A Phase Ib/ II Study of Sorafenib and Pembrolizumab in Advanced Hepatocellular Cancer (HCC)
Phase: PHASE1
Conditions: Advanced Adult Hepatocellular Carcinoma, Child-Pugh Class A, Stage III Hepatocellular Carcinoma, Stage IIIA Hepatocellular Carcinoma, Stage IIIB Hepatocellular Carcinoma, Stage IIIC Hepatocellular Carcinoma, Stage IV Hepatocellular Carcinoma, Stage IVA Hepatocellular Carcinoma, Stage IVB Hepatocellular Carcinoma
Sponsor: Roswell Park Cancer Institute

Document Coversheet 
 
 Study Title: 
 A Phase Ib/ II Study of Sorafenib and Pembrolizumab in Advanced Hepatocellular Cancer (HCC) 
 
 
 
Institution/Site:  
Roswell Park Comprehensive Cancer Center 
Document (Approval/Update) Date: 
09/16/2021 
NCT Number: 
NCT03211416 
IRB Number 
I 35316 
 

Roswell Park Protocol No.: I 35316
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PROTOCOL TITLE:
A Phase Ib/ II Study of Sorafenib and Pembrolizumab in Advanced Hepatocellular Cancer 
(HCC)
PROTOCOL NUMBER:
I 35316
PRINCIPAL INVESTIGATOR:
Renuka Iyer, MD
Roswell Park Cancer Institute
Elm and Carlton Street
Buffalo, New York 14263
716-845-3099
Renuka.Iyer@roswellpark.org
VERSION NUMBER: V.1 -DATE: 01/04/17
Amendment#1: 053117
Amendment#2: 092817
Amendment#3: 121517
Amendment#4: 033018
Amendment#5: 101519
Amendment#6: 071720
Amendment#7: 041421
Amendment#8: 091621
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party (ies) mentioned above (Roswell Park Cancer Institute 
Corporation d/b/a Roswell Park Comprehensive Cancer Center). The use of such confidential 
information must be restricted to the recipient for the agreed purpose and must not be disclosed, 
published, or otherwise communicated to any unauthorized persons, for any reason, in any form 
whatsoever without the prior written consent of the party(ies)above.
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Table of Contents
1.0
Objectives .............................................................................................................................4
1.1
Primary Objective.................................................................................................................4
1.2
Secondary Objective.............................................................................................................4
1.3
Exploratory Objectives .........................................................................................................4
2.0
Background...........................................................................................................................4
2.1
Hepatocellular Carcinoma and Sorafenib.............................................................................4
2.2
Hepatocellular Carcinoma and Immune Dysfunction ..........................................................4
2.3
Pembrolizumab.....................................................................................................................5
2.4
Correlative Studies................................................................................................................6
2.5
Rationale...............................................................................................................................7
3.0
Inclusion and Exclusion Criteria ..........................................................................................7
3.1
Inclusion Criteria ..................................................................................................................8
3.2
Exclusion Criteria ...............................................................................................................10
3.3      Special Populations.............................................................................................................12
3.4      Inclusion of Women and Minorities...................................................................................12
4.0
Local and Study-Wide Number of Subjects .......................................................................12
5.0
Local and Study-Wide Recruitment Methods ....................................................................12
6.0
Multi-Site Research ............................................................................................................12
7.0
Study Timelines..................................................................................................................12
8.0
Study Endpoints..................................................................................................................12
9.0
Design.................................................................................................................................13
10.0
Treatment............................................................................................................................14
10.1
Sorafenib.............................................................................................................................14
10.2
Pembrolizumab...................................................................................................................15
10.3
General Concomitant Medications .....................................................................................16
10.4
Rescue Medications & Supportive Care.............................................................................17
10.6
Duration of Treatment ........................................................................................................21
11.0
Procedures Involved ...........................................................................................................21
11.1
Pharmacokinetic Blood Sample Collection and Processing...............................................21
11.2
Correlative Studies Blood Sample Collection ....................................................................23
11.3
Pathology ............................................................................................................................25
12.0
Withdrawal of Subjects.......................................................................................................28
12.1
Treatment Discontinuation .................................................................................................28
13.0
Risks to Subjects.................................................................................................................28
13.1
Pembrolizumab...................................................................................................................28
13.2
Sorafenib.............................................................................................................................29
14.0
Potential Benefits to Subjects .............................................................................................29
15.0
Data and Specimen Banking...............................................................................................29
16.0
Measurement of Effect .......................................................................................................30
16.1
Solid Tumors ......................................................................................................................30
17.0
Safety Evaluation................................................................................................................30
17.1
Adverse Events ...................................................................................................................30
17.2
Grading and Reporting Adverse Events .............................................................................31
17.3
Serious Adverse Events ......................................................................................................32
17.4
Events of Clinical Interest ..................................................................................................33
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17.5
Protocol-Specific Exceptions to Serious Adverse Event Reporting...................................34
17.6
Investigator Reporting: .......................................................................................................35
17.7
Follow-Up for Serious Adverse Events..............................................................................35
17.8
Unanticipated Problems......................................................................................................35
18.0
Data Management and Confidentiality...............................................................................36
19.0
Statistical Plan ....................................................................................................................36
20.0
Provisions to Monitor the Data to Ensure the Safety of Subjects.......................................38
21.0
Vulnerable Populations.......................................................................................................38
22.0
Community-Based Participatory Research.........................................................................38
23.0
Sharing of Results with Subjects ........................................................................................38
24.0
Setting.................................................................................................................................38
25.0
Provisions to Protect the Privacy Interests of Subjects ......................................................38
26.0
Resources Available ...........................................................................................................38
27.0
Prior Approvals...................................................................................................................38
28.0
Compensation for Research-Related Injury........................................................................38
29.0
Economic Burden to Subjects.............................................................................................38
30.0
Consent Process..................................................................................................................39
31.0
Process to Document Consent in Writing...........................................................................39
32.0
Drugs or Devices ................................................................................................................39
33.0
REFERENCES ...................................................................................................................42
34.0
APPENDICES/SUPPLEMENTS.......................................................................................44
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1.0
Objectives
1.1
Primary Objective

To assess the overall response rate (ORR) related to the combination of 
sorafenib + pembrolizumab in advanced hepatocellular carcinoma patients.
1.2
Secondary Objective

To assess time to tumor progression in patients who received the combination therapy of 
sorafenib + pembrolizumab compared to historical data on sorafenib only treatment in 
patients with advanced hepatocellular carcinoma.
1.3
Exploratory Objectives

To obtain data on changes in immune cell function and in the tumor microenvironment 
pre- and post-treatment to screen for potential biomarkers that may be able to predict 
clinical benefit.

All patients will be followed for survival.
2.0
Background
Hepatocellular cancer (HCC) is a lethal malignancy and an increasing global health problem. 
With an estimated global incidence of 782,451 cases in 2012, it is the fifth-most common cancer 
and the sixth-most fatal.(1) HCC is a complex and heterogeneous tumor driven by angiogenesis 
and several genomic alterations including aberrant activation of signal transduction pathways 
such as EGFR, Ras/Erk, PI3K/mTOR and apoptotic signaling.(2)
2.1
Hepatocellular Carcinoma and Sorafenib
Sorafenib is a synthetic compound targeting growth signaling and angiogenesis. Sorafenib blocks 
the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that 
controls cell division and proliferation. Sorafenib has an antiangiogenic effect by targeting 
vascular endothelial growth factor receptor-2/-3 (VEGFR-2/-3) and platelet derived growth 
factor receptor-beta (PDGRF-beta) tyrosine kinases, FLT3 Ret and c-Kit.
Targeting angiogenesis with agents such as the tyrosine kinase inhibitor sorafenib is now the 
standard of first line therapy for advanced HCC, but treatment is not curative and survival of 
these patients remains less than one year. Agents with a similar mechanism of action have not 
proven to be superior or more tolerable than sorafenib. There is a clear unmet urgent need for 
tolerable, effective therapies for advanced HCC.
2.2
Hepatocellular Carcinoma and Immune Dysfunction
Presently there are no validated biomarkers that predict response to sorafenib in HCC or other 
malignancies where the drug is approved for use.(3) As trial eligible patients are few, rationally 
designed, biomarker driven studies are urgently needed. 
Since immune dysfunction from advanced cancer and hepatitis are hallmarks of HCC, new 
agents that target immune suppression are a major focus of HCC research. Studies from our 
laboratory on peripheral blood samples from HCC patients show that: (1) programmed cell 
death-1 (PD-1)+ T cell numbers and T cell PD-1 expression levels are elevated; (2) frequency of 
PD-1+ T cells and T cell PD-1 expression levels decreased in a patient with spontaneous HCC 
regression; (3) depletion of Tregs, MDSCs, and PD-1+ cells results in complete restoration of 
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HCC patient effector T cell granzyme B production in vitro.(4, 5) Others have shown that 
elevated cognate inhibitory molecule PD-1-ligand 1 (PD-L1) expression in HCC is associated 
with tumor aggressiveness and enhanced risk for postoperative recurrence.(6) Collectively, these 
observations support the rationale that immunotherapy may have therapeutic benefit in HCC.
Our laboratory has also studied whether sorafenib may impact the systemic immunological 
function in addition to its mechanism of action in the tumor and vasculature. Sorafenib targets 
multiple tyrosine kinase receptors, including Flt3 which is present on MDSC and Tregs.(7, 8) 
Multiple avenues for tumor-induced immunosuppression exist in HCC, including accumulation 
of MDSC and Tregs. Depletion or inhibition of these cells is considered an important clinical 
feature for successful immunotherapeutic treatment and we have determined that depletion of 
these immunosuppressive cells in vitro can restore important T cell effector functions. 
Importantly and relevant to the current application, our preliminary studies show evidence of 
decreased frequency of several immunosuppressive cells in vivo (including PD-1+ T cells) 4-6 
weeks after sorafenib treatment in some but not all HCC patients. The decrease in PD-1+ T cell 
frequency following sorafenib therapy correlated strongly with longer patient survival.
Preliminary in vitro data indicate that the immunomodulatory effects of sorafenib are dose-
dependent. Specifically, sorafenib at 10µM induced activation of nuclear factor of activated T 
cells (NFAT) NFAT1 and NFAT2 in CD4 and CD8 T cells. Of note, clinically achievable 
concentrations of sorafenib exceed 15µM. NFAT activation was associated with the gain of an 
anergic phenotype (gain of PD-1 expression, loss of CD25 expression in CD4 and CD8 T cells 
and loss of CD8 expression in effector cells). NFAT activation was irreversible upon SOR 
removal and occurred within a narrow window of activation (between 5 and 10µM), 
demonstrating the threshold of the immunosuppressive action is well above the reported IC50 of 
sorafenib. In addition to our work, other studies have shown that elevated programmed cell death 
1 ligand 1 (PD-L1) expression in HCC is significantly associated with tumor aggressiveness and 
enhanced risk for postoperative recurrence.(6) Targeted blockade of the PD-L1/PD-1 pathway 
could facilitate hepatitis virus clearance.(9) 
In a Phase 1/2 trial (LBA101) nivolumab another anti-PD-1 antibody showed safety in 47 
patients and a response rate of 19%. Although 68% of those patients had received prior 
sorafenib, no difference was seen in benefit from anti-PD-1 therapy. Based on our work, prior 
SOR may influence immunosuppressive phenotype and impact patient outcomes.(10)
2.3
Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2. Pembrolizumab is approved in the US for the treatment of patients with 
advanced/ metastatic melanoma, NSCLC, and HNSCC.
To-date, pembrolizumab is being used as both a monotherapy, and in combination with other 
therapies, in more than 30 tumor types.
Preclinical Studies with Pembrolizumab
A detailed discussion of the preclinical pharmacology, pharmacokinetics, and toxicology of 
pembrolizumab can be found in the Investigator’s Brochure v11.
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2.4
Correlative Studies

PD-L1/-L2 Expression
The current understanding on whether PD-L1 and PD-L2 status is a biomarker of response is 
limited, as there are no published data on frequency of PD-L1/-L2 expression in western 
populations and there is no uniformly accepted readily available validated assay. To test the 
hypothesis that PDL-1/-L2 status correlates with outcome, pre-and post-treatment formalin-
fixed, paraffin-embedded (FFPE) tissue will be evaluated using the validated assay by Merck. As 
ligand status was not tested in all patients in prior trials and, some PD-L1 / L2 + patients failed to 
respond, we as yet do not know if this should be an exclusion criterion. In patients whose tumors 
are PD-L1 / L2 positive before therapy commences and they do NOT respond to combination 
treatment, then an optional second biopsy will be performed to test our hypothesis that there may 
be a change in their PD-L1 / -L2 expression status.

Immune Biomarkers
Determining immune marker changes that can predict clinical benefit and toxicities (as some of 
them may have an immune basis) would be valuable to the clinician. To this end we propose to 
address our hypothesis that sorafenib+anti-PD-1 treatment will diminish checkpoint blockade 
and the accumulation of immunosuppressive networks in advanced stage HCC patients and 
thereby restore beneficial cytotoxic anti-tumor function in effector T cells. We will assess the 
alteration in the frequency and phenotype of immunosuppressive cells prior to treatment and, 
importantly, at three additional time points after commencement of the combination. In addition, 
the activity of the NFAT transcription factor which regulates PD-1 expression in these cells will 
be assessed. A longitudinal study of this nature is ideal to determine the kinetics and 
maintenance of sorafenib and anti-PD1 mediated immunomodulation. 
Baseline levels of immunosuppressive cells and the functional activity of effector T cells as 
measured by NFAT activity, proliferative capacity and IFN-gamma and granzyme B production 
will be correlated with OS to determine whether these could serve as biomarkers and identify 
patients most likely to benefit from the combination therapy.

Immune-Mediated Adverse Events: 
A number of serious AEs observed with pembrolizumab are immune-mediated pneumonitis, 
thyroiditis, renal insufficiency and transaminitis, and many of these are also seen with sorafenib 
therapy, although the mechanism for these effects remains unknown. We propose to assess TSH 
and anti-thyroid antibodies at baseline and while patients are on therapy and correlate them with 
immune suppression.

Immunomodulatory Effects of Sorafenib/Pembrolizumab:
Chronic hepatitis B and C virus infection are known risk factors for the development of cirrhosis 
and HCC. Since immune modulation could affect viral replication; resulting in potential liver 
function abnormalities or radiographic changes in the liver, viral titers for Hepatitis B and 
Hepatitis C (Hepatitis B Surface Antigen (HBsAg) and/or detectable HBV DNA and, Hepatitis C 
Antibody anti-HCV Ab) and detectable HCV RNA) will be measured at baseline (and as 
clinically indicated in patients who have elevated baseline titers) and at every 12 weeks from the 
start of combination therapy (C1D1) to assess possible effects on outcome.
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
Pharmacodynamic Markers
In our studies we have seen PK/PD modelling of a pharmacodynamics marker solubleVEGFR2 
along with drug exposure to predict clinical response in HCC patients receiving sunitinib and 
propose to test the hypothesis that this model could be used to predict response to this sorafenib 
combination.
2.5
Rationale
Inflammation and immune dysfunction are hallmarks of HCC. Our studies show that HCC is 
associated with increased levels of PD-1+ cells. Immunomodulation can partially restore effector 
function, suggesting that targeted blockade of PD-1 may be of clinical benefit in HCC. 
Importantly, the preliminary evidence that sorafenib dose-dependently affects PD-1 expression 
in T cells supports the concept of combining sorafenib with a PD-1 targeting drug. There remains 
a great need for rationally selected, noninvasive, prospectively validated biomarkers with the 
potential to provide mechanistic information on how the drug/combination worked or why it did 
not work. The studies we propose meet all these needs.
Pembrolizumab is a humanized IgG4 monoclonal antibody (mAb) which binds PD-1, and thus, 
inhibits cognate interaction with PD-L1 and PD-L2. PD-1 is an immune-checkpoint receptor 
expressed on T cells and high levels of PD-L1 expression are correlated with poor prognosis and 
survival in HCC. There is an urgent unmet need for novel therapies for patients with HCC that 
build on the backbone of the approved agent sorafenib. 
Successful completion of this study will significantly impact the development of pembrolizumab, 
the field of HCC research and biomarker development in oncology as a whole. In addition to the 
much-needed clinical impact this combination will have, new knowledge on the 
immunomodulatory effects of sorafenib alone, and how anti-PD-1 therapy augments efficacy 
will be gained from the biomarker work. In oncology biomarker research, the paradigm has 
always been prediction of response to the therapy being studied: having a marker that would 
allow for rational selection or prediction of benefit of a combination therapy, would be a major 
paradigm shift.
3.0
Inclusion and Exclusion Criteria
To be included in this study, participants must meet the criteria listed in Section 3.1.
Participants will be excluded from this study following the criteria listed in Section 3.2.
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3.1
Inclusion Criteria
INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM:
INCLUSION CRITERIA
Participant Name: (Multi-site use participant initials): ___________________________
Medical Record No.: (Multi-site use participant ID): _____________________________
Title: A Phase Ib/ II Study of Sorafenib and Pembrolizumab in Advanced Hepatocellular 
Cancer (HCC).
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Age ≥ 18 years.
2.
Participant must have histologically or radiographically confirmed HCC 
that is advanced or metastatic and if archival tissue is available, have 
archival tissue submitted for PD-L1, PD-L2 testing.
3.
Participants with measurable disease that has progressed are eligible if 
prior surgery or locoregional therapy occurred > 28 days prior to 
enrollment.
4.
Have an ECOG Performance Status of 0-1 (Karnofsky ≥ 60%). Refer to 
Appendix B.
5.
Child-Pugh Class-A liver function. Refer to Appendix C.
6.
Have the following clinical laboratory values:

ANC ≥ 1,500/ mcL

Hemoglobin ≥ 8.5 g/dL

Platelets ≥ 75,000/ mcL

total bilirubin ≤ 2.0 mg/dL 

AST and ALT ≤ 5 X ULN

Serum Creatinine ≤ 1.5 X ULN or Creatinine 
clearance > 50 mL/ minute if serum creatinine is elevated above 
1.5 X ULN 
7.
Have measurable disease per RECIST 1.1 criteria present.
8.
Ability to swallow and retain oral medication.
9.
Participants of child-bearing potential must agree to use adequate 
contraceptive methods (e.g., hormonal or barrier method of birth 
control; abstinence) prior to study entry. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician 
immediately.
10. Participant must understand the investigational nature of this study and 
sign an Independent Ethics Committee/Institutional Review Board 
approved written informed consent form prior to receiving any study 
related procedure.
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INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
11. Participants with past or ongoing hepatitis C virus (HCV) infection will 
be eligible for the study. The treated participants must have completed 
their treatment at least 1 month prior to starting study intervention. 
12. Participants with controlled hepatitis B will be eligible as long as they 
meet the following criteria: 

Antiviral therapy for HBV must be given for at least 12 weeks and 
HBV viral load must be less than 100 IU/mL prior to first dose of 
study drug. Participants on active HBV therapy with viral loads 
under 100 IU/mL should stay on the same therapy throughout study 
treatment.  

Participants who are anti-HBc (+), negative for Hepatitis B surface 
antigen (HBsAg), and negative or positive for anti-HBs, and who 
have an HBV viral load under 100 IU/mL, do not require HBV 
anti-viral prophylaxis.
Investigator Signature: ___________________________________
Date: ___________
Printed Name of Investigator: __________________________________________________
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3.2
Exclusion Criteria
INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM:
EXCLUSION CRITERIA
Participant Name: (Multi-site use participant initials): ___________________________
Medical Record No.: (Multi-site use participant ID): _____________________________
Title: A Phase Ib/ II Study of Sorafenib and Pembrolizumab in Advanced Hepatocellular 
Cancer (HCC).
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
1.
One prior line of therapy that may include a PDL1 blocker allowed, no 
prior sorafenib or PD1 blocker allowed.
2.
Participants who have had radiotherapy or chemotherapy within 
4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the 
study or those who have not recovered from adverse events due to 
agents administered more than 4 weeks earlier.
3.
Any evidence of bleeding diathesis (patients on therapeutic warfarin or 
heparin will be excluded).
4.
Participants with a history of variceal bleed within 6 months prior to 
enrollment.
5.
Known HIV-positive participants (even if on combination retrovirals, 
participant will be excluded because of the expected pharmacokinetic 
drug interactions and unknown safety of anti PD-1 therapy in that 
patient population).
6.
Participants with chronic autoimmune disease.
7.
Participants with known brain metastases should be excluded from this 
clinical trial because of their poor prognosis and because they often 
develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events.
8.
Uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements.
9.
Has known history of, or any evidence of active, non-infectious 
pneumonitis.
10. Pregnant or nursing female participants.
11. Unwilling or unable to follow protocol requirements.
12. Any condition which in the Investigator’s opinion deems the participant 
an unsuitable candidate to receive study drug.
13. Received a live vaccine within 30 days prior to start of study treatment.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
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Investigator Signature: ___________________________________
Date: __________
Printed Name of Investigator: _________________________________________________
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3.3      Special Populations
The following special populations are excluded from this study:

Cognitively impaired adults/adults with impaired decision-making capacity

Individuals who are not yet adults (infants, children, teenagers)

Prisoners

Pregnant women
3.4      Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this study
4.0
Local and Study-Wide Number of Subjects
A total of 41 participants will be accrued (with a maximum of n=27 evaluable for the primary 
endpoint) from multiple sites, including RPCI, will be enrolled. RPCI is expected to enroll 
38 participants over a period of 5 years.
5.0
Local and Study-Wide Recruitment Methods
Participants will be identified/recruited/screened from patients at the GI clinic at RPCI and 
participating sites and from multi-disciplinary conference discussion.
6.0
Multi-Site Research
It is the responsibility of the principal Investigator to ensure that:

All sites have the most current version of the protocol, consent document, and HIPAA 
authorization.

All required approvals (initial, continuing review and modifications) have been obtained 
at each site (including approval by the site’s IRB of record).

All modifications have been communicated to sites, and approved (including approval by 
the site’s IRB of record) before the modification is implemented.

All engaged participating sites will safeguard data, including secure transmission of data, 
as required by local information security policies.

All local site investigators will conduct the study in accordance with applicable federal 
regulations and local laws.

All non-compliance with the study protocol or applicable requirements will be reported in 
accordance with local policy.
Refer to Appendix A: Instructions for Multi-Site Studies
7.0
Study Timelines
A maximum of 41 participants at multiple sites, including RPCI will be enrolled. Accrual is 
expected to take 5 years, with follow-up for 12 months from the start of combination therapy. 
Upon completion of the 12-month follow-up period, patient survival status will be monitored 
every 6 months.
8.0
Study Endpoints

The primary endpoint is the Overall Response Rate (ORR), defined as partial or complete 
response (per irRECIST) within 6 months of initiating combination therapy.

The secondary endpoint is time to tumor progression (TTP), measured from the date of 
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study enrollment to the first observation of progressive disease.

Exploratory endpoints: Pre-treatment levels of immunosuppressive cells and the 
functional activity of effector T cells will be compared to post-treatment blood and tumor 
samples and will be correlated with overall survival. 
9.0
Design
This is an open-label, single arm, non-randomized, multi-center Phase Ib/II study of sorafenib 
when administered with pembrolizumab in patients with advanced hepatocellular carcinoma. The 
study will include an initial Phase Ib safety lead-in cohort of 6 patients.
Prior to starting on the combination therapy of sorafenib + pembrolizumab, patients will have 
completed initial treatment with sorafenib alone and must be stable on sorafenib (at least 200 mg 
BID for a minimum of 1 week) before the introduction of pembrolizumab. The sorafenib starting 
dose will be at the discretion of the treating physician based on clinical assessment of the patient.
All participants will sign an informed consent prior to any study-related tests.  All participants 
will meet the inclusion and exclusion criteria summarized in Section 3.1 and 3.2.
9.1
Phase Ib/II
The first 6 patients who have completed at least 4 weeks of sorafenib-only treatment and begin 
the combination therapy (addition of pembrolizumab at a fixed dose of 200 mg Q3W) will 
comprise the Phase 1b safety lead-in. Patients who withdraw from the study prior to initiation of 
combination therapy (for reasons other than DLT) will be replaced.
Definition of Dose-Limiting Toxicity: A dose-limiting toxicity will be defined as any ≥ grade 3 
clinically significant toxicity which is deemed possibly treatment related and occurs within the 
first cycle of combination therapy. Toxicity will be assessed according to the NCI Common 
Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0).
Patient data for the safety lead-in portion of the study will be discussed and monitored by The 
Early Phase Clinical Trials committee, which meets on a regular basis per the RPCI Data Safety 
Monitoring Plan. 
After a minimum of 6 have completed at least one cycle of sorafenib + pembrolizumab, the study 
will be suspended, and the safety/tolerability of the combination will be examined. At that time, 
the study team will decide what action to take, e.g., continue the study as is, make changes to the 
study with regard to treatment or dose modifications, or discontinue the study. 

If ≥ 2 of these patients experience an unexpected, treatment related toxicity of grade ≥3 
during the first cycle of combination therapy, the study will be stopped to reevaluate 
dosing. We anticipate that such limiting toxicities will be observed in ≤1 of the first 6 
patients. All evaluable patients who receive the Phase 2 dose of pembrolizumab (200 mg 
Q3W) will be included in the Phase 2 study.
Once analysis is complete and a safe treatment plan has been established, the Phase II study will 
commence.
Patients who have toxicity during the first 3 weeks of combination therapy that appears to be 
attributed to sorafenib will have sorafenib dose reduced to 2 x 200 mg every other day, as was 
done in the SHARP study(11). We anticipate such dose modifications to be infrequent. Patients 
will be considered evaluable if they receive more than 75% of prescribed sorafenib dosing during 
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the first 3 weeks of combination therapy (a medication diary will be provided during this time to 
monitor participant compliance: see Appendix F).  All toxicities will be assessed upon 
completion of the first 6 evaluable patients to see if any higher than anticipated occurrence of 
sorafenib toxicity is seen due to the addition of pembrolizumab.
The goal of the study is to evaluate efficacy of the combination therapy, therefore patients who 
are removed from the study prior to receiving the soraf+pembro combination treatment will be 
replaced. This includes replacing patients who do not tolerate sorafanib alone, as administered in 
the 1st 4 - 6 weeks of the treatment regimen.  In addition, the following patients will be replaced:

Patient withdraws consent

Withdrawal from study due to toxicity,

Withdrawal from study due to liver failure

Patients who withdraw before the Week 12 (±1 week) response assessment (for reasons 
other than progression)
Patients who withdraw due to disease progression prior to the Week 12 (±1 week) response 
assessment of the combination therapy will not be replaced and will be counted as non-
responders in the response rate calculations. 
Patients who complete the 4-6 week initial treatment with sorafenib alone, and withdraw from 
the study after being treated with the combination therapy will not be replaced and will be 
counted as non-responders in the response rate calculations.
Patients will receive sorafenib + pembrolizumab until progression. If a patient discontinues 
either agent due to toxicity, they will still be able to stay on study until progression. Clinical 
benefit will be considered when making decision to stop therapy as radiographic reflection of 
true failure of this combination is still unknown.
Disease assessment (imaging) will be done every 6 weeks from the start of C1D1 combination 
therapy, with a confirmatory assessment no less than 6 weeks after an irPR or irCR or irPD. 
Therapy will be continued until the confirmatory scan, even if progression is noted on the Week 
12 scan. After the 12-week scan disease assessment will be done every 9 weeks (±1 week). Note: 
Timing for assessing ORR in patients on immunotherapies is not clear. Disease stability is the 
commonly seen response to sorafenib alone. Allowing continuation until the confirmatory scan 
at Week 18, even if progression is seen, allows us to assess the true response to this novel 
combination.
10.0
Treatment
Dosing and Administration
1 cycle = 3 weeks of combination therapy
10.1
Sorafenib
During the first 4-6 weeks following enrollment (Days -28 to -1 or Days -42 to -1) patient will be 
on sorafenib alone.
The recommended daily dose of sorafenib is 800mg (2 x 200mg tablets taken twice daily) 
without food (at least 1 hour before or 2 hours after a meal.) However, the starting dose may be 
adjusted at the discretion of the treating physician based on clinical assessment of the patient 
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during screening with a minimum dose of sorafenib at 200mg BID.
All patients should report to clinic for toxicity evaluation 2 weeks after starting sorafenib.
NOTE: Management of suspected adverse drug reactions may require temporary interruption 
and/or dose reduction of sorafenib therapy. However, the sorafenib lead-in phase should not 
extend to greater than 6 weeks from the start of sorafenib to the start of pembrolizumab  (For 
example:  Patient develops toxicity 2 weeks after starting sorafenib,  which requires a dose hold 
for 1 week, then re-starts sorafenib with a dose reduction. That patient must be stable on the new 
dose for at least 1 week before starting pembrolizumab. In this case, the sorafenib lead-in phase 
is 5 weeks which is in the acceptable window of 6 weeks from start of sorafenib to start of 
pembrolizumab).  Patients will continue to take sorafenib (po), BID, during each 3-week cycle.
10.1.1 Dose Modifications for Suspected Adverse Drug Reactions

Temporary interruption of sorafenib is recommended in patients undergoing major 
surgical procedures (refer to package insert).
10.1.2 Dose Modifications for Hepatic Impairment at Baseline

Mild to moderate (Child-Pugh class A and B) impairment: No dosage adjustment is 
necessary.
The following adjustments have also been reported: 
Safety and pharmacokinetics were studied in varying degrees of hepatic dysfunction with the 
following empiric dose levels recommended based on patient tolerance (Miller, 2009) (12):

Mild hepatic dysfunction (bilirubin >1 to ≤1.5 times ULN and/or AST >ULN):
o
400 mg twice daily

Moderate hepatic dysfunction (bilirubin >1.5 to ≤3 times ULN; any AST): 
o
200 mg twice daily

Severe hepatic dysfunction:
o
Bilirubin >3 to 10 x ULN (any AST): 200 mg every 3 days was not tolerated
o
Albumin <2.5 g/dL (any bilirubin and any AST): 200 mg once daily
Drug-induced liver injury during treatment: 

Unexplained (e.g., not due to viral hepatitis or progressive underlying malignancy) 
significantly increased transaminases: 
o
Discontinue treatment
10.1.3 Suggested Dose Modifications for Dermatologic Toxicities

If Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, 
discontinue therapy.
Refer to Appendix I for suggested dose modifications for dermatologic toxicities in patients with 
hepatocellular carcinoma.
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10.2
Pembrolizumab
Starting with Cycle 1, treatment with pembrolizumab will be administered on Day 1 of each 3-
week treatment cycle, after all procedures and assessments have been completed (as detailed on 
the Schedule of Procedures: Appendix E).
Pembrolizumab will be administered at a fixed dose of 200 mg, using a 30-minute IV infusion. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window between -5 minutes 
and + 10 minutes is permitted (i.e., infusion time is 30 minutes -5 min and + 10 min).
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution.
Toxicities will be assessed upon completion of the first 6 evaluable patients to see if any higher 
than anticipated occurrence of sorafenib toxicity is seen due to the addition of pembrolizumab.
Reported adverse events (AEs) and potential risks are described in Section 13. Appropriate dose 
modifications are described in Table 1 (see Appendix F).
Pembrolizumab Dose Modifications
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 1 (Appendix F).
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Participants should be placed back on study therapy within 3 weeks of the 
scheduled interruption. The reason for interruption should be documented in the patient's study 
record.
Management and dose modifications associated with the above AEs are outlined in Appendix F.
10.3
General Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The final decision on any supportive therapy or vaccination rests 
with the primary investigator and/or the subject's primary physician.
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 
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administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 17.0.
Prohibited Concomitant Medications
Patients are prohibited from receiving the following therapies during the Baseline and Treatment 
Phase of this study:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy 
o
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.

Anti-viral medications for treatment of hepatitis C while receiving combination therapy
o
Note: Patients may continue on anti-viral medication for hepatitis C during the 4-
week sorafenib-only therapy.

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.
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. Patients may receive other 
medications that the investigator deems to be medically necessary.
10.4
Rescue Medications & Supportive Care
10.4.1 Supportive Care Guidelines
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below. Where appropriate, these guidelines include 
the use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids. Note 
that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to pembrolizumab.
Note: if after the evaluation the event is determined not to be related, the investigator does not 
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need to follow the treatment guidance (as outlined below). Refer to Appendix F for dose 
modification.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.
Pneumonitis: 

For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.

For Grade 3-4 events, immediately treat with intravenous steroids. Administer additional 
anti-inflammatory measures, as needed.

Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration.
Diarrhea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus).

All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis.

For Grade 2 diarrhea/colitis, administer oral corticosteroids. 

For Grade 3 or 4 diarrhea/ colitis, treat with intravenous steroids followed by high dose 
oral steroids.  

When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA)

For T1DM or Grade 3-4 Hyperglycemia
o
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 
3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
o
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.
Hypophysitis:

For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered.

For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
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may be required as the steroid dose is tapered.
Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment: Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.

Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):
o
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy.
o
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care.

Grade 3-4 hyperthyroidism 
o
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered.
Hepatic:
In addition to overdose (see Section 32.1.6), hepatic events of clinical interest will include any of 
the following events (see Appendix J: Guidance for Diagnosis and Management of Hepatic 
Events of Clinical Interest). All of these events will require holding study treatment and, 
notification to Merck within 2 days. 
Refer to Section 17.4 for reporting guidelines and the definition of hepatic events of clinical 
interest.
Renal Failure or Nephritis:

For Grade 2 events, treat with corticosteroids.

For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Table 2 (Appendix G) shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab.
10.5
Diet/ Activity/ Other Considerations
10.5.1 Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting.
10.5.2 Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
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pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male subjects 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 subjects will be considered of non-reproductive potential if they are either: 
(1) Post-menopausal (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.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:
(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)

Vasectomy of a female subject’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 participant’s preferred and usual lifestyle and if considered 
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acceptable by local regulatory agencies and ERCs/IRBs. 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 participants participating at sites in this 
country/region.
Participants 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 participants of childbearing potential must adhere to the contraception requirement 
(described above) 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 trial therapy. If there is any question that a subject of childbearing potential will not 
reliably comply with the requirements for contraception, that participant should not be entered 
into the study.
10.5.3 Use in Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study. The site will contact the subject at least 
monthly and document the participant’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to Roswell Park Compliance and 
within 2 working days to Merck if the outcome is a serious adverse experience (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 the Merck. If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to Roswell Park Compliance and to Merck and followed as described 
above and in Section 17.4.
10.6
Duration of Treatment
Participants may remain on study and continue to receive treatment in the absence of disease 
progression, unacceptable toxicity and withdrawal from study, intercurrent illness that prevents 
further administration of treatment, participant demonstrates an inability/refusal to comply with 
oral medication regime, participant withdraws from study or, death; whichever occurs first.
If patients have been on pembrolizumab for over 24 months the PI can decide if the patient can 
come off pembrolizumab and continue on with sorafenib treatment.
11.0
Procedures Involved
Eligibility of each participant will be established prior to enrollment.
Informed consent MUST be completed prior to receiving any study related procedures.
The schedule of procedures and observations for this study is summarized in Appendix E: 
Schedule of Procedures. 
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11.1
Pharmacokinetic Blood Sample Collection and Processing
Blood samples for Pharmacokinetic analysis (plasma) of sorafenib levels will be collected via 
venipuncture using 1, 10 mL green-top tube.
*Note: Patients to be advised to hold morning dose of sorafenib until after PK blood draw. 
The time of two doses of Sorafenib prior to the draw will need to be entered on the specimen 
requisition form for PK analysis, e.g., Cycle 3 Day 21, enter the time. Sorafenib was taken in the 
am and pm prior to the Cycle 4 Day 1 PK draw.
Pharmacokinetic sample collection will be obtained on:

Cycle 1-Day 1 (for sorafenib steady state PK), prior to sorafenib and IV pembrolizumab

Cycle 4-Day 1 prior to sorafenib and IV pembrolizumab and Day 1 of every subsequent 4 
cycles (prior to sorafenib and IV pembrolizumab) until end of study

End of study treatment
The whole blood samples should be maintained on ice and sent to the Hematological 
Procurement Facility for processing for plasma: Centrifuge whole blood as soon as possible, or 
within 30 minutes, at 4°C using a refrigerated centrifuge at approximately 3000 rpm for 10 
minutes.
Plasma will be aliquoted into (2) cryovials per time-point. The screw cap polypropylene 
cryogenic tube will be labeled with the participant’s clinical study number and patient study ID, 
protocol time point, dose, and protocol day and time. The label for each participant’s sample will 
be supplied by each site. The samples will immediately be frozen at -80ºC or below. At the 
completion of the study, all samples will be shipped on dry ice to the BMPK core facility at 
Roswell Park for analysis: 
Roswell Park Cancer Institute
Bioanalytics, Metabolomics & Pharmacokinetics (BMPK) Core Facility
Center for Genetics and Pharmacology, Room L1-140
Refer to Study Number– I 35316
Elm & Carlton Streets
Buffalo, New York 14263
PKPDCore@RoswellPark.org
For additional information regarding the handling of pharmacokinetic samples please contact 
RPCI’s Bioanalytics, Metabolomics & Pharmacokinetics Core Facility laboratory at 
716-845-3313 (Tel) or 716-845-1579 (Fax). Or email Katherine.Enderle@RoswellPark.org and 
Krystin.Mantione@RoswellPark.org.
EXTERNAL (NETWORK) SITES: Follow directions above for sample collection and 
processing. The cryogenic tubes will be labeled with the Subject ID # (unique to Network 
patients), the clinical study number, protocol time point, dose, and protocol day and time. The 
samples will immediately be frozen at -80ºC or below. Samples are to be stored and batch 
shipped to the RPCI BMPK Core Facility, on dry ice, at the completion of the study.
Note: Samples cannot be frozen in glass tubes – cryogenic vials must be used.
Frozen samples will be shipped via Fed Express Overnight on dry ice with delivery on Mon-Fri. 
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NO SATURDAY DELIVERY. Do not ship on a Friday or the day before a holiday.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. The 
Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in 
place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
11.2
Correlative Studies Blood Sample Collection
11.2.1 Immune Biomarker Blood Samples:
Blood samples for immune biomarker analysis (phenotyping ELISA, CYTOF) will be collected 
via venipuncture using 3, 10 mL green-top tubes and 2, 10 mL lavender -top tube. Samples will 
be processed and analyzed at RPCI’s Immune Analysis Facility.
In addition, 1, 10 mL STRECK Cell-Free DNA BCT® tube for plasma for future CT-DNA 
studies will also be collected at the same time points as for immune biomarker samples.
Note: ALL blood samples will be sent at ambient temperature to the RPCI Immune 
Analysis Facility (IAF). Samples for CT-DNA analysis (STRECK tube) will be sent 
(immediately after sample log-in) from RPCI’s IAF to RPCI’s Genomics Shared Resource 
facility (c/o Prashant Singh PhD, Assistant Director Genomics Shared Resource, CGP & COE 
L1-210, 716-845-3869 (office),email: Prashant.Singh@RoswellPark.org) for processing, storage 
and analysis upon study termination.
Note: Roswell Park Patients- notification of sample collection must be noted on public calendar 
for Immune Analysis prior to date of collection. 
Whole blood sample collection will be obtained at:

Baseline

Cycle 1-Day 1 (prior to start of sorafenib and IV pembrolizumab)

Cycle 4-Day 1 prior to sorafenib and IV pembrolizumab and Day 1 of every subsequent 
4 cycles (prior to sorafenib and IV pembrolizumab) until end of study

End of Study (or at time of progression; or any other reason that requires study 
termination, whichever occurs sooner) 
All of the above blood samples will be sent at ambient temperature to the Center for 
Immunotherapy at Roswell Park Cancer Institute: 
Roswell Park Cancer Institute
Immune Analysis Facility Shared Resource
Cancer Cell Center, 4th Floor, Room 416
Attn: Study# I 35316
Elm and Carlton Streets
Buffalo, NY 14263
Telephone #: (716) 845-1300, ext. 6555
Courtney.Ryan@RoswellPark.org
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EXTERNAL (NETWORK) SITES: Follow directions above for sample collection and 
processing. The tubes will be labeled with the Subject ID # (unique to Network patients), clinical 
study number, protocol time point, dose, and protocol day and time. Samples are to be shipped 
for OVERNIGHT delivery, at ambient temperature to:
Roswell Park Cancer Institute
Immune Analysis Facility Shared Resource
Cancer Cell Center, 4th Floor, Room 416
Attn: Study# I 35316
Elm and Carlton Streets
Buffalo, NY 14263
Telephone #: (716) 845-1300, ext. 6555
Courtney.Ryan@RoswellPark.org
Please send an email, once a sample has been shipped, that includes the tracking number to 
Courtney.Ryan@RoswellPark.org.
Samples will be shipped via Fed Express Overnight with delivery on Mon-Fri. NO SATURDAY 
DELIVERY. Do not ship on a Friday or the day before a holiday.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
11.2.2 NFAT Analysis Blood Samples:
Blood samples for NFAT analysis will be collected via venipuncture using 1, 10 mL green-top 
tube.
Whole blood sample collection will be obtained at:

Baseline

Cycle 1-Day 1 (prior to start of sorafenib and IV pembrolizumab)

Cycle 4-Day 1 prior to sorafenib and IV pembrolizumab and Day 1 of every subsequent 
4 cycles (prior to sorafenib and IV pembrolizumab) until end of study

End of Study (or at time of progression; or any other reason that requires study 
termination, whichever occurs sooner) 
Samples will be sent at ambient temperature to RPCI’s Flow Cytometry Department (pneumatic 
tube station #621) for processing and analysis:
Note: Include specimen tracking form with protocol kit and notify receiving lab.
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Roswell Park Cancer Center
Cancer Cell Center, Room C308 & C312
Attn: Dr. Hans Minderman
Attn: Study #: I 35316
Elm & Carlton Streets
Buffalo, NY 14263
Tel: 716-845-3528
Hans.Minderman@RoswellPark.org and Orla.Maguire@RoswellPark.org. 
For additional information regarding the handling of samples please contact Dr. Hans 
Minderman, Assistant Director Flow Cytometry Research Services at 716-845-1162 (office) or 
716-845-3470 (lab) or by email: Hans.Minderman@RoswellPark.org 
EXTERNAL (NETWORK) SITES: Follow directions above for sample collection and 
processing. The tubes will be labeled with the Subject ID # (unique to Network patients), initials, 
the participant’s study number, clinical study number, protocol time point, dose, and protocol 
day. Samples are to be shipped, packed with cold packs, for OVERNIGHT delivery to:
Roswell Park Cancer Center
Cancer Cell Center, Room C308 & C312
Attn: Dr. Hans Minderman, Study #: I 35316
Elm & Carlton Streets
Buffalo, NY 14263
Tel: 716-845-3528
Please send an email, once a sample has been shipped, that includes the tracking number to 
Hans.Minderman@RoswellPark.org 
Samples will be shipped via Fed Express Overnight with delivery on Mon-Fri. NO SATURDAY 
DELIVERY. Do not ship on a Friday or the day before a holiday.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
11.3
Pathology
11.3.1 Pre-treatment Formalin-Fixed Paraffin-Embedded (FFPE) Biopsy Samples 
The following sections of tissue from the most recent (or available) liver biopsy (neoplastic 
tissue) that exists in the Paraffin Archive in the Department of Pathology (or outside institution) 
will be collected if available:
1. Eight unstained sections cut at 4 microns on plus glass slides:
a.
Four (4) for PD-L1/-L2 testing (RPCI Pathology Resource Network for analysis)
b. Four (4) for Nanostring analysis (RPCI Genomics Shared Resource for analysis).
2. One H&E stained section (RPCI Pathology Resource Network).
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3. Five (5) unstained sections cut at 4-micron thickness on Fisher ProbeOn Plus slides for 
PD-L1 testing (QualTek). Refer to QualTek MISP Sample Handling Manual for detailed 
processing and shipping instructions. NOTE: ALL SITES will send these samples 
DIRECTLY to QualTek.
NOTE: If a fresh pre-treatment liver biopsy is obtained as a part of standard of care:

1 core: Fixed in formalin for 8 to 24 hours and processed as paraffin embedded block 
(FFPE block)

Section as per Section 11.3.1 prior to shipment
For External (Network) Sites, the de-identified tissue samples should be labeled using study-
specific subject ID number and tissue accession#. All of the above slides and/or block (except the 
slides to QualTek) are to be sent to RPCI Correlative Science Pathology Office (Attn: Protocol 
Lab Team). Please ship slides ambient (or with a refrigerated gel pack when temperatures will 
exceed 24°C). The shipping label should read as follows:
Roswell Park Cancer Institute
Elm & Carlton Streets
Correlative Science Pathology Office
Gratwick Basic Science Building, S-636
Attn: Protocol Lab Team, I 35316 Samples
Buffalo, NY 14263
(716) 845-8917
Email: CRSLabPathTeam@RoswellPark.org
Samples for NanoString analysis (4 unstained slides) will be batched and sent from the CSPO to 
Dr. Prashant Singh, Assistant Director Genomics Shared Resource, CGP & COE L1-210, for 
analysis. For additional information regarding the handling of samples please contact Dr. 
Prashant Singh at 716-845-3869 (office) or email Prashant.Singh@RoswellPark.org. 
Samples for PL-L1/-L2 testing (4 unstained slides and 1 H&E) will be batched and sent from the 
CSPO to Cassandra Whalen,  GBSB-S608, for analysis. For additional information regarding the 
handling of samples please contact Cassandra Whalen at 716-845-1515 (office) or email 
Cassandra.Whalen@RoswellPark.org.
NOTE: Samples for PD-L1 only testing (5 unstained sections cut at 4-micron thickness on 
Fisher ProbeOn Plus slides) should be sent DIRECTLY to QualTek Molecular 
Laboratories if available:
QualTek Molecular Laboratories
300 Pheasant Run
Newtown, PA 18940
Phone: 215-504-7402
Fax: 805-830-6379
Email: MISPsamples@qmlabs.com
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11.3.2 Post-treatment Liver Biopsy Samples
PD-L1,-L2 positive patients will be asked to undergo an optional, post-treatment biopsy for PD-
L1,-L2 at the end of treatment, to assess any change in ligand status (6 responders to treatment 
and 6 non-responders).
Optional Post-Treatment Biopsy Tissue Requirements
Four (4) cores each from tumor and adjacent normal liver tissue:

3 cores each of tumor and adjacent normal liver tissue (each core to be stored 
separately): Snap frozen in cryovials in liquid nitrogen for subsequent RNA/DNA 
analysis (2 cores each) and future biomarker studies (1 core each).

1 core each of tumor and adjacent normal liver tissue: Fixed in formalin for 8 to 24 hours 
and processed into separate paraffin embedded blocks (FFPE blocks) for subsequent 
CYTOF and PD-L1/L2 analysis 
All of the above tissue samples will be sent to RPCI Correlative Science Pathology Office (Attn: 
Protocol Lab Team). The shipping label should read as follows:
Roswell Park Cancer Institute
Elm & Carlton Streets
Correlative Science Pathology Office
Gratwick Basic Science Building, S-636
Attn: Protocol Lab Team, I 35316 Samples
Buffalo, NY 14263
(716) 845-8917
Email: CRSLabPathTeam@RoswellPark.org
For External (Network) Sites: Follow directions above for sample collection, processing and, 
shipping. The cryogenic tubes FFPE blocks are to be labeled with the clinical study number and 
patient study ID, collection date/study cycle and day and, “Tumor” or “Adjacent Normal Liver”. 
Snap-frozen samples are to be batch-shipped frozen, on dry ice. FFPE blocks may be batch-
shipped at ambient temperature (please include refrigerated gel pack when temperatures will 
exceed 24°C).
Frozen samples will be shipped via Fed Express Overnight on dry ice with delivery on Mon-Fri. 
NO SATURDAY DELIVERY. Do not ship on a Friday or the day before a holiday.
11.3.3 PD-L1/L2 and CYTOF analysis of Post-treatment Formalin-Fixed Paraffin-
Embedded (FFPE) Biopsy Samples
 At RPCI, the following sections will be prepared from the post-treatment biopsy FFPE blocks:
1. Eight unstained sections of each sample (tumor and adjacent normal liver) cut at 
4 microns on plus glass slides (4 of each sample for PD-L1/-L2 testing to RPCI 
Pathology Resource Network for analysis, 4 of each sample for Nanostring 
analysis).
2. Two H&E stained sections (1 from each block).
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3. Five (5) unstained sections (tumor tissue only) cut at 4-micron thickness on Fisher 
ProbeOn Plus slides for PD-L1 testing (QualTek). Refer to QualTek MISP Sample 
Handling Manual for detailed processing and shipping instructions.
Once all sections from the FFPE core have been taken, the remainder of the blocks will be sent 
to RPCI Immune Analysis facility (c/o Courtney Ryan) for CYTOF analysis.
Samples for NanoString analysis (FFPE sections) and the snap-frozen samples for RNA/DNA 
analysis and biomarker analysis will be sent from the CSPO to Dr. Prashant Singh, Assistant 
Director Genomics Shared Resource, CGP & COE L1-210, for analysis. For additional 
information regarding the handling of samples please contact Dr. Prashant Singh at 716-845-
3869 (office) or email Prashant.Singh@RoswellPark.org 
Samples for PL-L1/-L2 testing (4 unstained slides of each sample and 1 H&E of each sample) 
will be sent to RPCI’s Core Pathology Laboratory for analysis.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
12.0
Withdrawal of Subjects
12.1
Treatment Discontinuation
Upon treatment discontinuation all end of treatment evaluations and tests will be conducted. All 
participants who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, 
or until abnormal laboratory findings have returned to acceptable or pre-study limits. The final 
status of the AE will be reported in the participant’s medical records and the appropriate eCRF.
Reasons for treatment discontinuation should be classified as follows:

Death

Progressive disease

Toxicity; treatment related or unrelated

Investigator judgment

The Investigator may discontinue a participant if, in his/her judgment, it is in the best 
interest of the participant to do so.

Noncompliance

Participant voluntary withdrawal
o
A participant may withdraw from the study at any time, for any reason. If a 
participant discontinues treatment, an attempt should be made to obtain 
information regarding the reason for withdrawal
13.0
Risks to Subjects
13.1
Pembrolizumab
The most frequently reported adverse events in patients treated with pembrolizumab (reported in 
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≥ 20% of patients) are: fatigue (37.3%), nausea (24.5%), decreased appetite (22.5%), cough 
(22%) and, pruritis (20.1%).
The following AEs were reported in 10% - 20% of patients: dyspnea, arthralgia, rash, 
constipation, headache, vomiting, asthenia, pyrexia, back pain, anemia, and peripheral edema.
The most frequently reported SAEs were pneumonia (3%), pleural effusion (1.7%), pneumonitis 
(1.6%), dyspnea (1.6%), and pulmonary embolism (1.5%).
In addition, the following serious, life-threatening adverse effects have been reported:

Myocarditis: a complication of therapy reported to lead to death in less than 3 patients out 
of 1000 who receive the drug. 

Stevens-Johnson Syndrome 

Toxic Epidermal Necrolysis (TEN)
13.2
Sorafenib
The most common adverse reactions (≥ 20%) related to sorafenib in patients with HCC are 
diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased 
appetite, nausea, gastrointestinal and abdominal pains, hypertension, and hemorrhage.
14.0
Potential Benefits to Subjects
Studies of novel therapies for HCC which have been based on preclinical studies in mouse 
models have not translated into meaningful clinical benefit in patients. The strength of this study 
is the high translational value of studies performed in human T cells from advanced HCC 
patients. 
In our laboratory, we are currently testing the hypothesis that sorafenib treatment in patients with 
advanced HCC decreases immunosuppressive networks and thus increases the cytotoxic activity 
of the patient’s own effector T cells. This may be very important, as it is poorly studied and its 
mechanism of action is unknown. Results from our laboratory show that PD-1 levels are high in 
all advanced HCC patients, compared to normals.(4) In recently completed work (unpublished 
data) in HCC patients receiving sorafenib therapy, when the percentage of PD-1+ cells and the 
PD-1 expression levels remain unchanged patients do poorly (mean survival 4.7 months). In 
striking contrast, HCC patients with a statistically significant decline in the percentage of PD-1+ 
cells and the PD-1 levels following sorafenib therapy had the highest mean survival of 18.3 
months. A decrease in PD-1 levels was also seen in one patient with spontaneous regression of 
HCC, which is a rare but well described occurrence in the literature and, further supports the 
hypothesis that targeting PD-1 may have therapeutic benefit.
Thus, our results demonstrate that in a subset of patients, sorafenib therapy alone results in 
decreased numbers and level of expression of PD-1 and results in clinical benefit. These highly 
novel findings support our hypothesis that combining SOR with anti-PD-1 therapy may result in 
additional (additive or synergistic) significant clinical benefit in patients with advanced HCC.
15.0
Data and Specimen Banking
NA
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16.0
Measurement of Effect
16.1
Solid Tumors
Tumor response will be assessed at Week 6 (± 1 week) and Week 12 (±1 week) of combination 
therapy, and every subsequent 9 weeks (± 1 week) thereafter by immune-related response criteria 
(irRECIST) (13, 14). Conventional RECIST 1.1 (15) will also be documented during the trial, 
however RECIST 1.1 will not be used to determine disease progression, as it has been shown in 
prior clinical trials using pembrolizumab in large number of patients, that conventional RECIST 
might underestimate the benefit of pembrolizumab in approximately 15% of patients; thus using 
irRECIST could permit treatment beyond initial progression per RECIST v1.1 and prevent 
premature cessation of treatment.(14, 16, 17) 
The irRECIST will be used for tumor response assessment at time of continuing review and will 
be used for IRB reporting and formal analysis.
Refer to Appendix H for a summary of tumor response assessment using irRECIST criteria.
17.0
Safety Evaluation
17.1
Adverse Events
An adverse event or adverse experience (AE) is any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can 
be ANY unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product (attribution of ‘unrelated’, 
‘unlikely’, ‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.

Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases). However, if a constellation of signs and/or symptoms 
cannot be clinically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded as an AE or SAE on the CRF. If a 
diagnosis is subsequently established, it should be reported as follow-up information.

Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause. For example, if severe diarrhea 
is known to have resulted in dehydration, it is sufficient to record only diarrhea as an 
AE or SAE on the CRF. 
However, clinically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the CRF. For example, 
if a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
recorded separately on the CRF.
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
Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management 
will be recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study 
drug dose modification, discontinuation of study treatment, more frequent follow-up 
assessments, further diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or 
syndrome (e.g., alkaline phosphatase and bilirubin 5 x the upper limit of normal 
associated with cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be 
recorded on the Adverse Event CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or 
syndrome, the abnormality itself should be recorded as an AE or SAE on the CRF. If 
the laboratory abnormality can be characterized by a precise clinical term, the clinical 
term should be recorded as the AE or SAE. For example, an elevated blood potassium 
level of 7 mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit 
to visit should not be repeatedly recorded as AEs or SAEs on the CRF, unless their 
severity, seriousness, or etiology changes.

Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on an Adverse Event CRF, it is important to convey the 
concept that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).
17.2
Grading and Reporting Adverse Events
Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP 
Version 4 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.AEs not covered by 
specific terminology listed should be reported with common medical terminology, and 
documented according to the grading scales provided in the CTCAE Version 4.
The relationship of event to study drug will be documented by the Investigator as follows:

Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the participant.

Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.

Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs.

Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot 
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be reasonably explained by other factors such as the participant’s clinical state, 
therapeutic interventions or concomitant drugs.

Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, 
improves upon stopping the drug, or reappears on re-exposure.
Reporting Adverse Events: Routine AEs occurring between the start date of intervention until 
30 days after the last intervention, or until the event has resolved, the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as 
stable or irreversible, will be reported. New information will be reported after it is received.
Guidelines for Routine Adverse Event Reporting for Phase 1 Studies (Regardless of 
Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
X
X
Unlikely
X
X
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Guidelines for Routine Adverse Event Reporting for Pilot, Phase 2, and Phase 3 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
17.3
Serious Adverse Events
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of the 
investigator results in ANY of the following:

Death.

A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator, at immediate risk of death from the reaction 
as it occurred. It does NOT include an AE that, had it occurred in a more severe form, 
might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.
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
A congenital anomaly or birth defect.

Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the 
outcomes listed above.
Reporting Serious Adverse Events

The RPCI SAE Source Form is to be completed with all available information, including 
a brief narrative describing the SAE and any other relevant information. 

SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-661-6229, use Merck provided Global Safety 
Intake Form and Merck Fax Cover Sheet.

SAEs occurring after the 90 day follow-up period that the investigator determines to be 
possibly, probably or definitely related to the study intervention should be reported.

SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please 
refer to Section 17.8 for details on reporting Unanticipated Problems.

External (Network) Sites: see Appendix A for reporting requirement Section 7.
17.4
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to Roswell Park and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 661-6229).
For the time period beginning with the start of therapy until the safety follow-up visit, any ECI, 
or follow up to an ECI, that occurs to any subject must be reported within 24 hours to Roswell 
Park and within 2 working days to Merck Global Safety if it causes the subject to be excluded 
from the trial, or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.
Events of clinical interest for this trial include:
1. An overdose of Merck product, as defined in Section 32.1.6, that is not associated with 
clinical symptoms or abnormal laboratory results.
2. Hepatic Events of Clinical Interest include any of the following events. All of these 
events will require holding study treatment until the patient no longer meets the criteria 
listed below. Notification of the event(s) to Roswell Park within 24 hours via electronic 
media or paper is required:
a) ALT:
a.
Among subjects with Baseline ALT <2×ULN: ALT ≥5×ULN
b. Among subjects with Baseline ALT ≥2×ULN:  ALT >3× the Baseline 
level
c.
ALT >500 U/L regardless of baseline level
b) AST
a.
2×ULN:  AST ≥5×ULN
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b. Among subjects with Baseline AST ≥2×ULN:  AST >3× the Baseline 
level
c.
AST >500 U/L regardless of baseline level
c) Total Bilirubin
a.
Among subjects with Baseline levels <1.5 mg/dL: a value of >2 mg/dL
b. Among subjects with Baseline levels that are ≥1.5mg/dL: a value ≥2× the 
Baseline level 
c.
Total bilirubin >3.0 mg/dL regardless of baseline level
d) Regardless of laboratory values, hepatic decompensation diagnosed clinically, 
including:
a.
New onset clinically detectable ascites
b. Gastrointestinal bleeding suggestive of portal hypertension (e.g., 
esophageal or gastric varices)
c.
Hepatic Encephalopathy
Reporting of Pregnancy and Lactation
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before initiation of 
study treatment must be reported by the investigator if they cause the subject to be excluded from 
the trial, or are the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.
Pregnancies and lactations that occur from the time of initiation of study treatment through 120 
days following cessation of pembrolizumab, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator. 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.
Such events must be reported within 24 hours to the Roswell Park and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 661-6229)
17.5
Protocol-Specific Exceptions to Serious Adverse Event Reporting
For trials capturing Disease Progression as primary or secondary endpoint (PFS or ORR):
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 10, unless there is evidence suggesting a causal relationship between the drug and the 
event. Any such event will be submitted to the Roswell Park within 24 hours and to Merck 
Global Safety within 2 working days either by electronic or paper media.
Specifically, the suspected/actual events covered in this exception include any event that is 
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disease progression of the cancer under study.
Any suspected endpoint which upon review is not progression of the cancer under study will be 
forwarded to Merck Global Safety as a SAE within 2 working days of determination that the 
event is not progression of the cancer under study
Hospitalization related to convenience (e.g., transportation issues etc.) will not be considered a 
SAE.
17.6
Investigator Reporting: 
Investigators MUST report within 1 business day upon becoming aware, ANY Serious Adverse 
Events, whether or not they are considered related to the investigational agent(s)/intervention.
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-661-6229
EXTERNAL (NETWORK) SITES: see Appendix A Sections 7 & 8 for reporting requirements.
17.7
Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as 
stable or irreversible. New information will be reported when it is received.
17.8
Unanticipated Problems
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:

Unexpected (in terms of nature, severity, or frequency) given:
o
The research procedures that are described in the study-related documents, 
including study deviations, as well as issues related to compromise of participant 
privacy or confidentiality of data.
o
The characteristics of the participant population being studied.

Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research).

Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is deemed Serious per Section 17.3.
Reporting Unanticipated Problems:
Unanticipated problem reporting will begin at the time of participant consent. An Unanticipated 
Problem shall be submitted to the CRS Quality Assurance (QA) Office as “Reportable New 
Information” in the Click system within 1 business day of becoming aware of the Unanticipated 
Problem. After review, CRS QA Office will submit the RNI to the IRB. 
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS QA Office with an updated Reportable New Information Form.  The site 
Investigator or designated research personnel will report all unanticipated problems to the IRB in 
accordance with their local institutional guidelines.
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18.0
Data Management and Confidentiality
18.1
Data Collection
Full build studies are managed by RPCI CRS Data Management for analysis by RPCI 
Biostatisticians. All electronic case report form (eCRF) data are captured for these studies.
Data management activities are performed using a CTMS system that enables the collection, 
cleaning and viewing of clinical trial data. CRS data management designs the study-specific 
database and facilitates development by the Information Technology team. Once the database 
design is approved by the Investigator, Statistician, and Clinical Research Coordinator, the 
database is put into production and data entry can begin. Data can be entered and changed only 
by those with the rights to do so into the eCRFs.
18.2
Maintenance of Study Documents
Essential documents will be retained per RPCI’s policy for 6 years from the study termination 
date. These documents could be retained for a longer period, however, if required by the 
applicable local regulatory requirements or by an agreement with RPCI.
18.3
Revisions to the Protocol
RPCI may make such changes to the protocol as it deems necessary for safety reasons or as may 
be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to the 
IRB/ERC for written approval before implementation.
18.4
Termination of the Study
It is agreed that, for reasonable cause, either the RPCI Investigators or Merck, may terminate this 
study, provided a written notice is submitted within the time period provided for in the Clinical 
Trial Agreement. In addition, RPCI may terminate the study at any time upon immediate notice 
if it believes termination is necessary for the safety of participants enrolled in the study.
18.5
Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will 
be identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant
19.0
Statistical Plan
Primary interest is in the Overall Response Rate (ORR) related to sorafenib + pembrolizumab 
combination therapy in advanced stage HCC patients. The ORR is defined as the proportion of 
evaluable patients who attain either complete or partial response (by irRECIST) within 6 months 
of initiating combination therapy. Our working hypothesis is that sorafenib + pembrolizumab 
will increase the ORR by at least 15 percentage points over the standard of care (where responses 
are rare ~2-3%).
19.1
Sample Size Determination
Proposed is a one-stage, single arm, unblinded Phase II trial. ORR for patients receiving the 
standard of care therapy is around 0.05. An exact one-stage design proposed by Kepner and 
Chang tests the null hypothesis that the proposed treatment has an ORR that is equal to the 
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standard of care, against an alternative that it is greater. The design has 80% power to detect an 
ORR of 0.20 or greater with the study treatment, while controlling to 5% the nominal probability 
of erroneously finding a truly ineffective treatment as worthy of further research (21, 22).
The first 6 patients will comprise the Phase 1b safety lead-in. If ≥ 2 of these patients experience 
an unexpected, treatment related toxicity of grade ≥3 during the first cycle of therapy, the study 
will be stopped to reevaluate dosing. We anticipate that such limiting toxicities will be observed 
in ≤1 of the first 6 patients. All evaluable patients who receive the Phase 2 dose will be included 
in the Phase 2 study.
We expect 27 evaluable patients will be enrolled on the trial. If 4 or more of the 27 evaluable 
patients achieve complete or partial response, the treatment will be deemed effective and 
considered for further study.
19.2
Demographics and Baseline Characteristics
Descriptive statistics (as appropriate: n, percent, mean, median, min and max) will be used to 
summarize demographic and baseline characteristics.
19.3
Efficacy Analysis
The response rate will be estimated as the binomial proportion of responders among evaluable 
patients and supported by Jeffreys’ 95% confidence interval.
Time to tumor progression (TTP) will be measured from the date of study enrollment to the first 
observation of progressive disease. Overall survival (OS) will be measured from the date of 
study enrollment to the time of death from any cause. These variables will be estimated using the 
Kaplan-Meier method. Statistics describing the time to event distributions will be obtained from 
Kaplan-Meier methods and Proportional Hazards models. Continuous variables will be 
summarized with commonly used statistics (mean, standard deviation, median, etc.), with sub-
group associations tested using the Wilcoxon Rank Sum test. Categorical variables will be 
summarized in contingency tables, with associations of interest assessed using Fisher’s Exact 
Test. Given the exploratory nature of this study, all p-values less than 0.05 will be deemed 
statistically significant. No adjustment will be made to the significance threshold to control for 
the effects of multiple testing on the overall Type I error rate.
19.4
Correlative Data Analysis
Measurements for several immune parameters will be obtained before and after treatment. The 
effect of treatment will quantified as the post/pre-treatment mean ratio of the (potentially log 
transformed) expression measurements. Primary and derived immune marker expression 
measurements will be summarized with common descriptive statistics (mean / standard 
deviation). Associations between the paired pre- and post-measurements will be described with 
scatterplots and dot plots. The null hypothesis of no difference in the paired pre- and post-
treatment measurements was assessed using permutation paired t-tests.
In previous experiments, immune marker expression measurements varied widely, with means 
between 8.0 and 1,200; the coefficient of variation has been between 0.5 and 1.0. For power 
calculations, the (original scale) expressions are assumed to have mean (standard deviation) of 
100 (100), and within-patient correlation = 0.20. Comparing measurements at two time points, 
the within-patient effect of therapy on an immune marker can be assessed using a permutation 
paired t-test. A paired t-test with a two-sided significance threshold of 0.05 has 80% power to 
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detect a fold-change of at least 1.76 in the post/pre geometric means.
All data analyses were generated using SAS/STAT software, Version 9.4. Copyright 2012, SAS 
Institute Inc. SAS is a registered trademark of SAS Institute Inc., Cary, NC, USA.
20.0
Provisions to Monitor the Data to Ensure the Safety of Subjects
Phase 1 studies will be reviewed at the scheduled RPCI Phase 1 meetings and the minutes are 
forwarded to the IRB for review.
Phase 2 studies: The RPCI Data and Safety Monitoring Board will assess the progress of the 
study, the safety data, and critical efficacy endpoints. The DSMC will review the study annually 
and will make recommendations that include but not limited to; (a) continuation of the study, (b) 
modifications to the design, (c) suspension of, or (d) or termination of the study.
21.0
Vulnerable Populations
NA
22.0
Community-Based Participatory Research
NA
23.0
Sharing of Results with Subjects
Individual response data is shared with the participant as a part of their clinical care.
24.0
Setting
All treatment will be conducted on an outpatient basis at RPCI’s Gastrointestinal Center within 
Roswell Park Cancer Institute. Roswell. Potential study participants will be identified and 
recruited from current GI Center patients and from community referral.
25.0
Provisions to Protect the Privacy Interests of Subjects
Any data, specimens, forms, reports, video recordings, and other records that leave the site will 
be identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
26.0
Resources Available
NA
27.0
Prior Approvals
NA
28.0
Compensation for Research-Related Injury
Please refer to the informed consent form (Section 13) related to this study:
29.0
Economic Burden to Subjects
The participant and /or their insurance company will be responsible for charges related to the 
administration of drugs used in this clinical research study and for charges for medications that 
may be needed to prevent or control side effects.
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30.0
Consent Process
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, 
and sign an instrument of informed consent prior to performance of any study-specific 
procedure. It is the responsibility of the investigator to ensure that the participant is made aware 
of the investigational nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with 
good clinical practice and the applicable regulatory requirements and according to the guidelines 
in this protocol, including attached appendices.
31.0
Process to Document Consent in Writing
The Investigator (or IRB specified designee) is responsible for obtaining written consent from 
each participant in accordance with GCP guidelines using the approved informed consent form, 
before any study specific procedures (including screening procedures) are performed. The 
informed consent form acknowledges all information that must be given to the participant 
according to applicable GCP guidelines, including the purpose and nature of the study, the 
expected efficacy and possible side effects of the treatment(s), and specifying that refusal to 
participate will not influence further options for therapy. Any additional information that is 
applicable to the study must also be included. Additional national or institutionally mandated 
requirements for informed consent must also be adhered to. The participant should also be made 
aware that by signing the consent form, processing of sensitive clinical trial data and transfer to 
other countries for further processing is allowed.
The Investigator shall provide a copy of the signed consent form to the participant and the signed 
original shall be maintained in the Investigator File. A copy of the signed consent form must be 
filed in the participant file. At any stage, the participant may withdraw from the study and such a 
decision will not affect any further treatment options.
32.0
Drugs or Devices
32.1
Pembrolizumab
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 
and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an 
approximate molecular weight of 149 kDa.
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32.1.1 Active Substance and Source:
Product Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
Pembrolizumab for injection is a sterile, preservative-free, white-to off-white lyophilized powder 
in single-use vials. Each vial is reconstituted and diluted for intravenous infusion. Each 2 mL of 
reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 
mg), polysorbate 80 (0.4 mg), and sucrose (140 mg). May contain hydrochloric acid/sodium 
hydroxide-adjust pH to 5.5.
Pembrolizumab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to 
slightly yellow solution that requires dilution for intravenous infusion. Each vial contains 100 mg 
of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab 
and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water 
for Injection, USP.
32.1.2 Drug Shipment:
Pembrolizumab will be provided by Merck & Co., Inc. and shipped to the participating site. The 
investigational drug will be labeled in accordance with regulatory requirements (Drug identity, 
i.e., name, strength) is included in the label.
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee.
32.1.3 Preparation:
Refer to Pharmacy Manual.
32.1.4 Storage and Stability:
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility, in accordance with the applicable 
regulatory requirements.
Drug storage temperature will be maintained and recorded, as applicable.
Pembrolizumab for injection (lyophilized powder): Store vials under refrigeration at 2°C to 8°C 
(36°F to 46°F).
Pembrolizumab injection (solution): Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) 
in original carton to protect from light. Do not freeze. Do not shake.
Refer to Investigator’s Brochure for additional details.
32.1.5 Handling and Disposal:
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by Merck & Co., Inc., exercising accepted medical and 
pharmaceutical practices. Study drugs must be handled as cytotoxic agents and appropriate 
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precautions taken per the institution’s environmentally safe handling procedures. All 
investigational drugs will be dispensed in accordance with the Investigator’s prescription or 
written order.
All products dispensed will be recorded on a product accountability record. Records of product 
lot numbers and dates received will be entered on a product accountability form. This record will 
be reviewed during periodic monitoring visits. It is the Investigator’s responsibility to ensure that 
an accurate record of investigational drug issued and returned is maintained.
All unused and/or partially used investigational drug will be destroyed according to standard 
practices after properly accounting for the dispensing. Partially used vials of study drug will not 
be re-used for other participants.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
32.1.6 Overdose:
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥5 times the indicated dose). No specific information is available on the treatment of 
overdose of pembrolizumab.
In the event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
32.2
Sorafenib
Sorafenib will not be provided for this study and will be paid for by the patient’s insurance 
carrier as part of the standard-of-care treatment for unresectable hepatocellular carcinoma. The 
starting dose of sorafenib is at the discretion of the physician based on clinical assessment of the 
patient. 
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33.0
REFERENCES
1 Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: 
Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer. 
2015;136(5):E359-E86.
2 Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 
2008 Oct;48(4):1312-27.
3 Jain RK, Duda DG, Willett CG, et al. Biomarkers of response and resistance to antiangiogenic 
therapy. Nat Rev Clin Oncol. 2009 Jun;6(6):327-38.
4 Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y. Higher frequencies of GARP(+)CTLA-
4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular 
carcinoma patients are associated with impaired T-cell functionality. Cancer Res. 2013 Apr 
15;73(8):2435-44.
5 Lugade AA, Kalathil S, Miller A, Iyer R, Thanavala Y. High immunosuppressive burden in 
advanced hepatocellular carcinoma patients: Can effector functions be restored? 
Oncoimmunology. 2013 Jul 1;2(7):e24679.
6 Gao Q, Wang XY, Qiu SJ, et al. Overexpression of PD-L1 significantly associates with tumor 
aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer 
Res. 2009 Feb 1;15(3):971-9.
7 Klein O, Ebert LM, Zanker D, et al. Flt3 ligand expands CD4+ FoxP3+ regulatory T cells in 
human subjects. European journal of immunology. 2013 Feb;43(2):533-9.
8 Lechner MG, Megiel C, Russell SM, et al. Functional characterization of human Cd33+ and 
Cd11b+ myeloid-derived suppressor cell subsets induced from peripheral blood mononuclear 
cells co-cultured with a diverse set of human tumor cell lines. J Transl Med. 2011;9:90.
9 Golden-Mason L, Palmer B, Klarquist J, Mengshol JA, Castelblanco N, Rosen HR. 
Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ 
T cells associated with reversible immune dysfunction. Journal of virology. 2007 
Sep;81(17):9249-58.
10 El-Khoueiry AB, Melero, I, Crocenzi, T.S., Welling, T.H., Yau, T.C., Yeo, W., Chopra, A., 
Grosso, J., Lang, L., Anderson, J., Dela Cruz, C.M., Sangro, B. Phase I/II safety and antitumor 
activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040.  
ASCO; 2015: Journal of Clinical Oncology; 2015.
11 Llovet  JM, Ricci  S, Mazzaferro  V, et al. Sorafenib in Advanced Hepatocellular Carcinoma. 
New England Journal of Medicine. 2008;359(4):378-90.
12 Miller AA, Murry DJ, Owzar K, et al. Phase I and Pharmacokinetic Study of Sorafenib in 
Patients With Hepatic or Renal Dysfunction: CALGB 60301. Journal of Clinical Oncology. 
2009;27(11):1800-5.
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13 Bohnsack O, Hoos A, Ludajic K. 1070PADAPTATION OF THE IMMUNE RELATED 
RESPONSE CRITERIA: IRRECIST. Annals of Oncology. 2014 September 1, 2014;25(suppl 
4):iv369.
14 Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a 
common language for tumor response to immunotherapy: immune-related response criteria using 
unidimensional measurements. Clin Cancer Res. 2013 Jul 15;19(14):3936-43.
15 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer. 2009 
1//;45(2):228-47.
16 Ades F, Yamaguchi N. WHO, RECIST, and immune-related response criteria: is it time to 
revisit pembrolizumab results? Ecancermedicalscience. 2015;9:604.
17 Hodi FS, Ribas A, Daud A, et al. Evaluation of immune-related response criteria (irRC) in 
patients (pts) with advanced melanoma (MEL) treated with the anti-PD-1 monoclonal antibody 
MK-3475. ASCO Meeting Abstracts. 2014 June 11, 2014;32(15_suppl):3006.
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34.0
 APPENDICES/SUPPLEMENTS
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Appendix A Instructions for Multi-Site Studies
1.
CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Cancer Institute
CRS Quality Assurance (QA) Network Office
CRSNetworkCoordinators@RoswellPark.org
1930 GBSB
Buffalo, New York 14263
Telephone:
Monday - Friday; 8:00 AM to 4:30 PM EST
716-845-8084
After hours, weekends, and holidays request the RPCI Investigator
716-845-2300
Fax: 716-845-8743
2.
INFORMED CONSENT

Informed consent must be obtained by the site Investigator/designee from any 
participants wishing to participate, prior to any procedures or treatment.

An informed consent template is provided by Roswell Park and can be amended to 
reflect institutional requirements.

All consent changes must be reviewed by Roswell Park CRS QA Network Office prior 
to submission to the site IRB.

The informed consent must be IRB approved.

Always check that the most up to date version of the IRB approved consent is being 
used.

Within 5 business days, notify the Roswell Park CRS QA Network Office of all 
participant withdrawals or consent to limited study participation and appropriately 
document the discontinuation and the reason(s) why.
3.
PARTICIPANT REGISTRATION
The participant completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder.
RPCI does not grant exceptions to eligibility criteria.
Phase 1 Protocol Registration Instructions
Contact the Roswell Park Network QA Coordinator to verify that a slot is available in the open 
cohort when a participant has been identified. Do not have the participant sign consent prior to 
verifying an open slot.

After the participant signs consent, the Subject Screening and Enrollment Log must be 
faxed or emailed (CRSNetworkCoordinators@RoswellPark.org) to the Roswell Park 
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QA Coordinator Monitor  within 1 business day. The Roswell Park QA 
Coordinator/Monitor will confirm receipt of the Subject Screening and Enrollment Log 
and email the participant ID number.

When the participant has met eligibility, a signed eligibility checklist and other 
requested documentation will be faxed or emailed to the Roswell Park Network QA 
Coordinator.

Within 1 business day of receipt of the eligibility check list, the RPCI Network QA 
Coordinator will fax or email the cohort assignment and dose level.

An email must be sent by the site to confirm receipt of the cohort assignment and to 
provide the planned treatment start date.
Phase 2 Protocol Registration Instructions
The 
Subject 
Screening 
and 
Enrollment 
Log 
must 
be 
faxed 
or 
emailed 
(CRSNetworkCoordinators@RoswellPark.org) to the Roswell Park CRS QA Network Office 
within 1 business day of the date the participant is consented. Once the Investigator has determined 
that eligibility has been met, complete the eligibility check list and fax or email it to the Roswell 
Park Network QA Coordinator at 716-845-8743.
4.
STUDY DEVIATIONS

If a deviation has occurred to eliminate hazard, this must be reported to the RPCI 
Network, site IRB and any other regulatory authority involved in the study.

ALL study deviations will be recorded on the Study Deviation Log.

Participants inadvertently enrolled with significant deviation(s) from the study-
specified criteria will be removed from the study, at the discretion of the Principle 
Investigator.
5.
STUDY DOCUMENTATION

Study documents must be filled out completely and correctly. Ditto marks are not 
allowed.

If an entry has been documented in error put a single line through the entry and initial 
and date the change. The Roswell Park Network QA Coordinator must be able to read 
what has been deleted.

Do NOT use white-out, magic marker, scratch-outs.

Do NOT erase entries.

Use only black ink for documentation on the accountability form and any other study 
forms.

It is the responsibility of Roswell Park to inform the Investigator/ institution as to when 
these documents no longer need to be retained. If, for any reason, the Investigator 
desires to no longer maintain the study records, they may be transferred to another 
institution, another investigator, or to Roswell Park upon written agreement between 
the Investigator and Roswell Park.
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6.
DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.

Responsibility rests solely with the Investigator but can be delegated as appropriate 
(e.g., to pharmacy personnel).

A drug accountability record form (DARF) will record quantities of study drug 
received, dispensed to participants and wasted, lot number, date dispensed, participant 
ID number and initials, quantity returned, balance remaining, manufacturer, expiration 
date, and the initials of the person dispensing the medication.

Study drug supply will only be used in accordance with the IRB approved study.

Drug accountability forms are protocol and agent specific, they are study source 
documents and will be used to verify compliance with the study.

An inventory count must be performed with each transaction. Any discrepancies shall 
be documented and explained.

Drug accountability forms must be stored with study related documents.

Each medication provided for this study and each dosage form and strength must have 
its own DARF.

Dispensing the wrong study supply is considered a medication error.

NEVER replace investigational agents with commercial product.

Do NOT “transfer”, “borrow” or “replace” supplies between studies.
7.
SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the Roswell Park Network QA Coordinator within 1 business day 
of being made aware of the SAE. A preliminary written report must follow within 1 business day 
of the first notification using the Roswell Park SAE form:
A complete follow-up report must be sent to the Roswell Park Network QA Coordinator when 
new information becomes available.
8.
UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the criteria 
in Section 17.8.
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff from 
each site will notify their local IRB in accordance with their local institutional guidelines. The 
site must also notify the Roswell Park Network QA Coordinator within 1 business day of being 
made aware of the Unanticipated Problem by completing the RPCI Unanticipated Problem 
Report Form and faxing or emailing it to the Roswell Park Network QA Coordinator.
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Appendix B
ECOG/ Karnofsky Performance Scale
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Descriptions
100
Normal, no complaints; no evidence 
of disease
0
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
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 but unable to carry on 
normal activity or to do active work
60
Requires occasional assistance but is 
able to care for most of personal 
needs
2
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
Capable of only limited self-care; 
confined to bed or chair more than 
50% of waking hours
30
Severely disabled; hospitalization is 
indicated although death not 
imminent
20
Very ill; hospitalization and active 
supportive care necessary
4
Completely disabled; cannot carry on 
any self-care; totally confined to bed 
or chair
10
Moribund
5
Dead
0
Dead
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Appendix C
Child-Pugh Classification
Child-Pugh Classification of Severity of Liver Disease
Modified Child-Pugh classification of severity of liver disease according to the degree of ascites, 
the plasma concentrations of bilirubin and albumin, the prothrombin time and, the degree of 
encephalopathy.
Points assigned
Parameter
1
2
3
Ascites 
Absent
Slight
Moderate
Bilirubin, mg/dL
</= 2
2-3
>3
Albumin, g/dL
>3.5
2.8-3.5
<2.8
Prothrombin time
* Seconds over control
* INR
1-3
<1.8
4-6
1.8-2.3
>6
>2.3
Encephalopathy
None
Grade 1-2
Grade 3-4
A total score of 5-6 is considered grade A (well-compensated disease); 7-9 is grade B 
(significant functional compromise); and 10-15 is grade C (decompensated disease). These 
grades correlate with one- and two-year patient survival.
Grade
Points
One-year patient 
survival (%)
Two-year patient 
survival (%)
A: well-
compensated disease
5-6
100
85
B: significant 
functional 
compromise
7-9
80
60
C: decompensated 
disease
10-15
45
35
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Appendix D
Medication Dairy
Study No.: ______________
Subject’s Name: ______________________________
Drug Name: _____________
Cycle #: ______
Medical Record No.: _________________________
Study Medication Calendar for Sorafenib (Combination Therapy)
You should swallow your medication whole: without cutting, chewing, or crushing. The tablets should be taken in the 
morning and evening (about 1 hour before or 2 hours after eating.).
Please complete this calendar on a daily basis immediately after you take your tablets. Fill in the date for each day, 
write the drug dose that you take each day, and write the total number of tablets you take each day. If your dose 
changes; record the new dose level.
Start Date: _________________
Dose: ___________________________
Take _____ tablet(s) each time, about 12 hours apart and at least 1 hour before a meal or, 2 hours after a meal.
Cycle Day
Day 1
Day 2
Day 3 
Day 4
Day 5
Day 6
Day 7
Date
Time
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Number of 
tablets 
taken
Cycle Day
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Date
Time
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Number of 
tablets 
taken
Cycle Day
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Date
Time
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Number of 
tablets 
taken
Cycle Day
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date
Time
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Number of 
tablets 
taken
Cycle Day
Day 29
Day 30
Day 31
Date
Time
AM
PM
AM
PM
AM
PM
Number of 
tablets 
taken
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Please remember to bring this calendar with you to your next clinic appointment.
Note: On the day that you start your combination therapy (sorafenib + pembrolizumab) and on 
Day 1 of every four cycles of the combination after that, your blood will be drawn prior to 
receiving the intravenous pembrolizumab.
On those days (i.e. Cycle 1-Day 1, Cycle 4-Day 1, etc.), please do not take your morning dose of 
sorafenib until after you go to the clinic and have your blood drawn.
_______________________________________________________________________________________________
Coordinator’s Use Only
Subject’s Signature: __________________________________________
Date: ____________
CRC’s Signature: ____________________________________________
Date: ____________
Investigator’s Signature :_______________________________________
Date : ____________
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Study Medication Calendar for SORAFENIB ONLY (Lead-in Phase)
Study No.: ______________
Subject’s Name: ______________________________
Drug Name: _____________
Medical Record No.: _________________________
You should swallow your medication whole: without cutting, chewing, or crushing. The tablets should be taken in the 
morning and evening (about 1 hour before or 2 hours after eating.).
Please complete this calendar on a daily basis immediately after you take your tablets. Fill in the date for each day, 
write the drug dose that you take each day, and write the total number of tablets you take each day. If your dose 
changes; record the new dose level.
Start Date: _________________
Dose: ___________________________
Take _____ tablet(s) each time, about 12 hours apart and at least 1 hour before a meal or, 2 hours after a meal.
Day
Date
Time
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Number of 
tablets 
taken
Day
Date
Time 
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Number of 
tablets 
taken
Day
Date
Time
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Number of 
tablets 
taken
Day
Date
Time
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Number of 
tablets 
taken
* The day that you go into the clinic for your first dose of pembrolizumab is referred to as 
Cycle 1-Day 1. On the day of Cycle 1-Day, do not take your morning dose of sorafenib until 
after you have had your blood drawn at the Clinic: the blood draw will occur prior to 
pembrolizumab administration.
Please remember to bring this calendar with you to your next clinic appointment.
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Coordinator’s Use Only
Subject’s Signature: __________________________________________
Date: ____________
CRC’s Signature: ____________________________________________
Date: ____________
Investigator’s Signature :_______________________________________
Date : ____________
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Appendix E
Schedule of Procedures
Trial Period
Screening
Sorafenib
only
Combination
(sorafenib + pembrolizumab)
Treatment Cycles3
Post-Treatment
Phase Ib and Phase II:
Baseline1
 Day -28 
to Day -
1*
1
2
3
4
5
6 3a
End
of
Study4
Safety Follow-
Up5
Follow Up 6
Long Term 
Follow-Up7
Clinical Assessments
Medical History and Pre-
existing Conditions
X
X
Prior and Concomitant 
Medication Review
X8
X9
X9
X9
X9
X9
X9
X9
X9
X9
Physical Examination10; 
including vital signs, body 
weight, & height11
X
X2
X
X
X
X
X
X
X
X
Child Pugh A
X
ECOG Performance 
Status
X
X
X
X
X
X
Adverse Events
X2
X
X
X
X
X
X
X
X
X
Survival Status
X
X
X
X
X
X
X
X
X
Laboratory Procedures
Hematology: CBC with 
Differential12
X
X2
X
X
X
X
X
X
X
X
Chemistry: CMP13
X
X2
X
X
X
X
X
X
X
X
T3, FT4, and TSH14
X
X
X
X
Viral Titers: Hepatitis B 
and C22: Hepatitis B 
Surface Antigen 
(HBsAg) and/or 
detectable HBV DNA 
and, Hepatitis C 
Antibody (anti-HCV 
X
X
X

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Trial Period
Screening
Sorafenib
only
Combination
(sorafenib + pembrolizumab)
Treatment Cycles3
Post-Treatment
Phase Ib and Phase II:
Baseline1
 Day -28 
to Day -
1*
1
2
3
4
5
6 3a
End
of
Study4
Safety Follow-
Up5
Follow Up 6
Long Term 
Follow-Up7
Ab), and detectable 
HCV RNA
Coagulation15
X
Tumor Marker (AFP)16
X
X
X
X
Serum Pregnancy Test
X
Imaging
CT of chest, abdomen, 
and pelvis17
X
X
X
X
Study Drugs
Sorafenib, po
X
X
X
X
X
X
X
Pembrolizumab, IV
X
X
X
X
X
X
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Archival Tissue 
Collection18
X
Tumor biopsy
X18
X19
Correlative Studies Blood 
Collection20
X
X
X
X
Pharmacokinetic Blood 
Sampling21
X
X
X
*The sorafenib lead in phase can extend up to Day-42 to Day-1 to allow stabilized dosing.
1
Within 28 days prior to start of sorafenib only study treatment (unless otherwise noted.)
2
Toxicity assessment within 2 weeks of starting sorafenib lead-in to include a directed physical exam and vitals.
3
One cycle = 3 weeks (sorafenib + pembrolizumab). Pembrolizumab to be administered on Day 1 (± 3 days) of each 3-week cycle. Note: After Cycle 1 
Day 1, all on-study visit procedures are allowed a window of ± 3 days unless otherwise noted. 3ͣ  The number of cycles may vary (with each patient) and 
additional cycles may occur, as clinically indicated.  After a patient has been on pembrolizumab for more than 24 months the PI can decide if the patient 
can come off pembrolizumab and continue on with sorafenib treatment.

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4
End of study or, at time decision is made to discontinue treatment (e.g. toxicity, physician decision, or patient withdraws consent).
5
Safety follow up to be conducted approximately 30 days (± 3 days) after last dose of trial treatment, or until resolution of any drug-related toxicity or 
before the initiation of a new anti-cancer treatment, whichever comes first.
6
Participants who discontinue treatment for other than disease progression will move into the follow-up phase: assessments every 3 months for 1 year or 
until death. Telephone contact is acceptable.
7
All patients will be followed by medical review every 6 months for survival.
8
List any medications that are ongoing, or that will be discontinued, within 1 week prior to first dose of study drug (refer to Section 10.3 for Acceptable 
and Prohibited concomitant medications). All concomitant medications received within 28 days before the first dose of trial treatment and 30 days after 
that last dose of trial treatment should be recorded.
9
List any ongoing medications with dose changes, as applicable. Concomitant medications administered after 30 days after the last dose of trial treatment 
should be recorded for SAEs and ECIs as defined in Section 17.0.
10
A physical exam within 1 week of consent is acceptable.
11
Vital signs (temperature, heart rate, respiratory rate, blood pressure), body weight and height. Height collected at baseline only.
12
Hematology (CBC with automated differentials): WBC,RBC, HGB, HCT, platelets, MCV, MCH, MCHC, % neutrophils, absolute neutrophils, % 
monocytes, absolute monocytes, % eosinophils, absolute eosinophils, % basophils, absolute basophils, % lymphocyte, absolute lymphocyte, platelet 
confirmation (as clinically indicated), differential confirmation (as clinically indicated). Note: Participants experiencing Grade 4 neutropenia should be 
monitored according to institutional guidelines. As needed at each study visit as determined by the treating physician or Investigator.
13
Chemistry (CMP): chloride, CO2, potassium, sodium, BUN, glucose, calcium, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, 
AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), anion gap).
14
Every 12 weeks starting from C1D1.
15
PT/INR and aPTT at screening and as clinically indicated.
16
AFP at screening and at disease assessment: six weeks after C1D1 (end of Cycle two), 12 weeks after C1D1 (end of Cycle four), every nine weeks 
thereafter, and at disease progression.
17
Imaging at Baseline, at Cycle 2 (± 1 week), at Cycle 4 (± 1 week), and then every 9 weeks (± 1week).
18
Archival tissue collection. If available at baseline. Refer to Section 11.3.1. 
19
Tumor biopsy: Optional at end of treatment Refer to Section 11.3.2
20
Prior to the start of sorafenib, at start of Cycle 1, at start of Cycle 4 and Day 1 of every subsequent 4 cycles (Cycle 8, 12, etc.), and end of study 
treatment. NOTE: At onset of Cycle 1, confirm that patient will actually start pembrolizumab before collecting samples. Refer to Section 11.2 for 
collection and processing requirements. 
21
Pharmacokinetic samples will be collected at the start of combination treatment and processed according to Section 11.1. Patients will be advised to 
hold morning dose of sorafenib until after PK blood draw but before pembrolizumab.
22
Viral titers will be measured at baseline (and as clinically indicated in patients who have elevated baseline titers) and at every 12 weeks starting from 
C1D1 to assess possible effects on outcome: Hepatitis B Surface Antigen (HBsAg) and/or detectable HBV DNA and, Hepatitis C Antibody (anti-HCV 
Ab), and detectable HCV RNA.

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Appendix F
Table 1
Table 1: Dose Modification Guidelines for Non-Hepatic Pembrolizumab-Related Adverse 
Events
Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting 
Treatment
Treatment Discontinuation
2-3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks
Diarrhea/Colitis
4
Permanently discontinue
Permanently discontinue
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia
T1DM or 
3-4
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-
4 hyperglycemia associated with 
evidence of beta cell failure
Resume pembrolizumab when patients are clinically and 
metabolically stable
Hypophysitis
2-4
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab can 
be continued while endocrine 
replacement therapy is instituted
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks
3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks
Hyperthyroidism 
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
Therapy with pembrolizumab can 
be continued while thyroid 
replacement therapy is instituted
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted
2a
Toxicity resolves to Grade 0-1 
Permanently discontinue if toxicity develops despite 
adequate premedication 
Infusion 
Reaction
3-4
Permanently discontinue
Permanently discontinue
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks
2
Recurrent grade 2
Permanently discontinue
Pneumonitis
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks
Renal Failure or 
Nephritis
3-4
Permanently discontinue
Permanently discontinue
3 or Severe
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks
All Other Drug-
Related 
Toxicityb
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event.
a If symptoms resolve within one 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 subject should be premedicated for the next 
scheduled dose; Refer to Appendix G-Table 2: Infusion Treatment Guidelines, for further management details.
b Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue 
study drug 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.
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Appendix G
Table 2
Table 2: Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within one 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 subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration.
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
(MK-3475) with:
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic).
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:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued 
from further trial treatment 
administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
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Appendix H
Immune-Related Response Criteria: irRECIST
Tumor response will be assessed using the Immune-Related response Criteria as described by 
Nishino et al, (14) and Bohnsack et al, (13).
1
Baseline
1.1
Measurable Lesion Definitions and Target Lesion Selection

All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, will be identified as target lesions and recorded and 
measured at baseline

Measurable lesions must be accurately measured in at least one dimension with a minimum 
size of:
o
10 mm in the longest diameter by CT or MRI scan (or no less than double the slice 
thickness) for non- nodal lesions and ≥ 15 mm in short axis for nodal lesions.
o
10 mm caliber measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).
o
20 mm by chest X-ray

A sum of the longest diameter (short axis for lymph nodes) of all target lesions will be 
calculated and reported as the baseline sum diameters. This will be used as reference to 
further characterize the objective tumor response of the measurable dimension of the 
disease.
1.2
Non-measurable Lesion Definitions

Non-target lesions will include:
o
Measurable lesions not selected as target lesions
o
All sites of non-measurable disease, such as neoplastic masses that are too small to 
measure because their longest uninterrupted diameter is < 10 mm (or < two times 
the axial slice thickness), i.e., the longest perpendicular diameter is ≥ 10 and 
< 15 mm.
o
Other types of lesions that are confidently felt to represent neoplastic tissue but are 
difficult to measure in a reproducible manner. These include bone metastases, 
leptomeningeal metastases, malignant ascites, pleural or pericardial effusions, 
ascites, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, 
ill-defined abdominal masses, skin lesions, etc.

All lesions or sites of disease not recorded as target lesions (e.g., small lesions and non-
measurable lesions) should be identified as non-target lesions and indicated as present in 
the source documents at baseline. There is no limit to the number of non-target lesions that 
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can be recorded at baseline. The general location will also be documented on the images, 
drawing a regularly-shaped Region of Interest. 

Measurements of the non-target lesions will not be performed, but the presence or absence 
of each should be noted throughout follow-up and evaluation.
1.3
Target and Non-Target Lymph Node Lesion Definitions

To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm 
in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed.
1.4
Non-Target Lesion Selection

All lesions or sites of disease not recorded as target lesions should be recorded as non-
target lesions at baseline. There is no limit to the number on non-target lesions that can be 
recorded at baseline.
1.5
Bone Lesions

Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Regardless of the imaging modality blastic bone lesions will not be selected as target 
lesions. Lytic or mixed lytic-blastic lesions with a measurable soft tissue component 
≥ 10 mm can be selected as target lesions.
1.6
Brain Lesions

Brain Lesions detected on brain scans can be considered as both target or non-target 
lesions.
1.7
Cystic and Necrotic Lesions as Target Lesions

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts.

Lesions that are partially cystic or necrotic can be selected as target lesions.

The longest diameter of such a lesion will be added to the Total Measured Tumor Burden 
(TMTB) of all target lesions at baseline. 
If other lesions with a non-liquid/non-necrotic component are present, those should be preferred.
1.8
Lesions with Prior Local Treatment

During target lesion selection the radiologist will consider information on the anatomical 
sites of previous intervention (e.g. previous irradiation, RF-ablation, TACE, surgery, etc.).
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
Lesions undergoing prior intervention will not be selected as target lesions unless there has 
been a demonstration of progress in the lesion.
1.9
No Disease at Baseline

If a patient has no measurable and no non-measurable disease at baseline the radiologist 
will assign ‘No Disease’ (irND) as the overall tumor assessment for any available follow-
up time-points unless new measurable lesions are identified and contribute to the TMTB.
2
Follow-Up
2.1
Recording of Target and New Measurable Lesion Measurements

The longest diameters of non-nodal target and new non-nodal measurable lesions, and short 
axes of nodal target and new nodal measurable lesions will be recorded. Together they 
determine the Total Measured Tumor Burden (TMTB) at follow-up.
2.2
Definition of New Measurable Lesions

In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, 
per time-point), new lesions must meet criteria as defined for baseline target lesion 
selection and meet the same minimum size requirements of 10 mm in long diameter and 
minimum 15 mm in short axis for new measurable lymph nodes. New measurable lesions 
shall be prioritized according to size, and the largest lesions shall be selected as new 
measured lesions.
2.3
Non-Target Lesion Assessment

The RECIST 1.1 definitions (15) for the assessment of non-target lesions apply (i.e., 
measurements of the non-target lesions will not be performed, but the presence or absence 
of each should be noted throughout follow-up and evaluation).

The response of non-target lesions primarily contributes to the overall response 
assessments of irCR and irNon-CR/Non-PD (irNN).

Non-target lesions do not affect irPR and irSD assessments. 

Only a massive and unequivocal worsening of non-target lesions alone, even without 
progress in the TMTB is indicative of irPD.
2.4
New Non-Measurable Lesions Definition and Assessment

All new lesions not selected as new measurable lesions are considered new non-measurable 
lesions and are followed qualitatively. 

Only a massive and unequivocal progression of new non-measurable lesions leads to an 
overall assessment of irPD for the time-point.

Persisting new non- measurable lesions prevent irCR.
2.5
irRECIST Overall Tumor Assessments
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The irRECIST overall tumor assessment is based on the TMTB (total measured tumor burden) of 
measured target and new lesions, non-target lesion assessment and new non-measurable lesions.

irCR: Complete disappearance of all measurable and non-measurable lesions. Lymph 
nodes must decrease to < 10 mm in short axis.

irPR: Decrease of ≥ 30% in TMTB relative to baseline, non-target lesions are irNN, and 
no unequivocal progression of new non-measurable lesions.

irSD: Failure to meet criteria for irCR or irPR in the absence of irPD.

irNN: No target disease was identified at baseline and at follow-up the patient fails to meet 
criteria for irCR or irPD.

irPD: Minimum 20% increase and minimum 5 mm absolute increase in TMTB compared 
to nadir, or irPD for non-target or new non-measurable lesions. Confirmation of 
progression is recommended minimum 6 weeks after the first irPD assessment.

irNE: Used in exceptional cases where insufficient data exists.

irND: In adjuvant setting when no disease is detected.
New Lesions: the presence of new lesion(s) does not define progression. The measurements of the 
new lesion(s) are included in the sum of the measurements (the sum of the measurements = the 
sum of the longest diameters of all target lesions and new lesions, if any).
2.6
Confirmation Measurement
A confirmatory assessment is required no less than 6 weeks after an irPR or irCR is deemed by 
irRECIST (14)
3
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation. All baseline evaluations should 
be performed as closely as possible to the beginning of treatment and never more than 4 weeks 
before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.  The preferred imaging modality for this clinical trial 
is conventional CT scan using IV contrast.

Clinical Lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.

Chest x-ray: Chest x-ray is not accurate in assessment of lesion size in the lung and 
should not be used as a method of measurement. Conventional chest CT is the preferred 
imaging modality to evaluate response to treatment.
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
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans) 
however, conventional CT scan is the preferred modality to determine response to 
treatment.
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
irRECIST or RECIST 1.1 guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans should 
be performed with breath-hold scanning techniques, if possible.

Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, 
MRI may be used instead of CT in selected instances.

Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.

Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.

Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
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Appendix I
Suggested Dose Modifications for Dermatologic Toxicities in Patients with 
Hepatocellular Carcinoma
Dermatologic Toxicity Grade 
Occurrence 
Suggested Dose Modification 
Grade 1: Numbness, dysesthesia, 
paresthesia, tingling, painless swelling, 
erythema or discomfort of the hands or feet 
which does not disrupt the patient’s normal 
activities 
Any occurrence
Continue treatment with sorafenib and 
consider topical therapy for symptomatic 
relief 
1st occurrence
Continue treatment with sorafenib and 
consider topical therapy for symptomatic 
relief If no improvement within 7 days, 
see below
Grade 2: Painful erythema and swelling of 
the hands or feet and/or discomfort affecting 
the patient’s normal activities 
No improvement 
within 7 days or 2nd 
or 3rd occurrence
Interrupt sorafenib treatment until toxicity 
resolves to Grade 0–1 When resuming 
treatment, decrease sorafenib dose by one 
dose level (400 mg daily or 400 mg every 
other day) 
4th occurrence
Discontinue sorafenib treatment 
1st or 2nd occurrence
Interrupt sorafenib treatment until toxicity 
resolves to Grade 0–1 When resuming 
treatment, decrease sorafenib dose by one 
dose level (400 mg daily or 400 mg every 
other day) 
Grade 3: Moist desquamation, ulceration, 
blistering or severe pain of the hands or feet, 
or severe discomfort that causes the patient 
to be unable to work or perform activities of 
daily living 
3rd occurrence
Discontinue sorafenib treatment 
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Appendix J
Guidance for Diagnosis and Management of Hepatic Events of Clinical 
Interest
In addition to overdose, hepatic events of clinical interest (ECIs) will include any of the 
following events. All of these events will require holding study treatment until the patient no 
longer meets the criteria below.  Notification of events to Roswell Park within 24 hours is 
required. Refer to Section 17.4 for reporting guidelines and the definition of hepatic ECIs. 
Roswell Park will report within 2 working days to Merck Global safety.
All cases of retreatment and permanent discontinuation must be reported to the Sponsor and 
recorded in the database.
a) ALT:
i)
Among subjects with baseline ALT < 2 x ULN: ALT ≥ 5 x ULN
ii) Among subjects with baseline ALT ≥ 2 x ULN: ALT > 3 x the baseline level
iii) ALT >500 U/L regardless of baseline level
b) AST:
i)
Among subjects with baseline AST <2xULN:  AST ≥ 5 x ULN
ii) Among subjects with baseline AST ≥ 2 x ULN: AST > 3 x the baseline level
iii) AST >500 U/L regardless of baseline level
c) Total Bilirubin:
i)
Among subjects with baseline
levels < 1.5 mg/dL: a value of > 2 mg/dL
ii) Among subjects with baseline levels that are ≥ 1.5mg/dL: a value ≥ 2 x the baseline 
level
iii) Total bilirubin > 3.0 mg/dL regardless of baseline level
d) Regardless of laboratory values, hepatic decompensation diagnosed clinically, including:
i)
New onset clinically detectable ascites
ii) Gastrointestinal bleeding suggestive of portal hypertension (e.g., esophageal or 
gastric varices)
iii)  Hepatic Encephalopathy
Immediate assessment
All subjects

All subjects should be evaluated according to directions below within 72 hours of 
alert for non-overdose ECI

Procedures:

Obtain a work-up for hepatitis if there is no underlying hepatitis, including 
hepatitis A, B, C, D, E, Epstein-Barr virus, and cytomegalovirus

Assess for ingestion of drugs/supplements with hepatotoxic potential

Assess for alcohol ingestion
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
Assess for potential bacterial infection, biliary obstruction, or occult 
gastrointestinal bleeding

Repeat ALT, AST, total bilirubin (Tbil), direct bilirubin (Dbil), alkaline 
phosphatase (ALP), y-glutamyl transpeptidase (GGT), INR, and complete 
blood count (CBC) with differential

Other laboratories or imaging studies as clinically indicated

Consider liver biopsy if indicated 
Hepatitis C-Infected Subjects (including subjects who previously achieved SVR 12)

In addition to the above, measure HCV RNA viral load
Hepatitis B-infected Subjects

HBV DNA, HBsAg, HBeAg, anti-HBc (total and IgM), anti-HBe, and anti-HBs

Subjects should be questioned about compliance with the use of anti-viral agents
Permanent Discontinuation Criteria for Subjects with Non-overdose Hepatic ECI
Therapy should also be permanently discontinued for any of the following:

ALT > 20 x ULN

CP score of ≥ 9 points

Gastrointestinal bleeding suggestive of portal hype1tension (e.g., esophageal or 
gastric varices)

New onset of clinically detectable ascites

Hepatic Encephalopathy

Recurrence of a severe or life-threatening event, or of any of the laboratory 
abnormalities listed above, that are presumed to be immune-related
Diagnosis and Management of Non-Overdose Hepatic ECIs
HCC patients are at risk for a range of complications that can cause hepatic laboratory 
abnormalities with or without clinical decompensation. Those with a history of chronic HCV or 
HBV infection also have the potential to experience virologic flares. Immune-related hepatitis 
has been observed in approximately1% of subjects who received pembrolizumab. The following 
section provides further guidance on the diagnosis and management of potential hepatic 
complications among HCC subjects in this study.
a) Hepatitis B Flare
Hepatitis B flares are characterized by rapid elevations of ALT and AST to > 5 x ULN and/or 
> 3 x baseline. ALT elevation to ≥ l0 x ULN is common. In the absence of hepatic 
decompensation, ALT/AST elevations are typically isolated (i.e., limited/no elevations of 
bilirubin/ALP). Subjects who are compliant with anti-viral therapy should have continued 
suppression of HBV DNA at the time of flare; thus, detection of HBV DNA should prompt 
questioning of subjects for compliance. Laboratory abnormalities secondary to flare are typically 
observed for 3-5 weeks.
Among subjects with HBV, a flare should be considered if this pattern is observed and there is 
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no evidence of an alternative etiology. Guidelines for subjects with a diagnosis of HBV flare are 
no evidence of an alternative etiology; Guidelines for subjects with a diagnosis of HBV flare are 
as follows:

Care should be instituted in consultation with a hepatologist if available.

For subjects who have detectable HBV DNA, re-institute anti-viral therapy.

If the subject is clinically stable, study treatment dosing may be interrupted for up to 12 
weeks. Subjects should undergo weekly laboratory tests including: AST, ALT, ALP, 
Tbil, Dbil, INR, HBsAg and, HBV DNA (if detected at the onset of the flare). Obtain 
anti-HBe, anti-HBs, and HBV DNA levels (if not detected at the onset of the flare) every 
2-3 weeks.

If ALT returns to normal or Grade 1 (if normal at baseline), or to baseline grade (if Grade 
2 at baseline) within 12 weeks, and subjects are clinically stable, subjects may restart 
study treatment. If these conditions are not met, then study treatment should be 
permanently discontinued.
b) Hepatitis C Recurrence or Flare
Subjects who achieved SVR 12 and subjects with ongoing HCV infection are eligible for 
enrollment. In rare circumstances, HCV subjects who achieve SVR 12 may relapse at later time 
points. Relapse is characterized by detection of HCV RNA, often accompanied by ALT 
elevations to > 5 x ULN. In the absence of hepatic decompensation, ALT/AST elevations are 
typically isolated (i.e., limited/no elevations of bilirubin/ALP).
Among subjects with uncontrolled hepatitis C, virologic flares are possible. Hepatitis C flares are 
characterized by rapid elevations of ALT and AST to > 5 x ULN and/or > 3 x baseline along 
with a rise in HCV RNA. ALT elevation to ≥ 10 x ULN and a 1 log elevation in HCV RNA level 
are common. In the absence of hepatic decompensation, ALT/AST elevations are typically 
isolated (i.e., limited/no elevations of bilirubin/ ALP). Laboratory abnormalities secondary to 
flare or recurrence are typically observed for 3-5 weeks.
Guidelines for subjects with recurrent HCV infection or an HCV flare are described below:
i)
Recurrent HCV infection:
If the subject entered the study with an HCV RNA test of "Target not Detected" and has 
confirmed detectable HCV RNA (2 specimens, 1 week apart), then the subject has experienced a 
late HCV relapse or a recurrent infection.

Question the subject about use of injection or inhalation drugs

At the time of first detection of HCV RNA, send a specimen for HCV genotyping

Measure AST, ALT, ALP, Tbil, Dbil, and INR weekly

Measure HCV RNA levels every 2 weeks

Therapy with HCV anti-viral treatments should be strongly considered.
ii) HCV Flare:

At the time of first detection of HCV RNA, send a specimen for HCV genotyping
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
Measure AST, ALT, ALP, Tbil, Dbil, INR weekly

Measure HCV RNA levels every 2 weeks

Therapy with HCV anti-viral treatments should be strongly considered.
iii) For both recurrent infection and HCV flare: if ALT returns to normal or Grade 1 (if 
normal at baseline), or to baseline grade (if Grade 2 at baseline) within 12 weeks, and the 
subjects are clinically stable, subjects may restart study treatment. If these conditions are 
not met, then study treatment should be permanently discontinued.
c) Immune-related hepatitis
i)
Description: Immune-related hepatitis due to study treatment should be suspected if 
any of the following is seen:
a.
AST or ALT baseline values are less than 2 x ULN, and AST or ALT 
laboratory values increase to ≥ 5 x ULN
b. Among subjects with baseline ALT or AST ≥ 2 x ULN, levels increase to > 3 
x the baseline level
c.
AST/ALT >500 U/L regardless of baseline level
d. Among subjects with baseline Tbil levels < 1.5 mg/dL: a value of > 2 mg/dL
e.
Among subjects with baseline Tbil levels that are ≥ 1.5 mg/dL: a value of ≥ 2 
x the baseline level
f.
Total bilirubin > 3.0 mg/dL regardless of baseline level.
Immune-related hepatitis is a diagnosis made after excluding other possible etiologies for 
the change. Viral flare (if applicable), biliary or vascular obstruction, infection, 
medications, and alcohol use must be ruled out (see below).
ii) Management
a.
Interrupt study treatment and alert the Sponsor as per ECI criteria above for 
ALT, AST, bilirubin, and hepatic decompensation.
b. Start IV corticosteroid (methylprednisolone: 125 mg or equivalent) followed 
by oral corticosteroid.
c.
Monitor with biweekly laboratory tests including AST, ALT, Tbil, Dbil, ALP, 
and INR.
d. If symptoms and laboratory tests resolve to Grade ≤ 1 or baseline (if abnormal 
at baseline), taper steroids over 28 days. Study treatment may be restarted 
after steroid treatment has been tapered to prednisone ≤ 10 mg/day (or 
equivalent dose of another agent). Treatment and laboratory results must be 
reported on a case report form (CRF).
e.
If laboratory abnormalities do not resolve within 3 weeks, or steroids cannot 
be lowered to ≤ 10 mg/day (or prednisone equivalent) within 12 weeks, or 
subjects show evidence of decompensation to CP C status or have esophageal 
or variceal bleeding at any point, treatment must be permanently discontinued. 
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This must be reported on a CRF.
d) Other Hepatic Events of Clinical Interest

Infection needs to be ruled out with cultures of blood, urine, and ascites (if possible), 
as well as chest X-ray and abdominal imaging if relevant. If an infection is found, 
antibiotics should be started.

If Tbil is elevated above baseline, magnetic resonance cholangiopancreatography or 
ultrasound with Doppler should be obtained to rule out vascular compromise, biliary 
obstruction, and/or tumor progression. If biliary obstruction is present, consultation 
with a gastroenterologist and/or an interventional radiologist should be obtained to 
see if the obstruction may be relieved.

A careful review of drugs, including herbal and alternative medications, should be 
obtained, and alcohol use should be ruled out. 
o
Drugs known to be hepatotoxic (i.e., drugs with a warning of hepatotoxicity in 
the package insert) should be avoided during the dosing period. Investigators 
are encouraged to review each medication for potential hepatotoxicity by 
searching the www.livertox.nih.gov website.

For all of these cases, subjects may resume study treatment if they are clinically 
stable after appropriate therapy or discontinue the causative agent, as long as 
laboratory values have returned to Grade 1 or baseline (if normal or Grade 1 at start) 
or to baseline grade within 3 weeks.

Treatment must be permanently discontinued if the subject is off study treatment 
therapy for infection, obstruction, or drug/alcohol-related toxicity for more than 3 
weeks, or if they have esophageal bleeding, or become CP C at any point.
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