, or AEs that may occur. The patient should be 
informed that he/she is free to withdraw from the study at any time. The patient will receive all 
information that is required by regulatory authorities and ICH guidelines. The Investigator or 


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designee will provide the Sponsor with a copy of the IRB/IEC-approved ICF prior to the start of 
the study. 
The ICF must be signed and dated; 1 copy will be given to the patient and the Investigator will 
retain a copy as part of the clinical study records. The Investigator will not undertake any 
investigation specifically required for the clinical study until written consent has been obtained. 
The terms of the consent and when it was obtained must also be documented in the medical 
record. 
If a protocol amendment is required, then the ICF may need to be revised to reflect the changes 
to the protocol. If the ICF is revised, it must be reviewed and approved by the responsible 
IRB/IEC and signed by all patients subsequently enrolled in the clinical study, as well as those 
currently enrolled in the clinical study. 
9.8. 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. The 
Sponsor must ensure that all ethical and legal requirements have been met before the first patient 
is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate). In the US, following approval, the protocol 
amendment(s) will be submitted to the Investigational New Drug Application under which the 
study is being conducted. Administrative changes (not affecting the patient benefit/risk ratio) 
may be made without the need for a formal amendment. All amendments will be distributed to 
all protocol recipients with appropriate instructions. 
9.9. 
Patient Confidentiality and Data Protection 
All clinical study findings and documents will be regarded as confidential. Study documents 
(protocols, IBs, and other material) will be stored appropriately to ensure their confidentiality. 
The Investigator and members of his/her research team (including the IRB/IEC) must not 
disclose such information without prior written approval from the Sponsor, except to the extent 
necessary to obtain informed consent from patients who wish to participate in the trial or to 
comply with regulatory requirements. 
The anonymity of participating patients must be maintained. Patients will not be identified on 
study documents by name, but rather by their enrollment number or birth date, or in accordance 
with local regulations. Documents that identify the patient (eg, the signed ICF) must be 
maintained in confidence by the Investigator. 
9.10. 
Study Monitoring 
Monitoring and auditing procedures approved by the Sponsor will be followed in order to 
comply with GCP guidelines. On-site checking of the eCRFs for completeness and clarity, 
cross-checking with source documents, and clarification of administrative matters will be 
performed. 


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The study will be monitored by the Sponsor or its designee. Monitoring will be done by personal 
visits from a representative of the Sponsor (site monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and by communications (letter, 
telephone, and fax). 
All unused study treatment and other study materials will be returned to the Sponsor after the 
clinical phase of the study has been completed. 
9.11. 
Audits and Inspections 
Regulatory Authorities, the IRB/IEC, and/or the Sponsor’s clinical quality assurance group (or 
its designee) may request access to all source documents, eCRFs, and other study documentation 
for on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. 
9.12. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB/IEC will review all appropriate study documentation in order to safeguard the 
rights, safety, and well-being of the patients. The study will only be conducted at sites where 
IRB/IEC approval has been obtained. The protocol, IB, ICF, advertisements (if applicable), 
written information given to the patients, safety updates, annual progress reports, and any 
revisions to these documents will be provided to the IRB/IEC by the Investigator. 
9.13. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval or, if not approved, 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for TESARO, Inc. or 
the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records. 
9.14. 
Study Termination 
If the Sponsor, an Investigator, or Clinical Monitor discovers conditions arising during the study 
that indicate that the clinical development of an investigational product should be placed on hold 
due to an unacceptable patient risk, then TESARO, Inc. will determine whether the study must 
be terminated after appropriate consultation with the Investigators. In addition, TESARO, Inc. 
may independently decide at any time to suspend or discontinue development of the 
investigational product. 
Within 15 days of premature closure, TESARO Inc. must notify the competent authorities and 
IECs of any member state where the study is being conducted, providing the reasons for study 
closure. 


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10. 
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APPENDIX 1. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST), V1.1 
Evaluation of Target Lesions 
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 diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters 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. (Note: the appearance of 1 or more new lesions is also 
considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be nonpathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the ULN, they must normalize for a patient to be 
considered in complete clinical response. 
Non-CR/Non-PD: 
Persistence of 1 or more non-target lesion(s) or maintenance of tumor 
marker level, or both, above the normal limits. 
Progressive Disease (PD): 
Appearance of 1 or more new lesions or unequivocal progression 
of existing non-target lesions, or both. Unequivocal progression should not normally trump target 
lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or the Investigator). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
PD/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). The patient's best response assignment will depend on the achievement of 
both measurement and confirmation criteria. 


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Table 19: 
RECIST Response for Patients with Measurable Disease (ie, Target Disease) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
Best Overall Response 
When Confirmation is 
Requireda 
CR 
CR 
No 
CR 
>4 weeks. Confirmationb 
CR 
Non-CR/Non-PD 
No 
PR 
>4 weeks. Confirmationb 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 weeks from baselineb 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PDc 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; RECIST=Response 
Evaluation Criteria in Solid Tumors; SD=stable disease. 
a See RECIST v1.1 publication for further details on what is evidence of a new lesion. 
b Only for nonrandomized trials with response as primary endpoint.53 
c In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease PD. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of PD at that time should be reported as “symptomatic deterioration.” Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
Table 20: 
RECIST Response for Patients with Nonmeasurable Disease 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR=complete response; PD=progressive disease. 
Note: A “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since SD is increasingly used as 
an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised. 


T M F -1 4 4 0 3 2 3 6  
C O N FI D E N TI A L  
2 1 3 3 4 9  ( 4 0 4 0-0 1 -0 0 1, CI T RI N O)  
A m d  0 5 ( Versi o n  6. 0)  
1 2 9  
 
C CI


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APPENDIX 3. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Description 
ECOG Grade55 
Fully active, able to carry on all pre-disease performance without restriction. 
0 
Restricted in physically strenuous activity, but ambulatory and able to carry out work 
of a light or sedentary nature, ie, light house work, office work. 
1 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
2 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
4 


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APPENDIX 4. COCKCROFT-GAULT FORMULA 
A commonly used equation for calculating an estimate of CrCL, which estimates glomerular 
filtration rate (GFR) in mL/min. The formula is: 
Ccr= 
Source: Cockcroft and Gault56 
(140 –  age) x weight (in kilograms) x [0.85 if female] 
72 x serum creatinine (in mg/dL) 


Si g nat ure Pa ge f or  2 1 3 3 4 9 T M F- 1 4 4 0 3 2 3 6 v 1. 0
Si g nat ure Pa ge f or T M F- 1 4 4 0 3 2 3 6 v 1. 0
Reas o n f or si g ni n g: A p pr o ve d
Na me:
R ole: A p pr o ver
Date of si g nat ure: 2 3- Fe b- 2 0 2 2 2 2: 0 2: 2 5 G M T + 0 0 0 0
P P D

SAP_001.pdf: 
 
CONFIDENTIAL 
The GlaxoSmithKline group of companies  
213349 
Page 1 of 49 
 
TITLE PAGE 
 
Statistical Analysis Plan 
 A Phase 1 Dose Escalation and Cohort Expansion Study of 
TSR-033, an anti-LAG-3 Monoclonal Antibody, alone and in 
combination with an anti-PD-1 in Patients with Advanced 
Solid Tumors 
 
Protocol Number: 
4040-01-001 
 
Protocol Version and 
Date: 
6.0 23 February 2022 (Amendment 5) 
5.0 29 January 2020 (Amendment 4) 
4.0 24 June 2019 (Amendment 3) 
3.0 02 January 2018 (Amendment 2) 
2.0 19 June 2017 (Amendment 1) 
1.0 19 April 2017 (Original) 
Study Drug Name:  
TSR 033 (also known as: encelimab, GSK4074386A) 
Dostarlimab (also known as: TSR 042, GSK4057190A) 
Phase:  
Phase 1 
Methodology:  
Open-Label, Single-Arm 
Sponsor:  
GlaxoSmithKline (Formerly Tesaro, Inc) 
Analysis Plan Date: 
20 Jun 2022 
Analysis Plan Version:  
Version 1.0 
 
 
 
 
Copyright 2022 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorized copying or use of this information is prohibited. 
 


 
C O N FI D E N TI A L  
 
 
2 1 3 3 4 9  
P a g e 2  of 4 9  
 
S P O N S O R SI G N A T U R E  P A G E  
 
Pr ot oc ol Title:  
A P hase 1 D ose Escalati o n a n d C o h ort E x pa nsi o n 
St u d y of T S R -0 3 3,  a n a nti -L A G -3 M o n ocl o nal 
A nti b o d y, al o ne a n d i n c o m bi nati o n wit h a n a nti -P D -1 
i n Patie nts wit h A d va nce d S oli d T u m ors 
Pr ot oc ol N u m ber:  
2 1 3 3 4 9  (4 0 4 0 -0 1 -0 0 1 ) 
S p o ns or:  
Gla x o S mit h Kli ne  
1 2 5 0 S o ut h C oll e g e vill e R o a d  
C oll e g e vill e, P A, 1 9 4 2 6  
 
B y si g ni n g t his d oc u me nt, I ac k n o wle d ge t hat I ha ve rea d t h e d oc u me nt a n d a p pr o ve of 
t he pla n ne d statistical a n al yses d escri b e d herei n. I a gree t h at t he pla n ne d st atistical 
a nal ys es are a p pr o priate f or t his st u d y, are i n acc or da nce wit h t he st u d y o bj ecti ves, a n d 
are c o nsi ste nt wit h t he st atistical met h o d ol o g y des cri be d i n t he pr ot oc ol, cli nical 
de vel o p me nt pla n, a n d all a p plica ble re g ul at or y g ui da nce a n d g ui d eli nes.  
 
A ut h or:  
 
Ass oci ate St atistici a n,  
Gl a x o S mit h Kli ne  
 
 
Si g nat ure:  
Date:  
 
A p pr o ver :  
 
 
 
Gl a x o S mit h Kli ne  
Si g nat ure:  
Date:  
P P D
P P D
P P D


 
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Page 3 of 49 
TABLE OF CONTENTS 
 
TABLE OF CONTENTS ................................................................................................................ 3 
1 
INFORMATION FROM THE STUDY PROTOCOL ................................................... 8 
1.1 
Introduction and Objectives ............................................................................................ 8 
1.1.1 
Introduction ............................................................................................................. 8 
1.1.2 
Study Objectives .................................................................................................... 10 
1.1.3 
Scope and Revision History .................................................................................. 12 
1.2 
Study Design ................................................................................................................. 13 
1.2.1 
Synopsis of Study Design ...................................................................................... 13 
1.2.2 
Study Part 1 ........................................................................................................... 15 
1.2.3 
Study Part 2 ........................................................................................................... 17 
1.2.4 
Randomization Methodology ................................................................................ 17 
1.2.5 
Stopping Rules and Unblinding ............................................................................. 17 
1.2.6 
Study Procedures ................................................................................................... 18 
1.2.7 
Efficacy, Safety, and Pharmacokinetic parameters ............................................... 18 
2 
PATIENT POPULATION ............................................................................................ 19 
2.1 
Population Definitions .................................................................................................. 19 
2.2 
Protocol Deviations ....................................................................................................... 20 
3 
GENERAL STATISTICAL METHODS ..................................................................... 21 
3.1 
Sample Size Justification .............................................................................................. 21 
3.2 
General Methods ........................................................................................................... 22 
3.3 
Baseline Definitions ...................................................................................................... 23 
3.4 
Methods of Pooling Data .............................................................................................. 23 
3.5 
Adjustments for Covariates ........................................................................................... 24 
3.6 
Multiplicity Adjustment ................................................................................................ 24 
3.7 
Subpopulations .............................................................................................................. 24 
3.8 
Withdrawals, Drop-outs, Loss to Follow-up ................................................................. 24 
3.9 
Missing Data ................................................................................................................. 24 
3.10 
Visit Windows .............................................................................................................. 26 
3.11 
Interim Analysis ............................................................................................................ 27 
4 
STUDY ANALYSES ................................................................................................... 27 


 
C O N FI D E N TI A L  
 
 
2 1 3 3 4 9  
P a g e 4  of 4 9  
4. 1  
Partici pa nt Dis p ositi o n  .................................................................................................. 2 7  
4. 2  
De m o gra p hics, Baseli ne C haracteristics a n d Me dical Hist or y  ..................................... 2 7  
4. 3  
Efficac y E val uati o n  ....................................................................................................... 2 8  
4. 3. 1  
Pri mar y Efficac y E n d p oi nt ( O R R)  ........................................................................ 2 8  
4. 3. 2  
Sec o n dar y Efficac y E n d p oi nt  ................................................................................ 3 3  
4. 4  
Safet y E val uati o n  .......................................................................................................... 3 4  
4. 4. 1  
Treat me nt E x p os ure a n d C o m plia nce  .................................................................... 3 4  
4. 4. 2  
A d verse E ve nts  ...................................................................................................... 3 5  
4. 4. 3  
La b o rat or y Data ..................................................................................................... 3 8  
4. 4. 4  
Electr ocar di o gra m  ................................................................................................. 4 0  
4. 4. 5  
C o nc o mita nt Me dicati o ns  ...................................................................................... 4 0  
4. 5  
P K a n d A D A E val uati o n  ............................................................................................... 4 1  
4. 5. 1  
P h ar m ac oki netic A n alyses  ..................................................................................... 4 1  
4. 5. 3  
I m m u n o ge nicit y A nal yses ..................................................................................... 4 4  
4. 7  
A d diti o nal A nal yses D ue t o t he C O VI D -1 9 Pa n de mic  ................................................. 4 5  
5  
C H A N G E S T O P L A N N E D A N A L Y S E S  .................................................................... 4 6  
6  
R E F E R E N C E S  ............................................................................................................. 4 7  
7  
A P P E N DI X  ................................................................................................................... 4 8  
7. 1  
I m m u n e-r el at e d A d v er s e E v e nt s.............................................................................. 4 8  
7. 2  
D efi niti o n of w h e n C O VI D -1 9 P a n d e mic M e as ur es B e g a n  ........................................... 4 9  
 
C CI
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TABLES INCLUDED IN THE TEXT 
TABLE 1 
REVISION HISTORY ........................................................................................................................... 12 
TABLE 2 
RECIST V1.1 RESPONSE CRITERIA OF TARGET LESIONS AT EACH ASSESSMENT ............................................ 29 
TABLE 3 
RECIST V1.1 RESPONSE CRITERIA OF NON-TARGET LESIONS AT EACH ASSESSMENT .................................... 30 
TABLE 4 
RECIST V1.1 OVERALL RESPONSE AT EACH ASSESSMENT FOR PARTICIPANTS WITH MEASURABLE DISEASE AT 
STUDY ENTRY ........................................................................................................................................... 30 
TABLE 5 
RECIST V1.1 OVERALL RESPONSE AT EACH ASSESSMENT FOR PARTICIPANTS WITHOUT MEASURABLE DISEASE AT 
STUDY ENTRY ........................................................................................................................................... 30 
TABLE 6 
RECIST V1.1 BEST OVERALL RESPONSE WHEN CONFIRMATION OF CR AND PR REQUIRED ............................. 31 
TABLE 7 
CENSORING RULES USED IN DOR ANALYSIS ........................................................................................... 33 
TABLE 8 
DERIVED PHARMACOKINETIC PARAMETERS ........................................................................................... 43 


 
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LIST OF ABBRIVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE(s) 
adverse event(s) 
BMI 
body mass index 
BOR 
best overall response 
CI 
confidence interval 
CR 
complete response 
CRC 
colorectal cancer 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
end-of-treatment 
FDA 
Food and Drug Administration 
FUP 
follow-up 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
KM 
Kaplan-Meier  
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 


 
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Abbreviation 
Definition 
PD-1 
programmed cell death-1 receptor 
PD-L1 
programmed death ligand-1 
PD-L2 
programmed death ligand-2 
PDv 
Protocol deviation 
PDy 
pharmacodynamic 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
PT 
preferred term 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TIL 
tumor-infiltrating lymphocytes 
TIM-3 
T-cell immunoglobulin and mucin containing protein-3 
ULN 
upper limit of normal 


 
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1 INFORMATION FROM THE STUDY PROTOCOL 
1.1 Introduction and Objectives 
1.1.1 Introduction 
The recognition of tumors by the immune system has been appreciated for multiple 
decades and has provided an impetus to utilize the immune system to control tumor 
growth. Studies have reported the presence of tumor-infiltrating lymphocytes (TILs) as a 
positive prognostic feature in multiple tumors, supporting a role for the immune system 
in limiting tumor growth. Despite evidence of immune reactivity, tumors are able to grow 
in the presence of an immune system, suggesting a suboptimal innate immune response. 
Emerging research into this inadequate immune response has identified an important 
family of proteins that play key roles in immune checkpoint pathways, regulatory 
cascades that ordinarily maintain immune homeostasis, but are co-opted by cancer cells 
so that they may evade detection and subsequent destruction by the immune system. 
Prominent proteins within this immune checkpoint family include programmed cell death 
receptor (PD-1), associated with immune system downregulation and self-tolerance, and 
lymphocyte activation gene-3 (LAG-3) which is widely associated with exhausted or 
dysfunctional T cells that show varying degrees of functional impairment in the context 
of chronic antigen exposure. 
To date, PD-1 has been a popular development target of anti-cancer therapies. However, 
despite favorable response rates observed with these therapies, there remains a large 
number of patients who derive little clinical benefit from this treatment approach 
(primary resistance) or suffer a relapse post-treatment (acquired or adaptive immune 
resistance). To potentially engender a stronger and more durable anti-tumor response, it is 
thought that a combined treatment approach that targets both PD-1 and LAG-3, 
complementary immune pathways in intrinsic tumor-cell resistance, may be successful. 
This belief is bolstered by internal results in the mixed lymphocyte reaction (MLR) assay 
and efficacy in syngeneic tumor models, which, taken together, provide a rationale for 
combination therapy with anti-PD-1 and anti-LAG-3 antibodies in cancer. 
Two such therapeutic antibodies that target PD-1 and LAG-3 are dostarlimab and TSR-
033, respectively. Dostarlimab is a potent humanized immunoglobulin G4 (IgG4) κ 
monoclonal antibody (mAb) that binds to PD-1 and blocks the interaction between PD-1 
and its ligands, programmed cell death ligand-1 (PD-L1) and programmed cell death 
ligand-2 (PD-L2). The functional antagonist activity of dostarlimab was confirmed in a 
MLR assay demonstrating enhanced interleukin-2 (IL-2) production upon addition of 
dostarlimab. Dostarlimab is being studied as monotherapy and in combination in several 
tumor types to evaluate its safety and tolerability, pharmacokinetics (PK), 
pharmacodynamics (PDy), and clinical activity in participants with advanced or 
metastatic solid tumors. TSR-033 is a potent and selective humanized IgG4κ mAb that 


 
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will undergo dose-limiting studies and safety and tolerability assessment in participants 
with advanced or metastatic solid tumors, both alone and in combination with 
dostarlimab, in Part 1 of this study. 
Colorectal cancer (CRC) is one of the most common malignancies worldwide and 
remains a deadly disease (second most common cause of cancer death in the United 
States [US]) despite current therapeutic options, which include the current standard of 
care (SOC), chemotherapy with or without anti-angiogenic antibodies or anti-epidermal 
growth factor receptor (EGFR) antibodies as first- and second-line regimens. In the US, 
although the incidence rate of CRC in adults aged ≥50 years has declined in recent 
decades, it has increased by 13% in those aged <50 years. In addition, if the disease 
progresses to become metastatic CRC (mCRC), it is usually incurable. While colorectal 
cancers with microsatellite instability are frequently sensitive to check point inhibitor 
therapy, they make up only about 3% of patients with metastatic disease. Unfortunately, 
in contrast to many other areas of cancer therapy, the advances achieved with 
immunotherapy have not yet been replicated in the remaining 97% of patients whose 
mCRC is microsatellite stable CRC (MSS-CRC). Therefore, MSS-CRC remains an area 
of great and urgent medical need. 
Among the cytotoxic chemotherapy choices for CRC, oxaliplatin- and irinotecan-based 
chemotherapy regimens are most commonly utilized, with clinical outcomes improved by 
the addition of biologics targeting EGFR or vascular endothelial growth factor (VEGF) or 
its receptor (VEGFR) in appropriate patients4. With regard to oxaliplatin-based regimens, 
FOLFOX and its variants (ie, modified FOLFOX6 [mFOLFOX6], FOLFOX4) remain 
popular and are used globally. FOLFOX consists of folinic acid (FOL) or leucovorin, 5-
fluorouracil (F), and oxaliplatin (OX). mFOLFOX6, given with or without bevacizumab 
(anti-VEGF mAb), is by far the most commonly used regimen, clinically and in studies, 
for first-line therapy in CRC. An alternative 3-drug combination is FOLFIRI, which 
consists of irinotecan (IRI) in addition to FOL and F.This combination can also be given 
with biologics. While it is generally considered that FOLFOX and FOLFIRI are 
equivalent regimens, particularly with regard to overall survival (OS), the oxaliplatin-
based regimens are utilized more frequently than irinotecan-based regimens in the first-
line metastatic setting globally. In the second-line metastatic setting, a number of 
contemporary trials have established reliable benchmarks for overall response rates and 
progression-free survival (PFS), as well as OS, with FOLFOX- or FOLFIRI-based 
regimens. Taken together, the overall response rate with FOLFOX or FOLFIRI 
chemotherapy with or without biologics appears to be modest in CRC, in the 4% to 15% 
range. 
 
Beyond second-line therapy, TAS-102, an oral fluoropyrimidine analogue and thymidine 
phosphorylase inhibitor, has demonstrated an improvement of OS by 1.8 months in 
participants with refractory disease versus best supportive care (5.3 versus 7.1 months 
[HR 0.68, 95% CI 0.58 to 0.81; p<0.001]). In addition, two anti-EGFR monoclonal 
antibodies, cetuximab and panitumumab, have shown efficacy as monotherapy in the 


 
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third-line setting in participants with KRAS wild type tumors. Monotherapy with the 
anti-angiogenic drug regorafenib has also yielded a modest survival benefit of 1.4 months 
(6.4 versus 5.0 months [HR ratio 0.77; 95% CI 0.64 to 0.94; one-sided p=0.0052). 
Finally, immunotherapy with checkpoint inhibitors as monotherapy appears to be active 
only in patients with microsatellite instability–high (MSI-H) or mismatch repair–deficient 
(dMMR) CRC. Both nivolumab and pembrolizumab are currently approved for MSI-H or 
dMMR CRC that has progressed following treatment with fluoropyrimidine, oxaliplatin, 
and irinotecan. In summary, the current treatment options in first- through fourth-line 
CRC, their response rates, and the growing knowledge around subtypes of CRC patients, 
highlight the need for more efficacious therapeutics and support the decision to study 
TSR-033 and dostarlimab combination therapy in MSS-CRC. 
The purpose of Part 2A of the study is to assess the safety and initial efficacy of the 
combination of TSR-033 and dostarlimab in third- or fourth-line MSS-CRC. Part 2B will 
assess the safety profile and initial efficacy of mFOLFOX6 (Cohort B1) or FOLFIRI 
(Cohort B2) plus bevacizumab in combination with TSR-033 and dostarlimab in 
participants with second-line MSS-CRC who have progressed on a prior first-line 
regimen.  
1.1.2 Study Objectives 
The primary objectives of this study are as follows: 
Part 1: Dose Escalation Cohorts (1a, 1b, and 1c): 
• To define the recommended Phase 2 dose (RP2D) and schedule of TSR-033 as 
monotherapy (1a, 1b) and in combination with dostarlimab (1c). 
• To evaluate the safety and tolerability (eg, number of patients experiencing DLTs, 
AEs/serious adverse events [SAEs]/irAEs, and abnormal hematology/clinical 
chemistry results) of TSR-033 as monotherapy (1a, 1b) and in combination with 
dostarlimab (1c) in patients with advanced or metastatic solid tumors 
           Part 2A: CRC Dose Expansion Cohort A: 
• To evaluate the anti-tumor activity of TSR-033 in combination with dostarlimab 
in anti-PD(L)-1 naïve patients with advanced or metastatic MSS-CRC who have 
progressed following 2 or 3 prior lines of therapy as measured by objective 
response rate (ORR) assessed by the Investigators using Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1. 
         Part 2B: CRC Dose Expansion Cohorts B1 and B2: 
• B1:  
To evaluate the safety and tolerability (eg, number of patients experiencing DLTs, 
AEs/SAEs/irAEs, and abnormal hematology/clinical chemistry results) of TSR-


 
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0 3 3 a n d d ostarli ma b i n c o m bi nati o n a d de d t o m F O L F O X 6 a n d be v aciz u ma b i n 
a nti-P D -1 -naï ve p atie nts wit h a d va nce d or metastatic M S S -C R C f oll o wi n g 
pr o gressi o n o n fr o n tli ne treat me nt wit h F O L FI RI ( or varia nt), wit h or wit h o ut 
bi ol o gics.  
•  B 2:  
T o e val uate t he s afet y a n d t olera bilit y (e g, n u m ber of patie nts e x perie nci n g D L Ts, 
A Es/ S A Es/ir A Es, a n d a b n or mal he mat ol o g y/ cli nical c he mistr y res ults) of T S R -0 3 3 a n d 
d ostarli ma b i n c o m bi nati o n a d de d t o F O L FI RI a n d be vaciz u ma b i n a nti -P D -1 -naï ve 
patie nts wit h a d va nce d or metastatic M S S -C R C f oll o wi n g pr o gressi o n o n fr o ntli ne 
treat me nt wit h F O L F O X ( or varia nt), wit h or wit h o ut bi ol o gics. 
T he sec o n d ar y o bjecti ves  (i n Part 1 a n d Part 2, u nless ot her wise s pecifie d)  of t he st u d y 
are as f oll o ws:  
•  T o c haracteriz e t he P K (e g, ser u m c o nce ntrati o ns f or Part 1 a n d Part 2 a n d 
deri ve d P K para meters f or Part 1, as data per mit) a n d i m m u n o ge nicit y of T S R -
0 3 3 al o ne, T S R -0 3 3 a n d d ostarli ma b i n c o m bi nati o n , a n d T S R-0 3 3 a n d 
d ostarli ma b i n c o m bi nati o n wit h c he m ot hera p y a n d be vaciz u ma b.  
•  T o e val uate a d diti o nal meas ures of cli nical be nefit, i ncl u di n g  
o  O R R b y R E CI S T v 1. 1 ( P art 1 a n d Part 2 B)  
o  D urati o n of res p o ns e ( D O R) b y R E CI S T v 1. 1 ( P art 2)  
o  Disease c o ntr ol rate ( D C R) b y R E CI S T v 1. 1 ( Part 2) 
 
•  B 1:  
T o e val uate t he a nti -t u m or acti vit y of T S R-0 3 3 a n d d ostarli ma b a d de d t o m F O L F O X 6 
a n d be vaciz u ma b i n patie nts wit h a d va nce d or m etastatic M S S -C R C f oll o wi n g 
pr o gressi o n o n fr o ntli ne treat me nt wit h F O L FI RI, wit h or wit h o ut b i ol o gics, meas ure d b y 
t he O R R as assesse d b y t he i n vesti gat or usi n g R E CI S T v 1. 1. 
•  B 2:  
T o e val uate t he a nti -t u m or acti vit y of T S R-0 3 3 a n d d ostarli ma b a d de d t o F O L FI RI a n d 
be vaciz u ma b i n patie nts wit h a d va nce d or metastatic M S S -C R C f oll o wi n g pr o gressi o n o n 
fro ntli ne treat me nt wit h F O L F O X ( or varia nt), wit h or wit h o ut bi ol o gics, meas ure d b y 
t he O R R as assesse d b y t he i n vesti gat or usi n g R E CI S T v 1. 1.  
C CI


 
C O N FI D E N TI A L  
 
 
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P a g e 1 2  of 4 9  
1. 1. 3  Sc o pe a n d Re visi o n Hist or y  
T his statistical a nal ysis pla n ( S A P) is desi g ne d t o o utli ne t he met h o ds t o be use d i n t he 
a nal ys es of st u d y data  i n or der t o a ns w er t he st u d y o bjecti ves. Partici pa nt  p o p ulati o ns t o 
be use d f or a nal yses, d ata ha n dli n g r ules, statistical met h o ds, a n d f or mats f or data 
prese ntati o n are i de ntifie d a n d pr o vi de d. T he statistical a nal yses a n d s u m m ar y ta b ulati o ns 
descri be d i n t his S A P will pr o vi de t he basis f or t he res ults secti o ns of t he cli nical st u d y 
re p ort ( C S R) f or t his trial. 
T h e S A P will o utli ne a n y differe n ces i n t he c urre ntl y pla n ne d a nal ytical o bj ecti ves 
relati ve t o t h ose pla n ne d i n t he st u d y pr ot oc ol. 
T he S A P is a li vi n g d oc u me nt t hat will be creat e d d uri n g t he tri al c o n d uct. It will be 
mai ntai ne d t hr o u g h o ut t h e lifec ycl e of t he trial. A w or ki n g S A P ( versi o n 1. 0) will be 
fi nalize d t o start pr o gra m mi n g acti vities. I m p orta nt c ha n ges f oll o wi n g a p pr o val of S A P 
v 1. 0 will  be trac ke d i n t his secti o n. A fi nal versi o n of t he S A P will be si g n e d off pri or t o 
t he fi nal data bas e l oc k. A n y c h a n ges t o t he met h o ds descri be d i n t he pla n will be 
descri be d a n d j ustifie d i n t he fi nal C S R.  
A ll P K data will be s u m marize d descri pti vel y a n d dis pla ye d i n t he listi n gs ass ociate d 
wit h t his S A P.  
T a ble 1  
Re visi o n Hist or y  
S A P versi o n  
Pr ot oc ol versi o n  
e C R F versi o n  
C ha n ges fr o m 
pre vi o us versi o n  
1. 0  
6 . 0 
1 6 A pril 2 0 2 0  
N/ A  
C CI


 
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P a g e 1 3  of 4 9  
1. 2  St u d y Desi g n  
1. 2. 1  S y n o psis of St u d y Desi g n  
T his is a m ulti -ce nter, o p e n -la bel, first-i n-h u ma n, P hase 1 st u d y e v al uati n g t he a nti -L A G -
3 a nti b o d y T S R -0 3 3 1) al o ne, 2)  i n c o m bi nati o n wit h t he a nti-P D 1 a nti b o d y d ostarli ma b, 
a n d 3) t he c o m bi nati o n of T S R-0 3 3 a n d d ostarli ma b wit h m F O L F O X 6 or F O L FI RI a n d 
be vaciz u ma b. T he st u d y will be c o n d ucte d i n 2 parts, wit h Part 1 c o nsisti n g of d ose 
escalati o n t o deter mi ne t he R P 2 D of T S R -0 3 3 as a si n gle a ge nt ( Part 1 a) a n d i n 
c o m bi nati o n wit h d ost arli ma b ( Part 1c). R P 2 D decisi o ns will be base d o n t he occ urre n ce 
of D L Ts or P K 
 d ata, as a vaila ble. Part 1 b of t he st u d y will ai m t o better c haracterize 
t he P K pr ofile of T S R-0 3 3 
. T hese 
a d diti o nal partici pa nts  will n ot be c o nsi dere d e v al ua ble f or d ose escalati o n p ur p oses (ie, 
n ot i ncl u de d i nt o t he D L T -e val ua bl e p o p ulati o n) b ut will c o ntri b ute t o t he o verall safet y 
assess me nt at t he d ose le vel bei n g e val uate d. I n Part 2, t hese re gi me ns will be e val uat e d 
i n partici pa nts  wit h a d va nce d or metast atic M S S -C R C w h o ha ve li mite d a vaila ble 
treat me nt o pti o ns as deter mi ne d b y t he I n vesti gat or. 
Part 2 A of t he st u d y will i n vesti gate t he a nti -t u m or acti vit y of T S R-0 3 3 a n d d ostarli ma b 
i n c o m bi nati o n i n partici pa nts  wit h a d va nce d or metastatic M S S -C R C. W hile t he pri mar y 
o bjecti ve of t his part of t he st u d y is O R R b y I n vesti gat or ass ess me nt, c o pi es of sca ns will 
be c ollecte d a n d st ore d at a re p osit or y f or p ote ntial e val uati o n . 
Part 2 B of t he st u d y will i n vesti gate t he s afet y a n d a nti -t u m or acti vit y of T S R-0 3 3 a n d 
d ostarli ma b i n c o m bi nati o n wit h c he m ot hera p y ( C o h ort B 1: m F O L F O X 6, C o h ort B 2: 
F O L FI RI) a n d be vaciz u ma b i n partici pa nts  wit h a d va nce d or metastatic M S S -C R C. As 
t he pri mar y o bjecti ve of t his part of t he st u d y will be safet y, b ot h Part 2 B C o h orts will 
be gi n b y e nr olli n g 6 p arti ci pa nts  eac h, wit h e nr oll me nt bei n g p a use d u ntil t he e n d of t he 
D L T o bs er vati o n peri o d bef ore a n y f urt h er e nr oll me nt i n t his ar m. W hile t he sec o n dar y 
o bjecti ve of t his part of t he st u d y is O R R b y I n v esti gat or ass ess me nt, c o pi es of sca ns will 
be c ollecte d a n d st ore d at a re p osit or y f or p ote ntial e val uati o n.  
T o xicities will be assesse d acc or di n g t o C o m m o n Ter mi n ol o g y Criteri a f or A d verse 
E ve nts ( C T C A E) v 5. 0.  
T he st u d y will be c o n d ucte d i n c o nf or ma nce wi t h G o o d Cli nical Practice ( G C P). 
T he desi g n sc he ma prese nte d bel o w (starti n g d oses f or Part 1 b, Part 1c, a n d Part 2 are 
c o nti n ge nt o n safet y fi n di n gs i n earlier c o h orts).  
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2 1 3 3 4 9  
P a g e 1 4  of 4 9  
Fi g ure 1  
St u d y Desi g n Sc he m a  
 
A b bre viati o ns: C R C = c ol orectal ca ncer; D L T = d ose -li miti n g t o xicit y; m g = milli gra ms; 
P D y = p h ar mac o d y na mics; P K = p har mac o ki netics; Q 2 W = e ver y 2 wee ks; Q 3 W = e ver y 
3 wee ks; Q 6 W = e v er y 6 wee ks; R P 2 D = rec o m me n de d P hase 2 d ose  
a. A p pr o xi matel y 7 2 p artici pa nts  i n Parts 1a, 1 b a n d 1c are e x pecte d, b ut t his ma y 
i ncreas e t o a p pr o xi matel y 1 3 2 partici pa nts  i n t otal if t he s p o ns or a n d i n vesti gat ors 
deter mi ne t hat a d diti o nal safet y a n d/ or P K 
 data are n ee de d t o c o nfir m t he 
R P 2 D f or m o n ot hera p y. T hese e nr oll me nt n u m b ers c o ul d i ncrease if t he S p o ns or, 
i n c o ns ultati o n wit h t he I n vesti gat or, d eter mi ne t h at a d diti o nal c o h orts c o nsisti n g 
of 6 -1 2 partici pa nts  are n ee de d t o e xa mi ne a d diti o nal d ose le vels. At a n y d ose 
le vel, w here D L Ts w ere o bser ve d i n less t ha n ⅓ of partici p a nts, i n Part 1 b, u p t o 6 
a d diti o nal partici pa nts  ma y b e e nr olle d t o e na ble a better c h aracterizati o n of t he 
P K 
 d ata i n or d er t o c o nfir m t he R P 2 D. T hese e nr oll me nt n u m bers c o ul d 
f urt her i ncreas e if t he S p o ns or, i n c o ns ultati o n wit h t he I n v esti gat ors deter mi ne 
t hat a n i nter me diate d ose le vel(s), c o nsisti n g of a p pr o xi matel y 6 p artici pa nts  
re q uires e x pl orati o n t o better u n dersta n d P K 
. 
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2 1 3 3 4 9  
P a g e 1 5  of 4 9  
b.  T he starti n g d os e of T S R -0 3 3 w he n use d i n c o m bi nati o n wit h d ostarli ma b m ust 
be o ne d ose le v el bel o w t he hi g h est d ose at  w hic h < ⅓ of 6 -1 2 partici pa nts  
e x perie nce d D L Ts wit h si n gle -a ge nt T S R -0 3 3.  
c. D oses prese nt e d i n t he sc he ma re prese nt t he pla n ne d T S R -0 3 3 d ose le vels 
(s u bject t o c ha n ge base d o n safet y a n d/ or P K 
 data). d ostarli ma b will b e 
gi ve n at a d ose of 5 0 0 m g ( Q 3 W) i n Part 1c a n d 1 0 0 0 m g Q 6 W i n Part 2 of t he 
st u d y. T hes e e nr oll me nt n u m bers c o ul d i ncrease if t he S p o ns or, i n c o ns ultati o n 
wit h t he I n v esti gat or, det er mi ne t hat a d diti o nal c o h orts c o nsisti n g of 6 -1 2 
partici pa nts  are nee d e d t o e x a mi ne a d diti o nal d ose le vels.  
d.  Part 2 will e nr oll 2 disease -s pecifi c c o h orts: C o h ort A (t hir d- or f o urt h -li ne M S S-
C R C) a n d C o h ort B (sec o n d -li ne M S S-C R C). T he o pe ni n g of e nr oll me nt of t he 
e x pa nsi o n c o h orts ma y n ot be si m ulta ne o us a n d is de pe n de nt o n e m er gi n g data 
fr o m o n g oi n g st u dies. 
1. 2. 2  St u d y P art 1  
St u d y Part 1 c o nsists of t hree sta ges: Part 1a, Part 1 b, a n d Part 1c.  
Part 1a ( m o n ot hera p y d ose escal ati o n) will e val uate T S R -0 3 3 at asce n di n g d oses ( 2 0 m g, 
8 0 m g, a n d 2 4 0 m g). A hi g her d os e le vel of 7 2 0 m g, or i nter me diate d ose l e vels ma y b e  
e x pl ore d, if warra nte d base d o n tar get e x p os ure a n d safet y fi n di n gs. T S R -0 3 3 will be 
a d mi nistere d via 3 0 -mi n ute, I V i nf usi o n Q 2 W. T he D L T o bser vati o n peri o d i n Part 1a is 
defi ne d as 2 8 d a ys, e nc o m passi n g 2 Q 2 W a d mi nistrati o ns of T S R -0 3 3.  
C o h orts will be e nr olle d se q ue ntiall y a n d will i nitiall y f oll o w a 3 + 3 desi g n at a starti n g 
d ose of 2 0 m g, as deter mi ne d b y precli nical s afet y a n d p har mac ol o g y st u di es. I nitiall y, 3 
partici pa nts  will be a d mi nistere d T S R -0 3 3, a n d d ose escal ati o n or e x pa nsi o n t o 6 
partici pa nt s will be c o nsi dere d after all 3 partici pa nts  at t he 2 0-m g le vel ha ve c o m plete d 
t he D L T o bser vati o n peri o d a n d are f o u n d t o be e v al ua ble f or s afet y u p o n re vie w of 
safet y data c o n d ucte d b y t he I n v esti gat ors a n d S p o ns or. I n s u bse q ue nt d ose le vels, 6 
partici p a nts will i nitiall y be e nr olle d i nt o eac h c o h ort t o e val uate as ce n di n g d oses of 
T S R -0 3 3. At a n y d ose l e vel w here D L Ts are o bser ve d i n ⅓ of partici pa nts , u p t o 6 
a d diti o nal partici pa nts  ma y b e e nr olle d i n t hat d os e le vel. T he p ote ntial e nr oll me nt of 
a d diti onal partici pa nts  will ta ke place f oll o wi n g disc ussi o n wit h t he I n v esti gat ors, t a ki n g 
i nt o acc o u nt se verit y a n d d urati o n of o bser ve d D L Ts as well as t he o verall safet y of a 
d ose le vel.  
At a n y d os e le vel, a n i nitial 3 or 6 partici pa nts  will be e nr olle d, t he n : 
•  If t he o bser ve d D L T rate is < ⅓, t he d ose ma y be escalate d. 
•  If t he o bser ve d D L T rate is > ⅓, n o f urt her d ose es calati o n will be c o nsi dere d, a n d 
t his d ose le vel will be c o nsi dere d t he ma xi m u m a d mi nistere d d ose ( M A D). 
•  If t he o bser ve d D L T rate is ⅓, t he S p o nsor ma y e nr oll u p t o 6 a d diti o nal 
partici pa nts  f oll o wi n g dis c ussi o n wit h t he I n v esti gat ors. 
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C O N FI D E N TI A L  
 
 
2 1 3 3 4 9  
P a g e 1 6  of 4 9  
-  If t he o bser ve d D L T rate i n a t otal c o h ort of 9 t o 1 2 partici pa nts  is > ⅓, n o f urt her 
d ose escal ati o n will be c o nsi dere d, a n d t his d ose l e vel will be c o nsi dere d t he 
M A D.  
T he M T D will be c o nsi d ere d t he d os e o ne le vel bel o w t he M A D if ≥⅓ of partici pa nts  
e x perie nce D L Ts, or, at M A D if < ⅓ of p artici pa nts  e x perie nce D L Ts.  
Acc or di n gl y, t he R P 2 D ma y b e at t he M A D or 1 d ose le vel bel o w t he M A D. 
Alter nati vel y, a n i nter me diate d ose le vel bel o w t h e M A D ma y be i ntr o d uce d a n d 
assesse d f or D L Ts. D ose escalati o n will c o nti n ue u ntil t he R P 2 D is i de ntifie d or ma y be 
st o p pe d at a n y d ose le v el base d o n e mer gi n g s afet y a n d P K 
 data, s u bj ect t o 
a gree m e nt bet wee n t he I n vesti gat ors a n d  S p o ns or. A R P 2 D will b e d efi n e d as t h e d ose 
wit h D L Ts o bser ve d i n < ⅓ of at least 6 partici p a nts  a n d desire d P K  
 
c haracteristics as d eter mi ne d b y t h e S p o ns or, i n a gree me nt wit h t he I n v esti gat ors. A 
partici pa nt  will be c o nsi d ere d n o n -e val ua bl e if, f or a n y reas o n ot h er t ha n safet y, t h e 
partici pa nts  is u na ble t o c o m plete t he D L T o bser vati o n peri o d, or if t he P K assess me nts 
were i ns ufficie nt t o defi n e t he P K pr ofile. Partici p a nts  i n Part 1a c o nsi dere d n o n-
e val ua ble ma y b e re pl ace d after c o ns ultati o n bet wee n t he I n v esti gat ors a n d S p o ns or.  
Part 1 b (P K 
 C o h ort ): T o better c haract erize t he P K pr ofile 
 fr o m 
bl o o d a n d t u m or tiss ue sa m ples f oll o wi n g T S R -0 3 3 treat me nt, a n a d diti o nal c o h ort of 
partici pa n ts ( u p t o 6 parti ci pa nts  per d ose le vel) m a y s u bs e q ue ntl y be e nr olle d at a d ose 
le vel wit h D L Ts o bser ve d i n < ⅓ of partici pa nts . T he p ote ntial e nr oll me nt of a d diti o nal 
partici pa nts  will ta ke pla ce f oll o wi n g disc ussi o n wit h t he I n v esti gat ors, ta ki n g i nt o 
acc o u nt se v erit y a n d d urati o n of o bser ve d D L Ts, as well as t he o verall safet y of a d ose 
le vel. T hese p artici pa nts  will be gi n treat me nt wit h T S R -0 3 3 o n Da y 1, f oll o we d b y o n -
treat me nt visits d uri n g t h e f oll o wi n g 2 8 d a ys f or s afet y assess m e nts a n d bl o o d sa m pli n g 
f or P K 
. Partici p a nts  will recei ve t heir s ec o n d d ose of T S R -0 3 3 o n Da y 2 9 a n d e ver y 
1 4 da ys t h ereafter ( Q 2 W). T hese a d diti o nal partici pa nts  will n ot be c o nsi dere d e val u a ble 
f or d ose es calati o n p ur p oses (ie, n ot i ncl u de d i nt o t he D L T-e v al ua ble p o p ul ati o n), b ut 
will c o ntri b ute t o t he o verall safet y ass ess me nt at t he d ose le vel bei n g e val u ate d  
 
Partici pa nts  e nr olle d i n t his c o h ort are re q uire d t o ha ve t u m or tiss ue a vaila ble (arc hi val or 
ne wl y o bt ai ne d bi o ps y) pri or t o start of st u d y tr eat me nt a n d m ust c o nse nt t o u n der g o 
a d diti o nal t u m or bi o ps y a p pr o xi matel y 4 t o 6 wee ks after i nitiati n g st u d y tr eat me nt, a n d 
at t he e n d of tr eat me nt ( E O T) visit (f or partici pa nts  wit h pr o gressi ve dise as e [ P D]). 
Part 1c  (T S R -0 3 3 i n C o m bi nati o n wit h d ostarli ma b ):  T he starti n g d ose of T S R -0 3 3 w he n 
use d i n c o m bi nati o n wit h d ostarli ma b m ust be 1 d ose le vel bel o w t he hi g hest d ose at 
w hic h < ⅓ of at least 6 partici pa nts  e x perie nce d D L Ts wit h si n gle a ge nt T S R -0 3 3.  
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TSR-033 will be administered with dostarlimab Q3W throughout Part 1c, and 
participants will receive dostarlimab at a dose of 500 mg in combination with ascending 
doses of TSR-033 Q3W. The starting dose of TSR-033 when used in combination with 
dostarlimab must be one dose level below the highest dose at which <⅓ of participants 
experienced DLTs with single-agent TSR-033. Planned dose levels of TSR-033 include 
80 and 240 mg. A higher dose level of 720 mg Q3W may be explored if warranted based 
on target exposure and safety findings. Additional cohorts consisting of 6-12 participants 
are needed to examine additional dose levels may also be explored if warranted following 
agreement between the Investigators and Sponsor. dostarlimab at a dose of 1000 mg may 
also be tested with the RP2D of TSR-033 given on a Q6W schedule. For all 
administrations of the combination regimen, TSR-033 will be given first, followed by 
dostarlimab. 
1.2.3 Study Part 2 
Part 2 will commence using the RP2D established for the combination regimen in Part 1c 
of the study. Study treatment in Part 2 will be administered on a Q2W schedule for TSR-
033 and a Q6W schedule for dostarlimab. In Part 2B, TSR-033 and dostarlimab will be 
administered on Day 3 of a dose cycle following chemotherapy and bevacizumab therapy 
on Day 1 of a dose cycle. 
The expansion cohorts will evaluate the preliminary activity of TSR-033 in combination 
with dostarlimab in anti-PD-1 naïve participants with a specific tumor type as follows: 
• Cohort A – Third- and fourth-line MSS-CRC 
• Cohorts B1 and B2 – Second-line MSS-CRC 
For Cohorts B1 and B2, if within 12 weeks of initiating study treatment, delayed irAEs 
consistent with DLT criteria occur in ≥⅓ of participants at a particular dose level, a lower 
dose level will be considered by the Sponsor following discussion with study 
Investigators for: 
• Further refinement of RP2D and dose for expansion cohorts and/or 
• All participants on treatment if in the best interest of the participant 
1.2.4 Randomization Methodology 
Randomization is not applicable in this study.  
1.2.5 Stopping Rules and Unblinding 
Prespecified stopping rules are included for dose escalation in Part 1 as per the modified 
3+3 design.  
Unblinding is not applicable as this is an open-label uncontrolled study with dose 
escalation in Part 1 and parallel single-arm cohorts in Part 2.   


 
C O N FI D E N TI A L  
 
 
2 1 3 3 4 9  
P a g e 1 8  of 4 9  
1. 2. 6  St u d y Pr oce d ures  
Refer t o t he latest pr ot o c ol a me n d me nt f or t he  sc h e d ule of assessm e nts . 
1. 2. 7  Effic ac y, S afet y, a n d P h ar m ac o ki netic p ar a meters  
1. 2. 7. 1  Pri m ar y p ar a meters  
St u d y Part 1  
•  D L Ts  of T S R -0 3 3   
•  D L Ts of T S R -0 3 3 i n c o m bi nati o n wit h d ostarli ma b   
T he ma xi m u m t olerate d d ose ( M T D) is defi ne d as t he hi g hest d ose o bs er ve d i n at least 6 
partici pa nts  wit h D L Ts i n less t ha n o ne -t hir d of p artici pa nts  t hr o u g h o ut t he D L T 
o bser vati o n peri o d.   
T he R P 2 D will be base d o n t he D L Ts, o verall safet y, a n d P K 
 data of T S R -0 3 3  as a 
m o n ot hera p y a n d i n c o m bi nati o n wit h d ostarli ma b . T he R P 2 D d ose of T S R-0 3 3  as a 
m o n ot hera p y ma y differ fr o m t he R P 2 D d ose use d i n c o m bi nati o n.  
St u d y Part 2  
•  2 A: O R R usi n g R E CI S T v 1. 1 base d o n In vesti gat or assess me nt  
•  2 B 1 a n d 2 B 2: D L Ts  
O bjecti ve res p o ns e rat e (O R R ) is defi ne d as t he pr o p orti o n of partici pa nts  w h o se best 
o bjecti ve res p o nse ( B O R)  is a c o nfir me d C R or c o nfir me d P R.   
B O R is defi ne d as t he best res p o nse bet wee n t he date of first d ose a n d t he date of first 
d oc u me nte d pr o gressi o n or t he date of s u bs e q ue nt a nti -ca ncer t hera p y or t h e date of 
deat h , w hic he v er occ urs first. F or partici pa nts  wit h o ut d oc u me nte d pr o gressi o n or 
s u bse q ue nt a nti-ca n cer t hera p y a n d ali ve at t he ti m e of a nal ysis, all a v aila ble res p o nse 
data will c o ntri b ute t o t he B O R  det er mi nati o n.  
1. 2. 7. 2  Sec o n d ar y p ar a meters  
Efficac y  para meters    
I n Part 1 a n d Part 2, u nless ot her wise s pecifi e d: 
•  O R R b y R E CI S T v 1. 1  ( P art 1 a n d Part 2 B ) 
•  D O R, D C R  
 
F or partici pa nts  wit h c o nfir me d C R or P R, D O R is defi ne d as t he ti me fr o m first 
d oc u me nte d  res p o ns e u ntil t he ti me of first d oc u me ntati o n of disease pr o gressi o n  or 
deat h, w hic he v er occ urs first . Ce ns ori n g r ules of D O R are s u m marize d i n Secti o n 4  
(Ta ble 5 ). F or p artici pa nts  wit h sta ble disease ( S D) as B O R, d urati o n of sta ble disease 
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(DOSD) is defined as the time from the date of first dose to the date of the first 
documented tumor progression or death, whichever occurs first. Censoring rules will be 
the same as for DOR analysis.    
DCR is defined as the proportion of participants whose BOR is a confirmed CR, 
confirmed PR, or SD. According to the protocol, SD is defined as to meet a minimum 
duration of 12 weeks (+/- 14 days) from the date of first dose. 
Safety parameters  
• DLTs 
• Treatment emergent adverse events (TEAE) 
• Changes in clinical laboratory parameters (hematology, chemistry, thyroid 
function) 
• ECOG performance status 
• ECG parameters 
• Concomitant medications 
• Immunogenicity: anti-TSR-033 antibodies 
1.2.7.3 PK parameters 
• Serum PK AUC from time 0 to last assessment (AUC0-last), AUC from time 0 to 
infinity (AUC0-∞), AUCtau, minimum concentration (Cmin), maximum 
concentration (Cmax), clearance (CL), volume of distribution (Vz), volume of 
distribution at steady state (Vss) and terminal half-life (t1/2), if data permit. 
2 PATIENT POPULATION 
2.1 Population Definitions 
Analysis populations will be defined as follows for Part 1 and Part 2, respectively: 
• Screened Population: All participants who were screened for eligibility. 
• Enrolled Population: All participants who sign the informed consent and 
entered the study. Screening failures (who never passed screening even if 
rescreened) are excluded from the Enrolled analysis set as they did not enter 
the study.  
• Safety Population: All participants who receive any amount of any study drug 
(TSR-033, TSR-042, mFOLFOX6 or FOLFIRI).  
• Efficacy Population: All participants who receive any amount of TSR-033.  
• DLT Evaluable Population: The assessment of DLTs in Part 1a, Part 1c, and 
Part 2B will include only those participants completing the DLT observation 
period throughout the course of 2 TSR-033 administrations (ie, Day 1 and 
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TSR-033 + dostarlimab administrations (ie, Day 1 and Day 21 in the first 42 
days of study treatment) for Part 1c, the course of 2 TSR-033 + dostarlimab 
administrations (ie, Day 3 and Day 17 in the first 30 days of study treatment) 
unless the participant discontinued TSR-033 (Part 1a) or TSR-033 + 
dostarlimab (Part 1c and Part 2B) due to a DLT. 
• Per Protocol Population: All participants in the Efficacy Population who have 
no major (i.e. important) protocol violations during the study and have ≥1 
post-baseline disease assessment. 
This population may be used for the efficacy assessment of cohort 2A after 
reviewing important protocol deviations during DBR. 
• Pharmacokinetic (PK) Population: All participants who receive any amount of 
TSR-033 and/or dostarlimab and have at least 1 measurable drug 
concentration.  
• Immunogenicity (ADA) Population: The immunogenicity population includes 
all participants who receive at least 1 dose of TSR-033 and who have at least 
1 ADA sample with a result. 
2.2 Protocol Deviations 
Protocol deviations (PDv) will be assessed and classified as important per Sponsor’s 
SOP.  If a reported PDv does not meet classification criteria for importance, the PDv will 
be reported as a protocol deviation without a classification. 
• A PDv is classified as important if it is confirmed to adversely impact the 
completeness, accuracy, and/or reliability of the study data, or affect a subject’s 
rights, safety, or well-being.  
All PDvs will be identified and finalized prior to database lock. Important PDvs would 
result in a participant being excluded from the PP population. 
Examples of important protocol deviations and any action to be taken regarding the 
exclusion of participants or affected data from specific analyses are outlined below.   
Significant Protocol Deviation (Example)  
Population Exclusions 
Failed to meet eligibility criteria but entered study 
Exclude from PP 
Non-compliant with study medication other than as 
allowed by protocol 
Exclude from PP 
Took prohibited concomitant medication that impacts 
efficacy 
Exclude from PP 
The following PDv outputs will be provided using the Enrolled population: 


 
C O N FI D E N TI A L  
 
 
2 1 3 3 4 9  
P a g e 2 1  of 4 9  
•  N u m ber a n d p erce nta ge of partici pa nts  wit h a n  i m p orta nt pr ot oc ol de viati o n b y 
t y pe of de viati o n. 
•  N u m ber a n d p erce nta ge of partici pa nts  wit h a n i m p orta nt pr ot oc ol de viati o n b y 
relati o ns hi p (relat e d, n ot relate d) t o C O VI D-1 9 p a n de mic  
•  A listi n g of all pr ot oc ol d e viati o ns  
•  A listi n g of all n o n -i m p orta nt C O VI D -1 9 relate d pr ot oc ol de viati o ns  
3  G E N E R A L S T A TI S TI C A L M E T H O D S  
3. 1  S a m ple Size J ustific ati o n  
Asce n di n g d oses of T S R -0 3 3 i n Part 1a a n d i n c o m bi nati o n wit h d ostarli ma b i n Part 1c 
will be e val uate d t o i de ntif y t he res pecti ve R P 2 Ds. T he act ual n u m ber of partici pa nts  
accr ue d d uri n g t his p hase will be deter mi ne d lar gel y b y t he safet y a n d P K fi n di n gs 
o b ser ve d d uri n g t he c o urse of t heir treat me nt. R P 2 D decisi o ns f or Part 1 a a n d Part 1c will 
be base d o n a mi ni m u m of 6 partici pa nts  f or eac h re gi me n. Partici pa nts  i n Part 1 b 
( P K 
 c o h ort) will n ot be c o nsi dere d e val u a ble f or d ose es calati o n p ur p oses (ie, n ot 
i ncl u de d i nt o t he D L T-e v al ua ble p o p ulati o n), b ut will c o ntri b ute t o t he o verall safet y 
assess me nt at t he d ose le vel bei n g e val uate d. It is e x pecte d t hat u p t o a p pr o xi matel y 1 3 2 
partici pa nts  will be e nr olle d i n Part 1 as f oll o ws:  
Part 1a ( T S R -0 3 3 m o n ot her a p y d ose escal ati o n): A p pr o xi matel y 3 0 -5 4 partici pa nts  
Part 1 b ( T S R -0 3 3 m o n ot hera p y P K 
 c haract erizati o n): A p pr o xi matel y 1 8 -3 0 
partici pa nts  
Part 1c ( T S R -0 3 3 + d ostarli ma b c o m bi nati o n d ose escalati o n): A p pr o xi matel y 2 4 -4 8 
partici pa nts  
A t otal of u p t o a p pr o xi matel y 5 5 p artici pa nts  are a ntici pate d i n t he e x pa nsi o n c o h orts i n 
Part 2.  
Part 2 A ( T S R -0 3 3 + d ostarli ma b c o m bi nati o n d ose e x pa nsi o n i n a nti -P D -1 -naï ve t hir d - 
or f o urt h -li ne M S S-C R C partici pa nts ): A n ull h y p ot hesis of O R R 1 0 % will be teste d 
a gai nst a n alter nati ve h y p ot hesis of O R R 2 5 %. T he trial is desi g n e d usi n g a o ne -si de d 
e x act test t hat ac hie ves a mi ni m u m of 8 0 % p o wer at al p ha le vel of 0. 1. A sa m ple siz e of 
3 1 will pr o vi de a n attai ne d p o wer o f 8 2. 4 % a n d a n attai ne d t y p e-1 err or of 0. 0 8 3. T he 
n ull h y p ot hesis will be rejecte d if 6 or m or e res p o nses are o bs er ve d i n t he 3 1 partici pa nts . 
Part 2 B ( T S R -0 3 3 + d ost arli ma b c o m bi nati o n gi v e n wit h m F O L F O X 6 or F O L FI RI a n d 
be vaciz u ma b [ S O C] i n a nti -P D -1 -naï ve sec o n d -li ne M S S-C R C partici pa nts ): A n ull 
h y p ot hesis of O R R 2 0 % will be teste d a gai nst a n alter nati ve h y p ot hesis of O R R 4 0 %. 
T he trial is desi g n e d usi n g a o n e -si de d e x act test t hat ac hie ves a mi ni m u m of 8 0 % p o wer 
at al p ha le vel of 0. 1. A sa m ple siz e of 2 4 will pr o vi de a n attai ne d p o wer of 8 0. 8 % a n d a n 
C CI
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attained type-1 error of 0.089. The null hypothesis will be rejected if 8 or more responses 
are observed in the 24 participants. 
3.2 General Methods 
All descriptive statistics and statistical analyses will be performed using the most recently 
released and available SAS statistical software, unless otherwise noted. All outputs will 
be incorporated into Microsoft Word or Excel files or Adobe Acrobat PDF files, sorted 
and labeled according to the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) recommendations, and 
formatted to the appropriate page size(s). 
Tables, listings, and figures will display data overall and by dose level, separately for 
each part in the following order unless otherwise specified: Part 1ab, Part 1c, Part 2A, 
Part 2B1, and Part 2B2.  
All safety analyses will be performed for any participant who received any amount of any 
study drug. All analyses for efficacy will use Dose 1, Day 1 as the reference start time. 
 
Tabulations will be produced for appropriate demographic, baseline, efficacy, and safety 
parameters.  
For categorical variables, summary tabulations of the number and percentage of 
participants within each category of the parameter will be presented. Percentages will be 
based on the participants with a non-missing parameter unless missing category is 
presented. Percentages will be reported to one decimal place. Percentages will not be 
presented for zero counts. 
For continuous variables, the number of participants, mean, standard deviation, median, 
first quartile (Q1), third quartile (Q3), minimum, and maximum values will be presented. 
Mean, median, Q1, and Q3 will be reported to 1 more decimal place than the raw data, 
while the standard deviation will be reported to 2 more decimal places than the raw data. 
Minimum and maximum will have the same number of decimal places as the raw data. 
Time-to-event data will be summarized using Kaplan-Meier (KM) methodology using 
25th, 50th (median), and 75th percentiles with associated 2-sided 95% confidence intervals 
(CIs), as well as percentage of censored observations. 
Formal statistical hypothesis testing will be performed on the primary and/or secondary 
efficacy endpoint as described in the protocol. 
All data listings that contain an evaluation date will also contain a relative study day. 
Pre-treatment and on-treatment study days are numbered relative to the day of the first 
dose of study drug which is designated as Day 1. The preceding day is Day -1, the day 


 
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before that is Day -2, etc. Post-treatment study days are numbered relative to the first 
dose and are designated as Day +1, Day +2, etc. The last day of study drug is designated 
with an “L” (e.g., Day 14L). In addition to relative day, cycle and day of treatment within 
cycle will be calculated and presented when applicable. 
In addition: 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) v24.1 or later.  
Laboratory parameter changes will be described using shift tables, relative to the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
v5.0.  
• Concomitant medications will be coded using the latest version of the World 
Health Organization’s Anatomical Therapeutic Chemical (ATC) classification 
(dated March 2021 or later). 
• P-values greater than or equal to 0.001, in general, will be presented to three 
decimal places. P-values less than 0.001 will be presented as “<0.001” 
• CIs will be presented to one more decimal place than the raw data 
• Weeks will be calculated as Number of days divided by 7 
• Months will be calculated as Number of days divided by 30.4375 
• Years will be calculated as Number of days divided by 365.25 
• Day 1 will be considered as the first day of treatment 
• End of Study is defined as the last available post-treatment assessment 
• For the laboratory data if the parameter value is collected as ‘<xx’ or ‘>xx’, then 
the corresponding integer after the ‘<’ or ‘>’ symbol will be used for summarizing 
the data. 
• All tables, figures, and listings will include footers at the bottom of the page 
reflecting the path and date of the datasets, datasets used to generate the tables, 
figures, and listings, and date and time of the generation of the output. 
3.3 Baseline Definitions 
For all analyses unless otherwise noted, baseline is defined as the most recent non-
missing measurement prior to the first administration of study drug. Baseline can be the 
same date as first dose, given the measurement is expected prior to first dose when only 
date information is available.  
3.4 Methods of Pooling Data 
Data will be pooled across study sites. When applicable, data from all disease cohorts 
will be pooled to provide an integrated summary.  


 
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3.5 Adjustments for Covariates 
No formal statistical analyses that adjust for possible covariate effects are planned for the 
efficacy or safety endpoints.  
3.6 Multiplicity Adjustment 
Multiplicity is not adjusted in this study. 
3.7 Subpopulations 
Not applicable.  
3.8 Withdrawals, Drop-outs, Loss to Follow-up 
After consultation between the Investigators and Sponsor, enrollment may be extended to 
replace participant(s) that become non-evaluable for DLT evaluation, safety or if there is 
insufficient PK data during Part 1. 
In Part 2, if a participant discontinues study treatment prior to the first assessment of 
disease (either scheduled radiological assessment at 6 weeks post treatment initiation or 
clinically indicated disease assessment prior to 6 weeks), the participant may be replaced 
after consultation between the Investigators and Sponsor unless the participant 
discontinued study treatment due to clear clinical progression without radiographic 
evidence of progression. In these participants, obtaining a subsequent confirmatory 
radiographic image is necessary if feasible (eg, participant’s condition allows for 
imaging). 
3.9 Missing Data 
In general, there will be no imputations made to accommodate missing data points. All 
data recorded on the eCRF will be included in data listings for the CSR. 
The following rules will be applied if there are values that are below the lower limit of 
quantification (BLQ) or if there are missing values (e.g., no result [NR]) in a plasma 
concentration data series to be summarized.  
• In summary statistics, BLQ values will be set to zero. 
• In categorical summary, BLQ category will be listed.   
• NR result will be set to missing.  
When tabulating AE data, partial dates will be handled as follows.  
• If the day of the month is missing, the onset day will be set to the first day of the 
month unless it is the same month and year as study treatment start date. In this 
case, in order to conservatively report the event as treatment-emergent, the onset 
date will be assumed to be the study treatment start date.  
• If the onset day and month are both missing, the day and month will be assumed 
to be January 1, unless the event occurred in the same year as the study treatment 


 
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start date. In this case, the event onset will be coded to the day of treatment in 
order to conservatively report the event as treatment-emergent.  
• A missing onset date will be coded as the study treatment start date. If the 
resulting onset date is after a reported date of resolution, the onset date will be set 
equal to the date of resolution.  
• Imputation of partial dates is used only to determine whether an event is 
treatment-emergent; data listings will present the partial date as recorded in the 
eCRF. 
• For initial diagnosis and prior anti-cancer treatment for primary cancer, partial 
dates will be handled as follows: 
For start dates: 
o If the day of the month is missing, the day will be imputed with the first day of 
the month.  
o If both the day and month are missing, the day and month will be assumed as first 
day of the year i.e. January 1. 
For end dates: 
o If the end day is missing, the day will be imputed to the last day of the month. 
o If both the end day and month are missing, the day and month will be assumed as 
last day of the year i.e. December 31.  
o If the imputed end date is after the first dose date of study treatment, use the first 
dose date as the imputed end date. 
• Incomplete start date of follow-up anti-cancer treatment will be imputed as 
follows:  
o If only ‘day’ is missing, then impute day with last day of the month.  
o If ‘day’ and ‘month’ are missing, and ‘year’ is not missing or the same as the year 
of last dose, then impute as December 31st.  
o If the imputed start date is greater than last contact date, then set to last contact 
date.  
• For disease progression, partial dates will be handled as follows: 
o If the day is missing 
▪ If the progression month and year is the same as the last treatment 
stop month and year, the progression day will be set to the last 
treatment stop day  
▪ If the progression month and year is after the last treatment stop 
month and year, the progression day will be set to the first day of 
the month of progression 
o If both the day and month are missing  
▪ If the progression year is the same as the last treatment stop year, 
the day and month will be set to the last treatment stop day and 
month 


 
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▪ If the progression year is after the last treatment stop year, the day 
and month will be set to the first day and month of the year. 
o If day, month, and year are missing, no imputation is needed.  
3.10 Visit Windows 
All participants will undergo serial radiographic assessments to assess tumor response. 
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
the first dose of study treatment. Scans performed prior to the signing of the ICF as part 
of routine clinical management are acceptable for use as initial tumor imaging if they are 
of diagnostic quality and performed within 28 days prior to first dose date. 
Tumor imaging should be performed Q6W (42 ±7 days) for the first 3 assessments and 
then every 9 (63 ±7 days) weeks thereafter, or more frequently if clinically indicated and 
at the time of suspected PD. After 1 year of radiographic assessments, participants will 
have imaging performed every 12 weeks (84 ±7 days). Imaging should not be delayed for 
delays in dosing. 
Continue to perform imaging until whichever of the following occurs: 
• The start of new anti-cancer treatment 
• Withdrawal of consent 
• Death 
• End of the study (when responder or discontinuation status for all participants is 
known) 
Participants who discontinue study treatment for reasons other than PD will continue 
post-treatment imaging studies for disease status FUP at the same frequency as already 
followed (every 6, 9, or 12 weeks [±7 days] depending on the length of treatment with the 
study drug) until PD, start of a non-study anti-cancer treatment, withdrawal of consent to 
study participation, loss to FUP, death, or end of the study. 
By-visit summaries and analyses will be performed by nominal visit. All data will be 
tabulated per the evaluation visit as recorded on the eCRF even if the assessment is 
outside of the visit window for analysis. In data listings, the relative day of all dates will 
be presented. 


 
C O N FI D E N TI A L  
 
 
2 1 3 3 4 9  
P a g e 2 7  of 4 9  
3. 1 1  I nteri m A n al ysis 
N o f or mal i nteri m a nal ysis is pla n ne d f or t his st u d y. H o w e ver, a re vie w of safet y data 
a n d a vaila ble preli mi nar y P K data will be c o n d uct e d b y t h e S p o ns or a n d I n vesti gat ors 
f oll o wi n g c o m pleti o n of t he D L T o bser vati o n peri o ds i n Part 1a a n d Part 1c. 
Deter mi nati o n of t he R P 2 D will be base d o n re vie w of safet y, P K, a n d 
 dat a.  
4  S T U D Y A N A L Y S E S  
4. 1  P artici p a nt  Dis p ositi o n  
Partici pa nt dis p ositi o n will be ta b ulate d a n d i ncl u d e t he n u m bers of s cree ne d a n d e nr olle d 
partici pa nts , t he n u m ber treate d i n t otal, t he n u m ber i n eac h a nal ysis p o p ulati o n, t he 
n u m bers w h o disc o nti n ue d treat me nt a n d dis c o nti n ue d st u d y a n d reas o n(s) f or 
wit h dra wal, a n d t he n u m ber of partici pa nts  w h o die d. Partici pa nt  dis p ositi o n will be 
s u m marize d f or t he E nr olle d p o p ulati o n usi n g des cri pti ve statistics.  
A b y -partici pa nt d ata listi n g of st u d y c o m pleti o n i nf or mati o n i ncl u di n g t he reas o n of  
st u d y wit h dra w al will be prese nte d. 
4. 2  De m o gr a p hics, B aseli ne C h ar acteristics a n d Me dic al Hist or y  
De m o gra p hics, b aseli ne c h aracteristics, a n d me dical hist or y i nf or mati o n will be 
s u m marize d f or t he Safet y p o p ulati o n i n Part 1 a n d Efficac y p o p ulati o n i n Part 2 usi n g 
descri pti ve statistics. N o f or mal statistical c o m paris o ns will be perf or me d.  
De m o gra p hic a n d baseli n e data f or eac h partici p a nt will be pr o vi de d i n data listi n gs.  
T he de m o gra p hi c a n d baseli ne c haracteristics ta bles will i ncl u de t he f oll o wi n g vari a bles:  
•  Ge n der  
•  A ge at ti me of scree ni n g ( years) cal c ulate d as d ate of scree ni n g mi n us da t e of 
birt h / 3 6 5. 2 5  if date of birt h is re p orte d, or  a ge as re p orte d o n t he e C R F will be 
use d  
•  A ge cat e g ories ( ≤1 8, 1 9  t o 6 4 , ≥ 6 5)  
•  Race ( W hite, Bla c k, Asia n, A merica n I n dia n/ Alas ka Nati ve, Nati ve Ha waiia n or 
ot her Pacific Isl a n der, Ot her, U n k n o w n, a n d N ot  Re p orte d)  
•  Et h nicit y ( His pa nic  or Lati n o , n o n-His pa nic  or Lati n o , U n k n o w n, a n d N ot 
Re p orte d)  
•  Ti me fr o m first dia g n osis t o first d ose of st u d y dr u g ( years) 
•  Pri mar y t u m or site  
•  Baseli ne wei g ht (i n kil o gra ms, last n o n -missi n g val ue pri or t o first d ose ; if weig ht 
is re p orte d i n p o u n ds, c o n vert t o kil o gra ms b y di vi di n g b y 2. 2) 
Baseli ne h ei g ht (i n ce nti meters,  last n o n-missi n g val ue pri or t o first d ose; if hei g ht 
is re p orte d i n i nc hes, c o n vert t o ce nti meters b y m ulti pl yi n g b y 2. 5 4) 
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• Baseline body mass index (BMI) (kg/m2), calculated using the participant’s height 
and weight at screening [BMI (kg/m2) = weight (kg) / height (m)2] 
• ECOG performance status at baseline 
• Prior cancer treatment including number of prior treatments. For Part 2 of the 
study, prior anti-cancer treatment will be defined as any prior regimen where: 
o Extent of disease is metastatic, and reason is palliative 
o OR Extent of disease is locoregional, reason is neoadjuvant or adjuvant, 
and last prior anti-cancer treatment stop date is within 1 year of date of 
enrollment 
• Histology and grade of disease at diagnosis  
• Best response during last treatment 
• Months from start of last treatment to progression or recurrence calculated as the 
date of recurrence after the last treatment minus the start date of last treatment +1 
divided by 30.4375 
• Months from end of last treatment to first dose of study drug calculated as the 
date of first dose minus end date of last treatment +1 divided by 30.4375 
Prior anti-cancer therapy, medical history and prior and concomitant medications will be 
summarized. Medical history will be coded using MedDRA v24.1 or later, and the 
number and percentage of participants experiencing at least one such diagnosis by 
MedDRA preferred term (PT) will be reported. 
COVID-19 cases will be captured on the COVID-19 CRF based on the WHO criteria 
using the categories of: suspected, probable, and confirmed cases. The COVID-19 
infected subpopulation will be summarized in a table including the number of subjects 
with suspected, probable, or confirmed COVID-19 diagnosis and the number of subjects 
who had a diagnosis test performed with the number of subjects with positive, negative, 
or indeterminate results. 
4.3 Efficacy Evaluation 
Efficacy analyses will be conducted in the Efficacy population unless stated otherwise.  
4.3.1 Primary Efficacy Endpoint (ORR) 
In Study Part 2A, the primary efficacy endpoint is ORR, defined as the proportion of 
participants who have achieved confirmed CR or PR using Investigator assessment per 
the RECIST v1.1 criteria.  
In Study Part 2B, ORR will also be evaluated by combining cohort 2B1 and 2B2 using 
Investigator assessment per the RECIST v1.1 criteria.  
Tumor assessments should be made at each time point specified in the protocol: every 
6 weeks (42±7 days) for the first 3 assessments and then every 9 weeks (63±7 days) 
thereafter while on study treatment, or more frequently if clinically indicated and at the 
time of suspected PD.  After 1 year, tumor assessments may be performed every 12 


 
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weeks (84±7 days) until disease progression or death or discontinuation from study. 
Tumor imaging for confirmation of response may be performed at the earliest 28 days 
after the first indication of response. 
A summary of criteria for the target lesions and the non-target lesions at each tumor 
assessment is included in Table 2 and Table 3. For participants who have measurable 
disease at baseline, Table 4 provides a summary of the overall response status at each 
time point. For participants who are enrolled in this study without measurable disease, 
Table 5 will be used to evaluate those participants at each time point. As confirmed 
CR/PR is required in the protocol, the best overall response (BOR) will be determined as 
shown in Table 6.  
Table 2 
RECIST v1.1 Response Criteria of Target Lesions at Each Assessment 
Tumor assessment 
CR 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 
10 mm.   
PR 
At least 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.  
SD 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD. 
PD 
At least 20% increase in the sum of diameters 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. (Note: the appearance of one or more new lesions is also 
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Table 3 
RECIST v1.1 Response Criteria of Non-Target Lesions at Each 
Assessment 
Tumor assessment 
CR 
Disappearance of all non-target lesions and normalization of tumor 
marker level. Any lymph nodes must be non-pathological in size (< 10 
mm short axis).   
Non-
CR/Non-PR 
Persistence of one or more non-target lesions(s) and/or maintenance of 
tumor marker level above the normal limits.  
PD 
Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered 
progression). 
 
Table 4 
RECIST v1.1 Overall Response at Each Assessment for Participants 
with Measurable Disease at Study Entry 
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-CR/Non-PD/Not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/Not evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Not all 
evaluated 
Non-PD 
No 
NE 
 
Table 5 
RECIST v1.1 Overall Response at Each Assessment for Participants 
without Measurable Disease at Study Entry 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 


 
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Table 6 
RECIST v1.1 Best Overall Response when confirmation of CR and 
PR required 
Overall 
Response first 
timepoint 
Overall Response 
subsequent 
timepoint 
Best Overall Response 
CR 
CR 
CR provided minimum criteria for CR met, 
otherwise, SD provided minimum criteria for SD 
met, otherwise, NE 
CR 
PR 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
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 provided minimum criteria for PR met, 
otherwise, SD provided minimum criteria for SD 
met, otherwise, NE 
PR 
PR 
PR provided minimum criteria for PR met, 
otherwise, SD provided minimum criteria for SD 
met, otherwise, NE 
PR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
SD 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
SD 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
SD 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 
 
Note: Minimum 12 weeks (84 - 14 = 70 days) for SD and at least 28 days for CR/PR. 
For each participant, BOR will be determined based on the overall responses at all time 
points between the date of first dose and the date of first documented progression, or the 
date of subsequent anti-cancer therapy, or the date of study discontinuation, whichever 
occurs first.  
Specifically: 
• Day 1 can be determined from the “date of infusion” field on the “Infusion Study 
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• The date of disease progression can be determined by selecting the earliest date 
from the “date of the radiological scan or assessment on which the response 
evaluation was based” field on the “evaluation of response (RECIST)” form 
where “overall response” = PD.  
• Subsequent anti-cancer therapy can be determined by checking for any entries 
made on the “follow up anti-cancer therapy” form. 
• The date of study discontinuation can be determined by using the “date of study 
discontinuation” field on the “discontinuation of study” form.   
• For each participant, select all “evaluation of response (RECIST)” forms meeting 
the following criteria: 
o The “date of the radiological scan or assessment on which the response 
evaluation was based” is after Day 1. 
o The “date of the radiological scan or assessment on which the response 
evaluation was based” is on or before the date of disease progression, date 
that anti-cancer therapy first began, and the date of study discontinuation. 
If the participant did not experience disease progression, begin anti-cancer 
therapy, or discontinue the study prematurely, select all forms after Day 1. 
Participants with a BOR of either confirmed CR or confirmed PR are considered to have 
responded to treatment (“responders”) for the primary efficacy variable (ORR). All other 
participants are considered to have not responded to treatment (“non-responders”) for the 
primary efficacy variable.  
The point estimate and two-sided 95% CI for the ORR will be calculated. The exact 
(Clopper-Pearson) method will be used to calculate the two-sided 95% CI. This can be 
programmed in SAS by appending the “/ BINOMIAL (EXACT)” option to the end of the 
appropriate “TABLE” statement.   
Summary tables will be generated in the Efficacy population for all cohorts.  The 
following figures will be generated for the cohorts in Part 2 only: 
• Tumor burden (sum of longest diameters of target lesions) will be presented 
graphically using waterfall plots, to present each subject’s best percentage change 
in tumor size as a separate vertical bar, with the bars ordered from the largest 
increase to the largest decrease. BOR for each subject will be presented above or 
below each bar along with indicators for new lesions. 
• Tumor burden (sum of longest diameters of target lesions) will also be presented 
graphically using spider plots, to present each subject’s percentage change in 
tumor size over time as a separate line along with indicators for new lesions. 
Unconfirmed ORR may also be evaluated as needed. Participants with a BOR of either 
CR or PR are considered to have responded to treatment (“responders”) for the evaluation 
of unconfirmed BOR. All other participants are considered to have not responded to 
treatment (“non-responders”).  


 
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4.3.2 Secondary Efficacy Endpoint 
KM summary tables and figures will only be produced for the cohorts in Part 2. 
4.3.2.1 
Duration of response (DOR) based on RECIST v1.1 
For participants who responded to treatment, DOR (in months) will be calculated as: 
[Earliest date of PD or death – Earliest date of confirmed CR or PR + 1] / 30.4375 
Table 7 provides a summary of the censoring rules used in primary analysis of DOR. A 
time-to-event analysis of DOR will be performed using KM methods including 
quartile/median estimates and associated 95% CIs. A KM plot will be produced.  
Table 7 
Censoring rules used in DOR analysis 
Situation 
Date of Event or Censoring 
Outcome 
Start of subsequent anti-cancer 
therapy prior to a documented 
progression or death 
Date of last evaluable radiologic 
tumor assessment prior to or on the 
date of initiation of the subsequent 
anti-cancer therapy 
Censored 
Free of progression and no 
subsequent anti-cancer therapy 
started and no death 
Date of last evaluable radiologic 
tumor assessment  
Censored 
Documented progression or death 
after two or more consecutive 
missing radiologic assessments 
Date of last evaluable radiologic 
tumor assessment prior to the two 
or more consecutive missing 
radiologic assessments 
Censored 
Documented progression or death 
Earliest date of documented tumor 
progression or death 
Event 
 
4.3.2.2 
Disease control rate (DCR) based on RECIST v1.1 
Participants who achieved a best overall response rate of confirmed CR/PR confirmed 
with at least 28 days duration, or SD confirmed with a minimum of 12 weeks duration 
(84-14=70 days), will be considered “responders” for this endpoint. All other participants 
will be considered “non-responders” for this endpoint.  
Since radiographic evaluations to assess extent of disease will be conducted every 6 
weeks (42±7 days), the minimum of 12 weeks duration for confirmed SD corresponds to 
2 consecutive scans (i.e. at least 84-14= 70 days). For confirmed CR/PR, the two 
consecutive CR/PR assessments need to be at least 28 days apart. 
Unconfirmed DCR may also be evaluated as needed. 
The point estimate and two-sided 95% CI will be calculated. The exact (Clopper-
Pearson) method will be used to calculate the 95% CI. This can be programmed in SAS 


 
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by appending the “/BINOMIAL(EXACT)” option to the end of the appropriate 
“TABLE” statement.   
4.4 Safety Evaluation 
The safety analyses will be based on the Safety population, unless otherwise specified. 
4.4.1 Treatment Exposure and Compliance 
Study treatment exposure and compliance will be summarized by dose level, phase of the 
study, including: 
• Number of infusions as a continuous variable  
• Number and percentage of participants treated by maximum number of infusions 
(1, 2, 3 … and ≥12) 
• Duration of treatment (months), defined as  
o [last dose date - first dose date + duration of dosing interval (day)] / 
30.4375 
• Duration on study (months), defined as  
o [last contact date - first dose date + 1] / 30.4375, where last contact date is 
the last visit date or date of death.  
• Number of participants with dose interruptions   
• Number of participants with dose delays 
• Intended cumulative dose (mg), defined as the sum of intended dose at each 
infusion. 
o If the intended dose is recorded in “mg/kg”, then, intended dose at an infusion is = 
(intended dose in mg/kg) * weight of the subject in kg’s. 
o Else if intended dose is recorded in “mg/m^2”, then intended dose at an infusion 
is = (intended dose in mg/m^2) * BSA.  
Where BSA (Body Surface Area) is calculated using DuBois formula, 
BSA(m2) = 0.20247(height in m)0.725(weight in kg)0.425 
• Intended Dose Intensity (mg/dose) defined as, 
o Intended cumulative dose (mg) divided by the number of infusions. 
• Actual cumulative dose (mg), defined as   
o Sum of all doses actually administered. 
• Actual dose intensity (mg/dose), defined as  
o Actual cumulative dose (mg) divided by the number of infusions 
• Relative dose intensity (%), defined as  
Actual dose intensity (mg/dose) divided by the intended dose per infusion (mg/dose), 
expressed in percentage.  


 
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A by-participant listing based on the safety population will be produced. 
 
Treatment Period (i.e. on-treatment) 
The period from the date of first dose of study treatment up to and including 90 days after 
the EOT visit or the earliest date of subsequent anti-cancer drug therapy, whichever 
occurs first, unless otherwise stated. 
4.4.2 Adverse Events 
All AEs will be classified by PT using MedDRA v24.1 or later.  
Any Treatment Emergent AEs (TEAEs) will be defined per protocol as: 
• Any new AE (one that was not seen prior to the start of treatment) that occurs for 
the first time after at least 1 dose of study treatment has been administered until 
90 days after cessation of study treatment (or until the start of alternative 
anti-cancer therapy, whichever occurs earlier); or, 
• A preexisting condition (one that was seen prior to the start of treatment) that 
worsens in severity (according to the CTCAE grade) or subsequently is 
considered drug-related by the Investigator after at least 1 dose of study treatment 
has been administered until 90 days after cessation of study treatment (or until the 
stat of alternative anti-cancer therapy, whichever occurs earlier). 
If the start date is missing for an AE and the actual start date cannot be determined from a 
partial date, the AE will be considered treatment-emergent. 
All AEs will be collected from the time of signing the ICF until 90 days after cessation of 
study treatment (or until alternative anti-cancer therapy is initiated, whichever occurs 
first), and any pregnancies are to be captured through 150 days post-treatment. Any AEs 
recorded in the database that occur from the time of ICF to first dose will be listed only 
and not included in safety analyses. Pre-existing conditions will be recorded in the eCRF 
on the Medical History or appropriate page. 
The severity of the toxicities will be graded according to the NCI CTCAE v5.0. Within 
the same MedDRA PT, only the most severe AE for each participant will be counted in 
tabulations by severity.  
Related TEAEs are defined as TEAEs considered likely related or related to treatment as 
judged by the Investigator. Any AEs for which the relationship to study drug is missing 
will be considered as related to study treatment. Within the same MedDRA PT, only the 
AE with the highest ranked relationship to treatment for each participant will be counted 
in tabulations by relationship to treatment. The imputation for a missing relationship will 
take place prior to determining the most related AE within a SOC or PT for a given 
participant. 


 
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A high-level overview of TEAEs will be presented in a summary table. This table will 
include the number and percentage of participants for the following categories:  
• any TEAE  
• any related TEAEs  
• any TEAEs with toxicity grade 3 or above 
• any related TEAEs with toxicity grade 3 or above 
• any treatment-emergent serious adverse events (SAEs), 
• any related SAEs  
• any TEAEs leading to treatment discontinuation 
• any TEAEs leading to treatment interruption 
• any TEAEs leading to death 
• any related TEAEs leading to death  
The number and percentage of participants reporting a TEAE will be summarized by PT, 
toxicity grade, and relationship to study drug, respectively. AE tabulations will be 
ordered in terms of decreasing frequency for PT.  
The incidence of COVID-19 reported as an AE and SAE will be reported in the standard 
AE and SAE tables. The incidence of treatment discontinuation due to AE of COVID-19 
infection will be reported in the table of TEAEs leading to treatment discontinuation.  
The following AE tables will be produced. 
• Overview of AEs 
• DLTs by PT (Part 1) 
• TEAE by PT (sorted by decreasing frequency) 
• Related TEAE by PT (sorted by decreasing frequency) 
• TEAE with toxicity grade 3 or above by PT 
• Related TEAE with toxicity grade 3 or above by PT 
• Treatment emergent SAEs by PT (sorted by decreasing frequency) 
• Related treatment emergent SAEs by PT (sorted by decreasing frequency) 
• TEAEs leading to treatment discontinuation by PT 
• TEAEs leading to treatment interruption by PT 
• TEAEs leading to death by PT 
• Non-serious TEAEs ≥5% in the study arm (for clinicaltrials.gov) 
• Exposure Adjusted Incidence rates of common TEAEs (≥5%) over the time 
course of the trial (pre, during, and post pandemic, as appropriate) 
• Exposure Adjusted Incidence rates of Any TEAEs, any treatment emergent SAEs 
and Any Grade 3/4/5 TEAEs over the time course of the trial (pre, during, and 
post pandemic, as appropriate) by overall, country or analysis region, age group, 
and gender. 


 
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The definition of when COVID-19 Pandemic Measures Began is given in Appendix 7.2. 
Participants may be counted in more than one-time course of the trial (pre, during, and 
post pandemic, as appropriate). The number of subjects at risk at the start of the given 
time interval will be calculated.  
 
Exposure adjusted incidence rate (rate/100 PY) = (number of participants with 
occurrence of a specific treatment emergent adverse event /total exposure duration in 
years across all participants at risk at the start of the given time interval) * 100, where 
exposure duration for each participant is calculated as: 
• (treatment stop date – treatment start date + duration of dosing interval 
[day])/365.25 for participants who DO NOT experience the event 
• (start date of first TEAE – treatment start date + 1)/365.25 for participants that 
DO experience the event. 
 
For recurring events, the first occurrence of an event (by MedDRA PT) will be reported, 
with the appropriate corresponding exposure years. 
Immune-related adverse events of interest (irAEs) are defined as any >= Grade 2 AEs 
based on a pre-specified search list of PTs.  
 
The following AE tables will be produced for treatment emergent immune-related AEs 
irAEs by SOC and PT: 
• irAEs by PT (sorted by frequency) 
• irAEs with toxicity grade 3 or above by PT 
• Serious irAEs by PT 
• irAEs leading to treatment discontinuation by PT 
• irAEs leading to death by PT 
The following by-participant listings will be produced. 
• All AEs 
• DLTs  
• Deaths 
• Treatment emergent SAEs 
• TEAEs leading to treatment interruption. 
• TEAEs leading to treatment discontinuation  
• irAEs 


 
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4.4.3 Laboratory Data 
Laboratory assessments for safety oversight are performed locally at each center’s 
laboratory by means of their established methods. All laboratory values will be converted 
to SI units and classified as normal, low, or high based on normal ranges supplied by the 
local laboratories and upon employing standardization.  
NCI CTCAE v5.0 grades will be applied for the following lab parameters: 
• Hematology: hemoglobin (anemia), WBC (leukopenia), lymphocytes 
(lymphopenia), neutrophils (neutropenia) platelets and (thrombocytopenia)  
• Chemistry: albumin (hypoalbuminemia), alkaline phosphatase (alkaline 
phosphatase increased), ALT, AST, total bilirubin (blood bilirubin increased), 
corrected calcium (hypocalcemia, hypercalcemia), creatinine (creatinine 
increased), glucose (hyperglycemia, hypoglycemia), magnesium 
(hypermagnesemia, hypomagnesemia), potassium (hyperkalemia, hypokalemia), 
and sodium (hyponatremia, hypernatremia) 
Where corrected calcium is derived with the following formula: Corrected calcium 
(mmol/L) = Serum calcium (mmol/L) + (0.02 * (Normal albumin (g/L) – Patient’s 
albumin (g/L))) where normal albumin is 40 g/L. 
Laboratory results will be summarized by maximum CTCAE grade as available. 
Continuous results will be analyzed using change from baseline and shift values. 
A shift summary of baseline to maximum severity during the treatment period for all 
parameters noted above will be produced for the coded hematology and chemistry 
parameters. Participants without an assessment present at baseline or on-study treatment 
will be included as a missing category. 
Shift from baseline to the smallest, largest, and EOT will be reported using number and 
percentage of participants.  
Liver function tests during the treatment period will be summarized by the following 
categories. 
• ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
• AST ≥ 3×ULN, AST ≥ 5xULN, AST ≥ 10×ULN, AST ≥ 20×ULN 
• (ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, 
(ALT or AST) ≥ 20×ULN 
• Total bilirubin ≥ 2×ULN 
• Concurrent ALT ≥ 3×ULN and total bilirubin ≥ 2×ULN 
• Concurrent AST ≥ 3×ULN and total bilirubin ≥ 2×ULN 
• Concurrent (ALT or AST) ≥ 3×ULN and total bilirubin ≥ 2×ULN 


 
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• Concurrent (ALT or AST) ≥ 3×ULN and total bilirubin ≥ 2×ULN and ALP > 
2×ULN 
• Hy’s law: Concurrent (ALT or AST) ≥ 3×ULN and total bilirubin ≥ 2×ULN and 
ALP < 2×ULN or missing and concurrent measurements are those occurring on 
the same date. 
A by- participant listing of all laboratory data will be provided, with laboratory reference 
ranges and abnormal values highlighted, and including center, participant identifier, and 
visit. 


 
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4.4.4 Electrocardiogram 
Standard 12-lead ECGs will be performed locally for participants in the study. Any ECG 
findings that were assessed as clinically significant and were reported as an AE or SAE 
will be summarized in the AE tables and listings. 
ECG results will be summarized descriptively. ECG measurements include Heart rate, 
PR interval, QT interval, RR interval, and QRS complex. 
QTc will be used for the data analysis and interpretation. Commonly used techniques 
including Bazett’s (QTcB) and Fridericia’s (QTcF) methods are applied. QTcF will be 
used for the primary QT evaluation. 
The following analyses will be performed during the treatment period: 
• A summary of the number and percentage of participants with QTc interval 
exceeding some predefined upper limit (e.g., >450 ms, >480 ms, >500 ms) will be 
provided. A summary of the number and percentage of participants with change 
from baseline in QTc interval exceeding some predefined upper limit 
(e.g., >30 ms, >60 ms) will be provided.  
• A separate summary will be provided which summarizes the change from 
baseline to the most extreme high or low value at any time during treatment.  
Change from baseline will be summarized and analyzed according to the largest increase, 
decrease, and at EOT. Graphical line mean changes over time may be provided. 
All ECG data for each participant will be provided in a data listing. 
4.4.5 Concomitant Medications 
Medications collected at Screening and during the study will be coded using the current 
version of the World Health Organization (WHO) Drug dictionary (version 201809). 
Medication start and stop dates will be compared to the date of first dose of study drug to 
allow medications to be classified as Prior-only, Prior-and-Concomitant, or Concomitant-
only. Medications starting after the treatment withdrawal date will be listed but will not 
be classified or summarized. 
Medications that start and stop prior to the date of first dose of study drug will be 
classified as Prior-only. If a medication starts before the date of first dose of study drug 
and stops on or after the date of first dose of study drug then the medication will be 
classified as Prior-and-Concomitant. Medications will be classified as Concomitant-only 
if they have a start date on or after the date of first dose of study drug, but prior to the 
treatment withdrawal date. Concomitant medication will be summarized by ATC level 3 
and PT in frequency tables by treatment. Participants with more than 1 medication in a 
given ATC level and PT will be counted only once in that category. 


 
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If medication start and/or stop dates are missing or partial, the dates will be compared as 
far as possible with the date of first dose of study drug. Medications will be assumed to 
be Concomitant-only, unless there is clear evidence (through comparison of partial dates) 
to suggest that the medication started prior to the first dose of study drug. If there is clear 
evidence to suggest that the medication started prior to the first dose of study drug, the 
medication will be assumed to be Prior-and-Concomitant, unless there is clear evidence 
to suggest that the medication stopped prior to the first dose of study drug. If there is 
clear evidence to suggest that the medication stopped prior to the first dose of study drug, 
the medication will be assumed to be Prior-only.  
The following lists the concomitant medication tables to be displayed: 
• Number and percentage with at least 1 Prior-only medication by ATC level 3 and 
PT 
• Number and percentage with at least 1 Prior-and-Concomitant medication by 
ATC level 3 and PT 
• Number and percentage with at least 1 Concomitant-only medication by ATC 
level 3 and PT 
The use of concomitant medications will be included in a by-participant data listing. 
4.5 PK and ADA Evaluation 
The PK analyses will be based on the PK population, unless otherwise specified. TSR-
033 and TSR-042 concentration-time data from each arm of the study will be analyzed 
using standard non-compartmental methods. Combined PK data from this study and other 
studies may also be analyzed in a population PK approach using nonlinear mixed effects 
modeling and the results of which, if performed, may be reported separately. 
4.5.1 Pharmacokinetic Analyses 
4.5.1.1 Endpoint / Variables 
Drug Concentration Measures 
Blood sampling time will be related to the start of dosing. Serum concentrations will be 
listed and summarized by cohort, dose and nominal time.  
Derived Pharmacokinetic Parameters 
TSR-033 and TSR-042 PK parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using Phoenix. 
All calculations of non-compartmental PK parameters will be based on actual sampling 
times. For each participant and for each dose, PK parameters described in Table 8 will be 
determined from the TSR-033 and TSR-042 serum concentration-time data and 
additional parameters may be explored as data permit. 


 
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All PK parameters will be listed and summarized descriptively by cohort and dose. 
Summary statistics will include mean, standard deviation, coefficient of variation (CV), 
geometric mean, geometric mean CV, median, minimum, and maximum. 


 
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Table 8 
Derived Pharmacokinetic Parameters 
 
Parameter State Parameter Description 
AUC(0-
last) 
sd, 
md 
Area under the serum concentration-time curve from time zero 
to the time of the last quantifiable concentration (C(t)) will be 
calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental 
trapezoid. 
AUC(0-
∞)* 
sd, 
md 
Area under the serum concentration-time curve from time zero 
extrapolated to infinity will be calculated as, if data permit:  
AUC(0-∞) = AUC(0-t) + C(t) / lambda_z 
AUCtau 
md 
Area under the serum concentration-time curve during the 
dosing interval using the linear/log trapezoidal rule; AUC0-336 - 
Area under the serum concentration-time curve from time zero 
to 336 hours; AUC0-504 - Area under the serum concentration-
time curve from time zero to 504 hours 
Cmax 
sd, 
md 
Maximum observed serum concentration, determined directly 
from the serum concentration-time data. 
Cmin 
sd, 
md 
Minimum observed serum concentration, determined directly from the 
serum concentration-time data. 
 
tmax 
sd, 
md 
Time to reach Cmax, determined directly from the serum 
concentration-time data. 
Lambda_z 
sd, 
md 
Apparent terminal phase elimination rate constant.  The lambda_z 
lower and upper limits and number of points used to determine 
lambda_z will also be reported. 
t½* 
sd, 
md 
Apparent terminal phase half-life will be calculated as:  
t½ = ln2 / lambda_z (terminal phase elimination rate constant) 
CL 
sd, 
md 
Clearance. CL=dose / AUC(0-∞) for sd 
Vz 
sd, 
md 
Volume of distribution. For non-steady-state data: 
Vd=dose/ (z x AUC(0-∞)) for sd; Vd=dose/(z x AUCtau) for 
md 
Vss 
md 
Volume of distribution at steady state, calculated from: Vss = CL x MRT 
(mean residence time), if data permit. 
AR(cmax) 
md 
Accumulation ratio based on Cmax. 
AR(AUC) 
md 
Accumulation ratio based on AUC. 
• sd: single dose; md: multiple dose 
• *: if data permit 
• Additional parameters 
may be included as 
required. 


 
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2 1 3 3 4 9  
P a g e 4 4  of 4 9  
4. 5. 1. 2  Str ate gy f or I nterc urre nt ( P ost -R a n d o miz ati o n) Eve nts  
Missi n g c o nce ntrati o ns a n d c o nce ntr ati o ns bel o w t he li mit of q ua ntificati o n of t he assa y 
will be ha n dle d as des cri be d i n G ui da nce D oc u me nt V Q D -G UI -0 0 0 7 2 2 .  
Dr u g c o nce ntrati o n data w hic h are b el o w t he l o wer li mit of q ua ntificati o n, L L Q  (7 0. 0 
n g/ m L f or T S R -0 3 3 a n d 3 2. 0 n g/ m L f or T S R -0 4 2)  will be i m p ute d t o zer o.   
C o nce ntrati o ns t hat are i nc o nsiste nt p har mac o ki n eticall y wit h t he dr u g c o n ce ntrati o n -
ti me pr ofile wit hi n a n i n di vi d ual ma y be c o nsi dere d as o utliers a n d s u bse q ue ntl y 
e x cl u de d fr o m t he dataset or  a nal ysis. Vis ual i ns pecti o n of i n di vi d ual a n d p o ole d data a n d 
wei g ht e d resi d uals d uri n g a n al ysis ma y b e use d t o i de ntif y s uc h o utliers. A n y s u c h 
e x cl usi o n will be re p orte d a n d disc usse d i n t he fi n al re p ort.  
Missi n g data will be ha n dle d i n t he f oll o wi n g wa y:  
• 
Partici pa nts w h o wit h dre w fr o m t he st u d y a n d di d n ot pr o vi de a n y P K sa m ples 
a n d d o n ot ha ve a d e q uate sa m pli n g a n d/ or c o variat e i nf or mati o n will be e x cl u de d fr o m 
t he a nal ysis 
• 
If d osi n g a n d/ or sa m pli n g ti mes are missi n g, t he rele va nt c o nce ntrati o ns m ay b e 
e x cl u de d fr o m t he a nal ysis dataset a n d s u m marize d i n a n e x cl usi o n listi n g file. 
Alter nati vel y, t he n o mi nal ti mes of t he res pecti ve d oses a n d/ or sa m ples ma y be utilize d  
4. 5. 3  I m m u n o ge nicit y A n al ys es 
T he i m m u n o ge nicit y of a nti -T S R -0 3 3  a nti b o dies  a nti b o dies will be s u m marize d a n d 
liste d. I m m u n o ge nicit y will be base d o n t he I m m u n o ge ni cit y ( A D A) p o p ulati o n.  
T he A D A sa m ple res ults f or t he sa m ples at eac h a vaila ble ti me p oi nt, i ncl u di n g pre -d ose 
a n d p ost -d ose will be cat e g orize d i nt o differe nt A D A sa m ple stat us: A D A -p ositi ve 
sa m ples, A D A-n e gati ve sa m ples, a n d A D A -i nc o ncl usi ve sam ples. A D A -p ositi ve sa m ple 
is i de ntifie d w he n A D A is detecte d ( A D A res p o ns e is a b o ve t he c ut p oi nt i n t he 
c o nfir mat or y ass a y). A D A -ne gati ve s a m ple is i de ntifie d w he n A D A is n ot detecte d 
( A D A res p o nse is bel o w t he c ut p oi nt i n t he scree ni n g assa y, or a b o v e t he c ut p oi nt i n t he 
scree ni n g assa y b ut bel o w t he c ut p oi nt i n t he c o nfir mat or y assa y). A D A -i nc o ncl usi ve 
sa m ple is i de ntifie d w he n A D A is n ot detecte d i n a sa m ple, b ut t he dr u g is prese nt i n t he 
sa m ple at a le vel hi g her t ha n t he dr u g t olera nce f or t he A D A assa y. U ne v al ua ble sa m ples 
w hic h c o ul d n ot be teste d f or A D A stat us d ue t o i n a de q uate s a m ple v ol u me, mis ha n dli n g, 
or err ors i n sa m ple c ollecti o n, pr ocessi n g, st or a ge, etc. will n ot ha ve a n y A D A data a n d 
t h us n o res ults will be re p orte d. 
C CI


 
C O N FI D E N TI A L  
 
 
2 1 3 3 4 9  
P a g e 4 5  of 4 9  
T he n u m ber a n d p er ce nt of partici pa nts  w h o bec o me p ositi ve f or A D As a n d w h o de vel o p 
ne utralizi n g a nti b o dies will be s u m marize d b y d ose re gi me n, part, visit/ti me a n d o verall.  
4. 7   A d diti o n al A n al yses D ue t o t he C O VI D -1 9 P a n de mic  
T he defi niti o n of t he p hases of t he C O VI D -1 9 pa n de mic meas ures is gi ve n i n A p pe n di x 
7. 2   
 
C O VI D -1 9 cases will be ca pt ure d o n t he C O VI D -1 9 C or o na vir us I nfecti o n Dia g n osis 
a n d Assess me nt C R F pa ges b ase d o n t he W H O criteria usi n g t h e cat e g ories of: s us pecte d, 
pr o ba ble, a n d c o nfir me d case s. T he C O VI D-1 9 i nfecte d s u b p o p ulati o n will be 
s u m marize d i n a ta ble i ncl u di n g t he n u m ber of s u bjects wit h s us pecte d, pr o ba ble, or 
c o nfir me d C O VI D -1 9 di a g n osis, t he n u m ber of s u bjects wit h s us pecte d, pr o ba ble, or 
c o nfir me d w orst case C O VI D -1 9 case dia g n osi s, t he n u m ber of s u bjects wit h s us pecte d, 
pr o ba bl y, or c o nfir me d C O VI D -1 9 Cas e Dia g n osis E ve nts, t he n u m ber of s u bjects w h o 
ha d a C O VI D -1 9 test perf or me d, a n d t he n u m b er of s u bjects wit h p ositi ve, ne gati ve, or 
i n deter mi nate C O VI D-1 9 test res ults.  
 
A s u m mar y of t he n u m ber of partici pa nts  recr uite d b y c o u ntr y a n d site rel ati ve t o t he 
C O VI D -1 9 pa n d e mic me as ures ma y be pr o vi de d. A fi g ure of t h e n u m ber of partici pa nts  
recr uite d o v er ti me b y c o u ntr y relati ve t o t he C O VI D-1 9 pa n d e mic meas ures ma y als o b e 
prese nte d . 
 
A listi n g of t he start dat es of C O VI D -1 9 p a n de mi c meas ures o verall a n d b y c o u ntr y m a y 
be liste d.  
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5 CHANGES TO PLANNED ANALYSES 
In the protocol, the Per Protocol Population is defined as, “All participants in the Efficacy 
Population who do not have protocol violations during the study that may significantly 
impact the interpretation of efficacy results and have ≥1 post-baseline disease 
assessment”. This definition is changed in the SAP to, “All participants in the Efficacy 
Population who have no major (i.e. important) protocol violations during the study and 
have ≥1 post-baseline disease assessment”. The original language in the protocol was as 
per the TESARO PDMS, and this language was updated in the SAP to align with GSK 
PDMS. 


 
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Beal S L. Ways to fit a PK model with some data below the quantification limit. J 
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DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and 
weight be known. Arch Intern Medicine. 1916; 17:863-71. 
Hing J P, et al. Is mixed effects modeling or naïve pooled data analysis preferred for the 
interpretation of single sample per subject toxicokinetic data?. J Pharmacokinet 
Pharmacodyn. 2001 Apr;28(2):193-210. 
Kaplan EL MP. Nonparametric estimation from incomplete observations. Journal of the 
American Statistical Association 1958;53:457–481. 
 
 


 
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7 APPENDIX 
7.1 Immune-related Adverse Events 
A list of MedDRA PTs and system organ class (SOC) that will be used to identify immune-
related adverse events will be shared with the programming team separately for reference. 
 


 
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7.2 Definition of when COVID-19 Pandemic Measures Began 
 
Pandemic measures began in different countries at different times. A dataset containing 
the date when pandemic measures began, as determined by the GSK country Issue 
Management Teams (IMT), will be used to determine the start date of pandemic 
measures within each country. A copy of this dataset will be taken at the time of database 
freeze (DBF). 
The alert levels are escalated and de-escalated over time and the scale used for the 
recording of alerts is standardized: green (low impact), yellow (low to moderate impact), 
orange (moderate to high impact), red (high impact), and black (high impact with severe 
disruption). Date of when pandemic measures began was defined based on the IMT alert 
levels and used in analyses. 
Adverse events will be summarizing according to whether the onset date was before, 
during or after the start of the COVID-19 pandemic measures. 
The initial start date is being defined as when the COVID-19 IMT alerts for each country 
were all initially activated with an alert level of Yellow or above. The end date of this 
first wave will be defined as when the alert level has de-escalated to green. 
 
Pandemic Measures Phase Definition 
Pre 
AE onset date < pandemic measures start date 
During 
Pandemic measures start date ≤ AE onset date < pandemic 
measures end date 
Post 
AE onset date ≥ pandemic measures end date 
 


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Si g nat ure Pa ge f or T M F- 1 4 6 9 4 0 2 8 v 1. 0
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Date of si g nat ure: 2 1-J u n- 2 0 2 2 1 2: 3 4: 4 3 G M T + 0 0 0 0
P P D