A Phase II Study of Preoperative Immunotherapy in Patients With Colorectal Cancer and Resectable Hepatic Metastases
Phase: PHASE2
Conditions: Metastatic Malignant Neoplasm in the Liver, Stage IV Colorectal Cancer AJCC v8, Stage IVA Colorectal Cancer AJCC v8, Stage IVB Colorectal Cancer AJCC v8, Stage IVC Colorectal Cancer AJCC v8
Sponsor: Chloe Atreya, MD, PhD

Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws. Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.
A Phase 2 Study of Perioperative Immunotherapy in 
Patients with Colorectal Cancer and Resectable Hepatic 
Metastases
Protocol Number: CC #187015
Study Drugs: Pembrolizumab, Vactosertib
Version Number: 9.0
Version Date:  25-Jan-2024
IND Number: 155292
Principal Investigator (Sponsor-Investigator)
Chloe E. Atreya, MD, PhD
University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
San Francisco, CA 94143
Statistician
Li Zhang, PhD
Revision History
Version 9.0
25-Jan-2024
Version 8.0
Version 7.0
Version 6.0
04-Dec-2023
31-Oct-2022
12-Oct-2022
Version 5.0
Version 4.0
Version 3.0
Version 2.0
31-May-2022
18-Feb-2022
03-Jun-2021
14-Apr-2021
Version 1.4
06-Nov-2019
Version 1.3
15-Jan-2019
Version 1.2
24-Oct-2018
Version 1.1
30-Jul-2018
Version 1.0
08-Mar-2017
NCT03844750

Version date: 25-Jan-2024
Protocol CC#: 187015
Phase 2, Pembrolizumab, Vactosertib
Page 1 of 96
Protocol Signature Page
1.
I agree to follow this protocol version as approved by the University of California San 
Francisco (UCSF) Protocol Review Committee (PRC), Institutional Review Board (IRB), and 
Data Safety Monitoring Committee (DSMC).
2.
I will conduct the study in accordance with applicable IRB requirements, Federal regulations, 
and state and local laws to maintain the protection of the rights and welfare of study 
participants. 
3.
I certify that I, and the study staff, have received the requisite training to conduct this research 
protocol. 
4.
I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in 
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the 
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In 
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website. 
5.
I agree to maintain adequate and accurate records in accordance with IRB policies, Federal, 
state and local laws and regulations.
UCSF Principal Investigator / Study Chair
Printed Name
Signature
Date
Principal Investigator
Site
Printed Name
Signature
Date

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Abstract
Title
A Phase 2 Study of Preoperative Immunotherapy in Patients with Colorectal 
Cancer and Resectable Hepatic Metastases
Patient 
population
Patients with colorectal cancer (CRC) with liver-dominant or liver-only 
metastases who have received prior 5-fluorouracil (5-FU), leucovorin, and 
oxaliplatin (FOLFOX) chemotherapy and are appropriate candidates for 
resection of liver metastases.
Rationale for 
Study
We hypothesize that pembrolizumab plus vactosertib will increase tumor-
infiltrating lymphocytes (TILs) and promote response without increasing 
perioperative complications.
Primary 
Objective
To characterize the change in the populations of TILs induced by 
neoadjuvant pembrolizumab plus vactosertib in patients with metastatic 
CRC.
Secondary 
Objectives
To establish the safety/toxicity profile of pembrolizumab-based treatment in 
the perioperative setting for patients with CRC with potentially resectable 
hepatic metastases, including rates of perioperative complications.
To explore the efficacy of this strategy in this patient population. Clinical 
outcome measures will include response to pembrolizumab plus vactosertib 
as measured by R0 resection rate; pathologic response; and 1-year and 2-
year relapse-free survival (RFS).
Study Design
Phase 2, single-site, open-label prospective clinical trial. See schema below. 
Additional cohorts exploring novel pembrolizumab-based combinations during 
this same perioperative window (e.g., pembrolizumab in combination with 
other immuno- or molecularly targeted agents, following FOLFOX) may be 
added and enrolled to in sequential fashion via a protocol amendment.
Number of 
patients
Up to 19 patients will be enrolled in the initial cohort (17 evaluable patients 
with paired pre-treatment biopsy and post-pembrolizumab plus vactosertib 
analyzable tumor specimens).
Duration of 
Therapy
Patients will receive a single cycle of pembrolizumab plus vactosertib prior to 
planned hepatic metastasectomy. Additionally, up to 8 cycles of adjuvant 
pembrolizumab plus vactosertib may be administered after hepatic 
metastasectomy.
Duration of 
Follow up
Patients will be followed for up to 1 year after the last dose of pembrolizumab 
is administered or 2 years after surgery (whichever is longer).
Duration of 
study
The study will reach completion 3 years from the time the study opens to 
accrual.
Study Drugs
Neoadjuvant pembrolizumab will be administered at a fixed dose of 200 mg 
(IV) for 1 cycle plus 200 mg vactosertib (PO QD, 5 days per week x 2 weeks).
Adjuvant pembrolizumab (400 mg IV) + vactosertib (200 mg PO QD Cycle 1, 
5 days per week, Cycles 2 and beyond 200 mg BID, 5 days per week) will be 
administered for up to eight 6-week cycles.

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Safety 
Assessments
Safety assessments will include adverse events, clinical laboratory 
evaluations, and vital signs.
Efficacy 
Assessments
Objective response rate, pathologic response rate, R0 resection rate, and 
1-year and 2-year RFS.
Unique 
Aspects of 
this Study
This is the first study to evaluate the safety and efficacy of pembrolizumab plus 
vactosertib following FOLFOX chemotherapy in patients with metastatic CRC 
undergoing liver resection with curative intent. Biopsy of a liver metastasis 
prior to administering pembrolizumab plus vactosertib and resection of the liver 
metastases following 1 cycle of pembrolizumab plus vactosertib will enable 
extensive scientific correlatives. 
Study Schema
The above timeline is approximate with further guidelines below:

A screening computed tomography (CT) chest/abdomen/pelvis with intravenous (IV) 
contrast must be performed and reviewed to confirm candidacy for hepatic resection prior 
to study entry.

If chemotherapy is a direct lead-in to study enrollment, then liver resection surgery should 
be performed within 4-6 weeks of the final chemotherapy administration. During this 4-6 
week window, 1 cycle of pembrolizumab plus vactosertib will be administered 
approximately 2 weeks (minimum 1 week) after the last dose of chemotherapy, and 
surgery will occur approximately 2 weeks (minimum 1 week) after C1D1.

Labs, including liver function testing will be performed after C1D1, as close to surgery as 
possible.

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
In the event that the surgery is canceled, and the first liver biopsy yielded adequate tumor 
material, a second liver biopsy will be requested (same lesion as the first biopsy preferred).

Participants will be followed for up to 2 years after surgery or will be offered optional 
adjuvant treatment (described below).
Optional Adjuvant Treatment

Participants who meet study eligibility criteria (Section 3.3) and have adequately 
recovered from toxicity or complications of a surgery or other procedure, per the 
assessment of the treating investigator will be offered participation in the adjuvant 
treatment cohort (pembrolizumab plus vactosertib).  Patients who still have their primary 
tumor in place (i.e. not surgically removed) would not be eligible for the optional adjuvant 
treatment.

If the participant meets all other eligibility criteria to receive pembrolizumab plus 
vactosertib (e.g., no safety issues), then they will receive adjuvant treatment 6 weeks (±2 
weeks) after hepatic metastasectomy. Participants will receive adjuvant pembrolizumab 
plus vactosertib for up to eight 6-week cycles (approximately 1 year) or until disease 
progression is radiographically documented, unacceptable adverse event(s), intercurrent 
illness that prevents further administration of treatment, investigator’s decision to 
discontinue the patient, administrative reasons requiring cessation of treatment, or 
withdrawal of consent, whichever occurs first.

Correlative labs will be performed every 12 weeks during the adjuvant treatment period.

Participants will be followed for up to 1 year after the last dose of pembrolizumab is 
administered, or until disease progression, the start of new anticancer treatment, or 
withdrawal of consent, whichever occurs first.

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List of Abbreviations
5-FU
5-fuorouracil
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
Absolute neutrophil count
AST
BID
aspartate aminotransferase
twice a day (bis in die)
CBC
complete blood cell (count)
CD
Cluster of differentiation
CEA
Carcinoembryonic antigen
CNB
core needle biopsy
CR
complete response
CRC
Colorectal cancer
CrCl
creatinine clearance
CRF
case report form
CT
computerized tomography
CTCEA
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTMS
Clinical Trial Management System
dMMR
Mismatch repair deficient
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECI
events of clinical interest
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal growth factor receptor
ELISA
enzyme-linked immunoassay
EORTC
European Organisation for Research and Treatment of Cancer
EPO
Erythropoietin
ERC
Ethics Review Committee
FDA
United States Food and Drug Administration
FFPE
Formalin-fixed paraffin-embedded
FOLFIRI
Chemotherapy regimen: 5-FU, leucovorin and irinotecan
FOLFOX
Chemotherapy regimen: 5-FU, leucovorin and oxaliplatin 
FSH
Follicle stimulating hormone

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List of Abbreviations
FT4
Free thyroxine
GCP
Good Clinical Practice
GEP
Gene expression profiling
GFR
glomerular filtration rate
GI
Gastrointestinal
HBeAg
Hepatitis B “e” antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HIPAA
Health Insurance Portability and Accountability Act
HIS PDX
human immune system patient-derived xenografts
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonization
IF
Immunofluorescence
IgG4
immunoglobulin G4
IHC
Immunohistochemistry
IND
investigational new drug application
INR
International Normalized Ratio
IO
Immuno-oncology
irAEs
Immune-related adverse events
IRB
Institutional Review Board
IV
Intravenous(ly)
IVD
in vitro diagnostic
JSC
Joint Steering Committee
LD
Longest dimension
LDH
lactate dehydrogenase
mAb
monoclonal antibody
MEK
Mitogen-activated protein kinase
MHC
major histocompatibility complex
MRI
magnetic resonance imaging
MSI-H
Microsatellite instability high

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List of Abbreviations
MSS
microsatellite stable
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
ORR
objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cells
PBPK
Physiologically-based pharmacokinetics
PD
progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death 1 ligand 1
PD-L2
Programmed cell death 1 ligand 2
PFS
Progression-free survival
PK
Pharmacokinetic
PKCθ
protein kinase C-theta
pMMR
Mismatch repair proficient
PO
by mouth (per os)
PR
partial response
PRMC
QD
Protocol Review & Monitoring Committee (UCSF)
once a day (quaque die)
Q6W
Every 6 weeks
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors 
RFS
relapse-free survival
RNAseq
RNA sequencing
SAE
Serious adverse event
SD
Stable disease
SNP
single-nucleotide polymorphism
T3
Triiodothyronine
TIICs
Tumor-infiltrating immune cells
TILs
Tumor-infiltrating lymphocytes
Tregs
regulatory T cells
TSH
Thyroid stimulating hormone
ULN
upper limit of normal

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List of Abbreviations
US
United States

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Table of Contents
Protocol Signature Page ......................................................................................................1
Abstract
2
List of Abbreviations.............................................................................................................5
Table of Contents.................................................................................................................8
1
Introduction................................................................................................11
1.1
Background on Indication
11
1.2
Background on the Compounds
11
1.2.1
Pembrolizumab
11
1.2.2
Vactosertib13
1.3
Rationale for the Proposed Study
15
1.3.1
Rationale for Perioperative Pembrolizumab-Based Treatment
16
1.3.2
Rationale for Dose Regimen
17
1.3.3
Correlative Studies Background
17
1.3.4
Correlative Studies Hypotheses
18
1.3.5
Biomarker Research
19
1.3.6
Future Biomedical Research Sample Collection 22
2
Objectives of the Study .............................................................................22
2.1
Hypothesis
22
2.2
Primary Objective and Endpoint
22
2.3
Secondary Objectives and Endpoints
23
2.4
Exploratory Objectives and Endpoints
23
3
Study Design.............................................................................................24
3.1
Characteristics
24
3.2
Number of Patients
24
3.3
Eligibility Criteria
24
3.3.1
Inclusion Criteria
24
3.3.2
Exclusion Criteria 26
3.4
Duration of Therapy 28
3.5
Duration of Follow Up
28
3.6
Randomization Procedures 28
3.7
Study Timeline
29
3.7.1
Primary Completion
29
3.7.2
Study Completion 29
4
Study Drugs...............................................................................................29
4.1
Description, Supply and Storage of Investigational Drugs 29
4.1.1
Pembrolizumab
29
4.1.2
Vactosertib30
4.2
Drug Accountability 31
4.3
Drug Ordering
31
4.4
Packaging and Labeling of Study Drugs
31
5
Treatment Plan..........................................................................................32
5.1
Dosage and Administration 32
5.1.1
Pembrolizumab
32

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5.1.2
Vactosertib32
5.1.3
Other Modality(ies) or Procedures
33
5.1.4
Dose Limiting Toxicity
33
5.2
Dose Modifications and Dosing Delays
33
5.3
Monitoring and Toxicity Management
34
5.3.1
Toxicity Management for Immune-Related AEs Associated with 
Pembrolizumab
34
5.3.2
Toxicity Management of Infusion-Reactions Related to Pembrolizumab
38
5.3.3
Other Allowed Dose Interruption for Pembrolizumab
41
5.3.4
Rescue Medication and Supportive Care for AEs Associated with 
Pembrolizumab
41
5.3.5
Monitoring and Management for AEs Associated with Vactosertib
41
6
Study Procedures and Observations.........................................................43
6.1
Schedule of Procedures and Observations 43
6.1.1
Screening Assessments
43
6.1.2
Neoadjuvant Pembrolizumab + Vactosertib Dosing Day 1
44
6.1.3
Pre-surgical Evaluation
45
6.1.4
Liver Resection Surgery
45
6.1.5
Post-surgical Safety Follow-up Visit
45
6.1.6
Optional Adjuvant Treatment
46
6.1.7
Follow-up Phase
48
6.2
Trial Flow Chart
50
6.3
Duration of Follow-up
56
6.4
Withdrawal Criteria
56
6.4.1
Withdrawal from the Study
56
6.4.2
Lost to Follow-up 57
6.5
Usage of Concurrent/Concomitant Medications/Vaccinations
57
6.5.1
Acceptable Concomitant Medications
57
6.5.2
Prohibited Medications
57
6.6
Dietary Restrictions 58
6.7
Pregnancy/Contraception
59
6.7.1
Contraception
59
6.7.2
Use in Pregnancy 60
6.7.3
Use in Nursing Women
60
6.7.4
Pregnancy Tests
61
6.8
Clinical Criteria for Early Trial Termination 61
6.9
Laboratory Procedures/Assessments
61
6.9.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
61
7
Reporting and Documentation of Results..................................................62
7.1
Evaluation of Efficacy (or Activity)
62
7.2
Evaluation of Safety 63
7.2.1
Sponsor Responsibility for Reporting Adverse Events
63
7.3
Definitions of Adverse Events
63
7.3.1
Adverse Event
63
7.3.2
Adverse reaction
65

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7.3.3
Serious Adverse Event
66
7.3.4
Definition of an Overdose Definition
67
7.3.5
Events of Clinical Interest 67
7.3.6
Protocol-Specific Exceptions to Serious Adverse Event Reporting
68
7.4
Recording of an Adverse Event
68
7.5
Reporting Adverse Events to Merck 69
7.5.1
Reporting of Pregnancy and Lactation
71
7.6
Reporting Adverse Events to MedPacto
72
7.7
Follow-up of Adverse Events
72
7.8
Adverse Events Monitoring 73
8
Statistical Considerations and Evaluation of Results ................................74
8.1
Study Endpoints
74
8.1.1
Study Design
75
8.1.2
Randomization
75
8.1.3
Stratification Factors
75
8.2
Determination of Sample Size and Accrual Rate
75
8.2.1
Sample Size and Power Estimate75
8.2.2
Replacement Policy
75
8.2.3
Accrual estimates 75
8.3
Interim Analyses and Stopping Rules
76
8.4
Analyses Plans
76
8.4.1
Analysis Population
76
8.4.2
Primary Analysis (or Analysis of Primary Endpoints)
77
8.4.3
Secondary Analysis (or Analysis of Secondary Endpoints)
77
8.4.4
Exploratory Analysis (or Analysis of Exploratory Endpoints)
77
9
Study Management ...................................................................................77
9.1
Pre-study Documentation
77
9.2
Institutional Review Board Approval 78
9.3
Informed Consent
78
9.4
Changes in the Protocol
78
9.5
Handling and Documentation of Clinical Supplies
78
9.6
Case Report Forms (CRFs) 79
9.7
Oversight and Monitoring Plan
79
9.8
Record Keeping and Record Retention
79
9.9
Coordinating Center Documentation of Distribution 80
10
Protection of Human Patients....................................................................80
10.1
Protection from Unnecessary Harm 80
10.2
Protection of Privacy 81
References
82
Appendices
85
Appendix 1:
Performance Status Criteria......................................................................85
Appendix 2:
UCSF Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional 
Study .........................................................................................................86
[DSMP language updated 08/21/2020] ..............................................................................88

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Appendix 3:
Common Terminology Criteria for Adverse Events V5.0 (CTCAE)...........89
Appendix 4: The Clavien-Dindo Classification of Surgical Complications..........................90

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1
Introduction
1.1
Background on Indication
Colorectal cancer (CRC) is a major global public health problem. Approximately 1 in 20 Americans 
will be diagnosed with CRC in their lifetime. Metastatic CRC is the second leading cause of cancer 
death in the United States (US), with nearly 50,000 deaths attributed to this disease each year. 
The 5-year survival rate is only 13% for patients with distant metastases [1]. The liver is the most 
common site of metastases for CRC, occurring in ~40-50% of patients either at the time of initial 
diagnosis (synchronous) or at disease progression (metachronous). Due to the closed portal 
circulation, liver metastases from CRC are potentially resectable with curative intent, with a 5-
year survival rate approaching 50% [2]. Factors that influence likelihood of cure with 
metastasectomy include the presence of extrahepatic disease, node-positive primary tumor, size 
and number of metastases, disease-free interval between original diagnosis and development of 
metastases, and preoperative carcinoembryonic antigen (CEA) level [3, 4]. However, progression 
is common and ultimately occurs in up to 75% of patients. About 30% of patients who undergo 
liver resection with curative intent are indeed cured, defined by 10-year survival without evidence 
of CRC.
Perioperative chemotherapy is now an established standard of care for patients with CRC with 
resectable hepatic metastases. Neoadjuvant chemotherapy can improve clinical risk scores to 
predict outcomes of patients with CRC liver metastases who undergo metastasectomy [5]. A 
Phase 3 study, European Organisation for Research and Treatment of Cancer (EORTC) 
Intergroup trial 40893 [6], randomized 364 patients with CRC and up to 4 liver metastases to 
receive either 6 cycles of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) pre- and 
post-operatively, or surgery alone. The absolute increase in 3-year progression-free survival 
(PFS) associated with perioperative FOLFOX was 7.3% (35.4 vs. 28.1%; HR 0.79, p=0.058) in 
randomized patients, and 9.2% (42.4 vs. 33.1%; HR 0.73, p=0·025) in patients actually 
undergoing resection. However, the postoperative complication rate was higher in the 
chemotherapy arm (25 vs 16%; p=0.04); and long-term follow-up data showed no difference in 
median overall survival (OS) between the 2 groups (61.3 vs 54.3 months) [7].
There remains a significant unmet need for new agents that may increase the survival of patients 
with CRC undergoing liver metastasectomy. The need is particularly great for the ~95% of patients 
with mismatch repair proficient (pMMR) metastatic CRC, whose cancers have not responded to 
pembrolizumab monotherapy [8]. As detailed below, there is evidence of immune-stimulatory 
effects induced by both 5-FU and oxaliplatin, which we hypothesize will promote tumor response 
to pembrolizumab.
1.2
Background on the Compounds
1.2.1
Pembrolizumab
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with PD-1 ligand 1 (PD-L1) and PD-L2. Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. Pembrolizumab 
has an acceptable preclinical safety profile and is in clinical development as an intravenous (IV) 

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immunotherapy for advanced malignancies. KEYTRUDA® (pembrolizumab) is indicated for the 
treatment of patients across a number of indications. For more details on specific indications. For 
more details on specific indications refer to the Investigator’s Brochure (IB).
1.2.1.1
Pharmaceutical and Therapeutic Background on Pembrolizumab
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [9]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of cluster of differentiation 8 positive (CD8+) T cells and 
the ratio of CD8+ effector T cells/FoxP3+ regulatory T cells (Tregs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma 
(RCC). Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [9] [10].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-
L2) [11] [12].
The structure of murine PD-1 has been resolved [13]. PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-
based inhibition motif, and an immunoreceptor tyrosine-based switch motif. After T-cell stimulation, 
PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor tyrosine-
based switch motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated 
protein kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade [12, 14-16]. The 
mechanism by which PD-1 down-modulates T cell responses is similar to, but distinct from, that 
of CTLA-4, because both molecules regulate an overlapping set of signaling proteins [17, 18]. As 
a consequence, the PD 1/PD-L1 pathway is an attractive target for therapeutic intervention in 
CRC.
1.2.1.2
Preclinical and Clinical Trial Data
Refer to the pembrolizumab IB for detailed Preclinical and Clinical data.
1.2.1.3 Clinical Trials Testing Pembrolizumab in Colorectal Cancer
Immune checkpoint inhibitors such as pembrolizumab have shown robust single-agent antitumor 
activity in the ~5% of patients with metastatic CRCs harboring microsatellite instability (MSI-high 
[MSI-H]) or mismatch repair deficiency (dMMR). Preliminary reporting indicated an (immune-
related) objective response rate of 40% (4 of 10 patients). On the other hand, 0% (0 of 18 patients) 

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with microsatellite stable (MSS) or pMMR metastatic CRCs achieved an objective response 
(NCT01876511)[8]. As a result, additional studies are underway for patients with metastatic CRC 
and MSI-H or dMMR to test pembrolizumab monotherapy in the previously-treated with 
chemotherapy setting [19] or pembrolizumab versus standard chemotherapy in the first-line 
setting [20].
Pembrolizumab is approved for use in CRC or other tumors that are MSI-H. Specifically, for the 
treatment of adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR:

solid tumors that have progressed following prior treatment and who have no satisfactory 
alternative treatment options, or

colorectal cancer that has progressed following treatment with a fluoropyrimidine, 
oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and 
durability of response. Continued approval for this indication may be contingent upon verification 
and description of clinical benefit in the confirmatory trials.
1.2.2
Vactosertib
Transforming growth factor beta (TGF-β) has been shown to be a potent growth inhibitor for 
normal epithelial, hematopoietic, and immune cells, and has a major role in normal tissue 
homeostasis. In the early stage of cancer development, TGF-β acts as a tumor suppressor, 
whereas in late stages, TGF-β can take on tumor promoter roles, favoring invasion and 
metastasis. In the TGF-β signaling pathway, TGF-β receptor type I (TGFBR1) inhibitors have 
shown promise blocking TGF-β-mediated tumor progression, metastasis, and suppression of 
antitumor immunity in nonclinical animal models. TGFBR1 inhibitors specifically inhibit the Smad 
pathway by occupying the ATP binding site of the TGFBR1 kinase domain, which is essential for 
the phosphorylation of its substrates, Smad2 and Smad3.
Vactosertib (International non-proprietary name [INN] name; also known as TEW-7197, EW-
7197) is a potent, highly selective, oral inhibitor of TGFBR1. 
Refer to the IB for detailed background information on vactosertib.
1.2.2.1
Pharmaceutical and Therapeutic Background on Vactosertib
The Enhanced antitumor activity with the combination of TGF-β inhibition with anti-PD-(L)1 was 
observed in a number of preclinical studies.
In a recent publication, quadruple-mutant mice developed metastatic intestinal tumors that display 
key hallmarks of human MSS colorectal cancers, including low mutational burden, T-cell exclusion 
and TGF-β-activated stroma. Inhibition of the PD-1-PD-L1 immune checkpoint provoked a limited 
response in this model system. By contrast, inhibition of TGF-β unleashed a potent and enduring 
cytotoxic T cell response against tumor cells that prevented metastasis. In mice with progressive 
liver metastatic disease, blockade of TGF-β signaling rendered tumors susceptible to anti-PD-1–
PD-L1 therapy. These results show that increased TGF-β in the tumor microenvironment 
represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks 
acquisition of the TH1-effector phenotype [21].

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In an autochthonous BRAFV600EPTEN-/- melanoma model, vactosertib (25 mg/kg, PO daily) in 
combination with CTLA4 antibody (100 µg IP every 3 days) induced a suppression of primary 
melanoma growth, a reduction of pulmonary metastatic lesions, and a significant improvement in 
the overall survival of tumor-bearing mice [22]. An increased number of CD8+ T cells are observed 
in primary melanoma lesions as well as draining lymph nodes. Using syngeneic 
BRAFV600EPTEN-/- melanoma model, addition of vactosertib to anti-PD-1 treatment enhanced 
antitumor response in this study.
Combination of vactosertib and anti-mouse-PD-1 significantly increased antitumor activity and 
survival rate compared to control, vactosertib monotherapy and anti-PD-1 monotherapy in a 
mouse CEA2-MC38 colorectal cancer model (MedPacto data, TED-229, refer to IB). In another 
syngeneic mouse model using NCC-S1M, a diffuse type gastric cancer cell line, synergistic 
antitumor effect resulting in decreases in tumor volume and weight were observed with the 
combined vactosertib and anti-PD-1 treatment comparing to anti-PD-1 monotherapy (MedPacto 
data, refer to IB).
Enabling immune infiltration using TGF-β inhibitors is sufficient to confer susceptibility to anti-
PD-1 checkpoint-based therapies, a strategy that may have broad applications for treatment of 
cancers that grow in a TGF-β-rich environment.
1.2.2.2
Preclinical and Clinical Trial Data
Preclinical studies showed anti-tumor efficacy and sufficient target gene suppression with 
vactosertib of human equivalent dose to 125 mg QD. The pharmacokinetics and 
pharmacodynamics of vactosertib were analyzed in mouse melanoma SC model (B16F10) after 
single oral administration of vactosertib at a dose of 25 mg/kg (MedPacto data, TED-199). Refer 
to the vactosertib IB for detailed preclinical and clinical data.
1.2.2.3 Clinical Trials Testing Vactosertib in Colorectal Cancer
The MP-VAC-204 study (NCT03724851) is a phase 1b/2a, open-label, multi-center, dose finding 
study to assess safety, tolerability, pharmacokinetics and anti-tumor activity of vactosertib in 
combination with pembrolizumab in previously treated mCRC. The study includes dose escalation 
(Phase 1b) and dose expansion (Phase 2a).
Seventeen patients were enrolled in the 200 mg BID group and 33 patients enrolled in the 300 
mg BID group.  Six patients in the 300 mg BID group are currently being treated, describing the 
preliminary result as of April 1, 2021. Ninety-four percent of the 200 mg group and 48% of the 300 
mg group were previously treated with more than third line therapy. Most patients have received 
fluoropyrimidine, irinotecan and oxaliplatin treatment. Ninety-four percent of patients in both 
groups were previously treated with bevacizumab while 53% of the 200 mg group and 42% of the 
300 mg group received prior anti-EGFR inhibitors (panitumumab/cetuximab). In addition, patients 
in 53% of the 200 mg group and 18% of the 300 mg group received regorafenib treatment. In the 
MP-VAC-204 study, 11 of the 50 subjects (22.0%) were found to have treatment-related adverse 
event (TRAE) of grade 3 or higher with 9 (18.0%) reported to have TRAE of grade 3 or higher 
related to vactosertib. Two patients (4%) discontinued treatment due to grade 2 pneumonitis and 
grade 3 rash. Most frequently reported TRAEs were rash followed by pruritus, fatigue, decreased 
appetite and amylase/lipase increase. Two cases of adrenal insufficiency, asthma, decreased 

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appetite, diarrhea, vomiting, pneumonia, tuberculosis, and rash have also been reported as grade 
3 treatment related serious adverse event (SAE). No cardiac toxicity was observed during the 
study. Both 200 mg or 300 mg BID vactosertib doses in combination with pembrolizumab were 
well tolerated in this metastatic mCRC patients who had previously been treated with oxaliplatin 
and irinotecan based chemotherapy.
Based on the available tolerability data from 11 patients enrolled as of March 5, 2021, a decision 
was made to decrease the vactosertib dose from 300 mg BID to either 200 mg BID or 200 mg 
QD. Dose adjustment or withdrawal was required in 4 out of 11 patients and 2 Gr 3 events (acute 
hepatitis and skin rash) were considered to be related to the enhanced immune response to the 
study treatment. This reduced tolerability was unexpected as vactosertib 300 mg BID with 
pembrolizumab had shown acceptable tolerability in metastatic colorectal cancer patients inMP-
VAC-204. The differences in tolerability between the two studies may be attributed to differences 
in the host immune status and prior exposures to cytotoxic chemotherapy. Subjects in MP-VAC-
204 study had experienced 4 lines (median) of prior chemotherapy. Vactosertib 200 mg showed 
effective decrease in TGF-β downstream markers including phospho-SMAD, PAI-1, CTGF and 
PDGF. 
In a mouse model, vactosertib 25 mg/kg, equivalent to human dose of approximately 120 mg QD, 
exerted antitumor activity when combined with anti-PD-1 treatment. 
Arm 1 will evaluate the vactosertib dose escalation strategy. Vactosertib 200 mg QD will be 
administered with pembrolizumab during the 1st Cycle.  If no significant drug-related toxicity is 
observed, vactosertib 200 mg BID will be administered with pembrolizumab during subsequent 
cycles. This will allow patients to develop tolerability. Such dose-escalation strategy based on 
tolerability has been successfully tested in other trials [Bekaii-Saab, T.S., et al., The Lancet 
Oncology, 2019]. Set dose of vactosertib 200 mg QD with pembrolizumab will be evaluated in 
Arm 2.
1.3
Rationale for the Proposed Study
Metastatic CRC is the second leading cause of cancer death in the US, accounting for nearly 
50,000 deaths each year. Approximately 95% of patients with metastatic CRC have pMMR 
disease, and are in need of new therapies with manageable side-effects which can produce 
durable treatment responses, as has been observed with pembrolizumab monotherapy in patients 
with MSI-H/dMMR CRC[8]. First- and second-line standard of care regimens for metastatic CRC 
are FOLFOX and 5-FU, leucovorin, and irinotecan (FOLFIRI) with or without a biologic agent 
(bevacizumab or, if RAS wild-type, an epidermal growth factor receptor [EGFR]-targeted 
antibody). Recently US Food and Drug Administration (FDA)-approved third-line therapies are 
regorafenib and TAS-102. Regorafenib was approved based on a median OS of 6.4 months 
compared to 5 months with placebo and is associated with a median PFS of 2 months and 
objective response rate (ORR) of 1% [35]. TAS-102 was approved based on a median OS of 7.1 
months, versus 5.3 months with placebo; with a median PFS of 2 months and ORR of 1.6% [23].
Patients with resectable liver metastases have a chance for cure with metastasectomy. 
Perioperative chemotherapy is standard of care in such cases, with a goal to eliminate any extra-
hepatic micrometastatic disease [6]. FOLFOX (or CapeOx) is the preferred preoperative 

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chemotherapy regimen in patients with resectable metastatic disease at diagnosis (synronous 
metastases), as it is associated with reversible morbidity (sinusoidal injury) without increased 
mortality. By contrast, the other first-line chemotherapy regimen, FOLFIRI, is associated with 
increased mortality related to steatohepatitis (especially in high-risk populations or with extended 
resections)[6, 24]. Moreover, the addition of biologics to chemotherapy in the context of 
(potentially) resectable metastatic CRC remains uncertain, with agents such as cetuximab not 
clearly demonstrating benefit in this setting [25]. Bevacizumab is also typically not used in this 
context, as it should be stopped at least a month prior to surgery to avoid bleeding or wound 
healing complications. Additionally, there is evidence that once started bevacizumab should be 
continued even beyond progression [26].
As in the Nordlinger study, we typically give 6 cycles of FOLFOX to patients with synchronous 
metastases who are candidates for liver resection [6]. Practice patterns vary greatly for patients 
with metachronous metastatic disease, based on the specific circumstances, hence flexibly was 
built into this protocol for feasibility. When applicable, it is then standard to wait 4 to 8 weeks from 
the time of last FOLFOX administration until surgery. This waiting period represents a window of 
opportunity to intervene.
Additionally, only about 30% of patients with hepatic metastases treated with curative intent 
actually achieve cure [2, 27]. Most recurrences occur within 2 years of surgery, so 2-year relapse-
free survival (RFS) is a common intervention endpoint [28, 29]. Importantly, despite the high 
recurrence rate, observation is recommended after surgery for resectable metastases in patients 
who have received prior oxaliplatin-based therapy because no standard chemotherapy has been 
proven to improve RFS [30]. Introduction of experimental adjuvant therapy after metastasectomy 
offers another opportunity for intervention, with a goal to clear any remaining micrometastatic 
disease.
1.3.1
Rationale for Perioperative Pembrolizumab-Based Treatment 
Identification of new strategies to augment immune-related responses in the broader population 
of metastatic CRC patients, without dMMR or MSI-H tumors, is essential[31]. Whereas immune 
checkpoint inhibitors such as pembrolizumab have shown robust single-agent antitumor activity 
in the ~5% of patients with metastatic CRCs harboring MSI-H or dMMR, novel strategies are 
needed for the ~95% of patients with MSS or pMMR metastatic CRC [8]. These strategies may 
include combining pembrolizumab with cytotoxic, targeted, or other immunotherapy agents.
Potentially resectable metastatic CRC represents an ideal clinical setting to assess both the 
clinical efficacy and immunologic/pharmacodynamics effects of pembrolizumab-based therapies, 
as the majority of carefully selected patients are ultimately taken to surgery following preoperative 
therapy (87.3% in the Nordlinger EORTC study)[6]; therefore, a large quantity of tumor tissue is 
available for immune cell characterization and immune/molecular profiling.
The Primary Objective of this study is to characterize change in the populations of TILs induced 
by neoadjuvant pembrolizumab-based therapy in patients with metastatic CRC with potentially 
resectable hepatic metastases. The Primary Endpoint is specifically defined as the proportion of 
patients with a ≥2-fold increase in the TILs in post- vs. pre-pembrolizumab-based treatment tumor 
specimens. A ≥2 fold increase was the threshold used for 2 prior trials of neoadjuvant 
immunotherapy [28, 29]. Including a prospective study evaluating the direct immune effects of 
sipuleucel-T on prostate cancer tissue in the peri-operative setting.  Sipuleucel-T, which was FDA-

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approved for improved OS in prostate cancer, induced a >2 fold increase in TILs per unit area of 
tissue [28]. We believe that a doubling in immune infiltration would be deemed as biologic 
meaningful, whereas magnitudes of change less than that can be more arguable for publication. 
In two published trials of prostate cancer we have shown that neoadjuvant immunotherapies can 
induce a >3x increase  in TILs[36]. This is in excess of the doubling with which we set the threshold 
in this trial.
This concept is part of a larger collaboration between UCSF and Merck to dissect the changes 
within the tumor microenvironment induced with pembrolizumab-based combinations in 3 distinct 
indications (non-small cell lung cancer [NSCLC], RCC, and CRC). The combinations and cohorts 
that will move forward will be selected by a Joint Steering Committee (JSC) comprised of both 
UCSF and Merck researchers. We anticipate flexibility in the design to “go where the science 
takes us.” Thus, patient accruals may ultimately shift between the indications.
The Secondary Objectives of this study are to establish the safety/toxicity profile and explore the 
efficacy of pembrolizumab + vactosertib in patients with CRC with potentially resectable hepatic 
metastases. The following outcomes will be measured: adverse events (AEs) and perioperative 
complications, pathologic response, R0 resection rate, and 2-year RFS. Two-year RFS rates will 
be compared between participants who do and do not receive adjuvant pembrolizumab-based 
therapy.
While the current protocol focuses on pembrolizumab + vactosertib following chemotherapy, we 
anticipate exploring other novel pembrolizumab-based combinations during this same post-
chemotherapy/preoperative window (e.g., pembrolizumab in combination with other immuno- or 
molecularly targeted agents following FOLFOX). These novel combinations will be incorporated 
into the study as protocol amendments, and patients will be enrolled to them in a sequential, non-
randomized fashion.
1.3.2
Rationale for Dose Regimen
The planned dose of pembrolizumab for this study is 200 mg (IV) for 1 neoadjuvant cycle and 
400 mg (IV) for up to eight 6-week adjuvant cycles (optional). The pembrolizumab doses used in 
this trial have been demonstrated to be well tolerated in earlier clinical trials.
The planned dose of vactosertib for this study is 200 mg PO QD, 5 days per week for 2 weeks 
during the neoadjuvant treatment period, and 200 mg PO QD, 5 days per week for 6 weeks (1 
cycle) and depending on tolerability, patients will receive 200 mg PO BID, 5 days per week for 
up to  42 weeks (7 cycles) during the optional adjuvant treatment period. The vactosertib dosing 
regimen used in this trial has been demonstrated to be well tolerated in the ongoing early phase 
clinical trials.
1.3.3
Correlative Studies Background
Correlative science to inform optimal use of pembrolizumab + vactosertib with chemotherapy in 
patients with metastatic CRC and to identify candidate biomarkers of response, resistance or 
toxicity, is an integral part of this study. As a result, serial blood samples as well as tissues from 
biopsies and surgical resection will be used to perform deep immunologic and molecular profiling 
prior to, during and following treatment.

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Correlative research will be performed on:

Baseline liver tumor biopsies (just prior to administration of neoadjuvant treatment).

Surgical resection specimens (after neoadjuvant pembrolizumab-based treatment). Note 
that if patients undergo resection of multiple liver metastases, surgical removal of liver 
metastases plus colon primary, or other cases where surgical specimens are available 
from multiple sites, collection of multiple specimens is encouraged, with priority given to 
the liver metastasis corresponding to the pre-treatment biopsy.

If a patient is unable to undergo surgery but had a pre-treatment biopsy that was confirmed 
to contain adequate tumor material for analysis and received one cycle of neoadjuvant 
pembrolizumab-based treatment, a second liver biopsy should be performed after the 
cycle of neoadjuvant treatment (biopsy of same liver metastasis as sampled in the pre-
treatment biopsy preferred).

Serial blood samples (pre-neoadjuvant treatment, pre-surgery, post-surgery, and at 
progression or end of study, whichever comes first).

Stool samples collected at screening (-4 and -2 days of first pembrolizumab dose), at pre-
surgical evaluation, and at the safety follow-up visit [optional].
Goals of the correlative research are to determine how immunotherapy perturbs both the 
circulating and intratumoral immune responses. Assays will be detailed in the Procedure Manual.
Stool will be collected, and a stool questionnaire will be completed at screening (-4 and -2 days 
of first pembrolizumab dose), at pre-surgical evaluation, and at the safety follow-up visit [optional] 
to assess the microbiome associated with clinical activity. This research may help identify factors 
predictive of pembrolizumab-based treatment response and resistance and novel targets for 
cancer immunotherapy.
Additionally, a dietary and physical activity questionnaire will be administered at screening (-28 to 
-1 day prior to first pembrolizumab dose).
1.3.4
Correlative Studies Hypotheses
Translational research hypotheses to be investigated are:
a) Pembrolizumab-based treatment will induce increased populations of TILs within 
metastatic CRC tumor samples.
b) Increase in TILs induced by pembrolizumab-based treatment is correlated with 
pathological 
response 
in 
patients 
with 
metastatic 
CRC.
c)
Pembrolizumab-based treatment will increase PD-L1 expression in TIICs and may be 
associated with pathological response.
d) Distinct T cell repertoire changes in tumor tissue will be associated with response, 
resistance, or toxicity to pembrolizumab-based treatment.
e) Pembrolizumab-based treatment will induce characteristic changes in circulating T cell 
populations. 

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f)
Distinct T cell repertoires in tumor tissue as well as in circulating T cells may be associated 
with response/resistance or toxicity to pembrolizumab-based treatment, and may in turn 
serve as biomarkers of response/resistance or toxicity. 
g) Molecular characteristics beyond MSI/MMR (candidates include BRAF, BAP1, and 
SETD2) may be associated with higher levels of TIICs or PD-L1 expression on TIICs in 
response to pembrolizumab-based treatment, and thus be candidates for further study as 
predictive biomarkers in patients with metastatic CRC treated with immunotherapy.
h) Genomic mutations and gene copy variants may associate with clinical and/or 
immunologic response to therapy.
i)
Correlate changes in microbiome composition and diversity (by metagenomic sequencing 
and untargeted metabolomics of stool collected before, during, and after immunotherapy), 
with diet and lifestyle factors.
1.3.5
Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. However, 
the mechanism of action of these exciting new therapies is not completely understood and much 
remains to be learned regarding how best to leverage these new drugs in treating patients. Thus, 
to aid future patients, it is important to investigate the determinants of response or resistance to 
cancer immunotherapy and other treatments administered, as well as determinants of AEs in the 
course of our clinical trials. These efforts will identify novel predictive/pharmacodynamic 
biomarkers and generate information that will better guide single-agent and combination therapy 
with immuno-oncology (IO) drugs. To identify novel biomarkers, biospecimens (i.e., blood 
components, tumor material, and microbiome) will be collected to support analyses of cellular 
components (e.g., protein, DNA, RNA, metabolites) and other circulating molecules. Procedures 
are detailed in the Lab Manual. Investigations may include but are not limited to:
Tissue proteomic analysis by immunohistochemistry (IHC) and Immunofluorescence (IF)
IHC staining of PD-L1 protein in tumor sections has been shown to correlate with response to 
pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device has been 
developed for use with pembrolizumab in NSCLC. Preliminary data indicates that this association 
may also be true in additional cancer types (i.e., triple negative breast, head and neck, and gastric 
cancer). Additional proteins expressing in the tumor microenvironment at baseline or following 
treatment may also correlate with response to pembrolizumab. Therefore, tumor tissue may be 
subjected to proteomic analyses using a variety of platforms that could include but are not limited 
to IHC and IF. Multiplex IHC and IF may be performed on tumor core samples and resected 
tissues utilizing immune marker panels to assess for different cell types, including T cells, antigen 
presenting cells and stromal cells. Stained sections will be scanned, and the number of stained 
cells enumerated per area of tissue by computerized image analysis. The staining panels to be 
utilized will be developed in collaboration and agreement with Merck and the Principal 
Investigator. This approach could identify novel protein biomarkers that could aid in patient 
selection for pembrolizumab (MK-3475) therapy.
For the Primary Endpoint, defined as the proportion of patient with a ≥2-fold increase in TILs in 
post- vs. pre-pembrolizumab-based treatment tumor specimens, TILs will be enumerated per area 
of tissue (5 high power fields). We have developed this methodology and applied it to other 

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neoadjuvant immunotherapy trials (28, 29). This automated methodology can be applied to 
biopsies and resection tissues.
Gene Expression Profile (GEP) 
Intratumoral expression levels of select genes will be analyzed using an analytically validated 
platform, such as the NanoString nCounter Analysis System and RNAseq. Association between 
the immune-related GEP and response to pembrolizumab has been established using these 
genes in melanoma and in cancers from clinical studies KN012 (head and neck, bladder, and 
gastric cancers) and KN028 (ovarian, esophageal, and other cancers). Data from these cohorts 
has been used to derive a GEP, which combines the expression levels of several key genes into 
a single scalar score. The GEP includes genes from immune-regulatory pathways and a GEP 
score will be tested for association with response to pembrolizumab-based treatment in 
retrospective fashion. 
Flow Cytometry
Peripheral blood mononuclear cells (PBMC) and dissociated single cell suspensions of fresh 
tissue (where available) will be assessed for immune cell composition and functional status using 
flow cytometry staining. Other cell types (including stroma and tumor cells) may also be assessed 
by flow cytometry. 
Additional biomarker research to identify factors important for pembrolizumab-based treatment 
therapy may also be pursued. For example, tumor and blood samples (including serum and 
plasma) from this study may undergo proteomic, genomic, metabolomic, and transcriptional 
analyses. Additional research may evaluate factors important for predicting responsiveness or 
resistance to pembrolizumab-based treatment and other immunologic targets.
Germline (blood) genetic analyses (e.g. single-nucleotide polymorphism [SNP] analyses, whole 
exome sequencing, whole genome sequencing) 
This research will also evaluate whether genetic variation within a clinical trial population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
correlate with efficacy or AEs, the data might inform hypotheses regarding optimal use of 
therapies in the patient population. Furthermore, it is important to evaluate germline DNA variation 
across the genome in order to interpret tumor-specific DNA mutations. Finally, MSI may be 
evaluated as this is an important biomarker for some cancers (i.e. CRC). 
Other blood-derived biomarkers- Proteomic Analysis
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and released into 
the blood. Assays such as enzyme-linked immunoassay (ELISA) can measure PD-L1 in serum. 
Correlation of expression with response to pembrolizumab (MK-3475) therapy may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers. This research would serve to develop such assays for 
future clinical use.

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Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided scientists 
the opportunity to identify tumor-specific DNA changes (i.e. mutations, methylation status, MSI). 
Key molecular changes of interest to immune-oncology drug development include the mutational 
burden of tumors and the clonality of T cells in the tumor microenvironment. Increased mutational 
burden (sometimes referred to as a ”hyper-mutated” state) may generate neo-antigen 
presentation in the tumor microenvironment. To conduct this type of research, it is important to 
identify tumor-specific mutations that occur across all genes in the tumor genome. Thus, genome-
wide approaches may be used for this effort. Note that in order to understand tumor-specific 
mutations; it is necessary to compare the tumor genome with the germline genome. 
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and sequencing 
in tumor tissue and in blood may be performed to define gene signatures that correlate to clinical 
response to pembrolizumab-based treatment or other immunotherapies. Pembrolizumab induces 
a response in tumors that likely reflects an inflamed/immune phenotype. Specific immune-related 
gene sets (i.e. those capturing interferon-gamma transcriptional pathways) may be evaluated and 
new signatures may be identified. Individual genes related to the immune system may also be 
evaluated (e.g. IL-10). MicroRNA profiling may also be pursued.
Planned Genetic Analysis 
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity and 
progression of disease. Variable response to therapy may be due to genetic determinants that 
impact drug absorption, distribution, metabolism, and excretion; mechanism of action of the drug; 
disease etiology; and/or molecular subtype of the disease being treated. Therefore, where local 
regulations and Institutional Review Boards (IRBs)/Ethics Review Committees (ERCs) allow, a 
sample will be collected for DNA analysis from consenting patients.
DNA samples will be used for research related to the study treatment(s), the disease under study 
and related diseases. They may also be used to develop tests/assays including diagnostic tests 
related to the disease under study, related diseases and study drug(s). Genetic research may 
consist of the analysis of 1 or more candidate genes or the analysis of genetic markers throughout 
the genome (or analysis of the entire genome, as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data. 
The samples may be analyzed as part of a multi-study assessment of genetic factors involved in 
the response to understand study disease or related conditions.
Whole Exome Sequencing
Flash freezing of fresh biopsy cores in liquid nitrogen may allow for RNA-sequencing and Whole 
Exome Sequencing of tumor. This analysis will be performed using fresh frozen tissue specimens 
from both core needle biopsy (CNB) and resected tumor tissues.

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Microbiome analysis of stool
Stool samples from this study will be collected for analyses including, but not limited to, 
metagenomic sequencing and untargeted metabolomics to reveal changes in gut microbial 
structure and function during treatment, including overall diversity and relative abundance of gut 
bacterial species, genes, and metabolites implicated in response to immunotherapy.
1.3.6
Future Biomedical Research Sample Collection
The investigators will conduct Future Biomedical Research on specimens for which consent was 
provided during this clinical trial. This research may include flow cytometry, genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma), microbiome 
analysis of stool, characterization of circulating cell free DNA, and/or the measurement of other 
analytes, depending on which specimens are consented for future biomedical research. 
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for Future Biomedical Research is to 
explore and identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, more 
effective drugs/vaccines, and/or to ensure that participants receive the correct dose of the correct 
drug/vaccine at the correct time. Decisions on Future Biomedical Research will be made by the 
Joint Steering Committee. 
1.3.6.1 Future Biomedical Research Samples
The following specimens could be obtained as part of Future Biomedical Research:

DNA for future research

Leftover tumor for future research

Leftover DNA and RNA from Correlative Studies

Leftover plasma and serum from Biomarker Studies

Leftover PBMC from whole blood from Correlative Studies

Microbiome
2
Objectives of the Study
2.1
Hypothesis
We hypothesize that pembrolizumab plus vactosertib will increase tumor-infiltrating immune 
cells (TIICs) and promote response without increasing perioperative complications.
2.2
Primary Objective and Endpoint
Primary Objective
Endpoint
Time Frame 
To characterize the change in the 
populations of TILs induced by 
The primary endpoint is the proportion of 
patients with a ≥2-fold increase in the 
From pre-treatment 
to surgery.

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Primary Objective
Endpoint
Time Frame 
neoadjuvant pembrolizumab plus 
vactosertib in patients with metastatic 
CRC.
TILs per unit area (5 high power fields) 
in post- vs. pre-pembrolizumab-based 
treatment tumor specimens.
2.3
Secondary Objectives and Endpoints
Secondary Objectives
Endpoints
Time Frame
1.
To establish the safety/toxicity 
profile of pembrolizumab-based 
treatment in the perioperative 
setting for patients with CRC with 
resectable hepatic metastases.

Proportion of participants with 
Adverse Events, as graded by NCI 
CTCAE version 5.0

Proportion of participants with 
events of clinical interest (ECIs)

Rates of perioperative 
complications
From initiation of 
study treatment 
until 1 year post 
last dose of 
pembrolizumab.

R0 resection rate

Pathologic response in resected 
tumor

Objective response rate
From baseline to 
surgery.
2.
To explore the efficacy of 
pembrolizumab plus vactosertib 
in patients with CRC with 
resectable hepatic metastases.

2-year relapse-free survival (RFS) From surgery to up 
to 2 years post-
surgery.
2.4
Exploratory Objectives and Endpoints 
Exploratory Objectives
Endpoints
1.
To determine the impact of pembrolizumab-
based treatment on PD L1 expression in 
tumor cells and TIICs, in patients with 
mCRC.
2.
To determine the change in T cell repertoire 
within the tumor and blood induced by 
neoadjuvant pembrolizumab-based treatment 
in patients with mCRC.
3.
To explore molecular profiles to identify 
potentially predictive biomarkers for patients 
with metastatic CRC treated with 
immunotherapy (including but not limited to 
MSI testing).
4.
To correlate change in TIICs, PDL-1 
expression, and T cell repertoires as well as 
molecular profiles with response/resistance 
and toxicity. 
5.
To identify immune response mRNA 
expression analysis to derive signatures 
associated with tumor response

Change in T-cell repertoire in pre-
neoadjuvant treatment liver biopsies vs. 
surgical tumor specimens as well as in 
blood samples from the same time-points

Change in PD-L1 expression and other 
molecular markers in pre-neoadjuvant 
treatment liver biopsies vs. surgical 
tumor specimens

Correlate changes in microbiome 
composition and diversity (by 
metagenomic sequencing and 
untargeted metabolomics of stool 
collected before, during, and after 
immunotherapy), with diet and lifestyle 
factors determined by self-reported 
questionnaires.

Explore the correlation between change 
in TILs and T-cell repertoire. 

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Exploratory Objectives
Endpoints
6.
To identify genomic mutations and gene copy 
aberrations associated with response and 
resistance to therapy
7.
To correlate changes in microbiome 
composition and diversity with diet and 
lifestyle factors
3
Study Design
3.1
Characteristics
This is a single arm, open-label trial evaluating the feasibility, immune effects, safety, and efficacy 
of pembrolizumab-based treatment in the preoperative setting for patients with CRC undergoing 
planned liver resection for hepatic metastases. The primary endpoint is the proportion of patients 
with a ≥2-fold increase in the number of TILs in post- vs. pre-pembrolizumab-based treatment 
tumor specimens. 
Based on the results of this initial cohort, this trial may be subsequently amended to explore other 
novel pembrolizumab-based combinations (such as pembrolizumab in combination with another 
IO agent, chemotherapeutic, or a molecularly targeted agent that potentiates the efficacy of 
pembrolizumab) that will be decided by the Joint Steering Committee (JSC). Each of these new 
cohorts will be tested and enrolled to in sequential, non-randomized fashion. The trial is not 
designed to compare arms.
3.2
Number of Patients
In order to accrue 17 patients who are evaluable for the primary endpoint, the plan is to enroll a 
total of 19 patients. If 2 or more of first 6 patients are unable to undergo planned surgical resection 
of their liver metastases in timely fashion (i.e., within 4-6 weeks of the final chemotherapy 
administration [if applicable]) or experience surgical complications attributed to pembrolizumab-
based treatment, accrual will be suspended, and our strategy will be revisited.
3.3
Eligibility Criteria
Patients must have baseline evaluations performed prior to dosing of study drug and must meet 
all of the inclusion and none of the exclusion criteria. In addition, the patient must be thoroughly 
informed about all aspects of the study, including the study visit schedule and required evaluations 
and all regulatory requirements for informed consent. The written informed consent form (ICF) 
must be obtained from the patient prior to enrollment. The following criteria apply to all patients 
enrolled onto the study unless otherwise specified.
3.3.1
Inclusion Criteria
Patients are eligible for this trial if all of the following inclusion criteria are met:
1.
Has histologically or cytologically confirmed CRC with liver metastases. In addition to liver 
metastases, extrahepatic metastases (e.g. pulmonary metastases) may be permitted if all 

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other eligibility criteria are met. Patients are permitted to have primary tumor in situ 
(Neoadjuvant Arm only).
2.
Has received previous oxaliplatin-based chemotherapy.
a.
FOLFOX or CapeOx does not need to be a direct lead-in to this study.
b.
If chemotherapy is a direct lead-in to this study, concurrent mAb therapy 
(bevacizumab, cetuximab, or panitumumab) is acceptable, however the antibody must 
be omitted from the final cycle of chemotherapy prior to pembrolizumab. 
3.
Is an appropriate candidate to undergo liver biopsy and resection (±ablation) of liver 
metastases (Neoadjuvant Arm Only)
4.
Is willing and able to provide written informed consent/assent for the trial. The patient may 
also provide consent for Future Biomedical Research. However, the patient may participate 
in the main trial without participating in Future Biomedical Research.
5.
Is ≥18 years of age on day of signing informed consent.
6.
Has measurable disease based on RECIST 1.1 as assessed by the investigator. Lesions 
situated in a previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions. (Neoadjuvant Arm Only)
7.
Is willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. 
Newly-obtained is defined as a specimen obtained after last dose of standard of care lead-
in chemotherapy [if applicable] and within 28 days prior to first dose of pembrolizumab. 
(Neoadjuvant Arm Only)
8.
Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) 
Performance Scale (Appendix 1). 
9.
Has adequate organ function as defined in Table 1,  within 10 days of treatment initiation.
Table 1 Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500/µL
Platelets
≥100,000/µL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
erythropoietin (EPO) dependency (within 7 days of 
assessment)
Renal
Serum creatinine OR
Measured or calculateda creatinine 
clearance
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 × upper limit of normal (ULN) OR
≥60 mL/min for patient with creatinine levels 
>1.5 × institutional ULN
Hepatic
Serum total bilirubin
≤1.5 × ULN OR
Direct bilirubin ≤ULN for patients with total bilirubin 
levels > 1.5 ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN 
Albumin
>2.5 mg/dL

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System
Laboratory Value
Coagulation
International 
Normalized 
Ratio 
(INR) or Prothrombin Time (PT)
Activated Partial Thromboplastin 
Time (aPTT)
≤1.5 × ULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants
≤1.5 × ULN unless patient is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
10. Female patients of childbearing potential must have a negative urine or serum pregnancy 
test within 72 hours prior to receiving the first dose of study medication (Day 1). If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
11. Female patients of childbearing potential must be willing to use an adequate method of 
contraception* as outlined in Section 6.6, for the course of the study through 120 days after 
the last dose of study medication.
12. Male patients of childbearing potential must agree to use an adequate method of 
contraception* as outlined in Section 6.6, starting with the first dose of study therapy 
through 120 days after the last dose of study therapy.
*Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the patient.
13. Have locally confirmed MSS or pMMR CRC. MSS is defined as 0-1 allelic shifts among 3- 
5 tumor microsatellite loci using a PCR-based assay. pMMR is defined as presence of 
protein expression of 4 MMR enzymes (MLH1, MSH2, MSH6 and PMS2) by 
immunohistochemistry.
14. Have no radiographic evidence of malignancy as assessed by Investigator (Adjuvant 
Phase Only)
3.3.2
Exclusion Criteria
The patient must be excluded from participating in the trial if the patient:
1.
Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 
weeks of the first dose of treatment.
Note: Patients who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks since the last dose of the previous investigational 
agent or device use.
2.
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 
3.
Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is 
required unless mandated by local health authority. 

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4.
Has an active autoimmune disease that has required systemic treatment in past 2 years 
(i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment 
and is allowed.
5.
Has active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or  active 
Hepatitis C virus (defined as HCV RNA [qualitative] [32] is detected) infection. 
6.
 Has received prior anti-cancer mAb, systemic anticancer therapy other than FOLFOX 
(including investigational agents), targeted small molecule therapy, or radiation therapy 
within 14 days prior to the first dose of study treatment (Day 1). Note: patients must have 
recovered from all AEs due to a previous therapies to ≤Grade 1 or baseline. Patients with 
Grade 2 neuropathy or alopecia are eligible. If a patient received major surgery, they must 
have recovered adequately from the toxicity and/or complications from the intervention 
prior to starting study treatment. 
7.
Has received FOLFOX less than 7 days prior to the first dose of study treatment (Day 1). 
Has not recovered (i.e., ≤Grade 1 or at baseline) from AEs due to FOLFOX chemotherapy. 
Note: Patients with ≤Grade 2 neuropathy or alopecia are exceptions to this criterion and 
may qualify for the study.
8.
Has not recovered adequately from toxicity or complications of a surgery or other 
procedure, per the assessment of the treating investigator. 
9.
Has received liver-directed therapy such as radiotherapy or yttrium-90 in the past year 
involving the lesion to be biopsied.  (Neoadjuvant Arm only)
10. Has a known additional malignancy that is progressing or has required active treatment 
within 5 years prior. Note: Patients with basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that 
have undergone potentially curative therapy are not excluded. 
11. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Patients with previously treated brain metastases may participate provided they 
are radiologically stable (i.e., without evidence of progression by imaging for at least 4 
weeks by repeat imaging [repeat imaging should be performed during the study 
screening]), clinically stable, and without requirement of steroid treatment for at least 14 
days prior to trial treatment. This exception does not include carcinomatous meningitis 
which is excluded regardless of clinical stability. 
12. Has a history of (noninfectious) pneumonitis that required steroids or has current 
pneumonitis.
13. Has an active infection requiring systemic therapy.
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the patient’s participation for the full 
duration of the trial, or is not in the best interest of the patient to participate, in the opinion 

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of the treating investigator. Anticoagulation that cannot be safely held to perform the liver 
biopsy is an example of a contraindication to participation.
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
16. Has received any prior immunotherapy including anti–PD-1, anti–PD-L1, or anti-PD-L2 or 
with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4, 
OX-40, CD137) (Neoadjuvant Arm Only).
17. Has severe hypersensitivity (≥Grade 3) to pembrolizumab or vactosertib and/or to any of 
their excipients.
18. Has received a live or live-attenuated vaccine within 30 days prior to first dose of the trial 
drug. Administration of killed vaccines are allowed.
19. Has inferior vena cava/cardiac involvement based on imaging. 
20. Has had encephalopathy in the last 6 months. Those patients on rifaximin or lactulose to 
control their encephalopathy are not allowed. 
21. Has had a solid organ or hematologic transplant.
22. Has symptomatic ascites or pleural effusion. A patient who is clinically stable following 
treatment for these conditions (including therapeutic thora- or paracentesis) is eligible.
23. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure (New York Heart Association Class III/IV), 
uncontrolled hypertension (≥150/90mmHg), unstable angina pectoris or myocardial 
infarction (≤ 6 months prior to screening), uncontrolled cardiac arrhythmia, clinically 
significant cardiac valvulopathy requiting treatment, active interstitial lung disease, or 
serious chronic gastrointestinal conditions associated with diarrhea.
3.4
Duration of Therapy
All participants will receive a single dose of pembrolizumab and 20 doses of vactosertib (QD, 5 
days per week for 2 weeks) prior to surgery.
Participants who undergo surgical resection and have adequately receovered from toxicity or 
complications of a surgery or other procedure, per the assessment of the treating investigator, 
may receive optional adjuvant treatment of pembrolizumab + vactosertib for up to eight 6-week 
cycles.
3.5
Duration of Follow Up
Due to the potential for late toxicities from pembrolizumab, patients will be followed for at least 1 
year after their last dose of pembrolizumab or up to 2 years post-surgery for RFS whichever 
occurs last.

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3.6
Randomization Procedures
This is a single-arm non-randomized trial. Additionally, this is an open-label trial; therefore, Merck, 
the investigator, and the patient will know the treatment administered. The trial is not designed to 
compare arms.
3.7
Study Timeline
3.7.1
Primary Completion
The study will reach primary completion, at the time the last participant has data collected for 
the primary objective to be measure.  We estimate this occurring from the time the study opens 
to accrual. 
3.7.2
Study Completion
The study will reach study completion 72 months from the time the study opens to accrual. 
4
Study Drugs
4.1
Description, Supply and Storage of Investigational Drugs
4.1.1
Pembrolizumab
Details on the preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual and package insert. Refer to the IB for additional information on pembrolizumab.
Classification
PD-L1 inhibitor, immunotherapy
Mechanism of Action
Pembrolizumab (MK-3475) is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in vitro 
data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. For more 
details see Section 1.2.1.1 and the IB.
Contraindications
Immunodeficiency, autoimmune diseases requiring treatment with disease modifying agents, 
corticosteroids or immunosuppressive drugs, active infections.
Availability
Pembrolizumab will be provided to patients enrolled on this study by Merck.
Handling, Storage, and Specific Accountability
The local country Merck personnel or designee will provide appropriate documentation that must 
be completed for drug accountability and return, or local discard and destruction if appropriate. 

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Where local discard and destruction is appropriate, the investigator is responsible for ensuring 
that a local discard/destruction procedure is documented.
The trial site is responsible for recording the lot number, manufacturer, and expiry date for any 
locally purchased product as per local guidelines unless otherwise instructed by Merck.
Clinical Supplies will be provided by Merck as summarized in Table 2.
Table 2
Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 25 mg/mL
Solution for Injection
Clinical Supplies Disclosure
This trial is open-label; therefore, the patient, the trial site personnel, Merck and/or designee are 
not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided.
4.1.2
Vactosertib
Refer to the IB for additional information on vactosertib.
Classification
Serine/threonine kinase inhibitor
Mechanism of Action
For more details see section 1.2.2 and the IB.
Contraindications
Vactosertib is predominately metabolized by CYP3A4. Because grapefruit and grapefruit juice are 
strong CYP3A4 inhibitors, these should be avoided in this study.
Description
The vactosertib film-coated tablets contain the following inactive ingredients: lactose 
monohydrate (Fastflo 316), microcrystalline cellulose (Avicel PH 102), crospovidone (Kollidon CL 
F), povidone Kollidon 30, magnesium stearate, and opadry white. The proposed clinical drug 
product vactosertib (50 mg, 100 mg and 200 mg film-coated tablets) is compressed from 
10%w/w(50 mg), 40%w/w(100 mg, 200 mg) drug loaded common stock wet granulation.
Availability
Vactosertib will be provided to patients enrolled on this study by MedPacto.
Handling, Storage, and Specific Accountability
Clinical Supplies will be provided by MedPacto as summarized in Table 3.

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Table 3
Product Descriptions
Product Name & Potency
Dosage Form
Vactosertib 50 mg
Film-coated tablets
Vactosertib 100 mg
Film-coated tablets
Vactosertib 200 mg
Film-coated tablets
Vactosertib tablets are packaged in tightly closed, white, opaque, HDPE bottles with a 1-g silica 
gel desiccant canister. The bottles are heat-induction sealed with a child-resistant cap. Based on 
the available laboratory stability data, vactosertib tablets should be stored at 15°C to 25°C (59°F 
to 77°F) and protected from light. Recent data indicate that 50 mg vactosertib remain stable up to 
36 months, 100 mg and 200 mg vactosertib remain stable up to 9 months, respectively, under the 
same testing conditions as above. Stability test for a longer time period is underway: 50 mg, 100 
mg and 200 mg vactosertib up to 60 months. 
Clinical Supplies Disclosure
This trial is open-label; therefore, the patient, the trial site personnel, MedPacto and/or designee 
are not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided.
4.2
Drug Accountability
The Investigational Pharmacist will manage drug accountability records.
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.
Only patients enrolled in the study may receive study treatment and only authorized site staff may 
supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
The study site is responsible for recording the lot number, manufacturer, and expiry date for any 
locally purchased product (if applicable) as per local guidelines unless otherwise instructed by 
Merck.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.

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4.3
Drug Ordering
UCSF will obtain pembrolizumab directly from Merck as study supply. Commercial drug will be 
supplied locally. UCSF will obtain Vactosertib directly from MedPacto as study supply.
4.4
Packaging and Labeling of Study Drugs
Drugs will be packaged and affixed with a clinical label per UCSF institutional standards, adhering 
to applicable local and federal laws.
5
Treatment Plan
5.1
Dosage and Administration
Trial treatment should be administered at the time points specified in the Trial Flow Charts (section 
6.2). The treatment to be used in this trial is outlined in Table 4 and Table 5. On Day 1 of each 
cycle, administer vactosertib after the subject completes their pembrolizumab infusion. 
Vactosertib may be administered as soon as the pembrolizumab infusion is completed. 
Vactosertib and pembrolizumab may be administered without regard to meals.
Table 4
Main Trial Treatment
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
Pembrolizumab
200 mg
Once
IV infusion
C1D1 
Experimental
Vactosertib
200 mg
QD, 5 days 
per week
PO
C1D1 through 
C1D14
Experimental
Abbreviation: IV = intravenous, PO = per os, C = cycle, D = day, QD = once a day
Table 5
Optional Adjuvant Treatment Cohort
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
Pembrolizumab
400 mg
Q6W
IV infusion
Up to 8 cycles
Experimental
Vactosertib
200 mg
Cycle 1: QD, 
5 days per 
week
Cycles 
2+: 
BID, 5 days 
per week
PO
Up to 8 cycles
Experimental
Abbreviation: IV = intravenous, PO = per os, C = cycle, D = day, Q6W = every 6 weeks, QD = once a 
day, BID = twice a day
5.1.1
Pembrolizumab
Pembrolizumab will be administered as a 30-minute IV infusion. Every effort will be made to target 
infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion 
pumps, a window of -5 minutes and +10 minutes is permitted (i.e. infusion time is 30 minutes: -5 
min/+10 min). All IV infusion treatments will be administered on an outpatient basis. 

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Note: Treatment with pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons (such as holidays).  
5.1.2
Vactosertib
Vactosertib will be administered once daily at 200 mg PO for 5 days followed by a 2-day resting 
period (5 days on/2 days off) for two weeks during the neoadjuvant treatment phase.
During the optional adjuvant treatment phase, vactosertib will be administered once daily at 200 
mg PO (dose level -1) for 5 days followed by a 2-day resting period during Cycle 1.  If no 
significant drug-related toxicities are observed, vactosertib will be administered twice daily at 
200 mg PO (dose level 0)  for 5 days followed by a 2-day resting period (5 days on/2 days off) 
for up to 8 cycles. 
Please see Section 5.2, Dose Modifications and Dosing Delays for additional details.
5.1.3
Other Modality(ies) or Procedures
Patients are expected to undergo standard of care surgical resection of liver metastases within 
4-6 weeks of the final chemotherapy administration (if applicable) and approximately 2 weeks 
(minimum 1 week) after their neoadjuvant dose of pembrolizumab-base treatment. Standard of 
care operative plan is at the discretion of the treating surgeon.
5.1.4
Dose Limiting Toxicity
As the toxicities of pembrolizumab are well-established and not necessarily dose-dependent, this 
study will not use formal dose-limiting toxicity definitions according to NCI CTCAE grading criteria. 
However, to avoid compromising patient safety in this potentially curative setting, early stopping 
rules will be followed such that the study will be stopped, and this approach re-evaluated, if 2 or 
more of the first 6 patients experience any 1 of the following: 

A delay in planned surgery beyond the 8-week window after final chemotherapy treatment 
due to any grade toxicity attributable to study treatment. Delays in surgery due to other 
reasons (scheduling, available operating room time, patient preference) will not count.

Grade IV and V surgical complications according to Clavien-Dindo classification (Appendix 
4).
Note: Surgical complications associated with liver metastastectomy are very common, and 
we recognize that it may be difficult to attribute any such complications to preoperative 
administration of pembrolizumab-based treatment. Therefore, the occurrence of such 
events may not necessarily require stopping the study early, but will be discussed amongst 
members of the JSC, and Merck with particular attention paid to specific complications 
such as liver failure, severe colitis, etc.
Moreover, enrollment will be paused for 4 weeks after the sixth patient undergoes surgery (or 
receives their dose of pembrolizumab-based treatment if unable to undergo surgery). During this 
interval the study investigators will meet with the participating surgeons and Merck to review the 
first 6 cases. A recommendation will be made regarding whether or not to enroll additional patients 
and if any changes are needed to optimize safety or feasibility. 

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5.2
Dose Modifications and Dosing Delays
Dose modification guidelines for pembrolizumab-related AEs during the adjuvant period are 
provided in Table 7. Dose modification guidelines for pembrolizumab-related AEs during the 
neoadjuvant period do not apply as only a single dose of pembrolizumab will be administered. 
Vactosertib dose reduction based on treatment-related adverse events observed is permitted. 
According to the dose levels in Table 6, participants who receive vactosertib below the initially 
assigned treatment level (200 mg QD or BID) due to vactosertib-related AEs, will have the option 
to re-escalate to the assigned vactosertib dose if AE(s) resolves to baseline and does not recur 
for at least 3 consecutive weeks (one treatment cycle). 
For the optional adjuvant treatment phase, participants who experience the following drug-related 
toxicities may escalate to dose level 0 based on the judgement of the investigator:

Grade 1 or 2 Hematologic Toxicity

Grade 1  non-hematologic toxicity and/or other drug related toxicities. 

Grade 1  ALT or AST elevation possibly related with total bilirubin <2x ULN
If a Grade 2 or lower vactosertib treatment-related toxicity is experienced but not specified, above 
dose escalation could be considered after discussions with MedPacto.  
If a participant experiences several adverse events and there are conflicting recommendations, 
the investigator should use the recommended dose adjustment that reduces the dose to the 
lowest level or if warranted, discontinues therapy.
Table 6
Vactosertib Dose Modification
Neoadjuvant Treatment Phase
Optional Adjuvant Treatment Phase
Treatment Level
Vactosertib Dose
Treatment Level
Vactosertib Dose
0
200 mg QD
0
200 mg BID
-1
100 mg QD
-1
200 mg QD
-2
100 mg QD 
-2
100 mg QD 
Vactosertib dose can be reduced to manage a treatment related AE as indicated in Table 9.
5.3
Monitoring and Toxicity Management
Each patient receiving pembrolizumab-based treatment will be evaluable for safety. The safety 
parameters include all laboratory tests and hematological abnormalities, physical findings, and 
spontaneous reports of AEs reported to the investigator by patients.
Each patient will be assessed periodically for the development of any toxicity as outlined in 5.3.5. 
Toxicity will be assessed according to NCI CTCAE v5.0 (Appendix 3).

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5.3.1
Toxicity Management for Immune-Related AEs Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. Therefore, 
early recognition and initiation of treatment is critical to reduce complications. Based on existing 
clinical study data, most irAEs were reversible and could be managed with interruptions of 
pembrolizumab, administration of corticosteroids and/or other supportive care. For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of 
the evaluation. 
Dose modification and toxicity management guidelines for irAEs associated with pembrolizumab 
monotherapy, coformulations, or IO combinations are provided in Table 7.

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Table 7
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations and IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral 
steroids. Other immunosuppressive treatment should begin if the irAEs are not controlled by 
corticosteroids.
2.
Pembrolizumab monotherapy, coformulations, or IO combinations must be permanently 
discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 
weeks of the last study intervention treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 
4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations has been withheld, study 
intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper.
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations 
or IO 
Combinations
Corticosteroid 
and/or Other 
Therapies
Monitoring and 
Follow-up
Grade 2
Withhold
Pneumonitis 
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
  Administer 
corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone 
or equivalent) 
followed by taper
  Add prophylactic 
antibiotics for 
opportunistic 
infections
  Monitor 
participants for 
signs and 
symptoms of 
pneumonitis
  Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment
Diarrhea/Colitis 
Grade 2 or 3
Withhold
  Administer 
corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone 
or equivalent) 
  Monitor 
participants for 
signs and 
symptoms of 
enterocolitis (i.e., 
diarrhea, 

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations 
or IO 
Combinations
Corticosteroid 
and/or Other 
Therapies
Monitoring and 
Follow-up
Recurrent 
Grade 3 or 
Grade 4
Permanently 
discontinue
followed by taper
abdominal pain, 
blood or mucus in 
stool with or 
without fever) and 
of bowel 
perforation (i.e., 
peritoneal signs 
and ileus)
  Participants with 
≥Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing 
endoscopy to rule 
out colitis
  Participants with 
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
Grade 2 a
Withhold
  Administer 
corticosteroids 
(initial dose of 0.5 to 
1 mg/kg prednisone 
or equivalent) 
followed by taper
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 3 b or 4 c
Permanently 
discontinue
  Administer 
corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone 
or equivalent) 
followed by taper
  Monitor with liver 
function tests 
(consider weekly or 
more frequently 
until liver enzyme 
value returned to 
baseline or is 
stable)

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations 
or IO 
Combinations
Corticosteroid 
and/or Other 
Therapies
Monitoring and 
Follow-up
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure
Withhold d
  Initiate insulin 
replacement therapy 
for participants with 
T1DM
  Administer 
antihyperglycemic 
in participants with 
hyperglycemia
  Monitor 
participants for 
hyperglycemia or 
other signs and 
symptoms of 
diabetes
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold or 
permanently 
discontinue d
  Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated
  Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency)
Grade 2
Continue
Hyperthyroidism
Grade 3 or 4
Withhold or 
permanently 
discontinue d
  Treat with 
nonselective beta-
blockers (e.g., 
propranolol) or 
thionamides as 
appropriate
  Monitor for signs 
and symptoms of 
thyroid disorders
Hypothyroidism
Grade 2, 3 or 4
Continue
  Initiate thyroid 
replacement 
hormones (e.g., 
levothyroxine or 
liothyronine) per 
standard of care
  Monitor for signs 
and symptoms of 
thyroid disorders
Grade 2
Withhold
Nephritis:
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 3 or 4
Permanently 
discontinue
  Administer 
corticosteroids 
(prednisone 1 to 
2 mg/kg or 
equivalent) followed 
by taper
  Monitor changes of 
renal function
Grade 2
Withhold
Neurological 
Toxicities
Grade 3 or 4
Permanently 
discontinue
  Based on severity of 
AE administer 
corticosteroids
  Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations 
or IO 
Combinations
Corticosteroid 
and/or Other 
Therapies
Monitoring and 
Follow-up
Asymptomatic 
cardiac enzyme 
elevation with 
clinical 
suspicion of 
myocarditis 
(which was 
previously 
myocarditis 
Grade 1 using 
CTCAE v4.0)
Withhold
Myocarditis
Grade 2, 3 or 4
Permanently 
discontinue
  Based on severity of 
AE administer 
corticosteroids
  Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes
Suspected SJS, 
TEN, or DRESS
Withhold
Exfoliative 
Dermatologic 
Conditions
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
  Based on severity of 
AE administer 
corticosteroids
  Ensure adequate 
evaluation to 
confirm etiology or 
exclude other 
causes
Persistent Grade 
2
Withhold
Grade 3
Withhold or 
discontinue based 
on the event e 
All Other irAEs
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
  Based on severity of 
AE administer 
corticosteroids
  Ensure adequate 
evaluation to 
confirm etiology or 
exclude other 
causes

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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations 
or IO 
Combinations
Corticosteroid 
and/or Other 
Therapies
Monitoring and 
Follow-up
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common 
Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; 
GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson 
Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to 5.0 × ULN if baseline normal; >3.0 to 5.0 × baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 × ULN if baseline normal; >1.5 to 3.0 × baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 × ULN, if baseline normal; >5.0 to 20.0 × baseline, if baseline abnormal;
bilirubin:>3.0 to 10.0 × ULN if baseline normal; >3.0 to 10.0 × baseline if baseline abnormal
c
AST/ALT: >20.0 × ULN, if baseline normal; >20.0 × baseline, if baseline abnormal; 
bilirubin: >10.0 × ULN if baseline normal; >10.0 × baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO 
combinations is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab monotherapy, coformulations, or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important 
irAEs (e.g., vasculitis and sclerosing cholangitis).
5.3.2
Toxicity Management of Infusion-Reactions Related to Pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion reaction 
are provided in Table 8. 

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Table 8
Pembrolizumab Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
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.
Grade 2
Requires therapy or infusion interruption but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for 
≤24 hrs.
Stop Infusion.
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 (e.g. from 100 mL/hr. to 50 mL/hr.). Otherwise dosing will be 
held until symptoms resolve and the patient should be premedicated for the next scheduled 
dose.
Patients who develop Grade 2 toxicity despite adequate premedication should be 
permanently discontinued from further study drug treatment
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
other clinical sequelae (e.g., 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:

Epinephrine**

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids
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.
**In cases of anaphylaxis, epinephrine should be used immediately.

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NCI CTCAE Grade
Treatment
Patient is permanently discontinued from further study drug treatment.
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer Institute; NSAIDs = non-steroidal anti-
inflammatory drugs; PO = by mouth.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the CTCAE v5.0 at http://ctep.cancer.gov

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5.3.3
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. For 
patients who receive optional adjuvant therapy with pembrolizumab and vactosertib, 
pembrolizumab is to be restarted within 42 days (6 weeks) of the originally scheduled dose for 
Q6W dosing and within 84 days of the previously administered dose, unless otherwise discussed 
with Merck. The reason for study treatment interruption is to be documented in the patient's study 
record.
5.3.4
Rescue Medication and Supportive Care for AEs Associated with Pembrolizumab
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined with the dose modification guidelines in Section 5.3.1.
5.3.5
Monitoring and Management for AEs Associated with Vactosertib
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested monitoring and dose modifications are for the management of a 
treatment related AE are outlined in Table 9. Refer to Table 6 in section 5.2 for vactosertib 
treatment levels.
Table 9
Vactosertib Dose Modifications for Treatment-Related Toxicity
Toxicity
Severity 
Grade
Vactosertib Dose Modification
Hematologic 
toxicity
1/2
Continue at the same Treatment Level
3
Withhold until toxicity is Grade ≤2, or has returned to baseline, then 
resume treatment at the same Treatment Level or reduce the dose by 
1 Treatment Level after discussion with the Sponsor a
4
Withhold until toxicity is Grade ≤2, or has returned to baseline, then 
reduce by 1 Treatment Level
Non-hematologic 
toxicity and/or 
other drug related 
toxicities b
1
Continue at the same Treatment Level
2
For persistent (>1-2 week) Grade 2 events, consider holding study 
drug until resolution to Grade ≤1 or baseline. If the study drug is 
withheld and the toxicity resolved to Grade ≤1 or baseline, resume 
treatment at the same Treatment Level or reduce by 1 Treatment 
Level
3
Withhold until toxicity is Grade ≤1, or has returned to baseline, then 
resume treatment at the same Treatment Level or reduce the dose by 
1 Treatment Level after discussion with the Sponsor 
4
Discontinue vactosertib

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ALT or AST 
elevation possibly 
related with total 
bilirubin <2x ULN
1
Continue at the same Treatment Level
2
Continue at the same Treatment Level
Repeat ALT or AST and total bilirubin within 7 days when subject is 
symptomatic; If not symptomatic, monitor weekly.
For persistent (>1-2 week) Grade 2 events, consider holding study 
drug until resolution to Grade ≤1 or baseline. If the study drug is 
withheld and the toxicity resolved to Grade ≤1 or baseline, resume 
treatment at the same Treatment Level or reduce by 1 Treatment 
Level
3/4
Withhold dose until toxicity is Grade ≤ 1, or has returned to baseline, 
then resume treatment by reducing by one Treatment Level.  
Repeat within 48~72 hours until resolution to Grade ≤1.
If Grade 3 ALT or AST elevation recurs at dose level -2, then discuss 
with Sponsor whether to discontinue permanently. 
ALT or AST 
elevation and total 
bilirubin ≥ 2x ULN 
(in the absence of 
cholestasis or 
haemolysis)
1
Continue at the same Treatment Level
 Repeat ALT or AST and total bilirubin within 48 hours and monitor 
every 48 hours until Grade<1.
2
Withhold until resolution to baseline then resume treatment by 
reducing by one Treatment Level.  
Repeat ALT or AST and total bilirubin within 48~72 hours until 
resolution to Grade ≤1 or baseline.
Discontinue if not resolved to Grade≤1 or baseline within 3 weeks
3/4
Discontinue vactosertib.
Repeat ALT or AST and total bilirubin within 48 hours and monitor 
every 48 hours until Grade ≤1.
Left ventricular 
systolic 
dysfunction c
G3/4
Permanently discontinue vactosertib
a.
Subjects who develop Grade 3 or 4 lymphopenia without other dose-limiting events (e.g., opportunistic 
infection) may continue study treatment without interruption
b.
Subjects with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion. Permanently discontinue study medication for persistent Grade 2 adverse reactions for which 
treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose
c.
According to CTCAE v5.0, development of LV systolic dysfunction is considered AE of grade ≥ 3. 
Therefore, subjects who develop left ventricular (LV) systolic dysfunction will permanently discontinue both 
of study drugs
d.
If vactosertib dose modification is required due to treatment-related toxicity, changing a dose level of 
vactosertib, or temporarily holding IP(s) not specified in the table could be considered in discussion with 
sponsor 

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6
Study Procedures and Observations
6.1
Schedule of Procedures and Observations
The study-specific assessments are detailed in this section and outlined in Table 10. Screening 
assessments must be performed within 28 days prior to the first dose of investigational product. 
Any results falling outside of the reference ranges may be repeated at the discretion of the 
investigator. All on-study visit procedures are allowed a window of ±3 days unless otherwise 
noted. Treatment or visit delays for public holidays or weather conditions do not constitute a 
protocol violation.
A signed informed consent form (ICF) and a Health Insurance Portability and Accountability Act 
(HIPAA) authorization will be obtained prior to performing screening procedures (see section 9.3 
for details).
6.1.1
Screening Assessments
The screening procedures and assessments must be completed within 28 days prior to the dose 
of pembrolizumab, unless specified otherwise. Note that the cycle of pembrolizumab-based 
treatment should begin ≥7 days after the final chemotherapy administration. 
Note: A screening CT chest/abdomen/pelvis with IV contrast must be performed and reviewed to 
re-confirm candidacy for hepatic resection prior to liver tumor biopsy. 
Screening procedures and assessments:

Review of eligibility

Complete physical examination

Vital sign measurements and weight

Complete medical history (including MMR/MSI status) and demographics

Documentation of disease status assessment/measurable disease

ECOG performance status performed within 7 days prior to treatment administration

History of prior treatments and any residual toxicity relating to prior treatment. Include 
number of cycles of FOLFOX/CapeOx received prior to pembrolizumab; interval 
between last FOLFOX/CapeOx treatment and pembrolizumab; addition of monoclonal 
antibodies to chemotherapy; growth factor support.

Baseline medications taken within 28 days of Day 1

Tumor marker assessments (CEA): also record CEA at diagnosis, prior to and after 
lead-in FOLFOX/CapeOx (if applicable). 

Complete blood count (CBC) with differential and platelet count

Hematology labs (other than CBC w/ Diff)

Blood chemistry assessment, including:
o
Alkaline 
phosphatase 
(ALP), 
aspartate 
aminotransferase/alanine 
aminotransferase (ALT/AST), total bilirubin, direct bilirubin (If total bilirubin is 
elevated above the upper limit of normal), calcium, phosphorus, blood urea 
nitrogen (BUN), creatinine, total protein, albumin, fasting glucose, potassium, 

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sodium, magnesium, chloride, bicarbonate, uric acid, lactate dehydrogenase 
(LDH)

Thyroid function tests: thyroid-stimulating hormone (TSH), free thyroxine (FT4); free 
and total triiodothyronine (T3) 

Coagulation assessment (prothrombin time [PT], partial thromboplastin time [PTT], 
international normalized ratio [33])

Serum Hepatitis assessment, including Hepatitis B surface antigen (HBsAg), Hepatitis 
B surface antibody (HBsAb), Hepatitis B core antibody (HBcAb), HCV RNA

Urinalysis

Serum or urine pregnancy test within 72 hours prior to the start of study drug

Echocardiogram (ECHO)

Imaging (CT chest/abdomen/pelvis with IV contrast) for tumor/lesion assessment and 
to confirm candidacy for liver resection surgery.

Archival specimen collection for banking (formalin-fixed paraffin-embedded [FFPE] 
tumor specimen, if available)Biopsy of liver metastasis. Criteria for selecting the lesion 
for biopsy are that it is safely accessible and is expected to contain viable tumor (rather 
than necrotic material) based on radiographic appearance. If there are several such 
liver metastases to choose from, select the largest one

Stool collection and stool questionnaire (-4 and -2 days of first pembrolizumab dose)

Dietary and physical activity questionnaire
6.1.2
Neoadjuvant Pembrolizumab + Vactosertib Dosing Day 1
One cycle of pembrolizumab + vactosertib will be administered approximately 2 weeks (minimum 
1 week) after the last dose of chemotherapy (if applicable).
Study procedures and assessments:

Directed physical examination

Vital sign measurements and weight

ECOG Performance status

Evaluation of AEs

Concomitant medications

Hematology (other than CBC with diff), CBC with Differential and platelet count

Comprehensive Serum Chemistry (see Table 12)

ECG* (within 7 days of Cycle 1)

Urinalysis

T3 (free and total), FT4 and TSH

Tumor Marker: CEA

Correlative studies blood collection

Pembrolizumab administration (see section 5.1)

Vactosertib administration (see section 5.1)

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
Dispense vactosertib supply
6.1.3
Pre-surgical Evaluation
A pre-surgical visit will be scheduled 1-2 weeks after pembrolizumab dosing, prior to surgery.
Study procedures and assessments:

Disease status assessment/measurable disease

Directed physical examination

Vital sign measurements and weight

ECOG Performance status

Evaluation of AEs

Concomitant medications

Hematology (other than CBC with diff), CBC with Differential and platelet count

Comprehensive Serum Chemistry (see Table 12)

PT/INR and aPTT

Urinalysis

T3 (free and total), FT4 and TSH

Tumor Marker: CEA

Correlative studies blood collection

Stool collection and stool questionnaire
6.1.4
Liver Resection Surgery
Liver resection for hepatic metastases will be performed per standard of care. Patients are 
expected to undergo surgical resection of liver metastases within 4-6 weeks of the final 
chemotherapy administration (if applicable) and approximately 2 weeks (minimum 1 week) after 
their neoadjuvant dose of experimental therapy. If vactosertib must be held for toxicity, and full 
course of treatment cannot be completed, the surgery will still proceed as planned unless there 
are safety concerns regarding the surgery. Standard of care operative plan is at the discretion of 
the treating surgeon.
In the event that the surgery is canceled, and the first liver biopsy yielded adequate tumor material, 
a second liver biopsy will be requested (same lesion as the first biopsy preferred). Do not perform 
second liver biopsy if the first liver biopsy yielded inadequate tumor cells for analysis or 
excessively high procedural risk due to location or other factors.
6.1.5
Post-surgical Safety Follow-up Visit
A post-surgical safety follow-up visit should be conducted approximately 14 days (±7 days) after 
surgery.
Study procedures and assessments:

Directed Physical examination

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
Vital sign measurements and weight

ECOG Performance Status

Evaluation of AEs

Concomitant medications

Hematology (other than CBC with diff), CBC with Differential and platelet count

Comprehensive Serum Chemistry Panel (see Table 12)

Urinalysis

T3 (free and total), FT4 and TSH

Tumor Marker: CEA

Correlative studies blood collection

Optional stool collection and stool questionnaire

Obtain standard of care MSI/MMR and expanded RAS/BRAF mutation testing from 
liver resection specimen if not tested previously. Review pathology report.

Optional adjuvant treatment (pembrolizumab + vactosertib) recruitment.
o
Interested participants will complete the adjuvant pre-treatment procedures 
outlined in Table 11 and section 6.1.6.1.
o
Participants who are not interested or are ineligible for the adjuvant treatment 
cohort will be followed every 90 days (±14d) for up to 2 years post-surgery as 
outlined in Table 10 and section 6.1.7.
6.1.6
Optional Adjuvant Treatment
6.1.6.1 Pre-treatment
Participants interested in participating in the optional adjuvant treatment cohort (pembrolizumab 
+ vactosertib) will complete the pre-treatment procedures 2 weeks (±7 days) after surgery.
Study procedures and assessments:

Informed consent for adjuvant treatment

Review of eligibility (per the investigator’s discretion). The rationale for enrolling (or not 
enrolling) participants in adjuvant therapy will be recorded, along with any supporting 
test results (e.g., circulating tumor DNA analysis).

Concomitant medications

Evaluation of AEs

Directed physical examination

Vital sign measurements and weight

ECOG Performance status

Serum or urine pregnancy test within 72 hours prior to the start of adjuvant treatment

PT/INR and aPTT

Hematology (other than CDC with diff), CBC with differential and platelet count

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
Comprehensive serum chemistry (see Table 12)

Urinalysis

T3 (free and total), FT4 and TSH
Participants who are ineligible for the adjuvant treatment cohort will be followed every 90 days 
(Q90D; ±14 days) for up to 2 years post-surgery per Table 10 and section 6.1.7.
6.1.6.2 Cycle 1 through Cycle 8
Eligible participants will receive adjuvant treatment 6 weeks (±2 weeks) after hepatic 
metastasectomy. Participants will receive adjuvant pembrolizumab + vactosertib for up to eight, 
6-week cycles (approximately 1 year) or until disease recurrence is radiographically documented, 
unacceptable AE(s), intercurrent illness that prevents further administration of treatment, 
investigator’s decision to discontinue the patient, administrative reasons requiring cessation of 
treatment, or withdrawal of consent, whichever occurs first.
Perform the following procedures and assessments on day 1 of each cycle unless specified 
otherwise:

Concomitant medications

Evaluation of AEs

Directed physical examination

Vital sign measurements and weight

ECOG Performance status

Hematology (other than CBC with diff), CBC with differential and platelet count*

Comprehensive serum chemistry (see Table 12)*

Urinalysis*

T3 (free and total), FT4 and TSH*

ECHO - perform at cycle 2 only

Tumor Marker: CEA

Tumor imaging with IV contrast to monitor disease status - perform every 12 weeks 
(i.e., day 1 of every other cycle)

Correlative studies blood collection - perform every 12 weeks (i.e., day 1 of every 
other cycle)

Pembrolizumab administration (see section 5.1)

Vactosertib administration (see section 5.1)

Dispense vactosertib supply as needed
*Tests do not need to be repeated at adjuvant C1D1 treatment visit if they were performed 
within 7 days prior to C1D1.
6.1.6.3 End of Treatment Visit
An End of Treatment Visit should be conducted at treatment discontinuation (+7 days).

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Procedures and assessments:

Concomitant medications

Evaluation of AEs

Directed Physical examination

Vital sign measurements and weight

ECOG Performance Status

Hematology (other than CBC with diff), CBC with Differential and platelet count

Comprehensive Serum Chemistry Panel (see Table 12)

Urinalysis

T3 (free and total), FT4 and TSH

ECHO – only if echocardiography is not performed within the past 12 weeks.

Tumor Marker: CEA

Tumor imaging with IV contrast
6.1.6.4 Safety Follow-up Visit
For patients receiving adjuvant treatment with pembrolizumab and vactosertib, the mandatory 
Safety Follow-Up Visit should be conducted approximately 30 days (+7 days) after the last dose 
of study treatment or before the initiation of a new anticancer treatment, whichever comes first.
Procedures and assessments:

Concomitant medications

Evaluation of AEs
6.1.7
Follow-up Phase
All participants will be followed for up to 1 year after the last dose of pembrolizumab and 
vactosertib is administered or up to 2 years after surgery, whichever occurs last. Follow-up may 
end sooner if disease progression, withdrawal of consent, or death occur.
Additional post-operative chemotherapy, subsequent anti-neoplastic therapy, and follow-up 
assessments will be at the discretion of the treating physician. Information regarding post-study 
anti-neoplastic treatment will be collected if such treatment is initiated.
The following study procedures and assessments will be done Q90D (±14 days) for up to one 
year after last dose of pembrolizumab and vactosertib or up to two years after surgery, whichever 
occurred last:

Disease status assessment/measurable disease

Concomitant medications

Post-study anticancer therapy status

Survival Status

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
Evaluation of AEs for the timeframe defined in Section 7.5

Radiologic CT imaging with IV contrast to monitor disease status.

Correlative studies blood collection
Note: Safety labs and correlative labs will be collected up to 1 year post-pembrolizumab.

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6.2
Trial Flow Chart
Table 10
Main Trial Flow Chart
Trial Period:
Preoperative Treatment 
Treatment 
Cycle/Visit:
Screening
C1D1
Pre-
Surgery
Surgery
Post-
Surgery 
Safety 
F/U
Follow 
Up 
Phasea,m
Scheduling 
Window:
-28d to
 -1d
≥7d post-last chemotherapy
+7-14d 
post-
C1D1
+7-14d 
post-
C1D1, 
28-42d 
post-last 
chemo
14d ±7d 
post-op
Q90D 
±14d 
post-op 
for up to 
2y
Directed Medical 
History
X
Main Trial Study 
Informed Consent
Xb
Future Biomedical 
Research consent 
(optional)
Xb
Inclusion/ 
Exclusion Criteria
X
Demographics 
and Full Medical 
History, including 
MMR/MSI status
X
Xc
Prior and 
Concomitant 
Medication 
Review
Xd
X
X
X
Xk
History of Prior 
Treatments and 
residual toxicity to 
prior treatment
X
Trial Treatment 
Administrationj
X
Dispense 
vactoserib supply
X

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Trial Period:
Preoperative Treatment 
Treatment 
Cycle/Visit:
Screening
C1D1
Pre-
Surgery
Surgery
Post-
Surgery 
Safety 
F/U
Follow 
Up 
Phasea,m
Scheduling 
Window:
-28d to
 -1d
≥7d post-last chemotherapy
+7-14d 
post-
C1D1
+7-14d 
post-
C1D1, 
28-42d 
post-last 
chemo
14d ±7d 
post-op
Q90D 
±14d 
post-op 
for up to 
2y
Post-study 
anticancer 
therapy status
Xk
Survival Status
X
Review Adverse 
Events
X
X
X
Xk
Complete 
Physical 
Examination
X
Directed Physical 
Examination
X
X
X
Vital Signs and 
Weight
X
X
X
X
ECOG 
Performance 
Status
Xi
X
X
X
Pregnancy Test – 
Urine or Serum 
X
PT/INR and aPTT
Xn
X
Hematology, CBC 
with Differential 
and platelet count
Xn
X
X
X
Xa.
Comprehensive 
Serum Chemistry 
Panel (see Table 
12)
Xn
X
X
X
Xa.
Urinalysis
X
X
X
X
Xa.

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Trial Period:
Preoperative Treatment 
Treatment 
Cycle/Visit:
Screening
C1D1
Pre-
Surgery
Surgery
Post-
Surgery 
Safety 
F/U
Follow 
Up 
Phasea,m
Scheduling 
Window:
-28d to
 -1d
≥7d post-last chemotherapy
+7-14d 
post-
C1D1
+7-14d 
post-
C1D1, 
28-42d 
post-last 
chemo
14d ±7d 
post-op
Q90D 
±14d 
post-op 
for up to 
2y
T3 (free and 
total), FT4 and 
TSH
X
X
X
X
Xa.
Tumor Marker: 
CEA p.
X
X
X
X
Hep B surf Ag, 
Hep B sur Ab, 
Hep B core Ab, 
Hep C RNA
X
Echocardiogram 
(ECHO)
X
Electrocardiogram 
(ECG)
Xi 
Disease Status 
Assessment/ 
Measurable 
disease
X
X
X
Tumor Imagingh
Xg
X
Archival Tissue 
Collection
Xo
Biopsy of Liver 
Metastasis
X
Xe
Hepatic 
metastasectomy
X
Correlative 
Studies: Blood 
Collection
X
X
X
Xk
Correlative 
Studies: Stool 
X
X
(X)

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Trial Period:
Preoperative Treatment 
Treatment 
Cycle/Visit:
Screening
C1D1
Pre-
Surgery
Surgery
Post-
Surgery 
Safety 
F/U
Follow 
Up 
Phasea,m
Scheduling 
Window:
-28d to
 -1d
≥7d post-last chemotherapy
+7-14d 
post-
C1D1
+7-14d 
post-
C1D1, 
28-42d 
post-last 
chemo
14d ±7d 
post-op
Q90D 
±14d 
post-op 
for up to 
2y
Collection and 
Questionnairef
Dietary and 
physical activity 
questionnaire
X
Optional Adjuvant 
TX Recruitmentl,m
X
Abbreviations: aPTT – activated partial thromboplastin time; CBC = complete blood count; CEA = carcinoembryonic antigen; ECOG = Easter Cooperative Oncology 
Group; FT4 = free thyroxine; GI = gastrointestinal; INR = international normalized ratio; LDH = lactate dehydrogenase; MMR = mismatch repair; MSI = 
microsatellite instability; post-op = post-operation; PT = prothrombin time; T3 = triiodothyronine; TSH = thyroid stimulating hormone; DC = discontinuation; 
F/U = follow-up; TX = treatment; d = day(s); w = week(s); y = year(s); c = cycle.
a.
Follow-up: every effort should be made to collect information regarding disease status for 1 year after pembrolizumab dosing, progressive disease or death, 
whichever comes first. Follow-up assessments and subsequent anti-neoplastic therapy are at the discretion of the treating investigator. It is advised that 
patients should be assessed every 90 days (±14 days) for 1 year after liver resection surgery by radiologic CT imaging with IV contrast to monitor disease 
status. Additional post-operative chemotherapy will be at the discretion of the treating physician. Information regarding post-study anti-neoplastic treatment 
will be collected if such treatment is initiated. Safety labs and correlative labs will be collected up to 1 year post-pembrolizumab.
b.
Screening procedures and assessments must be completed within 28 days prior to C1D1. C1D1 should occur approximately 2 weeks (minimum 1 week) after 
the final chemotherapy administration (if applicable). Screening CT chest/abdomen/pelvis with IV contrast must be performed and reviewed to confirm 
candidacy for hepatic resection prior to liver tumor biopsy. Every effort shall be made to collect future biomedical research samples, but failure to collect this 
sample due to patient refusal or logistical constraints shall not constitute a protocol deviation or violation and does not prevent the patient from enrolling on-
study.
c.
Obtain standard of care MSI/MMR and expanded RAS/BRAF mutation testing from liver resection specimen if not tested previously. Review pathology report.
d.
Baseline medications taken within 28 days of C1D1.
e.
Repeat liver biopsy if patient unable to undergo liver resection surgery.

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f.
Stool collection at following time points ±2 day window: mandatory collection post-chemo/ pre-C1D1 on day minus 4 and day minus 2, mandatory collection 
post-C1D1/ pre-surgery; optional at post-surgical follow-up.
g.
Review of baseline imaging to establish anticipated candidacy for liver resection.
h.
Baseline imaging should include a CT chest and IV contrast-enhanced CT or magnetic resonance imaging (MRI) abdomen/pelvis.
i.
Can be performed within 7 days prior to C1D1.
j.
Pembrolizumab will be administered at a fixed dose of 200 mg (IV) and vactosertib will be taken QD, PO 5 days per week C1D1 through C1D14 . See section 
5.1.
k.
All participants will be followed for up to 1 year after the last dose of pembrolizumab is administered or up to 2 years after surgery whichever occurs last.
l.
Interested participants will complete the pre-treatment procedures outlined in Table 11 below and section 6.1.6.1.
m.
Participants who are not interested or are ineligible for the adjuvant treatment cohort will be followed Q90D ±14d post-surgery for up to 2 years as outlined in 
Table 10 and section 6.1.7.
n. 
Can be performed within 10 days of C1D1
o.
Not needed for eligibility.  Every effort should be made to collect archival tissue samples but if sample is not collected or unavailable it should not constitute a 
protocol deviation.
p.
For tumor marker assessments (CEA): record CEA at diagnosis, prior to and after lead-in FOLFOX/CapeOx

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Table 11
Flow Chart for Adjuvant Treatment Cohort
Trial Period:
Adjuvant Treatment
Post-Treatment
Treatment Cycle/Visit:
Pre-
Treatment
C1 D1
C2 D1
C3 D1
C4-8 D1
End of TX
Safety F/U
Follow Up 
Phaseg
Scheduling Window:
2w ±14d post-
op
6w ±14d post-
op
12w ±3d
post-op
18w ±3d
post-op
24w-48w ±3d
post-op
At DC +7d
30d after DC 
+7d
D90D ±14d 
post-last 
pembro dose 
for 1y or post-
surgery for 2y 
(whichever 
occurs last)
Adjuvant TX Informed Consent
X
Review of Eligibilitya
X
Disease Status 
Assessment/Measurable 
disease
Xe
X
Tumor Imaging
Xe
Xe
Xe
X
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
Trial Treatment Administrationf
X
X
X
X
Dispense vactosertib
X
X
X
X
Post-study anticancer therapy 
status
X
Survival Status
X
Review Adverse Events
X
X
X
X
X
X
X
X
Directed Physical Examination
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X

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Trial Period:
Adjuvant Treatment
Post-Treatment
Treatment Cycle/Visit:
Pre-
Treatment
C1 D1
C2 D1
C3 D1
C4-8 D1
End of TX
Safety F/U
Follow Up 
Phaseg
Scheduling Window:
2w ±14d post-
op
6w ±14d post-
op
12w ±3d
post-op
18w ±3d
post-op
24w-48w ±3d
post-op
At DC +7d
30d after DC 
+7d
D90D ±14d 
post-last 
pembro dose 
for 1y or post-
surgery for 2y 
(whichever 
occurs last)
Pregnancy Test – Urine or 
Serum 
X
PT/INR and aPTT
X
Hematology, CBC with 
Differential and Platelet Count
X
Xc
X
X
X
X
X
Comprehensive Serum 
Chemistry Panel (see Table 12)
X
Xc
X
X
X
X
X
Urinalysis
X
Xc
X
X
X
X
X
T3, FT4 and TSH
X
Xc
X
X
X
X
X
Tumor Marker: CEA
X
X
X
X
ECHO
X
Xd
Correlative studies:  Blood 
collection
Xe
Xe
Xe
X
Abbreviations: aPTT – activated partial thromboplastin time; CBC = complete blood count; CEA = carcinoembryonic antigen; ECOG = Easter Cooperative 
Oncology Group; FT4 = free thyroxine; GI = gastrointestinal; INR = international normalized ratio; LDH = lactate dehydrogenase; pembro = pembrolizumab; 
post-op = post-operation; PT = prothrombin time; T3 = triiodothyronine; TSH = thyroid stimulating hormone; DC = discontinuation; F/U = follow-up; TX = 
treatment; d = day(s); w = week(s); y = year(s).
a.
Enrollment of eligible patients in the optional adjuvant therapy arm will be based on criteria listed in Section 3.3 and per the investigator’s discretion. The 
rationale for enrolling (or not enrolling) participants in adjuvant therapy will be recorded, along with any supporting test results (e.g., circulating tumor DNA 
analysis). Ineligible participants will be followed q90d ±14d post-surgery for up to 2y as outlined in Table 10 and section 6.1.7.
b.
Test within 72 hours prior to the start of adjuvant treatment
c.
Tests do not need to be repeated at adjuvant C1D1 treatment visit if they were performed within 14 days prior to C1D1.

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d.
ECHO does not need to be repeated at the End of Treatment visit if it was performed within the past 12 weeks.
e.
Perform every 12 weeks (i.e., day 1 of every other cycle) during the adjuvant treatment period. For imaging, it will be reviewed to note no evidence of 
radiographic progression or malignancy as determined by the PI.
f.
Pembrolizumab will be administered at a fixed dose of 400 mg (IV) Q6W and vactosertib will be taken PO 5 days per week. See section 5.1.
g.
Follow-up: every effort should be made to collect information regarding disease status for 1 year after last pembrolizumab dosing, progressive disease or 
death, whichever comes first. Follow-up assessments and subsequent anti-neoplastic therapy are at the discretion of the treating investigator. It is advised 
that patients should be assessed every 90 days (±14 days)  for 1 year after liver resection surgery by radiologic CT imaging with IV contrast to monitor disease 
status. Additional post-operative chemotherapy will be at the discretion of the treating physician. Information regarding post-study anti-neoplastic treatment 
will be collected if such treatment is initiated  Safety labs and correlative labs will be collected up to 1 year post-pembrolizumab.

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6.3
Duration of Follow-up
Follow-up visit procedures are listed in Section 6.1.5 and Section 6.1.7. All participants will be 
followed for up to 1 year after the last dose of pembrolizumab and vactosertib is administered or 
2 years after surgery, whichever occurs last. Follow-up assessments will occur according to 
Section 6.1.5, if discontinuation occurs post-surgery, or according to Section 6.1.7 if 
discontinuation occurs during and/or after post-adjuvant treatment. Follow-up assessments will 
occur until PD, death, withdrawing consent or becoming lost to follow-up, whichever occurs first.
6.4
Withdrawal Criteria
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be important to 
the study, they must be collected through the participant’s last scheduled follow-up, even if the 
participant has discontinued study intervention. Therefore, all participants who discontinue study 
intervention before completion of the protocol-specified treatment period will still continue to be 
monitored in this study and participate in the study visits and procedures as specified in Section 
6.1.5, if discontinuation occurs during post-surgery, and as specified in Section 6.1.6.3 and 
Section 6.1.6.4, if discontinuation occurs during and/or after post-adjuvant treatment.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect occur. 
In addition, a participant may be discontinued from study intervention by the investigator or the 
Sponsor if study intervention is inappropriate, the study plan is violated, or for administrative 
and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in the 
study for any of the following reasons, but are not limited to, disease progression, the occurrence 
of an adverse event or a concurrent illness, a patient’s request to end participation, or a patient’s 
non-compliance.  
6.4.1
Withdrawal from the Study
A patient must be withdrawn from the study if the patient or patient’s legally acceptable 
representative withdraws consent from the study.
If a patient withdraws from the study, they will no longer receive study treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the study 
are outlined in Section 6.2 (post-surgery visit). The procedures to be performed should a 
participant repeatedly fail to return for scheduled visits and/or if the study site is unable to contact 
the participant are outlined in Section 6.3.2.

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6.4.2
Lost to Follow-up
If a patient fails to return to the clinic for a required study visit and/or if the site is unable to contact 
the patient, the following procedures are to be performed:

The site must attempt to contact the patient and reschedule the missed visit. If the patient 
is contacted, the patient should be counseled on the importance of maintaining the 
protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the patient at 
each missed visit (e.g., phone calls and/or a certified letter to the patient’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the patient’s medical record.

Note: A patient is not considered lost to follow-up until the last scheduled visit for the 
individual patient. The amount of missing data for the patient will be managed via the pre-
specified data handling and analysis guidelines.
6.5
Usage of Concurrent/Concomitant Medications/Vaccinations
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the treatment period. If there is a clinical indication for any medication or vaccination specifically 
prohibited, discontinuation from trial therapy may be required. The investigator should discuss 
prohibited medications/vaccinations with the Merck Clinical Director. The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the patient's primary physician. 
However, the decision to continue the patient on study treatment requires the mutual agreement 
of the investigator, Merck, and the patient. 
6.5.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) including 
all prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and date 
may also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment and 30 
days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 90 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.5.
6.5.2
Prohibited Medications
If during the course of the trial, a patient requires treatment with following medicines for a limited 
period of time, it should not be given concurrently with the study treatment and its use should be 
reviewed with the Sponsor-Investigator who will provide guidance based on the half-life of the 
medication as well as other clinical considerations. The Investigator is also advised to consider 

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alternative medicines. Listed below are specific restrictions for concomitant therapy or vaccination 
during the study:

Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab and vactosertib

Radiation therapy 
o
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion. 

Live or live attenuated vaccines within 30 days prior to the first dose of triaQl treatment 
and while participating in the trial. Note: killed vaccines are allowed. 

Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with Merck.

Liver directed therapy such as radiotherapy or yttrium-90

Rifaximin or lactulose to control encephalopathy

Strong CYP3A inhibitors including but not limited to clarithromycin, itraconazole, 
ketoconazole, nefazodone, nelfinavir, saquinavir, voriconazole - Grapefruit juice is not 
allowed in the study. The topical use of medications, such as 2% ketoconazole cream, 
may be allowed when discussed with the Sponsor-Investigator.

Potent CYP3A inducers, including but not limited to carbamazepine, phenytoin, rifampin - 
St. John’s Wort is not allowed

Drugs that prolong QT Interval and have a risk of Torsades de Pointes
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. 
All concomitant medications received within 28 days prior to the first dose of study treatment and 
up to 30 days after the last dose of study treatment should be recorded. Concomitant medications 
administered 90 days after the last dose of study treatment should be recorded for SAEs and 
ECIs as defined in Section 7.5.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
6.6
Dietary Restrictions
There are no dietary restrictions on this study. Patients should maintain a normal diet unless 
modifications are required to manage an AE such as diarrhea, nausea or vomiting.

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6.7
Pregnancy/Contraception
6.7.1
Contraception
Pembrolizumab and vactosertib may have adverse effects on a fetus in utero. Furthermore, it is 
not known if pembrolizumab has transient adverse effects on the composition of sperm.
Patients should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study, patients of childbearing potential must adhere to the contraception requirement from the 
time of screening throughout the total duration of the drug treatment and the drug washout period. 
If there is any question that a patient of childbearing potential will not reliably comply with the 
requirements for contraception, that patient should not be entered into the study. 
For this trial, male patients will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).
Female patients will be considered of non-reproductive potential if they are either: 
(1) Postmenopausal (defined as at least 12 months with no menses without an alternative medical 
cause; in women <45 years of age a high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing.
Those who, in the opinion of the investigator, are sexually active and at risk for pregnancy, must 
agree to use highly effective contraception throughout the study and continue for at least 90 days 
after the last dose of vactosertib or 120 days after the last dose of pembrolizumab, whichever is 
later. Female and male patients of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, by complying with one of the following effective 
contraception methods:
(1) Practice abstinence† from heterosexual activity; 
OR 
(2) Use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
•
intrauterine device (IUD)

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•
vasectomy of a female patient’s male partner 
•
contraceptive rod implanted into the skin
Combination method (requires use of two of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only) 
•
contraceptive sponge (nulliparous women only) 
•
male condom or female condom (cannot be used together)
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the patient’s preferred and usual lifestyle and 
if considered acceptable by local regulatory agencies and IRBs/ERCs. Periodic abstinence 
(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for patients participating at sites 
in this country/region.
Patients should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study, patients of childbearing potential must adhere to the contraception requirements from the 
day of study medication initiation (or 14 days prior to the initiation of study medication for oral 
contraception) throughout the study period up to 120 days after the last dose of study medication. 
If there is any question that a patient of childbearing potential will not reliably comply with the 
requirements for contraception, that patient should not be entered into the study.
6.7.2
Use in Pregnancy
If a patient inadvertently becomes pregnant while on pembrolizumab-based treatment, the patient 
will be immediately discontinued from study treatment. The site will contact the patient at least 
monthly and document the patient’s status until the pregnancy has been completed or terminated. 
The outcome of the pregnancy will be reported to Merck without delay and within 24 hours if the 
outcome is a SAE (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The study Investigator will make every effort to obtain 
permission to follow the outcome of the pregnancy and report the condition of the fetus or newborn 
to Merck. If a male patient impregnates his female partner, the study personnel at the site must 
be informed immediately and the pregnancy must be reported to Merck and followed as described 
in Section 7.5.

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6.7.3
Use in Nursing Women
It is unknown whether pembrolizumab and vactosertib is excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions in 
the nursing infant, patients who are breast-feeding are not eligible for enrollment.
6.7.4
Pregnancy Tests
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours of each cycle of trial 
treatment and 30 days post treatment. If a urine test is positive or not evaluable a serum test will 
be required. Patients must be excluded/discontinued from the study in the event of a positive or 
borderline-positive test result. 
6.8
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1.
Quality or quantity of data recording is inaccurate or incomplete
2.
Poor adherence to protocol and regulatory requirements
3.
Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to patients
4.
Plans to modify or discontinue the development of the study drug
In the event of Merck’s decision to no longer supply study drug, ample notification will be provided 
so that appropriate adjustments to patient treatment can be made.
6.9
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of the trial 
(from pre-trial to post-trial visits), including approximate blood/tissue volumes drawn/collected by 
visit and by sample type per patient can be found in the laboratory manual. 
Refer to the Trial Flow Chart (Table 10) for the schedule of laboratory assessments.
6.9.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 12.
Table 12
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin†
Hemoglobin
Alkaline phosphatase
Glucose

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Hematology
Chemistry
Urinalysis
Other
Platelet count
Alanine 
aminotransferase (ALT)
Protein
PT (INR)
WBC (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
aPTT
Red Blood Cell Count
Lactate dehydrogenase 
(LDH)
Microscopic exam (If 
abnormal) 
Total triiodothyronine (T3)
Absolute Neutrophil 
Count
Carbon Dioxide ‡
(CO2 or bicarbonate)
results are noted
Free thyroxine (T4)
Absolute Lymphocyte 
Count
 Creatinine 
Urine pregnancy test † Thyroid stimulating 
hormone (TSH)
Uric Acid
CEA
Calcium
Hepatitis B surface antigen 
(HBsAg)
Chloride
Hepatitis B surface 
antibody (HBsAb)
Fasting glucose
Hepatitis B core antibody 
(HBcAb)
Phosphorus
Hepatitis C virus RNA
Potassium 
Blood for correlative 
science
Sodium
 
Magnesium
 
Total Bilirubin
 
Direct Bilirubin (If total 
bilirubin is elevated 
above the upper limit of 
normal)
Total protein
Blood Urea Nitrogen
Abbreviations: aPTT = activated partial thromboplastin time; INR = international normalized ratio; PT = prothrombin 
time; WBC = white blood cell.
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required within 72 hours prior to Day 1 of cycle 1. 
‡ If considered standard of care in your region.
Screening hematology, chemistry and urinalaysis laboratory tests should be performed within 10 
days prior to treatment. Results must be reviewed by the investigator or qualified designee and 
found to be acceptable prior to dose of trial treatment. Unresolved abnormal laboratory values 
that are drug-related AEs should be followed until resolution. Laboratory tests do not need to be 
repeated after the end of treatment if laboratory results are within normal range.

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7
Reporting and Documentation of Results
7.1
Evaluation of Efficacy (or Activity)
The 2-year RFS rate is defined as the proportion of patients without radiographic PD within 2 
years of liver resection surgery with curative intent. 
Pathologic response rate is defined as the proportion of patients with no residual cancer cells 
(complete response) or 1% to 49% residual cancer cells remaining (major response) in the liver 
resection specimen.
7.2
Evaluation of Safety
7.2.1
Sponsor Responsibility for Reporting Adverse Events
All AEs will be reported to regulatory authorities, IRB/ERCs and investigators in accordance with 
all applicable global laws and regulations. 
Analyses will be performed for all patients having received at least 1 dose of study drug. The 
study will use the NCI CTCAE v5.0 for reporting of non-hematologic AEs and modified criteria for 
hematologic AEs, see Section 7.3.1.1.
7.3
Definitions of Adverse Events
7.3.1
Adverse Event
An AE is defined as any untoward medical occurrence 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 an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product or protocol-specified procedure, whether or not 
considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., 
any clinically significant adverse change in frequency and/or intensity) of a preexisting condition 
that is temporally associated with the use of the Merck’s product, is also an AE.
Changes resulting from normal growth and development that do not vary significantly in frequency 
or severity from expected levels are not to be considered AEs. Examples of this may include, but 
are not limited to, teething, typical crying in infants and children and onset of menses or 
menopause occurring at a physiologically appropriate time.
Merck’s product includes any pharmaceutical product, biological product, device, diagnostic agent 
or protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for 
human use.
Adverse events may occur during the course of the use of Merck product in clinical trials, or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and 
from withdrawal.

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Progression of the cancer under study is not considered an AE. 
7.3.1.1 Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
CTCAE, version 5.0 (Table 13). Any AE which changes NCI CTCAE grade over the course of a 
given episode will have each change of grade recorded on the AE CRFs/worksheets.
All AEs regardless of NCI CTCAE grade must also be evaluated for seriousness. 
Table 13
Evaluating Adverse Events
V5.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic 
observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-
threatening; unplanned hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any 
use of Pembrolizumab that:
†Results in death; or
†Is life threatening; or places the patient, in the view of the investigator, at 
immediate risk of death from the event as it occurred (Note: This does not include 
an adverse event that, had it occurred in a more severe form, might have caused 
death.); or
†Results in a persistent or significant disability/incapacity (substantial 
disruption of one’s ability to conduct normal life functions); or
†Results in unplanned hospitalization or prolongs an existing inpatient 
hospitalization (hospitalization is defined as an inpatient admission, regardless of 
length of stay, even if the hospitalization is a precautionary measure for continued 
observation. Note: Hospitalization for an elective procedure to treat a pre-existing 
condition that has not worsened is not a serious adverse event. A pre-existing 
condition is a clinical condition that is diagnosed prior to the use of pembrolizumab 
and is documented in the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of patient taking the product 
regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH 
definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or
Is an overdose (whether accidental or intentional). Any adverse event associated 
with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious 
event of clinical interest and must be reported within 24 hours to the Sponsor and 
to Merck within 2 working days..
Other important medical events that may not result in death, not be life 
threatening, or not require hospitalization may be considered a serious adverse 
event when, based upon appropriate medical judgment, the event may jeopardize 
the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed previously (designated above by a †).

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Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate 
the appropriate length of time and units
Action taken 
Did the adverse event cause pembrolizumab to be discontinued?
Relationship to 
pembrolizumab 
Did pembrolizumab cause the adverse event? The determination of the likelihood 
that pembrolizumab caused the adverse event will be provided by an investigator 
who is a qualified physician. The investigator’s signed/dated initials on the source 
document or worksheet that supports the causality noted on the AE form, ensures 
that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria 
below are intended as reference guidelines to assist the investigator in assessing 
the likelihood of a relationship between the test drug and the adverse event based 
upon the available information.
The following components are to be used to assess the relationship between 
pembrolizumab and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely 
pembrolizumab caused the adverse event (AE):
Exposure
Is there evidence that the patient was actually exposed to 
pembrolizumab such as: reliable history, acceptable compliance 
assessment (pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen?
Time 
Course
Did the AE follow in a reasonable temporal sequence from 
administration of pembrolizumab? 
Is the time of onset of the AE compatible with a drug-induced effect 
(applies to trials with investigational medicinal product)?
Likely 
Cause
Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or 
environmental factors
7.3.2
Adverse reaction
An adverse reaction is defined as any AE caused by the use of a drug. Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event.
7.3.2.1 Suspected
A suspected adverse reaction is defined as any AE for which there is a reasonable possibility that 
the drug caused the AE. For the purposes of Investigational New Drug Application (IND) safety 
reporting, “reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction.
7.3.2.2 Unexpected
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the 
IB or package insert(s), or is not listed at the specificity or severity that has been observed, or, if 
an IB is not required or available, is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current application. 

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“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions that 
are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.
Adverse events that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the IB. For example, 
a certain number of non-acute deaths in a cancer trial would be anticipated as an outcome of the 
underlying disease, but such deaths would generally not be listed as a suspected adverse 
reaction in the IB.
Some AEs are listed in the IB as occurring with the same class of drugs, or as anticipated from 
the pharmacological properties of the drug, even though they have not been observed with the 
drug under investigation. Such events would be considered unexpected until they have been 
observed with the drug under investigation. For example, although angioedema is anticipated to 
occur in some patients exposed to drugs in the ACE inhibitor class and angioedema would be 
described in the investigator brochure as a class effect, the first case of angioedema observed 
with the drug under investigation should be considered unexpected for reporting purposes.
7.3.3
Serious Adverse Event
An AE or suspected adverse reaction is considered serious if, in the view of either the investigator 
or Merck, it results in any of the following outcomes: 

In death

Is life-threatening adverse event (Section 7.3.3.1)

In persistent or significant disability/incapacity;

An unplanned inpatient hospitalization or prolongation of an existing inpatient 
hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function

Is a congenital anomaly/birth defect

Is another important medical event 
 Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or unplanned surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
Note: In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per International Council for Harmonisation (ICH) definition, are reportable to Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes.

Is a new cancer (that is not a condition of the study);

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
Is associated with an overdose.
Additionally, any SAE, considered by an Investigator who is a qualified physician to be related to 
Merck's product that is brought to the attention of the Investigator at any time following consent 
through the end of the specified safety follow-up period specified in the paragraph above, or at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Merck clinical team. 
All patients with SAEs must be followed up for outcome.
7.3.3.1 Life-threatening
An AE or suspected adverse reaction is considered life-threatening if, in the view of either the 
investigator or Merck, its occurrence places the patient or subject at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death. 
7.3.4
Definition of an Overdose Definition
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater. No specific information is available on the treatment of overdose of pembrolizumab. In 
the event of overdose, the patient should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.
Vactosertib overdose is defined as any daily dose more than 900 mg or more than 1.5 times of 
weekly indicated dose. The effects of an overdose with vactosertib are unknown. 
7.3.5
Events of Clinical Interest
Selected non-serious and SAE are also known as ECIs.
Events of clinical interest that must be reported to Merck include:
1.
An overdose of Merck's product, as defined in Section 7.3.4, that is not associated with 
clinical symptoms or abnormal laboratory results.
2. An elevated AST or ALT lab value that is greater than 5 × ULN and an elevated total 
bilirubin lab value that is greater than or equal to 2 × ULN and, at the same time, an ALP 
lab value that is less than 2 × ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
Note: Liver function test abnormalities are expected after hepatic metastatectomy. 
Therefore, AST, ALT or total bilirubin elevations occurring after hepatic metastatectomy 
and considered by an investigator who is a qualified physician to be related to surgery 
(unlikely related to pembrolizumab), must be reported to the Sponsor and to Merck at the 
time of the first post-surgical safety follow-up visit or within 30 days of hepatic 
metastatectomy surgery, whichever comes first.
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.

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Events of clinical interest that must be reported to MedPacto include:
1.
Any abnormal changes in cardiac valves detected by ECHO which will be conducted at 
the screening, cycle 2 during adjuvant treatment, and EOT.
7.3.6
Protocol-Specific Exceptions to Serious Adverse Event Reporting 
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.5, unless there is evidence suggesting a causal relationship between the drug and the 
event.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. Hospitalization related to convenience (e.g. 
transportation issues etc.) or planned surgery will not be considered a SAE.
The Investigator will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the patients in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck as a SAE within 2 working days 
of determination that the event is not progression of the cancer under study.
7.4
Recording of an Adverse Event
All Grade 3 and above AEs will be entered into OnCore®, whether or not the event is believed to 
be associated with use of the study drug. Data about these events and their severity will be 
recorded using the NCI CTCAE v5.0. 
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed in Table 14.
Table 14
Classification System for Assigning Attribute to Adverse Events
Relationship 
Attribution 
Description 
Unrelated
The AE is clearly NOT related to the intervention 
Unrelated to investigational 
drug/intervention
Unlikely
The AE is doubtfully related to the intervention 
Possible
The AE may be related to the intervention 
Probable
The AE is likely related to the intervention 
Related 
to 
investigational 
drug/intervention
Definite
The AE is clearly related to the intervention 
Signs or symptoms reported as AEs will be graded and recorded by the Investigator according to 
the NCI CTCAE v5.0. When specific AEs are not listed in the NCI CTCAE they will be graded by 

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the Investigator as none, mild, moderate or severe according to the following grades and 
definitions:
Grade 0
No AE (or within normal limits)
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL)
Grade 3:
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL
Grade 4:
Life-threatening consequences; urgent intervention indicated
Grade 5:
Death related to AE
7.5
Reporting Adverse Events to Merck
All AEs, SAEs and other reportable safety events that occur after the ICF is signed but before 
treatment allocation must be reported by the investigator if the patient is receiving placebo run-
in or other run-in treatment, if the event cause the patient to be excluded from the study, or is 
the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure. 
●
All AEs from the time of treatment allocation through 30 days following cessation of 
study treatment must be reported by the investigator. 
●
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy, whichever is earlier 
must be reported by the investigator. 
●
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 
30 days following cessation of study treatment if the participant initiates new anticancer 
therapy must be reported by the investigator. 
●
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Merck clinical team 
if the event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event 
to be reasonably related to the study treatment or study participation, the investigator must 
promptly notify the Merck clinical team.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the Merck clinical team or designee within the timeframes as indicated in Table 15.

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Table 15
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events to Merck
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting 
Time Period:
Randomization
/ Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-
up Period
Timeframe to 
Report Event 
and Follow-up 
Information to 
Mercka:
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- patient is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome.)
Within 24 hours 
of learning of 
event*
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- patient is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 days of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- Potential DILI
- Require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event*

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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting 
Time Period:
Randomization
/ Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-
up Period
Timeframe to 
Report Event 
and Follow-up 
Information to 
Mercka:
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 days of 
learning of 
event*
Cancer
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Not required
Within 5 days of 
learning of 
event
Pregnancy/ 
Lactation Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported 
– Follow to 
completion/terminati
on; report outcome
Within 24 hours 
of learning of 
event
a.
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety 
.
* Note: Serious AEs and ECIs occurring after hepatic metastatectomy, considered by an 
investigator who is a qualified physician to be related to surgery (unlikely related to 
pembrolizumab), must be reported to the Sponsor and to Merck Global Safety at the time of the 
first post-surgical safety follow-up visit or within 30 days of hepatic metastatectomy surgery, 
whichever comes first.
7.5.1
Reporting of Pregnancy and Lactation
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a patient (spontaneously reported to the 
investigator or their designee) that occurs during the trial are reportable to the Merck clinical team.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.

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Such events must be reported within 24 hours to the Merck clinical team by either electronic media 
or paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
7.6
Reporting Adverse Events to MedPacto
All SAEs and AESIs that occur from the time of the patient signing the informed consent form until 
90 days after the last dose of IP, whether or not considered causally related to vactosertib, will be 
reported to the MedPacto via e-mail or fax within one calendar day (i.e., immediately but no later 
than 24 hours) of the investigator’s knowledge of the event. For fatal or life-threatening AEs where 
important or relevant information is missing, active follow-up should be undertaken immediately. 
The Investigator or designee will submit any updated SAE or AESI data to the MedPacto via e-
mail or fax within one calendar day (i.e., immediately but no later than 24 hours) of the 
investigator’s knowledge of the information.
If an SAE or AESI starts/occurs after the defined safety follow-up period noted above and is 
considered to be due to a late onset toxicity to vactosertib, it should be recorded in the eCRFs 
and reported to the MedPacto.
Investigators are not obligated to actively seek AEs in former study patients. However, if the 
Investigator learns of any SAE, including a death, or AESI at any time after a patient’s last visit 
and he/she considers the event to be reasonably related to vactosertib, it should be reported to 
the MedPacto. 
A copy of all SAEs should be submitted to MedPacto at the contact information below.
MedPacto contact:
7.7
Follow-up of Adverse Events
All AEs will be followed with appropriate medical management until resolved. All AEs that occur 
prior to the post-surgery follow-up visit should be recorded. Patients with an AE of Grade >1 will 
be followed until the resolution of the AE to Grade 0 to 1 or until the beginning of a new anticancer 
therapy, whichever occurs first. Serious AEs that occur within 90 days of the end of treatment or 
before initiation of a new anticancer treatment should also be followed and recorded.
Patients removed from study for unacceptable AEs will be followed until resolution or stabilization 
of the AE. For selected AEs for which administration of the investigational drug was stopped, a 
re-challenge of the patient with the investigational drug may be conducted if considered both safe 
and ethical by the Investigator.

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7.8
Adverse Events Monitoring 
All AEs, whether or not unexpected, and whether or not considered to be associated with the use 
of the study drug, will be entered into OnCore®, as noted above.
The Investigator will assess all AEs and determine reportability requirements to the UCSF Data 
and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board, the IRB; and, 
when the study is conducted under an IND, to the FDA if it meets the FDA reporting criteria.
All AEs entered into OnCore® will be reviewed by the Helen Diller Family Comprehensive Cancer 
Center Site Committee on a weekly basis. The Site Committee will review and discuss at each 
weekly meeting the selected toxicity, the toxicity grade, and the attribution of relationship of the 
AE to the administration of the study drug(s).
All grade(s) 3-5 AEs entered into OnCore® will be reviewed on a monthly basis at the Site 
Committee meetings. The Site Committee will review and discuss the selected toxicity, the toxicity 
grade, and the attribution of relationship of the AE to the administration of the study drug(s).
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
reviewed and monitored by the DSMC on an ongoing basis and discussed at DSMC meetings, 
which take place every six weeks.
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) or 
to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or qualified 
alternate) within 1 business day of knowledge of the event. The contact may be by phone or e-
mail.
Reporting to UCSF Institutional Review Board
The Principal Investigator must report events meeting the UCSF IRB definition of “Unanticipated 
Problem” (UP) within 10 business days of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected. The Sponsor-Investigator needs to ensure that the event meets all three 
definitions: 

Suspected adverse reaction (as defined in Section 7.3.2.1)

Unexpected (as defined in Section 7.3.2.2)

Serious (as defined in Section 7.3.3)
If the AE does not meet all 3 of the definitions, it should not be submitted as an expedited IND 
safety report.

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The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the information 
is available (21 CFR 312.32(d)(2)). 
8
Statistical Considerations and Evaluation of Results
8.1
Study Endpoints
Primary endpoint: the proportion of patients with a >2 fold increase in the number of tumor 
infiltrating TILs cells per unit area (5 high power fields) post- vs. pre-pembrolizumab-based 
neoadjuvant treatment tumor specimens.
Secondary endpoints:

Safety: An important secondary objective of this study is to characterize the safety and 
tolerability of pembrolizumab-based treatment in patients with resectable liver metastases. 
The safety analysis will be based on patients who experience toxicities as defined by NCI 
CTCAE 5.0 criteria (Appendix 3). Safety will be assessed by quantifying the toxicities and 
grades experienced by patients who have received pembrolizumab-based treatment, 
including all AEs and ECIs.
The attribution to drug, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. AEs will be analyzed including 
but not limited to all AEs, SAEs, and fatal AEs. Furthermore, specific immune-related AEs 
(irAEs) will be collected and designated as immune-related ECIs as described in Section 
7.3.5.
Surgical complications will be characterized using Clavien-Dindo criteria (Appendix 4). 
Early stopping rules have been defined to mitigate risk of perioperative complications (see 
section 8.3). 

Efficacy: Endpoints for preliminary estimation of the clinical efficacy of pembrolizumab-
based treatment in the perioperative setting for patients with CRC with resectable hepatic 
metastases are as follows: 
o
Pathologic response rate [34]
o
R0 resection rate
o
2-year RFS with and without adjuvant pembrolizumab-based therapy
o
Objective Response Rate

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Exploratory endpoints:

Change in T-cell repertoire in pre-neoadjuvant treatment liver biopsies vs. surgical tumor 
specimens as well as in blood samples from the same time-points

Change in PD-L1 expression and other molecular markers in pre-neoadjuvant treatment 
liver biopsies vs. surgical tumor specimens

Correlate changes in microbiome composition and diversity (by metagenomic sequencing 
and untargeted metabolomics of stool collected before, during, and after immunotherapy), 
with diet and lifestyle factors determined by self-reported questionnaires.

Explore the correlation between change in tumor infiltrating TILs and T-cell repertoire. 
8.1.1
Study Design
This is a single-site, single-arm, open-label Phase 2 clinical trial of pembrolizumab + vactosertib 
in patients with CRC with resectable hepatic metastases.
8.1.2
Randomization
This is a non-randomized study.
8.1.3
Stratification Factors
None. There are no planned patient stratification factors.
8.2
Determination of Sample Size and Accrual Rate
8.2.1
Sample Size and Power Estimate
For the primary objective, there will be a binary classification (28). A patient will be considered to 
have a “positive response” if there is a ≥2-fold increase (from pre- to post-treatment) in the number 
of TILs, and a “negative response” if there is <2-fold increase. Obtaining paired specimens from 
17 patients will be sufficient to determine whether 40% or more achieve a “positive response,” 
compared to a null hypothesis of 10% or less. This comparison has a power of 0.91 at a 
significance level of 0.05 for a directional binomial test. 
8.2.2
Replacement Policy
We plan to enroll 19 patients to achieve our goal of 17 patients evaluable for the primary study 
outcome. If more than 2 patients turn out not to be evaluable for the primary study outcome (i.e., 
do not have available post-pembrolizumab-based neoadjuvant treatment tumor tissue available 
for analysis), they may be replaced upon discussion with the study Principal Investigator and JSC. 

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8.2.3
Accrual estimates
Based on current estimates of the number of eligible patients seen at UCSF annually, as well as 
strong interest among patients in receiving immunotherapy, we anticipate completing accrual 
within 1 year. 
8.3
Interim Analyses and Stopping Rules
The trial will be stopped early if 2 of the first 6 patients fail to undergo liver resection surgery within 
6 weeks of their final chemotherapy treatment (if applicable) due to AEs attributed to 
pembrolizumab-based treatment, or experience Grade IV-V surgical complications according to 
Clavien-Dindo classification attributed to pembrolizumab -base treatment (Appendix 4).
Of particular significance to this study, enrolling patients being treated with curative intent, are 
perioperative complications attributed to pembrolizumab-based treatment. These may include 
delaying surgery due to pre-operative AEs and complications during or after surgery attributed to 
pembrolizumab-based treatment. Early stopping rules have been defined to mitigate risk of 
perioperative complications. The study will be stopped and the approach will be re-evaluated if 2 
or more of the first 6 patients experience any one of the following:

A delay in planned surgery beyond the 6-week window from final chemotherapy (if 
applicable), due to any grade toxicity attributable to study treatment. Delays in surgery 
due to other reasons (scheduling, available O.R time, patient preference) will not count.

Grade IV and V surgical complications according to Clavien-Dindo classification (Appendix 
4). Note: Surgical complications associated with liver metastastectomy are very common, 
and we recognize that it may be difficult to attribute any such complications to preoperative 
administration of pembrolizumab. Therefore, the occurrence of such events may not 
necessarily require stopping the study early, but will be discussed amongst members of 
the JSC, with particular attention paid to specific complications such as liver failure, severe 
colitis, etc.
Enrollment will be paused for 4 weeks after the sixth patient undergoes surgery (or receives their 
last dose of pembrolizumab if unable to undergo surgery). During this interval the study 
investigators will meet with the participating surgeons to review the first 6 cases. A 
recommendation will be made regarding whether or not to enroll additional patients and if any 
changes are needed to optimize safety or feasibility.
8.4
Analyses Plans
8.4.1
Analysis Population
The analysis population for the primary outcome will be all patients with pre- and post-
pembrolizumab-based neoadjuvant treatment tumor specimens that are evaluable for TILs. 
The All Patients as Treated (APaT) population will be used for the analysis of the secondary 
safety/toxicity outcomes and the clinical efficacy endpoint, ORR. The APaT population consists 
of all patients who received at least one dose of pembrolizumab and/or vactosertib and at least 
one laboratory or vital sign measurement. To assess change from baseline, a baseline 
measurement is also required.

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Patients who undergo surgical resection of liver metastases will be evaluable for the secondary 
clinical efficacy endpoints: pathologic response rate, R0 resection rate and RFS at 2-years. 
Safety analyses will be performed for all patients having received at least one dose of 
pembrolizumab and/or vactosertib. The study will use the NCI CTCAE v5.0.
8.4.2
Primary Analysis (or Analysis of Primary Endpoints)
TILs will be analyzed in pre- and post-pembrolizumab-based neoadjuvant treatment tumor 
specimens. Testing for evidence of an increase in CD3+ T-cells will be conducted using a paired 
t-test and the Wilcoxon signed-rank test and results compared for consistency.  Testing for a 
difference in the central tendency of the change in CD3+ T-cells for responders vs. non-
responders under either the objective radiographic or pathological response definitions of will use 
a two-sample t-test and a Wilcoxon rank-sum test and results compared for consistency.  All tests 
will be conducted at a nominal significance level of 0.05 with no adjustment for multiplicity.
8.4.3
Secondary Analysis (or Analysis of Secondary Endpoints)
The study will use descriptive statistics to report on the safety/toxicity and efficacy of pre-operative 
pembrolizumab-based treatment, including adverse events by NCI CTCAE (v 5.0) criteria and 
perioperative complications; pathologic response; R0 resection rate; and 2-year RFS. The sample 
size of each cohort will be too small to compare these results to historic data (i.e. from the 
Nordlinger EORTC study). However, we would consider the approach feasible if (1) ≥14 of 17 
patients (≥83%) are able to successfully undergo R0 resection within 6 weeks of last 
chemotherapy administration (if applicable); and (2) the rate of serious postoperative 
complications attributable to pembrolizumab-based treatment does not exceed 33% (6 of 
17 patients).
The study will also use descriptive statistics to compare 2-year RFS rates in patients who do or 
do not receive adjuvant pembrolizumab-based therapy. 
8.4.4
 Exploratory Analysis (or Analysis of Exploratory Endpoints)
Wilcoxon rank-sum test will be used to assess whether there is a relationship between any of the 
immune cell subsets and objective radiographic response as well as pathologic response. Cox-
proportional hazard models will be applied to assess if there is relationship between any of the 
immune cell subsets and RFS. Parallel analysis will be performed for PD-L1 expression. Wilcoxon 
rank-sum test will also be used to assess whether the T cell receptor clonality diversity index is 
different between responders vs. non-responders (defined by objective radiographic response or 
pathologic response), and between patients who have progression within 1-year vs. those whose 
disease has not progressed. Additional analyses of immunocorrelative data are detailed in the 
Lab Manual.

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9
Study Management
9.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable 
regulatory requirements.
Before initiating this trial, the Investigator will have written and dated approval from the IRB for 
the protocol, written ICF, patient recruitment materials, and any other written information to be 
provided to patients before any protocol related procedures are performed on any patients. 
The clinical investigation will not begin until either FDA has determined that the study under the 
IND is allowed to proceed or the Investigator has received a letter from FDA stating that the study 
is exempt from IND requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable regulatory 
requirements.
9.2
Institutional Review Board Approval
The protocol, the proposed ICF, and all forms of participant information related to the study (e.g. 
advertisements used to recruit participants) will be reviewed and approved by the UCSF IRB. 
Prior to obtaining IRB approval, the protocol must be approved by the Helen Diller Family 
Comprehensive Cancer Center Site Committee and by the Protocol Review Committee (PRC). 
The initial protocol and all protocol amendments must be approved by the IRB prior to 
implementation. 
9.3
Informed Consent
A signed informed consent form (ICF) and a Health Insurance Portability and Accountability Act 
(HIPAA) authorization must be obtained before any study-specific assessments are initiated. The 
investigator or qualified designee will explain the study to the patient and answer all of his/her 
questions.
All patients must be provided a consent form describing the study with sufficient information for 
each participant to make an informed decision regarding their participation. Participants must sign 
the IRB-approved ICF prior to participation in any study specific procedure. The participant must 
receive a copy of the signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file.
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS). The system is 
password protected and meets HIPAA requirements.

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9.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the Investigator 
and approved by PRC and the IRB prior to implementation. 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the 
Investigator must then notify the IRB in writing within 5 working days after implementation. The 
Study Chair and the UCSF study team will be responsible for updating any participating sites.
9.5
Handling and Documentation of Clinical Supplies
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs. The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included. The sponsor-
investigator will maintain written records of any disposition of the study drug.
The Principal Investigator shall not make the investigational drug available to any individuals other 
than to qualified study patients. Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol.
9.6
Case Report Forms (CRFs)
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study 
specific CRFs will document safety and treatment outcomes for safety monitoring and data 
analysis. All study data will be entered into OnCore® via standardized CRFs in accordance with 
the CTMS study calendar, using single data entry with a secure access account. The Clinical 
Research Coordinator will complete the CRFs as soon as possible upon completion of the study 
visit; the Investigator will review and approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained by UCSF 
personnel. All source documentation should be kept in separate research folders for each patient.
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The Principal Investigator will 
approve all completed CRFs to attest that the information contained on the CRFs is true and 
accurate. 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.
The Principal Investigator will be responsible for ensuring the accurate capture of study data. At 
study completion, when the CRFs have been declared to be complete and accurate, the database 
will be locked. Any changes to the data entered into the CRFs after that time can only be made 
by joint written agreement among the Study Chair, the Trial Statistician, and the Protocol Project 
Manager.

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9.7
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring entity 
for this study. The UCSF DSMC will monitor the study in accordance with the NCI-approved Data 
and Safety Monitoring Plan (DSMP). The DSMC will routinely review all adverse events and 
suspected adverse reactions considered “serious”. The DSMC will audit study-related activities 
to ensure that the study is conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP). Significant results of the DSMC 
audit will be communicated to the IRB and the appropriate regulatory authorities at the time of 
continuing review, or in an expedited fashion, as applicable. See Appendix 2 Data and Safety 
Monitoring Plan for a Phase 2 or 3 Institutional Study, for additional information.
9.8
Record Keeping and Record Retention
The Principal Investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by patients, as well as written records of the disposition of the 
drug when the study ends. 
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. Case 
histories include the case report forms and supporting data including, for example, signed and 
dated consent forms and medical records including, for example, progress notes of the physician, 
the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall 
document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study.
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it is 
being investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and FDA is notified.
9.9
Coordinating Center Documentation of Distribution
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that the 
Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, 
drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.

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At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed.
10 Protection of Human Patients
10.1
Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all patients involved in human experimentation. This 
is accomplished through the IRB mechanism and the process of informed consent. The IRB 
reviews all proposed studies involving human experimentation and ensures that the patient’s 
rights and welfare are protected and that the potential benefits and/or the importance of the 
knowledge to be gained outweigh the risks to the individual. The IRB also reviews the informed 
consent document associated with each study in order to ensure that the consent document 
accurately and clearly communicates the nature of the research to be done and its associated 
risks and benefits. 
10.2
Protection of Privacy
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the individuals 
described in the informed consent document.

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Appendices
Appendix 1:
Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease
0
Normal activity
Fully active, able to carry on all 
pre-disease performance without 
restriction
90
Able to carry on normal activity; 
minor signs or symptoms of disease
80
Normal activity with effort; some 
signs or symptoms of disease
1
Symptoms, but ambulatory
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work)
70
Cares for self, unable to carry on 
normal activity or to do active work
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs
2
In bed < 50% of the time
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities
Up and about more than 50% of 
waking hours
50
Requires considerable assistance 
and frequent medical care
40
Disabled, requires special care and 
assistance
3
In bed > 50% of the time
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours
30
Severely disabled, hospitalization 
indicated
Death not imminent
20
Very sick, hospitalization indicated
Death not imminent
4
100% bedridden
Completely disabled
Cannot carry on any self-care
Totally confined to bed or chair
10
Moribund, fatal processes 
progressing rapidly
5
Dead
0
Dead

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Appendix 2:
UCSF Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study
2.
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical studies. A summary of DSMC activities for this study includes:

Semiannual auditing (depending on study accrual)

Review of serious adverse events

Minimum of biennial regulatory auditing
3.
Monitoring and Reporting Guidelines
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes. 
All institutional Phase 2 and 3 studies are designated with a moderate risk assessment. The data 
is audited semiannually with a random selection of twenty percent of the participants audited (or 
at least three participants if the calculated value is less than three). The DSMC Monitor/Auditor 
will audit a maximum of 5 cycles of treatment in the participants selected for the review, or until 
the selected participants discontinue study participation or the trial is closed with the IRB. 
Additionally, the assigned DSMC Monitor/Auditor will review no more than a total of 10 participant 
charts during the course of auditing this trial. DSMC Monitor/Auditors will send a follow-up report 
to the study team within 20 business days after the auditing visit is complete for the PI and the 
study team to resolve all action items from this report within 20 business days. Additionally, a 
regulatory audit will occur on a biennial basis to review all regulatory documents for the trial.
4.
Review and Oversight Requirements
1.1 Adverse Event Review and Monitoring
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or unexpected 
and whether or not considered to be associated with the use of the investigational agent(s) or 
study procedure, will be entered into OnCore®, UCSF’s Clinical Trial Management System.
Adverse events are graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of 
the National Cancer Institute. Adverse events are further given an assignment of attribution 
or relationship to investigational agent or study procedure. Attribution categories are:

Definite – The adverse event is clearly related to the investigational agent(s) or study 
procedure.

Probable – The adverse event is likely related to the investigational agent(s) or study 
procedure.

Possible – The adverse event may be related to the investigational agent(s) or study 
procedure.

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
Unrelated – the adverse event is clearly not related to the investigational agent(s) or 
study procedure.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at 
the Site Committee meetings. The Site Committee will review and discuss the selected 
toxicity, the toxicity grade, and attribution assignment.
1.2 Serious Adverse Event Reporting
By definition, an adverse event is defined as a serious adverse event (SAE) according to the 
following criteria:

Death.

Life-threatening (i.e. results in an immediate risk of death).

Requires inpatient hospitalization or prolongation of existing hospitalization,

Permanent or significant disability/incapacity

Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed above. 

Event occurring in a gene therapy study.

Event that changes the risk/benefit ratio of a study.

Any other event the Principal Investigator judges to be serious or which would suggest 
a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported in 
accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported on a 
Med Watch form.
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event
Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All serious adverse events are entered into OnCore®, as well as submitted to the IRB (per 
IRB guidelines). The SAEs are reviewed and monitored by the Data and Safety Monitoring 
Committee on an ongoing basis and discussed at DSMC meetings, which take place every 
six weeks. The date the SAE is sent to all required reporting agencies will be documented in 
OnCore®. 
If the SAE involves a subject death, and is determined to be possibly, probably or definitely 
related to the investigational drug or any research related procedure, the event must be 
reported to the DSMC Chair (or Vice Chair) and DSMC Director within one business day.
1.3 Review of Adverse Event Rates

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If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, the Principal Investigator will 
notify the DSMC via report at the time the increased rate is identified. The report will indicate 
if the incidence of adverse events observed in the study is above the range stated in the 
Investigator Brochure or package insert.
If at any time the Investigator voluntarily holds enrollment or stops the study due to safety 
issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be notified within one 
business day and the IRB must be notified as per IRB reporting regulations.
Data and Safety Monitoring Committee Contacts:
Katie Kelly, MD (DSMC Chair)
UCSF HDFCCC
San Francisco, CA 94158
John McAdams (DSMC Director)
UCSF HDFCCC
San Francisco, CA 94143
[DSMP language updated 08/21/2020]

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Appendix 3:
Common Terminology Criteria for Adverse Events V5.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse 
Events 
(CTCAE) 
version 
5.0 
will 
be 
utilized 
for 
adverse 
event 
reporting.(http://ctep.cancer.gov/reporting/ctc.html)

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Appendix 4: The Clavien-Dindo Classification of Surgical Complications 
Full Scale 
Contracted Form 
Grades 
Definition 
Grades
Definition
Any deviation from the normal 
postoperative course without 
the need for pharmacological 
treatment or surgical, 
endoscopic and radiological 
interventions. 
Grade I: 
Allowed therapeutic regimens 
are: drugs as antiemetics, 
antipyretics, analgesics, 
diuretics and electrolytes and 
physiotherapy. This grade also 
includes wound infections 
opened at the bedside. 
Grade I: 
Same as for Full Scale 
Grade II: 
Requiring pharmacological 
treatment with drugs other than 
such allowed for grade I 
complications.
Blood transfusions and total 
parenteral nutrition are also 
included. 
Grade II:
Same as for Full Scale 
Grade III: 
Requiring surgical, endoscopic 
or radiological intervention 
Grade III-a: 
intervention not under general 
anesthesia 
Grade III-b: 
intervention under general 
anesthesia 
Grade III: 
 
Grades IIIa & IIIb 
Grade IV: 
Life-threatening complication 
(including CNS complications)‡ 
requiring IC/ICU-management 
Grade IV-a: 
single organ dysfunction 
(including dialysis) 
Grade IV-b: 
multi organ dysfunction 
Grade IV: 
Grades IVa & IVb 

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Full Scale 
Contracted Form 
Grades 
Definition 
Grades
Definition
Grade V: 
Death of a patient 
Grade V: 
Same as for Full Scale 
Suffix 'd': 
If the patients suffers from a 
complication at the time of 
discharge, the suffix “d” (for 
‘disability’) is added to the 
respective grade of 
complication. This label 
indicates the need for a follow-
up to fully evaluate the 
complication. 
 
‡ brain hemorrhage, ischemic stroke, subarachnoid bleeding, but excluding transient ischemic attacks (TIA);IC: 
Intermediate care; ICU: Intensive care unit.
Dindo D., Demartines N., Clavien P.A.; Ann Surg. 2004; 244: 931-937